Maudsley's guidelines

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 1 ANTIPSYCHOTIC DRUGS General introduction Classification of antipsychotics Before the 1990s, antipsychotics (or major tranquillisers as they were then known) were classified according to their chemistry. The first antipsychotic, chlorpromazine, was a phenothiazine compound – a tricyclic structure incorporating a nitrogen and a sulphur atom. Further phenothiazines were generated and marketed, as were chemically similar thioxanthenes such as flupentixol. Later, entirely different chemical structures were developed according to pharmacological paradigms. These included butyrophenones (haloperidol), diphenylbutylpiperidines (pimozide) and substituted benzamides (sulpiride, amisulpride). Chemical classification remains useful but is rendered somewhat redundant by the broad range of chemical entities now available and by the absence of any clear structure– activity relationships for newer drugs. The chemistry of some older drugs does relate to their propensity to cause movement disorders. Piperazine phenothiazines (e.g. fluphenazine, trifluoperazine), butyrophenones and thioxanthenes are most likely to cause extrapyramidal effects, while piperidine phenothiazines (e.g. pipotiazine) and benzamides are the least likely. Aliphatic phenothiazines (e.g. chlorpromazine) and diphenylbutylpiperidines (pimozide) are perhaps somewhere in between. Relative liability for inducing extrapyramidal side effects (EPSEs) was originally the primary factor behind the typical/atypical classification. Clozapine had long been known as an atypical antipsychotic on the basis of its low liability to cause EPSEs and its failure in animal-based antipsychotic screening tests. Its remarketing in 1990 signalled the beginning of a series of new medications, all of which were introduced with claims (to varying degrees of accuracy) of ‘atypicality’. Of these medications, perhaps only clozapine, and possibly quetiapine, is completely atypical, seemingly having a Schizophrenia and related psychoses

06 - Chapter 1 Schizophrenia and related psychoses

04 - Choosing an antipsychotic

Choosing an antipsychotic

2 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 very low or zero liability for extrapyramidal symptoms (EPS). Others show dose-related effects, although, unlike with typical drugs, therapeutic activity can usually be achieved without EPSEs. This is possibly the real distinction between typical and atypical drugs: the ease with which a dose can be chosen within the licensed dosage range that is effective but does not cause EPSEs (for example, compare haloperidol with olanzapine). The typical/atypical dichotomy does not lend itself well to classification of antipsychotics in the middle ground of EPSE liability. Thioridazine was widely described as atypical in the 1980s but is a ‘conventional’ phenothiazine. Sulpiride was marketed as an atypical but is often classified as typical. Risperidone, at its maximum dose of 16mg/day, is just about as ‘typical’ as a drug can be. Alongside these difficulties is the fact that there is nothing either pharmacologically or chemically which clearly binds these so-called atypicals together as a group, save perhaps a general but not universal finding of preference for D2 receptors outside the striatum. Nor are atypicals characterised by improved efficacy over older drugs (clozapine and one or two others excepted) or the absence of hyperprolactinaemia (which is usually worse with risperidone, paliperidone and amisulpride than with typical drugs). Lastly, some more recently introduced agents (e.g. pimavanserin, xanomeline) have antipsychotic activity and do not cause EPS but have almost nothing in common with other atypicals in respect to chemistry, pharmacology or adverse-effect profile. In an attempt to get round some of these problems, typicals and atypicals were reclassified as first- or second-generation antipsychotics (FGA/SGA). All drugs introduced since 1990 are classified as SGAs (i.e. all atypicals) but the new nomenclature dispenses with any connotations regarding atypicality, whatever that may mean. However, the FGA/SGA classification remains problematic because neither group is defined by anything other than time of introduction – hardly the most sophisticated pharmacological classification system. Perhaps more importantly, date of introduction is often wildly distant from date of first synthesis. Clozapine is one of the oldest antipsychotics (synthesised in 1959) while olanzapine is hardly in its first flush of youth, having first been patented in 1971. These two drugs are of course SGAs, apparently the most modern of antipsychotics. In this edition of the Maudsley Prescribing Guidelines, we conserve the FGA/SGA distinction more because of convention than some scientific basis. Also, we feel that most people know which drugs belong to each group – it thus serves as a useful shorthand. However, it is clearly more sensible to consider the properties of individual anti psychotics when choosing drugs to prescribe or in discussions with patients and carers. With this in mind, the use of Neuroscience-based Nomenclature (NbN)1 – a naming system that reflects pharmacological activity – is strongly recommended. Choosing an antipsychotic In the UK, the National Institute for Health and Care Excellence (NICE) guideline for medicines adherence2 recommends that patients should be as involved as possible in decisions about the choice of medicines that are prescribed for them, and that clinicians should be aware that illness beliefs and beliefs about medicines influence adherence. Consistent with this general advice that covers all healthcare, the NICE guideline for schizophrenia emphasises the importance of patient choice rather than specifically recommending a class or individual antipsychotic as first-line treatment.3

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05 - Relative efficacy

Relative efficacy

Schizophrenia and related psychoses CHAPTER 1 Antipsychotics are effective in both the acute and maintenance treatment of schizophrenia and other psychotic disorders. They differ in their pharmacology, pharmacokinetics, overall efficacy/effectiveness and tolerability, and, perhaps more importantly, response and tolerability differ between patients. This variability of individual response means that there is no clear first-line antipsychotic medication that is preferable for all. Relative efficacy After the publication of the independent CATIE4 and CUtLASS5 studies, the World Psychiatric Association reviewed the evidence relating to the relative efficacy of 51 FGAs and 11 SGAs and concluded that, if differences in EPS could be minimised (by careful dosing) and anticholinergic use avoided, there was no convincing evidence to support any advantage for SGAs over FGAs.6 As a class, SGAs may have a lower propensity for EPS and tardive dyskinesia (TD),7 but this was somewhat offset by a higher propensity to cause metabolic adverse effects. A meta-analysis of antipsychotic medications for first-episode psychosis8 found few differences between FGAs and SGAs as groups of drugs but minor advantages for olanzapine and amisulpride individually. A later network meta-analysis of first-episode studies found small efficacy advantages for olanzapine and amisulpride and overall poor performance for haloperidol.9 When individual non-clozapine SGAs are compared, summary data suggest that olanzapine is marginally more effective than aripiprazole, risperidone, quetiapine and ziprasidone, and that risperidone has a minor advantage over quetiapine and ziprasidone.10 FGA-controlled trials also suggest an advantage for olanzapine, risperidone and amisulpride over older drugs.11,12 A network meta-analysis13 broadly confirmed these findings, ranking amisulpride second behind clozapine and olanzapine third. These three drugs were the only ones to show clear efficacy advantages over haloperidol. The magnitude of differences was again small (but potentially substantial enough to be clinically important)13 and must be weighed against the very different adverse effect profiles associated with individual antipsychotics. A 2019 network meta- analysis of 32 antipsychotics14 ranked amisulpride as the most effective drug for positive symptoms and clozapine as the best for both negative symptoms and overall symptom improvement. Olanzapine and risperidone were also highly ranked for positive symptom response. The greatest (beneficial) effect on depressive symptoms was seen with sulpiride, clozapine, amisulpride, olanzapine and the dopamine partial agonists, perhaps reflecting the relative absence of neuroleptic-induced dysphoria common to most FGAs.15 In the longer term, olanzapine may have advantages over some other antipsychotics.16 There was a tendency for more recently introduced drugs to have a lower estimated efficacy – a phenomenon that derives from the substantial increase in placebo response since 1970.17 Clozapine is clearly the drug of choice in refractory schizophrenia,18 although bizarrely, this is not a universal finding,19 probably because of the biased nature and quality of many active–comparator trials.20,21 Both FGAs and SGAs are associated with a number of adverse effects. These include weight gain, dyslipidaemia, increases in plasma glucose/diabetes,22,23 hyperprolactinaemia, hip fracture,24 sexual dysfunction, EPS including neuroleptic malignant syndrome,25 anticholinergic effects, venous thromboembolism (VTE),26 sedation and postural hypotension. The exact profile is drug specific (see individual sections on

4 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 specific adverse effects), although comparative data are not robust27 (see large-scale meta-analyses13,28 for rankings of some adverse-effect risks). Adverse effects are a common reason for treatment discontinuation,29 particularly when efficacy is poor.13 Patients do not always spontaneously report adverse effects, however,30 and psychiatrists’ views of the prevalence and importance of adverse effects differ markedly from patient experience.31 Systematic enquiry, together with a physical examination and appropriate biochemical tests, is the only way accurately to assess their presence and severity or perceived severity. Patient-completed checklists such as the Glasgow Antipsychotic Side-effect Scale (GASS)32 can be a useful first step in this process. The clinician-completed Antipsychotic Non-Neurological Side-Effects Rating Scale facilitates more detailed and comprehensive assessment.33 Non-adherence to antipsychotic treatment is common and here the guaranteed medication delivery associated with depot/long-acting injectable antipsychotic preparations (LAIs) is unequivocally advantageous. In comparison with oral antipsychotics, there is strong evidence that depots are associated with a reduced risk of relapse and rehospitalisation,34–36 although randomised controlled trials (RCTs) do not always reflect this difference.37 Any logical assessment of the benefits of LAIs and the damage caused by relapse would conclude that LAIs should be first-line treatments, rather than reserved for those who have already relapsed on oral medication. Moreover, the wider use of SGA LAIs has to some extent changed the image of depots, which were sometimes perceived as punishments for miscreant patients. Their tolerability advantage probably relates partly to the better definition of their therapeutic dose range, meaning that the optimal dose is more likely to be prescribed (compare aripiprazole, with a licensed dose 300mg or 400mg/month, with flupentixol, which has a licensed dose in the UK of 50mg every 4 weeks to 400mg/week). The optimal dose of flupentixol is around 40mg every 2 weeks28 – just 5% of the maximum allowed. As already mentioned, for patients whose symptoms have not responded sufficiently to adequate, sequential trials of two or more antipsychotic drugs, clozapine is the most effective treatment.38–40 Its use in these circumstances is recommended by NICE3 and probably every schizophrenia guideline besides. The biological basis for the superior efficacy of clozapine is uncertain.41 Olanzapine should probably be one of the two drugs used before clozapine.10,42 A case might also be made for a trial of amisulpride: it has a uniformly high ranking in meta-analyses and one trial found continuation with amisulpride to be as effective as switching to olanzapine.43 This same trial also suggested clozapine might be best placed as the second drug used, given that switching provided no benefit over continuing with the first prescribed drug. This chapter covers the treatment of schizophrenia with antipsychotic drugs, the relative adverse effect profile of these drugs and how adverse effects can be managed.

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06 - References

References

Schizophrenia and related psychoses CHAPTER 1 References

Zohar J, et al. Neuroscience-based Nomenclature (NbN): a call for action. World J Biol Psychiatry 2016; 17:318–320.
National Institute for Health and Care Excellence. Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. Clinical guideline [CG76]. 2009 (last updated March 2019, last checked December 2024); https://www.nice.org.uk/ Guidance/CG76.
National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management. Clinical guideline [CG178]. 2014 (last checked November 2024); https://www.nice.org.uk/guidance/cg178.
Lieberman JA, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209–1223.
Jones PB, et al. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63:1079–1087.
Tandon R, et al. World Psychiatric Association Pharmacopsychiatry Section statement on comparative effectiveness of antipsychotics in the treatment of schizophrenia. Schizophr Res 2008; 100:20–38.
Tarsy D, et al. Epidemiology of tardive dyskinesia before and during the era of modern antipsychotic drugs. Handb Clin Neurol 2011; 100:601–616.
Zhang JP, et al. Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis. Int J Neuropsychopharmacol 2013; 16:1205–1218.
Zhu Y, et al. Antipsychotic drugs for the acute treatment of patients with a first episode of schizophrenia: a systematic review with pairwise and network meta-analyses. Lancet Psychiatry; 4:694–705.
Leucht S, et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry 2009; 166:152–163.
Davis JM, et al. A meta-analysis of the efficacy of second-generation antipsychotics. Archives of General Psychiatry 2003; 60:553–564.
Leucht S, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373:31–41.
Leucht S, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382:951–962.
Huhn M, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet 2019; 394:939–951.
Voruganti L, et al. Neuroleptic dysphoria: towards a new synthesis. Psychopharmacology (Berl) 2004; 171:121–132.
Leucht S, et al. Long-term efficacy of antipsychotic drugs in initially acutely ill adults with schizophrenia: systematic review and network meta-analysis. World Psychiatry 2023; 22:315–324.
Leucht S, et al. Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, Bayesian meta-analysis, and meta-regression of efficacy predictors. Am J Psychiatry 2017; 174:927–942.
Siskind D, et al. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta- analysis. Br J Psychiatry 2016; 209:385–392.
Samara MT, et al. Efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia: a network meta-analysis. JAMA Psychiatry 2016; 73:199–210.
Taylor DM. Clozapine for treatment-resistant schizophrenia: still the gold standard? CNS Drugs 2017; 31:177–180.
Kane JM, et al. The role of clozapine in treatment-resistant schizophrenia. JAMA Psychiatry 2016; 73:187–188.
Manu P, et al. Prediabetes in patients treated with antipsychotic drugs. J Clin Psychiatry 2012; 73:460–466.
Rummel-Kluge C, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res 2010; 123:225–233.
Sorensen HJ, et al. Schizophrenia, antipsychotics and risk of hip fracture: a population-based analysis. Eur Neuropsychopharmacol 2013; 23:872–878.
Trollor JN, et al. Comparison of neuroleptic malignant syndrome induced by first- and second-generation antipsychotics. Br J Psychiatry 2012; 201:52–56.
Masopust J, et al. Risk of venous thromboembolism during treatment with antipsychotic agents. Psychiatry Clin Neurosci 2012; 66:541–552.
Pope A, et al. Assessment of adverse effects in clinical studies of antipsychotic medication: survey of methods used. Br J Psychiatry 2010; 197:67–72.
Bailey L, et al. Estimating the optimal dose of flupentixol decanoate in the maintenance treatment of schizophrenia: a systematic review of the literature. Psychopharmacology (Berl) 2019; 236:3081–3092.
Falkai P. Limitations of current therapies: why do patients switch therapies? Eur Neuropsychopharmacol 2008; 18 Suppl 3:S135–S139.
Yusufi B, et al. Prevalence and nature of side effects during clozapine maintenance treatment and the relationship with clozapine dose and plasma concentration. Int Clin Psychopharmacol 2007; 22:238–243.
Day JC, et al. A comparison of patients’ and prescribers’ beliefs about neuroleptic side-effects: prevalence, distress and causation. Acta Psychiatr Scand 1998; 97:93–97.
Waddell L, et al. A new self-rating scale for detecting atypical or second-generation antipsychotic side effects. J Psychopharmacol 2008; 22:238–243.
Ohlsen RI, et al. Interrater reliability of the Antipsychotic Non-Neurological Side-Effects Rating Scale measured in patients treated with clozapine. J Psychopharmacol 2008; 22:323–329.

6 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 34. Tiihonen J, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ 2006; 333:224. 35. Leucht C, et al. Oral versus depot antipsychotic drugs for schizophrenia—a critical systematic review and meta-analysis of randomised long- term trials. Schizophr Res 2011; 127:83–92. 36. Leucht S, et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012; 379:2063–2071. 37. Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral and long-acting injectable antipsychotics for the maintenance treatment of adults with schizophrenia: a systematic review and network meta-analysis. Lancet 2022; 399:824–836. 38. Kane J, et al. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45:789–796. 39. McEvoy JP, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006; 163:600–610. 40. Lewis SW, et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull 2006; 32:715–723. 41. Stone JM, et al. Review: the biological basis of antipsychotic response in schizophrenia. J Psychopharmacol 2010; 24:953–964. 42. Agid O, et al. An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry 2011; 72:1439–1444. 43. Kahn RS, et al. Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching study. Lancet Psychiatry 2018; 5:797–807.

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07 - General principles of prescribing

General principles of prescribing

Schizophrenia and related psychoses CHAPTER 1 General principles of prescribing ■ ■The lowest possible dose should be used. For each patient, the dose should be titrated to the lowest known to be effective (see section on minimum effective doses in this chapter). Dose increases should then take place only after 1–2 weeks of assessment, during which the patient is clearly showing poor or no response. ■ ■With regular dosing of LAIs, plasma levels rise for at least 6–12 weeks after initiation, even without a change in dose (see section on depot pharmacokinetics in this chapter). Dose increases during this time are therefore difficult to evaluate. The preferred method is to establish efficacy and tolerability of oral medication at a particular dose and then give the equivalent dose of the oral drug in LAI form. Where this is not possible, the target dose of LAI for an individual should be the dose established to be optimal in clinical trials (although such data are not always available for older LAIs). ■ ■Antipsychotic LAIs provide better relapse protection than oral treatment. LAIs should be used as first-line treatment aimed at preventing relapse. They should not be reserved only for those who have already relapsed on oral treatment. ■ ■Clozapine should be offered as soon as treatment resistance is apparent. The sooner clozapine is prescribed, the more effective it will be. ■ ■For the large majority of patients, the use of a single antipsychotic (with or without additional mood stabiliser or sedatives) is recommended. Apart from some exceptional circumstances (e.g. clozapine augmentation or adjunctive aripiprazole for prolactin elevation) antipsychotic polypharmacy should generally be avoided because of the increased adverse-effect burden and risks associated with QT prolongation and sudden cardiac death (see section on antipsychotic polypharmacy in this chapter). ■ ■Combinations of antipsychotics should only be used where response to a single anti psychotic (including clozapine) has been clearly demonstrated to be inadequate. In such cases, the effect of the combination against target symptoms and on adverse effects should be carefully evaluated and documented. Where there is no clear benefit, treatment should revert to single antipsychotic therapy. ■ ■In general, antipsychotics should not be used as ‘when necessary’ sedatives. Time- limited prescriptions of benzodiazepines or general sedatives (e.g. promethazine) are preferred (see section on rapid tranquillisation in this chapter). ■ ■Response to antipsychotic drug treatment should be assessed using recognised rating scales and outcomes documented in patients’ records. ■ ■Those receiving antipsychotics should undergo close monitoring of physical health (including blood pressure, pulse, ECG, plasma glucose and plasma lipids; see appropriate sections in this chapter). ■ ■When withdrawing antipsychotics, reduce the dose slowly in a hyperbolic regimen, which minimises the risks of withdrawal symptoms and rebound psychosis. Note – this section is not referenced. Please see relevant individual sections in this chapter for detailed and referenced guidance.

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08 - Antipsychotics minimum effective doses

Antipsychotics – minimum effective doses

8 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Antipsychotics – minimum effective doses Table 1.1 suggests the minimum dose of individual antipsychotics likely to be effective in first- or multi-episode schizophrenia. Most patients will respond to the dose suggested, although others may require higher doses. Given the variation in individual response, all doses should be considered approximate. Primary references are provided where available, but some consensus opinion has also been used. Only oral treatment with commonly used drugs is covered. Table 1.1 Minimum effective dose/day – antipsychotics Drug First episode Multi-episode First-generation Chlorpromazine1 200mg* 300mg Haloperidol2–6 2mg 4mg Sulpiride7 400mg* 800mg Trifluoperazine8,9 10mg* 15mg Second-generation Amisulpride10,11 300mg* 400mg* Aripiprazole6,12–16 10mg 10mg Asenapine6,16,17 5mg* 10mg Blonanserin18 Not known 8mg Brexpiprazole19,20 2mg* 4mg Cariprazine21,22 1.5mg* 1.5mg Clotiapine23,24 Not known 120mg Iloperidone6,16,25 4mg* 8mg Lumateperone26 Not known 42mg* Lurasidone6,27 40mg HCl/37mg base* 40mg HCl/37mg base Olanzapine6,28–31 5mg 7.5mg Paliperidone16 3mg* 3mg Pimavanserin32–34 Not known 34mg** Quetiapine35,36 150mg* (but higher doses often used37) 300mg IR 500mg MR38 Risperidone3,6,39–42 2mg 4mg Xanomeline43,44 200mg* 200mg* Ziprasidone6,15,45–47 40mg* 80mg * Estimate – too few data available. ** US Food and Drug Administration-approved for Parkinson’s disease psychosis; dose in schizophrenia not clear.

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09 - References

References

Schizophrenia and related psychoses CHAPTER 1 References

Dudley K, et al. Chlorpromazine dose for people with schizophrenia. Cochrane Database Syst Rev 2017; 4(4):CD007778.
McGorry PD. Recommended haloperidol and risperidone doses in first-episode psychosis. J Clin Psychiatry 1999; 60:794–795.
Schooler N, et al. Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial. Am J Psychiatry 2005; 162:947–953.
Donnelly L, et al. Haloperidol dose for the acute phase of schizophrenia. Cochrane Database Syst Rev 2013; (8):CD001951.
Oosthuizen P, et al. A randomized, controlled comparison of the efficacy and tolerability of low and high doses of haloperidol in the treatment of first-episode psychosis. Int J Neuropsychopharmacol 2004; 7:125–131.
Leucht S, et al. Dose equivalents for second-generation antipsychotics: the minimum effective dose method. Schizophr Bull 2014; 40:314–326.
Soares BG, et al. Sulpiride for schizophrenia. Cochrane Database Syst Rev 2000; (2):CD001162.
Armenteros JL, et al. Antipsychotics in early onset schizophrenia: systematic review and meta-analysis. Eur Child Adolesc Psychiatry 2006; 15:141–148.
Koch K, et al. Trifluoperazine versus placebo for schizophrenia. Cochrane Database Syst Rev 2014; (1):CD010226.
Sparshatt A, et al. Amisulpride - dose, plasma concentration, occupancy and response: implications for therapeutic drug monitoring. Acta Psychiatr Scand 2009; 120:416–428.
Buchanan RW, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010; 36:71–93.
Cutler AJ, et al. The efficacy and safety of lower doses of aripiprazole for the treatment of patients with acute exacerbation of schizophrenia. CNS Spectr 2006; 11:691–702.
Mace S, et al. Aripiprazole: dose–response relationship in schizophrenia and schizoaffective disorder. CNS Drugs 2008; 23:773–780.
Sparshatt A, et al. A systematic review of aripiprazole: dose, plasma concentration, receptor occupancy and response: implications for therapeutic drug monitoring. J Clin Psychiatry 2010; 71:1447–1456.
Liu CC, et al. Aripiprazole for drug-naive or antipsychotic-short-exposure subjects with ultra-high risk state and first-episode psychosis: an open-label study. J Clin Psychopharmacol 2013; 33:18–23.
Leucht S, et al. Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry 2020; 177:342–353.
Citrome L. Role of sublingual asenapine in treatment of schizophrenia. Neuropsychiatr Dis Treat 2011; 7:325-339.
Tenjin T, et al. Profile of blonanserin for the treatment of schizophrenia. Neuropsychiatr Dis Treat 2013; 9:587–594.
Correll CU, et al. Efficacy of brexpiprazole in patients with acute schizophrenia: review of three randomized, double-blind, placebo- controlled studies. Schizophr Res 2016; 174:82–92.
Antoun Reyad A, et al. Efficacy and safety of brexpiprazole in acute management of psychiatric disorders: a meta-analysis of randomized controlled trials. Int Clin Psychopharmacol 2020; 35:119–128.
Garnock-Jones KP. Cariprazine: a review in schizophrenia. CNS Drugs 2017; 31:513–525.
Citrome L. Cariprazine for acute and maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy. Neuropsychiatr Dis Treat 2018; 14:2563–2577.
Lokshin P, et al. Clotiapine: an old neuroleptic with possible clozapine-like properties. Progr Neuro Psychopharmacol Biol Psychiatry 1998; 22:1289–1293.
Lyseng-Williamson K. Clotiapine in schizophrenia: a guide to its use. Drugs Ther Perspect 2015; 31:365–371.
Crabtree BL, et al. Iloperidone for the management of adults with schizophrenia. Clin Ther 2011; 33:330–345.
Peng H, et al. Efficacy and safety of lumateperone for bipolar depression and schizophrenia: a systematic review and meta-analysis. Int J Neuropsychopharmacol 2024; 27:pyae052.
Meltzer HY, et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry 2011; 168:957–967.
Sanger TM, et al. Olanzapine versus haloperidol treatment in first-episode psychosis. Am J Psychiatry 1999; 156:79–87.
Kasper S. Risperidone and olanzapine: optimal dosing for efficacy and tolerability in patients with schizophrenia. Int Clin Psychopharmacol 1998; 13:253–262.
Keefe RS, et al. Long-term neurocognitive effects of olanzapine or low-dose haloperidol in first-episode psychosis. Biol Psychiatry 2006; 59:97–105.
Bishara D, et al. Olanzapine: a systematic review and meta-regression of the relationships between dose, plasma concentration, receptor occupancy, and response. J Clin Psychopharmacol 2013; 33:329–335.
Mathis MV, et al. The US Food and Drug Administration’s perspective on the new antipsychotic pimavanserin. J Clin Psychiatry 2017; 78:e668–e673.
Ballard C, et al. Pimavanserin in Alzheimer’s disease psychosis: efficacy in patients with more pronounced psychotic symptoms. J Prev Alzheimers Dis 2019; 6:27–33.
Nasrallah HA, et al. Successful treatment of clozapine-nonresponsive refractory hallucinations and delusions with pimavanserin, a serotonin 5HT-2A receptor inverse agonist. Schizophr Res 2019; 208:217–220.
Sparshatt A, et al. Quetiapine: dose–response relationship in schizophrenia. CNS Drugs 2008; 22:49–68.
Sparshatt A, et al. Relationship between daily dose, plasma concentrations, dopamine receptor occupancy, and clinical response to quetiapine: a review. J Clin Psychiatry 2011; 72:1108–1123.
Pagsberg AK, et al. Quetiapine extended release versus aripiprazole in children and adolescents with first-episode psychosis: the multicentre, double-blind, randomised tolerability and efficacy of antipsychotics (TEA) trial. Lancet Psychiatry 2017; 4:605–618.

10 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 38. Terao I, et al. Comparative efficacy of quetiapine by dose and formulation for psychosis in schizophrenia: a systematic review and dose- response model-based network meta-analysis. J Psychopharmacol 2023; 37:953–959. 39. Lane HY, et al. Risperidone in acutely exacerbated schizophrenia: dosing strategies and plasma levels. J Clin Psychiatry 2000; 61:209–214. 40. Williams R. Optimal dosing with risperidone: updated recommendations. J Clin Psychiatry 2001; 62:282–289. 41. Ezewuzie N, et al. Establishing a dose-response relationship for oral risperidone in relapsed schizophrenia. J Psychopharmacol 2006; 20:86–90. 42. Li C, et al. Risperidone dose for schizophrenia. Cochrane Database Syst Rev 2009; (4):CD007474. 43. Kaul I, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet 2024; 403:160–170. 44. Kaul I, et al. Efficacy of xanomeline and trospium chloride in schizophrenia: pooled results from three 5-week, randomized, double-blind, placebo-controlled, EMERGENT trials. Schizophrenia (Heidelb) 2024; 10:102. 45. Bagnall A, et al. Ziprasidone for schizophrenia and severe mental illness. Cochrane Database Syst Rev 2000; (4):CD001945. 46. Taylor D. Ziprasidone: an atypical antipsychotic. Pharmaceutical J 2001; 266:396401. 47. Joyce AT, et al. Effect of initial ziprasidone dose on length of therapy in schizophrenia. Schizophr Res 2006; 83:285–292.

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10 - Quick reference for licensed maximum doses

Quick reference for licensed maximum doses

Schizophrenia and related psychoses CHAPTER 1 Quick reference for licensed maximum doses Table 1.2 lists the licensed maximum doses of antipsychotics according to the European Medicines Agency, as of January 2025.1 Table 1.2 Maximum doses of antipsychotics according to European Medicines Agency labelling.1 Drug Maximum dose FGAs – oral Chlorpromazine 1000mg/day Flupentixol 18mg/day Haloperidol 20mg/day Levomepromazine 1200mg/day Pericyazine 300mg/day Perphenazine 24mg/day (64mg/day hospitalised patients) Pimozide 20mg/day Sulpiride 2400mg/day Trifluoperazine 20mg/day (maximum dose not formally specified) Zuclopenthixol 150mg/day SGAs – oral Amisulpride 1200mg/day Aripiprazole 30mg/day Asenapine 20mg/day (sublingual) Cariprazine 6mg/day Clozapine 900mg/day Lurasidone 160mg (HCl)/148mg (base)/day Olanzapine 20mg/day Paliperidone 12mg/day Quetiapine 750mg/day schizophrenia (800mg/day MR) 800mg/day bipolar disorder Risperidone 16mg/day Sertindole 24mg/day Long-acting injections Aripiprazole 1-monthly 400mg/month (SPC implies ‘every 4 weeks’) Aripiprazole 2-monthly 960mg/2 months (SPC states ’every 56 days’) Flupentixol decanoate 400mg/week Haloperidol decanoate 300mg/4 weeks Olanzapine pamoate 300mg/2 weeks Paliperidone palmitate 1-monthly 150mg/month Paliperidone palmitate 3-monthly 525mg/3 months (Continued)

12 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Table 1.3 lists the licensed maximum doses of antipsychotics available outside the EU, according to the US Food and Drug Administration, where available (as of December 2024).2 Table 1.2 (Continued) Drug Maximum dose Paliperidone depot 6-monthly 1000mg/6 months Risperidone (Consta®) 50mg/2 weeks Risperidone (Okedi®) 100mg/4 weeks Zuclopenthixol decanote 600mg/week Table 1.3 Licensed maximum doses of antipsychotics, according to US Food and Drug Administration labelling, where available.2 Drug Maximum dose FGAs – oral Fluphenazine 40mg/day Thiothixene 60mg/day SGAs – oral Blonanserin* 24mg/day3 Brexpiprazole 4mg/day Iloperidone 24mg/day Lumateperone 42mg/day Molindone 225mg/day Perospirone** 48mg/day Pimavanserin 34mg/day Xanomeline and trospium chloride 250mg/60mg/day Ziprasidone 160mg/day Long-acting injections Aripiprazole lauroxil (Aristada Initio®)† 675mg Aripiprazole lauroxil (Aristada®) 882mg/month or 1064mg/2 months Fluphenazine decanoate 100mg/14 days Risperidone (Uzedy®) 125mg/month or 250mg/2 months Risperidone (Rykindo®) 50mg/2 weeks Transdermal patch Asenapine 7.6mg/24hr Blonanserin* 80mg/24hr patch4 * Available only in China, Japan and South Korea at the time of writing. ** Available only in Japan at the time of writing. † Used to initiate treatment with Aristada, not for repeat dosing.

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Clinical effectiveness

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Adverse effects

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Summary

106 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Penfluridol weekly Background Penfluridol is a diphenylbutylpiperidine FGA available in countries such as Brazil, China, India, Israel and the Netherlands and can be imported to other countries. Penfluridol is unusual in having a very long plasma half-life – at least 60 hours.1 After oral administration, peak levels are reached within 12 hours and drug can still be detected 168 hours after a single oral dose.2 Its long duration of action seems to be a result of rapid distribution into fat tissue which acts as a drug reservoir.3 This property allows penfluridol to be used as a once-weekly oral therapy for supervised ingestion – an alternative to long-acting injectable antipsychotics. Clinical effectiveness Several trials have examined the use of once-weekly oral penfluridol, in doses ranging from 5mg to 160mg per week.4 When given in this manner it is at least as effective as depot FGAs5,6 and may be better tolerated overall.4 A Dutch retrospective cohort study (n = 8,257) found that discontinuation trends for oral penfluridol and depot formulations were similar.7 In a small retrospective observational study of 19 patients (most of whom were treatment resistant), Dunnett and colleagues found just over half of the people prescribed penfluridol (n = 9) continued taking it during a 1-year follow-up,8 suggesting some efficacy in these patients. Although the dose–response relationship remains unclear, a weekly dose of 30mg is thought to be adequately effective,9 although a dose of 120mg a day (that is, a total of 840mg a week) has been used.10 Steady-state levels and plasma elimination half-lives of people taking penfluridol can vary significantly, probably because of differences in adiposity.3 An early study found that a loading dose regimen (first dose 80mg; a total of 200mg over the first week) is effective and well tolerated11 but this regimen remains unlicensed and untested in larger studies. Penfluridol is probably underused considering the high rates of non-adherence with oral antipsychotics and the reluctance to prescribe depots.12 Adverse effects Adverse effects include acute EPS, increased prolactin and TD, as might be expected.8 It is usually not sedative. Like pimozide (another diphenylbutylpiperidine), penfluridol appears to prolong the QT interval.13 Penfluridol is a cytotoxic agent which may have anticancer properties.14 Summary ■ ■Penfluridol can be given orally once a week. ■ ■Supervised weekly administration is at least as effective as long-acting injections. ■ ■The usual dose is 20–40mg a week, but much higher doses have been used. ■ ■Adverse effects are those common to FGAs and include QT prolongation. ■ ■Sedation is minimal.

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References

Schizophrenia and related psychoses CHAPTER 1 In practice, penfluridol is usually started at a dose of 20mg and increased to a maximum of 40mg after assessment. Steady-state levels are effectively reached after 2–3 weeks. Monitoring includes investigations of renal and hepatic function, changes in cardiometabolic parameter such as lipids, blood glucose, ECG and general adverse effect screening. Other antipsychotics which may be suitable for once-weekly oral administration include pimozide, aripiprazole and cariprazine.12 References

Janssen PA, et al. The pharmacology of penfluridol (R 16341) a new potent and orally long-acting neuroleptic drug. Eur J Pharmacol 1970; 11:139–154.
Cooper SF, et al. Penfluridol steady-state kinetics in psychiatric patients. Clin Pharmacol Ther 1975; 18:325–329.
Migdalof BH, et al. Penfluridol: a neuroleptic drug designed for long duration of action. Drug Metab Rev 1979; 9:281–299.
Soares BG, et al. Penfluridol for schizophrenia. Cochrane Database Syst Rev 2006; (2):CD002923.
Iqbal MJ, et al. A long term comparative trial of penfluridol and fluphenazine decanoate in schizophrenic outpatients. J Clin Psychiatry 1978; 39:375–379.
Quitkin F, et al. Long-acting oral vs injectable antipsychotic drugs in schizophrenics: a one-year double-blind comparison in multiple episode schizophrenics. Arch Gen Psychiatry 1978; 35:889–892.
van der Lee APM, et al. The impact of antipsychotic formulations on time to medication discontinuation in patients with schizophrenia: a Dutch registry-based retrospective cohort study. CNS Drugs 2021; 35:451–460.
Dunnett D, et al. Evaluation of the effectiveness and acceptability of the long-acting oral antipsychotic penfluridol: illustrative case series. J Psychopharmacol 2021; 36:223–231.
van Praag HM, et al. Controlled trial of penfluridol in acute psychosis. Br Med J 1971; 4:710–713.
Shopsin B, et al. Penfluridol: an open phase III study in acute newly admitted hospitalized schizophrenic patients. Psychopharmacology (Berl) 1977; 55:157–164.
Munitz H, et al. Loading: a beneficial therapeutic effect using an oral long-acting drug, Penfluridol (SEMAP). A pilot study. Isr J Psychiatry Relat Sci 1986; 23:215–220.
Brissos S, et al. Weekly supervised administration of oral antipsychotics: an alternative to long-acting injections? CNS Drugs 2022; 36:315–325.
Bhattacharyya R, et al. Resurgence of penfluridol: merits and demerits. Eastern J Psychiatry 2015; 18:23–29.
Ashraf-Uz-Zaman M, et al. Analogs of penfluridol as chemotherapeutic agents with reduced central nervous system activity. Bioorg Med Chem Lett 2018; 28:3652–3657.

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104 - Electroconvulsive therapy and psychosis

Electroconvulsive therapy and psychosis

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105 - Treatment refractory schizophrenia

Treatment-refractory schizophrenia

108 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Electroconvulsive therapy and psychosis Evidence from prospective RCTs and retrospective studies suggests that ECT augmentation of antipsychotic medication can have a beneficial effect on persistent positive symptoms in schizophrenia, including medication-resistant schizophrenia.1–7 However, there is a relative lack of data on long-term effectiveness and efficacy, cognitive deficits and quality of life. A 2005 Cochrane systematic review8 assessed RCTs that had compared ECT with placebo, sham ECT, non-pharmacological interventions and antipsychotic medication for patients with schizophrenia, schizoaffective disorder or chronic mental disorder. In studies where ECT was compared with placebo or sham ECT, more participants improved in the real ECT group and there was a suggestion that real ECT resulted in fewer relapses in the short term and a greater likelihood of being discharged from hospital. The review concluded that ECT combined with continuing antipsychotic medication is a valid treatment option for schizophrenia, particularly when rapid global improvement and reduction of symptoms are desired (for example, treating patients with a high risk of aggression or self-harm),9 and where the illness has shown only a limited response to medication alone. A naturalistic, mirror-image study compared 2,074 people with schizophrenia on antipsychotic medication who had received ECT with a control group of patients prescribed continuing antipsychotic medication.10 The rate of psychiatric hospitalisation over a 1-year post-treatment period decreased in those treated with ECT, but not in the control group. The effectiveness of ECT was more pronounced among those treated with clozapine or a medium to high antipsychotic dosage. Treatment-refractory schizophrenia The benefits and harms of adding ECT to standard care for people with TRS were examined in a 2019 Cochrane systematic review.6 The investigators were able to reach the limited conclusion that the moderate-quality RCT evidence available suggested a positive effect for ECT on medium-term clinical response. It was noted that further evidence of better quality was required before a stronger conclusion could be made. Several studies have focused on ECT augmentation of antipsychotic medication for TRS.1–3,11,12 For example, in a small sample of patients with TRS characterised by ‘dominant negative symptoms’, ECT augmentation of a variety of antipsychotic medications produced a significant decrease in symptom severity.13 A 2016 meta-analysis of RCTs3 in TRS that examined the efficacy of the combination of ECT and (non-clozapine) antipsychotic medication versus the same antipsychotic medication as monotherapy found that the combination proved to be superior in terms of symptom improvement, study-defined response and remission rate. ECT augmentation of clozapine may be at least as effective as ECT augmentation of other antipsychotic medications, if not more so.4,12,14–16 Response is probably unrelated to post-ECT changes in clozapine levels.17 In a retrospective study1 assessing the effectiveness and safety of the combination of clozapine and ECT in a sample of patients with TRS, almost two-thirds were responders (defined as a 30% or greater reduction in Positive and Negative Syndrome Scale [PANSS] total score).18 Follow-up data on a sub- sample of these patients over a mean of 30 months revealed that the majority had

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Adverse effects

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Summary

Schizophrenia and related psychoses CHAPTER 1 maintained their symptomatic improvement or improved further. Another small retrospective study of ECT augmentation of clozapine reported an acute response (defined as improvement rated on the Clinical Global Impression Improvement scale)19 in around three-quarters of the patient sample, and three-quarters of the responders remained out of hospital over a 1-year follow-up period.20 In a randomised, single-blind study,2 participants with clozapine-refractory schizophrenia either continued solely on their clozapine treatment or had it augmented with a course of bilateral ECT. After 8 weeks, a predefined response criterion (which included a 40% or greater reduction in the psychotic symptom subscale of the Brief Psychiatric Rating Scale)21 was met by half the participants receiving clozapine plus ECT but none of the group on clozapine alone. When the non-responders from the clozapine-alone group crossed over to an 8-week, open trial of ECT, nearly half met the response criterion. A 2016 systematic review and meta-analysis22 looking specifically at ECT augmentation of clozapine treatment found a paucity of controlled studies, although the authors acknowledged the methodological challenges of such investigations. They concluded that ECT may be an effective augmentation strategy for schizophrenia that has failed to respond to clozapine monotherapy, but that further research was required to determine the place of such a strategy in any TRS treatment algorithm. A subsequent meta-analysis of RCTs addressing ECT augmentation for clozapine- resistant schizophrenia noted the lack of studies with sham ECT as a control, but reached the conclusion that such a treatment strategy was effective and relatively safe.23 In 2021, Chakrabarti9 reinforced the point that such meta-analyses were based on limited and low-quality evidence and only addressed the short-term efficacy of ECT augmentation. Counter to the relatively encouraging conclusions of these meta-analyses, in a more recent, 10-week RCT24 involving 40 participants with clozapine-resistant schizophrenia, augmentation with real ECT was not found to be superior to sham treatment in terms of symptom response. The primary outcome was a 50% reduction in PANSS total score, but this was achieved for only one participant (in the real ECT group). There is some provisional evidence that maintenance ECT may be effective when combined with clozapine.25 Adverse effects Although ECT augmentation of continuing antipsychotic medication appears to be generally well tolerated, adverse effects such as transient retrograde and anterograde amnesia, drowsiness, headaches and nausea have been reported for a minority of cases3,12,13,24,26 and there are reports of an increase in blood pressure after ECT and prolonged seizures.1 The cognitive adverse effects are generally considered to be mild and transient.20,23,27 Summary While the evidence remains rather inconclusive, it tends to support ECT augmentation of antipsychotic treatment, particularly clozapine, as a potentially efficacious and relatively safe augmentation strategy in TRS.7,28–30 However, further, well-controlled trials are required to establish the clinical benefit–risk balance of such a treatment strategy in both the short and long term.

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References

110 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

Grover S, et al. Effectiveness of electroconvulsive therapy in patients with treatment resistant schizophrenia: a retrospective study. Psychiatry Res 2017; 249:349–353.
Petrides G, et al. Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: a prospective, randomized study. Focus 2019; 17:76–82.
Zheng W, et al. Electroconvulsive therapy added to non-clozapine antipsychotic medication for treatment resistant schizophrenia: meta- analysis of randomized controlled trials. PLoS One 2016; 11:e0156510.
Kim HS, et al. Effectiveness of electroconvulsive therapy augmentation on clozapine-resistant schizophrenia. Psychiatry Investig 2017; 14:58–62.
Vuksan Ćusa B, et al. The effects of electroconvulsive therapy augmentation of antipsychotic treatment on cognitive functions in patients with treatment-resistant schizophrenia. J ECT 2018; 34:31–34.
Sinclair DJM, et al. Electroconvulsive therapy for treatment-resistant schizophrenia. Schizophr Bull 2019; 45:730–732.
Grover S, et al. ECT in schizophrenia: a review of the evidence. Acta Neuropsychiatr 2019; 31:115–127.
Tharyan P, et al. Electroconvulsive therapy for schizophrenia. Cochrane Database Syst Rev 2005; (2):CD000076.
Chakrabarti S. Clozapine resistant schizophrenia: newer avenues of management. World J Psychiatry 2021; 11:429–448.
Lin HT, et al. Impacts of electroconvulsive therapy on 1-year outcomes in patients with schizophrenia: a controlled, population-based mirror- image study. Schizophr Bull 2018; 44:798–806.
Masoudzadeh A, et al. Comparative study of clozapine, electroshock and the combination of ECT with clozapine in treatment-resistant schizophrenic patients. Pak J Biol Sci 2007; 10:4287–4290.
Kaster TS, et al. Clinical effectiveness and cognitive impact of electroconvulsive therapy for schizophrenia: a large retrospective study. J Clin Psychiatry 2017; 78:e383–e389.
Pawełczyk T, et al. Augmentation of antipsychotics with electroconvulsive therapy in treatment-resistant schizophrenia patients with dominant negative symptoms: a pilot study of effectiveness. Neuropsychobiology 2014; 70:158–164.
Ahmed S, et al. Combined use of electroconvulsive therapy and antipsychotics (both clozapine and non-clozapine) in treatment resistant schizophrenia: a comparative meta-analysis. Heliyon 2017; 3:e00429.
Grover S, et al. Augmentation strategies for clozapine resistance: a systematic review and meta-analysis. Acta Neuropsychiatr 2023; 35:65–75.
Yeh TC, et al. Pharmacological and nonpharmacological augmentation treatments for clozapine-resistant schizophrenia: a systematic review and network meta-analysis with normalized entropy assessment. Asian J Psychiatr 2023; 79:103375.
Schoretsanitis G, et al. Lack of ECT effects on clozapine plasma levels in patients with treatment-resistant schizophrenia: pharmacokinetic evidence from a randomized clinical trial. Schizophr Res 2020; 218:309–311.
Kay SR, et al. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13:261–276.
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976.
Lally J, et al. Augmentation of clozapine with ECT: a retrospective case analysis. Acta Neuropsychiatr 2021; 33:31–36.
Overall JE, et al. The Brief Psychiatric Rating Scale. Psychol Rep 1962; 10:812.
Lally J, et al. Augmentation of clozapine with electroconvulsive therapy in treatment resistant schizophrenia: a systematic review and meta- analysis. Schizophr Res 2016; 171:215–224.
Wang G, et al. ECT augmentation of clozapine for clozapine-resistant schizophrenia: a meta-analysis of randomized controlled trials. J Psychiatr Res 2018; 105:23–32.
Melzer-Ribeiro DL, et al. Randomized, double-blind, sham-controlled trial to evaluate the efficacy and tolerability of electroconvulsive therapy in patients with clozapine-resistant schizophrenia. Schizophr Res 2023; 268:252–260.
George R, et al. Examining the clinical effectiveness of continuation and maintenance electroconvulsive therapy in schizophrenia. Asian J Psychiatr 2024; 92:103895.
Zheng W, et al. Memory impairment following electroconvulsive therapy in Chinese patients with schizophrenia: meta-analysis of randomized controlled trials. Perspect Psychiatr Care 2018; 54:107–114.
Sanghani SN, et al. Electroconvulsive therapy (ECT) in schizophrenia: a review of recent literature. Curr Opin Psychiatry 2018; 31:213–222.
Zervas IM, et al. Using ECT in schizophrenia: a review from a clinical perspective. World J Biol Psychiatry 2012; 13:96–105.
Wagner E, et al. Clozapine combination and augmentation strategies in patients with schizophrenia-recommendations from an international expert survey among the Treatment Response and Resistance in Psychosis (TRRIP) working group. Schizophr Bull 2020; 46:1459–1470.
Arumugham SS, et al. Efficacy and safety of combining clozapine with electrical or magnetic brain stimulation in treatment-refractory schizophrenia. Expert Rev Clin Pharmacol 2016; 9:1245–1252.

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109 - Omega 3 fatty acid (fish oils) in schizophren

Omega-3 fatty acid (fish oils) in schizophrenia

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11 - References

References

Schizophrenia and related psychoses CHAPTER 1 References

Electronic Medicines Compendium. Summaries of Product Characteristics. (Last accessed January 2025); https://www.medicines.org.uk/emc.
US Food and Drug Administration. Highlights of Prescribing Information. 2024; https://www.fda.gov/drugs.
Inoue Y, et al. Safety and effectiveness of oral blonanserin for schizophrenia: a review of Japanese post-marketing surveillances. J Pharmacolog Sci 2021; 145:42–51.
Nishibe H, et al. Striatal dopamine D2 receptor occupancy induced by daily application of blonanserin transdermal patches: phase 2 study in Japanese patients with schizophrenia. Int J Neuropsychopharmacol 2021; 24:108–117.

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Treatment

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111 - Prevention

Prevention

Schizophrenia and related psychoses CHAPTER 1 Omega-3 fatty acid (fish oils) in schizophrenia Fish oils contain the omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA) – also known as polyunsaturated fatty acids or PUFAs. These compounds are thought to be involved in maintaining neuronal membrane structure, in the modulation of membrane proteins and in the production of prostaglandins and leuko trienes.1 Imaging studies suggest that the ratio between omega-6 and omega-3 may be relevant in the development of psychotic disorders.2 One genetic study has suggested that people with schizophrenia may have difficulty converting short-chain fatty acids to long-chain polyunsaturated fatty acids.3 High dietary intake of PUFAs may protect against psychosis4 and antipsychotic treatment seems to normalise PUFA deficits.5 Animal models suggest a protective effect for PUFAs.6 They have been suggested as treatments for a variety of psychiatric illnesses.7,8 In schizophrenia, case reports,9–12 case series13 and prospective trials originally suggested useful efficacy.14–18 Treatment A 2012 meta-analysis of these RCTs19 concluded that EPA had ‘no beneficial effect in established schizophrenia’. Since then, an RCT comprising 71 patients with first-episode schizophrenia given 2.2g EPA + DHA daily for 6 months showed a reduction in symptom severity for patients in the active arm, finding a number needed to treat (NNT) of 4 to produce a 50% reduction in symptoms measured by PANSS.20 However, a further RCT of 97 patients in acute psychosis showed no advantage for EPA 2g daily21 and a relapse prevention study of EPA 2g + DHA 1g/day failed to demonstrate any value for PUFAs over placebo (relapse rate was 90% with PUFAs, 75% with placebo).22 The limitations affecting the published data in this area (small sample sizes, heterogeneity of diagnosis and stage of illness, differences in intervention combinations and doses) mean that overall findings remain at best inconclusive.23,24 A 2019 meta-review of published meta-analyses found no evidence for the use of PUFAs in the treatment of schizophrenia.25 On balance, evidence now suggests that EPA (2–3g daily) is unlikely to be a worthwhile option in schizophrenia when added to standard treatment. Omega-3 fatty acids are not recommended by the World Federation of Societies of Biological Psychiatry for use in schizophrenia.26 Set against doubts over efficacy are the facts that fish oils are relatively cheap, well tolerated27 (mild gastrointestinal [GI] symptoms may occur) and benefit physical health.1,28–32 A few small RCTs suggest some benefit to neurocognition (social cognition),33 verbal fluency and working memory34 in recent-onset psychosis or young people at ultra-high risk of psychosis. Other studies have failed to show any benefit on aggressive behaviour.35 Prevention The Vienna High Risk study (VHR) gave 700mg EPA + 480mg DHA to adolescents and young adults at high risk of psychosis, and showed that such treatment greatly reduced emergence of psychotic symptoms compared with placebo36 (although a review described this study as ‘very low quality evidence’).37 Since publication of this single-site study, the large, multi-site NEURAPRO trial38 gave adult patients at high risk of psychosis 840mg EPA + 560mg DHA for 6 months and failed to find any evidence of efficacy either for

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112 - Overall

Overall

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113 - Summary recommendations fish oils (PUFAs)

Summary recommendations – fish oils (PUFAs)

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114 - References

References

112 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 reduction in transition to psychosis or improvement in symptoms. From these RCTs, Cochrane concluded that omega-3 fatty acids ‘may’ prevent transition to psychosis in the prodromal phase, but that the evidence is of low quality and this conclusion unconfirmed.39 The non-randomised North American Prodromal Longitudinal Studies (NAPLS)40 found a positive correlation between functional improvement and frequency of dietary intake of EPA. The Program of Rehabilitation and Therapy (PORT) study41 found that young people at ultra-high risk of psychosis who then developed the condition had lower dietary intake of omega-3 and higher consumption of omega-6 fatty acids compared with healthy controls. Taken together, these two RCTs (VHR and NEURAPRO) and two non- randomised trials (PORT and NAPLS) indicate a possible positive correlation between dietary omega-3 and functional status, but more studies are required before a clinical benefit can be confirmed.42 A 2024 network meta-analysis concluded that omega-3 fatty acids are correlated with a lower risk of transition to psychosis compared with placebo, antipsychotics, mood stabilisers or antidepressants.43 However, this result was derived from only two studies (VHR and NEURAPRO) and just 194 participants. Overall PUFAs are no longer recommended for the treatment of residual symptoms of schizophrenia or for the prevention of transition to psychosis in young people at high risk.25,44–46 If used, careful assessment of response is important and fish oils should be withdrawn if no effect is observed after 3 months’ treatment, unless required for their beneficial metabolic effects. Summary recommendations – fish oils (PUFAs) ■ ■Patients at high risk of first-episode psychosis: ■ ■Not recommended. If used, suggest EPA 700mg/day. ■ ■Residual symptoms of multi-episode schizophrenia (added to antipsychotic): ■ ■Not recommended. If used, suggest dose of EPA 2g/day. References

Fenton WS, et al. Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia. Biol Psychiatry 2000; 47:8–21.
Mongan D, et al. Plasma polyunsaturated fatty acids and mental disorders in adolescence and early adulthood: cross-sectional and longitudinal associations in a general population cohort. Transl Psychiatry 2021; 11:321.
Jones HJ, et al. Associations between plasma fatty acid concentrations and schizophrenia: a two-sample Mendelian randomisation study. Lancet Psychiatry 2021; 8:1062–1070.
Hedelin M, et al. Dietary intake of fish, omega-3, omega-6 polyunsaturated fatty acids and vitamin D and the prevalence of psychotic-like symptoms in a cohort of 33,000 women from the general population. BMC Psychiatry 2010; 10:38.
Sethom MM, et al. Polyunsaturated fatty acids deficits are associated with psychotic state and negative symptoms in patients with schizophrenia. Prostaglandins Leukot Essent Fatty Acids 2010; 83:131–136.
Zugno AI, et al. Omega-3 prevents behavior response and brain oxidative damage in the ketamine model of schizophrenia. Neuroscience 2014; 259:223–231.
Freeman MP. Omega-3 fatty acids in psychiatry: a review. Ann Clin Psychiatry 2000; 12:159–165.
Ross BM, et al. Omega-3 fatty acids as treatments for mental illness: which disorder and which fatty acid? Lipids Health Dis 2007; 6:21.
Richardson AJ, et al. Red cell and plasma fatty acid changes accompanying symptom remission in a patient with schizophrenia treated with eicosapentaenoic acid. Eur Neuropsychopharmacol 2000; 10:189–193.

Schizophrenia and related psychoses CHAPTER 1 10. Puri BK, et al. Eicosapentaenoic acid treatment in schizophrenia associated with symptom remission, normalisation of blood fatty acids, reduced neuronal membrane phospholipid turnover and structural brain changes. Int J Clin Pract 2000; 54:57–63. 11. Su KP, et al. Omega-3 fatty acids as a psychotherapeutic agent for a pregnant schizophrenic patient. Eur Neuropsychopharmacol 2001; 11:295–299. 12. Cuéllar-Barboza AB, et al. Use of omega-3 polyunsaturated fatty acids as augmentation therapy in treatment-resistant schizophrenia. Prim Care Companion CNS Disord 2017; 19:16l02040. 13. Sivrioglu EY, et al. The impact of omega-3 fatty acids, vitamins E and C supplementation on treatment outcome and side effects in schizophrenia patients treated with haloperidol: an open-label pilot study. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:1493–1499. 14. Mellor JE, et al. Schizophrenic symptoms and dietary intake of n-3 fatty acids. Schizophr Res 1995; 18:85–86. 15. Peet M, et al. Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophr Res 2001; 49:243–251. 16. Fenton WS, et al. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry 2001; 158:2071–2074. 17. Emsley R, et al. Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am J Psychiatry 2002; 159:1596–1598. 18. Berger GE, et al. Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial. J Clin Psychiatry 2007; 68:1867–1875. 19. Fusar-Poli P, et al. Eicosapentaenoic acid interventions in schizophrenia: meta-analysis of randomized, placebo-controlled studies. J Clin Psychopharmacol 2012; 32:179–185. 20. Pawelczyk T, et al. A randomized controlled study of the efficacy of six-month supplementation with concentrated fish oil rich in omega-3 polyunsaturated fatty acids in first episode schizophrenia. J Psychiatr Res 2016; 73:34–44. 21. Bentsen H, et al. A randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E+C in schizophrenia. Transl Psychiatry 2013; 3:e335. 22. Emsley R, et al. A randomized, controlled trial of omega-3 fatty acids plus an antioxidant for relapse prevention after antipsychotic discontinuation in first-episode schizophrenia. Schizophr Res 2014; 158:230–235. 23. Bozzatello P, et al. Polyunsaturated fatty acids: what is their role in treatment of psychiatric disorders? Int J Mol Sci 2019; 20:5257. 24. Hsu MC, et al. Beneficial effects of omega-3 fatty acid supplementation in schizophrenia: possible mechanisms. Lipids Health Dis 2020; 19:159. 25. Firth J, et al. The efficacy and safety of nutrient supplements in the treatment of mental disorders: a meta-review of meta-analyses of randomized controlled trials. World Psychiatry 2019; 18:308–324. 26. Sarris J, et al. Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: the World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce. World J Biol Psychiatry 2022; 23:424–455. 27. Schlögelhofer M, et al. Polyunsaturated fatty acids in emerging psychosis: a safer alternative? Early Interv Psychiatry 2014; 8:199–208. 28. Scorza FA, et al. Omega-3 fatty acids and sudden cardiac death in schizophrenia: if not a friend, at least a great colleague. Schizophr Res 2007; 94:375–376. 29. Caniato RN, et al. Effect of omega-3 fatty acids on the lipid profile of patients taking clozapine. Aust N Z J Psychiatry 2006; 40:691–697. 30. Emsley R, et al. Safety of the omega-3 fatty acid, eicosapentaenoic acid (EPA) in psychiatric patients: results from a randomized, placebo- controlled trial. Psychiatry Res 2008; 161:284–291. 31. Das UN. Essential fatty acids and their metabolites could function as endogenous HMG-CoA reductase and ACE enzyme inhibitors, anti- arrhythmic, anti-hypertensive, anti-atherosclerotic, anti-inflammatory, cytoprotective, and cardioprotective molecules. Lipids Health Dis 2008; 7:37. 32. Pawełczyk T, et al. Omega-3 fatty acids reduce cardiometabolic risk in first-episode schizophrenia patients treated with antipsychotics: findings from the OFFER randomized controlled study. Schizophr Res 2021; 230:61–68. 33. Szeszko PR, et al. Longitudinal investigation of the relationship between omega-3 polyunsaturated fatty acids and neuropsychological functioning in recent-onset psychosis: a randomized clinical trial. Schizophr Res 2021; 228:180–187. 34. McLaverty A, et al. Omega-3 fatty acids and neurocognitive ability in young people at ultra-high risk for psychosis. Early Interv Psychiatry 2021; 15:874–881. 35. de Bles NJ, et al. Effects of multivitamin, mineral and n-3 polyunsaturated fatty acid supplementation on aggression among long-stay psychiatric in-patients: randomised clinical trial. BJPsych Open 2022; 8:e42. 36. Amminger GP, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry 2010; 67:146–154. 37. Stafford MR, et al. Early interventions to prevent psychosis: systematic review and meta-analysis. BMJ 2013; 346:f185. 38. McGorry PD, et al. Effect of omega-3 polyunsaturated fatty acids in young people at ultrahigh risk for psychotic disorders: the NEURAPRO randomized clinical trial. JAMA Psychiatry 2017; 74:19–27. 39. Bosnjak Kuharic D, et al. Interventions for prodromal stage of psychosis. Cochrane Database Syst Rev 2019; (11):CD012236. 40. Cadenhead KS, et al. Metabolic abnormalities and low dietary omega 3 are associated with symptom severity and worse functioning prior to the onset of psychosis: findings from the North American Prodrome Longitudinal Studies Consortium. Schizophr Res 2019; 204:96–103.

114 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 41. Kotlicka-Antczak M, et al. PORT (Programme of Recognition and Therapy): the first Polish recognition and treatment programme for patients with an at-risk mental state. Early Interv Psychiatry 2015; 9:339–342. 42. Susai SR, et al. Omega-3 fatty acid in ultra-high-risk psychosis: a systematic review based on functional outcome. Early Interv Psychiatry 2022; 16:3–16. 43. Chen C, et al. Network meta-analysis indicates superior effects of omega-3 polyunsaturated fatty acids in preventing the transition to psychosis in individuals at clinical high-risk. Int J Neuropsychopharmacol 2024; 27:pyae014. 44. Devoe DJ, et al. Attenuated psychotic symptom interventions in youth at risk of psychosis: a systematic review and meta-analysis. Early Interv Psychiatry 2019; 13:3–17. 45. Nasir M, et al. Trim the fat: the role of omega-3 fatty acids in psychopharmacology. Ther Adv Psychopharmacol 2019; 9:2045125319869791. 46. Cho M, et al. Adjunctive use of anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Aust N Z J Psychiatry 2019; 53:742–759.

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Alternative routes of administration

Schizophrenia and related psychoses CHAPTER 1 Alternative routes of administration The main routes of administration for antipsychotics are oral or intramuscular. Preparations formulated for these routes of administration are readily available and discussed elsewhere in the Guidelines. There may be some rare circumstances where these routes of administration are unsuitable, for example due to medical illness or surgery affecting the GI tract and/or patient preference. Below and in Table 1.26 we list some alternative routes of administration and the drugs available in formulations suitable for these routes. Table 1.26 Alternative formulations and routes of administration of antipsychotics. Drug name and route Dosing information Manufacturer Notes Inhaled Loxapine inhaled (Adasuve) 9.1mg (10mg), can be repeated after 2 hours Angelini Pharma (UK) Teva (USA) ■ ■Licensed for the rapid control of mild to moderate agitation in patients with schizophrenia or bipolar disorder in the UK and USA ■ ■Administration requires co-operation of the patient ■ ■Associated with increased risk of bronchospasms Intranasal Droperidol IV 5–10mg (higher doses have been used) Off-label, see notes ■ ■ECG monitoring is recommended Haloperidol IV 5–10mg (higher doses have been used) Off-label, see notes ■ ■Used off-label for acute disturbance, limited evidence ■ ■ECG monitoring is recommended ■ ■EPSEs reported in case studies Olanzapine IV 1.25–30mg Off-label, see notes ■ ■Used off-label for acute disturbance, limited evidence ■ ■Hypoxia, respiratory depression and bradycardia reported Sublingual Asenapine sublingual (Sycrest, Saphris) 5mg twice daily, up to a maximum dose of 10mg twice daily Organon Pharma (UK) ■ ■Licensed for moderate to severe manic episodes associated with bipolar disorder in the UK ■ ■Licensed for schizophrenia and bipolar disorder in the USA ■ ■Eating and drinking should be avoided for 10 minutes after administration (Continued)

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116 - Inhaled

Inhaled

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117 - Intranasal

Intranasal

116 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Inhaled Loxapine is the only antipsychotic licensed as an inhalation powder. It is indicated for adults with mild to moderate agitation associated with schizophrenia and bipolar disorder in the hospital setting. It was licensed in Europe and the USA in 2013 but has since been discontinued in the UK. Inhaled loxapine remains available in the EU and USA but use is restricted. Onset of tranquillising effect is around 10 minutes. Administration requires co-operation with the patient, which may not be possible in medically unwell patients. It is not clear if repeated administration of inhaled loxapine has an antipsychotic effect. Intranasal There are no commercially available preparations designed for intranasal and clinical investigations in humans are limited.1 Nanotechnology delivery systems have been developed for intranasal delivery of various antipsychotics, but this system remains clinically untested.2–4 One small study compared the pharmacokinetics of intranasal and intramuscular haloperidol in healthy volunteers.5 Using a compounded nasal spray, intranasal Table 1.26 (Continued) Drug name and route Dosing information Manufacturer Notes Transdermal Asenapine transdermal patch (Secuado) Starting dose 3.8mg/24 hr, may increase to 5.7mg/24 hr or 7.6mg/24 hr after 1 week Noven Pharmaceuticals Inc (USA) ■ ■Licensed in the USA ■ ■Can be applied to upper arm, upper back, abdomen and hip ■ ■Patients may shower with the patch on. Avoid bathing or swimming. Blonanserin transdermal patch (Lonasen) Starting dose 40mg/24 hr up to 80mg/24 hr Sumitomo Pharma ■ ■Licensed in China, Japan and South Korea ■ ■Can be applied to upper arm, upper back, abdomen and hip ■ ■Patients may shower with the patch on. However, avoid bathing or swimming. Rectal Chlorpromazine rectal 100mg every 6–8 hr Special order ■ ■25mg and 100mg suppositories available. Limited information about this route for the treatment of psychosis. Olanzapine rectal 2.5–10mg suppositories used Suppositories have been manufactured by pharmacies ■ ■Has been used for delirium, nausea and vomiting in terminally ill patients rather than for psychosis Prochlorperazine rectal 25mg every 12 hr Suppositories available in some countries ■ ■Case report only

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118 - Intravenous

Intravenous

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119 - Sublingual

Sublingual

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12 - Equivalent doses

Equivalent doses

14 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Equivalent doses Knowledge of equivalent dosages is useful when switching between FGAs. Estimates of ‘neuroleptic’ or ‘chlorpromazine’ equivalence, in mg/day, between these medications are based on clinical experience, expert panel opinion (using various methods) and any dopamine binding studies available. Table 1.4 provides approximate equivalent doses for FGAs.1–3 The values given should be seen as a rough guide when switching from one FGA to another and are no substitute for clinical titration of the new medication dose against adverse effects and response. Equivalent doses of SGAs may be less clinically relevant, as these medications tend to have better defined, evidence-based licensed dose ranges. There are several different ways of calculating equivalence based on, for example, defined daily dose,4 minimum effective dose5,6 and average dose.7 These methods give different estimates of equivalence. A very rough guide to equivalent SGA daily dosages is given in Table 1.5.3,6–10 There is considerable disagreement about exact equivalencies, even among the references cited here. Clozapine is not included because this has a distinct initial titration schedule and a high dose–plasma level variability and because it probably has a different mechanism of action. Comparing potencies of FGAs with SGAs introduces yet more uncertainty in respect to dose equivalence. Very approximately, 100mg chlorpromazine is equivalent to 1.5mg risperidone.3 An online calculator is available from the American Association of Psychiatric Pharmacists.11 Table 1.4 Equivalent doses of first-generation antipsychotic medications. Drug Equivalent dose (consensus) Range of values in literature FGAs – oral Chlorpromazine 100mg/day Reference Flupentixol 3mg/day 2–3mg/day Fluphenazine 2mg/day 1–5mg/day Haloperidol 2mg/day 1.5–5mg/day Pericyazine 10mg/day 10mg/day Perphenazine 10mg/day 5–10mg/day Pimozide 2mg/day 1.33–2mg/day Sulpiride 200mg/day 133–300mg/day Trifluoperazine 5mg/day 2.5–5mg/day Zuclopenthixol 25mg/day 25–60mg/day FGAs – long-acting injections Flupentixol decanoate 10mg/week 10–20mg/week Fluphenazine decanoate 5mg/week 1–12.5mg/week Haloperidol decanoate 15mg/week 5–25mg/week Zuclopenthixol decanoate 100mg/week 40–100mg/week

Schizophrenia and related psychoses CHAPTER 1 Table 1.5 Second-generation antipsychotics – approximate equivalent doses.3–10 Drug Approximate equivalent dose SGAs – oral Amisulpride 400mg Aripiprazole 15mg Asenapine 10mg Blonanserin ~ Brexpiprazole 2mg Cariprazine 1.5mg Clotiapine 100mg Iloperidone 12mg Lumateperone 21mg* Lurasidone 80mg (74mg base) Melperone 300mg Molindone 50mg Olanzapine 10mg Pimavaserin 17mg* Quetiapine 400mg Risperidone 4mg Sertindole 10mg* Xanomeline ~ Ziprasidone 80mg SGAs – long-acting injections Aripiprazole 1-monthly 300mg/month Aripiprazole lauroxil 441mg every 2 months Olanzapine pamoate 405mg/4 weeks Paliperidone palmitate 100mg/month Risperidone (Consta) 50mg/2 weeks Risperidone (Okedi) 100mg/4 weeks Risperidone (Uzedy) 100mg/month or 200mg every 2 months Transdermal patch Asenapine 5.7mg/24 hr ~ Unknown equivalence at time of writing. * Expert consensus recommendation.

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120 - Buccal

Buccal

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121 - Transdermal

Transdermal

Schizophrenia and related psychoses CHAPTER 1 haloperidol had a shorter time to peak levels (15 minutes) and a bioavailability comparable to oral routes of administration. Similar findings have been reported with droperidol.6 Intravenous Intravenous haloperidol is often used off-label to manage acute behavioural disturbance or agitation and psychosis in patients with delirium in a general hospital setting. However, antipsychotics are probably not effective in delirium. A large clinical trial (n = 566) showed no evidence that either IV haloperidol or ziprasidone provided benefit over placebo in patients with delirium in intensive care.7 Other studies have reported similar findings.8 In respect to toxicity, a systematic review found that IV haloperidol did not cause greater QT prolongation than placebo, but close ECG monitoring is officially advised for IV haloperidol.9 Doses between 5 and 10mg are typically recommended but doses in the literature have ranged from 50 to 1500mg (over hours to days).9 A review of observational studies reported effectiveness of off-label IV olanzapine.10 Bolus doses from 2.5 to 10mg (maximum dose of 30mg/day) have apparently been safely administered. IV droperidol is used off-label to manage acute behavioural disturbance. Low- dose IV prochlorperazine (a piperazine phenothiazine)11 has been used in migraine.12 Sublingual Asenapine is the only commercially available antipsychotic designed for sublingual use. When used sublingually, the bioavailability of asenapine is 35%, compared with only 2% when taken orally.13 Other drugs may be absorbed sublingually but this has not been investigated. Dexmedetomidine is used sublingually in acute agitation.14,15 Buccal Buccally administered drugs are absorbed through the lining of the cheek. Compared with sublingual use, buccal administration results in somewhat slower absorption.13 There are no commercially available preparations licensed for buccal use and there has been little clinical investigation into this route of administration for antipsychotics. Prochlorperazine is available in the UK as a buccal tablet16 but it is indicated for the treatment of nausea and vomiting associated with migraines.17 Prochlorperazine is now rarely used for psychiatric indications and the dose needed for an antipsychotic effect (75–100mg a day) is much greater than that used for nausea. Transdermal Asenapine is available in the USA as a daily transdermal patch (Secuado) for treatment of adults with schizophrenia. Blonanserin (Lonasen) is commercially available as a daily transdermal patch in China, Japan and South Korea. Transdermal drug delivery minimises fluctuations in plasma drug concentrations and allows for lower doses (by bypassing first-pass metabolism) and possibly reduced systemic adverse effects. At the time of writing, proof of concept clinical trials of once-weekly aripiprazole transdermal patch had been successfully conducted.18 Chlorpromazine, haloperidol, olanzapine, prochlorperazine, quetiapine and risperidone have been developed as transdermal delivery systems but are not commercially available.19,20

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122 - Rectal

Rectal

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123 - References

References

118 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Rectal Chlorpromazine suppositories are available from specials manufacturers in the UK in 25mg and 100mg strengths.21 The rectal route is not licensed in adults.17 100mg given rectally as a suppository is approximately equivalent to 20–25mg chlorpromazine hydrochloride given by IM injection or 40–50mg of chlorpromazine base or hydrochloride given orally.17 Prochlorperazine suppositories were used successfully short term for the treatment of psychosis in one case report.22 Olanzapine suppositories have been manufactured by a hospital pharmacy and administered for the treatment of delirium or nausea and vomiting in terminally ill patients.23 References

Katare YK, et al. Intranasal delivery of antipsychotic drugs. Schizophr Res 2017; 184:2–13.
Majcher MJ, et al. In situ-gelling starch nanoparticle (SNP)/O-carboxymethyl chitosan (CMCh) nanoparticle network hydrogels for the intranasal delivery of an antipsychotic peptide. J Control Release 2021; 330:738–752.
Pandey M, et al. Advances and challenges in intranasal delivery of antipsychotic agents targeting the central nervous system. Front Pharmacol 2022; 13:865590.
Pires PC, et al. Antipsychotics-loaded nanometric emulsions for brain delivery. Pharmaceutics 2022; 14:2174.
Miller JL, et al. Comparison of intranasal administration of haloperidol with intravenous and intramuscular administration: a pilot pharmacokinetic study. Pharmacotherapy 2008; 28:875–882.
Cooper I, et al. The pharmacokinetics of intranasal droperidol in volunteers characterised via population modelling. SAGE Open Med 2018; 6:2050312118813283.
Bleck TP. Dopamine antagonists in ICU delirium. N Engl J Med 2018; 379:2569–2570.
Smit L, et al. Efficacy of haloperidol to decrease the burden of delirium in adult critically ill patients: the EuRIDICE randomized clinical trial. Crit Care 2023; 27:413.
Beach SR, et al. Intravenous haloperidol: a systematic review of side effects and recommendations for clinical use. Gen Hosp Psychiatry 2020; 67:42–50.
Khorassani F, et al. Intravenous olanzapine for the management of agitation: review of the literature. Ann Pharmacother 2019; 53:853–859.
Wilson IC, et al. A double-blind trial to investigate the effects of Thorazine (Largactil, chlorpromazine), Compazine (Stemetil, prochlorperazine) and Stelazine (trifluoperazine) in paranoid schizophrenia. J Ment Sci 1961; 107:90–99.
Kostic MA, et al. A prospective, randomized trial of intravenous prochlorperazine versus subcutaneous sumatriptan in acute migraine therapy in the emergency department. Ann Emerg Med 2010; 56:1–6.
Kaminsky BM, et al. Alternate routes of administration of antidepressant and antipsychotic medications. Ann Pharmacother 2015; 49:808–817.
Karlin DM, et al. Dexmedetomidine sublingual film: a new treatment to reduce agitation in schizophrenia and bipolar disorders. Ann Pharmacother 2024; 58:54–64.
Citrome L, et al. Sublingual dexmedetomidine for the treatment of acute agitation in adults with schizophrenia or schizoaffective disorder: a randomized placebo-controlled trial. J Clin Psychiatry 2022; 83:22m14447.
Fernando T, et al. Buccally absorbed vs intravenous prochlorperazine for treatment of migraines headaches. Acta Neurol Scand 2019; 140:72–77.
National Institute for Health and Care Excellence. British National Formulary (BNF). 2024; https://bnf.nice.org.uk.
Citrome L, et al. Patches: established and emerging transdermal treatments in psychiatry. J Clin Psychiatry 2019; 80:18nr12554.
Abruzzo A, et al. Transdermal delivery of antipsychotics: rationale and current status. CNS Drugs 2019; 33:849–865.
El-Tokhy FSe, et al. Transdermal delivery of second-generation antipsychotics for management of schizophrenia; disease overview, conventional and nanobased drug delivery systems. J Drug Delivery Sci Technol 2021; 61:102104.
National Health Service UK. dm+d browser. 2024; https://dmd-browser.nhsbsa.nhs.uk.
Servis M, et al. Treatment of psychosis with prochlorperazine in the ICU setting. Psychosomatics 1997; 38:589–590.
Matsumoto K, et al. Pharmaceutical studies on and clinical application of olanzapine suppositories prepared as a hospital preparation. J Pharm Health Care Sci 2016; 2:20.

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124 - Stopping antipsychotics

Stopping antipsychotics

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125 - Withdrawal effects of antipsychotics

Withdrawal effects of antipsychotics

Schizophrenia and related psychoses CHAPTER 1 Stopping antipsychotics Antipsychotics are recommended for long-term treatment of schizophrenia because they reduce symptoms and lessen the risk of relapse.1 However, antipsychotics have many adverse effects, including metabolic complications, TD, emotional blunting and anatomical brain changes.2 There is some (hotly disputed) evidence that reducing or stopping antipsychotics may improve social functioning (relationships, education or employment, independent living) without worsening the rate of relapse or symptom burden in the medium term,3 although it might increase risk of relapse in the short term.4,5 Reducing antipsychotic burden may also improve cognitive functioning.6 It is also worth considering that much of the evidence for the relapse prevention properties of antipsychotics relies on discontinuation trials in which antipsychotics are stopped quickly (over a matter of weeks), and that process may have elevated the apparent rate of relapse in the discontinuation group, so exaggerating the relapse prevention properties of antipsychotics.7 Patients often ask to reduce or stop medication and, in light of the above, this may be a reasonable course of action. Cautious deprescribing should be a component of high-quality prescribing practice, depending on the condition being treated. More than half of antipsychotic prescriptions in the UK are given to patients without a psychotic or manic disorder and instead are prescribed for insomnia, anxiety, personality disorders and symptoms of dementia.8 In the UK, NICE strongly cautions against medium- or long-term use of antipsychotics in personality disorder,9 and only limited use in dementia.10 The principles for deprescribing outlined below also apply to these patients. Withdrawal effects of antipsychotics Stopping or reducing the dose of an antipsychotic can cause a variety of withdrawal symptoms reflecting their various actions (blocking dopamine, histamine, acetylcholine, serotonin and noradrenaline receptors).11,12 Symptoms are listed in Figure 1.2.11–15 Importantly, withdrawal/discontinuation symptoms from antipsychotics can include psychotic symptoms.12,16 This is suggested by a number of case studies in which people without a psychotic disorder treated with dopamine antagonists for reasons such as nausea or lactation difficulties develop psychotic symptoms when these medications are abruptly stopped.17–19 Non-psychotic withdrawal effects (e.g. insomnia, agitation and anxiety) may also precipitate genuine relapse that would not have occurred in the absence of antipsychotic dose reduction (perhaps clumsily named withdrawal-associated relapse).20 In patients with psychotic disorders, relapse often occurs when antipsychotics are withdrawn. This has been widely thought to represent an unmasking of the underlying chronic illness, but the nature of the process of withdrawing antipsychotics may itself be causally related to relapse.7 This suggestion is supported by the marked preponderance of relapses soon after abrupt antipsychotic cessation in patients with schizophrenia. In one analysis 60% of all relapses over 4 years occurred within 3 months of drug cessation,21 the time most likely for withdrawal effects to be evident. The idea that speed of stopping is an influence on relapse is also supported by evidence that slower tapering can reduce the rate of relapse.22,23 Withdrawal effects can be delayed in onset for weeks and sometimes months, for reasons that are poorly understood.20

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126 - Neurobiology of withdrawal

Neurobiology of withdrawal

120 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Neurobiology of withdrawal Withdrawal-associated relapse has been attributed to neural adaptations to long-term antipsychotic treatment (dopaminergic hypersensitivity, among other effects) that persist after antipsychotic cessation.24 Indeed, molecular imaging studies in schizophrenia have found increased D2/D3 receptor availability in those patients who had been exposed to antipsychotic medication but not in antipsychotic-naïve patients.25 This hypersensitivity to dopamine may render patients more susceptible to psychotic relapse when D2 blockade is diminished by antipsychotic dose reduction.11,24 There are converging lines of evidence that suggest that the neuroadaptive effects of antipsychotics can persist for months or years after stopping. Dopaminergic hypersensitivity in animals persists for the equivalent of a human year after treatment is stopped.26,27 TD – widely attributed to dopaminergic hypersensitivity – can persist for years after antipsychotic medication has been ceased.28 There is also evidence that patients who have discontinued antipsychotics have increased rates of relapse for 3 years compared with people maintained on their antipsychotics, after which relapse rates converge,1 perhaps suggesting that adaptations may have resolved by this point. Persisting dopaminergic hypersensitivity may lower the threshold for precipitating relapse from other triggers for as long as they persist (which may be months or years).20 It follows that the risk of relapse on cessation of antipsychotics might be minimised by more gradual dose tapering because these neuroadaptations would then have time to resolve during the tapering process and the rate of decline of receptor antagonism is more modest.20 Studies in which antipsychotics are tapered over months or years show reduced rates of relapse compared with relatively faster tapers,23,29,30 with one study finding that reducing dose over a year reduced the hazard rate of relapse by 3.5-fold compared with reducing over days.29 Cholinergic withdrawal symptoms Agitation, insomnia, anxiety or depression Dizziness, light-headedness, tachycardia Nausea, vomiting, salivation Diarrhoea, abdominal cramp Tremor, parkinsonism, restlessness Myalgia, rigidity, paraesthesia Agitation, fear, hallucinations Confusion or disorientation Hypothermia, sweating Histaminergic withdrawal symptoms Irritability, insomnia, agitation Depressed affect Loss of appetite or nausea Tremulousness, incoordination Lethargy or amnesia Dopaminergic withdrawal symptoms – nigrostriatal Withdrawal dyskinesia Parkinsonism Neuroleptic malignant syndrome Akathisia Antipsychotic withdrawal syndrome Dopaminergic withdrawal symptoms – mesolimbic or striatal Auditory hallucinations Persecutory delusions Other psychotic symptoms Serotonin withdrawal symptoms Flu-like symptoms, sweating or chills, dizziness, lightheadedness or tachycardia Paraesthesia, electric shock sensations Anxiety, agitation, low mood Insomnia, nightmares Nausea, vomiting, diarrhoea Confusion, decreased concentration Adrenergic withdrawal symptoms Headache, anxiety or agitation Hypertension, tachycardia, angina, palpitations Risk of myocardial infarction Presyncope, tremulousness Sweating Figure 1.2 Antipsychotic withdrawal symptoms. Source: adapted from Chouinard et al. (2017).12

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127 - Pattern of tapering

Pattern of tapering

Schizophrenia and related psychoses CHAPTER 1 Pattern of tapering Positron emission tomography demonstrates a hyperbolic relationship between dose of antipsychotic and D2 receptor occupancy.31 This hyperbolic relationship applies to other receptor targets of antipsychotics as well (including histaminergic, cholinergic and serotonergic receptors) because it arises from the law of mass action (whereby each additional molecule of a drug has incrementally less effect as receptor targets become saturated).32 The nature of this relationship is often obscured by the habit of plotting dose–response curves on semi-logarithmic axes.32 A hyperbolic relationship between dose of antipsychotic and its therapeutic effects (as measured by symptoms scales) has also been shown,33 suggesting that clinical response mirrors the neurobiological pattern of effects. This brings into question the rationale for a linear reduction of antipsychotic dose – for example, a reduction from 20 to 15 to 10 to 5 to 0mg of olanzapine. Although this regimen appears logical, the hyperbolic relationship between dose and effect on D2 blockade dictates that these linear dose decreases will produce increasingly larger reductions of D2 blockade (and there may be clinical consequences of this; Figure 1.3a). Indeed, the reduction of dose from 5 to 0mg will produce a reduction in D2 blockade (52.6%) that is larger than that produced by the reduction from 40 to 5mg of olanzapine (37.3%). These increasingly large reductions in D2 blockade are more likely to provoke relapse.34,35 Linear or ‘evenly spaced’ reductions in D2 blockade require hyperbolically reducing doses of antipsychotic (Figure 1.3b).36 These hyperbolic reductions are approximated by sequential halving of dose: for example, olanzapine doses of 20mg, 10mg, 5mg, 2.5mg, 1.25mg, 0.6mg, 0.3mg, 0mg produce roughly 15 percentage point reductions in D2 blockade. This pattern of reduction may be less likely to provoke relapse because it avoids large increases in dopaminergic signalling. Example regimens are shown in Table 1.27 and Box 1.1. Preliminary support for this approach comes from a study in which antipsychotics were reduced hyperbolically by on average 40% in people with chronic psychotic disorders, with no difference in relapse rates from the maintenance group but improved clinical outcomes.30 (a) (b) 60 D2 occupancy (%) 0 10 Olanzapine dose (mg) 40 100 60 D2 occupancy (%) 0 10 Olanzapine dose (mg) 40 Figure 1.3 (a) Linear dose reductions of olanzapine cause increasingly large reductions in D2 dopaminergic receptor blockade. The relationship between dose of olanzapine and D2 blockade is derived from the line of best fit from meta-analysis of positron emission tomography studies.31 (b) Linear reductions of D2 dopaminergic occupancy (in this case 20% reductions) correspond to hyperbolically decreasing doses of olanzapine. The doses in this case correspond to 6.9mg (80% D2 occupancy), 2.0mg (60% D2 occupancy), 0.82 mg (40% D2 occupancy) and 0.30mg (20% D2 occupancy). Approximations to this regimen that correspond to available formulations are given in the text.

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128 - Tapering in practice

Tapering in practice

122 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Exponentially reducing regimens (reducing by a fixed proportion of the most recent dose, e.g. 10%) will produce roughly linear reductions at all receptor targets of anti psychotics, making it applicable to a wide range of antipsychotic medication. Tapering in practice All patients should be informed of the risk of withdrawal symptoms on stopping or reducing the dose of any antipsychotic, including insomnia and a potential increase in psychotic symptoms. Patients should be warned not to stop antipsychotics abruptly or too quickly, because this is the method thought to be most likely to precipitate a relapse and severe withdrawal effects. Table 1.27 Reductions of olanzapine dose by up to 5 percentage points of D2 occupancy at each step, adjusted to allow use of quarter tablets. Liquid versions of drug will be needed for smaller doses. Period Olanzapine dose (mg) D2 occupancy (%) Period Olanzapine dose (mg) D2 occupancy (%) 20 72.9 4.375 37.5 17.5 70.9 3.75 34.0 15 66.9 3.125 30.4 12.5 62.8 2.5 26.3 10 58.8 2 22.3 8.75 54.7 1.5 17.3 7.5 50.7 1.1 13.1 6.25 46.6 0.7 9.1 5.625 43.5 0.35 4.0 5 40.5 0 Box 1.1 A summary of a slow hyperbolic reduction schedule for olanzapine Reduce olanzapine by 5–10mg every 1–3 months until reaching 20mg per day, then Reduce dose by 2.5–5mg every 1–3 months until reaching 10mg per day, then Reduce dose by 1.25–2.5mg every 1–3 months until reaching 5mg per day, then Reduce dose by 0.6–1.25mg every 1–3 months until reaching 2.5mg per day, then Reduce dose by 0.3–0.6mg every 1–3 months until reaching 1.25mg per day, then Reduce dose by 0.15–0.3mg every 1–3 months until reaching 0.6mg per day, then Reduce dose by 0.07–0.15mg every 1–3 months until olanzapine is completely stopped. This process could take 12–48 months, depending on how the patient tolerates the reductions. Liquid versions of drug or other options will be required for smaller doses.

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129 - When to attempt discontinuation

When to attempt discontinuation

Schizophrenia and related psychoses CHAPTER 1 When to attempt discontinuation Longstanding or lifelong antipsychotic treatment is something of a modern-day phenomenon. In the 1960s, discontinuation of antipsychotics was usually attempted after acute response. There are currently no evidence-based recommendations for antipsychotic withdrawal but we suggest that it only be considered in patients who have been in remission for 6 months (first episode) or 1 year (multi-episode). Relapse rates using fast linear tapers generally exceed 90% for both groups of patients. This might suggest that abrupt tapering always precipitates relapse or that relapse is inevitable when anti psychotics are withdrawn. Certainly, some people (probably the majority with a schizophrenia diagnosis) will relapse no matter how the antipsychotic is stopped. A cautious approach to antipsychotic reduction is recommended, especially in long- term users, where a test reduction of 5–10% of dose might be a sensible starting point. In people who have been on medication for shorter periods (e.g. <1 year) a reduction as large as 25% might be feasible. The patient should then be monitored for several weeks following this reduction for any withdrawal symptoms or worsening of psychotic symptoms. These symptoms may be transitory withdrawal effects rather than signs of inevitable relapse necessitating reinstatement of the regular dose of medication.20 If a patient tolerates this reduction with no significant effect on their overall mental state (or perhaps only mild symptoms) then further reductions could be made at the same rate (for example, a reduction of 10–25% of the dose every 2–3 months). Patients may require increased psychosocial support during this period of withdrawal. If a patient experiences significant withdrawal symptoms or worsening of psychotic symptoms then an increase in dose back one or two steps or back to the original dose may be necessary.20 This does not preclude further attempts at reduction, but these attempts should be delayed until stability is established and should be performed more gradually than previously attempted (some long-term users can only tolerate <5% dose reductions per month). Final doses before complete cessation may need to be very small to prevent a large decrease in D2 blockade. This may need to be as small as 1/80th the original therapeutic dose (for example, 0.25mg of olanzapine) or smaller. Delivery of these small doses will require splitting tablets or using liquid formulations of the medications. Use of adjunctive medication to manage withdrawal symptoms may lead to accumulation of further medications and so pausing or slowing the taper is generally more advisable.20 Every- other-day dosing of antipsychotics with half-lives of less than 24 hours leads to fluctuating plasma levels, which can precipitate withdrawal effects and so should generally be avoided. Reducing depot medication may facilitate gradual tapering because of the longer half-lives of elimination. However, depots cannot be said to be ‘self-tapering’ for long- term users because the time taken for elimination may be shorter than the time required for many patients to adapt to lower blood levels of medication, and will require switching from the lowest depot dose to oral medication in order to continue a gradual taper.37,38 Example reducing regimens are presented in Table 1.27 and Box 1.1.

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References

16 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

Foster P. Neuroleptic equivalence. Pharmaceutical J 1989; 243:431–432.
Atkins M, et al. Chlorpromazine equivalents: a consensus of opinion for both clinical and research implications. Psychiatr Bull 1997; 21:224–226.
Patel MX, et al. How to compare doses of different antipsychotics: a systematic review of methods. Schizophr Res 2013; 149:141–148.
Leucht S, et al. Dose equivalents for antipsychotic drugs: the DDD method. Schizophr Bull 2016; 42 Suppl 1:S90–S94.
Rothe PH, et al. Dose equivalents for second generation long-acting injectable antipsychotics: the minimum effective dose method. Schizophr Res 2018; 193:23–28.
Leucht S, et al. Dose equivalents for second-generation antipsychotics: the minimum effective dose method. Schizophr Bull 2014; 40:314–326.
Leucht S, et al. Dose equivalents for second-generation antipsychotic drugs: the classical mean dose method. Schizophr Bull 2015; 41:1397–1402.
Woods SW. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry 2003; 64:663–667.
McAdam MK, et al. Second International Consensus Study of Antipsychotic Dosing (ICSAD-2). J Psychopharmacol 2023; 37:982–991.
Leucht S, et al. Dose–response meta-analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry 2020; 177:342–353.
American Association of Psychiatric Pharmacists. Antipsychotic dose conversion website (last accessed February 2025); https://aapp. org/guideline/essentials/antipsychotic-dose-equivalents.

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Leucht S, et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012; 379:2063–2071.
Murray RM, et al. Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics? Br J Psychiatry 2016; 209:361–365.
Wunderink L, et al. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry 2013; 70:913–920.
Wunderink L, et al. Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry 2007; 68:654–661.
Moncrieff J, et al. Antipsychotic dose reduction and discontinuation versus maintenance treatment in people with schizophrenia and other recurrent psychotic disorders in England (the RADAR trial): an open, parallel-group, randomised controlled trial. Lancet Psychiatry 2023; 10:848–859.
Omachi Y, et al. Dose reduction/discontinuation of antipsychotic drugs in psychosis; effect on cognition and functional outcomes. Front Psychiatry 2018; 9:447.
Moncrieff J. Antipsychotic maintenance treatment: time to rethink? PLoS Med 2015; 12:e1001861.
Marston L, et al. Prescribing of antipsychotics in UK primary care: a cohort study. BMJ Open 2014; 4:e006135.
National Institute for Health and Care Excellence. Borderline personality disorder: recognition and management. Clinical guideline [CG78]. 2009 (last checked April 2022, last accessed January 2024); https://www.nice.org.uk/guidance/CG78.
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Cerovecki A, et al. Withdrawal symptoms and rebound syndromes associated with switching and discontinuing atypical antipsychotics: theoretical background and practical recommendations. CNS Drugs 2013; 27:545–572.
Chouinard G, et al. Antipsychotic-induced dopamine supersensitivity psychosis: pharmacology, criteria, and therapy. Psychother Psychosom 2017; 86:189–219.
Brandt L, et al. Antipsychotic withdrawal symptoms: a systematic review and meta-analysis. Front Psychiatry 2020; 11:569912.
Brandt L, et al. Adverse events after antipsychotic discontinuation: an individual participant data meta-analysis. Lancet Psychiatry 2022; 9:232–242.
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Moncrieff J. Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatr Scand 2006; 114:3–13.
Lu ML, et al. Metoclopramide-induced supersensitivity psychosis. Ann Pharmacother 2002; 36:1387–1390.
Roy-Desruisseaux J, et al. Domperidone-induced tardive dyskinesia and withdrawal psychosis in an elderly woman with dementia. Ann Pharmacother 2011; 45:e51.
Seeman P. Breast is best but taper domperidone when stopping [e-letter]. Br J Gen Pract 2014; https://bjgp.org/content/ yes-breast-best-taper-domperidone-when-stopping.
Horowitz MA, et al. Gradually tapering off antipsychotics: lessons for practice from case studies and neurobiological principles. Curr Opin Psychiatry 2024; 37:320–330.
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Bogers JPAM, et al. Risk factors for psychotic relapse after dose reduction or discontinuation of antipsychotics in patients with chronic schizophrenia: a systematic review and meta-analysis. Schizophr Bull Open 2020; 50:722.
Bogers J, et al. Risk factors for psychotic relapse after dose reduction or discontinuation of antipsychotics in patients with chronic schizophrenia. A meta-analysis of randomized controlled trials. Schizophr Bull 2023; 49:11-23.
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Schizophrenia and related psychoses CHAPTER 1 34. Leucht S, et al. Examination of dosing of antipsychotic drugs for relapse prevention in patients with stable schizophrenia: a meta-analysis. JAMA Psychiatry 2021; 78:1238–1248. 35. Horowitz MA, et al. Limitations in research on maintenance treatment for individuals with schizophrenia. JAMA Psychiatry 2022; 79:83–85. 36. Horowitz MA, et al. Tapering antipsychotic treatment. JAMA Psychiatry 2020; 78:125–126. 37. O’Neill JR, et al. Implementing gradual, hyperbolic tapering of long-acting injectable antipsychotics by prolonging the inter-dose interval: an in silico modelling study. Ther Adv Psychopharmacol 2023; 13:20451253231198463. 38. O’Neill J, et al. Using in silico methods to determine optimal tapering regimens for decanoate-based long-acting injectable psychosis drugs. Ther Adv Psychopharmacol 2024; 14:20451253241272790.

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131 - ANTIPSYCHOTIC ADVERSE EFFECTS

ANTIPSYCHOTIC ADVERSE EFFECTS

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132 - Extrapyramidal symptoms

Extrapyramidal symptoms

126 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 ANTIPSYCHOTIC ADVERSE EFFECTS Extrapyramidal symptoms The EPS associated with antipsychotic medication can be stigmatising, distressing, potentially disabling and act as a disincentive to taking medication.1,2 EPS are commonly overlooked and underdiagnosed or misdiagnosed in clinical practice.3,4 These movement disorders tend to be dose-related and are less likely to occur with SGAs, particularly clozapine, olanzapine, quetiapine and aripiprazole,2,5 compared with FGAs such as haloperidol. Generally it is agreed that the greater use of SGAs has led to a reduction in the frequency of EPS,6 although the prevalence of EPS of any description in community samples may exceed 30%.7 The incidence of EPS is often steeply dose- related for most drugs (clozapine and quetiapine are possible exceptions) and this relationship extends beyond the licensed dose range for some drugs.8 Patients who experience one type of EPS may be more vulnerable to developing others.9 Substance misuse increases the risk of dystonia, akathisia and TD,10,11 and there is some evidence for an association between alcohol use and akathisia.12,13 Vulnerability to EPS may be partly genetically determined.14–16 Establishing the prevalence of antipsychotic-induced EPS is problematic, given that similar movement disorders may be seen in never-medicated patients with schizophrenia.17–19 In one study of such patients at first episode, 1% had dystonia, 8% parkinsonian symptoms and 11% akathisia.19 Parkinsonian symptoms and other motor abnormalities in this context may be associated with cognitive impairment19,20 and poor long-term psychosocial functioning.21 In another study of never-treated patients with established psychotic illness, 9% exhibited spontaneous dyskinesias and 17% parkinsonian symptoms.22 Table 1.28 details the most common EPSEs.

Table 1.28 Most common extrapyramidal side effects. Dystonia (uncontrolled muscular spasm) Pseudoparkinsonism (bradykinesia, tremor, muscle rigidity, etc.) Akathisia (restlessness)23 Tardive dyskinesia (TD) (abnormal involuntary movements) Signs and symptoms24 ■ ■Muscle spasm in any part of the body, e.g. ■ ■eyes rolling upwards (oculogyric spasm) ■ ■head and neck twisted to the side (torticollis) ■ ■The patient may be unable to swallow or speak clearly. In extreme cases, the back may arch or the jaw dislocate. ■ ■Acute dystonia can be both painful and very frightening ■ ■Tremor and/or rigidity ■ ■Bradykinesia (decreased facial expression, flat monotone voice, slow body movements, inability to initiate movement) ■ ■Bradyphrenia (slowed thinking) ■ ■Salivation ■ ■Pseudoparkinsonism can be mistaken for depression or negative symptoms of schizophrenia ■ ■A subjectively unpleasant state of inner restlessness with a desire or compulsion to move23,25 ■ ■Foot stamping when seated ■ ■Constantly crossing/uncrossing legs ■ ■Rocking from foot to foot when standing ■ ■Constantly pacing up and down ■ ■Akathisia can be mistaken for psychotic agitation and has been linked with suicidal ideation26 and aggression towards others27 ■ ■A wide variety of movements can occur,28 such as: ■ ■lip smacking or chewing ■ ■tongue protrusion (‘fly catching’) ■ ■choreiform hand movements (‘piano playing’) ■ ■dystonic and choreoathetoid movements of the limbs ■ ■Severe orofacial movements can lead to difficulty speaking, eating or breathing. Movements are worse when under stress. Rating scales (see Martino et al. 2023)29 ■ ■No specific scale ■ ■Small component of general EPS scales ■ ■Simpson–Angus EPS Rating Scale30 ■ ■Barnes Akathisia Rating Scale3,31 ■ ■Abnormal Involuntary Movement Scale32,33 Prevalence ■ ■Approximately 10%34 but more common:35 ■ ■in young males ■ ■in those who are antipsychotic-naïve ■ ■with high-potency medications (e.g. haloperidol) ■ ■Dystonic reactions are rare in the elderly ■ ■Approximately 20%36 but more common in: ■ ■elderly females ■ ■those with pre-existing neurological damage (head injury, stroke, etc.) ■ ■Wide variation but approximately 25%37 for acute akathisia with FGAs, lower with SGAs ■ ■The relative liability of individual antipsychotic medications for akathisia is uncertain,2 but there is consensus that the incidence is lowest for olanzapine, quetiapine and clozapine38,39 ■ ■5% of patients per year of antipsychotic exposure.40 More common in respect to:41 ■ ■age ■ ■affective illness ■ ■schizophrenia ■ ■higher doses ■ ■acute EPS early in treatment ■ ■Lower incidence in those on SGAs.42,43 TD may be associated with neurocognitive deficits.44 (Continued)

Table 1.28 (Continued) Dystonia (uncontrolled muscular spasm) Pseudoparkinsonism (bradykinesia, tremor, muscle rigidity, etc.) Akathisia (restlessness)23 Tardive dyskinesia (TD) (abnormal involuntary movements) Time taken to develop ■ ■Acute dystonia can occur within hours of starting antipsychotic medication (minutes if the IM or IV route is used) ■ ■TD occurs after months to years of antipsychotic treatment ■ ■Days to weeks after the start of antipsychotic medication or an increase in dose ■ ■Acute akathisia occurs within hours to weeks of starting antipsychotic medication or increasing the dose ■ ■Akathisia that has persisted for several months or so is called ‘chronic akathisia’. Tardive akathisia tends to occur later in treatment and may be exacerbated or provoked by antipsychotic dose reduction or withdrawal.23 ■ ■Months to years ■ ■The proportion of cases showing reversibility on cessation of antipsychotic medication is unclear and may partly depend on age28 Treatment ■ ■Anticholinergic drugs given orally, IM or IV depending on the severity of symptoms35 ■ ■Remember the patient may be unable to swallow ■ ■Response to IV administration will be seen within 5 minutes ■ ■Response to IM administration takes around 20 minutes ■ ■TD may respond to ECT45,46 ■ ■Where severe symptoms do not respond to simpler measures including switching to an antipsychotic with a low propensity for EPS, botulinum toxin may be effective47,48 ■ ■Several options are available depending on the clinical circumstances: ■ ■Reduce the antipsychotic dose ■ ■Change to an antipsychotic medication with a lower propensity for pseudoparkinsonism (see section on relative liability of antipsychotic medications for adverse effects) ■ ■Prescribe an anticholinergic. The majority of patients do not require long-term anticholinergic agents. Use should be reviewed at least every 3 months. Do not prescribe at night (symptoms usually absent during sleep). ■ ■Reduce the antipsychotic dose ■ ■Change to an antipsychotic drug with lower propensity for akathisia (see sections on akathisia and relative liability of antipsychotic medications for adverse effects) ■ ■A reduction in symptoms may be seen with25,49,50 low-dose propranolol, 30–80mg/day; clonazepam (low dose); 5HT2 antagonists such as cyproheptadine,46 mirtazapine,49 trazodone,51,52 mianserin53 and cyproheptadine46 may help, as may possibly diphenhydramine54 ■ ■Note that all of the above medications are unlicensed for this indication ■ ■Anticholinergics are generally unhelpful unless possibly if akathisia is part of a general EPS spectrum55,56 ■ ■Stop anticholinergic if prescribed ■ ■Reduce dose of antipsychotic medication ■ ■Change to an antipsychotic with lower propensity for TD;57–60 note that data are conflicting61,62 ■ ■Clozapine is the antipsychotic most likely to be associated with resolution of symptoms.63,64 Quetiapine may also be useful in this regard.65 ■ ■Both valbenazine66 and deutetrabenazine67–69 have a positive risk–benefit balance as add-on treatments.67,70 There is also some evidence for tetrabenazine and Ginkgo biloba71 as add-on treatments. For other treatment options,72,73 see the review by the American Academy of Neurology74 and the section on treatment of TD in this chapter.

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References

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Systematic review of interventions for treating or preventing antipsychotic-induced tardive dyskinesia. Health Technol Assess 2017; 21:1–218. 73. Ricciardi L, et al. Treatment recommendations for tardive dyskinesia. Can J Psychiatry 2019; 64:388–399. 74. Bhidayasiri R, et al. Evidence-based guideline: treatment of tardive syndromes: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2013; 81:463–469.

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134 - Akathisia

Akathisia

Schizophrenia and related psychoses CHAPTER 1 Akathisia Akathisia is a fairly common adverse effect of most antipsychotic medications, although the risk of developing akathisia varies markedly between such medications.1–3 For example, a 2023 dose–response meta-analysis4 investigating antipsychotic-induced akathisia with haloperidol and 16 SGAs (not including clozapine) found that the risk was minimal with sertindole and quetiapine but high with haloperidol and lurasidone. The risk of akathisia tended to increase with dose, but the dose–response curves differed between medications, plateauing at a certain dose with some medications, such as amisulpride, haloperidol and risperidone, but increasing beyond the licensed dose range with others, such as lurasidone and lumateperone. This meta-analysis4 also confirmed the risk of akathisia with partial agonist to be greatest with cariprazine and lowest with brexpiprazole. The core feature of akathisia is mental unease and dysphoria characterised by a sense of restlessness.5,6 There is commonly a compulsion to move and a characteristic pattern of motor restlessness, which, when severe, can cause patients to pace up and down and be unable to stay seated for more than a short time.5,6 There is a phenomenological overlap between antipsychotic-induced akathisia and the restless legs syndrome and possibly an overlap in pathophysiology.7,8 The subjective experience of akathisia can be discomfiting and distressing; an association with suicidal ideation has been postulated9,10 but remains uncertain. There is some evidence to suggest that the risk of akathisia may be mitigated by avoiding high-dose antipsychotic medication, antipsychotic polypharmacy and a rapid increase in dosage.5,11–13 There is limited evidence on the benefit–risk balance for pharmacological treatments of antipsychotic-induced akathisia, even those most commonly used, such as switching to an antipsychotic medication with a lower risk of akathisia or adding a beta- adrenergic blocker, 5-HT2A antagonist or anticholinergic agent.14,15 Nevertheless, a 2024 systematic review and meta-analysis of adjunctive treatments identified 15 eligible studies of 10 treatments.16 Mirtazapine, biperiden and vitamin B6 emerged as the most efficacious, with vitamin B6 judged to have the most favourable efficacy and tolerability profile. Trazodone, mianserin and propranolol were considered effective alternative treatments, albeit with a slightly less favourable risk–benefit balance. However, given the lack of robust evidence of efficacy for such adjunctive treatments, particularly in the medium to long term, it is probably prudent to initially consider reduction of the antipsychotic dose or switching to an antipsychotic medication with a lower liability for the condition. The following diagram suggests a programme of treatment options for persistent, antipsychotic-induced akathisia.

Reduce the dose of the patient’s current antipsychotic medication, switch from antipsychotic polypharmacy to monotherapy (if possible) or slow rate of dosage increase17,18 CHAPTER 1 Ineffective/not appropriate Switch to an antipsychotic medication with a lower liability for akathisia, such as quetiapine or olanzapine19–21 (lowest effective dose possible) (Clozapine also an option in treatment-resistant schizophrenia)22 Ineffective/not appropriate to switch Consider propranolol: 30–80mg/day11,23,24 (start at 10mg three times a day) NB Note contraindications (asthma, bradycardia, hypotension etc.) Not effective/contraindicated Consider mirtazapine (15mg/day) or trazodone (50mg/day) or mianserin (30mg/day) (5HT2A antagonists)16,25–28 Not effective/not tolerated Consider an antimuscarinic drug18 (e.g. benzatropine 6mg/day) Weak support for efficacy29–31 and risk of anticholinergic adverse effects, including cognitive impairment, but may be effective where other EPS present5,11,14 Ineffective/no other EPS Consider cyproheptadine 16mg/day24,32 Ineffective Consider a benzodiazepine17,18 (e.g. diazepam up to 15mg/day, clonazepam 0.5–3mg/day) Ineffective Consider clonidine 0.2–0.8mg/day18,33 Effective Continue at reduced dose Effective Continue Effective Continue if no contraindications Continue Effective Continue, but attempt withdrawal after several months Effective Effective Continue, if no contraindications Continue, but attempt slow withdrawal after 2–4 weeks (risk of dependence) Effective Effective Continue if tolerated; withdraw very slowly (Continued)

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References

Schizophrenia and related psychoses CHAPTER 1 Notes ■ ■Akathisia can be difficult to diagnose with certainty and is commonly overlooked or misdiagnosed in clinical practice. Clinical physical examination schedules for EPS and akathisia have been proposed.34,35 ■ ■Evaluate the efficacy of each treatment option over at least 1 month if possible. Some effect may be seen after a few days, but it may take much longer to become apparent in those with chronic akathisia. ■ ■Withdraw previously ineffective add-on akathisia treatments before starting the next option in the algorithm. ■ ■Combinations of treatments may be considered for refractory cases, if carefully monitored. ■ ■Other possible treatments for acute akathisia that have been investigated include vitamin B6,16,36,37 pregabalin,38 diphenhydramine,39 trazodone25,40 and zolmitriptan.41,42 Always read the primary literature before considering any of the treatment options. ■ ■Parenteral midazolam (1.5mg) has been successfully used to prevent akathisia associated with IV metoclopramide,43 suggesting a specific therapeutic effect for midazolam against akathisia and perhaps benzodiazepines more generally. ■ ■In some cases where agitation/akathisia are recognised as short-lived effects of antipsychotic medication when initiated (e.g. with aripiprazole, cariprazine), prophylactic or rescue benzodiazepines may be prescribed for a limited period. Clinical experience suggests this practice can be effective. (Continued) References

Demyttenaere K, et al. Medication-induced akathisia with newly approved antipsychotics in patients with a severe mental illness: a systematic review and meta-analysis. CNS Drugs 2019; 33:549–566.
Chow CL, et al. Akathisia and newer second-generation antipsychotic drugs: a review of current evidence. Pharmacotherapy 2020; 40:565–574.
Martino D, et al. Movement disorders associated with antipsychotic medication in people with schizophrenia: an overview of Cochrane reviews and meta-analysis. Can J Psychiatry 2018; 63:706743718777392.
Wu H, et al. Antipsychotic-induced akathisia in adults with acute schizophrenia: a systematic review and dose-response meta-analysis. Eur Neuropsychopharmacol 2023; 72:40–49.
Braude WM, et al. Clinical characteristics of akathisia: a systematic investigation of acute psychiatric inpatient admissions. Br J Psychiatry 1983; 143:139–150.
Barnes TRE. A rating scale for drug-induced akathisia. Br J Psychiatry 1989; 154:672–676.
Ferré S, et al. Restless legs syndrome, neuroleptic-induced akathisia, and opioid-withdrawal restlessness: shared neuronal mechanisms? Sleep 2024; 47:zsad273.
Walters AS. Restless legs syndrome, neuroleptic-induced akathisia, and the iron opioid dopamine link. Sleep 2024; 47:zsae008.
Seemuller F, et al. Akathisia and suicidal ideation in first-episode schizophrenia. J Clin Psychopharmacol 2012; 32:694–698.
Seemuller F, et al. The relationship of akathisia with treatment emergent suicidality among patients with first-episode schizophrenia treated with haloperidol or risperidone. Pharmacopsychiatry 2012; 45:292–296.
Miller CH, et al. Managing antipsychotic-induced acute and chronic akathisia. Drug Saf 2000; 22:73–81.
Berardi D, et al. Clinical correlates of akathisia in acute psychiatric inpatients. Int Clin Psychopharmacol 2000; 15:215–219.
Yoshimura B, et al. Incidence and predictors of acute akathisia in severely ill patients with first-episode schizophrenia treated with aripiprazole or risperidone: secondary analysis of an observational study. Psychopharmacology (Berl) 2019; 236:723–730.
Pringsheim T, et al. The assessment and treatment of antipsychotic-induced akathisia. Can J Psychiatry 2018; 63:719–729.
Stroup TS, et al. Management of common adverse effects of antipsychotic medications. World Psychiatry 2018; 17:341–356.
Gerolymos C, et al. Drug efficacy in the treatment of antipsychotic-induced akathisia: a systematic review and network meta-analysis. JAMA Netw Open 2024; 7:e241527.
Fleischhacker WW, et al. The pharmacologic treatment of neuroleptic-induced akathisia. J Clin Psychopharmacol 1990; 10:12–21.
Sachdev P. The identification and management of drug-induced akathisia. CNS Drugs 1995; 4:28–46.
Kumar R, et al. Akathisia and second-generation antipsychotic drugs. Curr Opin Psychiatry 2009; 22:293–299.
Miller DD, et al. Extrapyramidal side-effects of antipsychotics in a randomised trial. Br J Psychiatry 2008; 193:279–288.
Rummel-Kluge C, et al. Second-generation antipsychotic drugs and extrapyramidal side effects: a systematic review and meta-analysis of head-to-head comparisons. Schizophr Bull 2012; 38:167–177.
Kane JM, et al. Akathisia: an updated review focusing on second-generation antipsychotics. J Clin Psychiatry 2009; 70:627–643.
Adler L, et al. A controlled assessment of propranolol in the treatment of neuroleptic-induced akathisia. Br J Psychiatry 1986; 149:42–45.
Fischel T, et al. Cyproheptadine versus propranolol for the treatment of acute neuroleptic-induced akathisia: a comparative double-blind study. J Clin Psychopharmacol 2001; 21:612–615.
Laoutidis ZG, et al. 5-HT2A receptor antagonists for the treatment of neuroleptic-induced akathisia: a systematic review and meta-analysis. Int J Neuropsychopharmacol 2014; 17:823–832.

134 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 26. Poyurovsky M, et al. Treatment of antipsychotic-induced akathisia: role of serotonin 5-HT(2a) receptor antagonists. Drugs 2020; 80:871–882. 27. Poyurovsky M. Acute antipsychotic-induced akathisia revisited. Br J Psychiatry 2010; 196:89–91. 28. Shams-Alizadeh N, et al. Trazodone as an alternative treatment for neuroleptic-associated akathisia: a placebo-controlled, double-blind, clinical trial. J Clin Psychopharmacol 2020; 40:611–614. 29. Rathbone J, et al. Anticholinergics for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev 2006; (4):CD003727. 30. Baskak B, et al. The effectiveness of intramuscular biperiden in acute akathisia: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol 2007; 27:289–294. 31. Vanegas-Arroyave N, et al. An evidence-based update on anticholinergic use for drug-induced movement disorders. CNS Drugs 2024; 38:239–254. 32. Weiss D, et al. Cyproheptadine treatment in neuroleptic-induced akathisia. Br J Psychiatry 1995; 167:483–486. 33. Zubenko GS, et al. Use of clonidine in treating neuroleptic-induced akathisia. Psychiatry Res 1984; 13:253–259. 34. Gervin M, et al. Assessment of drug-related movement disorders in schizophrenia. Advances in Psychiatric Treatment 2000; 6:332–341. 35. Cunningham Owens D. A Guide to the Extrapyramidal Side Effects of Antipsychotic Drugs. Cambridge: Cambridge University Press; 1999. 36. Miodownik C, et al. Vitamin B6 versus mianserin and placebo in acute neuroleptic-induced akathisia: a randomized, double-blind, controlled study. Clin Neuropharmacol 2006; 29:68–72. 37. Lerner V, et al. Vitamin B6 treatment in acute neuroleptic-induced akathisia: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2004; 65:1550–1554. 38. De BD, et al. Reversal of aripiprazole-induced tardive akathisia by addition of pregabalin. J Neuropsychiatry Clin Neurosci 2013; 25:E9–E10. 39. Friedman BW, et al. A randomized trial of diphenhydramine as prophylaxis against metoclopramide-induced akathisia in nauseated emergency department patients. Ann Emerg Med 2009; 53:379–385. 40. Stryjer R, et al. Trazodone for the treatment of neuroleptic-induced acute akathisia: a placebo-controlled, double-blind, crossover study. Clin Neuropharmacol 2010; 33:219–222. 41. Gross-Isseroff R, et al. The 5-HT1D receptor agonist zolmitriptan for neuroleptic-induced akathisia: an open label preliminary study. Int Clin Psychopharmacol 2005; 20:23–25. 42. Avital A, et al. Zolmitriptan compared to propranolol in the treatment of acute neuroleptic-induced akathisia: a comparative double-blind study. Eur Neuropsychopharmacol 2009; 19:476–482. 43. Erdur B, et al. A trial of midazolam vs diphenhydramine in prophylaxis of metoclopramide-induced akathisia. Am J Emerg Med 2012; 30:84–91.

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136 - Treatment of tardive dyskinesia

Treatment of tardive dyskinesia

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137 - Treatment first steps

Treatment – first steps

Schizophrenia and related psychoses CHAPTER 1 Treatment of tardive dyskinesia Tardive dyskinesia is a somewhat less commonly encountered problem now than in previous decades,1,2 probably because of the more widespread use of SGAs,3–6 which generally have a lower risk for the condition than FGAs. Treatment of established TD is often unsuccessful, so prevention, early detection and early remedial action are essential.7,8 There is evidence to suggest that TD is associated with greater cognitive impairment,7,9 more severe psychopathology10,11 and higher mortality.12,13 While the majority of patients seem to be unaware of the involuntary movements, the condition can still impose a substantial burden on physical, psychological and social well-being.14–16 While SGAs are less likely to cause TD,17–23 the condition still occurs with these medications. An extensive meta-analysis of relevant studies found the annualised incidence of TD across all FGA treatment groups was 6.5%, while the respective figure for SGA treatment groups was 2.6%.24 However, there is a significant variation in liability between individual SGA medications.24–28 The risk of developing TD may be related to the extent of D2 receptor occupancy (greater occupancy, higher risk) with a medication,29 although data from the meta-analysis mentioned above did not support the notion that the lower risk of TD with SGAs is a consequence of the use of relatively high equivalent doses of FGAs.24 There is a hint that dopamine partial agonists (or, at least, aripiprazole) may have the lowest liability for TD.24 Whether the risk of TD differs between LAI FGA and LAI SGA preparations is unclear30 but there is one report suggesting that the risk of TD with LAI SGAs is lower than with the equivalent oral SGA preparations.31 TD can occur even with low doses of haloperidol (and in the absence of prior acute movement disorder)32 and with the use of other dopamine antagonists such as metoclopramide.33 The characteristic abnormal involuntary movements of TD have also been observed in never-medicated patients with both first-episode34,35 and established36 schizophrenia. This suggests that the use of antipsychotic medication adds to an inherent risk of TD that is present in people with a diagnosis of schizophrenia. Treatment – first steps Most authorities recommend the withdrawal of any co-prescribed anticholinergic agents and a reduction in the dose of antipsychotic medication (which may initially worsen TD) as initial steps in those with early signs of TD,37,38 although there is a lack of robust evidence to support such a strategy.14,39–41 Nevertheless, it is common practice to withdraw the antipsychotic prescribed when TD is first observed and to substitute it with an antipsychotic medication that is perceived to have a lower liability for the condition. However, the evidence for a beneficial effect on TD when switching to any particular SGA is limited.42 Changing to clozapine37,43 is probably best supported,37,43–45 but quetiapine, another weak striatal dopamine antagonist, may also be effective.46–52 Olanzapine39–42,53,54 and aripiprazole55 are also potential options.

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138 - Treatment additional agents

Treatment – additional agents

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139 - Treatment other possible options

Treatment – other possible options

136 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Treatment – other possible options The large number of proposed treatments for TD undoubtedly reflects the somewhat limited effectiveness of standard remedies, at least before the introduction of valbenazine and deutetrabenazine.14 Table 1.30 lists some of these putative treatments, most of which have a low level of evidence.8,62 Treatment – additional agents Given that there is insufficient evidence to recommend dose reduction as a treatment for TD, and that switching or withdrawing antipsychotic medication is not always effective or advisable, add-on agents are often considered. Evidence-based, pharmacological treatment algorithms for TD have been published.41,56 A 2020 meta- analysis57 concluded that vesicular monoamine transporter 2 (VMAT-2) inhibitors (such as deutetrabenazine and valbenazine), vitamin E, amantadine and vitamin B6 (pyridoxine) are probably effective treatments. VMAT-2 inhibitors are considered agents of first choice, given the body of evidence supporting their use58–60 and their additional antipsychotic action.61 Table 1.29 describes the most frequently prescribed add-on medications for TD. Table 1.29 First-choice agents prescribed for tardive dyskinesia (alphabetical order; no preference implied). Drug Comments Amantadine56,57,62–64 Rarely used and evidence for efficacy is limited. Dose is 100–300mg/day. Benzodiazepines37,38 Widely used for TD, but a Cochrane review considered that the limited evidence for efficacy was inconclusive.65 Intermittent use may be necessary to avoid tolerance to effects. Most commonly used are clonazepam 1–4mg/day and diazepam 6–25mg/ day, with better supporting evidence for clonazepam.42,66 Deutetrabenazine8,56,58,60,67,68 Deutetrabenazine (a VMAT-2 inhibitor) is effective as a treatment for TD. Licensed for TD in the USA.69 Better supporting evidence than for tetrabenazine. Longer half-life than tetrabenazine but still needs to be taken twice a day (a once daily slow-release tablet is in development).70 Low incidence of psychiatric and neurological effects. Dose is 12–48mg/day. Ginkgo biloba56,71,72 Well tolerated. A Cochrane review concluded that while Ginkgo biloba could reduce TD symptoms, the available evidence did not justify its routine use as a treatment.73 A meta-analysis of three Chinese RCTs showed a good effect with 240mg/day.74 Pyridoxine75 Supported by a Cochrane review76 and a 2020 meta-analysis.57 Dose is up to 400mg/day. Tetrabenazine77,78 The only licensed treatment for moderate to severe TD in UK. Depression, drowsiness, parkinsonism and akathisia may occur.66,79 Dose is 25–200mg/day. Reserpine (similar mode of action) also effective but rarely, if ever, used. Valbenazine8,59,67,73,80 Evidence supports a favourable benefit–risk ratio for valbenazine (VMAT-2 inhibitor) as a treatment for TD. Licensed for TD in the USA.81 A dose of 80mg once daily is effective. It has a benign cardiovascular profile and a low incidence of depression and akathisia. Vitamin E57,82 Numerous studies but efficacy remains to be conclusively established. A Cochrane review suggested that there is evidence only for slowing the deterioration of TD,8,83 but a 2022 meta-analysis also suggested a treatment effect.84 Dose is in the range 400–1600 IU/day.

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14 - High dose antipsychotic medication prescribin

High-dose antipsychotic medication: prescribing and monitoring

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References

Schizophrenia and related psychoses CHAPTER 1 Table 1.30 Other options for the treatment of tardive dyskinesia (in alphabetical order). Drug Comments Amino acids85 Use is supported by a small randomised, placebo-controlled trial. Low risk of toxicity. Botulinum toxin86–89 Case reports of success for localised dyskinesia. Probably now treatment of choice for disabling or distressing focal symptoms. Calcium antagonists90 A few published studies but not widely used. A Cochrane review is dismissive.91 A 2020 meta-analysis found no effect.57 DBS8,92,93 Reports refer most commonly to stimulation of the globus pallidus internus. The evidence is limited but DBS may potentially have a role when TD symptoms are severe and distressing and unresponsive to pharmacological treatment. Donepezil94–96 Supported by a single open study and a case series. One very small, negative RCT. Dose is 10mg/day. No clear evidence of efficacy for rivastigmine or galantamine.97 Fish oils98,99 Very limited support for use of EPA at dose of 2g/day Fluvoxamine100 Three case reports. Dose is 100mg/day. Beware interactions. Gabapentin101 Adds weight to the theory that GABAergic mechanisms improve TD. Dose is 900– 1200mg/day. Inconclusive data on other GABA agonists.102 Levetiracetam103–106 Three published case studies. One RCT. Dose up to 3000mg/day. Melatonin107 Use is supported by a meta-analysis of four trials.108 Usually well tolerated. Dose is 10mg/day. Some evidence that melatonin receptor genotype determines risk of TD.109 Naltrexone110 May be effective when added to benzodiazepines. Well tolerated. Dose is 200mg/day. Ondansetron111,112 Limited evidence but low toxicity. Dose is up to 12mg/day. Propranolol113–115 Formerly a relatively widely used treatment. Open-label studies only but a prospective randomised trial is probably warranted. Dose is 40–120mg/day. Beware contraindications, such as asthma, bradycardia and hypotension. Quercetin116 Plant compound which is thought to be an antioxidant. Some promising case reports.116–118 Sodium oxybate119 One case report. Dose was 8g/day. rTMS120,121 RCT data on patients with ‘tardive syndromes’ suggest that bilateral hemispheric high-frequency rTMS has the potential to be a feasible treatment where TD is unresponsive to ‘first-line’ pharmacological treatment120 Zolpidem122 Three case reports. Dose is 10–30mg a day. DBS, deep brain stimulation; EPA, eicosapentaenoic acid; GABA, gamma-aminobutyric acid; rTMS, repetitive transcranial magnetic stimulation. References

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Wu JQ, et al. Tardive dyskinesia is associated with greater cognitive impairment in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2013; 46:71–77.

138 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 8. Ricciardi L, et al. Treatment recommendations for tardive dyskinesia. Can J Psychiatry 2019; 64:388–399. 9. Strassnig M, et al. Tardive dyskinesia: motor system impairments, cognition and everyday functioning. CNS Spectr 2018; 23:370–377. 10. Yuen O, et al. Tardive dyskinesia and positive and negative symptoms of schizophrenia: a study using instrumental measures. Br J Psychiatry 1996; 168:702–708. 11. Ascher-Svanum H, et al. Tardive dyskinesia and the 3-year course of schizophrenia: results from a large, prospective, naturalistic study. J Clin Psychiatry 2008; 69:1580–1588. 12. Dean CE, et al. Mortality and tardive dyskinesia: long-term study using the US National Death Index. Br J Psychiatry 2009; 194:360–364. 13. Chong SA, et al. Mortality rates among patients with schizophrenia and tardive dyskinesia. J Clin Psychopharmacol 2009; 29:5–8. 14. Caroff SN. Overcoming barriers to effective management of tardive dyskinesia. Neuropsychiatr Dis Treat 2019; 15:785–794. 15. Barer Y, et al. The clinical and economic burden of tardive dyskinesia in Israel: real-world data analysis. J Clin Psychopharmacol 2022; 42:454–460. 16. Jain R, et al. Impact of tardive dyskinesia on physical, psychological, social, and professional domains of patient lives: a survey of patients in the United States. J Clin Psychiatry 2023; 84:22m14694. 17. Beasley C, et al. Randomised double-blind comparison of the incidence of tardive dyskinesia in patients with schizophrenia during long-term treatment with olanzapine or haloperidol. Br J Psychiatry 1999; 174:23–30. 18. Glazer WM. Expected incidence of tardive dyskinesia associated with atypical antipsychotics. J Clin Psychiatry 2000; 61 Suppl 4:21–26. 19. Correll CU, et al. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry 2004; 161:414–425. 20. Dolder CR, et al. Incidence of tardive dyskinesia with typical versus atypical antipsychotics in very high risk patients. Biol Psychiatry 2003; 53:1142–1145. 21. Correll CU, et al. Tardive dyskinesia and new antipsychotics. Current Opin Psychiatry 2008; 21:151–156. 22. Carbon M, et al. Tardive dyskinesia prevalence in the period of second-generation antipsychotic use: a meta-analysis. J Clin Psychiatry 2017; 78:e264–e278. 23. O’Brien A. Comparing the risk of tardive dyskinesia in older adults with first-generation and second-generation antipsychotics: a systematic review and meta-analysis. Int J Geriatr Psychiatry 2016; 31:683–693. 24. Carbon M, et al. Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis. World Psychiatry 2018; 17:330–340. 25. Keck ME, et al. Ziprasidone-related tardive dyskinesia [Letter]. Am J Psychiatry 2004; 161:175–176. 26. Maytal G, et al. 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A systematic review on the use of clozapine in treatment of tardive dyskinesia and tardive dystonia in patients with psychiatric disorders. Psychopharmacology (Berl) 2022; 239:3393–3420. 46. Vesely C, et al. Remission of severe tardive dyskinesia in a schizophrenic patient treated with the atypical antipsychotic substance quetiapine. Int Clin Psychopharmacol 2000; 15:57–60.

Schizophrenia and related psychoses CHAPTER 1 47. Alptekin K, et al. Quetiapine-induced improvement of tardive dyskinesia in three patients with schizophrenia. Int Clin Psychopharmacol 2002; 17:263–264. 48. Nelson MW, et al. Adjunctive quetiapine decreases symptoms of tardive dyskinesia in a patient taking risperidone. Clin Neuropharmacol 2003; 26:297–298. 49. Emsley R, et al. A single-blind, randomized trial comparing quetiapine and haloperidol in the treatment of tardive dyskinesia. J Clin Psychiatry 2004; 65:696–701. 50. Bressan RA, et al. Atypical antipsychotic drugs and tardive dyskinesia: relevance of D2 receptor affinity. J Psychopharmacol 2004; 18:124–127. 51. Sacchetti E, et al. Quetiapine, clozapine, and olanzapine in the treatment of tardive dyskinesia induced by first-generation antipsychotics: a 124-week case report. Int Clin Psychopharmacol 2003; 18:357–359. 52. Gourzis P, et al. Quetiapine in the treatment of focal tardive dystonia induced by other atypical antipsychotics: a report of 2 cases. Clin Neuropharmacol 2005; 28:195–196. 53. Soutullo CA, et al. Olanzapine in the treatment of tardive dyskinesia: a report of two cases. J Clin Psychopharmacol 1999; 19:100-101. 54. Kinon BJ, et al. Olanzapine treatment for tardive dyskinesia in schizophrenia patients: a prospective clinical trial with patients randomized to blinded dose reduction periods. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28:985–996. 55. Chan CH, et al. Switching antipsychotic treatment to aripiprazole in psychotic patients with neuroleptic-induced tardive dyskinesia: a 24-week follow-up study. Int Clin Psychopharmacol 2018; 33:155–162. 56. Bhidayasiri R, et al. Updating the recommendations for treatment of tardive syndromes: a systematic review of new evidence and practical treatment algorithm. J Neurol Sci 2018; 389:67–75. 57. Artukoglu BB, et al. Pharmacologic treatment of tardive dyskinesia: a meta-analysis and systematic review. J Clin Psychiatry 2020; 81:19r12798. 58. Hauser RA, et al. Long-term deutetrabenazine treatment for tardive dyskinesia is associated with sustained benefits and safety: a 3-year, open-label extension study. Front Neurol 2022; 13:773999. 59. Golsorkhi M, et al. Comparative analysis of deutetrabenazine and valbenazine as VMAT2 inhibitors for tardive dyskinesia: a systematic review. Tremor Other Hyperkinet Mov 2024; 14:13. 60. Frank S, et al. Clinical utility of deutetrabenazine as a treatment option for chorea associated with Huntington’s disease and tardive dyskinesia. Ther Clin Risk Manag 2023; 19:1019–1024. 61. Connolly A, et al. Meta-analysis and systematic review of vesicular monoamine transporter (VMAT-2) inhibitors in schizophrenia and psychosis. Psychopharmacology (Berl) 2024; 241:225–241. 62. Takeuchi H, et al. Pathophysiology, prognosis and treatment of tardive dyskinesia. Ther Adv Psychopharmacol 2022; 12:20451253221117313. 63. Angus S, et al. A controlled trial of amantadine hydrochloride and neuroleptics in the treatment of tardive dyskinesia. J Clin Psychopharmacol 1997; 17:88–91. 64. Pappa S, et al. Effects of amantadine on tardive dyskinesia: a randomized, double-blind, placebo-controlled study. Clin Neuropharmacol 2010; 33:271–275. 65. Bergman H, et al. Benzodiazepines for antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev 2018; 1:CD000205. 66. Rana AQ, et al. New and emerging treatments for symptomatic tardive dyskinesia. Drug Des Devel Ther 2013; 7:1329–1340. 67. Solmi M, et al. Treatment of tardive dyskinesia with VMAT-2 inhibitors: a systematic review and meta-analysis of randomized controlled trials. Drug Des Devel Ther 2018; 12:1215–1238. 68. Claassen DO, et al. Deutetrabenazine for tardive dyskinesia and chorea associated with Huntington’s disease: a review of clinical trial data. Expert Opin Pharmacother 2019; 20:2209–2221. 69. Citrome L. Deutetrabenazine for tardive dyskinesia: a systematic review of the efficacy and safety profile for this newly approved novel medication. What is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract 2017; 71:e13030. 70. Sunzel EM, et al. A bioequivalence comparison between the once-daily extended-release tablet and the twice-daily tablet formulations of deutetrabenazine at steady state. Clin Pharmacol Drug Dev 2024; 13:224–232. 71. Zhang WF, et al. Extract of Ginkgo biloba treatment for tardive dyskinesia in schizophrenia: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2011; 72:615–621. 72. Petridis PD, et al. Tardive dyskinesia suppressed with Ginkgo biloba. J Clin Psychopharmacol 2023; 43:549–551. 73. Soares-Weiser K, et al. Miscellaneous treatments for antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev 2018; 3:CD000208. 74. Zheng W, et al. Extract of ginkgo biloba for tardive dyskinesia: meta-analysis of randomized controlled trials. Pharmacopsychiatry 2016; 49:107–111. 75. Lerner V, et al. Vitamin B(6) in the treatment of tardive dyskinesia: a double-blind, placebo-controlled, crossover study. Am J Psychiatry 2001; 158:1511–1514. 76. Adelufosi AO, et al. Pyridoxal 5 phosphate for neuroleptic-induced tardive dyskinesia. Cochrane Database Syst Rev 2015; (4): CD010501. 77. Jankovic J, et al. Long-term effects of tetrabenazine in hyperkinetic movement disorders. Neurology 1997; 48:358–362. 78. Leung JG, et al. Tetrabenazine for the treatment of tardive dyskinesia. Ann Pharmacother 2011; 45:525–531. 79. Kenney C, et al. Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders. Mov Disord 2007; 22:193–197. 80. Kishi T, et al. Valbenazine for tardive dyskinesia: a systematic review and network meta-analysis. Int Clin Psychopharmacol 2023; 38:369–374. 81. Citrome LL. Medication options and clinical strategies for treating tardive dyskinesia. J Clin Psychiatry 2020; 81:TV18059BR18052C. 82. Zhang XY, et al. The effect of vitamin E treatment on tardive dyskinesia and blood superoxide dismutase: a double-blind placebo-controlled trial. J Clin Psychopharmacol 2004; 24:83–86.

140 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 83. Soares-Weiser K, et al. Vitamin E for antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev 2018; 1:CD000209. 84. Xu H, et al. Vitamin E in the treatment of tardive dyskinesia: a meta-analysis. Int Clin Psychopharmacol 2022; 37:60–66. 85. Richardson MA, et al. Efficacy of the branched-chain amino acids in the treatment of tardive dyskinesia in men. Am J Psychiatry 2003; 160:1117–1124. 86. Tarsy D, et al. An open-label study of botulinum toxin A for treatment of tardive dystonia. Clin Neuropharmacol 1997; 20:90–93. 87. Brashear A, et al. Comparison of treatment of tardive dystonia and idiopathic cervical dystonia with botulinum toxin type A. Mov Disord 1998; 13:158–161. 88. Hennings JM, et al. Successful treatment of tardive lingual dystonia with botulinum toxin: case report and review of the literature. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:1167–1171. 89. Beckmann YY, et al. Treatment of intractable tardive lingual dyskinesia with botulinum toxin. J Clin Psychopharmacol 2011; 31:250–251. 90. Essali A, et al. Calcium channel blockers for neuroleptic-induced tardive dyskinesia. Cochrane Database Syst Rev 2011; (11):CD000206. 91. Essali A, et al. Calcium channel blockers for antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev 2018; 3:CD000206. 92. Macerollo A, et al. Deep brain stimulation for tardive syndromes: systematic review and meta-analysis. J Neurol Sci 2018; 389:55–60. 93. Szczakowska A, et al. Deep brain stimulation in the treatment of tardive dyskinesia. J Clin Med 2023; 12:1868. 94. Caroff SN, et al. Treatment of tardive dyskinesia with donepezil. J Clin Psychiatry 2001; 62:128–129. 95. Bergman J, et al. Beneficial effect of donepezil in the treatment of elderly patients with tardive movement disorders. J Clin Psychiatry 2005; 66:107–110. 96. Ogunmefun A, et al. Effect of donepezil on tardive dyskinesia. J Clin Psychopharmacol 2009; 29:102–104. 97. Tammenmaa-Aho I, et al. Cholinergic medication for antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev 2018; 3:CD000207. 98. Emsley R, et al. The effects of eicosapentaenoic acid in tardive dyskinesia: a randomized, placebo-controlled trial. Schizophr Res 2006; 84:112–120. 99. Vaddadi K, et al. Tardive dyskinesia and essential fatty acids. Int Rev Psychiatry 2006; 18:133–143. 100. Albayrak Y, et al. Benefical effects of sigma-1 agonist fluvoxamine for tardive dyskinesia and tardive akathisia in patients with schizophrenia: report of three cases. Psychiatry Investig 2013; 10:417–420. 101. Hardoy MC, et al. Gabapentin in antipsychotic-induced tardive dyskinesia: results of 1-year follow-up. J Affect Disord 2003; 75:125–130. 102. Alabed S, et al. Gamma-aminobutyric acid agonists for antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev 2018; 4:CD000203. 103. McGavin CL, et al. Levetiracetam as a treatment for tardive dyskinesia: a case report. Neurology 2003; 61:419. 104. Meco G, et al. Levetiracetam in tardive dyskinesia. Clin Neuropharmacol 2006; 29:265–268. 105. Woods SW, et al. Effects of levetiracetam on tardive dyskinesia: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2008; 69:546–554. 106. Chen PH, et al. Rapid improvement of neuroleptic-induced tardive dyskinesia with levetiracetam in an interictal psychotic patient. J Clin Psychopharmacol 2010; 30:205–207. 107. Shamir E, et al. Melatonin treatment for tardive dyskinesia: a double-blind, placebo-controlled, crossover study. Arch Gen Psychiatry 2001; 58:1049–1052. 108. Sun CH, et al. Adjunctive melatonin for tardive dyskinesia in patients with schizophrenia: a meta-analysis. Shanghai Arch Psychiatry 2017; 29:129–136. 109. Lai IC, et al. Analysis of genetic variations in the human melatonin receptor (MTNR1A, MTNR1B) genes and antipsychotics-induced tardive dyskinesia in schizophrenia. World J Biol Psychiatry 2011; 12:143–148. 110. Wonodi I, et al. Naltrexone treatment of tardive dyskinesia in patients with schizophrenia. J Clin Psychopharmacol 2004; 24:441–445. 111. Sirota P, et al. Use of the selective serotonin 3 receptor antagonist ondansetron in the treatment of neuroleptic-induced tardive dyskinesia. Am J Psychiatry 2000; 157:287–289. 112. Naidu PS, et al. Reversal of neuroleptic-induced orofacial dyskinesia by 5-HT3 receptor antagonists. Eur J Pharmacol 2001; 420:113–117. 113. Perenyi A, et al. Propranolol in the treatment of tardive dyskinesia. Biol Psychiatry 1983; 18:391–394. 114. Pitts FN, Jr. Treatment of tardive dyskinesia with propranolol. J Clin Psychiatry 1982; 43:304. 115. Hatcher-Martin JM, et al. Propranolol therapy for tardive dyskinesia: a retrospective examination. Parkinsonism Relat Disord 2016; 32:124–126. 116. Naidu PS, et al. Reversal of haloperidol-induced orofacial dyskinesia by quercetin, a bioflavonoid. Psychopharmacology (Berl) 2003; 167:418–423. 117. Naidu PS, et al. Quercetin, a bioflavonoid, attenuates haloperidol-induced orofacial dyskinesia. Neuropharmacology 2003; 44:1100–1106. 118. Naidu PS, et al. Reversal of reserpine-induced orofacial dyskinesia and cognitive dysfunction by quercetin. Pharmacology 2004; 70:59–67. 119. Berner JE. A case of sodium oxybate treatment of tardive dyskinesia and bipolar disorder. J Clin Psychiatry 2008; 69:862. 120. Khedr EM, et al. Repetitive transcranial magnetic stimulation for treatment of tardive syndromes: double randomized clinical trial. J Neural Transm (Vienna) 2019; 126:183–191. 121. Brambilla P, et al. Transient improvement of tardive dyskinesia induced with rTMS. Neurology 2003; 61:1155. 122. Waln O, et al. Zolpidem improves tardive dyskinesia and akathisia. Mov Disord 2013; 28:1748–1749.

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Antipsychotic-induced weight gain

Schizophrenia and related psychoses CHAPTER 1 Antipsychotic-induced weight gain Weight gain is a common adverse effect of antipsychotic medication.1 This may reflect interference with the homeostatic control of appetite and metabolism, leading to increased food intake and reduced energy expenditure, although the various mechanisms involved are not well understood.2–4 Factors such as 5HT2C antagonism, H1 antagonism, D2 antagonism and increased serum leptin (leading to leptin desensitisation)5–7 are commonly implicated, as well as, possibly, effects on gut microbiota.8–11 The risk of weight gain appears to be related to clinical response12,13 (although the association may be too small to be clinically important)14 and may have a genetic basis.15 Weight gain may be more pronounced in antipsychotic-naïve patients and during the early stages of the treatment of psychotic illness16–18 and women may be at greater risk than men.19,20 Almost all available antipsychotic medications have been associated with weight gain,16 although the mean gain in body weight varies substantially between the medications. There is also marked inter-individual variation among those treated, with some losing weight, some gaining no weight and some gaining a great deal of weight. Thus, knowledge of the mean increase in weight reported for a particular medication may not be a helpful predictor of how much weight an individual might gain. Assessment of the relative liability for weight gain of different antipsychotic medications is based largely on short-term studies. Notwithstanding these limitations, the results of indirect and direct meta-analyses suggest that these medications can be clustered into three groups based on their relative risk of weight gain (Table 1.31).21,22 Table 1.31 Risk/extent of antipsychotic-induced weight gain (drugs in alphabetical order).23–26 Risk/extent of weight gain Drug High Clozapine Olanzapine Moderate Chlorpromazine FGAs* Iloperidone Haloperidol Quetiapine Paliperidone Risperidone Sertindole (Continued)

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Time course

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Dose–response

142 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Time course Antipsychotic-induced weight gain occurs primarily in the first few months of treatment but continues for many months or even years afterwards. In a 10-year study of patients with first-episode schizophrenia, the mean weight gain was 15kg. Most of this (9kg) was gained in the first year.27 In those gaining the most weight, increase in weight continues at the same rate for at least 2 years.28 Dose–response The relationship between dose and weight gain is complex and varies from one antipsychotic medication to another.22,29 Two broad patterns have emerged: an increase in weight gained over a lower dose range, which then reaches a plateau (e.g. risperidone, haloperidol and quetiapine), and an increasing risk of weight gain up to and beyond the maximum dose (e.g. clozapine and olanzapine). Both patterns suggest that dose reduction might reverse or mitigate weight gain and there is some evidence that this is possible.30 However, the dose–response relationships identified indicate that the risk of weight gain emerges at doses that are subtherapeutic for psychosis, meaning that there is no effective dose that does not carry a risk of weight gain. See following section for advice on the treatment of antipsychotic-induced weight gain. Risk/extent of weight gain Drug Low Amisulpride Aripiprazole Asenapine Brexpiprazole Cariprazine Lumateperone Lurasidone Sulpiride Trifluoperazine Ziprasidone * Data on individual FGAs other than chlorpromazine and haloperidol are scarce but one comprehensive analysis showed that FGAs (not including haloperidol) had a moderate risk of weight gain: 20–30% of people gained more than 7% of original body weight in the medium term.16 Individual FGAs are likely to vary in their propensity for weight gain. Traditionally low-potency FGAs (e.g. chlorpromazine) were considered to have a higher risk of weight gain. Table 1.31 (Continued)

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References

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Barton BB, et al. Update on weight-gain caused by antipsychotics: a systematic review and meta-analysis. Expert Opin Drug Saf 2020; 19:295–314.
Correll CU, et al. Antipsychotic drugs and obesity. Trends Mol Med 2011; 17:97–107.
Stogios N, et al. Antipsychotic-induced weight gain in severe mental illness: risk factors and special considerations. Curr Psychiatry Reps 2023; 25:707–721.
Cuerda C, et al. The effects of second-generation antipsychotics on food intake, resting energy expenditure and physical activity. Eur J Clin Nutr 2014; 68:146–152.
Nielsen MO, et al. Striatal reward activity and antipsychotic-associated weight change in patients with schizophrenia undergoing initial treatment. JAMA Psychiatry 2016; 73:121–128.
Ragguett RM, et al. Association between antipsychotic treatment and leptin levels across multiple psychiatric populations: an updated meta- analysis. Hum Psychopharmacol 2017; 32:e2631.
Reynolds GP, et al. Mechanisms underlying metabolic disturbances associated with psychosis and antipsychotic drug treatment. J Psychopharmacol 2017; 31:1430–1436.
Kanji S, et al. The microbiome–gut–brain axis: implications for schizophrenia and antipsychotic induced weight gain. Eur Arch Psychiatry Clin Neurosci 2018; 268:3–15.
Qian L, et al. Longitudinal gut microbiota dysbiosis underlies olanzapine-induced weight gain. Microbiol Spectr 2023; 11:e0005823.
Fang X, et al. The role of the gut microbiome in weight-gain in schizophrenia patients treated with atypical antipsychotics: evidence based on altered composition and function in a cross-sectional study. Psychiatry Res 2023; 328:115463.
Ye W, et al. Mechanism and treatments of antipsychotic-induced weight gain. Int J Obes (Lond) 2023; 47:423–433.
Garcia-Rizo C. Antipsychotic-induced weight gain and clinical improvement: a psychiatric paradox. Front Psychiatry 2020; 11:560006.
Smith ECC, et al. Clinical improvement in schizophrenia during antipsychotic treatment in relation to changes in glucose parameters: a systematic review. Psychiatry Res 2023; 328:115472.
Hermes E, et al. The association between weight change and symptom reduction in the CATIE schizophrenia trial. Schizophr Res 2011; 128:166–170.
Zhang JP, et al. Pharmacogenetic associations of antipsychotic drug-related weight gain: a systematic review and meta-analysis. Schizophr Bull 2016; 42:1418–1437.
Bak M, et al. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS One 2014; 9:e94112.
McEvoy JP, et al. Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry 2007; 164:1050–1060.
Vochoskova K, et al. Weight and metabolic changes in early psychosis—association with daily quantification of medication exposure during the first hospitalization. Acta Psychiatr Scand 2023; 148:265–276.
Seeman MV. Secondary effects of antipsychotics: women at greater risk than men. Schizophr Bull 2009; 35:937–948.
Stamoula E, et al. Weight gain, gender, and antipsychotics: a disproportionality analysis of the FDA Adverse Event Reporting System database (FAERS). Expert Opin Drug Saf 2024; 23:239–245.
Cooper SJ, et al. BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment. J Psychopharmacol 2016; 30:717–748.
Sabé M, et al. Comparative effects of 11 antipsychotics on weight gain and metabolic function in patients with acute schizophrenia: a dose- response meta-analysis. J Clin Psychiatry 2023; 84:22r14490.
Leucht S, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382:951–962.
Leucht S, et al. Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, Bayesian meta-analysis, and meta-regression of efficacy predictors. Am J Psychiatry 2017; 174:927–942.
Musil R, et al. Weight gain and antipsychotics: a drug safety review. Expert Opin Drug Saf 2015; 14:73–96.
Pillinger T, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry 2020; 7:64–77.
Vázquez-Bourgon J, et al. Pattern of long-term weight and metabolic changes after a first episode of psychosis: results from a 10-year prospective follow-up of the PAFIP program for early intervention in psychosis cohort. Eur Psychiatry 2022; 65:e48.
Chua YC, et al. A retrospective database study on 2-year weight trajectories in first-episode psychosis. Front Psychiatry 2023; 14:1185874.
Wu H, et al. Antipsychotic-induced weight gain: dose-response meta-analysis of randomized controlled trials. Schizophr Bull 2022; 48:643–654.
Speyer H, et al. Reversibility of antipsychotic-induced weight gain: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2021; 12:577919.

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Treatment of antipsychotic-induced weight gain

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146 - Monitoring

Monitoring

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Treatment and prevention

144 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Treatment of antipsychotic-induced weight gain Weight gain is an important adverse effect of nearly all antipsychotic medications.1,2 Women may be at greater risk than men.3 An increase in body weight has obvious consequences for self-image, morbidity and mortality, so prevention and treatment are matters of some clinical urgency. Monitoring Patients starting antipsychotic treatment or changing medication should, as an absolute minimum, have their body weight recorded in their clinical records. Ideally, BMI and waist circumference should also be recorded.4,5 Early in treatment, monitoring of body weight every week or two is recommended, for at least the first 6 months.5,6 Rapid weight gain in early treatment (e.g. an increase of ≥5% above baseline after a month of treatment) strongly predicts long-term weight gain and should prompt consideration of preventative or remedial measures.7–10 With continuing antipsychotic treatment, annual measurement of body weight is recommended as a minimum.5,6,11 In clinical practice, the monitoring of body weight and other metabolic adverse effects in people on continuing antipsychotic medication is inconsistent and limited, falling short of recommended best practice.12–16 Treatment and prevention Most of the relevant literature in this area addresses attempts to reduce body weight gained during treatment with medication, although there are useful data suggesting that early interventions can prevent or mitigate weight gain.17,18 When weight gain occurs, initial options involve switching a patient’s antipsychotic medication or instituting behavioural programmes (or both). Switching always presents a risk of relapse and treatment discontinuation,19 but there is fairly strong support for switching to aripiprazole,20 ziprasidone21 or lurasidone as a method for reversing weight gain.20,22,23 Another option is adjunctive aripiprazole:5 weight loss has been observed when aripiprazole has been added to antipsychotic medications such as clozapine and olanzapine.18,24 Stopping antipsychotic treatment altogether can be associated with weight loss25,26 but this course of action would not be clinically appropriate for the vast majority of people with multi-episode schizophrenia. Note that, while some switching and augmentation strategies may minimise further weight gain or facilitate weight loss, the overall effect is generally modest, and many patients continue to be overweight.27 Additional lifestyle interventions are often required if BMI is to remain within or move towards the normal range. A variety of lifestyle interventions have been proposed and evaluated with generally good results.5,17,28–31 Interventions do vary, but they are mainly ‘behavioural lifestyle programmes’ aimed at improving diet and increasing physical activity. Meta-analyses of RCTs have generally found a positive effect for both prevention and intervention with these non-pharmacological interventions.17,29,32,33 Pharmacological methods should be considered only where behavioural treatment strategies or switching to a medication with a lower liability for weight gain have failed

Schizophrenia and related psychoses CHAPTER 1 or where obesity presents a clear, immediate physical risk to the patient. Some drug treatment options for antipsychotic-induced weight gain are listed in Table 1.32. Metformin is now probably considered to be the drug of choice for the prevention and treatment of antipsychotic-induced weight gain, although glucagon-like peptide-1 (GLP-1) agonists may ultimately prove to be more effective and better tolerated.34 Bariatric surgery may have a role in a few rare, severe cases where all else has failed.35 However, the efficacy of bariatric surgery for drug-induced weight gain is not known.5 Table 1.32 Drug treatment of antipsychotic-induced weight gain (alphabetical order). Drug Comments Alpha-lipoic acid36–38 (1200mg/day) Supplementation may lead to a small, short-term, weight loss. Limited data for antipsychotic-induced weight gain. Not recommended. Amantadine39,40 (100–300mg/day) May attenuate olanzapine-related weight gain. Seems to be well tolerated apart from insomnia and abdominal discomfort. May (theoretically, at least) exacerbate psychosis. Evidence base too limited to recommend.5 Aripiprazole augmentation18,31,41 (5–15mg/day) RCTs show beneficial effects on weight loss and possibly other metabolic parameters when used as an adjunct to clozapine or olanzapine. Adjunctive use appears to be safe and unlikely to worsen psychosis. Recommended as a possible option for weight gain associated with clozapine or olanzapine. Not recommended with other antipsychotic medications. Betahistine42,43 (48mg/day) May attenuate olanzapine-induced weight gain. Limited data. Not recommended. Bupropion44,45 (formerly amfebutamone) Seems to be effective in obesity when combined with calorie-restricted diets. Appears to not exacerbate psychosis symptoms, at least when used for smoking cessation.46 One small (positive) RCT in antipsychotic-related weight gain.47 Bupropion + naltrexone (Contrave/Mysimba)48 Combination approved for weight management as an adjunct to diet and exercise. No data in drug-induced weight gain. Not recommended but should not be ruled out. Fluvoxamine49–51 (50mg/day) Earlier conflicting data but one short-term RCT shows attenuated clozapine-induced weight gain (possibly related to a higher clozapine to norclozapine ratio). Co- administration markedly increases clozapine levels, requiring extreme caution. Evidence base is too limited to recommend. Liraglutide52–54 (3mg/day via SC injection) GLP-1 agonist that was previously approved for type 2 diabetes and more recently approved as an anti-obesity agent in non-diabetic patients. Dose for weight loss (3mg/day) is higher than the dose used for diabetes (≤1.8mg). Limited data in drug-induced weight gain. One RCT shows significant weight loss in overweight pre-diabetic patients stable on olanzapine or clozapine.52 Beneficial effects on other metabolic parameters. Well tolerated but can cause GI disturbances. Recommended option in pre-diabetic/diabetic patients and clozapine-induced weight gain. Other GLP-1 agonists are currently only approved for diabetes and have a more limited dose range. Exenatide LA (a once-weekly GLP-1 agonist) may be effective for weight loss in clozapine-treated patients55 but perhaps not with other antipsychotics.56 (Continued)

146 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Drug Comments Melatonin57–59 (up to 5mg at night) One small RCT showing attenuation of olanzapine-induced weight gain. Other studies show negative results. Effect, if any, is small. Metformin5,31,60–62 (500–2000mg/day) There is a substantial database (in non-diabetic patients) supporting the use of metformin in both reducing and reversing weight gain caused by antipsychotic medications (mainly olanzapine). A Cochrane review in 2022 concluded that there was ‘low-certainty evidence to suggest that metformin may be effective in preventing weight gain’ in people with schizophrenia.62 There may also be beneficial effects on other metabolic parameters. A later cohort study63 showed that metformin prevented weight gain with clozapine. One positive RCT64 and extension study65 in children and adolescents with autism spectrum disorder. May be ideal for those with weight gain and diabetes or polycystic ovary syndrome. Note that metformin treatment increases the risk of vitamin B12 deficiency.66 Modafinil67,68 (up to 300mg/day) Limited positive data and one negative RCT for clozapine-induced weight gain. Not recommended. Naltrexone69,70 (25–50mg/day) Some positive results but evidence is limited to two small pilot RCTs. Not recommended. Orlistat71–76 (120mg shortly before or after each meal). Official maximum is three times daily. Reliable effect in obesity, especially when combined with calorie restriction. Few published data in medication-induced weight gain but widely used in practice with some success. In trials for clozapine or olanzapine-induced weight gain effect was only seen in men.75,76 When used without calorie restriction in psychiatric patients, the effects are very limited. Failure to adhere to a low-fat diet will result in fatty diarrhoea and possible malabsorption of orally administered medication. Overall, a good choice for clozapine-induced weight gain where it reduces both weight and the incidence of constipation.77 Reboxetine18 (4–8mg/day) Attenuates olanzapine-induced weight gain. Reverses some metabolic changes.78 Effective when combined with betahistine. Samidorphan (μ–opioid receptor antagonist)79–85 There is good evidence from RCTs that the combination of samidorphan and olanzapine can mitigate olanzapine-associated weight gain. But these findings need to be confirmed ‘through further high-quality research’.83 The combination was approved by the US FDA in 2021 for indications including the treatment of schizophrenia and bipolar I disorder. Semaglutide (weekly injectable, glucagon–like peptide-1RA)86,87 A small case series suggested that semaglutide, up to 2mg/week, might reduce antipsychotic-associated weight gain that had not responded to metformin. Topiramate31,58,88,89 (up to 300mg/day) Reliably reduces weight even when medication induced. Meta-analyses of RCTs suggest a greater effect for prevention rather than treatment. Problems may arise because of topiramate’s propensity for causing sedation, confusion and cognitive impairment. May have antipsychotic properties. Zonisamide90 (100–600mg/day) Antiepileptic drug with weight-reducing properties. An RCT of 150mg/day showed significant weight reduction in people receiving SGAs. Another RCT (up to 600mg/ day) shows attenuated olanzapine-induced weight gain. Sedation, diarrhoea and cognitive impairment are the most common problems. Not recommended. Table 1.32 (Continued)

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References

Schizophrenia and related psychoses CHAPTER 1 References

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Bak M, et al. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS One 2014; 9:e94112.
Stamoula E, et al. Weight gain, gender, and antipsychotics: a disproportionality analysis of the FDA Adverse Event Reporting System database (FAERS). Expert Opin Drug Saf 2024; 23:239–245.
Marder SR, et al. Physical health monitoring of patients with schizophrenia. Am J Psychiatry 2004; 161:1334–1349.
Cooper SJ, et al. BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment. J Psychopharmacol 2016; 30:717–748.
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Mitchell AJ, et al. Guideline concordant monitoring of metabolic risk in people treated with antipsychotic medication: systematic review and meta-analysis of screening practices. Psychol Med 2012; 42:125–147.
Barnes TR, et al. Screening for the metabolic side effects of antipsychotic medication: findings of a 6-year quality improvement programme in the UK. BMJ Open 2015; 5:e007633.
Crawford MJ, et al. Assessment and treatment of physical health problems among people with schizophrenia: national cross-sectional study. Br J Psychiatry 2014; 205:473–477.
Hammoudeh S, et al. Risk factors of metabolic syndrome among patients receiving antipsychotics: a retrospective study. Community Ment Health J 2020; 56:760–770.
Ward T, et al. Who is responsible for metabolic screening for mental health clients taking antipsychotic medications? Int J Ment Health Nurs 2018; 27:196–203.
Bruins J, et al. The effects of lifestyle interventions on (long-term) weight management, cardiometabolic risk and depressive symptoms in people with psychotic disorders: a meta-analysis. PLoS One 2014; 9:e112276.
Mizuno Y, et al. Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: a systematic review and meta-analysis. Schizophr Bull 2014; 40:1385–1403.
Stroup TS, et al. A randomized trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk: comparison of antipsychotics for metabolic problems (CAMP). Am J Psychiatry 2011; 168:947–956.
Mukundan A, et al. Antipsychotic switching for people with schizophrenia who have neuroleptic-induced weight or metabolic problems. Cochrane Database Syst Rev 2010; (12):CD006629.
Montes JM, et al. Improvement in antipsychotic-related metabolic disturbances in patients with schizophrenia switched to ziprasidone. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:383–388.
Wu H, et al. Antipsychotic-induced weight gain: dose-response meta-analysis of randomized controlled trials. Schizophr Bull 2022; 48:643–654.
Akinola PS, et al. Antipsychotic-induced metabolic syndrome: a review. Metab Syndr Relat Disord 2023; 21:294–305.
Galling B, et al. Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis. World Psychiatry 2017; 16:77–89.
de Kuijper G, et al. Effects of controlled discontinuation of long-term used antipsychotics on weight and metabolic parameters in individuals with intellectual disability. J Clin Psychopharmacol 2013; 33:520–524.
Chen EY, et al. Maintenance treatment with quetiapine versus discontinuation after one year of treatment in patients with remitted first episode psychosis: randomised controlled trial. BMJ 2010; 341:c4024.
Speyer H, et al. Reversibility of antipsychotic-induced weight gain: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2021; 12:577919.
Werneke U, et al. Behavioural management of antipsychotic-induced weight gain: a review. Acta Psychiatr Scand 2003; 108:252–259.
Caemmerer J, et al. Acute and maintenance effects of non-pharmacologic interventions for antipsychotic associated weight gain and metabolic abnormalities: a meta-analytic comparison of randomized controlled trials. Schizophr Res 2012; 140:159–168.
Rice J, et al. Integrative management of metabolic syndrome in youth prescribed second-generation antipsychotics. Med Sci (Basel) 2020; 8:34.
Vancampfort D, et al. The impact of pharmacological and non-pharmacological interventions to improve physical health outcomes in people with schizophrenia: a meta-review of meta-analyses of randomized controlled trials. World Psychiatry 2019; 18:53–66.
Naslund JA, et al. Lifestyle interventions for weight loss among overweight and obese adults with serious mental illness: a systematic review and meta-analysis. Gen Hosp Psychiatry 2017; 47:83–102.

148 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 33. Mohanty K, et al. Effectiveness of lifestyle intervention on prevention/management of antipsychotic-induced weight gain among persons with severe mental illness: a systematic review and meta-analysis. J Health Psychol 2024; 29:690–706. 34. Lee K, et al. Antipsychotic-induced weight gain: exploring the role of psychiatrists in managing patients’ physical health – challenges, current options and direction for future care. BJPsych Bull 2024; 48:24–29. 35. Manu P, et al. Weight gain and obesity in schizophrenia: epidemiology, pathobiology, and management. Acta Psychiatr Scand 2015; 132:97–108. 36. Kucukgoncu S, et al. Alpha-lipoic acid (ALA) as a supplementation for weight loss: results from a meta-analysis of randomized controlled trials. Obes Rev 2017; 18:594–601. 37. Kim E, et al. A preliminary investigation of alpha-lipoic acid treatment of antipsychotic drug-induced weight gain in patients with schizophrenia. J Clin Psychopharmacol 2008; 28:138–146. 38. Ratliff JC, et al. An open-label pilot trial of alpha-lipoic acid for weight loss in patients with schizophrenia without diabetes. Clin Schizophr Relat Psychoses 2015; 8:196–200. 39. Praharaj SK, et al. Amantadine for olanzapine-induced weight gain: a systematic review and meta-analysis of randomized placebo-controlled trials. Ther Adv Psychopharmacol 2012; 2:151–156. 40. Zheng W, et al. Amantadine for antipsychotic-related weight gain: meta-analysis of randomized placebo-controlled trials. J Clin Psychopharmacol 2017; 37:341–346. 41. Zheng W, et al. Efficacy and safety of adjunctive aripiprazole in schizophrenia: meta-analysis of randomized controlled trials. J Clin Psychopharmacol 2016; 36:628–636. 42. Barak N, et al. A randomized, double-blind, placebo-controlled pilot study of betahistine to counteract olanzapine-associated weight gain. J Clin Psychopharmacol 2016; 36:253–256. 43. Lian J, et al. Ameliorating antipsychotic-induced weight gain by betahistine: mechanisms and clinical implications. Pharmacol Res 2016; 106:51–63. 44. Gadde KM, et al. Bupropion for weight loss: an investigation of efficacy and tolerability in overweight and obese women. Obes Res 2001; 9:544–551. 45. Jain AK, et al. Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms. Obes Res 2002; 10:1049–1056. 46. Tsoi DT, et al. Interventions for smoking cessation and reduction in individuals with schizophrenia. Cochrane Database Syst Rev 2013; 2:CD007253. 47. Weizman S, et al. A double-blind, placebo-controlled trial of bupropion add-on to olanzapine or risperidone in overweight individuals with schizophrenia. J Clin Psychopharmacol 2021; 41:629–631. 48. Greig SL, et al. Naltrexone ER/bupropion ER: a review in obesity management. Drugs 2015; 75:1269–1280. 49. Hinze-Selch D, et al. Effect of coadministration of clozapine and fluvoxamine versus clozapine monotherapy on blood cell counts, plasma levels of cytokines and body weight. Psychopharmacology (Berl) 2000; 149:163–169. 50. Lu ML, et al. Effects of adjunctive fluvoxamine on metabolic parameters and psychopathology in clozapine-treated patients with schizophrenia: a 12-week, randomized, double-blind, placebo-controlled study. Schizophr Res 2017; 193:126–133. 51. Lu ML, et al. Adjunctive fluvoxamine inhibits clozapine-related weight gain and metabolic disturbances. J Clin Psychiatry 2004; 65:766–771. 52. Larsen JR, et al. Effect of liraglutide treatment on prediabetes and overweight or obesity in clozapine- or olanzapine-treated patients with schizophrenia spectrum disorder: a randomized clinical trial. JAMA Psychiatry 2017; 74:719–728. 53. Mayfield K, et al. Glucagon-like peptide-1 agonists combating clozapine-associated obesity and diabetes. J Psychopharmacol 2016; 30:227–236. 54. Lee K, et al. A systematic review of licensed weight-loss medications in treating antipsychotic-induced weight gain and obesity in schizophrenia and psychosis. Gen Hosp Psychiatry 2022; 78:58–67. 55. Siskind D, et al. Treatment of clozapine-associated obesity and diabetes with exenatide (CODEX) in adults with schizophrenia: a randomised controlled trial. Diabetes Obes Metab 2017; 20:1050–1055. 56. Ishoy PL, et al. Effect of GLP-1 receptor agonist treatment on body weight in obese antipsychotic-treated patients with schizophrenia: a randomized, placebo-controlled trial. Diabetes Obes Metab 2017; 19:162–171. 57. Agahi M, et al. Effect of melatonin in reducing second-generation antipsychotic metabolic effects: a double blind controlled clinical trial. Diabetes Metab Syndr 2017; 12:9–15. 58. Wang HR, et al. The role of melatonin and melatonin agonists in counteracting antipsychotic-induced metabolic side effects: a systematic review. Int Clin Psychopharmacol 2016; 31:301–306. 59. Porfirio MC, et al. Can melatonin prevent or improve metabolic side effects during antipsychotic treatments? Neuropsychiatr Dis Treat 2017; 13:2167–2174. 60. Zheng W, et al. Metformin for weight gain and metabolic abnormalities associated with antipsychotic treatment: meta-analysis of randomized placebo-controlled trials. J Clin Psychopharmacol 2015; 35:499–509. 61. Wang C, et al. Outcomes and safety of concomitant topiramate or metformin for antipsychotics-induced obesity: a randomized-controlled trial. Ann Gen Psychiatry 2020; 19:68. 62. Agarwal SM, et al. Pharmacological interventions for prevention of weight gain in people with schizophrenia. Cochrane Database Syst Rev 2022; 10:CD013337. 63. Stogios N, et al. Metformin for the prevention of clozapine-induced weight gain: a retrospective naturalistic cohort study. Acta Psychiatr Scand 2022; 146:190–200. 64. Anagnostou E, et al. Metformin for treatment of overweight induced by atypical antipsychotic medication in young people with autism spectrum disorder: a randomized clinical trial. JAMA Psychiatry 2016; 73:928–937.

Schizophrenia and related psychoses CHAPTER 1 65. Handen BL, et al. A randomized, placebo-controlled trial of metformin for the treatment of overweight induced by antipsychotic medication in young people with autism spectrum disorder: open-label extension. J Am Acad Child Adolesc Psychiatry 2017; 56:849-856.e6. 66. Chapman LE, et al. Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: a systematic review and meta-analysis. Diabetes Metab 2016; 42:316–327. 67. Henderson DC, et al. Effects of modafinil on weight, glucose and lipid metabolism in clozapine-treated patients with schizophrenia. Schizophr Res 2011; 130:53–56. 68. Roerig JL, et al. An exploration of the effect of modafinil on olanzapine associated weight gain in normal human subjects. Biol Psychiatry 2009; 65:607–613. 69. Taveira TH, et al. The effect of naltrexone on body fat mass in olanzapine-treated schizophrenic or schizoaffective patients: a randomized double-blind placebo-controlled pilot study. J Psychopharmacol 2014; 28:395–400. 70. Tek C, et al. A randomized, double-blind, placebo-controlled pilot study of naltrexone to counteract antipsychotic-associated weight gain: proof of concept. J Clin Psychopharmacol 2014; 34:608–612. 71. Sjostrom L, et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet 1998; 352:167–172. 72. Hilger E, et al. The effect of orlistat on plasma levels of psychotropic drugs in patients with long-term psychopharmacotherapy. J Clin Psychopharmacol 2002; 22:68–70. 73. Pavlovic ZM. Orlistat in the treatment of clozapine-induced hyperglycemia and weight gain. Eur Psychiatry 2005; 20:520. 74. Carpenter LL, et al. A case series describing orlistat use in patients on psychotropic medications. Med Health R I 2004; 87:375–377. 75. Joffe G, et al. Orlistat in clozapine- or olanzapine-treated patients with overweight or obesity: a 16-week randomized, double-blind, placebo- controlled trial. J Clin Psychiatry 2008; 69:706–711. 76. Tchoukhine E, et al. Orlistat in clozapine- or olanzapine-treated patients with overweight or obesity: a 16-week open-label extension phase and both phases of a randomized controlled trial. J Clin Psychiatry 2011; 72:326–330. 77. Chukhin E, et al. In a randomized placebo-controlled add-on study orlistat significantly reduced clozapine-induced constipation. Int Clin Psychopharmacol 2013; 28:67–70. 78. Amrami-Weizman A, et al. The effect of reboxetine co-administration with olanzapine on metabolic and endocrine profile in schizophrenia patients. Psychopharmacology (Berl) 2013; 230:23–27. 79. Gao J, et al. Samidorphan for the treatment of weight gain associated with olanzapine in patients with schizophrenia and bipolar disorder. Expert Rev Clin Pharmacol 2022; 15:1011–1016. 80. Laguado SA, et al. Opioid antagonists to prevent olanzapine-induced weight gain: a systematic review. Ment Health Clin 2022; 12:254–262. 81. Meyer JM, et al. Olanzapine/samidorphan combination consistently mitigates weight gain across various subgroups of patients. CNS Spectr 2023; 28:478–481. 82. Grywińska WB, et al. Combining samidorphan with olanzapine to mitigate weight gain as a side effect in schizophrenia treatment. Postep Psychiatr Neurol 2023; 32:128–137. 83. Peng Z, et al. Effects of combined therapy of olanzapine and samidorphan on safety and metabolic parameters in schizophrenia patients: a meta-analysis. Neuropsychiatr Dis Treat 2023; 19:2295–2308. 84. Kahn RS, et al. Olanzapine/samidorphan in young adults with schizophrenia, schizophreniform disorder, or bipolar I disorder who are early in their illness: results of the randomized, controlled ENLIGHTEN-Early study. J Clin Psychiatry 2023; 84:22m14674. 85. Correll CU, et al. Reduction in multiple cardiometabolic risk factors with combined olanzapine/samidorphan compared with olanzapine: post hoc analyses from a 24-week phase 3 study. Schizophr Bull 2023; 49:454–463. 86. Prasad F, et al. Semaglutide for the treatment of antipsychotic-associated weight gain in patients not responding to metformin: a case series. Ther Adv Psychopharmacol 2023; 13:20451253231165169. 87. Stogios N, et al. Antipsychotic-induced weight gain in severe mental illness: risk factors and special considerations. Curr Psychiatry Rep 2023; 25:707–721. 88. Correll CU, et al. Efficacy for psychopathology and body weight and safety of topiramate-antipsychotic cotreatment in patients with schizophrenia spectrum disorders: results from a meta-analysis of randomized controlled trials. J Clin Psychiatry 2016; 77:e746–e756. 89. Zheng W, et al. Efficacy and safety of adjunctive topiramate for schizophrenia: a meta-analysis of randomized controlled trials. Acta Psychiatr Scand 2016; 134:385–398. 90. Buoli M, et al. The use of zonisamide for the treatment of psychiatric disorders: a systematic review. Clin Neuropharmacol 2017; 40:85–92.

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149 - Neuroleptic malignant syndrome

Neuroleptic malignant syndrome

150 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Neuroleptic malignant syndrome NMS occurs as a rare but potentially serious or even fatal adverse effect of antipsychotics and other dopamine antagonists (Table 1.33).1,2 It is an acute disorder of thermoregulation and neuromotor control, characterised by muscular rigidity, hyperthermia, altered consciousness and autonomic dysfunction, although there is considerable heterogeneity in the clinical presentation.1,3–5 In many cases, the presentation is atypical, lacking key signs and symptoms such as hyperthermia and muscle rigidity.6–8 Asymptomatic rises in plasma creatine kinase (CK) seem to be fairly common and so CK cannot be used as a diagnostic marker of NMS.9 Table 1.33 Neuroleptic malignant syndrome. Signs and symptoms10–13 (presentation varies considerably)14 Fever, diaphoresis, muscle rigidity, confusion, fluctuating level of consciousness, labile or high BP, tachycardia Elevated CK, often >1000 units/L,2,15 leukocytosis, altered LFTs Risk factors12,13,16–21 High-potency FGAs, recent or rapid dose increase, rapid dose reduction, abrupt withdrawal of anticholinergic agents, antipsychotic polypharmacy Psychosis, organic brain disease, alcoholism, Parkinson’s disease, hyperthyroidism, psychomotor agitation, cognitive impairment Male gender, younger age Agitation, dehydration Treatments10,12,22–25 (note that guideline recommendations for NMS vary widely and are based on limited evidence)26 In the psychiatric unit: withdraw antipsychotic medication, monitor temperature, pulse, BP. Consider benzodiazepines if not already prescribed – IM lorazepam has been used.27 In the medical/emergency unit: rehydration, bromocriptine + dantrolene, sedation with benzodiazepines, artificial ventilation if required l-dopa, apomorphine and carbamazepine have also been used, among many other drugs. ECT may be effective for NMS, even after pharmacotherapy has failed.28–30 Restarting antipsychotics12,22,31,32 Antipsychotic treatment will be required in most instances and rechallenge is associated with acceptable risk Stop antipsychotic medication for at least 5 days, preferably longer. Allow time for symptoms and signs of NMS to resolve completely Begin with very small dose and increase very slowly with close monitoring of temperature, pulse and blood pressure. CK monitoring may be used but is controversial.13,33 Close monitoring of physical and biochemical parameters is effective in reducing progression to ‘full-blown’ NMS.34,35 Consider using an antipsychotic medication structurally unrelated to that previously associated with NMS or a drug with low dopamine affinity (quetiapine or clozapine). Aripiprazole may also be considered36 but it has a long plasma half-life and has been linked to an increased risk of NMS.17 Avoid depot/LAI antipsychotic preparations (of any kind) and high-potency FGAs CK, creatine kinase; FGA, first-generation antipsychotic.

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15 - Efficacy

Efficacy

Schizophrenia and related psychoses CHAPTER 1 High-dose antipsychotic medication: prescribing and monitoring ‘High-dose’ antipsychotic medication can result from the prescription of either a single antipsychotic medication at a dose above the recommended maximum or two or more antipsychotic medications concurrently that, when expressed as a percentage of their respective maximum recommended doses and added together, results in a cumulative dose of more than 100%.1 In clinical practice, antipsychotic polypharmacy and prn antipsychotic medication are strongly associated with high-dose prescribing.2,3 Efficacy There is no firm evidence that high doses of antipsychotic medication are any more effective than standard doses for schizophrenia. This holds true for the use of antipsychotic medication for rapid tranquillisation, relapse prevention, persistent aggression and the management of acute psychotic episodes.1 Nevertheless, the prescription of high-dose antipsychotic medication remains relatively common in clinical practice.4–6 In the UK, the national audit of schizophrenia in 2013, reporting on prescribing practice for over 5,000 predominantly community-based patients, found that, overall, 10% were prescribed a high dose of antipsychotic medication.7 A 2022 audit of adult inpatients in mental health services8 found that in over 4,000 patients on acute adult wards, just under 10% were prescribed high-dose antipsychotic medication, and for over 2,000 patients on forensic wards, the respective figure was 13%. In both settings, a high-dose prescription was predominantly a consequence of combined antipsychotic medications. Examination of the dose–response effects of a variety of antipsychotic medications has not found any evidence of greater efficacy for doses above accepted licensed ranges.9,10 Efficacy appears to be optimal at relatively low doses, such as 4mg/day risperidone,11 300mg/day quetiapine,12 and olanzapine 10mg.13,14 Similarly, treatment with LAI risperidone at a dose of 100mg 2-weekly offers no benefits over 50mg 2-weekly,15 and 320mg/day ziprasidone16 is no better than 160mg/day. All currently available antipsychotic medications (with the possible exception of clozapine) exert their antipsychotic effect primarily through antagonism (or partial agonism) at post- synaptic dopamine receptors. But there is increasing evidence that refractory symptoms in some patients with treatment-resistant schizophrenia may not be driven by dysfunction of dopamine pathways,17–20 so prescribing a higher dosage to increase dopamine blockade in such patients would seem to be of uncertain value. Dold and colleagues21 conducted a meta-analysis of RCTs that compared continuation of standard-dose antipsychotic medication with dose escalation in patients whose schizophrenia had proved to be unresponsive to a prospective trial of standard-dose pharmacotherapy with the same antipsychotic medication. In this context, there was no evidence of any benefit associated with the increased dosage. In a study of patients with first-episode schizophrenia, increasing the dose of olanzapine up to 30mg/day and the dose of risperidone up to 10mg/day in those cases where the illness was non-responsive to treatment with standard doses yielded only a 4% absolute increase in overall response rate. Switching to an alternative antipsychotic, including clozapine, was considerably more successful.22

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150 - References

References

Schizophrenia and related psychoses CHAPTER 1 Risk factors for developing NMS include being male, dehydration, exhaustion and confusion/agitation.4,37 Although NMS has commonly been reported to occur at standard doses of antipsychotics, there is some evidence that higher dosage or combined antipsychotic medications may also be risk factors.2 Young adult males seem to be particularly at risk, while the condition is more likely to be lethal in older people.4,16,38,39 Other predictors of mortality with NMS are the presence of respiratory difficulties, the severity of hyperthermia, and failing to stop antipsychotic medication.39 The incidence and mortality rate of NMS are difficult to establish and probably vary as medication regimens change and recognition of NMS waxes and wanes. The incidence of NMS has been estimated at 0.02–0.03%, with a mortality rate of 5.6%.25 However, data from a drug safety programme from 1993 to 2015 yielded an overall incidence of 0.16%,10 while a similar study, covering the period 2004 to 2017, reported an incidence of 0.11%.40 High-potency FGAs seem to be associated with the greatest incidence, while SGAs and low-potency FGAs seem to have a lower incidence.3,10,17 Most available antipsychotic medications have been reported to be associated with NMS,41–45 including more recently introduced SGAs such as lurasidone,46 ziprasidone,47,48 iloperidone,49 aripiprazole,6,50,52 paliperidone53 (including paliperidone palmitate),54 asenapine55 and risperidone injection.56 Mortality is probably lower with SGAs than with FGAs,3,57–59 although the clinical picture is essentially similar58 except that rigidity and fever may be less common.3,58 In 2020, NMS had yet to be associated with pimavanserin, cariprazine, brexpiprazole or lumateperone,60 and we could find no reports of NMS being linked to these drugs in mid-2024. NMS is also sometimes seen with other medications, such as antidepressants,61–64 valproate,65,66 phenytoin31 and lithium.67,68 The co-prescription of SSRIs69 or cholinesterase inhibitors70,71 with antipsychotic medication may increase the risk of NMS. NMS- type syndromes induced by combinations of SGA and SSRI medications may share their symptoms and pathogenesis with the serotonin syndrome.72,73 Benzodiazepines are a recommended treatment for NMS,26 but an association between their use and NMS has been reported, possibly confounded by diagnosis or explained by the occurrence of NMS-like symptoms during benzodiazepine withdrawal.17,18,74 NMS is also occasionally seen in people given non-psychotropic dopamine antagonists such as metoclopramide75 and prochlorperazine.76,77 References

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Drug Intell Clin Pharm 1988; 22:475–480. 33. Klein JP, et al. Massive creatine kinase elevations with quetiapine: report of two cases. Pharmacopsychiatry 2006; 39:39–40. 34. Shiloh R, et al. Precautionary measures reduce risk of definite neuroleptic malignant syndrome in newly typical neuroleptic-treated schizophrenia inpatients. Int Clin Psychopharmacol 2003; 18:147–149. 35. Hatch CD, et al. Failed challenge with quetiapine after neuroleptic malignant syndrome with conventional antipsychotics. Pharmacotherapy 2001; 21:1003–1006. 36. Trutia A, et al. Neuroleptic rechallenge with aripiprazole in a patient with previously documented neuroleptic malignant syndrome. J Psychiatr Pract 2008; 14:398–402. 37. Keck PE, Jr., et al. Risk factors for neuroleptic malignant syndrome: a case–control study. Arch Gen Psychiatry 1989; 46:914–918. 38. Isik AT, et al. Neuroleptic malignant syndrome in patients with dementia: experiences of a single memory clinic. Clin Neuropharmacol 2023; 46:209–213. 39. Guinart D, et al. A systematic review and pooled, patient-level analysis of predictors of mortality in neuroleptic malignant syndrome. Acta Psychiatr Scand 2021; 144:329–341. 40. Lao KSJ, et al. Antipsychotics and risk of neuroleptic malignant syndrome: a population-based cohort and case-crossover study. CNS Drugs 2020; 34:1165–1175. 41. Sierra-Biddle D, et al. Neuropletic malignant syndrome and olanzapine. J Clin Psychopharmacol 2000; 20:704–705. 42. Hasan S, et al. Novel antipsychotics and the neuroleptic malignant syndrome: a review and critique. Am J Psychiatry 1998; 155:1113–1116. 43. Tsai JH, et al. Zotepine-induced catatonia as a precursor in the progression to neuroleptic malignant syndrome. Pharmacotherapy 2005; 25:1156–1159. 44. Gortney JS, et al. Neuroleptic malignant syndrome secondary to quetiapine. Ann Pharmacother 2009; 43:785–791. 45. Saraiva R, et al. Quetiapine-induced neuroleptic malignant syndrome. Prim Care Companion CNS Disord 2023; 25:22cr03332. 46. Pàmpols-Pérez S, et al. Neuroleptic malignant syndrome associated with lurasidone: a case report. J Clin Psychopharmacol 2023; 43:548–549. 47. Leibold J, et al. Neuroleptic malignant syndrome associated with ziprasidone in an adolescent. Clin Ther 2004; 26:1105–1108. 48. Borovicka MC, et al. Ziprasidone- and lithium-induced neuroleptic malignant syndrome. Ann Pharmacother 2006; 40:139–142. 49. Guanci N, et al. Atypical neuroleptic malignant syndrome associated with iloperidone administration. Psychosomatics 2012; 53:603–605. 50. Spalding S, et al. Aripiprazole and atypical neuroleptic malignant syndrome. J Am Acad Child Adolesc Psychiatry 2004; 43:1457–1458. 51. Chakraborty N, et al. Aripiprazole and neuroleptic malignant syndrome. Int Clin Psychopharmacol 2004; 19:351–353.

Schizophrenia and related psychoses CHAPTER 1 52. Srephichit S, et al. Neuroleptic malignant syndrome and aripiprazole in an antipsychotic-naive patient. J Clin Psychopharmacol 2006; 26:94–95. 53. Duggal HS. Possible neuroleptic malignant syndrome associated with paliperidone. J Neuropsychiatry Clin Neurosci 2007; 19:477–478. 54. Langley-DeGroot M, et al. Atypical neuroleptic malignant syndrome associated with paliperidone long-acting injection: a case report. J Clin Psychopharmacol 2016; 36:277–279. 55. Singh N, et al. Neuroleptic malignant syndrome after exposure to asenapine: a case report. Prim Care Companion J Clin Psychiatry 2010; 12:e1. 56. Mall GD, et al. Catatonia and mild neuroleptic malignant syndrome after initiation of long-acting injectable risperidone: case report. J Clin Psychopharmacol 2008; 28:572–573. 57. Ananth J, et al. Neuroleptic malignant syndrome and atypical antipsychotic drugs. J Clin Psychiatry 2004; 65:464–470. 58. Trollor JN, et al. Comparison of neuroleptic malignant syndrome induced by first- and second-generation antipsychotics. Br J Psychiatry 2012; 201:52–56. 59. Nakamura M, et al. Mortality of neuroleptic malignant syndrome induced by typical and atypical antipsychotic drugs: a propensity-matched analysis from the Japanese Diagnosis Procedure Combination database. J Clin Psychiatry 2012; 73:427–430. 60. Orsolini L, et al. Up-to-date expert opinion on the safety of recently developed antipsychotics. Expert Opinion on Drug Safety 2020; 19:981–998. 61. Kontaxakis VP, et al. Neuroleptic malignant syndrome after addition of paroxetine to olanzapine. J Clin Psychopharmacol 2003; 23:671–672. 62. Young C. A case of neuroleptic malignant syndrome and serotonin disturbance. J Clin Psychopharmacol 1997; 17:65–66. 63. June R, et al. Neuroleptic malignant syndrome associated with nortriptyline. Am J Emerg Med 1999; 17:736–737. 64. Lu TC, et al. Neuroleptic malignant syndrome after the use of venlafaxine in a patient with generalized anxiety disorder. J Formos Med Assoc 2006; 105:90–93. 65. Verma R, et al. An atypical case of neuroleptic malignant syndrome precipitated by valproate. BMJ Case Rep 2014; 2014:bcr2013202578. 66. Menon V, et al. Atypical neuroleptic malignant syndrome in a young male precipitated by oral sodium valproate. Aust N Z J Psychiatry 2016; 50:1208–1209. 67. Gill J, et al. Acute lithium intoxication and neuroleptic malignant syndrome. Pharmacotherapy 2003; 23:811–815. 68. Ramadas S, et al. Neuroleptic malignant syndrome with low dose lithium, without concomitant antipsychotics. Indian J Psychol Med 2023; 45:92–94. 69. Stevens DL. Association between selective serotonin-reuptake inhibitors, second-generation antipsychotics, and neuroleptic malignant syndrome. Ann Pharmacother 2008; 42:1290–1297. 70. Stevens DL, et al. Olanzapine-associated neuroleptic malignant syndrome in a patient receiving concomitant rivastigmine therapy. Pharmacotherapy 2008; 28:403–405. 71. Warwick TC, et al. Neuroleptic malignant syndrome variant in a patient receiving donepezil and olanzapine. Nat Clin Pract Neurol 2008; 4:170–174. 72. Odagaki Y. Atypical neuroleptic malignant syndrome or serotonin toxicity associated with atypical antipsychotics? Curr Drug Saf 2009; 4:84–93. 73. Maktabi L, et al. Serotonin syndrome and neuroleptic malignant syndrome: a case report of intersecting symptomatology. Ment Health Clin 2024; 14:23–27. 74. Kishimoto S, et al. Postoperative neuroleptic malignant syndrome-like symptoms improved with intravenous diazepam: a case report. J Anesth 2013; 27:768–770. 75. Wittmann O, et al. Neuroleptic malignant syndrome associated with metoclopramide use in a boy: case report and review of the literature. Am J Ther 2016; 23:e1246–e1249. 76. Pesola GR, et al. Prochlorperazine-induced neuroleptic malignant syndrome. J Emerg Med 1996; 14:727–729. 77. Tee ZJ. A rare case of prochlorperazine-induced neuroleptic malignant syndrome. Am J Emerg Med 2024; 81:160.e1–160.e2.

06 - Chapter 1 Schizophrenia and related psychoses

151 - Catatonia

Catatonia

154 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Catatonia Catatonia is a neuropsychiatric disorder that presents with a wide range of signs and symptoms, covering focal and generalised motor activity, speech, affect, complex behaviour and autonomic function.1 A comprehensive meta-analysis of international data from 74 studies, conducted between 1935 and 2017 and involving 107,304 individuals, found an overall pooled, mean prevalence of catatonia of just over 9% in patients diagnosed with a range of psychiatric and medical conditions.2 Three main catatonia subtypes are recognised: a retarded or stuporous form with decreased psychomotor behaviour; an excited form, characterised by agitation, combativeness, impulsivity and apparently purposeless overactivity; and malignant catatonia, a life-threatening state that presents as catatonia with clinically significant autonomic abnormalities, including raised blood pressure and body temperature, and change in heart rate and respiratory rate.1,3–5 The retarded form tends to present as stupor – the key features include mutism, rigidity, marked psychomotor retardation, negativism, posturing, waxy flexibility and catalepsy. While historically associated with schizophrenia, stupor is also seen in other psychiatric conditions such as depression and, less commonly, mania,6–11 alcohol12 or benzodiazepine withdrawal,13 and conversion disorder.6,7,14–20 If psychiatric stupor is left untreated, physical health complications are unavoidable and develop rapidly. Prompt treatment is crucial to prevent serious complications such as dehydration, venous thrombosis, pulmonary embolism, pneumonia and, ultimately, death.21 A catatonic syndrome is most commonly associated with psychiatric conditions such as bipolar disorder, schizophrenia and major depressive disorder,1,2 but may also be seen in patients with postpartum psychosis,22–24 post-traumatic stress disorder,25,26 developmental disorders such as autism spectrum disorder, neurodegenerative conditions,27,28 and a range of underlying medical conditions, including: ■ ■subarachnoid haemorrhages ■ ■basal ganglia disorders ■ ■non-convulsive status epilepticus ■ ■locked-in and akinetic mutism states ■ ■endocrine and metabolic disorders (e.g. Wilson’s)29 ■ ■Prader–Willi syndrome ■ ■antiphospholipid syndrome30 ■ ■autoimmune encephalitis, such as anti-NMDAR encephalitis1,31–33 ■ ■systemic lupus erythematosus34,35 ■ ■infections (especially CNS infections) ■ ■dementia ■ ■drug withdrawal and toxic drug states (e.g. after abrupt withdrawal of clozapine and withdrawal of zolpidem, benzodiazepines36 and many non-psychotropic medications, including medicines used in oncology). Treatment The treatment of stupor in the context of catatonia is somewhat dependent on its cause but should usually include benzodiazepines. Benzodiazepine monotherapy is the treatment of choice for stupor occurring in the context of affective and conversion

Schizophrenia and related psychoses CHAPTER 1 disorders.8,9,37 It is postulated that benzodiazepines may act by increasing gamma-aminobutyric acid (GABA)ergic transmission or reducing levels of brain- derived neurotropic factor.38 There is most clinical experience with lorazepam.32,39 Many patients will respond to standard doses (up to 4mg/day) but repeated and higher doses (between 8 and 24mg per day) may be needed.40 One small, observational study of patients with catatonic stupor in the context of a mood disorder8 (either major depressive disorder or bipolar I disorder) used a lorazepam–diazepam treatment protocol and reported a response in 10 of the 12 patients with intramuscular lorazepam 2–4mg. In another study, which followed a very similar protocol, relief of symptoms was achieved in 18 of 21 patients with catatonia caused by general medical conditions or substance misuse.41 Where benzodiazepines are effective, onset effect is rapid. A test dose of zolpidem (10mg) may predict response to benzodiazepines42 and frequent dosing of zolpidem may provide effective treatment.43,44 IV lorazepam has also been used to predict response.45 Catatonia in schizophrenia may be somewhat less likely to respond to benzodiazepines alone, with a response in 40–50%46 of cases. A double-blind, placebo-controlled, crossover trial with lorazepam up to 6mg/day demonstrated no effect on chronic catatonic symptoms in patients with established schizophrenia,47 similar to the poor effect of lorazepam seen in a non-randomised trial.48 A Cochrane review49 searched for RCTs in which people with schizophrenia or other similar severe mental illness had received benzodiazepines or another relevant treatment for catatonia. Only one study was eligible, which involved 17 participants treated with lorazepam or oxazepam; there was no clear difference in effect. The authors noted that no data were available for benzodiazepines compared with either placebo or standard care. A further complication in schizophrenia is that of differential diagnosis, which includes EPSEs and the NMS. Debate continues regarding the similarities and differences between catatonic stupor in psychosis and NMS.50–53 Malignant catatonia5 may not be distinguishable from NMS, either clinically or by laboratory testing, which has prompted the view that NMS may be a variant form of malignant catatonia.54 However, NMS can probably be ruled out in the absence of any prior or recent administration of a dopamine antagonist. The vast majority of evidence published recently and over previous decades suggests that prompt ECT remains the most successful treatment for catatonia.39,45,48,55–71 ECT- responsive catatonia has been recognised in the context of NMS, delirious mania, autism spectrum disorder and limbic encephalitis.53,72 While it has been suggested that response to ECT may be lower in patients with schizophrenia (or in those who have been treated with antipsychotic medication) than in patients with mood disorders,73 ECT is still considered the treatment of choice for catatonic schizophrenia that has failed to respond to an adequate trial of benzodiazepines.1,74 In malignant catatonia, every effort should be made to maximise the effect of ECT by using liberal stimulus dosing to induce well-generalised seizures.75 Physical health needs should be prioritised, with inpatient medical care being provided, when necessary, especially for those showing autonomic instability and those for whom dietary intake cannot be managed in psychiatric care. A 2024 systematic review76 of studies of ‘non-invasive brain stimulation’ techniques for catatonia reinforced ECT as an effective treatment and suggested that it may be considered as first-line therapy in certain cases, but also identified rTMS and

156 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 tDCS as promising treatments, although high-quality RCTs are required to establish efficacy.76,77 The use of antipsychotic medication should be carefully considered. Some authors recommend that such treatment should be avoided altogether in patients with catatonia, although there are reports of successful treatment of catatonia with clozapine,78 as well as other SGAs, such as olanzapine, aripiprazole, risperidone and ziprasidone1,79–85 (particularly in cases of catatonic schizophrenia).86 There are also case reports of combination treatment with antipsychotic and benzodiazepine medication proving effective when each has failed individually.87,88 When considering the use of antipsychotic medication, account should be taken of the patient’s history, their psychiatric diagnosis and previous response to antipsychotic treatment. If stupor develops in a patient on antipsychotic medication, any treatment with antipsychotic medication should be avoided if there are any signs or symptoms of NMS. Where NMS can be ruled out and stupor occurs in the context of non-adherence to antipsychotic treatment, early re-establishment of antipsychotic medication is recommended, with consideration of adjunctive benzodiazepines. This may be particularly relevant when catatonic symptoms have occurred following discontinuation of clozapine.36,89 Catatonia has also been reported after withdrawal of long-term benzodiazepine treatment.36 When physical health conditions, as in the examples listed earlier this section, are associated with a catatonia-like clinical picture, treatment of the underlying medical condition (e.g. lupus)90 is warranted. A treatment algorithm for catatonic stupor91 is provided in Figure 1.4. The 2023 British Association for Psychopharmacology consensus guideline for the management of catatonia1 includes a more detailed referenced algorithm for the management of the condition. Medications other than benzodiazepines reported as treatments for catatonia/ stupor are listed in Table 1.34.

Schizophrenia and related psychoses CHAPTER 1 Stupor in the context of affective/conversion disorder Stupor in the context of psychotic illness NMS possible No response after 1–2 days Not taking antipsychotic medication No response after 1–2 days No response after 1–2 days Exclude or treat underlying physical illness Lorazepam up to 4mg/day* Start with 2mg and give a further 2mg if no effects after 3 hours Use IM route subsequently Rule out NMS Lorazepam** high dose 8–24mg/day ECT† Consider SGA‡ e.g. clozapine, olanzapine Some authorities recommend co-therapy with benzodiazepines Follow benzodiazepine/ECT protocol opposite NMS ruled out *Lorazepam is absorbed sublingually and is tasteless. This route may be preferred in non-cooperative patients or those who cannot swallow. **Intravenous diazepam or lorazepam may be considered here. †Do not wait to give ECT if there is significant danger to life. ‡There is considerable uncertainty about the use of antipsychotic medication for catatonic stupor. Antipsychotics can induce catatonia92 and risk of NMS in catatonic schizophrenia is much higher than with non-catatonic schizophrenia.93 An alternative approach is to use antipsychotic medication either once catatonia has resolved or when benzodiazepines or ECT have failed and there is clear evidence of a psychotic illness.91 Figure 1.4 Algorithm for treating catatonic stupor.91

06 - Chapter 1 Schizophrenia and related psychoses

152 - References

References

158 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

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Delvi A, et al. Catatonia in the peripartum: a cohort study using electronic health records. Schizophr Res 2024; 263:252–256. Table 1.34 Medications other than benzodiazepines reported as treatments for catatonia/stupor (listed in alphabetical order – no ranking or judgement is implied by the order). Antipsychotic medications1,78–84,94–97 aripiprazole clozapine olanzapine risperidone ziprasidone Experimental treatments*9,10,43,44,64,98–103 amantadine amitriptyline carbamazepine fluoxetine fluvoxamine lithium memantine methylphenidate mirtazapine tramadol valproate zolpidem * Always read the primary literature before using any of the medications listed in this section.

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Electroconvulsive therapy as an effective treatment in neuroleptic malignant syndrome: purposely a case. Eur Psychiatry 2013; 28 Suppl 1:1. 61. Unal A, et al. Effective treatment of catatonia by combination of benzodiazepine and electroconvulsive therapy. J ECT 2013; 29:206–209. 62. Kaliora SC, et al. The practice of electroconvulsive therapy in Greece. J ECT 2013; 29:219–224. 63. Girardi P, et al. Life-saving electroconvulsive therapy in a patient with near-lethal catatonia. Riv Psichiatr 2012; 47:535–537. 64. Kumar V, et al. Electroconvulsive therapy in pregnancy. Indian J Psychiatry 2011; 53 Suppl 5:S100–S101. 65. Weiss M, et al. Treatment of catatonia with electroconvulsive therapy in adolescents. J Child Adolesc Psychopharmacol 2012; 22:96–100. 66. Bauer J, et al. Should the term catatonia be explicitly included in the ICD-10 description of acute transient psychotic disorder F23.0? Nord J Psychiatry 2012; 66:68–69. 67. Mohammadbeigi H, et al. Electroconvulsive therapy in single manic episodes: a case series. Afr J Psychiatry 2011; 14:56–59. 68. Dragasek J. [Utilisation of electroconvulsive therapy in treatment of depression disorders]. Psychiatrie 2011; 15:1211–1219. 69. Luchini F, et al. Electroconvulsive therapy in catatonic patients: efficacy and predictors of response. World J Psychiatry 2015; 5:182–192. 70. Lloyd JR, et al. Electroconvulsive therapy for patients with catatonia: current perspectives. Neuropsychiatr Dis Treat 2020; 16:2191–2208. 71. Breit S, et al. The effect of electroconvulsive therapy on specific catatonia symptoms and predictors of late response. Pharmacopsychiatry 2024; 57:13–20.

160 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 72. Sajith SG, et al. Response to electroconvulsive therapy in patients with autism spectrum disorder and intractable challenging behaviors associated with symptoms of catatonia. J ECT 2017; 33:63–67. 73. van Waarde JA, et al. Electroconvulsive therapy for catatonia: treatment characteristics and outcomes in 27 patients. J ECT 2010; 26:248–252. 74. Jain A, et al. Catatonic Schizophrenia. StatPearls. Treasure Island (FL): StatPearls Publishing LLC; 2020. 75. Kellner CH, et al. Electroconvulsive therapy for catatonia. Am J Psychiatry 2010; 167:1127–1128. 76. Xiao H, et al. Non-invasive brain stimulation for treating catatonia: a systematic review. Front Psychiatry 2023; 14:1135583. 77. Hansbauer M, et al. rTMS and tDCS for the treatment of catatonia: a systematic review. Schizophr Res 2020; 222:73–78. 78. Saini A, et al. Clozapine as a treatment for catatonia: a systematic review. Schizophr Res 2024; 263:275–281. 79. Van Den EF, et al. The use of atypical antipsychotics in the treatment of catatonia. Eur Psychiatry 2005; 20:422–429. 80. Caroff SN, et al. Movement disorders associated with atypical antipsychotic drugs. J Clin Psychiatry 2002; 63 Suppl 4:12–19. 81. Guzman CS, et al. Treatment of periodic catatonia with atypical antipsychotic, olanzapine. Psychiatry Clin Neurosci 2008; 62:482. 82. Babington PW, et al. Treatment of catatonia with olanzapine and amantadine. Psychosomatics 2007; 48:534–536. 83. Bastiampillai T, et al. Catatonia resolution and aripiprazole. Aust N Z J Psychiatry 2008; 42:907. 84. Strawn JR, et al. Successful treatment of catatonia with aripiprazole in an adolescent with psychosis. J Child Adolesc Psychopharmacol 2007; 17:733–735. 85. Kufert Y, et al. Catatonic symptoms successfully treated with olanzapine in an adolescent with schizophrenia. J Child Adolesc Psychopharmacol 2021; 31:327–330. 86. Gazdag G, et al. Diagnosing and treating catatonia: an update. Curr Psychiatr Rev 2013; 9:130–135. 87. Spiegel DR, et al. A case of schizophrenia with catatonia resistant to lorazepam and olanzapine monotherapy but responsive to combination treatment: is it time to consider using select second-generation antipsychotics earlier in the treatment algorithm for this patient type? Clin Neuropharmacol 2019; 42:57–59. 88. Cevher Binici N, et al. Response of catatonia to amisulpride and lorazepam in an adolescent with schizophenia. J Child Adolesc Psychopharmacol 2018; 28:151–152. 89. Bilbily J, et al. Catatonia secondary to sudden clozapine withdrawal: a case with three repeated episodes and a literature review. Case Rep Psychiatry 2017; 2017:2402731. 90. Grover S, et al. Catatonia in systemic lupus erythematosus: a case report and review of literature. Lupus 2013; 22:634–638. 91. Rosebush PI, et al. Catatonia and its treatment. Schizophr Bull 2010; 36:239–242. 92. Caroff SN, et al. Movement disorders induced by antipsychotic drugs: implications of the CATIE schizophrenia trial. Neurol Clin 2011; 29:127–148, viii. 93. Funayama M, et al. Catatonic stupor in schizophrenic disorders and subsequent medical complications and mortality. Psychosom Med 2018; 80:370–376. 94. Voros V, et al. [Use of aripiprazole in the treatment of catatonia]. Neuropsychopharmacol Hung 2010; 12:373–376. 95. Yoshimura B, et al. Is quetiapine suitable for treatment of acute schizophrenia with catatonic stupor? A case series of 39 patients. Neuropsychiatr Dis Treat 2013; 9:1565–1571. 96. Todorova K. Olanzapine in the treatment of catatonic stupor - two case reports and discussion. Eur Neuropsychopharmacol 2012; 22 Suppl 2:S326. 97. Prakash O, et al. Catatonia and mania in patient with AIDS: treatment with lorazepam and risperidone. Gen Hosp Psychiatry 2012; 34:321–326. 98. Daniels J. Catatonia: clinical aspects and neurobiological correlates. J Neuropsychiatry Clin Neurosci 2009; 21:371–380. 99. Obregon DF, et al. Memantine and catatonia: a case report and literature review. J Psychiatr Pract 2011; 17:292–299. 100. Hervey WM, et al. Treatment of catatonia with amantadine. Clin Neuropharmacol 2012; 35:86–87. 101. Consoli A, et al. Lorazepam, fluoxetine and packing therapy in an adolescent with pervasive developmental disorder and catatonia. J Physiol Paris 2010; 104:309–314. 102. Lewis AL, et al. Malignant catatonia in a patient with bipolar disorder, B12 deficiency, and neuroleptic malignant syndrome: one cause or three? J Psychiatr Pract 2009; 15:415–422. 103. Padhy SK, et al. The catatonia conundrum: controversies and contradictions. Asian J Psychiatr 2014; 7:6–9.

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ECG changes – QT prolongation

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Introduction

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QT prolongation

Schizophrenia and related psychoses CHAPTER 1 ECG changes – QT prolongation Introduction Many psychotropic drugs are associated with ECG changes and some are causally linked to serious ventricular arrhythmia and sudden cardiac death. Specifically, some antipsychotics block cardiac potassium channels and are linked to prolongation of the cardiac QT interval, a risk factor for the ventricular arrhythmia TdP, which is sometimes fatal.1 Case–control studies have suggested that the use of most antipsychotics is associated with an increase in the rate of sudden cardiac death.2–8 This risk is probably a result of the arrhythmogenic potential of antipsychotics,9,10 although schizophrenia itself may be associated with QT prolongation,11 QT interval is longer in patients with schizophrenia than in controls (e.g. 418ms vs 393ms in one study)12 and in one study prolonged QTc was identified in 7.6% of psychiatric in-patients who had an ECG.13 A more recent systematic review14 suggested that 4% of people with schizophrenia and receiving an antipsychotic had a prolonged QTc. Antipsychotic-related risk is probably dose-related and, although the absolute risk is low, it is substantially higher than, say, the risk of fatal agranulocytosis with clozapine.9 One report of cases gathered by a national database put the risk of TdP at between 0 and 19.2 cases per 100,000 patient years, depending on the individual antipsychotic and age of patients.15 The effect of antipsychotic polypharmacy on QT is somewhat uncertain,16 but the extent of QT prolongation is probably a function of overall dose.17 ECG monitoring of drug-induced changes in mental health settings is complicated by a number of factors. Psychiatrists may have limited expertise in ECG interpretation, for example, and still less expertise in manually measuring QT intervals. Even cardiologists show an inter-rater reliability in QT measurement of up to 20ms.18 Self-reading, computerised ECG devices are now widely available and compensate for some lack of expertise, but different models use different algorithms and different correction formulae.19 ECG machines may not be as readily available as they are in general medicine. Also, there may be insufficient time for ECG determination in many areas (e.g. out- patients). Lastly, ECG determination may be difficult to perform in acutely disturbed, physically uncooperative patients. ECG monitoring is nonetheless essential for all patients prescribed antipsychotics. An estimate of QTc interval should be made on admission to in-patient units (in the UK this is recommended in the NICE schizophrenia guideline)20 and yearly thereafter. QT prolongation ■ ■The cardiac QT interval (usually cited as QTc – QT corrected for heart rate) is a useful but imprecise indicator of risk of TdP and of increased cardiac mortality.21 Different correction factors and methods may give markedly different values.22 The most widely used formula is Bazett’s. This tends to overestimate QT length, especially when heart rate is increased.23 ■ ■The QT interval broadly reflects the duration of cardiac repolarisation. Lengthening of repolarisation duration induces heterogeneity of electrical phasing in different ventricular structures (a phenomenon known as dispersion), which in turn allows the emergence of early after-depolarisations, which may provoke ventricular extrasystole and TdP. Measures have been developed (QT dispersion ratio, dispersion transmural repolarisation time) which may better predict arrhythmia.12

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Other ECG changes

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Quantifying risk

162 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 ■ ■There is some controversy over the exact association between QTc and risk of arrhythmia. Very limited evidence suggests that risk is exponentially related to the extent of prolongation beyond normal limits (440ms for men; 470ms for women), although there are well-known exceptions which appear to disprove this theory24 (some drugs prolong QT without increasing dispersion). Rather stronger evidence links QTc values over 500ms to a clearly increased risk of arrhythmia.25 QT intervals of >650ms may be more likely than not to induce torsades.26 Overall, despite some uncertainties, QTc determination remains an important measure in estimating risk of arrhythmia and sudden death. ■ ■Individual components of the QT interval may have particular importance. The time from the start of the T wave to T-wave peak has been shown to be an important aspect of QT prolongation associated with sudden cardiac deaths;27 T-wave peak to end interval may also be predictive of arrhythmia.12 ■ ■QTc measurements and evaluation are complicated by: ■ ■difficulty in determining the end of the T wave, particularly where U waves are present (this applies to both manual and self-reading ECG machines)25 ■ ■normal physiological variation in QTc interval: QT varies with gender, time of day, food intake, alcohol intake, menstrual cycle, ECG lead, etc.22,24 ■ ■variation in the extent of drug-induced prolongation of QTc because of changes in plasma levels. QTc prolongation is most prominent at peak drug plasma levels and least obvious at trough levels.22,24 Other ECG changes Other reported antipsychotic-induced changes include atrial fibrillation, giant P waves, T-wave changes and heart block.24 Quantifying risk Drugs are categorised here according to data available on their effects on the cardiac QTc interval as reported, mostly using Bazett’s correction formula (Table 1.35). ‘No- effect’ drugs are those with which QTc prolongation has not been reported either at therapeutic doses or in overdose. ‘Low-effect’ drugs are those for which severe QTc prolongation has been reported only following overdose or where only small average increases (<10ms) have been observed at clinical doses. ‘Moderate-effect’ drugs are those which have been observed to prolong QTc by >10ms on average when given at normal clinical doses or where ECG monitoring is officially recommended in some circumstances. ‘High-effect’ drugs are those for which there is extensive average QTc prolongation (usually >20ms at normal clinical doses). As outlined above, effect on QTc may not necessarily equate directly to risk of TdP or sudden death,28 although this is often assumed.29 (A good example here is ziprasidone – a drug with a moderate effect on QTc but with minimal evidence of cardiac toxicity.30) Also, categorisation is inevitably approximate given the problems associated with QTc measurements. Lastly, keep in mind that differences in the effects of different antipsychotics on the QT interval rarely reach statistical significance even in meta-analyses.31

Schizophrenia and related psychoses CHAPTER 1 Outside these guidelines, readers are directed to the RISQ-PATH study,32 which provides a scoring system for the prediction of QT prolongation (to above normal ranges) in any patient. RISQ-PATH has a 98% negative predictive value, so allowing a reduction in monitoring in low-risk patients. The RISQ-PATH method uses CredibleMeds categorisation for drug effects on QT – this, too, is recommended.33 Table 1.35 Antipsychotics – effect on QTc.12,22,24,34–59 Effect on QTc Drug No effect Brexpiprazole Cariprazine Lurasidone Lumateperone* Low effect Aripiprazole** Asenapine Clozapine Flupentixol Fluphenazine Perphenazine Prochlorperazine Olanzapine† Paliperidone Risperidone Sulpiride Zuclopenthixol Moderate effect Amisulpride‡ Chlorpromazine Haloperidol Iloperidone Levomepromazine Melperone Pimavanserin Quetiapine Ziprasidone High effect Pimozide Sertindole Unknown effect Loxapine Pipotiazine Trifluoperazine * Limited clinical experience (association with QT prolongation may emerge). ** One case of TdP reported,60 two cases of QT prolongation61,62 and an association with TdP found in database studies.63,64 Healthy volunteer data suggest aripiprazole causes QTc prolongation of around 8ms.65 Aripiprazole may increase QT dispersion.66 Low-dose aripiprazole has no effect on QT when added to another antipsychotic.67 † Isolated cases of QTc prolongation38,68 and has effects on cardiac ion channel, IKr.69 Other data suggest no effect on QTC.24,36,37,70 ‡ TdP common in overdose,26,71 strong association with TdP in clinical doses.63

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Other risk factors

164 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Aripiprazole remains in the low-effect group having previously been firmly placed in ‘no effect’. Data are rather contradictory, with most studies showing a decrease in QTc associated with aripiprazole use,51 even in children and adolescents.72 However, later data60,61,63,65,73 cast doubt on assumptions of cardiac safety. Nonetheless, a 2020 paper analysing reports of events in >400,000 in-patients over 20 years found aripiprazole had the lowest rate of cardiac events (0.06%) of all antipsychotics.74 Lurasidone remains in the ‘no-effect’ group,51 although one study mentioned in the US labelling75 reports a QT lengthening of 7.5ms in people receiving 120mg (111mg) a day. Those receiving 600mg (555mg) daily showed a lower change (+4.6ms). These findings are in some contrast with those from studies in patients which uniformly suggest no or minimal effect.76–78 This disparity is probably explained by the use of different correction factors and by random change, as often seen in placebo-treated patients78 and as suggested by the apparent lack of dose-related effect. One case of QTc >500ms has been reported with lurasidone in which lurasidone was judged the ‘probable’ cause.79 Brexpiprazole remains in the ‘no-effect’ group although one study of 16 patients found an increase in QTc (Hodges’ formula) of 10.1ms and an important increase in dispersion transmural repolarisation time.12 All other data suggest no effect. Other risk factors A number of physiological, pathological and genetic80 factors are associated with an increased risk of QT changes and of arrhythmia (Table 1.36) and many non-psychotropic drugs are linked to QT prolongation (Table 1.37).25 These additional risk factors seem almost always to be present in cases of antipsychotic-induced TdP.81 Table 1.36 Physiological risk factors for QTc prolongation and arrhythmia. Cardiac Long QT syndrome Bradycardia Ischaemic heart disease Myocarditis Myocardial infarction Left ventricular hypertrophy Metabolic Hypokalaemia Hypomagnesaemia Hypocalcaemia Others Extreme physical exertion Stress or shock Anorexia nervosa Extremes of age – children and elderly may be more susceptible to QT changes Female gender Note: Hypokalaemia-related QTc prolongation is more commonly observed in acute psychotic admissions.82 There are a number of physical and genetic factors (related to cardiac potassium channels or CYP enzyme function),80 which may not be discovered on routine examination but which probably predispose patients to arrhythmia.83,84

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ECG monitoring

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Adverse effects

18 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 A small number of RCTs have examined the efficacy of high versus standard dosage in patients with treatment-resistant schizophrenia (TRS).1 Some have demonstrated benefit23 but the majority of these studies are old, the number of patients randomised is small and study design is poor by current standards. Some studies used daily doses equivalent to more than 10g chlorpromazine. One small (n = 12) open study of high- dose quetiapine (up to 1400mg/day) in refractory schizophrenia found modest benefits in a third of patients24 but other, larger studies of quetiapine for such patients have shown no benefit for higher doses.22,23 A further RCT of high-dose olanzapine (up to 45mg/day) versus clozapine for TRS found similar efficacy for the two treatments but concluded that, given the small sample size, it would be premature to conclude that they were equivalent.25 Subsequent systematic reviews of relevant studies addressing high-dose olanzapine for TRS have similarly concluded that while such a regimen may be superior to other, non-clozapine antipsychotic medications, it may be seen as a safe and effective alternative for refractory illness only when clozapine use is not appropriate.26,27 Perhaps the most comprehensive systematic analysis of dose–response28 largely confirmed the observation that the dose–response curve reaches a plateau above a certain dose for nearly all antipsychotic medications, with the possible exceptions of olanzapine and lurasidone. (With these two medications there is some evidence that doses at the upper end of the licensed range are somewhat more effective than lower doses.)14,29 This systematic review also suggested that the doses above which no additional benefit was likely (e.g. risperidone 6.3mg/day; quetiapine 482mg/day) were somewhat higher than the doses of optimal efficacy previously determined (see above). Importantly, however, there was no evidence to support the use of doses of any antipsychotic medication above its licensed dose range. Consensus panel recommendations are broadly in line with clinical trial outcomes. A 2023 international consensus study30 suggested maximum effective doses exceeded licensed doses in only two cases: olanzapine (30mg/day) and quetiapine (800mg/day). A 2023 systematic review of dose–response relationships31 found that the effect of all antipsychotics reached a plateau within the licensed dose range, with the possible exceptions of lumateperone, olanzapine and lurasidone. Adverse effects The majority of adverse effects associated with antipsychotic treatment are doserelated.32 These include EPS,31 weight gain,33 sedation, postural hypotension, anticholinergic effects, QTc prolongation34 and coronary heart disease mortality.35–38 High-dose antipsychotic treatment is clearly associated with a greater adverse-effect burden.16,35,39–41 There is some evidence that antipsychotic dose reduction from a very high (mean 2253mg chlorpromazine equivalents per day) to a high (mean 1315mg chlorpromazine equivalents per day) dose can lead to improvements in cognition and negative symptoms.42

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Metabolic inhibition

Schizophrenia and related psychoses CHAPTER 1 Table 1.37 Non-psychotropics associated with QT prolongation (see Crediblemeds.org for latest information; this is not a complete list). Antibiotics Erythromycin Clarithromycin Ampicillin Co-trimoxazole Pentamidine (Some 4 quinolones affect QTc – see manufacturers’ literature) Antimalarials Chloroquine Mefloquine Quinine Antiarrhythmics Quinidine Disopyramide Procainamide Sotalol Amiodarone Bretylium Others Amantadine Cyclosporin Diphenhydramine Hydroxyzine Methadone Nicardipine Tamoxifen Note: β2 agonists and sympathomimetics may provoke TdP in patients with prolonged QTc. ECG monitoring Measure QTc in all patients prescribed antipsychotics: ■ ■on admission ■ ■if previous abnormality or known additional risk factor, at annual physical health check. Consider measuring QTc within a week of achieving a therapeutic dose of a newly prescribed antipsychotic that is associated with a moderate or high risk of QTc prolongation or of newly prescribed combined antipsychotics. Management of QT prolongation in patients receiving antipsychotic drugs is detailed in Table 1.38. Metabolic inhibition The effect of drugs on the QTc interval is usually plasma level dependent. Drug interactions are therefore important, especially when metabolic inhibition results in increased plasma levels of the drug affecting QTc. Commonly used metabolic inhibitors include fluvoxamine, fluoxetine, paroxetine and valproate.

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Other cardiovascular risk factors

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Summary

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163 - References

References

166 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Other cardiovascular risk factors The risk of drug-induced arrhythmia and sudden cardiac death with psychotropics is an important consideration. With respect to cardiovascular disease, note that other risk factors such as smoking, obesity and impaired glucose tolerance present a much greater risk to patient morbidity and mortality than the uncertain outcome of QT changes. See the relevant sections for discussion of these problems. Summary Table 1.38 Management of QT prolongation in patients receiving antipsychotic drugs. QTc Action Refer to cardiologist <440ms (men) or <470ms (women) None unless abnormal T-wave morphology Consider if in doubt

440ms (men) or >470ms (women) but <500ms Consider reducing dose or switching to drug of lower effect; repeat ECG Consider 500ms Repeat ECG. Stop suspected causative drug(s) and switch to drug of lower effect. Immediately Abnormal T-wave morphology Review treatment. Consider reducing dose or switching to drug of lower effect. Immediately ■ ■In the absence of conclusive data, assume that all antipsychotics are linked to sudden cardiac death. ■ ■Prescribe the lowest dose possible and avoid polypharmacy/metabolic interactions. ■ ■Perform ECG on admission and, if previous abnormality or additional risk factor, at yearly check-up. ■ ■Consider measuring QTc within a week of achieving a therapeutic dose of a moderate/high-risk antipsychotic. References

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Torsade de pointes in a patient with complex medical and psychiatric conditions receiving low-dose quetiapine. Acta Psychiatr Scand 2005; 112:318–322. 44. Huang BH, et al. Sulpiride induced torsade de pointes. Int J Cardiol 2007; 118:e100–e102. 45. Kane JM, et al. Long-term efficacy and safety of iloperidone: results from 3 clinical trials for the treatment of schizophrenia. J Clin Psychopharmacol 2008; 28:S29–S35. 46. Kim MD, et al. Blockade of HERG human K+ channel and IKr of guinea pig cardiomyocytes by prochlorperazine. Eur J Pharmacol 2006; 544:82–90. 47. Meltzer H, et al. Efficacy and tolerability of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 6-week placebo-controlled studies. J Clin Psychiatry 2006; 69:817–829. 48. Chapel S, et al. Exposure-response analysis in patients with schizophrenia to assess the effect of asenapine on QTc prolongation. J Clin Pharmacol 2009; 49:1297–1308. 49. Ozeki Y, et al. QTc prolongation and antipsychotic medications in a sample of 1017 patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:401–405. 50. Girardin FR, et al. Drug-induced long QT in adult psychiatric inpatients: the 5-year cross-sectional ECG Screening Outcome in Psychiatry study. Am J Psychiatry 2013; 170:1468–1476.

168 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 51. Leucht S, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382:951–962. 52. Hong HK, et al. Block of hERG K+ channel and prolongation of action potential duration by fluphenazine at submicromolar concentration. Eur J Pharmacol 2013; 702:165–173. 53. Vieweg WV, et al. Risperidone, QTc interval prolongation, and torsade de pointes: a systematic review of case reports. Psychopharmacology (Berl) 2013; 228:515–524. 54. Suzuki Y, et al. QT prolongation of the antipsychotic risperidone is predominantly related to its 9-hydroxy metabolite paliperidone. Hum Psychopharmacol 2012; 27:39–42. 55. Polcwiartek C, et al. The cardiac safety of aripiprazole treatment in patients at high risk for torsade: a systematic review with a meta-analytic approach. Psychopharmacology (Berl) 2015; 232:3297–3308. 56. Citrome L. Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy. Adv Ther 2013; 30:114–126. 57. Das S, et al. Brexpiprazole: so far so good. Ther Adv Psychopharmacol 2016; 6:39–54. 58. Meyer JM, et al. Lurasidone: a new drug in development for schizophrenia. Expert Opin Investig Drugs 2009; 18:1715–1726. 59. Kim K, et al. Clozapine blood concentration predicts corrected QT-interval prolongation in patients with psychoses. J Clin Psychopharmacol 2022; 42:536–543. 60. Nelson S, et al. Torsades de pointes after administration of low-dose aripiprazole. Ann Pharmacother 2013; 47:e11. 61. Hategan A, et al. Aripiprazole-associated QTc prolongation in a geriatric patient. J Clin Psychopharmacol 2014; 34:766–768. 62. Suzuki Y, et al. Dose-dependent increase in the QTc interval in aripiprazole treatment after risperidone. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:643–644. 63. Raschi E, et al. The contribution of national spontaneous reporting systems to detect signals of torsadogenicity: issues emerging from the ARITMO Project. Drug Saf 2016; 39:59–68. 64. He L, et al. Characteristics and spectrum of cardiotoxicity induced by various antipsychotics: a real-world study from 2015 to 2020 based on FAERS. Front Pharmacol 2021; 12:815151. 65. Belmonte C, et al. Evaluation of the relationship between pharmacokinetics and the safety of aripiprazole and its cardiovascular effects in healthy volunteers. J Clin Psychopharmacol 2016; 36:608–614. 66. Germano E, et al. ECG parameters in children and adolescents treated with aripiprazole and risperidone. Prog Neuropsychopharmacol Biol Psychiatry 2014; 51:23–27. 67. Pilunthanakul T, et al. The impact of adjunctive aripiprazole on QT interval: A 12-week open label study in patients on olanzapine, clozapine or risperidone. Hum Psychopharmacol 2023; 38:e2863. 68. Su KP, et al. Olanzapine-induced QTc prolongation in a patient with Wolff–Parkinson–White syndrome. Schizophr Res 2004; 66:191–192. 69. Morissette P, et al. Olanzapine prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current. J Psychopharmacol 2007; 21:735–741. 70. Bar KJ, et al. Influence of olanzapine on QT variability and complexity measures of heart rate in patients with schizophrenia. J Clin Psychopharmacol 2008; 28:694–698. 71. Berling I, et al. Prolonged QT risk assessment in antipsychotic overdose using the QT nomogram. Ann Emerg Med 2015; 66:154–164. 72. Jensen KG, et al. Corrected QT changes during antipsychotic treatment of children and adolescents: a systematic review and meta-analysis of clinical trials. J Am Acad Child Adolesc Psychiatry 2015; 54:25–36. 73. Karz AJ, et al. Effects of aripiprazole on the QTc: a case report. J Clin Psychiatry 2015; 76:1648–1649. 74. Friedrich ME, et al. Cardiovascular adverse reactions during antipsychotic treatment: results of AMSP, a drug surveillance program between 1993 and 2013. Int J Neuropsychopharmacol 2020; 23:67–75. 75. Sunovion Pharmaceuticals Inc. Highlights of Prescribing Information: LATUDA (lurasidone hydrochloride) tablets for oral use. 2022 (last checked December 2024); http://www.latuda.com/LatudaPrescribingInformation.pdf. 76. Potkin SG, et al. Double-blind comparison of the safety and efficacy of lurasidone and ziprasidone in clinically stable outpatients with schizophrenia or schizoaffective disorder. Schizophr Res 2011; 132:101–107. 77. Nakamura M, et al. Lurasidone in the treatment of acute schizophrenia: a double-blind, placebo-controlled trial. J Clin Psychiatry 2009; 70:829–836. 78. Meltzer HY, et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry 2011; 168:957–967. 79. Naguy A, et al. Possible lurasidone-associated dose-dependent QTc prolongation in first-episode psychosis. Psychopharmacol Bull 2022; 52:68–71. 80. Vaiman EE, et al. Genetic biomarkers of antipsychotic-induced prolongation of the QT interval in patients with schizophrenia. Int J Mol Sci 2022; 23:15786. 81. Hasnain M, et al. Quetiapine, QTc interval prolongation, and torsade de pointes: a review of case reports. Ther Adv Psychopharmacol 2014; 4:130–138. 82. Hatta K, et al. Prolonged QT interval in acute psychotic patients. Psychiatry Res 2000; 94:279–285. 83. Priori SG, et al. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999; 99:529–533. 84. Frassati D, et al. Hidden cardiac lesions and psychotropic drugs as a possible cause of sudden death in psychiatric patients: a report of 14 cases and review of the literature. Can J Psychiatry 2004; 49:100–105.

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Effects of antipsychotic medications on plasma lipids

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Effect of antipsychotic medications on lipids

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Olanzapine

Schizophrenia and related psychoses CHAPTER 1 Effects of antipsychotic medications on plasma lipids Morbidity and mortality from cardiovascular disease are higher in people with schizophrenia than in the general population.1–3 Dyslipidaemia is an established risk factor for cardiovascular disease, together with obesity, hypertension, smoking, diabetes and sedentary lifestyle. Specifically, reduced high-density lipoprotein (HDL) cholesterol and raised triglyceride levels are included in the definition of the metabolic syndrome.4 The majority of patients with schizophrenia have several of these cardiometabolic risk factors and can be considered at ‘high risk’ of developing cardiovascular disease. Dyslipidaemia is treatable and intervention is known to reduce morbidity and mortality.5 Aggressive treatment is particularly important in people with diabetes, the prevalence of which is increased two- to three-fold over population norms in people with schizophrenia (see section on diabetes and impaired glucose tolerance). Effect of antipsychotic medications on lipids Antipsychotic medications show a marked variation in their effects on total cholesterol, low-density lipoprotein (LDL) cholesterol, HDL cholesterol and triglycerides.6,7 Regarding FGAs, phenothiazines are known to be associated with increases in trigly cerides and LDL cholesterol and decreases in HDL8 cholesterol, but the magnitude of these effects is poorly quantified.9 Haloperidol seems to have minimal effect on lipid profiles.8 Although there are relatively more data pertaining to some SGAs, they are derived from a variety of sources and are reported in different ways, making it difficult to compare such medications directly. While cholesterol levels can rise, the most profound effect of antipsychotic medications seems to be on triglycerides. Raised triglycerides are, in general, associated with obesity and diabetes. From the available data, clozapine and olanzapine6,10 would seem to have the greatest propensity to increase lipids, while quetiapine and risperidone have a moderate propensity.11,12 Aripiprazole, lurasidone and ziprasidone appear to have minimal adverse effect on blood lipids6,10,13–18 and may even modestly reverse dyslipidaemias associated with previous antipsychotics.17,19,20 For cariprazine and brexpiprazole, the effects on plasma lipids would also appear to be relatively limited.6,21–24 Iloperidone causes some weight gain but may not have an equivalent impact on cholesterol or triglycerides.6,25,26 Early RCT data suggest that lumateperone is not associated with any significant effects on plasma cholesterol or triglycerides in the short term, compared with placebo.27 Olanzapine In people with schizophrenia, olanzapine has a relatively high propensity to induce dyslipidaemia,6,7 which is characterised by elevated levels of plasma triglyceride, total cholesterol and LDL cholesterol and can occur in the first 4 weeks of treatment.28 Triglyceride levels have been shown to increase by 40% over the short (12 weeks) and medium (16 months) term.29,30 Levels may continue to rise for up to a year.31 Up to two- thirds of patients treated with olanzapine have raised triglycerides32 and just under 10% may develop severe hypertriglyceridaemia.33 While weight gain with olanzapine is generally associated with increases in both cholesterol30,34 and triglycerides,33 severe hypertriglyceridaemia can occur independently of weight gain.33 In one study, patients

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Clozapine

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Screening and monitoring

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Clinical management of dyslipidaemia

170 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 treated with olanzapine or risperidone gained a similar amount of weight, but with olanzapine, serum triglyceride levels increased by four times as much (105mg/dL) as for risperidone (32 mg/dL).35 Quetiapine36 seems to have more modest effects than olanzapine, although the data are conflicting.37 A case–control study conducted in the UK found that patients with schizophrenia who were treated with olanzapine were five times more likely to develop hyperlipidaemia than those with no antipsychotic exposure and three times more likely to develop hyperlipidaemia than patients receiving FGAs.38 Risperidone treatment was not associated with an increased likelihood of hyperlipidaemia compared with no antipsychotic exposure or treatment with an FGA. Clozapine Clozapine also has a relatively high propensity to induce dyslipidaemia.6,7 Mean trigly ceride levels have been shown to double and cholesterol levels to increase by at least 10% after 5 years of treatment with clozapine.39 Patients treated with clozapine have triglyceride levels that are almost double those of patients who are treated with FGA medications.40,41 Cholesterol levels are also increased.10 Particular care should be taken before prescribing clozapine or olanzapine for patients who are obese, diabetic or known to have pre-existing hyperlipidaemia.42 Screening and monitoring In patients with schizophrenia treated with antipsychotic medication, the monitoring of plasma lipids by mental health services and in primary care is generally insufficient,43–47 falling short of recommended practice.48,49 All patients should have their lipids measured at baseline, 3 months after starting treatment with a new antipsychotic medication and then annually. Those prescribed clozapine and olanzapine should ideally have their serum lipids measured every 3 months for the first year of treatment, and then annually. Clinically significant changes in cholesterol are unlikely over the short term but triglycerides can increase dramatically.50 In practice, dyslipidaemia is widespread in patients on long-term antipsychotic treatment irrespective of the medication prescribed or of diagnosis.51–53 Severe hypertriglyceridaemia (fasting level of >5mmol/L) is a risk factor for pancreatitis. Note that antipsychotic-induced dyslipidaemia can occur independent of weight gain.54 Clinical management of dyslipidaemia Patients with raised cholesterol may benefit from dietary advice, lifestyle changes and/ or treatment with statins.49,55 Statins seem to be effective in this patient group, although pharmacokinetic and pharmacodynamic interactions are possible.56,57 The outline of a systematic approach to the diagnosis and management of hypercholesterolaemia is available,58 based on NICE guidance in the UK.59 Further, risk tables and treatment guidelines can be found in the BNF. Evidence supports the treatment of cholesterol concentrations as low as 4mmol/L in high-risk patients60 and this is the highest level

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Recommendations

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Summary of monitoring

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References

Schizophrenia and related psychoses CHAPTER 1 recommended by NICE for secondary prevention of cardiovascular events.61 NICE makes no recommendations on target levels for primary prevention but recent advice promotes the use of statins for anyone with a >10% 10-year risk of cardiovascular disease.61 Coronary heart disease and stroke risk can be reduced by a third by reducing cholesterol to as low as 3.5mmol/L. When triglycerides alone are raised, diets low in saturated fats and the taking of fish oil and fibrates are effective treatments,31,62,63 although there is no proof that mortality is reduced. Such patients should be screened for impaired glucose tolerance and diabetes. If moderate to severe hyperlipidaemia develops during antipsychotic treatment, a switch to another antipsychotic medication less likely to cause this problem should be considered in the first instance. Although not recommended as a strategy in patients with treatment-resistant illness, clozapine-induced hypertriglyceridaemia has been shown to reverse after a switch to risperidone.64 This may hold true with other switching regimens but data are scarce.65 Aripiprazole and other D2 partial agonists seem to be the treatments of choice in those with prior antipsychotic-induced dyslipidaemia (lumateperone and ziprasidone are options outside the UK).20,66 There is evidence to suggest that adjunctive aripiprazole may have beneficial effects on measures of plasma cholesterol and triglycerides when combined with clozapine or olanzapine19,49,67 and that metformin added to antipsychotic medication may improve total cholesterol and triglyceride levels49,68 (see Buzea et al. 202257 and the ‘BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment’49 for discussion of the potential risks and benefits of these two strategies). Summary of monitoring Medication Suggested monitoring schedule Clozapine Fasting lipids at baseline then every 3 months for a year, then annually Olanzapine Other antipsychotic medications Fasting lipids at baseline, 3 months, and then annually66 References

Brown S, et al. Causes of the excess mortality of schizophrenia. Br J Psychiatry 2000; 177:212–217.
Correll CU, et al. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls. World Psychiatry 2017; 16:163–180.
Lemogne C, et al. Management of cardiovascular health in people with severe mental disorders. Curr Cardiol Rep 2021; 23:7.
Alberti KG, et al. The metabolic syndrome: a new worldwide definition. Lancet 2005; 366:1059–1062.
Durrington P. Dyslipidaemia. Lancet 2003; 362:717–731.
Pillinger T, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry 2020; 7:64–77.
Burschinski A, et al. Metabolic side effects in persons with schizophrenia during mid- to long-term treatment with antipsychotics: a network meta-analysis of randomized controlled trials. World Psychiatry 2023; 22:116–128.
Sasaki J, et al. Lipids and apolipoproteins in patients treated with major tranquilizers. Clin Pharmacol Ther 1985; 37:684–687.
Henkin Y, et al. Secondary dyslipidemia: inadvertent effects of drugs in clinical practice. JAMA 1992; 267:961–968.
Chaggar PS, et al. Effect of antipsychotic medications on glucose and lipid levels. J Clin Pharmacol 2011; 51:631–638.
Smith RC, et al. Effects of olanzapine and risperidone on lipid metabolism in chronic schizophrenic patients with long-term antipsychotic treatment: a randomized five month study. Schizophr Res 2010; 120:204–209.

172 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 12. Perez-Iglesias R, et al. Glucose and lipid disturbances after 1 year of antipsychotic treatment in a drug-naive population. Schizophr Res 2009; 107:115–121. 13. Olfson M, et al. Hyperlipidemia following treatment with antipsychotic medications. Am J Psychiatry 2006; 163:1821–1825. 14. L’Italien GJ, et al. Comparison of metabolic syndrome incidence among schizophrenia patients treated with aripiprazole versus olanzapine or placebo. J Clin Psychiatry 2007; 68:1510–1516. 15. Fenton WS, et al. Medication-induced weight gain and dyslipidemia in patients with schizophrenia. Am J Psychiatry 2006; 163:1697–1704. 16. Meyer JM, et al. Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE schizophrenia trial: prospective data from phase 1. Schizophr Res 2008; 101:273–286. 17. Potkin SG, et al. Double-blind comparison of the safety and efficacy of lurasidone and ziprasidone in clinically stable outpatients with schizophrenia or schizoaffective disorder. Schizophr Res 2011; 132:101–107. 18. Correll CU, et al. Long-term safety and effectiveness of lurasidone in schizophrenia: a 22-month, open-label extension study. CNS Spectr 2016; 21:393–402. 19. Fleischhacker WW, et al. Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol 2010; 13:1115–1125. 20. Chen Y, et al. Comparative effectiveness of switching antipsychotic drug treatment to aripiprazole or ziprasidone for improving metabolic profile and atherogenic dyslipidemia: a 12-month, prospective, open-label study. J Psychopharmacol 2012; 26:1201–1210. 21. Lao KS, et al. Tolerability and safety profile of cariprazine in treating psychotic disorders, bipolar disorder and major depressive disorder: a systematic review with meta-analysis of randomized controlled trials. CNS Drugs 2016; 30:1043–1054. 22. Earley W, et al. Tolerability of cariprazine in the treatment of acute bipolar I mania: a pooled post hoc analysis of 3 phase II/III studies. J Affect Disord 2017; 215:205–212. 23. McEvoy J, et al. Brexpiprazole for the treatment of schizophrenia: a review of this novel serotonin-dopamine activity modulator. Clin Schizophr Relat Psychoses 2016; 9:177–186. 24. Correll CU, et al. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind, placebo- controlled trial. Am J Psychiatry 2015; 172:870–880. 25. Citrome L. Iloperidone: chemistry, pharmacodynamics, pharmacokinetics and metabolism, clinical efficacy, safety and tolerability, regulatory affairs, and an opinion. Expert Opin Drug Metab Toxicol 2010; 6:1551–1564. 26. Cutler AJ, et al. Long-term safety and tolerability of iloperidone: results from a 25-week, open-label extension trial. CNS Spectr 2013; 18:43–54. 27. Correll CU, et al. Efficacy and safety of lumateperone for treatment of schizophrenia: a randomized clinical trial. JAMA Psychiatry 2020; 77:349–358. 28. Li R, et al. Effects of olanzapine treatment on lipid profiles in patients with schizophrenia: a systematic review and meta-analysis. Sci Rep 2020; 10:17028. 29. Sheitman BB, et al. Olanzapine-induced elevation of plasma triglyceride levels. Am J Psychiatry 1999; 156:1471–1472. 30. Osser DN, et al. Olanzapine increases weight and serum triglyceride levels. J Clin Psychiatry 1999; 60:767–770. 31. Meyer JM. Effects of atypical antipsychotics on weight and serum lipid levels. J Clin Psychiatry 2001; 62 Suppl 27:27–34. 32. Melkersson KI, et al. Elevated levels of insulin, leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses. J Clin Psychiatry 2000; 61:742–749. 33. Meyer JM. Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol 2001; 21:369–374. 34. Kinon BJ, et al. Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. J Clin Psychiatry 2001; 62:92–100. 35. Meyer JM. A retrospective comparison of weight, lipid, and glucose changes between risperidone- and olanzapine-treated inpatients: metabolic outcomes after 1 year. J Clin Psychiatry 2002; 63:425–433. 36. Atmaca M, et al. Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics. J Clin Psychiatry 2003; 64:598–604. 37. de Leon J, et al. A clinical study of the association of antipsychotics with hyperlipidemia. Schizophr Res 2007; 92:95–102. 38. Koro CE, et al. An assessment of the independent effects of olanzapine and risperidone exposure on the risk of hyperlipidemia in schizophrenic patients. Arch Gen Psychiatry 2002; 59:1021–1026. 39. Henderson DC, et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study. Am J Psychiatry 2000; 157:975–981. 40. Ghaeli P, et al. Serum triglyceride levels in patients treated with clozapine. Am J Health Syst Pharm 1996; 53:2079–2081. 41. Spivak B, et al. Diminished suicidal and aggressive behavior, high plasma norepinephrine levels, and serum triglyceride levels in chronic neuroleptic-resistant schizophrenic patients maintained on clozapine. Clin Neuropharmacol 1998; 21:245–250. 42. Baptista T, et al. Novel antipsychotics and severe hyperlipidemia: comments on the Meyer paper. J Clin Psychopharmacol 2002; 22:536–537. 43. Barnes TR, et al. Screening for the metabolic side effects of antipsychotic medication: findings of a 6-year quality improvement programme in the UK. BMJ Open 2015; 5:e007633. 44. Fond G, et al. How can we improve the care of patients with schizophrenia in the real-world? A population-based cohort study of 456,003 patients. Mol Psychiatry 2023; 28:5328–5336. 45. Ali RA, et al. Guideline adherence for cardiometabolic monitoring of patients prescribed antipsychotic medications in primary care: a retrospective observational study. Int J Clin Pharm 2023; 45:1241–1251.

Schizophrenia and related psychoses CHAPTER 1 46. Mitchell AJ, et al. Guideline concordant monitoring of metabolic risk in people treated with antipsychotic medication: systematic review and meta-analysis of screening practices. Psychol Med 2012; 42:125–147. 47. Al-Awad FA, et al. Adherence to the monitoring of metabolic syndrome in patients receiving antipsychotics in outpatient clinics in Saudi Arabia. J Family Community Med 2024; 31:42–47. 48. National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management. Clinical guideline [CG178]. 2014 (last checked February 2024); https://www.nice.org.uk/guidance/cg178. 49. Cooper SJ, et al. BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment. J Psychopharmacol 2016; 30:717–748. 50. Meyer JM, et al. The effects of antipsychotic therapy on serum lipids: a comprehensive review. Schizophr Res 2004; 70:1–17. 51. Paton C, et al. Obesity, dyslipidaemias and smoking in an inpatient population treated with antipsychotic drugs. Acta Psychiatr Scand 2004; 110:299–305. 52. De Hert M, et al. The METEOR study of diabetes and other metabolic disorders in patients with schizophrenia treated with antipsychotic drugs. I. Methodology. Int J Methods Psychiatr Res 2010; 19:195–210. 53. Jin H, et al. Comparison of longer-term safety and effectiveness of 4 atypical antipsychotics in patients over age 40: a trial using equipoise- stratified randomization. J Clin Psychiatry 2013; 74:10–18. 54. Birkenaes AB, et al. Dyslipidemia independent of body mass in antipsychotic-treated patients under real-life conditions. J Clin Psychopharmacol 2008; 28:132–137. 55. Ojala K, et al. Statins are effective in treating dyslipidemia among psychiatric patients using second-generation antipsychotic agents. J Psychopharmacol 2008; 22:33–38. 56. Tse L, et al. Pharmacological treatment of antipsychotic-induced dyslipidemia and hypertension. Int Clin Psychopharmacol 2014; 29:125–137. 57. Buzea CA, et al. Drug-drug interactions involving combinations of antipsychotic agents with antidiabetic, lipid-lowering, and weight loss drugs. Expert Opin Drug Metab Toxicol 2022; 18:729–744. 58. Ryan A, et al. Dyslipidaemia and cardiovascular risk. BMJ 2018; 360:k835. 59. Rabar S, et al. Lipid modification and cardiovascular risk assessment for the primary and secondary prevention of cardiovascular disease: summary of updated NICE guidance. BMJ 2014; 349:g4356. 60. Group HPSC. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:7–22. 61. National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modification. NICE guideline [NG238]. 2023 (last accessed February 2024); https://www.nice.org.uk/guidance/ng238. 62. Caniato RN, et al. Effect of omega-3 fatty acids on the lipid profile of patients taking clozapine. Aust N Z J Psychiatry 2006; 40:691–697. 63. Freeman MP, et al. Omega-3 fatty acids for atypical antipsychotic-associated hypertriglyceridemia. Ann Clin Psychiatry 2015; 27:197–202. 64. Ghaeli P, et al. Elevated serum triglycerides with clozapine resolved with risperidone in four patients. Pharmacotherapy 1999; 19:1099–1101. 65. Weiden PJ. Switching antipsychotics as a treatment strategy for antipsychotic-induced weight gain and dyslipidemia. J Clin Psychiatry 2007; 68 Suppl 4:34–39. 66. Newcomer JW, et al. A multicenter, randomized, double-blind study of the effects of aripiprazole in overweight subjects with schizophrenia or schizoaffective disorder switched from olanzapine. J Clin Psychiatry 2008; 69:1046–1056. 67. Henderson DC, et al. Aripiprazole added to overweight and obese olanzapine-treated schizophrenia patients. J Clin Psychopharmacol 2009; 29:165–169. 68. Jiang WL, et al. Adjunctive metformin for antipsychotic-induced dyslipidemia: a meta-analysis of randomized, double-blind, placebo- controlled trials. Transl Psychiatry 2020; 10:117.

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Diabetes and impaired glucose tolerance

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Schizophrenia

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Antipsychotic medications

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First-generation antipsychotic medications

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Second-generation antipsychotic medications

174 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Diabetes and impaired glucose tolerance Schizophrenia Schizophrenia is associated with relatively high rates of insulin resistance and type 2 diabetes1,2 – an observation that predates the discovery and widespread use of antipsychotic medication.3–5 Lifestyle interventions (healthy diet, losing weight, regular physical activity) are effective in preventing diabetes6,7 and should be considered for all people with a diagnosis of schizophrenia. Antipsychotic medications The data relating to diabetes and the use of antipsychotic medication are numerous but less than perfect.8–12 The main problem is that while incidence and prevalence studies assume full or uniform screening for diabetes, this is unlikely to be occurring in clinical practice.13 Many studies do not account for other factors affecting the risk of developing diabetes.14 Small differences between medications are therefore difficult to substantiate but may, in any case, be ultimately unimportant: risk is probably increased for all those with schizophrenia receiving any antipsychotic medication. This risk is fairly strongly linked to increased diabetes-related mortality.11 The mechanisms involved in the development of antipsychotic-related diabetes are unclear, but may include 5HT2A/5HT2C antagonism, increased plasma lipids, weight gain and leptin resistance.15 Pancreatic insulin secretion is controlled by dopamine16 and this may explain why so many antipsychotics cause impaired glucose tolerance.17 Insulin resistance may occur in the absence of weight gain.18 First-generation antipsychotic medications Phenothiazine derivatives have long been associated with impaired glucose tolerance and diabetes.19 Diabetes prevalence was reported to have substantially increased following the introduction and widespread use of FGA medications.20 The prevalence of impaired glucose tolerance seems to be higher with the aliphatic phenothiazines than with fluphenazine or haloperidol.21 Hyperglycaemia has also been reported with other FGAs, such as loxapine,22 and other data confirm an association with haloperidol.23 Some studies have suggested that FGAs are no different from SGAs in their propensity to cause diabetes,24,25 whereas others suggest a modest but statistically significant excess incidence of diabetes with SGAs.26 Second-generation antipsychotic medications Clozapine Clozapine is strongly linked to hyperglycaemia, impaired glucose tolerance and diabetic ketoacidosis.27 The risk of diabetes appears to be higher with clozapine than with other SGAs or FGAs, especially in younger patients,28–31 although this is not a consistent finding.32,33 As many as a third of patients on continuing treatment with clozapine might develop diabetes after 5 years.34 Many cases of diabetes occur in the first 6 months of treatment,

Schizophrenia and related psychoses CHAPTER 1 some within a month,35 and some only after many years.33 Death from ketoacidosis has also been reported.35 Diabetes associated with clozapine is not necessarily linked to obesity or to family history of diabetes,27,36 although these factors greatly increase the risk of developing diabetes on this medication.37 Clozapine appears to increase plasma levels of insulin in a clozapine level-dependent fashion.38,39 It has been shown to be more likely than FGAs to increase plasma glucose and insulin following oral glucose challenge.40 Testing for diabetes is essential, given the high prevalence of the condition in people receiving clozapine.41,42 Olanzapine As with clozapine, olanzapine has been strongly linked to impaired glucose tolerance, diabetes and diabetic ketoacidosis.43 Olanzapine and clozapine appear to directly induce insulin resistance.44,45 Risk of diabetes has also been reported to be higher with olanzapine than with FGA drugs,46 again with a particular risk in younger patients.29 The time course of development of diabetes has not been established, but impaired glucose tolerance seems to occur even in the absence of obesity and family history of diabetes.27,36 Olanzapine is probably more diabetogenic than risperidone.47–51 Olanzapine is also associated with plasma levels of glucose and insulin higher than those seen with FGAs (after oral glucose load).40,52 Risperidone Risperidone has been linked, mainly in case reports, to impaired glucose tolerance,53 diabetes54 and ketoacidosis.55 The number of reports of such adverse effects is substantially smaller than with either clozapine or olanzapine.56 At least one study has suggested that changes in fasting glucose are significantly less common with risperidone than with olanzapine,47 but other studies have detected no difference.57 Risperidone seems no more likely than FGA drugs to be associated with diabetes,29,46,48 although there may be an increased risk in patients under 40 years of age.29 Risperidone has, however, been observed to adversely affect fasting glucose and plasma glucose (following glucose challenge) compared with the levels seen in healthy volunteers (but not compared with patients taking FGAs).40 Quetiapine Like risperidone, quetiapine has been linked to cases of new-onset diabetes and ketoacidosis,58–60 and associated with an increased risk of diabetes.61,62 Two studies showed quetiapine to be equal to olanzapine in the incidence of diabetes.57,63 The risk with quetiapine may be dose related, with daily doses of 400mg or more being clearly linked to changes in HbA1C.64 Other SGAs Amisulpride appears not to elevate plasma glucose,65 although there is one reported case of ketoacidosis occurring in a patient given the closely related medication sulpiride.66 Data for aripiprazole67–70 and ziprasidone71,72 suggest that neither drug alters

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Predicting antipsychotic-related diabetes

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Monitoring

176 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 glucose homeostasis. Aripiprazole may even reverse diabetes caused by other drugs73 (although ketoacidosis has been reported with aripiprazole).74–76 Further, studies have not found amisulpride or aripiprazole to be associated with a significantly greater risk of diabetes.61,77,78 So, these three drugs (amisulpride, aripiprazole and ziprasidone) are recommended for those with a history of, or predisposition to, diabetes mellitus or as an alternative to other antipsychotic medications known to be diabetogenic. Data suggest that neither lurasidone79,80 nor asenapine81,82 has any effect on glucose homeostasis. Likewise, early data on brexpiprazole83,84 and cariprazine85–87 suggest minimal effects on glucose tolerance. Thus, for patients developing prediabetes or diabetes who are being treated with clozapine, olanzapine or quetiapine, switching to antipsychotic medications with a lower cardiometabolic risk, such as aripiprazole, brexpiprazole, cariprazine, lurasidone or ziprasidone, has been recommended.88 Lumateperone appears to have no effect on glucose parameters89 but clinical experience is limited. Predicting antipsychotic-related diabetes The risk of diabetes is increased to a much greater extent in younger adults than in the elderly90,91 (for whom antipsychotic medication may show no increased risk).92 Patients with first-episode schizophrenia seem particularly prone to the development of diabetes with a variety of antipsychotic medications.93–95 During treatment, rapid weight gain and a rise in plasma triglycerides seem to be predictive of the development of diabetes.96,97 Monitoring of abnormal glucose metabolism is particularly warranted in those with obesity or hypertriglyceridaemia.42 Monitoring Diabetes is a growing problem in western society and has a strong association with obesity, (older) age, (lower) educational achievement and certain ethnic groups.98,99 Diabetes markedly increases cardiovascular mortality, largely as a consequence of atherosclerosis.100 Likewise, the use of antipsychotic medication also increases cardiovascular mortality.101–103 Intervention to reduce plasma glucose levels and minimise other risk factors (obesity, hypercholesterolaemia) is therefore essential.104 There is no clear consensus on diabetes monitoring practice for those receiving anti psychotic medication,105 and the recommendations in formal guidelines vary considerably.106 Given the previous known parlous state of testing for diabetes in the UK13,107–109 and elsewhere,110 arguments over precisely which tests are done and when seem to miss the point. There is an overwhelming need to improve monitoring by any means and so any tests for diabetes are supported – urine glucose and random plasma glucose included. Ideally, though, all patients should have oral glucose tolerance tests (OGTT) performed as this is the most sensitive method of detection.111,112 Fasting plasma glucose (FPG) tests are less sensitive but recommended.113 Any abnormality in FPG should provoke an OGTT. Fasting tests are often difficult to obtain in acutely ill, disorganised patients, so measurement of random plasma glucose or glycated haemoglobin (HbA1c) may also be used (fasting not required). HbA1C is recognised as a useful tool in detecting and monitoring diabetes.7 In the UK, NICE114 recommendations for monitoring people with a psychotic disorder, treated with antipsychotic medication, include the measurement of plasma glucose or HbA1C 3 months after starting treatment and then annually (Table 1.39).

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179 - Treatment of antipsychotic related diabetes

Treatment of antipsychotic-related diabetes

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18 - Prescribing high dose antipsychotic medicatio

Prescribing high-dose antipsychotic medication

Schizophrenia and related psychoses CHAPTER 1 ■ ■The use of high-dose antipsychotic medication should be an exceptional clinical practice and only ever employed when adequate trials of such medication (including clozapine) at standard dosage have failed. ■ ■If high-dose antipsychotic medication is prescribed, it should be standard practice to review and document the target symptoms, therapeutic response and adverse effects, ideally using validated rating scales, so that there is ongoing consideration of the risk–benefit balance for the patient. Close physical monitoring (including ECG) is essential. Recommendations Before using high doses, ensure that: ■ ■Sufficient time has been allowed for response (see section on ‘time to response’). ■ ■There have been adequate trials of at least two different antipsychotic medications (including, if possible, olanzapine), conducted sequentially. ■ ■Clozapine has failed or not been tolerated because of agranulocytosis or other serious adverse effects. Most other adverse effects can be managed. A small proportion of patients may also decline to take clozapine. Prescribing high-dose antipsychotic medication The decision to prescribe high doses should: ■ ■Be made by a senior psychiatrist. ■ ■Involve the multidisciplinary team. ■ ■Be done, if possible, with a patient’s informed consent. Process ■ ■Rule out contraindications (e.g. ECG abnormalities, hepatic impairment). ■ ■Consider and minimise any risks posed by concomitant medication (e.g. potential to cause QTc prolongation, electrolyte disturbance or pharmacokinetic interactions via CYP inhibition). ■ ■Document the decision to prescribe high dosage in the clinical notes, together with a description of the target symptoms. The use of an appropriate rating scale is advised. ■ ■Adequate time for response should be allowed after each dosage increment before a further increase is made. Monitoring ■ ■Physical monitoring should be carried out as outlined in the section on ‘monitoring’. ■ ■All patients on high doses should have regular ECGs (at baseline, when steady-state serum levels have been reached after each dosage increment, and then every 6–12 months). Additional biochemical/ECG monitoring is advised if drugs that are known to cause electrolyte disturbances or QTc prolongation are subsequently co-prescribed. ■ ■Target symptoms should be assessed after 6 weeks and 3 months. If insufficient improvement in these symptoms has occurred, the dose should be decreased to the normal range.

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180 - Summary antipsychotic medications risk of di

Summary: antipsychotic medications – risk of diabetes and impaired glucose tolerance

Schizophrenia and related psychoses CHAPTER 1 Frequency of monitoring should be determined by physical factors (e.g. weight gain) and known risk factors (e.g. family history of diabetes, lipid abnormalities, smoking status). In addition, all patients should be asked to look out for and report signs and symptoms of diabetes (fatigue, candida infection, thirst polyuria). Treatment of antipsychotic-related diabetes Switching to an antipsychotic medication with a lower cardiometabolic risk is often effective in reversing changes in glucose tolerance. In this respect, the most compelling evidence is for switching to aripiprazole,115,116 but also to ziprasidone116 and lurasidone.80,117 Standard antidiabetic treatments are otherwise recommended.88 Pioglitazone118 may have particular benefit, but note the hepatotoxic potential of this drug. GLP-1 agonists such as liraglutide, exenatide and semaglutide are increasingly used.119–121 Summary: antipsychotic medications – risk of diabetes and impaired glucose tolerance High risk Clozapine, olanzapine Moderate risk Phenothiazines, quetiapine, risperidone Low risk High-potency FGAs (e.g. haloperidol) Minimal risk Aripiprazole, amisulpride, asenapine, brexpiprazole, cariprazine, lumateperone, lurasidone, ziprasidone Table 1.39 Recommended monitoring for diabetes in patients receiving antipsychotic drugs. Treatment stage Recommended monitoring Ideally Minimum At baseline OGTT or FPG. HbA1C if fasting not possible. UG, RPG Continuing All antipsychotic medications: OGTT or FPG + HbA1C at 4–6 months then every 12 months UG or RPG every 12 months, with symptom monitoring For clozapine and olanzapine or if other risk factors present: OGTT or FPG after 1 month, then every 4–6 months HbA1C is a suitable test for monitoring. But note that this test is not suitable for detecting short-term change. FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; OGTT, oral glucose tolerance tests; RPG, random plasma glucose; UG, urine glucose.

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181 - References

References

178 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

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Schizophrenia and related psychoses CHAPTER 1 37. Zhang R, et al. The prevalence and clinical-demographic correlates of diabetes mellitus in chronic schizophrenic patients receiving clozapine. Hum Psychopharmacol 2011; 26:392–396. 38. Melkersson KI, et al. Different influences of classical antipsychotics and clozapine on glucose-insulin homeostasis in patients with schizophrenia or related psychoses. J Clin Psychiatry 1999; 60:783–791. 39. Melkersson K. Clozapine and olanzapine, but not conventional antipsychotics, increase insulin release in vitro. Eur Neuropsychopharmacol 2004; 14:115–119. 40. Newcomer JW, et al. Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch Gen Psychiatry 2002; 59:337–345. 41. Lamberti JS, et al. Diabetes mellitus among outpatients receiving clozapine: prevalence and clinical-demographic correlates. J Clin Psychiatry 2005; 66:900–906. 42. Miyakoshi T, et al. Risk factors for abnormal glucose metabolism during antipsychotic treatment: a prospective cohort study. J Psychiatr Res 2023; 168:149–156. 43. Wirshing DA, et al. Novel antipsychotics and new onset diabetes. Biol Psychiatry 1998; 44:778–783. 44. Engl J, et al. Olanzapine impairs glycogen synthesis and insulin signaling in L6 skeletal muscle cells. Mol Psychiatry 2005; 10:1089–1096. 45. Vestri HS, et al. Atypical antipsychotic drugs directly impair insulin action in adipocytes: effects on glucose transport, lipogenesis, and antilipolysis. Neuropsychopharmacology 2007; 32:765–772. 46. Koro CE, et al. Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case-control study. BMJ 2002; 325:243. 47. Meyer JM. A retrospective comparison of weight, lipid, and glucose changes between risperidone- and olanzapine-treated inpatients: metabolic outcomes after 1 year. J Clin Psychiatry 2002; 63:425–433. 48. Gianfrancesco F, et al. Antipsychotic-induced type 2 diabetes: evidence from a large health plan database. J Clin Psychopharmacol 2003; 23:328–335. 49. Leslie DL, et al. Incidence of newly diagnosed diabetes attributable to atypical antipsychotic medications. Am J Psychiatry 2004; 161:1709–1711. 50. Duncan E, et al. Relative risk of glucose elevation during antipsychotic exposure in a Veterans Administration population. Int Clin Psychopharmacol 2007; 22:1–11. 51. Meyer JM, et al. Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE schizophrenia trial: prospective data from phase 1. Schizophr Res 2008; 101:273–286. 52. Ebenbichler CF, et al. Olanzapine induces insulin resistance: results from a prospective study. J Clin Psychiatry 2003; 64:1436–1439. 53. Mallya A, et al. Resolution of hyperglycemia on risperidone discontinuation: a case report. J Clin Psychiatry 2002; 63:453–454. 54. Wirshing DA, et al. Risperidone-associated new-onset diabetes. Biol Psychiatry 2001; 50:148–149. 55. Croarkin PE, et al. Diabetic ketoacidosis associated with risperidone treatment? Psychosomatics 2000; 41:369–370. 56. Koller EA, et al. Risperidone-associated diabetes mellitus: a pharmacovigilance study. Pharmacotherapy 2003; 23:735–744. 57. Lambert BL, et al. Diabetes risk associated with use of olanzapine, quetiapine, and risperidone in Veterans Health Administration patients with schizophrenia. Am J Epidemiol 2006; 164:672–681. 58. Henderson DC. Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? CNS Drugs 2002; 16:77–89. 59. Koller EA, et al. A survey of reports of quetiapine-associated hyperglycemia and diabetes mellitus. J Clin Psychiatry 2004; 65:857–863. 60. Nanasawa H, et al. Development of diabetes mellitus associated with quetiapine: a case series. Medicine (Baltimore) 2017; 96:e5900. 61. Ulcickas Yood M, et al. Association between second-generation antipsychotics and newly diagnosed treated diabetes mellitus: does the effect differ by dose? BMC Psychiatry 2011; 11:197. 62. Correll CU, et al. Cardiovascular and cerebrovascular risk factors and events associated with second-generation antipsychotic compared to antidepressant use in a non-elderly adult sample: results from a claims-based inception cohort study. World Psychiatry 2015; 14:56–63. 63. Bushe C, et al. Comparison of metabolic and prolactin variables from a six-month randomised trial of olanzapine and quetiapine in schizophrenia. J Psychopharmacol 2010; 24:1001–1009. 64. Guo Z, et al. A real-world data analysis of dose effect of second-generation antipsychotic therapy on hemoglobin A1C level. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:1326–1332. 65. Vanelle JM, et al. A double-blind randomised comparative trial of amisulpride versus olanzapine for 2 months in the treatment of subjects with schizophrenia and comorbid depression. Eur Psychiatry 2006; 21:523–530. 66. Toprak O, et al. New-onset type II diabetes mellitus, hyperosmolar non-ketotic coma, rhabdomyolysis and acute renal failure in a patient treated with sulpiride. Nephrol Dial Transplant 2005; 20:662–663. 67. Keck PE, Jr., et al. Aripiprazole: a partial dopamine D2 receptor agonist antipsychotic. Expert Opin Invest Drugs 2003; 12:655–662. 68. Pigott TA, et al. Aripiprazole for the prevention of relapse in stabilized patients with chronic schizophrenia: a placebo-controlled 26-week study. J Clin Psychiatry 2003; 64:1048–1056. 69. van WR, et al. Major changes in glucose metabolism, including new-onset diabetes, within 3 months after initiation of or switch to atypical antipsychotic medication in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2008; 69:472–479. 70. Baker RA, et al. Atypical antipsychotic drugs and diabetes mellitus in the US Food and Drug Administration Adverse Event Database: a systematic Bayesian signal detection analysis. Psychopharmacol Bull 2009; 42:11–31. 71. Simpson GM, et al. Randomized, controlled, double-blind multicenter comparison of the efficacy and tolerability of ziprasidone and olanzapine in acutely ill inpatients with schizophrenia or schizoaffective disorder. Am J Psychiatry 2004; 161:1837–1847. 72. Sacher J, et al. Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers. Neuropsychopharmacology 2008; 33:1633–1641.

180 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 73. De Hert M, et al. A case series: evaluation of the metabolic safety of aripiprazole. Schizophr Bull 2007; 33:823–830. 74. Church CO, et al. Diabetic ketoacidosis associated with aripiprazole. Diabet Med 2005; 22:1440–1443. 75. Reddymasu S, et al. Elevated lipase and diabetic ketoacidosis associated with aripiprazole. J Pancreas 2006; 7:303–305. 76. Campanella LM, et al. Severe hyperglycemic hyperosmolar nonketotic coma in a nondiabetic patient receiving aripiprazole. Ann Emerg Med 2009; 53:264–266. 77. Kessing LV, et al. Treatment with antipsychotics and the risk of diabetes in clinical practice. Br J Psychiatry 2010; 197:266–271. 78. Vancampfort D, et al. Diabetes mellitus in people with schizophrenia, bipolar disorder and major depressive disorder: a systematic review and large scale meta-analysis. World Psychiatry 2016; 15:166–174. 79. McEvoy JP, et al. Effectiveness of lurasidone in patients with schizophrenia or schizoaffective disorder switched from other antipsychotics: a randomized, 6-week, open-label study. J Clin Psychiatry, 2013; 74:170–179. 80. Stahl SM, et al. Effectiveness of lurasidone for patients with schizophrenia following 6 weeks of acute treatment with lurasidone, olanzapine, or placebo: a 6-month, open-label, extension study. J Clin Psychiatry 2013; 74:507–515. 81. McIntyre RS, et al. Asenapine for long-term treatment of bipolar disorder: a double-blind 40-week extension study. J Affect Disord 2010; 126:358–365. 82. McIntyre RS, et al. Asenapine versus olanzapine in acute mania: a double-blind extension study. Bipolar Disord 2009; 11:815–826. 83. Garnock-Jones KP. Brexpiprazole: a review in schizophrenia. CNS Drugs 2016; 30:335–342. 84. Newcomer JW, et al. Changes in metabolic parameters and body weight in patients with major depressive disorder treated with adjunctive brexpiprazole: pooled analysis of phase 3 clinical studies. J Clin Psychiatry 2019; 80:18m12680. 85. Lao KS, et al. Tolerability and safety profile of cariprazine in treating psychotic disorders, bipolar disorder and major depressive disorder: a systematic review with meta-analysis of randomized controlled trials. CNS Drugs 2016; 30:1043–1054. 86. Earley W, et al. Tolerability of cariprazine in the treatment of acute bipolar I mania: a pooled post hoc analysis of 3 phase II/III studies. J Affect Disord 2017; 215:205–212. 87. Barabássy Á, et al. Safety and tolerability of cariprazine in patients with schizophrenia: a pooled analysis of eight phase II/III studies. Neuropsychiatr Dis Treat 2021; 17:957–970. 88. Cernea S, et al. Pharmacological management of glucose dysregulation in patients treated with second-generation antipsychotics. Drugs 2020; 80:1763–1781. 89. Correll CU, et al. Efficacy and safety of lumateperone for treatment of schizophrenia: a randomized clinical trial. JAMA Psychiatry 2020; 77:349–358. 90. Hammerman A, et al. Antipsychotics and diabetes: an age-related association. Ann Pharmacother 2008; 42:1316–1322. 91. Galling B, et al. Type 2 diabetes mellitus in youth exposed to antipsychotics: a systematic review and meta-analysis. JAMA Psychiatry 2016; 73:247–259. 92. Albert SG, et al. Atypical antipsychotics and the risk of diabetes in an elderly population in long-term care: a retrospective nursing home chart review study. J Am Med Dir Assoc 2009; 10:115–119. 93. De Hert M, et al. Typical and atypical antipsychotics differentially affect long-term incidence rates of the metabolic syndrome in first- episode patients with schizophrenia: a retrospective chart review. Schizophr Res 2008; 101:295–303. 94. Saddichha S, et al. Metabolic syndrome in first episode schizophrenia: a randomized double-blind controlled, short-term prospective study. Schizophr Res 2008; 101:266–272. 95. Saddichha S, et al. Diabetes and schizophrenia – effect of disease or drug? Results from a randomized, double-blind, controlled prospective study in first-episode schizophrenia. Acta Psychiatr Scand 2008; 117:342–347. 96. Reaven GM, et al. In search of moderators and mediators of hyperglycemia with atypical antipsychotic treatment. J Psychiatr Res 2009; 43:997–1002. 97. Heald AH, et al. Changes in metabolic parameters in patients with severe mental illness over a 10-year period: a retrospective cohort study. Aust N Z J Psychiatry 2017; 51:75–82. 98. Mokdad AH, et al. The continuing increase of diabetes in the US. Diabetes Care 2001; 24:412. 99. Mokdad AH, et al. Diabetes trends in the US: 1990–1998. Diabetes Care 2000; 23:1278–1283. 100. Beckman JA, et al. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002; 287:2570–2581. 101. Henderson DC, et al. Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10-year naturalistic study. J Clin Psychiatry 2005; 66:1116–1121. 102. Lamberti JS, et al. Prevalence of the metabolic syndrome among patients receiving clozapine. Am J Psychiatry 2006; 163:1273–1276. 103. Goff DC, et al. A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls. Schizophr Res 2005; 80:45–53. 104. Haupt DW, et al. Hyperglycemia and antipsychotic medications. J Clin Psychiatry 2001; 62 Suppl 27:15–26. 105. Cohn TA, et al. Metabolic monitoring for patients treated with antipsychotic medications. Can J Psychiatry 2006; 51:492–501. 106. De Hert M, et al. Guidelines for screening and monitoring of cardiometabolic risk in schizophrenia: systematic evaluation. Br J Psychiatry 2011; 199:99–105. 107. Barnes TR, et al. Screening for the metabolic syndrome in community psychiatric patients prescribed antipsychotics: a quality improvement programme. Acta Psychiatr Scand 2008; 118:26–33. 108. Barnes TR, et al. Screening for the metabolic side effects of antipsychotic medication: findings of a 6-year quality improvement programme in the UK. BMJ Open 2015; 5:e007633. 109. Crawford MJ, et al. Assessment and treatment of physical health problems among people with schizophrenia: national cross-sectional study. Br J Psychiatry 2014; 205:473–477. 110. Morrato EH, et al. Metabolic screening after the ADA’s consensus statement on antipsychotic drugs and diabetes. Diabetes Care 2009; 32:1037–1042.

Schizophrenia and related psychoses CHAPTER 1 111. De Hert M, et al. Oral glucose tolerance tests in treated patients with schizophrenia. Data to support an adaptation of the proposed guidelines for monitoring of patients on second generation antipsychotics? Eur Psychiatry 2006; 21:224–226. 112. Pillinger T, et al. Impaired glucose homeostasis in first-episode schizophrenia: a systematic review and meta-analysis. JAMA Psychiatry 2017; 74:261–269. 113. Marder SR, et al. Physical health monitoring of patients with schizophrenia. Am J Psychiatry 2004; 161:1334–1349. 114. National Institute for Health and Care Excellence. Prescribing information: monitoring. Psychosis and schizophrenia: what monitoring is required? (Last revised October 2024; last checked January 2025); https://cks.nice.org.uk/topics/psychosis-schizophrenia/prescribing- information. 115. Stroup TS, et al. Effects of switching from olanzapine, quetiapine, and risperidone to aripiprazole on 10-year coronary heart disease risk and metabolic syndrome status: results from a randomized controlled trial. Schizophr Res 2013; 146:190–195. 116. Chen Y, et al. Comparative effectiveness of switching antipsychotic drug treatment to aripiprazole or ziprasidone for improving metabolic profile and atherogenic dyslipidemia: a 12-month, prospective, open-label study. J Psychopharmacol 2012; 26:1201–1210. 117. Wang YH, et al. Lurasidone successfully reversed clozapine-induced type 2 diabetes mellitus and hypertriglyceridemia in a patient with schizophrenia. Am J Ther 2023; 30:e490–e491. 118. Smith RC, et al. Effects of pioglitazone on metabolic abnormalities, psychopathology, and cognitive function in schizophrenic patients treated with antipsychotic medication: a randomized double-blind study. Schizophr Res 2013; 143:18–24. 119. Larsen JR, et al. Effect of liraglutide treatment on prediabetes and overweight or obesity in clozapine- or olanzapine-treated patients with schizophrenia spectrum disorder: a randomized clinical trial. JAMA Psychiatry 2017; 74:719–728. 120. Patoulias D, et al. Effect of glucagon-like peptide-1 receptor agonists on cardio-metabolic risk factors among obese/overweight individuals treated with antipsychotic drug classes: an updated systematic review and meta-analysis of randomized controlled trials. Biomedicines 2023; 11:669. 121. Noda K, et al. Semaglutide is effective in type 2 diabetes and obesity with schizophrenia. Diabetol Int 2022; 13:693–697.

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182 - Blood pressure changes with antipsychotics

Blood pressure changes with antipsychotics

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183 - Orthostatic hypotension

Orthostatic hypotension

182 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Blood pressure changes with antipsychotics Orthostatic hypotension Orthostatic hypotension (postural hypotension) is one of the most common cardiovascular adverse effects of antipsychotics and some antidepressants. Orthostatic hypotension generally presents acutely, during the initial dose titration period, but it can also be a chronic problem.1 Symptoms include dizziness, light-headedness, asthenia, headache and visual disturbance. Patients may not be able to communicate the severity of these symptoms effectively and subjective reports of postural dizziness correlate only weakly with the magnitude of measured postural hypotension.2 Blood pressure monitoring is recommended in suspected cases to confirm orthostatic hypotension (usually defined as a ≥20mmHg fall in systolic blood pressure and/or a ≥10mmHg fall in diastolic blood pressure within 3 minutes of standing).3 Orthostatic hypotension impairs quality of life and is associated with an increased risk of falls, cardiovascular disease, depression and death.3 Risk factors are shown in Table 1.40. Slow dose titration is a commonly used and often effective strategy to avoid or minimise orthostatic hypotension. However, in some cases orthostasis may be a dose-limiting side effect, preventing optimal treatment. Potential management strategies are shown in Table 1.41. Table 1.40 Risk factors for orthostatic hypotension.2 Treatment factors ■ ■IM administration route (peak levels higher and achieved more rapidly) ■ ■Rapid dose increases ■ ■Antipsychotic polypharmacy ■ ■Drug interactions (e.g. tricyclic antidepressants, antihypertensive drugs – particularly alpha blockers, beta blockers and diuretics, although the number of antihypertensive drugs prescribed may be more predictive than the class)3 Patient factors ■ ■Old age (young patients may have sinus tachycardia with minimal change in blood pressure) ■ ■Disease states associated with autonomic dysfunction (e.g. Parkinson’s disease) ■ ■Dehydration ■ ■Cardiovascular disease Table 1.41 Management of antipsychotic-induced orthostatic hypotension.2,4 Minimise the risk of treatment ■ ■Limit initial doses and titrate slowly according to tolerability (most people develop a tolerance to the hypotensive effect) ■ ■Consider a temporary dose reduction if hypotension develops ■ ■Reduce peak plasma levels by using smaller and more frequent dosing or by using modified-release preparations Non-pharmacological therapies ■ ■Advice to patients (e.g. sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position) ■ ■Abdominal binders and compression stockings can be used ■ ■Increasing fluid intake to 1.25–2.5L/day is advisable for all patients who are not fluid restricted (Continued)

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184 - Hypertension

Hypertension

Schizophrenia and related psychoses CHAPTER 1 Antipsychotics with a high affinity for postsynaptic α1-adrenergic receptors are most frequently implicated in postural hypotension. Among the SGAs, the reported incidence is highest with clozapine (24%), quetiapine (27%) and iloperidone (19.5%) and lowest with lurasidone (<2%) and asenapine (<2%).2 There are limited quantitative data for FGAs,6 but low-potency phenothiazines (e.g. chlorpromazine) are considered most likely to cause orthostatic hypotension.7 All reported frequencies are somewhat dependent on titration schedules used. Please see the section on relative adverse effects – a rough guide in this chapter for a summary of the relative incidence and severity of hypotension with antipsychotics. Hypertension There are two ways in which antipsychotic drugs may be associated with the development or worsening of hypertension: ■ ■Slow steady rise in blood pressure over time. This may be linked to weight gain. Being overweight increases the risk of developing hypertension. The magnitude of the effect has been modelled using the Framingham data: for every 30 people who gain 4kg, one will develop hypertension over the next 10 years.8 Note that this is a very modest weight gain. The majority of patients treated with some antipsychotics gain more than this, increasing further the risk of developing hypertension (see section on antipsychotic-induced weight gain in this chapter). ■ ■Unpredictable rapid sharp increase in blood pressure on starting a new drug or increasing the dose. Increases in blood pressure occur shortly after starting, ranging from within hours of the first dose to a month. The mechanism for the rapid increase in blood pressure (i.e. that independent of obesity) is uncertain, so the risk of hypertension cannot be predicted from antipsychotic pharmacology. One review of the literature suggested a possible mechanism related to Pharmacological therapies for patients with a compelling indication for treatment where alternatives are not suitable (e.g. clozapine) and management strategies have failed ■ ■Sodium chloride supplementation may help antidepressant-induced orthostatic hypotension ■ ■Fludrocortisone has been used to treat clozapine-induced orthostatic hypotension where other measures have failed (electrolyte and blood pressure monitoring essential). Long-term use is not recommended.4 ■ ■Midodrine, an α1 receptor agonist, has been used in one small case series (including one patient on clozapine) to reduce symptom severity.4 Of note, midodrine has been linked to acute dystonia when used alongside antipsychotics.5 A review suggests that midodrine should be considered second line in clozapine-induced orthostatic hypotension or where fludrocortisone is contraindicated or poorly tolerated.4 ■ ■Other sympathomimetic drugs have also been used to treat orthostatic hypotension, although for most there is an absence of evidence in the treatment of psychotropic-related cases. Etilefrine has shown benefit in psychotropic-induced hypotension but cannot be recommended owing to unfavourable risk–benefit profile.4 Table 1.41 (Continued)

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185 - References

References

184 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 dopamine receptor antagonism.9 All five dopamine receptor subtypes (D1–5) are known to be involved in renal sodium excretion and blood pressure regulation.9 Antipsychotics vary in their affinity for these dopamine receptor subtypes, and the relative importance of each receptor subtype is unclear. Other suggested mechanisms include α2 antagonism leading to prolonged noradrenaline release, hypertension through renal potassium loss, and sodium and fluid retention, possibly owing to D4 receptor antagonism.10 Some antipsychotics are more commonly implicated than others, although individual patient factors are also likely to be important. Most case reports involve clozapine,11,12 with some clearly describing normal blood pressure before clozapine was introduced, a sharp rise during treatment and return to normal when clozapine was discontinued or doses were decreased.12 Blood pressure has also been reported to rise again on rechallenge and increased urinary catecholamines mimicking phaeochromocytoma have been noted in some cases. Clozapine can usually be continued with antihypertensive drugs.12 Case reports also implicate aripiprazole,13–16 sulpiride,17,18 risperidone,19 quetiapine20 and ziprasidone.21 Olanzapine has been linked to water retention and hypertension in a pregnant woman22 and intracranial hypertension in an adolescent.23 Data available through the UK Medicines and Healthcare products Regulatory Authority yellow card system indicate that clozapine is the antipsychotic drug most associated with hypertension. There are substantially fewer reports with aripiprazole, olanzapine, quetiapine and risperidone.24 The timing of the onset of hypertension in these reports with respect to antipsychotic initiation is unknown. In long-term treatment, hypertension is seen in around 30–40% of patients regardless of antipsychotic prescribed.25 A cross-sectional study found an increased risk of hypertension only for perphenazine,26 a finding not readily explained by its pharmacology. No antipsychotic is contraindicated in essential hypertension, but extreme care is needed when clozapine is prescribed. Concomitant treatment with SSRIs may increase risk of hypertension, possibly via inhibition of the metabolism of the co-prescribed antipsychotic.20 It is also theoretically possible that α2 antagonism may be at least partially responsible for clozapine-induced tachycardia and nausea.27 Treatment of antipsychotic-associated hypertension should follow standard protocols. Switching to alternative antipsychotics with a lower cardiometabolic risk should be considered where possible. There is specific evidence for the efficacy of valsartan and telmisartan in antipsychotic-related hypertension.28 References

Silver H, et al. Postural hypotension in chronically medicated schizophrenics. J Clin Psychiatry 1990; 51:459–462.
Gugger JJ. Antipsychotic pharmacotherapy and orthostatic hypotension: identification and management. CNS Drugs 2011; 25:659–671.
Gilani A, et al. Postural hypotension. BMJ 2021; 373:n922.
Tanzer TD, et al. Treatment strategies for clozapine-induced hypotension: a systematic review. Ther Adv Psychopharmacol 2022; 12:20451253221092931.
Stroup TS, et al. Management of common adverse effects of antipsychotic medications. World Psychiatry 2018; 17:341–356.
Bhanu C, et al. Drug-induced orthostatic hypotension: a systematic review and meta-analysis of randomised controlled trials. PLoS Med 2021; 18:e1003821.
Li XQ, et al. Antipsychotics cardiotoxicity: what’s known and what’s next. World J Psychiatry 2021; 11:736–753.
Fontaine KR, et al. Estimating the consequences of anti-psychotic induced weight gain on health and mortality rate. Psychiatry Res 2001; 101:277–288.
Gonsai NH, et al. Effects of dopamine receptor antagonist antipsychotic therapy on blood pressure. J Clin Pharm Ther 2018; 43:1–7.

Schizophrenia and related psychoses CHAPTER 1 10. Deepak MB, et al. Clozapine induced hypertension and its association with autonomic dysfunction. Psychopharmacol Bull 2021; 51:122–127. 11. Yuen JWY, et al. Clozapine-induced cardiovascular side effects and autonomic dysfunction: a systematic review. Front Neurosci 2018; 12:203. 12. Grover S, et al. Clozapine-induced hypertension: a case report and review of literature. Ind Psychiatry J 2017; 26:103–105. 13. Hsiao YL, et al. Aripiprazole augmentation induced hypertension in major depressive disorder: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:305–306. 14. Yasui-Furukori N, et al. Worsened hypertension control induced by aripiprazole. Neuropsychiatr Dis Treat 2013; 9:505–507. 15. Seven H, et al. Aripiprazole-induced asymptomatic hypertension: a case report. Psychopharmacol Bull 2017; 47:53–56. 16. Alves BB, et al. Use of atypical antipsychotics and risk of hypertension: a case report and review literature. SAGE Open Med Case Rep 2019; 7:2050313x19841825. 17. Mayer RD, et al. Acute hypertensive episode induced by sulpiride: a case report. Hum Psychopharmacol 1989; 4:149–150. 18. Corvol P, et al. Hypertensive episodes initiated by sulpiride (Dogmatil). Ann Med Interne (Paris) 1973; 124:647–649. 19. Thomson SR, et al. Risperidone induced hypertension in a young female: a case report. Advanced Science Letters 2017; 23:1980–1982. 20. Coulter D. Atypical antipsychotics may cause hypertension. Prescriber Update 2003; 24:4. 21. Villanueva N, et al. Probable association between ziprasidone and worsening hypertension. Pharmacotherapy 2006; 26:1352–1357. 22. Izsak J, et al. Case report: olanzapine-associated water retention, high blood pressure, and subsequent preterm preeclampsia. Front Psychiatry 2023; 14:1301348. 23. Naguy A, et al. Probable olanzapine-related idiopathic intracranial hypertension in an adolescent with first-episode psychosis. Psychopharmacol Bull 2023; 53:69–72. 24. Medicines and Healthcare products Regulatory Agency. Drug Analysis Profiles (iDAPs). 2024; https://www.gov.uk/drug-analysis-prints. 25. Kelly AC, et al. A naturalistic comparison of the long-term metabolic adverse effects of clozapine versus other antipsychotics for patients with psychotic illnesses. J Clin Psychopharmacol 2014; 34:441–445. 26. Boden R, et al. A comparison of cardiovascular risk factors for ten antipsychotic drugs in clinical practice. Neuropsychiatr Dis Treat 2013; 9:371–377. 27. Pandharipande P, et al. Alpha-2 agonists: can they modify the outcomes in the postanesthesia care unit? Curr Drug Targets 2005; 6:749–754. 28. Tse L, et al. Pharmacological treatment of antipsychotic-induced dyslipidemia and hypertension. Int Clin Psychopharmacol 2014; 29:125–137.

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186 - Antipsychotic associated hyponatraemia

Antipsychotic-associated hyponatraemia

186 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Antipsychotic-associated hyponatraemia Hyponatraemia can occur in the context of: ■ ■Water intoxication, where water consumption exceeds the maximal renal clearance capacity. Serum and urine osmolality are low. Cross-sectional studies of chronically ill, hospitalised, psychiatric patients have found the prevalence of water intoxication to be 6–17%.1,2 A longitudinal study found that 10% of severely ill patients with a diagnosis of schizophrenia had episodic hyponatraemia secondary to fluid overload.3 The primary aetiology is poorly understood. It may be driven, at least in part, by an extreme compensatory response to the anticholinergic adverse effects of some antipsychotic drugs.4 An alternative theory is that postsynaptic dopamine receptor antagonism results in receptor supersensitivity, increased presynaptic dopamine release, and elevated dopamine in the hypothalamus, driving thirst and polydipsia.5 The fact that many reported cases occur in patients with long illness histories and treatment with antipsychotics with high D2 receptor affinity (and that clozapine can improve polydipsia independent of improvement in psychosis) appears to support this suggestion.5 ■ ■Drug-induced syndrome of inappropriate antidiuretic hormone (SIADH), where the kidney retains an excessive quantity of solute-free water. Serum osmolality is low and urine osmolality relatively high. The prevalence of SIADH may be as high as 11% in acutely ill psychiatric patients.6 Risk factors for antidepressant-induced SIADH (increasing age, female gender, medical comorbidity and polypharmacy) seem to be less relevant to the population of patients treated with antipsychotic drugs.7 SIADH usually develops in the first few weeks of treatment with the offending drug8 but can appear at a later time.8 Case reports/series7,9–30 implicate various phenothiazines, haloperidol, pimozide, risperidone, paliperidone, quetiapine, olanzapine, aripiprazole, cariprazine and clozapine. Systematic review31 and case–control studies32,33 suggest a clear increase in risk of hyponatraemia with antipsychotics. One large Swedish study found a stronger association for first- generation antipsychotics than for SGAs.33 Analysis of pharmacovigilance reports appears to support this.34 Another review35 confirmed that drug-induced hyponatraemia is associated with concentrated urine and suggested that antipsychotic treatment was five times more likely than water intoxication to be the cause of hyponatraemia. Overall prevalence of antipsychotic-induced hyponatraemia has been estimated at 0.004%36 and 26.1%.37 It is assumed that the true figure is somewhere between these two widely different extremes. Desmopressin, when used for clozapine-induced enuresis, can also result in hyponatraemia.38 Other drugs, including antidepressants and anticonvulsants (especially carbamazepine),39 valbenazine40 and many drugs for physical health conditions (diuretics, angiotensin- converting-enzyme [ACE] inhibitors, angiotensin II receptor blockers, proton pump inhibitors), have also been implicated.41 The risk of hyponatraemia is probably additive with concomitant prescriptions.42–44 ■ ■Severe hyperlipidaemia and/or hyperglycaemia lead to secondary increases in plasma volume and ‘pseudohyponatraemia’.4 Both are more common in people treated with antipsychotic drugs than in the general population and should be excluded as causes.

Schizophrenia and related psychoses CHAPTER 1 Mild to moderate hyponatraemia presents as confusion, nausea, headache and lethargy. As the plasma sodium falls, these symptoms become increasingly severe, and seizures and coma can develop. Monitoring of plasma sodium is desirable for all those receiving antipsychotics, particularly if several risk factors for hyponatraemia are present. A risk-scoring algorithm has been proposed.45 Signs of confusion or lethargy should provoke thorough diagnostic analysis, including plasma sodium determination and urine osmolality (Table 1.42). Tolvaptan,46 a so-called vaptan (non-peptide arginine-vasopressin antagonist, also known as aquaretics because they induce a highly hypotonic diuresis),47 shows promise in the treatment of hyponatraemia of various aetiologies, including that caused by drug-related SIADH and psychogenic polydipsia.48 Table 1.42 Treatment of hyponatraemia associated with antipsychotic treatment.4,6 Cause of hyponatraemia Antipsychotic drugs implicated Treatment Water intoxication (serum and urine osmolality low) Only very speculative evidence to support drugs as a cause. ■ ■Fluid restriction with careful monitoring of serum sodium, particularly diurnal variation (Na drops as the day progresses). Refer urgently to specialist medical care if Na <125 mmol/L. Note that over-rapid correction of sodium levels can cause irreversible osmotic demyelination syndrome.49 ■ ■Consider treatment with clozapine, which has been shown to increase plasma osmolality into the normal range and increase urine osmolality.50,51 These effects are consistent with reduced fluid intake but are not clearly related to improvements in mental state.52 ■ ■There are both7 positive and negative reports for olanzapine53 and risperidone54 and one positive case report for quetiapine.55 Compared with clozapine, the evidence base is weak. ■ ■There is no evidence that either reducing or increasing the dose of an antipsychotic results in improvements in serum sodium in water-intoxicated patients56 although reducing the number and dose of antipsychotics prescribed may decrease dopamine receptor supersensitivity and drug adverse effects5 ■ ■Demeclocyline may be used57,58 and it is included in some practice guidelines for psychogenic polydipsia.59 However, it exerts its effect by interfering with alcohol dehydrogenase and increasing water excretion, which is already at capacity in these patients. Any rationale for its use in the absence of SIADH is therefore debatable (and some cases in the literature may have been complicated by undiagnosed SIADH).60 A single small RCT showed no benefit.61 ■ ■Many other drugs have been used (naloxone, enalapril, clonidine, naltrexone, acetazolamide, captopril, propranolol, losartan, carbamazepine, fluoxetine, bupropion, trazodone, mianserin) but data are limited.62 Successful use of the carbonic anhydrase inhibitor acetazolamide has also been reported.63,64 Core part of illness in a minority of patients (e.g. psychotic polydipsia) (Continued)

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References

188 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

de Leon J, et al. Polydipsia and water intoxication in psychiatric patients: a review of the epidemiological literature. Biol Psychiatry 1994; 35:408–419.
Patel JK. Polydipsia, hyponatremia, and water intoxication among psychiatric patients. Hosp Community Psychiatry 1994; 45:1073–1074.
de Leon J. Polydipsia: a study in a long-term psychiatric unit. Eur Arch Psychiatry Clin Neurosci 2003; 253:37–39.
Siegel AJ, et al. Primary and drug-induced disorders of water homeostasis in psychiatric patients: principles of diagnosis and management. Harv Rev Psychiatry 1998; 6:190–200.
Kirino S, et al. Relationship between polydipsia and antipsychotics: a systematic review of clinical studies and case reports. Prog Neuropsychopharmacol Biol Psychiatry 2020; 96:109756.
Siegler EL, et al. Risk factors for the development of hyponatremia in psychiatric inpatients. Arch Intern Med 1995; 155:953–957.
Madhusoodanan S, et al. Hyponatraemia associated with psychotropic medications: a review of the literature and spontaneous reports. Adverse Drug React Toxicol Rev 2002; 21:17–29.
Takeda K, et al. Analysis of the frequency and onset time of hyponatremia/syndrome of inappropriate antidiuretic hormone induced by antidepressants or antipsychotics. Ann Pharmacother 2022; 56:303–308.
Bachu K, et al. Aripiprazole-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH). Am J Ther 2006; 13:370–372.
Dudeja SJ, et al. Olanzapine induced hyponatraemia. Ulster Med J 2010; 79:104–105.
Yam FK, et al. Syndrome of inappropriate antidiuretic hormone associated with aripiprazole. Am J Health Syst Pharm 2013; 70:2110–2114.
Kaur J, et al. Paliperidone inducing concomitantly syndrome of inappropriate antidiuretic hormone, neuroleptic malignant syndrome, and rhabdomyolysis. Case Rep Crit Care 2016; 2016:2587963.
Lin MW, et al. Aripiprazole-related hyponatremia and consequent valproic acid-related hyperammonemia in one patient. Aust N Z J Psychiatry 2017; 51:296–297.
Koufakis T. Quetiapine-induced syndrome of inappropriate secretion of antidiuretic hormone. Case Rep Psychiatry 2016; 2016:4803132.
Chen LC, et al. Polydipsia, hyponatremia and rhabdomyolysis in schizophrenia: a case report. World J Psychiatry 2014; 4:150–152.
Bakhla AK, et al. A suspected case of olanzapine induced hyponatremia. Indian J Pharmacol 2014; 46:441–442.
Kane JM, et al. Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: results from an international, phase III clinical trial. J Clin Psychopharmacol 2015; 35:367–373.
Tibrewal P, et al. Paliperidone-induced hyponatremia. Prim Care Companion CNS Disord 2017; 19:16l02088.
McNally MA, et al. Olanzapine-induced hyponatremia presenting with seizure requiring intensive care unit admission. Cureus 2020; 12:e8212.
Sachdeva A, et al. Hyponatremia with olanzapine: a suspected association. Shanghai Arch Psychiatry 2017; 29:177–179.
Kumar PNS, et al. Hyponatremia secondary to SIADH in a schizophrenic patient treated with Quetiapine. Asian J Psychiatr 2018; 35:89–90.
Mazhar F, et al. Paliperidone-associated hyponatremia: report of a fatal case with analysis of cases reported in the literature and to the US Food and Drug Administration Adverse Event Reporting System. J Clin Psychopharmacol 2020; 40:202–205.
Chowdhury W, et al. Management of persistent hyponatremia induced by long-acting injectable risperidone therapy. Cureus 2018; 10:e2657.
Anil SS, et al. A case report of rapid-onset hyponatremia induced by low-dose olanzapine. J Family Med Prim Care 2017; 6:878–880.
Kang SG, et al. Addendum: low-dose quetiapine-induced syndrome of inappropriate antidiuretic hormone in a patient with traumatic brain syndrome. Clin Psychopharmacol Neurosci 2021; 19:179.
Aruachán S, et al. Hyponatraemia associated with the use of quetiapine: case report. Rev Colomb Psiquiatr 2020; 49:297–300. Cause of hyponatraemia Antipsychotic drugs implicated Treatment SIADH (serum osmolality low; urine osmolality relatively high) All antipsychotic drugs ■ ■If mild, fluid restriction with careful monitoring of serum sodium. Refer urgently to specialist medical care if Na <125mmol/L. ■ ■Dose reduction of the antipsychotic has been suggested45 but evidence to support this strategy is lacking ■ ■Switching to a different antipsychotic drug. There are insufficient data available to guide choice. Be aware that cross-sensitivity may occur (the individual may be predisposed overall and the choice of drug unimportant). ■ ■Consider demeclocycline (see formal prescribing information for details) ■ ■Lithium may be effective7 but is a potentially toxic drug (and hyponatraemia predisposes to lithium toxicity) Table 1.42 (Continued )

Schizophrenia and related psychoses CHAPTER 1 27. Zhu X, et al. Rhabdomyolysis and elevated liver enzymes after rapid correction of hyponatremia due to pneumonia and concurrent use of aripiprazole: a case report. Aust N Z J Psychiatry 2018; 52:206. 28. Mc Donald D, et al. Extreme hyponatraemia due to primary polydipsia and quetiapine-induced SIAD. Endocrinol Diabetes Metab Case Rep 2021; 2021:21-0028. 29. Younes N, et al. Olanzapine induced hyponatremia and rhabdomyolysis. Clin Case Rep 2023; 11:e5951. 30. Soenarti S, et al. Chlorpromazine-induced severe hyponatremia in 66 years old patient. Acta Med Indones 2023; 55:444–448. 31. Meulendijks D, et al. Antipsychotic-induced hyponatraemia: a systematic review of the published evidence. Drug Saf 2010; 33:101–114. 32. Mannesse CK, et al. Hyponatraemia as an adverse drug reaction of antipsychotic drugs: a case-control study in VigiBase. Drug Saf 2010; 33:569–578. 33. Falhammar H, et al. Antipsychotics and severe hyponatremia: a Swedish population-based case–control study. Eur J Intern Med 2019; 60:71–77. 34. Mazhar F, et al. Hyponatremia following antipsychotic treatment: in silico pharmacodynamics analysis of spontaneous reports from the US Food and Drug Administration Adverse Event Reporting System Database and an updated systematic review. Int J Neuropsychopharmacol 2021; 24:477–489. 35. Atsariyasing W, et al. A systematic review of the ability of urine concentration to distinguish antipsychotic- from psychosis-induced hyponatremia. Psychiatry Res 2014; 217:129–133. 36. Letmaier M, et al. Hyponatraemia during psychopharmacological treatment: results of a drug surveillance programme. Int J Neuropsychopharmacol 2012; 15:739–748. 37. Serrano A, et al. Safety of long-term clozapine administration. Frequency of cardiomyopathy and hyponatraemia: two cross-sectional, naturalistic studies. Aust N Z J Psychiatry 2014; 48:183–192. 38. Sarma S, et al. Severe hyponatraemia associated with desmopressin nasal spray to treat clozapine-induced nocturnal enuresis. Aust N Z J Psychiatry 2005; 39:949. 39. Yang HJ, et al. Antipsychotic use is a risk factor for hyponatremia in patients with schizophrenia: a 15-year follow-up study. Psychopharmacology 2017; 234:869–876. 40. Adelakun AA, et al. Severe syndrome of inappropriate antidiuretic hormone secretion (SIADH) following the initiation of valbenazine for tardive dyskinesia: a case report. Cureus 2024; 16:e58493. 41. Shepshelovich D, et al. Medication-induced SIADH: distribution and characterization according to medication class. Br J Clin Pharmacol 2017; 83:1801–1807. 42. Yamamoto Y, et al. Prevalence and risk factors for hyponatremia in adult epilepsy patients: large-scale cross-sectional cohort study. Seizure 2019; 73:26–30. 43. Fabrazzo M, et al. The unmasking of hidden severe hyponatremia after long-term combination therapy in exacerbated bipolar patients: a case series. Int Clin Psychopharmacol 2019; 34:206–210. 44. Seifert J, et al. Psychotropic drug-induced hyponatremia: results from a drug surveillance program—an update. J Neural Transm (Vienna) 2021; 128:1249–1264. 45. Pinkhasov A, et al. Management of SIADH-related hyponatremia due to psychotropic medications – an expert consensus from the Association of Medicine and Psychiatry. J Psychosom Res 2021; 151:110654. 46. Josiassen RC, et al. Tolvaptan: a new tool for the effective treatment of hyponatremia in psychotic disorders. Expert Opin Pharmacother 2010; 11:637–648. 47. Decaux G, et al. Non-peptide arginine-vasopressin antagonists: the vaptans. Lancet 2008; 371:1624–1632. 48. Bhatia MS, et al. Psychogenic polydipsia – management challenges. Shanghai Arch Psychiatry 2017; 29:180–183. 49. Zaidi AN. Rhabdomyolysis after correction of hyponatremia in psychogenic polydipsia possibly complicated by ziprasidone. Ann Pharmacother 2005; 39:1726–1731. 50. Canuso CM, et al. Clozapine restores water balance in schizophrenic patients with polydipsia-hyponatremia syndrome. J Neuropsychiatry Clin Neurosci 1999; 11:86–90. 51. Fujimoto M, et al. Clozapine improved the syndrome of inappropriate antidiuretic hormone secretion in a patient with treatment-resistant schizophrenia. Psychiatry Clin Neurosci 2016; 70:469. 52. Spears NM, et al. Clozapine treatment in polydipsia and intermittent hyponatremia. J Clin Psychiatry 1996; 57:123–128. 53. Littrell KH, et al. Effects of olanzapine on polydipsia and intermittent hyponatremia. J Clin Psychiatry 1997; 58:549. 54. Kawai N, et al. Risperidone failed to improve polydipsia-hyponatremia of the schizophrenic patients. Psychiatry Clin Neurosci 2002; 56:107–110. 55. Montgomery JH, et al. Adjunctive quetiapine treatment of the polydipsia, intermittent hyponatremia, and psychosis syndrome: a case report. J Clin Psychiatry 2003; 64:339–341. 56. Canuso CM, et al. Does minimizing neuroleptic dosage influence hyponatremia? Psychiatry Res 1996; 63:227–229. 57. Nixon RA, et al. Demeclocycline in the prophylaxis of self-induced water intoxication. Am J Psychiatry 1982; 139:828–830. 58. Vieweg WV, et al. The use of demeclocycline in the treatment of patients with psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome). Psychiatr Q 1988; 59:62–68. 59. Srinivasan S, et al. Psychogenic polydipsia. 2022 (last updated April 2024, last checked May 2024); https://bestpractice.bmj.com/topics/ en-gb/865. 60. Walter-Ryan WG. Water intoxication, demeclocycline, and antidiuretic hormone. Am J Psychiatry 1983; 140:815. 61. Alexander RC, et al. A double blind, placebo-controlled trial of demeclocycline treatment of polydipsia-hyponatremia in chronically psychotic patients. Biol Psychiatry 1991; 30:417–420. 62. Havens TH, et al. Non-antipsychotic pharmacotherapy of psychogenic polydipsia: a systematic review. J Psychosom Res 2021; 152:110674. 63. Ahmed SE, et al. Acetazolamide: treatment of psychogenic polydipsia. Cureus 2017; 9:e1553. 64. Takagi S, et al. Treatment of psychogenic polydipsia with acetazolamide: a report of 5 cases. Clin Neuropharmacol 2011; 34:5–7.

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188 - Hyperprolactinaemia

Hyperprolactinaemia

190 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Hyperprolactinaemia is often superficially asymptomatic (that is, the patient does not spontaneously report problems) and there is some evidence that hyperprolactinaemia does not affect subjective quality of life.13 Nonetheless, persistent elevation of plasma prolactin is associated with suppression of the hypothalamic–pituitary–gonadal axis.14 Symptoms of this include sexual dysfunction15 (but note that other pharmacological activities also give rise to sexual dysfunction),16 menstrual disturbances,4,17 breast growth and galactorrhoea,17 and may include delusions of pregnancy.18 Long- term adverse consequences are reductions in bone mineral density19,20 and a possible increase in the risk of breast cancer.21 Prolactin can also be raised because of stress, pregnancy and lactation, seizures, renal impairment and other medical conditions,7,22,23 including prolactinoma. When measuring prolactin, the sample should be taken early in the morning and stress during venepuncture should be minimised.23 Hyperprolactinaemia Dopamine inhibits prolactin release and so dopamine antagonists can be expected to increase prolactin plasma levels. The degree of prolactin elevation is probably dose- related,1 and for most antipsychotic medications the threshold activity (D2 occupancy) for increased prolactin is very close to that of therapeutic efficacy.2 Genetic differences may also play a part.3 Table 1.43 groups individual antipsychotics according to their effect on prolactin concentrations. Table 1.43 Effects of antipsychotic medication on prolactin concentration.4–12 Effect Risk Drug Prolactin-sparing Prolactin increase very rare Aripiprazole Asenapine Brexpiprazole Cariprazine Clozapine Iloperidone Lumateperone Pimavanserin Quetiapine Xanomeline Prolactin-elevating Low risk, minor changes only Lurasidone Olanzapine Ziprasidone Prolactin-elevating High risk; major changes Amisulpride Paliperidone Risperidone Sulpiride First-generation antipsychotics

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189 - Contraindications

Contraindications

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19 - References

References

20 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

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Patel MX, et al. Quality of prescribing for schizophrenia: evidence from a national audit in England and Wales. Eur Neuropsychopharmacol 2014; 24:499–509.
Royal College of Psychiatrists. Prescribing Observatory for Mental Health. Topic 1h & 3e: Prescribing of antipsychotic medication in adult mental health services, including high dose, combined, and PRN. CCQI 422. 2022 (last accessed February 2025); https://www.rcpsych.ac.uk/ improving-care/ccqi/national-clinical-audits/pomh.
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Egerton A, et al. Dopamine and glutamate in antipsychotic-responsive compared with antipsychotic-nonresponsive psychosis: a multicenter positron emission tomography and magnetic resonance spectroscopy study (STRATA). Schizophr Bull 2021; 47:505–516.
Kapur S, et al. Relationship between dopamine D2 occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 2000; 157:514–520.
Demjaha A, et al. Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. Am J Psychiatry 2012; 169:1203–1210.
Gillespie AL, et al. Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? A systematic review. BMC Psychiatry 2017; 17:12.
Dold M, et al. Dose escalation of antipsychotic drugs in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Res 2015; 166:187–193.
Agid O, et al. An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry 2011; 72:1439–1444.
Aubree JC, et al. High and very high dosage antipsychotics: a critical review. J Clin Psychiatry 1980; 41:341–350.
Boggs DL, et al. Quetiapine at high doses for the treatment of refractory schizophrenia. Schizophr Res 2008; 101:347–348.
Meltzer HY, et al. A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia. J Clin Psychiatry 2008; 69:274–285.
Souza JS, et al. Efficacy of olanzapine in comparison with clozapine for treatment-resistant schizophrenia: evidence from a systematic review and meta-analyses. CNS Spectr 2013; 18:82–89.
Gannon L, et al. High-dose olanzapine in treatment-resistant schizophrenia: a systematic review. Ther Adv Psychopharmacol 2023; 13:20451253231168788.
Leucht S, et al. Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry 2020; 177:342–353.
Loebel A, et al. Lurasidone dose escalation in early nonresponding patients with schizophrenia: a randomized, placebo-controlled study. J Clin Psychiatry 2016; 77:1672–1680.
McAdam MK, et al. Second International Consensus Study of Antipsychotic Dosing (ICSAD-2). J Psychopharmacol 2023; 37:982–991.
Siafis S, et al. Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose-response meta-analysis. Mol Psychiatry 2023; 28:3267–3277.
Yoshida K, et al. Dose-dependent effects of antipsychotics on efficacy and adverse effects in schizophrenia. Behav Brain Res 2021; 402:113098.
Wu H, et al. Antipsychotic-induced weight gain: dose-response meta-analysis of randomized controlled trials. Schizophr Bull 2022; 48:643–654.
He L, et al. A real-world study of risk factors for QTc prolongation in schizophrenia patients receiving atypical antipsychotics. J Clin Psychopharmacol 2022; 42:71–74.
Osborn DP, et al. Relative risk of cardiovascular and cancer mortality in people with severe mental illness from the United Kingdom’s General Practice Research Database. Arch Gen Psychiatry 2007; 64:242–249.

Schizophrenia and related psychoses CHAPTER 1 36. Ray WA, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009; 360:225–235. 37. Barbui C, et al. Antipsychotic dose mediates the association between polypharmacy and corrected QT interval. PLoS One 2016; 11:e0148212. 38. Weinmann S, et al. Influence of antipsychotics on mortality in schizophrenia: systematic review. Schizophr Res 2009; 113:1–11. 39. Honer WG, et al. A randomized, double-blind, placebo-controlled study of the safety and tolerability of high-dose quetiapine in patients with persistent symptoms of schizophrenia or schizoaffective disorder. J Clin Psychiatry 2012; 73:13–20. 40. Bollini P, et al. Antipsychotic drugs: is more worse? A meta-analysis of the published randomized control trials. Psychol Med 1994; 24:307–316. 41. Baldessarini RJ, et al. Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses. Arch Gen Psychiatry 1988; 45:79–90. 42. Kawai N, et al. High-dose of multiple antipsychotics and cognitive function in schizophrenia: the effect of dose-reduction. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:1009–1014.

06 - Chapter 1 Schizophrenia and related psychoses

190 - Management

Management

06 - Chapter 1 Schizophrenia and related psychoses

191 - Summary of management

Summary of management

Schizophrenia and related psychoses CHAPTER 1 Contraindications Prolactin-elevating drugs with high risk should, if possible, be avoided in the following patient groups: ■ ■Patients under 25 years of age (i.e. before peak bone mass). ■ ■Patients with osteoporosis. ■ ■Patients with a history of hormone-dependent breast cancer. ■ ■Young women. Management Treatment of hyperprolactinaemia depends more on symptoms and long-term risk than on the reported plasma prolactin level. Below, we suggest an algorithm for managing antipsychotic-induced hyperprolactinaemia (Figure 1.5). If treatment of hyperprolactinaemia is required, switching to an antipsychotic with a lower liability for prolactin elevation is usually the first choice, although switching always carries a risk of destabilising the illness and of relapse.24 An alternative is to add aripiprazole to existing treatment.25 Aripiprazole lowers prolactin levels in a dose-dependent manner: 3mg/day is effective but 6mg/day more so. Higher doses appear unnecessary.26 Other strategies to reduce long-term risk to bone mineral density should also be discussed (e.g. stopping smoking, increasing weight-bearing exercise and ensuring adequate calcium and vitamin D3 intake).19,27 For patients who need to remain on a prolactin-elevating antipsychotic medication and who cannot tolerate aripiprazole, dopamine agonists can be effective.28–30 Amantadine, cabergoline and bromocriptine have all been used, but each has, theoretically at least, the potential to worsen psychosis (although this has not been reported in trials). High-dose vitamin B6 (600mg/day) seems to be effective in reducing antipsychotic-induced hyperprolactinaemia and is well tolerated.31 A herbal remedy – Peony–Glycyrrhiza Decoction – has also been shown to improve prolactin-related symptoms,32,33 but the data are limited. A reduction in prolactin levels was also achieved by taking high daily doses (2.5–3g) of metformin34 in a study of women with diabetes on antipsychotic medication. A 2022 network meta- analysis of all the above treatments confirmed the efficacy of aripiprazole 5mg a day and of vitamin B6 600mg/day in patients whose baseline prolactin exceeded 50ng/mL.35 Two other meta-analyses concluded that adjunctive aripiprazole was the most effective treatment.36,37 Summary of management First-choice adjunct treatment Aripiprazole 5mg/day Second-choice adjunct Vitamin B6 600mg/day Third-choice adjunct (in no particular order) DA agonists – cabergoline, bromocriptine, amantadine Peony–Glycyrrhiza Decoction Metformin 2.5–3g/day

192 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 For all patients, measure plasma prolactin level at baseline Add adjunctive aripiprazole* At 3 months:

Ask about prolactin-related symptoms
If hyperprolactinaemia suspected or patient is prescribed a prolactin-elevating antipsychotic, obtain plasma prolactin level Prolactin concentration interpretation Normal Women 0–25ng/ml (~0–530mIU/L)

Men 0–20ng/ml (~0–424mIU/L) Elevated

25–118ng/ml (530–2500mIU/L) Systematically assess prolactinrelated adverse effects

Discuss clinical consequences of

prolonged raised prolactin levels Highly elevated

118ng/ml 2500mIU/L Refer for tests to rule out prolactinoma Elevated Symptomatic Successful Not appropriate/not successful Switch not appropriate Not tolerated Unsuccessful Elevated Asymptomatic *May not normalise prolactin levels in amisulpride-induced hyperprolactinaemia.34 Discuss clinical implications of the test results with the patient and take a joint decision on whether to continue current treatment with annual monitoring or switch to another antipsychotic Switch to an antipsychotic with a lower liability for plasma prolactin elevation Consider slowly reducing dose of prolactin-raising drug and aim for aripiprazole as sole treatment Only if this strategy fails or is considered clinically inappropriate should long-term combined antipsychotics be considered Consider treatment with vitamin B6 600mg/day Consider treatment with dopamine agonists or metformin or Peony–Glycyrrhiza decoction Figure 1.5 Management of antipsychotic-induced hyperprolactinaemia.38

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192 - References

References

Schizophrenia and related psychoses CHAPTER 1 References

Suzuki Y, et al. Differences in plasma prolactin levels in patients with schizophrenia treated on monotherapy with five second-generation antipsychotics. Schizophr Res 2013; 145:116–119.
Tsuboi T, et al. Hyperprolactinemia and estimated dopamine D2 receptor occupancy in patients with schizophrenia: analysis of the CATIE data. Prog Neuropsychopharmacol Biol Psychiatry 2013; 45:178–182.
Young RM, et al. Prolactin levels in antipsychotic treatment of patients with schizophrenia carrying the DRD2*A1 allele. Br J Psychiatry 2004; 185:147–151.
Haddad PM, et al. Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs 2004; 64:2291–2314.
Holt RI, et al. Antipsychotics and hyperprolactinaemia: mechanisms, consequences and management. Clin Endocrinol (Oxf) 2011; 74:141–147.
Leucht S, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382:951–962.
Peuskens J, et al. The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review. CNS Drugs 2014; 28:421–453.
Citrome L. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol 2013; 9:193–206.
Marder SR, et al. Brexpiprazole in patients with schizophrenia: overview of short- and long-term phase 3 controlled studies. Acta Neuropsychiatr 2017; 29:278–290.
Vanover KE, et al. Dopamine D(2) receptor occupancy of lumateperone (ITI-007): a positron emission tomography study in patients with schizophrenia. Neuropsychopharmacology 2019; 44:598–605.
Yunusa I, et al. Pimavanserin: a novel antipsychotic with potentials to address an unmet need of older adults with dementia-related psychosis. Front Pharmacol 2020; 11:87.
Correll CU, et al. Safety and tolerability of KarXT (xanomeline-trospium) in a phase 2, randomized, double-blind, placebo-controlled study in patients with schizophrenia. Schizophrenia (Heidelb) 2022; 8:109.
Kaneda Y. The impact of prolactin elevation with antipsychotic medications on subjective quality of life in patients with schizophrenia. Clin Neuropharmacol 2003; 26:182–184.
Smith S, et al. The effects of antipsychotic-induced hyperprolactinaemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002; 22:109–114.
De Hert M, et al. Second-generation and newly approved antipsychotics, serum prolactin levels and sexual dysfunctions: a critical literature review. Expert Opin Drug Saf 2014; 13:605–624.
Baldwin D, et al. Sexual side-effects of antidepressant and antipsychotic drugs. Adv Psychiatr Treat 2003; 9:202–210.
Wieck A, et al. Antipsychotic-induced hyperprolactinaemia in women: pathophysiology, severity and consequences. Selective literature review. Br J Psychiatry 2003; 182:199–204.
Ali JA, et al. Delusions of pregnancy associated with increased prolactin concentrations produced by antipsychotic treatment. Int J Neuropsychopharmacol 2003; 6:111–115.
De Hert M, et al. Relationship between antipsychotic medication, serum prolactin levels and osteoporosis/osteoporotic fractures in patients with schizophrenia: a critical literature review. Expert Opin Drug Saf 2016; 15:809–823.
Tseng PT, et al. Bone mineral density in schizophrenia: an update of current meta-analysis and literature review under guideline of PRISMA. Medicine (Baltimore) 2015; 94:e1967.
De Hert M, et al. Relationship between prolactin, breast cancer risk, and antipsychotics in patients with schizophrenia: a critical review. Acta Psychiatr Scand 2016; 133:5–22.
Holt RI. Medical causes and consequences of hyperprolactinaemia: a context for psychiatrists. J Psychopharmacol 2008; 22:28–37.
Melmed S, et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96:273–288.
Montejo AL, et al. Multidisciplinary consensus on the therapeutic recommendations for iatrogenic hyperprolactinemia secondary to antipsychotics. Front Neuroendocrinol 2017; 45:25–34.
Sá Esteves P, et al. Low doses of adjunctive aripiprazole as treatment for antipsychotic-induced hyperprolactinemia: a literature review. Eur Psychiatry 2015; 30 Suppl 1:393.
Yasui-Furukori N, et al. Dose-dependent effects of adjunctive treatment with aripiprazole on hyperprolactinemia induced by risperidone in female patients with schizophrenia. J Clin Psychopharmacol 2010; 30:596–599.
Meaney AM, et al. Bone mineral density changes over a year in young females with schizophrenia: relationship to medication and endocrine variables. Schizophr Res 2007; 93:136–143.
Hamner MB, et al. Hyperprolactinaemia in antipsychotic-treated patients: guidelines for avoidance and management. CNS Drugs 1998; 10:209–222.
Duncan D, et al. Treatment of psychotropic-induced hyperprolactinaemia. Psychiatr Bull 1995; 19:755–757.
Cavallaro R, et al. Cabergoline treatment of risperidone-induced hyperprolactinemia: a pilot study. J Clin Psychiatry 2004; 65:187–190.
Zhuo C, et al. Safety and efficacy of high-dose vitamin B6 as an adjunctive treatment for antipsychotic-induced hyperprolactinemia in male patients with treatment-resistant schizophrenia. Front Psychiatry 2021; 12:681418.
Yuan HN, et al. A randomized, crossover comparison of herbal medicine and bromocriptine against risperidone-induced hyperprolactinemia in patients with schizophrenia. J Clin Psychopharmacol 2008; 28:264–370.

194 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 33. Man SC, et al. Peony–glycyrrhiza decoction for antipsychotic-related hyperprolactinemia in women with schizophrenia: a randomized controlled trial. J Clin Psychopharmacol 2016; 36:572–579. 34. Krysiak R, et al. The effect of metformin on prolactin levels in patients with drug-induced hyperprolactinemia. Eur J Intern Med 2016; 30:94–98. 35. Lu Z, et al. Pharmacological treatment strategies for antipsychotic-induced hyperprolactinemia: a systematic review and network meta- analysis. Transl Psychiatry 2022; 12:267. 36. Zhang L, et al. Efficacy and safety of adjunctive aripiprazole, metformin, and paeoniae-glycyrrhiza decoction for antipsychotic-induced hyperprolactinemia: a network meta-analysis of randomized controlled trials. Front Psychiatry 2021; 12:728204. 37. Jiang Q, et al. Treatment of antipsychotic-induced hyperprolactinemia: an umbrella review of systematic reviews and meta-analyses. Front Psychiatry 2024; 15:1337274. 38. Walters J, et al. Clinical questions and uncertainty: prolactin measurement in patients with schizophrenia and bipolar disorder. J Psychopharmacol 2008; 22:82–89. 39. Chen CK, et al. Differential add-on effects of aripiprazole in resolving hyperprolactinemia induced by risperidone in comparison to benzamide antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:1495–1499.

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193 - Sexual dysfunction and antipsychotics

Sexual dysfunction and antipsychotics

06 - Chapter 1 Schizophrenia and related psychoses

194 - The human sexual response

The human sexual response

06 - Chapter 1 Schizophrenia and related psychoses

195 - Effects of psychosis

Effects of psychosis

Schizophrenia and related psychoses CHAPTER 1 Sexual dysfunction and antipsychotics A 2023 meta-analysis found the global prevalence of sexual dysfunction in people with schizophrenia to be 56% in men and 60% in women.1 Problems are not always reported by patients. In one study of patients with psychosis, 37% spontaneously reported sexual problems but 46% were found to be experiencing difficulties when directly questioned.2 Baseline sexual functioning should be determined if possible (questionnaires may be useful) because sexual function can affect both quality of life3 and compliance with medication (sexual dysfunction is one of the major causes of treatment dropout).4,5 Complaints of sexual dysfunction may also indicate progression or inadequate treatment of underlying medical or psychiatric conditions.6,7 Sexual problems may also be caused by drug treatment and are associated with early discontinuation of antipsychotics.8 Intervention may greatly improve quality of life.9 The human sexual response There are four phases of the human sexual response, as detailed in Table 1.44.10–12 Effects of psychosis Sexual dysfunction is a well-established phenomenon in first-episode schizophrenia.13,14 Up to 82% of men and 96% of women report problems, with associated reductions in quality of life.3 Antipsychotic adverse effects are not solely responsible, because prevalence is also high (17–70%) in patients who are unmedicated.15 Men complain of reduced desire,16 inability to achieve an erection and premature ejaculation,1 whereas women complain of lowered libido and orgasm dysfunction.1 Women with psychosis also have reduced fertility.17 Table 1.44 The human sexual response. Desire ■ ■Related to testosterone levels in men ■ ■Possibly increased by dopamine and decreased by prolactin ■ ■Psychosocial context and conditioning significantly affect desire Arousal ■ ■Influenced by testosterone in men and oestrogen in women ■ ■Other potential mechanisms include central dopamine stimulation, modulation of the cholinergic/adrenergic balance, peripheral α1 agonism and nitric oxide pathways ■ ■Physical pathology such as hypertension or diabetes can have a significant effect Orgasm ■ ■May be related to oxytocin ■ ■Inhibition of orgasm may be caused by an increase in serotonin activity and raised prolactin, as well as α1 blockade Resolution ■ ■Occurs passively after orgasm Note: Many other hormones and neurotransmitters may interact in a complex way at each phase.

06 - Chapter 1 Schizophrenia and related psychoses

196 - Effects of antipsychotic drugs

Effects of antipsychotic drugs

196 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 People with psychosis are less able to develop good psychosexual relationships and, for some, treatment with an antipsychotic can improve sexual functioning via an improvement in psychotic symptoms.18 Assessment of sexual functioning can clearly be difficult in someone who is psychotic. The Arizona Sexual Experience Scale may be useful in this respect.19 Effects of antipsychotic drugs Sexual dysfunction is an adverse effect of most antipsychotics. Individual susceptibility varies and effects are usually reversible. Psychosis, physical illness and drugs other than antipsychotics can also contribute to sexual dysfunction. Many studies do not control for these factors, making the prevalence of sexual dysfunction with different antipsychotics difficult to compare.20 Antipsychotics decrease dopaminergic transmission, which in itself can decrease libido but may also increase prolactin levels via negative feedback. Hyperprolactinaemia is a key factor in sexual dysfunction21,22 but may only explain 40% of the sexual dysfunction that is associated with antipsychotic medication.23 Hyperprolactinaemia can also cause amenorrhoea and infertility24 in women, and breast enlargement and galactorrhoea in both men and women.25 The overall propensity of an antipsychotic to cause sexual dysfunction is a function of the facility to raise prolactin (i.e. risperidone > haloperidol > olanzapine > quetiapine > aripiprazole).6,20,26 Aripiprazole is relatively free of sexual adverse effects when used as monotherapy27 and may improve symptoms in combination with another antipsychotic.28,29 The same is probably true for brexpiprazole, and cariprazine is a theoretically appropriate alternative.30 Anticholinergic effects of drugs can cause disorders of arousal31 and concomitant anticholinergics may thus contribute to sexual dysfunction.32 Drugs that block peripheral α1 receptors cause particular problems with erection and ejaculation in men.9 Antipsychotic- induced sedation and weight gain may reduce sexual desire.33 Table 1.45 gives details of the nature and frequency of sexual adverse effects caused by antipsychotics. Table 1.45 Sexual adverse effects of antipsychotics. Drug Type of problem Aripiprazole ■ ■No effect on prolactin or α1 receptors. No reported adverse effects on sexual function. Improves sexual function in those switched from other antipsychotics27,29,34–36 and when added as an adjunct.37 Case reports of aripiprazole-induced hypersexuality have been published.38,39 Asenapine ■ ■Does not appear to significantly affect prolactin levels40 ■ ■No reported cases of sexual dysfunction Brexpiprazole ■ ■Similar mechanism of action to aripiprazole (5-HT1A agonist, 5-HT2A antagonist and partial D2 agonist) ■ ■Causes negligible increases in prolactin41 ■ ■No problems with sexual dysfunction reported in clinical trials42 (Continued)

Schizophrenia and related psychoses CHAPTER 1 Table 1.45 (Continued) Drug Type of problem Cariprazine ■ ■Similar mechanism of action to aripiprazole (5-HT1A agonist, 5-HT2A antagonist and partial D2 agonist) ■ ■Not associated with hyperprolactinaemia43 ■ ■Very low rates of sexual dysfunction reported in clinical trials44 Clozapine ■ ■Significant α1 adrenergic blockade and anticholinergic effects.45 No effect on prolactin.46 ■ ■Probably fewer problems than with typical antipsychotics47 Haloperidol ■ ■Similar problems to phenothiazines48 but anticholinergic effects reduced49 ■ ■Prevalence of sexual dysfunction up to 70%50 Lurasidone ■ ■Does not appear to affect prolactin levels51 ■ ■No reported cases of sexual dysfunction52 Olanzapine ■ ■Possibly less sexual dysfunction than drugs such as haloperidol owing to relative lack of prolactin-related effects48 ■ ■Priapism reported rarely53,54 ■ ■Prevalence of sexual dysfunction >50%50 Paliperidone ■ ■Similar prolactin elevations to risperidone ■ ■One small study55 and one case report56 showing reduction in sexual dysfunction following switching to paliperidone depot from risperidone oral or depot Phenothiazines (e.g. chlorpromazine) ■ ■Hyperprolactinaemia and anticholinergic effects. May cause delayed orgasm at lower doses followed by normal orgasm but without ejaculation at higher doses.57 ■ ■Priapism has been reported with thioridazine and chlorpromazine (probably due to α1 blockade)49,58,59 Quetiapine ■ ■No effect on prolactin60 ■ ■Possibly associated with low risk of sexual dysfunction,61–64 but studies are conflicting65,66 Risperidone ■ ■Potent elevator of serum prolactin ■ ■Less anticholinergic than some other antipsychotics (olanzapine, quetiapine) ■ ■Specific peripheral α1 adrenergic blockade leads to a moderately high reported incidence of ejaculatory problems such as retrograde ejaculation67,68 ■ ■Priapism reported rarely33 ■ ■Prevalence of sexual dysfunction 60–70%50 Sulpiride/amisulpride ■ ■Potent elevators of serum prolactin69 but note that sulpiride was not associated with greater sexual dysfunction than SGAs in CUtLASS-118 Thioxanthenes (e.g. flupentixol) ■ ■Arousal problems and anorgasmia70 Lumateperone ■ ■Does not appear to affect prolactin71 ■ ■No sexual adverse effects reported in clinical trials72 Pimavanserin ■ ■Does not bind to dopamine receptors,73 so has no effect on prolactin ■ ■May improve sexual function in patients with depression74 Iloperidone ■ ■Does not usually affect prolactin75 ■ ■Some reports of sexual dysfunction in adverse event reporting databases,76 case reports of retrograde ejaculation77 CUtLASS-1, Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study; SGA, second-generation antipsychotic.

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197 - Treatment of sexual dysfunction

Treatment of sexual dysfunction

198 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Treatment of sexual dysfunction Before attempting to treat sexual dysfunction, a thorough assessment is essential to determine the most likely cause. A large meta-analysis of 72 studies from 33 different countries found that for patients with schizophrenia spectrum disorders, concurrent antidepressant and mood stabiliser prescriptions were associated with lower rates of erection and ejaculation disorders.1 This suggests that treating a comorbid depression or mood disorder is an important strategy to improve sexual health. Assuming that psychiatric comorbidity or physical pathology (diabetes, hypertension, cardiovascular disease, etc.) has been excluded or treated (e.g. obesity),78 the following principles apply when considering the prescribing of antipsychotics: ■ ■Spontaneous remission may occasionally occur33 but may take 6 months to become apparent, if at all,30 and may be more likely related to a reduction in severity of illness, rather than tolerance to the antipsychotic itself. ■ ■When symptoms persist, the most obvious first step is to decrease the dose (although a correlation between dose and all types of sexual dysfunction has not been conclusively demonstrated)79 or discontinue the offending drug, where appropriate. ■ ■The next step is to switch to a different drug that is less likely to cause the specific sexual problem experienced (Table 1.46). Another option is to add 5–10mg aripiprazole – this can normalise prolactin and improve sexual function.37,80 ■ ■If this fails or is not practicable, ‘antidote’ drugs can be tried: for example, cyproheptadine (a 5HT2 antagonist at doses of 4–16mg/day) has been used to treat SSRI- induced sexual dysfunction but sedation is a common adverse effect. There is some evidence that mirtazapine (also a 5HT2 antagonist as well as an α2 antagonist) may relieve orgasmic dysfunction in patients treated with FGAs.81 Amantadine, bupropion, buspirone, bethanechol and yohimbine have all been used with varying degrees of success but have several adverse effects and interactions with other drugs. Given that hyperprolactinaemia contributes to sexual dysfunction, selegiline, which enhances dopamine activity, has been investigated but was not effective.82 Testosterone patches have been shown to increase libido in women, although breast cancer risk may be significantly increased.83,84 Table 1.46 lists remedial treatments for psychotropic-induced sexual dysfunction.

Schizophrenia and related psychoses CHAPTER 1 Table 1.46 Remedial treatments for psychotropic-induced sexual dysfunction. Drug Pharmacology Potential treatment for Adverse effects Alprostadil12,85 Prostaglandin Erectile dysfunction Pain, fibrosis, hypotension, priapism Amantadine85,86,87 Dopamine agonist Prolactin-induced reduction in desire and arousal (dopamine increases libido and facilitates ejaculation) Return of psychotic symptoms, GI effects, nervousness, insomnia, rash Bethanechol88 Cholinergic or cholinergic potentiation of adrenergic neurotransmission Anticholinergic-induced arousal problems and anorgasmia (from TCAs, antipsychotics, etc.) Nausea and vomiting, colic, bradycardia, blurred vision, sweating Bromocriptine9 Dopamine agonist Prolactin-induced reduction in desire and arousal Return of psychotic symptoms, GI effects Bupropion89,90 Noradrenaline and dopamine reuptake inhibitor SSRI-induced sexual dysfunction Concentration problems, reduced sleep, tremor Buspirone91 5HT1a partial agonist SSRI-induced sexual dysfunction, particularly decreased libido and anorgasmia Nausea, dizziness, headache Cyproheptadine85,91,92 5HT2 antagonist Sexual dysfunction caused by increased serotonin transmission (e.g. SSRIs), particularly anorgasmia Sedation and fatigue. Reversal of the therapeutic effect of antidepressants. Flibanserin (licensed in USA)93 5HT1A agonist, 5HT2A antagonist, dopamine antagonist Lack or loss of sexual desire in premenopausal women. Appears to be safe in women taking antidepressants.94 Hypotension, syncope, sedation, dizziness, nausea, dry mouth Sildenafil,12,95–98 tadalafil,99 lodenafil,100 vardenafil101 Phosphodiesterase inhibitors Erectile dysfunction of any aetiology. Anorgasmia in women. Effective even when prolactin raised. Mild headaches, dizziness, nasal congestion Yohimbine12,85,102–104 Central and peripheral α2 adrenoceptor antagonist SSRI-induced sexual dysfunction, particularly erectile dysfunction, decreased libido and anorgasmia Anxiety, nausea, fine tremor, increased blood pressure, sweating, fatigue Pimavanserin74 Inverse agonist at 5HT2A and 5HT2C Sexual dysfunction in depression with inadequate response to antidepressants. Improvement in sexual function independent of effect on depression unconfirmed. Peripheral oedema, nausea, confusion Bremelanotide105 Melanocortin receptor agonist Hypoactive sexual desire in premenopausal women. No published data on use in patients with psychiatric diagnoses. Flushing, nausea, headache Note: The use of the drugs listed above should ideally be under the care or supervision of a specialist in sexual dysfunction. GI, gastrointestinal; TCA, tricyclic antidepressant.

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198 - References

References

200 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 The evidence base supporting the use of ‘antidotes’ is often poor and specific to particular drug-induced problems.33,106 The generalisability of results from positive trials is limited by small sample sizes, short trial durations and lack of controlling for confounding factors (age, concurrent medication, antipsychotic switches for reasons other than baseline sexual dysfunction).106 Comparison of data between studies is further complicated by the use of varying assessment tools to measure outcomes.107 Drugs such as sildenafil (Viagra) or alprostadil (Caverject) are effective only in the treatment of erectile dysfunction (they have no effect on libido or central arousal). Psychological approaches used by sexual dysfunction clinics may be difficult for clients with mental health problems to engage in.9 References

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Zhang Y, et al. Prolactin and thyroid stimulating hormone (TSH) levels and sexual dysfunction in patients with schizophrenia treated with conventional antipsychotic medication: a cross-sectional study. Med Sci Monit 2018; 24:9136–9143.
Martínez-Giner G, et al. Sexual dysfunction in people treated with long-acting injectable antipsychotics in monotherapy or polypharmacy: a naturalistic study. Int J Ment Health Nurs 2022; 31:576–590.
Nunes LV, et al. Strategies for the treatment of antipsychotic-induced sexual dysfunction and/or hyperprolactinemia among patients of the schizophrenia spectrum: a review. J Sex Marital Ther 2012; 38:281–301.
Edinoff AN, et al. Hyperprolactinemia, clinical considerations, and infertility in women on antipsychotic medications. Psychopharmacol Bull 2021; 51:131–148.
Adverse effects of the atypical antipsychotics. Collaborative Working Group on Clinical Trial Evaluations. J Clin Psychiatry 1998; 59 Suppl 12:17–22.
Knegtering H, et al. Are sexual side effects of prolactin-raising antipsychotics reducible to serum prolactin? Psychoneuroendocrinology 2008; 33:711–717.
Hanssens L, et al. The effect of antipsychotic medication on sexual function and serum prolactin levels in community-treated schizophrenic patients: results from the Schizophrenia Trial of Aripiprazole (STAR) study (NCT00237913). BMC Psychiatry 2008; 8:95.
Mir A, et al. Change in sexual dysfunction with aripiprazole: a switching or add-on study. J Psychopharm 2008; 22:244–253.

Schizophrenia and related psychoses CHAPTER 1 29. Byerly MJ, et al. Effects of aripiprazole on prolactin levels in subjects with schizophrenia during cross-titration with risperidone or olanzapine: analysis of a randomized, open-label study. Schizophr Res 2009; 107:218–222. 30. Montejo AL, et al. Management strategies for antipsychotic-related sexual dysfunction: a clinical approach. J Clin Med 2021; 10:308. 31. Aldridge SA. Drug-induced sexual dysfunction. Clin Pharm 1982; 1:141–147. 32. Fond G, et al. Sexual dysfunctions are associated with major depression, chronic inflammation and anticholinergic consumption in the real- world schizophrenia FACE-SZ national cohort. Prog Neuropsychopharmacol Biol Psychiatry 2019; 94:109654. 33. Baldwin D, et al. Sexual side-effects of antidepressant and antipsychotic drugs. Adv Psychiatr Treat 2003; 9:202–210. 34. Rykmans V, et al. P0106: A comparision of switching strategies from risperidone to aripiprazole in patients with schizophrenia with insufficient efficacy/tolerability on risperidone (cn138-169). Eur Psychiatry 2008; 23 Suppl 2:S111. 35. Potkin SG, et al. Reduced sexual dysfunction with aripiprazole once-monthly versus paliperidone palmitate: results from QUALIFY. Int Clin Psychopharmacol 2017; 32:147–154. 36. Kelly DL, et al. Analysis of prolactin and sexual side effects in patients with schizophrenia who switched from paliperidone palmitate to aripiprazole lauroxil. Psychiatry Res 2021; 302:114030. 37. Kelly DL, et al. Adjunct aripiprazole reduces prolactin and prolactin-related adverse effects in premenopausal women with psychosis: results from the DAAMSEL clinical trial. J Clin Psychopharmacol 2018; 38:317–326. 38. Chen CY, et al. Improvement of serum prolactin and sexual function after switching to aripiprazole from risperidone in schizophrenia: a case series. Psychiatry Clin Neurosci 2011; 65:95–97. 39. Vrignaud L, et al. [Hypersexuality associated with aripiprazole: a new case and review of the literature]. Therapie 2014; 69:525–527. 40. Ajmal A, et al. Psychotropic-induced hyperprolactinemia: a clinical review. Psychosomatics 2014; 55:29–36. 41. Kane JM, et al. A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophr Res 2015; 164:127–135. 42. Citrome L. Brexpiprazole for schizophrenia and as adjunct for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antipsychotic – what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract 2015; 69:978–997. 43. Nasrallah HA, et al. The safety and tolerability of cariprazine in long-term treatment of schizophrenia: a post hoc pooled analysis. BMC Psychiatry 2017; 17:305. 44. Barabássy Á, et al. Safety and tolerability of cariprazine in patients with schizophrenia: a pooled analysis of eight phase II/III studies. Neuropsychiatr Dis Treat 2021; 17:957–970. 45. Coward DM. General pharmacology of clozapine. Br J Psychiatry Suppl 1992; 160:5–11. 46. Meltzer HY, et al. Effect of clozapine on human serum prolactin levels. Am J Psychiatry 1979; 136:1550–1555. 47. Aizenberg D, et al. Comparison of sexual dysfunction in male schizophrenic patients maintained on treatment with classical antipsychotics versus clozapine. J Clin Psychiatry 2001; 62:541–544. 48. Crawford AM, et al. The acute and long-term effect of olanzapine compared with placebo and haloperidol on serum prolactin concentrations. Schizophr Res 1997; 26:41–54. 49. Mitchell JE, et al. Antipsychotic drug therapy and sexual dysfunction in men. Am J Psychiatry 1982; 139:633–637. 50. Serretti A, et al. Sexual side effects of pharmacological treatment of psychiatric diseases. Clin Pharmacol Ther 2011; 89:142–147. 51. Citrome L, et al. Long-term safety and tolerability of lurasidone in schizophrenia: a 12-month, double-blind, active-controlled study. Int Clin Psychopharmacol 2012; 27:165–176. 52. Clayton AH, et al. Safety of flibanserin in women treated with antidepressants: a randomized, placebo-controlled study. J Sex Med 2018; 15:43–51. 53. Dossenbach M, et al. Effects of atypical and typical antipsychotic treatments on sexual function in patients with schizophrenia: 12-month results from the Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study. Eur Psychiatry 2006; 21:251–258. 54. Aurobindo Pharma - Milpharm Ltd. Summary of Product Characteristics. Olanzapine 10 mg tablets 2023 (last checked May 2024); http://www.medicines.org.uk/emc/medicine/27661/SPC/Olanzapine++10+mg+tablets/. 55. Montalvo I, et al. Changes in prolactin levels and sexual function in young psychotic patients after switching from long-acting injectable risperidone to paliperidone palmitate. Int Clin Psychopharmacol 2013; 28:46–49. 56. Shiloh R, et al. Risperidone-induced retrograde ejaculation. Am J Psychiatry 2001; 158:650. 57. Smith S. Effects of antipsychotics on sexual and endocrine function in women: implications for clinical practice. J Clin Psychopharmacol 2003; 23(3 Suppl 1):S27–S32. 58. Loh C, et al. Risperidone-induced retrograde ejaculation: case report and review of the literature. Int Clin Psychopharmacol 2004; 19:111–112. 59. Thompson JW, Jr., et al. Psychotropic medication and priapism: a comprehensive review. J Clin Psychiatry 1990; 51:430–433. 60. Peuskens J, et al. A comparison of quetiapine and chlorpromazine in the treatment of schizophrenia. Acta Psychiatr Scand 1997; 96:265–273. 61. Bobes J, et al. Frequency of sexual dysfunction and other reproductive side-effects in patients with schizophrenia treated with risperidone, olanzapine, quetiapine, or haloperidol: the results of the EIRE study. J Sex Marital Ther 2003; 29:125–147. 62. Byerly MJ, et al. An open-label trial of quetiapine for antipsychotic-induced sexual dysfunction. J Sex Marital Ther 2004; 30:325–332. 63. Knegtering R, et al. A randomized open-label study of the impact of quetiapine versus risperidone on sexual functioning. J Clin Psychopharmacol 2004; 24:56–61. 64. Montejo Gonzalez AL, et al. A 6-month prospective observational study on the effects of quetiapine on sexual functioning. J Clin Psychopharmacol 2005; 25:533–538. 65. Atmaca M, et al. A new atypical antipsychotic: quetiapine-induced sexual dysfunctions. Int J Impot Res 2005; 17:201–203.

202 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 66. Kelly DL, et al. A randomized double-blind 12-week study of quetiapine, risperidone or fluphenazine on sexual functioning in people with schizophrenia. Psychoneuroendocrinology 2006; 31:340–346. 67. Tran PV, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997; 17:407–418. 68. Raja M. Risperidone-induced absence of ejaculation. Int Clin Psychopharmacol 1999; 14:317–319. 69. Smith SM, et al. Sexual dysfunction in patients taking conventional antipsychotic medication. Br J Psychiatry 2002; 181:49–55. 70. Aizenberg D, et al. Sexual dysfunction in male schizophrenic patients. J Clin Psychiatry 1995; 56:137–141. 71. Correll CU, et al. Safety and tolerability of lumateperone 42 mg: an open-label antipsychotic switch study in outpatients with stable schizophrenia. Schizophr Res 2021; 228:198–205. 72. Correll CU, et al. Efficacy and safety of lumateperone for treatment of schizophrenia: a randomized clinical trial. JAMA Psychiatry 2020; 77:349–358. 73. Cruz MP. Pimavanserin (Nuplazid): a treatment for hallucinations and delusions associated with Parkinson’s disease. P T 2017; 42:368–371. 74. Freeman MP, et al. Improvement of sexual functioning during treatment of MDD with adjunctive pimavanserin: a secondary analysis. Depress Anxiety 2020; 37:485–495. 75. Peuskens J, et al. The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review. CNS Drugs 2014; 28:421–453. 76. Subeesh V, et al. Novel adverse events of iloperidone: a disproportionality analysis in US Food and Drug Administration Adverse Event Reporting System (FAERS) Database. Curr Drug Saf 2019; 14:21–26. 77. Freeman SA. Iloperidone-induced retrograde ejaculation. Int Clin Psychopharmacol 2013; 28:156. 78. Theleritis C, et al. Sexual dysfunction and central obesity in patients with first episode psychosis. Eur Psychiatry 2017; 42:1–7. 79. Yoshida K, et al. Dose-dependent effects of antipsychotics on efficacy and adverse effects in schizophrenia. Behav Brain Res 2021; 402:113098. 80. Besag FMC, et al. Is adjunct aripiprazole effective in treating hyperprolactinemia induced by psychotropic medication? A narrative review. CNS Drugs 2021; 35:507–526. 81. Terevnikov V, et al. Add-on mirtazapine improves orgasmic functioning in patients with schizophrenia treated with first-generation anti psychotics. Nord J Psychiatry 2017; 71:77–80. 82. Kodesh A, et al. Selegiline in the treatment of sexual dysfunction in schizophrenic patients maintained on neuroleptics: a pilot study. Clin Neuropharmacol 2003; 26:193–195. 83. Davis SR, et al. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med 2008; 359:2005–2017. 84. Schover LR. Androgen therapy for loss of desire in women: is the benefit worth the breast cancer risk? Fertil Steril 2008; 90:129–140. 85. Baldwin DS, et al. Effects of antidepressant drugs on sexual function. Int J Psychiatry Clin Pract 1997; 1:47–58. 86. Krzystanek M, et al. Amantadine in the treatment of sexual inactivity in schizophrenia patients taking atypical antipsychotics: the pilot case series study. Pharmaceuticals (Basel) 2021; 14:947. 87. Valevski A, et al. Effect of amantadine on sexual dysfunction in neuroleptic-treated male schizophrenic patients. Clin Neuropharmacol 1998; 21:355–357. 88. Gross MD. Reversal by bethanechol of sexual dysfunction caused by anticholinergic antidepressants. Am J Psychiatry 1982; 139:1193–1194. 89. Masand PS, et al. Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double- blind, placebo-controlled, parallel-group study. Am J Psychiatry 2001; 158:805–807. 90. Rezaei O, et al. The effect of bupropion on sexual function in patients with Schizophrenia: a randomized clinical trial. Eur J Psychiatry 2017; 32:11–15. 91. Rothschild AJ. Sexual side effects of antidepressants. J Clin Psychiatry 2000; 61 Suppl 11:28–36. 92. Lauerma H. Successful treatment of citalopram-induced anorgasmia by cyproheptadine. Acta Psychiatr Scand 1996; 93:69–70. 93. IBM Watson Health. IBM Micromedex Solutions. 2024; https://www.ibm.com/watson-health/about/micromedex. 94. Clayton AH, et al. Effect of lurasidone on sexual function in major depressive disorder patients with subthreshold hypomanic symptoms (mixed features): results from a placebo-controlled trial. J Clin Psychiatry 2018; 79:18m12132. 95. Nurnberg HG, et al. Sildenafil for women patients with antidepressant-induced sexual dysfunction. Psychiatr Serv 1999; 50:1076–1078. 96. Salerian AJ, et al. Sildenafil for psychotropic-induced sexual dysfunction in 31 women and 61 men. J Sex Marital Ther 2000; 26:133–140. 97. Gopalakrishnan R, et al. Sildenafil in the treatment of antipsychotic-induced erectile dysfunction: a randomized, double-blind, placebo- controlled, flexible-dose, two-way crossover trial. Am J Psychiatry 2006; 163:494–499. 98. Mazzilli R, et al. Erectile dysfunction in patients taking psychotropic drugs and treated with phosphodiesterase-5 inhibitors. Arch Ital Urol Androl 2018; 90:44–48. 99. de Boer MK, et al. Efficacy of tadalafil on erectile dysfunction in male patients using antipsychotics: a double-blind, placebo-controlled, crossover pilot study. J Clin Psychopharmacol 2014; 34:380–382. 100. Nunes LV, et al. Adjunctive treatment with lodenafil carbonate for erectile dysfunction in outpatients with schizophrenia and spectrum: a randomized, double-blind, crossover, placebo-controlled trial. J Sex Med 2013; 10:1136–1145. 101. Mitsonis CI, et al. Vardenafil in the treatment of erectile dysfunction in outpatients with chronic schizophrenia: a flexible-dose, open-label study. J Clin Psychiatry 2008; 69:206–212. 102. Jacobsen FM. Fluoxetine-induced sexual dysfunction and an open trial of yohimbine. J Clin Psychiatry 1992; 53:119–122.

Schizophrenia and related psychoses CHAPTER 1 103. Michelson D, et al. Mirtazapine, yohimbine or olanzapine augmentation therapy for serotonin reuptake-associated female sexual dysfunction: a randomized, placebo controlled trial. J Psychiatr Res 2002; 36:147–152. 104. Woodrum ST, et al. Management of SSRI-induced sexual dysfunction. Ann Pharmacother 1998; 32:1209–1215. 105. Kingsberg SA, et al. Bremelanotide for the treatment of hypoactive sexual desire disorder: two randomized phase 3 trials. Obstet Gynecol 2019; 134:899–908. 106. Allen K, et al. Management of antipsychotic-related sexual dysfunction: systematic review. J Sex Med 2019; 16:1978–1987. 107. Basson R, et al. Women’s sexual dysfunction associated with psychiatric disorders and their treatment. Womens Health 2018; 14:1745506518762664.

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Pneumonia

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20 - Combined antipsychotics (antipsychotic polyph

Combined antipsychotics (antipsychotic polypharmacy)

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Background

204 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Pneumonia Background A 2018 meta-analysis of 14 observational studies (n = 206,899) reported that antipsychotic use was associated with a near doubling of pneumonia incidence compared with no use.1 This same analysis found no difference in incidence of pneumonia between FGAs and SGAs and no increase in fatality rate. A later analysis of spontaneous reporting to the US FDA uncovered relatively greater incidence of pneumonia in people prescribed clozapine, olanzapine and antipsychotic polypharmacy (compared with haloperidol).2 In 2024, a 20-year observational study (n = 61,889) in Finland found increased risk of hospitalisation with pneumonia in people prescribed antipsychotic monotherapy compared with no antipsychotic use.3 There is some dispute over the causal association between antipsychotic use and risk of pneumonia. One study looked at the incidence of pneumonia in over 8,000 people before and after starting various antipsychotics and found no change overall (or for any individual antipsychotic).4 Another analysis, a case–control study, found that duration of antipsychotic use was just one of three factors linked to increased risk of pneumonia (the others being severity of illness and comorbidity index).5 Schizophrenia itself seems to afford a higher risk of complications (e.g. admission to intensive care) in people diagnosed with pneumonia,6 although neither diagnosis nor age appears to modify the effect of antipsychotic use on pneumonia.7 Risk of antipsychotic-associated pneumonia is increased in patients with Alzheimer’s disease and those without.8 Factors associated with antipsychotic-induced pneumonia are listed in Table 1.47. The risk of pneumonia seems to be most pronounced in people prescribed antipsychotics with high anticholinergic effects (notably clozapine and high-dose olanzapine or quetiapine) and is probably dose dependent.3,9 Among antipsychotics, clozapine is most often associated with pneumonia, with an estimated incidence of up to 30%16 (although TRS itself increases risk of pneumonia by two-thirds).18 In two studies, clozapine re-exposure was associated with a greater risk for recurrent pneumonia than the risk of baseline pneumonia with initial clozapine treatment.16,19 Aripiprazole (and probably other Table 1.47 Factors associated with antipsychotic-induced pneumonia. Treatment factors ■ ■Antipsychotics with high anticholinergic effects (e.g. clozapine and olanzapine)3,9 ■ ■High antipsychotic doses10 ■ ■Antipsychotic polypharmacy*11–13 ■ ■Concomitant benzodiazepines14,15 ■ ■Concomitant mood stabilisers** Patient factors ■ ■Decreased CYP2C19 and CYP1A2 activity16 ■ ■Smoking17 ■ ■Obesity17 ■ ■Diagnosis of schizophrenia (especially TRS)17 * Not found in one study.3 ** Lithium seems to have a protective effect.

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Mechanisms

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Summary

Schizophrenia and related psychoses CHAPTER 1 ■ ■Assume that the use of all antipsychotics increases the risk of pneumonia, but especially clozapine and high-dose olanzapine or quetiapine. ■ ■Concomitant benzodiazepine use should be avoided, where possible. ■ ■Monitor all patients for signs of chest infection and treat promptly. ■ ■Offer vaccination against COVID-19, influenza and pneumococcus to all high-risk patients. dopamine partial agonists) seem to have a lower risk of pneumonia than pure dopamine antagonists.9 Another study found amisulpride (a dopamine antagonist with minimal anticholinergic activity) is not linked to pneumonia.11 Mechanisms Although studies rarely distinguish between the various forms of pneumonia, cases of antipsychotic-induced aspiration, infective (viral and bacterial) and hypersensitivity pneumonia have been documented.16 The mechanism by which antipsychotics increase the risk of such pneumonia is not known but is probably multifactorial. Proposed mechanisms are outlined in Box 1.2. An increased risk of pneumonia should probably be assumed for all patients taking any antipsychotic (but especially clozapine)21 for any period. All patients should be very carefully monitored for signs of chest infection and effective treatment started promptly. Consideration should be given to using COVID-19, influenza and pneumococcal vaccines, although there is no direct evidence to support benefit for pneumonia prevention in this specific group of patients. Those patients prescribed clozapine should be proactively monitored and treated for hypersalivation. Pneumonia is likely to increase clozapine levels (see section on clozapine: common adverse effects in this chapter) so close monitoring is required. Slower-than-usual clozapine titration may prevent cases of hypersensitivity pneumonia.14 Extra vigilance is required when re-exposing to patients with history of clozapine-induced pneumonia who are taking clozapine. With all cases, early referral to general medical services should be considered where there is any doubt about the severity or type of chest infection. Summary Box 1.2 Proposed mechanisms for antipsychotic-induced pneumonia ■ ■Sedation ■ ■Dystonia or dyskinesia ■ ■Dry mouth ■ ■General poor physical health ■ ■Reduced immune response* ■ ■Clozapine-specific: hypersalivation, constipation * Clozapine is associated with antibody deficiency and greater use of antibiotics. This increased risk of infection is not related to neutrophil counts.20

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References

206 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

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Cepaityte D, et al. Exploring a safety signal of antipsychotic-associated pneumonia: a pharmacovigilance–pharmacodynamic study. Schizophr Bull 2020; 47:672–681.
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Cepaityte D, et al. Exploring a safety signal of antipsychotic-associated pneumonia: a pharmacovigilance-pharmacodynamic study. Schizophr Bull 2021; 47:672–681.
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de Leon J, et al. Pneumonia may be more frequent and have more fatal outcomes with clozapine than with other second-generation antipsychotics. World Psychiatry 2020; 19:120–121.

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Switching antipsychotics

Schizophrenia and related psychoses CHAPTER 1 Switching antipsychotics Table 1.48 gives a summary of recommendations for switching antipsychotic medications because of poor tolerability. Table 1.48 Switching antipsychotic medications because of poor tolerability – a summary of recommendations. Adverse effect Suggested medications Alternative medications Acute EPS1–8 (dystonia, parkinsonism, bradykinesia) Aripiprazole Clozapine Brexpiprazole Lurasidone Cariprazine Ziprasidone Olanzapine Quetiapine Akathisia2,9,10 Olanzapine Clozapine Quetiapine Brexpiprazole Dyslipidaemia7,8,11–16 Amisulpride Asenapine Aripiprazole* Brexpiprazole Lurasidone Cariprazine Ziprasidone Impaired glucose tolerance7,8,15,17–21 Amisulpride Brexpiprazole Aripiprazole* Cariprazine Lurasidone Haloperidol Ziprasidone Hyperprolactinaemia7,8,15,22–29 Aripiprazole* Clozapine Brexpiprazole Olanzapine Cariprazine Ziprasidone Lurasidone Quetiapine Postural hypotension8,15,30 Amisulpride Haloperidol Aripiprazole Sulpiride Brexpiprazole Trifluoperazine Cariprazine Lurasidone QT prolongation27,31–38 Brexpiprazole Low-dose monotherapy of any drug not formally contraindicated in QT prolongation (with ECG monitoring) Cariprazine Lurasidone Paliperidone Sedation7,8,27 Amisulpride Haloperidol Aripiprazole Trifuoperazine Brexpiprazole Ziprasidone Cariprazine Risperidone Sulpiride Sexual dysfunction8,29,39–46 Aripiprazole Clozapine Brexpiprazole Cariprazine Lurasidone Quetiapine (Continued)

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References

208 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Lumateperone and pimavanserin are not listed in the table because of their limited availability. Both drugs cause few or no EPSEs or akathisa, have no effect on prolactin or blood pressure and cause minimal weight gain and metabolic disturbance.70,71 Pimvanserin prolongs QT,72 whereas lumateperone seems to have no effect on the ECG.73 To see the relative effect of all antipsychotics on these parameters, please see the Psymatik Treatment Optimizer.74 References

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Mir S, et al. Atypical antipsychotics and hyperglycaemia. Int Clin Psychopharmacol 2001; 16:63–74. Table 1.48 (Continued) Adverse effect Suggested medications Alternative medications Tardive dyskinesia47–53 Clozapine Aripiprazole Olanzapine Quetiapine Weight gain16,36,38,54–65 Amisulpride Asenapine Aripiprazole* Haloperidol Brexpiprazole Trifluoperazine Cariprazine Lurasidone Ziprasidone * There is evidence that both switching to and co-prescription of aripiprazole can be associated with reductions in body weight and plasma prolactin levels, better lipid profiles and a decrease in plasma glucose levels.66–69

Schizophrenia and related psychoses CHAPTER 1 21. Cernea S, et al. Pharmacological management of glucose dysregulation in patients treated with second-generation antipsychotics. Drugs 2020; 80:1763–1781. 22. Turrone P, et al. Elevation of prolactin levels by atypical antipsychotics. Am J Psychiatry 2002; 159:133–135. 23. David SR, et al. The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia. Clin Ther 2000; 22:1085–1096. 24. Hamner MB, et al. Hyperprolactinaemia in antipsychotic-treated patients: guidelines for avoidance and management. CNS Drugs 1998; 10:209–222. 25. Trives MZ, et al. Effect of the addition of aripiprazole on hyperprolactinemia associated with risperidone long-acting injection. J Clin Psychopharmacol 2013; 33:538–541. 26. Suzuki Y, et al. Differences in plasma prolactin levels in patients with schizophrenia treated on monotherapy with five second-generation antipsychotics. Schizophr Res 2013; 145:116–119. 27. Leucht S, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382:951–962. 28. Keks N, et al. Comparative tolerability of dopamine D2/3 receptor partial agonists for schizophrenia. CNS Drugs 2020; 34:473–507. 29. Kelly DL, et al. Analysis of prolactin and sexual side effects in patients with schizophrenia who switched from paliperidone palmitate to aripiprazole lauroxil. Psychiatry Res 2021; 302:114030. 30. Citrome L. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol 2013; 9:193–206. 31. Glassman AH, et al. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001; 158:1774–1782. 32. Taylor D. Antipsychotics and QT prolongation. Acta Psychiatr Scand 2003; 107:85–95. 33. Titier K, et al. Atypical antipsychotics: from potassium channels to torsade de pointes and sudden death. Drug Saf 2005; 28:35–51. 34. Ray WA, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009; 360:225–235. 35. Loebel A, et al. Efficacy and safety of lurasidone 80 mg/day and 160 mg/day in the treatment of schizophrenia: a randomized, double-blind, placebo- and active-controlled trial. Schizophr Res 2013; 145:101–109. 36. Das S, et al. Brexpiprazole: so far so good. Ther Adv Psychopharmacol 2016; 6:39–54. 37. Citrome L. Cariprazine for the treatment of schizophrenia: a review of this dopamine D3-preferring D3/D2 receptor partial agonist. Clin Schizophr Relat Psychoses 2016; 10:109–119. 38. Huhn M, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet 2019; 394:939–951. 39. Byerly MJ, et al. An open-label trial of quetiapine for antipsychotic-induced sexual dysfunction. J Sex Marital Ther 2004; 30:325–332. 40. Byerly MJ, et al. Sexual dysfunction associated with second-generation antipsychotics in outpatients with schizophrenia or schizoaffective disorder: an empirical evaluation of olanzapine, risperidone, and quetiapine. Schizophr Res 2006; 86:244–250. 41. Montejo Gonzalez AL, et al. A 6-month prospective observational study on the effects of quetiapine on sexual functioning. J Clin Psychopharmacol 2005; 25:533–538. 42. Dossenbach M, et al. Effects of atypical and typical antipsychotic treatments on sexual function in patients with schizophrenia: 12-month results from the Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study. Eur Psychiatry 2006; 21:251–258. 43. Kerwin R, et al. A multicentre, randomized, naturalistic, open-label study between aripiprazole and standard of care in the management of community-treated schizophrenic patients Schizophrenia Trial of Aripiprazole: (STAR) study. Eur Psychiatry 2007; 22:433–443. 44. Hanssens L, et al. The effect of antipsychotic medication on sexual function and serum prolactin levels in community-treated schizophrenic patients: results from the Schizophrenia Trial of Aripiprazole (STAR) study (NCT00237913). BMC Psychiatry 2008; 8:95. 45. Loebel A, et al. Effectiveness of lurasidone vs. quetiapine XR for relapse prevention in schizophrenia: a 12-month, double-blind, noninferiority study. Schizophr Res 2013; 147:95–102. 46. Silva C, et al. Managing antipsychotic-related sexual dysfunction in patients with schizophrenia. Expert Rev Neurother 2023; 23:1147–1155. 47. Lieberman J, et al. Clozapine pharmacology and tardive dyskinesia. Psychopharmacology (Berl) 1989; 99 Suppl 1:S54–S59. 48. O’Brien J, et al. Marked improvement in tardive dyskinesia following treatment with olanzapine in an elderly subject. Br J Psychiatry 1998; 172:186. 49. Sacchetti E, et al. Quetiapine, clozapine, and olanzapine in the treatment of tardive dyskinesia induced by first-generation antipsychotics: a 124-week case report. Int Clin Psychopharmacol 2003; 18:357–359. 50. Witschy JK, et al. Improvement in tardive dyskinesia with aripiprazole use. Can J Psychiatry 2005; 50:188. 51. Ricciardi L, et al. Treatment recommendations for tardive dyskinesia. Can J Psychiatry 2019; 64:388–399. 52. Lee D, et al. Long-term response to clozapine and its clinical correlates in the treatment of tardive movement syndromes: a naturalistic observational study in patients with psychotic disorders. J Clin Psychopharmacol 2019; 39:591–596. 53. Takeuchi H, et al. Pathophysiology, prognosis and treatment of tardive dyskinesia. Ther Adv Psychopharmacol 2022; 12:20451253221117313. 54. Taylor DM, et al. Atypical antipsychotics and weight gain: a systematic review. Acta Psychiatr Scand 2000; 101:416–432. 55. Allison D, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156:1686–1696. 56. Brecher M, et al. The long term effect of quetiapine (SeroquelTM) monotherapy on weight in patients with schizophrenia. Int J Psychiatry Clin Pract 2000; 4:287–291. 57. Casey DE, et al. Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study. Psychopharmacology (Berl) 2003; 166:391–399. 58. Newcomer JW, et al. A multicenter, randomized, double-blind study of the effects of aripiprazole in overweight subjects with schizophrenia or schizoaffective disorder switched from olanzapine. J Clin Psychiatry 2008; 69:1046–1056.

210 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 59. McEvoy JP, et al. Effectiveness of lurasidone in patients with schizophrenia or schizoaffective disorder switched from other antipsychotics: a randomized, 6-week, open-label study. J Clin Psychiatry 2013; 74:170–179. 60. McEvoy JP, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA 2014; 311:1978–1987. 61. Nasrallah HA, et al. The safety and tolerability of cariprazine in long-term treatment of schizophrenia: a post hoc pooled analysis. BMC Psychiatry 2017; 17:305. 62. Speyer H, et al. Reversibility of antipsychotic-induced weight gain: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2021; 12:577919. 63. Siskind D, et al. Does switching antipsychotics ameliorate weight gain in patients with severe mental illness? A systematic review and meta- analysis. Schizophr Bull 2021; 47:948–958. 64. Miura I, et al. Lurasidone for the treatment of schizophrenia: design, development, and place in therapy. Drug Des Devel Ther 2023; 17:3023–3031. 65. Pillinger T, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry 2020; 7:64–77. 66. Shim JC, et al. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo- controlled trial. Am J Psychiatry 2007; 164:1404–1410. 67. Fleischhacker WW, et al. Weight change on aripiprazole-clozapine combination in schizophrenic patients with weight gain and suboptimal response on clozapine: 16-week double-blind study. Eur Psychiatry 2008; 23 Suppl 2:S114–S115. 68. Henderson DC, et al. Aripiprazole added to overweight and obese olanzapine-treated schizophrenia patients. J Clin Psychopharmacol 2009; 29:165–169. 69. Preda A, et al. A safety evaluation of aripiprazole in the treatment of schizophrenia. Expert Opin Drug Saf 2020; 19:1529–1538. 70. Correll CU, et al. Safety and tolerability of lumateperone 42mg: an open-label antipsychotic switch study in outpatients with stable schizophrenia. Schizophr Res 2021; 228:198–205. 71. Mathis MV, et al. The US Food and Drug Administration’s perspective on the new antipsychotic pimavanserin. J Clin Psychiatry 2017; 78:e668–e673. 72. Cruz MP. Pimavanserin (Nuplazid): a treatment for hallucinations and delusions associated with Parkinson’s disease. P T 2017; 42:368–371. 73. Greenwood J, et al. Lumateperone: a novel antipsychotic for schizophrenia. Ann Pharmacother 2021; 55:98–104. 74. Pillinger T, et al. Antidepressant and antipsychotic side-effects and personalised prescribing: a systematic review and digital tool development. Lancet Psychiatry 2023; 10:860–876.

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Venous thromboembolism

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207 - Evidence of an association

Evidence of an association

Schizophrenia and related psychoses CHAPTER 1 Venous thromboembolism Evidence of an association Antipsychotic treatment was first linked to an increased risk of thromboembolism in 1965.1 Over a 10-year observation period, 3.1% of 1,590 patients developed thromboembolism, of whom 9 (0.6%) died. However, the use of antipsychotic medication is a proxy for severe and enduring mental illness and so observed associations with anti psychotics may at least partly reflect inherent pathological processes in the conditions for which they are prescribed. To some extent, the relative contributions to the risk of thromboembolism of antipsychotic treatment and the conditions they treat remain to be clearly defined. In a case–control study of nearly 30,000 patients,2 risk of thromboembolism was greatly increased overall in people prescribed antipsychotics (odds ratio [OR] 7.1). The increased risk was driven by low-potency phenothiazines (thioridazine, chlorpromazine; OR 24.1) and was seen chiefly in the first few weeks of treatment. Absolute risk of VTE was low – it was seen in only 0.14% of patients (about 1 in every 714 people). A secondary analysis suggested no association with diagnosis, apparently ruling out an association with schizophrenia itself. A later meta-analysis of seven case–control studies3 confirmed an increased risk of thromboembolism with low-potency FGAs (OR 2.91) and suggested lower but significantly increased risks with all types of antipsychotics. Later, a meta-analysis of 17 studies4 reported a small increased risk of thromboembolism with antipsychotics as a whole (OR 1.54) and with FGAs (OR 1.74) and SGAs (OR 2.07) as individual groups. Risk of thromboembolism clearly decreased with age. The authors suggested that the best that could be said was that antipsychotics probably increased the risk by about 50% but that residual confounding could not be discounted (i.e. other factors may have accounted for the effect seen). Since this time, several more case–control studies have confirmed both the slightly increased risk of thromboembolism and the small risk overall.5–7 One study reported a risk for older people taking antipsychotics as 43 per 10,000 patient years.7 Other noteworthy findings were a substantially increased association with thromboembolism for prochlorperazine – a drug not always (or even often) prescribed for psychotic disorders5 – and an increased risk linked to antipsychotic dosage (risk was quadrupled in high-dose patients).6 An association with prochlorperazine prescribing had previously been suggested by a UK study.8 These findings add weight to the theory that antipsychotic medication (and not only the conditions it treats) is responsible for the increased hazard of thromboembolism. The highest risk of pathological blood clotting may be in the first 3 months or so of treatment.9,10 Several meta-analyses have been published in recent years. The findings of two studies are presented in Table 1.49.

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Mechanisms

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209 - Outcomes

Outcomes

212 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Mechanisms Several mechanisms have been suggested to explain the association between antipsychotics and thromboembolism. These proposed mechanisms are outlined in Box 1.3. Outcomes Increased risk of thromboembolism is reflected in numerous published reports of elevated incidence of pulmonary embolism,17 stroke18 and myocardial infarction.19 A 2022 study suggested that antipsychotics increase the risk of fatal thromboembolism (OR 6.68),17 although, again, the absolute risk remains low. Box 1.3 Proposed mechanisms for antipsychotic-associated venous thromboembolism11–15 Sedation* Obesity* Hyperprolactinaemia* Elevated phospholipid antibodies Elevated platelet aggregation** Elevated plasma homocysteine Elevated tissue plasminogen activator Elevated platelet count * Some evidence that these factors are not the mechanism for antipsychotic-induced thromboembolism.16 ** In vitro data suggest radically different effects on platelet aggregation for different antipsychotics.12 Table 1.49 Findings of meta-analyses of the risk of pathological blood clotting. Reference Relative risk vs no use Comments Number of studies included FGAs (OR) SGAs (OR) All anti- psychotics (OR) Di et al, 20219 1.83 VTE/PE 1.75 VTE 1.53 VTE Highest risk in younger patients (<60 years). Low-potency FGAs highest risk. 3.79 PE 3.69 PE 2.06 VTE/PE 1.60 VTE/PE Liu et al, 202110 1.47 VTE/PE 1.62 VTE/PE 1.55 VTE New users of antipsychotics had higher risk than continuing patients. Risk slightly elevated with higher doses vs low doses. Similar effect sizes for FGA vs SGA. 3.68 PE 2.01 VTE/PE FGA, first-generation antipsychotic; OR, odds ratio; PE, pulmonary embolism; SGA, second-generation antipsychotic; VTE, venous thromboembolism.

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21 - Poor response to antipsychotic monotherapy

Poor response to antipsychotic monotherapy

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210 - Summary

Summary

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211 - Practice points

Practice points

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212 - References

References

Schizophrenia and related psychoses CHAPTER 1 Summary Antipsychotics are almost certainly associated with a small but important increased risk of venous thromboembolism and associated hazards of pulmonary embolism, stroke and myocardial infarction. Risk appears to be greatest during the early part of treatment and in younger people and is probably dose-related. Practice points ■ ■Monitor closely all patients (but especially younger patients) starting antipsychotic treatment for signs of venous thromboembolism: ■ ■calf pain or swelling ■ ■sudden breathing difficulties ■ ■signs of myocardial infarction (chest pain, nausea, etc.) ■ ■signs of stroke (sudden unilateral weakness, etc.). ■ ■Use the lowest therapeutic dose. ■ ■Encourage good hydration and physical mobility. References

Häfner H, et al. Thromboembolic complications in neuroleptic treatment. Compr Psychiatry 1965; 6:25–34.
Zornberg GL, et al. Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case-control study. Lancet 2000; 356:1219–1223.
Zhang R, et al. Antipsychotics and venous thromboembolism risk: a meta-analysis. Pharmacopsychiatry 2011; 44:183–188.
Barbui C, et al. Antipsychotic drug exposure and risk of venous thromboembolism: a systematic review and meta-analysis of observational studies. Drug Saf 2014; 37:79–90.
Ishiguro C, et al. Antipsychotic drugs and risk of idiopathic venous thromboembolism: a nested case–control study using the CPRD. Pharmacoepidemiol Drug Saf 2014; 23:1168–1175.
Wang MT, et al. Use of antipsychotics and risk of venous thromboembolism in postmenopausal women: a population-based nested case– control study. Thromb Haemost 2016; 115:1209–1219.
Letmaier M, et al. Venous thromboembolism during treatment with antipsychotics: results of a drug surveillance programme. World J Biol Psychiatry 2018; 19:175–186.
Parker C, et al. Antipsychotic drugs and risk of venous thromboembolism: nested case–control study. BMJ 2010; 341:c4245.
Di X, et al. Antipsychotic use and risk of venous thromboembolism: a meta-analysis. Psychiatry Res 2021; 296:113691.
Liu Y, et al. Current antipsychotic agent use and risk of venous thromboembolism and pulmonary embolism: a systematic review and meta- analysis of observational studies. Ther Adv Psychopharmacol 2021; 11:2045125320982720.
Hagg S, et al. Risk of venous thromboembolism due to antipsychotic drug therapy. Expert Opin Drug Saf 2009; 8:537–547.
Dietrich-Muszalska A, et al. The first- and second-generation antipsychotic drugs affect ADP-induced platelet aggregation. World J Biol Psychiatry 2010; 11:268–275.
Tromeur C, et al. Antipsychotic drugs and venous thromboembolism. Thromb Res 2012; 130 Suppl 1:S29–S31.
Zheng C, et al. Hypercoagulable state in patients with schizophrenia: different effects of acute and chronic antipsychotic medications. Ther Adv Psychopharmacol 2023; 13:20451253231200257.
Zhang Y, et al. New role of platelets in schizophrenia: predicting drug response. Gen Psychiatr 2024; 37:e101347.
Ferraris A, et al. Antipsychotic use among adult outpatients and venous thromboembolic disease: a retrospective cohort study. J Clin Psychopharmacol 2017; 37:405–411.
Manoubi SA, et al. Fatal pulmonary embolism in patients on antipsychotics: case series, systematic review and meta-analysis. Asian J Psychiatr 2022; 73:103105.
Zivkovic S, et al. Antipsychotic drug use and risk of stroke and myocardial infarction: a systematic review and meta-analysis. BMC Psychiatry 2019; 19:189.
Papola D, et al. Antipsychotic use and risk of life-threatening medical events: umbrella review of observational studies. Acta Psychiatr Scand 2019; 140:227–243.

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213 - REFRACTORY SCHIZOPHRENIA AND CLOZaPINE

REFRACTORY SCHIZOPHRENIA AND CLOZaPINE

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214 - Clozapine initiation schedules

Clozapine initiation schedules

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215 - Clozapine dosing regimen

Clozapine dosing regimen

214 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Table 1.50 Clozapine dose (in mg/day) with the highest likelihood of providing a plasma concentration of 350mcg/L, estimated by extrapolation of concentrations reported for different populations. Patient group Rostami-Hodjegan3 (ethnicity not described) Schoretsanitis4 (White Europeans) Reeves5 Asian White Afro- Caribbean Female non-smoker 236 225 Female smoker 357 300 Male non-smoker 256 275 Male smoker 368 375 REFRACTORY SCHIZOPHRENIA AND CLOZAPINE Clozapine initiation schedules Clozapine dosing regimen Many of the adverse effects of clozapine are dose dependent and linked to speed of titration. Adverse effects tend to be more common and severe at the beginning of treatment. Titration is required to allow tolerance to develop to the pharmacological effects of clozapine. The degree to which tolerance ultimately develops is evidenced by the fact that standard maintenance doses would be fatal in a clozapine-naïve person.1 To minimise adverse effects and maximise the chances of successful titration, it is clearly important to start treatment at a low dose and to increase dosage slowly. There are many different opinions on exactly how slowly clozapine should be titrated. Titration schedules should certainly be individualised. This is something everyone agrees on. There are, however, competing imperatives: the need to establish an effective dose quickly, the need to allow time for the patient to gain tolerance to adverse effects, the need to minimise the risk of myocarditis and the need to account for very different rates of clozapine metabolism. The aim of dose titration is to attain a minimum therapeutic plasma concentration of approximately 350mcg/L over the course of about 3 weeks. The average dose at which this plasma concentration is achieved varies according to sex, smoking status and genetic variability in cytochrome enzyme activity, such as lower CYP1A2 activity for people of Asian or Native American heritage.2 Achieving a therapeutic concentration over a period of 2–3 weeks will require very different titration schedules for people with different metabolic capacities. A dose that will achieve a plasma concentration of 350mcg/L for an individual patient can be estimated by extrapolation of concentrations reported for different populations. This method groups patients according to sex and smoking status to produce predictive models.3–5 Results are summarised in Table 1.50.

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216 - Faster titrations

Faster titrations

Schizophrenia and related psychoses CHAPTER 1 Alternatively, an attempt can be made to include other factors into the predictive models, such as cytochrome enzyme metaboliser status, ancestry and concurrent medication to predict target dose and corresponding titration schedule.2,6 The most accurate dose prediction is given by a genetic test that incorporates gene variant activity scores into a mathematical algorithm.7 Results from this test can be used to select a titration schedule from the four provided here by choosing the schedule with the calculated target dose closest to the final dose in the schedule. Clozapine should normally be started at a dose of 6.25mg – this is effectively a test dose for everyone. On subsequent days, the dose can be increased according to the selected schedule, provided the patient is tolerating clozapine. A flexible approach should be taken, altering schedules in response to adverse effects if needed (e.g. pausing titration, returning temporarily to a dose that was previously tolerated, or slowing the speed and/or reducing the magnitude of dose increases). Wherever possible, plasma concentration testing should be used in conjunction with adverse effect monitoring to inform dosing. Monitoring blood levels can help ensure that titration does not overshoot the target blood level. Use of point of care testing (delivering results within minutes) means this is possible without interrupting the dose regimen.8,9 If results cannot be obtained rapidly then levels should be checked when titration is complete or if adverse effects cause problems during titration. The dose should be divided (usually into two daily doses) and, if sedation is a problem, the larger portion of the dose can be given at night. The following tables outline four different starting regimens for clozapine. These are based on over 30 years’ clinical experience and the published protocols described above. The concept behind the schedules is that every patient reaches, over 20 days, the lowest dose estimated to give a therapeutic blood concentration. The schedules should ensure that the rate of increase in clozapine plasma concentration is approximately the same for all people. This is important to note: the rate of dose increase may be very different in these schedules, but the rate of increase in blood concentration is the same. The reason we have moved away from providing a single titration schedule is because a single schedule has the opposite effect: the rate of change of plasma level will be vastly different for people with different metabolic capacities. More rapid increases than those suggested here have been used, as has an extremely slow titration (the ‘Laitman protocol’ allows dose increases of only 25mg per week). Slower titration may be necessary where sedation or other dose-related side effects are severe, in the elderly, the very young, those who are physically compromised or those who have poorly tolerated other antipsychotics. The target dose for patients with Asian ancestry should be around 65–75% of that given below. For older patients (>70 years), the target dose is around 50% of that given in the tables. Faster titrations The titration schedules listed here are aimed at maximising the likelihood of a successful titration – the aim is to establish the patient on a well-tolerated and therapeutic dose of clozapine. Faster titrations can be used and have been widely used in the past. The main risk with faster titrations, assuming the patient tolerates such a regimen, is myocarditis (see section on clozapine: serious cardiovascular adverse effects in this chapter). If tolerability is not assumed, the main risk is titration failure resulting from the patient’s inability or unwillingness to tolerate rapid titration.

216 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Female non-smoker – target dose 225mg/day. Day Morning dose (mg) Evening dose (mg) Total daily dose (mg) – 6.25 6.25 – 6.25 6.25 6.25 6.25 12.5 6.25 12.5 18.75 12.5 12.5 6 12.5 12.5 7 25 8 25 9 50 10 50 11 50 12 50 13 75 14 75 15 75 16 75 17 100 18 100 19 100 20 100 Female smoker – target dose 300mg/day. Day Morning dose (mg) Evening dose (mg) Total daily dose (mg) – 6.25 6.25 6.25 6.25 12.5 12.5 12.5 4 12.5 12.5 5 25 6 25 7 50 8 50 9 50 10 50 11 75

Schizophrenia and related psychoses CHAPTER 1 Day Morning dose (mg) Evening dose (mg) Total daily dose (mg) 50 125 75 150 75 150 75 175 100 200 100 225 125 250 125 275 150 300 Male non-smoker – target dose 250mg/day. Day Morning dose (mg) Evening dose (mg) Total daily dose (mg) – 6.25 6.25 – 6.25 6.25 6.25 6.25 12.5 6.25 12.5 18.75 12.5 12.5 6 12.5 12.5 7 25 8 25 9 50 10 50 11 50 12 50 13 75 14 75 15 75 16 75 17 100 18 100 19 125 20 125

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217 - References

References

218 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Male smoker – target dose 375mg/day. Day Morning dose (mg) Evening dose (mg) Total daily dose (mg) – 6.25 6.25 6.25 6.25 12.5 12.5 12.5 4 12.5 37.5 25 50 25 50 25 75 25 75 50 100 50 125 75 150 75 175 100 200 100 225 125 250 125 275 150 300 150 325 175 350 175 375 References

Stanworth D, et al. Clozapine: a dangerous drug in a clozapine-naive subject. Forensic Sci Int 2011; 214:e23–e25.
Ruan CJ, et al. Is there a future for CYP1A2 pharmacogenetics in the optimal dosing of clozapine? Pharmacogenomics 2020; 21:369–373.
Rostami-Hodjegan A, et al. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol 2004; 24:70–78.
Schoretsanitis G, et al. European whites may need lower minimum therapeutic clozapine doses than those customarily proposed. J Clin Psychopharmacol 2021; 41:140–147.
Reeves S, et al. A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status. Br J Clin Pharmacol 2024; 90:135–145.
de Leon J, et al. An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels. Pharmacopsychiatry 2022; 55:73–86.
Taylor D, et al. Predicting clozapine dose required to achieve a therapeutic plasma concentration: a comparison of a population algorithm and three algorithms based on gene variant models. J Psychopharmacol 2023; 37:1030–1039.
Atkins M, et al. Haematological point of care testing for clozapine monitoring. J Psychiatr Res 2023; 157:66–71.
Atkins M, et al. Acceptability of point of care testing for antipsychotic medication levels in schizophrenia. Psychiatry Research Communications 2022; 2:100070.

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218 - Intramuscular clozapine

Intramuscular clozapine

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219 - References

References

Schizophrenia and related psychoses CHAPTER 1 Intramuscular clozapine Intramuscular clozapine is a short-term intervention for patients with a treatment- refractory psychotic disorder who refuse oral medication. It is always used with a view to converting to oral clozapine once treatment is established.1 IM clozapine has also been used for patients who are unable to take oral medication because of physical illness.2 Although evidence is relatively limited, observational data indicate that initiating treatment with IM clozapine does not adversely affect long-term adherence to oral treatment.1,3 IM clozapine is similar to oral clozapine in respect to short-term safety and tolerability.4,5 The IM preparation is unlicensed in the UK and many other countries, so adequate precautions should be taken and patient or carer consent obtained. General recommendations for prescribing intramuscular clozapine in adults are summarised in Table 1.51. References

Casetta C, et al. A retrospective study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis. Br J Psychiatry 2020; 217:506–513.
Gee S, et al. Intramuscular clozapine in the acute medical hospital: experiences from a liaison psychiatry team. SAGE Open Med Case Rep 2021; 9:2050313x211004796.
Henry R, et al. Evaluation of the effectiveness and acceptability of intramuscular clozapine injection: illustrative case series. BJPsych Bull 2020:1–5.
Schulte PF, et al. Compulsory treatment with clozapine: a retrospective long-term cohort study. Int J Law Psychiatry 2007; 30:539-545.
Gee S, et al. Alternative routes of administration of clozapine. CNS Drugs 2022; 36:105–111. Table 1.51 General recommendations for prescribing intramuscular clozapine. Strength 25mg/mL Maximum dose* 100mg (4mL) per site Oral equivalent dose The oral bioavailability of clozapine is about half that of the IM injection (e.g. 50mg IM injection daily = 100mg tablets/oral solution daily) Site of administration† The manufacturer states deep intramuscular gluteal injection Maximum treatment length‡ Before administering each injection, the patient should be offered oral clozapine. Clozapine injection should be used for the shortest duration possible (maximum 2 weeks consecutively). Dosing frequency To minimise the number of injections, once daily dosing is preferred Monitoring After each administration, patients should be observed every 15 minutes for the first 2 hours to check for excess sedation. Routine clozapine monitoring also applies. * For doses >100mg, the dose may be divided and administered into two sites. † Case series data report administration via lateral thigh or deltoid – note that the injection is painful3 and the maximum volume for the deltoid route is 2mL (50mg). ‡ Case series data report use of intramuscular clozapine for up to 96 days.3,4 Injection site reactions become common with longer-term treatment. Note: Simultaneous injection of IM clozapine and parenteral benzodiazepines has not been studied. If IM benzodiapines are required leave at least 1 hour between administration of IM clozapine and IM benzodiapines.

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22 - Long term antipsychotic treatment

Long-term antipsychotic treatment

22 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Combined antipsychotics (antipsychotic polypharmacy) In psychiatric practice, prescriptions for combined antipsychotic medications are common1–3 and often long term.4 The medications combined are likely to include LAI anti psychotic preparations,5,6 quetiapine7 and FGAs,8 the last of these perhaps reflecting the frequent use of haloperidol and chlorpromazine as prn medications. Poor response to antipsychotic monotherapy A national clinical audit conducted in the UK in 20229 found that by far the most common reason recorded for prescribing regular, combined antipsychotic medications was an insufficient response to antipsychotic monotherapy. The use of combined anti psychotic medications has been found to be associated with younger patient age, male gender, increased illness severity, complexity and chronicity, as well as poorer functioning, inpatient status and a diagnosis of schizophrenia.2,7,10–12 These associations largely reinforce the notion that antipsychotic polypharmacy is used where schizophrenia has proved to be refractory to trials of antipsychotic monotherapy.10,13–15 Importantly, there is a lack of robust evidence that the efficacy of combined antipsychotic medications is superior to treatment with a single antipsychotic.16,17 A meta- analysis of 16 RCTs in schizophrenia, comparing augmentation with a second antipsychotic with continued antipsychotic monotherapy, found that combining anti psychotic medications lacked double-blind/high-quality evidence of efficacy.18 In addition, in patients with schizophrenia, the effects of a change back from antipsychotic polypharmacy to monotherapy, even when carefully conducted, are uncertain. The findings of two randomised studies suggested that the majority of patients may be successfully switched from antipsychotic polypharmacy to monotherapy without loss of symptom control,19,20 and an open-label trial in institutionalised patients with chronic psychotic disorders found that such a switch did not increase the likelihood of relapse.21 However, an RCT in outpatients with schizophrenia reported greater increases in symptoms 6 months after a switch from two co-prescribed antipsychotic medications to one,22 although the expectation is that such exacerbations can be successfully managed.19 Long-term antipsychotic treatment A non-interventional, population-based study in Hungary sought to compare the effectiveness of antipsychotic monotherapy with the use of combined antipsychotic medications over a 1-year observation period. While the results provided evidence for the superiority of monotherapy over poly pharmacy for SGAs in terms of all-cause treatment discontinuation in schizophrenia, polypharmacy was associated with a lower likelihood of mortality and psychiatric hospitalisations.23 Similarly, a 20-year observational study in Finland reported on the risk of rehospitalisation in a cohort of 62,250 hospital-treated patients with schizophrenia. To minimise selection bias, the investigators used within-individual analyses, with each patient used as their own control. The main finding was that antipsychotic combinations, particularly those including clozapine and LAI antipsychotic medications, were associated with a slightly lower risk of psychiatric rehospitalisation than

06 - Chapter 1 Schizophrenia and related psychoses

220 - Optimising clozapine treatment

Optimising clozapine treatment

06 - Chapter 1 Schizophrenia and related psychoses

221 - Using clozapine alone

Using clozapine alone

06 - Chapter 1 Schizophrenia and related psychoses

222 - Clozapine augmentation

Clozapine augmentation

220 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Optimising clozapine treatment Using clozapine alone Target dose (dose is best adjusted according to patient tolerability and plasma level) ■ ■Average dose in UK is around 450mg/day1 ■ ■Response usually seen in the range 150–900mg/day2 ■ ■Lower doses required in the elderly, females, people of Asian or Native American heritage, non-smokers, and those prescribed certain enzyme inhibitors3,4 ■ ■Genetic testing of CYP enzymes accurately predicts therapeutic dose5 Plasma levels ■ ■Most studies indicate that threshold for response is in the range 350–420mcg/L.6,7 Threshold in some may be as high as 500mcg/L.8 One study suggests a minority of patients only respond at levels between 500 and 1000mcg/L.9 ■ ■In male smokers who cannot achieve therapeutic plasma levels, metabolic inhibitors (fluvoxamine10,11 or cimetidine,12 for example) can be co-prescribed, but extreme caution is required13 ■ ■Importance of norclozapine levels not established. Clozapine/norclozapine ratio is not a reliable indicator of partial adherence nor of clozapine metabolism.14 Clozapine augmentation Clozapine augmentation has become common practice because inadequate response to clozapine on its own is a frequent clinical event. The evidence base supporting augmentation strategies is fairly large but, despite more than 50 reviews and meta-analyses on the subject, it remains insufficient to allow the development of any algorithm or schedule of treatment options.15 In practice, the result of clozapine augmentation is often disappointing and substantial changes in symptom severity are rarely observed. This clinical impression is supported by the equivocal results of many studies, which suggest a small effect size at best. Network meta-analyses examining pharmacological augmentation options often draw conclusions based on only a few studies of dubious merit and may come to different conclusions.16–19 That mirtazapine augmentation has the largest effect size (and the addition of memantine, the second largest) is something most recent systematic reviews agree on17–19 although, with both strategies, the supporting evidence was, at best, weak. Meta-analyses of antipsychotic augmentation of clozapine suggest either no effect,20 a small effect in long-term studies,21 a very small effect overall22 or small effects in specific symptom domains.23 Few high-quality studies in this area exist – when only large, high- quality studies are included, most meta-analyses report no benefit to pharmacological augmentation.24 This is consistent with imaging studies – investigations into dopaminergic activity in refractory schizophrenia suggest there is no overproduction of dopamine.25,26 Dopamine antagonists are thus unlikely to be effective. All augmentation attempts should be carefully monitored and, if no clear benefit is forthcoming, abandoned after 3–6 months. The addition of another drug to clozapine treatment might be expected to worsen overall adverse effect burden, so continuing ineffective treatment is only likely to be detrimental. In some cases, however, the addition of an augmenting agent may reduce the severity of some adverse effects (e.g. weight gain, dyslipidaemia – see below) or allow a reduction in clozapine dose. The addition of aripiprazole to clozapine may be particularly effective in reversing metabolic effects.27,28 International consensus guidelines recommend (after optimising plasma levels) tailoring augmentation agent choice to residual symptoms, and adding amisulpride or aripiprazole

Schizophrenia and related psychoses CHAPTER 1 for positive symptoms, antidepressants for negative symptoms, and mood stabilisers for suicidal ideation or aggression.24 Recent data on cariprazine suggest particular benefit on negative symptoms unresponsive to clozapine.29–32 Table 1.52 shows suggested treatment options (in alphabetical order) where 3–6 months of optimised clozapine alone at maximum tolerated dose has provided unsatisfactory benefit. Table 1.52 Suggested options for augmenting clozapine. Option Comment Add amisulpride33–40 (400–800mg/day) Some evidence and experience suggest that amisulpride augmentation may be worthwhile. Five small RCTs (not all positive), the largest of which showed some benefit to positive symptoms and cognition, two of which found an increased adverse-effect burden, including cardiac adverse effects.41,42 May allow clozapine dose reduction.43 Add antipsychotic long-acting injection15,44–48 Case series and observational studies suggest benefits to residual symptoms as well as number and length of hospitalisations. Appears to be well tolerated. Does not protect against relapse if clozapine is not taken. Add aripiprazole27,49–52 (15–30mg/day) Very limited evidence of therapeutic benefit, although a meta-analysis suggests some effect.53 Reduces weight and LDL cholesterol.53 LAI has been used.54,55 Add cariprazine56 Three small case series and one pilot study suggest benefit, particularly for negative symptoms.29–32 Two case reports of worsening psychosis.57 Add haloperidol51,58,59 (2–3mg/day) Modest evidence of benefit Add lamotrigine60–62 (25–300mg/day) May be useful in partial or non-responders. May reduce alcohol consumption.63 Several equivocal reports.64–66 Some meta-analyses suggest moderate effect size67 but this is largely influenced by two outlying studies.68 Add lurasidone32,69 One case series, one retrospective chart review and a case report. Appears to be well tolerated. Add omega-3 triglycerides70,71 (2–3g EPA daily) Modest, and somewhat contested, evidence to support efficacy in non- or partial responders to antipsychotics, including clozapine Add risperidone72,73 (2–6mg/day) Supported by an RCT but there are also two negative RCTs, each with minuscule response rates.74,75 Small number of reports of increases in clozapine plasma levels. LAI also an option.55,76 Paliperidone LAI has also been used.48,55 Add sodium valproate68,77 (400–800mg/day) Pooled effects from five Chinese RCTs68 suggest improvement in positive symptoms, although studies are mostly of poor quality. Cochrane suggests benefit of adding valproate to antipsychotics in general, especially for excitement and aggression.78 Add sulpiride79 (400mg/day) May be useful in partial or non-responders. Supported by a single randomised trial in English and three in Chinese.80 Overall effect modest. Add topiramate81–85 (50–300mg/day) Two positive RCTs, two negative. Can worsen psychosis in some.61,86 Two meta- analyses including hitherto unknown Chinese data68,87 suggested robust effect on positive and negative symptoms, substantial weight loss but often with psychomotor slowing and attention difficulties. Add ziprasidone88–91 (80–160mg/day) Supported by three RCTs.91,92 Associated with QTc prolongation. Rarely used. Note: consider the use of mood stabilisers and/or antidepressants especially where mood disturbance is thought to contribute to symptoms.93–95 EPA, eicosapentaenoic acid; LAI, long-acting injection; LDL, low-density lipoprotein.

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223 - References

References

222 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Other options include adding pimozide, olanzapine or sertindole. None is recommended: pimozide and sertindole have important cardiac toxicity and the addition of olanzapine is poorly supported96 and likely to exacerbate metabolic adverse effects. Studies of pimozide97,98 and sertindole99 have shown no effect. One small RCT supports the use of Ginkgo biloba100 and another two support the use of memantine.101,102 Another study suggests possible benefit of augmentation with acetyl-L-carnitine103 and a case study reports good outcome with thyroxine.104 A single RCT describes successful use of sodium benzoate.105 Minocycline is probably not effective.77,106 Glycine may be effective for positive symptoms, but studies are of poor quality.107 A small case series (n = 6) found benefit from adding pimavanserin.108 N-acetylcysteine is probably of no benefit.109–111 References

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Mishra A, et al. Augmentation strategies for partial or non-responders to clozapine in patients with schizophrenia: a Bayesian network meta- analysis of randomized controlled trials. Clin Psychopharmacol Neurosci 2024; 22:232–252.
Grover S, et al. Augmentation strategies for clozapine resistance: a systematic review and meta-analysis. Acta Neuropsychiatr 2023; 35:65–75.
Yeh TC, et al. Pharmacological and nonpharmacological augmentation treatments for clozapine-resistant schizophrenia: a systematic review and network meta-analysis with normalized entropy assessment. Asian J Psychiatr 2023; 79:103375.
Barbui C, et al. Does the addition of a second antipsychotic drug improve clozapine treatment? Schizophr Bull 2009; 35:458–468.
Paton C, et al. Augmentation with a second antipsychotic in patients with schizophrenia who partially respond to clozapine: a meta-analysis. J Clin Psychopharmacol 2007; 27:198–204.
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Bartoli F, et al. Adjunctive second-generation antipsychotics for specific symptom domains of schizophrenia resistant to clozapine: a meta- analysis. J Psychiatr Res 2019; 108:24–33.
Wagner E, et al. Clozapine combination and augmentation strategies in patients with schizophrenia: recommendations from an international expert survey among the Treatment Response and Resistance in Psychosis (TRRIP) working group. Schizophr Bull 2020; 46:1459–1470.
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Demjaha A, et al. Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function. Biol Psychiatry 2014; 75:e11–e13.
Fleischhacker WW, et al. Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol 2010; 13:1115–1125.
Correll CU, et al. Selective effects of individual antipsychotic cotreatments on cardiometabolic and hormonal risk status: results from a systematic review and meta-analysis. Schizophr Bull 2013; 39 Suppl 1:S29–S30.

Schizophrenia and related psychoses CHAPTER 1 29. Oloyede E, et al. Clozapine augmentation with cariprazine for negative symptoms: a case series and literature review. Ther Adv Psychopharmacol 2022; 12:20451253211066642. 30. Berardis D, et al. Cariprazine add-on in inadequate clozapine response: a report on two cases. Clin Psychopharmacol Neurosci 2021; 19:174–178. 31. Pappa S, et al. Efficacy and safety of cariprazine augmentation in patients treated with clozapine: a pilot study. Ther Adv Psychopharmacol 2022; 12:20451253221132087. 32. Siwek M, et al. Cariprazine augmentation of clozapine in schizophrenia—a retrospective chart review. Front Pharmacol 2024; 14:1321112. 33. Matthiasson P, et al. Relationship between dopamine D2 receptor occupancy and clinical response in amisulpride augmentation of clozapine non-response. J Psychopharmacol 2001; 15:S41. 34. Munro J, et al. Amisulpride augmentation of clozapine: an open non-randomized study in patients with schizophrenia partially responsive to clozapine. Acta Psychiatr Scand 2004; 110:292–298. 35. Zink M, et al. Combination of clozapine and amisulpride in treatment-resistant schizophrenia: case reports and review of the literature. Pharmacopsychiatry 2004; 37:26–31. 36. Ziegenbein M, et al. Augmentation of clozapine with amisulpride in patients with treatment-resistant schizophrenia: an open clinical study. German J Psychiatry 2006; 9:17–21. 37. Kampf P, et al. Augmentation of clozapine with amisulpride: a promising therapeutic approach to refractory schizophrenic symptoms. Pharmacopsychiatry 2005; 38:39–40. 38. Assion HJ, et al. Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to clozapine: a randomized, double-blind, placebo-controlled trial. Pharmacopsychiatry 2008; 41:24–28. 39. Poonia S, et al. Amisulpride augmentation of clozapine in clozapine-resistant schizophrenia: a case series. Can J Hosp Pharm 2022; 75:234–238. 40. Zhu MH, et al. Amisulpride augmentation therapy improves cognitive performance and psychopathology in clozapine-resistant treatment- refractory schizophrenia: a 12-week randomized, double-blind, placebo-controlled trial. Mil Med Res 2022; 9:59. 41. Barnes TR, et al. Amisulpride augmentation in clozapine-unresponsive schizophrenia (AMICUS): a double-blind, placebo-controlled, randomised trial of clinical effectiveness and cost-effectiveness. Health Technol Assess 2017; 21:1–56. 42. Barnes TRE, et al. Amisulpride augmentation of clozapine for treatment-refractory schizophrenia: a double-blind, placebo-controlled trial. Ther Adv Psychopharmacol 2018; 8:185–197. 43. Croissant B, et al. Reduction of side effects by combining clozapine with amisulpride: case report and short review of clozapine-induced hypersalivation – a case report. Pharmacopsychiatry 2005; 38:38–39. 44. Oloyede E, et al. Clozapine augmentation with long-acting antipsychotic injections: a case series and systematic review. Acta Psychiatr Scand 2023; 148:538–552. 45. Joo SW, et al. Comparative effectiveness of antipsychotic monotherapy and polypharmacy in schizophrenia patients with clozapine treatment: a nationwide, health insurance data-based study. Eur Neuropsychopharmacol 2022; 59:36–44. 46. Nováková M, et al. Potential impact on mental health in patients with treatment-resistant schizophrenia: clozapine augmentation with long- acting parenteral antipsychotics: a case series. Ceska Slov Farm 2024; 72:277–287. 47. Mukherjee H, et al. Predictors of functioning and clinical outcomes in inpatient with schizophrenia on clozapine augmented with antipsychotics. Australas Psychiatry 2022; 30:100–104. 48. Bioque M, et al. Clozapine and paliperidone palmitate antipsychotic combination in treatment-resistant schizophrenia and other psychotic disorders: a retrospective 6-month mirror-image study. Eur Psychiatry 2020; 63:e71. 49. Chang JS, et al. Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2008; 69:720–731. 50. Muscatello MR, et al. Effect of aripiprazole augmentation of clozapine in schizophrenia: a double-blind, placebo-controlled study. Schizophr Res 2011; 127:93–99. 51. Cipriani A, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia: a 12-month, randomized, naturalistic trial. J Clin Psychopharmacol 2013; 33:533–537. 52. Tiihonen J, et al. Association of antipsychotic polypharmacy vs monotherapy with psychiatric rehospitalization among adults with schizophrenia. JAMA Psychiatry 2019; 76:499–507. 53. Srisurapanont M, et al. Efficacy and safety of aripiprazole augmentation of clozapine in schizophrenia: a systematic review and meta-analysis of randomized-controlled trials. J Psychiatr Res 2015; 62:38–47. 54. Balcioglu YH, et al. One plus one sometimes equals more than two: long-acting injectable aripiprazole adjunction in clozapine-resistant schizophrenia. Clin Neuropharmacol 2020; 43:166–168. 55. Grimminck R, et al. Combination of clozapine with long-acting injectable antipsychotics in treatment-resistant schizophrenia: preliminary evidence from health care utilization indices. Prim Care Companion CNS Disord 2020; 22:19m02560. 56. Karoline RD, et al. Cariprazine augmentation in a patient with clozapine-resistant schizophrenia. Ind Psychiatry J 2023; 32:S279–S280. 57. Weise J, et al. Add-on cariprazine in patients with long-term clozapine treatment and treatment resistant schizophrenia: two cases of psychotic deterioration and Pisa syndrome. Clin Psychopharmacol Neurosci 2022; 20:398–401. 58. Rajarethinam R, et al. Augmentation of clozapine partial responders with conventional antipsychotics. Schizophr Res 2003; 60:97–98. 59. Barbui C, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia in routine clinical care: a randomized, controlled trial. J Clin Psychopharmacol 2011; 31:266–273. 60. Dursun SM, et al. Clozapine plus lamotrigine in treatment-resistant schizophrenia. Arch Gen Psychiatry 1999; 56:950. 61. Dursun SM, et al. Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study. J Psychopharmacol 2001; 15:297–301.

224 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 62. Tiihonen J, et al. Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial. Biol Psychiatry 2003; 54:1241–1248. 63. Kalyoncu A, et al. Use of lamotrigine to augment clozapine in patients with resistant schizophrenia and comorbid alcohol dependence: a potent anti-craving effect? J Psychopharmacol 2005; 19:301–305. 64. Goff DC, et al. Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials. J Clin Psychopharmacol 2007; 27:582–589. 65. Heck AH, et al. Addition of lamotrigine to clozapine in inpatients with chronic psychosis. J Clin Psychiatry 2005; 66:1333. 66. Vayisoglu S, et al. Lamotrigine augmentation in patients with schizophrenia who show partial response to clozapine treatment. Schizophr Res 2013; 143:207–214. 67. Tiihonen J, et al. The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res 2009; 109:10–14. 68. Zheng W, et al. Clozapine augmentation with antiepileptic drugs for treatment-resistant schizophrenia: a meta-analysis of randomized controlled trials. J Clin Psychiatry 2017; 78:e498–e505. 69. Olivola M, et al. Lurasidone augmentation of clozapine in refractory schizophrenia: a case series. J Clin Psychopharmacol 2023; 43:157–160. 70. Peet M, et al. Double-blind placebo controlled trial of N-3 polyunsaturated fatty acids as an adjunct to neuroleptics. Schizophr Res 1998; 29:160–161. 71. Puri BK, et al. Sustained remission of positive and negative symptoms of schizophrenia following treatment with eicosapentaenoic acid. Arch Gen Psychiatry 1998; 55:188–189. 72. Josiassen RC, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2005; 162:130–136. 73. Raskin S, et al. Clozapine and risperidone: combination/augmentation treatment of refractory schizophrenia: a preliminary observation. Acta Psychiatr Scand 2000; 101:334–336. 74. Anil Yagcioglu AE, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry 2005; 66:63–72. 75. Honer WG, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med 2006; 354:472–482. 76. Se HK, et al. The combined use of risperidone long-acting injection and clozapine in patients with schizophrenia non-adherent to clozapine: a case series. J Psychopharmacol 2010; 24:981–986. 77. Siskind DJ, et al. Augmentation strategies for clozapine refractory schizophrenia: a systematic review and meta-analysis. Aust N Z J Psychiatry 2018; 52:751–767. 78. Wang Y, et al. Valproate for schizophrenia. Cochrane Database Syst Rev 2016; 11:CD004028. 79. Shiloh R, et al. Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double-blind, placebo-controlled study. Br J Psychiatry 1997; 171:569–573. 80. Wang J, et al. Sulpiride augmentation for schizophrenia. Schizophr Bull 2010; 36:229–230. 81. Tiihonen J, et al. Topiramate add-on in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial. J Clin Psychiatry 2005; 66:1012–1015. 82. Afshar H, et al. Topiramate add-on treatment in schizophrenia: a randomised, double-blind, placebo-controlled clinical trial. J Psychopharmacol 2009; 23:157–162. 83. Muscatello MR, et al. Topiramate augmentation of clozapine in schizophrenia: a double-blind, placebo-controlled study. J Psychopharmacol 2011; 25:667–674. 84. Hahn MK, et al. Topiramate augmentation in clozapine-treated patients with schizophrenia: clinical and metabolic effects. J Clin Psychopharmacol 2010; 30:706–710. 85. Behdani F, et al. Effect of topiramate augmentation in chronic schizophrenia: a placebo-controlled trial. Arch Iran Med 2011; 14:270–275. 86. Millson RC, et al. Topiramate for refractory schizophrenia. Am J Psychiatry 2002; 159:675. 87. Zheng W, et al. Efficacy and safety of adjunctive topiramate for schizophrenia: a meta-analysis of randomized controlled trials. Acta Psychiatr Scand 2016; 134:385–398. 88. Zink M, et al. Combination of ziprasidone and clozapine in treatment-resistant schizophrenia. Hum Psychopharmacol 2004; 19:271–273. 89. Ziegenbein M, et al. Clozapine and ziprasidone: a useful combination in patients with treatment-resistant schizophrenia. J Neuropsychiatry Clin Neurosci 2006; 18:246–247. 90. Ziegenbein M, et al. Combination of clozapine and ziprasidone in treatment-resistant schizophrenia: an open clinical study. Clin Neuropharmacol 2005; 28:220–224. 91. Zink M, et al. Efficacy and tolerability of ziprasidone versus risperidone as augmentation in patients partially responsive to clozapine: a randomised controlled clinical trial. J Psychopharmacol 2009; 23:305–314. 92. Muscatello MR, et al. Augmentation of clozapine with ziprasidone in refractory schizophrenia: a double-blind, placebo-controlled study. J Clin Psychopharmacol 2014; 34:129–133. 93. Citrome L. Schizophrenia and valproate. Psychopharmacol Bull 2003; 37 Suppl 2:74–88. 94. Tranulis C, et al. Somatic augmentation strategies in clozapine resistance: what facts? Clin Neuropharmacol 2006; 29:34–44. 95. Suzuki T, et al. Augmentation of atypical antipsychotics with valproic acid. An open-label study for most difficult patients with schizophrenia. Hum Psychopharmacol 2009; 24:628–638. 96. Gupta S, et al. Olanzapine augmentation of clozapine. Ann Clin Psychiatry 1998; 10:113–115. 97. Friedman JI, et al. Pimozide augmentation of clozapine inpatients with schizophrenia and schizoaffective disorder unresponsive to clozapine monotherapy. Neuropsychopharmacology 2011; 36:1289–1295.

Schizophrenia and related psychoses CHAPTER 1 98. Gunduz-Bruce H, et al. Efficacy of pimozide augmentation for clozapine partial responders with schizophrenia. Schizophr Res 2013; 143:344–347. 99. Nielsen J, et al. Augmenting clozapine with sertindole: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol 2012; 32:173–178. 100. Doruk A, et al. A placebo-controlled study of extract of ginkgo biloba added to clozapine in patients with treatment-resistant schizophrenia. Int Clin Psychopharmacol 2008; 23:223–227. 101. de Lucena D, et al. Improvement of negative and positive symptoms in treatment-refractory schizophrenia: a double-blind, randomized, placebo-controlled trial with memantine as add-on therapy to clozapine. J Clin Psychiatry 2009; 70:1416–1423. 102. Veerman SR, et al. Adjunctive memantine in clozapine-treated refractory schizophrenia: an open-label 1-year extension study. Psychol Med 2017; 47:363–375. 103. Bruno A, et al. Acetyl-L-carnitine augmentation of clozapine in partial-responder schizophrenia: a 12-week, open-label uncontrolled preliminary study. Clin Neuropharmacol 2016; 39:277–280. 104. Seddigh R, et al. Levothyroxine augmentation in clozapine resistant schizophrenia: a case report and review. Case Rep Psychiatry 2015; 2015:678040. 105. Lin CH, et al. Sodium benzoate, a D-amino acid oxidase inhibitor, added to clozapine for the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Biol Psychiatry 2018; 84:422–432. 106. Kelly DL, et al. Adjunctive minocycline in clozapine-treated schizophrenia patients with persistent symptoms. J Clin Psychopharmacol 2015; 35:374–381. 107. Correll CU, et al. Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia: systematic overview and quality appraisal of the meta-analytic evidence. JAMA Psychiatry 2017; 74:675–684. 108. Nasrallah HA, et al. Successful treatment of clozapine-nonresponsive refractory hallucinations and delusions with pimavanserin, a serotonin 5HT-2A receptor inverse agonist. Schizophr Res 2019; 208:217–220. 109. Yolland CO, et al. Meta-analysis of randomised controlled trials with N-acetylcysteine in the treatment of schizophrenia. Aust N Z J Psychiatry 2020; 54:453–466. 110. Neill E, et al. N-acetylcysteine (NAC) in schizophrenia resistant to clozapine: a double-blind, randomized, placebo-controlled trial targeting negative symptoms. Schizophr Bull 2022; 48:1263–1272. 111. Andrade C. Antipsychotic augmentation with N-acetylcysteine for patients with schizophrenia. J Clin Psychiatry 2022; 83:22f14664.

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224 - Alternatives to clozapine

Alternatives to clozapine

226 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Alternatives to clozapine Clozapine has the strongest evidence for efficacy for schizophrenia that has proved refractory to adequate trials of standard antipsychotic medication. About three-quarters of these patients are treatment resistant from the onset of illness.1 Where treatment resistance has been established, clozapine treatment should not be delayed or withheld.2,3 The practice of using successive antipsychotic medications (or the latest) instead of clozapine is widespread but not supported by any research. Where clozapine cannot be used because of toxicity or patient refusal or unwillingness to comply with the mandatory monitoring tests, other drugs or drug combinations may be tried (Table 1.53). In practice, outcome is usually disappointing and long-term data on efficacy and safety are generally lacking. Available data do not allow any distinction between treatment regimens to be drawn, particularly choice of antipsychotic medication,4,5 but it seems wise to use single drugs before trying polypharmacy options. Olanzapine is perhaps the most often used antipsychotic monotherapy, usually in doses above the licensed range. If this fails, then the addition of a second antipsychotic (amisulpride, for example) is a possible next step, although the risk–benefit balance of combined antipsychotic medication regimens remains unclear.6 In people who have stopped clozapine, clozapine reintroduction and olanzapine are the only effective treatments.7 Among unconventional agents, minocycline and ondansetron have the advantage of low toxicity and good tolerability. With advances in the understanding of the neurobiology of TRS, non-dopaminergic treatments are an area of active research. Glutamatergic drugs such as evenamide8 (although bitopertin is inactive),9 5HT2A inverse agonists,10 trace amine-associated receptor 1 (TAAR1) agonists and muscarinic receptor agonists such as xanomeline may hold some promise.11 Many of the treatments listed in Table 1.53 are somewhat experimental and some of the compounds difficult to obtain (e.g. glycine, D-serine, sarcosine, etc.). Before using any of the regimens outlined, readers should consult the primary literature cited. Particular care should be taken to inform patients where prescribing is off-label and to ensure that they understand the potential adverse effects of the more experimental treatments. Table 1.53 Alternatives to clozapine (treatments are listed in alphabetical order – no preference is implied by position in table). Treatment Comments Allopurinol 300–600mg/day (+ antipsychotic)12–15 Increases adenosinergic transmission, which may reduce effects of dopamine. Three positive RCTs.12,13,15 Amisulpride16 (up to 1200mg/day) Single, small open study Antipsychotic polypharmacy Various antipsychotics in combination have been used. Data are limited, mainly in the form of case reports, open and naturalistic studies. RCTs show no advantage for polypharmacy over monotherapy.17 Aripiprazole18,19 (15–30mg/day) Single RCT indicating moderate effect in patients resistant to risperidone or olanzapine (+ others). Higher doses (60mg/day) have been used.20

Schizophrenia and related psychoses CHAPTER 1 Table 1.53 (Continued) Treatment Comments Asenapine (+ antipsychotic)21 A post-hoc analysis of a phase III extension study showed that add-on asenapine may be beneficial in some patients with TRS Blonanserin (+ antipsychotic)22 Atypical antipsychotic licensed in Japan and Korea. A retrospective cohort study involving 69 patients showed improved PANSS scores with add-on blonanserin23 Cariprazine (+ antipsychotic)24–26 Case reports of successful use of cariprazine as monotherapy or as add-on CBT27 Non-drug therapies should always be considered28 Deep brain stimulation Effectiveness of nucleus accumbens and subgenual anterior cingulate cortex targeted deep brain stimulation demonstrated in 4 of 7 patients with TRS29 D–Alanine 100mg/kg/day (+ antipsychotic)30 Glycine (NMDA) agonist. One positive RCT. D–Serine 30mg/kg/day (+ olanzapine)31 Glycine (NMDA) agonist. One positive RCT. D–Serine up to 3g as monotherapy32 Improved negative symptoms in one RCT, but inferior to high-dose olanzapine for treatment of positive symptoms ECT33 Open studies suggest moderate effect, as does a retrospective study.34 Often reserved for last-line treatment in practice but can be successful in the short35 and long36 term. A 2024 RCT was negative.37 Estradiol 100–200mcg transdermal/day (+ antipsychotic)38 Oestrogens may be psychoprotective and/or antipsychotic in women of child- bearing age especially on positive symptoms, at higher doses.39 Contraindications include being post-menopausal, history of VTE, stroke, breast cancer, migraine with aura. Unopposed estradiol increases risk of endometrial hyperplasia and malignancy – consult an endocrinologist. Evidence in men is lacking. Famotidine 100mg bd + antipsychotic40 H2 antagonist. One short (4-week) RCT suggested some benefit in overall PANSS and CGI scale scores. Ginkgo biloba (+ antipsychotic)41 A systematic review of studies published in China showed improvements in total and negative symptoms Lurasidone up to 240mg/day42 (+ vortioxetine) One RCT comparing standard with high-dose lurasidone produced comparable improvements in TRS when given up to 24 weeks.43 Appears to be well tolerated. The addition of vortioxetine to lurasidone was effective in a small case series.44 Memantine 20mg/day (+ antipsychotic)45–47 Memantine is an NMDA antagonist. Two RCTs. The larger of the two (n = 138) was negative. In the smaller (n = 21), memantine improved positive and negative symptoms when added to clozapine. In another study in non-refractory schizophrenia, memantine improved negative symptoms when added to risperidone. Minocycline 200mg/day (+ antipsychotic)48,49 May be anti-inflammatory and neuroprotective. One open study (n = 22) and one RCT (n = 54) suggest good effect on negative and cognitive symptoms. Also, one RCT (n = 52) of augmentation of clozapine showed improvement in some symptoms.50 RCT evidence of neuroprotective effect in early psychosis.51 Mirtazapine 30mg/day (+ antipsychotic)52–54 Two RCTs, one negative,53 one positive.52 Effect seems to be mainly on positive symptoms. N–acetylcysteine 2g/day (+ antipsychotic)40 One RCT suggests small benefits in negative symptoms and rates of akathisia. Another RCT showed benefits in chronic schizophrenia.55 Case study of successful use of 600mg/day.56 A large RCT failed to show any benefit when added to clozapine.57 (Continued)

228 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Table 1.53 (Continued) Treatment Comments Olanzapine58–63 5–25mg/day Supported by some well-conducted trials but clinical experience disappointing. Some patients show moderate response. Olanzapine 30–60mg/day High-dose olanzapine is more effective than other non-clozapine antipsychotics.64 High-dose olanzapine is not atypical65 and can be poorly tolerated66 with gross metabolic changes.67 Olanzapine + glycine68 (0.8g/kg/day) Small, double-blind crossover trial suggests clinically relevant improvement in negative symptoms Olanzapine + lamotrigine66,69 (up to 400mg/day) Reports contradictory and rather unconvincing. Reasonable theoretical basis for adding lamotrigine which is usually well tolerated. Ondansetron 8mg/day (+ antipsychotic) A systematic review of RCTs showed improvements in negative symptoms and general psychopathology. Effect on cognition inconclusive.70 Paliperidone LAI Improvement in endocrine and hepatic parameters and lower antipsychotic exposure in a small number of patients switched from clozapine to paliperidone 3-monthly. No data on clinical outcomes.71 Pimavanserin (+ antipsychotics) Clinical improvement with pimavanserin alone or as adjunct to clozapine or other antipsychotics in 10 patients, 6 of whom had failed to respond to clozapine72 Propentofylline + risperidone73 (900mg + 6mg/day) One RCT suggests some activity against positive symptoms Quetiapine74–77 Very limited evidence and clinical experience not encouraging. High doses (>1200mg/day) have been used but are no more effective.78 Raloxifene 60–120mg/day (+ antipsychotic)39 Selective oestrogen receptor modulator. May offer benefits of estradiol without long-term risks, but sexual dysfunction and weight gain may occur.39 Data in non-treatment resistance are rather conflicting, with two overlapping positive trials79,80 and one negative trial.81 One positive RCT in refractory psychosis in women.82 Evidence in men is lacking. Riluzole 100mg/day + risperidone up to 6mg/day83 Glutamate modulating agent. One RCT demonstrated improvement in negative symptoms. Risperidone84–86 4–8mg/day Doubtful efficacy in true TRS but some supporting evidence. May also be tried in combination with glycine68 or lamotrigine60 or indeed with other SGAs.87 Risperidone LAI 50/100mg 2/5288 One RCT showing good response for both doses in refractory schizophrenia. Plasma levels for 100mg dose similar to 6–8mg/day oral risperidone. Ritanserin + risperidone (12mg + 6mg/day) 5HT2A/2C antagonist. One RCT suggests small effect on negative symptoms. Sarcosine (2g/day)89,90 (+ antipsychotic) Enhances glycine action. Supported by two RCTs. Benefits may be in patients with non-TRS.91 Sertindole92 (12–24mg/day) One large RCT (conducted in 1996–68 but published in 2011) suggested good effect and equivalence to risperidone. Around half of subjects responded. Another RCT93 showed no effect at all when added to clozapine. Little experience in practice. Topiramate (300mg/day) (+ antipsychotic)94 Small effect shown in single RCT. Induces weight loss. Cognitive adverse effects likely. Teratogenic. (Continued)

06 - Chapter 1 Schizophrenia and related psychoses

225 - Summary of alternatives to clozapine

Summary of alternatives to clozapine

Schizophrenia and related psychoses CHAPTER 1 Summary of alternatives to clozapine Table 1.54 provides a summary of alternatives to clozapine in refractory schizophrenia. Table 1.54 Summary of alternatives to clozapine in refractory schizophrenia. Treatment Examples Comments Strength of evidence Monotherapy using non-clozapine antipsychotics in standard or high doses Aripiprazole 15–30mg daily Olanzapine 25–60mg daily Evidence of efficacy for any antipsychotic other than clozapine in refractory schizophrenia is controversial. Some data suggest efficacy for olanzapine above licensed doses but at the risk of metabolic adverse effects. Weak + Non-clozapine antipsychotic polypharmacy Amisulpride + olanzapine, quetiapine + amisulpride, aripiprazole + olanzapine, and various other combinations Polypharmacy is common in clinical practice. Evidence from controlled studies limited but open studies and real-world data suggest some effectiveness. Burden of adverse effects is increased. Weak + Anti-inflammatory agents as adjuncts to antipsychotics N-acetylcysteine, NSAIDs, minocycline, oestrogens, aspirin, omega-3 fatty acids A heterogeneous group of medicinal agents with inflammatory properties have been tried as adjuncts. Possible benefits in negative and cognitive symptoms but sample sizes have been small. Very weak ± NMDA receptor modulators as adjuncts Memantine, glycine, D-serine and sarcosine Rarely used in clinical practice. May have some benefit in negative symptoms. Very weak ± Treatment Comments Transcranial magnetic stimulation95,96 Conflicting results Ursodeoxycholic acid97 Single case reports Valproate98 Doubtful effect but may be useful where there is a clear affective component Yokukansan (+ antipsychotic)99 Japanese herbal medicine, partial agonist at D2 and 5HT1A, antagonist at 5HT2A and glutamate receptors. Potential small benefit in excitement/hostility symptoms. Another 12-week double-blind placebo-controlled RCT showed modest symptomatic improvement.100 Ziprasidone 80–160mg/day101–103 Two good RCTs. One103 suggests superior efficacy to chlorpromazine in refractory schizophrenia, the other101 suggests equivalence to clozapine in subjects with treatment intolerance/resistance. Disappointing results in practice. Supratherapeutic doses offer no advantage.104 Zotepine 300mg/day+105 One study showed that some patients do not deteriorate when switched from clozapine to zotepine CGI, Clinical Global Impression; LAI, long-acting injection; NMDA, N-methyl-D-aspartate; PANSS, Positive and Negative Syndrome Scale; TRS, treatment-resistant schizophrenia; VTE, venous thromboembolism. Table 1.53 (Continued) (Continued)

06 - Chapter 1 Schizophrenia and related psychoses

226 - References

References

230 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

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Hsu WY, et al. Aripiprazole in treatment-refractory schizophrenia. J Psychiatr Pract 2009; 15:221–226. Treatment Examples Comments Strength of evidence Physical treatments ECT, rTMS, tDCS, DBS Best evidence for ECT as adjunct to clozapine. Others still largely experimental. Modest ++ Adjunctive antidepressants Mirtazapine, vortioxetine, SSRIs Limited data available suggest small benefits in negative and cognitive symptoms. Weak + Adjunctive anticonvulsants Lamotrigine, topiramate, sodium valproate, carbamazepine Data difficult to interpret Weak + Psychological therapies CBT Conflicting findings, effects small. Very weak ± CBT, cognitive behavioural therapy; DBS, deep brain stimulation; NSAIDs, non-steroidal anti-inflammatory drugs; rTMS, repetitive transcranial magnetic stimulation; tDCS, transcranial direct current stimulation. Table 1.54 (Continued)

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Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Am J Psychiatry 1999; 156:294–298. 85. Bondolfi G, et al. Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group. Am J Psychiatry 1998; 155:499–504.

Schizophrenia and related psychoses CHAPTER 1 86. Conley RR, et al. Risperidone, quetiapine, and fluphenazine in the treatment of patients with therapy-refractory schizophrenia. Clin Neuropharmacol 2005; 28:163–168. 87. Lerner V, et al. Combination of ‘atypical’ antipsychotic medication in the management of treatment-resistant schizophrenia and schizoaffective disorder. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28:89–98. 88. Meltzer HY, et al. A six month randomized controlled trial of long acting injectable risperidone 50 and 100mg in treatment resistant schizophrenia. Schizophr Res 2014; 154:14–22. 89. Lane HY, et al. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo- controlled study. Arch Gen Psychiatry 2005; 62:1196–1204. 90. Tsai G, et al. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 2004; 55:452–456. 91. Marchi M, et al. Sarcosine as an add-on treatment to antipsychotic medication for people with schizophrenia: a systematic review and meta- analysis of randomized controlled trials. Expert Opin Drug Metab Toxicol 2021; 17:483–493. 92. Kane JM, et al. A double-blind, randomized study comparing the efficacy and safety of sertindole and risperidone in patients with treatment- resistant schizophrenia. J Clin Psychiatry 2011; 72:194–204. 93. Nielsen J, et al. Augmenting clozapine with sertindole: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol 2012; 32:173–178. 94. Tiihonen J, et al. Topiramate add-on in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial. J Clin Psychiatry 2005; 66:1012–1015. 95. Lorentzen R, et al. The efficacy of transcranial magnetic stimulation (TMS) for negative symptoms in schizophrenia: a systematic review and meta-analysis. Schizophrenia (Heidelb) 2022; 8:35. 96. Guttesen LL, et al. Repetitive transcranial magnetic stimulation and transcranial direct current stimulation for auditory hallucinations in schizophrenia: systematic review and meta-analysis. J Psychiatr Res 2021; 143:163–175. 97. Khosravi M. Ursodeoxycholic acid augmentation in treatment-refractory schizophrenia: a case report. J Med Case Rep 2020; 14:137. 98. Basan A, et al. Valproate as an adjunct to antipsychotics for schizophrenia: a systematic review of randomized trials. Schizophr Res 2004; 70:33–37. 99. Miyaoka T, et al. Efficacy and safety of yokukansan in treatment-resistant schizophrenia: a randomized, multicenter, double-blind, placebo- controlled trial. Evid Based Complement Alternat Med 2015; 2015:201592. 100. Horiguchi J, et al. A multicenter, double-blind, randomized, controlled study of patients with treatment-resistant schizophrenia treated with yokukansan for 12 weeks. PCN Rep 2023; 2:e155. 101. Sacchetti E, et al. Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study. Schizophr Res 2009; 110:80–89. 102. Loebel AD, et al. Ziprasidone in treatment-resistant schizophrenia: a 52-week, open-label continuation study. J Clin Psychiatry 2007; 68:1333–1338. 103. Kane JM, et al. Efficacy and tolerability of ziprasidone in patients with treatment-resistant schizophrenia. Int Clin Psychopharmacol 2006; 21:21–28. 104. Goff DC, et al. High-dose oral ziprasidone versus conventional dosing in schizophrenia patients with residual symptoms: the ZEBRAS study. J Clin Psychopharmacol 2013; 33:485–490. 105. Lin CC, et al. Switching from clozapine to zotepine in patients with schizophrenia: a 12-week prospective, randomized, rater blind, and parallel study. J Clin Psychopharmacol 2013; 33:211–214.

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Restarting clozapine after a break in treatment

234 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Restarting clozapine after a break in treatment Interruptions in clozapine treatment are commonplace.1 Patients prescribed clozapine should be advised to contact their prescriber if they stop taking the medication. This is partly because, if clozapine treatment is stopped abruptly, there is a need to monitor for symptoms of cholinergic rebound, such as nausea, vomiting, diarrhoea, sweating and headache,2,3 as well as the possible emergence of dystonias, dyskinesias and catatonic symptoms.4–7 If the last dose of clozapine was more than 48 hours ago, it should be re- introduced using a suitable dosage titration schedule.8 Depending on the time since clozapine was last taken, it may be feasible to re-titrate the dose to a therapeutic level more rapidly than is recommended for initial treatment. While there is some evidence to suggest that faster titrations may be safe in those patients naïve to clozapine2 as well as those re-starting it,3 there is the risk that such schedules could lead to drug discontinuation because of adverse effects. The risk of myocarditis, pneumonia, agranulocytosis and seizures, as well as the occurrence of adverse effects such as tachycardia and orthostatic hypotension, are probably reduced with slower initial titration schedules,8,9 and the same may apply to restarting. More cautious dosage titration will be appropriate for certain patients, such as those who are elderly, people with Parkinson’s disease and outpatients starting clozapine who are uncertain about the potential benefits of the medication.10–12 Furthermore, there is some evidence that tolerance to the effects of clozapine is lost after only a few weeks,13,14 so people who have missed clozapine treatment for more than a week should probably restart clozapine as if it were being initiated for the first time. Restarting clozapine after gaps of various lengths should take account of the need to regain antipsychotic activity with clozapine while ensuring safety during titration. Examples of slow, fast and ultra-fast titration schedules are available15 but it is probably best to individualise titration according to patient tolerability. A key element is flexibility: the dosage schedule prescribed for a patient will depend upon how previous dosages within the schedule are tolerated. In broad terms, this means starting with 12.5mg and increasing to 25mg for the next dose if the initial dose caused no adverse effects, such as sedation, increased heart rate or lowered blood pressure. If the 25mg dose is well tolerated then 50mg can be given for the next dose, and so on. In other words, the dose is doubled each time until the target daily dosage is reached (which is likely to be the dose the patient was taking before the break in medication). Twice daily dosing allows for a faster rate of titration than once daily dosing. Some centres use three times daily dosing, which allows for even quicker titration but may increase the risk of adverse effects caused by accumulation. For example, if a patient were to receive 12.5mg, 25mg and 50mg doses of clozapine on the first day of re- titration, then each successive dose would be added to what remains of previous doses. Thus, the effect of the 50mg dose in this schedule would be greater than a single (i.e. stat) dose of 50mg. The same phenomenon occurs with twice daily dosing, but with 12 hours between doses the contribution of the prior dose is more limited. Where a given dose in the titration schedule is not tolerated, the next dose should usually be delayed and not increased (or possibly decreased). Therefore, it is usually better to prescribe a series of single ‘stat’ doses, one at a time, rather than write up a complete schedule of doses that may then have to be changed.

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References

Schizophrenia and related psychoses CHAPTER 1 References

John AP, et al. Rates and reasons for clozapine treatment interruptions: impact of the frequency of hematologic monitoring and cardiac adverse events. J Clin Psychopharmacol 2023; 43:233–238.
Shiovitz TM, et al. Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal. Schizophr Bull 1996; 22:591–595.
Galova A, et al. A case report of cholinergic rebound syndrome following abrupt low-dose clozapine discontinuation in a patient with type I bipolar affective disorder. BMC Psychiatry 2019; 19:73.
Ahmed S, et al. Clozapine withdrawal-emergent dystonias and dyskinesias: a case series. J Clin Psychiatry 1998; 59:472–477.
Shrivastava M, et al. Relapse of tardive dyskinesia due to reduction in clozapine dose. Indian J Pharmacol 2009; 41:201–202.
Boazak M, et al. Catatonia due to clozapine withdrawal: a case report and literature review. Psychosomatics 2019; 60:421–427.
Lander M, et al. Review of withdrawal catatonia: what does this reveal about clozapine? Transl Psychiatry 2018; 8:139.
Flanagan RJ, et al. Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals. Br Med Bull 2020; 135:73–89.
de Leon J, et al. An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels. Pharmacopsychiatry 2022; 55:73–86.
Gee SH, et al. Patient attitudes to clozapine initiation. Int Clin Psychopharmacol 2017; 32:337–342.
Schulte PF, et al. Comment on ‘effectiveness and safety of rapid clozapine titration in schizophrenia’. Acta Psychiatr Scand 2014; 130:69–70.
Correll CU, et al. A guideline and checklist for initiating and managing clozapine treatment in patients with treatment-resistant schizophrenia. CNS Drugs 2022; 36:659–679.
National Association of Boards of Pharmacy (NABP). ISMP: Restarting clozapine too rapidly can cause severe cardiovascular effects. 2022 (last accessed February 2025); https://nabp.pharmacy/news/blog/regulatory_news/ismp-restarting-clozapine-too-rapidly-can-cause-severe- cardiovascular-effects.
Shastay A. Caution when restarting clozapine. Home Healthc Now 2022; 40:54–55.
Rubio JM, et al. How and when to use clozapine. Acta Psychiatr Scand 2020; 141:178–189.

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Initiation of clozapine in the community

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23 - Adverse effects

Adverse effects

Schizophrenia and related psychoses CHAPTER 1 monotherapy.24 Although the interpretation of such real-world findings is hindered by the issue of confounding by indication,25 there are perhaps several plausible explanations for improved efficacy with polypharmacy. It may be that combining antipsychotic medications with different receptor profiles can be more effective and lead to better therapeutic efficacy and/or a lower adverse-effect burden and therefore better outcomes. It may be also that co-prescribing two antipsychotic medications improves medication adherence in that it increases the likelihood that a patient may use at least one of them.24 Notably, clozapine and LAI antipsychotic preparations appear to be the most effective monotherapies for relapse prevention in schizophrenia.26 Thus, adding a second antipsychotic medication to clozapine or an LAI antipsychotic medication in an attempt to mitigate metabolic adverse effects (e.g. by adding aripiprazole) or manage symptoms of agitation, anxiety or sleep disturbance (e.g. by adding olanzapine or quetiapine) might enhance a patient’s engagement in their treatment and improve adherence to the effective antipsychotic treatment that has been augmented. Adverse effects Evidence for possible harm with combined antipsychotic medications is perhaps more convincing. Clinically significant adverse effects have been associated with combined antipsychotic medications, which may partly reflect that polypharmacy regimens are commonly a high-dose prescription.8,27 There is an increased prevalence and severity of EPS,28,29 increased metabolic adverse effects and diabetes,22,30,31 sexual dysfunction,32 an increased risk of hip fracture,33 paralytic ileus,34 grand mal seizures,35 prolonged QTc,36 hypertension37 and arrhythmias.13 Switching from antipsychotic polypharmacy to monotherapy has been shown to lead to worthwhile improvements in cognitive functioning.20 The evidence relating to an increased mortality with a continuing antipsychotic polypharmacy regimen is inconsistent. Two large case–control studies and a database study38–40 found no increased mortality in patients with schizophrenia receiving anti psychotic polypharmacy compared with antipsychotic monotherapy. However, a 10-year prospective study of a cohort of 88 patients with schizophrenia found that receiving more than one antipsychotic medication concurrently was associated with substantially increased mortality.18,41 These investigators explored the possibility that the use of combined antipsychotic medications might be a proxy for greater severity/increased refractoriness of psychiatric illness but found no association between mortality and any measured index of illness severity, although these measures focused on negative symptoms and cognitive deficits. Further, analysis of data from a large anonymised mental healthcare database (2007–2014) of 10,945 adult patients with serious mental illness who had been prescribed a single antipsychotic or polypharmacy for 6 months or more revealed a weak association between regular, long-term antipsychotic polypharmacy and all-cause mortality and natural causes of death.42 However, the authors concluded that the evidence for the association was limited, even after controlling for the effect of dose. Another study, involving the follow-up of 99 patients with schizophrenia over a 25-year period, found that those prescribed three antipsychotics simultaneously were twice as likely to die as those who had been prescribed only one.43 These authors also considered the possibility of indication bias influencing the findings, speculating that combined antipsychotic medication might be more likely to be prescribed for the most severe schizophrenia.

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230 - Relative contraindications to community initi

Relative contraindications to community initiation

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231 - Essential criteria for suitability for commun

Essential criteria for suitability for community initiation

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232 - Initial work up

Initial work-up

236 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Initiation of clozapine in the community While in-patient initiation remains the main method of starting clozapine, community initiation is fairly common in many countries. The likelihood of successful titration is similar for both methods (about 60%),1 indicating that any risks associated with reduced monitoring frequency are offset by the relatively slower initiation schedules employed in the community. Relative contraindications to community initiation ■ ■History of uncontrolled seizures, significant cardiac disease, unstable diabetes, paralytic ileus, significant blood dyscrasia, neuroleptic malignant syndrome or other disorder that increases the risk of serious adverse effects (initiation with close monitoring in hospital may still be possible). ■ ■Previous severe adverse effects on titration of clozapine or other antipsychotics. ■ ■Unreliable or chaotic lifestyle that may affect adherence to the medication or the monitoring regimen. ■ ■Significant abuse of alcohol or other drugs likely to increase the risk of adverse effects (e.g. cocaine). Essential criteria for suitability for community initiation ■ ■Is the patient likely to be adherent with oral medication and to monitoring requirements or is there support for these? ■ ■Has the patient understood the need for regular physical monitoring and blood tests? ■ ■Has the patient understood the possible adverse effects and what to do about them (particularly the rare but serious ones)? ■ ■Is the patient readily contactable (e.g. in the event of a result that needs follow-up)? ■ ■Is it possible for the patient to be seen weekly or more often during the early titration phase? ■ ■Is the patient able to collect medication every week or can medication be delivered to their home? ■ ■Is the patient likely to be able to seek help out-of-hours if they experience potentially serious adverse effects (e.g. indicators of myocarditis or infection such as fever, malaise, chest pain)? ■ ■Has the patient understood what needs to be done in the event of an abnormal blood test (e.g. daily monitoring of FBC until normalisation in the case of a RED result)? Initial work-up To screen for risk factors and provide a baseline: ■ ■Physical examination, FBC (see below), liver function tests, urea and electrolytes, lipids, glucose/HbA1c. Also, C-reactive protein (CRP), CK, troponin, beta-natriuretic peptide (BEN; as baseline for further tests). ■ ■ECG: particularly to screen for evidence of past myocardial infarction or ventricular abnormality.

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Mandatory blood monitoring and registration

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Dosing

Schizophrenia and related psychoses CHAPTER 1 ■ ■Echocardiogram if clinically indicated. ■ ■Consider work-up for BEN where baseline neutrophil counts are low (see section on clozapine, neutropenia and lithium in this chapter). Genetic testing for BEN is also available (see section on clozapine: genetic testing for clozapine treatment in this chapter). Mandatory blood monitoring and registration ■ ■Register with the relevant monitoring service. ■ ■Perform baseline blood tests (white cell and differential counts) before starting clozapine. ■ ■Further blood testing continues weekly for the first 18 weeks and then every 2 weeks for the remainder of the year. After that, the blood monitoring is usually done monthly. ■ ■Inform the patient’s GP. Dosing Starting clozapine in the community requires a slow and flexible titration schedule. Prior antipsychotics should be slowly discontinued during the titration phase (depots can usually be stopped at the start of titration). Clozapine can, of course, cause marked postural hypotension. The initial monitoring is partly aimed at detecting and managing this, partly at ensuring sedative effects are manageable. There are two approaches to giving the first dose of clozapine in the community. One is to give the first dose in the morning in clinic and then monitor the patient for postural hypotension for at least 1 hour. If the dose is well tolerated, the patient is then allowed home with a dose to take before going to bed. The second approach involves giving the patient the first dose to take immediately before bed, thereby avoiding the need for close physical monitoring immediately after administration. All initiations should take place early in the week (e.g. on a Monday) so that adequate staffing and monitoring are assured. Unless there are significant concerns regarding tolerability (e.g. postural hypotension), the 1-hour monitoring for morning doses in clinic can be omitted. Previous guidelines2,3 recommended physical observations on 5 days/week during weeks one and two of community clozapine initiations, followed by 3 days/week for weeks three and four. A 2023 study showed that this frequency can be reduced when using a slower titration schedule.4 Example titration schedules for these two protocols are shown in Table 1.55. These dose increase schedules are examples and may need to be adjusted based on tolerability and target dose. Additional reviews may be necessary to manage adverse effects. The low-frequency monitoring (on the left of the table) is suitable for most patients and even lower frequency of monitoring may be feasible in some patients (e.g. re-titration of clozapine where the patient tolerated it well previously). The standard monitoring frequency is recommended for patients who may be more sensitive to adverse effects (e.g. female non-smokers) or who may struggle to adhere to frequent dose adjustments. The two protocols do not differ in the frequency of physical monitoring after week four (i.e. both reduce to once a week). As with in-patient initiation, estimating the target dose for each individual patient is recommended before starting clozapine. This gives some idea of the likely duration of the titration schedule. Genetic testing appears to be the most accurate method of predicting an effective dose.5

238 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Table 1.55 Suggested titration regimens for initiation of clozapine in the community. Day Low-frequency monitoring Morning dose (mg) Evening dose (mg) Standard- frequency monitoring Morning dose (mg) Evening dose (mg) Approximate percentage dose of previous antipsychotic Mon #* 6.25 Mon #* 6.25 6.25 2 Tue 12.5 Tue # 6.25 12.5 Wed # 6.25 12.5 Wed # 12.5 12.5 Thu 6.25 Thu # 12.5 5 Fri # 12.5 Fri # 25 Sat 12.5 Sat 25 Sun 12.5 37.5 Sun 50 Mon #* 37.5 Mon #* 50 9 Tue 50 Tue # 50 Wed # 62.5 Wed # 50 Thu 75 Thu # 75 Fri # 37.5 Fri # 75 Sat 37.5 Sat 75 Sun 37.5 87.5 Sun 75 Mon #* 87.5 Mon #* 100 16 Tue 100 Tue 100 Wed 125 Wed # 125 Thu # 125 Thu 125 Fri 125 Fri # 150 Sat 125 Sat 150 Sun 150 Sun 150 Mon #* 150 Mon #* 175 23 Tue 150 Tue 175 Wed 150 Wed 200 Thu # 150 Thu # 200 Fri 150 Fri 225 Sat 150 Sat 225 Sun 175 Sun 225 Further increments should be 25–50mg/day (generally 25mg/day) until target dose is reached (use plasma levels). Beware of sudden increase in plasma levels due to saturation of first-pass metabolism (watch for increase in sedation/other adverse effects). # Face-to-face assessments including physical observations (sitting and standing blood pressure, heart rate, oxygen saturation, temperature and respiratory rate), adverse effect and mental state review, actively manage adverse effects (e.g. behavioural advice, slow clozapine titration or reduce dose of other antipsychotic, start adjunctive treatments – see sections on clozapine adverse effects in this chapter). * Full blood count; also consider C-reactive protein, CK, troponin, beta-natriuretic peptide.

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235 - Adverse effects

Adverse effects

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236 - Recommended additional monitoring

Recommended additional monitoring

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237 - Switching from other antipsychotics

Switching from other antipsychotics

Schizophrenia and related psychoses CHAPTER 1 Adverse effects Sedation, hypersalivation and hypotension are common at the start of treatment. These effects can usually be managed (see section on clozapine: common adverse effects in this chapter) but require particular attention in community titration. Consider regular systematic assessment of adverse effects using a recognised scale such as the GASS for Clozapine. The formal carer (usually the community psychiatric nurse) should inform the prescriber if: ■ ■temperature rises above 38°C (this is very common and is not a good reason, on its own, for stopping clozapine) ■ ■pulse is >100bpm (also common and not, on its own, a reason for stopping, but may sometimes be linked to myocarditis) ■ ■postural drop of >30mmHg ■ ■patient is clearly over-sedated ■ ■any signs of constipation (initiate laxatives early) ■ ■flu-like symptoms (malaise, fatigue, etc.) ■ ■chest pain, dyspnoea, tachypnoea ■ ■any other adverse effect that is intolerable ■ ■changes in smoking habit. The patient should be reviewed at least once a week for the first month to assess mental and physical state. Recommended additional monitoring Baseline 1 month 3 months 4–6 months 12 months Weight/BMI/waist Weight/BMI/weight Weight/BMI/ waist Weight/BMI/waist Weight/BMI/waist Plasma glucose and lipids Plasma glucose and lipids Plasma glucose and lipids Plasma glucose and lipids LFTs LFTs Monitor CRP, CK, troponin weekly in the first four weeks of treatment or if temperature is above 38°C (see section on clozapine and myocarditis). CK, B-natriuretic peptide and echocardiogram should be used to confirm or rule out myocarditis if CRP and troponin are raised above thresholds.6 Switching from other antipsychotics ■ ■The switching regimen will be largely dependent on the patient’s mental state. ■ ■Consider potential additive adverse effects of antipsychotics (e.g. hypotension, sedation, effect on QTc interval). ■ ■Consider drug interactions (e.g. some SSRIs may increase clozapine levels). ■ ■Other antipsychotics and clozapine may be cross-tapered with varying degrees of caution. ECG monitoring is prudent when clozapine is co-prescribed with other drugs known to affect QT interval. (Pimozide and ziprasidone should be stopped before clozapine is started.)

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238 - Serious cardiac adverse effects

Serious cardiac adverse effects

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239 - References

References

240 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Serious cardiac adverse effects See section on clozapine: serious cardiovascular adverse effects in this chapter. Patients should be closely observed for signs or symptoms of myocarditis, particularly during the first month,7 and advised to inform staff if they experience cardiac symptoms and to seek out-of-hours review if necessary. These symptoms include persistent tachycardia (although commonly benign), palpitations, shortness of breath, fever, arrhythmia, symptoms mimicking myocardial infarction, chest pain, unusually low blood pressure and other unexplained symptoms of heart failure. Myocarditis risk is probably lower when using the slow titrations used in the community.8 References

Butler E, et al. Real-world clinical and cost-effectiveness of community clozapine initiation: mirror cohort study. Br J Psychiatry 2022; 221:740–747.
Beck K, et al. The practical management of refractory schizophrenia—the Maudsley Treatment REview and Assessment Team service approach. Acta Psychiatr Scand 2014; 130:427–438.
Taylor DM, et al. The Maudsley Prescribing Guidelines in Psychiatry, 14th edn. Oxford: Wiley-Blackwell; 2021.
Mizuno Y, et al. Low-frequency monitoring for community clozapine initiations: a comparative study relative to standard frequency assessments. J Psychopharm 2023; 37:627–629.
Taylor D, et al. Predicting clozapine dose required to achieve a therapeutic plasma concentration: a comparison of a population algorithm and three algorithms based on gene variant models. J Psychopharmacol 2023; 37:1030–1039.
Clark SR, et al. Dotting the I’s and crossing the T’s: a South Australian perspective on variability in troponin thresholds for myocarditis risk in clozapine treatment. Schizophr Res 2023; 268:114–117.
Correll CU, et al. A guideline and checklist for initiating and managing clozapine treatment in patients with treatment-resistant schizophrenia. CNS Drugs 2022; 36:659–679.
de Leon J, et al. Escaping the long shadow cast by agranulocytosis: reflections on clozapine pharmacovigilance focused on the United Kingdom. J Clin Psychopharmacol 2023; 43:239–245.

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24 - The use of combined antipsychotic medications

The use of combined antipsychotic medications in clinical practice

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240 - CLOZAPINE ADVERSE EFFECTS

CLOZAPINE ADVERSE EFFECTS

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241 - Clozapine common adverse effects

Clozapine: common adverse effects

Schizophrenia and related psychoses CHAPTER 1 CLOZAPINE ADVERSE EFFECTS Clozapine: common adverse effects This section provides a summary of management of the common adverse effects of clozapine. Adverse effect Time course Action Constipation First 4 months are the highest risk.1 Usually persists and so requires continuous monitoring and treatment. Advise patients of the risks before starting, screen regularly, ensure adequate fibre, fluid and exercise. Consider early or even prophylactic laxatives. Stimulant laxatives (senna or bisacodyl) are first-line treatments, with emollients (docusate) and/or osmotics (macrogols).2 Bulk-forming laxatives should be avoided. Stop other medicines that may be contributing and reduce clozapine dose if possible. Effective treatment or prevention of constipation is essential, as death may result.3,4 See section on clozapine-induced gastrointestinal hypomotility in this chapter. Fever5 First 4 weeks6 Clozapine induces inflammatory response (increased CRP, interleukin-6 and eosinophils).7–9 Give paracetamol but check FBC for neutropenia. Reduce rate of dose titration.10 Concurrent valproate or quetiapine may increase risk.11 This fever is not usually related to blood dyscrasias12 but beware myocarditis, NMS, pneumonia and other rarer types of inflammatory organ damage (see section on clozapine: uncommon or unusual adverse effects in this chapter). Gastro-esophageal reflux disease13,14 Any time Proton pump inhibitors often prescribed but some are CYP1A2 inducers and possibly increase risk of neutropenia and agranulocytosis.15,16 Reasons for GERD association unclear – clozapine is an H2 antagonist.17 Hypersalivation First few months. Usually persists but sometimes wears off. Often very troublesome at night. Reduce dose if possible.18 Many options available19 (see section on clozapine-induced hypersalivation in this chapter). Systemic anticholinergic drugs worsen constipation and cognition and so should not be used first line. Hypertension20 First 4 weeks, sometimes longer Monitor closely and increase dose as slowly as is necessary. Hypotensive therapy is sometimes necessary.21 Hypotension First 4 weeks Advise patient to stand up in stages. Reduce dose or slow down rate of increase. Ensure fluid intake of >2L daily.22 If severe, consider fludrocortisone 0.05–0.3mg daily first line (monitor fluid intake, potassium and sodium) or midodrine 2.5–5mg three times a day (maximum 30mg/day).23 Other options include moclobemide and Bovril® in combination or etilefrine.23 Myoclonus24–27 During dose titration or plasma level increases May precede full tonic-clonic seizure. May present as knee- buckling.28 Reduce dose. Antiseizure drugs may help and will reduce the likelihood of progression to seizures. Valproate is first choice but has limited utility. Referral to neurology specialist is advised. Nausea First 6 weeks May give anti-emetic. Avoid prochlorperazine if previous EPS. Avoid domperidone if underlying cardiac risk or QTc prolongation. Ondansetron is a good choice, but it may worsen constipation. Metoclopramide may help with hypersalivation. Nausea and vomiting can be the only presenting symptoms of myocarditis.29 (Continued)

242 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Adverse effect Time course Action Nocturnal enuresis May occur at any time Try reducing the dose or manipulating dose schedule to avoid periods of deep sedation. Avoid fluids before bedtime. Consider scheduled night-time toileting. May resolve spontaneously,30 but may persist for months or years.31 Seems to affect 1 in 5 people on clozapine.32 Try aripiprazole (10–15mg daily) or desmopressin (10mcg/mL nasal spray into each nostril at night, or 200–400mcg orally at night).33 Monitoring for hyponatraemia is essential. Other options include oxybutynin, trihexyphenidyl, imipramine, amitriptyline and verapamil.33 Pneumonia34,35 Usually early in treatment, but may be any time May result from saliva aspiration (this may be why pneumonia appears to be dose related),36,37 and very rarely from constipation.38 Pneumonia is a common cause of death in people on clozapine.39 Infections in general may be more common in those on clozapine40 and use of antibiotics is also increased.41 Obesity,34 anticholinergic burden35 and treatment-resistant schizophrenia itself may also contribute to risk.34 Respiratory infections may give rise to elevated clozapine levels.42,43–45 This may be an artefact: smoking usually ceases during an infection and inflammation itself causes a reduction in CYP1A2 activity.46,47 Clozapine is often successfully continued after the pneumonia has resolved, but recurrence may be more likely.48–50 Sedation First few months. May persist, but usually wears off to some extent. Give smaller dose in the morning. Give evening dose earlier if morning waking is troublesome. Once daily dosing in the evening seems effective and well tolerated.51,52 Case reports of successful use of psychostimulants (methylphenidate53) and betahistine.54 Modafinil does not appear to be effective.55 Aripiprazole may help.56 Seizures57 May occur at any time58 Related to dose, plasma level and rapid dose escalation.25 There is no step-change in risk at a particular dose or level. Consider prophylactic, topiramate, lamotrigine, gabapentin or valproate* if there are risk factors for seizures and or plasma level is high (≥600mcg/L). Some suggest risk of seizures below 1300mcg/L is not enough to support primary prophylaxis.59 After a seizure: withhold clozapine for one day; restart at half previous dose; give antiseizure medication.** Tachycardia First 4 weeks, but usually persists Very common in early stages of treatment but usually benign. May be dose-related.60 Tachycardia, if persistent at rest and associated with fever, hypotension or chest pain, may indicate myocarditis or pericarditis (see section on clozapine: serious cardiovascular adverse effects in this chapter). Referral to a cardiologist is advised. Benign sinus tachycardia can be treated with bisoprolol61 or atenolol,62 although evidence base is poor.63,64 Ivabradine may be used if hypotension or contraindications limit the use of beta blockers.65 Prolonged tachycardia can itself precipitate cardiomyopathy66 or other cardiovascular consequences.22 Weight gain Usually during the first year of treatment, but may continue Dietary counselling is essential. Advice may be more effective if given before weight gain occurs. Weight gain is common and often profound (4.5kg in the first 10 weeks).67 Many treatments available (see section on treatment of antipsychotic-induced weight gain in this chapter). * Usual dose is 1000–2000mg/day. Plasma levels may be useful as a rough guide to dosing – aim for 50–100mg/L. Use of modified-release preparation (Epilim Chrono) may aid compliance: can be given once daily and may be better tolerated. ** Lamotrigine may be helpful if poor response to clozapine or continued negative symptoms; topiramate if weight loss required (but beware cognitive adverse effects); gabapentin if other anticonvulsants are poorly tolerated.25 Valproate should be avoided in most cases because of the risks of neurodevelopmental disorders and birth defects if valproate is taken during pregnancy or prior to conception (in the case of men). EEG abnormalities are common in those on clozapine.68,69 CRP, C-reactive protein; EPS, extrapyramidal symptoms; GERD, gastro-esophageal reflux disease. (Continued)

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References

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Palmer SE, et al. Life-threatening clozapine-induced gastrointestinal hypomotility: an analysis of 102 cases. J Clin Psychiatry 2008; 69:759–768.
Taylor D, et al. The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry. Chichester: Wiley-Blackwell; 2021.
Handley SA, et al. Clozapine-induced gastrointestinal hypomotility: presenting features and outcomes, UK pharmacovigilance reports, 1992–2017. Br J Psychiatry 2022; 220:355–363.
Partanen JJ, et al. High burden of ileus and pneumonia in clozapine-treated individuals with schizophrenia: a Finnish 25-year follow-up register study. Am J Psychiatry 2024; 181:879–892.
Verdoux H, et al. Clinical determinants of fever in clozapine users and implications for treatment management: a narrative review. Schizophr Res 2019; 211:1–9.
Martins PLB, et al. Immunoinflammatory and oxidative alterations in subjects with schizophrenia under clozapine: a meta-analysis. Eur Neuropsychopharmacol 2023; 73:82–95.
Hung YP, et al. Role of cytokine changes in clozapine-induced fever: a cohort prospective study. Psychiatry Clin Neurosci 2017; 71:395–402.
Kohen I, et al. Increases in C-reactive protein may predict recurrence of clozapine-induced fever. Ann Pharmacother 2009; 43:143–146.
Kluge M, et al. Effects of clozapine and olanzapine on cytokine systems are closely linked to weight gain and drug-induced fever. Psychoneuroendocrinology 2009; 34:118–128.
Chung JP, et al. The incidence and characteristics of clozapine- induced fever in a local psychiatric unit in Hong Kong. Can J Psychiatry 2008; 53:857–862.
Kikuchi Y, et al. Effects of titration speed, gender, obesity and concomitant medications on the risk and onset time of clozapine-associated fever among Japanese patients with schizophrenia: retrospective review of charts from 21 hospitals. Br J Psychiatry 2024; 6:1–7.
Tham JC, et al. Clozapine-induced fevers and 1-year clozapine discontinuation rate. J Clin Psychiatry 2002; 63:880–884.
Taylor D, et al. Use of antacid medication in patients receiving clozapine: a comparison with other second-generation antipsychotics. J Clin Psychopharmacol 2010; 30:460–461.
Van Veggel M, et al. Clozapine and gastro-oesophageal reflux disease (GORD): an investigation of temporal association. Acta Psychiatr Scand 2013; 127:69–77.
Wicinski M, et al. Potential mechanisms of hematological adverse drug reactions in patients receiving clozapine in combination with proton pump inhibitors. J Psychiatr Pract 2017; 23:114–120.
Shuman MD, et al. Exploring the potential effect of polypharmacy on the hematologic profiles of clozapine patients. J Psychiatr Pract 2014; 20:50–58.
Humbert-Claude M, et al. Involvement of histamine receptors in the atypical antipsychotic profile of clozapine: a reassessment in vitro and in vivo. Psychopharmacology (Berl) 2011; 220:225–241.
Schoretsanitis G, et al. Elevated clozapine concentrations in clozapine-treated patients with hypersalivation. Clin Pharmacokinet 2021; 60:329–335.
Fornaro M, et al. Pharmacological interventions for antipsychotic-related sialorrhea: a systematic review and network meta-analysis of randomized trials. Mol Psychiatry 2023; 28:3648–3660.
Gonsai NH, et al. Effects of dopamine receptor antagonist antipsychotic therapy on blood pressure. J Clin Pharm Ther 2017; 43:1–7.
Henderson DC, et al. Clozapine and hypertension: a chart review of 82 patients. J Clin Psychiatry 2004; 65:686–689.
Ronaldson KJ. Cardiovascular disease in clozapine-treated patients: evidence, mechanisms and management. CNS Drugs 2017; 31:777–795.
Tanzer TD, et al. Treatment strategies for clozapine-induced hypotension: a systematic review. Ther Adv Psychopharmacol 2022; 12:20451253221092931.
Osborne IJ, et al. Clozapine-induced myoclonus: a case report and review of the literature. Ther Adv Psychopharmacol 2015; 5:351–356.
Varma S, et al. Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Ther Adv Psychopharmacol 2011; 1:47–66.
Praharaj SK, et al. Clozapine-induced myoclonus: a case study and brief review. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:242–243.
Sajatovic M, et al. Clozapine-induced myoclonus and generalized seizures. Biol Psychiatry 1996; 39:367–370.
Sahib Din J, et al. Knee buckling as an atypical adverse effect of clozapine: a case report. Cureus 2024; 16:e55865.
van der Horst MZ, et al. Isolated nausea and vomiting as the cardinal presenting symptoms of clozapine-induced myocarditis: a case report. BMC Psychiatry 2020; 20:568.
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Harrison-Woolrych M, et al. Nocturnal enuresis in patients taking clozapine, risperidone, olanzapine and quetiapine: comparative cohort study. Br J Psychiatry 2011; 199:140–144.
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244 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 36. Trigoboff E, et al. Sialorrhea and aspiration pneumonia: a case study. Innov Clin Neurosci 2013; 10:20–27. 37. Kuo CJ, et al. Second-generation antipsychotic medications and risk of pneumonia in schizophrenia. Schizophr Bull 2013; 39:648–657. 38. Galappathie N, et al. Clozapine-associated pneumonia and respiratory arrest secondary to severe constipation. Med Sci Law 2014; 54:105–109. 39. Taylor DM, et al. Reasons for discontinuing clozapine: matched, case-control comparison with risperidone long-acting injection. Br J Psychiatry 2009; 194:165–167. 40. Landry P, et al. Increased use of antibiotics in clozapine-treated patients. Int Clin Psychopharmacol 2003; 18:297–298. 41. Nielsen J, et al. Increased use of antibiotics in patients treated with clozapine. Eur Neuropsychopharmacol 2009; 19:483–486. 42. Raaska K, et al. Bacterial pneumonia can increase serum concentration of clozapine. Eur J Clin Pharmacol 2002; 58:321–322. 43. de Leon J, et al. Serious respiratory infections can increase clozapine levels and contribute to side effects: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27:1059–1063. 44. Ruan CJ, et al. Pneumonia can cause clozapine intoxication: a case report. Psychosomatics 2017; 58:652–656. 45. Leung JG, et al. Necrotizing pneumonia in the setting of elevated clozapine levels. J Clin Psychopharmacol 2016; 36:176–178. 46. de Leon J, et al. A rational use of clozapine based on adverse drug reactions, pharmacokinetics, and clinical pharmacopsychology. Psychother Psychosom 2020; 89:200–214. 47. Clark SR, et al. Elevated clozapine levels associated with infection: a systematic review. Schizophr Res 2018; 192:50–56. 48. Hung GC, et al. Antipsychotic reexposure and recurrent pneumonia in schizophrenia: a nested case-control study. J Clin Psychiatry 2016; 77:60–66. 49. Galappathie N, et al. Clozapine re-trial in a patient with repeated life threatening pneumonias. Acta Biomed 2014; 85:175–179. 50. Schmidinger S, et al. Pulmonary embolism and aspiration pneumonia after reexposure to clozapine: pulmonary adverse effects of clozapine. J Clin Psychopharmacol 2014; 34:385–387. 51. Tsukahara M, et al. Impact of clozapine once-daily versus multiple-daily dosing regimen on relapse in patients with treatment-resistant schizophrenia: a 1-year retrospective cohort study. Psychopharmacology 2025; 242:161–171. 52. Sathienluckana T, et al. Comparison of the effectiveness and safety of clozapine between once-daily and divided dosing regimen in patients with treatment-resistant schizophrenia. Ann Pharmacother 2024; 58:598–604. 53. Sarfati D, et al. Methylphenidate as treatment for clozapine-induced sedation in patients with treatment-resistant schizophrenia. Clin Schizophr Relat Psychoses 2018; doi: 10.3371/CSRP.SALA.061518. 54. Poyurovsky M, et al. Beneficial effect of betahistine, a structural analog of histamine, in clozapine-related sedation. Clin Neuropharmacol 2019; 42:145. 55. Freudenreich O, et al. Modafinil for clozapine-treated schizophrenia patients: a double-blind, placebo-controlled pilot trial. J Clin Psychiatry 2009; 70:1674–1680. 56. Fernandez-Egea E, et al. The effect of clozapine on self-reported duration of sleep and its interaction with 23 other medications: a 5-year naturalistic study. J Clin Psychopharmacol 2021; 41:534–539. 57. Grover S, et al. Association of clozapine with seizures: a brief report involving 222 patients prescribed clozapine. East Asian Arch Psychiatry 2015; 25:73–78. 58. Pacia SV, et al. Clozapine-related seizures: experience with 5,629 patients. Neurology 1994; 44:2247–2249. 59. Caetano D. Use of anticonvulsants as prophylaxis for seizures in patients on clozapine. Australas Psychiatry 2014; 22:78–83. 60. Nilsson BM, et al. Tachycardia in patients treated with clozapine versus antipsychotic long-acting injections. Int Clin Psychopharmacol 2017; 32:219–224. 61. Nilsson BM, et al. Persistent tachycardia in clozapine treated patients: a 24-hour ambulatory electrocardiogram study. Schizophr Res 2018; 199:403–406. 62. Stryjer R, et al. Beta-adrenergic antagonists for the treatment of clozapine-induced sinus tachycardia: a retrospective study. Clin Neuropharmacol 2009; 32:290–292. 63. Lally J, et al. Pharmacological interventions for clozapine-induced sinus tachycardia. Cochrane Database Syst Rev 2016; (6):CD011566. 64. Yuen JWY, et al. Clozapine-induced cardiovascular side effects and autonomic dysfunction: a systematic review. Front Neurosci 2018; 12:203. 65. Lally J, et al. Ivabradine, a novel treatment for clozapine-induced sinus tachycardia: a case series. Ther Adv Psychopharmacol 2014; 4:117–122. 66. Shinbane JS, et al. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. 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243 - Clozapine uncommon or unusual adverse effects

Clozapine: uncommon or unusual adverse effects

Schizophrenia and related psychoses CHAPTER 1 Clozapine: uncommon or unusual adverse effects Adverse effect Time course Comment Agranulocytosis (delayed)1–4 Usually first 3 months but may occur at any time Occasional reports of apparent clozapine-related blood dyscrasia even after 1 year of treatment. Some suggest risk may be elevated for up to 9 years.5 It is very likely that clozapine is not the causative agent in most, if not all late cases6,7 (see section on clozapine: serious haematological adverse effects in this chapter). Colitis/gastrointestinal necrosis8–15 Usually within the first month but may be any time16 Growing body of case reports. Any severe or chronic diarrhoea should prompt specialist referral as there is a substantial risk of death. Use of drugs with anticholinergic effects probably increases risk of colitis and necrosis.17 Delirium18–20 Any time Reported rates vary (0.1–10%)18,21,22 but rarely seen in practice if dose is titrated slowly and plasma level determinations are used. Older age and medical comorbidity increase the risk of delirium. Ensure common causes of delirium are treated. Cholinergic rebound resulting from abrupt cessation of clozapine can cause delirium. Eosinophilia23–25 First week,26,27 but can be any time Reasonably common but significance unclear. Eosinophilia may predict neutropenia but this is disputed. Usually benign but investigate for signs of inflammatory organ damage28 (myocarditis,29 interstitial nephritis,27,30 interstitial lung disease, hepatitis, pancreatitis).31 May be associated with colitis and related symptoms.15,32 DRESS syndrome described in case reports.33,34 Successful rechallenge is possible.35 Concomitant antidepressants may increase risk.36,37 Heat stroke38,39 Any time Two cases reported, both occurred during a heatwave. May be mistaken for NMS (CK was elevated in both cases). Hepatic failure/enzyme abnormalities40–46 First few months Benign changes in LFTs are common (up to 50% of patients) but worth monitoring because of the very small risk of fulminant hepatic failure.47 Rash may be associated with clozapine-related hepatitis48 (see section on hepatic impairment in Chapter 8). Hypothermia49 Any time A few case reports and events in pharmacovigilance databases. Can be fatal. Interstitial nephritis50,51 Usually first 3 weeks, possibly up to 3 months27 A handful of reports implicating clozapine. Probably immune mediated. May occur after only a few doses. Symptoms include fever, tachycardia, nausea, vomiting, diarrhoea, raised creatinine, urinary difficulties and eosinophilia. The classic nephritis- associated rash may not be present.27 There are no published cases of successful rechallenge.27 Interstitial lung disease Usually first few months, possibly later in treatment Six case reports.52 May be caused by aspiration or an immune reaction. Symptoms are non-specific: shortness of breath, fever, cough, fatigue. Pneumonitis has also been reported.53 Knee-buckling54,55 Usually at the start of treatment Several cases reported. May be mistaken for postural hypotension. Ocular effects56 Any time Single case report of ocular pigmentation,57 five of periorbital oedema.58 Clozapine may cause dry eye syndrome.59 (Continued)

246 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Adverse effect Time course Comment Pancreatitis60–69 Usually first 6 weeks, possibly later in treatment70 Several reports of asymptomatic and symptomatic pancreatitis. Symptoms include fever, abdominal pain and distension, nausea and vomiting, raised CRP and raised lipase and/or amylase. Concomitant valproate may increase the risk.27 The majority of attempts to rechallenge fail63,71–74 but one successful case is reported.75 Parotid gland swelling76–80 Usually first few weeks, but may occur later81 Several case reports. Unclear mechanism, possibly immunological or thickening of saliva leading to calcium precipitation. Can be recurrent. May resolve spontaneously.82 Terazosin in combination with benztropine may be helpful. Pericarditis and pericardial effusion69,83–90 Any time Several reports in the literature. Symptoms include fatigue, chest pain, dyspnoea, orthostatic hypotension and tachycardia, but may be asymptomatic.91 Signs include raised inflammatory markers (specifically trop I) and pro-BNP levels.91 Use echocardiogram to confirm/rule out effusion. Successful rechallenge possible.92–94 Stuttering95,96 Any time Case reports only. Check plasma levels, consider dose reduction and/or antiseizure drugs – may be a warning sign for impending generalised seizures.97 Thrombocytopenia98–101 First 3 months Few data but apparently fairly common (incidence over 1 year of 3102–8%103). Probably transient and clinically unimportant, but persistent in some cases104,105 and recurrent on rechallenge in others.106,107 Thrombocytosis also reported.108 Skin reactions109 Any time Presence of skin diseases in general is higher in those with schizophrenia.110 Four reports of vasculitis111–114 in which patients developed confluent erythematous rash on lower limbs. One report of Stevens–Johnson syndrome,115 two of pityriasis rosea,116,117 one of a papular rash,118 one of exanthematic pustulosis,119 one of cholinergic urticaria120 and two of Sweet’s syndrome,121 one fatal.122 Rash is often reported in DRESS syndrome.123 Thromboembolism124–126 Any time127 Weight increase and sedation may contribute to risk. Mechanism may be increased platelet aggregation via 5HT2A receptor activation.128 Clozapine increases risk of pulmonary thromboembolism by 28 times compared with the general population.129 The risk may be dose related130 but cases are reported across the dose range.131,132 Consider prophylactic antithrombotic treatment where additional risk factors are present (surgery, immobility). Continuation of therapy after embolism may be possible133 but consult haematologist as without prophylactic antithrombotic treatment recurrence is likely134,135 and may be fatal.131,136 Polyserositis Usually first few weeks, but can occur at any time Case reports describe a wide variety of symptoms related to inflammatory processes, including flu-like symptoms, fever, eosinophilia, diarrhoea, shortness of breath, tachycardia, thoracic pain.137 Other inflammatory conditions may be present (hepatitis, pancreatitis, dermatosis). Suggested to be either IgE-mediated hypersensitivity or an immunomodulatory effect.138 All reported cases have resolved on discontinuation of clozapine.138 CK, creatine kinase; CRP, C-reactive protein; DRESS, drug rash with eosinophilia and systemic symptoms; IgE, immunoglobulin E; NMS, neuroleptic malignant syndrome; pro-BNP, pro-brain natriuretic peptide. (Continued)

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244 - References

References

Schizophrenia and related psychoses CHAPTER 1 References

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Clozapine drug-induced pancreatitis of intermediate latency of onset confirmed by de-challenge and re-challenge. Int J Clin Pharmacol Ther 2019; 57:37–40. 76. Immadisetty V, et al. A successful treatment strategy for clozapine-induced parotid swelling: a clinical case and systematic review. Ther Adv Psychopharmacol 2012; 2:235–239. 77. Gouzien C, et al. [Clozapine-induced parotitis: a case study]. Encephale 2014; 40:81–85. 78. Saguem BN, et al. Eosinophilia and parotitis occurring early in clozapine treatment. Int J Clin Pharm 2015; 37:992–995. 79. Vohra A. Clozapine-induced recurrent and transient parotid gland swelling. Afr J Psychiatry (Johannesbg) 2013; 16:236, 238. 80. Kathirvel N, et al. Recurrent transient parotid gland swelling with clozapine therapy. Ir J Psychol Med 2014; 25:69–70. 81. Brodkin ES, et al. Treatment of clozapine-induced parotid gland swelling. Am J Psychiatry 1996; 153:445. 82. Vasile JS, et al. Clozapine and the development of salivary gland swelling: a case study. J Clin Psychiatry 1995; 56:511–513. 83. Bhatti MA, et al. Clozapine-induced pericarditis, pericardial tamponade, polyserositis, and rash. J Clin Psychiatry 2005; 66:1490–1491. 84. Boot E, et al. Pericardial and bilateral pleural effusion associated with clozapine treatment. Eur Psychiatry 2004; 19:65. 85. Murko A, et al. Clozapine and pericarditis with pericardial effusion. Am J Psychiatry 2002; 159:494. 86. Imon Paul MD, et al. Clozapine induced pericarditis: an overlooked adverse effect. Clin Schizophr Relat Psychoses 2014; 8:133–134. 87. Bath AS, et al. Pericardial effusion: rare adverse effect of clozapine. Cureus 2019; 11:e4890.

Schizophrenia and related psychoses CHAPTER 1 88. Johal HK, et al. Clozapine-induced pericarditis: an ethical dilemma. BMJ Case Rep 2019; 12:e229872. 89. Sahyouni C, et al. Clozapine induced pericarditis: a case report. Psychiatry Res 2021; 305:114250. 90. Gilbreth N, et al. Clozapine-induced pericardial effusion presenting with persistent tachycardia. Case Rep Med 2021; 2021:5523562. 91. Prisco V, et al. Brain natriuretic peptide as a biomarker of asymptomatic clozapine-related heart dysfunction: a criterion for a more cautious administration. Clin Schizophr Relat Psychoses 2016; 12:185–188. 92. Crews MP, et al. Clozapine rechallenge following clozapine-induced pericarditis. J Clin Psychiatry 2010; 71:959–961. 93. Sarathy K, et al. A successful re-trial after clozapine myopericarditis. J R Coll Physicians Edinb 2017; 47:146–147. 94. Boscutti A, et al. Successful clozapine rechallenge after myopericarditis: a case report. Int Clin Psychopharmacol 2022; 37:179–181. 95. Nikvarz N, et al. Drug-induced stuttering: a comprehensive literature review. World J Psychiatry 2022; 12:236–263. 96. Trenque T, et al. Drug induced stuttering: pharmacovigilance data. Expert Opin Drug Saf 2021; 20:373–378. 97. Duggal HS, et al. Clozapine-induced stuttering and seizures. Am J Psychiatry 2002; 159:315. 98. Jagadheesan K, et al. Clozapine-induced thrombocytopenia: a pilot study. Hong Kong J Psychiatry 2003; 13:12–15. 99. Mihaljevic-Peles A, et al. Thrombocytopenia associated with clozapine and fluphenazine. Nord J Psychiatry 2001; 55:449–450. 100. Rudolf J, et al. Clozapine-induced agranulocytosis and thrombopenia in a patient with dopaminergic psychosis. J Neural Transm (Vienna) 1997; 104:1305–1311. 101. Assion HJ, et al. Lymphocytopenia and thrombocytopenia during treatment with risperidone or clozapine. Pharmacopsychiatry 1996; 29:227–228. 102. Lee J, et al. The effect of clozapine on hematological indices: a 1-year follow-up study. J Clin Psychopharmacol 2015; 35:510–516. 103. Grover S, et al. Haematological side effects associated with clozapine: a retrospective study from India. Asian J Psychiatr 2020; 48:101906. 104. Kate N, et al. Clozapine associated thrombocytopenia. J Pharmacol Pharmacother 2013; 4:149–151. 105. Gonzales MF, et al. Evidence for immune etiology in clozapine-induced thrombocytopenia of 40 months’ duration: a case report. CNS Spectr 2000; 5:17–18. 106. Hauseux PA, et al. Clozapine rechallenge after thrombocytopenia: a case report. Schizophr Res 2020; 222:477–479. 107. Thapaliya S, et al. Effective and safe use of intramuscular clozapine in a patient presenting with catatonia and thrombocytopenia. BMJ Case Rep 2024; 17:e260197. 108. Hampson ME. Clozapine-induced thrombocytosis. Br J Psychiatry 2000; 176:400. 109. Warnock JK, et al. Adverse cutaneous reactions to antipsychotics. Am J Clin Dermatol 2002; 3:629–636. 110. Wu BY, et al. Prevalence and associated factors of comorbid skin diseases in patients with schizophrenia: a clinical survey and national health database study. Gen Hosp Psychiatry 2014; 36:415–421. 111. Voulgari C, et al. Clozapine-induced late agranulocytosis and severe neutropenia complicated with streptococcus pneumonia, venous thromboembolism, and allergic vasculitis in treatment-resistant female psychosis. Case Rep Med 2015; 2015:703218. 112. Penaskovic K, et al. Clozapine-induced allergic vasculitis [Letter]. Am J Psychiatry 2005; 162:1543–1542. 113. Mukherjee S, et al. Leukocytoclastic vasculitis secondary to clozapine. Indian J Psychiatry 2019; 61:94–96. 114. Fujimoto S, et al. Clozapine-induced antineutrophil cytoplasmic antibody-associated vasculitis: a case report. Mod Rheumatol Case Rep 2020; 4:70–73. 115. Wu MK, et al. The severe complication of Stevens–Johnson syndrome induced by long-term clozapine treatment in a male schizophrenia patient: a case report. Neuropsychiatr Dis Treat 2015; 11:1039–1041. 116. Lai YW, et al. Pityriasis rosea-like eruption associated with clozapine: a case report. Gen Hosp Psychiatry 2012; 34:703.e5–e7. 117. Bhatia MS, et al. Clozapine induced pityriasiform eruption. Indian J Dermatol 1997; 42:245–246. 118. Stanislav SW, et al. Papular rash and bilateral pleural effusion associated with clozapine. Ann Pharmacother 1999; 33:1008–1009. 119. Bosonnet S, et al. [Acute generalized exanthematic pustulosis after intake of clozapine (leponex). First case]. Ann Dermatol Venereol 1997; 124:547–548. 120. El Ouni Amami N, et al. Clozapine-induced cholinergic urticaria: a case report. Ther Adv Psychopharmacol 2024; 14:20451253241241056. 121. Bunting A, et al. Clozapine and Sweet’s syndrome: case report. BJPsych Open 2023; 9:e166. 122. Kleinen JM, et al. [Clozapine-induced agranulocytosis and Sweet’s syndrome in a 74-year-old female patient: a case study]. Tijdschr Psychiatr 2008; 50:119–123. 123. de Filippis R, et al. Clozapine-related drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: a systematic review. Expert Rev Clin Pharmacol 2020; 13:875–883. 124. Chate S, et al. Pulmonary thromboembolism associated with clozapine. J Neuropsychiatry Clin Neurosci 2013; 25:E3–E6. 125. Yang TY, et al. Massive pulmonary embolism in a young patient on clozapine therapy. J Emerg Med 2004; 27:27–29. 126. Huang J, et al. Association between antipsychotics and pulmonary embolism: a pharmacovigilance analysis. Expert Opin Drug Saf 2024; doi: 10.1080/14740338.2024.2396390. 127. Gami RK, et al. Pulmonary embolism and clozapine use: a case report and literature review. Psychosomatics 2017; 58:203–208. 128. Hagg S, et al. Risk of venous thromboembolism due to antipsychotic drug therapy. Expert Opin Drug Saf 2009; 8:537–547. 129. De Fazio P, et al. Rare and very rare adverse effects of clozapine. Neuropsychiatr Dis Treat 2015; 11:1995–2003. 130. Sarvaiya N, et al. Clozapine-associated pulmonary embolism: a high-mortality, dose-independent and early-onset adverse effect. Am J Ther 2018; 25:e434–e438. 131. Pallares Vela E, et al. Clozapine-related thromboembolic events. Cureus 2021; 13:e16883. 132. Robbins-Welty GA, et al. Pulmonary embolism during a retrial of low-dose clozapine. Clin Psychopharmacol Neurosci 2022; 20:578–580.

250 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 133. Goh JG, et al. A case report of clozapine continuation after pulmonary embolism in the context of other risk factors for thromboembolism. Aust N Z J Psychiatry 2016; 50:1205–1206. 134. Munoli RN, et al. Clozapine-induced recurrent pulmonary thromboembolism. J Neuropsychiatry Clin Neurosci 2013; 25:E50–E51. 135. Selten JP, et al. Clozapine and venous thromboembolism: further evidence. J Clin Psychiatry 2003; 64:609. 136. Manoubi SA, et al. Fatal pulmonary embolism in patients on antipsychotics: case series, systematic review and meta-analysis. Asian J Psychiatr 2022; 73:103105. 137. Mouaffak F, et al. Clozapine-induced serositis: review of its clinical features, pathophysiology and management strategies. Clin Neuropharmacol 2009; 32:219–223. 138. Bonnet U, et al. Late-onset polyserositis emerging during long-term clozapine treatment and persisting after clozapine discontinuation: is clozapine really innocent? J Clin Psychopharmacol 2022; 42:106–107.

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245 - Clozapine serious haematological adverse effe

Clozapine: serious haematological adverse effects

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246 - Agranulocytosis

Agranulocytosis

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247 - Summary

Summary

Schizophrenia and related psychoses CHAPTER 1 Clozapine: serious haematological adverse effects Agranulocytosis Clozapine is a somewhat toxic drug. Despite this, clozapine reduces overall mortality in schizophrenia,1 in part owing to a reduction in the rate of suicide.2–4 Non-clozapine antipsychotics also reduce natural-cause mortality,5 possibly because of improved adherence to cardiometabolic medication.6 Clozapine is more effective than any other antipsychotic in this regard.6 Clozapine can cause serious, life-threatening adverse effects, of which agranulocytosis is the best known, and which is seen in 0.4% of patients.7 The incidence of death related to agranulocytosis following clozapine prescription is 0.013%, with a case fatality rate for agranulocytosis of 2.1%.8 Risk is clearly well managed by the approved clozapine monitoring systems. The incidence of severe neutropenia declines to negligible levels after the first year of treatment.8 Successful rechallenge after neutropenia occurring during clozapine treatment may be possible,9 but rechallenge should not be attempted after confirmed clozapine-related agranulocytosis.10 Most neutropenia occurring in the context of clozapine treatment is coincidental to the use of clozapine.11 Distinguishing between benign, clinically insignificant neutropenia and clozapine-related life-threatening agranulocytosis (CRLTA) is vital. CRLTA is usually characterised by a continuous and rapid neutrophil count decline to zero, or near zero, mostly within the first 18 weeks of clozapine treatment. A prolonged nadir and delayed recovery (range 4–16 days) follow12 unless GCSF is given. Non-CRLTA episodes are more often brief, show a non-continuous and/or slow decline in neutrophils, or have an obvious cause that is not clozapine.12,13 However, if clozapine is withdrawn very early, the typical catastrophic fall in neutrophil counts may not develop.13 Distinguishing between non-clozapine-related neutropenia and CRLTA is difficult, but cases can usually reliably be classified as non-CRLTA, possible CRLTA and definite CRLTA. The mandatory threshold-based method of detecting agranulocytosis has a very low specificity for CRLTA – the system creates a huge number of false positives. Pattern- based criteria based on the above factors are more specific without loss of sensitivity.14 Misdiagnosing benign neutropenia as CRLTA has resulted in many thousands of patients being denied access to clozapine.11 The most common reason for misdiagnosis is the failure to detect BEN.15 Summary ■ ■Overall mortality is lower for those on clozapine than in schizophrenia as a whole. ■ ■Risk of fatal agranulocytosis is less than 1 in 8,000 during standard monitoring. ■ ■Real clozapine-related agranulocytosis usually follows a distinctive, catastrophic pattern. ■ ■Pattern-based criteria are more specific for clozapine-related agranulocytosis than standard threshold-based monitoring.

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References

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Vermeulen JM, et al. Clozapine and long-term mortality risk in patients with schizophrenia: a systematic review and meta-analysis of studies lasting 1.1–12.5 years. Schizophr Bull 2019; 45:315–329.
Walker AM, et al. Mortality in current and former users of clozapine. Epidemiology 1997; 8:671–677.
van der Zalm Y, et al. Clozapine and mortality: a comparison with other antipsychotics in a nationwide Danish cohort study. Acta Psychiatr Scand 2021; 143:216–226.
Munro J, et al. Active monitoring of 12760 clozapine recipients in the UK and Ireland. Br J Psychiatry 1999; 175:576–580.
Correll CU, et al. Mortality in people with schizophrenia: a systematic review and meta-analysis of relative risk and aggravating or attenuating factors. World Psychiatry 2022; 21:248–271.
Solmi M, et al. Antipsychotics use is associated with greater adherence to cardiometabolic medications in patients with schizophrenia: results from a nationwide, within-subject design study. Schizophr Bull 2022; 48:166–175.
Li XH, et al. The prevalence of agranulocytosis and related death in clozapine-treated patients: a comprehensive meta-analysis of observational studies. Psychol Med 2020; 50:583–594.
Myles N, et al. Meta-analysis examining the epidemiology of clozapine-associated neutropenia. Acta Psychiatr Scand 2018; 138:101–109.
Prokopez CR, et al. Clozapine rechallenge after neutropenia or leucopenia. J Clin Psychopharmacol 2016; 36:377–380.
Manu P, et al. Clozapine rechallenge after major adverse effects: clinical guidelines based on 259 cases. Am J Ther 2018; 25:e218–e223.
Oloyede E, et al. There is life after the UK Clozapine Central Non-Rechallenge Database. Schizophr Bull 2021; 47:1088–1098.
Taylor D, et al. Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis. Schizophrenia (Heidelb) 2022; 8:21.
Taylor D, et al. Severe neutropenia unrelated to clozapine in patients receiving clozapine. J Psychopharmacol 2024; 38:624–635.
Oloyede E, et al. Identifying clinically relevant agranulocytosis in people registered on the UK clozapine Central Non-Rechallenge Database: retrospective cohort study. Br J Psychiatry 2024; 225:484–491.
Oloyede E, et al. Benign ethnic neutropenia: an analysis of prevalence, timing and identification accuracy in two large inner-city NHS hospitals. BMC Psychiatry 2021; 21:502.

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249 - Clozapine serious cardiovascular adverse effe

Clozapine: serious cardiovascular adverse effects

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25 - Conclusion

Conclusion

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250 - Thromboembolism

Thromboembolism

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251 - Myocarditis

Myocarditis

Schizophrenia and related psychoses CHAPTER 1 Clozapine: serious cardiovascular adverse effects Thromboembolism Over 30 years ago a possible association between clozapine and thromboembolism was first suggested.1,2 Later, data from Sweden3 suggested the risk of thromboembolism was 1 in 2,000 to 1 in 6,000 patients treated. Thromboembolism may be related to clozapine’s effects on antiphospholipid antibodies4 and platelet aggregation.5 It seems most likely to occur in the first 6 months of treatment6 but can occur at any time. The risk may be independent of dose,6 but some studies suggest a correlation with higher doses.7 Other antipsychotics are also strongly linked to thromboembolism,8 although clozapine may present the highest risk.7,9 With all drugs, the causes of thromboembolism are probably multifactorial.10 Sedation may lead to a reduction in movement and consequent venous stasis. Obesity, hyperprolactinaemia and smoking are additional independent risk factors for thromboembolism.11,12 Encouraging exercise and ensuring good hydration are essential precautionary measures.13 Myocarditis Clozapine is associated with myocarditis and cardiomyopathy. Myocarditis is a hypersensitivity response to clozapine, resulting in inflammation of the myocardium. Some debate surrounds the prevalence of myocarditis, with several Australian studies reporting an incidence of 3%14–16 and one finding a rate of 9.8%.17 Studies conducted outside Australia18–20 have suggested an incidence of 1% or less. The reason for such variation is unclear but it may be that a lack of robust monitoring leads to missed diagnoses in those countries reporting lower incidences.21 Geography, environment and higher starting doses may also play a role.17,22 A 2020 meta-analysis suggested an event rate of less than 1% – 7/1,000 patients.23 Myocarditis is potentially fatal (case fatality rate of 12.7%)23 and is most likely to occur in the first 6–8 weeks of starting clozapine treatment (median 3 weeks),24 but may occur at any time. Despite uncertainty over incidence, all patients should be closely monitored for signs and symptoms of myocarditis especially in the first few months of treatment.25 Symptoms include hypotension, tachycardia, fever, flu-like symptoms, fatigue, dyspnoea (with increased respiratory rate) and chest pain.26 Signs include ECG changes (ST depression), enlarged heart on radiography/echo and eosinophilia. Many of these symptoms occur in patients on clozapine not developing myocarditis27 and, conversely, their absence does not rule out myocarditis.28,29 Nonetheless, signs of heart failure should provoke immediate cessation of clozapine and referral to a cardiologist. Rechallenge has been successfully completed29–36 (the use of beta blockers, ACE inhibitors and mineralocorticoid receptor antagonists may help)37–39 but recurrence is also possible.29,40–43 Published cases suggest a success rate of 62%.44 Use of echocardiography, measurement of CRP and troponin are obviously absolutely essential in cases of rechallenge.45–47 Effective treatment of comorbid metabolic syndrome and diabetes may also help.23 Most cases of successful rechallenge employ a very slow rate of titration.44 One proposed schedule is to limit dose increases to 6.25mg increments every

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252 - Cardiomyopathy

Cardiomyopathy

254 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 4 days until a daily dose of 75mg is reached.22 Dose increases (of 6.25mg) can then be made every 3 days after this point, and every 2 days after reaching a daily dose of 150mg. Autopsy findings suggest that fatal myocarditis can occur in the absence of clear cardiac symptoms, although tachycardia and fever are usually present.48 A monitoring programme which is said to detect 100% of symptomatic cases of myocarditis49 using measurement of troponin I or T and CRP has been developed (Table 1.56). The additional measuring of NT-proBNP (an indicator of cardiac failure) and continuing cardiac and blood marker monitoring for 8 weeks have also been suggested50 (5-8% of cases occur in the second month of treatment,50,51 almost all of these in weeks four to six).52 Echocardiography at baseline, 6 months and yearly thereafter is routine practice in Australia, although the benefit of this monitoring in the absence of other symptoms has been questioned.53 Baseline echocardiography may at least be useful to establish a comparator if concerns arise later, especially in those with known cardiac disease, structural abnormalities or other cardiac risk factors.54 The absence of resources to provide monitoring beyond routine blood tests (including CRP and troponin) and ECG should not be a barrier to prescribing for most patients.20 Factors that may increase the risk of developing myocarditis include rapid titration, concurrent use of sodium valproate55 and older age (31% increased risk for each additional decade).56 Other psychotropics, including lithium, risperidone, haloperidol, chlorpromazine and fluphenazine, have also been associated with myocarditis.57 It is probably preferable to avoid concomitant use of other medicines that may contribute to the risk, but this may be practically difficult. Any pre-existing cardiac disorder, previous cardiac event, use of illicit drugs15 or family history of cardiac disease should provoke extra caution. Cardiomyopathy Cardiomyopathy is usually diagnosed from echocardiography to establish left ventricular dilatation (resulting in a reduced ejection fraction) and/or hypertrophy. It may develop following myocarditis (if clozapine is not stopped), but other causative factors may include persistent tachycardia, obesity, diabetes and previous personal or familial cardiac events.21 Long-term clozapine seems to induce cardiac myocyte autophagy and structural remodelling of the heart.58 Most incidence data originate from Australia and range from 0.02 to 5%.16,59 Meta-analysis suggests an event rate of 6 per 1,000 patients, with a case fatality rate of 7.8%.23 Cardiomyopathy occurs later in treatment than myocarditis (median 9 months)24 but, as with myocarditis, it may occur at any time. Cardiomyopathy should be suspected in any patient showing signs of heart failure, which should provoke immediate cessation of clozapine and referral. Presentation of cardiomyopathy varies somewhat60,61 and is often asymptomatic in the early stages,16 so any reported symptoms of palpitations, chest pain, syncope, sweating, decreased exercise capacity or breathing difficulties should be closely investigated. Successful rechallenge with rigorous cardiac monitoring (including ECHO) and instigation of disease-modifying cardiac medications may be possible,39,62–66 including in cases of pre-existing cardiomyopathy or heart failure (as opposed to clozapine-induced cardiomyopathy). Despite an overall reduction in mortality, younger patients may have an increased risk of sudden death,67 perhaps because of clozapine-induced ECG changes.68 There may, of course, be similar problems with other antipsychotics.57,69,70

Schizophrenia and related psychoses CHAPTER 1 Table 1.56 Suggested monitoring for myocarditis.22,49,71,72 Baseline* Pulse, BP, temperature, respiratory rate FBC CRP Troponin Echocardiography (if available) ECG Daily, if possible Pulse, BP, temperature, respiratory rate Ask about: chest pain, fever, cough, shortness of breath, exercise capacity On days 7, 14, 21, and 28 CRP Troponin FBC ECG if possible If CRP >100mg/L or troponin > twice upper limit of normal Stop clozapine; repeat echo NT-proBNP If fever + tachycardia* + raised CRP or troponin (but not as above) Daily CRP and troponin measures NT-proBNP * Tachycardia is not a good indicator of myocarditis – almost all cases have tachycardia, but tachycardia is very common in people who do not have myocarditis.52 CRP, C-reactive protein; NT-proBNP, N-terminal pro b-type brain natriuretic peptide.

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References

256 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

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Floreani J, et al. Successful re-challenge with clozapine following development of clozapine-induced cardiomyopathy. Aust N Z J Psychiatry 2008; 42:747–748.
Patel RK, et al. Clozapine and cardiotoxicity: a guide for psychiatrists written by cardiologists. Psychiatry Res 2019; 282:112491.

Schizophrenia and related psychoses CHAPTER 1 40. Roh S, et al. Cardiomyopathy associated with clozapine. Exp Clin Psychopharmacol 2006; 14:94–98. 41. Masopust J, et al. Repeated occurrence of clozapine-induced myocarditis in a patient with schizoaffective disorder and comorbid Parkinson’s disease. Neuro Endocrinol Lett 2009; 30:19–21. 42. Ronaldson KJ, et al. Observations from 8 cases of clozapine rechallenge after development of myocarditis. J Clin Psychiatry 2012; 73:252–254. 43. Nielsen J, et al. Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? 2013; 74: 603–613; quiz 613. 44. Holden J, et al. Successful rechallenge after clozapine-associated myocarditis. BMJ Case Rep 2022; 15:e248909. 45. Hassan I, et al. Monitoring in clozapine rechallenge after myocarditis. Australas Psychiatry 2011; 19:370–371. 46. Bray A, et al. Successful clozapine rechallenge after acute myocarditis. Aust N Z J Psychiatry 2011; 45:90. 47. Rosenfeld AJ, et al. Successful clozapine retrial after suspected myocarditis. Am J Psychiatry 2010; 167:350–351. 48. Ronaldson KJ, et al. Clinical course and analysis of ten fatal cases of clozapine-induced myocarditis and comparison with 66 surviving cases. Schizophr Res 2011; 128:161–165. 49. Ronaldson KJ, et al. A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. Aust N Z J Psychiatry 2011; 45:458–465. 50. Griffin JM, et al. Clozapine-associated myocarditis: a protocol for monitoring upon clozapine initiation and recommendations for how to conduct a clozapine rechallenge. J Clin Psychopharmacol 2021; 41:180–185. 51. De Las Cuevas C, et al. Clozapine-associated myocarditis in the World Health Organization’s pharmacovigilance database: focus on reports from various countries. Rev Psiquiatr Salud Ment (Engl Ed) 2022; 15:238–250. 52. Segev A, et al. Clozapine-induced myocarditis: electronic health register analysis of incidence, timing, clinical markers and diagnostic accuracy. Br J Psychiatry 2021; 219:644–651. 53. Robinson G, et al. Echocardiography and clozapine: is current clinical practice inhibiting use of a potentially life-transforming therapy? Aust Fam Physician 2017; 46:169–170. 54. Knoph KN, et al. Clozapine-induced cardiomyopathy and myocarditis monitoring: a systematic review. Schizophr Res 2018; 199:17–30. 55. Vickers M, et al. Risk factors for clozapine-induced myocarditis and cardiomyopathy: a systematic review and meta-analysis. Acta Psychiatr Scand 2022; 145:442–455. 56. Ronaldson KJ, et al. Rapid clozapine dose titration and concomitant sodium valproate increase the risk of myocarditis with clozapine: a case-control study. Schizophr Res 2012; 141:173–178. 57. Coulter DM, et al. Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study. BMJ 2001; 322:1207–1209. 58. Zhang S, et al. Exploration of clozapine-induced cardiomyopathy and its mechanism. Cardiovasc Toxicol 2024; 24:1192–1203. 59. Curto M, et al. Systematic review of clozapine cardiotoxicity. Curr Psychiatry Rep 2016; 18:68. 60. Pastor CA, et al. Masked clozapine-induced cardiomyopathy. J Am Board Fam Med 2008; 21:70–74. 61. Sagar R, et al. Clozapine-induced cardiomyopathy presenting as panic attacks. J Psychiatr Pract 2008; 14:182–185. 62. Nederlof M, et al. Clozapine re-exposure after dilated cardiomyopathy. BMJ Case Rep 2017; 2017:bcr2017219652. 63. Alawami M, et al. A systematic review of clozapine induced cardiomyopathy. Int J Cardiol 2014; 176:315–320. 64. Williams F, et al. Continuing clozapine treatment after a diagnosis of cardiomyopathy. Ir J Psychol Med 2021; 38:227–231. 65. Grover S, et al. Safe use of clozapine in a patient with treatment resistant schizophrenia with co-morbid dilated cardiomyopathy: a case report. Asian J Psychiatr 2022; 68:102971. 66. Whiskey E, et al. Resolution without discontinuation: heart failure during clozapine treatment. Ther Adv Psychopharmacol 2020; 10:2045125320924786. 67. Modai I, et al. Sudden death in patients receiving clozapine treatment: a preliminary investigation. J Clin Psychopharmacol 2000; 20:325–327. 68. Kang UG, et al. Electrocardiographic abnormalities in patients treated with clozapine. J Clin Psychiatry 2000; 61:441–446. 69. Thomassen R, et al. Antipsychotic drugs and venous thromboembolism [Letter]. Lancet 2000; 356:252. 70. Hagg S, et al. Antipsychotic-induced venous thromboembolism: a review of the evidence. CNS Drugs 2002; 16:765–776. 71. Ronaldson KJ, et al. Diagnostic characteristics of clozapine-induced myocarditis identified by an analysis of 38 cases and 47 controls. J Clin Psychiatry 2010; 71:976–981. 72. Yuen JWY, et al. Clozapine-induced cardiovascular side effects and autonomic dysfunction: a systematic review. Front Neurosci 2018; 12:203.

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Clozapine-induced hypersalivation

258 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Clozapine-induced hypersalivation Clozapine is well known to be causally associated with hypersalivation (sialorrhoea):1 excess salivary pooling in the mouth and drooling, particularly at night. Hypersalivation is dose-2 and plasma concentration-related3 but some degree of excess salvation may be seen in the vast majority of patients.4 Clinical observation suggests that hypersalivation reduces in severity somewhat over time (usually several months) but normally persists to some extent. Clozapine-induced hypersalivation is socially embarrassing and discomfiting, has a negative impact on quality of life4 and is often a reason for patients stopping clozapine treatment.5 Further, hypersalivation has been implicated as a contributory factor in the development of aspiration pneumonia and so is potentially life-threatening.6–10 Effective treatment is a matter of some urgency. The pharmacological basis of clozapine-related hypersalivation remains unclear.11 Suggested mechanisms include muscarinic M4 agonism, adrenergic α2 antagonism, and inhibition of the swallowing reflex.12,13 The last of these is supported by trials which suggest that saliva production is not increased in patients treated with clozapine,14,15 although at least one study has observed marked increases in salivary flow in the first 3 weeks of treatment.16 Whatever the mechanism, medications that reduce saliva production might be expected to diminish the severity of clozapine-induced sialorrhoea. However, there are no medications licensed for this condition and many of the relevant published studies have limitations that preclude any confident treatment recommendations.17 A 2023 network analysis of RCTs testing a range of pharmacological interventions for clozapine- induced sialorrhoea in adults18 yielded ‘low confidence’ findings of efficacy, ranking metoclopramide highest, and decreasing through cyproheptadine, sulpiride, propantheline, diphenhydramine, benzhexol, doxepin, amisulpride, chlorpheniramine, to amitriptyline and atropine. Overall, the evidence, such as it is, seems to favour antimuscarinic agents, such as propantheline and diphenhydramine.19,20 Use of antimuscarinic agents should take account of the risk of compounding clozapine’s liability for serious, potentially life-threatening, gastrointestinal hypomotility.21,22 Topical antimuscarinic treatment might be preferred. Several topical agents have been shown to be effective and a small RCT of sofpironium bromide gel in 2023 produced encouraging results.23 In 2024, another small RCT24 found topical atropine to be more effective than amitriptyline and ipratropium bromide nasal spray. Metoclopramide and other benzamide compounds are probably second-line treatments.25 Table 1.57 describes pharmacological treatments that have been examined. Non- drug treatments may be used if appropriate – these include chewing gum during the day, elevating pillows and placing a towel on the pillow to prevent soaking.11 Nonetheless, problematic hypersalivation should not be considered an inevitable consequence of clozapine use and strenuous efforts should be made to minimise its severity.

Schizophrenia and related psychoses CHAPTER 1 Table 1.57 Clozapine-related hypersalivation – summary. Treatment Comments Amisulpride 100–400mg/day20,26,27 Supported by a positive RCT compared with placebo, one other in which it was compared with moclobemide and numerous case studies.28–32 May allow dose reduction of clozapine. Amitriptyline 25–100 mg/day33–36 Limited literature support. Adverse effects may be troublesome. Worsens constipation. Atropine given sublingually37–41 or as solution (1mg/10mL) used as a mouthwash Limited literature support and the benefit–risk balance is uncertain, although case reports suggest that it may be a relatively effective and tolerable treatment for some patients in clinical practice41,42 and a 2024 RCT yielded positive findings.24 But one meta-analysis18 failed to find atropine superior to placebo for nocturnal sialorrhoea. Problems with administration have been reported.43 Benzhexol (trihexyphenidyl) 5–15mg/day44 Small, open study suggests useful activity. Used in some centres but may impair cognitive function. Lower doses (2mg) may be effective.45 Benztropine 2mg/day

terazosin 2mg/day46 Combination shown to be better than either drug alone. Terazosin is an α1 antagonist so may cause hypotension. Botulinum toxin47–50 (Botox) bilateral parotid gland injections (150IU into each gland) Effective in treating sialorrhoea associated with neurological disorders. Six cases of successful treatment of clozapine-related hypersalivation in the literature. Widely used in some US centres. Slow onset of effect. Some botulinum preparations are formally licensed for chronic sialorrhoea caused by neurological conditions in adults. Bupropion 100–150mg/day51 Single case report. May lower seizure threshold. Chlorphenamine20 Antihistamine and relatively weak antimuscarinic. One high-quality study. Clonidine 0.1–0.2mg patch weekly or 0.1mg orally at night52,53 α2 partial agonist. Limited literature support. May exacerbate psychosis, depression and cause hypotension. Diphenhydramine19,20 Antihistamine and potent antimuscarinic. Few high-quality studies. Glycopyrrolate 0.5–4mg bd54–59 One RCT showed glycopyrrolate to be more effective than biperiden without worsening cognitive function while another found significant clinical improvement of ‘nocturnal sialorrhoea’ with 2mg a day, compared with placebo. May worsen constipation. Guanfacine 1mg/day60 α2 agonist. Single case report. May cause hypotension. Hyoscine 0.3mg tablet sucked or chewed up to three times daily or 1.5mg/72 hr patch61–64 Hyoscine hydrobromide is a peripheral and central anticholinergic that is commonly prescribed for clozapine-induced hypersalivation,59 but in the UK is an unlicensed use.65 There is one double-blind RCT.53 May cause cognitive impairment, drowsiness and worsen constipation. Ipratropium nasal spray (0.03% or 0.06%) given sublingually up to two sprays three times a day of the 0.06% or intranasally, one spray into each nostril daily of the 0.03%66,67 Limited literature support. The only placebo-controlled RCT conducted was negative.68 Lofexidine 0.2 mg twice daily69 α2 agonist. Very few data. May exacerbate psychosis, depression and cause hypotension. (Continued)

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References

260 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

Man WH, et al. Reporting patterns of sialorrhea comparing users of clozapine to users of other antipsychotics: a disproportionality analysis using VigiBase. J Clin Psychopharmacol 2020; 40:283–286.
Subramanian S, et al. Clozapine dose for schizophrenia. Cochrane Database Syst Rev 2017; 6:CD009555.
Schoretsanitis G, et al. Elevated clozapine concentrations in clozapine-treated patients with hypersalivation. Clin Pharmacokinet 2021; 60:329–335.
Sanagustin D, et al. Prevalence of clozapine-induced sialorrhea and its effect on quality of life. Psychopharmacology (Berl) 2023; 240:203–211.
Grover S, et al. Patient and caregivers perspective about clozapine: a systematic review. Schizophr Res 2024; 268:223–232.
Hinkes R, et al. Aspiration pneumonia possibly secondary to clozapine-induced sialorrhea. J Clin Psychopharmacol 1996; 16:462–463.
Saenger RC, et al. Aspiration pneumonia due to clozapine-induced sialorrhea. Clin Schizophr Relat Psychoses 2016; 9:170–172.
Gurrera RJ, et al. Aspiration pneumonia: an underappreciated risk of clozapine treatment. J Clin Psychopharmacol 2016; 36:174–176.
Kaplan J, et al. Clozapine-associated aspiration pneumonia: case series and review of the literature. Psychosomatics 2017; 58:199–203.
Cicala G, et al. A comprehensive review of swallowing difficulties and dysphagia associated with antipsychotics in adults. Expert Rev Clin Pharmacol 2019; 12:219–234.
Praharaj SK, et al. Clozapine-induced sialorrhea: pathophysiology and management strategies. Psychopharmacology (Berl) 2006; 185:265–273.
Davydov L, et al. Clozapine-induced hypersalivation. Ann Pharmacother 2000; 34:662–665.
Rogers DP, et al. Therapeutic options in the treatment of clozapine-induced sialorrhea. Pharmacotherapy 2000; 20:1092–1095.
Rabinowitz T, et al. The effect of clozapine on saliva flow rate: a pilot study. Biol Psychiatry 1996; 40:1132–1134.
Ben Aryeh H, et al. Salivary flow-rate and composition in schizophrenic patients on clozapine: subjective reports and laboratory data. Biol Psychiatry 1996; 39:946–949.
Praharaj SK, et al. Salivary flow rate in patients with schizophrenia on clozapine. Clin Neuropharmacol 2010; 33:176–178.
Sockalingam S, et al. Review: insufficient evidence to guide use of drugs for clozapine induced hypersalivation. Evid Based Ment Health 2009; 12:12. Table 1.57 (Continued) Treatment Comments Metoclopramide Starting dose of 10mg/day20,70,71 Double-blind, RCT trial found metoclopramide was associated with a significant reduction in nocturnal hypersalivation and drooling. Described as an ‘effective and tolerated’ treatment in cases in clinical practice.72 Moclobemide 150–300mg/day45 Effective in 9 of 14 patients treated in one open study. Appears to be as effective as amisulpride (see above). N–acetylcysteine73 An antioxidant that also modulates glutamatergic, neurotrophic and inflammatory pathways. Small case series reported with significant decrease in sialorrhea. Oxybutynin 5mg up to twice daily74 Single case report Pirenzepine 50–150mg/day75–77 Selective M1, M4 antagonist. Extensive clinical experience suggests efficacy in some but only randomised trial suggested no effect. Still widely used. Does not have a UK or US licence for any indication. May cause constipation. Propantheline 7.5mg at night19,20 Peripheral anticholinergic. No central effects. Meta-analyses of relevant trials have found that propantheline outperforms placebo for the treatment of antipsychotic-induced sialorrhoea.18–20 May worsen constipation. Quetiapine51 May reduce hypersalivation by allowing lower doses of clozapine to be used Sofpironium bromide 5% gel23 A small RCT reported a 40% reduction in saliva flow at 4 weeks. Very limited availability – Japan only. Sulpiride 150–300mg/day20,78–80 Supported by one, small positive RCT and a Cochrane review of clozapine augmentation with sulpiride (at higher sulpiride doses). May allow dose reduction of clozapine.

Schizophrenia and related psychoses CHAPTER 1 18. Fornaro M, et al. Pharmacological interventions for antipsychotic-related sialorrhea: a systematic review and network meta-analysis of randomized trials. Mol Psychiatry 2023; 28:3648–3660. 19. Syed R, et al. Pharmacological interventions for clozapine-induced hypersalivation. Cochrane Database Syst Rev 2008; (3):CD005579. 20. Chen SY, et al. Treatment strategies for clozapine-induced sialorrhea: a systematic review and meta-analysis. CNS Drugs 2019; 33:225–238. 21. Palmer SE, et al. Life-threatening clozapine-induced gastrointestinal hypomotility: an analysis of 102 cases. J Clin Psychiatry 2008; 69:759–768. 22. West S, et al. Clozapine induced gastrointestinal hypomotility: a potentially life threatening adverse event: a review of the literature. Gen Hosp Psychiatry 2017; 46:32–37. 23. Amano Y, et al. Efficacy of sofpironium bromide gel on clozapine-induced hypersalivation in patients with treatment-resistant schizophrenia: double-blind, controlled crossover study. BJPsych Open 2023; 9:e14. 24. Mohammad-Gholizad F, et al. Evaluation and comparison of the effectiveness of atropine eye drops, ipratropium bromide nasal spray, and amitriptyline tablet in the management of clozapine-associated sialorrhea in patients with refractory schizophrenia: a randomized clinical trial. J Clin Psychopharmacol 2024; 44:9–15. 25. Miodownik C, et al. Treatment of clozapine-associated sialorrhea: the role of benzamide derivatives. J Clin Psychopharmacol 2023; 43:171–177. 26. Kreinin A, et al. Amisulpride treatment of clozapine-induced hypersalivation in schizophrenia patients: a randomized, double-blind, placebo- controlled cross-over study. Int Clin Psychopharmacol 2006; 21:99–103. 27. Kreinin A, et al. Amisulpride versus moclobemide in treatment of clozapine-induced hypersalivation. World J Biol Psychiatry 2010; 12:620–626. 28. Praharaj SK, et al. Amisulpride treatment for clozapine-induced sialorrhea. J Clin Psychopharmacol 2009; 29:189–190. 29. Aggarwal A, et al. Amisulpride for clozapine induced sialorrhea. Psychopharmacol Bull 2009; 42:69–71. 30. Croissant B, et al. Reduction of side effects by combining clozapine with amisulpride: case report and short review of clozapine-induced hypersalivation—a case report. Pharmacopsychiatry 2005; 38:38–39. 31. Praharaj SK, et al. Amisulpride improved debilitating clozapine-induced sialorrhea. Am J Ther 2011; 18:e84–e85. 32. Kulkarni RR. Low-dose amisulpride for debilitating clozapine-induced sialorrhea: case series and review of literature. Indian J Psychol Med 2015; 37:446–448. 33. Copp P, et al. Amitriptyline in clozapine-induced sialorrhoea. Br J Psychiatry 1991; 159:166. 34. Praharaj SK, et al. Amitriptyline for clozapine-induced nocturnal enuresis and sialorrhoea. Br J Clin Pharmacol 2007; 63:128–129. 35. Sinha S, et al. Very low dose amitriptyline for clozapine-associated sialorrhea. Curr Drug Saf 2016; 11:262–263. 36. Cereda G, et al. Amitriptyline for clozapine-induced hypersalivation: a case series. Schizophr Res 2022; 243:110–111. 37. Antonello C, et al. Clozapine and sialorrhea: a new intervention for this bothersome and potentially dangerous side effect. J Psychiatry Neurosci 1999; 24:250. 38. Mustafa FA, et al. Sublingual atropine for the treatment of severe and hyoscine-resistant clozapine-induced sialorrhea. Afr J Psychiatry 2013; 16:242. 39. Matos Santana TE, et al. Sublingual atropine in the treatment of clozapine-induced sialorrhea. Schizophr Res 2017; 182:144–145. 40. Mubaslat O, et al. The effect of sublingual atropine sulfate on clozapine-induced hypersalivation: a multicentre, randomised placebo- controlled trial. Psychopharmacology (Berl) 2020; 237:2905–2915. 41. Van der Poorten T, et al. The sublingual use of atropine in the treatment of clozapine-induced sialorrhea: a systematic review. Clin Case Rep 2019; 7:2108–2113. 42. Mutlu E, et al. A systematic chart review of pharmacological interventions in patients with clozapine-induced hypersalivation. Schizophr Res 2024; 268:138–144. 43. Leung JG, et al. Potential problems surrounding the use of sublingually administered ophthalmic atropine for sialorrhea. Schizophr Res 2017; 185:202–203. 44. Spivak B, et al. Trihexyphenidyl treatment of clozapine-induced hypersalivation. Int Clin Psychopharmacol 1997; 12:213–215. 45. Praharaj SK, et al. Complete resolution of clozapine-induced sialorrhea with low dose trihexyphenidyl. Psychopharmacol Bull 2010; 43:73–75. 46. Reinstein M, et al. Comparative efficacy and tolerability of benzatropine and terazosin in the treatment of hypersalivation secondary to clozapine. Clin Drug Investig 1999; 17:97–102. 47. Kahl KG, et al. Botulinum toxin as an effective treatment of clozapine-induced hypersalivation. Psychopharmacology (Berl) 2004; 173:229–230. 48. Steinlechner S, et al. Botulinum toxin B as an effective and safe treatment for neuroleptic-induced sialorrhea. Psychopharmacology (Berl) 2010; 207:593–597. 49. Kahl KG, et al. [Pharmacological strategies for clozapine-induced hypersalivation: treatment with botulinum toxin B in one patient and review of the literature]. Nervenarzt 2005; 76:205–208. 50. Verma R, et al. Botulinum toxin: a novel therapy for clozapine-induced sialorrhoea. Psychopharmacology (Berl) 2018; 235:369–371. 51. Stern RG, et al. Clozapine-induced sialorrhea alleviated by bupropion: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:1578–1580. 52. Grabowski J. Clonidine treatment of clozapine-induced hypersalivation. J Clin Psychopharmacol 1992; 12:69–70. 53. Praharaj SK, et al. Is clonidine useful for treatment of clozapine-induced sialorrhea? J Psychopharmacol 2005; 19:426–428. 54. Duggal HS. Glycopyrrolate for clozapine-induced sialorrhea. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:1546–1547. 55. Robb AS, et al. Glycopyrrolate for treatment of clozapine-induced sialorrhea in three adolescents. J Child Adolesc Psychopharmacol 2008; 18:99–107.

262 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 56. Liang CS, et al. Comparison of the efficacy and impact on cognition of glycopyrrolate and biperiden for clozapine-induced sialorrhea in schizophrenic patients: a randomized, double-blind, crossover study. Schizophr Res 2010; 119:138–144. 57. Man WH, et al. The effect of glycopyrrolate on nocturnal sialorrhea in patients using clozapine: a randomized, crossover, double-blind, placebo-controlled trial. J Clin Psychopharmacol 2017; 37:155–161. 58. Praharaj SK, et al. Low-dose glycopyrrolate for clozapine-associated sialorrhea. J Clin Psychopharmacol 2014; 34:392. 59. Qurashi I, et al. Glycopyrrolate in comparison to hyoscine hydrobromide and placebo in the treatment of hypersalivation induced by cloza pine (GOTHIC1): a feasibility study. Pilot Feasibility Stud 2019; 5:79. 60. Webber MA, et al. Guanfacine treatment of clozapine-induced sialorrhea. J Clin Psychopharmacol 2004; 24:675–676. 61. McKane JP, et al. Hyoscine patches in clozapine-induced hypersalivation. Psychiatr Bull 2001; 25:277. 62. Gaftanyuk O, et al. Scolpolamine patch for clozapine-induced sialorrhea. Psychiatr Serv 2004; 55:318. 63. Segev A, et al. Hyoscine for clozapine-induced hypersalivation: a double-blind, randomized, placebo-controlled cross-over trial. Int Clin Psychopharmacol 2019; 34:101–107. 64. Takeuchi I, et al. Effect of scopolamine butylbromide on clozapine-induced hypersalivation in schizophrenic patients: a case series. Clin Psychopharmacol Neurosci 2015; 13:109–112. 65. British National Formulary JFC. Hyoscine hydrobromide – unlicensed use. 2023 (last accessed December 2023); https://bnf.nice.org.uk/ drugs/hyoscine-hydrobromide/#unlicensed-use. 66. Calderon J, et al. Potential use of ipatropium bromide for the treatment of clozapine-induced hypersalivation: a preliminary report. Int Clin Psychopharmacol 2000; 15:49–52. 67. Freudenreich O, et al. Clozapine-induced sialorrhea treated with sublingual ipratropium spray: a case series. J Clin Psychopharmacol 2004; 24:98–100. 68. Sockalingam S, et al. Treatment of clozapine-induced hypersalivation with ipratropium bromide: a randomized, double-blind, placebo- controlled crossover study. J Clin Psychiatry 2009; 70:1114–1119. 69. Corrigan FM, et al. Clozapine-induced hypersalivation and the alpha 2 adrenoceptor. Br J Psychiatry 1995; 167:412. 70. Kreinin A, et al. Double-blind, randomized, placebo-controlled trial of metoclopramide for hypersalivation associated with clozapine. J Clin Psychopharmacol 2016; 36:200–205. 71. Hallahan B. Metoclopramide may be effective for clozapine-induced hypersalivation. Evid Based Ment Health 2016; 19:124. 72. Livermore C, et al. A retrospective case notes review of the effectiveness and tolerability of metoclopramide in the treatment of clozapine- induced hypersalivation (CIH). BMC Psychiatry 2022; 22:277. 73. Uzun Ö, et al. Effect of N-acetylcysteine on clozapine-induced sialorrhea in schizophrenic patients: a case series. Int Clin Psychopharmacol 2020; 35:229–231. 74. Leung JG, et al. Immediate-release oxybutynin for the treatment of clozapine-induced sialorrhea. Ann Pharmacother 2011; 45:e45. 75. Fritze J, et al. Pirenzepine for clozapine-induced hypersalivation. Lancet 1995; 346:1034. 76. Bai YM, et al. Therapeutic effect of pirenzepine for clozapine-induced hypersalivation: a randomized, double-blind, placebo-controlled, cross- over study. J Clin Psychopharmacol 2001; 21:608–611. 77. Schneider B, et al. Reduction of clozapine-induced hypersalivation by pirenzepine is safe. Pharmacopsychiatry 2004; 37:43–45. 78. Kreinin A, et al. Sulpiride addition for the treatment of clozapine-induced hypersalivation: preliminary study. Isr J Psychiatry Relat Sci 2005; 42:61–63. 79. Wang J, et al. Sulpiride augmentation for schizophrenia. Cochrane Database Syst Rev 2010; (1):CD008125. 80. Prljača E, et al. Clozapine-induced hypersalivation treated with sulpiride: is it a solution? Psychiatr Danub 2021; 33:1230–1232.

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256 - Clozapine induced gastrointestinal hypomotili

Clozapine-induced gastrointestinal hypomotility

Schizophrenia and related psychoses CHAPTER 1 Clozapine-induced gastrointestinal hypomotility Constipation is a common adverse effect of clozapine treatment with a prevalence of more than 30%, three times that seen with other antipsychotics.1 The mechanism of action is not completely understood but is thought to be a combination of the drug’s anticholinergic2,3 and antihistaminergic properties,4 which are further complicated by antagonism at 5-HT3 receptors.2,3,5 In addition, clozapine-induced sedation can result in a sedentary lifestyle,4 which is itself a risk factor for constipation. Clozapine causes constipation by slowing transit time through the gut. Mean transit times are four times longer than normal and 80% of patients taking clozapine show reduced transit time.6 Clozapine-induced GI hypomotility (CIGH) is a much greater risk to life than clozapine- related agranulocytosis.4 When constipation is severe, the case fatality rate is around 20–30%.4,7–9 One long-term study10 found an incidence of 37/10,000 cases of severe hypomotility and 7/10,000 constipation-related deaths. Case fatality was 18%. Enhanced monitoring and effective treatment of CIGH are clearly needed to reduce the likelihood of constipation-related fatality. A GI history and abdominal examination are recommended prior to starting treatment and, if the patient is constipated, clozapine should not be initiated until this has resolved.8 CIGH is most severe during the first 4 months of treatment,8 but may occur at any time. Adopting the Rome III criteria11 at routine FBCs might be a successful strategy to combat preventable deaths due to CIGH, but even this does not guarantee identification of hypomotility.12 A study that examined the diagnostic accuracy of constipation screening found self-reporting to have a sensitivity of just 18%. Adding the Rome criteria improved this to 50%, but this means half of cases were still missed.13 Opinions differ on the relationship between clozapine dose and constipation, and between clozapine plasma level and constipation.8,14,15 However, most studies report that deaths that have occurred as a result of CIGH have higher than average daily doses.8,9,16 Older age, male sex and higher daily doses have been proposed as possible risk factors for death based on case series review16 and pharmacovigilance database studies (Box 1.4).9 Box 1.4 Risk factors for developing clozapine-induced constipation8,17–20 ■ ■Increasing age ■ ■Female sex ■ ■Anticholinergic medication ■ ■Higher clozapine dose/plasma concentration ■ ■Hypercalcaemia ■ ■GI disease ■ ■Obesity ■ ■Diaphoresis ■ ■Low-fibre diet ■ ■Poor bowel habit ■ ■Dehydration (exacerbated by hypersalivation) ■ ■Diabetes ■ ■Hypothyroidism ■ ■Parkinson’s disease ■ ■Multiple sclerosis

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Prevention and simple management of CIGH

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258 - Management of suspected acute CIGH

Management of suspected acute CIGH

264 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Prevention and simple management of CIGH A slow clozapine titration may reduce the risk of developing constipation, with dose increments not exceeding 25mg/day or 100mg/week.21 Increasing dietary fibre intake to at least 20–25g/day can increase stool weight but can decrease gut transit time20,22 (fibre decreases or increases transit time depending on the initial transit time).23 If fibre intake is increased it is important that adequate fluid intake (1.5–2L/day) is also maintained to avoid intestinal obstruction.8,20,24 Daily food and fluid charts would be ideal to monitor fibre and fluid intake, especially during the titration phase of clozapine. Regular exercise (150 minutes/week)25 in addition to a high-fibre diet and increased fluid intake also assists in the prevention of CIGH.26,27 Active monitoring of patients, including direct questioning, is essential. Patients often do not self-report even life-threatening constipation.8 Use of stool charts daily for the first 4 weeks and weekly or monthly thereafter is recommended. If there is a change from usual baseline bowel habit or fewer than three bowel movements a week,11 an abdominal examination is indicated.8 Where this excludes intestinal obstruction, both a stimulant and stool-softening laxative should be started, as suggested by the Porirua protocol28 (for example senna 15mg at night and docusate 100mg three times daily).8,28,29 Bulk-forming laxatives are not usually effective in slow-transit constipation2,30 and therefore should be avoided. There is some evidence that lactulose and polyethylene glycol (for example Movicol®) are effective2,31 and could be considered in addition to the stimulant and softener combination.28 Most people with CIGH will need a stimulant laxative such as senna or bisacodyl, or both. These should not be withheld on the basis that long-term use of stimulants is usually proscribed. In addition to laxative treatment, a review of the anticholinergic burden of other prescribed medicines should be undertaken. Consideration may be made of reducing the clozapine dose, but this step alone cannot be considered treatment of CIGH – use of laxatives is still essential. Choice of laxative should also be guided by the patient’s previous response to certain agents in association with consideration of the required speed of action. Lactulose takes up to 72 hours of regular use to work,32 so is of no use for urgent treatment. Stimulant laxatives are usually the fastest acting (6–10 hours). Laxative doses should be increased every 24 hours until resolution of symptoms (usual maximum daily dose of senna is 30mg, bisacodyl 20mg and docusate 500mg). Glycerin or bisacodyl suppositories can be used and are usually effective within 30 minutes but there are no data on their use in CIGH. In fact, published data supporting laxative choice for antipsychotic-related constipation are sparse and of poor quality.12 Management of suspected acute CIGH Up to 30% of patients on long-term clozapine will suffer severe GI hypomotility unless preventative steps are taken.33 Signs and symptoms that warrant immediate medical attention are abdominal pain, distension, vomiting, overflow diarrhoea, absent bowel sounds, acute abdomen, feculent vomitus and symptoms of sepsis.7,8,21,34–38 There have been case reports of fatalities occurring only hours after first symptoms present,39 and this emphasises the urgency for prompt assessment and management (including cessation of clozapine). There should therefore be a low threshold for referral to emergency medical services when conservative management fails or constipation is severe and acute.8,40

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259 - Clozapine rechallenge following severe consti

Clozapine rechallenge following severe constipation

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26 - Summary

Summary

24 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Given the association between combined antipsychotic medication and a greater adverse-effect burden,15,44 it follows that it should be standard practice to document in the clinical records the rationale for prescribing combined antipsychotics in individual cases, together with a clear account of the benefits and adverse effects of an individual trial of the strategy. Medicolegally, this would seem to be prudent, although in practice it is not always done.45 The use of combined antipsychotic medications in clinical practice There are myriad possible antipsychotic medication combinations but very limited data on their relative risk–benefit profiles in relation to overall therapeutic response or target symptom clusters. The clinical disadvantages of antipsychotic polypharmacy include an increased adverse-effect burden, higher total dosage, increased risk of drug–drug interactions, poorer medication adherence related to the complexity of the treatment and difficulties in the attribution of any response to one or more of the individual anti psychotic medications prescribed, leading to difficulty in determining the implications for an optimal longer-term regimen.6 Despite the limited supportive evidence base, the use of antipsychotic polypharmacy is an established custom and practice in many countries.46–48 Further, the general consensus across treatment guidelines that the use of combined antipsychotic medication for the treatment of refractory psychotic illness should be considered only after other, evidence-based, pharmacological treatments such as clozapine have been exhausted is not consistently followed in clinical practice.6,12,13,49–51 However, a trial of clozapine augmentation with a second antipsychotic medication to enhance efficacy is a potentially supportable practice52–56 (see section on optimising clozapine treatment in this chapter). Other antipsychotic polypharmacy strategies with potentially valid rationales are the addition of aripiprazole to reduce body weight in patients receiving clozapine.57,58 Adjunctive aripiprazole can also normalise prolactin levels, although, while the study findings on resolving hyperprolactinaemia are generally positive, they are not entirely consistent.59–64 Such polypharmacy with aripiprazole may be seen as worthwhile, evidence-based practice, albeit in the absence of regulatory trials demonstrating safety. In some cases, the use of aripiprazole alone might be a more logical choice. Conclusion Prescribing more than one antipsychotic medication may improve efficacy and very probably increases medical morbidity.65,66 Nevertheless, based on evidence currently available relating to efficacy and the potential for serious adverse effects, the routine use of combined, non-clozapine, antipsychotic medications is probably best avoided. Summary ■ ■There is a dearth of robust evidence supporting the superiority of combined, non- clozapine, antipsychotic medications over antipsychotic monotherapy. ■ ■There is more substantial evidence supporting the potential for harm and so the use of combined antipsychotic medications, which is commonly a high-dose prescription, should generally be avoided.

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260 - Key message

Key message

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261 - References

References

Schizophrenia and related psychoses CHAPTER 1 Clozapine rechallenge following severe constipation Some patients have been successfully rechallenged following severe cases of CIGH, but this process does not come without risk. Prophylactic measures should be used for those with a history of CIGH or who are deemed high risk of developing CIGH. Minimise the use of other constipating drugs and ensure other modifiable risk factors are addressed (fibre and fluid intake, exercise). Conventional laxatives should be started in regular and adequate doses to prevent constipation from developing. A number of more experimental options are available. Prescribers must familiarise themselves with the literature (at the very least by reading the SPC) before using any of these treatments and involvement of gastrointestinal specialists is encouraged. Orlistat, a drug used to aid weight loss, is also known to have a laxative effect, particularly when a high-fat diet is consumed. It was reported as being successfully used for three patients with severe constipation associated with opioid use (hypomotility- induced constipation).41 A small, randomised placebo controlled study of orlistat for clozapine-induced constipation found a favourable difference at study endpoint (week 16) for the prevalence of constipation, diarrhoea and normal stools for orlistat compared with placebo,42 although 47 of the 54 participants required conventional laxatives. Orlistat is known to reduce the absorption of some drugs from the GI tract. It is therefore important to monitor plasma clozapine levels if starting treatment with orlistat. Bethanechol, a cholinergic agonist, was effective at 30mg/day in reducing the amount of laxatives and enemas required to maintain regular bowel movements for a patient diagnosed with clozapine-related CIGH.43 Another case report described use in a patient with a gastrostomy, where up to 200mg/day bethanechol was given to reduce dilation of the bowel.44 Bethanechol should only ever be initiated after other options have failed and in consultation with a gastroenterologist.43 Prucalopride is a 5HT4 agonist which increases gut motility and is licensed for chronic constipation where laxatives have failed to provide adequate relief. Case reports of successful use for clozapine-induced constipation have been described,45,46 and superior efficacy to lactulose for this indication was demonstrated in an open-label study.47 Linaclotide (licensed in the UK for constipation in irritable bowel syndrome) and plecanatide (available in the USA for chronic idiopathic constipation) are oral guanylate cyclase C agonists. Neither has any published data to date supporting use in antipsychotic-induced constipation, beyond a single case report for linaclotide.44 Key message ■ ■Prevent clozapine-related constipation by aggressive use of stimulant laxatives. References

Shirazi A, et al. Prevalence and predictors of clozapine-associated constipation: a systematic review and meta-analysis. Int J Mol Sci 2016; 17:863.
Hibbard KR, et al. Fatalities associated with clozapine-related constipation and bowel obstruction: a literature review and two case reports. Psychosomatics 2009; 50:416–419.
Rege S, et al. Life-threatening constipation associated with clozapine. Australas Psychiatry 2008; 16:216–219.
De Hert M, et al. Second-generation antipsychotics and constipation: a review of the literature. Eur Psychiatry 2011; 26:34–44.
Meltzer HY, et al. Effects of antipsychotic drugs on serotonin receptors. Pharmacol Rev 1991; 43:587–604.

266 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 6. Every-Palmer S, et al. Clozapine-treated patients have marked gastrointestinal hypomotility, the probable basis of life-threatening gastrointestinal complications: a cross sectional study. EBioMedicine 2016; 5:125–134. 7. Cohen D, et al. Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy. J Clin Psychiatry 2012; 73:1307–1312. 8. Palmer SE, et al. Life-threatening clozapine-induced gastrointestinal hypomotility: an analysis of 102 cases. J Clin Psychiatry 2008; 69:759–768. 9. Handley SA, et al. Clozapine-induced gastrointestinal hypomotility: presenting features and outcomes, UK pharmacovigilance reports, 1992–2017. Br J Psychiatry 2022; 220:355–363. 10. Every-Palmer S, et al. Clozapine-induced gastrointestinal hypomotility: a 22-year bi-national pharmacovigilance study of serious or fatal ‘slow gut’ reactions, and comparison with international drug safety advice. CNS Drugs 2017; 31:699–709. 11. Rome Foundation. Rome IV Disorders and Criteria. 2021 (last accessed October 2024). https://theromefoundation.org. 12. Every-Palmer S, et al. Pharmacological treatment for antipsychotic-related constipation. Cochrane Database Syst Rev 2017; 1:CD011128. 13. Every-Palmer S, et al. Constipation screening in people taking clozapine: a diagnostic accuracy study. Schizophr Res 2020; 220:179–186. 14. Chengappa KN, et al. Anticholinergic differences among patients receiving standard clinical doses of olanzapine or clozapine. J Clin Psychopharmacol 2000; 20:311–316. 15. Vella-Brincat J, et al. Clozapine-induced gastrointestinal hypomotility. Australas Psychiatry 2011; 19:450–451. 16. West S, et al. Clozapine induced gastrointestinal hypomotility: a potentially life threatening adverse event: a review of the literature. Gen Hosp Psychiatry 2017; 46:32–37. 17. Nielsen J, et al. Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? J Clin Psychiatry 2013; 74:603–613; quiz 613. 18. Nielsen J, et al. Risk factors for ileus in patients with schizophrenia. Schizophr Bull 2012; 38:592–598. 19. Longmore M, et al. Oxford Handbook of Clinical Medicine. Oxford: Oxford University Press; 2010. 20. ZTAS. Zaponex Fact Sheet – Constipation. 2023 (last accessed February 2025); https://www.ztas.com/PDF/FS_Constipation_jan2023.pdf. 21. Hayes G, et al. Clozapine-induced constipation. Am J Psychiatry 1995; 152:298. 22. Muller-Lissner SA. Effect of wheat bran on weight of stool and gastrointestinal transit time: a meta analysis. Br Med J 1988; 296:615–617. 23. Harvey RF, et al. Effects of increased dietary fibre on intestinal transit. Lancet 1973; 1:1278–1280. 24. National Prescribing Centre. The management of constipation. Med Rec Bulletin 2011; 21:1–8. 25. NHS. Exercise. Physical activity guidelines for adults aged 19 to 64. 2024 (last accessed October 2024); https://www.nhs.uk/live-well/ exercise. 26. Fitzsimons J, et al. A review of clozapine safety. Expert Opin Drug Saf 2005; 4:731–744. 27. Young CR, et al. Management of the adverse effects of clozapine. Schizophr Bull 1998; 24:381–390. 28. Every-Palmer S, et al. The Porirua protocol in the treatment of clozapine-induced gastrointestinal hypomotility and constipation: a pre- and post-treatment study. CNS Drugs 2017; 31:75–85. 29. Swegle JM, et al. Management of common opioid-induced adverse effects. Am Fam Physician 2006; 74:1347–1354. 30. Voderholzer WA, et al. Clinical response to dietary fiber treatment of chronic constipation. Am J Gastroenterol 1997; 92:95–98. 31. Brandt LJ, et al. Systematic review on the management of chronic constipation in North America. Am J Gastroenterol 2005; 100 Suppl 1:S5–S21. 32. Esteve Pharmaceuticals (formerly Intrapharm Laboratories). Summary of Product Characteristics. Lactulose 10g / 15ml oral solution sachets. 2023 (last accessed October 2024); https://www.medicines.org.uk/emc/medicine/25597. 33. Partanen JJ, et al. High burden of ileus and pneumonia in clozapine-treated individuals with schizophrenia: a Finnish 25-year follow-up register study. Am J Psychiatry 2024; 181:879–892. 34. Leong QM, et al. Necrotising colitis related to clozapine? A rare but life threatening side effect. World J Emerg Surg 2007; 2:21. 35. Townsend G, et al. Case report: rapidly fatal bowel ischaemia on clozapine treatment. BMC Psychiatry 2006; 6:43. 36. Karmacharya R, et al. Clozapine-induced eosinophilic colitis. Am J Psychiatry 2005; 162:1386–1387. 37. Erickson B, et al. Clozapine-associated postoperative ileus: case report and review of the literature. Arch Gen Psychiatry 1995; 52:508–509. 38. Schwartz BJ, et al. A case report of clozapine-induced gastric outlet obstruction. Am J Psychiatry 1993; 150:1563. 39. Drew L, et al. Clozapine and constipation: a serious issue. Aust N Z J Psychiatry 1997; 31:149. 40. Ikai S, et al. Reintroduction of clozapine after perforation of the large intestine: a case report and review of the literature. Ann Pharmacother 2013; 47:e31. 41. Guarino AH. Treatment of intractable constipation with orlistat: a report of three cases. Pain Med 2005; 6:327–328. 42. Chukhin E, et al. In a randomized placebo-controlled add-on study orlistat significantly reduced clozapine-induced constipation. Int Clin Psychopharmacol 2013; 28:67–70. 43. Poetter CE, et al. Treatment of clozapine-induced constipation with bethanechol. J Clin Psychopharmacol 2013; 33:713–714. 44. Tomulescu S, et al. Managing recurrent clozapine-induced constipation in a patient with resistant schizophrenia. Case Rep Psychiatry 2021; 2021:9649334. 45. Thomas N, et al. Prucalopride in clozapine-induced constipation. Aust N Z J Psychiatry 2018; 52:804. 46. Hui KO. Prucalopride for the treatment of clozapine induced constipation: a case report. Juniper Online J Case Stud 2018; 6:555683. 47. Damodaran I, et al. An open-label, head to head comparison study between prucalopride and lactulose for clozapine induced constipation in patients with treatment resistant schizophrenia. Healthcare (Basel) 2020; 8:533.

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262 - Clozapine, neutropenia and lithium

Clozapine, neutropenia and lithium

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263 - Mild neutropenia

Mild neutropenia

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264 - Severe neutropenia or agranulocytosis

Severe neutropenia or agranulocytosis

Schizophrenia and related psychoses CHAPTER 1 Clozapine, neutropenia and lithium Mild neutropenia Around 3.8% of patients treated with clozapine develop neutropenia.1 Most of these cases are unrelated to clozapine treatment, and clozapine in fact may not cause neutropenia per se.2 The risk of neutropenia (<1.5×109/L) in patients treated with clozapine is broadly similar to the cross-sectional prevalence of neutropenia in otherwise healthy individuals (0.4– 4.5% depending on ethnicity).3 Indeed, a meta-analysis comparing the risk of neutropenia between clozapine and other antipsychotics found that clozapine did not have a stronger association with neutropenia than other antipsychotic medications.4 Most people developing mild neutropenia will not develop severe neutropenia or agranulocytosis. Risk factors for neutropenia include being Afro-Caribbean, younger age and having a low baseline white cell count (WCC).5 The vast majority of patients who stop clozapine because they have developed neutropenia can be successfully rechallenged.6 Adopting the US monitoring criteria would eliminate the requirement to discontinue clozapine treatment in cases of mild neutropenia (absolute neutrophil count [ANC] between 1 and 1.5×109/L). Confusion arises because of the various possible reasons for a low neutrophil count in people taking clozapine. A single low count might just be a coincidental finding of no clinical relevance, as is common with all drugs. Several low counts (consecutive or intermittent) might be seen in people with BEN (see below) or as a result of clozapine- associated bone marrow suppression (especially if consecutive and progressively falling). Full-blown agranulocytosis can probably always be interpreted as being the result of severe bone marrow suppression caused by clozapine. Severe neutropenia or agranulocytosis The risk of agranulocytosis during clozapine treatment is 1 in 250 (0.4%),7 lower than previously thought, and risk of death resulting from this is 0.05% – a rare event. Most cases of agranulocytosis develop within the first 18 weeks of treatment. Thereafter, the risk diminishes steeply.8 The mechanism of clozapine-induced agranulocytosis is not fully understood but is thought to be immune mediated, given the significant association with certain human leucocyte antigen variants.9 Identifying with certainty whether an episode of severe neutropenia is clozapine-related may be difficult. However, the pattern of neutrophil count change is important. A single episode of a below-threshold ANC <0.5×109/L may be unrelated to clozapine but would normally promptly lead to treatment cessation. In patients without BEN, agranulocytosis is generally preceded by normal neutrophil counts, which are then followed by a precipitous fall in neutrophils (usually over a week or less) and a prolonged period of counts near to zero (assuming that it has not been treated).10 Neutrophil counts that do not follow this characteristic pattern are difficult to interpret. The Netherlands Clozapine Collaboration Group11 considers the risk of agranulocytosis so low that a mentally competent patient may stop routine haematological monitoring after 6 months of treatment. The group still nevertheless recommends low-frequency testing (for example four times a year if routine monitoring is stopped).

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265 - Benign ethnic neutropenia

Benign ethnic neutropenia

268 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Risk factors for agranulocytosis include increasing age and Asian race.5 Unlike neutropenia, risk of agranulocytosis appears to be higher in people of European ancestry than in those of African descent.12 Some patients may be genetically predisposed13 (see section on clozapine: genetic testing for clozapine treatment in this chapter). Although the timescale and individual risk factors for the development of agranulocytosis are different from those associated with neutropenia/coincidental low neutrophil counts, it is difficult to be certain in any given patient that neutropenia is not a precursor to agranulocytosis. However, it is notable that only 30% of confirmed cases of agranulocytosis pass through a neutropenia phase during the precipitous fall in counts.12 Haematological monitoring is mandatory to mitigate haematological risk. However, worldwide, there are marked variations in the recommendations for monitoring frequency and the threshold for clozapine cessation,14 reflecting, perhaps, the weak evidence on which they are based. In 2015, the US FDA introduced changes to the clozapine monitoring system making only the ANC mandatory and effectively lowering the threshold for cessation of clozapine treatment.15 It is recommended that treatment with clozapine be stopped when neutrophils fall below 1000/mm16 (compared with UK recommendations for cessation if ANC <1500/mm).16 There is evidence that clozapine is grossly under-used worldwide, with very wide variation in prescribing frequency from one country to another.17 This may be explained at least in part by the stringent blood monitoring requirements. The worldwide outbreak of COVID-19 in 2020 prompted a re-evaluation of clozapine haematological monitoring, with a group proposing a reduction from monthly to 3-monthly for patients who have received clozapine for more than 1 year without a history of neutropenia.18 Implementation of the extended 3-monthly monitoring found no difference in the rates of severe neutropenia compared with monthly monitoring.19 In addition to this, when considering that the development of true agranulocytosis occurs over 10 days or less, the value of monthly monitoring is clearly questionable, especially in patients for whom the overall risk of agranulocytosis is near to zero. Benign ethnic neutropenia BEN is a widely recognised hereditary condition in which the neutrophil count is relatively low – there is a left shift in the normal distribution of counts. People of African or Middle Eastern descent have a high prevalence. BEN is characterised by low WCC, which may frequently fall below the lower limit of normal. This pattern may be observed before, during and after the use of clozapine and very probably accounts for a proportion of observed or apparent clozapine-associated neutropenias and treatment cessation. Many countries allow registration of BEN status whereby different (lower) limits are set for neutrophil counts in these patients. While true clozapine- induced neutropenia can occur in the context of BEN, evidence suggests that BEN does not pose an increased risk of dyscrasias during clozapine treatment.20,21 The use of genetic testing to identify BEN may be useful in reducing the risk of unnecessary termination of treatment and is strongly recommended for all patients starting clozapine, regardless of ethnicity.22,23

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266 - Concurrent medications

Concurrent medications

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267 - Management options

Management options

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268 - Lithium

Lithium

Schizophrenia and related psychoses CHAPTER 1 Concurrent medications Different classes of medicines associated with haematological adverse effects are co- prescribed with clozapine. These include other antipsychotics, anticonvulsants such as sodium valproate and carbamazepine, antibacterials and GI agents such as proton- pump inhibitors. Many patients develop neutropenia on clozapine but not all are clozapine-related or even pathological. The possible contributory role of these agents should always be considered and these drugs discontinued if clozapine rechallenge is attempted.24 Management options Before treatment initiation, it is important to evaluate baseline haematological values. All patients should be genetically tested for BEN.25 In those already taking clozapine, there are three distinct patient groups: those with normal neutrophil counts, those with neutropenia unrelated to clozapine, and those with clozapine-related agranulocytosis. Here, we discuss options for the middle group – those with mild neutropenia unrelated to clozapine. The use of iatrogenic agents to elevate WCC in patients with clear prior clozapine-induced severe neutropenia or agranulocytosis (i.e. there is certainty that clozapine was the cause) is not recommended. Lithium or other medicines should only be used to elevate WCC where it is strongly felt that prior neutropenic episodes were unrelated to clozapine. Patients who have had a previous episode of agranulocytosis that is attributable to clozapine should not be rechallenged either with or without lithium. Lithium Lithium increases the neutrophil count and total WCC both acutely and chronically. The magnitude of this effect is poorly quantified, but a mean neutrophil count of 11.9×109/L has been reported in patients treated with lithium, and a mean rise in neutrophil count of 2×109/L was seen in patients treated with clozapine after the addition of lithium. This effect does not seem to be clearly dose-related, although a minimum lithium serum level of at least 0.4mmol/L may be required. The mechanism is not completely understood.26 Lithium has been used to increase the WCC in patients who have developed neutropenia while taking clozapine, allowing clozapine treatment to continue. Several case reports in adults27–31 and in children32,33 have been published. Almost all patients had plasma lithium levels of >0.6mmol/L. In a case series (n = 25) of patients who had stopped clozapine because of an apparent blood dyscrasia and were rechallenged in the presence of lithium, only one developed a subsequent dyscrasia.34 If considering lithium, discuss with the medical adviser at the relevant monitoring service to determine the optimum pharmacological strategy for the particular patient. Increased risk of neurological adverse effects such as myoclonus, ataxia and seizures should be considered when using the combination.35 Where there are valid concerns regarding neurotoxic effect, it may be prudent to use clozapine alone (off-licence) with US monitoring criteria (Figure 1.6).36

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269 - Granulocyte colony stimulating factor

Granulocyte colony-stimulating factor

270 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Lithium does not protect against true clozapine-induced agranulocytosis. One case of fatal agranulocytosis has occurred with this combination25 and a second case of agranulocytosis has been reported with the combination with subsequent resistant to treatment with granulocyte colony-stimulating factor (G-CSF).37 Granulocyte colony-stimulating factor The use of G-CSF to facilitate uninterrupted clozapine therapy in patients with previous neutropenia is a strategy that is attracting increasing interest but is somewhat controversial. In one study, clozapine was successfully rechallenged using G-CSF in 76% of patients for an average follow-up period of 1.9 years.38 As well as the commonly reported adverse effects of bone pain39 and neutrophil dysplasia,40 the administration of Treatment/rechallenge with clozapine considered desirable Discontinue, if possible, other drugs that are known to suppress the bone marrow Genetic testing/refer to haematologist for BEN dx if appropriate Baseline U&Es, TFTs, FBC Borderline/ low WCC WCC in right range Prescribe lithium 400mg daily Titrate dose to achieve a plasma level

0.4mmol/L (higher plasma levels may be appropriate for patients who have an affective component to their illness). Repeat WCC If WCC result is in the normal range, start/restart clozapine Ensure ongoing monitoring for clozapine and lithium (note that lithium does not protect against agranulocytosis: if the WCC continues to fall despite lithium treatment, consideration should be given to discontinuing clozapine. Particular vigilance is required in high-risk patients during the first 18 weeks of treatment) Lithium contraindicated or inappropriate Haematology referral/ consultation with clozapine registry Unlicensed US monitoring criteria Treatment plan with G-CSF Figure 1.6 The use of lithium with clozapine.

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27 - References

References

Schizophrenia and related psychoses CHAPTER 1 ■ ■Combined antipsychotic medications are commonly prescribed and this practice seems to be relatively resistant to change. ■ ■As a minimum requirement, all patients who are prescribed combined antipsychotic medications should be systematically monitored for adverse effects (including an ECG) and any beneficial effect on the symptoms of psychotic illness carefully documented. ■ ■Some antipsychotic polypharmacy strategies (e.g. combinations with aripiprazole) show clear benefits for tolerability but not efficacy. References

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Gallego JA, et al. Prevalence and correlates of antipsychotic polypharmacy: a systematic review and meta-regression of global and regional trends from the 1970s to 2009. Schizophr Res 2012; 138:18–28.
Sneider B, et al. Frequency and correlates of antipsychotic polypharmacy among patients with schizophrenia in Denmark: a nation-wide pharmacoepidemiological study. Eur Neuropsychopharmacol 2015; 25:1669–1676.
Procyshyn RM, et al. Persistent antipsychotic polypharmacy and excessive dosing in the community psychiatric treatment setting: a review of medication profiles in 435 Canadian outpatients. J Clin Psychiatry 2010; 71:566–573.
Aggarwal NK, et al. Prevalence of concomitant oral antipsychotic drug use among patients treated with long-acting, intramuscular, antipsychotic medications. J Clin Psychopharmacol 2012; 32:323–328.
Barnes T, et al. Antipsychotic long acting injections: prescribing practice in the UK. Br J Psychiatry Suppl 2009; 52:S37–S42.
Novick D, et al. Antipsychotic monotherapy and polypharmacy in the treatment of outpatients with schizophrenia in the European Schizophrenia Outpatient Health Outcomes Study. J Nerv Ment Dis 2012; 200:637–643.
Paton C, et al. High-dose and combination antipsychotic prescribing in acute adult wards in the UK: the challenges posed by p.r.n. prescribing. Br J Psychiatry 2008; 192:435–439.
Royal College of Psychiatrists. Prescribing Observatory for Mental Health. Topic 1h & 3e: Prescribing of antipsychotic medication in adult mental health services, including high dose, combined, and PRN. CCQI 442. 2022 (last accessed February 2025); https://www.rcpsych.ac.uk/ improving-care/ccqi/national-clinical-audits/pomh.
Correll CU, et al. Antipsychotic polypharmacy: a comprehensive evaluation of relevant correlates of a long-standing clinical practice. Psychiatr Clin North Am 2012; 35:661–681.
Baandrup L, et al. Association of antipsychotic polypharmacy with health service cost: a register-based cost analysis. Eur J Health Econ 2012; 13:355–363.
Kadra G, et al. Predictors of long-term (≥6months) antipsychotic polypharmacy prescribing in secondary mental healthcare. Schizophr Res 2016; 174:106–112.
Grech P, et al. Long-term antipsychotic polypharmacy: how does it start, why does it continue? Ther Adv Psychopharmacol 2012; 2:5–11.
Malandain L, et al. Correlates and predictors of antipsychotic drug polypharmacy in real-life settings: results from a nationwide cohort study. Schizophr Res 2018; 192:213–218.
Fleischhacker WW, et al. Critical review of antipsychotic polypharmacy in the treatment of schizophrenia. Int J Neuropsychopharmacol 2014; 17:1083–1093.
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Galling B, et al. Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis. World Psychiatry 2017; 16:77–89.
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Shakir M, et al. The effect on relapse rate and psychiatric symptomatology: switching a combination of first- and second-generation anti psychotic polypharmacy to antipsychotic monotherapy in long-term inpatients with schizophrenia and related disorders: a pragmatic randomized open-label trial (SwAP trial). Schizophr Res 2022; 243:187–194.
Constantine RJ, et al. The risks and benefits of switching patients with schizophrenia or schizoaffective disorder from two to one antipsychotic medication: a randomized controlled trial. Schizophr Res 2015; 166:194–200.
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Tiihonen J, et al. Association of antipsychotic polypharmacy vs monotherapy with psychiatric rehospitalization among adults with schizophrenia. JAMA Psychiatry 2019; 76:499–507.
Goff DC. Can adjunctive pharmacotherapy reduce hospitalization in schizophrenia? Insights from administrative databases. JAMA Psychiatry 2019; 76:468–470.

26 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 26. Tiihonen J, et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29823 patients with schizophrenia. JAMA Psychiatry 2017; 74:686–693. 27. López de Torre A, et al. Antipsychotic polypharmacy: a needle in a haystack? Gen Hosp Psychiatry 2012; 34:423–432. 28. Carnahan RM, et al. Increased risk of extrapyramidal side-effect treatment associated with atypical antipsychotic polytherapy. Acta Psychiatr Scand 2006; 113:135–141. 29. Gomberg RF. Interaction between olanzapine and haloperidol. J Clin Psychopharmacol 1999; 19:272–273. 30. Suzuki T, et al. Effectiveness of antipsychotic polypharmacy for patients with treatment refractory schizophrenia: an open-label trial of olanzapine plus risperidone for those who failed to respond to a sequential treatment with olanzapine, quetiapine and risperidone. Hum Psychopharmacol 2008; 23:455–463. 31. Gallego JA, et al. Safety and tolerability of antipsychotic polypharmacy. Expert Opin Drug Saf 2012; 11:527–542. 32. Hashimoto Y, et al. Effects of antipsychotic polypharmacy on side-effects and concurrent use of medications in schizophrenic outpatients. Psychiatry Clin Neurosci 2012; 66:405–410. 33. Sorensen HJ, et al. Schizophrenia, antipsychotics and risk of hip fracture: a population-based analysis. Eur Neuropsychopharmacol 2013; 23:872–878. 34. Dome P, et al. Paralytic ileus associated with combined atypical antipsychotic therapy. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:557–560. 35. Hedges DW, et al. New-onset seizure associated with quetiapine and olanzapine. Ann Pharmacother 2002; 36:437–439. 36. Beelen AP, et al. Asymptomatic QTc prolongation associated with quetiapine fumarate overdose in a patient being treated with risperidone. Hum Exp Toxicol 2001; 20:215–219. 37. Eyles E, et al. Antipsychotic medication and risk of metabolic disorders in people with schizophrenia: a longitudinal study using the UK clinical practice research datalink. Schizophr Bull 2024; 50:447–459. 38. Baandrup L, et al. Antipsychotic polypharmacy and risk of death from natural causes in patients with schizophrenia: a population-based nested case–control study. J Clin Psychiatry 2010; 71:103–108. 39. Chen Y, et al. Antipsychotics and risk of natural death in patients with schizophrenia. Neuropsychiatr Dis Treat 2019; 15:1863–1871. 40. Tiihonen J, et al. Polypharmacy with antipsychotics, antidepressants, or benzodiazepines and mortality in schizophrenia. Arch Gen Psychiatry 2012; 69:476–483. 41. Waddington JL, et al. Mortality in schizophrenia: antipsychotic polypharmacy and absence of adjunctive anticholinergics over the course of a 10-year prospective study. Br J Psychiatry 1998; 173:325–329. 42. Kadra G, et al. Long-term antipsychotic polypharmacy prescribing in secondary mental health care and the risk of mortality. Acta Psychiatr Scand 2018; 138:123–132. 43. Joukamaa M, et al. Schizophrenia, neuroleptic medication and mortality. Br J Psychiatry 2006; 188:122–127. 44. Centorrino F, et al. Multiple versus single antipsychotic agents for hospitalized psychiatric patients: case-control study of risks versus benefits. Am J Psychiatry 2004; 161:700–706. 45. Taylor D, et al. Co-prescribing of atypical and typical antipsychotics: prescribing sequence and documented outcome. Psychiatr Bull 2002; 26:170–172. 46. Kreyenbuhl J, et al. Adding or switching antipsychotic medications in treatment-refractory schizophrenia. Psychiatr Serv 2007; 58:983–990. 47. Nielsen J, et al. Psychiatrists’ attitude towards and knowledge of clozapine treatment. J Psychopharmacol 2010; 24:965–971. 48. Ascher-Svanum H, et al. Comparison of patients undergoing switching versus augmentation of antipsychotic medications during treatment for schizophrenia. Neuropsychiatr Dis Treat 2012; 8:113–118. 49. Goren JL, et al. Antipsychotic prescribing pathways, polypharmacy, and clozapine use in treatment of schizophrenia. Psychiatr Serv 2013; 64:527–533. 50. Howes OD, et al. Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. Br J Psychiatry 2012; 201:481–485. 51. Thompson JV, et al. Antipsychotic polypharmacy and augmentation strategies prior to clozapine initiation: a historical cohort study of 310 adults with treatment-resistant schizophrenic disorders. J Psychopharmacol 2016; 30:436–443. 52. Shiloh R, et al. Sulpiride augmentation in people with schizophrenia partially responsive to clozapine: a double-blind, placebo-controlled study. Br J Psychiatry 1997; 171:569–573. 53. Josiassen RC, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2005; 162:130–136. 54. Paton C, et al. Augmentation with a second antipsychotic in patients with schizophrenia who partially respond to clozapine: a meta-analysis. J Clin Psychopharmacol 2007; 27:198–204. 55. Barbui C, et al. Does the addition of a second antipsychotic drug improve clozapine treatment? Schizophr Bull 2009; 35:458–468. 56. Taylor DM, et al. Augmentation of clozapine with a second antipsychotic: a meta-analysis of randomized, placebo-controlled studies. Acta Psychiatr Scand 2009; 119:419–425. 57. Fleischhacker WW, et al. Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol 2010; 13:1115–1125. 58. Cooper SJ, et al. BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment. J Psychopharmacol 2016; 30:717–748. 59. Byerly MJ, et al. Effects of aripiprazole on prolactin levels in subjects with schizophrenia during cross-titration with risperidone or olanzapine: analysis of a randomized, open-label study. Schizophr Res 2009; 107:218–222. 60. Liu X, et al. Co-prescription of aripiprazole on prolactin levels in long-term hospitalized chronic schizophrenic patients with co-morbid type 2 diabetes: a retrospective clinical study. Front Psychiatry 2023; 14:1124691.

Schizophrenia and related psychoses CHAPTER 1 61. Jiang Q, et al. Treatment of antipsychotic-induced hyperprolactinemia: an umbrella review of systematic reviews and meta-analyses. Front Psychiatry 2024; 15:1337274. 62. Shim JC, et al. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo- controlled trial. Am J Psychiatry 2007; 164:1404–1410. 63. Trives MZ, et al. Effect of the addition of aripiprazole on hyperprolactinemia associated with risperidone long-acting injection. J Clin Psychopharmacol 2013; 33:538–541. 64. Chen CK, et al. Differential add-on effects of aripiprazole in resolving hyperprolactinemia induced by risperidone in comparison to benzamide antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:1495–1499. 65. Lin SK. Antipsychotic polypharmacy: a dirty little secret or a fashion? Int J Neuropsychopharmacol 2020; 23:125–131. 66. Guinart D, et al. Antipsychotic polypharmacy in schizophrenia: why not? J Clin Psychiatry 2020; 81:19ac13118.

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References

Schizophrenia and related psychoses CHAPTER 1 G-CSF in the face of a low or declining neutrophil count may mask an impending neutropenia or agranulocytosis, leading to dire consequences. The long-term safety of G-CSF has not been determined but bone density and spleen size should probably be monitored. ‘When required’ G-CSF, to be administered if neutrophils drop below a defined threshold, may allow rechallenge with clozapine of patients in whom lithium is insufficient to prevent ‘dipping’ of WCC below the normal range. Again, this strategy risks masking a severe neutropenia/agranulocytosis. It is also likely to be practically difficult to manage outside a specialist unit, as frequent blood testing (twice to three times a week) is required, as well as immediate access to medical review and the G-CSF itself. Consultation with a haematologist and discussion with the medical adviser at the clozapine monitoring service are essential before considering the use of G-CSF. A patient’s individual clinical circumstances should be considered. In particular, patients should be considered to be very high risk for rechallenge with clozapine if the first episode of dyscrasia fulfilled any of the following criteria, all of which suggest that the low counts are clozapine-related: ■ ■inconsistent with previous WCCs (i.e. not part of a pattern of repeated low WCCs) ■ ■occurred within the first 18 weeks of treatment ■ ■severe (neutrophils <0.5×109/L) or ■ ■prolonged. While G-CSF has been reported as allowing successful rechallenge with clozapine in some people with previous episodes of clozapine-induced neutropenia,41 the available evidence should exclude this course of action for someone with a true clozapine-related agranulocytosis.42 Lithium is indicated in the management of patients with: ■ ■low initial WCC (<4×109/L) or neutrophils (< 2.5×109/L) ■ ■leucopenia (WCC <3×109/L) or neutropenia (neutrophils <1.5×109/L) thought to be linked to benign ethnic neutropenia. Such patients may be of African or Middle Eastern descent, have no history of susceptibility to infection and have morphologically normal white blood cells3 ■ ■recurrent ‘amber’ results during clozapine treatment ■ ■a ‘red’ result probably unrelated to clozapine. References

Myles N, et al. Meta-analysis examining the epidemiology of clozapine-associated neutropenia. Acta Psychiatr Scand 2018; 138:101–109.
Johannsen CF, et al. Clozapine- and non-clozapine-associated neutropenia in patients with schizophrenia: a retrospective cohort study. Ther Adv Psychopharmacol 2022; 12:20451253211072341.
Hsieh MM, et al. Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences. Ann Intern Med 2007; 146:486–492.
Myles N, et al. A meta-analysis of controlled studies comparing the association between clozapine and other antipsychotic medications and the development of neutropenia. Aust N Z J Psychiatry 2019; 53:403–412.
Munro J, et al. Active monitoring of 12760 clozapine recipients in the UK and Ireland. Br J Psychiatry 1999; 175:576–580.
Oloyede E, et al. Relaxation of the criteria for entry to the UK Clozapine Central Non-Rechallenge Database: a modelling study. Lancet Psychiatry 2022; 9:636–644.
Li XH, et al. The prevalence of agranulocytosis and related death in clozapine-treated patients: a comprehensive meta-analysis of observational studies. Psychol Med 2020; 50:583–594.

272 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 8. Northwood K, et al. Evaluating the epidemiology of clozapine-associated neutropenia among people on clozapine across Australia and Aotearoa New Zealand: a retrospective cohort study. Lancet Psychiatry 2024; 11:27–35. 9. Islam F, et al. Pharmacogenomics of clozapine-induced agranulocytosis: a systematic review and meta-analysis. Pharmacogenomics J 2022; 22:230–240. 10. Taylor D, et al. Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis. Schizophrenia (Heidelb) 2022; 8:21. 11. Netherlands Clozapine Collaboration Group. Guideline for the use of Clozapine version 05-02-2013. 2013 (last accessed February 2025); https://www.clozapinepluswerkgroep.nl/wp-content/uploads/2013/07/Guideline-for-the-use-of-Clozapine-2013.pdf. 12. Oloyede E, et al. Identifying clinically relevant agranulocytosis in people registered on the UK clozapine Central Non-Rechallenge Database: retrospective cohort study. Br J Psychiatry 2024; 225:484–491. 13. Dettling M, et al. Further evidence of human leukocyte antigen-encoded susceptibility to clozapine-induced agranulocytosis independent of ancestry. Pharmacogenetics 2001; 11:135–141. 14. Nielsen J, et al. Worldwide differences in regulations of clozapine use. CNS Drugs 2016; 30:149–161. 15. FDA. FDA Drug Safety Communication: FDA modifies monitoring for neutropenia associated with schizophrenia medicine clozapine; approves new shared REMS program for all clozapine medicines. 2016 (last accessed November 2024); https://www.fda.gov/Drugs/ DrugSafety/ucm461853.htm. 16. Dunk LR, et al. Rechallenge with clozapine following leucopenia or neutropenia during previous therapy. Br J Psychiatry 2006; 188:255–263. 17. Bachmann CJ, et al. International trends in clozapine use: a study in 17 countries. Acta Psychiatr Scand 2017; 136:37–51. 18. Siskind D, et al. Consensus statement on the use of clozapine during the COVID-19 pandemic. J Psychiatry Neurosci 2020; 45:222–223. 19. Oloyede E, et al. Clinical impact of reducing the frequency of clozapine monitoring: controlled mirror-image cohort study. Br J Psychiatry 2023; 223:382–388. 20. Manu P, et al. Benign ethnic neutropenia and clozapine use: a systematic review of the evidence and treatment recommendations. J Clin Psychiatry 2016; 77:e909–e916. 21. Richardson CM, et al. Evaluation of the safety of clozapine use in patients with benign neutropenia. J Clin Psychiatry 2016; 77:e1454–e1459. 22. Aziri H, et al. Genetic identification of undiagnosed benign ethnic neutropenia in patients receiving clozapine treatment. Br J Psychiatry 2024; doi: 10.1192/bjp.2024.236. 23. Borinstein SC, et al. Frequency of benign neutropenia among black versus white individuals undergoing a bone marrow assessment. J Cell Mol Med 2022; 26:3628–3635. 24. Shuman MD, et al. Exploring the potential effect of polypharmacy on the hematologic profiles of clozapine patients. J Psychiatr Pract 2014; 20:50–58. 25. Whiskey E, et al. The importance of the recognition of benign ethnic neutropenia in black patients during treatment with clozapine: case reports and database study. J Psychopharmacol 2011; 25:842–845. 26. Paton C, et al. Managing clozapine-induced neutropenia with lithium. Psychiatr Bull 2005; 29:186–188. 27. Adityanjee A. Modification of clozapine-induced leukopenia and neutropenia with lithium carbonate. Am J Psychiatry 1995; 152:648–649. 28. Silverstone PH. Prevention of clozapine-induced neutropenia by pretreatment with lithium. J Clin Psychopharmacol 1998; 18:86–88. 29. Boshes RA, et al. Initiation of clozapine therapy in a patient with preexisting leukopenia: a discussion of the rationale of current treatment options. Ann Clin Psychiatry 2001; 13:233–237. 30. Papetti F, et al. Treatment of clozapine-induced granulocytopenia with lithium (two observations). Encephale 2004; 30:578–582. 31. Kutscher EC, et al. Clozapine-induced leukopenia successfully treated with lithium. Am J Health Syst Pharm 2007; 64:2027–2031. 32. Sporn A, et al. Clozapine-induced neutropenia in children: management with lithium carbonate. J Child Adolesc Psychopharmacol 2003; 13:401–404. 33. Mattai A, et al. Adjunctive use of lithium carbonate for the management of neutropenia in clozapine-treated children. Hum Psychopharmacol 2009; 24:584–589. 34. Kanaan RA, et al. Lithium and clozapine rechallenge: a restrospective case analysis. J Clin Psychiatry 2006; 67:756–760. 35. Verdoux H, et al. Risks and benefits of clozapine and lithium co-prescribing: a systematic review and expert recommendations. Schizophr Res 2024; 268:233–242. 36. Silva E, et al. Understanding clozapine-related blood dyscrasias. Developments, genetics, ethnicity and disparity: it’s a CIN. BJPsych Bull 2024:1–6. 37. Valevski A, et al. Clozapine–lithium combined treatment and agranulocytosis. Int Clin Psychopharmacol 1993; 8:63–65. 38. Corbeil O, et al. Clozapine rechallenge or continuation despite neutropenia or agranulocytosis using colony-stimulating factor: a systematic review. J Psychopharmacol 2023; 37:370–377. 39. Puhalla S, et al. Hematopoietic growth factors: personalization of risks and benefits. Mol Oncol 2012; 6:237–241. 40. Bain BJ, et al. Neutrophil dysplasia induced by granulocyte colony-stimulating factor. Am J Hematol 2010; 85:354. 41. Myles N, et al. Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: a systematic review of the literature and clinical recommendations. Aust N Z J Psychiatry 2017:4867417720516. 42. Lally J, et al. The use of granulocyte colony-stimulating factor in clozapine rechallenge: a systematic review. J Clin Psychopharmacol 2017; 37:600–604.

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Clozapine and chemotherapy

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272 - Summary

Summary

Schizophrenia and related psychoses CHAPTER 1 Clozapine and chemotherapy The use of clozapine with agents that cause neutropenia is formally contraindicated. Most chemotherapy treatments cause significant bone marrow suppression. When the white blood cell count drops below 3.0×109/L clozapine is usually discontinued. This is an important safety precaution outlined in the formal licence/labelling. For many regimens it can be predicted that chemotherapy will reduce the white blood cell (WBC) count below this level, irrespective of the use of clozapine. The use of chemotherapy may be more likely in people taking clozapine because of its association with malignancy.1,2 Ideally, clozapine should be discontinued before chemotherapy starts. However, this will place most patients at high risk of relapse or at least significant deterioration of their psychotic illness, which may then affect their capacity to consent to chemotherapy. This poses a therapeutic dilemma in patients prescribed clozapine and requiring chemotherapy. In practice, most patients do continue on clozapine treatment during chemotherapy. Liaison with regulatory bodies is essential in ensuring continuity of clozapine treatment for patients who are also receiving chemotherapy. Severe clozapine-induced neutropenia is very rare in people taking clozapine for longer than a year, while neutropenia is a known adverse effect of many chemotherapy regimens. Chemotherapy has a predictable effect on neutrophil counts, both in terms of magnitude of effect and the timing, so knowledge of these factors should help determine the cause of any neutropenia that develops. There are a number of case reports supporting continuing clozapine during chemotherapy,3–18 but interpretation of this literature should take account of possible publication bias.3 Before initiating chemotherapy for a patient receiving clozapine, it is essential to put in place a treatment plan that is agreed with all relevant healthcare staff involved and, of course, the patient and family members/carers. This will include the oncologist/ physician, psychiatrist, haematologist, pharmacist and the clozapine monitoring service. Plans should be made in advance for the action that should be taken when the WBC count drops below the normally accepted minimum. This plan should cover the frequency of haematological monitoring, increased vigilance regarding the clinical consequences of neutropenia/agranulocytosis, if and when clozapine should be stopped, and the place of medication such as lithium and G-CSF19,20 to try and support the maintenance of normal neutrophil counts. In the UK, the clozapine monitoring service will normally ask the psychiatrist to sign an ‘unlicensed use’ form and will request additional blood monitoring. Complications appear to be rare but there is one case report of neutropenia persisting for 6 months after doxorubicin, radiotherapy and clozapine.6 G-CSF has been used to treat agranulocytosis associated with chemotherapy and clozapine in combination.7,8,21 As discussed above, the risks of life-threatening blood dyscrasia are probably lowest in those who have received clozapine for longer than a year, in whom a clozapine-induced severe neutropenia would be highly unusual. Summary ■ ■If possible, clozapine should be discontinued before starting chemotherapy but, for almost all people, the risk–benefit analysis will be judged to be in favour of continuing clozapine.

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References

274 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 ■ ■The likelihood of relapse or deterioration of the psychotic illness must be considered before discontinuing clozapine. ■ ■Consideration should be given to the possibility that, if the patient’s mental state deteriorates, they may retract their consent for chemotherapy. ■ ■When clozapine treatment is continued during chemotherapy, a collaborative approach is strongly recommended, involving an oncologist, a psychiatrist, a haematologist, a pharmacist, the patient and their relatives/carers and the relevant clozapine monitoring service. References

Chrétien B, et al. Haematologic malignancies associated with clozapine v. all other antipsychotic agents: a pharmacovigilance study in VigiBase(®). Psychol Med 2021; 51:1459–1466.
Tiihonen J, et al. Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland. Lancet Psychiatry 2022; 9:353–362.
Cunningham NT, et al. Continuation of clozapine during chemotherapy: a case report and review of literature. Psychosomatics 2014; 55:673–679.
Bareggi C, et al. Clozapine and full-dose concomitant chemoradiation therapy in a schizophrenic patient with nasopharyngeal cancer. Tumori 2002; 88:59–60.
Hundertmark J, et al. Reintroduction of clozapine after diagnosis of lymphoma. Br J Psychiatry 2001; 178:576.
Rosenstock J. Clozapine therapy during cancer treatment. Am J Psychiatry 2004; 161:175.
Lee SY, et al. Combined antitumor chemotherapy in a refractory schizophrenic receiving clozapine. J Korean Neuropsychiatr Assoc 2000; 39:234–239.
Usta NG, et al. Clozapine treatment of refractory schizophrenia during essential chemotherapy: a case study and mini review of a clinical dilemma. Ther Adv Psychopharmacol 2014; 4:276–281.
Rosenberg I, et al. Restarting clozapine treatment during ablation chemotherapy and stem cell transplant for Hodgkin’s lymphoma. Am J Psychiatry 2007; 164:1438–1439.
Goulet K, et al. Case report: clozapine given in the context of chemotherapy for lung cancer. Psychooncology 2008; 17:512–516.
Frieri T, et al. Maintaining clozapine treatment during chemotherapy for non-Hodgkin’s lymphoma. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:1611–1612.
Sankaranarayanan A, et al. Clozapine, cancer chemotherapy and neutropenia: dilemmas in management. Psychiatr Danub 2013; 25:419–422.
De Berardis D, et al. Safety and efficacy of combined clozapine-azathioprine treatment in a case of resistant schizophrenia associated with Behcet’s disease: a 2-year follow-up. Gen Hosp Psychiatry 2013; 35:213–211.
Deodhar JK, et al. Clozapine and cancer treatment: adding to the experience and evidence. Indian J Psychiatry 2014; 56:191–193.
Monga V, et al. Clozapine and concomitant chemotherapy in a patient with schizophrenia and new onset esophageal cancer. Psychooncology 2015; 24:971–972.
Overbeeke MR, et al. Successful clozapine continuation during chemotherapy for the treatment of malignancy: a case report. Int J Clin Pharm 2016; 38:199–202.
Campbell G, et al. Clozapine and chemotherapy: a dangerous couple or a necessary partnership? Drug Ther Bull 2022; 60:29–31.
Wright T, et al. Should clozapine be discontinued in a patient receiving chemotherapy? Current Psychiatry 2022; 21:44–49.
Whiskey E, et al. Restarting clozapine after neutropenia: evaluating the possibilities and practicalities. CNS Drugs 2007; 21:25–35.
Silva E, et al. Clozapine rechallenge and initiation despite neutropenia- a practical, step-by-step guide. BMC Psychiatry 2020; 20:279.
Kolli V, et al. Treating chemotherapy induced agranulocytosis with granulocyte colony-stimulating factors in a patient on clozapine. Psychooncology 2013; 22:1674–1675.

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274 - Genetic testing for clozapine treatment

Genetic testing for clozapine treatment

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275 - Response

Response

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Agranulocytosis

Schizophrenia and related psychoses CHAPTER 1 Genetic testing for clozapine treatment A great number of studies have sought to detect genetic predictors of clozapine outcomes, both therapeutic and adverse. Generally, only small effects have been uncovered and clinical utility is limited unless genetic variant effects are mathematically combined. Sensitivity (the likelihood of accurately predicting a specific outcome) is usually low but specificity (the likelihood of correctly excluding that outcome) is often very high. Numerical values for these categories can be combined with population incidence data to generate positive predictive value (PPV – the % of people who will experience the outcome when predicted) and negative predictive value (NPV – the % of people who will not experience that outcome when it is not predicted). This concept is applicable to genetic variants linked to agranulocytosis. The presence of a candidate variant (see PPV below) should provoke caution and perhaps more frequent testing. The absence of a candidate variant (see NPV) may give some reassurance about the likelihood of agranulocytosis, especially if the NPV is >99.6% (that is, 100 minus 0.4%, the risk of agranulocytosis in the wider population). Response Three variants have been reliably shown to predict therapeutic outcome with clozapine:1 HTR2A rs6313C CC carriers less likely to respond than T carriers CC 146/272 response, CT/TT 366/596 response (54% vs 62%) HTR2A rs6314 C allele more likely to respond than T allele C allele response 685/1,215, T allele 55/127 (56% vs 43%) HTR3A rs1062613 C allele less likely to respond than T allele C allele response 528/841, T allele 134/185 (63% vs 72%) Mathematical modelling of these three variants can generate an overall percentage chance of response with confidence intervals. Other variants may be linked to response. Agranulocytosis Several genetic variants are reliably associated with altered risk of agranulocytosis. Some variants are found only in certain ethnic groups. HLA-DQB1 Sequence variant 6672G>C (REC 21G) confers 1,175% higher risk of agranulocytosis than general population. Sensitivity 21.5%, specificity 98.4%.2 PPV 5.1%, NPV 99.7%. In people of European ancestry, sensitivity is 53.7% and this variant confers a 10-fold greater risk of agranulocytosis.3 HLA-DQB1 DQB1*0502 allele is associated with agranulocytosis in 5 of 7 studies (e.g. Dettling and colleagues,4 Yunis and colleagues5). Effect size variable.

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277 - Benign ethnic neutropenia

Benign ethnic neutropenia

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278 - Metabolism

Metabolism

276 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 HLA-B59:01 Presence of allele highly predictive of agranulocytosis but is rare in East Asian populations and almost absent in people of European descent. Sensitivity 31.8%, specificity 95.3%.6 PPV 6.4%, NPV 99.3%. HLA DQB1/HLA-B Single amino acid changes HLA DQB1 126Q and HLA-B 158T associated with increased risk of agranulocytosis. Overall, 39 of 95 cases had one or both alleles; 175 of 206 controls had neither allele. Sensitivity 41.0%, specificity 85.0%7,8 (36% and 89% figures given elsewhere).9 PPV/NPV not given but can be calculated. HLA-DRB1 DRB104:02 confers a six-fold higher risk of agranulocytosis. NPV is 99.3%.10 The HLA-DQB1 variants and the HLA-B variants are in linkage disequilibrium9 and are likely to convey the same association signal. Variants in linkage disequilibrium are inherited together. Benign ethnic neutropenia ACKR1 rs2814778 CC genotype at rs2814778 (Duffy Null Status) is considered to be the cause of BEN.11 All patients starting clozapine should undergo genetic testing for BEN.12 Metabolism Clozapine is largely metabolised by CYP1A2 and, to a lesser extent in most people, CYP3A4/5. Despite early reports, CYP2D6 plays almost no role in the metabolism of clozapine.13 Metabolic rate is usually classified as poor (PM), intermediate (IM) or extensive (EM) and each is associated with a particular genetic variant. Genetic analysis can therefore allow an estimate of the target dose of clozapine for an individual. This is the most accurate method of predicting clozapine dose.14 Cytochrome p4501A2 PM/IM/EM status as normally defined by analysis of e.g. CYP1A2*1F/1C/1A/1K.15 Cytochrome p4503A4 PM/IM/EM status. CYP3A4 is usually a minor route of clozapine metabolism but metaboliser status affects blood concentration.16 Cytochrome p4503A5 PM/IM/EM status. CYP3A5 PM status associated with elevated clozapine blood levels.17 Other non-CYP genetic associations have also been demonstrated.

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279 - Other adverse effects

Other adverse effects

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28 - Antipsychotic prophylaxis

Antipsychotic prophylaxis

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280 - References

References

Schizophrenia and related psychoses CHAPTER 1 NFIB rs28379954 T>C CT carriers have much lower blood concentrations than TT carriers in both smokers and non-smokers.18 Also, the rs2472297 genotype independently predicts clozapine plasma levels.19 Levels are highest in C/C carriers and lowest in T/T carriers (C/T somewhere in between). Genetic analysis of CYP function can identify the cause of low clozapine blood concentrations and allow selection of appropriate enzyme inhibitors.20 Other adverse effects Genetic predictors of myocarditis21 and weight gain22 have also been found, but associations are probably too weak to allow clinical application.15 References

Gressier F, et al. Pharmacogenetics of clozapine response and induced weight gain: a comprehensive review and meta-analysis. Eur Neuropsychopharmacol 2016; 26:163–185.
Athanasiou MC, et al. Candidate gene analysis identifies a polymorphism in HLA-DQB1 associated with clozapine-induced agranulocytosis. J Clin Psychiatry 2011; 72:458–463.
Konte B, et al. HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry. Transl Psychiatry 2021; 11:214.
Dettling M, et al. Genetic determinants of clozapine-induced agranulocytosis: recent results of HLA subtyping in a non-Jewish Caucasian sample. Arch Gen Psychiatry 2001; 58:93–94.
Yunis JJ, et al. HLA associations in clozapine-induced agranulocytosis. Blood 1995; 86:1177–1183.
Saito T, et al. Pharmacogenomic study of clozapine-induced agranulocytosis/granulocytopenia in a Japanese population. Biol Psychiatry 2016; 80:636–642.
Girardin FR, et al. Cost-effectiveness of HLA-DQB1/HLA-B pharmacogenetic-guided treatment and blood monitoring in US patients taking clozapine. Pharmacogenomics J 2019; 19:211–218.
Goldstein JI, et al. Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles. Nat Commun 2014; 5:4757.
Legge SE, et al. Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective. Pharmacogenomics 2019; 20:279–290.
Islam F, et al. Pharmacogenomics of clozapine-induced agranulocytosis: a systematic review and meta-analysis. Pharmacogenomics J 2022; 22:230–240.
Charles BA, et al. Analyses of genome wide association data, cytokines, and gene expression in African-Americans with benign ethnic neutropenia. PLoS One 2018; 13:e0194400.
Aziri H, et al. Genetic identification of undiagnosed benign ethnic neutropenia in patients receiving clozapine treatment. Br J Psychiatry 2024; doi: 10.1192/bjp.2024.236.
Olesen OV, et al. Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. J Clin Pharmacol 2001; 41:823–832.
Taylor D, et al. Predicting clozapine dose required to achieve a therapeutic plasma concentration: a comparison of a population algorithm and three algorithms based on gene variant models. J Psychopharmacol 2023; 37:1030–1039.
Thorn CF, et al. PharmGKB summary: clozapine pathway, pharmacokinetics. Pharmacogenet Genomics 2018; 28:214–222.
Tóth K, et al. Potential role of patients’ CYP3A-status in clozapine pharmacokinetics. Int J Neuropsychopharmacol 2017; 20:529–537.
John AP, et al. Unusually high serum levels of clozapine associated with genetic polymorphism of CYP3A enzymes. Asian J Psychiatr 2020; 10:21283.
Smith RL, et al. Identification of a novel polymorphism associated with reduced clozapine concentration in schizophrenia patients: a genome- wide association study adjusting for smoking habits. Transl Psychiatry 2020; 10:198.
Pardiñas AF, et al. Pharmacogenomic variants and drug interactions identified through the genetic analysis of clozapine metabolism. Am J Psychiatry 2019; 176:477–486.
Okon-Rocha E, et al. Genetic analysis of clozapine metabolism in a patient with subtherapeutic clozapine plasma concentrations: the importance of CYP3A5: a case report. J Clin Psychopharmacol 2022; 42:604–606.
Lacaze P, et al. Genetic associations with clozapine-induced myocarditis in patients with schizophrenia. Transl Psychiatry 2020; 10:37.
Li N, et al. Progress in genetic polymorphisms related to lipid disturbances induced by atypical antipsychotic drugs. Front Pharmacol 2020; 10:1669.

06 - Chapter 1 Schizophrenia and related psychoses

29 - First episode of psychosis

First episode of psychosis

28 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Antipsychotic prophylaxis First episode of psychosis Antipsychotics provide effective protection against relapse, at least in the short to medium term,1 and the introduction of antipsychotics in the 1950s seems to have improved outcomes overall.2 A meta-analysis of placebo-controlled trials found that 26% of patients with first-episode schizophrenia on maintenance antipsychotic relapsed after 6–12 months compared with 61% on placebo.3 Although the current consensus is that antipsychotics should be prescribed for 1–2 years after a first episode of schizophrenia,4,5 one study6 found that withdrawing antipsychotic treatment in line with this view led to a relapse rate of almost 80% after 1 year medication-free and 98% after 2 years. A 2019 Swedish population study revealed that the longer the treatment with antipsychotics, the lower the risk of hospitalisation (e.g. those with 5 years’ treatment had half the hospitalisation rate of those treated for less than 6 months).7 Other studies in first-episode schizophrenia confirmed that only a small minority of patients who discontinue remain well 1–2 years later8–11 (e.g. a small study found 94% of patients with first-episode schizophrenia relapsed within 2 years of stopping risperidone long-acting injection; 97% at three years).12 A 2018 meta-analysis of eight RCTs was rather more optimistic and found relapse rates averaged 35% (treated) and 61% (discontinued) at 18–24 months.13 A 5-year follow-up of a 2-year RCT, during which patients either received maintenance antipsychotic treatment or had their antipsychotic dose reduced or discontinued completely, found that while there was a clear advantage for maintenance treatment with respect to reducing short-term relapse this advantage was lost in the medium term. Further, the dose-reduction/discontinuation group were receiving lower doses of anti psychotic drugs at follow-up and had better functional outcomes.14 There are numerous interpretations of these outcomes but the most that can be concluded is that dose reduction is a possible option in first-episode psychosis. The study has been heavily criticised15 and there are certainly other studies showing disastrous outcomes from antipsychotic discontinuation,16 albeit over shorter periods with fewer patients. Nonetheless, some patients with first-episode psychosis will not need long-term anti psychotics to stay well – figures as high as 18–30% have been put forward.17 There are no reliable patient factors linked to outcome following discontinuation of antipsychotics in patients with first-episode psychosis (other than cannabis use)18 and there remains more evidence in favour of continuing antipsychotics than for stopping them.19 There are indications that very prolonged discontinuation regimens using hyperbolic tapering (see section on stopping antipsychotics in this chapter) may offer the best chance of successfully withdrawing from antipsychotic treatment.20,21 Definitions of relapse usually focus on the severity of positive symptoms and largely ignore cognitive and negative symptoms: positive symptoms are more likely to lead to hospitalisation while cognitive and negative symptoms (which respond less well, and in some circumstances may even be exacerbated by antipsychotic treatment) have a greater overall impact on quality of life. With respect to antipsychotic choice, in the context of an RCT, clozapine did not offer any advantage over chlorpromazine in the medium term in patients with first-episode non-refractory schizophrenia.22 However, in a large naturalistic study of patients with

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30 - Multi episode schizophrenia

Multi-episode schizophrenia

06 - Chapter 1 Schizophrenia and related psychoses

31 - Summary

Summary

Schizophrenia and related psychoses CHAPTER 1 a first admission for schizophrenia, clozapine and olanzapine fared better with respect to preventing readmission than other oral antipsychotics.23 In this same study, the use of a long-acting antipsychotic injection seemed to offer advantages over oral antipsychotics, despite confounding by indication (depots will have been prescribed to those considered to be poor adherers, oral to those perceived to have good adherence).23 Later studies show a huge advantage for long-acting risperidone over oral risperidone in the first episode24 and a smaller but substantial benefit for paliperidone LAI over oral antipsychotics in ‘recently diagnosed schizophrenia’.25 In a later study, amisulpride was shown to give good outcomes and staying on amisulpride after not initially reaching remission was as successful as switching to olanzapine.26 In practice, a firm diagnosis of schizophrenia is rarely made after a first episode and the majority of prescribers and/or patients will have at least attempted to stop antipsychotic treatment within one year.27 Ideally, patients should have their dose reduced very gradually and all relevant family members and healthcare staff should be aware of the discontinuation (such a situation is most likely to be achieved by using LAI). It is vital that patients, carers and keyworkers are aware of the early signs of relapse and how to access help. Antipsychotics should not be considered the only intervention. Evidence- based psychosocial and psychological interventions are clearly also important.28 Multi-episode schizophrenia The majority of those who have one episode of schizophrenia will go on to have further episodes. Patients with residual symptoms, a greater adverse-effect burden and a less positive attitude to treatment are at greater risk of relapse.29 With each subsequent episode, the baseline level of functioning deteriorates30 and the majority of this decline is seen in the first decade of illness. Suicide risk (10%) is also concentrated in the first decade of illness. Antipsychotic drugs, when taken regularly, protect against relapse in the short, medium and (with less certainty) long term.3,31 Those who receive targeted anti psychotics (i.e. only when symptoms re-emerge) seem to have a worse outcome than those who receive prophylactic antipsychotics32,33 and the risk of TD may also be higher. Similarly, low-dose antipsychotics are less effective than standard doses.34 The optimal dose to prevent relapse is 5mg/day risperidone equivalents.35 Higher doses offer no benefit and ensure poorer tolerability. Depot preparations may have an advantage over oral in maintenance treatment, most likely because of guaranteed medication delivery (or at least guaranteed awareness of medication delivery). Meta-analyses of clinical trials have shown that the relative and absolute risks of relapse with depot maintenance treatment were 30% and 10% lower, respectively, than with oral treatment.3,36 Long-acting preparations of antipsychotics may thus be preferred by both prescribers and patients. Summary ■ ■Relapse rates in patients discontinuing antipsychotics are extremely high. ■ ■Antipsychotics significantly reduce relapse, readmission and violence/aggression. ■ ■Long-acting depot formulations provide the best protection against relapse.

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32 - Adherence to antipsychotic treatment

Adherence to antipsychotic treatment

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33 - Dose for prophylaxis

Dose for prophylaxis

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34 - How and when to stop55

How and when to stop55

30 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 A large meta-analysis concluded that the risk of relapse with newer SGAs is similar to that associated with older drugs.3 (Note that lack of relapse is not the same as good functioning.37) The proportion of patients with multi-episode schizophrenia who achieve remission is small and may differ between antipsychotic drugs. The CATIE study38 reported that only 12% of patients treated with olanzapine achieved remission for at least 6 months, compared with 8% treated with quetiapine and 6% with risperidone. The advantage seen here for olanzapine is consistent with that seen in an acute efficacy network meta-analysis,39 and in two recent meta-analyses of long-term efficacy.40,41 Adherence to antipsychotic treatment Among people with schizophrenia, non-adherence to antipsychotic treatment is high. Only 10 days after discharge from hospital, up to 25% are partially or non-adherent, rising to 50% at 1 year and 75% at 2 years.42 Not only does non-adherence increase the risk of relapse, it may also increase the severity of relapse and the duration of hospitalisation.42 The risk of suicide attempts also increases four-fold42 (see section on working towards adherence in Chapter 14). Given these low rates of adherence and the near certainty of relapse if antipsychotics are not taken, the use of oral antipsychotics is difficult to justify. Dose for prophylaxis Many patients probably receive higher doses than necessary (particularly of the older drugs) when acutely psychotic.43,44 In the longer term, a balance needs to be made between effectiveness and adverse effects. Lower doses of the older drugs (8mg haloperidol/day or equivalent) are, when compared with higher doses, associated with less severe adverse effects,45 better subjective state and better community adjustment.46 Very low doses increase the risk of psychotic relapse.43,47,48 The largest meta-analysis showed very clearly that prophylactic efficacy begins to be lost at doses below around 5mg/day risperidone equivalents.35 Doses that are acutely effective should generally be continued as prophylaxis,49,50 although an exception to this is prophylaxis after a first episode, where very careful dose reduction is probably supportable. There is some recent support for dose reduction in multi-episode schizophrenia.51 The concept of guided antipsychotic dose reduction has gained attention in the past few years, following the apparent success of the famous Wunderink study.14 Later studies have suggested that guided dose reduction is associated with a substantially greater risk of relapse compared with continuation.52,53 However (and perhaps most importantly), guided dose reduction or stopping treatment does not result in relapse in everyone, at least over the time periods examined.54 So some people (probably a small minority) appear to be able to stop antipsychotic treatment without relapsing. How and when to stop55 The decision to stop antipsychotic drugs requires a thorough risk–benefit analysis for each patient. Withdrawal of antipsychotic drugs after long-term treatment should be gradual and closely monitored. The relapse rate in the first 6 months after abrupt withdrawal is double that seen after gradual withdrawal (defined as slow taper down over

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35 - Alternative views

Alternative views

Schizophrenia and related psychoses CHAPTER 1 at least 3 weeks for oral antipsychotics or abrupt withdrawal of depot preparations).56 One analysis of incidence of relapse after switch to placebo found time to relapse to be very much longer for 3-monthly paliperidone than for 1-monthly and oral.57 Overall percentage relapse was also reduced. Abrupt withdrawal of oral treatment may also lead to discontinuation symptoms (e.g. headache, nausea, insomnia) in some patients.58 The following factors should be considered:55 ■ ■Is the patient symptom-free and, if so, for how long? Long-standing, non-distressing symptoms which have not previously been responsive to medication may be excluded. ■ ■What is the severity of adverse effects (EPS, TD, sedation, obesity, etc.)? ■ ■What was the previous pattern of illness? Consider the speed of onset, duration and severity of episodes and any danger posed to self and others. ■ ■Has dosage reduction been attempted before and, if so, what was the outcome? ■ ■What are the patient’s current social circumstances? Is it a period of relative stability or are stressful life events anticipated? ■ ■What is the social cost of relapse (e.g. is the patient the sole breadwinner for a family)? ■ ■Is the patient/carer able to monitor symptoms and, if so, will they seek help? As with patients having their first episode, patients, carers and keyworkers should be aware of the early signs of relapse and how to access help. Be aware that targeted relapse treatment is much less effective than continuous prophylaxis.10 Those with a history of aggressive behaviour or serious suicide attempts and those with residual psychotic symptoms should be considered for life-long treatment. Alternative views While it is clear that antipsychotics effectively reduce symptom severity and rates of relapse, a minority view is that antipsychotics might also sensitise patients to psychosis. The hypothesis is that relapse on withdrawal can be seen as a type of discontinuation reaction resulting from super-sensitivity of dopamine receptors, although the evidence for this remains uncertain.59 This phenomenon might explain better outcomes seen in patients with first-episode schizophrenia who receive lower doses of antipsychotics, but it also suggests the possibility that the use of antipsychotics might ultimately worsen outcomes. It might also explain the poor outcomes seen with abrupt discontinuation of antipsychotics.56 This observation in turn leads some to question the validity of long-term studies in which active and successful treatment is abruptly stopped, since rebound phenomena and withdrawal reactions may account for at least some of the observed high relapse rates.60 The concept of ‘super-sensitivity psychosis’ was much discussed decades ago61,62 and has more recently seen a resurgence.59,63 It is striking that dopamine antagonists used for non- psychiatric conditions can induce withdrawal psychosis.64–66 While these theories and observations do not alter recommendations made in this section, they do emphasise the need for using the lowest possible dose of antipsychotic in all patients and the balancing of observed benefit with adverse outcomes, including those that might be less clinically obvious (e.g. the possibility of structural brain changes).67 Clinicians should remain open- minded about the possibility that long-term antipsychotics may worsen, or at least not improve, outcomes in some people with schizophrenia.

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36 - References

References

32 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

Karson C, et al. Long-term outcomes of antipsychotic treatment in patients with first-episode schizophrenia: a systematic review. Neuropsychiatr Dis Treat 2016; 12:57–67.
Taylor M, et al. Are we getting any better at staying better? The long view on relapse and recovery in first episode nonaffective psychosis and schizophrenia. Ther Adv Psychopharmacol 2019; 9:2045125319870033.
Leucht S, et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012; 379:2063–2071.
American Psychiatric Association. Practice Guideline for the Treatment of Patients with Schizophrenia, 3rd edn. Washington, DC: APA; 2020 (last accessed December 2024); https://psychiatryonline.org/doi/book/10.1176/appi.books.9780890424841.
Sheitman BB, et al. The evaluation and treatment of first-episode psychosis. Schizophrenia Bulletin 1997; 23:653–661.
Gitlin M, et al. Clinical outcome following neuroleptic discontinuation in patients with remitted recent-onset schizophrenia. Am J Psychiatry 2001; 158:1835–1842.
Hayes JF, et al. Psychiatric hospitalization following antipsychotic medication cessation in first episode psychosis. J Psychopharmacol 2019; 33:532–534.
Wunderink L, et al. Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry 2007; 68:654–661.
Chen EY, et al. Maintenance treatment with quetiapine versus discontinuation after one year of treatment in patients with remitted first episode psychosis: randomised controlled trial. BMJ 2010; 341:c4024.
Gaebel W, et al. Relapse prevention in first-episode schizophrenia. Maintenance vs intermittent drug treatment with prodrome-based early intervention: results of a randomized controlled trial within the German Research Network on Schizophrenia. J Clin Psychiatry 2011; 72:205–218.
Caseiro O, et al. Predicting relapse after a first episode of non-affective psychosis: a three-year follow-up study. J Psychiatr Res 2012; 46:1099–1105.
Emsley R, et al. Symptom recurrence following intermittent treatment in first-episode schizophrenia successfully treated for 2 years: a 3-year open-label clinical study. J Clin Psychiatry 2012; 73:e541–e547.
Kishi T, et al. Effect of discontinuation v. maintenance of antipsychotic medication on relapse rates in patients with remitted/stable first- episode psychosis: a meta-analysis. Psychol Med 2019; 49:772–779.
Wunderink L, et al. Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry 2013; 70:913–920.
Correll CU, et al. What is the risk-benefit ratio of long-term antipsychotic treatment in people with schizophrenia? World Psychiatry 2018; 17:149–160.
Boonstra G, et al. Antipsychotic prophylaxis is needed after remission from a first psychotic episode in schizophrenia patients: results from an aborted randomised trial. Int J Psychiatry Clin Pract 2011; 15:128–134.
Murray RM, et al. Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics? Br J Psychiatry 2016; 209:361–365.
Bowtell M, et al. Rates and predictors of relapse following discontinuation of antipsychotic medication after a first episode of psychosis. Schizophr Res 2018; 195:231–236.
Emsley R, et al. How long should antipsychotic treatment be continued after a single episode of schizophrenia? Curr Opin Psychiatry 2016; 29:224–229.
Horowitz MA, et al. Tapering antipsychotic treatment. JAMA Psychiatry 2020; 78:125–126.
Liu CC, et al. Achieving the lowest effective antipsychotic dose for patients with remitted psychosis: a proposed guided dose-reduction algorithm. CNS Drugs 2020; 34:117–126.
Girgis RR, et al. Clozapine v. chlorpromazine in treatment-naive, first-episode schizophrenia: 9-year outcomes of a randomised clinical trial. Br J Psychiatry 2011; 199:281–288.
Tiihonen J, et al. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry 2011; 168:603–609.
Subotnik KL, et al. Long-acting injectable risperidone for relapse prevention and control of breakthrough symptoms after a recent first episode of schizophrenia. a randomized clinical trial. JAMA Psychiatry 2015; 72:822–829.
Schreiner A, et al. Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia. Schizophr Res 2015; 169:393–399.
Kahn RS, et al. Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching study. Lancet Psychiatry 2018; 5:797–807.
Johnson DAW, et al. Professional attitudes in the UK towards neuroleptic maintenance therapy in schizophrenia. Psychiatr Bull 1997; 21:394–397.
National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management. Clinical guideline [CG178]. 2014 (last checked November 2024); https://www.nice.org.uk/guidance/cg178.
Schennach R, et al. Predictors of relapse in the year after hospital discharge among patients with schizophrenia. Psychiatr Serv 2012; 63:87–90.
Wyatt RJ. Neuroleptics and the natural course of schizophrenia. Schizophrenia Bulletin 1991; 17:325–351.
Almerie MQ, et al. Cessation of medication for people with schizophrenia already stable on chlorpromazine. Schizophr Bull 2008; 34:13–14.
Jolley AG, et al. Trial of brief intermittent neuroleptic prophylaxis for selected schizophrenic outpatients: clinical and social outcome at two years. BMJ 1990; 301:837–842.

Schizophrenia and related psychoses CHAPTER 1 33. Herz MI, et al. Intermittent vs maintenance medication in schizophrenia: two-year results. Arch Gen Psychiatry 1991; 48:333–339. 34. Schooler NR, et al. Relapse and rehospitalization during maintenance treatment of schizophrenia. The effects of dose reduction and family treatment. Arch Gen Psychiatry 1997; 54:453–463. 35. Leucht S, et al. Examination of dosing of antipsychotic drugs for relapse prevention in patients with stable schizophrenia: a meta-analysis. JAMA Psychiatry 2021; 78:1238–1248. 36. Leucht C, et al. Oral versus depot antipsychotic drugs for schizophrenia—a critical systematic review and meta-analysis of randomised long- term trials. Schizophr Res 2011; 127:83–92. 37. Schooler NR. Relapse prevention and recovery in the treatment of schizophrenia. J Clin Psychiatry 2006; 67 Suppl 5:19–23. 38. Levine SZ, et al. Extent of attaining and maintaining symptom remission by antipsychotic medication in the treatment of chronic schizophrenia: evidence from the CATIE study. Schizophr Res 2011; 133:42–46. 39. Leucht S, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382:951–962. 40. Leucht S, et al. Long-term efficacy of antipsychotic drugs in initially acutely ill adults with schizophrenia: systematic review and network meta-analysis. World Psychiatry 2023; 22:315–324. 41. Ostuzzi G, et al. Oral and long-acting antipsychotics for relapse prevention in schizophrenia-spectrum disorders: a network meta-analysis of 92 randomized trials including 22,645 participants. World Psychiatry 2022; 21:295–307. 42. Leucht S, et al. Epidemiology, clinical consequences, and psychosocial treatment of nonadherence in schizophrenia. J Clin Psychiatry 2006; 67 Suppl 5:3–8. 43. Baldessarini RJ, et al. Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses. Arch Gen Psychiatry 1988; 45:79–90. 44. Harrington M, et al. The results of a multi-centre audit of the prescribing of antipsychotic drugs for in-patients in the UK. Psychiatr Bull 2002; 26:414–418. 45. Geddes J, et al. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ 2000; 321:1371–1376. 46. Hogarty GE, et al. Dose of fluphenazine, familial expressed emotion, and outcome in schizophrenia. Results of a two-year controlled study. Arch Gen Psychiatry 1988; 45:797–805. 47. Marder SR, et al. Low- and conventional-dose maintenance therapy with fluphenazine decanoate. Two-year outcome. Arch Gen Psychiatry 1987; 44:518–521. 48. Uchida H, et al. Low dose vs standard dose of antipsychotics for relapse prevention in schizophrenia: meta-analysis. Schizophr Bull 2011; 37:788–799. 49. Rouillon F, et al. Strategies of treatment with olanzapine in schizophrenic patients during stable phase: results of a pilot study. Eur Neuropsychopharmacol 2008; 18:646–652. 50. Wang CY, et al. Risperidone maintenance treatment in schizophrenia: a randomized, controlled trial. Am J Psychiatry 2010; 167:676–685. 51. Huhn M, et al. Reducing antipsychotic drugs in stable patients with chronic schizophrenia or schizoaffective disorder: a randomized controlled pilot trial. Eur Arch Psychiatry Clin Neurosci 2021; 271:293–302. 52. Liu CC, et al. Guided antipsychotic reduction to reach minimum effective dose (GARMED) in patients with remitted psychosis: a 2-year randomized controlled trial with a naturalistic cohort. Psychol Med 2023; 53:7078–7086. 53. Moncrieff J, et al. Antipsychotic dose reduction and discontinuation versus maintenance treatment in people with schizophrenia and other recurrent psychotic disorders in England (the RADAR trial): an open, parallel-group, randomised controlled trial. Lancet Psychiatry 2023; 10:848–859. 54. Ostuzzi G, et al. Continuing, reducing, switching, or stopping antipsychotics in individuals with schizophrenia-spectrum disorders who are clinically stable: a systematic review and network meta-analysis. Lancet Psychiatry 2022; 9:614–624. 55. Wyatt RJ. Risks of withdrawing antipsychotic medications. Arch Gen Psychiatry 1995; 52:205–208. 56. Viguera AC, et al. Clinical risk following abrupt and gradual withdrawal of maintenance neuroleptic treatment. Arch Gen Psychiatry 1997; 54:49–55. 57. Weiden PJ, et al. Does half-life matter after antipsychotic discontinuation? A relapse comparison in schizophrenia with 3 different formulations of paliperidone. J Clin Psychiatry 2017; 78:e813–e820. 58. Chouinard G, et al. Withdrawal symptoms after long-term treatment with low-potency neuroleptics. J Clin Psychiatry 1984; 45:500–502. 59. Yin J, et al. Antipsychotic induced dopamine supersensitivity psychosis: a comprehensive review. Curr Neuropharmacol 2017; 15:174–183. 60. Cohen D, et al. Discontinuing psychotropic drugs from participants in randomized controlled trials: a systematic review. Psychother Psychosom 2019; 88:96–104. 61. Chouinard G, et al. Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics. Am J Psychiatry 1980; 137:16–21. 62. Kirkpatrick B, et al. The concept of supersensitivity psychosis. J Nerv Ment Dis 1992; 180:265–270. 63. Lugg W. Antipsychotic-induced supersensitivity: a reappraisal. Aust N Z J Psychiatry 2022; 56:437–444. 64. Chaffin DS. Phenothiazine-induced acute psychotic reaction: the ‘psychotoxicity’ of a drug. Am J Psychiatry 1964; 121:26–32. 65. Lu ML, et al. Metoclopramide-induced supersensitivity psychosis. Ann Pharmacother 2002; 36:1387–1390. 66. Roy-Desruisseaux J, et al. Domperidone-induced tardive dyskinesia and withdrawal psychosis in an elderly woman with dementia. Ann Pharmacother 2011; 45:e51. 67. Huhtaniska S, et al. Long-term antipsychotic use and brain changes in schizophrenia - a systematic review and meta-analysis. Hum Psychopharmacol 2017; 32:e2574.

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37 - Negative symptoms

Negative symptoms

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38 - Pharmacological treatment of negative symptom

Pharmacological treatment of negative symptoms

34 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Negative symptoms Negative symptoms in schizophrenia represent the absence or diminution of normal behaviours and functions and constitute an important dimension of psychopathology. A subdomain of ‘expressive deficits’ manifests as a decrease in verbal output and verbal expressiveness, and flattened or blunted affect, which is assessed by diminished facial emotional expression, poor eye contact, decreased spontaneous movement and lack of spontaneity. A second ‘avolition/amotivation’ subdomain is characterised by a subjective reduction in interests, desires and goals, and a behavioural reduction in purposeful acts, including a lack of self-initiated social interactions.1,2 While there is some consensus around this two-dimensional model, five-factor models of negative symptoms have also been propounded.3,4 Persistent negative symptoms are held to account for much of the long-term morbidity and poor functional outcome of patients with schizophrenia.5–8 The aetiology of negative symptoms is complex, and it is important to determine the most likely cause in any individual case before embarking on a treatment regimen. An important clinical distinction is between primary negative symptoms, which constitute an enduring deficit state, predict a poor prognosis and are stable over time, and secondary negative symptoms, which are consequent upon positive psychotic symptoms, depression or demoralisation, or adverse medication effects, such as dysphoria and bradykinesia as part of drug-induced parkinsonism.7,9 Other sources of secondary negative symptoms may include chronic substance or alcohol use, high-dose antipsychotic medication, social deprivation, lack of stimulation and hospitalisation.10 Secondary negative symptoms may be best tackled by treating the relevant underlying cause. In people with established schizophrenia, prominent, clinically relevant negative symptoms are seen in around 60%, with up to 20% judged to have persistent, primary negative symptoms.11–13 The literature pertaining to the pharmacological treatment of negative symptoms partly comprises sub-analyses of acute efficacy studies, correlational analyses and path analyses.14 There is often no reliable distinction between primary and secondary negative symptoms or between the two subdomains of expressive deficits and avolition/ amotivation, and relatively few studies specifically recruit patients with persistent or predominant negative symptoms. While the evidence suggests short- and medium-term efficacy for a few interventions, there is no widely accepted evidence for an effective treatment for persistent primary negative symptoms. Pharmacological treatment of negative symptoms ■ ■In first-episode psychosis, the presence of negative symptoms is related to poor outcome in terms of recovery and level of social functioning.6,11 There is evidence to suggest that the earlier a psychotic illness is effectively treated, the less likely is the development of negative symptoms over time.15–17 However, when interpreting such data, it should be borne in mind that an early clinical picture characterised by negative symptoms, being a less socially disruptive and more subtle signal of psychotic illness than positive symptoms, may contribute to delay in presentation to clinical services and thus be associated with a longer duration of untreated psychosis. In other words, patients with an inherently poorer prognosis in terms of persistent negative symptoms may be diagnosed and treated later.

Schizophrenia and related psychoses CHAPTER 1 ■ ■While antipsychotic medication has been shown to improve negative symptoms, this benefit has mainly been shown in secondary negative symptoms in acute psychotic episodes.18 Against expectations, there is no consistent evidence for the superiority of SGAs over FGAs in the treatment of negative symptoms.19–23 Similarly, early analyses found no consistent evidence for the superiority of any individual SGA.24 A 2015 meta- analysis of 38 RCTs found a statistically significant reduction in negative symptoms with SGAs, but the effect size did not reach a threshold for ‘minimally detectable clinical improvement over time’.25 ■ ■There are some relatively robust data suggesting superior efficacy for negative symptoms with certain antipsychotics, such as cariprazine,26–28 aripiprazole and amisulpride, and single trials suggesting that olanzapine and quetiapine may be more effective than risperidone.26,29–37 A 2023 review included amisulpride and cariprazine among the medications considered to have the most promise as treatments for primary negative symptoms.38 ■ ■While clozapine remains the only medication with convincing superiority for TRS, whether or not it has superior efficacy for negative symptoms in such cases, at least in the short term, remains uncertain.39–41 One potential confound in studies of clozapine for negative symptoms is that the medication has a low liability for parkinsonian adverse effects, including bradykinesia. These are symptoms which have a phenomenological overlap with negative symptoms, particularly the subdomain of expressive deficits. There is some evidence to suggest that for patients being treated with clozapine who have residual negative symptoms, the addition of cariprazine may help.42,43 ■ ■With respect to the effect of decreasing glutamate transmission on negative symptoms, three meta-analyses have suggested a beneficial response with add-on memantine44–46 but there have been inconsistent meta-analysis findings for lamotrigine augmentation of clozapine.47,48 Adding minocycline, an antibiotic and inflammatory drug, initially showed promise46,49,50 but a relatively large RCT of adjunctive minocycline found it was not efficacious in treating negative symptoms.51 Further, the BeneMin study,49 which was designed to determine whether adjunctive minocycline, administered early in the course of schizophrenia, protected against the development of negative symptoms over a year, also failed to find any evidence of clinical benefit. The glutamate antagonist topiramate may have some efficacy for symptom reduction in schizophrenia spectrum disorders, including negative symptoms.52 ■ ■A 2006 Cochrane review concluded that antidepressant augmentation of an antipsychotic for negative symptoms may be an effective strategy for reducing affective flattening, alogia and avolition.53 RCTs and meta-analyses addressing antidepressant augmentation of antipsychotic medication have yielded somewhat inconsistent evidence of modest efficacy.54–59 One meta-analysis of placebo-controlled studies in people with established schizophrenia found that adjunctive antidepressant treatment was associated with a limited reduction in negative symptoms, and only when added to treatment with FGAs.58 Another review of meta-analyses concluded that the evidence suggested a beneficial effect for some SSRIs, such as fluvoxamine, citalopram, and the α2 receptor antagonists mirtazapine and mianserin.18 Reboxetine (a noradrenaline reuptake inhibitor) may also have some activity.60 ■ ■A host of other augmentation agents have been tested.46,61,62 For example, meta- analyses provide some support for adjunctive treatment with Ginkgo biloba63 and a COX-2 (cyclooxygenase-2) inhibitor (albeit with a small effect size),64 while small

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39 - Summary and recommendations

Summary and recommendations

36 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 RCTs have demonstrated some benefit for selegiline,65,66 pramiprexole,67 topical testosterone,68 ondansetron,69 granisetron,70 palmitoylethanolamide (an endogenous analogue of anandamide, an endocannabinoid) added to risperidone71 and pimavanserin, a potent 5-HT2A inverse agonist and antagonist.72,73 The 5HT2 antagonist roluperidone may also be effective.74,75 ■ ■Other experimental treatments for which promising data exist include pregnenolone,76 raloxifene (in women),77 levetiracetam,78 clonidine,79 nanocurcumin,80 xanomeline (as Cobenfy)81 and the anti-inflammatory drugs berberine82 and fingolimod.61 ■ ■The findings from studies of repetitive transcranial magnetic stimulation (rTMS) are mixed but promising.83 Transcranial direct current stimulation (tDCS) may also have some potential as a treatment for negative symptoms, but the evidence thus far is limited and rather inconsistent.18,84–87 Patients who misuse psychoactive substances may experience less severe negative symptoms than patients who do not.88 But rather than any pharmacological effect, it may be that this association at least partly reflects that those people who develop psychosis in the context of substance use, specifically cannabis, have fewer neurodevelopmental risk factors and thus better cognitive and social function.89,90 Summary and recommendations These recommendations are derived from the British Association for Psychopharmacology (BAP) schizophrenia guideline (2020),91 Galderisi et al. (2021),87 Veerman et al. (2017),10 Aleman et al. (2017)18 and Howes et al. (2023).38 ■ ■There are no well-replicated, large trials or meta-analyses of trials with negative symptoms as the primary outcome measure that have yielded convincing evidence for enduring and clinically significant benefit. ■ ■Where some improvement has been demonstrated in clinical trials, this may be limited to secondary negative symptoms. ■ ■Psychotic illness should be identified and treated as early as possible, as this may offer some protection against the development of negative symptoms. ■ ■For any given patient, the antipsychotic medication that provides the best balance between overall efficacy and adverse effects should be used, at the lowest dose that maintains control of positive symptoms. ■ ■Where negative symptoms persist beyond an acute episode of psychosis: ■ ■Ensure that EPS (specifically bradykinesia) and depression are detected and treated if present, and consider the contribution of the environment to negative symptoms (e.g. institutionalisation, lack of stimulation). ■ ■There is insufficient evidence at present to support a recommendation for any specific pharmacological treatment for negative symptoms. Nevertheless, a trial of add-on medication for which there is some RCT evidence for efficacy, such as an antidepressant or an antipsychotic, may be worth considering in some cases, ensuring that the choice of the augmenting agent is based on minimising the potential for compounding adverse effects through pharmacokinetic or pharmacodynamic drug interactions.

06 - Chapter 1 Schizophrenia and related psychoses

40 - References

References

Schizophrenia and related psychoses CHAPTER 1 References

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38 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 35. Galling B, et al. Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis. World Psychiatry 2017; 16:77–89. 36. Earley W, et al. Efficacy of cariprazine on negative symptoms in patients with acute schizophrenia: a post hoc analysis of pooled data. Schizophr Res 2019; 204:282–288. 37. Brasso C, et al. Efficacy of serotonin and dopamine activity modulators in the treatment of negative symptoms in schizophrenia: a rapid review. Biomedicines 2023; 11:921. 38. Howes O, et al. Treating negative symptoms of schizophrenia: current approaches and future perspectives. Br J Psychiatry 2023; 223:332–335. 39. Siskind D, et al. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta- analysis. Br J Psychiatry 2016; 209:385–392. 40. Souza JS, et al. Efficacy of olanzapine in comparison with clozapine for treatment-resistant schizophrenia: evidence from a systematic review and meta-analyses. CNS Spectr 2013; 18:82–89. 41. Asenjo Lobos C, et al. Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2010; (11):CD006633. 42. Oloyede E, et al. Clozapine augmentation with cariprazine for negative symptoms: a case series and literature review. Ther Adv Psychopharmacol 2022; 12:20451253211066642. 43. Siwek M, et al. Cariprazine augmentation of clozapine in schizophrenia: a retrospective chart review. Front Pharmacol 2023; 14:1321112. 44. Kishi T, et al. Memantine add-on to antipsychotic treatment for residual negative and cognitive symptoms of schizophrenia: a meta-analysis. Psychopharmacology (Berl) 2017; 234:2113–2125. 45. Zheng W, et al. Adjunctive memantine for schizophrenia: a meta-analysis of randomized, double-blind, placebo-controlled trials. Psychol Med 2018; 48:72–81. 46. Etchecopar-Etchart D, et al. Comprehensive evaluation of 45 augmentation drugs for schizophrenia: a network meta-analysis. EClinicalMedicine 2024; 69:102473. 47. Tiihonen J, et al. The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res 2009; 109:10–14. 48. Veerman SR, et al. Clozapine augmented with glutamate modulators in refractory schizophrenia: a review and metaanalysis. Pharmacopsychiatry 2014; 47:185–194. 49. Oya K, et al. Efficacy and tolerability of minocycline augmentation therapy in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Hum Psychopharmacol 2014; 29:483–491. 50. Xiang YQ, et al. Adjunctive minocycline for schizophrenia: a meta-analysis of randomized controlled trials. Eur Neuropsychopharmacol 2017; 27:8–18. 51. Weiser M, et al. The effect of minocycline on symptoms in schizophrenia: results from a randomized controlled trial. Schizophr Res 2019; 206:325–332. 52. Afshar H, et al. Topiramate add-on treatment in schizophrenia: a randomised, double-blind, placebo-controlled clinical trial. J Psychopharmacol 2009; 23:157–162. 53. Rummel C, et al. Antidepressants for the negative symptoms of schizophrenia. Cochrane Database Syst Rev 2006; (3):CD005581. 54. Kishi T, et al. Meta-analysis of noradrenergic and specific serotonergic antidepressant use in schizophrenia. Int J Neuropsychopharmacol 2014; 17:343–354. 55. Sepehry AA, et al. Selective serotonin reuptake inhibitor (SSRI) add-on therapy for the negative symptoms of schizophrenia: a meta-analysis. J Clin Psychiatry 2007; 68:604–610. 56. Singh SP, et al. Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis. Br J Psychiatry 2010; 197:174–179. 57. Barnes TR, et al. Antidepressant Controlled Trial For Negative Symptoms In Schizophrenia (ACTIONS): a double-blind, placebo-controlled, randomised clinical trial. Health Technol Assess 2016; 20:1–46. 58. Galling B, et al. Efficacy and safety of antidepressant augmentation of continued antipsychotic treatment in patients with schizophrenia. Acta Psychiatr Scand 2018; 137:187–205. 59. Helfer B, et al. Efficacy and safety of antidepressants added to antipsychotics for schizophrenia: a systematic review and meta-analysis. Am J Psychiatry 2016; 173:876–886. 60. Zheng W, et al. Adjunctive reboxetine for schizophrenia: meta-analysis of randomized double-blind, placebo-controlled trials. Pharmacopsychiatry 2020; 53:5–13. 61. Karbalaee M, et al. Efficacy and safety of adjunctive therapy with fingolimod in patients with schizophrenia: a randomized, double-blind, placebo-controlled clinical trial. Schizophr Res 2023; 254:92–98. 62. Correll CU, et al. Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia: systematic overview and quality appraisal of the meta-analytic evidence. JAMA Psychiatry 2017; 74:675–684. 63. Singh V, et al. Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia. Int J Neuropsychopharmacol 2010; 13:257–271. 64. Sommer IE, et al. Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry 2012; 73:414–419. 65. Amiri A, et al. Efficacy of selegiline add on therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study. Hum Psychopharmacol 2008; 23:79–86. 66. Bodkin JA, et al. Double-blind, placebo-controlled, multicenter trial of selegiline augmentation of antipsychotic medication to treat negative symptoms in outpatients with schizophrenia. Am J Psychiatry 2005; 162:388–390.

Schizophrenia and related psychoses CHAPTER 1 67. Kelleher JP, et al. Pilot randomized, controlled trial of pramipexole to augment antipsychotic treatment. Eur Neuropsychopharmacol 2012; 22:415–418. 68. Ko YH, et al. Short-term testosterone augmentation in male schizophrenics: a randomized, double-blind, placebo-controlled trial. J Clin Psychopharmacol 2008; 28:375–383. 69. Zhang ZJ, et al. Beneficial effects of ondansetron as an adjunct to haloperidol for chronic, treatment-resistant schizophrenia: a double-blind, randomized, placebo-controlled study. Schizophr Res 2006; 88:102–110. 70. Khodaie-Ardakani MR, et al. Granisetron as an add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized double-blind placebo-controlled study. J Psychiatr Res 2013; 47:472–478. 71. Salehi A, et al. Adjuvant palmitoylethanolamide therapy with risperidone improves negative symptoms in patients with schizophrenia: a randomized, double-blinded, placebo-controlled trial. Psychiatry Res 2022; 316:114737. 72. Bugarski-Kirola D, et al. Pimavanserin for negative symptoms of schizophrenia: results from the ADVANCE phase 2 randomised, placebo- controlled trial in North America and Europe. Lancet Psychiatry 2022; 9:46–58. 73. Davis J, et al. Evaluating pimavanserin as a treatment for psychiatric disorders: a pharmacological property in search of an indication. Expert Opin Pharmacother 2021; 22:1651–1660. 74. Davidson M, et al. Efficacy and safety of roluperidone for the treatment of negative symptoms of schizophrenia. Schizophr Bull 2022; 48:609–619. 75. Romeo B, et al. Efficacy of 5-HT2A antagonists on negative symptoms in patients with schizophrenia: a meta-analysis. Psychiatry Res 2023; 321:115104. 76. Ritsner MS, et al. Pregnenolone treatment reduces severity of negative symptoms in recent-onset schizophrenia: an 8-week, double-blind, randomized add-on two-center trial. Psychiatry Clin Neurosci 2014; 68:432–440. 77. Brand BA, et al. The direct and long-term effects of raloxifene as adjunctive treatment for schizophrenia-spectrum disorders: a double-blind, randomized clinical trial. Schizophr Bull 2023; 49:1579–1590. 78. Behdani F, et al. Can levetiracetam improve clinical symptoms in schizophrenic patients? A randomized placebo-controlled clinical trial. Int Clin Psychopharmacol 2022; 37:159–165. 79. Kruiper C, et al. Clonidine augmentation in patients with schizophrenia: a double-blind, randomized placebo-controlled trial. Schizophr Res 2023; 255:148–154. 80. Hosseininasab M, et al. Nanocurcumin as an add-on to antipsychotic drugs for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol 2021; 41:25–30. 81. Kaul I, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet 2024; 403:160–170. 82. Li M, et al. Improvement of adjunctive berberine treatment on negative symptoms in patients with schizophrenia. Eur Arch Psychiatry Clin Neurosci 2022; 272:633–642. 83. Yi S, et al. Efficacy of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms and cognitive functioning in schizophrenia: an umbrella review of systematic reviews and meta-analyses. Psychiatry Res 2024; 333:115728. 84. Mondino M, et al. Transcranial direct current stimulation for the treatment of refractory symptoms of schizophrenia. Current evidence and future directions. Curr Pharm Des 2015; 21:3373–3383. 85. Kim J, et al. A meta-analysis of transcranial direct current stimulation for schizophrenia: ‘is more better?’ J Psychiatr Res 2019; 110:117–126. 86. Galderisi S, et al. EPA guidance on treatment of negative symptoms in schizophrenia. Eur Psychiatry 2021; 64:e21. 87. Valiengo L, et al. Efficacy and safety of transcranial direct current stimulation for treating negative symptoms in schizophrenia: a randomized clinical trial. JAMA Psychiatry 2020; 77:121–129. 88. Potvin S, et al. A meta-analysis of negative symptoms in dual diagnosis schizophrenia. Psychol Med 2006; 36:431–440. 89. Arndt S, et al. Comorbidity of substance abuse and schizophrenia: the role of pre-morbid adjustment. Psychol Med 1992; 22:379–388. 90. Leeson VC, et al. The effect of cannabis use and cognitive reserve on age at onset and psychosis outcomes in first-episode schizophrenia. Schizophr Bull 2012; 38:873–880. 91. Barnes T, et al. Evidence-based guidelines for the pharmacological treatment of schizophrenia: updated recommendations from the British Association for Psychopharmacology. J Psychopharm 2020; 34:3–78.

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41 - Monitoring

Monitoring

40 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Monitoring Table 1.6 summarises suggested monitoring for those receiving antipsychotic medication.1 Monitoring of people taking antipsychotics is very poor in most countries.2–5 The guidance given here is strongly recommended to ensure safer use of these drugs. Other sections in this chapter provide further background information and relevant references. This table is a summary; see the individual sections for details and discussion. Table 1.6 Suggested monitoring for people receiving antipsychotic medication. Parameter/test Suggested frequency Action to be taken if results outside reference range Medications with special precautions Medications for which monitoring is not required Urea and electrolytes (including creatinine or eGFR) Baseline, then yearly as part of a routine physical health check Investigate all abnormalities detected Amisulpride and sulpiride renally excreted – consider reducing dose if eGFR reduced None Full blood count6–8 Baseline, then yearly as part of a routine physical health check and to detect chronic bone marrow suppression (small risk associated with some antipsychotic medications) Stop suspect medication if neutrophils fall below 1.5×109/L (unless diagnosed with BEN). Refer to specialist medical care if neutrophils below 0.5×109/L. Clozapine FBC weekly for 18 weeks, then 2-weekly up to 1 year, then monthly (schedule varies from country to country) None Blood lipids9,10 (cholesterol, triglycerides; fasting sample, if possible) Baseline, at 3 months, then yearly to detect antipsychotic- induced changes and to generally monitor physical health Offer lifestyle advice. Consider changing antipsychotic medication and/or initiating statin therapy. Clozapine, olanzapine: 3-monthly for first year, then yearly Some antipsychotic medications (e.g. aripiprazole, brexpiprazole cariprazine,11 lurasidone) not clearly associated with dyslipidaemia but prevalence is high in this patient group12–14 so all patients should be monitored Weight9,10,14 (include waist size and BMI, if possible) Baseline, frequently for 3 months, then yearly to detect antipsychotic- induced changes and generally monitor physical health Offer lifestyle advice. Consider changing antipsychotic medication and/or dietary/ pharmacological intervention. Clozapine, olanzapine – frequently for 3 months then 3-monthly for first year, then yearly Aripiprazole, ziprasidone, brexpiprazole, cariprazine and lurasidone not clearly associated with weight gain but monitoring strongly recommended Plasma glucose (fasting sample, if possible) Baseline, at 4–6 months, then yearly to detect antipsychotic-induced changes and generally monitor physical health Offer lifestyle advice. Obtain fasting sample or non-fasting and HbA1C. Refer to GP or specialist. Clozapine, olanzapine, chlorpromazine – test at baseline, one month, then 4–6 monthly Some antipsychotic medications not clearly associated with IFG but prevalence is high,15,16 so all patients should be monitored (Continued)

CHAPTER 1 Table 1.6 (Continued) Parameter/test Suggested frequency Action to be taken if results outside reference range Medications with special precautions Medications for which monitoring is not required ECG17,18 Baseline, when the target dose is reached (ECG changes are rare in practice),19 on admission to hospital, if there are cardiac symptoms, or when medication is changed (e.g. to high-dose or combined antipsychotic medications)17 Discuss with/refer to cardiologist if abnormality detected Haloperidol, pimozide, sertindole – ECG mandatory Risk of sudden cardiac death increased with most antipsychotic medications.20 Ideally, all patients should be offered an ECG at least yearly. Ziprasidone – ECG mandatory in some situations Pimavanserin – ECG strongly recommended Blood pressure Baseline and then frequently during dose titration and after dosage changes If severe hypotension or hypertension (clozapine) observed, slow rate of titration. Consider switching to another antipsychotic if symptomatic postural hypotension. Treat hypertension in line with national guidelines. Clozapine, chlorpromazine and quetiapine most likely to be associated with postural hypotension Amisulpride, aripiprazole, brexpiprazole, cariprazine, lumateperone, lurasidone, trifluoperazine, sulpiride Prolactin Baseline, at 6 months, then yearly Switch medications if hyperprolactinaemia confirmed and symptomatic. Consider tests of bone mineral density (e.g. DEXA) for those with chronically raised prolactin. Amisulpride, sulpiride, risperidone and paliperidone particularly associated with hyperprolactinaemia Asenapine, aripiprazole, brexpiprazole, cariprazine, clozapine, lumateperone, lurasidone, quetiapine, olanzapine (low dose), xanomeline and ziprasidone do not usually elevate plasma prolactin, but measure if symptoms arise Liver function tests21–23 Baseline, then yearly as part of a routine physical health check Stop suspect medication if LFTs indicate hepatitis (transaminases × 3 normal) or functional damage (PT/albumin change) Clozapine and chlorpromazine associated with hepatic failure Amisulpride, sulpiride Creatinine phosphokinase Baseline, then if NMS suspected See section on NMS in this chapter NMS most likely with high-potency FGAs but can occur with any dopamine antagonist or partial agonist None Other tests Patients on clozapine may benefit from an EEG24,25 as this may help determine the need for antiseizure treatment (although interpretation is obviously complex). Those on quetiapine should have thyroid function tests yearly, although the risk of abnormality is very small.26,27 BEN, benign ethnic neutropenia; BMI, body mass index; DEXA, dual-energy x-ray absorptiometry; eGFR, estimated glomerular filtration rate; FGA, first-generation antipsychotic; HbA1c, glycated haemoglobin; IFG, impaired fasting glucose; NMS, neuroleptic malignant syndrome; PT, prothrombin time.

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42 - References

References

42 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

National Institute for Health and Care Excellence. Clinical Knowledge Summaries. Psychosis and schizophrenia: what monitoring is required? 2014 (last revised November 2021, checked January 2024); https://cks.nice.org.uk/topics/psychosis-schizophrenia/prescribing- information/monitoring/#:~:text=References,What%20monitoring%20is%20required%3F,stabilized%20(whichever%20is%20longer).
Bulteau S, et al. Advocacy for better metabolic monitoring after antipsychotic initiation: based on data from a French health insurance database. Expert Opin Drug Saf 2021; 20:225–233.
Lydon A, et al. Routine screening and rates of metabolic syndrome in patients treated with clozapine and long-acting injectable antipsychotic medications: a cross-sectional study. Ir J Psychol Med 2021; 38:40–48.
Poojari PG, et al. Identification of risk factors and metabolic monitoring practices in patients on antipsychotic drugs in South India. Asian J Psychiatr 2020; 53:102186.
Perry BI, et al. Prolactin monitoring in the acute psychiatry setting. Psychiatry Res 2016; 235:104–109.
Burckart GJ, et al. Neutropenia following acute chlorpromazine ingestion. Clin Toxicol 1981; 18:797–801.
Montgomery J. Ziprasidone-related agranulocytosis following olanzapine-induced neutropenia. Gen Hosp Psychiatry 2006; 28:83–85.
Cowan C, et al. Leukopenia and neutropenia induced by quetiapine. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:292–294.
Marder SR, et al. Physical health monitoring of patients with schizophrenia. Am J Psychiatry 2004; 161:1334–1349.
Fenton WS, et al. Medication-induced weight gain and dyslipidemia in patients with schizophrenia. Am J Psychiatry 2006; 163:1697–1704.
Taylor D, et al. Dopamine partial agonists: a discrete class of antipsychotics. Int J Psychiatry Clin Pract 2023; 27:272–284.
Weissman EM, et al. Lipid monitoring in patients with schizophrenia prescribed second-generation antipsychotics. J Clin Psychiatry 2006; 67:1323–1326.
Cohn TA, et al. Metabolic monitoring for patients treated with antipsychotic medications. Can J Psychiatry 2006; 51:492–501.
Paton C, et al. Obesity, dyslipidaemias and smoking in an inpatient population treated with antipsychotic drugs. Acta Psychiatr Scand 2004; 110:299–305.
Taylor D, et al. Undiagnosed impaired fasting glucose and diabetes mellitus amongst inpatients receiving antipsychotic drugs. J Psychopharmacol 2005; 19:182–186.
Citrome L, et al. Incidence, prevalence, and surveillance for diabetes in New York State psychiatric hospitals, 1997–2004. Psychiatr Serv 2006; 57:1132–1139.
Barnes T, et al. Evidence-based guidelines for the pharmacological treatment of schizophrenia: updated recommendations from the British Association for Psychopharmacology. J Psychopharm 2020; 34:3–78.
Shah AA, et al. QTc prolongation with antipsychotics: is routine ECG monitoring recommended? J Psychiatr Pract 2014; 20:196–206.
Novotny T, et al. Monitoring of QT interval in patients treated with psychotropic drugs. Int J Cardiol 2007; 117:329–332.
Ray WA, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009; 360:225–235.
Hummer M, et al. Hepatotoxicity of clozapine. J Clin Psychopharmacol 1997; 17:314–317.
Erdogan A, et al. Management of marked liver enzyme increase during clozapine treatment: a case report and review of the literature. Int J Psychiatry Med 2004; 34:83–89.
Regal RE, et al. Phenothiazine-induced cholestatic jaundice. Clin Pharm 1987; 6:787–794.
Centorrino F, et al. EEG abnormalities during treatment with typical and atypical antipsychotics. Am J Psychiatry 2002; 159:109–115.
Gross A, et al. Clozapine-induced QEEG changes correlate with clinical response in schizophrenic patients: a prospective, longitudinal study. Pharmacopsychiatry 2004; 37:119–122.
Twaites BR, et al. The safety of quetiapine: results of a post-marketing surveillance study on 1728 patients in England. J Psychopharmacol 2007; 21:392–399.
Kelly DL, et al. Thyroid function in treatment-resistant schizophrenia patients treated with quetiapine, risperidone, or fluphenazine. J Clin Psychiatry 2005; 66:80–84.

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43 - Relative adverse effects a rough guide

Relative adverse effects – a rough guide

Schizophrenia and related psychoses CHAPTER 1 Relative adverse effects – a rough guide Table 1.7 provides approximate estimates of relative incidence and severity of adverse effects. It serves as a rough guide and does not replace the detailed and referenced sections included elsewhere. For further details, refer to the dedicated sections in this chapter. Other adverse effects not mentioned in this table also occur. Table 1.7 Approximate estimates of relative incidence and severity of adverse effects. Drug Sedation Weight gain Akathisia Parkin sonism Anti- cholinergic Hypotension Prolactin elevation Prolonged QT interval Amisulpride – + + + – – +++ ++ Aripiprazole – + + – – – – – Asenapine + + + + – – + – Benperidol + + + +++ + + +++ + Blonanserin – – + – – – + – Brexpiprazole – + + – – – – – Cariprazine – + + – – – – – Chlorpromazine +++ ++ + ++ ++ +++ ++ ++ Clozapine +++ +++ – – +++ +++ – +++ Flupentixol + ++ ++ ++ ++ + +++ – Fluphenazine + + ++ +++ + + +++ + Haloperidol + + +++ +++ – + +++ ++ Iloperidone – ++ + + – + – ++ Levomepromazine +++ + + + ++ ++ ++ + Lumateperone ++ – – – – – – – Loxapine ++ + + ++ + ++ +++ – Lurasidone + + + + – – – – Olanzapine +++ +++ + – + + + + Paliperidone + ++ ++ + – ++ +++ + Penfluridol – ++ ++ ++ ++ + +++ ++ Perphenazine + + ++ +++ + + +++ + Pimavanserin – – – – – – – ++ Pimozide + ++ ++ + ++ + +++ +++ Promazine +++ ++ + + ++ ++ + ++ Quetiapine +++ ++ + – + ++ – ++ Risperidone + ++ ++ + – ++ +++ + Sertindole – + + – – +++ – +++ Sulpiride – + + + – – +++ + (Continued)

44 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Drug Sedation Weight gain Akathisia Parkin sonism Anti- cholinergic Hypotension Prolactin elevation Prolonged QT interval Thiothixene ++ ++ + + ++ ++ + + Trifluoperazine + + + +++ + + +++ ? Xanomeline – – – – – – – + Ziprasidone + – + – – + – ++ Zuclopenthixol ++ ++ ++ ++ ++ + +++ + Key: +++ high incidence/severity, ++ moderate, + low, – very low/zero. Table 1.7 (Continued)

06 - Chapter 1 Schizophrenia and related psychoses

44 - Treatment algorithms for schizophrenia

Treatment algorithms for schizophrenia

06 - Chapter 1 Schizophrenia and related psychoses

45 - First episode schizophrenia

First-episode schizophrenia

Schizophrenia and related psychoses CHAPTER 1 Either: Agree the choice of antipsychotic medication with patient1 and/or carer Or, if not possible: Start second-generation antipsychotic medication (select one that is available in long-acting injection formulation)2,3 Treatment algorithm Titrate, as necessary, to minimum effective dose (see section on ‘minimum effective dose in this chapter) Adjust dosage regimen according to therapeutic response and tolerability/safety Change drug and follow above process Assess over 2–3 weeks* Clozapine*** If poor adherence related to poor tolerability, discuss with patient and change to drug with more favourable adverse-effect profile When efficacy and tolerability established, switch to long-acting injection Continue at dose established as effective Switch to depot/long-acting injection before discharge** Effective No effect Not effective Not tolerated or poor medication adherence

Any improvement is likely to be apparent within 2–3 weeks of receiving an effective dose.4 Most improvement occurs during this period.5 If no effect by 2–3 weeks, increase the dose or change the drug. If some response detected, continue for a total of 10 weeks before abandoning treatment.6 ** Relapse and readmission rates are vastly reduced by early use of depot/long-acting injections in this patient group.7–9 Patients with first-episode schizophrenia will accept long-acting injections.10 *** Early use of clozapine much more likely than anything else to be successful.6,11 Reluctance to use clozapine is associated with poor outcomes.12 Delaying the use of clozapine diminishes response to clozapine.13 Treatment algorithms for schizophrenia First-episode schizophrenia

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46 - Relapse or acute exacerbation of schizophreni

Relapse or acute exacerbation of schizophrenia

46 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Investigate social or psychological precipitants Provide appropriate support and/or therapy Continue usual drug treatment Add short-term sedative or Switch to a different, more acceptable antipsychotic medication if appropriate Discuss medication choice with patient and/or carer Assess over 6–8 weeks Switch to clozapine Acute drug treatment required Treatment algorithm Treatment ineffective Notes ■ ■First-generation drugs may be slightly less efficacious than some SGAs.14,15 FGAs should probably be reserved for second- or third-line use (or not used at all) because of the possibility of poorer outcome compared with SGAs and the higher risk of movement disorder, particularly TD.16,17 ■ ■Choice should be based largely on comparative adverse-effect profile and relative toxicity. Patients seem able to make informed choices based on these factors,18,19 although in practice they are rarely involved in drug choice.20 Allowing patients informed choice seems to improve outcomes.1 ■ ■Where there is prior treatment failure (but not confirmed treatment refractoriness), olanzapine or risperidone may be better options than quetiapine.21 Olanzapine, because of the wealth of evidence suggesting slight superiority over other antipsychotics, should probably be tried before clozapine unless contraindicated.22–25 However, one RCT6 found that continuing with amisulpride was as effective as switching to olanzapine. ■ ■Before considering clozapine, ensure adherence to prior therapy using depot/LAI formulation or plasma drug level monitoring of oral treatment. Most non-adherence is undetected in practice,21,26 and apparent treatment resistance may simply be a result of inadequate treatment.27 ■ ■Time to response is increased and total response decreased in exacerbations of multi-episode schizophrenia.28 ■ ■Where there is confirmed treatment resistance (failure to respond to adequate trials of at least two antipsychotic medications), evidence supporting the use of clozapine (and only clozapine) is overwhelming.29,30

In patients taking oral antipsychotics, non-compliance often goes undetected.26 Absolute non-compliance (blood levels of zero) is surprisingly common.27 Relapse or acute exacerbation of schizophrenia (full adherence to medication confirmed)*

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47 - Relapse or acute exacerbation of schizophreni

Relapse or acute exacerbation of schizophrenia

Schizophrenia and related psychoses CHAPTER 1 Relapse or acute exacerbation of schizophrenia (adherence doubtful or known to be poor)

Compliance aids (e.g. Medi-Dose® system in the UK) are not a substitute for patient education. The ultimate aim should be to promote independent living, perhaps with patients filling their own compliance aid, having first been given support and training. Note that such compliance aids are of little use unless the patient is clearly motivated to adhere to prescribed treatment. Some medicines are not suitable for storage in compliance aids. ** Patients generally have positive views of depot medication.10,31 Investigate reasons for poor adherence Discuss with patient Switch to antipsychotic medication with a more favourable adverse-effect profile Use LAI if patient agrees Discuss with patient Consider depot/LAI antipsychotic medication** Simplify drug regimen Reduce any anticholinergic load Consider ‘compliance aids’* Consider depot/LAI** Forgetful or disorganised Treatment algorithm Lack of insight or support Poorly tolerated treatment

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48 - References

References

48 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

Robinson DG, et al. Psychopharmacological treatment in the RAISE-ETP study: outcomes of a manual and computer decision support system based intervention. Am J Psychiatry 2018; 175:169–179.
Zhu Y, et al. Antipsychotic drugs for the acute treatment of patients with a first episode of schizophrenia: a systematic review with pairwise and network meta-analyses. Lancet Psychiatry 2017; 4:694–705.
Zhang JP, et al. Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis. Int J Neuropsychopharmacol 2013; 16:1205–1218.
Leucht S, et al. Early-onset hypothesis of antipsychotic drug action: a hypothesis tested, confirmed and extended. Biol Psychiatry 2005; 57:1543–1549.
Agid O, et al. The ‘delayed onset’ of antipsychotic action: an idea whose time has come and gone. J Psychiatry Neurosci 2006; 31:93–100.
Kahn RS, et al. Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching study. Lancet Psychiatry 2018; 5:797–807.
Subotnik KL, et al. Long-acting injectable risperidone for relapse prevention and control of breakthrough symptoms after a recent first episode of schizophrenia. A randomized clinical trial. JAMA Psychiatry 2015; 72:822–829.
Schreiner A, et al. Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia. Schizophr Res 2015; 169:393–399.
Alphs L, et al. Treatment effect with paliperidone palmitate compared with oral antipsychotics in patients with recent-onset versus more chronic schizophrenia and a history of criminal justice system involvement. Early Interv Psychiatry 2018; 12:55–65.
Kane JM, et al. Patients with early-phase schizophrenia will accept treatment with sustained-release medication (long-acting injectable anti psychotics): results from the recruitment phase of the PRELAPSE trial. J Clin Psychiatry 2019; 80:18m12546.
Agid O, et al. An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry 2011; 72:1439–1444.
Drosos P, et al. One-year outcome and adherence to pharmacological guidelines in first-episode schizophrenia: results from a consecutive cohort study. J Clin Psychopharmacol 2020; 40:534–540.
Rajalingham K. Clozapine delay results in poorer outcomes for treatment-resistant schizophrenia patients. Psiquiatría Biológica 2024; 31:100493.
Davis JM, et al. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003; 60:553–564.
Leucht S, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373:31–41.
Schooler N, et al. Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial. Am J Psychiatry 2005; 162:947–953.
Oosthuizen PP, et al. Incidence of tardive dyskinesia in first-episode psychosis patients treated with low-dose haloperidol. J Clin Psychiatry 2003; 64:1075–1080.
Whiskey E, et al. Evaluation of an antipsychotic information sheet for patients. Int J Psychiatry Clin Pract 2005; 9:264–270.
Stroup TS, et al. Results of phase 3 of the CATIE schizophrenia trial. Schizophr Res 2009; 107:1–12.
Olofinjana B, et al. Antipsychotic drugs: information and choice: a patient survey. Psychiatr Bull 2005; 29:369–371.
Stroup TS, et al. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry 2006; 163:611–622.
Haro JM, et al. Remission and relapse in the outpatient care of schizophrenia: three-year results from the Schizophrenia Outpatient Health Outcomes study. J Clin Psychopharmacol 2006; 26:571–578.
Novick D, et al. Recovery in the outpatient setting: 36-month results from the Schizophrenia Outpatients Health Outcomes (SOHO) study. Schizophr Res 2009; 108:223–230.
Tiihonen J, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ 2006; 333:224.
Leucht S, et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry 2009; 166:152–163.
Remington G, et al. The use of electronic monitoring (MEMS) to evaluate antipsychotic compliance in outpatients with schizophrenia. Schizophr Res 2007; 90:229–237.
McCutcheon R, et al. Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia. Acta Psychiatr Scand 2018; 137:39–46.
Takeuchi H, et al. Does relapse contribute to treatment resistance? Antipsychotic response in first- vs. second-episode schizophrenia. Neuropsychopharmacology 2019; 44:1036–1042.
McEvoy JP, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006; 163:600–610.
Lewis SW, et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull 2006; 32:715–723.
Mace S, et al. Positive views on antipsychotic long-acting injections: results of a survey of community patients prescribed antipsychotics. Ther Adv Psychopharmacol 2019; 9:2045125319860977.

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49 - First generation antipsychotics place in the

First-generation antipsychotics – place in therapy

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50 - Nomenclature

Nomenclature

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51 - Role of older antipsychotics

Role of older antipsychotics

Schizophrenia and related psychoses CHAPTER 1 First-generation antipsychotics – place in therapy Nomenclature First-generation (‘typical’) and second-generation (‘atypical’) antipsychotic medications are not categorically differentiated. Drugs in both groups differ substantially in pharmacological and adverse-effect profiles and there is some overlap between the two groups in pharmacological characteristics. FGA medications were introduced before 1990 and tend to be associated with acute EPS, hyperprolactinaemia and, in the longer term, TD. It might be expected that these adverse effects are less likely or absent with SGA medications (introduced after 1990), although in practice most SGAs show dose- related EPS, some induce hyperprolactinaemia (some to a greater extent than FGAs) and all will give rise to TD, albeit at a lower incidence than FGAs. SGA medications tend to be associated with metabolic and cardiac complications,1–3 although this is not true of all SGAs and it is true of some FGAs. To complicate matters further, it has been suggested that the therapeutic and adverse effects of FGAs can be separated by careful dosing.4 That is, FGAs can be indistinguishable from SGAs if used in small enough doses (there is much evidence to the contrary).5–7 Given these observations, it seems unwise and unhelpful to consider so-called FGAs and SGAs as distinct groups of drugs. Perhaps the essential difference between the two groups is the size of the therapeutic index in relation to acute EPS. For instance, haloperidol has an extremely narrow range of doses at which it is effective but does not cause EPSEs (perhaps 4.0–4.5mg/day) whereas olanzapine has a wide range of therapeutic doses (5–40mg/day) at which it does not generally cause such adverse effects. The use of NbN1,2 (for which there is a free application for smartphones and other devices) obviates the need for classification into an FGA or SGA and describes individual drug by their pharmacological activity. NbN is certainly a useful alternative to standard classifications, but one possible limitation is that it preselects specific pharmacological features to create categories while ignoring others, based on the opinion of experts that these features are essential to drug action (despite exact mechanisms of action being unknown). In 2023, a different approach based on in vitro binding profiles was proposed.3 Four clusters of effects were identified, one with high affinity for muscarinic receptors (e.g. olanzapine and quetiapine), one with relatively low antagonism of the dopamine D2 receptor (e.g. the partial agonists and lurasidone), one with serotonergic antagonism (e.g. risperidone) and one with relatively pure dopaminergic antagonism (e.g. amisulpride). These clusters mapped to adverse-effect profiles with greater accuracy than the other classification systems. One possible disadvantage of this so-called data-driven approach is that all receptors are assigned an equal level of importance regardless of their magnitude of impact in producing clinically relevant effects. The wider use of NbN or the data-driven approach will undoubtedly improve understanding of individual drug effects and perhaps forestall future redundant categorisation. Role of older antipsychotics FGAs still play an important role in schizophrenia. For example, haloperidol is a frequent choice for ‘when necessary’ medication and depot preparations of haloperidol, zuclopenthixol and flupentixol are still commonly prescribed. FGAs can offer a valid

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52 - References

References

50 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 alternative to SGAs where SGAs are poorly tolerated (usually because of metabolic changes) or where FGAs are preferred by patients themselves. Some FGAs may be less effective than some non-clozapine SGAs (amisulpride, olanzapine and risperidone may be slightly more efficacious)4,5 but any differences in therapeutic efficacy seem to be modest. Two large, independent and pragmatic studies, CATIE6 and CUtLASS,7 found few important differences between SGAs and FGAs (mainly perphenazine and sulpiride, respectively). The main drawbacks of FGAs are acute EPS, hyperprolactinaemia and TD. Hyperprolactinaemia is probably unavoidable in practice because the dose that achieves efficacy is too close to the dose that causes hyperprolactinaemia. Even when not symptomatic, hyperprolactinaemia may grossly affect hypothalamic function.8 Raised prolactin is also associated with sexual dysfunction,9 as are the autonomic effects of some SGAs.10 Notably, some SGAs (risperidone, paliperidone, amisulpride) increase prolactin to a greater extent than FGAs.11 All FGAs are potent dopamine antagonists, which are liable to induce dysphoria.12 Perhaps as a consequence, some FGAs may produce smaller benefits in quality of life than some SGAs.6 Tardive dyskinesia very probably occurs more frequently with FGAs than SGAs13–16 (notwithstanding difficulties in defining what is ‘atypical’), although there remains some uncertainty16–18 and the dose of FGA used is a crucial factor.19 A complicating aspect is the occurrence of TD in untreated schizophrenia,20 which may mean that antipsychotics do not necessarily cause TD but simply fail to suppress it to varying degrees. Among SGAs, partial agonists may have the lowest risk of TD.21 Careful observation of patients and the prescribing of the lowest effective dose are essential to help reduce the risk of this serious adverse event.22,23 Even with these precautions, the risk of TD with some FGAs may be unacceptably high.24 A good example of the relative merits of SGAs and a carefully dosed FGA comes from a trial comparing paliperidone palmitate with low-dose haloperidol decanoate.25 Paliperidone produced more weight gain and prolactin change but haloperidol was associated with significantly more frequent akathisia and parkinsonism, and, numerically, a higher incidence of TD. Efficacy was identical. References

Blier P, et al. Progress on the Neuroscience-Based Nomenclature (NbN) for psychotropic medications. Neuropsychopharmacology 2017; 42:1927–1928.
Caraci F, et al. A new nomenclature for classifying psychotropic drugs. Br J Clin Pharmacol 2017; 83:1614–1616.
McCutcheon RA, et al. Data-driven taxonomy for antipsychotic medication: a new classification system. Biol Psychiatry 2023; 94:561–568.
Davis JM, et al. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003; 60:553–564.
Leucht S, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373:31–41.
Grunder G, et al. Effects of first-generation antipsychotics versus second-generation antipsychotics on quality of life in schizophrenia: a double-blind, randomised study. Lancet Psychiatry 2016; 3:717–729.
Jones PB, et al. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63:1079–1087.
Smith S, et al. The effects of antipsychotic-induced hyperprolactinaemia on the hypothalamic-pituitary-gonadal axis. J Clin Psychopharmacol 2002; 22:109–114.
Smith SM, et al. Sexual dysfunction in patients taking conventional antipsychotic medication. Br J Psychiatry 2002; 181:49–55.
Aizenberg D, et al. Comparison of sexual dysfunction in male schizophrenic patients maintained on treatment with classical antipsychotics versus clozapine. J Clin Psychiatry 2001; 62:541–544.
Leucht S, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382:951–962.

Schizophrenia and related psychoses CHAPTER 1 12. King DJ, et al. Antipsychotic drug-induced dysphoria. Br J Psychiatry 1995; 167:480–482. 13. Tollefson GD, et al. Blind, controlled, long-term study of the comparative incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol. Am J Psychiatry 1997; 154:1248–1254. 14. Beasley C, et al. Randomised double-blind comparison of the incidence of tardive dyskinesia in patients with schizophrenia during long-term treatment with olanzapine or haloperidol. Br J Psychiatry 1999; 174:23–30. 15. Correll CU, et al. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry 2004; 161:414–425. 16. Novick D, et al. Tolerability of outpatient antipsychotic treatment: 36-month results from the European Schizophrenia Outpatient Health Outcomes (SOHO) study. Eur Neuropsychopharmacol 2009; 19:542–550. 17. Halliday J, et al. Nithsdale Schizophrenia Surveys 23: movement disorders. 20-year review. Br J Psychiatry 2002; 181:422–427. 18. Miller DD, et al. Extrapyramidal side-effects of antipsychotics in a randomised trial. Br J Psychiatry 2008; 193:279–288. 19. Takeuchi H, et al. Pathophysiology, prognosis and treatment of tardive dyskinesia. Ther Adv Psychopharmacol 2022; 12:20451253221117313. 20. Kalniunas A, et al. Prevalence of spontaneous movement disorders (dyskinesia, parkinsonism, akathisia and dystonia) in never-treated patients with chronic and first-episode psychosis: a systematic review and meta-analysis. BMJ Ment Health 2024; 27:e301184. 21. Carbon M, et al. Tardive dyskinesia prevalence in the period of second-generation antipsychotic use: a meta-analysis. J Clin Psychiatry 2017; 78:e264–e278. 22. Jeste DV, et al. Tardive dyskinesia. Schizophr Bull 1993; 19:303–315. 23. Cavallaro R, et al. Recognition, avoidance, and management of antipsychotic-induced tardive dyskinesia. CNS Drugs 1995; 4:278–293. 24. Oosthuizen P, et al. A randomized, controlled comparison of the efficacy and tolerability of low and high doses of haloperidol in the treatment of first-episode psychosis. Int J Neuropsychopharmacol 2004; 7:125–131. 25. McEvoy JP, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA 2014; 311:1978–1987.

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53 - NICE guidelines for the treatment of schizoph

NICE guidelines for the treatment of schizophrenia1

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54 - NICE guidelines a summary

NICE guidelines – a summary

52 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 NICE guidelines for the treatment of schizophrenia1 The UK NICE guidelines1 were published in February 2014 and last reviewed in September 2024 but have remained largely unchanged. NICE guidelines – a summary First-episode psychosis For people with newly diagnosed schizophrenia, offer oral antipsychotic medication as well as psychological interventions (cognitive behavioural therapy [CBT] or family intervention). Provide information and discuss the benefits and adverse-effect profile of each drug with the service user. The choice of drug should be made by the service user and healthcare professional together, considering: ■ ■the relative potential of individual antipsychotic drugs to cause extrapyramidal adverse effects (EPSEs; including akathisia), cardiovascular adverse effects, metabolic adverse effects (including weight gain), hormonal adverse effects (including raised prolactin levels) and other adverse effects (including unpleasant subjective experiences) ■ ■the views of the carer where the service user agrees. Before starting antipsychotic medication, undertake a thorough assessment of physical health and offer an ECG if specified in the summary of product characteristics (SPC) or clinically indicated. Treatment with antipsychotic medication should be considered an explicit individual therapeutic trial and the following should be considered: ■ ■Recording of indications and expected benefits and risks of oral antipsychotic medication, and the expected time for a change in symptoms and appearance of adverse effects. ■ ■At the start of treatment, give a dose at the lower end of the licensed range and slowly titrate upwards within the dose range given in the BNF or SPC. ■ ■Justify and record reasons for dosages outside the range given in the BNF or SPC. ■ ■Record the rationale for continuing, changing or stopping medication and the effects of such changes. ■ ■Carry out a trial of medication at optimum dosage for 4–6 weeks (although half of this period is probably sufficient if no effect at all is seen). ■ ■Monitor and record the following regularly and systematically throughout treatment, but especially during titration: ■ ■efficacy, including changes in symptoms and behaviour ■ ■adverse effects of treatment, taking into account overlap between certain adverse effects and clinical features of schizophrenia (e.g. the overlap between akathisia and agitation or anxiety) ■ ■adherence ■ ■weight, weekly for the first 6 weeks, then at 12 weeks, 1 year and annually ■ ■waist circumference annually

Schizophrenia and related psychoses CHAPTER 1 ■ ■pulse and blood pressure at 12 weeks, 1 year and annually ■ ■fasting blood glucose, HbA1c and blood lipids at 12 weeks, 1 year and annually ■ ■nutritional status, diet and physical activity. ■ ■Physical monitoring is to be the responsibility of the secondary care team for 1 year or until the patient is stable. ■ ■Discuss the use of alcohol, tobacco, prescription and non-prescription medication, as well as the use of illicit drugs, with the service user and carer if appropriate. Discuss their potential interactions with the prescribed therapy and psychological treatments. ■ ■Do not use a loading dose of antipsychotic medication (note that this does not apply to loading doses of depot forms of olanzapine and paliperidone). ■ ■Do not routinely initiate regular combined antipsychotic medication, except for short periods (e.g. when changing medication). Subsequent episodes of psychosis/maintenance treatment of schizophrenia ■ ■Consider the clinical response and adverse effects of the service user’s current and previous medication. ■ ■Consider offering depot/LAI antipsychotic medication to people with schizophrenia: ■ ■who would prefer such treatment after an acute episode ■ ■known to be non-adherent to oral treatment and/or those who prefer this method of administration. GPs and other primary healthcare professionals should monitor the physical health of people with psychosis or schizophrenia when responsibility for monitoring is first transferred from secondary care, and then at least annually. The health check should be comprehensive, focusing on physical health problems that are common in people with psychosis and schizophrenia. Treatment-resistant schizophrenia Offer clozapine to people with schizophrenia whose illness has not responded adequately to treatment despite the sequential use of adequate doses of at least two different anti psychotic drugs alongside psychological therapies. The misuse of illicit substances (including alcohol) and the use of other prescribed medication or physical illness should be excluded. At least one of the drugs should be a non-clozapine SGA (see section on treatment algorithms for schizophrenia in this chapter – we recommend that one of the drugs should be olanzapine). For people with schizophrenia whose illness has not responded adequately to clozapine at an optimised dose, healthcare professionals should establish prior compliance with optimised antipsychotic treatment (including measuring drug levels) and engagement with psychological treatment before adding a second antipsychotic to augment treatment with clozapine. An adequate trial of such an augmentation may need to be up to 8–10 weeks. Choose a drug that does not compound the common adverse effects of clozapine. There are some notable differences with some more recently published guidelines. In first-episode psychosis, NICE makes no specific antipsychotic recommendation, whereas the Royal Australian and New Zealand College of Psychiatrists (RANZCP)2 guidelines recommend atypical antipsychotics. They also explicitly suggest or at least

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References

54 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 allow the use of long-acting agents, as do the BAP guidelines.3 The duration of antipsychotic treatment in first episode is not clearly defined in the NICE guidelines. The Canadian Psychiatric Association guidelines4 recommend at least 18 months, the BAP at least 2 years, and RANZCP 2–5 years. There is scant mention of the treatment of negative symptoms in any of the guidelines. UK NICE guidelines recommend psychological approaches while RANZCP tentatively recommends rTMS. Reflecting the paucity of evidence in clozapine-resistant schizophrenia there is little detail or difference in guideline recommendations – all suggest adding a second antipsychotic. References

National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management. Clinical guideline [CG178]. 2014 (last checked November 2024); https://www.nice.org.uk/guidance/cg178.
Galletly C, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders. Aust N Z J Psychiatry 2016; 50:410–472.
Barnes T, et al. Evidence-based guidelines for the pharmacological treatment of schizophrenia: updated recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2020; 34:3–78.
Remington G, et al. Guidelines for the pharmacotherapy of schizophrenia in adults. Can J Psychiatry 2017; 62:604–616.

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56 - Antipsychotic response to increase the dose,

Antipsychotic response – to increase the dose, to switch, to add or just wait – what is the right move?

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57 - Optimal dosage

Optimal dosage

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58 - High dosage

High dosage

Schizophrenia and related psychoses CHAPTER 1 Antipsychotic response – to increase the dose, to switch, to add or just wait – what is the right move? For any clinician actively involved in the care of people with schizophrenia, perhaps the single most common clinical dilemma is what to do when treatment with the current antipsychotic medication seems to be suboptimal (symptoms are well controlled but adverse effects are problematic or the therapeutic response is inadequate). Fortunately, with regard to poor tolerability, the diversity of the available antipsychotic medications means that it is usually possible to find one that has an adverse-effect profile that is more appropriate and more tolerable. With regard to inadequate symptom response, what to do next is a more difficult question. If the illness has not shown sufficient improvement despite serial adequate trials, in terms of dosage, duration and adherence, of at least two antipsychotic medications, then a trial of clozapine should be considered. However, should the person be reluctant to try clozapine, the clinician has four main options: to increase the dose of the current medication, to switch to another anti psychotic medication, to add an adjunctive medication, or just to monitor the illness in the hope that changing external factors will allow recovery. Unfortunately, the evidence base supporting these management options is limited.1–3 Optimal dosage While the optimal doses for FGAs were always a matter of debate, the recommended doses of the SGAs are generally based on careful and extensive (fixed-dose) clinical trials. Despite this, the consensus on optimal SGA dosages has changed over time. For example, when risperidone was first introduced it was suggested that the optimal dose was 6mg or more for all patients. However, subsequently clinical practice moved towards the use of lower doses.4 On the other hand, when quetiapine was introduced, 300mg was considered the optimal dose. The overall consensus now is towards higher doses,5 although RCT and other evidence does not consistently support this shift.5,6 Nonetheless, most clinicians feel comfortable in navigating within the recommended clinical dose ranges for the SGAs. The more critical question is what should be done if the upper limit of the dose range has been reached and, while the individual is tolerating the medication well, there is only limited benefit. High dosage For antipsychotic medications, the dose–response relationships for the treatment of schizophrenia are not that well defined. Davis and Chen7 performed the first comprehensive systematic meta-analysis of relevant dose–response data available up to 2004 and concluded that the average dose that produces maximal benefit was 4mg for risperidone, 16mg olanzapine, 120mg ziprasidone and 10–15mg aripiprazole (they could not determine such a dose for quetiapine using their method). In 2020, Leucht and colleagues8 carried out a similar meta-analysis of dose–response in acute schizophrenia and concluded that doses higher than standard doses were not more efficacious. However, they did suggest that for a few medications (such as olanzapine, lurasidone, ziprasidone) with clearly increasing dose curves (i.e. did not plateau), it might be worth testing higher-than-licensed doses in clinical trials. For example, the findings of a

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59 - Plasma level variations

Plasma level variations

56 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 network meta-analysis of the dose–response effects of lurasidone in acute schizophrenia suggested that 160mg/day might be the most effective and acceptable dose.9 Several trials have tried to compare high-dose antipsychotic medication with standard dosage. For example, one study10 explored the dose–response relationship of olanzapine in a randomised, double-blind, 8-week, fixed-dose study, comparing doses of 10mg, 20mg and 40mg. While no additional benefit was found with the higher doses (i.e. 40mg was no better than 10mg), there was clear evidence of a greater adverse- effect burden (weight gain and raised plasma prolactin level). Similarly, early studies of risperidone11 compared the usual daily doses of 2mg and 6mg with higher doses, up to 16mg. There was no additional benefit with the higher doses but a clear signal for a greater risk of adverse effects (EPS and raised plasma prolactin). The findings of these studies are in accord with older studies involving fixed doses of haloperidol,12 where 8mg/day is clearly the dose above which no additional benefit is seen.13 Interestingly, the likelihood of inducing EPSEs is not constrained by dose in the same way – the frequency of EPS continues to increase at doses well beyond standard or even high doses.14 Despite the lack of evidence for the benefit of higher doses, it is important to keep in mind that these doses are extracted from group evidence where patients are assigned to different doses, which is a different situation from the clinical one where the prescriber considers increasing the dose only in those patients whose illnesses have failed to respond to the initial dosage regimen. In 1993, Kinon and colleagues15 examined patients who failed to respond to the (then) standard dose of fluphenazine (20mg) and tested three strategies: increasing the dose to 80mg, switching to haloperidol or watchful waiting (on the original dose). All three strategies proved to be equivalent in terms of efficacy. These findings provide little supportive evidence at a group level (as opposed to an individual level) for treatment beyond the recommended dose range. Such RCT evidence is corroborated by the clinical practice norms – Hermes and colleagues examined the CATIE data to identify clinical factors that predicted a prescriber’s decision to increase the dose (within the standard ranges) and found that such decisions were only weakly associated with clinical measures.16 A later trial of lurasidone17 for early, non- responsive schizophrenia showed that after 2 weeks on lurasidone 80mg/day, a dose increase to 160mg/day was associated with significant symptom improvement compared with continuing on lurasidone 80mg/day. However, the clinical implications of these findings are uncertain, given the limitations of the trial: it lasted only 4 weeks, and there was no testing of the intermediate dose of 120mg/day. A 2018 Cochrane systematic review of relevant studies concluded that there was no good-quality evidence that for illness not responding to initial antipsychotic treatment there was any difference between increasing the antipsychotic dose and continuing antipsychotic treatment at the same dose.1 A similar meta-analysis in 20233 concluded that, for early non-responsive schizophrenia, the evidence for treatment strategies such as dose escalation or switching antipsychotic medication was too limited to allow for any strong clinical recommendations. Plasma level variations There are significant inter-individual variations in plasma drug levels in patients treated with antipsychotic medication. Patients may be encountered who, when receiving medication at the higher end of the dose range (say 6mg of risperidone or 20mg of olanzapine),

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60 - Treatment options for schizophrenia that is p

Treatment options for schizophrenia that is poorly responsive to standard antipsychotic treatment

Schizophrenia and related psychoses CHAPTER 1 have plasma drug levels that are well below the range expected for 2mg risperidone or 10mg olanzapine, and these levels may not reach the threshold required for a therapeutic effect. In such patients, a rational case could be made for increasing the dose, provided the patient is informed and the adverse effects are tolerable, to bring the plasma levels into the optimal range for the particular medication. Genetic analysis is helpful in identifying ultrafast metabolisers of aripiprazole, risperidone18 and clozapine.19 Treatment options for schizophrenia that is poorly responsive to standard antipsychotic treatment So what are the treatment possibilities when a lack of therapeutic response is encountered despite a patient’s adherence to their medication regimen, the prescription of a dosage at the top of the recommended range, and apparently sufficient plasma drug levels? There are essentially three options: a trial of clozapine, switching to another antipsychotic medication or adding another (non-clozapine) antipsychotic medication. If the patient meets the criteria for clozapine treatment, this is undoubtedly the preferred option. Yet, in a clinical audit of community (not inpatient) practice in the UK, covering some 5,000 patients in 60 different NHS trusts, it was found that 40% of the patients whose illnesses met the criteria for TRS had not received clozapine. For the vast majority (85%) of those who had started clozapine, this had been delayed after the failure of two serial trials of antipsychotic medication for much longer than is advised in most guidelines.20 Significant delay in the commencement of clozapine treatment has also been found in early intervention in psychosis services.21 However, when reflecting on the findings suggesting delay or underuse of clozapine, it should be borne in mind that among those patients with a diagnosis of treatment-resistant illness who have not had a trial of clozapine, there will be some who have declined this treatment, some who have yet to be persuaded, and some for whom the prescribing clinician considers, perhaps because of factors such as comorbid physical illness, substance use or adverse social circumstances, that another intervention has a more favourable risk–benefit balance.22 Some patients may be averse to the mandatory regular blood testing, the adverse effects and the regular appointments required as part of the clozapine regimen. In such patients, the options are switching to another antipsychotic medication or adding one. The data on switching are sparse. While almost every clinical trial in patients with established schizophrenia has entailed the patient switching from one antipsychotic medication to another, there are no rigorous studies addressing preferred medication switches (e.g. if risperidone fails – what next? Olanzapine, quetiapine, aripiprazole or ziprasidone?). If one looks at only the switching trials which have been sponsored by the drug companies it leads to a rather confusing picture, with the trial results being very closely linked to the sponsors’ interest (see ‘Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics’).23 Further, switching can be associated with destabilisation of the illness and the emergence of adverse effects, which may be a consequence of stopping the original antipsychotic medication and/or a response to the subsequent medication and/or differences between the pharmacological profiles of the two medications. The extent to which the management of a switch can minimise such problems is not entirely clear, but a gradual cross- tapering approach is usually recommended.24–26

58 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 CATIE, the major US-based publicly funded comparative trial, examined participants whose illness had failed to respond to a first SGA and were then randomly assigned to a different second one.27 Participants switched to olanzapine and risperidone did better than those switched to quetiapine and ziprasidone. This greater effectiveness is supported by a meta-analysis that compared a number of SGAs with FGAs and concluded that, other than clozapine, only amisulpride, risperidone and olanzapine were superior to FGAs in efficacy.28 Further, the findings of a meta-analysis comparing SGAs among themselves suggested that olanzapine and risperidone (in that order) may be modestly more effective than the others.29 Thus, if olanzapine or risperidone have not yet been tried, it would be a reasonable decision to switch to these medications, provided the risk–benefit balance was considered likely to be favourable for the particular patient. Comparing these two medications, the data are somewhat limited. However, a number of controlled and open-label studies do show an asymmetrical advantage, with a switch to olanzapine being more effective than to risperidone.30,31 Such findings have been reinforced recently: a systematic review32 found high-dose olanzapine to be superior to other commonly used FGAs and SGAs, including risperidone, for TRS, while a network meta-analysis33 confirmed olanzapine as the second most effective antipsychotic, behind clozapine, for such illness. The best medication regimen (aside from clozapine) to choose for a patient whose illness has failed trials of olanzapine and risperidone remains unclear. Should one switch to, say, aripiprazole or ziprasidone or even an older FGA, or should another antipsychotic medication be added? Interestingly, studies that have switched patients to aripiprazole for reasons of tolerability (weight gain, etc.) find either no loss of efficacy34,35 or an improvement in symptom severity.24,36 After switching, adding another antipsychotic is probably the most common clinical strategy chosen. A 2022 clinical audit in the UK37 found that of 4,156 people on acute adult psychiatric wards, 14% were prescribed more than one antipsychotic medication. By far the most common reason for such a prescription was an insufficient response of symptoms and/or behavioural disturbance with antipsychotic monotherapy at standard dosage. A second antipsychotic may also be added for additional properties (e.g. quetiapine for sedation or aripiprazole to decrease plasma prolactin – these matters are discussed elsewhere) but here we are concerned solely with the use of combined anti psychotic medications to increase efficacy. From a theoretical point of view, since all currently available antipsychotic medications (with xanomeline and pimavanserin as exceptions) block D2 receptors (unlike, say, antihypertensive drugs which use different mechanisms) there is a limited rationale for addition. Studies of add-ons have often chosen combinations on the basis of convenience or clinical lore and perhaps the most systematic evidence is available for the addition of a second antipsychotic to clozapine,38–40 a strategy that may be supported by the rationale that since clozapine has relatively low D2 occupancy, increasing its D2 occupancy may yield additional benefits.41 However, a meta-analysis of RCTs comparing augmentation with a second antipsychotic with continuing monotherapy in schizophrenia42 found a lack of double-blind/high- quality evidence for efficacy, in terms of treatment response and symptom improvement, for a range of antipsychotic combinations. Further, compared with antipsychotic monotherapy, combined antipsychotics seem to be associated with an increased adverse-effect

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Summary

Schizophrenia and related psychoses CHAPTER 1 When treatment fails ■ ■If the dose of antipsychotic medication has been optimised, consider watchful waiting. ■ ■Consider increasing the antipsychotic dose according to tolerability and plasma levels (little supporting evidence for most drugs).2,50 ■ ■If this fails, consider switching to olanzapine or risperidone (if not already used). ■ ■If this fails, use clozapine (supporting evidence very strong). ■ ■If clozapine fails, use time-limited augmentation strategies (supporting evidence variable). burden and a greater risk of high-dose prescribing.43,44 Nonetheless, at a population level, antipsychotic polypharmacy does not appear to result in increased rates of hospitalisation for either physical or specifically cardiovascular illness.45 While augmentation with another antipsychotic medication as a treatment strategy should probably be avoided, under some conditions of acute exacerbation or agitation the prescriber may see this as the only practicable solution. Or quite often the prescriber may inherit the care of a patient on antipsychotic polypharmacy. Most RCT evidence suggests that such a regimen can be safely switched back to antipsychotic monotherapy without symptom exacerbation, at least in the majority of patients,46–48 although this is not a universal finding.49 Essock and co-workers48 conducted a trial involving 127 patients with schizophrenia who were stable on antipsychotic polypharmacy. Over a 12-month period, a switch to monotherapy was successful in about two-thirds of the participants in whom it was tested. And in those cases where the move to monotherapy resulted in a return of symptoms, the most common recourse was a return to the original polypharmacy. This was achieved without any significant worsening in this group. The advantages for the monotherapy group were exposure to less medication, equivalent symptom severity and some loss of weight. So when should the prescriber just continue with the current regimen? The evidence reviewed above suggests that no one strategy, such as increasing the dose, switching to another antipsychotic medication or augmentation with a second antipsychotic medication, is the clear winner in all situations. But increasing the dose if plasma drug levels are low, switching to olanzapine if this has not been tried, or augmentation if there is insufficient response to clozapine may be beneficial in some cases. Given the limited efficacy of these manoeuvres perhaps an equally important call by the treating doctor is when to just stay with the current pharmacotherapy and focus on non-pharmacological means: engagement in case management, targeted psychological treatments and vocational rehabilitation as means of enhancing patient well-being. While it may seem a passive option, staying with the current medication regimen may often do less harm than aimless switching and dosage increments. Summary

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References

60 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

Samara MT, et al. Increasing antipsychotic dose versus switching antipsychotic for non response in schizophrenia. Cochrane Database Syst Rev 2018; (5):CD011884.
Barnes T, et al. Evidence-based guidelines for the pharmacological treatment of schizophrenia: updated recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2020; 34:3–78.
Rubio JM, et al. Early non-response to antipsychotic treatment in schizophrenia: a systematic review and meta-analysis of evidence-based management options. CNS Drugs 2023; 37:499–512.
Ezewuzie N, et al. Establishing a dose–response relationship for oral risperidone in relapsed schizophrenia. J Psychopharm 2006; 20:86–90.
Sparshatt A, et al. Quetiapine: dose–response relationship in schizophrenia. CNS Drugs 2008; 22:49–68.
Honer WG, et al. A randomized, double-blind, placebo-controlled study of the safety and tolerability of high-dose quetiapine in patients with persistent symptoms of schizophrenia or schizoaffective disorder. J Clin Psychiatry 2012; 73:13–20.
Davis JM, et al. Dose response and dose equivalence of antipsychotics. J Clin Psychopharmacol 2004; 24:192–208.
Leucht S, et al. Dose–response meta-analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry 2020; 177:342–353.
Srisurapanont M, et al. A network meta-analysis of the dose-response effects of lurasidone on acute schizophrenia. Sci Rep 2021; 11:5571.
Kinon BJ, et al. Standard and higher dose of olanzapine in patients with schizophrenia or schizoaffective disorder: a randomized, double- blind, fixed-dose study. J Clin Psychopharmacol 2008; 28:392–400.
Marder SR, et al. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994; 151:825–835.
Van Putten T, et al. A controlled dose comparison of haloperidol in newly admitted schizophrenic patients. Arch Gen Psychiatry 1990; 47:754–758.
Zimbroff DL, et al. Controlled, dose-response study of sertindole and haloperidol in the treatment of schizophrenia. Sertindole Study Group. Am J Psychiatry 1997; 154:782–791.
Siafis S, et al. Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose–response meta-analysis. Mol Psychiatry 2023; 28:3267–3277.
Kinon BJ, et al. Treatment of neuroleptic-resistant schizophrenic relapse. Psychopharmacol Bull 1993; 29:309–314.
Hermes E, et al. Predictors of antipsychotic dose changes in the CATIE schizophrenia trial. Psychiatry Res 2012; 199:1–7.
Loebel A, et al. Lurasidone dose escalation in early nonresponding patients with schizophrenia: a randomized, placebo-controlled study. J Clin Psychiatry 2016; 77:1672–1680.
Jukic MM, et al. Effect of CYP2D6 genotype on exposure and efficacy of risperidone and aripiprazole: a retrospective, cohort study. Lancet Psychiatry 2019; 6:418–426.
Taylor D, et al. Predicting clozapine dose required to achieve a therapeutic plasma concentration: a comparison of a population algorithm and three algorithms based on gene variant models. J Psychopharmacol 2023; 37:1030–1039.
Patel MX, et al. Quality of prescribing for schizophrenia: evidence from a national audit in England and Wales. Eur Neuropsychopharmacol 2014; 24:499–509.
Stokes I, et al. Prevalence of treatment resistance and clozapine use in early intervention services. BJPsych Open 2020; 6:e107.
Paton C, et al. Is clozapine really under-used? Investigating clinical practice in a community psychosis team. J Psychiatry Behav Sci 2023; 6:1089.
Heres S, et al. Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. Am J Psychiatry 2006; 163:185–194.
Obayashi Y, et al. Switching strategies for antipsychotic monotherapy in schizophrenia: a multi-center cohort study of aripiprazole. Psychopharmacology (Berl) 2020; 237:167–175.
Lambert TJ. Switching antipsychotic therapy: what to expect and clinical strategies for improving therapeutic outcomes. J Clin Psychiatry 2007; 68 Suppl 6:10–13.
Takeuchi H, et al. Immediate vs gradual discontinuation in antipsychotic switching: a systematic review and meta-analysis. Schizophr Bull 2017; 43:862–871.
Stroup TS, et al. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry 2006; 163:611–622.
Leucht S, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373:31–41.
Leucht S, et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry 2009; 166:152–163.
Hong J, et al. Clinical consequences of switching from olanzapine to risperidone and vice versa in outpatients with schizophrenia: 36-month results from the Worldwide Schizophrenia Outpatients Health Outcomes (W-SOHO) study. BMC Psychiatry 2012; 12:218.
Agid O, et al. Antipsychotic response in first-episode schizophrenia: efficacy of high doses and switching. Eur Neuropsychopharmacol 2013; 23:1017–1022.
Gannon L, et al. High-dose olanzapine in treatment-resistant schizophrenia: a systematic review. Ther Adv Psychopharmacol 2023; 13:20451253231168788.
Dong S, et al. A network meta-analysis of efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia. Eur Arch Psychiatry Clin Neurosci 2023; 274:917–928.
Stroup TS, et al. A randomized trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk: comparison of antipsychotics for metabolic problems (CAMP). Am J Psychiatry 2011; 168:947–956.
Montastruc F, et al. Association of aripiprazole with the risk for psychiatric hospitalization, self-harm, or suicide. JAMA Psychiatry 2019; 76:409–417.

Schizophrenia and related psychoses CHAPTER 1 36. Pae CU, et al. Effectiveness and tolerability of switching to aripiprazole once monthly from antipsychotic polypharmacy and/or other long acting injectable antipsychotics for patients with schizophrenia in routine practice: a retrospective, observation study. Clin Psychopharmacol Neurosc 2020; 18:153–158. 37. Prescribing Observatory for Mental Health. Topic 1h & 3e: Prescribing of antipsychotic medication in adult mental health services, including high dose, combined, and PRN. CCQI 422. 2022 (last accessed February 2025); https://www.rcpsych.ac.uk/improving-care/ccqi/national- clinical-audits/pomh. 38. Wagner E, et al. Clozapine combination and augmentation strategies in patients with schizophrenia - recommendations from an international expert survey among the Treatment Response and Resistance in Psychosis (TRRIP) working group. Schizophr Bull 2020; 46:1459–1470. 39. Taylor DM, et al. Augmentation of clozapine with a second antipsychotic: a meta-analysis of randomized, placebo-controlled studies. Acta Psychiatr Scand 2009; 119:419–425. 40. Grover S, et al. Augmentation strategies for clozapine resistance: a systematic review and meta-analysis. Acta Neuropsychiatr 2023; 35:65–75. 41. Kapur S, et al. Increased dopamine D2 receptor occupancy and elevated prolactin level associated with addition of haloperidol to clozapine. Am J Psychiatry 2001; 158:311–314. 42. Galling B, et al. Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis. World Psychiatry 2017; 16:77–89. 43. Gallego JA, et al. Safety and tolerability of antipsychotic polypharmacy. Expert Opin Drug Saf 2012; 11:527–542. 44. Barnes T, et al. Antipsychotic polypharmacy in schizophrenia: benefits and risks. CNS Drugs 2011; 25:383–399. 45. Taipale H, et al. Safety of antipsychotic polypharmacy versus monotherapy in a nationwide cohort of 61,889 patients with schizophrenia. Am J Psychiatry 2023; 180:377–385. 46. Borlido C, et al. Switching from 2 antipsychotics to 1 antipsychotic in schizophrenia: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2016; 77:e14–e20. 47. Hori H, et al. Switching to antipsychotic monotherapy can improve attention and processing speed, and social activity in chronic schizophrenia patients. J Psychiatr Res 2013; 47:1843–1848. 48. Essock SM, et al. Effectiveness of switching from antipsychotic polypharmacy to monotherapy. Am J Psychiatry 2011; 168:702–708. 49. Constantine RJ, et al. The risks and benefits of switching patients with schizophrenia or schizoaffective disorder from two to one antipsychotic medication: a randomized controlled trial. Schizophr Res 2015; 166:194–200. 50. Royal College of Psychiatrists. The Risks and Benefits of High-Dose Antipsychotic Medication. College Report CR190. London: Royal College of Psychiatrists; 2014.

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63 - Acutely disturbed or violent behaviour

Acutely disturbed or violent behaviour

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64 - Oralinhaled treatment

Oral/inhaled treatment

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65 - Parenteral treatment

Parenteral treatment

62 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Acutely disturbed or violent behaviour Acute behavioural disturbance can occur in the context of psychiatric illness, physical illness, substance abuse or personality disorder. Psychotic symptoms are common and the patient may be aggressive towards others secondary to persecutory delusions or auditory, visual or tactile hallucinations. This section deals with behavioural disturbance in the context of severe mental illness. Agitated states caused by illicit substance misuse are dealt with in Chapter 9. The clinical practice of rapid tranquillisation is used when appropriate psychological and behavioural approaches have failed to de-escalate acutely disturbed behaviour. It is, essentially, a treatment of last resort. Patients who require rapid tranquillisation (RT) are often too disturbed to give informed consent and therefore participate in RCTs but, with the use of a number of creative methodologies, the evidence base with respect to the efficacy and tolerability of pharmacological strategies has grown substantially. A comprehensive and up-to-date consensus guideline was published in 20181 and, more recently, a systematic review and meta-analysis.2 A network meta-analysis of RT in the emergency department has also been published.3 Oral/inhaled treatment Several studies supporting the efficacy of oral SGAs have been conducted.4–7 The level of behavioural disturbance exhibited by the patients in these studies was moderate at most, and all participants accepted oral treatment (this degree of compliance would be unusual in clinical practice). Patients recruited to these studies received the SGA as antipsychotic monotherapy. The efficacy and safety of adding a second antipsychotic as a ‘when necessary’ treatment have not been explicitly tested in formal RCTs. A single-dose RCT showed sublingual asenapine to be more effective than placebo for acute agitation.8 The efficacy of inhaled loxapine in behavioural disturbance that is moderate in severity is also supported by RCTs.9–11 The use of this preparation is now restricted in many countries owing to the risk of bronchospasm. Dexmedetomidine, an α2 receptor agonist used in anaesthesia, has been developed as a sublingual film. It seems to be rapidly effective in acute agitation.12 Parenteral treatment Large, placebo-controlled RCTs support the efficacy of IM preparations of olanzapine, ziprasidone and aripiprazole. When considered together, these trials suggested that IM olanzapine is more effective than IM haloperidol, which in turn is more effective than IM aripiprazole, which itself is more effective than ziprasidone.2,13,14 The level of behavioural disturbance in these studies was moderate at most and differences between treatments small. A large observational study supported the efficacy and tolerability of IM olanzapine in clinical emergencies (where disturbance was severe).15 A study comparing IM haloperidol with a combination of IM midazolam and IM haloperidol found the combination more effective than haloperidol alone for controlling agitation in palliative care patients.16

Schizophrenia and related psychoses CHAPTER 1 Several RCTs have investigated the effectiveness of parenteral medication in ‘real-life’ acutely disturbed patients. Overall: ■ ■Compared with IV midazolam alone, a combination of IV olanzapine or IV droperidol with IV midazolam was more rapidly effective and resulted in fewer subsequent doses of medication being required.17 ■ ■IM midazolam 7.5–15mg was more rapidly sedating than a combination of haloperidol 5–10mg and promethazine 50mg (TREC 1).18 ■ ■Olanzapine 10mg was as effective as a combination of haloperidol 10mg and promethazine 25–50mg in the short term, but the effect did not last as long (TREC 4).19 ■ ■A combination of haloperidol 5–10mg and promethazine 50mg was more effective and better tolerated than haloperidol 5–10mg alone; 6% of patients had an acute dystonic reaction (TREC 3).20 ■ ■A combination of haloperidol 10mg and promethazine 25–50mg was more effective than lorazepam 4mg (TREC 2).21 ■ ■A combination of IM chlorpromazine 100mg, haloperidol 5mg and promethazine 25mg was no better than IM haloperidol 5mg plus promethazine 25mg (TREC Lebanon).22 ■ ■A combination of IV midazolam and IV droperidol was more rapidly sedating than either IV droperidol or IV olanzapine alone. Fewer patients in the midazolam– droperidol group required additional medication doses to achieve sedation.23 ■ ■IM olanzapine was more effective than IM aripiprazole in the treatment of agitation in schizophrenia in the short-term (at 2 hours) but there was no significant difference between treatments at 24 hours.24 ■ ■IM midazolam 5mg was faster acting and more effective than olanzapine 10mg, ziprasidone 20mg and both 5 and 10mg haloperidol in a large (n = 737) emergency room study.25 ■ ■In an open-label study, the combination of IM haloperidol and IM lorazepam was found to be similar in efficacy to IM olanzapine.26 ■ ■IM droperidol and IM haloperidol were equally effective.27 ■ ■IM droperidol with IM midazolam was more effective than IM haloperidol with IM lorazepam.28 Nearly 10 years ago, Cochrane concluded that haloperidol alone is effective in the management of acute behavioural disturbance but poorly tolerated, and that co- administration of promethazine (but not lorazepam) improves tolerability.29,30 However NICE considers the evidence relating to the use of promethazine for this purpose to be inconclusive.31 The authors also stated that ‘haloperidol used on its own without something to offset its frequent and serious adverse effects is difficult to justify’.32 A systematic review and meta-analysis of IM olanzapine for agitation found IM olanzapine and IM haloperidol to be equally effective, but IM olanzapine was associated with a lower incidence of EPSEs.33 Cochrane suggests that droperidol is effective and may be used to control disturbed and aggressive behaviours caused by psychosis.34 Droperidol has seen a resurgence in use in some countries having become available again (its initial withdrawal was voluntary, so reintroduction is not prohibited).

64 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 In a meta-analysis that examined the tolerability of IM antipsychotics when used for the treatment of agitation, the incidence of acute dystonia with haloperidol was reported to be 5%, with SGAs performing considerably better.35 Acute EPSEs may adversely affect longer-term compliance.36 In addition, the formal prescribing information in most countries for haloperidol calls for a pretreatment ECG37,38 and recommends that concomitant antipsychotics are not prescribed. The mean increase in QTc after 10mg IM haloperidol can be up to 15ms but the range is wide.39 Promethazine may inhibit the metabolism of haloperidol;40 a pharmacokinetic interaction that is potentially clinically significant given the potential of haloperidol to prolong QTc. While this is unlikely to be problematic if a single dose is administered, repeat dosing may confer risk. Droperidol is also associated with QT changes (the reason for its withdrawal). In an observational study set in hospital emergency departments, of the 1,009 patients administered parenteral droperidol, only 13 patients (1.28%) had an abnormal QT after dose administration. In seven of these cases, another contributory factor was identified. There were no cases of torsades de pointes (TdP).27 In all RT studies of IM droperidol, the overall rate of QTc measurements greater than 500ms was less than 2%.2 Intravenous treatment is now rarely used in RT but where benefits are thought to outweigh risks it may be considered as a last resort. A small study comparing highdose IV haloperidol with IV diazepam found both drugs to be effective at 24 hours.41 Two large observational studies have examined the safety of IV olanzapine when used in the emergency department. The indications for its use varied, agitation being the most common. In one study,42 in the group treated for agitation (n = 265), over a third of patients required an additional sedative dose after the initial IV olanzapine dose. Hypoxia was reported in 17.7% of patients and supplemental oxygen was used in 20.4%. Six patients required intubation (two of these because of olanzapine treatment). In the other study,43 IV olanzapine (n = 295) was compared with IM olanzapine (n = 489). Additional doses were not required for 81% of patients in the IV group and 84% of patients in the IM group. Respiratory depression was more commonly observed in the group receiving IV olanzapine. Five patients in the IM group and two in the IV group required intubation. In an acute psychiatric setting, ‘high-dose sedation’ (defined as a dose of more than 10mg of haloperidol, droperidol or midazolam) was not more effective than lower doses but was associated with more adverse effects (hypotension and oxygen desaturation).44 Consistent with this, a small RCT supports the efficacy of low-dose haloperidol, although both efficacy and tolerability were superior when midazolam was co-prescribed.45 These data broadly support the use of standard doses in clinical emergencies but the need for further physical restraint after lower doses needs to be considered. A small observational study supported the effectiveness of buccal midazolam in a PICU setting.46 Parenteral administration of midazolam, particularly in higher doses, may cause over-sedation accompanied by respiratory depression.47 Lorazepam IM is an established treatment and TREC 221 supports its efficacy, although combining all results from the TREC studies suggests that midazolam 7.5–15mg is probably more effective. More recent studies have used 5mg IM midazolam and found it to be rapidly effective.28,48 A Cochrane review of benzodiazepines for psychosis-induced aggression and agitation concluded that most trials were too small to highlight differences in either

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66 - Practical measures

Practical measures

Schizophrenia and related psychoses CHAPTER 1 positive or negative effects and while adding a benzodiazepine to another drug may not be clearly advantageous it may lead to unnecessary adverse effects.49 With respect to those who are behaviourally disturbed secondary to acute intoxication with alcohol or illicit drugs, there are fewer data to guide practice. A large observational study of IV sedation in patients intoxicated with alcohol found that combination treatment (most commonly haloperidol 5mg and lorazepam 2mg) was more effective and reduced the need for subsequent sedation than either drug given alone.50 A case series (n = 59) of patients who received modest doses of oral, IM or IV haloperidol to manage behavioural disturbance in the context of phencyclidine consumption showed that haloperidol was effective and well tolerated (one case each of mild hypotension and mild hypoxia).51 A section on the treatment of behavioural disturbance caused by substance misuse is included in Chapter 9. Ketamine is widely used for agitation in hospital emergency departments. In a systematic review of 18 studies of ketamine,52 a mean dose of 315mg IM ketamine achieved adequate sedation in an average of 7.2 minutes. Over 30% of 650 patients were eventually intubated and more than 1% experienced laryngospasm. Ketamine is not suitable for RT where facilities for intubation are not available, although it may be the most effective treatment.3 Overall, the current broad consensus is that midazolam and droperidol are the fastest-acting single-drug, intramuscular treatments53 and that haloperidol alone should be avoided and perhaps abandoned completely even in combination.54 Second-line treatments are combinations of benzodiazepines and antipsychotics and third line would probably be intravenous benzodiazepines and then ketamine (2–5mg/kg IM), assuming intubation facilities are available. Practical measures Plans for the management of individual patients should ideally be made in advance. The aim is to prevent disturbed behaviour and reduce risk of violence. Nursing interventions (de-escalation, time out, seclusion),55 increased nursing levels, transfer of the patient to a psychiatric intensive care unit and pharmacological management are options that may be employed. Care should be taken to avoid combinations and high cumulative doses of antipsychotic drugs. The monitoring of routine physical observations after RT is essential. RT is often, of course, viewed as punitive by patients. There is little research into the patient experience of RT. The aims of RT are threefold: ■ ■To reduce suffering for the patient: psychological or physical (through self-harm or accidents). ■ ■To reduce risk of harm to others by maintaining a safe environment. ■ ■To do no harm (by prescribing safe regimens and monitoring physical health). Note: Despite the need for rapid and effective treatment, concomitant use of two or more antipsychotics (antipsychotic polypharmacy) should be avoided on the basis of risk associated with QT prolongation (common to almost all antipsychotics). This is a particularly important consideration in RT, where the patient’s physical state predisposes to cardiac arrhythmia.

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67 - Zuclopenthixol acetate

Zuclopenthixol acetate

66 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Zuclopenthixol acetate Zuclopenthixol acetate (ZA) is widely used in the UK and elsewhere in Europe, and is best known by its trade name Acuphase®. Zuclopenthixol itself is a thioxanthene dopamine antagonist first introduced in the early 1960s. ZA is not a rapidly tranquillising agent. Its elimination half-life is around 20 hours. IM injection of zuclopenthixol base results in rapid absorption and a duration of action of 12–24 hours. By slowing absorption after IM injection, the biological half-life (and so duration of action) becomes dependent on the rate of release from the IM reservoir. This can be achieved by esterification of the zuclopenthixol molecule, the rate of release being broadly proportional to the length of the ester carbon chain. Thus, zuclopenthixol decanoate is slow to act but very long-acting as a result of retarded release after IM injection. ZA (with eight carbon atoms fewer) would be expected to provide relatively prompt release but with an intermediate duration of action. The intention of the manufacturers was that the use of ZA would obviate the need for repeated IM injections in disturbed patients. An initial pharmacokinetic study of ZA included 19 patients ‘in whom calming effect by parenteral neuroleptic was considered necessary’.56 Zuclopenthixol was detectable in the plasma after 1–2 hours but did not reach peak concentrations until around 36 hours after dosing. At 72 hours, plasma levels were around one-third of those at 36 hours. The clinical effect of ZA was not rapid – 10 of 17 patients exhibited minimal or no change in psychotic symptoms at 4 hours. Sedation was evident at 4 hours but it had effectively abated by 72 hours. A follow-up study by the same research group57 examined more closely the clinical effects of ZA in 83 patients. The authors concluded that ZA produced ‘pronounced and rapid reduction in psychotic symptoms’. In fact, psychotic symptoms were first assessed only after 24 hours and so a claim of rapid effect is not reasonably supported. Sedative effects were measured after 2 hours when a statistically significant effect was observed – at baseline mean sedation score was 0.0 (0 = no sign of sedation) and at 2 hours 0.6 (1 = slightly sedated). Maximum sedation was observed at 8 hours (mean score 2.2; 2 = moderately sedated). At 72 hours mean score was 1.1. Dystonia and rigidity were the most commonly reported adverse effects. Two independently conducted open studies produced similar results – a slow onset of effect peaking at 24 hours and still being evident at 72 hours.58,59 The first UK study was reported in 1990.60 In the trial, a significant reduction in psychosis score was first evident at 8 hours and scores continued to fall until the last measurement at 72 hours. Of 25 patients assessed only 4 showed signs of tranquillisation at 1 hour (19 at 2 hours and 22 at 24 hours). A comparative trial of ZA61 examined its effects and those of IM/oral haloperidol and IM/oral zuclopenthixol base (in multiple doses over 6 days). The two non-ester, IM/ oral preparations produced a greater degree of sedation at 2 hours than did ZA but the effect of ZA and zuclopenthixol was more sustained than with haloperidol over 144 hours (although patients received more zuclopenthixol doses). No clear differences between treatments were detected, with the exception of the slow onset of effect of ZA. The number of doses given varied substantially: ZA 1–4; haloperidol 1–26; and zuclopenthixol 1–22. This is the key (and perhaps unique) advantage of ZA – it reduces the need for repeat doses in acute psychosis. Indeed, this was the principal finding of the first double-blind study of ZA.62 Participants were given either ZA or haloperidol IM

Schizophrenia and related psychoses CHAPTER 1 and assessed over 3 days. Changes in Brief Psychiatric Rating Scale and Clinical Global Impression scores were near identical on each daily assessment. However, only 1 of 23 patients taking ZA required a second injection, whereas 7 of 21 required a repeat dose of haloperidol. Speed of onset was not examined. Similar findings were reported by Thai researchers comparing the same treatments63 and in three other studies of moderate size (n = 44,64 n = 40,65 n = 5066). In each study, the timing of assessments was such that time to onset of effect could not be determined. Overall, the utility of ZA in rapid tranquillisation is limited by a somewhat delayed onset of both sedative and antipsychotic actions. Sedation may be apparent in a minority of patients after 2–4 hours, but antipsychotic action is evident only after 8 hours. If ZA is given to a restrained patient, their behaviour on release from restraint is likely to be unchanged and will remain as such for several hours. ZA has a role in reducing the number of restraints for IM injection but it has no role in rapid tranquillisation. Guidelines for the use of zuclopenthixol acetate (Acuphase) ■ ■ZA is not a rapidly tranquillising agent. It should be used only after an acutely psychotic patient has required (or is likely to require) repeated injections of short-acting antipsychotic drugs such as haloperidol or olanzapine, or sedative drugs such as lorazepam. It is perhaps best reserved for those few patients who have a prior history of good response to Acuphase. ■ ■ZA should be given only when enough time has elapsed to assess the full response to previously injected drugs: allow 15 minutes after IV injections; 60 minutes after IM. ■ ■ZA should never be administered for rapid tranquillisation (the onset of effect is too slow) or to a patient who is physically resistant (risk of intravasation and oil embolus) or to neuroleptic-naïve patients (risk of prolonged EPSEs).

68 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Rapid tranquillisation summary In an emergency situation: Assess whether there may be a medical cause.67 Optimise regular prescription. The aim of pharmacological treatment is to calm the patient but not to over-sedate. Note that lower doses should be used for children, adolescents and older adults. Patients’ levels of consciousness and physical health should be monitored after administration of parenteral medication (see protocol). Step intervention 1 De-escalation, time out, placement, etc., as appropriate 2 Offer oral treatment If patient is prescribed a regular antipsychotic: Lorazepam 1–2mg Promethazine 25–50mg Monotherapy with buccal midazolam may avoid the need for IM treatment Dose: 10mg Note that this preparation is unlicensed If patient is not already taking a regular oral or LAI antipsychotic: ■ ■Olanzapine 10mg or ■ ■Risperidone 1–2mg or ■ ■Quetiapine 50–100mg or ■ ■Haloperidol 5mg (with promethazine 25mg). ECG is required in UK/EU Repeat after 45–60 minutes, if necessary. Consider combining sedative and antipsychotic treatment. Go to step 3 if two doses fail or sooner if the patient is placing themselves or others at significant risk. 3 Consider IM treatment Lorazepam 2mgab Have flumazenil to hand in case of benzodiazepine-induced respiratory depression Promethazine 50mg IM promethazine is a useful option in a benzodiazepine-tolerant patient Olanzapine 10mgd IM olanzapine should not be combined with an IM benzodiazepine, particularly if alcohol has been consumed68 Aripiprazole 9.75mg Less hypotension than olanzapine, but less effective6,13,69 Haloperidol 5mg Haloperidol should be the last drug considered. The incidence of acute dystonia is high; combine with IM promethazine and ensure IM procyclidine is available. Pretreatment ECG required Repeat after 30–60 minutes if insufficient effect. Combinations of haloperidol and lorazepam or haloperidol and promethazine may be considered if single drug treatment fails. Drugs must not be mixed in the same syringe. IM olanzapine must never be combined with IM benzodiazepine. 4 Consider IV treatment Diazepam 10mg over at least 2 minutesbe Repeat after 5–10 minutes if insufficient effect (up to 3 times) Have flumazenil to hand 5 Seek expert advicef Consider transfer to medical unit for administration of IM ketamine Notes a. Carefully check administration and dilution instructions, which differ between manufacturers. Many centres use 4mg. An alternative is IM midazolam 5–15mg. 5mg is usually sufficient. The risk of respiratory depression is dose-related with both drugs but generally greater with midazolam. b. Caution in the very young and elderly and those with pre-existing brain damage or impulse control problems, as disinhibition reactions are more likely.70 (Continued)

Schizophrenia and related psychoses CHAPTER 1 Rapid tranquillisation summary (Continued) c. Promethazine has a slow onset of action but is often an effective sedative. Dilution is not required before IM injection. May be repeated up to a maximum of 100mg/day. Wait 1–2 hours after injection to assess response. Note that promethazine alone has been reported, albeit very rarely, to cause NMS,71 although it is an extremely weak dopamine antagonist. Note also the potential pharmacokinetic interaction between promethazine and haloperidol (reduced metabolism of haloperidol) which may confer risk if repeated doses of both are administered. d. Recommended by NICE only for moderate behavioural disturbance, but data from a large observational study also support efficacy in clinical emergencies. e. Use diazepam to avoid injection site reactions. Lorazepam can also be given IV. IV therapy may be used instead of IM when a very rapid effect is required. IV therapy also ensures near immediate delivery of the drug to its site of action and effectively avoids the danger of inadvertent accumulation of slowly absorbed IM doses. IV doses can be repeated after only 5–10 minutes if no effect is observed. Midazolam can also be used IV but respiratory depression is common.1 f. Options at this point are limited, although the wider use of IM ketamine has improved the range of options available. IM amylobarbitone and IM paraldehyde have been used in the past but are used now only extremely rarely and are generally not easy to obtain. IV olanzapine, IV droperidol and IV haloperidol are possible but adverse effects are fairly common. ECT is also an option. Rapid tranquillisation – physical monitoring After any parenteral drug administration, monitor as follows: ■ ■Temperature ■ ■Pulse ■ ■Blood pressure ■ ■Respiratory rate Every 15 minutes for 1 hour and then hourly until the patient is ambulatory. Patients who refuse to have their vital signs monitored or who remain too behaviourally disturbed to be approached should be observed for signs/symptoms of pyrexia, hypoxia, hypotension, over-sedation and general physical well-being. All patients should be continuously observed (‘in sight’) for at least 1 hour and until clearly ambulatory. If the patient is asleep or unconscious, the continuous use of pulse oximetry to measure oxygen saturation is desirable. A nurse should remain with the patient until ambulatory. ECG and haematological monitoring are also strongly recommended when parenteral antipsychotics are given, especially when higher doses are used.72,73 Hypokalaemia, stress and agitation place the patient at risk of cardiac arrhythmia74 (see section on ‘QT prolongation’). ECG monitoring is formally recommended for all patients who receive haloperidol.

70 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Remedial measures in rapid tranquillisation Problem Remedial measures Acute dystonia (including oculogyric crises) Give procyclidine 5–10mg IM or IV Reduced respiratory rate (<10/minute) or oxygen saturation (<90%) Give oxygen, raise legs, ensure patient is not lying face down Give flumazenil if benzodiazepine-induced respiratory depression suspected (see protocol) If induced by any other sedative agent: transfer to a medical bed and ventilate mechanically Irregular or slow (<50/minute) pulse Refer to specialist medical care immediately Fall in blood pressure (>30mmHg orthostatic drop or <50mmHg diastolic) Have patient lie flat, tilt bed towards head Monitor closely Increased temperature Risk of NMS and perhaps arrhythmia; check creatine kinase urgently Guidelines for the use of flumazenil Indication for use If, after the administration of lorazepam, midazolam or diazepam, respiratory rate falls below 10/minute Contraindications Patients with epilepsy who have been receiving long-term benzodiazepines Caution Dose should be carefully titrated in hepatic impairment Dose and route of administration Initial: 200mcg intravenously over 15 seconds if required level of consciousness not achieved after 60 seconds, then Subsequent dose: 100mcg over 15 seconds Time before dose can be repeated 60 seconds Maximum dose 1mg in 24 hours (one initial dose and eight subsequent doses) Adverse effects75 Patients may become agitated, anxious or fearful on awakening. Seizures may occur in regular benzodiazepine users. Cardiac arrhythmia (supraventricular tachycardia) Management Adverse effects usually subside Monitoring: ■ ■What to monitor? Respiratory rate ■ ■How often? Continuously until respiratory rate returns to baseline level Flumazenil has a short half-life (much shorter than diazepam) and respiratory function may recover and then deteriorate again Note: If respiratory rate does not return to normal or patient is not alert after initial doses given, assume that sedation is from some other cause

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68 - References

References

Schizophrenia and related psychoses CHAPTER 1 References

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Schizophrenia and related psychoses CHAPTER 1 66. Al-Haddad MK, et al. Zuclopenthixol versus haloperidol in the initial treatment of schizophrenic psychoses, affective psychoses and paranoid states: a controlled clinical trial. Arab J Psychiatry 1996; 7:44–54. 67. Garriga M, et al. Assessment and management of agitation in psychiatry: expert consensus. World J Biol Psychiatry 2016; 17:86–128. 68. Wilson MP, et al. Potential complications of combining intramuscular olanzapine with benzodiazepines in emergency department patients. J Emerg Med 2012; 43:889–896. 69. Villari V, et al. Oral risperidone, olanzapine and quetiapine versus haloperidol in psychotic agitation. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:405–413. 70. Paton C. Benzodiazepines and disinhibition: a review. Psychiatr Bull 2002; 26:460–462. 71. Chan-Tack KM. Neuroleptic malignant syndrome due to promethazine. South Med J 1999; 92:1017–1018. 72. Appleby L, et al. Sudden unexplained death in psychiatric in-patients. Br J Psychiatry 2000; 176:405–406. 73. Yap YG, et al. Risk of torsades de pointes with non-cardiac drugs. Doctors need to be aware that many drugs can cause QT prolongation. BMJ 2000; 320:1158–1159. 74. Taylor DM. Antipsychotics and QT prolongation. Acta Psychiatr Scand 2003; 107:85–95. 75. Penninga EI, et al. Adverse events associated with flumazenil treatment for the management of suspected benzodiazepine intoxication: a systematic review with meta-analyses of randomised trials. Basic Clin Pharmacol Toxicol 2016; 118:37–44.

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69 - Antipsychotic depotslong acting injections

Antipsychotic depots/long-acting injections

74 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Antipsychotic depots/long-acting injections Long-acting injectable preparations of antipsychotic medication are commonly prescribed in clinical practice, especially in the UK, Australasia and the EU. Real-world, observational studies of patients with schizophrenia have confirmed that continued treatment with such medication is associated with fewer relapses and readmissions to hospital compared with oral antipsychotic treatment,1–5 although there are confounding factors in such studies, such as indication bias. A 2020 Cochrane systematic review of RCTs comparing antipsychotic maintenance treatment with placebo for people with schizophrenia found that LAI antipsychotic medications (in particular, LAI haloperidol and LAI fluphenazine) were more effective than oral antipsychotic medications.6 However, the authors noted that only head-to- head comparisons of LAI and oral antipsychotic medications can determine whether the former are more effective. The findings of such RCTs have generally failed to show the superiority of LAI antipsychotic medications that is apparent in real-world studies,7–9 and it has been postulated that this is partly related to study design and methodology issues.2 Specifically, double-blind RCTs are generally relatively short term and the study samples will tend to be biased towards patients with rather less severe illness, fewer comorbid conditions and better adherence to medication.10,11 Nevertheless, a 2021 systematic review and meta-analysis of RCTs, observational cohort studies and pre–post (mirror-image) studies comparing LAIs with oral antipsychotic medications found that LAIs were associated with a lower risk of hospitalisation or relapse, across all the study designs.12 There are also hints from meta-analyses of relevant RCTs that some adverse effects are less frequent with LAIs than with their oral counterparts.8,13 While it is generally accepted that treatment with LAI antipsychotic medication reduces the risk of relapse, the findings of studies of all designs suggest that treatment with LAIs does not confer complete protection against relapse.14 In clinical practice, relapse is strongly linked to delayed or missed doses of LAIs. Two UK studies showed that patients receiving 10 doses a year (or fewer) of monthly paliperidone palmitate were at a substantially higher risk of relapse than those receiving 11 or 12 doses.15,16 Very long-acting injections given consistently on time may offer better protection against relapse.17–19 LAI antipsychotic medication is recommended for all patients, but especially where a patient has expressed a preference for such a formulation because of its convenience or where avoidance of covert non-adherence is considered a clinical priority.10,20,21 While LAI medication does not ensure adherence, it does ensure clinical awareness of adherence, unlike the use of oral medication. Thus, failure to adhere, which may be a sign of relapse or a potential cause, will be signalled by delayed attendance for, or refusal of, an injection, allowing the clinical team to intervene promptly. Another advantage for LAI antipsychotic medication is that its use may help clarify whether an unsatisfactory therapeutic response to antipsychotic medication is because of adherence problems or treatment resistance. Patients with an apparently refractory illness may simply be non-adherent to their oral medication, sometimes completely so.22 Further, an LAI antipsychotic regimen provides the opportunity for regular scrutiny of a patient’s mental state and adverse effects.23 The proportion of patients with schizophrenia prescribed LAI antipsychotic medications varies between and across countries, suggesting that the use of such medication is influenced by factors beyond the extent of poor adherence. Greater

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Advice on prescribing LAIs

Schizophrenia and related psychoses CHAPTER 1 understanding of these factors might allow for possible barriers to the optimal implementation of this treatment to be identified.24–26 A study in the USA found that patients with first-episode schizophrenia were largely willing to accept long-acting treatment.27 This suggests that the relatively low usage of LAIs in the USA might be partly a result of reluctance on the part of clinicians, rather than resistance from patients.28,29 Advice on prescribing LAIs ■ ■Test doses Because of its long half-life, any adverse effects that result from the administration of LAI antipsychotic medication are likely to be long lived. Therefore, such treatment should be avoided in patients with a history of serious adverse effects that would warrant immediate discontinuation of the medication, such as neuroleptic malignant syndrome (NMS). For LAI FGAs, a test dose, consisting of a small dose of active drug in a small volume of oil, serves a dual purpose: it is a test of the patient’s sensitivity to EPS and of any sensitivity to the base oil. For LAI SGAs, test doses may not be required (there is a lower propensity to cause EPS and the aqueous base is not known to be allergenic), although they could be considered appropriate where a patient is suspected of being non-adherent to oral antipsychotic medication and the LAI preparation will be the first exposure to guaranteed antipsychotic medication delivery. For both LAI FGAs and SGAs, prior treatment with the equivalent oral formulation, establishing the optimally effective and tolerated dose, is advised,30 but may not be necessary from a pharmacokinetic viewpoint. Most LAI SGAs can be used as sole treatment from the outset, although loading doses are usually necessary (e.g. for paliperidone and aripiprazole). ■ ■Begin with the lowest therapeutic dose For LAI FGA medications, there is limited evidence for a clear dose–response effect and a near absence of data on optimal dosing. However, low doses (within the licensed range) may be at least as effective as higher ones.31–34 For the LAI antipsychotic medications that are commonly used, it remains uncertain that the dosages and frequency of injections achieve the optimal benefit–risk balance.35–37 ■ ■Administer at the longest possible licensed interval All LAI antipsychotic medications can be safely administered at their licensed dosing intervals, bearing in mind the maximum recommended single dose. There is no evidence to suggest that shortening the dose interval improves efficacy. Moreover, less frequent administration may be desirable, as the IM injection site can be a cause of discomfort and pain; these reactions may be more common with LAIs that have oil- based formulations.38,39 Although there are reports of illness deterioration in some patients in the days before their next injection is due, plasma drug concentrations may continue to fall for some hours (or even days with some preparations) after each injection. In this context, a patient’s apparent recovery soon after the injection makes little sense. More importantly, at steady state, trough plasma levels (immediately before and after the dose) are usually substantially above the threshold concentration required for therapeutic effect.30,40,41

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Differences between LAIs

76 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 ■ ■Adjust doses only after an adequate period of assessment Attainment of peak plasma levels, therapeutic effect and steady-state plasma levels are all delayed with LAI antipsychotic medications, compared with oral antipsychotics. Doses may be reduced if adverse effects occur but should only be increased after careful assessment over at least 1 month, and preferably longer. Note that with most LAI antipsychotic preparations, at the start of treatment, plasma drug levels increase over several weeks to months without any increase in the dosage. This is due to accumulation: steady state is only achieved after at least 6–8 weeks. Dose increases during this initial period are therefore illogical and impossible to evaluate properly. With continued LAI antipsychotic treatment, the monitoring and recording of therapeutic efficacy, adverse effects and any impact on physical health are recommended, although in clinical practice there seems to be a relatively low frequency of assessment of adverse effects.42 Table 1.8 gives doses and frequencies for LAI antipsychotic medications for adults. ■ ■Adding an oral antipsychotic medication risks a high-dose prescription The regular prescription of an oral antipsychotic medication in addition to an LAI antipsychotic preparation was once common with LAI FGAs.22,43 While this may be a possible strategy for the control of breakthrough symptoms and may offer greater flexibility in dosage titration, the safety and tolerability of such a combination are uncertain, particularly over the longer term.44 The co-prescription of an LAI and oral antipsychotic medication may well result in a possibly inadvertent high-dose prescription, with an increased adverse effect burden and implications for physical health monitoring.10,23 Differences between LAIs A 2021 network meta-analysis of 86 RCTs45 comparing LAIs with each other, with placebo or with oral antipsychotic medication concluded that the LAI formulations of paliperidone (3-month formulation), aripiprazole, olanzapine and paliperidone (1-month formulation) had the largest effect sizes and greater certainty of evidence for both relapse prevention and acceptability. The LAI SGAs, aripiprazole, paliperidone, risperidone and olanzapine, have generally been reported to have comparable efficacy, although they vary in their liability for particular adverse effects, such as weight gain, metabolic effects, EPS and raised plasma prolactin.46–49 For example, LAI paliperidone is associated with substantial increases in serum prolactin48 and LAI olanzapine can cause significant weight gain and is associated with a post- injection delirium/sedation syndrome, assumed to be caused by unintended partial intravascular injection or blood vessel injury.50,51 Details on dosing of individual SGAs are given elsewhere in this chapter.

Table 1.8 Long-acting injectable antipsychotic medications – doses and frequencies.* Drug UK trade name Licensed injection site Test dose (mg) Dose range (mg/day or week or month) Dosing interval (weeks) Comments Aripiprazole Abilify Maintena Buttock Not required** 300–400mg monthly Monthly Does not increase prolactin Aripiprazole Abilify Asimtufil Gluteal Not required** 720–960mg every 2 months Can be started after oral loading or as continuation of monthly injections Aripiprazole Aristada Initio Deltoid or gluteal Not required** 675mg Single dose, not for repeat dosing Given together with 30mg dose of oral aripiprazole. The first Aristata injection can be given on the same day or up to 10 days after Aristada Initio. Aripiprazole Aristada Deltoid† or gluteal Not required** 441mg, 662mg monthly, 882mg every 4–6 weeks and 1062mg every 2 months 4–8 Can be given with 30mg dose of oral aripiprazole and 675mg Aristada Initio or continue with oral aripiprazole for 21 consecutive days Flupentixol decanoate Depixol Buttock or thigh 50mg every 4 weeks to 400mg a week 2–4 Maximum licensed dose is high relative to other LAIs Fluphenazine decanoate Modecate Gluteal region 12.5 12.5mg every 2 weeks to 100mg every 2 weeks 2–5 High risk of EPS Haloperidol decanoate Haldol Gluteal region 25†† 50–300mg every 4 weeks High risk of EPS Olanzapine pamoate ZypAdhera Gluteal Not required** 150mg every 4 weeks to 300mg every 2 weeks 2–4 Risk of post-injection syndrome Paliperidone palmitate (monthly) Xeplion Deltoid or gluteal Not required** 50–150mg monthly Monthly Loading dose required at treatment initiation Paliperidone palmitate (3-monthly) Trevicta Deltoid or gluteal Not required‡ 175–525mg every 3 months 3 months Not suitable for acutely agitated patients Paliperidone palmitate (6-monthly) Byannli Gluteal region Not required§ 700–1000mg every 6 months 6 months Contraindicated in mild renal impairment (creatinine clearance ≥50 to ≤80 mL/minute) (Continued)

Table 1.8 (Continued) Drug UK trade name Licensed injection site Test dose (mg) Dose range (mg/day or week or month) Dosing interval (weeks) Comments Pipothiazine palmitate Piportil Gluteal region 50–200mg every 4 weeks Lower incidence of EPS (relative to other FGAs) Risperidone microspheres Risperidal Consta Deltoid or gluteal Not required** 25–50mg every 2 weeks Drug release delayed for 2–3 weeks – oral therapy required Risperidone Perseris Abdomen Not required** 90–120mg every month Given subcutaneously in the abdomen Risperidone Okedi Deltoid or gluteal Not required** 75–100mg every 28 days Loading dose not required at treatment initiation Zuclopenthixol decanoate Clopixol Buttock or thigh 200mg every 3 weeks to 600mg/week 2–4 High risk of EPS * Refer to manufacturer‘s official documentation for full details. ** Tolerability and response to the oral preparation should be established before administering the LAI. With respect to paliperidone LAI, oral risperidone can be used for this purpose. † Aripiprazole 441mg dose only. †† Test dose not stated by manufacturer. ‡ May not be started until the completion of 4 months’ treatment with monthly LAI. § For patients stabilised on 100mg or 150mg of monthly LAI for at least 4 months or for patients given at least one injection of 350mg or 525mg of 3-monthly LAI. EPS, extrapyramidal symptoms; FGA, first-generation antipsychotic; LAI, long-acting injection. Notes: The doses in this table are for adults. Check formal labelling for appropriate doses in the elderly. After a test dose, wait 4–10 days then titrate to maintenance dose according to response (see product information for individual drugs). Avoid using shorter dose intervals than those recommended except in exceptional circumstances (e.g. long interval necessitates high volume [>3–4 mL?] injection). Maximum licensed single dose overrides longer intervals and lower volumes. For example, zuclopenthixol 500mg every week is licensed whereas 1000mg every 2 weeks is not (more than the licensed maximum of 600mg is administered). Always check official manufacturer’s information.

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References

Schizophrenia and related psychoses CHAPTER 1 References

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Efthimiou O, et al. Efficacy and effectiveness of antipsychotics in schizophrenia: network meta-analyses combining evidence from randomised controlled trials and real-world data. Lancet Psychiatry 2024; 11:102–111.
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Wang D, et al. Efficacy, acceptability and side-effects of oral versus long-acting - injectables antipsychotics: systematic review and network meta-analysis. Eur Neuropsychopharmacol 2024; 83:11–18.
Rubio JM, et al. Psychosis relapse during treatment with long-acting injectable antipsychotics in individuals with schizophrenia-spectrum disorders: an individual participant data meta-analysis. Lancet Psychiatry 2020; 7:749–761.
Laing E, et al. Relapse and frequency of injection of monthly paliperidone palmitate—a retrospective case-control study. Eur Psychiatry 2021; 64:e11.
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Turkoz I, et al. Comparative effectiveness study of paliperidone palmitate 6-month with a real-world external comparator arm of paliperidone palmitate 1-month or 3-month in patients with schizophrenia. Ther Adv Psychopharmacol 2023; 13:20451253231200258.
Clark I, et al. Clinical outcomes with paliperidone palmitate 3-monthly injection as monotherapy: observational 3-year follow-up of patients with schizophrenia. Eur Psychiatry 2024; 67:e15.
Clark I, et al. Long term impact of 3-monthly paliperidone palmitate on hospitalisation in patients with schizophrenia: six-year mirror image study. Acta Psychiatr Scand 2024; 150:48–50.
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Boyer L, et al. Real-world effectiveness of long-acting injectable antipsychotic treatments in a nationwide cohort of 12,373 patients with schizophrenia-spectrum disorders. Mol Psychiatry 2023; 28:3709–3716.
McCutcheon R, et al. Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia. Acta Psychiatr Scand 2018; 137:39–46.
Barnes T, et al. Antipsychotic long acting injections: prescribing practice in the UK. Br J Psychiatry Suppl 2009; 52:S37–S42.
Brissos S, et al. The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal. Ther Adv Psychopharmacol 2014; 4:198–219.
Lambert P. Prescribing patterns and determinants of use of antipsychotic long-acting injections: an international perspective. In: Antipsychotic Long-Acting Injections, 2nd edn. Oxford: Oxford University Press; 2016:279–310.
Patel MX, et al. Attitudes of European physicians towards the use of long-acting injectable antipsychotics. BMC Psychiatry 2020; 20:123.
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Iyer S, et al. A qualitative study of experiences with and perceptions regarding long-acting injectable antipsychotics: part II-physician perspectives. Can J Psychiatry 2013; 58:23s–29s.
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Kane JM, et al. A multidose study of haloperidol decanoate in the maintenance treatment of schizophrenia. Am J Psychiatry 2002; 159:554–560.
Taylor D. Establishing a dose–response relationship for haloperidol decanoate. Psychiatr Bull 2005; 29:104–107.

80 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 33. McEvoy JP, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA 2014; 311:1978–1987. 34. Bailey L, et al. Estimating the optimal dose of flupentixol decanoate in the maintenance treatment of schizophrenia: a systematic review of the literature. Psychopharmacology (Berl) 2019; 236:3081–3092. 35. Uchida H, et al. Monthly administration of long-acting injectable risperidone and striatal dopamine D2 receptor occupancy for the management of schizophrenia. J Clin Psychiatry 2008; 69:1281–1286. 36. Ikai S, et al. Plasma levels and estimated dopamine D(2) receptor occupancy of long-acting injectable risperidone during maintenance treatment of schizophrenia: a 3-year follow-up study. Psychopharmacology (Berl) 2016; 233:4003–4010. 37. Hill AL, et al. Dose-associated changes in safety and efficacy parameters observed in a 24-week maintenance trial of olanzapine long-acting injection in patients with schizophrenia. BMC Psychiatry 2011; 11:28. 38. Jones JC, et al. Investigation of depot neuroleptic injection site reactions. Psychiatr Bull 1998; 22:605–607. 39. Zolezzi M, et al. Long-acting injectable antipsychotics: a systematic review of their non-systemic adverse effect profile. Neuropsychiatr Dis Treat 2021; 17:1917–1926. 40. Coppola D, et al. A one-year prospective study of the safety, tolerability and pharmacokinetics of the highest available dose of paliperidone palmitate in patients with schizophrenia. BMC Psychiatry 2012; 12:26. 41. Mallikaarjun S, et al. Pharmacokinetics, tolerability and safety of aripiprazole once-monthly in adult schizophrenia: an open-label, parallel- arm, multiple-dose study. Schizophr Res 2013; 150:281–288. 42. Paton C, et al. Side-effect monitoring of continuing LAI antipsychotic medication in UK adult mental health services. Ther Adv Psychopharmacol 2021; 11:2045125321991278. 43. Doshi JA, et al. Concurrent oral antipsychotic drug use among schizophrenia patients initiated on long-acting injectable antipsychotics post- hospital discharge. J Clin Psychopharmacol 2015; 35:442–446. 44. Correll CU, et al. Practical considerations for managing breakthrough psychosis and symptomatic worsening in patients with schizophrenia on long-acting injectable antipsychotics. CNS Spectr 2019; 24:354–370. 45. Ostuzzi G, et al. Maintenance treatment with long-acting injectable antipsychotics for people with nonaffective psychoses: a network meta- analysis. Am J Psychiatry 2021; 178:424–436. 46. Jann MW, et al. Long-acting injectable second-generation antipsychotics: an update and comparison between agents. CNS Drugs 2018; 32:241–257. 47. Correll CU, et al. The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry 2016; 77:1–24. 48. Nussbaum AM, et al. Paliperidone palmitate for schizophrenia. Cochrane Database Syst Rev 2012; (6):CD008296. 49. Sampson S, et al. Risperidone (depot) for schizophrenia. Cochrane Database Syst Rev 2016; 4:CD004161. 50. Citrome L. Olanzapine pamoate: a stick in time? Int J Clin Pract 2009; 63:140–150. 51. Luedecke D, et al. Post-injection delirium/sedation syndrome in patients treated with olanzapine pamoate: mechanism, incidence, and management. CNS Drugs 2015; 29:41–46. 52. Harrison TS, et al. Long-acting risperidone: a review of its use in schizophrenia. CNS Drugs 2004; 18:113–132. 53. Knox ED, et al. Clinical review of a long-acting, injectable formulation of risperidone. Clin Ther 2004; 26:1994–2002.

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Depot antipsychotics – summary of pharmacokinetics

Schizophrenia and related psychoses CHAPTER 1 Depot antipsychotics – summary of pharmacokinetics Table 1.9 provides a summary of the pharmacokinetics of depot antipsychotic medications. Table 1.9 Depot antipsychotics – summary of pharmacokinetics. Drug UK trade name Time to peak (days)* Plasma half-life (days) Time to steady state (weeks or months)** Aripiprazole1–3 Abilify Maintena Deltoid: 4 ~20 weeks Gluteal: 5–7 Aripiprazole 2-monthly injection3–6 Abilify Maintena ~29 ~6 months Aripiprazole lauroxil2 Aristada in USA 44–50 ~54–57 ~4 months Aripiprazole lauroxil nanocrystal2,7† Aristada Initio in USA ~15–18 Flupentixol decanoate8,9 Depixol 4–7 8–17 ~8–12 weeks Fluphenazine decanoate2,10–12 Modecate 8–12d†† 7–10 ~8 weeks Haloperidol decanoate2 Haldol 3–9 ~14 weeks Olanzapine pamoate2,13 ZypAdhera 2–6 ~12 weeks Paliperidone palmitate2 (monthly) Xeplion 25–49 ~20 weeks Paliperidone palmitate14,15 (3-monthly) Trevicta Deltoid: 84–95 ~52 weeks Gluteal: 118–139 Paliperidone palmitate (6-monthly)16 Byannli 700mg: 29 700mg: 148 Not known 1000mg: 32 1000mg: 159 Pipotiazine palmitate17,18 Piportil 7–14 ~9 weeks RBP-70002,19 (risperidone SC monthly) Perseris in USA 1st peak ~1 ~8–9 ~8 weeks 2nd peak ~11 Risperidone extended-release injectable suspension20,21 Rykindo in USA 25mg: 14 50mg: 17 3–6 ~4 weeks Risperidone in situ microimplants (ISM)22,23 Okedi 1st peak: 1–2 7–9 ~4 weeks 2nd peak: 18–25 Risperidone microspheres2 Risperidal Consta ~28 3–6 ~8 weeks TV-4600024 (risperidone SC) Uzedy in USA 8–14 14–22 ~2 months Zuclopenthixol decanoate2,8,17,25 Clopixol 4–7 ~12 weeks * Time to peak is not the same as time to reach therapeutic plasma concentration but both are dependent on dose. For large (loading) doses, therapeutic activity is often seen before attaining peak levels. For low (test) doses, the initial peak level may be subtherapeutic. ** Attainment of steady state (SS) follows logarithmic, not linear characteristics: nearly 90% of SS levels are achieved in three half-lives. Time to attain steady state is independent of dose and dosing frequency (i.e. you cannot hurry it up by giving more, more often). Loading doses can be used to produce prompt therapeutic plasma levels but time to SS remains the same. SS is not the same as the concentration required for therapeutic effect. For most depots, SS concentrations during the dosing interval are some way above the concentration needed to give a therapeutic response. † Used to initiate treatment with Aristada, IM injection with one 30mg oral dose of aripiprazole; not designed for repeat dosing. †† Some estimates suggest peak concentrations after only a few hours.25,26 It is likely that fluphenazine decanoate produces two peaks – one on the day of injection and a second slightly higher peak a week or so later.

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References

82 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

Mallikaarjun S, et al. Pharmacokinetics, tolerability and safety of aripiprazole once-monthly in adult schizophrenia: an open-label, parallel-arm, multiple-dose study. SchizophrRes 2013; 150:281–288.
Correll CU, et al. Pharmacokinetic characteristics of long-acting injectable antipsychotics for schizophrenia: an overview. CNS Drugs 2021; 35:39–59.
Wang Y, et al. Population pharmacokinetics and dosing simulations for aripiprazole 2-month ready-to-use long-acting injectable in adult patients with schizophrenia or bipolar I disorder. Clin Pharmacol Drug Dev 2024; 13:631–643.
Otsuka Pharmaceutical Co Ltd. Highlights of Prescribing Information. ABILIFY ASIMTUFII® (aripiprazole) extended-release injectable suspension for intramuscular use. 2023 (last accessed November 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2023/217006s000lbl.pdf.
Harlin M, et al. A randomized, open-label, multiple-dose, parallel-arm, pivotal study to evaluate the safety, tolerability, and pharmacokinetics of aripiprazole 2-month long-acting injectable in adults with schizophrenia or bipolar I disorder. CNS Drugs 2023; 37:337–350.
Baune BT. Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU): review of its possible role in schizophrenia therapy. Curr Med Res Opin 2024; 40:87–96.
Alkermes Inc. ARISTADA INITIO™ (aripiprazole lauroxil) extended-release injectable suspension [product monograph]. 2020 (last accessed February 2025); https://www.aristadacaresupport.com/downloadables/ARISTADA-INITIO-ARISTADA-Payer-Hospital-Monograph.pdf.
Jann MW, et al. Clinical pharmacokinetics of the depot antipsychotics. Clin Pharmacokinet 1985; 10:315–333.
Bailey L, et al. Estimating the optimal dose of flupentixol decanoate in the maintenance treatment of schizophrenia: a systematic review of the literature. Psychopharmacology 2019; 236:3081–3092.
Simpson GM, et al. Single-dose pharmacokinetics of fluphenazine after fluphenazine decanoate administration. J Clin Psychopharmacol 1990; 10:417–421.
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Walling DP, et al. Pharmacokinetics and safety of a novel extended-release microsphere formulation of risperidone in patients with schizophrenia or schizoaffective disorder. J Clin Pharmacology 2024; doi: 10.1002/jcph.6143.
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75 - Management of patients on long term treatment

Management of patients on long-term treatment with long-acting injectable antipsychotic medication

Schizophrenia and related psychoses CHAPTER 1 Management of patients on long-term treatment with long-acting injectable antipsychotic medication For people with multi-episode schizophrenia prescribed maintenance LAI antipsychotic treatment, long-term follow-up is essential. Treatment and progress should be reviewed at least once a year (ideally more frequently) by the responsible psychiatrist, including a systematic assessment of the efficacy, tolerability and safety of the medication. The assessment of adverse effects should include cardiovascular and metabolic adverse effects, and EPS (principally parkinsonism, akathisia and TD).1–3 Whether LAI antipsychotic medications are more or less likely to be associated with TD than oral antipsychotic medications remains uncertain,4–7 but the risk of TD does not appear to be different when the LAI and oral formulations of the same antipsychotic medication are compared.8,9 Any reduction in dosage should be cautious and closely monitored, given the increased risk of relapse and rehospitalisation with lower than standard doses,2,10,11 particularly in the longer term.12–15 In a 2022 naturalistic study16 of the risk of rehospitalisation associated with maintenance treatment with a range of antipsychotic medications, both oral and LAI formulations, in a nationwide cohort (n = 61,889), the risk of severe relapse was lowest with continuing standard dose LAI, two exceptions being better outcomes for high-dose olanzapine LAI and relatively low-dose oral perphenazine. There is no simple formula for deciding when or whether to reduce the dose of continuing LAI antipsychotic treatment, so a risk–benefit analysis must be carried out for every patient. Many patients, it should be noted, prefer LAI antipsychotic preparations to oral medication.9,17 When considering dose reduction, the patient’s individual circumstances should be considered, including the severity of the illness, the risk of relapse and its possible consequences, their response to treatment and their social situation:1,2 ■ ■Is the patient symptom-free and, if so, for how long? ■ ■How severe, tolerable, distressing and disabling are the current adverse effects? ■ ■What is the previous pattern of illness? Consider the speed of onset, duration and severity of past relapses and any dangers or risks posed to self or others. ■ ■Has dosage reduction been attempted before? If so, what was the outcome? ■ ■What are the patient’s current social circumstances? Is it a period of relative stability or should stressful life events be anticipated? ■ ■What is the potential social cost of relapse (e.g. is the patient the sole breadwinner for a family)? ■ ■Is the patient able to monitor their own symptoms? If so, will they seek appropriate help? If, after consideration of the above, the decision is taken to reduce the medication dose, the patient’s family should be involved, and a clear explanation given of what should be done if and when symptoms return or worsen. If it has not already been done, any co-prescribed oral antipsychotic medication should be discontinued. ■ ■Where the product labelling allows, the interval between injections should be increased to 4 weeks before starting to decrease the dose given each time. ■ ■The dose should be reduced by no more than a third of the previous dose at any one time. ■ ■Decrements should, if possible, be made no more frequently than every 3 months, preferably every 6 months or more.

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References

84 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 ■ ■Discontinuation of medication should not be seen as the ultimate aim of the above process although it sometimes results. ■ ■Because of their longer half-lives, relapse following discontinuation of LAI antipsychotic formulations may be delayed compared with their oral equivalents and shorter- acting LAIs, probably because of longer exposure and prolonged dopamine receptor blockade following discontinuation.18 ■ ■While an intermittent, targeted (i.e. symptom-triggered) treatment approach with antipsychotic medication is not as effective as continuous treatment, it may be preferable to no treatment.2,19,20 ■ ■If a patient becomes symptomatic following antipsychotic dose reduction, this should be seen as information relevant to the determination of the minimum effective dose for that patient. ■ ■Complex hyperbolic tapering regimens have been proposed21 and these may offer protection against relapse. For more discussion, see the section on antipsychotic prophylaxis in this chapter. References

Galletly C, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders. Aust N Z J Psychiatry 2016; 50:410–472.
Barnes T, et al. Evidence-based guidelines for the pharmacological treatment of schizophrenia: updated recommendations from the British Association for Psychopharmacology. J Psychopharm 2020; 34:3–78.
Arango C, et al. Delphi panel to obtain clinical consensus about using long-acting injectable antipsychotics to treat first-episode and early- phase schizophrenia: treatment goals and approaches to functional recovery. BMC Psychiatry 2023; 23:453.
Novick D, et al. Incidence of extrapyramidal symptoms and tardive dyskinesia in schizophrenia: thirty-six-month results from the European schizophrenia outpatient health outcomes study. J Clin Psychopharmacol 2010; 30:531–540.
Barnes TR, et al. Long-term depot antipsychotics: a risk-benefit assessment. Drug Saf 1994; 10:464–479.
Baldessarini RJ, et al. Incidence of extrapyramidal syndromes and tardive dyskinesia. J Clin Psychopharmacol 2011; 31:382–384; author reply 384–385.
Misawa F, et al. Tardive dyskinesia and long-acting injectable antipsychotics: analyses based on a spontaneous reporting system database in Japan. J Clin Psychiatry 2022; 83:21m14304.
Gopal S, et al. Incidence of tardive dyskinesia: a comparison of long-acting injectable and oral paliperidone clinical trial databases. Int J Clin Pract 2014; 68:1514–1522.
Patel MX, et al. Why aren’t depot antipsychotics prescribed more often and what can be done about it? Adv Psychiatr Treat 2005; 11:203–211.
Correll CU, et al. What is the risk–benefit ratio of long-term antipsychotic treatment in people with schizophrenia? World Psychiatry 2018; 17:149–160.
Rodolico A, et al. Antipsychotic dose reduction compared to dose continuation for people with schizophrenia. Cochrane Database Syst Rev 2022; 11:CD014384.
Marder SR, et al. Low- and conventional-dose maintenance therapy with fluphenazine decanoate: two-year outcome. Arch Gen Psychiatry 1987; 44:518–521.
Kane JM, et al. Low-dose neuroleptic treatment of outpatient schizophrenics: I. preliminary results for relapse rates. Arch Gen Psychiatry 1983; 40:893–896.
Kane JM, et al. A multidose study of haloperidol decanoate in the maintenance treatment of schizophrenia. Am J Psychiatry 2002; 159:554–560.
Højlund M, et al. Standard versus reduced dose of antipsychotics for relapse prevention in multi-episode schizophrenia: a systematic review and meta-analysis of randomised controlled trials. Lancet Psychiatry 2021; 8:471–486.
Taipale H, et al. Optimal doses of specific antipsychotics for relapse prevention in a nationwide cohort of patients with schizophrenia. Schizophr Bull 2022; 48:774–784.
Heres S, et al. The attitude of patients towards antipsychotic depot treatment. Int Clin Psychopharmacol 2007; 22:275–282.
Weiden PJ, et al. Does half-life matter after antipsychotic discontinuation? A relapse comparison in schizophrenia with 3 different formulations of paliperidone. J Clin Psychiatry 2017; 78:e813–e820.
National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management. Clinical guideline [CG178]. 2014 (last checked February 2024); https://www.nice.org.uk/guidance/cg178.
Sampson S, et al. Intermittent drug techniques for schizophrenia. Cochrane Database Syst Rev 2013; (7):CD006196.
O’Neill JR, et al. Implementing gradual, hyperbolic tapering of long-acting injectable antipsychotics by prolonging the inter-dose interval: an in silico modelling study. Ther Adv Psychopharmacol 2023; 13:20451253231198463.

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77 - Aripiprazole long acting injection

Aripiprazole long-acting injection

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78 - Aripiprazole 1 monthly

Aripiprazole 1-monthly

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79 - One injection start

One-injection start

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80 - Two injection start

Two-injection start

Schizophrenia and related psychoses CHAPTER 1 Aripiprazole long-acting injection Aripiprazole 1-monthly Aripiprazole lacks the prolactin-related and metabolic adverse effects of other SGA LAIs and so is a useful alternative to them. Placebo-controlled studies show a good acute and longer-term effect in the treatment of schizophrenia.1 In the USA, aripiprazole long-acting injection (ALAI) is approved for maintenance monotherapy in bipolar I disorder in adults.2 In the UK and some other countries, the use of aripiprazole LAI in bipolar is off-label. Oral aripiprazole 10–20mg/day should be given for 14 days to establish tolerability and response. This oral run-in is also a vital part of the loading process.3 In patients switching from another oral antipsychotic to ALAI, aripiprazole should have been effective and tolerated in the past. The current antipsychotic should be continued for the first 14 days following the initial ALAI administration.2 One of the following two regimens may be followed for administering the starting dose of aripiprazole LAI.4 One-injection start On the day of initiation, administer one injection of 400mg aripiprazole LAI and continue treatment with 10–20mg/day oral aripiprazole for 14 consecutive days (i.e. 28 days in total) to maintain therapeutic aripiprazole concentrations during initiation. In the absence of the 14-day oral overlap, plasma levels may not be sufficient to afford a therapeutic effect.3 Two-injection start On the day of initiation, administer two separate injections of 400mg aripiprazole LAI at separate injection sites in two different muscles (separate gluteal, separate deltoid or gluteal and deltoid injection sites), together with one 20mg dose of oral aripiprazole. Oral therapy should not continue after this point. The necessity for the single oral dose is doubtful, given it represents only 2.5% of the total dose given. One month after the day of initiation, begin a regimen of 400mg each month (the manufacturer appears to define ‘monthly’ as every 28 days).4 A monthly dose of 400mg aripiprazole is equivalent to 15–20mg of daily aripiprazole.5 After the one-injection plus oral starting regimen, peak plasma levels are reached 7 days post-injection, with trough levels occurring at 4 weeks.6 After two-injection start, peak plasma concentration is observed at 5–7 days when administered in the gluteal muscle and at 4 days for the deltoid muscle.7 Steady-state plasma levels are achieved after the fourth IM injection for both administration sites (see Table 1.10 for missed doses).7 A lower dose of 300mg a month can be used in those not tolerating 400mg or for those who are poor metabolisers via CYP2D6. A dose of 200mg/month may only be used for those patients receiving particular enzyme-inhibiting drugs. Most common adverse events are increased weight, akathisia, insomnia and injection site pain.4,7

86 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 While there are no official guidelines for switching to aripiprazole, the recommendations in Table 1.11 are based on our interpretation of existing pharmacokinetic data. Table 1.10 Delayed doses of aripiprazole long-acting injection.4 ALAI dose missed Regimen 2nd or 3rd ALAI dose is missed and time since last injection is >4 weeks and <5 weeks Administer as soon as possible 2nd or 3rd ALAI is missed and time since last injection is >5 weeks Give oral aripiprazole for 14 days and one dose of ALAI or Give two ALAI injections at different sites + single dose 20mg aripiprazole If ≥4th ALAI is missed and time since last injection is >4 weeks and <6 weeks Administer as soon as possible If ≥4th ALAI is missed and time since last injection is >6 weeks Give oral aripiprazole for 14 days and one dose of ALAI or Give two ALAI injections at different sites + single dose 20mg aripiprazole ALAI, aripiprazole long-acting injection. Table 1.11 Switching to 1-monthly aripiprazole long-acting injection. Switching from Aripiprazole LAI regimen Oral antipsychotics Cross-taper antipsychotic with oral aripiprazole* over 2 weeks One-injection start Start aripiprazole LAI, continue aripiprazole oral for another 2 weeks then stop Two-injection start Start aripiprazole LAI as indicated above after 2 weeks of oral aripiprazole, then stop oral treatment** Depot antipsychotics (not Risperidone Consta) Start oral aripiprazole* on day the last depot injection was due One-injection start Start aripiprazole LAI after 2 weeks then stop oral aripiprazole 2 weeks later Two-injection start Start aripiprazole LAI as indicated above after 2 weeks of oral aripiprazole, then stop oral treatment** Risperidone Consta Start oral aripiprazole* 4–5 weeks after the last risperidone injection One-injection start Start aripiprazole LAI 2 weeks later; discontinue oral aripiprazole 2 weeks after that Two-injection start Start aripiprazole LAI as indicated above after 2 weeks of oral aripiprazole, then stop oral treatment** * If prior response and tolerability to aripiprazole are known, pre-injection oral aripiprazole may not be strictly required. However, attainment of effective aripiprazole plasma levels is dependent upon 4 weeks of oral supplementation for the one-injection start regimen. Similarly, for the two-injection start regimen, the pharmacokinetic modelling study was based on plasma levels from oral aripiprazole being at (therapeutic) steady state on the day of initiation. It may be sufficient to start aripiprazole LAI in the absence of prior oral aripiprazole where the prior antipsychotic is at a therapeutic level. Continuation for 14 days is presumably also required. ** If oral aripiprazole cannot be given at all (e.g. patient refusal) always use the two-injection starting regimen. This 800mg dose is likely to afford sustained therapeutic plasma concentrations even in the absence of prior oral treatment. LAI, long-acting injection.

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81 - Aripiprazole 2 monthly8,9

Aripiprazole 2-monthly8,9

Schizophrenia and related psychoses CHAPTER 1 Aripiprazole 2-monthly8,9 Two-monthly ALAI (Aripiprazole 2-Month Ready-to-Use 960mg [Ari2MRTU]) is indicated for maintenance treatment of schizophrenia (in the USA it is also licensed for maintenance monotherapy treatment of bipolar-1 disorder9). It is available as 720mg and 960mg formulations and should only be administered into the gluteal muscle. The 960mg dose is equivalent to 10–20mg daily of oral aripiprazole. The initiation regimen is shown in Table 1.12. The maintenance dose of Ari 2MRTU should be administered into the gluteal muscle every 56 days (this seems to be the manufacturer’s definition of ‘2-monthly’). It may be given up to 2 weeks before or 2 weeks after the scheduled injection due date.8 Table 1.13 gives recommendations in the event of a missed or delayed maintenance dose of Ari 2MRTU. In the event of an adverse reaction, reduce the maintenance dose to 720mg every 2 months. For patients on concomitant treatment with CYP2D6 or CYP3A4 inhibitors or those who are confirmed CYP2D6 poor metabolisers, the 720mg dose is considered more appropriate.9 Ari 2MRTU 960 is generally well tolerated, with safety, tolerability, efficacy and pharmacokinetic profiles similar to those of the 1-monthly ALAI (400mg).10–13 Table 1.12 Aripiprazole 2-month ready-to-use initiation regimen.8 Switching from Initiation regimen Oral antipsychotics Establish tolerability with aripiprazole before initiating ALAI treatment One-injection start Administer one 960mg injection + give 10–20mg oral aripiprazole for 14 consecutive days Two-injection start Administer one 960mg injection and one 400mg injection at two different injection sites + give one 20mg dose of oral aripiprazole 400mg ALAI Initiate 960mg no sooner than 26 days after the last 400mg ALAI Table 1.13 Recommendations for delayed maintenance dose of Ari 2MRTU. Missed maintenance dose8 Recommendations

8weeks and <14 weeks since last injection Administer 960mg or 720mg as soon as possible 14 weeks since last injection Administer 960mg or 720mg + oral aripiprazole for 14 days or Maintenance dose 960mg: Administer 960mg + 400mg + one dose of 20mg oral aripiprazole Maintenance dose 720mg: Administer 720mg + 300mg + one dose of 20mg oral aripiprazole Resume 2-monthly dosing schedule

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82 - Other LAI aripiprazole brands

Other LAI aripiprazole brands

88 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Other LAI aripiprazole brands Another two long-acting formulations of aripiprazole lauroxil (Aristada Initio and Aristada) are approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia.14 Aristada Initio is given as a single 675mg IM injection to initiate treatment (Table 1.14). Aristada is administered at 1-monthly, 6-weekly or 2-monthly intervals by IM injection into the deltoid or gluteal muscle, depending on the dose (Table 1.15).15,16 It is available in four strengths (441mg, 662mg, 882mg and 1064mg doses to deliver 300mg, 450mg, 600mg and 724mg of aripiprazole, respectively).17 The most commonly reported adverse reaction is akathisia.14 The 1-day initiation regimen with 1064mg Aristada did not demonstrate any new safety or tolerability concerns and its adverse-effect profile was comparable to that of paliperidone palmitate 1-monthly injection.13,18 Most adverse reactions occurred within the first 4 weeks of treatment (injection-site pain, akathisia, increased weight).18 Aristada 1064mg and Ari 2MRTU both give therapeutic plasma levels over the entire 2-month dosing interval.19 The key differences between the two formulations lie in their dosing and the licensed indications. Aristada 1064mg corresponds to 15mg daily oral aripiprazole, while Ari 2MRTU is claimed to be suitable for patients taking 10–20mg of oral aripiprazole daily. While both formulations are licensed for the treatment of schizophrenia, Ari 2MRTU is also approved for the maintenance treatment of bipolar I disorder in the USA. Table 1.15 Equivalent doses and sites of administration for Aristada.17 Aripiprazole oral (mg/day) Aripiprazole lauroxil dose (mg) Dosing interval Site of IM administration 441 Monthly Deltoid or gluteal 662 Monthly Gluteal ≥20 Monthly Gluteal 882 Every 6 weeks Gluteal 1064 Every 2 months Gluteal Table 1.14 Starting treatment with Aristada.17 1-day initiation regimen Second option Establish tolerability with oral aripiprazole before initiating treatment Establish tolerability with oral aripiprazole before initiating treatment Give single dose of 675mg IM Aristada Initio* into the gluteal muscle Give IM Aristada on day one** and continue oral aripiprazole for 21 days Give single dose of 30mg aripiprazole Give IM Aristada on the same day or up to 10 days after initiation** * Avoid giving Aristada Initio and Aristada into the same muscle. ** Only the 441mg dose can be given in the deltoid muscle; 662mg, 882mg and 1064mg must be given into the gluteal muscle.

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References

Schizophrenia and related psychoses CHAPTER 1 References

Shirley M, et al. Aripiprazole (ABILIFY MAINTENA®): a review of its use as maintenance treatment for adult patients with schizophrenia. Drugs 2014; 74:1097–1110.
US Food and Drug Administration. Highlights of Prescribing Information. Abilify Maintena (aripiprazole) for extended-release suspension for intramuscular use. 2020 (last accessed August 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202971s013lbl.pdf.
Raoufinia A, et al. Initiation of aripiprazole once-monthly in patients with schizophrenia. Curr Med Res Opin 2015; 31:583–592.
Otsuka Pharmaceuticals (UK) Ltd. Summary of Product Characteristics. Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection. 2024 (last accessed October 2024); https://www.medicines.org.uk/emc/product/7965/smpc.
Raoufinia A, et al. Aripiprazole once-monthly 400 mg: comparison of pharmacokinetics, tolerability, and safety of deltoid versus gluteal administration. Int J Neuropsychopharmacol 2017; 20:295–304.
Mallikaarjun S, et al. Pharmacokinetics, tolerability and safety of aripiprazole once-monthly in adult schizophrenia: an open-label, parallel- arm, multiple-dose study. Schizophr Res 2013; 150:281–288.
Otsuka Pharmaceutical Co Ltd. Highlights of Prescribing Information. ABILIFY MAINTENA® (aripiprazole) for extended-release injectable suspension, for intramuscular use. 2017 (last accessed October 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/ 202971s013lbl.pdf.
Otsuka Pharmaceuticals (UK) Ltd. Summary of Product Characteristics. Abilify Maintena 960 mg prolonged-release suspension for injection in pre-filled syringe. 2024 (last accessed October 2024); https://www.medicines.org.uk/emc/product/15679/smpc.
Otsuka Pharmaceutical Co Ltd. Highlights of Prescribing Information. ABILIFY ASIMTUFII® (aripiprazole) extended-release injectable suspension for intramuscular use. 2023 (last accessed October 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/ 217006s000lbl.pdf.
Citrome L, et al. Safety and efficacy of aripiprazole 2-month ready-to-use 960 mg: secondary analysis of outcomes in adult patients with schizophrenia in a randomized, open-label, parallel-arm, pivotal study. J Clin Psychiatry 2023; 84:23m14873.
Harlin M, et al. A randomized, open-label, multiple-dose, parallel-arm, pivotal study to evaluate the safety, tolerability, and pharmacokinetics of aripiprazole 2-month long-acting injectable in adults with schizophrenia or bipolar I disorder. CNS Drugs 2023; 37:337–350.
McIntyre RS, et al. Safety and efficacy of aripiprazole 2-month ready-to-use 960 mg: secondary analysis of outcomes in adult patients with bipolar I disorder in a randomized, open-label, parallel-arm, pivotal study. Curr Med Res Opin 2023; 39:1021–1030.
Samalin L, et al. Evaluating the efficacy and safety of the currently available once-every-two months long-acting injectable formulations of aripiprazole for the treatment of schizophrenia or as a maintenance monotherapy for bipolar I disorder in adults. Expert Rev Neurother 2024; 24:291–298.
Alkermes Inc. ARISTADA INITIO™ (aripiprazole lauroxil) extended-release injectable suspension [product monograph]. 2020 (last accessed October 2024); https://www.aristadacaresupport.com/downloadables/ARISTADA-INITIO-ARISTADA-Payer-Hospital-Monograph.pdf.
Hard ML, et al. Aripiprazole lauroxil: pharmacokinetic profile of this long-acting injectable antipsychotic in persons with schizophrenia. J Clin Psychopharmacol 2017; 37:289–295.
Turncliff R, et al. Relative bioavailability and safety of aripiprazole lauroxil, a novel once-monthly, long-acting injectable atypical antipsychotic, following deltoid and gluteal administration in adult subjects with schizophrenia. Schizophr Res 2014; 159:404–410.
Alkermes Inc. Highlights of Prescribing Information. ARISTADA® (aripiprazole lauroxil) extended-release injectable suspension for intramuscular use. 2018 (last accessed October 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/207533s013lbl.pdf.
Citrome L, et al. Safety and tolerability of starting aripiprazole lauroxil with aripiprazole lauroxil nanocrystal dispersion in 1 day followed by aripiprazole lauroxil every 2 months using paliperidone palmitate monthly as an active control in patients with schizophrenia: a post hoc analysis of a randomized controlled trial. J Clin Psychiatry 2024; 85:23m15095.
Harlin M, et al. Aripiprazole plasma concentrations delivered from two 2-month long-acting injectable formulations: an indirect comparison. Neuropsychiatr Dis Treat 2023; 19:1409–1416.

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84 - Olanzapine long acting injection

Olanzapine long-acting injection

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85 - Switching

Switching

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86 - Stopping

Stopping

90 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Olanzapine long-acting injection Olanzapine pamoate (embonate, in some countries) is a very poorly water-soluble salt ester of olanzapine. An aqueous suspension of olanzapine pamoate, when injected deep in the gluteal muscle, affords both prompt and sustained release of olanzapine. Peak plasma levels are seen within 1 week of injection (in most people within 2–4 days)1,2 and efficacy can be demonstrated after only 3 days.3 Only gluteal injection is licensed – deltoid injection is less effective.2 Olanzapine LAI is effective when given every 4 weeks, with 2-weekly administrations only required when the highest dose is prescribed. Half- life is 30 days.1,4 Olanzapine has not been compared with other LAIs in RCTs, but naturalistic data suggest similar effectiveness to paliperidone LAI.5,6 Loading doses are recommended in some dose regimens (Table 1.16). The manufacturer recommends that patients be given oral olanzapine first to assess response and tolerability. Oral supplementation after the first depot injection is not necessary. Switching Direct switching to olanzapine LAI, ideally following an oral trial, is usually possible. When switching from another LAI, olanzapine oral or LAI can be started on the day the last LAI was due. Likewise, for switching from oral treatment, a direct switch is possible, but prior antipsychotics are probably best reduced slowly after starting olanzapine. When switching from risperidone Consta, olanzapine should be started, we suggest, 2 weeks after the last Consta injection was due. That is, 4 weeks after the last Consta injection (peak risperidone plasma levels occur 4–5 weeks after the last injection). Stopping Clinicians should consider the gradual release of olanzapine from the pamoate salt when discontinuing treatment. There are various methods of ensuring a linear reduction in drug activity.7 Olanzapine may remain detectable in the bloodstream for up to 8 months following the last dose.4 Table 1.16 Dosing regimen for olanzapine. Oral olanzapine (mg/day) Starting dose Maintenance dose (given 8 weeks after the first dose) 210mg every 2 weeks or 405mg every 4 weeks 300mg/4 weeks (or 150mg every 2 weeks) 300mg every 2 weeks 405mg/4 weeks (or 210mg every 2 weeks) 300mg every 2 weeks 300mg every 2 weeks

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87 - Post injection delirium sedation syndrome

Post-injection delirium sedation syndrome

Schizophrenia and related psychoses CHAPTER 1 Post-injection delirium sedation syndrome Although the precise mechanism of post-injection delirium sedation syndrome (PDSS) remains unclear, it is thought to occur when the pamoate salt of olanzapine is inadvertently exposed to a large volume of blood or plasma, such as through IV injection or a blood vessel injury.8,9 This exposure can cause the salt to dissolve more rapidly and release a large amount of olanzapine into the circulation.8 Olanzapine plasma levels may reach over 800mcg/L and confusion, delirium and somnolence result.10,11 Treatment is supportive and outcomes invariably good.9 The incidence of PDSS is less than 0.1% of injections and almost all reactions (86%) occur within 1 hour of injection (mean time is 30 minutes)12 and fully resolve within 72 hours.8,9,13 One study suggested an incidence of 0.044% of injections (less than 1 in 2,000) with 91% of reactions being apparent within 1 hour.14 There are very rare reports of events occurring after 3 hours, including one case where the reaction occurred 12 hours after the injection.15 In most countries, olanzapine LAI may only be given in healthcare facilities under supervision and patients need to be kept under observation for 3 hours after the injection is given. Given the tiny number of cases appearing only after 2 hours, a good case can be made for shortening the observation period to 2 hours (as in Australia, New Zealand16,17 and some other countries). Shorter monitoring periods were also employed during the COVID-19 pandemic.18 However, it is worth emphasising that PDSS may occur at any time and has no clear predictive risk factors,8 even after several uses in the same patient. That is to say, prior safe use of olanzapine LAI in an individual does not imply low risk of PDSS. The risk may be reduced in patients on 1-monthly injection intervals,8,19 presumably because they receive relatively fewer injections. In the EU and UK, the exact wording of the SPC4 is as follows: After each injection, patients should be observed in a healthcare facility by appropriately qualified personnel for at least 3 hours for signs and symptoms consistent with olanzapine overdose. Immediately prior to leaving the healthcare facility, it should be confirmed that the patient is alert, oriented, and absent of any signs and symptoms of overdose. If an overdose is suspected, close medical supervision and monitoring should continue until examination indicates that signs and symptoms have resolved. The 3-hour observation period should be extended as clinically appropriate for patients who exhibit any signs or symptoms consistent with olanzapine overdose. For the remainder of the day after injection, patients should be advised to be vigilant for signs and symptoms of overdose secondary to post-injection adverse reactions, be able to obtain assistance if needed, and should not drive or operate machinery. This monitoring requirement has undoubtedly adversely affected the popularity of olanzapine LAI. Interestingly some patients continue treatment even after an episode of post-injection syndrome.20 As stated, no patient or medical factor has been identified which definitively predicts PDSS,10 except perhaps that those experiencing the syndrome are somewhat more likely to have previously had an injection site-related adverse effect.21 Male gender and higher doses have also been suggested to be risk factors for PDSS.12,14

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References

92 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

Heres S, et al. Pharmacokinetics of olanzapine long-acting injection: the clinical perspective. Int Clin Psychopharmacol 2014; 29:299–312.
Mitchell M, et al. Single- and multiple-dose pharmacokinetic, safety, and tolerability profiles of olanzapine long-acting injection: an open- label, multicenter, nonrandomized study in patients with schizophrenia. Clin Ther 2013; 35:1890–1908.
Lauriello J, et al. An 8-week, double-blind, randomized, placebo-controlled study of olanzapine long-acting injection in acutely ill patients with schizophrenia. J Clin Psychiatry 2008; 69:790–799.
Eli Lily and Company Limited. Summary of Product Characteristics. Zypadhera (olanzapine pamoate monohydrate) 210mg powder and solvent for prolonged release suspension for injection. 2023 (last accessed August 2024); https://www.medicines.org.uk/emc/product/6429/ smpc.
Denee TR, et al. Treatment continuation and treatment characteristics of four long acting antipsychotic medications (paliperidone palmitate, risperidone microspheres, olanzapine pamoate and haloperidol decanoate) in the Netherlands. Value Health 2015; 18:A407.
Taipale H, et al. Comparative effectiveness of antipsychotic drugs for rehospitalization in schizophrenia-a nationwide study with 20-year follow-up. Schizophr Bull 2017; 44:1381–1387.
O’Neill JR, et al. Implementing gradual, hyperbolic tapering of long-acting injectable antipsychotics by prolonging the inter-dose interval: an in silico modelling study. Ther Adv Psychopharmacol 2023; 13:20451253231198463.
Citrome L. Long-acting injectable antipsychotics: what, when, and how. CNS Spectr 2021; 26:118–129.
Kochen SA, et al. Olanzapine postinjection delirium/sedation syndrome after long-acting olanzapine depot injection presenting to the emergency department: practical guidelines for diagnosis and management. Emerg Med J 2024; 41:759–763.
McDonnell DP, et al. Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, II: investigations of mechanism. BMC Psychiatry 2010; 10:45.
Podgorná G, et al. Post-injection delirium/sedation syndrome: a case report and 2-year follow-up. Am J Case Rep 2022; 23:e937579.
Seebaluck J, et al. Case series profile of olanzapine post-injection delirium/sedation syndrome. Br J Clin Pharmacol 2023; 89:903–907.
Bushes CJ, et al. Olanzapine long-acting injection: review of first experiences of post-injection delirium/sedation syndrome in routine clinical practice. BMC Psychiatry 2015; 15:65.
Meyers KJ, et al. Postinjection delirium/sedation syndrome in patients with schizophrenia receiving olanzapine long-acting injection: results from a large observational study. BJPsych Open 2017; 3:186–192.
Garg S, et al. Delayed onset postinjection delirium/sedation syndrome associated with olanzapine pamoate: a case report. J Clin Psychopharmacol 2019; 39:523–524.
Eli Lilly Australia Pty Ltd. Consumer Medicine Information: ZYPREXA RELPREVV® (olanzapine pamoate monohydrate). 2024 (last accessed August 2024); https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2024-CMI-01649-1&d= 20240807172310101.
Pharmaco (N.Z.) Ltd. Consumer Medicine Information: ZYPREXA RELPREVV® (olanzapine pamoate monohydrate). 2023 (last accessed August 2024); https://www.medsafe.govt.nz/consumers/cmi/z/zyprexarelprevvinj.pdf.
Siskind D, et al. Monitoring for post-injection delirium/sedation syndrome with long-acting olanzapine during the COVID-19 pandemic. Aust N Z J Psychiatry 2020; 54:759–761.
Venkatesan V, et al. Postinjection delirium/sedation syndrome after 31st long-acting olanzapine depot injection. Clin Neuropharmacol 2019; 42:64–65.
Anand E, et al. A 6-year open-label study of the efficacy and safety of olanzapine long-acting injection in patients with schizophrenia: a post hoc analysis based on the European label recommendation. Neuropsychiatr Dis Treat 2015; 11:1349–1357.
Atkins S, et al. A pooled analysis of injection site-related adverse events in patients with schizophrenia treated with olanzapine long-acting injection. BMC Psychiatry 2014; 14:7.

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89 - Paliperidone palmitate long acting injection

Paliperidone palmitate long-acting injection

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90 - Paliperidone long acting injection 1 monthly

Paliperidone long-acting injection 1-monthly

Schizophrenia and related psychoses CHAPTER 1 Paliperidone palmitate long-acting injection Paliperidone (9-hydroxyrisperidone) is the major active metabolite of risperidone. Paliperidone palmitate is the ester prodrug of paliperidone. It is available as a monthly, 3-monthly and 6-monthly LAI. The ester is an aqueous nanosuspension, which is hydrolysed to paliperidone after IM administration and slowly absorbed into the circulatory system.1,2 Paliperidone long-acting injection 1-monthly After the recommended initial loading dose of paliperidone LAI 1-monthly (PP1M), active paliperidone plasma levels are seen within a few days, so co-administration of oral paliperidone or risperidone during initiation is not required from a pharmacokinetic viewpoint but some patients may benefit from gradual withdrawal.3 Dosing consists of two initiation doses (deltoid) followed by monthly maintenance doses (deltoid or gluteal). Administering a single IM dose to the deltoid muscle results in an average 28% higher peak concentration compared with IM injection to the gluteal muscle.3 Therefore, the two deltoid muscle injections on days 1 and 8 help to attain therapeutic drug concentration quickly. Improvement in psychotic symptoms has been observed as early as day 4.3 Table 1.17 gives information on dose and administration of PP1M. Table 1.19, later in this section, provides guidance on how to switch to PP1M.3 The second initiation dose may be given 4 days before or after day 8 (after the first initiation dose on day 1).3 The manufacturer recommends that patients may be given maintenance doses up to 7 days before or after the monthly time point.3 This flexibility should help to minimise the number of missed doses. See the manufacturer’s information for full recommendations regarding missed doses.3 Points to note ■ ■No test dose is necessary for paliperidone palmitate. However, patients should ideally be stabilised on or have previously responded to oral paliperidone or risperidone. ■ ■After a single IM injection, paliperidone is continuously released into the systemic circulation from day 1 for at least 4 months.3 Table 1.17 Paliperidone dose and administration information.3 Dose Route Initiation Day 1 150mg IM Deltoid only Day 8 (±4 days) 100mg IM Deltoid only Maintenance Every month (±7 days) thereafter 50–150mg IM* Deltoid or gluteal** * The maintenance dose is perhaps best judged by consideration of what might be a suitable dose of oral risperidone and then giving paliperidone palmitate in an equivalent dose (Table 1.18). Pre-treatment with oral risperidone is helpful in establishing efficacy and tolerability of a given dose. ** Continuation with deltoid injections for the first 6 months may be considered in some patients who switch from higher doses of oral paliperidone or risperidone.3

94 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 ■ ■The median time to maximum plasma concentration is 13 days,3 and half-life ranges from 25 to 49 days. ■ ■Patients receiving fewer than 12 injections a year have an increased risk of relapse – correct dosing is critical to the effectiveness of paliperidone monthly.4,5 Paliperidone LAI has been compared with haloperidol depot given in a loading dose schedule matching that of paliperidone.9 The two formulations were equally effective in preventing relapse but paliperidone increased prolactin to a greater extent and caused more weight gain. Haloperidol caused more akathisia and more acute movement disorder, and there was a trend for a higher incidence of tardive dyskinesia. The average dose of haloperidol was around 75mg a month, a dose rarely used in practice. There are two studies comparing monthly paliperidone LAI with aripiprazole LAI. The first was a 28-week randomised head-to-head trial that found aripiprazole monthly injection superior in the improvement of quality of life and functioning in the short term, although the aripiprazole group included more younger patients.10 The second study compared the two LAIs in patients with psychosis and comorbid substance use disorder. Improvement in quality of life and reduced substance cravings were seen with both LAIs, although aripiprazole fared better. Overall, there was no clear clinically meaningful superiority for aripiprazole over paliperidone in either of these studies.11 Table 1.18 Approximate dose equivalence for paliperidone and risperidone.3,6 Risperidone oral (mg/day) (bioavailability = 70%)7 Paliperidone oral (mg/day) (bioavailability = 28%)8 Risperidone LAI (Consta) (mg/2 weeks) Paliperidone palmitate (mg/monthly) (bioavailability = 100%)3 3 50 6 37.5 4 50 6 – Table 1.19 Switching to paliperidone palmitate 1-monthly.3 Switching from Recommended method of switching Comments No treatment Give the two initiation doses: 150mg IM deltoid on day 1 and 100mg IM deltoid on day 8 The manufacturer recommends a dose of 75mg monthly for the general adult population.12 This is approximately equivalent to 3mg/day oral risperidone (Table 1.18). In practice, the modal dose is 100mg/month.13 Maintenance dose starts 1 month later Maintenance dose adjustments should be made monthly. However, the full effect of the dose adjustment may not be apparent for several months.3 Oral paliperidone/ risperidone Give the two initiation doses followed by the maintenance dose (see Table 1.18 and prescribe equivalent dose) Oral paliperidone/risperidone can be discontinued at the time of initiation; some patients may benefit from a gradual withdrawal (Continued)

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91 - Paliperidone long acting injection 3 monthly

Paliperidone long-acting injection 3-monthly

Schizophrenia and related psychoses CHAPTER 1 Paliperidone long-acting injection 3-monthly Paliperidone LAI 3-monthly (PP3M) is indicated for patients who are clinically stable on PP1M and do not require dose adjustment.15 It is recommended that before switching to PP3M, patients be treated for 4 months or more with PP1M and that the last two doses of PP1M are the same. PP3M is generally well tolerated, with a tolerability and safety profile similar to the 1-monthly preparation.16,17 PP3M has a lower risk of hospitalisations and emergency department visits compared with PP1M.18 Patient and family perspective of PP3M have been systematically examined.19 In this study, PP3M was reported to be as effective, or even more effective, than PP1M and had similar or fewer adverse effects. The majority of patients preferred PP3M over PP1M. The advantages for the patients included less frequent and painful injections, less travelling and fewer moments of experiencing shame. The switch did not influence the frequency of their interaction with healthcare professionals. Practical experience suggests that contacts with healthcare staff are reduced when LAIs are used. Healthcare workers should probably work towards ensuring that contact with patients is not reduced just because there are fewer antipsychotic administrations. When initiating PP3M, give the first dose in place of the next scheduled dose of PP1M (±7 days). The dose of PP3M should be based on the previous PP1M dose Switching from Recommended method of switching Comments Oral antipsychotics Reduce the dose of the oral antipsychotic over 1–2 weeks following the first injection of paliperidone. Give the two initiation doses followed by the maintenance dose. Depot antipsychotic Start paliperidone (at the maintenance dose) when the next injection is due Doses of paliperidone palmitate IM are difficult to predict from the dose of FGA depots. The manufacturer recommends a dose of 75mg monthly for the general adult population but in practice 100mg and 150mg are more often prescribed.13,14 If switching from risperidone LAI see Table 1.18 and prescribe equivalent dose. NB No initiation doses are required Maintenance dose adjustments should be made monthly. However, the full effect of the dose adjustment may not be apparent for several months.3 Antipsychotic polypharmacy with depot Start paliperidone (at the maintenance dose) when the next injection is due NB No initiation doses are required Aim to treat the patient with paliperidone palmitate IM as the sole antipsychotic Reduce the dose of the oral antipsychotic over 1–2 weeks following the first injection of paliperidone The maintenance dose should be governed as far as possible by the total dose of oral and injectable antipsychotic (see section on dose equivalence in this chapter) Table 1.19 (Continued)

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92 - Paliperidone LAI 6 monthly (PP6M)

Paliperidone LAI 6-monthly (PP6M)

96 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 (Table 1.20). Dose adjustments should not be necessary but may be made at 3-monthly intervals thereafter; however, the full response to the new dose may not be apparent for several months.15 The administration process is important for avoiding incomplete administration of the suspension. This requires shaking vigorously the prefilled syringe with the cap and a loose wrist, in a vertical motion for at least 15 seconds to ensure an evenly distributed suspension.15 Points to note ■ ■Patients should be on a stable and effective therapeutic dose of PP1M before changing to PP3M to ensure optimal dosing and avoid relapse and hospital admissions.14,20–22 ■ ■PP3M should be given in place of the next PP1M injection at an equivalent dose. ■ ■The median time to maximum plasma concentration is 30–33 days.15 ■ ■The median half-life for deltoid injection is 84–95 days and for gluteal injection is 118–139 days. ■ ■After IM injection of PP3M into the deltoid muscle, there was an average increase of 11–12% maximum concentration in plasma compared with gluteal injection. Paliperidone LAI 6-monthly (PP6M) PP6M is indicated for patients on maintenance treatment with 100mg or 150mg of PP1M (ideally for 4 months or more, same dose for the last two injections) or patients who have had at least one injection of 350mg or 525mg of PP3M and do not require any dose changes. It is designed to be given once every 6 months into the gluteal muscle. It should not be administered via any other route. There are no corresponding PP6M doses for 25mg, 50mg, 75mg of PP1M or for 263mg and 350mg of PP3M.23 Table 1.21 gives equivalent doses for paliperidone LAI. Table 1.20 Dosing of paliperidone long-acting injection 3-monthly.15 Dose of PP1M Dose of PP3M 50mg 175mg 75mg 263mg 100mg 350mg 150mg 525mg Table 1.21 Paliperidone long-acting injection – equivalent doses. Dose of PP1M (mg) Dose of PP3M (mg) Dose of PP6M (mg) 350 150 1000

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References

Schizophrenia and related psychoses CHAPTER 1 Dose adjustments should not be needed but can be made every 6 months based on patient response and tolerability. Any dose change may not be apparent in respect to clinical effects for several months owing to the long-acting nature of PP6M and the time needed for a new steady-state level to be reached.23 Points to note ■ ■PP6M is suitable for patients who are stable in their mental state and do not require any dose adjustments. ■ ■PP6M should be given only into the upper-outer quadrant of the gluteal muscle. ■ ■Before IM administration, the vial requires extensive and rapid shaking for a minimum of 30 seconds. ■ ■The median half-life is 148–159 days or longer.23,24 See the manufacturer’s information for full information on missed doses and re-initiation regimens. References

Cleton A, et al. A single-dose, open-label, parallel, randomized, dose-proportionality study of paliperidone after intramuscular injections of paliperidone palmitate in the deltoid or gluteal muscle in patients with schizophrenia. J Clin Pharmacol 2014; 54:1048–1057.
Lopez A, et al. Role of paliperidone palmitate 3-monthly in the management of schizophrenia: insights from clinical practice. Neuropsychiatr Dis Treat 2019; 15:449–456.
Janssen-Cilag Ltd. Summary of Product Characteristics. Xeplion (paliperidone) 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg prolonged-release suspension for injection. 2023 (last accessed May 2024); https://www.medicines.org.uk/emc/product/7652/smpc.
Pappa S, et al. Partial compliance with long-acting paliperidone palmitate and impact on hospitalization: a 6-year mirror-image study. Ther Adv Psychopharmacol 2020; 10:2045125320924789.
Laing E, et al. Relapse and frequency of injection of monthly paliperidone palmitate—a retrospective case-control study. Eur Psychiatry 2021; 64:e11. PP6M is generally well tolerated and has a tolerability profile similar to PP3M and PP1M.24 The most common adverse effect in one phase 3 trial was the injection site pain (which can be attributed to the large injection volume: 3.5mL or 5mL), followed by weight gain.24 Patients and clinicians seem to prefer PP6M over PP3M.25 Table 1.22 gives the regimen for switching to PP6M. Table 1.22 Switching to paliperidone 6-monthly.23 Switching from Recommended method of switching Comments 100mg PP1M Give 700mg of PP6M in place of the next scheduled dose of 100mg PP1M PP6M can be initiated ±7 days of the PP1M due date 150mg PP1M Give 1000mg of PP6M in place of the next scheduled dose of 150mg PP1M 350mg PP3M Give 700mg of PP6M in place of the next scheduled dose of 350mg PP3M PP6M can be initiated ±14 days of the PP3M due date 525mg PP3M Give 1000mg of PP6M in place of the next scheduled dose of 525mg PP3M

98 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 6. Russu A, et al. Maintenance dose conversion between oral risperidone and paliperidone palmitate 1 month: practical guidance based on pharmacokinetic simulations. Int J Clin Pract 2018; 72:e13089. 7. Dexcel Pharma Ltd. Summary of Product Characteristics. Risperidone 1mg Film-Coated Tablets. 2023 (last checked May 2024); https:// www.medicines.org.uk/emc/product/8207/smpc. 8. Janssen-Cilag Limited. Summary of Product Characteristics. Invega (paliperidone) 3 mg prolonged-release tablets. 2021 (last checked May 2024); https://www.medicines.org.uk/emc/product/6816. 9. McEvoy JP, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA 2014; 311:1978–1987. 10. Naber D, et al. Qualify: a randomized head-to-head study of aripiprazole once-monthly and paliperidone palmitate in the treatment of schizophrenia. Schizophr Res 2015; 168:498–504. 11. Cuomo I, et al. Head-to-head comparison of 1-year aripiprazole long-acting injectable (LAI) versus paliperidone LAI in comorbid psychosis and substance use disorder: impact on clinical status, substance craving, and quality of life. Neuropsychiatr Dis Treat 2018; 14:1645–1656. 12. Janssen Pharmaceuticals Inc. Highlights of Prescribing Information. INVEGA SUSTENNA (paliperidone palmitate) extended-release injectable suspension, for intramuscular use. 2022 (last accessed May 2024); http://www.janssenlabels.com/package-insert/product-monograph/ prescribing-information/INVEGA+SUSTENNA-pi.pdf. 13. Taylor DM, et al. Paliperidone palmitate: factors predicting continuation with treatment at 2 years. Eur Neuropsychopharmacol 2016; 26:2011–2017. 14. Clark I, et al. Clinical outcomes with paliperidone palmitate 3-monthly injection as monotherapy: observational 3-year follow-up of patients with schizophrenia. Eur Psychiatry 2024; 67:e15. 15. Janssen-Cilag Limited. Summary of Product Characteristics. TREVICTA (paliperidone) 175mg, 263mg, 350mg, 525mg prolonged release suspension for injection. 2023 (last accessed May 2024); https://www.medicines.org.uk/cmc/medicine/32050. 16. Ravenstijn P, et al. Pharmacokinetics, safety, and tolerability of paliperidone palmitate 3-month formulation in patients with schizophrenia: a phase-1, single-dose, randomized, open-label study. J Clin Pharmacol 2016; 56:330–339. 17. Cicala G, et al. Tolerability profile of paliperidone palmitate formulations: a pharmacovigilance analysis of the EUDRAVigilance database. Front Psychiatry 2023; 14:1130636. 18. Gutiérrez-Rojas L, et al. Impact of 3-monthly long-acting injectable paliperidone palmitate in schizophrenia: a retrospective, real-world analysis of population-based health records in Spain. CNS Drugs 2022; 36:517–527. 19. Spoelstra SK, et al. One-month versus three-month formulation of paliperidone palmitate treatment in psychotic disorders: patients’, relatives’, and mental health professionals’ perspectives. Patient Prefer Adherence 2022; 16:615–624. 20. Clark I, et al. Long term impact of 3-monthly paliperidone palmitate on hospitalisation in patients with schizophrenia: six-year mirror image study. Acta Psychiatr Scand 2024; 150:48–50. 21. Turkoz I, et al. Comparing relapse rates in real-world patients with schizophrenia who were adequately versus not adequately treated with paliperidone palmitate once-monthly injections before transitioning to once-every-3-months injections. Neuropsychiatr Dis Treat 2022; 18:1927–1937. 22. O’Donnell A, et al. Defining ’adequately treated’: a post hoc analysis examining characteristics of patients with schizophrenia successfully transitioned from once-monthly paliperidone palmitate to once-every-3-months paliperidone palmitate. Neuropsychiatr Dis Treat 2021; 17:1–9. 23. Janssen-Cilag Ltd. Summary of Product Characteristics. Byannli 700mg prolonged-release suspension for injection in pre-filled syringe (paliperidone). 2023 (last accessed February 2025); https://www.medicines.org.uk/emc/product/13307/smpc. 24. Cirnigliaro G, et al. Evaluating the 6-month formulation of paliperidone palmitate: a twice-yearly injectable treatment for schizophrenia in adults. Expert Rev Neurother 2024; 24:325–332. 25. García-Carmona JA, et al. Preliminary data from a 4-year mirror-image and multicentre study of patients initiating paliperidone palmitate 6-monthly long-acting injectable antipsychotic: the Paliperidone 2 per Year study. Ther Adv Psychopharmacol 2023; 13:20451253231220907.

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94 - Risperidone long acting injection

Risperidone long-acting injection

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95 - Risperidone intramuscular long acting injecti

Risperidone intramuscular long-acting injections

Schizophrenia and related psychoses CHAPTER 1 Risperidone long-acting injection In this section we give brief details on the range of risperidone LAIs (RLAIs) available around the world in 2024. We have done our best to identify each formulation by some unique property and by a trade name. These trade names do vary somewhat by country. Readers are directed to formal product information for full details of each formulation. Risperidone intramuscular long-acting injections Risperdal Consta – risperidone 2-weekly long-acting injection RLAI is now very rarely initiated in practice and here we give no information on starting doses or its therapeutic uses. It has been superseded by longer-acting risperidone and paliperidone injections with less complex pharmacokinetic profiles. Here we provide information on stopping RLAI and on switching to other formulations. In doing this, we have relied upon the following assumptions:1 Weeks after last injection 4 Consta injection given 0 10 20 2 6 Weeks Active moiety (ng/ml) 10 First missed dose Second missed dose Figure 1.1 Blood levels following discontinuation of treatment with 25mg every 2 weeks: last injection at week 4. Source: reproduced with permission from Wilson (2004).2 Timescale of plasma concentrations after last dose of RLAI 4–5 weeks Peak plasma concentration from last dose reached 6 weeks Plasma levels fall below threshold for therapeutic effect 7–8 weeks Plasma concentrations approach zero Switching from RLAI is complicated because, in regular dosing, plasma concentrations remain therapeutic for around 6 weeks following the last injection. Two weeks after the last injection (i.e. the time of the first missed injection) plasma levels are yet to peak and will in fact reach a peak on two occasions after this time (Figure 1.1).

100 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Table 1.23 provides general recommendations when switching from RLAI. These suggestions are aimed at ensuring that, when switching someone who is responsive to RLAI, a therapeutic plasma concentration of the new antipsychotic is established before risperidone concentrations become subtherapeutic. A further aim is to ensure that therapeutic levels of the new drug will be maintained during the first dosing interval. Rykindo® Rykindo is a 2-weekly injectable suspension of risperidone given in the gluteal muscle to patients who have previously responded and tolerated risperidone.8 After IM injection risperidone blood concentration peaks at 14 days and reaches steady state after two administrations. Oral supplementation is required for the first 7 days of treatment. The recommended starting dose is 25mg every 2 weeks, with a maximum dose of 50mg every 2 weeks. Dose adjustments can be made every 4 weeks. Patients on Consta can switch directly to Rykindo without needing oral supplementation. The first IM injection should be given 4–5 weeks after the last Consta administration (refer to Table 1.25 later in this section for equivalent doses). Like Consta, Rykindo must be stored in the refrigerator and allowed to sit at room temperature for at least 30 minutes before reconstitution. The reconstitution process is similar to that for Consta. Please refer to manufacturer’s advice for further details. Table 1.23 Switching from risperidone long-acting injections.3,4 Switching to Recommended method of switching Comments Oral risperidone Start oral tablets 4–5 weeks after the last RLAI injection 25mg/2 weeks = 2mg/day 37.5mg/2 weeks = 3mg/day 50mg/2 weeks = 4 mg/day5 Oral antipsychotic (not risperidone) Start oral antipsychotic 4–5 weeks after the last RLAI injection Monitor for adverse effects Paliperidone LAI6 Initiate the equivalent dose of the paliperidone LAI in place of the next scheduled dose of RLAI, then continue monthly administration (a second loading dose is not required and should not be given) 25mg/2 weeks = 50mg/monthly 37.5mg/2 weeks = 75mg/monthly 50mg/2 weeks = 100mg/monthly Risperidone ISM®* (Okedi, Risvan, and others)7 Initiate the equivalent dose of risperidone ISM in place of the next scheduled dose of RLAI and continue risperidone ISM at 28-day intervals 37.5mg/2 weeks = 75mg/28 days 50mg/2 weeks = 100mg/28 days Aripiprazole LAI Start oral aripiprazole 4–5 weeks after the last RLAI dose. Initiate ALAI 2 weeks after starting oral aripiprazole. Note that aripiprazole LAI can be initiated in two ways. For more information refer to the relevant section of this book and manufacturer’s advice. Antipsychotic LAI (not paliperidone or risperidone ISM) Start the new LAI 4–5 weeks after the last RLAI For some LAIs, oral trial and/or test dose may be required to establish response and tolerability * Formal recommendations recommend giving risperidone ISM in place of the next RLAI injection; i.e. 2 weeks after the last injection. A 4-week interval makes more sense because risperidone ISM will then be given shortly before the time of peak plasma levels from the last RLAI injection.

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96 - Risperidone subcutaneous long acting injectio

Risperidone subcutaneous long-acting injections

Schizophrenia and related psychoses CHAPTER 1 Risperidone ISM® (Risvan, Okedi) Risperidone ISM is an injectable suspension of risperidone suitable for stable patients who have previously responded and tolerated risperidone.7 Risperidone ISM employs in situ microparticle technology (ISM) to provide effective plasma levels as early as 2 hours following IM administration without requiring a loading dose or oral supplementation. An initial peak in plasma concentration is seen within 24–48 hours of administration with a second peak appearing between days 18 and 25. The delayed appearance of the second peak should be noted when assessing clinical efficacy, tolerability and when making changes to dose.7 The dosing interval for the injection is every 28 days (Table 1.24). Risperidone ISM is effective both as an acute9 and maintenance10 treatment and is generally well tolerated, although increased prolactin is common, as with all risperidone formulations.9 An indirect comparison with other SGA LAIs suggested somewhat better tolerability for risperidone ISM, but this study was authored by researchers linked to risperidone ISM’s manufacturers.11 Its main advantages are the absence of a loading dose requirement and the 28-day administration interval. The main disadvantages of risperidone ISM are that it is not suitable for patients requiring 2mg or 6mg/day of oral risperidone and that it may not be given to patients with a creatinine clearance of less than 60mL/minute. Risperidone subcutaneous long-acting injections Perseris® RBP-7000 (Perseris) is SC risperidone LAI that is available in 90mg and 120mg dosage forms. It is given every 28 days. The lower dose is equivalent to 3mg/day oral risperidone and the higher dose 4mg/day.12 There are no specific formulations corresponding to 2mg or 6mg/day of oral risperidone. However, two SC injections of 90mg RBP-7000 can be given to afford a similar plasma concentration to 6mg oral risperidone.13 Table 1.24 Initiation of risperidone ISM. Dose Route Initiation Day 1* 75mg or 100mg IM Deltoid or gluteal Maintenance Every 28 days (±3 days) thereafter 75mg IM or 100mg** IM Deltoid or gluteal * No loading dose is required but response and tolerability to oral risperidone must be assured by prior oral supplementation for at least 14 days. ** 75mg risperidone ISM is recommended as maintenance treatment by the manufacturer. It seems likely that 100mg will be required by most people (equivalent to 4mg/day oral risperidone).

102 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 RBP-7000 is suitable for SC administration in the abdominal region or back of the upper arm.14 It has a biphasic release pattern, with the first peak occurring 4–6 hours after administration and the second at 10–14 days post-dose.15 The active metabolite, paliperidone, has its first peak at 4–48 hours post-injection and the second at 7–11 days. Steady state is achieved after the second SC injection.16 The injection is acutely effective at both licensed doses (although 120mg may be better than 90mg), without the need for oral pre-treatment or oral supplementation, although tolerability with oral risperidone should be established before commencing treatment.17,18 In the longer term, monthly doses of 120mg are effective in maintaining response.19,20 RBP-7000 is rapidly active, achieving therapeutic plasma concentration on the first day.21 Disadvantages include the need for refrigerated storage and a complex multi-step injection procedure. The complexity of preparation and subcutaneous administration are new to psychiatry and failure to follow the instructions might result in dosage errors.14,21,22 RBP-7000 appears to be well tolerated and has a safety profile similar to that of oral risperidone. In clinical trials, the most commonly reported adverse effects were injection site pain and weight gain.16,19 See manufacturer’s advice on how to initiate RBP-7000.21 Uzedy® (TV-46000) Uzedy is a risperidone extended-release injectable suspension licensed for SC administration in the abdominal region or upper arm. It is available as a 1- or 2-monthly injection (see Table 1.25 for equivalent doses).23 Uzedy does not require oral supplementation or loading doses but response and tolerability to oral risperidone should be established before initiating treatment. The pre-filled syringe must be stored in the fridge and allowed to sit at room temperature for at least 30 minutes before administration. The syringe content is solid at refrigerated temperatures and converts to liquid at 20–25°C. Steady-state plasma level of Uzedy is reached after two SC injections. Therapeutic concentrations are seen on day one. Like other risperidone injections, Uzedy has a biphasic release pattern with two peak levels. In clinical trials,24–26 Uzedy was effective both acutely and as relapse prevention. One- monthly administration afforded numerically better protection against relapse than two-monthly injections.27 The most commonly reported adverse effects were injection site pain, injection site nodules, weight gain and EPSEs. Most participants had an F20 diagnosis for 20 years and were stabilised on oral risperidone for at least 12 weeks before trial entry.

Table 1.25 Equivalent doses – risperidone-based long-acting injections.6,7,28–33 Risperidone oral (mg/day) (bioavailability = 70%) Paliperidone oral (mg/day) (bioavailability = 28%) Risperidone LAI RBP-7000* (mg/28 days) Uzedy* (mg/ monthly) Uzedy* (mg/2 monthly) Paliperidone palmitate** (mg/monthly) Paliperidone palmitate** (mg/3-monthly) (Consta)* (mg/2weeks) Rykindo* (mg/2 weeks) Risperidone ISM˜† (mg/28 days) – – 12.5*** – – – – – – 3 25 – – 100 175 6 37.5 37.5 90 150 263 9 50 120 200 350 12 – – – –†† 250 525 * Bioavailability assumed to be 100%. ** Bioavailability has been confirmed to be 100%. ˜ Initiate risperidone ISM 24 hours after the last oral dose of risperidone. † Recommended starting dose for patients with renal or hepatic impairment8 or poor antipsychotic tolerability, not studied in clinical trials.34 †† 180mg (two SC injections of 90mg) of RBP-7000 is equivalent to 6mg daily risperidone dose.

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References

104 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References

Knox ED, et al. Clinical review of a long-acting, injectable formulation of risperidone. Clin Ther 2004; 26:1994–2002.
Wilson WH. A visual guide to expected blood levels of long-acting injectable risperidone in clinical practice. J Psychiatr Pract 2004; 10:393–401.
Royal Pharmaceutical Society. Psychotropic Drug Directory. Pharmaceutical Press; 2024 (last accessed May 2024); https://www.pharmaceuticalpress.com/products/psychotropic-drug-directory.
Datapharm. Electronic Medicines Compendium. 2024 (last accessed February 2025); https://www.medicines.org.uk/emc.
Nesvag R, et al. Serum concentrations of risperidone and 9-OH risperidone following intramuscular injection of long-acting risperidone compared with oral risperidone medication. Acta Psychiatr Scand 2006; 114:21–26.
Janssen-Cilag Ltd. Summary of Product Characteristics. Xeplion (paliperidone) 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg prolonged-release suspension for injection. 2023 (last accessed May 2024); https://www.medicines.org.uk/emc/product/7652/smpc.
ROVI Biotech Limited. Summary of Product Characteristics. Okedi (risperidone) 100mg powder and solvent for prolonged-release suspension for injection pre-filled syringes. 2023 (last accessed August 2024); https://www.medicines.org.uk/emc/product/13778/smpc.
Shandong Luye Pharmaceutical Co Ltd. Highlights of Prescribing Information. RYKINDO® (risperidone) for extended-release injectable suspension for intramuscular use. 2023 (last checked June 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/212849s000lbl.pdf.
Correll CU, et al. Efficacy and safety of once-monthly Risperidone ISM(®) in schizophrenic patients with an acute exacerbation. NPJ Schizophr 2020; 6:37.
Álamo C. Risperidone ISM as a new option in the clinical management of schizophrenia: a narrative review. Adv Ther 2022; 39: 4875–4891.
Sánchez P, et al. Extrapyramidal adverse events and anticholinergics use after the long-term treatment of patients with schizophrenia with the new long-acting antipsychotic Risperidone ISM(®): results from matching-adjusted indirect comparisons versus once-monthly formulations of paliperidone palmitate and aripiprazole monohydrate in 52-week studies. Ann Gen Psychiatry 2023; 22:33.
US Food and Drug Administration. Cross-Discipline Team Leader Review. RBP-7000 (risperidone-ATRIGEL). 2018 (last accessed February 2025); https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210655Orig1s000SumR.pdf.
Walling DP, et al. An open-label study to assess monthly risperidone injections (180 mg) following switch from daily oral risperidone (6 mg) in stable schizophrenic patients. Clin Drug Investig 2024; 44:251–260.
Invidior UK Limited. Highlights of Prescribing Information. Perseris (risperidone) for extended-release suspension, for subcutaneous use. 2022 (last checked June 2024); https://www.perserishcp.com/prescribing-information.pdf.
Højlund M, et al. Switching to long-acting injectable antipsychotics: pharmacological considerations and practical approaches. Expert Opin Pharmacother 2023; 24:1463–1489.
Tchobaniouk LV, et al. Once-monthly subcutaneously administered risperidone in the treatment of schizophrenia: patient considerations. Patient Prefer Adherence 2019; 13:2233–2241.
Nasser AF, et al. Efficacy, safety, and tolerability of rbp-7000 once-monthly risperidone for the treatment of acute schizophrenia: an 8-week, randomized, double-blind, placebo-controlled, multicenter phase 3 study. J Clin Psychopharmacol 2016; 36:130–140.
Le Moigne A, et al. Reanalysis of a phase 3 trial of a monthly extended-release risperidone injection for the treatment of acute schizophrenia. J Clin Psychopharmacol 2021; 41:76–77.
Andorn A, et al. Monthly extended-release risperidone (rbp-7000) in the treatment of schizophrenia: results from the phase 3 program. J Clin Psychopharmacol 2019; 39:428–433.
Le Moigne A, et al. PANSS individual item and marder dimension analyses from a pivotal trial of RBP-7000 (monthly extended-release risperidone) in schizophrenia patients. J Clin Psychiatry 2021; 82:21m13906.
Indivior UK Limited. Highlights of Prescribing Information: Perseris (risperidone) for extended-release injectable suspension, for subcutaneous use. 2018 (last accessed June 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210655s000lbl.pdf.
Citrome L. Sustained-release risperidone via subcutaneous injection: a systematic review of RBP-7000 (PERSERIS™) for the treatment of schizophrenia. Clin Schizophr Relat Psychoses 2018; 12:130–141.
Teva Neuroscience Inc. Highlights of Prescribing Information. UZEDY (risperidone) extended-release injectable suspension for subcutaneous use. 2024 (last checked June 2024); https://www.uzedy.com/globalassets/uzedy/prescribing-information.pdf.
Clinical Trials.gov. Study to Evaluate TV-46000 as Maintenance Treatment in Adult and Adolescent Participants With Schizophrenia (RISE). 2023 (last accessed February 2025); https://clinicaltrials.gov/study/NCT03503318.
Clinical Trials.gov. A Study to Test if TV-46000 is Safe for Maintenance Treatment of Schizophrenia (SHINE). 2022 (last accessed February 2025); https://classic.clinicaltrials.gov/ct2/show/NCT03893825.
Kane JM, et al. A long-term safety and tolerability study of tv-46000 for subcutaneous use in patients with schizophrenia: a phase 3, randomized, double-blinded clinical trial. CNS Drugs 2024; 38:625–636.
Kane JM, et al. Efficacy and safety of TV-46000, a long-acting, subcutaneous, injectable formulation of risperidone, for schizophrenia: a randomised clinical trial in the USA and Bulgaria. Lancet Psychiatry 2023; 10:934–943.
Karas A, et al. Perseris(TM): A new and long-acting, atypical antipsychotic drug-delivery system. P T 2019; 44:460–466.
Dexcel Pharma Ltd. Summary of Product Characteristics. Risperidone 1mg Film-Coated Tablets. 2023 (last checked May 2024); https:// www.medicines.org.uk/emc/product/8207/smpc.
Janssen Pharmaceutical Companies. Highlights of Prescribing Information: RISPERDAL® (risperidone) tablets, RISPERDAL® (risperidone) oral solution, RISPERDAL® M-TAB® (risperidone) orally disintegrating tablets. 2019 (last checked May 2024); https://www.accessdata.fda. gov/drugsatfda_docs/label/2019/020272s082,020588s070,021444s056lbl.pdf.

Schizophrenia and related psychoses CHAPTER 1 31. Janssen-Cilag Limited. Summary of Product Characteristics. Invega (paliperidone) 3 mg prolonged-release tablets. 2021 (last checked May 2024); https://www.medicines.org.uk/emc/product/6816. 32. Walling DP, et al. The steady-state comparative bioavailability of intramuscular risperidone ISM and oral risperidone: an open-label, one-sequence study. Drug Des Devel Ther 2021; 15:4371–4382. 33. Perlstein I, et al. Population pharmacokinetic modeling and simulation of tv-46000: a long-acting injectable formulation of risperidone. Clin Pharmacol Drug Dev 2022; 11:865–877. 34. Drugs.com. Risperidone Dosage. 2023 (last accessed June 2024); https://www.drugs.com/dosage/risperidone.html.

06 - Chapter 1 Schizophrenia and related psychoses

98 - Penfluridol weekly

Penfluridol weekly

06 - Chapter 1 Schizophrenia and related psychoses

99 - Background

Background

07 - Chapter 2 Bipolar disorder

01 - Lithium

Lithium

07 - Chapter 2 Bipolar disorder

02 - Mechanism of action

Mechanism of action

07 - Chapter 2 Bipolar disorder

03 - Clinical indications

Clinical indications

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 2 Lithium Mechanism of action Lithium is implicated in a wide range of biological processes, with a multiplicity of effects. Consequently it has proven very difficult to ascertain the key mechanism(s) of action of lithium in regulating mood and behaviour. For example, there is some older evidence that people with bipolar illness have higher intracellular concentrations of sodium and calcium than controls and that lithium can reduce these. Interestingly, calcium-related genes have been implicated by genetic studies in bipolar disorder.1 GSK3 (glycogen synthase kinase 3), CREB (cAMP response element-binding protein) and Na+/K+ adenosine triphosphatase (ATPase) related mechanisms may be important for lithium’s effects.2 Lithium may have neuroprotective effects that preserve the function of neurons and neuronal circuits.3 Lithium also promotes neurogenesis in the hippocampus, which is important for learning, memory and stress responses.4 A meta- analysis suggests lithium may prevent transition to dementia5 and lithium appears to be more effective than aducanumab in preventing cognitive decline.6 However, the largest study to date showed no beneficial effect on risk of neurocognitive disorders.7 Both reversible and irreversible neurotoxicity related to lithium are recognised adverse effects.8,9 Lithium is present in low levels in the environment (e.g. in drinking water sources) and environmental lithium concentration has been reported to be inversely related to suicide and dementia at a population level.10,11 Clinical indications Acute treatment of mania Lithium is effective for the treatment of mania, at a plasma level of 0.8–1.0mmol/L.12 If a faster onset of action is needed an adjunctive or single-agent antipsychotic with an evidence base for treating mania is recommended.12 It can be difficult to achieve Bipolar disorder

280 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 therapeutic plasma lithium levels rapidly and monitoring may be problematic if the patient is uncooperative. Treatment may be most successful in those without psychotic symptoms or evidence of rapid cycling.13 Treatment of acute mania in patients already on long-term lithium The 2016 British Association for Psychopharmacology guidelines12 suggest that in the event of relapse, an urgent plasma lithium level should be obtained to indicate the level of compliance with lithium therapy and inform possible dose adjustment. If lithium level measurement indicates non-compliance, the reason should be ascertained. If the lithium level is confirmed to be optimal, but the control of mania is inadequate, then adding a dopamine antagonist, dopamine partial agonist or valproate (given the conditions with regard to reproductive potential) is recommended.12 Bipolar depression Lithium is widely used in bipolar depression but evidence supporting robust efficacy for acute episodes is somewhat unconvincing.14,15 Evidence for prevention of depressive episodes is more compelling. Maintenance treatment of bipolar disorder Aim for the highest tolerable lithium plasma level in the range of 0.6–0.8mmol/L12,16 with the option to reduce it to 0.4–0.6mmol/L in case of good response but poor tolerance, or to increase it to 0.8–1.0mmol/L in case of insufficient response and good tolerance. The aim of treatment is complete remission and prevention of both manic and depressive episodes.17 Lithium is the best-performing mood stabiliser for bipolar disorder in practice with a prophylactic effectiveness similar to long-acting antipsychotics.18 In 2024, it remains the gold standard treatment for bipolar disorder.19 Augmentation of antidepressants in unipolar depression Approximately 30–50% of patients fail to respond to trials of first- or second-line antidepressants and outcomes from treatment-resistant depression are poor.20 Evidence- based guidelines for treating depressive disorders with antidepressants21 suggest that either lithium or quetiapine is the agent of first choice for augmenting the existing antidepressant and that lithium augmentation is most effective at a lithium plasma level of 0.6–1.0mmol/L. Recent meta-analyses suggest robust efficacy for lithium, alongside quetiapine, D2 partial agonists and ketamine.22,23 One meta-analysis suggested lithium to be most effective.24 Clinical predictors associated with a better outcome in lithium augmentation for treatment-resistant depression included more severe depressive symptomatology, psychomotor retardation, significant weight loss, a family history of major depression or a personal experience of more than three episodes.25 Of course, compliance with lithium augmentation should also be added to this list. Lithium is widely underused in resistant depression.26

07 - Chapter 2 Bipolar disorder

04 - Lithium and suicide

Lithium and suicide

07 - Chapter 2 Bipolar disorder

05 - Plasma levels

Plasma levels

Bipolar disorder CHAPTER 2 Prophylaxis of unipolar depression Lithium is significantly superior to antidepressants in preventing relapses that require hospitalisation, with a relative risk of 0.34.27 Lithium prophylaxis is indicated in unipolar depression (i) if a patient has suffered two depressive episodes in 5 years; (ii) after one episode if the episode is severe and there is a strong suicide risk; (iii) with indefinite treatment if there is adherence and adverse events are not problematic, particularly if a bipolar background is suspected.28 Other uses of lithium Lithium is also used to treat aggressive and self-mutilating behaviour and studies have confirmed benefits29 to both prevent and treat steroid-induced psychosis30 and to raise the white blood cell count in patients receiving clozapine.31 Lithium and suicide It is estimated that 15% of people with bipolar disorder eventually take their own life.32 A meta-analysis of clinical trials concluded that lithium reduced the risk of both attempted and completed suicide by 80% in patients with bipolar illness,33 and large database studies have shown that lithium-treated patients are less likely to complete suicide than patients treated with other mood-stabilising drugs.34 In patients with unipolar depression, lithium also seems to protect against suicide although the mechanism of this protective effect is unknown.33 As noted, environmental lithium has been reported to be inversely related to suicide at a population level.10,35 Plasma levels The minimum effective plasma level for prophylaxis of mood disorder episodes is probably 0.4mmol/L, with the optimal concentration being in the range 0.6–0.8mmol/L.36 Levels above 0.75mmol/L offer additional protection only against manic symptoms37 so the target range for prophylaxis is effectively 0.6–0.8mmol/L.16,38 Changes in plasma levels in either direction seem to worsen the risk of relapse.37 The optimal plasma level range in patients who have unipolar depression is less clear.39 Taking account of evidence from clinical trials, naturalistic studies and lithium in drinking water, studies seem to suggest that various benefits of lithium begin at a low concentration and increase over a narrow range up to 1.0mmol/L. Low-dose lithium regimens are under investigation but not yet clinically recommended.40 Children and adolescents may require higher plasma levels than adults to ensure that an adequate concentration of lithium is present in the central nervous system (CNS).41 Lithium is rapidly absorbed from the gastrointestinal tract but has a long distribution phase. Blood samples for plasma lithium level estimations should be taken 10–14 (ideally 12) hours post-dose in patients who are prescribed a single daily dose of a prolonged-release preparation at bedtime.12

07 - Chapter 2 Bipolar disorder

06 - Formulations

Formulations

07 - Chapter 2 Bipolar disorder

07 - Adverse effects

Adverse effects

07 - Chapter 2 Bipolar disorder

08 - Lithium toxicity

Lithium toxicity

282 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 Formulations There is no clinically significant difference in the pharmacokinetics of the two most widely prescribed brands of lithium in the UK: Priadel and Camcolit. In other countries, standard lithium carbonate tablets are often given twice or three times daily. The amount of elemental lithium varies by salt used. ■ ■Lithium carbonate 400mg tablets each contain 10.8mmol lithium. ■ ■Lithium citrate liquid is available in two strengths: ■ ■5.4mmol/5mL (equivalent to 200mg lithium carbonate). ■ ■10.8mmol/5mL (equivalent to 400mg lithium carbonate). Lack of clarity over which liquid preparation is intended when prescribing can lead to the patient receiving a sub-therapeutic or toxic dose. Liquid preparations need to be given 12-hourly. Adverse effects Most adverse effects are dose- and plasma level-related. These include mild gastrointestinal upset, fine tremor, polyuria and polydipsia. Polyuria may occur more frequently with twice daily dosing.42,43 Propranolol can be useful in lithium-induced tremor. Some skin conditions such as psoriasis and acne can be aggravated by lithium therapy. Lithium can also cause a metallic taste in the mouth, ankle oedema and weight gain. Lithium can cause a reduction in urinary concentrating capacity – nephrogenic diabetes insipidus – hence the occurrence of thirst and polyuria. This effect is usually reversible in the short to medium term, but renal effects may be irreversible after long- term treatment (>15 years).44 Lithium treatment can also lead to a reduction in the glomerular filtration rate (GFR) although the magnitude of the risk is uncertain.44 Lithium levels of >0.8mmol/L are associated with a higher risk of renal toxicity and prolonged lithium treatment of course requires regular monitoring of kidney function.45 Hypertension and a diagnosis of bipolar disorder worsen the risk of lithium-related chronic kidney disease.46 In the longer term, lithium increases the risk of hypothyroidism;47 in middle-aged women the risk may be up to 20%.48 A case has been made for testing thyroid autoantibodies in this group before starting lithium (to better estimate risk) and for performing thyroid function tests (TFTs) more frequently in the first year of treatment.49 Hypothyroidism is readily treated with thyroxine. TFTs usually return to normal when lithium is discontinued. Lithium also more rarely causes hyperthyroidism.50 Hyperparathyroidism causes hypercalcaemia in about 4% of patients51 and calcium levels should be monitored in patients on long-term treatment.50,52 Clinical consequences of chronically increased serum calcium include renal stones, osteoporosis, dyspepsia, hypertension and renal impairment. Lithium toxicity Toxic effects reliably occur at levels >1.5mmol/L and usually consist of gastrointestinal symptoms (increasing anorexia, nausea and diarrhoea) and CNS effects (muscle weakness, drowsiness, confusion, ataxia, coarse tremor and muscle twitching).53

07 - Chapter 2 Bipolar disorder

09 - Pre treatment tests

Pre-treatment tests

07 - Chapter 2 Bipolar disorder

10 - On treatment monitoring12,58

On-treatment monitoring12,58

07 - Chapter 2 Bipolar disorder

11 - Discontinuation

Discontinuation

Bipolar disorder CHAPTER 2 Above 2mmol/L, increased disorientation and seizures usually occur, which can progress to coma and ultimately death. In the presence of more severe symptoms, osmotic or forced alkaline diuresis should be used in a medical facility. Above 3mmol/L, peritoneal or haemodialysis is often used. These plasma levels are only a guide and individuals vary in their susceptibility to symptoms of toxicity. Neurotoxicity at normal plasma levels has also been described, as brain lithium levels may not be reflected by concentration in the plasma.54,55 Most risk factors for toxicity involve changes in sodium levels or in the way the body handles sodium, for example low salt diets, dehydration, drug interactions (see later Table 2.2) and some uncommon physical illnesses such as Addison’s disease. Information relating to the symptoms of toxicity and the common risk factors (especially drug interactions) should always be given to patients when treatment with lithium is initiated.56 This information should be repeated at appropriate intervals to make sure that it is clearly understood. Pre-treatment tests Before prescribing lithium, renal, thyroid and cardiac function should be checked. As a minimum, the estimated GFR (eGFR),57 urea and electrolytes (U&Es) and TFTs should be checked. A baseline calcium level is also helpful. An electrocardiogram (ECG) is also recommended in patients who have risk factors for, or existing, cardiovascular disease. A baseline measure of weight is also desirable. Lithium is a putative human teratogen. Women of child-bearing age should be advised to use a reliable form of contraception. See the section on psychotropics and pregnancy (Chapter 7). On-treatment monitoring12,58 Plasma lithium, eGFR, U&Es and TFTs should be checked every 6 months. More frequent tests may be required in those who are prescribed interacting drugs, who are elderly or who have established chronic kidney disease. Weight (or body mass index [BMI]) should also be monitored. Lithium monitoring in clinical practice in the UK is known to be suboptimal59 although there has been a modest improvement over time.60 The use of automated reminder systems has been shown to improve monitoring rates.61 Discontinuation Intermittent treatment with lithium may worsen the natural course of bipolar illness. A much greater than expected incidence of manic relapse is seen in the first few months after abruptly discontinuing lithium,62 even in patients who have been symptom-free for as long as 5 years.63 Lithium treatment should not be started unless there is a clear intention to continue it for several years and where compliance can be reasonably assured.64 This advice has obvious implications for initiating lithium treatment against a patient’s will (or in a patient known to be non-compliant with medication) during a period of acute illness. The risk of relapse is probably reduced by decreasing the dose gradually over a period of at least a month65 and avoiding decremental plasma level reductions of >0.2mmol/L.37

07 - Chapter 2 Bipolar disorder

12 - Interactions with other drugs7072

Interactions with other drugs70–72

284 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 In contrast with these recommendations, a naturalistic study found that, in patients who had been in remission for at least 2 years and had discontinued lithium very slowly, the recurrence rate was at least three times greater than in patients who continued lithium and that significant survival differences persisted for many years. Patients maintained on high lithium levels before discontinuation were particularly prone to relapse.66 One large US study based on prescription records found that half of those prescribed lithium took almost all of their prescribed doses, a quarter took between 50% and 80% and the remaining quarter took less than 50%. A third of patients took lithium for less than 6 months in total.67 A large audit found that 1 in 10 patients prescribed long-term lithium treatment had a plasma level below the therapeutic range.68 It is clear that suboptimal adherence limits the effectiveness of lithium in clinical practice. One database study suggested the extent to which lithium was taken was directly related to the risk of suicide (more prescriptions were associated with lower suicide rate).69 Less convincing data support the emergence of depressive symptoms in bipolar patients after lithium discontinuation.62 There are few data relating to patients with unipolar depression. Table 2.1 summarises the prescribing and monitoring of lithium. Interactions with other drugs70–72 Because of lithium’s relatively narrow therapeutic index, pharmacokinetic interactions with other drugs can precipitate lithium toxicity. Most clinically significant interactions are largely with drugs that alter renal sodium handling. Rarely, neurotoxicity results from co-prescribing lithium and antipsychotics.73,74 ACE inhibitors Angiotensin-converting enzyme (ACE) inhibitors can (i) reduce thirst, which can lead to mild dehydration; and (ii) increase renal sodium loss leading to increased sodium reabsorption by the kidney, resulting in an increase in lithium plasma levels. The magnitude of Table 2.1 Lithium: prescribing and monitoring. Indications Mania, hypomania, prophylaxis of bipolar affective disorder and recurrent depression. Reduces aggression and suicidality. Pre-lithium work-up Estimated glomerular filtration rate (eGFR) and thyroid function tests (TFTs). ECG recommended in patients who have risk factors for, or existing, cardiovascular disease. Baseline measure of weight desirable. U&Es (including calcium). Prescribing Start at 400mg at night (200mg in the elderly). Plasma level after 7 days, then 7 days after every dose change until the desired level is reached (0.4mmol/L may be effective in unipolar depression, 0.6–1.0mmol/L in bipolar illness, slightly higher levels in this range in difficult to treat mania). Blood should be taken 12 hours after the last dose. Take care when prescribing liquid preparations to clearly specify the strength required. Monitoring Plasma lithium every 6 months (more frequent monitoring is necessary in those prescribed interacting drugs, the elderly and those with established renal impairment or other relevant physical illness). eGFR, U&Es and TFTs every 6 months. Weight (or body mass index) should also be monitored. Stopping Reduce slowly over at least 1 month and preferably 3 months. Avoid reductions in plasma levels of

0.2mmol/L at a time (see section on discontinuation).

Bipolar disorder CHAPTER 2 this effect is variable, from no increase to a fourfold increase. The full effect can take several weeks to develop. The risk seems to be increased in patients with heart failure, dehydration and renal impairment (presumably because of changes in fluid balance/handling). In the elderly, ACE inhibitors increase sevenfold the risk of hospitalisation due to lithium toxicity. ACE inhibitors can also precipitate renal failure so, if co-prescribed with lithium, more frequent monitoring of eGFR and plasma lithium is required. The following drugs are ACE inhibitors: captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril. Care is also required with the angiotensin II receptor antagonists candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan. Diuretics Diuretics can reduce the renal clearance of lithium, the magnitude of this effect being greater with thiazide than with loop diuretics. Lithium levels usually rise within 10 days of a thiazide diuretic being prescribed; the magnitude of the rise is unpredictable and can vary from an increase of 25% to 400%. The following drugs are thiazide (or related) diuretics: bendroflumethiazide, chlortalidone, cyclopenthiazide, indapamide, metolazone and xipamide. Although there are case reports of lithium toxicity induced by loop diuretics, many patients receive this combination of drugs without apparent problems. The risk of an interaction seems to be greatest in the first month after the loop diuretic has been prescribed and additional lithium plasma level monitoring during this time is recommended if these drugs are co-prescribed. Loop diuretics can increase sodium loss and subsequent reabsorption by the kidney. Patients taking loop diuretics may also have been advised to restrict their salt intake; this may contribute to the risk of lithium toxicity in these individuals. The following drugs are loop diuretics: bumetanide, furosemide and torasemide. Non-steroidal anti-inflammatory drugs Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the synthesis of renal prostaglandins, thereby reducing renal blood flow and possibly increasing renal reabsorption of sodium and therefore lithium. The magnitude of the rise in lithium concentration is unpredictable for any given patient; case reports vary from increases of around 10% to over 400%. The onset of effect also seems to be variable, from a few days to several months. Risk appears to be increased in those patients who have impaired renal function, renal artery stenosis or heart failure and who are dehydrated or on a low salt diet. There are a number of case reports of an interaction between lithium and COX-2 inhibitors. NSAIDs do not appear to diminish the therapeutic effects of lithium,75 as has previously been reported. NSAIDs (or COX-2 inhibitors) can be very carefully combined with lithium, but they should be prescribed regularly, not intermittently, and more frequent plasma lithium monitoring is essential. Some NSAIDs can be purchased without a prescription, so it is particularly important that patients are aware of the potential for interaction. The following drugs are NSAIDs or COX-2 inhibitors: aceclofenac, acemetacin, celecoxib, dexibuprofen, dexketoprofen, diclofenac, diflunisal, etodolac, etoricoxib,

07 - Chapter 2 Bipolar disorder

13 - References

References

286 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, lumiracoxib, mefenamic acid, meloxicam, nabumetone, naproxen, piroxicam, sulindac, tenoxicam and tiaprofenic acid. Carbamazepine There are rare reports of neurotoxicity when carbamazepine is combined with lithium. Most reports are old and in the context of treatment involving high plasma lithium levels. It is of note though that carbamazepine can cause hyponatraemia, which may in turn lead to lithium retention and toxicity. Similarly, rare reports of CNS toxicity implicate selective serotonin reuptake inhibitors (SSRIs), another group of drugs that can cause hyponatraemia. Table 2.2 summarises drugs that may clinically interact with lithium. References

Bray NJ, et al. The genetics of neuropsychiatric disorders. Brain Neurosci Adv 2019; 2:2398212818799271.
Bortolozzi A, et al. New advances in the pharmacology and toxicology of lithium: a neurobiologically oriented overview. Pharmacol Rev 2024; 76:323–357.
Jope RS, et al. Lithium to the rescue. Cerebrum 2016; 2016:cer-02-16.
Hanson ND, et al. Lithium, but not fluoxetine or the corticotropin-releasing factor receptor 1 receptor antagonist R121919, increases cell proliferation in the adult dentate gyrus. J Pharmacol Exp Ther 2011; 337:180–186.
Matsunaga S, et al. Lithium as a treatment for Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis 2015; 48:403–410.
Terao I, et al. Comparative efficacy of lithium and aducanumab for cognitive decline in patients with mild cognitive impairment or Alzheimer’s disease: a systematic review and network meta-analysis. Ageing Res Rev 2022; 81:101709.
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Netto I, et al. Reversible lithium neurotoxicity: review of the literature. Prim Care Companion CNS Disord 2012; 14:PCC.11r01197.
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Hui TP, et al. A systematic review and meta-analysis of clinical predictors of lithium response in bipolar disorder. Acta Psychiatr Scand 2019; 140:94–115. Table 2.2 Lithium: clinically relevant drug interactions. Drug group Magnitude of effect Timescale of effect Additional information ACE inhibitors Unpredictable Up to fourfold increases in [Li] Develops over several weeks Sevenfold increased risk of hospitalisation for lithium toxicity in the elderly Angiotensin II receptor antagonists may be associated with similar risk Thiazide diuretics Unpredictable Up to fourfold increases in [Li] Usually apparent in first 10 days Loop diuretics are safer Any effect will be apparent in the first month NSAIDs Unpredictable From 10% to over fourfold increases in [Li] Variable; few days to several months NSAIDs are widely used on a when necessary basis Can be bought without a prescription ACE, angiotensin-converting enzyme; [Li], lithium concentraction; NSAIDs, non-steroidal anti-inflammatory drugs.

Bipolar disorder CHAPTER 2 14. Bahji A, et al. Comparative efficacy and tolerability of pharmacological treatments for the treatment of acute bipolar depression: a systematic review and network meta-analysis. J Affect Disord 2020; 269:154–184. 15. Taylor DM, et al. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis. Acta Psychiatr Scand 2014; 130:452–469. 16. Nolen WA, et al. What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium. Bipolar Disord 2019; 21:394–409. 17. Severus E, et al. Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis. Int J Bipolar Disord 2014; 2:15. 18. Lähteenvuo M, et al. Real-world effectiveness of pharmacological treatments for bipolar disorder: register-based national cohort study. Br J Psychiatry 2023; 223:456–464. 19. Airainer M, et al. Lithium, the gold standard drug for bipolar disorder: analysis of current clinical studies. Naunyn Schmiedebergs Arch Pharmacol 2024; 397:9723–9743. 20. Dunner DL, et al. Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression. J Clin Psychiatry 2006; 67:688–695. 21. Cleare A, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol 2015; 29:459–525. 22. Scott F, et al. Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression. J Psychopharmacol 2023; 37:268–278. 23. Nuñez NA, et al. Augmentation strategies for treatment resistant major depression: a systematic review and network meta-analysis. J Affect Disord 2022; 302:385–400. 24. Vázquez GH, et al. Efficacy and tolerability of combination treatments for major depression: antidepressants plus second-generation antipsychotics vs. esketamine vs. lithium. J Psychopharmacol 2021; 35:890–900. 25. Bauer M, et al. Role of lithium augmentation in the management of major depressive disorder. CNS Drugs 2014; 28:331–342. 26. Ercis M, et al. When and how to use lithium augmentation for treating major depressive disorder. J Clin Psychiatry 2023; 84:23ac14813. 27. Cipriani A, et al. Lithium versus antidepressants in the long-term treatment of unipolar affective disorder. Cochrane Database Syst Rev 2006; 4:CD003492. 28. Abou-Saleh MT, et al. Lithium in the episode and suicide prophylaxis and in augmenting strategies in patients with unipolar depression. Int J Bipolar Disord 2017; 5:11. 29. Correll CU, et al. Biological treatment of acute agitation or aggression with schizophrenia or bipolar disorder in the inpatient setting. Ann Clin Psychiatry 2017; 29:92–107. 30. Sirois F. Steroid psychosis: a review. Gen Hosp Psychiatry 2003; 25:27–33. 31. Aydin M, et al. Continuing clozapine treatment with lithium in schizophrenic patients with neutropenia or leukopenia: brief review of literature with case reports. Ther Adv Psychopharmacol 2016; 6:33–38. 32. Harris EC, et al. Excess mortality of mental disorder. Br J Psychiatry 1998; 173:11–53. 33. Cipriani A, et al. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ 2013; 346:f3646. 34. Hayes JF, et al. Self-harm, unintentional injury, and suicide in bipolar disorder during maintenance mood stabilizer treatment: a UK population-based electronic health records study. JAMA Psychiatry 2016; 73:630–637. 35. Fadaei A. An investigation into the association between suicide mortality rate and lithium levels in potable water: a review study. Int Clin Psychopharmacol 2023; 38:73–80. 36. Nolen WA, et al. The association of the effect of lithium in the maintenance treatment of bipolar disorder with lithium plasma levels: a post hoc analysis of a double-blind study comparing switching to lithium or placebo in patients who responded to quetiapine (Trial 144). Bipolar Disord 2013; 15:100–109. 37. Severus WE, et al. What is the optimal serum lithium level in the long-term treatment of bipolar disorder—a review? Bipolar Disord 2008; 10:231–237. 38. Manchia M, et al. Lithium and its effects: does dose matter? Int J Bipolar Disord 2024; 12:23. 39. Young AH. Lithium for long-term treatment of unipolar depression. Lancet Psychiatry 2017; 4:511–512. 40. Strawbridge R, et al. Lithium: how low can you go? Int J Bipolar Disord 2024; 12:4. 41. Moore CM, et al. Brain-to-serum lithium ratio and age: an in vivo magnetic resonance spectroscopy study. Am J Psychiatry 2002; 159:1240–1242. 42. Bowen RC, et al. Less frequent lithium administration and lower urine volume. Am J Psychiatry 1991; 148:189–192. 43. Ljubicic D, et al. Lithium treatments: single and multiple daily dosing. Can J Psychiatry 2008; 53:323–331. 44. Gong R, et al. What we need to know about the effect of lithium on the kidney. Am J Physiol Renal Physiol 2016; 311:F1168–F1171. 45. Aiff H, et al. Effects of 10 to 30 years of lithium treatment on kidney function. J Psychopharmacol 2015; 29:608–614. 46. Parsaik AK, et al. Effects of long-term lithium therapy on kidney functioning in mood disorders: a population-based historical cohort study. Bipolar Disord 2024; doi: 10.1111/bdi.13501. 47. Frye MA, et al. Depressive relapse during lithium treatment associated with increased serum thyroid-stimulating hormone: results from two placebo-controlled bipolar I maintenance studies. Acta Psychiatr Scand 2009; 120:10–13. 48. Johnston AM, et al. Lithium-associated clinical hypothyroidism. Prevalence and risk factors. Br J Psychiatry 1999; 175:336–339. 49. Livingstone C, et al. Lithium: a review of its metabolic adverse effects. J Psychopharmacol 2006; 20:347–355. 50. McKnight RF, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet 2012; 379:721–728. 51. Vandermeulen L, et al. Lithium-associated hypercalcemia and hyperparathyroidism: a systematic review and meta-analysis. World J Biol Psychiatry 2024; 25:417–429.

288 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 52. Czarnywojtek A, et al. Effect of lithium carbonate on the function of the thyroid gland: mechanism of action and clinical implications. J Physiol Pharmacol 2020; 71:191–199. 53. Ott M, et al. Lithium intoxication: incidence, clinical course and renal function – a population-based retrospective cohort study. J Psychopharmacol 2016; 30:1008–1019. 54. Bell AJ, et al. Lithium neurotoxicity at normal therapeutic levels. Br J Psychiatry 1993; 162:689–692. 55. Smith FE, et al. 3D 7Li magnetic resonance imaging of brain lithium distribution in bipolar disorder. Mol Psychiatry 2018; 23:2184–2191. 56. Gerrett D, et al. Prescribing and monitoring lithium therapy: summary of a safety report from the National Patient Safety Agency. BMJ 2010; 341:c6258. 57. Morriss R, et al. Lithium and eGFR: a new routinely available tool for the prevention of chronic kidney disease. Br J Psychiatry 2008; 193:93–95. 58. National Institute for Health and Care Excellence. Bipolar disorder: assessment and management. Clinical guideline [CG185]. 2014 (last updated December 2023, last accessed October 2024); https://www.nice.org.uk/guidance/cg185. 59. Collins N, et al. Standards of lithium monitoring in mental health trusts in the UK. BMC Psychiatry 2010; 10:80. 60. Paton C, et al. Monitoring lithium therapy: the impact of a quality improvement programme in the UK. Bipolar Disord 2013; 15:865–875. 61. Kirkham E, et al. Impact of active monitoring on lithium management in Norfolk. Ther Adv Psychopharmacol 2013; 3:260–265. 62. Cavanagh J, et al. Relapse into mania or depression following lithium discontinuation: a 7-year follow-up. Acta Psychiatr Scand 2004; 109:91–95. 63. Yazici O, et al. Controlled lithium discontinuation in bipolar patients with good response to long-term lithium prophylaxis. J Affect Disord 2004; 80:269–271. 64. Goodwin GM. Recurrence of mania after lithium withdrawal. Implications for the use of lithium in the treatment of bipolar affective disorder. Br J Psychiatry 1994; 164:149–152. 65. Baldessarini RJ, et al. Effects of the rate of discontinuing lithium maintenance treatment in bipolar disorders. J Clin Psychiatry 1996; 57:441–448. 66. Biel MG, et al. Continuation versus discontinuation of lithium in recurrent bipolar illness: a naturalistic study. Bipolar Disord 2007; 9:435–442. 67. Sajatovic M, et al. Treatment adherence with lithium and anticonvulsant medications among patients with bipolar disorder. Psychiatr Serv 2007; 58:855–863. 68. Paton C, et al. Lithium in bipolar and other affective disorders: prescribing practice in the UK. J Psychopharmacol 2010; 24:1739–1746. 69. Kessing LV, et al. Suicide risk in patients treated with lithium. Arch Gen Psychiatry 2005; 62:860–866. 70. Pharmaceutical Press. Medicines Complete 2024; https://www.pharmaceuticalpress.com/services/medicinescomplete/. 71. Juurlink DN, et al. Drug-induced lithium toxicity in the elderly: a population-based study. J Am Geriatr Soc 2004; 52:794–798. 72. Finley PR. Drug interactions with lithium: an update. Clin Pharmacokinet 2016; 55:925–941. 73. Netto I, et al. Lithium neurotoxicity due to second-generation antipsychotics combined with lithium: a systematic review. Prim Care Companion CNS Disord 2019; 21:17r02225. 74. Konieczny K, et al. The syndrome of irreversible lithium-effectuated neurotoxicity: a scoping review. Alpha Psychiatry 2024; 25:190–205. 75. Kohler-Forsberg O, et al. Nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol do not affect 6-month mood-stabilizing treatment outcome among 482 patients with bipolar disorder. Depress Anxiety 2017; 34:281–290.

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14 - Valproate

Valproate

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15 - Mechanism of action1

Mechanism of action1

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Formulations

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Indications

Bipolar disorder CHAPTER 2 Valproate Mechanism of action1 Valproate is a simple branched-chain fatty acid. Its mechanism of action is complex and not fully understood. Valproate inhibits the catabolism of gamma-aminobutyric acid (GABA), reduces the turnover of arachidonic acid, activates the extracellular signal- regulated kinase (ERK) pathway and thus alters synaptic plasticity, interferes with intracellular signalling, promotes brain-derived neurotrophic factor (BDNF) expression and reduces levels of protein kinase C. Research has focused on the ability of valproate to alter the expression of various genes that are involved in transcription regulation, cytoskeletal modifications and ion homeostasis. Other mechanisms that have been proposed include depletion of inositol and indirect effects on non-GABA pathways through the inhibition of voltage-gated sodium channels. There is a growing literature relating to the potential use of valproate as an adjunctive treatment in several types of cancer,2 a property which may also confer some effects on neuroplasticity.3 Formulations Valproate is available in the UK in three forms: sodium valproate and valproic acid (licensed for the treatment of epilepsy) and semi-sodium valproate (licensed for the treatment of acute mania). Both semi-sodium and sodium valproate are metabolised to valproic acid, which is responsible for the pharmacological activity of all three preparations.4 Clinical studies of the treatment of affective disorders variably use sodium valproate, semi-sodium valproate, ‘valproate’ or valproic acid. The great majority have used semi-sodium valproate. It is unclear if there is any difference in efficacy between valproic acid, valproate semi-sodium and sodium valproate. One large US quasi-experimental study found that in-patients who initially received the semi-sodium preparation had a hospital stay that was a third longer than patients who initially received valproic acid.5 One clear difference is that controlled-release sodium valproate (Epilim Chrono6) can be administered as a once daily dose whereas other sodium and semi-sodium valproate preparations require at least twice daily administration. Overall, there are probably no important differences between different valproate forms,7 except for the small differences in bioavailability related to valproate content. Indications Randomised controlled trials (RCTs) have shown valproate to be effective in the treatment of mania,8,9 with a response rate of 50% and a number needed to treat (NNT) of 2–4,10 although large negative studies do exist.11 One RCT found lithium to be more effective overall than valproate9 but a large (n = 300) randomised open trial of 12 weeks’ duration found lithium and valproate to be equally effective in the treatment of acute mania.12 Valproate may be effective in patients who have failed to respond to lithium.13 It may be less effective than olanzapine, both as monotherapy14 and as an adjunctive treatment to lithium12 in acute mania. One network meta-analysis reported that valproate was

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18 - Plasma levels

Plasma levels

290 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 less effective but better tolerated than lithium.15 Overall, data relating to efficacy in mania are less convincing for valproate than for lithium and a range of antipsychotics.16,17 A meta-analysis of four small RCTs concluded that valproate is effective in bipolar depression with a small to medium effect size.18 A 2020 meta-analysis placed divalproex fifth out of 21 treatments for bipolar depression.19 Valproate has limited utility in rapid-cycling bipolar disorder.20 Although open-label studies suggest that valproate is effective in the prophylaxis of bipolar affective disorder,21 RCT data are limited.22,23 Bowden et al.24 found no difference between lithium, valproate and placebo in the primary outcome measure, time to any mood episode, although valproate was superior to lithium and placebo on some secondary outcome measures. In another RCT22 there was no difference in relapse rates between valproate and olanzapine. A post-hoc analysis of data from this study found that patients with rapid-cycling illness had a better very early response to valproate than to olanzapine but that this advantage was not maintained.23 Outcomes with respect to manic symptoms for those who did not have a rapid-cycling illness were better at 1 year with olanzapine than with valproate. In a further 20-month RCT of lithium versus valproate in patients with rapid-cycling illness, both the relapse and attrition rates were high, and no difference in efficacy between valproate and lithium was apparent.25 The independent BALANCE study found lithium to be numerically superior to valproate, and the combination of lithium and valproate statistically superior to valproate alone.26 Aripiprazole in combination with valproate is superior to valproate alone.27 Overall, data suggest that adjunctive valproate provides additional protection against relapse.28 In the UK, the National Institute for Health and Care Excellence (NICE) recommends valproate as a first-line option for the treatment of acute episodes of mania, in combination with an antidepressant for the treatment of acute episodes of depression, and for prophylaxis,29 but importantly NOT in women of child-bearing potential.29,30 A Cochrane review concluded that the evidence supporting the use of valproate as prophylaxis is limited.31 Valproate is sometimes used to treat aggressive behaviours of variable aetiology.32 One RCT (n = 16) failed to detect any advantage for risperidone augmented with valproate over risperidone alone in reducing hostility in patients with schizophrenia.33 A mirror-image study found that, in patients with schizophrenia or bipolar disorder in a secure setting, valproate decreased agitation.34 There is a small positive placebo-controlled RCT of valproate in generalised anxiety disorder.35 Valproate may also have preventive benefits against COVID-19.36 Plasma levels The pharmacokinetics of valproate are complex, following a three-compartmental model and showing protein-binding saturation. Plasma level monitoring is supposedly of more limited use than with lithium or carbamazepine.37 There may be a linear association between valproate serum levels and response in acute mania, with serum levels <55mg/L being no more effective than placebo, and levels >94mg/L being associated with the most robust response.38 Optimal serum levels during the maintenance phase are unknown, but are likely to be at least 50mg/L.39 Achieving therapeutic plasma levels rapidly using a loading dose regimen is generally well tolerated. Plasma levels can also be used to detect non-compliance or toxicity. Using total valproate concentration (the standard method) is no less useful than free valproate levels in most situations.40

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19 - Adverse effects

Adverse effects

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20 - Pre treatment tests

Pre-treatment tests

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21 - On treatment monitoring

On-treatment monitoring

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22 - Discontinuation

Discontinuation

Bipolar disorder CHAPTER 2 Adverse effects Valproate can cause both gastric irritation and hyperammonaemia,41 both of which can lead to nausea. Lethargy and confusion can occasionally occur with starting doses above 750mg/day. Weight gain can be significant,42 particularly when valproate is used in combination with clozapine. Valproate causes dose-related tremor in up to a quarter of patients.43 In most of these patients, it is intention/postural tremor that is problematic, but a very small proportion develop parkinsonism associated with cognitive decline; these symptoms are reversible when valproate is discontinued.44 Hair loss (with curly regrowth)45 and peripheral oedema can occur, as can thrombocytopenia, leucopenia, red cell hypoplasia and pancreatitis.46 Valproate can cause hyperandrogenism in women47 and has been linked with the development of polycystic ovaries although the evidence supporting this association is conflicting. Valproate is a major human teratogen (see Chapter 7). Valproate may also affect male fertility48 but its teratogenic effect in men is disputed.49–51 Valproate may very rarely cause fulminant hepatic failure. Young children receiving multiple anticonvulsants are most at risk. Any patient with raised liver function tests (LFTs; common in early treatment52) should be evaluated clinically and other markers of hepatic function such as albumin and clotting time should be checked. Many adverse effects of valproate are dose-related (and often peak plasma level related) and increase sharply in frequency and severity when the plasma concentration is >100mg/L. The once daily modified-release form of sodium valproate does not produce as high peak plasma levels as the conventional formulation, and so may be better tolerated. Valproate and other antiseizure medications have been associated with an increased risk of suicidal behaviour53 but this finding is not consistent across studies.54 Patients with depression55 or who take another antiseizure medication that increases the risk of developing depression may be a subgroup at greater risk.56 Pre-treatment tests Baseline full blood count (FBC), LFTs and weight or BMI are recommended by NICE in the UK. On-treatment monitoring In the UK, NICE recommends that an FBC and LFTs should be repeated after 6 months, and that BMI should be monitored. Valproate summary of product characteristics (SPCs) recommends more frequent LFTs during the first 6 months with albumin and clotting measured if enzyme levels are abnormal. Where there is clear hypalbuminaemia, free valproate levels should be measured. Discontinuation It is unknown if abrupt discontinuation of valproate worsens the natural course of bipolar illness in the same manner as lithium. One small naturalistic retrospective study suggested that it might.57 Until further data are available, if valproate is to be discontinued, it should be done slowly over at least a month, preferably longer. In people with epilepsy, valproate withdrawal is associated with depression, falls and hospital admissions.58

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23 - Use in women of child bearing age

Use in women of child-bearing age

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24 - Interactions with other drugs

Interactions with other drugs

292 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 Use in women of child-bearing age Valproate is an established human teratogen. NICE recommends that alternative antiseizure medications are preferred in women with epilepsy59 and that valproate should not be used to treat bipolar illness in women of child-bearing age.29 The teratogenic potential of valproate is not widely appreciated and in the past many women of child-bearing age were not advised of the need for contraception or prophylactic folate.60,61 Valproate may also cause impaired cognitive function in children exposed to valproate in utero.62 Valproate is now contraindicated in women of child-bearing potential in many countries (see Chapter 7). Interactions with other drugs Valproate is highly protein bound and can be displaced by other protein bound drugs such as aspirin, leading to toxicity. Aspirin also inhibits the metabolism of valproate; a dose of at least 300mg aspirin is required.63 Other, less strongly protein bound drugs such as warfarin can be displaced by valproate, leading to higher free levels and toxicity. Valproate is hepatically metabolised; drugs that inhibit CYP enzymes can increase valproate levels (e.g. erythromycin, fluoxetine and cimetidine). Valproate can increase the plasma levels of some drugs by inhibition of glucuronidation. Examples include tricyclic antidepressants (TCAs; particularly clomipramine64), lamotrigine,65 quetiapine,66 warfarin67 and phenobarbital. Valproate may also significantly lower plasma olanzapine concentrations although the mechanism is unknown.68 Pharmacodynamic interactions also occur. The anticonvulsant effect of valproate is antagonised by drugs that lower the seizure threshold (e.g. antipsychotics). Weight gain can be exacerbated by other drugs such as clozapine and olanzapine. Table 2.3 summarises the prescribing and monitoring of valproate. Table 2.3 Valproate: prescribing and monitoring. Indications Mania, hypomania, bipolar depression and prophylaxis of bipolar affective disorder. May reduce aggression in a range of psychiatric disorders (although data are weak). Pre-valproate work-up FBC and LFTs. Baseline measure of weight desirable. Prescribing Titrate dose upwards against response and adverse effects. Loading doses can be used and are generally well tolerated. Modified-release sodium valproate (Epilim Chrono6) can be given once daily. All other formulations must be administered at least twice daily. Plasma levels can be used to assure adequate dosing and treatment compliance. Blood should be taken immediately before the next dose. Monitoring FBC and LFTs if clinically indicated. Weight (or body mass index). Stopping Reduce slowly over at least 1 month, preferably longer.

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25 - References

References

Bipolar disorder CHAPTER 2 References

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294 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 33. Citrome L, et al. Risperidone alone versus risperidone plus valproate in the treatment of patients with schizophrenia and hostility. Int Clin Psychopharmacol 2007; 22:356–362. 34. Gobbi G, et al. Efficacy of topiramate, valproate, and their combination on aggression/agitation behavior in patients with psychosis. J Clin Psychopharmacol 2006; 26:467–473. 35. Aliyev NA, et al. Valproate (depakine-chrono) in the acute treatment of outpatients with generalized anxiety disorder without psychiatric comorbidity: randomized, double-blind placebo-controlled study. Eur Psychiatry 2008; 23:109–114. 36. Watson A, et al. Valproic acid use is associated with diminished risk of contracting COVID-19, and diminished disease severity: epidemiologic and in vitro analysis reveal mechanistic insights. PLoS One 2024; 19:e0307154. 37. Haymond J, et al. Does valproic acid warrant therapeutic drug monitoring in bipolar affective disorder? 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The frequency of reversible parkinsonism and cognitive decline associated with valproate treatment: a study of 364 patients with different types of epilepsy. Epilepsia 2006; 47:2183–2185. 45. Praharaj SK, et al. Valproate-associated hair abnormalities: pathophysiology and management strategies. Hum Psychopharmacol 2022; 37:e2814. 46. Gerstner T, et al. Valproic acid-induced pancreatitis: 16 new cases and a review of the literature. J Gastroenterol 2007; 42:39–48. 47. Joffe H, et al. Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism in women with bipolar disorder. Biol Psychiatry 2006; 59:1078–1086. 48. Asghar MA, et al. Understanding the impact of valproate on male fertility: insights from preclinical and clinical meta-analysis. BMC Pharmacol Toxicol 2024; 25:69. 49. Garey JD, et al. Paternal valproate treatment and risk of childhood neurodevelopmental disorders: precautionary regulatory measures are insufficiently substantiated. Birth Defects Res 2024; 116:e2392. 50. Christensen J, et al. Valproate use during spermatogenesis and risk to offspring. JAMA Netw Open 2024; 7:e2414709. 51. Angus-Leppan H, et al. New valproate regulations, informed choice and seizure risk. J Neurol 2024; 271:5671–5686. 52. Bjornsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scand 2008; 118:281–290. 53. Patorno E, et al. Anticonvulsant medications and the risk of suicide, attempted suicide, or violent death. JAMA 2010; 303:1401–1409. 54. Gibbons RD, et al. Relationship between antiepileptic drugs and suicide attempts in patients with bipolar disorder. Arch Gen Psychiatry 2009; 66:1354–1360. 55. Arana A, et al. Suicide-related events in patients treated with antiepileptic drugs. N Engl J Med 2010; 363:542–551. 56. Andersohn F, et al. Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior. Neurology 2010; 75:335–340. 57. Franks MA, et al. Bouncing back: is the bipolar rebound phenomenon peculiar to lithium? A retrospective naturalistic study. J Psychopharmacol 2008; 22:452–456. 58. Mbizvo GK, et al. Morbidity and mortality risks associated with valproate withdrawal in young adults with epilepsy. Brain 2024; 147:3426–3441. 59. National Institute for Health and Care Excellence. Epilepsies in children, young people and adults. NICE guideline [NG217]. 2022 (last accessed October 2024); https://www.nice.org.uk/guidance/ng217. 60. James L, et al. Informing patients of the teratogenic potential of mood stabilising drugs; a case notes review of the practice of psychiatrists. J Psychopharmacol 2007; 21:815–819. 61. James L, et al. Mood stabilizers and teratogenicity – prescribing practice and awareness amongst practising psychiatrists. J Mental Health 2009; 18:137–143. 62. Meador KJ, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009; 360:1597–1605. 63. Sandson NB, et al. An interaction between aspirin and valproate: the relevance of plasma protein displacement drug-drug interactions. Am J Psychiatry 2006; 163:1891–1896. 64. Fehr C, et al. Increase in serum clomipramine concentrations caused by valproate. J Clin Psychopharmacol 2000; 20:493–494. 65. Morris RG, et al. Clinical study of lamotrigine and valproic acid in patients with epilepsy: using a drug interaction to advantage? Ther Drug Monit 2000; 22:656–660. 66. Aichhorn W, et al. Influence of age, gender, body weight and valproate comedication on quetiapine plasma concentrations. Int Clin Psychopharmacol 2006; 21:81–85. 67. Gunes A, et al. Inhibitory effect of valproic acid on cytochrome P450 2C9 activity in epilepsy patients. Basic Clin Pharmacol Toxicol 2007; 100:383–386. 68. Bergemann N, et al. Valproate lowers plasma concentration of olanzapine. J Clin Psychopharmacol 2006; 26:432–434.

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26 - Carbamazepine

Carbamazepine

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27 - Mechanism of action1

Mechanism of action1

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28 - Formulations

Formulations

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29 - Indications

Indications

Bipolar disorder CHAPTER 2 Carbamazepine Mechanism of action1 Carbamazepine blocks voltage-dependent sodium channels, thus inhibiting repetitive neuronal firing. It reduces glutamate release and decreases the turnover of dopamine and noradrenaline. While carbamazepine has a similar molecular structure to TCAs, it is radically different in respect to both therapeutic and adverse effects. Oxcarbazepine (a structural derivative of carbamazepine), as well as blocking voltage-dependent sodium channels, also increases potassium conductance and modulates high-voltage activated calcium channels. Eslicarbazepine is available in some countries. Like oxcarbazepine it acts as a pro-drug for licarbazepine, the likely active molecule of all three drugs. Formulations Carbamazepine is available as a liquid, chewable and immediate-release and controlled- release tablets. Non-modified release formulations generally have to be administered two to three times daily. The controlled-release preparation can be given once or twice daily, and the reduced fluctuation in serum levels usually leads to improved tolerability. This modified-release preparation has a lower bioavailability and an increase in dose of 10–15% may be required. Indications Carbamazepine is primarily used as an antiseizure medication. It is also used in the treatment of trigeminal neuralgia and, in the UK and elsewhere, is licensed for the treatment of bipolar illness in patients who do not respond to lithium. With respect to the treatment of mania, two placebo-controlled randomised studies have found the extended-release formulation of carbamazepine to be effective. In both studies, the response rate in the carbamazepine arm was twice that in the placebo arm.2,3 Carbamazepine was not particularly well tolerated – the incidence of dizziness, somnolence and nausea was high. Another study found carbamazepine alone to be as effective as carbamazepine plus olanzapine.4 Most formal guidelines do not recommend carbamazepine as a first-line treatment for mania.5 A Cochrane review concluded that there were insufficient trials of adequate methodological quality of oxcarbazepine in the acute treatment of bipolar disorder to inform its efficacy and acceptability.6 More recent reviews suggest oxcarbazepine has useful efficacy in mania.7 Two 2022 network meta-analyses8,9 confirmed the efficacy and relatively poor tolerability of carbamazepine. Open studies suggest that carbamazepine monotherapy has some efficacy in bipolar depression10 but evidence supporting other strategies is stronger (see section on treatment of bipolar depression later in this chapter). Carbamazepine may also be useful in unipolar depression either alone11 or as an augmentation strategy.12 Carbamazepine is generally considered to be less effective than lithium in the prophylaxis of bipolar illness.13 A 2009 meta-analysis failed to find a significant difference in efficacy between lithium and carbamazepine, but those who received carbamazepine were more likely to drop out of treatment because of adverse effects.14 Lithium is

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Plasma levels

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Adverse effects1

296 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 considered to be superior to carbamazepine in reducing suicidal behaviour,15 although data are not consistent16 and carbamazepine may have anti-suicidal properties.17 In the UK, NICE considers carbamazepine to be a third-line prophylactic agent5 and data emerging since this guidance support this positioning.18 Three small studies suggest the related oxcarbazepine may have some prophylactic efficacy when used in combination with other mood-stabilising drugs.19–21 There are data supporting the use of carbamazepine in the management of alcohol withdrawal symptoms,22 although the high initial doses required are often poorly tolerated. A Cochrane review did not consider the evidence strong enough to support the use of carbamazepine for this indication.23 Carbamazepine has also been used to manage aggressive behaviour in patients with schizophrenia;24 the quality of data is weak and the mode of action unknown. There are a number of case reports and open case series that report on the use of carbamazepine in various psychiatric illnesses such as panic disorder, borderline personality disorder and episodic dyscontrol syndrome. Plasma levels When carbamazepine is used as an antiseizure medication, the therapeutic range is generally considered to be 4–12mg/L, although the supporting evidence is not strong. In patients with affective illness, a dose of at least 600mg/day and a plasma level of at least 7mg/L may be required,25 although this is not a consistent finding.4,11,26 Levels above 12mg/L are associated with a higher adverse effect burden. Carbamazepine blood concentrations vary markedly within the dosage interval. It is therefore important to sample at a point in time where levels are likely to be reproducible for any given individual. The most appropriate way of monitoring is to take a trough level before the first dose of the day. Carbamazepine metabolism is genetically determined and so genetic testing may be helpful before starting carbamazepine.27 Carbamazepine is a hepatic enzyme inducer that induces its own metabolism as well as that of other drugs, including some antipsychotics.28 An initial plasma half-life of around 30 hours is reduced to around 12 hours on chronic dosing. For this reason, plasma levels should be checked 2–4 weeks after starting or after an increase in dose to ensure that the desired level is still being obtained. Most published clinical trials that demonstrated the efficacy of carbamazepine as a mood stabiliser used doses that are significantly higher (800–1200mg/day) than those commonly prescribed in UK clinical practice.29 Adverse effects1 The main adverse effects associated with carbamazepine therapy are dizziness, diplopia, drowsiness, ataxia, nausea and headaches. They can sometimes be avoided by starting with a low dose and increasing slowly. Avoiding high peak blood levels by splitting the dose throughout the day or using a controlled-release formulation may also help. Dry mouth, oedema and hyponatraemia are also common. Sexual dysfunction can occur, probably mediated through reduced testosterone levels.30 Around 3% of patients treated with carbamazepine develop a generalised erythematous rash. Serious exfoliative dermatological reactions can rarely occur and vulnerability is genetically determined.31 The human lymphocyte antigen (HLA) variant B*15:02 has a sensitivity of around 70%

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32 - Pre treatment tests

Pre-treatment tests

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33 - On treatment monitoring

On-treatment monitoring

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34 - Discontinuation

Discontinuation

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35 - Use in women of child bearing age

Use in women of child-bearing age

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36 - Interactions with other drugs4144

Interactions with other drugs41–44

Bipolar disorder CHAPTER 2 and a specificity approaching 100% in certain populations.32 Genetic testing in people from South-East Asia is recommended before carbamazepine is prescribed. Carbamazepine is a known human teratogen (see Chapter 7). Carbamazepine commonly causes a chronic low white blood cell (WBC) count. One patient in 20,000 develops agranulocytosis and/or aplastic anaemia.33 Raised alkaline phosphate (ALP) and gamma-glutamyl transferase (GGT) are common (a GGT of 2–3 times normal is rarely a cause for concern34). A delayed multiorgan hypersensitivity reaction rarely occurs, mainly manifesting itself as various skin reactions, a low WBC count and abnormal LFTs. Fatalities have been reported.34,35 There is no clear timescale for these events. Some antiseizure drugs have been associated with an increased risk of suicidal behaviour. Carbamazepine has not been implicated, either in general36,37 or more specifically in those with bipolar illness.38 Pre-treatment tests Baseline U&Es, FBC and LFTs are recommended by NICE. A baseline measure of weight is also desirable. On-treatment monitoring In the UK, NICE recommends that U&Es, FBC and LFTs should be repeated after 6 months, and that weight (or BMI) should also be monitored. Discontinuation It is not known if abrupt discontinuation of carbamazepine worsens the natural course of bipolar illness in the same way that abrupt cessation of lithium does. In one small case series (n = 6), one patient developed depression within a month of discontinuation,39 while in another small case series (n = 4), three patients had a recurrence of their mood disorder within 3 months.40 Until further data are available, if carbamazepine is to be discontinued, it should be done slowly (over at least a month). Use in women of child-bearing age Carbamazepine is an established human teratogen (see Chapter 7). Women who have mania are likely to be sexually disinhibited. The risk of unplanned pregnancy is likely to be above population norms (where 50% of pregnancies are unplanned). If carbamazepine cannot be avoided, adequate contraception should be ensured (note the interaction between carbamazepine and oral contraceptives outlined in the next section) and prophylactic folate prescribed. Interactions with other drugs41–44 Carbamazepine is a potent inducer of hepatic cytochrome enzymes and is metabolised by CYP3A4. Plasma levels of most antidepressants, most antipsychotics, benzodiazepines, warfarin, zolpidem, some cholinesterase inhibitors, methadone, thyroxine, theophylline, oestrogens and other steroids may be reduced by carbamazepine, possibly

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References

298 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 resulting in treatment failure. Patients requiring contraception should either receive a preparation containing not less than 50mcg oestrogen or use a non-hormonal method. Drugs that inhibit CYP3A4 will increase carbamazepine plasma levels and may precipitate toxicity. Examples include fluconazole, cimetidine, diltiazem, verapamil, erythromycin and some SSRIs. Pharmacodynamic interactions also occur. The antiseizure activity of carbamazepine is reduced by drugs that lower the seizure threshold (e.g. antipsychotics and antidepressants); the potential for carbamazepine to cause neutropenia may be increased by other drugs that depress the bone marrow function (e.g. clozapine); and the risk of hyponatraemia may be increased by other drugs that have the potential to deplete sodium (e.g. diuretics). Neurotoxicity has very rarely been reported when carbamazepine is used in combination with lithium. As carbamazepine is structurally similar to TCAs, in theory it should not be given within 14 days of discontinuing a monoamine oxidase inhibitor (MAOI). There seems to be no clinical basis to this restriction. Table 2.4 summarises the prescribing and monitoring of carbamazepine. References

Novartis Pharmaceuticals UK Ltd. Summary of product characteristics. Tegretol tablets 100mg, 200mg, 400mg. 2024 (last accessed October 2024); https://www.medicines.org.uk/emc/medicine/1328.
Weisler RH, et al. A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry 2004; 65:478–484.
Weisler RH, et al. Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: a multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2005; 66:323–330.
Tohen M, et al. Olanzapine plus carbamazepine v. carbamazepine alone in treating manic episodes. Br J Psychiatry 2008; 192:135–143.
National Institute for Health and Care Excellence. Bipolar disorder: assessment and management. Clinical guideline [CG185]. 2014 (last updated December 2023, last accessed October 2024); https://www.nice.org.uk/guidance/cg185.
Vasudev A, et al. Oxcarbazepine for acute affective episodes in bipolar disorder. Cochrane Database Syst Rev 2011; 12:CD004857.
Grunze A, et al. Efficacy of carbamazepine and its derivatives in the treatment of bipolar disorder. Medicina (Kaunas) 2021; 57:433. Table 2.4 Carbamazepine: prescribing and monitoring. Indications Mania (not first line), bipolar depression (evidence weak), unipolar depression (evidence weak) and prophylaxis of bipolar disorder (third line after antipsychotics and valproate). Alcohol withdrawal (may be poorly tolerated). Carbamazepine is licensed for the treatment of bipolar illness in patients who do not respond to lithium. Pre-carbamazepine work-up U&Es, FBC and LFTs. Baseline measure of weight desirable. HLA genotyping. CYP3A4 genotyping. Prescribing Titrate dose upwards against response and adverse effects; start with 100–200mg twice a day and aim for 400mg twice a day (some patients will require higher doses). The modified-release formulation (Tegretol Retard) can be given once to twice daily, is associated with less severe fluctuations in serum levels and is generally better tolerated. Plasma levels can be used to assure adequate dosing and treatment compliance. Blood should be taken immediately before the next dose. Carbamazepine induces its own metabolism. Blood levels should be re-checked 2 weeks after an increase in dose. Monitoring U&Es, FBC and LFTs yearly and when clinically indicated. Weight (or body mass index). Stopping Reduce slowly over at least 1 month, preferably longer. Hyperbolic tapering has theoretical support.

Bipolar disorder CHAPTER 2 8. Kishi T, et al. Pharmacological treatment for bipolar mania: a systematic review and network meta-analysis of double-blind randomized controlled trials. Mol Psychiatry 2022; 27:1136–1144. 9. Hong Y, et al. A cumulative Bayesian network meta-analysis on the comparative efficacy of pharmacotherapies for mania over the last 40 years. Psychopharmacology (Berl) 2022; 239:3367–3375. 10. Dilsaver SC, et al. Treatment of bipolar depression with carbamazepine: results of an open study. Biol Psychiatry 1996; 40:935–937. 11. Zhang ZJ, et al. The effectiveness of carbamazepine in unipolar depression: a double-blind, randomized, placebo-controlled study. J Affect Disord 2008; 109:91–97. 12. Kramlinger KG, et al. The addition of lithium to carbamazepine. Antidepressant efficacy in treatment-resistant depression. Arch Gen Psychiatry 1989; 46:794–800. 13. Nasrallah HA, et al. Carbamazepine and valproate for the treatment of bipolar disorder: a review of the literature. J Affect Disord 2006; 95:69–78. 14. Ceron-Litvoc D, et al. Comparison of carbamazepine and lithium in treatment of bipolar disorder: a systematic review of randomized controlled trials. Hum Psychopharmacol 2009; 24:19–28. 15. Kleindienst N, et al. Differential efficacy of lithium and carbamazepine in the prophylaxis of bipolar disorder: results of the MAP study. Neuropsychobiology 2000; 42 Suppl 1:2–10. 16. Yerevanian BI, et al. Bipolar pharmacotherapy and suicidal behavior. Part I: Lithium, divalproex and carbamazepine. J Affect Disord 2007; 103:5–11. 17. Tsai CJ, et al. The rapid suicide protection of mood stabilizers on patients with bipolar disorder: a nationwide observational cohort study in Taiwan. J Affect Disord 2016; 196:71–77. 18. Peselow ED, et al. Prophylactic efficacy of lithium, valproic acid, and carbamazepine in the maintenance phase of bipolar disorder: a naturalistic study. Int Clin Psychopharmacol 2016; 31:218–223. 19. Vieta E, et al. A double-blind, randomized, placebo-controlled prophylaxis trial of oxcarbazepine as adjunctive treatment to lithium in the long-term treatment of bipolar I and II disorder. Int J Neuropsychopharmacol 2008; 11:445–452. 20. Conway CR, et al. An open-label trial of adjunctive oxcarbazepine for bipolar disorder. J Clin Psychopharmacol 2006; 26:95–97. 21. Juruena MF, et al. Bipolar I and II disorder residual symptoms: oxcarbazepine and carbamazepine as add-on treatment to lithium in a double- blind, randomized trial. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:94–99. 22. Malcolm R, et al. The effects of carbamazepine and lorazepam on single versus multiple previous alcohol withdrawals in an outpatient randomized trial. J Gen Intern Med 2002; 17:349–355. 23. Minozzi S, et al. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev 2010; 3:CD005064. 24. Brieden T, et al. Psychopharmacological treatment of aggression in schizophrenic patients. Pharmacopsychiatry 2002; 35:83–89. 25. Taylor D, et al. Doses of carbamazepine and valproate in bipolar affective disorder. Psychiatric Bulletin 1997; 21:221–223. 26. Simhandl C, et al. The comparative efficacy of carbamazepine low and high serum level and lithium carbonate in the prophylaxis of affective disorders. J Affect Disord 1993; 28:221–231. 27. Riffi R, et al. Pharmacogenetics of carbamazepine: a systematic review on CYP3A4 and CYP3A5 polymorphisms. CNS Neurol Disord Drug Targets 2024; 23:1463–1473. 28. Cohen H, et al. The extent of cytochrome P450 3A induction by antiseizure medications: a systematic review and network meta-analysis. Epilepsia 2024; 65:445–455. 29. Taylor DM, et al. Prescribing and monitoring of carbamazepine and valproate – a case note review. Psychiatric Bulletin 2000; 24:174–177. 30. Lossius MI, et al. Reversible effects of antiepileptic drugs on reproductive endocrine function in men and women with epilepsy – a prospective randomized double-blind withdrawal study. Epilepsia 2007; 48:1875–1882. 31. Hung SI, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics 2006; 16:297–306. 32. Moutaouakkil Y, et al. Diagnostic utility of human leukocyte antigen B*15:02 screening in severe carbamazepine hypersensitivity syndrome. Ann Indian Acad Neurol 2019; 22:377–383. 33. Kaufman DW, et al. Drugs in the aetiology of agranulocytosis and aplastic anaemia. Eur J Haematol Suppl 1996; 60:23–30. 34. Bjornsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scand 2008; 118:281–290. 35. Ganeva M, et al. Carbamazepine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: report of four cases and brief review. Int J Dermatol 2008; 47:853–860. 36. Patorno E, et al. Anticonvulsant medications and the risk of suicide, attempted suicide, or violent death. JAMA 2010; 303:1401–1409. 37. Andersohn F, et al. Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior. Neurology 2010; 75:335–340. 38. Gibbons RD, et al. Relationship between antiepileptic drugs and suicide attempts in patients with bipolar disorder. Arch Gen Psychiatry 2009; 66:1354–1360. 39. Macritchie KA, et al. Does ‘rebound mania’ occur after stopping carbamazepine? A pilot study. J Psychopharmacol 2000; 14:266–268. 40. Franks MA, et al. Bouncing back: is the bipolar rebound phenomenon peculiar to lithium? A retrospective naturalistic study. J Psychopharmacol 2008; 22:452–456. 41. Spina E, et al. Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs. Epilepsia 2002; 43 Suppl 2:37–44. 42. Patsalos PN, et al. The importance of drug interactions in epilepsy therapy. Epilepsia 2002; 43:365–385. 43. Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs 2002; 16:263–272. 44. Citrome L, et al. Pharmacokinetics of aripiprazole and concomitant carbamazepine. J Clin Psychopharmacol 2007; 27:279–283.

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38 - Antipsychotic drugs in bipolar disorder

Antipsychotic drugs in bipolar disorder

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39 - First generation antipsychotics

First-generation antipsychotics

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40 - Second generation antipsychotics

Second-generation antipsychotics

300 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 Antipsychotic drugs in bipolar disorder Antipsychotic drugs not only have activity that reduces psychotic symptoms,1 individual antipsychotics variously possess sedative, anxiolytic, anti-manic, mood-stabilising and antidepressant properties. Some antipsychotics (quetiapine and olanzapine) show all of these activities. Antipsychotics licensed by the US Food and Drug Administration (FDA) for use in bipolar disorder include aripiprazole (mania, mixed episodes, maintenance treatment), asenapine (mania, mixed states), cariprazine and lumateperone (bipolar depression), lurasidone (bipolar depression), olanzapine (mania, mixed episodes, maintenance), olanzapine and fluoxetine (bipolar depression), quetiapine (mania, maintenance, bipolar depression), risperidone (mania, mixed episodes) and ziprasidone (mania, maintenance). Risperidone LAI has been approved for monotherapy or adjunctive maintenance, and aripiprazole depot for monotherapy maintenance treatment. EU labelling is similar except that olanzapine/fluoxetine in combination is not licensed for any indication and no second-generation antipsychotic (SGA) long-acting injection (LAI) has a licence for maintenance. First-generation antipsychotics These agents have long been used in mania and several studies support their use in the acute phase of illness, with superiority over placebo and comparable effects to lithium.2,3 Their effectiveness is enhanced by combination with lithium.4,5 In the longer term maintenance treatment of bipolar disorder, first-generation antipsychotics (FGAs) are widely used6 but modern, robust supporting data are absent.7 FGAs are relatively more often associated with both depression and tardive dyskinesia in bipolar disorder7–9 and their use is declining. The higher rate of tardive dyskinesia with FGAs is not in doubt, but the greater risk of depression,10,11 while less well supported, is certainly worthy of consideration. Second-generation antipsychotics Mania Network meta-analyses indicate superiority of antipsychotics over placebo in mania, with similar activity to so-called mood stabilisers.12–14 In a 2023 network meta-analysis, efficacy of individual antipsychotics was broadly similar,15 with a suggestion of superiority of risperidone. Adjunctive treatment with antipsychotics is more effective than monotherapy with mood stabiliser medication, and augmentation with mood stabiliser medication is more effective than antipsychotic monotherapy. The combination is associated with more adverse effects, especially somnolence.16 Interpretation of outcomes is made difficult by trials including patients whose mania occurred in the context of failed mood stabiliser treatment. Participants receive either a failed mood stabiliser or a mood stabiliser plus an antipsychotic. The superior effect of the combination is not surprising in this context. Although the mechanism is difficult to discern, converging evidence suggests anti- manic effects of antipsychotics are related to their effects on the dopamine system.17,18

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41 - Specific antipsychotics

Specific antipsychotics

Bipolar disorder CHAPTER 2 Bipolar depression In acute treatment of bipolar depression, antipsychotics found to be effective include cariprazine, lumateperone, lurasidone, olanzapine (± fluoxetine) and quetiapine.14,19,20 In terms of mechanism, this does not appear to be a dopamine-mediated effect as aripiprazole and most dopamine-blocking antipsychotics do not show efficacy in acute bipolar depression.19 Efficacy is similar among those shown to be effective, although lurasidone may be superior to cariprazine.21,22 Maintenance Compounds that have efficacy in the acute phase of bipolar disorder, whether that be mania or depression, seem to exert effects in maintenance treatment.23 This is borne out by a network meta-analysis of maintenance treatments in bipolar disorder, in which olanzapine, quetiapine and risperidone LAIs showed effects against relapse.24 This analysis did not include more recent (positive) trials of aripiprazole (see next section),24 nor studies of cariprazine25 which may not be effective as maintenance treatment. Specific antipsychotics Aripiprazole Aripiprazole is effective in acute treatment of mania both alone,26–28 as an add-on agent29 and in long-term prophylaxis.30,31 No difference is seen when directly compared with lithium or haloperidol although one small RCT suggested lithium was more effective in mania.32 In trials in mania, aripiprazole is associated with nausea and movement disorder (mainly akathisia).33 Aripiprazole LAI is also effective for prophylaxis in bipolar I disorder with the effect predominantly on prevention of manic episodes.34 Asenapine Asenapine is given by the sublingual route and is effective in mania.35,36 Efficacy seems to be maintained in the longer term,37 with RCT evidence showing efficacy in preventing depression and manic episodes in people with bipolar I disorder.38 Asenapine is less likely to cause weight gain and metabolic disturbance39 than some other antipsychotics. Cariprazine Cariprazine is efficacious for treating mania as well as depression symptoms in people with mania with mixed features40 and has a low propensity for weight gain.39 Clozapine The earliest observational study of antipsychotics for maintenance treatment in bipolar disorder examined clozapine in people attending a service for resistant mood disorders.41 There is evidence from at least 15 trials to suggest improvements in treatment-resistant bipolar disorder (TRBD) (where two treatments have failed,

302 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 despite adequate dose and duration) and in depression, mania, rapid-cycling states and psychotic symptoms.42 Clozapine is fairly widely used in bipolar disorder, particularly in South-East Asia.43 Lurasidone Lurasidone is licensed by the FDA as monotherapy and adjunctive treatment to lithium and divalproex for acute treatment of bipolar depression, on the basis of RCTs of monotherapy versus placebo,44 and as an adjunct to lithium or valproate.45 The main adverse effects include nausea and akathisia, with minimal effects on weight and metabolic parameters.39 Olanzapine Olanzapine is effective in mania.46,47 As with other FGAs, olanzapine is most effective when used in combination with a mood stabiliser in acute mania and for symptomatic (though not syndromal) relapse prevention,48,49 although in one study, olanzapine + carbamazepine was no better than carbamazepine alone.50 Data suggest olanzapine may offer benefits in longer-term treatment.51,52 It may be more effective than lithium.53,54 Olanzapine is, of course, associated with significant metabolic effects, including weight gain, effects that are minimised by the use of the olanzapine/samidorphan combination available in some countries.55,56 Quetiapine Data relating to quetiapine57–59 suggest robust efficacy in all aspects of bipolar disorder including prevention of mania and bipolar depression.60 It has low propensity for extrapyramidal side effects (EPSEs), though there are significant effects on weight and metabolic parameters. Risperidone Risperidone has shown efficacy in mania,61 particularly in combination with a mood stabiliser.62,63 Risperidone LAI (as Risperdal Consta) is also effective64 (note though that the pharmacokinetics of this formulation generally render it an unsuitable choice for the acute treatment of mania). The long-acting version is used as prophylaxis (an unlicensed use in most countries). It is effective as prophylaxis against mania in the longer term.23 Paliperidone can be assumed to have similar effects, although prospective, controlled data are lacking.65 Other antipsychotics There are few data for amisulpride66 and rather more for ziprasidone,67 which is sometimes used for mania in the USA. Iloperidone may be effective in mixed episodes68 but data are insufficient to support its use. Lumateperone is effective in bipolar depression.69,70

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References

Bipolar disorder CHAPTER 2 References

ECNP. Neuroscience-based nomenclature (NbN). 2024; https://www.ecnp.eu/research-innovation/nomenclature.
Cipriani A, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet 2011; 378:1306–1315.
Goodwin GM, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2016; 30:495–553.
Chou JC, et al. Acute mania: haloperidol dose and augmentation with lithium or lorazepam. J Clin Psychopharmacol 1999; 19:500–505.
Small JG, et al. A placebo-controlled study of lithium combined with neuroleptics in chronic schizophrenic patients. Am J Psychiatry 1975; 132:1315–1317.
Soares JC, et al. Adjunctive antipsychotic use in bipolar patients: an open 6-month prospective study following an acute episode. J Affect Disord 1999; 56:1–8.
Keck PE, Jr, et al. Anticonvulsants and antipsychotics in the treatment of bipolar disorder. J Clin Psychiatry 1998; 59 Suppl 6:74–81.
Tohen M, et al. Antipsychotic agents and bipolar disorder. J Clin Psychiatry 1998; 59 Suppl 1:38–48.
Zarate CA, Jr, et al. Double-blind comparison of the continued use of antipsychotic treatment versus its discontinuation in remitted manic patients. Am J Psychiatry 2004; 161:169–171.
Gigante AD, et al. Long-acting injectable antipsychotics for the maintenance treatment of bipolar disorder. CNS Drugs 2012; 26:403–420.
Goikolea JM, et al. Lower rate of depressive switch following antimanic treatment with second-generation antipsychotics versus haloperidol. J Affect Disord 2013; 144:191–198.
Yildiz A, et al. A network meta-analysis on comparative efficacy and all-cause discontinuation of antimanic treatments in acute bipolar mania. Psychol Med 2015; 45:299–317.
Kishi T, et al. Pharmacological treatment for bipolar mania: a systematic review and network meta-analysis of double-blind randomized controlled trials. Mol Psychiatry 2022; 27:1136–1144.
Baldessarini RJ, et al. Pharmacological treatment of adult bipolar disorder. Mol Psychiatry 2019; 24:198–217.
Yu CL, et al. Comparison of antipsychotic dose equivalents for acute bipolar mania and schizophrenia. BMJ Ment Health 2023; 26:e300546.
Ogawa Y, et al. Mood stabilizers and antipsychotics for acute mania: a systematic review and meta-analysis of combination/augmentation therapy versus monotherapy. CNS Drugs 2014; 28:989–1003.
Ashok AH, et al. The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Mol Psychiatry 2017; 22:666–679.
Jauhar S, et al. A test of the transdiagnostic dopamine hypothesis of psychosis using positron emission tomographic imaging in bipolar affective disorder and schizophrenia. JAMA Psychiatry 2017; 74:1206–1213.
Taylor DM, et al. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis. Acta Psychiatr Scand 2014; 130:452–469.
Yildiz A, et al. Comparative efficacy and tolerability of pharmacological interventions for acute bipolar depression in adults: a systematic review and network meta-analysis. Lancet Psychiatry 2023; 10:693–705.
Kadakia A, et al. Efficacy and tolerability of atypical antipsychotics for acute bipolar depression: a network meta-analysis. BMC Psychiatry 2021; 21:249.
Martins-Correia J, et al. Cariprazine in the acute treatment of unipolar and bipolar depression: a systematic review and meta-analysis. J Affect Disord 2024; 362:297–307.
Taylor MJ. Bipolar treatment efficacy. Lancet Psychiatry 2014; 1:418.
Miura T, et al. Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a systematic review and network meta-analysis. Lancet Psychiatry 2014; 1:351–359.
McIntyre RS, et al. Cariprazine as a maintenance therapy in the prevention of mood episodes in adults with bipolar I disorder. Bipolar Disord 2024; 26:442–453.
Sachs G, et al. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study. J Psychopharmacol 2006; 20:536–546.
Keck PE, et al. Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium- controlled study. J Affect Disord 2009; 112:36–49.
Young AH, et al. Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study. Br J Psychiatry 2009; 194:40–48.
Vieta E, et al. Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients partially nonresponsive to valproate/ lithium monotherapy: a placebo-controlled study. Am J Psychiatry 2008; 165:1316–1325.
Keck PE, Jr, et al. Aripiprazole monotherapy for maintenance therapy in bipolar I disorder: a 100-week, double-blind study versus placebo. J Clin Psychiatry 2007; 68:1480–1491.
Vieta E, et al. Assessment of safety, tolerability and effectiveness of adjunctive aripiprazole to lithium/valproate in bipolar mania: a 46-week, open-label extension following a 6-week double-blind study. Curr Med Res Opin 2010; 26:1485–1496.
Shafti SS. Aripiprazole versus lithium in management of acute mania: a randomized clinical trial. East Asian Arch Psychiatry 2018; 28:80–84.
Brown R, et al. Aripiprazole alone or in combination for acute mania. Cochrane Database Syst Rev 2013; 12:CD005000.
Calabrese JR, et al. Efficacy and safety of aripiprazole once-monthly in the maintenance treatment of bipolar I disorder: a double-blind, placebo-controlled, 52-week randomized withdrawal study. J Clin Psychiatry 2017; 78:324–331.

304 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 35. McIntyre RS, et al. Asenapine in the treatment of acute mania in bipolar I disorder: a randomized, double-blind, placebo-controlled trial. J Affect Disord 2010; 122:27–38. 36. McIntyre RS, et al. Asenapine versus olanzapine in acute mania: a double-blind extension study. Bipolar Disord 2009; 11:815–826. 37. McIntyre RS, et al. Asenapine for long-term treatment of bipolar disorder: a double-blind 40-week extension study. J Affect Disord 2010; 126:358–365. 38. Szegedi A, et al. Randomized, double-blind, placebo-controlled trial of asenapine maintenance therapy in adults with an acute manic or mixed episode associated with bipolar I disorder. Am J Psychiatry 2018; 175:71–79. 39. Pillinger T, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry 2020; 7:64–77. 40. McIntyre RS, et al. Cariprazine for the treatment of bipolar mania with mixed features: a post hoc pooled analysis of 3 trials. J Affect Disord 2019; 257:600–606. 41. Zarate CA, Jr, et al. Clozapine in severe mood disorders. J Clin Psychiatry 1995; 56:411–417. 42. Li XB, et al. Clozapine for treatment-resistant bipolar disorder: a systematic review. Bipolar Disord 2015; 17:235–247. 43. Loo LWJ, et al. Clozapine use for bipolar disorder: an Asian Psychotropic Prescription Patterns Consortium Study. J Clin Psychopharmacol 2023; 43:278–282. 44. Loebel A, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry 2014; 171:160–168. 45. Loebel A, et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, double- blind, placebo-controlled study. Am J Psychiatry 2014; 171:169–177. 46. Tohen M, et al. Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am J Psychiatry 1999; 156:702–709. 47. Tohen M, et al. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzipine HGGW Study Group. Arch Gen Psychiatry 2000; 57:841–849. 48. Tohen M, et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry 2002; 59:62–69. 49. Tohen M, et al. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br J Psychiatry 2004; 184:337–345. 50. Tohen M, et al. Olanzapine plus carbamazepine v. carbamazepine alone in treating manic episodes. Br J Psychiatry 2008; 192:135–143. 51. Sanger TM, et al. Long-term olanzapine therapy in the treatment of bipolar I disorder: an open-label continuation phase study. J Clin Psychiatry 2001; 62:273–281. 52. Vieta E, et al. Olanzapine as long-term adjunctive therapy in treatment-resistant bipolar disorder. J Clin Psychopharmacol 2001; 21:469–473. 53. Tohen M, et al. Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial. Am J Psychiatry 2005; 162:1281–1290. 54. McKnight RF, et al. Lithium for acute mania. Cochrane Database Syst Rev 2019; 6:CD004048. 55. Corrao MM, et al. Olanzapine/samidorphan: a new combination treatment for schizophrenia and bipolar I disorder intended to reduce weight gain. CNS Drugs 2022; 36:605–616. 56. Faden J, et al. Olanzapine-samidorphan combination tablets for the treatment of schizophrenia and bipolar I disorder – what is it, and will it be used? Expert Rev Neurother 2022; 22:365–376. 57. Ghaemi SN, et al. The use of quetiapine for treatment-resistant bipolar disorder: a case series. Ann Clin Psychiatry 1999; 11:137–140. 58. Sachs G, et al. Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study. Bipolar Disord 2004; 6:213–223. 59. Altamura AC, et al. Efficacy and tolerability of quetiapine in the treatment of bipolar disorder: preliminary evidence from a 12-month open label study. J Affect Disord 2003; 76:267–271. 60. Young AH, et al. A randomised, placebo-controlled 52-week trial of continued quetiapine treatment in recently depressed patients with bipolar I and bipolar II disorder. World J Biol Psychiatry 2014; 15:96–112. 61. Segal J, et al. Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial. Clin Neuropharmacol 1998; 21:176–180. 62. Sachs GS, et al. Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo- controlled comparison of efficacy and safety. Am J Psychiatry 2002; 159:1146–1154. 63. Vieta E, et al. Risperidone in the treatment of mania: efficacy and safety results from a large, multicentre, open study in Spain. J Affect Disord 2002; 72:15–19. 64. Quiroz JA, et al. Risperidone long-acting injectable monotherapy in the maintenance treatment of bipolar I disorder. Biol Psychiatry 2010; 68:156–162. 65. Taylor DM, et al. Paliperidone palmitate: factors predicting continuation with treatment at 2 years. Eur Neuropsychopharmacol 2016; 26:2011–2017. 66. Vieta E, et al. An open-label study of amisulpride in the treatment of mania. J Clin Psychiatry 2005; 66:575–578. 67. Vieta E, et al. Ziprasidone in the treatment of acute mania: a 12-week, placebo-controlled, haloperidol-referenced study. J Psychopharmacol 2010; 24:547–558. 68. Singh V, et al. An open trial of iloperidone for mixed episodes in bipolar disorder. J Clin Psychopharmacol 2017; 37:615–619. 69. McIntyre RS, et al. The efficacy of lumateperone in patients with bipolar depression with mixed features. J Clin Psychiatry 2023; 84:22m14739. 70. Calabrese JR, et al. Efficacy and safety of lumateperone for major depressive episodes associated with bipolar I or bipolar II disorder: a phase 3 randomized placebo-controlled trial. Am J Psychiatry 2021; 178:1098–1106.

07 - Chapter 2 Bipolar disorder

43 - Antipsychotic long acting injections in bipol

Antipsychotic long-acting injections in bipolar disorder

Bipolar disorder CHAPTER 2 Antipsychotic long-acting injections in bipolar disorder LAIs are widely used in bipolar disorder although none is formally licensed in the UK for this indication (Abilify Maintena is approved by the FDA in the USA). Support for their use is rather limited: there have been dozens of open-label trials or case series published, but few included more than a handful of subjects.1–3 Retrospective cohort studies, mirror-image studies and population-level studies do, nonetheless, offer some support for the use of LAIs (mainly SGAs) in bipolar maintenance.1 Mirror-image studies uniformly show a reduction in admissions and bed days when patients are switched from oral medication to LAI formulations of aripiprazole4–6 and paliperidone,6,7 although study numbers were small. Prospective open-label studies also support the prophylactic effect of aripiprazole LAI, both monthly and two-monthly.8,9 There have also been seven RCTs, only five of which were sufficiently powered to produce interpretable results (the remaining two trials included only 30 subjects in total10,11). These five RCTs represent the highest level of evidence for LAIs in bipolar disorder. Their details are set out in Table 2.5. Few firm conclusions can be drawn from the controlled trials outlined in Table 2.5. Risperidone LAI is clearly effective either as the sole treatment or as an adjunct but provides protection only against manic, hypomanic and mixed-manic episodes and Table 2.5 Randomised controlled trials (RCTs) of the use of long-acting injections (LAIs) in bipolar affective disorder. Reference Number LAI Comparator Duration Outcome Ahlfors et al., 198112 (19/14) Flupentixol decanoate Lithium 18 months Neither treatment improved main outcome (number of mood episodes) Macfadden et al., 200913* (65/59) Risperidone (adjunct) Placebo (adjunct) 12 months Risperidone LAI reduced rate of relapse compared with placebo (relative risk 2.3) Quiroz et al., 201014* (154/149) Risperidone monotherapy Placebo monotherapy 24 months Overall relapse rate was 30% with risperidone, 56% with placebo. Risperidone did not protect against depressive relapse. Vieta et al., 201215* (132/135/131) Risperidone monotherapy Placebo or oral olanzapine monotherapy 18 months Recurrence of any mood episode: oral olanzapine 23.8%; risperidone LAI 38.9%; placebo 56.4%. Olanzapine and risperidone reduced risk of elevated mood episode but only olanzapine reduced risk of depression. Calabrese et al., 201716* (133/133) Aripiprazole monotherapy Placebo monotherapy 12 months Relapse to any mood episode 26.5% with aripiprazole; 51.1% with placebo. No clear effect on recurrence of depression. An open follow-on study of this RCT (that also included patients newly prescribed aripiprazole) showed somewhat better levels of protection: 87–98% of participants remained well over 12 months.17 *Trial sponsored by manufacturer.

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44 - Conclusion

Conclusion

306 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 neither decreases nor increases the risk of depressive relapse. Risperidone LAI may be less effective than oral olanzapine. It might be assumed that paliperidone LAI has similar effects to risperidone LAI. Oral paliperidone prevents manic relapse in bipolar disorder,18 there are a few supportive mirror-image studies6,7 and case reports describe good outcomes with the LAI form.19,20 Aripiprazole LAI protects against manic relapse but does not appear to affect risk of depression. Data for FGAs in bipolar disorder are scarce and generally of low quality (open trials, case series and retrospective analyses). In these studies, FGA LAIs seem to reduce the risk of relapse compared with prior treatments. The largest (open) study12 (n = 85) suggested flupentixol decanoate (20mg every 2–3 weeks) reduced the risk of elevated mood episodes. Reports describe similar effects for other FGA LAIs. The one RCT conducted with flupentixol LAI12 showed no effect and no superiority over lithium. Considering this single RCT and all of the small and uncontrolled observations, there is very little evidence to support the often-repeated lore that flupentixol LAI increases the risk of manic relapse and haloperidol LAI and fluphenazine LAI increase the risk of depressive relapse (or that FGAs provoke depression). It is notable that authors of systematic reviews21,22 reiterate this view, which seems to be based on solely the observed increase in depressive episodes in the open study conducted by Ahlfors and colleagues.12 In fact, this increase occurred only in subjects whose lithium treatment had been stopped immediately before the study began. Nonetheless, oral haloperidol, when used for mania, is more likely than oral SGAs to cause a switch to depression23 so some caution is clearly required. There are no controlled comparisons of FGA and SGA LAIs.1–3 A Taiwanese retrospective cohort study24 reported a higher risk of depressive episode recurrence and a higher likelihood of hospitalisation in those prescribed FGA LAIs (50% were prescribed flupentixol, 25% haloperidol and 25% other drugs) compared with those prescribed risperidone LAI. Of particular note was the substantial rate of treatment discontinuation. At 1 year only 7.2% of those initially prescribed risperidone and 2.2% of those initiated on FGA LAIs remained on the original treatment. Another observational study found both SGA and FGA LAIs to be effective but only when treatment continued for at least 6 months.25 Conclusion ■ ■Support for the use of FGA LAIs in bipolar disorder is weak. ■ ■Very limited evidence suggests FGA LAIs may be effective in reducing recurrence of mania/hypomania but they do not prevent recurrence of depression and may increase the risk. ■ ■Risperidone LAI and aripiprazole LAI are robustly associated with a reduced risk of recurrence of episodes of mania/hypomania compared with placebo. ■ ■Risperidone LAI and aripiprazole LAI have no effect on the risk of depressive recurrence. ■ ■There is limited evidence to support the benefit of LAIs over oral antipsychotic treatment in bipolar maintenance. ■ ■As with other conditions, the use of LAIs offers the advantage of transparency in respect to compliance: the LAI injection is either given or it is not.

07 - Chapter 2 Bipolar disorder

45 - References

References

Bipolar disorder CHAPTER 2 References

Keramatian K, et al. Long-acting injectable second-generation/atypical antipsychotics for the management of bipolar disorder: a systematic review. CNS Drugs 2019; 33:431–456.
Pacchiarotti I, et al. Long-acting injectable antipsychotics (LAIs) for maintenance treatment of bipolar and schizoaffective disorders: a systematic review. Eur Neuropsychopharmacol 2019; 29:457–470.
Prajapati AR, et al. Second-generation antipsychotic long-acting injections in bipolar disorder: systematic review and meta-analysis. Bipolar Disord 2018; 20:687–696.
Goto J, et al. Preventive effect of aripiprazole once monthly on rehospitalization for bipolar disorder: a multicenter 1-year retrospective mirror image study. Neuropsychopharmacol Rep 2023; 43:425–433.
Woo YS, et al. Preventive effect of aripiprazole once-monthly on relapse into mood episodes in bipolar disorder: a multicenter, one-year, retrospective, mirror image study. J Affect Disord 2024; 351:381–386.
Yıldızhan E, et al. Effect of long acting injectable antipsychotics on course and hospitalizations in bipolar disorder – a naturalistic mirror image study. Nord J Psychiatry 2022; 76:37–43.
Caliskan AM, et al. Impact of initiating long-acting injectable paliperidone palmitate on relapse and hospitalization in patients with bipolar I disorder: a mirror image retrospective study. Asian J Psychiatr 2020; 54:102457.
Harlin M, et al. A randomized, open-label, multiple-dose, parallel-arm, pivotal study to evaluate the safety, tolerability, and pharmacokinetics of aripiprazole 2-month long-acting injectable in adults with schizophrenia or bipolar I disorder. CNS Drugs 2023; 37:337–350.
McIntyre RS, et al. Safety and efficacy of aripiprazole 2-month ready-to-use 960 mg: secondary analysis of outcomes in adult patients with bipolar I disorder in a randomized, open-label, parallel-arm, pivotal study. Curr Med Res Opin 2023; 39:1021–1030.
Esparon J, et al. Comparison of the prophylactic action of flupenthixol with placebo in lithium treated manic-depressive patients. Br J Psychiatry 1986; 148:723–725.
Yatham L, et al. Randomised trial of oral vs. injectable antipsychotics in bipolar disorder. Presented at the 6th International Conference on Bipolar Disorder: 16–18 June 2005, Pittsburgh, PA.
Ahlfors UG, et al. Flupenthixol decanoate in recurrent manic-depressive illness. A comparison with lithium. Acta Psychiatr Scand 1981; 64:226–237.
Macfadden W, et al. A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently. Bipolar Disord 2009; 11:827–839.
Quiroz JA, et al. Risperidone long-acting injectable monotherapy in the maintenance treatment of bipolar I disorder. Biol Psychiatry 2010; 68:156–162.
Vieta E, et al. A randomized, double-blind, placebo-controlled trial to assess prevention of mood episodes with risperidone long-acting injectable in patients with bipolar I disorder. Eur Neuropsychopharmacol 2012; 22:825–835.
Calabrese JR, et al. Efficacy and safety of aripiprazole once-monthly in the maintenance treatment of bipolar I disorder: a double-blind, placebo-controlled, 52-week randomized withdrawal study. J Clin Psychiatry 2017; 78:324–331.
Calabrese JR, et al. Aripiprazole once-monthly as maintenance treatment for bipolar I disorder: a 52-week, multicenter, open-label study. Int J Bipolar Disord 2018; 6:14.
Berwaerts J, et al. A randomized, placebo- and active-controlled study of paliperidone extended-release as maintenance treatment in patients with bipolar I disorder after an acute manic or mixed episode. J Affect Disord 2012; 138:247–258.
Buoli M, et al. Paliperidone palmitate depot in the long-term treatment of psychotic bipolar disorder: a case series. Clin Neuropharmacol 2015; 38:209–211.
Li K, et al. Case report: paliperidone palmitate in the management of bipolar I disorder with non-compliance. Front Psychiatry 2020; 11:529672.
Bond DJ, et al. Depot antipsychotic medications in bipolar disorder: a review of the literature. Acta Psychiatr Scand Suppl 2007; 2007:3–16.
Gigante AD, et al. Long-acting injectable antipsychotics for the maintenance treatment of bipolar disorder. CNS Drugs 2012; 26:403–420.
Goikolea JM, et al. Lower rate of depressive switch following antimanic treatment with second-generation antipsychotics versus haloperidol. J Affect Disord 2013; 144:191–198.
Wu CS, et al. Comparative effectiveness of long-acting injectable risperidone vs. long-acting injectable first-generation antipsychotics in bipolar disorder. J Affect Disord 2016; 197:189–195.
Bartoli F, et al. Effect of long-acting injectable antipsychotics on 1-year hospitalization in bipolar disorder: a mirror-image study. Eur Arch Psychiatry Clin Neurosci 2023; 273:1579–1586.

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46 - Physical monitoring for people with bipolar d

Physical monitoring for people with bipolar disorder1,2

Physical monitoring for people with bipolar disorder1,2 Monitoring for all patients Additional monitoring for specific drugs Test or measurement Initial health check Annual check-up Antipsychotics Lithium Valproate Carbamazepine Thyroid function Yes Yes At start and every 6 months. More often if evidence of change. Liver function tests (LFTs) Yes Yes Every 3 months for the first year then annually Monthly for the first 3 months then annually Renal function (eGFR) Yes Yes At start and every 6 months. More often if there is evidence of deterioration or the patient starts taking interacting drugs. Electrolytes, urea and creatinine (EUC) Yes Yes At start and then every 3–6 months (include serum calcium) Monthly for the first 3 months then annually Full blood count (FBC) Yes Yes Only if clinically indicated Every 3 months for the first year then annually Monthly for the first 3 months then annually Blood (plasma) glucose Yes Yes, as part of a routine physical health check At start and then every 4–6 months (and at 1 month if taking olanzapine); more often if evidence of elevated levels Lipid profile Yes Yes, as part of a routine physical health check At start and at 3 months; more often initially if evidence of elevated levels Blood pressure and pulse Yes Yes, as part of a routine physical health check During dosage titration if antipsychotic prescribed is associated with postural hypotension

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47 - References

References

Prolactin Children and adolescents only At start and if symptoms of raised prolactin develop Raised prolactin unlikely with quetiapine or aripiprazole. Very occasionally seen with olanzapine and asenapine. Very common with risperidone and FGAs. ECG If indicated by cardiovascular disease or risk factors At start if there are risk factors for or existing cardiovascular disease (or haloperidol is prescribed). If relevant abnormalities are detected, re-check after each dose increase. At start if risk factors for or existing cardiovascular disease. If relevant abnormalities are detected re-check after each dose increase. At start if risk factors for or existing cardiovascular disease. If relevant abnormalities are detected, re-check after each dose increase. Waist circumference and/or body mass index Yes Yes, as part of a routine physical health check Monthly for the first 3 months then annually At start, and then every 6 months Every 3 months for the first year then annually At start and when needed if the patient gains weight rapidly Plasma levels of drug At least 3–4 days after initiation and 3–4 days after every dose change until levels stable, then every 3 months in the first year, then every 6 months for most patients (see NICE2) Titrate by effect and tolerability. Do not routinely measure unless there is evidence of lack of effectiveness, poor adherence or toxicity. Two weeks after initiation and 2 weeks after dose change. Thereafter, do not routinely measure unless there is evidence of lack of effectiveness, poor adherence or toxicity. For patients on lamotrigine, do an annual health check, but no special monitoring tests are needed although blood levels may indicate if high doses might be considered. References

Ng F, et al. The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments. Bipolar Disord 2009; 11:559–595.
National Institute for Health and Care Excellence. Bipolar disorder: assessment and management. Clinical guideline [CG185]. 2014 (last updated December 2023, last accessed October 2024); https://www.nice.org. uk/guidance/cg185.

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48 - Treatment of acute mania or hypomania

Treatment of acute mania or hypomania

310 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 Treatment of acute mania or hypomania Drug treatment is the mainstay of therapy for mania and hypomania. Both antipsychotics and mood stabilisers are effective (although the nomenclature here is unhelpful – most, possibly all, antipsychotics are anti-manic and most mood stabilisers reduce psychotic symptoms in mania). Sedative and anxiolytic drugs (e.g. benzodiazepines) may add to the effects of these treatments. Drug choice is made difficult by the small number of direct comparisons, such that no one individual drug can be recommended over another on efficacy grounds. However, an early network meta-analysis1 suggested that olanzapine, risperidone, haloperidol and quetiapine had the best combination of efficacy and acceptability. Cochrane reviews suggested olanzapine is more effective than both lithium2 and valproate3 when used as monotherapy. Olanzapine may also be more effective than asenapine.4 A 2024 network meta-analysis concluded that tamoxifen was the most effective individual drug.5 The benefit of antipsychotic mood stabiliser combinations (compared with a mood stabiliser alone) is established for those relapsing while on mood stabilisers but less clear for those presenting on no treatment.6–10 The most common study design is for participants to be randomised to continued mood stabiliser alone (a treatment that allows the emergence of mania) or to the failed mood stabiliser with a (newly introduced) No Stop antidepressant treatment Is patient taking anti-manic* medication? Yes *In this context anti-manic = antipsychotic or mood stabiliser. Lithium may be somewhat less effective in mixed states27 or substance misuse28 and in those with rapid cycling or exhibiting psychotic symptoms.29 Consider: An antipsychotic (if symptoms severe or behaviour disturbed) Or Valproate (avoid in women of child-bearing potential) Or Lithium (if future adherence likely) If response is inadequate after 1–2 weeks Combine antipsychotic and valproate or lithium All patients: consider adding short-term benzodiazepine22–24 (lorazepam or clonazepam) If taking an antipsychotic, check compliance and dose. Increase if necessary. Consider adding lithium or valproate If taking lithium, check plasma levels, consider increasing the dose to give levels 1.0–1.2mmol/L (to treat the acute episode) and/or adding an antipsychotic If taking valproate, check plasma levels,8,9,25,26 increase dose to give levels up to 125mg/L if tolerated. Consider adding an antipsychotic If taking lithium or valproate and mania is severe, check level, add an antipsychotic6 If taking carbamazepine, consider adding an antipsychotic (higher doses may be needed as antipsychotic levels reduced) All patients: consider adding short-term benzodiazepine22–24 (lorazepam or clonazepam) Figure 2.1 Treatment of acute mania or hypomania.6–21

Bipolar disorder CHAPTER 2 antipsychotic. Overall, combination treatment with an antipsychotic and a mood stabiliser is more effective and quicker to act than either individual drug used alone.5,30 Most formal guidelines recommend drug combinations as the first choice in mania,31 although single drug treatment may be considered, at least initially, for people presenting on no prior treatment. Figure 2.1 outlines a treatment strategy for mania and hypomania. These recommendations are based on somewhat dated UK NICE guidelines,7 British Association for Psychopharmacology (BAP) guidelines32 and individual references cited in the diagram. Where an antipsychotic is recommended, choose from those licensed for mania/bipolar disorder (i.e. most conventional drugs, aripiprazole, asenapine, olanzapine, risperidone and quetiapine). Valproate use is now heavily restricted, so lithium is likely to be the mood stabiliser most commonly used, at least in younger men and women. An alternative is carbamazepine, but this, like valproate, is teratogenic. Lamotrigine has no activity in mania33 and should not be used. Suggested doses and alternative treatments are outlined in Tables 2.6 and 2.7. Table 2.6 Mania: suggested drug doses. Drug Dose Mood stabilisers Carbamazepine 400mg MR twice daily increasing to 800–1600mg/day.34,35 Dose may need to be increased after 2 weeks owing to induction of metabolism. Lithium 400mg/day, increasing every 3–4 days according to plasma levels. At least one study has used 800mg as a starting dose.36 Valproate As semi-sodium – 250mg three times daily increasing according to tolerability and plasma levels. Slow-release semi-sodium valproate may also be effective (at 15–30mg/kg)37 but there is one failed study.38 As slow-release sodium valproate – 500mg/day increasing as above. Higher, ‘loading doses’ have been used, both oral39–41 and intravenous.42–44 The dose is 20–30mg/kg/day. Antipsychotics Aripiprazole 15mg/day increasing up to 30mg/day as required.45 Doses lower than 15mg may not be effective.46 Asenapine 5mg twice daily increasing to 10mg twice daily as required Cariprazine 3mg/day increasing up to 12mg a day as required47 Olanzapine 10mg/day increasing to 15 or 20mg as required Risperidone 2 or 3mg/day increasing to 6mg/day as required. The use of paliperidone in mania is not well supported.48 Quetiapine IR – 100mg/day increasing to 800mg as required. Higher starting doses have been used.49 XL – 300mg/day increasing to 600mg/day on day 2 Haloperidol 5–10mg/day increasing to 15mg if required Benzodiazepines Lorazepam23,24 Up to 4mg/day (some centres use higher doses) Clonzapam22,24 Up to 8mg/day

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References

312 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 References

Cipriani A, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet 2011; 378:1306–1315.
McKnight RF, et al. Lithium for acute mania. Cochrane Database Syst Rev 2019; 6:CD004048.
Jochim J, et al. Valproate for acute mania. Cochrane Database Syst Rev 2019; 10:CD004052.
Mahajan V, et al. Efficacy and safety of asenapine versus olanzapine in combination with divalproex for acute mania: a randomized controlled trial. J Clin Psychopharmacol 2019; 39:305–311.
Huang W, et al. Comparative efficacy, safety, and tolerability of pharmacotherapies for acute mania in adults: a systematic review and network meta-analysis of randomized controlled trials. Mol Psychiatry 2024; doi: 10.1038/s41380-024-02705-3. Table 2.7 Mania: other possible treatments.* Treatment Comments Allopurinol (300–600mg/day) A meta-analysis of five studies of adjunct allopurinol found an effect size of just less than 0.3.50 Celecoxib (400mg/day)51 Small RCT (n = 46) suggests benefit when used as adjunct to valproate. Clonidine (450–900mcg/day)52 Limited data Clozapine53–55 Established treatment option for refractory mania/bipolar disorder. Rapid titration has been reported.56 Endoxifen57 (4–8mg/day) RCT evidence of efficacy. Major metabolite of tamoxifen. Gabapentin58 (up to 2.4g/day) Probably only effective by virtue of an anxiolytic effect. Rarely used. Possibly useful as prophylaxis.59 Levetiracetam (up to 1500mg/day) Effective as adjunctive treatment in two RCTs.60,61 One case of levetiracetam causing mania.62 Melatonin (6mg/day)67 Preliminary evidence of benefit as an adjunct to standard treatment. One small negative study.68 Memantine63 (10–30mg/day) Conflicting evidence64–66 Oxcarbazepine69–76 (around 300–3000mg/day) Probably effective acutely and as prophylaxis although one controlled study (conducted in youths) was negative.77 Phenytoin78 (300–400mg/day) Rarely used. Limited data. Complex kinetics with narrow therapeutic range. Ritanserin79 (10mg/day) Supported by a single RCT. Well tolerated. May protect against EPSEs. Tamoxifen80 (20–140mg/day) Good evidence for efficacy as adjunct and as monotherapy, with large effect size. May provoke switch to depression. Topiramate81 (up to 300mg/day) Probably not effective. Less effective than lithium.2 Tryptophan depletion82 Supported by a small RCT. Ziprasidone83–85 Supported by three RCTs. Widely used outside UK. *Entries are given in alphabetical order; no preference is implied by order in the table. Consult specialist and primary literature before using any treatment listed. EPSEs, extrapyramidal side effects; RCT, randomised controlled trial.

Bipolar disorder CHAPTER 2 6. Smith LA, et al. Acute bipolar mania: a systematic review and meta-analysis of co-therapy vs. monotherapy. Acta Psychiatr Scand 2007; 115:12–20. 7. National Institute for Health and Care Excellence. Bipolar disorder: assessment and management. Clinical guideline [CG185]. 2014 (last updated December 2023, last accessed October 2024); https://www.nice.org.uk/guidance/cg185. 8. Goodwin GM. Evidence-based guidelines for treating bipolar disorder: revised second edition – recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2009; 23:346–388. 9. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry 2002; 159:1–50. 10. Sachs GS. Decision tree for the treatment of bipolar disorder. J Clin Psychiatry 2003; 64 Suppl 8:35–40. 11. Tohen M, et al. A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania. Arch Gen Psychiatry 2003; 60:1218–1226. 12. Baldessarini RJ, et al. Olanzapine versus placebo in acute mania treatment responses in subgroups. J Clin Psychopharmacol 2003; 23:370–376. 13. Sachs G, et al. Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study. Bipolar Disord 2004; 6:213–223. 14. Yatham LN, et al. Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania. J Clin Psychopharmacol 2004; 24:599–606. 15. Yatham LN, et al. Risperidone plus lithium versus risperidone plus valproate in acute and continuation treatment of mania. Int Clin Psychopharmacol 2004; 19:103–109. 16. Bowden CL, et al. Risperidone in combination with mood stabilizers: a 10-week continuation phase study in bipolar I disorder. J Clin Psychiatry 2004; 65:707–714. 17. Hirschfeld RM, et al. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial. Am J Psychiatry 2004; 161:1057–1065. 18. Bowden CL, et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry 2005; 66:111–121. 19. Khanna S, et al. Risperidone in the treatment of acute mania: double-blind, placebo-controlled study. Br J Psychiatry 2005; 187:229–234. 20. Young RC, et al. GERI-BD: a randomized double-blind controlled trial of lithium and divalproex in the treatment of mania in older patients with bipolar disorder. Am J Psychiatry 2017; 174:1086–1093. 21. Conus P, et al. Olanzapine or chlorpromazine plus lithium in first episode psychotic mania: an 8-week randomised controlled trial. Eur Psychiatry 2015; 30:975–982. 22. Sachs GS, et al. Adjunctive clonazepam for maintenance treatment of bipolar affective disorder. J Clin Psychopharmacol 1990; 10:42–47. 23. Modell JG, et al. Inpatient clinical trial of lorazepam for the management of manic agitation. J Clin Psychopharmacol 1985; 5:109–113. 24. Curtin F, et al. Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis. J Affect Disord 2004; 78:201–208. 25. Taylor D, et al. Doses of carbamazepine and valproate in bipolar affective disorder. Psychiatric Bulletin 1997; 21:221–223. 26. Allen MH, et al. Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania. Am J Psychiatry 2006; 163:272–275. 27. Swann AC, et al. Lithium treatment of mania: clinical characteristics, specificity of symptom change, and outcome. Psychiatry Res 1986; 18:127–141. 28. Goldberg JF, et al. A history of substance abuse complicates remission from acute mania in bipolar disorder. J Clin Psychiatry 1999; 60:733–740. 29. Hui TP, et al. A systematic review and meta-analysis of clinical predictors of lithium response in bipolar disorder. Acta Psychiatr Scand 2019; 140:94–115. 30. Tajika A, et al. Mood stabilizers and antipsychotics for acute mania: systematic review and meta-analysis of augmentation therapy vs monotherapy from the perspective of time to the onset of treatment effects. Int J Neuropsychopharmacol 2022; 25:839–852. 31. Yatham LN, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord 2018; 20:97–170. 32. Goodwin GM, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2016; 30:495–553. 33. Besag FMC, et al. Efficacy and safety of lamotrigine in the treatment of bipolar disorder across the lifespan: a systematic review. Ther Adv Psychopharmacol 2021; 11:20451253211045870. 34. Weisler RH, et al. A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry 2004; 65:478–484. 35. Weisler RH, et al. Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: a multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2005; 66:323–330. 36. Bowden CL, et al. Efficacy of valproate versus lithium in mania or mixed mania: a randomized, open 12-week trial. Int Clin Psychopharmacol 2010; 25:60–67. 37. McElroy SL, et al. Randomized, double-blind, placebo-controlled study of divalproex extended release loading monotherapy in ambulatory bipolar spectrum disorder patients with moderate-to-severe hypomania or mild mania. J Clin Psychiatry 2010; 71:557–565. 38. Hirschfeld RM, et al. A randomized, placebo-controlled, multicenter study of divalproex sodium extended-release in the acute treatment of mania. J Clin Psychiatry 2010; 71:426–432. 39. McElroy SL, et al. A randomized comparison of divalproex oral loading versus haloperidol in the initial treatment of acute psychotic mania. J Clin Psychiatry 1996; 57:142–146. 40. Hirschfeld RM, et al. Safety and tolerability of oral loading divalproex sodium in acutely manic bipolar patients. J Clin Psychiatry 1999; 60:815–818.

314 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 41. Hirschfeld RM, et al. The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder. J Clin Psychiatry 2003; 64:841–846. 42. Jagadheesan K, et al. Acute antimanic efficacy and safety of intravenous valproate loading therapy: an open-label study. Neuropsychobiology 2003; 47:90–93. 43. Sekhar S, et al. Efficacy of sodium valproate and haloperidol in the management of acute mania: a randomized open-label comparative study. J Clin Pharmacol 2010; 50:688–692. 44. Fontana E, et al. Intravenous valproate in the treatment of acute manic episode in bipolar disorder: a review. J Affect Disord 2020; 260:738–743. 45. Li DJ, et al. Efficacy, safety and tolerability of aripiprazole in bipolar disorder: an updated systematic review and meta-analysis of randomized controlled trials. Prog Neuropsychopharmacol Biol Psychiatry 2017; 79:289–301. 46. Romeo B, et al. Meta-analysis and review of dopamine agonists in acute episodes of mood disorder: efficacy and safety. J Psychopharmacol 2018; 32:385–396. 47. Vieta E, et al. Effect of cariprazine across the symptoms of mania in bipolar I disorder: analyses of pooled data from phase II/III trials. Eur Neuropsychopharmacol 2015; 25:1882–1891. 48. Chang HY, et al. The efficacy and tolerability of paliperidone in mania of bipolar disorder: a preliminary meta-analysis. Exp Clin Psychopharmacol 2017; 25:422–433. 49. Pajonk FG, et al. Rapid dose titration of quetiapine for the treatment of acute schizophrenia and acute mania: a case series. J Psychopharmacol 2006; 20:119–124. 50. Chen AT, et al. Allopurinol augmentation in acute mania: a meta-analysis of placebo-controlled trials. J Affect Disord 2018; 226:245–250. 51. Arabzadeh S, et al. Celecoxib adjunctive therapy for acute bipolar mania: a randomized, double-blind, placebo-controlled trial. Bipolar Disord 2015; 17:606–614. 52. Singal P, et al. Efficacy and safety of clonidine in the treatment of acute mania in bipolar disorder: a systematic review. Brain Sci 2023; 13:547. 53. Mahmood T, et al. Clozapine in the management of bipolar and schizoaffective manic episodes resistant to standard treatment. Aust NZ J Psychiatry 1997; 31:424–426. 54. Green AI, et al. Clozapine in the treatment of refractory psychotic mania. Am J Psychiatry 2000; 157:982–986. 55. Ifteni P, et al. Switching bipolar disorder patients treated with clozapine to another antipsychotic medication: a mirror image study. Neuropsychiatr Dis Treat 2017; 13:201–204. 56. Aksoy Poyraz C, et al. Effectiveness of ultra-rapid dose titration of clozapine for treatment-resistant bipolar mania: case series. Ther Adv Psychopharmacol 2015; 5:237–242. 57. Joseph JT, et al. Efficacy and safety of endoxifen in bipolar disorder: a systematic review. Hum Psychopharmacol 2024; 39:e2899. 58. Ng QX, et al. A systematic review of the clinical use of gabapentin and pregabalin in bipolar disorder. Pharmaceuticals (Basel) 2021; 14:834. 59. Vieta E, et al. A double-blind, randomized, placebo-controlled, prophylaxis study of adjunctive gabapentin for bipolar disorder. J Clin Psychiatry 2006; 67:473–477. 60. Zarezadeh F, et al. Levetiracetam adjunct to quetiapine for the acute manic phase of bipolar disorder: a randomized, double-blind and placebo-controlled clinical trial of efficacy, safety and tolerability. Int Clin Psychopharmacol 2022; 37:46–53. 61. Keshavarzi A, et al. Levetiracetam as an adjunctive treatment for mania: a double-blind, randomized, placebo-controlled trial. Neuropsychobiology 2022; 81:192–203. 62. Park EM, et al. Acute mania associated with levetiracetam treatment. Psychosomatics 2014; 55:98–100. 63. Koukopoulos A, et al. Antimanic and mood-stabilizing effect of memantine as an augmenting agent in treatment-resistant bipolar disorder. Bipolar Disord 2010; 12:348–349. 64. Veronese N, et al. Acetylcholinesterase inhibitors and memantine in bipolar disorder: a systematic review and best evidence synthesis of the efficacy and safety for multiple disease dimensions. J Affect Disord 2016; 197:268–280. 65. Serra G, et al. Three-year, naturalistic, mirror-image assessment of adding memantine to the treatment of 30 treatment-resistant patients with bipolar disorder. J Clin Psychiatry 2015; 76:e91–97. 66. Omranifard V, et al. Evaluation of the effect of memantine supplementation in the treatment of acute phase of mania in bipolar disorder of elderly patients: a double-blind randomized controlled trial. Adv Biomed Res 2018; 7:148. 67. Moghaddam HS, et al. Efficacy of melatonin as an adjunct in the treatment of acute mania: a double-blind and placebo-controlled trial. Int Clin Psychopharmacol 2020; 35:81–88. 68. Quested DJ, et al. Melatonin In Acute Mania Investigation (MIAMI-UK). A randomized controlled trial of add-on melatonin in bipolar disorder. Bipolar Disord 2021; 23:176–185. 69. Benedetti A, et al. Oxcarbazepine as add-on treatment in patients with bipolar manic, mixed or depressive episode. J Affect Disord 2004; 79:273–277. 70. Lande RG. Oxcarbazepine: efficacy, safety, and tolerability in the treatment of mania. Int J Psychiatry Clin Pract 2004; 8:37–40. 71. Ghaemi SN, et al. Oxcarbazepine treatment of bipolar disorder. J Clin Psychiatry 2003; 64:943–945. 72. Pratoomsri W, et al. Oxcarbazepine in the treatment of bipolar disorder: a review. Can J Psychiatry 2006; 51:540–545. 73. Juruena MF, et al. Bipolar I and II disorder residual symptoms: oxcarbazepine and carbamazepine as add-on treatment to lithium in a double- blind, randomized trial. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:94–99. 74. Suppes T, et al. Comparison of two anticonvulsants in a randomized, single-blind treatment of hypomanic symptoms in patients with bipolar disorder. Aust NZ J Psychiatry 2007; 41:397–402. 75. Vieta E, et al. A double-blind, randomized, placebo-controlled prophylaxis trial of oxcarbazepine as adjunctive treatment to lithium in the long-term treatment of bipolar I and II disorder. Int J Neuropsychopharmacol 2008; 11:445–452.

Bipolar disorder CHAPTER 2 76. Talaei A, et al. Oxcarbazepine versus sodium valproate in treatment of acute mania: a double-blind randomized clinical trial. Int Clin Psychopharmacol 2022; 37:116–121. 77. Wagner KD, et al. A double-blind, randomized, placebo-controlled trial of oxcarbazepine in the treatment of bipolar disorder in children and adolescents. Am J Psychiatry 2006; 163:1179–1186. 78. Mishory A, et al. Phenytoin as an antimanic anticonvulsant: a controlled study. Am J Psychiatry 2000; 157:463–465. 79. Akhondzadeh S, et al. Ritanserin as an adjunct to lithium and haloperidol for the treatment of medication-naive patients with acute mania: a double blind and placebo controlled trial. BMC Psychiatry 2003; 3:7. 80. Carmassi C, et al. Prescribing tamoxifen in patients with mood disorders: a systematic review of potential antimanic versus depressive effects. J Clin Psychopharmacol 2021; 41:450–460. 81. Pigott K, et al. Topiramate for acute affective episodes in bipolar disorder in adults. Cochrane Database Syst Rev 2016; 9:CD003384. 82. Applebaum J, et al. Rapid tryptophan depletion as a treatment for acute mania: a double-blind, pilot-controlled study. Bipolar Disord 2007; 9:884–887. 83. Keck PE, Jr, et al. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry 2003; 160:741–748. 84. Potkin SG, et al. Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial. J Clin Psychopharmacol 2005; 25:301–310. 85. Vieta E, et al. Ziprasidone in the treatment of acute mania: a 12-week, placebo-controlled, haloperidol-referenced study. J Psychopharmacol 2010; 24:547–558.

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50 - Rapid cycling bipolar affective disorder

Rapid-cycling bipolar affective disorder

316 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 Rapid-cycling bipolar affective disorder Rapid-cycling bipolar affective disorder is usually defined as bipolar disorder in which four or more episodes of (hypo-)mania or depression (or four clear switches in polarity) occur in a 12-month period. It is generally considered to be less responsive to drug treatment than non-rapid-cycling bipolar illness1 and entails considerable depressive morbidity and suicide risk.2 Bipolar patients with rapid cycling have more depressive morbidity, a higher incidence of anxiety disorders, addiction, bulimia and borderline personality disorder, as well as atypical features during depression and symptoms such as irritability, risky behaviour, impulsivity and agitation. Rapid-cycling patients have poorer overall functioning, more obesity and are treated with a greater number of drugs.3 Drug doses tend to be somewhat higher in rapid-cycling than in other bipolar patients.4 Recent electroconvulsive therapy (ECT) treatment is associated with greater risk of rapid cycling.5 Table 2.8 outlines a treatment strategy for rapid cycling based on rather limited data and few direct comparisons of drugs.6 This strategy is broadly in line with the findings of published systematic reviews.7,8 NICE concluded that there is no evidence to support rapid-cycling illness being managed any differently from that with a more conventional course.9 There is no formal first choice agent or combination – prescribing depends partly on what treatments have already been used to prevent or treat mood episodes. Lithium is less likely to be effective in rapid cycling than in non-rapid cycling,10 a finding supported by psychiatrists’ experiences.11 In practice, response to treatment is sometimes idiosyncratic: individuals may show significant response to a particular drug. Spontaneous or treatment-related remissions occur in around a third of rapid cyclers12 and rapid cycling may come and go in many patients.13

07 - Chapter 2 Bipolar disorder

51 - References

References

Bipolar disorder CHAPTER 2 References

Miola A, et al. Prevalence and outcomes of rapid cycling bipolar disorder: mixed method systematic meta-review. J Psychiatr Res 2023; 164:404–415.
Coryell W, et al. The long-term course of rapid-cycling bipolar disorder. Arch Gen Psychiatry 2003; 60:914–920.
Furio M, et al. Characterization of rapid cycling bipolar patients presenting with major depressive episode within the BRIDGE-II-MIX study. Bipolar Disord 2020; 23:391–399.
Yasui-Furukori N, et al. Factors associated with doses of mood stabilizers in real-world outpatients with bipolar disorder. Clin Psychopharmacol Neurosci 2020; 18:599–606.
Xu JJ, et al. Sociodemographic, clinical and treatment characteristics of current rapid-cycling bipolar disorder: a multicenter Chinese study. Int J Bipolar Disord 2024; 12:11.
Miola A, et al. Current status and treatment of rapid cycling bipolar disorder. J Clin Psychopharmacol 2024; 44:86–88.
Strawbridge R, et al. A systematic review and meta-analysis of treatments for rapid cycling bipolar disorder. Acta Psychiatr Scand 2022; 146:290–311.
Roosen L, et al. Evidence-based treatment strategies for rapid cycling bipolar disorder, a systematic review. J Affect Disord 2022; 311:69–77.
National Institute for Health and Care Excellence. Bipolar disorder: assessment and management. Clinical guideline [CG185]. 2014 (last updated December 2023, last accessed October 2024); https://www.nice.org.uk/guidance/cg185.
Hui TP, et al. A systematic review and meta-analysis of clinical predictors of lithium response in bipolar disorder. Acta Psychiatr Scand 2019; 140:94–115.
Montlahuc C, et al. Response to lithium in patients with bipolar disorder: what are psychiatrists’ experiences and practices compared to literature review? Pharmacopsychiatry 2019; 52:70–77.
Koukopoulos A, et al. Duration and stability of the rapid-cycling course: a long-term personal follow-up of 109 patients. J Affect Disord 2003; 73:75–85.
Carvalho AF, et al. Rapid cycling in bipolar disorder: a systematic review. J Clin Psychiatry 2014; 75:e578–e586. Table 2.8 Recommended treatment strategy fo rapid-cycling bipolar disorder. Step Suggested treatment Step 1 Withdraw antidepressants in all patients10,11 (some controversial evidence supports continuation of SSRIs12,13) Step 2 Evaluate possible precipitants e.g. alcohol, thyroid dysfunction (including antithyroid antibodies14), external stressors15 Step 3 Optimise mood stabiliser treatment16–19 (using plasma levels) and Consider combining mood stabilisers e.g. lithium + valproate, lithium + lamotrigine, valproate + carbamazepine or go to Step 4 Step 4 Consider other (usually adjunctive) treatment options (alphabetical order; preferred treatment options in bold8) Aripiprazole20,21 (15–30mg/day) Clozapine22 (usual doses) ECT23 Lamotrigine24–26 (up to 225mg/day) Levetiracetam27 (up to 2000mg/day) Lurasidone28,29 (40–120mg/day) Nimodipine30–32 (180mg/day) Olanzapine33 (usual doses) Quetiapine34–37 (300–600mg/day) Risperidone38,39 (up to 6mg/day) Thyroxine40,41 (150–400mcg/day) Topiramate42 (up to 300mg/day) Transcranial magnetic stimulation (rTMS)43,44 The choice of drug is determined by patient factors – there are few comparative efficacy data to guide choice at the time of writing. Quetiapine probably has the best supporting data34–36 but it has similar efficacy to aripiprazole or olanzapine. Supporting data for levetiracetam, nimodipine, thyroxine and topiramate are relatively limited. Clozapine has a clear role in treatment-resistant bipolar disorder,45 a definition that might include rapid cycling, in which it shows some acute and long-term efficacy.22,46

318 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 14. Wehr TA, et al. Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry 1987; 144:1403–1411. 15. El-Mallakh RS, et al. Antidepressants worsen rapid-cycling course in bipolar depression: a STEP-BD randomized clinical trial. J Affect Disord 2015; 184:318–321. 16. Amsterdam JD, et al. Efficacy and mood conversion rate during long-term fluoxetine v. lithium monotherapy in rapid- and non-rapid-cycling bipolar II disorder. Br J Psychiatry 2013; 202:301–306. 17. Amsterdam JD, et al. Effectiveness and mood conversion rate of short-term fluoxetine monotherapy in patients with rapid cycling bipolar II depression versus patients with nonrapid cycling bipolar II depression. J Clin Psychopharmacol 2013; 33:420–424. 18. Gan Z, et al. Rapid cycling bipolar disorder is associated with antithyroid antibodies, instead of thyroid dysfunction. BMC Psychiatry 2019; 19:378. 19. Kupka RW, et al. Rapid and non-rapid cycling bipolar disorder: a meta-analysis of clinical studies. J Clin Psychiatry 2003; 64:1483–1494. 20. Kemp DE, et al. A 6-month, double-blind, maintenance trial of lithium monotherapy versus the combination of lithium and divalproex for rapid-cycling bipolar disorder and co-occurring substance abuse or dependence. J Clin Psychiatry 2009; 70:113–121. 21. Da Rocha FF, et al. Addition of lamotrigine to valproic acid: a successful outcome in a case of rapid-cycling bipolar affective disorder. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:1548–1549. 22. Woo YS, et al. Lamotrigine added to valproate successfully treated a case of ultra-rapid cycling bipolar disorder. Psychiatry Clin Neurosci 2007; 61:130–131. 23. Zhihan G, et al. Lamotrigine and lithium combination for treatment of rapid cycling bipolar disorder: results from meta-analysis. Front Psychiatry 2022; 13:913051. 24. Suppes T, et al. Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I disorder. J Affect Disord 2008; 107:145–154. 25. Muzina DJ, et al. Aripiprazole monotherapy in patients with rapid-cycling bipolar I disorder: an analysis from a long-term, double-blind, placebo-controlled study. Int J Clin Pract 2008; 62:679–687. 26. Calabrese JR, et al. Clozapine prophylaxis in rapid cycling bipolar disorder. J Clin Psychopharmacol 1991; 11:396–397. 27. Mosolov S, et al. Electroconvulsive therapy (ECT) in bipolar disorder patients with ultra-rapid cycling and unstable mixed states. Medicina (Kaunas) 2021; 57:624. 28. Fatemi SH, et al. Lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry 1997; 58:522–527. 29. Calabrese JR, et al. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group. J Clin Psychiatry 2000; 61:841–850. 30. Wang Z, et al. Lamotrigine adjunctive therapy to lithium and divalproex in depressed patients with rapid cycling bipolar disorder and a recent substance use disorder: a 12-week, double-blind, placebo-controlled pilot study. Psychopharmacol Bull 2010; 43:5–21. 31. Braunig P, et al. Levetiracetam in the treatment of rapid cycling bipolar disorder. J Psychopharmacol 2003; 17:239–241. 32. Siwek M, et al. Lurasidone in therapy of treatment-resistant ultra-rapid cycling bipolar disorder: case report. Clin Psychopharmacol Neurosci 2021; 19:568–571. 33. Kato M, et al. The efficacy and safety of lurasidone in bipolar I depression with and without rapid cycling: a pooled post-hoc analysis of two randomized, placebo-controlled trials. J Affect Disord 2023; 337:150–158. 34. Goodnick PJ. Nimodipine treatment of rapid cycling bipolar disorder. J Clin Psychiatry 1995; 56:330. 35. Pazzaglia PJ, et al. Preliminary controlled trial of nimodipine in ultra-rapid cycling affective dysregulation. Psychiatry Res 1993; 49:257–272. 36. Romanov DV, et al. [Nimodipine in treatment of bipolar disorder]. Zh Nevrol Psikhiatr Im S S Korsakova 2023; 123:20–26. 37. Sanger TM, et al. Olanzapine in the acute treatment of bipolar I disorder with a history of rapid cycling. J Affect Disord 2003; 73:155–161. 38. Goldberg JF, et al. Effectiveness of quetiapine in rapid cycling bipolar disorder: a preliminary study. J Affect Disord 2008; 105:305–310. 39. Vieta E, et al. Quetiapine monotherapy in the treatment of patients with bipolar I or II depression and a rapid-cycling disease course: a randomized, double-blind, placebo-controlled study. Bipolar Disord 2007; 9:413–425. 40. Langosch JM, et al. Efficacy of quetiapine monotherapy in rapid-cycling bipolar disorder in comparison with sodium valproate. J Clin Psychopharmacol 2008; 28:555–560. 41. Vieta E, et al. Quetiapine in the treatment of rapid cycling bipolar disorder. Bipolar Disord 2002; 4:335–340. 42. Bobo WV, et al. A randomized open comparison of long-acting injectable risperidone and treatment as usual for prevention of relapse, rehospitalization, and urgent care referral in community-treated patients with rapid cycling bipolar disorder. Clin Neuropharmacol 2011; 34:224–233. 43. Vieta E, et al. Treatment of refractory rapid cycling bipolar disorder with risperidone. J Clin Psychopharmacol 1998; 18:172–174. 44. Extein IL. High doses of levothyroxine for refractory rapid cycling. Am J Psychiatry 2000; 157:1704–1705. 45. Walshaw PD, et al. Adjunctive thyroid hormone treatment in rapid cycling bipolar disorder: a double-blind placebo-controlled trial of levothyroxine (L-T4) and triiodothyronine (T3). Bipolar Disord 2018; 20:594–603. 46. Chen CK, et al. Combination treatment of clozapine and topiramate in resistant rapid-cycling bipolar disorder. Clin Neuropharmacol 2005; 28:136–138. 47. Zamar AC, et al. A new treatment protocol of combined high-dose levothyroxine and repetitive transcranial magnetic stimulation for the treatment of rapid-cycling bipolar spectrum disorders: a cohort evaluation of 55 patients. J Clin Med 2022; 11:5830. 48. Tao S, et al. Case report: rTMS in combination with aripiprazole and sodium valproate for the maintenance treatment of rapid cycling bipolar disorder. Front Psychiatry 2023; 14:1070046. 49. Delgado A, et al. Clozapine in bipolar disorder: a systematic review and meta-analysis. J Psychiatr Res 2020; 125:21–27. 50. Kılınçel O, et al. The role of clozapine as a mood regulator in the treatment of rapid cycling bipolar affective disorder. Turk Psikiyatri Derg 2019; 30:268–271.

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52 - Bipolar depression

Bipolar depression

07 - Chapter 2 Bipolar disorder

53 - Meta analysis in bipolar depression

Meta-analysis in bipolar depression

Bipolar disorder CHAPTER 2 Bipolar depression Bipolar depression shares the diagnostic criteria for an episode of major depressive disorder, but episodes may differ in severity, time course, liability to recurrence and response to drug treatment. Episodes of bipolar depression are, compared with unipolar depression, more rapid in onset, more frequent, more severe, shorter and more likely to involve delusions and reverse neuro-vegetative symptoms such as hyperphagia and hypersomnia.1–3 Around 15% of people with bipolar disorder commit suicide,4 a statistic that reflects the severity and frequency of depressive episodes. Bipolar depression affords greater socioeconomic burden than either mania or unipolar major depression5 and comprises the majority of symptomatic illness in bipolar affective disorder with respect to time.6,7 In the UK, NICE recommends the combination of fluoxetine with olanzapine or quetiapine on its own (assuming an antipsychotic is not already prescribed).8 Lamotrigine is considered to be second-line treatment. BAP guidelines9 have lamotrigine as a first- line option, albeit with the caveat that a mood stabiliser or antipsychotic will be needed to protect against mania in the longer term. Lurasidone is also a first-line option in the BAP guidelines. The 2020 RANZCP guidelines10 recommend the use of lithium, lamotrigine, valproate, quetiapine, lurasidone and cariprazine either as individual agents or in combinations of two or three different drugs (including the addition of an antidepressant). Olanzapine and carbamazepine are considered second-line drugs. Similar recommendations are made in the more recent (2023) Canadian guidelines.11 Differences include the relegation of valproate to a second-line treatment and the inclusion of lumateperone (also as a second- line drug). Lurasidone is suggested as a first-line agent but only as an adjunct. Olanzapine plus fluoxetine is second line but olanzapine itself is demoted to third-line use. Tables 2.9, 2.10 and 2.11 give some broad guidance on treatment options in bipolar depression. Meta-analysis in bipolar depression Meta-analytical studies in bipolar depression are constrained by the variety of methods used to assess efficacy. This means that many scientifically robust studies cannot be included in some meta-analyses because their parameters (outcomes, duration, etc.) are not shared with other studies and so cannot be compared with them. Early lithium studies are an important example – their short duration and cross-over design preclude their inclusion in meta-analysis. BAP guidelines are somewhat dismissive (perhaps correctly) of network meta-analyses because outcome is heavily influenced by inclusion criteria and because findings often contradict direct comparisons.9 A 2021 network meta-analysis of 18 RCTs found that, looking only at antipsychotic drugs, lurasidone, quetiapine, olanzapine and cariprazine were all effective, with cariprazine having the smallest effect size.12 A more recent (2024) review13 of 16 RCTs of FDA-licensed antipsychotics added lumateperone to the list of robustly effective agents. Olanzapine showed the lowest rate of withdrawals from trials and quetiapine was the least well tolerated. The largest network meta-analysis (101 RCTs) was published in 2023.14 In this, olanzapine plus fluoxetine was the most effective, followed in order by quetiapine, olanzapine alone, lurasidone, lumateperone, cariprazine and lamotrigine (the least effective). Recent meta-analyses of ketamine and esketamine15,16 have concluded that ketamine formulations are probably effective in bipolar depression but with a low certainty of evidence.

320 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 Table 2.9 Established treatments (listed in alphabetical order). Drug/regimen Comments Lamotrigine1,17–21 Lamotrigine appears to be effective both as a treatment for bipolar depression and as prophylaxis against further episodes. It does not induce switching or rapid cycling. It is as effective as citalopram and causes less weight gain than lithium. Overall, the effect of lamotrigine is difficult to be clear about, with numerous equivocal trials22 that perhaps failed to allow for the time taken for full titration of the drug. It may be useful as an adjunct to lithium23 or as an alternative to it in pregnancy.24 A later trial25 suggested robust efficacy when combined with quetiapine. There is a small anti-manic effect of lamotrigine.26 Treatment is somewhat complicated by the small risk of rash, which is associated with speed of dose titration. The necessity for titration may limit clinical utility. A further complication is the question of dose: 50mg/day has efficacy, but 200mg/day is probably better. In the USA, doses of up to 1200mg/day have been used (mean around 250mg/day). Plasma concentrations (only the range for anti-convulsant effects is known) may guide the need for higher doses. Lithium1,17,27–29 Lithium is probably effective in treating bipolar depression but supporting data are methodologically questionable.30 There is some evidence that lithium prevents depressive relapse but its effects on manic relapse are considered more robust. There is fairly strong support for lithium in reducing suicidality in bipolar disorder.31,32 Lurasidone Three RCTs show a good effect for lurasidone either alone33 or as an adjunct to mood stabilisers.34,35 A further RCT reported good outcome in bipolar depression with sub- syndromal hypomanic symptoms.36 Pooled analysis suggests response is dose-related.37 A network meta-analysis suggested lurasidone is more effective than aripiprazole and ziprasidone but not quetiapine or olanzapine.38 Mood stabiliser + antidepressant39–45 Antidepressants are still widely used in bipolar depression, particularly for breakthrough episodes occurring in those on mood stabilisers. They have been assumed to be effective, although there is a risk of cycle acceleration and/or switching. Studies suggest mood stabilisers alone are just as effective as mood stabilisers/antidepressant combination although subanalysis suggested higher doses of antidepressants may be effective.46–48 Tricyclics and MAOIs are usually best avoided. SSRIs are generally recommended if an antidepressant is to be prescribed. Venlafaxine and bupropion (amfebutamone) have also been used. Venlafaxine may be more likely to induce a switch to mania.49,50 Continuing antidepressant treatment after resolution of symptoms may protect against depressive relapse51,52 although only in the absence of a mood stabiliser.53 At the time of writing, there is no consensus on whether or not to continue antidepressants long term.54 The most recent findings suggest that switch rates are no higher with sertraline alone than with lithium + sertraline,55 but also that there may be no protective effect against depressive episodes.56 Some guidelines recommend the use of antidepressants in bipolar II depression57 and there is evidence that sertraline does not increase switch rates in these patients.55 Olanzapine ± fluoxetine17,30,58–61 This combination (Symbyax®) is more effective than both placebo and olanzapine alone in treating bipolar depression. The dose is 6 and 25mg or 12 and 50mg/day (so presumably 5/20mg and 10/40mg are effective). It may be more effective than lamotrigine. There is reasonable evidence of prophylactic effect. It is recommended as first-line treatment by NICE8 but not in other guidelines. Olanzapine alone is effective when compared with placebo62 but the combination with fluoxetine is more effective. (This is possibly the strongest evidence for a beneficial effect for an antidepressant in bipolar depression.)

Bipolar disorder CHAPTER 2 Table 2.10 Alternative treatments (refer to primary literature before using). Drug/regimen Comments Antidepressants76–84 ‘Unopposed’ antidepressants (i.e. without mood-stabiliser protection) are generally to be avoided in bipolar depression because of the risk of switching and inducing rapid cycling. There is also evidence that they are relatively less effective (perhaps not effective at all) in bipolar depression than in unipolar depression although dose may be critical.48 Short-term use of fluoxetine, venlafaxine and moclobemide seems reasonably effective and safe even as monotherapy. A meta-analysis suggested a large effect size for tranylcypromine in the absence of any risk of switching.85 Overall, however, unopposed antidepressant treatment should be avoided, especially in bipolar I disorder.54 Cariprazine86 One RCT suggests that cariprazine at 1.5mg/day is effective in bipolar I depression. A second, larger study showed 1.5 and 3mg/day to be effective.87 The most recent study87 found benefit for 1.5mg/day but not 3mg/day. Usually has lowest efficacy among effective drugs in meta-analyses. Ketamine88–91 An IV dose of 0.5mg/kg is effective in refractory bipolar depression with a very high response rate. Dissociative symptoms are common but brief. Now accepted as standard treatment for refractory bipolar depression.92,93 IV racemate is possibly more effective than intranasal esketamine.94 Switching to mania is a potential problem95 although probably a remote risk. Pramipexole96,97 Two small placebo-controlled trials suggested useful efficacy in bipolar depression. Effective dose averages around 1.7mg/day. Both studies used pramipexole as an adjunct to existing mood-stabiliser treatment. Neither study detected an increased risk of switching to mania/hypomania (a theoretical consideration) but data are insufficient to exclude this possibility. A meta-analysis of studies showed a robust effect on response but not remission.98 RCT, randomised controlled trial. Drug/regimen Comments Quetiapine63–67 Five large RCTs have demonstrated clear efficacy for doses of 300 and 600mg daily (as monotherapy) in bipolar I and bipolar II depression. A later study in Chinese patients demonstrated the efficacy of 300mg/day68 in bipolar I depression. It may be superior to both lithium and paroxetine. Quetiapine also prevents relapse into depression and mania69,70 and so is one of the treatments of choice in bipolar depression. It appears not to be associated with switching to mania. Valproate1,17,71–75 Limited evidence of efficacy as monotherapy but recommended in some guidelines. Several very small RCTs but many are negative; however meta-analyses do support antidepressant efficacy.74 Probably protects against depressive relapse but database is small. Not recommended because of its teratogenic effects in both men and women. MAOIs, monoamine oxidase inhibitors; RCT, randomised controlled trial. Table 2.9 (Continued)

07 - Chapter 2 Bipolar disorder

54 - Summary of drug choice

Summary of drug choice

07 - Chapter 2 Bipolar disorder

55 - References

References

322 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 Summary of drug choice The combination of olanzapine + fluoxetine is probably the most effective treatment available for bipolar depression but its use is constrained by the well-known adverse effect profile of olanzapine. SSRIs other than fluoxetine may be effective but should probably be avoided unless clear individual benefit is obvious.54 Alternative first-line choices are quetiapine, olanzapine, lurasidone, lamotrigine and cariprazine (and lumateperone in North America). These drugs differ substantially in adverse effect profile, tolerability and cost, each of which needs to be considered when prescribing for an individual. Lithium is also effective but supporting evidence is relatively weak. Second-line drugs include ketamine and, increasingly, modafinil. Aripiprazole, risperidone, ziprasidone, tricyclics (with the exception of imipramine) and MAOIs (with the exception of tranylcypromine) are probably not effective and should not be used routinely.114 References

Malhi GS, et al. Bipolar depression: management options. CNS Drugs 2003; 17:9–25.
Perlis RH, et al. Clinical features of bipolar depression versus major depressive disorder in large multicenter trials. Am J Psychiatry 2006; 163:225–231.
Mitchell PB, et al. Comparison of depressive episodes in bipolar disorder and in major depressive disorder within bipolar disorder pedigrees. Br J Psychiatry 2011; 199:303–309.
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Hirschfeld RM. Bipolar depression: the real challenge. Eur Neuropsychopharmacol 2004; 14 Suppl 2:S83–S88.
Judd LL, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002; 59:530–537.
Judd LL, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003; 60:261–269.
National Institute for Health and Care Excellence. Bipolar disorder: assessment and management. Clinical guideline [CG185]. 2014 (last updated December 2023, last accessed October 2024); https://www.nice.org.uk/guidance/cg185. Table 2.11 Other possible treatments (seek specialist advice before using). Drug/regimen Comments Aripiprazole99–102 Limited support from open studies as add-on treatment. One RCT was negative. Possibly not effective.98 Carbamazepine1,17,103 Occasionally recommended but database is poor and effect modest. May have useful activity when added to other mood stabilisers. Gabapentin1,104,105 Open studies suggest modest effect when added to mood stabilisers or antipsychotics. Doses average around 1750mg/day. Anxiolytic effect may account for apparent effect in bipolar depression. Inositol106 Small, randomised, pilot study suggests that 12g/day inositol is effective in bipolar depression. Mifepristone107,108 Some evidence of mood-elevating properties in bipolar depression although this was not replicated in a larger trial. Improved cognitive function in both trials. Dose used was 600mg/day. Modafinil109 Meta-analysis of five studies of modafinil/armodafinil suggests robust benefit on response and remission with good tolerability and no evidence of increased risk of switching. Some evidence of safety from a later study.110 Omega-3 fatty acids111–113 One positive RCT (1g/2g a day) and one negative (6g a day). The ratio of omega-6 may determine efficacy.113 RCT, randomised controlled trial.

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Neuropsychopharmacology 2004; 29:1538–1545. 108. Watson S, et al. A randomized trial to examine the effect of mifepristone on neuropsychological performance and mood in patients with bipolar depression. Biol Psychiatry 2012; 72:943–949. 109. Nunez NA, et al. Efficacy and tolerability of adjunctive modafinil/armodafinil in bipolar depression: a meta-analysis of randomized controlled trials. Bipolar Disord 2020; 22:109–120. 110. Lipschitz JM, et al. Modafinil’s effects on cognition and sleep quality in affectively-stable patients with bipolar disorder: a pilot study. Front Psychiatry 2023; 14:1246149. 111. Frangou S, et al. Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study. Br J Psychiatry 2006; 188:46–50. 112. Keck PE, Jr, et al. Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder. Biol Psychiatry 2006; 60:1020–1022. 113. Zhang M, et al. Assessment of causal relationships between omega-3 and omega-6 polyunsaturated fatty acids in bipolar disorder: a 2-sample bidirectional mendelian randomization study. Food Funct 2023; 14:6200–6211. 114. Taylor DM, et al. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis. Acta Psychiatr Scand 2014; 130:452–469.

07 - Chapter 2 Bipolar disorder

56 - Prophylaxis in bipolar disorder

Prophylaxis in bipolar disorder

326 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 Prophylaxis in bipolar disorder Any successful drug regimen used for an acute episode should be continued as prophylaxis. To a large extent, therefore, the choice of maintenance treatment for individual patients is dictated by the efficacy and tolerability of acute treatment. Possible exceptions include the consideration of withdrawing antipsychotic treatment from a mood-stabiliser combination after an episode of mania (recommended by some authorities1) and the withdrawal of antidepressants after the successful treatment of an acute episode of bipolar depression, assuming a mood stabiliser is continued (recommended by most authorities, at least implicitly2). Withdrawing antipsychotics from combination regimens with lithium or valproate may worsen the risk of relapse.3 Residual mood symptoms after an acute episode are a strong predictor of recurrence.4,5 In respect to monotherapy, most evidence supports the efficacy of lithium6,7 in preventing episodes of mania and depression.8 Carbamazepine is somewhat less effective6,9 and the long-term efficacy of valproate is uncertain,7,10–12 although it too may protect against relapse both into depression and mania.6,13 Lithium has the advantage of a proven anti-suicidal effect14–16 but perhaps, relative to other mood stabilisers, the disadvantage of a worsened outcome following abrupt discontinuation17–20 (although the effect of abrupt discontinuation of other drugs may be similar20). Early use of lithium might increase the likelihood of efficacy.21 The independent BALANCE study found that valproate as monotherapy was relatively less effective than lithium or the combination of lithium and valproate,11 casting doubt on its use as a first-line single treatment. Also, a large observational study has shown that lithium is much more effective than valproate in preventing relapse to any condition and in preventing rehospitalisation.22 Given this, valproate’s relative contraindication in women of child-bearing age and the fact that valproate is not licensed for prophylaxis, valproate should be considered a second- or third-line treatment. Conventional antipsychotics have traditionally been used and are perceived to be effective although the objective evidence base is rather weak.23,24 FGA depots probably protect against mania but may worsen depression25 (see ‘Antipsychotic long-acting injections in bipolar disorder’ earlier in this chapter). Evidence supports the efficacy of many SGAs particularly olanzapine,26,27 quetiapine,28 aripiprazole29 and risperidone.30 Most studies examine combinations with mood stabilisers and there are fewer supportive monotherapy trials, although asenapine, aripiprazole, olanzapine, quetiapine and risperidone monotherapy are all more effective than placebo. Olanzapine, quetiapine and aripiprazole are licensed for prophylaxis in many countries although only olanzapine and quetiapine offer protection against depression.7 Asenapine may also be effective,31 as may ziprasidone.32 There is some evidence to support maintenance treatment with lurasidone when added to valproate or lithium,33 but there are only acute data for lumateperone.34 Cariprazine may be ineffective as maintenance.35 All antipsychotic + mood stabiliser combinations were more effective than mood stabilisers alone in a meta-analysis of 41 studies and 9821 participants.36 Aripiprazole

valproate was numerically the best maintenance treatment (in terms of risk of relapse to any episode) in this analysis. A later meta-analysis of 14 monotherapy studies found that monotherapy with aripiprazole, olanzapine, lurasidone, risperidone or quetiapine was more effective than placebo over 6 months or longer.37 A 2022 network meta- analysis found the order of effectiveness to be olanzapine (most effective), quetiapine, aripiprazole, risperidone, lurasidone and paliperidone (least effective).7 Long-acting aripiprazole has been shown to delay the time to, and reduced the rate of recurrence of, manic episodes and was generally safe and well tolerated.38 The use of

07 - Chapter 2 Bipolar disorder

57 - Optimising lithium treatment45

Optimising lithium treatment45

07 - Chapter 2 Bipolar disorder

58 - Combination treatment

Combination treatment

Bipolar disorder CHAPTER 2 risperidone LAI is well supported by RCTs39 and naturalistic studies.40 The prescribing of LAI SGAs is generally encouraged despite some labelling restrictions41–44 (see ‘Antipsychotic long-acting injections in bipolar disorder’ earlier in this chapter). Box 2.1 summarises recommendations from NICE for prescribing in bipolar disorder. Optimising lithium treatment45 For adults with bipolar disorder the standard lithium plasma level should be 0.6–0.8mmol/L with the option to reduce it to 0.4–0.6mmol/L in cases of good response but poor tolerance, or to increase it to 0.8–1.0mmol/L in cases of insufficient response and good tolerance. For children and adolescents no consensus exists, but the majority of the International Society for Bipolar Disorders (ISBD)/International Study Group on Lithium (IGSLI) task force endorsed this same recommendation. For the elderly, a more conservative approach may be adopted, usually aiming for 0.4–0.6mmol/L, with the option to go to, at most, 0.7 or 0.8mmol/L at age 65–79 years, and only to 0.7mmol/L over age 80 years. Combination treatment A significant proportion of patients with bipolar illness fail to be treated adequately with a single mood stabiliser,11 so combinations of mood stabilisers46,47 or a mood stabiliser and an antipsychotic47,48 are commonly used.49 Also, there is evidence that where combination treatments are effective in mania or depression, then continuation with the same combination provides optimal prophylaxis.28,48 Overall, combination treatments offer better protection against relapse than monotherapy.7 The use of polypharmacy needs to be balanced against the likely increased adverse effect burden. Combinations of olanzapine, risperidone, quetiapine or haloperidol with lithium or valproate are recommended by NICE27 and by BAP guidelines.6 Alternative antipsychotics (e.g. aripiprazole) are also options in combinations with lithium or valproate, particularly if these have been found to be effective during the treatment of an acute episode of mania or depression.28,50 Carbamazepine is considered to be third line. Lamotrigine may be useful in bipolar II disorder27 but seems only to prevent recurrence of depression.51 Lurasidone may have broadly similar long-term efficacy, both as monotherapy and when combined with a mood stabiliser.33,52 Extrapolation of currently available data suggests that lithium plus an SGA is probably the polypharmacy regimen of choice. There are naturalistic data to support combinations of three treatments; in one study53 the two best treatments were lithium + valproate + quetiapine followed by lithium + valproate + olanzapine. Box 2.1 NICE recommendations27 ■ ■When planning long-term pharmacological interventions to prevent relapse, take into account drugs that have been effective during episodes of mania or bipolar depression. Discuss with the person whether they prefer to continue this treatment or switch to lithium, and explain that lithium is the most effective long-term treatment for bipolar disorder. ■ ■Offer lithium as a first-line, long-term pharmacological treatment for bipolar disorder and if lithium is insufficiently effective, consider adding valproate. If lithium is poorly tolerated, consider valproate or olanzapine instead, or if it has been effective during an episode of mania or bipolar depression, quetiapine. ■ ■Do not offer valproate to women of child-bearing potential. Ensure adequate contraception in men taking valproate. ■ ■Discuss with the person the possible benefits and risks of each drug for them.

328 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 Monotherapy with antipsychotics can be considered where mood stabilisers are poorly tolerated or where adherence cannot be assured.54 A meta-analysis of long-term antidepressant treatment found that continued treatment was more likely to induce a switch to mania than prevent a depressive episode.55 The STEP-BD study found no significant benefit for continuing (compared with discontinuing) an antidepressant and worse outcomes in those with rapid-cycling illness.56 A more recent study found that neither escitalopram nor bupropion had any effect on relapse of depression.57 There is thus essentially no strong support for long-term use of antidepressants in bipolar illness although some bipolar patients may relapse into depression when antidepressants are discontinued.20 Box 2.2 and Table 2.12 summarise prophylaxis and maintenance treatment, respectively, in bipolar disorder. Box 2.2 Summary of prophylaxis in bipolar disorder First line: lithium monotherapy Second line: olanzapine, aripiprazole, risperidone or quetiapine in combination with valproate* or lithium Third line: alternative antipsychotic (lurasidone, asenapine or ziprasidone) or alternative mood stabiliser (carbamazepine or lamotrigine) in combination Fourth line: antipsychotic with two mood stabilisers ■ ■Always maintain successful acute treatment regimens (e.g. mood stabiliser + antipsychotic) as prophylaxis ■ ■Avoid long-term antidepressants if possible *Not in women of child-bearing potential. Table 2.12 Summary of maintenance in bipolar disorder.7,57 Prevents mania Prevents depression Monotherapy Antipsychotics Aripiprazole Yes No Asenapine Yes No Olanzapine Yes Yes Paliperidone Yes No Risperidone Yes No Quetiapine Yes Yes Mood stabilisers (MS) Lamotrigine No Yes Lithium Yes Yes Valproate Yes (?) Yes Antidepressants No No Combination treatment Antipsychotic + MS Yes Yes Valproate + lamotrigine Yes (?) Yes

07 - Chapter 2 Bipolar disorder

59 - References

References

Bipolar disorder CHAPTER 2 References

Malhi GS, et al. The 2020 Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines for Mood Disorders: bipolar disorder summary. Bipolar Disord 2020; 22:805–821.
Yatham LN, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord 2018; 20:97–170.
Kang MG, et al. Lithium vs valproate in the maintenance treatment of bipolar I disorder: a post-hoc analysis of a randomized double-blind placebo-controlled trial. Aust NZ J Psychiatry 2020; 54:298–307.
Solomon DA, et al. Longitudinal course of bipolar I disorder: duration of mood episodes. Arch Gen Psychiatry 2010; 67:339–347.
Perlis RH, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry 2006; 163:217–224.
Goodwin GM, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2016; 30:495–553.
Nestsiarovich A, et al. Preventing new episodes of bipolar disorder in adults: systematic review and meta-analysis of randomized controlled trials. Eur Neuropsychopharmacol 2022; 54:75–89.
Sani G, et al. Treatment of bipolar disorder in a lifetime perspective: is lithium still the best choice? Clin Drug Investig 2017; 37:713–727.
Hartong EG, et al. Prophylactic efficacy of lithium versus carbamazepine in treatment-naive bipolar patients. J Clin Psychiatry 2003; 64:144–151.
Cipriani A, et al. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev 2013; 10:CD003196.
Geddes JR, et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 2010; 375:385–395.
Kemp DE, et al. A 6-month, double-blind, maintenance trial of lithium monotherapy versus the combination of lithium and divalproex for rapid-cycling bipolar disorder and co-occurring substance abuse or dependence. J Clin Psychiatry 2009; 70:113–121.
Smith LA, et al. Effectiveness of mood stabilizers and antipsychotics in the maintenance phase of bipolar disorder: a systematic review of randomized controlled trials. Bipolar Disord 2007; 9:394–412.
Cipriani A, et al. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry 2005; 162:1805–1819.
Kessing LV, et al. Suicide risk in patients treated with lithium. Arch Gen Psychiatry 2005; 62:860–866.
Song J, et al. Suicidal behavior during lithium and valproate treatment: a within-individual 8-year prospective study of 50,000 patients with bipolar disorder. Am J Psychiatry 2017; 174:795–802.
Mander AJ, et al. Rapid recurrence of mania following abrupt discontinuation of lithium. Lancet 1988; 2:15–17.
Faedda GL, et al. Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders. Arch Gen Psychiatry 1993; 50:448–455.
Macritchie KA, et al. Does ‘rebound mania’ occur after stopping carbamazepine? A pilot study. J Psychopharmacol 2000; 14:266–268.
Franks MA, et al. Bouncing back: is the bipolar rebound phenomenon peculiar to lithium? A retrospective naturalistic study. J Psychopharmacol 2008; 22:452–456.
Kessing LV, et al. Starting lithium prophylaxis early v. late in bipolar disorder. Br J Psychiatry 2014; 205:214–220.
Kessing LV, et al. Valproate v. lithium in the treatment of bipolar disorder in clinical practice: observational nationwide register-based cohort study. Br J Psychiatry 2011; 199:57–63.
Gao K, et al. Typical and atypical antipsychotics in bipolar depression. J Clin Psychiatry 2005; 66:1376–1385.
Hellewell JS. A review of the evidence for the use of antipsychotics in the maintenance treatment of bipolar disorders. J Psychopharmacol 2006; 20:39–45.
Gigante AD, et al. Long-acting injectable antipsychotics for the maintenance treatment of bipolar disorder. CNS Drugs 2012; 26:403–420.
Tohen M, et al. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study. Am J Psychiatry 2003; 160:1263–1271.
National Institute for Health and Care Excellence. Bipolar disorder: assessment and management. Clinical guideline [CG185]. 2014 (last updated December 2023, last accessed October 2024); https://www.nice.org.uk/guidance/cg185.
Vieta E, et al. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord 2008; 109:251–263.
McIntyre RS. Aripiprazole for the maintenance treatment of bipolar I disorder: a review. Clin Ther 2010; 32 Suppl 1:S32–S38.
Ghaemi SN, et al. Long-term risperidone treatment in bipolar disorder: 6-month follow up. Int Clin Psychopharmacol 1997; 12:333–338.
Szegedi A, et al. Randomized, double-blind, placebo-controlled trial of asenapine maintenance therapy in adults with an acute manic or mixed episode associated with bipolar I disorder. Am J Psychiatry 2017; 175:71–79.
Bowden CL, et al. Efficacy of valproate versus lithium in mania or mixed mania: a randomized, open 12-week trial. Int Clin Psychopharmacol 2010; 25:60–67.
Calabrese JR, et al. Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder. Eur Neuropsychopharmacol 2017; 27:865–876.
McIntyre RS, et al. The efficacy of lumateperone in patients with bipolar depression with mixed features. J Clin Psychiatry 2023; 84:22m14739.
McIntyre RS, et al. Cariprazine as a maintenance therapy in the prevention of mood episodes in adults with bipolar I disorder. Bipolar Disord 2024; 26:442–453.
Kishi T, et al. Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: a systematic review and network meta- analysis of randomized controlled trials. Mol Psychiatry 2021; 26:4146–4157.
Escudero MAG, et al. Second generation antipsychotics monotherapy as maintenance treatment for bipolar disorder: a systematic review of long-term studies. Psychiatr Q 2020; 91:1047–1060.

330 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 38. Calabrese JR, et al. Efficacy and safety of aripiprazole once-monthly in the maintenance treatment of bipolar I disorder: a double-blind, placebo-controlled, 52-week randomized withdrawal study. J Clin Psychiatry 2017; 78:324–331. 39. Kishi T, et al. Long-acting injectable antipsychotics for prevention of relapse in bipolar disorder: a systematic review and meta-analyses of randomized controlled trials. Int J Neuropsychopharmacol 2016; 19:pyw038. 40. Hsieh MH, et al. Bipolar patients treated with long-acting injectable risperidone in Taiwan: a 1-year mirror-image study using a national claims database. J Affect Disord 2017; 218:327–334. 41. Belge JB, et al. Long-acting second-generation injectable antipsychotics for the maintenance treatment of bipolar disorder: a narrative review. Expert Opin Pharmacother 2024; 25:295–299. 42. Kishi T, et al. A comparison of recurrence rates after discontinuation of second-generation antipsychotic long-acting injectable versus corresponding oral antipsychotic in the maintenance treatment of bipolar disorder: a systematic review. Psychiatry Res 2024; 333:115761. 43. Pacchiarotti I, et al. Long-acting injectable antipsychotics (LAIs) for maintenance treatment of bipolar and schizoaffective disorders: a systematic review. Eur Neuropsychopharmacol 2019; 29:457–470. 44. Yıldızhan E, et al. Effect of long acting injectable antipsychotics on course and hospitalizations in bipolar disorder – a naturalistic mirror image study. Nord J Psychiatry 2022; 76:37–43. 45. Nolen WA, et al. What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium. Bipolar Disord 2019; 21:394–409. 46. Freeman MP, et al. Mood stabilizer combinations: a review of safety and efficacy. Am J Psychiatry 1998; 155:12–21. 47. Muzina DJ, et al. Maintenance therapies in bipolar disorder: focus on randomized controlled trials. Aust NZ J Psychiatry 2005; 39:652–661. 48. Tohen M, et al. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br J Psychiatry 2004; 184:337–345. 49. Paton C, et al. Lithium in bipolar and other affective disorders: prescribing practice in the UK. J Psychopharmacol 2010; 24:1739–1746. 50. Marcus R, et al. Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double-blind, randomized study. Bipolar Disord 2011; 13:133–144. 51. Bowden CL, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 2003; 60:392–400. 52. Pikalov A, et al. Long-term use of lurasidone in patients with bipolar disorder: safety and effectiveness over 2 years of treatment. Int J Bipolar Disord 2017; 5:9. 53. Wingård L, et al. Monotherapy vs. combination therapy for post mania maintenance treatment: a population based cohort study. Eur Neuropsychopharmacol 2019; 29:691–700. 54. Jauhar S, et al. Controversies in bipolar disorder; role of second-generation antipsychotic for maintenance therapy. Int J Bipolar Disord 2019; 7:10. 55. Ghaemi SN, et al. Long-term antidepressant treatment in bipolar disorder: meta-analyses of benefits and risks. Acta Psychiatr Scand 2008; 118:347–356. 56. Ghaemi SN, et al. Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry 2010; 71:372–380. 57. Yatham LN, et al. Duration of adjunctive antidepressant maintenance in bipolar I depression. N Engl J Med 2023; 389:430–440.

07 - Chapter 2 Bipolar disorder

60 - Stopping lithium and mood stabilisers

Stopping lithium and mood stabilisers

07 - Chapter 2 Bipolar disorder

61 - Rationale for stopping

Rationale forÂ stopping

07 - Chapter 2 Bipolar disorder

62 - Withdrawal effects from lithium and other moo

Withdrawal effects from lithium and other mood stabilisers

Bipolar disorder CHAPTER 2 Stopping lithium and mood stabilisers Rationale for stopping Patients may ask to stop lithium and other mood stabilisers because of the range of adverse effects experienced. In one cohort 54% of patients discontinued lithium, mostly because of tolerability problems, including diarrhoea (13%), tremor (11%), polyuria/ polydipsia/diabetes insipidus (9%), creatinine increase (9%) and weight gain (7%).1 Alternatively, although lithium and mood stabilisers are useful in controlling acute symptoms and in preventing relapse, a clinician may judge that the balance of risks and benefits has shifted over time (e.g. adverse physical effects accumulate, alternative coping strategies developed) such that dose reduction or stopping may be considered. Other patients may be prescribed mood stabilisers for conditions such as personality disorders, for which there is a lack of evidence. Stopping should be done in a manner that minimises the risk of both withdrawal effects and relapse (the two key risks). Withdrawal effects from lithium and other mood stabilisers Discontinuation of lithium can cause withdrawal effects, including both physical and psychological symptoms (Table 2.13). These withdrawal effects include mood episodes (depression, but more commonly mania) and are sometimes called ‘rebound’ effects.2,3 The risk of relapse in the period following abrupt cessation greatly exceeds the rate of relapse in the untreated disorder.2 For example, a review of studies of lithium discontinuation in people with bipolar disorder found that the untreated disorder had a mean cycle length (the average time between episodes) of 11.6 months, whereas the time to a new episode following lithium discontinuation was 1.7 months.2 This represents a sevenfold increase in the rate of relapse and suggests that manic and depressive symptoms that occur following lithium withdrawal are largely because of lithium withdrawal effects rather than because of the untreated disorder. Nonetheless, it is to be expected that the withdrawal of an effective mood stabiliser leads to mood destabilisation simply because of the removal of an effective treatment for the condition. Relapse may sometimes indicate the need for continued treatment. Distinguishing between withdrawal-related rebound and true relapse of the underlying condition is made easier by extending the withdrawal period (so as to help rule out withdrawal effects). Withdrawal effects are thought to be due to the development of dopaminergic hypersensitivity6 and changes in neuronal membranes, cell transport function or other neurotransmitter systems during lithium treatment.7 Other mood stabilisers have also been associated with a withdrawal syndrome.8 Table 2.13 Withdrawal effects of lithium.3–5 Physical effects Psychological effects Tremor Polyuria Muscular weakness Polydipsia Dryness of mouth Anxiety Nervousness Irritability Alertness Sleep disturbances Elated mood/mania Depressed mood

07 - Chapter 2 Bipolar disorder

63 - Evidence for long term treatment

Evidence for long-term treatment

07 - Chapter 2 Bipolar disorder

64 - Duration of tapering

Duration ofÂ tapering

07 - Chapter 2 Bipolar disorder

65 - Pattern of tapering

Pattern of tapering

332 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 Evidence for long-term treatment Although lithium is accepted as the first-line choice for prophylaxis in bipolar disorder,9 evidence for long-term treatment with lithium and other mood stabilisers is derived from discontinuation studies where patients established on these medications were randomised to either continue or cease treatment.10,11 In these studies, lithium was sometimes stopped abruptly. As mentioned, rapid stopping of lithium is likely to produce withdrawal effects, which can include precipitating mood episodes.2 Indeed, in one study abruptly stopping lithium in patients with depression provoked manic episodes in 13%.12 There is evidence that abrupt cessation of other mood stabilisers can also precipitate mood episodes.3 Patients who are discontinued from these medications often demonstrate relapse rates that are greater than in the untreated disorder, suggesting that withdrawal effects may inflate the apparent rate and extent of relapse.2,13 Few maintenance studies extend beyond a 2-year follow-up period. Observational studies (over longer periods) have found lithium to be more effective than other mood stabilisers but these studies are somewhat limited by confounding effects.14 Duration of tapering With lithium, rapid discontinuation (1–14 days) has been shown to produce a much greater risk of relapse than gradual tapering over 15–30 days.15–17 Time to relapse is decreased and the proportion of patients relapsed at study end is greatly increased in the rapid discontinuation group. These robust and reproducible findings support a recommendation that lithium should not be stopped abruptly unless a serious adverse effect occurs, and that withdrawal should take place over at least a month or preferably longer. There are few studies examining the optimal rate or duration of tapering lithium. However, the finding that 50% of relapses occur in the first 3 months after lithium is stopped but then lessen over time2 suggests that this period of 3 months might be required for underlying adaptations to lithium to resolve. One study that discontinued lithium over 2–5 months found higher relapse rates in these patients than in those who stayed on lithium.18 This might conceivably suggest that tapering should be even slower than the 4-week to 3-month period suggested by NICE in the UK.19 Long withdrawal schedules are not unusual in different areas of medicine. Antiseizure drugs are tapered over between 1 month and 4 years in non-psychiatric conditions, with relapse rates increased in the first 6 months before converging with patients continuing with the antiseizure drugs.8 Pattern of tapering Lithium, like all pharmacological agents, conforms to the law of mass action and therefore demonstrates a hyperbolic pattern between dose and pharmacological effect.12 The mode of action of lithium is unknown, however it is known to affect GSK-3. The relationship between the dose of lithium and effect on this target is hyperbolic.13 As for other psychotropic agents this justifies a hyperbolically reducing dose pattern (in order to produce linearly reducing effects on its target receptors), which may be clinically approximated by a proportionate dose reduction (a reduction by the same proportion each step, so that the size of the reduction becomes smaller and smaller as the total dose gets lower) (Box 2.3).

07 - Chapter 2 Bipolar disorder

66 - Practice guide to tapering

Practice guide to tapering

07 - Chapter 2 Bipolar disorder

67 - References

References

Bipolar disorder CHAPTER 2 Practice guide to tapering ■ ■Patients should be told that there is the possibility of withdrawal effects, and that there may be an increased risk of affective relapse from stopping lithium or mood stabilisers more quickly. These effects will be reduced if these medications are reduced in a more gradual fashion. ■ ■There is no clear evidence on how to taper (or for how long), but following principles from other psychotropic medications, an initial reduction of 10–25% of the current dose should be offered, with withdrawal symptoms (Table 2.13) and symptoms monitored for at least 4 weeks to ensure stability. ■ ■Further reductions should be titrated against the tolerability of this dose decrease. Reductions should probably be made according to an exponentially reducing pattern, whereby each reduction is calculated as a fixed proportion (e.g. 10% or 25%) of the most recent dose (effectively becoming smaller and smaller as the total dose becomes lower) each month, or until stability is assured. ■ ■For a very few patients the final dose before completely stopping may be very small, because small doses have relatively large effects on target receptors. This may be as small as 1% of therapeutic doses, for example <10mg for lithium. To achieve small doses, liquid preparations (lithium) will be required. ■ ■As the process of reducing lithium or mood stabilisers might be destabilising it may be wise to pursue other strategies during the tapering period.20 Ongoing monitoring may be necessary for a number of months after complete cessation to ensure mood stability. ■ ■If withdrawal symptoms or symptoms of relapse emerge at any point, pausing the reduction, a small increase in dose or returning to a previously effective dose are all possible responses. Difficulty reducing medication does not preclude a further attempt at reduction but might indicate the need for a more gradual reduction regimen. ■ ■Other modalities for people with bipolar disorder, including family therapy, interpersonal therapy, cognitive behavioural therapy, psychoeducation and social rhythm therapy, may be considered as well as more individualised, idiosyncratic coping strategies.21–23 References

Öhlund L, et al. Reasons for lithium discontinuation in men and women with bipolar disorder: a retrospective cohort study. BMC Psychiatry 2018; 18:37.
Suppes T, et al. Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. Arch Gen Psychiatry 1991; 48:1082–1088.
Franks MA, et al. Bouncing back: is the bipolar rebound phenomenon peculiar to lithium? A retrospective naturalistic study. J Psychopharmacol 2008; 22:452–456.
Baastrup PC, et al. Prophylactic lithium: double blind discontinuation in manic-depressive and recurrent-depressive disorders. Lancet 1970; 2:326–330. Box 2.3 Suggested slow reduction regimen for lithium ■ ■Reduce by 200mg every month until dose is 800mg daily, then ■ ■Reduce by 100mg every month until dose is 400mg daily, then ■ ■Reduce by 50mg every month until dose is 100mg daily, then ■ ■Reduce by 25mg every month until completely stopped

334 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 2 5. Klein E, et al. Discontinuation of lithium treatment in remitted bipolar patients: relationship between clinical outcome and changes in sleep-wake cycles. J Nerv Ment Dis 1991; 179:499–501. 6. Ferrie L, et al. Effect of chronic lithium and withdrawal from chronic lithium on presynaptic dopamine function in the rat. J Psychopharmacol 2005; 19:229–234. 7. Balon R, et al. Lithium discontinuation: withdrawal or relapse? Compr Psychiatry 1988; 29:330–334. 8. Vernachio K, et al. A review of withdraw strategies for discontinuing antiepileptic therapy in epilepsy and pain management. Pharm Pharmacol Int J 2015; 3:232–235. 9. Nolen WA, et al. What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium. Bipolar Disord 2019; 21:394–409. 10. Geddes JR, et al. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry 2004; 161:217–222. 11. Moncrieff J. Lithium: evidence reconsidered. Br J Psychiatry 1997; 171:113–119. 12. Faedda GL, et al. Lithium discontinuation: uncovering latent bipolar disorder? Am J Psychiatry 2001; 158:1337–1339. 13. Goodwin GM. Recurrence of mania after lithium withdrawal. Implications for the use of lithium in the treatment of bipolar affective disorder. Br J Psychiatry 1994; 164:149–152. 14. Kessing LV, et al. Effectiveness of maintenance therapy of lithium vs other mood stabilizers in monotherapy and in combinations: a systematic review of evidence from observational studies. Bipolar Disord 2018; 20:419–431. 15. Faedda GL, et al. Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders. Arch Gen Psychiatry 1993; 50:448–455. 16. Baldessarini RJ, et al. Illness risk following rapid versus gradual discontinuation of antidepressants. Am J Psychiatry 2010; 167:934–941. 17. Baldessarini RJ, et al. Effects of the rate of discontinuing lithium maintenance treatment in bipolar disorders. J Clin Psychiatry 1996; 57:441–448. 18. Biel MG, et al. Continuation versus discontinuation of lithium in recurrent bipolar illness: a naturalistic study. Bipolar Disord 2007; 9:435–442. 19. National Institute for Health and Care Excellence. Bipolar disorder: assessment and management. Clinical guideline [CG185]. 2014 (last updated December 2023, last checked July 2024); https://www.nice.org.uk/guidance/cg185. 20. Guy. A, et al. Guidance for Psychological Therapists: Enabling Conversations with Clients Taking or Withdrawing from Prescribed Psychiatric Drugs. London: APPG for Prescribed Drug Dependence, 2019. 21. Reinares M, et al. Psychosocial interventions in bipolar disorder: what, for whom, and when. J Affect Disord 2014; 156:46–55. 22. Cappleman R, et al. Managing bipolar moods without medication: a qualitative investigation. J Affect Disord 2015; 174:241–249. 23. Miklowitz DJ. Adjunctive psychotherapy for bipolar disorder: state of the evidence. Am J Psychiatry 2008; 165:1408–1419.

08 - Chapter 3 Depression and anxiety disorders

01 - Introduction to depression

Introduction to depression

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 3 Introduction to depression Depression (major depressive disorder, MDD) is widely recognised as a major public health problem around the world. The mainstay of treatment is the prescription of antidepressants, although psychological treatments have a place as a first-line alternative to antidepressants in milder and moderate forms of depression.1 Other methods of treating depression (vagal nerve stimulation [VNS],2 repetitive transcranial magnetic stimulation [rTMS],3,4 transcranial direct current stimulation,3 etc.) are also used but are not widely available. The basic principles of prescribing are described in Table 3.1, together with a summary of National Institute for Health and Care Excellence (NICE) guidance. Depression and anxiety disorders Table 3.1 Basic principles of prescribing in depression. ■ ■Discuss with the patient choice of drug and utility/availability of other, non-pharmacological treatments. ■ ■Discuss with the patient likely outcomes, such as gradual relief from depressive symptoms over several weeks. ■ ■Prescribe a dose of antidepressant (after titration, if necessary) that is likely to be effective. ■ ■Assess the treatment’s efficacy within 2–4 weeks of initiation (sooner in young people). ■ ■Monitor treatment adherence and inform the patient about the risk of withdrawal symptoms. ■ ■Monitor for adverse effects. ■ ■For a single episode, continue treatment for at least 6 months after resolution of symptoms. Multiple episodes or high-risk patients may require longer; continuing treatment may reduce the risk of relapse. ■ ■For patients continuing treatment, review treatment every 6 months. ■ ■Withdraw antidepressants very gradually; always inform patients of the risk, duration and nature of discontinuation symptoms.

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02 - Official guidance on the treatment of depress

Official guidance on the treatment of depression: a summary of the NICE guidelines1

08 - Chapter 3 Depression and anxiety disorders

03 - References

References

336 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Official guidance on the treatment of depression: a summary of the NICE guidelines1 ■ ■Depression severity is categorised as less severe (includes subthreshold and mild depression) and more severe (includes moderate to severe depression). The severity of depression is determined by the combined influence of factors such as symptom severity, duration and the impact on personal and social functioning. ■ ■Antidepressants are not recommended as a first-line treatment in less severe depression. Other options such as counselling, guided self-help, cognitive behavioural therapy (CBT), behavioural activation, mindfulness, meditation, short-term psychodynamic psychotherapy, interpersonal psychotherapy or exercise are preferred. ■ ■Antidepressants are recommended for the treatment of more severe depression and for dysthymia. ■ ■When an antidepressant is prescribed, a generic selective serotonin reuptake inhibitor (SSRI) is recommended. ■ ■All patients should be informed about the withdrawal (discontinuation) effects of antidepressants and how they can be minimised or avoided. ■ ■For treatment-resistant depression, recommended strategies include implanted VNS, augmentation with lithium or an antipsychotic, or the addition of a second antidepressant (see section in this chapter). ■ ■Patients with a recurrent episode or at high risk should be treated for at least 2 years. ■ ■The use of electroconvulsive therapy (ECT) is supported for severe and treatment- resistant depression if patient prefers it and has responded in the past or when a rapid response is needed. Nasal esketamine is a licensed treatment for treatment-resistant MDD,5 but is not yet approved by NICE in the UK. It is widely used elsewhere. This chapter concentrates on the use of antidepressants and offers advice on drug choice, dosing, switching strategies and sequencing of treatments. The near exclusion of other non-drug treatment modalities does not imply any lack of confidence in their efficacy but simply reflects the need (in a prescribing guideline) to concentrate on medicines-related subjects. References

National Institute for Health and Care Excellence. Depression in adults: treatment and management. NICE guideline [NG222]. 2022 (last updated May 2024, last checked May 2024); https://www.nice.org.uk/guidance/ng222.
George MS, et al. Vagus nerve stimulation for the treatment of depression and other neuropsychiatric disorders. Expert Rev Neurother 2007; 7:63–74.
Hsu CW, et al. Comparing different non-invasive brain stimulation interventions for bipolar depression treatment: a network meta-analysis of randomized controlled trials. Neurosci Biobehav Rev 2024; 156:105483.
Loo CK, et al. A review of the efficacy of transcranial magnetic stimulation (TMS) treatment for depression, and current and future strategies to optimize efficacy. J Affect Disord 2005; 88:255–267.
Jannsen-Cilag Ltd. Summary of Product Characteristics. Spravato 28 mg nasal spray, solution (esketamine hydrochloride). 2024 (last checked May 2024); https://www.medicines.org.uk/emc/product/10977/smpc.

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04 - Antidepressants general overview

Antidepressants – general overview

08 - Chapter 3 Depression and anxiety disorders

05 - Effectiveness

Effectiveness

Depression and anxiety disorders CHAPTER 3 Antidepressants – general overview Effectiveness All antidepressants are more efficacious than placebo in adults with MDD1 and there is broadly equal benefit from antidepressant treatments for mild, moderate or severe major depression.2 Antidepressants are normally recommended as first-line treatment in patients whose depression is of at least moderate severity, with psychological treatments being used for milder forms. Of the moderate to severe patient group, approximately 20% will recover with no treatment at all, 30% will respond to placebo and 50% will respond to antidepressant drug treatment.3 This gives a number needed to treat (NNT) of 3 for antidepressant over true no-treatment control and an NNT of 5 for antidepressant over placebo. Response in clinical trials is generally defined by a particular percentage reduction in depression rating scale scores (e.g. 50%), a somewhat arbitrary dichotomy. Change measured using individual scale score tends to show a relatively small mean difference between active treatment and placebo (which itself is an effective treatment for depression). Drug–placebo differences may have diminished over time because of methodological changes.4 However, it is possible that rating scales obscure the beneficial effects of antidepressants to some extent. Hieronymus and colleagues5 undertook patient-level post-hoc analyses of 18 industry-sponsored placebo-controlled trials of paroxetine, citalopram, sertraline or fluoxetine, including in total 6,669 adults with major depression. The aim was to assess what the outcome would have been if the single item ‘depressed mood’ (rated 0–4) had been used as the sole measure of efficacy. While 18 of 32 comparisons (56%) failed to separate active drug from placebo with respect to reduction in total Hamilton Depression Rating Scale (HAM-D) score, only 3 of 32 comparisons (9%) were negative when depressed mood was used as the sole effect parameter (i.e. 91% of trials favoured the antidepressant). It is also noteworthy that even using total scale scores, placebo never performs better than an active treatment – antidepressants are always shown to be better than or the same as placebo, never worse than. This is arguably the most compelling evidence for the efficacy of antidepressants. As might be expected, network meta-analyses show robust superiority for antidepressants over placebo, with amitriptyline being the most efficacious.1 In the same study, mirtazapine was ranked as the second most efficacious antidepressant. However, in a post-hoc analysis, the observed superiority of mirtazapine was found to be attributable to its effects on sleep and appetite, and the absence of gastrointestinal (GI) symptoms. In contrast, when it came to improving depressed mood, suicidality and psychic anxiety, SSRIs and venlafaxine demonstrated relatively greater efficacy.6 In a 2023 network meta-analysis of people with depression and a wide range of chronic medical conditions, antidepressants more effectively reduced depressive symptoms than placebo.7 The 2019 PANDA trial results support the prescription of SSRI antidepressants in a wider group of participants than previously thought, including those with mild to moderate symptoms who do not meet diagnostic criteria for depression or generalised anxiety disorder.8 Antidepressant treatment seems to only modestly improve quality of life and social functioning in individuals with major depression.9,10

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06 - Onset of action

Onset of action

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07 - Choice of antidepressant and relative adverse

Choice of antidepressant and relative adverse effects

338 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Onset of action It is widely believed that antidepressants do not exert their effects for 2–4 weeks, or even longer. This is a myth. All antidepressants show a pattern of response where the rate of improvement is highest during weeks 1 and 2 and lowest during weeks 4 to 6. Early response strongly predicts later remission.11 Statistical separation from placebo is seen at 2–4 weeks in individual trials (hence the idea of a lag period of no effect) but after only 1 or 2 weeks in (statistically more powerful) meta-analyses.12,13 Thus, where large numbers of patients are treated and detailed rating scales are used, an antidepressant effect is usually statistically evident at 1 week. In clinical practice using simple observations, an antidepressant effect in an individual is usually seen by 2 weeks.14 In individuals where no antidepressant effect is evident after 2–3 weeks of treatment, a change in dose or drug should be considered. It is important, however, to be clear about what constitutes ‘no effect’. Different patterns of response have been identified,15 and in some individuals response is slow to emerge. However, in those ultimately responsive to treatment, all will very probably have begun to show at least minor improvement at 3–4 weeks. Thus, those showing no discernible improvement at this time will likely never respond to the prescribed drug at that dose. In contrast, those showing small improvements at 3–4 weeks (i.e. improvement not necessarily meeting criteria for ‘response’ but observable nonetheless) may go on to respond fully.16 A meta-analysis17 has shown that if antidepressant (citalopram, paroxetine or sertraline specifically) trials are examined for effects on depressed mood alone (rather than the total HAM-D score) then both a rapid effect and a dose–response relationship (as already noted) are clearly evident. Choice of antidepressant and relative adverse effects Selective serotonin reuptake inhibitors are well tolerated compared with older tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), and are universally recommended as first-line pharmacological treatment for depression.18 There is a suggestion from network meta-analyses1,19 that some individual antidepressants may be more effective overall than others but this has not been consistently demonstrated in head-to-head studies. Adverse effect profiles of antidepressants do differ. For example, paroxetine has been associated with more weight gain and a higher incidence of sexual dysfunction, and sertraline with a higher incidence of diarrhoea than other SSRIs.20 Dual reuptake inhibitors such as venlafaxine and duloxetine tend to be tolerated less well than SSRIs but better than TCAs. With all drugs there is marked inter-individual variation in tolerability, which is not easily predicted by knowledge of a drug’s likely adverse effects. A flexible approach is usually required in finding the right drug for a particular patient. The Psymatik Treatment Optimizer may be helpful.21 As well as headache and GI symptoms, SSRIs as a class are associated with a range of other adverse effects including sexual dysfunction (see relevant section in this chapter), hyponatraemia (see section on antidepressant-induced hyponatraemia in this chapter) and GI bleeds (see section on SSRIs and bleeding in this chapter). TCAs have a number of adverse cardiovascular effects (hypotension, tachycardia and QTc prolongation) and are particularly toxic in overdose22 (see section on overdose in Chapter 13). The now rarely used MAOIs have the potential to interact with tyramine-containing

08 - Chapter 3 Depression and anxiety disorders

08 - Drug interactions

Drug interactions

08 - Chapter 3 Depression and anxiety disorders

09 - Suicidality

Suicidality

Depression and anxiety disorders CHAPTER 3 foods to cause hypertensive crisis and much more commonly cause hypotension. All antidepressant drugs can cause discontinuation symptoms, with short half-life drugs probably being most problematic in this respect (see section on stopping antidepressants in this chapter). See following pages for a summary of the clinically relevant adverse effects of available antidepressant drugs. Drug interactions Some SSRIs are potent inhibitors of individual or multiple hepatic cytochrome P450 (CYP) pathways and the magnitude of these effects is dose related. Several clinically significant drug interactions can therefore be predicted. For example, fluvoxamine is a potent inhibitor of CYP1A2 which can result in increased theophylline serum levels, fluoxetine is a potent inhibitor of CYP2D6, which can result in increased seizure risk with clozapine, and paroxetine is a potent inhibitor of CYP2D6, which can result in treatment failure with tamoxifen (a pro-drug) leading to increased mortality.23 Antidepressants can also cause pharmacodynamic interactions. For example, the cardiotoxicity of TCAs may be exacerbated by drugs such as diuretics, which can cause electrolyte disturbances. A summary of clinically relevant drug interactions with antidepressants can be found later in this chapter. Potential pharmacokinetic and pharmacodynamic interactions between antidepressants must be considered when switching from one antidepressant to another (see section on switching antidepressants in this chapter). Suicidality Antidepressant treatment has been associated with an increased risk of suicidal thoughts and acts, particularly in adolescents and young adults,24–27 leading to the recommendation that patients should be warned of this potential adverse effect during the early weeks of treatment and know how to seek help if required. Suicide and self-harm rates tend to be higher when antidepressants are started or stopped so the same care over risk assessment should be carried out when treatment is stopped as when it is started.28 Furthermore, switching antidepressants may be a marker of increased risk of suicidal behaviours in those who initiate antidepressant treatment aged 75 years and over.29 All antidepressants have been implicated,30 including those that are marketed for an indication other than depression (e.g. atomoxetine). Although the relative risk may be elevated above placebo rates in some patient groups, the absolute risk remains very small. The most effective way to treat or prevent suicidal thoughts and acts is to treat depression31–33 and antidepressant drugs are the most effective treatment currently available.3,34 For the most part, suicidality is greatly reduced by the use of antidepressants.35–37 However, those who experience treatment-emergent or worsening suicidal ideation with one antidepressant may be more likely to have a similar experience with subsequent treatments.38 Some data suggest that an increasing proportion of young women who later committed suicide had been treated with antidepressants in the last few years before and at the time of their suicide.39 At the time of writing there is no clear consensus on the potential dangers of antidepressants except that young people are most at risk.40 Ketamine, in its various forms, may have rapidly apparent anti-suicidal effects.41

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10 - Duration of treatment

Duration ofÂ treatment

08 - Chapter 3 Depression and anxiety disorders

100 - References

References

430 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 References

McCabe MP, et al. Incidence and prevalence of sexual dysfunction in women and men: a consensus statement from the Fourth International Consultation on Sexual Medicine 2015. J Sex Med 2016; 13:144–152.
Chokka PR, et al. Assessment and management of sexual dysfunction in the context of depression. Ther Adv Psychopharmacol 2018; 8:13–23.
Pereira-Miranda E, et al. Overweight and obesity associated with higher depression prevalence in adults: a systematic review and meta- analysis. J Am Coll Nutr 2017; 36:223–233.
Semenkovich K, et al. Depression in type 2 diabetes mellitus: prevalence, impact, and treatment. Drugs 2015; 75:577–587.
Cohen BE, et al. State of the art review: depression, stress, anxiety, and cardiovascular disease. Am J Hypertens 2015; 28:1295–1302.
Montejo AL, et al. The impact of severe mental disorders and psychotropic medications on sexual health and its implications for clinical management. World Psychiatry 2018; 17:3–11.
McGahuey CA, et al. The Arizona Sexual Experience Scale (ASEX): reliability and validity. J Sex Marital Ther 2000; 26:25–40.
Papakostas GI. Identifying patients who need a change in depression treatment and implementing that change. J Clin Psychiatry 2016; 77:e1009.
Kennedy SH, et al. Sexual dysfunction before antidepressant therapy in major depression. J Affect Disord 1999; 56:201–208.
Clayton AH, et al. Antidepressants and sexual dysfunction: mechanisms and clinical implications. Postgrad Med 2014; 126:91–99.
Weber S, et al. Sexual function improves as depressive symptoms decrease during treatment with escitalopram: results of a naturalistic study of patients with major depressive disorder. J Sex Med 2023; 20:161–169.
Ishak WW, et al. Sexual satisfaction and quality of life in major depressive disorder before and after treatment with citalopram in the STAR*D study. J Clin Psychiatry 2013; 74:256–261.
Clayton AH, et al. Sexual dysfunction due to psychotropic medications. Psychiatr Clin North Am 2016; 39:427–463.
Sathianathen NJ, et al. Selective serotonin re-uptake inhibitors for premature ejaculation in adult men. Cochrane Database Syst Rev 2021; 3:CD012799.
Serretti A, et al. Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. J Clin Psychopharmacol 2009; 29:259–266.
Chiesa A, et al. Antidepressants and sexual dysfunction: epidemiology, mechanisms and management. J Psychopathol 2010; 16:104–113.
Lew-Starowicz M, et al. Impact of Psychotropic Medications on Sexual Functioning. Cham: Springer; 2021:353–371.
Reichenpfader U, et al. Sexual dysfunction associated with second-generation antidepressants in patients with major depressive disorder: results from a systematic review with network meta-analysis. Drug Saf 2014; 37:19–31.
Tabuteau H, et al. Effect of AXS-05 (dextromethorphan-bupropion) in major depressive disorder: a randomized double-blind controlled trial. Am J Psychiatry 2022; 179:490–499.
Wagner G, et al. Efficacy and safety of levomilnacipran, vilazodone and vortioxetine compared with other second-generation antidepressants for major depressive disorder in adults: a systematic review and network meta-analysis. J Affect Disord 2018; 228:1–12.
Gommoll CP, et al. A randomized, double-blind, placebo-controlled study of flexible doses of levomilnacipran ER (40-120 mg/day) in patients with major depressive disorder. J Drug Assess 2014; 3:10–19.
Watanabe N, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev 2011; (12):CD006528.
Cleare A, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol 2015; 29:459–525.
Montejo AL, et al. Management strategies for antidepressant-related sexual dysfunction: a clinical approach. J Clin Med 2019; 8:1640.
De Diego-Adeliño J, et al. Vortioxetine in major depressive disorder: from mechanisms of action to clinical studies: an updated review. Expert Opin Drug Saf 2022; 21:673–690.
Jacobsen PL, et al. Treatment-emergent sexual dysfunction in randomized trials of vortioxetine for major depressive disorder or generalized anxiety disorder: a pooled analysis. CNS Spectr 2016; 21:367–378.
Culos C, et al. Pharmacological interventions in paraphilic disorders: systematic review and insights. J Clin Med 2024; 13:1524.
McMahon CG. Dapoxetine: a new option in the medical management of premature ejaculation. Ther Adv Urol 2012; 4:233–251.
Khin NA, et al. Regulatory and scientific issues in studies to evaluate sexual dysfunction in antidepressant drug trials. J Clin Psychiatry 2015; 76:1060–1063.
Rothmore J. Antidepressant-induced sexual dysfunction. Med J Aust 2020; 212:329–334.
Gül M, et al. A clinical guide to rare male sexual disorders. Nat Rev Urol 2024; 21:35–49.
Tarchi L, et al. Selective serotonin reuptake inhibitors, post-treatment sexual dysfunction and persistent genital arousal disorder: a systematic review. Pharmacoepidemiol Drug Saf 2023; 32:1053–1067.
Francois D, et al. Antidepressant-induced sexual side effects: incidence, assessment, clinical implications, and management. Psychiatr Ann 2017; 47:154–160.
Montejo AL, et al. Switching to vortioxetine in patients with poorly tolerated antidepressant-related sexual dysfunction in clinical practice: a 3-month prospective real-life study. J Clin Med 2024; 13:546.
Alipour-Kivi A, et al. The effect of drug holidays on sexual dysfunction in men treated with selective serotonin reuptake inhibitors (SSRIs) other than fluoxetine: an 8-week open-label randomized clinical trial. BMC Psychiatry 2024; 24:67.
Lalegani E, et al. Safety and efficacy of drug holidays for women with sexual dysfunction induced by selective serotonin reuptake inhibitors (SSRIs) other than fluoxetine: an open-label randomized clinical trial. Brain Sci 2023; 13:1397.
Taylor MJ, et al. Strategies for managing sexual dysfunction induced by antidepressant medication. Cochrane Database Syst Rev 2013; 5:CD003382.

Depression and anxiety disorders CHAPTER 3 38. Luft MJ, et al. Pharmacologic interventions for antidepressant-induced sexual dysfunction: a systematic review and network meta-analysis of trials using the Arizona sexual experience scale. CNS Spectr 2021; doi: 10.1017/S1092852921000377. 39. Safarinejad MR. The effects of the adjunctive bupropion on male sexual dysfunction induced by a selective serotonin reuptake inhibitor: a double-blind placebo-controlled and randomized study. BJU Int 2010; 106:840–847. 40. Montejo AL, et al. Sexual side-effects of antidepressant and antipsychotic drugs. Curr Opin Psychiatry 2015; 28:418–423. 41. Amiaz R, et al. Testosterone gel replacement improves sexual function in depressed men taking serotonergic antidepressants: a randomized, placebo-controlled clinical trial. J Sex Marital Ther 2011; 37:243–254. 42. Barakeh D, et al. Pharmacotherapy of hypoactive sexual desire disorder in premenopausal women. Ann Pharmacother 2025; 59:148–161. 43. Clayton AH, et al. Effect of brexpiprazole on prolactin and sexual functioning: an analysis of short- and long-term study data in major depressive disorder. J Clin Psychopharmacol 2020; 40:560–567. 44. Freeman MP, et al. Improvement of sexual functioning during treatment of MDD with adjunctive pimavanserin: a secondary analysis. Depress Anxiety 2020; 37:485–495. 45. Bala A, et al. Post-SSRI sexual dysfunction: a literature review. Sex Med Rev 2018; 6:29–34. 46. Peleg LC, et al. Post-SSRI sexual dysfunction (PSSD): biological plausibility, symptoms, diagnosis, and presumed risk factors. Sex Med Rev 2022; 10:91–98. 47. Ben-Sheetrit J, et al. Estimating the risk of irreversible post-SSRI sexual dysfunction (PSSD) due to serotonergic antidepressants. Ann Gen Psychiatry 2023; 22:15. 48. Healy D, et al. Diagnostic criteria for enduring sexual dysfunction after treatment with antidepressants, finasteride and isotretinoin. Int J Risk Saf Med 2022; 33:65–76.

432 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 SSRIs and bleeding Serotonin is released from platelets in response to vascular injury, promoting vasoconstriction and morphological changes in platelets that lead to aggregation.1 SSRIs inhibit the serotonin transporter, which is responsible for the uptake of serotonin into platelets (Table 3.19). The resultant depletion of platelet serotonin leads to a reduced ability to form clots and a subsequent increase in the risk of bleeding. Broadly speaking, the relative risk of any bleeding event compared with no use of SSRI/SNRI is around 1.4, with the absolute risk being between around 0.5% and 6%2 (depending on numerous factors). SSRIs may also increase gastric acid secretion and therefore may be indirectly irritant to the gastric mucosa,3 increasing the risk of peptic ulcer.4 The risk of abnormal bleeding of any kind with SSRIs is highest during the first 30 days of treatment.5,6 The effect on bleeding is probably related to the affinity of individual SSRIs for the serotonin transporter.7,8 Table 3.19 Antidepressants and degree of serotonin reuptake inhibition.6,9 Degree of serotonin reuptake inhibition Antidepressant Strong Sertraline, paroxetine, fluoxetine, duloxetine, clomipramine Intermediate Citalopram, escitalopram, fluvoxamine, vilazodone, vortioxetine, venlafaxine Amitriptyline, imipramine Weak or none Agomelatine, dosulepin, doxepin, lofepramine, mirtazapine, moclobemide, nortriptyline, reboxetine, mianserin Risk factors for bleeding with SSRIs ■ ■Age, particularly those over 65 years ■ ■Alcohol misuse ■ ■Coronary artery disease ■ ■Drug misuse ■ ■Hypertension ■ ■History of GI bleed ■ ■History of stroke ■ ■History of major bleeding ■ ■Liver disease ■ ■Labile international normalised ratio (INR) ■ ■Medication predisposing to bleeding ■ ■Peptic ulcer ■ ■Renal disease ■ ■Smoking

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101 - SSRIs and bleeding

SSRIs andÂ bleeding

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102 - Gastrointestinal bleeding

Gastrointestinal bleeding

Depression and anxiety disorders CHAPTER 3 Caution should be exercised when prescribing serotonergic antidepressants for people with medical conditions such as gout, asthma, COPD, lupus, psoriasis, interferon- induced depression in patients with hepatitis C10 and arthritis, when patients might also be taking corticosteroids, aspirin or NSAIDS. Gastrointestinal bleeding The use of serotonergic antidepressants is an independent risk factor for all bleeding events. SSRIs increase the rate of upper GI bleeding (UGIB), with hazard ratio (HR) of 1.97, and lower GI bleeding (LGIB; HR 2.96) after adjusting for all relevant risk factors.11 In absolute terms, it is likely that SSRIs are responsible for an additional 3 episodes of bleeding in every 1,000 patient years of treatment,7,12,13 but this figure masks large variations in risk. For example, 1 in 85 patients with a history of GI bleeding will have a further bleed attributable to treatment with a SSRI.14 Gastroprotective drugs (proton-pump inhibitors, PPIs) decrease the risk of GI bleeds associated with SSRIs (either alone or in combination with NSAIDs), although not quite to control levels.15 A 2020 study found that SSRIs increased the risk of GI bleeding in people taking direct-acting anticoagulants for atrial fibrillation and that this risk was increased further in those not prescribed PPIs.16 Another found no increased risk of bleeding for SSRIs prescribed alongside any anticoagulants.17 People who take SSRIs are at significantly increased risk of being admitted to hospital with a UGIB compared with age- and sex-matched controls.7,15,18,19 This association holds when age, gender and the effects of other drugs such as aspirin and NSAIDs are controlled for.2 In addition to this, a meta-analysis of 22 studies concluded that current users of SSRIs are 55% more at risk of UGIB compared with those who do not take SSRIs. This risk was significantly and further increased by concurrent use of antiplatelet drugs or NSAIDs.5 Co-prescription of low-dose aspirin may double the risk of GI bleeding associated with SSRIs alone,20 as does co-prescription of NSAIDs.21 Combined use of SSRIs and NSAIDs greatly increases the use of anti-acid drugs.22 The elderly and those with a history of GI bleeding are at greatest risk of GI bleeds.14,15,19 Early studies found that in patients who take warfarin, SSRIs increase the risk of a non-GI bleed two- to three-fold (similar to the effect size of NSAIDs) but did not seem to increase the risk of a GI bleed.23,24 A later study11 showed an increased risk of UGIB and LGIB in concomitant users of warfarin and serotonergic antidepressant (Table 3.20). This effect does not seem to be associated with any change in INR, making it difficult to identify those at highest risk.24 In keeping with these findings, SSRI use in patients taking anticoagulants being treated for acute coronary syndromes may decrease the risk of minor cardiac events at the expense of an increased risk of a bleed.25 SSRIs may decrease mortality overall in this group.26 Thus, the increased risk of UGIBs associated with SSRIs may be balanced by a decreased risk of embolic events. One database study failed to find a reduction in the risk of a first MI in patients treated with SSRIs,27 while another28 found a reduction in the risk of being admitted to hospital with a first MI in smokers on SSRIs. The effect size in the second study was large: approximately 1 in 10 hospitalisations were avoided in patients treated with SSRIs.28 This is similar to the effect size of other antiplatelet therapies such as aspirin.29 A 2021 meta-analysis suggested that SSRIs halved the risk of MI in people with coronary artery disease.26

434 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Many studies do not state changes in absolute risk of intestinal bleeding and some of those that do fail to provide denominator details (i.e. duration of treatment). Ideally, risk should be defined as the number of additional cases per 1,000 patient years. Table 3.20 shows approximate absolute risks (without a denominator) derived from a single study11 and a personal communication.31 Risk decreases to the same level as controls in past users of SSRIs, indicating that bleeding is likely to be associated with treatment itself rather than some inherent characteristic of the patients being treated.7 It also means that the effect of SSRIs disappears after their withdrawal. The excess risk of bleeding is not confined to UGIBs (Table 3.20). The risk of LGIBs may also be increased32 and an increased risk of uterine bleeding (see later) has also been reported.12 Intracranial/intracerebral haemorrhage There is a clear association between the use of SSRIs and intracranial/intracerebral haemorrhage (ICH) and risk is further increased by concomitant use of NSAIDs and anticoagulants. Elevated risk of ICH has been observed across all classes of antidepressants with serotonergic activity. In a cohort study of 1,363,990 users of antidepressants,6 the overall rate of ICH was 3.8 per 10,000 patient years. Current use of SSRI increased the risk of ICH (relative risk 1.17) compared with TCA with an absolute adjusted rate difference of 6.7 per 100,000 persons per year. Among the SSRI group, the risk of ICH was 25% greater in those who used strong inhibitors of serotonin reuptake system in comparison with users of weak inhibitors (Table 3.20). This correlates to an absolute adjusted rate difference of 9.5 events per 100,000 persons per year. Overall risk was highest during the first 30 days of use. A 2018 meta-analysis of 12 studies confirmed an increased risk of ICH for SSRIs (OR 0.8–2.42), with an indication that stronger reuptake inhibitors had a greater effect.33 Since then, one study reported no increased risk of ICH with SSRIs, either alone or alongside anticoagulants,34 whereas another35 found that SSRIs increased risk of recurrence of ICH by 31%. A 2022 meta- analysis including nearly 2 million patients found an increased risk of ICH only when SSRIs were prescribed with anticoagulants.36 Table 3.20 Approximate absolute risk of GI bleeding with concomitant use of SSRIs. Drug Absolute risk of UGIB (%)* Absolute risk of LGIB (%)* Aspirin + SSRI 3 Warfarin + SSRI 3 NSAID + SSRI* 1 SSRI alone 1 LGIB, lower gastrointestinal bleeding; UGIB, upper gastrointestinal bleeding. * Percentage figures rounded to nearest integer. ** A 2023 meta-analysis suggested that the risk of a GI bleed was over 40% for people on SSRI + NSAIDs.30 This seems to be the result of erroneous interpretation of case–control study data.

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103 - Intracranialintracerebral haemorrhage

Intracranial/intracerebral haemorrhage

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104 - Gynaecological and obstetric haemorrhage

Gynaecological and obstetric haemorrhage

Depression and anxiety disorders CHAPTER 3 One database study37 also identified an increased risk of ICH in those who have been taking SSRIs alone or in combination with NSAIDs. This and other studies providing data on absolute risk are summarised in Table 3.21, which gives estimates of absolute risk of ICH derived from three studies. Gynaecological and obstetric haemorrhage A multicentre cross-sectional study39 found an association between the use of antidepressants and menstruation disorders (unusual or excess bleeding, irregular menstruation, menorrhagia, etc.). This study found that the prevalence of menstruation disorder in the study group who were taking SSRIs, venlafaxine or mirtazapine, either alone or in combination, was 24.6% compared with 12.2% in people not taking antidepressants. Abnormal vaginal bleeding Cases of abnormal vaginal bleeding associated with SSRIs have been reported in a young woman,40 a postmenopausal woman41 and a preadolescent girl aged 11.42 Postpartum haemorrhage While one study43 could not find an increased risk of postpartum haemorrhage (PPH) with the use of SSRI or non-SSRI antidepressants, a large cohort study44 found an association between PPH and all classes of antidepressants, with a number needed to harm of 80 for current users of SSRIs and 97 for those on other antidepressants. One hospital- based cohort study45 found an absolute risk of PPH of 18% and an absolute risk of postpartum anaemia of 12.8% after a non-surgical vaginal delivery in women who were current users of SSRIs. The absolute risk of both PPH and postpartum anaemia for those without any exposure to antidepressants was 8.7%. The blood loss during delivery was also higher for those who had SSRI exposure. The length of hospital stay was also significantly increased for those who had been taking an SSRI. A recent population study46 identified that the use of serotonergic medications was associated with 1.5 times increased risk of PPH. This study highlighted that women who have been taking other psychoactive medications such as antipsychotics and mood stabilisers Table 3.21 Absolute risk of intracranial haemorrhage with SSRI with or without anticoagulant or NSAIDs. Study Risk with SSRI alone Risk with SSRI + NSAID Risk with antidepressant

anticoagulant Shin et al. 201537 1 in 632* (0.16%) 1 in 175* (0.57%) – Renoux et al. 20176 1 in 450** (0.22%) – 1 in 260** (0.38%) Smoller et al. 200938 1 in 240*** (0.42%) – – * Within 30 days of taking antidepressant. ** Incident users (no time limit). *** Annual risk (older patients).

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105 - Abnormal vaginal bleeding

Abnormal vaginal bleeding

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106 - Postpartum haemorrhage

Postpartum haemorrhage

436 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 were three times more at risk of PPH compared with mothers who did not take any medications, suggesting that the occurrence of PPH might not be entirely due to serotonergic activity. In 2021, the UK Medicines and Healthcare products Regulatory Agency issued a warning regarding the use of SSRIs and postpartum blood loss.47 However, a 2024 meta- analysis of 20 studies concluded that SSRI use was a ‘minor risk factor for postpartum haemorrhage’.48 Surgical and postoperative bleeding Use of SSRIs in the preoperative period has been associated with a 20% increase in inpatient mortality (absolute risk 1 in 1,000), although patient factors rather than drug factors could not be excluded as the cause.49 One study50 found that patients prescribed SSRIs who underwent orthopaedic surgery had an almost four-fold risk of requiring a blood transfusion. This equated to 1 additional patient requiring transfusion for every 10 patients taking an SSRI and undergoing surgery and was double the risk of patients who were taking NSAIDs alone. It should be noted in this context that treatment with SSRIs has been associated with a 2.4-fold increase in the risk of hip fracture51 and a two- fold increase of fracture in old age51 (mirtazapine52 and TCAs50 also increase risk of hip fracture). One study recognised preoperative treatment with SSRIs, other antidepressants or antipsychotics as independent risk factors for blood transfusion in elective fast- track hip and knee arthroplasty.54 Table 3.22 shows the risk of perioperative blood loss and blood transfusion in patients taking SSRIs compared with those not taking SSRIs. The combination of advanced age, SSRI treatment, orthopaedic surgery and NSAIDs clearly presents a very high risk. However, there does not seem to be an increased risk of bleeding in patients who undergo coronary artery bypass surgery.55 During a 10-year review of women who underwent cosmetic breast surgery procedures, the use of SSRIs increased the risk of postoperative bleeding by a factor of 4.14 compared with those who did not take SSRIs. The authors emphasised the importance of balancing the risks and benefits of stopping antidepressants prior to elective surgeries, particularly in psychologically vulnerable patients.56 Table 3.22 Risk of perioperative blood loss and blood transfusion in SSRI users compared with non-SSRI users.57 Surgical procedure Need for reoperation due to bleeding event in users of SADs vs non-users, OR (95% CI) Need for blood product or red blood cell transfusion in users of SADs vs non-users, OR (95% CI) Increased risk of mortality in users of SADs vs non-users, OR (95% CI) CABG 1.07 (0.66–1.74) 1.06 (0.90–1.24) 1.53 (1.15–2.04) Breast cancer-directed surgery 2.7 (1.6–4.56) – – Orthopaedic surgery – 1.61 (0.97–2.68)* 0.83 (0.69–1.00) Major surgery – 1.19 (1.15–1.23) 1.19 (1.03–1.37) CABG, coronary artery bypass graft; CI, confidence interval; OR, odds ratio; SADs, serotonergic antidepressants. * In one study,58 absolute risk of blood transfusion was 5.7% for people on SSRIs and 5.1% for those not on SSRIs.

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Surgical and postoperative bleeding

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Alternatives to SSRIs/SNRIs

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Overall

Depression and anxiety disorders CHAPTER 3 A review of 13 studies found an increased odds ratio (a range of 1.21 to 4.14) of perioperative bleeding with SSRIs.59 One study noted an increased risk of bleeding in women undergoing breast surgery60 and the authors suggest withholding SSRIs for 2 weeks prior to such planned surgery. Venlafaxine may have similar effects59 but duloxetine may not affect bleeding risk.61 Alternatives to SSRIs/SNRIs Non-SSRI antidepressants such as mirtazapine and bupropion have been suggested as safer alternatives to SSRIs and SNRIs.62 Preliminary studies suggest mirtazapine, bupropion and nortriptyline have minimal effects on measurable clotting mechanisms.63 However, there is little evidence that these drugs are safer and one meta-analysis found an increased risk of UGIB with mirtazapine (vs no treatment) and no difference in bleeding risk between mirtazapine or bupropion and SSRIs.64 Overall Serotonergic antidepressants increase the risk of various types of bleeding, especially when prescribed alongside oral anticoagulants of any kind.36,65,66 Evidence is strongest for SSRIs and it is likely that risk of bleeding is related to affinity for the serotonin transporter. SSRIs increase the risk of GI bleeding, haemorrhagic stroke, perioperative bleeding, postpartum haemorrhage and uterine bleeding. Their effect is exacerbated by co-prescription with aspirin, anticoagulants and NSAIDs. In most cases, the use of SSRIs increases the risk of an event by a clinically meaningful extent, but especially when co-prescribed with other drugs that affect clotting. Summary ■ ■SSRIs increase the risk of GI, uterine, cerebral and perioperative bleeding. ■ ■Risk is increased still further in those also receiving aspirin, NSAIDs or oral anticoagulants. ■ ■Try to avoid SSRIs/SNRIs in patients receiving NSAIDs, aspirin or oral anticoagulants or in those with a history of cerebral or GI bleeds. ■ ■Safer alternatives have not been definitively identified but noradrenergic antidepressants (nortriptyline, bupropion) are preferred. ■ ■If SSRI/SNRI use cannot be avoided, monitor closely and prescribe gastroprotective PPIs. ■ ■Limited evidence suggests that bleeding risks may be lower with less potent serotonin reuptake inhibitors (Table 3.19). References

Skop BP, et al. Potential vascular and bleeding complications of treatment with selective serotonin reuptake inhibitors. Psychosomatics 1996; 37:12–16.
Laporte S, et al. Bleeding risk under selective serotonin reuptake inhibitor (SSRI) antidepressants: a meta-analysis of observational studies. Pharmacol Res 2017; 118:19–32.
Andrade C, et al. Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms. J Clin Psychiatry 2010; 71:1565–1575.
Dall M, et al. There is an association between selective serotonin reuptake inhibitor use and uncomplicated peptic ulcers: a population-based case–control study. Aliment Pharmacol Ther 2010; 32:1383–1391.

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Next-step treatments

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Summary

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References

438 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 5. Jiang HY, et al. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding: a systematic review and meta- analysis. Clin Gastroenterol Hepatol 2015; 13:42–50. 6. Renoux C, et al. Association of selective serotonin reuptake inhibitors with the risk for spontaneous intracranial hemorrhage. JAMA Neurol 2017; 74:173–180. 7. Dalton SO, et al. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med 2003; 163:59–64. 8. Verdel BM, et al. Use of serotonergic drugs and the risk of bleeding. Clin Pharmacol Ther 2011; 89:89–96. 9. Tatsumi M, et al. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 1997; 340:249–258. 10. Weinrieb RM, et al. A critical review of selective serotonin reuptake inhibitor-associated bleeding: balancing the risk of treating hepatitis C-infected patients. J Clin Psychiatry 2003; 64:1502–1510. 11. Cheng YL, et al. Use of SSRI, but not SNRI, increased upper and lower gastrointestinal bleeding: a nationwide population-based cohort study in Taiwan. Medicine (Baltimore) 2015; 94:e2022. 12. Meijer WE, et al. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med 2004; 164:2367–2370. 13. Yuet WC, et al. Selective serotonin reuptake inhibitor use and risk of gastrointestinal and intracranial bleeding. J Am Osteopath Assoc 2019; 119:102–111. 14. van Walraven C, et al. Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study. BMJ 2001; 323:655–658. 15. de Abajo FJ, et al. Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry 2008; 65:795–803. 16. Lee MT, et al. Concomitant use of NSAIDs or SSRIs with NOACs requires monitoring for bleeding. Yonsei Med J 2020; 61:741–749. 17. Quinn GR, et al. Selective serotonin reuptake inhibitors and bleeding risk in anticoagulated patients with atrial fibrillation: an analysis from the ROCKET AF trial. J Am Heart Assoc 2018; 7:e008755. 18. de Abajo FJ, et al. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case–control study. BMJ 1999; 319:1106–1109. 19. Lewis JD, et al. Moderate and high affinity serotonin reuptake inhibitors increase the risk of upper gastrointestinal toxicity. Pharmacoepidemiol Drug Saf 2008; 17:328–335. 20. Axelsson MAB, et al. Bleeding in patients on concurrent treatment with a selective serotonin reuptake inhibitor (SSRI) and low-dose acetylsalicylic acid (ASA) compared with SSRI or low-dose ASA alone-a systematic review and meta-analysis. Br J Clin Pharmacol 2024; 90:916–932. 21. Alam SM, et al. Selective serotonin reuptake inhibitors increase risk of upper gastrointestinal bleeding when used with NSAIDs: a systemic review and meta-analysis. Sci Rep 2022; 12:14452. 22. de Jong JC, et al. Combined use of SSRIs and NSAIDs increases the risk of gastrointestinal adverse effects. Br J Clin Pharmacol 2003; 55:591–595. 23. Schalekamp T, et al. Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins. Arch Intern Med 2008; 168:180–185. 24. Wallerstedt SM, et al. Risk of clinically relevant bleeding in warfarin-treated patients: influence of SSRI treatment. Pharmacoepidemiol Drug Saf 2009; 18:412–416. 25. Ziegelstein RC, et al. Selective serotonin reuptake inhibitor use by patients with acute coronary syndromes. Am J Med 2007; 120:525–530. 26. Fernandes N, et al. The impact of SSRIs on mortality and cardiovascular events in patients with coronary artery disease and depression: systematic review and meta-analysis. Clin Res Cardiol 2021; 110:183–193. 27. Meier CR, et al. Use of selective serotonin reuptake inhibitors and risk of developing first-time acute myocardial infarction. Br J Clin Pharmacol 2001; 52:179–184. 28. Sauer WH, et al. Selective serotonin reuptake inhibitors and myocardial infarction. Circulation 2001; 104:1894–1898. 29. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308:81–106. 30. Haghbin H, et al. Risk of gastrointestinal bleeding with concurrent use of NSAID and SSRI: a systematic review and network meta-analysis. Dig Dis Sci 2023; 68:1975–1982. 31. Cheng YL, personal communication, 2017. 32. Wessinger S, et al. Increased use of selective serotonin reuptake inhibitors in patients admitted with gastrointestinal haemorrhage: a multicentre retrospective analysis. Aliment Pharmacol Ther 2006; 23:937–944. 33. Douros A, et al. Risk of intracranial hemorrhage associated with the use of antidepressants inhibiting serotonin reuptake: a systematic review. CNS Drugs 2018; 32:321–334. 33. Liu L, et al. Selective serotonin reuptake inhibitors and intracerebral hemorrhage risk and outcome. Stroke 2020; 51:1135–1141. 35. Kubiszewski P, et al. Association of selective serotonin reuptake inhibitor use after intracerebral hemorrhage with hemorrhage recurrence and depression severity. JAMA Neurol 2020; 78:1–8. 36. Nochaiwong S, et al. Use of serotonin reuptake inhibitor antidepressants and the risk of bleeding complications in patients on anticoagulant or antiplatelet agents: a systematic review and meta-analysis. Ann Med 2022; 54:80–97. 37. Shin JY, et al. Risk of intracranial haemorrhage in antidepressant users with concurrent use of non-steroidal anti-inflammatory drugs: nationwide propensity score matched study. BMJ 2015; 351:h3517.

Depression and anxiety disorders CHAPTER 3 38. Smoller JW, et al. Antidepressant use and risk of incident cardiovascular morbidity and mortality among postmenopausal women in the Women’s Health Initiative study. Arch Intern Med 2009; 169:2128–2139. 39. Uguz F, et al. Antidepressants and menstruation disorders in women: a cross-sectional study in three centers. Gen Hosp Psychiatry 2012; 34:529–533. 40. Andersohn F, et al. Citalopram-induced bleeding due to severe thrombocytopenia. Psychosomatics 2009; 50:297–298. 41. Durmaz O, et al. Vaginal bleeding associated with antidepressants. Int J Gynaecol Obstet 2015; 130:284. 42. Turkoglu S, et al. Vaginal bleeding and hemorrhagic prepatellar bursitis in a preadolescent girl, possibly related to fluoxetine. J Child Adolesc Psychopharmacol 2015; 25:186–187. 43. Salkeld E, et al. The risk of postpartum hemorrhage with selective serotonin reuptake inhibitors and other antidepressants. J Clin Psychopharmacol 2008; 28:230–234. 43. Palmsten K, et al. Use of antidepressants near delivery and risk of postpartum hemorrhage: cohort study of low income women in the United States. BMJ 2013; 347:f4877. 45. Lindqvist PG, et al. Selective serotonin reuptake inhibitor use during pregnancy increases the risk of postpartum hemorrhage and anemia: a hospital-based cohort study. J Thromb Haemost 2014; 12:1986–1992. 46. Heller HM, et al. Increased postpartum haemorrhage, the possible relation with serotonergic and other psychopharmacological drugs: a matched cohort study. BMC Pregnancy Childbirth 2017; 17:166. 47. Medicines and Healthcare products Regulatory Agency. Drug Safety Update. SSRI/SNRI antidepressant medicines: small increased risk of postpartum haemorrhage when used in the month before delivery. 2021 (last accessed February 2025); https://www.gov.uk/drug-safety-update/ ssri-slash-snri-antidepressant-medicines-small-increased-risk-of-postpartum-haemorrhage-when-used-in-the-month-before-delivery? utm_source=e-shot&utm_medium=email&utm_campaign=DSU_January2021split1. 48. Bobo WV, et al. The association of antidepressants in late pregnancy with postpartum hemorrhage: systematic review of controlled observational studies. J Child Adolesc Psychopharmacol 2024; 34:428–466. 49. Auerbach AD, et al. Perioperative use of selective serotonin reuptake inhibitors and risks for adverse outcomes of surgery. JAMA Intern Med 2013; 173:1075–1081. 50. Movig KL, et al. Relationship of serotonergic antidepressants and need for blood transfusion in orthopedic surgical patients. Arch Intern Med 2003; 163:2354–2358. 51. Liu B, et al. Use of selective serotonin-reuptake inhibitors of tricyclic antidepressants and risk of hip fractures in elderly people. Lancet 1998; 351:1303–1307. 52. Richards JB, et al. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med 2007; 167:188–194. 53. Leach MJ, et al. The risk of hip fracture due to mirtazapine exposure when switching antidepressants or using other antidepressants as add-on therapy. Drugs Real World Outcomes 2017; 4:247–255. 54. Gylvin SH, et al. Psychopharmacologic treatment and blood transfusion in fast-track total hip and knee arthroplasty. Transfusion 2017; 57:971–976. 55. Andreasen JJ, et al. Effect of selective serotonin reuptake inhibitors on requirement for allogeneic red blood cell transfusion following coronary artery bypass surgery. Am J Cardiovasc Drugs 2006; 6:243–250. 56. Basile FV, et al. Use of selective serotonin reuptake inhibitors antidepressants and bleeding risk in breast cosmetic surgery. Aesthetic Plast Surg 2013; 37:561–566. 57. Singh I, et al. Influence of pre-operative use of serotonergic antidepressants (SADs) on the risk of bleeding in patients undergoing different surgical interventions: a meta-analysis. Pharmacoepidemiol Drug Saf 2015; 24:237–245. 58. Hoveidaei AH, et al. Preoperative SSRI use increases perioperative transfusion need in patients undergoing surgical procedures on the hip joint. Eur J Orthop Surg Traumatol 2024; 34:3903–3908. 59. Mahdanian AA, et al. Serotonergic antidepressants and perioperative bleeding risk: a systematic review. Expert Opin Drug Saf 2014; 13:695–704. 60. Jeong BO, et al. Use of serotonergic antidepressants and bleeding risk in patients undergoing surgery. Psychosomatics 2014; 55:213–220. 61. Perahia DG, et al. The risk of bleeding with duloxetine treatment in patients who use nonsteroidal anti-inflammatory drugs (NSAIDs): analysis of placebo-controlled trials and post-marketing adverse event reports. Drug Healthc Patient Saf 2013; 5:211–219. 62. Bixby AL, et al. Clinical management of bleeding risk with antidepressants. Ann Pharmacother 2019; 53:186–194. 63. Halperin D, et al. Influence of antidepressants on hemostasis. Dialogues Clin Neurosci 2007; 9:47–59. 64. Na K-S, et al. Can we recommend mirtazapine and bupropion for patients at risk for bleeding? A systematic review and meta-analysis. J Affect Disord 2018; 225:221–226. 65. Machado CM, et al. Impact of selective serotonin-reuptake inhibitors in hemorrhagic risk in anticoagulated patients taking non-vitamin K antagonist anticoagulants: a systematic review and meta-analysis. J Clin Psychopharmacol 2023; 43:267–272. 66. Rahman AA, et al. Concomitant use of selective serotonin reuptake inhibitors and oral anticoagulants and risk of major bleeding: a systematic review and meta-analysis. Thromb Haemost 2023; 123:54–63.

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St John’s wort

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Evidence for St John’s wort in the treatment of depression

440 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 St John’s wort St John’s wort (SJW), Hypericum perforatum, contains a combination of at least 10 different components, including hypericin, hyperforin and various flavonoids.1 Preparations of SJW are often unstandardised and this has complicated the interpretation of clinical trials. Both the active ingredient(s) and mechanism(s) of action of SJW are unclear.1 Constituents of SJW may inhibit monoamine oxidase (MAO), inhibit the reuptake of noradrenaline and serotonin, upregulate serotonin receptors and decrease serotonin receptor expression.1 Some preparations of SJW have been granted a traditional herbal registration certificate,2 but this is based on traditional use rather than proven efficacy and tolerability. SJW is licensed in Germany for the treatment of depression.2 Evidence for St John’s wort in the treatment of depression A number of trials have examined the efficacy of SJW in the treatment of depression. They have been extensively reviewed3–7 and most authors conclude that SJW is likely to be effective in the treatment of mild to moderate depression.3,5,6,8 Cochrane concludes that SJW is more effective than placebo in the treatment of mild to moderate depression, and is as effective as, and better tolerated than, standard antidepressants.4 Some formal guidelines recommended its use in mild to moderate depression.9 The supporting evidence, however, is not without several limitations. For example, studies in German-speaking countries showed more favourable results than studies elsewhere.4 Concerns have also been raised about the inadequate dosing of SSRIs in comparative studies.10,11 In two reanalyses of data from a large negative RCT of SJW, both participant and clinician beliefs about treatment assignment were more strongly associated with clinical outcomes than the actual treatment received: those who guessed randomisation to active treatment fared better than those who guessed randomisation to placebo.12,13 Efficacy in severe depression remains uncertain.4–6 Oddly, there appear to be no published studies of SJW in depression since 2020,14 perhaps reflecting the difficulties inherent in marketing for a profit an unpatentable natural product. There is a little evidence for SJW in postmenopausal depression15 or in pain syndromes.16 Other important observations include: ■ ■The active component of SJW for treating depression has not yet been determined. Trials used different preparations of SJW, most of which were standardised according to their total content of hypericins. However, evidence suggests that hypericins alone do not treat depression.5 ■ ■Many SJW preparations bought over the internet are sold as unregulated food supplements and are often of poor quality and/or are adulterated.2 One analysis of 47 different SJW preparations found that 36% were adulterated with other Hypericum species and 19% were adulterated with food dyes.2 ■ ■Published studies are generally acute treatment studies. There are only preliminary data to support the effectiveness of SJW in the medium term. Longer-term and relapse-prevention data are lacking.17 On balance, SJW should probably not be prescribed. We lack sufficient understanding of what the active ingredient is or what constitutes a therapeutic dose and most preparations of SJW are unlicensed.3

Depression and anxiety disorders CHAPTER 3 Adverse effects SJW appears to be well tolerated.5,6 In a systematic review of existing studies, adverse effects were significantly less common than with older antidepressants, slightly less than SSRIs and similar to placebo.6 The most common, if infrequent, adverse effects are nausea, rash, fatigue, restlessness and photosensitivity.18 Although severe phototoxic reactions seem to be rare, patients should be informed that SJW can increase light sensitivity.18 SJW may also share the propensity of SSRIs to increase the risk of bleeding; a case report describes prolonged epistaxis after nasal insertion of SJW.19 Case reports have also described mania, hypomania and mixed states associated with SJW.20 Manic symptoms associated with SJW have been documented in patients both with20,21 and without previously recognised bipolar affective disorder.20 The onset of manic symptoms ranged from 3 days to 2 months.20 Caution is advised with high doses and those with a known history of bipolar affective disorder.22 A single case report documented supraventricular tachycardia associated with SJW.23 Drug interactions SJW is a potent inducer of intestinal and hepatic CYP3A4, CYP2C9, CYP2C19, CYP2E1 and intestinal p-glycoprotein.18,24 Hyperforin is responsible for this effect.25 The hyperforin content of SJW preparations varies 50-fold, which will result in a different propensity for drug interactions between brands. Preparations providing a daily dose of less than 1mg hyperforin are less likely to induce CYP enzymes.25,26 CYP3A4 activity is induced over 1–2 weeks and returns to normal approximately 7 days after SJW is discontinued.27 SJW significantly reduces plasma concentrations of warfarin,28 hormonal contraceptives,29 digoxin and indinavir.18 According to case reports, SJW has lowered plasma concentrations of clozapine, theophylline, ciclosporin, gliclazide, rivaroxaban and statins.18,24,30–32 There is a theoretical risk that SJW may interact with some antiseizure medications. It has also been reported that SJW can increase the effects of clopidogrel (a pro-drug).24 Serotonin syndrome has been reported when SJW was taken together with sertraline, paroxetine, nefazodone and various triptans.33,34 SJW should not be taken with any drugs that have a predominantly serotonergic action. Box 3.5 details the key points that patients should know about SJW. Box 3.5 Key points that patients should know about St John’s wort ■ ■Evidence suggests that SJW may be effective in the treatment of mild to moderate depression, but we do not know enough about how much should be taken or what the adverse effects are. There is less evidence of benefit in severe depression. ■ ■SJW is not a licensed medicine. ■ ■Available preparations are not standardised and differ in potency.3 ■ ■SJW can interact with other medicine3 resulting in serious adverse effects. Some important drugs may be metabolised more rapidly and therefore become ineffective with serious consequences (e.g. increased viral load in human immunodeficiency virus, failure of oral contraceptives leading to unwanted pregnancy, reduced anticoagulant effect with warfarin leading to thrombosis). ■ ■The symptoms of depression can sometimes be caused by other physical or mental illness. It is important that these possible causes are investigated. ■ ■It is always best to consult the doctor if any herbal or natural remedy is being taken or the patient is thinking of taking one.

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Adverse effects

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Drug interactions

442 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 People may regard herbal remedies as ‘natural’ and therefore harmless.35 Many are not aware of the potential of such remedies for causing adverse effects or interacting with other drugs. A large study from Germany (n = 588), where SJW is a licensed antidepressant, found that for every prescription written for SJW, one person purchased SJW without seeking the advice of a doctor.36 Many of these people had severe or persistent depression but few told their doctor that they took SJW. A small US study (n = 22) found that people tend to take SJW because it is easy to obtain alternative medicines and also because they perceive herbal medicines as being purer and safer than prescription medicines. Few would discuss this medication with their conventional healthcare provider.37 Clinicians need to be proactive in asking patients if they use such treatments and try to dispel the myth that natural is a synonym for safe. References

Velingkar VS, et al. A current update on phytochemistry, pharmacology and herb–drug interactions of Hypericum perforatum. Phytochem Rev 2017; 16:725–744.
Booker A, et al. St John’s wort (Hypericum perforatum) products: an assessment of their authenticity and quality. Phytomedicine 2018; 40:158–164.
National Institute for Health and Care Excellence. Depression in adults: treatment and management. NICE guideline [NG222]. 2022 (last updated May 2024, last checked May 2024); https://www.nice.org.uk/guidance/ng222.
Linde K, et al. St John’s wort for major depression. Cochrane Database Syst Rev 2008; (4):CD000448.
Ng QX, et al. Clinical use of Hypericum perforatum (St John’s wort) in depression: a meta-analysis. J Affect Disord 2017; 210:211–221.
Apaydin EA, et al. A systematic review of St. John’s wort for major depressive disorder. Syst Rev 2016; 5:148.
Sarris J, et al. Plant-based medicines (phytoceuticals) in the treatment of psychiatric disorders: a meta-review of meta-analyses of randomized controlled trials. Can J Psychiatry 2021; 66:849–862.
Volz H.P. Hypericum and depression. In: Riederer P, Laux G, Nagatsu T, Le W, Riederer C (eds) NeuroPsychopharmacotherapy. Cham: Springer; 2020:1–8.
Sarris J, et al. Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: the World Federation of Societies of Biological Psychiatry and Canadian Network for Mood and Anxiety Treatments Taskforce. World J Biol Psychiatry 2022; 23:424–455.
Asher GN, et al. Comparative benefits and harms of complementary and alternative medicine therapies for initial treatment of major depressive disorder: systematic review and meta-analysis. J Altern Complement Med 2017; 23:907–919.
Gartlehner G, et al. Pharmacological and non-pharmacological treatments for major depressive disorder: review of systematic reviews. BMJ Open 2017; 7:e014912.
Chen JA, et al. Association between patient beliefs regarding assigned treatment and clinical response: reanalysis of data from the Hypericum Depression Trial Study Group. J Clin Psychiatry 2011; 72:1669–1676.
Chen JA, et al. Association between physician beliefs regarding assigned treatment and clinical response: re-analysis of data from the Hypericum Depression Trial Study Group. Asian J Psychiatr 2015; 13:23–29.
Zhao X, et al. The efficacy and safety of St. John’s wort extract in depression therapy compared to SSRIs in adults: a meta-analysis of randomized clinical trials. Adv Clin Exp Med 2023; 32:151–161.
Eatemadnia A, et al. The effect of Hypericum perforatum on postmenopausal symptoms and depression: a randomized controlled trial. Complement Ther Med 2019; 45:109–113.
Galeotti N. Hypericum perforatum (St John’s wort) beyond depression: a therapeutic perspective for pain conditions. J Ethnopharmacol 2017; 200:136–146.
Cleare A, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol 2015; 29:459–525.
Russo E, et al. Hypericum perforatum: pharmacokinetic, mechanism of action, tolerability, and clinical drug–drug interactions. Phytother Res 2014; 28:643–655.
Crampsey DP, et al. Nasal insertion of St John’s wort: an unusual cause of epistaxis. J Laryngol Otol 2007; 121:279–280.
Bostock E, et al. Mania associated with herbal medicines, other than cannabis: a systematic review and quality assessment of case reports. Front Psychiatry 2018; 9:280.
Rodrigues Cordeiro C, et al. Triggers for acute mood episodes in bipolar disorder: a systematic review. J Psychiatr Res 2023; 161:237–260.
Sarris J. Herbal medicines in the treatment of psychiatric disorders: 10-year updated review. Phytother Res 2018; 32:1147–1162.
Fisher KA, et al. St. John’s wort-induced supraventricular tachycardia. Cureus 2021; 13:e14356.
Soleymani S, et al. Clinical risks of St John’s wort (Hypericum perforatum) co-administration. Expert Opin Drug Metab Toxicol 2017; 13:1047–1062.
Chrubasik-Hausmann S, et al. Understanding drug interactions with St John’s wort (Hypericum perforatum L.): impact of hyperforin content. J Pharm Pharmacol 2018; 71:129–138.

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References

Depression and anxiety disorders CHAPTER 3 26. Nicolussi S, et al. Clinical relevance of St. John’s wort drug interactions revisited. Br J Pharmacol 2020; 177:1212–1226. 27. Imai H, et al. The recovery time-course of CYP3A after induction by St John’s wort administration. Br J Clin Pharmacol 2008; 65:701–707. 28. Choi S, et al. A systematic review of the pharmacokinetic and pharmacodynamic interactions of herbal medicine with warfarin. PLoS One 2017; 12:e0182794. 29. Berry-Bibee EN, et al. Co-administration of St. John’s wort and hormonal contraceptives: a systematic review. Contraception 2016; 94:668–677. 30. Xu H, et al. Effects of St John’s wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide. Br J Pharmacol 2008; 153:1579–1586. 31. Andren L, et al. Interaction between a commercially available St. John’s wort product (Movina) and atorvastatin in patients with hypercholesterolemia. Eur J Clin Pharmacol 2007; 63:913–916. 32. Scholz I, et al. Effects of Hypericum perforatum (St John’s wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans. Br J Clin Pharmacol 2021; 87:1466–1474. 33. Committee of Safety in Medicine and Medicines Control Agency. Reminder: St John’s wort (Hypericum perforatum) interactions. Curr Probl Pharmacovigilance 2000; 26:6–7. 34. Lantz MS, et al. St. John’s wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol 1999; 12:7–10. 35. Barnes J, et al. Different standards for reporting ADRs to herbal remedies and conventional OTC medicines: face-to-face interviews with 515 users of herbal remedies. Br J Clin Pharmacol 1998; 45:496–500. 36. Linden M, et al. Self medication with St. John’s wort in depressive disorders: an observational study in community pharmacies. J Affect Disord 2008; 107:205–210. 37. Wagner PJ, et al. Taking the edge off: why patients choose St. John’s wort. J Fam Pract 1999; 48:615–619.

444 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Antidepressants: relative adverse effects – a rough guide Table 3.23 gives a very approximate, unreferenced view of the absolute and relative risk of a small range of adverse effects associated with standard antidepressants. Further details can be found in specific sections in this chapter. Table 3.23 Common adverse effects of antidepressants. Drug Sedation Postural hypotension Cardiac conduction disturbance Anticholinergic effects Nausea/ vomiting Sexual dysfunction Tricyclics Amitriptyline +++ +++ +++ +++ + +++ Clomipramine ++ +++ +++ ++ ++ +++ Dosulepin +++ +++ +++ ++ + + Doxepin +++ ++ +++ +++ + + Imipramine ++ +++ +++ +++ + + Lofepramine + + + ++ + + Nortriptyline + ++ ++ + + + Protriptyline – + ++ ++ ++ + Trimipramine +++ +++ ++ ++ + + Other antidepressants Agomelatine + – – – – – Bupropion – – + – + – Dextromethorphan/ bupropion + – + – ++ – Duloxetine (SNRI) – –* – – ++ +++ Levomilnacipran (SNRI) – –* – – ++ ++ Mianserin ++ – – – – – Mirtazapine +++ + – + + – Reboxetine + –* – + + + Trazodone +++ + + + + + Venlafaxine/ desvenlafaxine – –* + – +++ +++ SSRIs Citalopram – – + – ++ +++ Escitalopram – – + – ++ +++ (Continued)

Depression and anxiety disorders CHAPTER 3 Table 3.23 (Continued) Drug Sedation Postural hypotension Cardiac conduction disturbance Anticholinergic effects Nausea/ vomiting Sexual dysfunction Fluoxetine – – – – ++ +++ Fluvoxamine + – – – +++ +++ Paroxetine + – – + ++ +++ Sertraline – – – – ++ +++ Vilazodone – – – – + ++ Vortioxetine – + – – + + Monoamine oxidase inhibitors Isocarboxazid + ++ + ++ + + Phenelzine + + + + + + Tranylcypromine – + + + + + Reversible inhibitor of monoamine oxidase A Moclobemide – – – – + + Key: Incidence/severity: +++, high; ++, moderate; +, low; –, very low/none. * Hypertension reported.

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446 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Anxiety spectrum disorders Anxiety disorders can occur in isolation, be comorbid with other psychiatric disorders (particularly depression), be a consequence of physical illness such as thyrotoxicosis or be drug-induced (e.g. by caffeine). Comorbidity with other psychiatric disorders is very common. These disorders tend to be chronic and treatment is often only partially successful. People with anxiety disorders may be especially prone to adverse effects.1 High initial doses of SSRIs in particular may be poorly tolerated, for example. Benzodiazepines Benzodiazepines provide rapid symptomatic relief from acute anxiety states.2 Nearly all guidelines and consensus statements recommend that this group of drugs should be used only to treat anxiety that is severe, disabling or subjecting the individual to extreme distress. Because of their potential to cause physical dependence and withdrawal symptoms, these drugs should be used at the lowest effective dose for the shortest period of time (maximum 4 weeks), while longer-term treatment strategies are put in place. For the majority of patients these recommendations are sensible and should be followed. A very small number of patients with severely disabling anxiety may benefit from long- term treatment with a benzodiazepine and these patients should not normally be denied treatment. Benzodiazepines are, however, known to be over-prescribed in the long term for treatment of both anxiety3 and depression,4 perhaps especially in the USA, where attitudes to benzodiazepines differ markedly from other developed countries.5 In the UK, NICE recommends that benzodiazepines should not be used to treat panic disorder.6 In other countries, alprazolam is widely used for this indication. Benzodiazepines should be used with some care in post-traumatic stress disorder (PTSD).7 SSRIs/SNRIs When used to treat generalised anxiety disorder (GAD), SSRIs should initially be prescribed at half the normal starting dose and titrated to the normal antidepressant dosage range as tolerated (initial worsening of anxiety may be seen when treatment is started).8 The same advice applies to the use of venlafaxine and duloxetine. Modest benefit is usually seen within 6 weeks and continues to increase over time.9 The optimal duration of treatment has not been determined but should probably be at least 1 year.10,11 Effective treatment of GAD may prevent the development of major depression.10 An early network meta-analysis suggested that fluoxetine is the most effective SSRI in GAD and sertraline the best tolerated.12 More recent analyses suggest that bupropion13 or agomelatine14 is the most effective drug in GAD. Neither analysis found clear effects over placebo for lorazepam or vortioxetine. When used to treat panic disorder, the same starting dose and dosage titration should be used as for GAD. Doses of clomipramine,15 citalopram16 and sertraline17 towards the bottom of the antidepressant range give the best balance between efficacy and adverse effects, whereas higher doses of paroxetine (≥40mg) may be required.18 Higher doses of

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Use of antidepressants in anxiety spectrum disorders

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Depression and anxiety disorders CHAPTER 3 all drugs may be effective when standard doses have failed. Efficacy of SSRIs (but not SNRIs) increases across the licensed dose range in anxiety disorders.19 Onset of action may be as long as 6 weeks. Women may respond better to SSRIs than men.20 Augmentation with clonazepam leads to a more rapid response but not a greater magnitude of response overall.18 The optimal duration of treatment is unknown but should be at least 8 months.21 A large naturalistic study showed convincing evidence of benefit for at least 3 years.22 Less than half are likely to remain well after medication is withdrawn.23 Lower starting doses are also required in PTSD, although high doses (e.g. fluoxetine 60mg) are usually required for full effect. Response is usually seen within 8 weeks, but can take up to 12 weeks.23 Treatment should be continued for at least 6 months and probably longer.11,24,25 Although the doses of SSRIs licensed for the treatment of obsessive compulsive disorder (OCD) are higher than those licensed for the treatment of depression (e.g. fluoxetine 60mg, paroxetine 40–60mg), lower (standard antidepressant) doses may be effective, particularly for maintenance treatment.26 Initial response is usually slower to emerge than in depression (it can take 10–12 weeks). Dose should be increased to gain maximal benefit. Treatment should continue for at least 1 year.11 The relapse rate in those who continue treatment for 2 years is half that of those who stop treatment after initial response (25–40% vs 80%).27 In most people with OCD, the condition is persistent and symptom severity fluctuates over time.28 Second-line treatment is usually the addition of either risperidone or aripiprazole. Very high doses of SSRIs have also been tried (e.g. 650mg/day sertraline), apparently without any major safety problems.29 Body dysmorphic disorder should be treated initially with CBT. If symptoms are moderate to severe, adding an SSRI may improve outcome.30 Buspirone may usefully augment the SSRI,30 although no RCT has been conducted. Standard antidepressant starting doses are well tolerated in social phobia,31,32 and dosage titration may benefit some patients but is not always required. Some benefit is usually seen within 8 weeks and treatment should be continued for at least 1 year and probably longer.32 In the UK, NICE recommends CBT as first-line treatment for social anxiety.33 All patients treated with SSRIs should be monitored for the development of akathisia, increased anxiety and the emergence of suicidal ideation; the risk is greatest in those younger than 30 years, those with comorbid depression and those already known to be at higher risk of suicide.30,34 SSRIs should not be stopped abruptly, as patients with anxiety spectrum disorders are particularly sensitive to discontinuation symptoms (see section on stopping antidepressants in this chapter). The dose should be reduced as slowly as tolerated over several months. Pregabalin Pregabalin is licensed for the treatment of GAD. Several large RCTs have demonstrated its efficacy and tolerability and comparable speed of onset of action to a benzodiazepine.2,35 The dose of pregabalin in GAD is initially 150mg, increased gradually to a maximum of 600mg in two to three divided doses. It is widely misused (often alongside opioids)36 and there is a significant risk of diversion.37 Pregabalin seems to worsen the

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448 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 overdose toxicity of opiates.38 Pregabalin should not be stopped abruptly as it may precipitate a severe withdrawal syndrome that includes seizures.39 Psychological approaches There is good evidence to support the efficacy of psychological interventions in anxiety spectrum disorders.11,40 Examples include exposure therapy in OCD and social phobia. Initial drug therapy may be required to help the patient become more receptive to psychological input, although evidence to support this assumption is slim. Some studies suggest that optimal outcome is achieved by combining psychological and drug therapies,6,41 but negative studies also exist.42,43 A discussion of the evidence base for psychological interventions is outside the scope of this text. It is recognised that for many patients psychological therapies are the appropriate first-line treatment, and this is supported by NICE.6 Summary of NICE guidelines for the treatment of GAD, panic disorder and OCD ■ ■A ‘stepped care’ approach is recommended to help in choosing the most effective intervention for GAD,6 panic disorder6 and OCD.30 ■ ■A comprehensive assessment is recommended, which considers the degree of distress and functional impairment, the effect of any comorbid mental illness, substance misuse or medical condition, and past response to treatment. ■ ■Treat the primary disorder first. ■ ■Psychological therapy is more effective than pharmacological therapy and should be used as first-line therapy where possible. Details of the types of therapy recommended and their duration can be found in the NICE guidelines. ■ ■Pharmacological therapy is also effective. Most evidence supports the use of the SSRIs (sertraline as first line). ■ ■Provide information on the probable benefits and disadvantages of each mode of treatment. ■ ■Consider combination therapy for complex anxiety disorders that are refractory to treatment. Panic disorder ■ ■Benzodiazepines should not be used except in a crisis. ■ ■An SSRI should be used as first-line therapy. If SSRIs are contraindicated or there is no response, imipramine or clomipramine can be used. ■ ■Self-help (based on CBT principles) should be encouraged, as should formal CBT. GAD ■ ■Benzodiazepines should not be used except for crises. ■ ■An SSRI should be used as first-line treatment. ■ ■SNRIs and pregabalin are second and third choices, respectively. ■ ■High-intensity psychological intervention and self-help (based on CBT principles) should be encouraged. ■ ■Antipsychotics should not be offered (presumably this includes quetiapine).

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Psychological approaches

Depression and anxiety disorders CHAPTER 3 OCD (where there is moderate or severe functional impairment) ■ ■Use an SSRI or intensive CBT. ■ ■Combine the SSRI and CBT if the response to a single strategy is suboptimal. ■ ■Use clomipramine if SSRIs fail. ■ ■If response is still suboptimal, add an antipsychotic or combine clomipramine and citalopram. Boxes 3.6–3.10 give details of specific drugs used in anxiety spectrum disorders. Box 3.6 Generalised anxiety disorder Drug Comment Crisis management Benzodiazepines Normally for short-term use only, maximum 2–4 weeks, although some are of the opinion that risks are overstated44 First-line treatment (in order of preference)30 SSRIs (up to maximum licensed dose) May initially exacerbate symptoms. A lower starting dose is recommended. Fluoxetine and sertraline are preferred options.12 Vortioxetine may not be effective.45 SNRIs14 (up to maximum licensed dose) May initially exacerbate symptoms. A lower starting dose is recommended. Pregabalin 150–600mg/day in divided doses Response may be seen in the first week of treatment.46 Increasingly misused. Significant withdrawal syndrome. Overdose risk with opiates. Second-line treatment (less well tolerated or weaker evidence base; no order of preference) Agomelatine47 10–50mg/day Agomelatine has been shown to prevent relapse over a 6-month period48,49 Betablockers Propranolol 40–120mg/day in divided doses Initiate at 40mg and titrate dose up to effect if needed. Useful for somatic symptoms, particularly tachycardia.50 Otherwise has limited efficacy. Highly toxic in overdose.51 Buspirone 15–60mg/day in divided doses Has a delayed onset of action; takes up to 6 weeks to show equal efficacy to benzodiazepines52 Hydroxyzine 50–100mg/day in divided doses Unclear that hydroxyzine is effective due to a direct anxiolytic effect or to a broader sedative effect53 Quetiapine (MR, 50–300mg) Recommended as monotherapy. Probably not effective as adjunctive therapy to SSRI/SNRI in treatment resistance.54 Tricyclic antidepressants Clomipramine 50–250mg/day55–57 Initiate at 10mg/day and increase the dose gradually Imipramine 75–200mg/day in divided doses58 Initiate at 25mg/day every 4 days and when at 100mg can increase in 50mg increments10 (Continued)

450 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Drug Comment Monoamine oxidase inhibitors Phenelzine 45–90mg/day in divided doses59 For mixed anxiety and depressive states. Patients need to avoid food high in tyramine. Mirtazapine 15–30mg at night60,61 Experimental Cannabidiol Large effect size62 Chamomile 220–1500mg/day Two RCTs, one positive, one negative using standardised doses of chamomile and placebo63 Gingko biloba 240–480mg/day One positive RCT using standardised doses of Gingko biloba and placebo64 Ketamine Seemingly rapidly effective65 Lavender oil preparation 80–160mg/day Substantial supporting evidence66 Riluzole 50–100mg/day doses67 Liver function monitoring required Box 3.7 Panic disorder Drug Comment Crisis management Benzodiazepines Rapid effect although panic symptoms return quickly if the drug is withdrawn.68 NICE does not recommend.6 Cochrane lukewarm.69 Probably the most effective treatment.70 Alprazolam is not superior to other benzodiazepines71 and its effects may have been overestimated.72 First-line treatment (in order of preference)6,73 SSRIs (up to maximum licensed dose) Therapeutic effect can be delayed (this applies to all antidepressants)74 and patients can experience an initial exacerbation of panic symptoms.6 Use supported by Cochrane75 and a 2022 meta-analysis.76 Venlafaxine MR 75–225mg73 Initiate at 37.5mg for 7 days (Continued)

Depression and anxiety disorders CHAPTER 3 Drug Comment Second-line treatment (less well tolerated or weak evidence base; no order of preference) Mirtazapine 15–60mg/day77 A meta-analysis suggests that mirtazapine does not help with panic symptoms but with the anxiety associated with this disorder.73 Rather limited data overall.78 Moclobemide 300–600mg/day79 One fixed dose study of 450mg/day and one flexible dose study suggest efficacy.79,80 Brofaromine (a similar drug) is also effective.70 Monoamine oxidase inhibitors Phenelzine 10–60mg/day74 No long-term studies; reserve for treatment-resistant cases due to poor tolerability74 Tricyclic antidepressants Clomipramine 25–250mg/day74 Start with a low dose and increase dose according to response and tolerability. Good evidence of effectiveness.70 Imipramine 25–300mg/day74 Lofepramine 70–210mg/day in divided doses81 Experimental Gabapentin 600–3600mg/day One RCT showed no difference between gabapentin and placebo. However, significant improvement was demonstrated in the more severely ill.82 Inositol 12g/day83 One positive RCT in 21 patients. Equivalent to fluvoxamine in one study.84 Well tolerated. Levetiracetam 250mg twice daily78 Usually well tolerated Pindolol 7.5mg/day Efficacy suggested in a small 21 patient RCT where 2.5mg tds was used to augment fluoxetine in treatment-resistant panic disorder85 Valproate 500–2250mg/day Two very small positive open studies86,87 Hydrocortisone Only acute treatment shown to prevent development of post-traumatic stress disorder88

Box 3.8 Post-traumatic stress disorder Drug Comments First-line treatment (in order of preference) (Psychological approaches should be used before drug treatments)89,90 SSRIs (up to maximum licensed doses) Paroxetine, sertraline or fluoxetine are the preferred SSRIs.91,92 Recommended by NICE.89 Good support but small effective size.93,94 Venlafaxine modified release 37.5–300mg95 Recommended by NICE89 Supported by meta-analyses93,96 Second-line treatment (less well tolerated or weak evidence base; no order of preference) Antipsychotics May be effective for the intrusion symptoms (flashbacks and nightmares) but not the avoidance and hyperarousal symptoms of post-traumatic stress disorder. Studies done as monotherapy or as adjunctive treatment.97 Olanzapine 5–20mg May be the most effective treatment96 Risperidone 0.5–6mg Specifically mentioned by NICE89 Quetiapine 50–800mg98 More robust support than for risperidone93,96 Mirtazapine 15–45mg/day99 Recommended by NICE89 Second most effective drug in a network meta-analysis100 Monoamine oxidase inhibitors Phenelzine 15–75mg/day101 Recommended by NICE89 Most effective drug in a network meta-analysis100 Prazosin 2–15mg at night102 For nightmares and sleep disturbances. Initiate at 1mg at night and titrate dose gradually to reduce the risk of hypotension. Supported by a systematic review103 and meta-analysis.93 Tricyclic antidepressants Start at a low dose and increase dose according to tolerability Amitriptyline 50–300mg/day104 Recommended by NICE89 For all TCAs start at a low dose and increase dose according to tolerability Imipramine 50–300mg/day Best supporting evidence is for desipramine but this drug is not widely available100 Ketamine IV105,106 Rapid reduction in symptom severity suggested. Developing evidence showing acute and chronic efficacy.107–109 Experimental Duloxetine 60–120mg Two small open studies suggest efficacy. Start at 30mg for 1 week110,111 Lamotrigine up to 500mg/day Small double-blind study in 15 patients112 MDMA-assisted therapy Developing database113 Phenytoin plasma concentration 10–20ng/ml114 Open-label study in 12 patients Valproate up to 2.5g115 Probably not effective100 MAOI, monoamine oxidase inhibitor; MDMA, 3,4-methylenedioxymethamphetamine.

Depression and anxiety disorders CHAPTER 3 Box 3.9 Obsessive–compulsive disorder Drug Comments First-line treatment (in order of preference) Any SSRI41 (up to maximum licensed dose) If the first SSRI is not tolerated or has a poor response an alternative SSRI may be tried30 Clomipramine (up to 250mg) Owing to poorer tolerability, recommended trying at least one SSRI first30 Second-line treatment (unlicensed or weaker evidence base; in no order of preference) Add antipsychotic to SSRI (low to moderate doses)116,117 Most evidence supports the use of aripiprazole or risperidone.116 Some evidence for haloperidol.117 Citalopram 40mg with clomipramine 150mg Based on small randomised open-label study.118 Recommended by NICE.30 ECG monitoring required. Acetylcysteine119 (up to 2400mg/day added to SSRI or clomipramine) GI adverse effects may be problematic. Two of five controlled studies negative. Pooled effect shows benefit.120 Lamotrigine 100mg+ added to SSRI121 Dose must be titrated gradually as indicated in the summary of product characteristics. May worsen OCD in some.122 Topiramate up to 400mg added to SSRI123,124 Not well tolerated; suggested benefits for compulsion but not obsessions.123 Two trials found it ineffective125,126 Experimental High-dose SSRIs Dose titrated gradually according to tolerability. ECG monitoring recommended. Higher doses have been safely used29 (e.g. sertraline 650mg, fluoxetine 120mg/day) Escitalopram 25–50mg127 Sertraline 250–400mg128 Memantine Good evidence for 20mg/day added to SSRIs.129 Most effective add-on treatment in a 2023 meta-analysis.130 NSAIDs (e.g. celecoxib 400mg/day) Some supporting evidence126 Amantadine 200mg/day One positive RCT131 SNRIs Venlafaxine up to 375mg132 Duloxetine 60mg133 Mirtazapine 30–60mg134 Small trial in 30 patients 5HT3 antagonists Granisetron 1mg with fluvoxamine 200mg135 Some evidence for each drug but ondansetron may be the more effective130,137,138 Ondansetron 4mg with fluoxetine 20mg136 (Continued)

454 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Drug Comments Pregabalin 75–225mg/day added to sertraline One small positive RCT139 Riluzole 50mg bd added to existing drug treatment140 Variable results in early trials126 Anti-androgen – triptorelin 3.75mg IM every 4 weeks added to existing drug treatment141 Open-label study done in six men Psilocybin Emerging evidence for effect142,143 IV treatment Quicker onset of action suggested compared with oral treatments Clomipramine IV144 IV may be more effective than oral clomipramine Ketamine IV145,146 Developing evidence base126 Once-weekly morphine 15–45mg added to existing drug treatment147 Small study involving 23 treatment-resistant patients. Positive effects were transient. Box 3.10 Social phobia (social anxiety disorder) Drug Comments First line drug treatment148 (in order of preference) SSRIs (up to maximum licensed dose) If no response to the first SSRI, try an alternative SSRI. Supporting meta-analyses for fluvoxamine149 and citalopram.150 Emerging data for vilazodone.151 Venlafaxine modified release 75–225mg/day Supporting meta-analysis152 Second line drug treatment (less well tolerated or weaker evidence base, no order of preference) Olanzapine 5–20mg153 Few studies with antipsychotics. Most evidence with olanzapine. Atenolol 25–100mg/day Reduces autonomic symptoms in performance situations.153 Probably not effective in social phobia.154 Benzodiazepines: Helpful on prn basis. Most evidence for treatment with clonazepam and bromazepam. Switching an SSRI to venlafaxine no more effective than adding clonazepam to SSRI.155 Clonazepam 0.3–6mg/day153 Sertraline plus clonazepam up to 3mg/day155 Gabapentin 900–3600mg/day153 (Continued)

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Summary of NICE guidelines for the treatment of GAD, panic disorder and OCD

Depression and anxiety disorders CHAPTER 3 References

Nash JR, et al. Pharmacotherapy of anxiety. HandbExp Pharmacol 2005; (169):469–501.
Munkholm K, et al. Minor tranquillizers for short-term treatment of newly onset symptoms of anxiety and distress: a systematic review with network meta-analysis of randomized trials. Eur Arch Psychiatry Clin Neurosci 2024; 274:475–486.
Benitez CI, et al. Use of benzodiazepines and selective serotonin reuptake inhibitors in middle-aged and older adults with anxiety disorders: a longitudinal and prospective study. Am J Geriatr Psychiatry 2008; 16:5–13.
Demyttenaere K, et al. Clinical factors influencing the prescription of antidepressants and benzodiazepines: results from the European study of the epidemiology of mental disorders (ESEMeD). J Affect Disord 2008; 110:84–93.
Hirschtritt ME, et al. Balancing the risks and benefits of benzodiazepines. JAMA 2021; 325:347–348.
National Institute for Health and Care Excellence. Generalised anxiety disorder and panic disorder in adults: management. Clinical guideline [CG113]. 2011 (last updated June 2020, reviewed May 2024, last checked November 2024); https://www.nice.org.uk/guidance/cg113.
Davidson JR. Use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. J Clin Psychiatry 2004; 65 Suppl 5:29–33.
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Ballenger JC. Remission rates in patients with anxiety disorders treated with paroxetine. J Clin Psychiatry 2004; 65:1696–1707.
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Baldwin DS, et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive- compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol 2014; 28:403–439.
Baldwin D, et al. Efficacy of drug treatments for generalised anxiety disorder: systematic review and meta-analysis. BMJ 2011; 342:d1199.
Slee A, et al. Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis. Lancet 2019; 393:768–777.
Kong W, et al. Comparative remission rates and tolerability of drugs for generalised anxiety disorder: a systematic review and network meta- analysis of double-blind randomized controlled trials. Front Pharmacol 2020; 11:580858.
Caillard V, et al. Comparative effects of low and high doses of clomipramine and placebo in panic disorder: a double-blind controlled study. French University Antidepressant Group. Acta Psychiatr Scand 1999; 99:51–58.
Wade AG, et al. The effect of citalopram in panic disorder. Br J Psychiatry 1997; 170:549–553.
Londborg PD, et al. Sertraline in the treatment of panic disorder: a multi-site, double-blind, placebo-controlled, fixed-dose investigation. Br J Psychiatry 1998; 173:54–60.
Pollack MH, et al. Combined paroxetine and clonazepam treatment strategies compared to paroxetine monotherapy for panic disorder. J Psychopharmacol 2003; 17:276–282. Drug Comments Levetiracetam 300–3000mg/day in divided doses156 Moclobemide 600mg/day in divided doses Initiate at 300mg/day in divided doses. Has a UK licence for social phobia. Recommended by NICE.148 Phenelzine 15–90mg/day157 Avoidance of tyramine-rich food important. Recommended by NICE.148 Pregabalin 150–600mg/day153 600mg/day superior to placebo153 Experimental Ketamine 0.5mg/kg IV One good RCT,158 one post hoc analysis159 Topiramate 25–400mg/day160 Small open-label study of 23 patients suggests efficacy but poorly tolerated Valproate 500–2500mg/day161 Small open-label study of 17 patients suggests efficacy

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GAD

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OCD (where there is moderate or severe functional impairment)

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References

456 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 19. Jakubovski E, et al. Systematic review and meta-analysis: dose-response curve of SSRIs and SNRIs in anxiety disorders. Depress Anxiety 2019; 36:198–212. 20. Clayton AH, et al. Sex differences in clinical presentation and response in panic disorder: pooled data from sertraline treatment studies. Arch Womens Ment Health 2006; 9:151–157. 21. Rickels K, et al. Panic disorder: long-term pharmacotherapy and discontinuation. J Clin Psychopharmacol 1998; 18:12S–18S. 22. Choy Y, et al. Three-year medication prophylaxis in panic disorder: to continue or discontinue? A naturalistic study. Compr Psychiatry 2007; 48:419–425. 23. Michelson D, et al. Continuing treatment of panic disorder after acute response: randomised, placebo-controlled trial with fluoxetine. The Fluoxetine Panic Disorder Study Group. Br J Psychiatry 1999; 174:213–218. 24. Davidson J, et al. Efficacy of sertraline in preventing relapse of posttraumatic stress disorder: results of a 28-week double-blind, placebo- controlled study. Am J Psychiatry 2001; 158:1974–1981. 25. Williams T, et al. Pharmacotherapy for post traumatic stress disorder (PTSD). Cochrane Database Syst Rev 2022; 3(3):CD002795. 26. Martenyi F, et al. Fluoxetine v. placebo in prevention of relapse in post-traumatic stress disorder. Br J Psychiatry 2002; 181:315–320. 27. The Expert Consensus Panel for obsessive–compulsive disorder: treatment of obsessive–compulsive disorder. J Clin Psychiatry 1997; 58 Suppl 4:2–72. 28. Catapano F, et al. Obsessive–compulsive disorder: a 3-year prospective follow-up study of patients treated with serotonin reuptake inhibitors OCD follow-up study. J Psychiatr Res 2006; 40:502–510. 29. Levy DM, et al. Off-label higher doses of serotonin reuptake inhibitors in the treatment of obsessive–compulsive disorder: safety and tolerability. Compr Psychiatry 2024; 133:152486. 30. 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Depression and anxiety disorders CHAPTER 3 55. Wingerson D, et al. Clomipramine treatment for generalized anxiety disorder. J Clin Psychopharmacol 1992; 12:214–215. 56. den Boer JA, et al. Effect of serotonin uptake inhibitors in anxiety disorders; a double-blind comparison of clomipramine and fluvoxamine. Int Clin Psychopharmacol 1987; 2:21–32. 57. Kahn RS, et al. Effect of a serotonin precursor and uptake inhibitor in anxiety disorders; a double-blind comparison of 5-hydroxytryptophan, clomipramine and placebo. Int Clin Psychopharmacol 1987; 2:33–45. 58. Rickels K, et al. Antidepressants for the treatment of generalized anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam. Arch Gen Psychiatry 1993; 50:884–895. 59. Robinson DS, et al. The monoamine oxidase inhibitor, phenelzine, in the treatment of depressive-anxiety states: a controlled clinical trial. Arch Gen Psychiatry 1973; 29:407–413. 60. Gambi F, et al. Mirtazapine treatment of generalized anxiety disorder: a fixed dose, open label study. J Psychopharmacol 2005; 19:483–487. 61. Sitsen JMA, et al. Mirtazapine, a novel antidepressant, in the treatment of anxiety symptoms. Drug Investigation 1994; 8:339–344. 62. Han K, et al. Therapeutic potential of cannabidiol (CBD) in anxiety disorders: a systematic review and meta-analysis. Psychiatry Res 2024; 339:116049. 63. Amsterdam JD, et al. A randomized, double-blind, placebo-controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalized anxiety disorder. J Clin Psychopharmacol 2009; 29:378–382. 64. Woelk H, et al. Ginkgo biloba special extract EGb 761 in generalized anxiety disorder and adjustment disorder with anxious mood: a randomized, double-blind, placebo-controlled trial. J Psychiatr Res 2007; 41:472–480. 65. Hull TD, et al. 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Pharmacological treatments in panic disorder in adults: a network meta-analysis. Cochrane Database Syst Rev 2023; (11):CD012729. 71. Moylan S, et al. The efficacy and safety of alprazolam versus other benzodiazepines in the treatment of panic disorder. J Clin Psychopharmacol 2011; 31:647–652. 72. Ahn-Horst RY, et al. Unpublished trials of alprazolam XR and their influence on its apparent efficacy for panic disorder. Psychol Med 2024; 54:1026–1033. 73. Andrisano C, et al. Newer antidepressants and panic disorder: a meta-analysis. Int Clin Psychopharmacol 2013; 28:33–45. 74. Batelaan NM, et al. Evidence-based pharmacotherapy of panic disorder: an update. Int J Neuropsychopharmacol 2012; 15:403–415. 75. Bighelli I, et al. Antidepressants versus placebo for panic disorder in adults. Cochrane Database Syst Rev 2018; (4):CD010676. 76. Chawla N, et al. Drug treatment for panic disorder with or without agoraphobia: systematic review and network meta-analysis of randomised controlled trials. BMJ 2022; 376:e066084. 77. Boshuisen ML, et al. The effect of mirtazapine in panic disorder: an open label pilot study with a single-blind placebo run-in period. Int Clin Psychopharmacol 2001; 16:363–368. 78. Zulfarina MS, et al. Pharmacological therapy in panic disorder: current guidelines and novel drugs discovery for treatment-resistant patient. Clin Psychopharmacol Neurosci 2019; 17:145–154. 79. Tiller JW, et al. Moclobemide for anxiety disorders: a focus on moclobemide for panic disorder. Int Clin Psychopharmacol 1997; 12 Suppl 6:S27–S30. 80. Kruger MB, et al. The efficacy and safety of moclobemide compared to clomipramine in the treatment of panic disorder. Eur Arch Psychiatry Clin Neurosci 1999; 249 Suppl 1:S19–S24. 81. Fahy TJ, et al. The Galway Study of Panic Disorder. I: Clomipramine and lofepramine in DSM III-R panic disorder: a placebo controlled trial. J Affect Disord 1992; 25:63–75. 82. Pande AC, et al. Placebo-controlled study of gabapentin treatment of panic disorder. 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National Institute for Health and Care Excellence. Post-traumatic stress disorder. NICE guideline [NG116]. 2018 (reviewed August 2024, last accessed November 2024); https://www.nice.org.uk/guidance/NG116. 90. Moore BA, et al. Management of post-traumatic stress disorder in veterans and military service members: a review of pharmacologic and psychotherapeutic interventions since 2016. Curr Psychiatry Rep 2021; 23:9.

458 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 91. Hoskins M, et al. Pharmacotherapy for post-traumatic stress disorder: systematic review and meta-analysis. Br J Psychiatry 2015; 206:93–100. 92. Lee DJ, et al. Psychotherapy versus pharmacotherapy for posttraumatic stress disorder: systematic review and meta-analyses to determine first-line treatments. Depress Anxiety 2016; 33:792–806. 93. Hoskins MD, et al. Pharmacological therapy for post-traumatic stress disorder: a systematic review and meta-analysis of monotherapy, augmentation and head-to-head approaches. Eur J Psychotraumatol 2021; 12:1802920. 94. Williams T, et al. Pharmacotherapy for post traumatic stress disorder (PTSD). Cochrane Database Syst Rev 2022; (3):CD002795. 95. Davidson J, et al. Treatment of posttraumatic stress disorder with venlafaxine extended release: a 6-month randomized controlled trial. Arch Gen Psychiatry 2006; 63:1158–1165. 96. Zhang ZX, et al. Clinical outcomes of recommended active pharmacotherapy agents from NICE guideline for post-traumatic stress disorder: network meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2023; 125:110754. 97. Han C, et al. The potential role of atypical antipsychotics for the treatment of posttraumatic stress disorder. J Psychiatr Res 2014; 56:72–81. 98. Villarreal G, et al. Efficacy of quetiapine monotherapy in posttraumatic stress disorder: a randomized, placebo-controlled trial. Am J Psychiatry 2016; 173:1205–1212. 99. Davidson JR, et al. Mirtazapine vs. placebo in posttraumatic stress disorder: a pilot trial. Biol Psychiatry 2003; 53:188–191. 100. Cipriani A, et al. Comparative efficacy and acceptability of pharmacological treatments for post-traumatic stress disorder in adults: a network meta-analysis. Psychol Med 2018; 48:1975–1984. 101. Kosten TR, et al. Pharmacotherapy for posttraumatic stress disorder using phenelzine or imipramine. J Nerv Ment Dis 1991; 179:366–370. 102. George KC, et al. Meta-analysis of the efficacy and safety of prazosin versus placebo for the treatment of nightmares and sleep disturbances in adults with posttraumatic stress disorder. J Trauma Dissociation 2016; 17:494–510. 103. Coventry PA, et al. Psychological and pharmacological interventions for posttraumatic stress disorder and comorbid mental health problems following complex traumatic events: systematic review and component network meta-analysis. PLoS Med 2020; 17:e1003262. 104. Davidson J, et al. Treatment of posttraumatic stress disorder with amitriptyline and placebo. Arch Gen Psychiatry 1990; 47:259–266. 105. Albott CS, et al. Efficacy, safety, and durability of repeated ketamine infusions for comorbid posttraumatic stress disorder and treatment- resistant depression. J Clin Psychiatry 2018; 79:17m11634. 106. Feder A, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry 2014; 71:681–688. 107. Feder A, et al. A randomized controlled trial of repeated ketamine administration for chronic posttraumatic stress disorder. Am J Psychiatry 2021; 178:193–202. 108. Sicignano DJ, et al. The impact of ketamine for treatment of post-traumatic stress disorder: a systematic review with meta-analyses. Ann Pharmacother 2024; 58:669–677. 109. Rohde J, et al. Combined effects of nasal ketamine and trauma-focused psychotherapy in treatment-resistant post-traumatic stress disorder: a pilot case series. Behav Sci (Basel) 2024; 14:717. 110. Walderhaug E, et al. Effects of duloxetine in treatment-refractory men with posttraumatic stress disorder. Pharmacopsychiatry 2010; 43:45–49. 111. Villarreal G, et al. Duloxetine in military posttraumatic stress disorder. Psychopharmacol Bull 2010; 43:26–34. 112. Hertzberg MA, et al. A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder. Biol Psychiatry 1999; 45:1226–1229. 113. Mitchell JM, et al. MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nat Med 2023; 29:2473–2480. 114. Bremner DJ, et al. Treatment of posttraumatic stress disorder with phenytoin: an open-label pilot study. J Clin Psychiatry 2004; 65:1559–1564. 115. Adamou M, et al. Valproate in the treatment of PTSD: systematic review and meta analysis. Curr Med Res Opin 2007; 23:1285–1291. 116. Veale D, et al. Atypical antipsychotic augmentation in SSRI treatment refractory obsessive–compulsive disorder: a systematic review and meta-analysis. BMC Psychiatry 2014; 14:317. 117. Dold M, et al. Antipsychotic augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: an update meta-analysis of double-blind, randomized, placebo-controlled trials. Int J Neuropsychopharmacol 2015; 18:pyv047. 118. Pallanti S, et al. Citalopram for treatment-resistant obsessive–compulsive disorder. Eur Psychiatry 1999; 14:101–106. 119. Costa DLC, et al. Randomized, double-blind, placebo-controlled trial of n-acetylcysteine augmentation for treatment-resistant obsessive– compulsive disorder. J Clin Psychiatry 2017; 78:e766–e773. 120. Couto JP, et al. Oral N-acetylcysteine in the treatment of obsessive–compulsive disorder: a systematic review of the clinical evidence. Prog Neuropsychopharmacol Biol Psychiatry 2018; 86:245–254. 121. Bruno A, et al. Lamotrigine augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a double- blind, placebo-controlled study. J Psychopharmacol 2012; 26:1456–1462. 122. Sharma V, et al. Lamotrigine-induced obsessive–compulsive disorder in patients with bipolar disorder. CNS Spectr 2019; 24:390–394. 123. Berlin HA, et al. Double-blind, placebo-controlled trial of topiramate augmentation in treatment-resistant obsessive–compulsive disorder. J Clin Psychiatry 2011; 72:716–721. 124. Mowla A, et al. Topiramate augmentation in resistant OCD: a double-blind placebo-controlled clinical trial. CNS Spectr 2010; 15:613–617. 125. Afshar H, et al. Topiramate augmentation in refractory obsessive-compulsive disorder: a randomized, double-blind, placebo-controlled trial. J Res Med Sci 2014; 19:976–981. 126. Grassi G, et al. Investigational and experimental drugs to treat obsessive–compulsive disorder. J Exp Pharmacol 2020; 12:695–706.

Depression and anxiety disorders CHAPTER 3 127. Rabinowitz I, et al. High-dose escitalopram for the treatment of obsessive–compulsive disorder. Int Clin Psychopharmacol 2008; 23:49–53. 128. Ninan PT, et al. High-dose sertraline strategy for nonresponders to acute treatment for obsessive-compulsive disorder: a multicenter double- blind trial. J Clin Psychiatry 2006; 67:15–22. 129. Modarresi A, et al. A systematic review and meta-analysis: memantine augmentation in moderate to severe obsessive-compulsive disorder. Psychiatry Res 2019; 282:112602. 130. Maiti R, et al. Pharmacological augmentation of serotonin reuptake inhibitors in patients with obsessive–compulsive disorder: a network meta-analysis. Acta Psychiatr Scand 2023; 148:19–31. 131. Naderi S, et al. Amantadine as adjuvant therapy in the treatment of moderate to severe obsessive-compulsive disorder: a double-blind randomized trial with placebo control. Psychiatry Clin Neurosci 2019; 73:169–174. 132. Dell’Osso B, et al. Serotonin-norepinephrine reuptake inhibitors in the treatment of obsessive-compulsive disorder: a critical review. J Clin Psychiatry 2006; 67:600–610. 133. Mowla A, et al. Duloxetine augmentation in resistant obsessive–compulsive disorder: a double-blind controlled clinical trial. J Clin Psychopharmacol 2016; 36:720–723. 134. Koran LM, et al. Mirtazapine for obsessive–compulsive disorder: an open trial followed by double-blind discontinuation. J Clin Psychiatry 2005; 66:515–520. 135. Askari N, et al. Granisetron adjunct to fluvoxamine for moderate to severe obsessive–compulsive disorder: a randomized, double-blind, placebo-controlled trial. CNS Drugs 2012; 26:883–892. 136. Soltani F, et al. A double-blind, placebo-controlled pilot study of ondansetron for patients with obsessive–compulsive disorder. Hum Psychopharmacol 2010; 25:509–513. 137. Sharafkhah M, et al. Comparing the efficacy of ondansetron and granisetron augmentation in treatment-resistant obsessive–compulsive disorder: a randomized double-blind placebo-controlled study. Int Clin Psychopharmacol 2019; 34:222–233. 138. Suhas S, et al. Treatment strategies for serotonin reuptake inhibitor-resistant obsessive–compulsive disorder: a network meta-analysis of randomised controlled trials. World J Biol Psychiatry 2023; 24:162–177. 139. Mowla A, et al. Pregabalin augmentation for resistant obsessive–compulsive disorder: a double-blind placebo-controlled clinical trial. CNS Spectr 2020; 25:552–556. 140. Coric V, et al. Riluzole augmentation in treatment-resistant obsessive–compulsive disorder: an open-label trial. Biol Psychiatry 2005; 58:424–428. 141. Eriksson T. Anti-androgenic treatment of obsessive–compulsive disorder: an open-label clinical trial of the long-acting gonadotropin- releasing hormone analogue triptorelin. Int Clin Psychopharmacol 2007; 22:57–61. 142. Owe-Larsson M, et al. 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460 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Benzodiazepines in the treatment of psychiatric disorders Benzodiazepines have a valid place in the treatment of some forms of epilepsy and severe muscle spasm, and as premedication agents in some surgical procedures. However, the vast majority of prescriptions are written for their hypnotic and anxiolytic effects. They are also used for rapid tranquillisation and, usually as adjuncts, in the treatment of depression and schizophrenia. Benzodiazepines are commonly both prescribed and misused. A European study found that almost 10% of adults had taken a benzodiazepine over the previous year1 and a 2019 US study reported past-year usage of 12.6% among adults.2 Generally speaking, the use of benzodiazepines in psychiatric disorders has gradually become less supportable over the past few decades.3 Benzodiazepines are sometimes divided into two groups depending on their half-life: hypnotics (short half-life) or anxiolytics (long half-life), although there are many exceptions (for example, nitrazepam and alprazolam, respectively). Anxiolytic effect Benzodiazepines reduce pathological anxiety, agitation and tension. Although useful in the short-term management of generalised anxiety disorder,4 either alone or to augment SSRIs, benzodiazepines are associated with tolerance and withdrawal. Despite awareness of this, many patients continue to take these drugs for years5 with unknown benefits and many likely harms. Most authorities agree that, where a benzodiazepine is prescribed, this should not routinely be for longer than 4 weeks.6 In the UK, NICE recommends that benzodiazepines should not be used in patients with generalised anxiety disorder except as a short-term measure during crisis.7 Evidence is mixed in other anxiety disorders, and potential benefits should be viewed in the context of the known problems associated with benzodiazepine use. A small number of trials report the efficacy of benzodiazepines in social anxiety disorder.8 Benzodiazepines are useful in the short-term treatment of panic disorders,9,10 but little is known about their efficacy and safety with long-term use.10,11 Benzodiazepines are, with some exceptions, relatively ineffective in the treatment of PTSD12,13 or phobias.14 Hypnotic effect Benzodiazepines are effective hypnotics but they inhibit rapid eye movement (REM) sleep and REM rebound is seen when they are discontinued.14 There is a debate over the clinical significance of this property.15 Benzodiazepines are effective in the short term.16 RCTs support the effectiveness of Z hypnotics over a period of at least 6 months,17 but it is unclear if this holds true for benzodiazepine hypnotics. Intermittent use probably extends the period over which benzodiazepines are effective as hypnotics. Physical causes (pain, dyspnoea, etc.) or substance misuse (most commonly high caffeine consumption) should always be excluded before a hypnotic drug is prescribed. Where possible, behavioural therapies (e.g. CBT for insomnia or sleep restriction) should be offered before prescribing hypnotics.17 A high proportion of hospitalised patients are prescribed hypnotics.18,19 These drugs should not be routinely continued at discharge.

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Anxiolytic effect

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13 - References

References

340 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Toxicity in overdose varies both between and within groups of antidepressants42 (see section on psychotropics in overdose in Chapter 13). Duration of treatment Antidepressants relieve the symptoms of depression but do not treat the underlying cause. A reasonable amount of evidence suggests that they should be taken for 6–9 months after recovery from a single episode (presumably to cover the duration of an untreated episode). In those patients who have had several episodes, there is evidence of benefit from maintenance treatment for at least 2 years, but no upper duration of treatment has been identified (see section on antidepressant prophylaxis in this chapter). Beyond 2 years, continued treatment offers some benefits, but many people can safely stop at this point.43 There are few data on which to base recommendations about the duration of treatment of augmentation regimens. A minority view is that antidepressants worsen outcome in the long term.44 Next-step treatments Approximately one-third of patients do not respond to the first antidepressant that is prescribed. Options in this group include dose escalation, switching to a different drug and several augmentation strategies. A small proportion of non-responders will respond with each treatment change, but effect sizes are modest and there is no clear difference in effectiveness between strategies (see sections on the management of treatment- resistant depression in this chapter). Use of antidepressants in anxiety spectrum disorders Antidepressants are first-line treatments in a number of anxiety spectrum disorders (see section on anxiety spectrum disorders in this chapter). References

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Furukawa TA, et al. Initial severity of major depression and efficacy of new generation antidepressants: individual participant data meta–analysis. Acta Psychiatr Scand 2018; 137:450–458.
Anderson IM, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol 2008; 22:343–396.
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Hieronymus F, et al. Consistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression. Mol Psychiatry 2016; 21:523–530.
Hieronymus F, et al. Impact of sedative and appetite-increasing properties on the apparent antidepressant efficacy of mirtazapine, selective serotonin reuptake inhibitors and amitriptyline: an item-based, patient-level meta-analysis. eClinicalMedicine 2024; 77:102904.
Köhler-Forsberg O, et al. Efficacy and safety of antidepressants in patients with comorbid depression and medical diseases: an umbrella systematic review and meta–analysis. JAMA Psychiatry 2023; 80:1196–1207.
Lewis G, et al. The clinical effectiveness of sertraline in primary care and the role of depression severity and duration (PANDA): a pragmatic, double-blind, placebo-controlled randomised trial. Lancet Psychiatry 2019; 6:903–914.
Wiesinger T, et al. Antidepressants and quality of life in patients with major depressive disorder: systematic review and meta-analysis of double-blind, placebo-controlled RCTs. Acta Psychiatr Scand 2023; 147:545–560.
Kremer S, et al. Antidepressants and social functioning in patients with major depressive disorder: systematic review and meta–analysis of double–blind, placebo–controlled RCTs. Psychother Psychosom 2023; 92:304–314.

Depression and anxiety disorders CHAPTER 3 11. Dos Santos Fernandes F, et al. Rapid response to antidepressants and correlation with response and remission after acute treatment. Journal of Affective Disorders Reports 2024; 16:100725. 12. Taylor MJ, et al. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry 2006; 63:1217–1223. 13. Papakostas GI, et al. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. J Clin Psychopharmacol 2006; 26:56–60. 14. Szegedi A, et al. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry 2009; 70:344–353. 15. Uher R, et al. Early and delayed onset of response to antidepressants in individual trajectories of change during treatment of major depression: a secondary analysis of data from the Genome-Based Therapeutic Drugs for Depression (GENDEP) study. J Clin Psychiatry 2011; 72:1478–1484. 16. Posternak MA, et al. Response rates to fluoxetine in subjects who initially show no improvement. J Clin Psychiatry 2011; 72:949–954. 17. Hieronymus F, et al. A mega-analysis of fixed-dose trials reveals dose-dependency and a rapid onset of action for the antidepressant effect of three selective serotonin reuptake inhibitors. Transl Psychiatry 2016; 6:e834. 18. National Institute for Health and Care Excellence. Depression in adults: treatment and management. NICE Guideline [NG222]. 2022 (last reviewed September 2024, last checked November 2024); https://www.nice.org.uk/guidance/ng222. 19. Cipriani A, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009; 373:746–758. 20. Gartlehner G, et al. Comparative benefits and harms of second-generation antidepressants: background paper for the American College of Physicians. Ann Intern Med 2008; 149:734–750. 21. Pillinger T, et al. Antidepressant and antipsychotic side-effects and personalised prescribing: a systematic review and digital tool development. Lancet Psychiatry 2023; 10:860–876. 22. Flanagan RJ. Fatal toxicity of drugs used in psychiatry. Hum Psychopharmacol 2008; 23 Suppl 1:43–51. 23. Kelly CM, et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ 2010; 340:c693. 24. Stone M, et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ 2009; 339:b2880. 25. Carpenter DJ, et al. Meta-analysis of efficacy and treatment-emergent suicidality in adults by psychiatric indication and age subgroup following initiation of paroxetine therapy: a complete set of randomized placebo-controlled trials. J Clin Psychiatry 2011; 72:1503–1514. 26. Barbui C, et al. Selective serotonin reuptake inhibitors and risk of suicide: a systematic review of observational studies. CMAJ 2009; 180:291–297. 27. Umetsu R, et al. Association between selective serotonin reuptake inhibitor therapy and suicidality: analysis of U.S. Food and Drug Administration adverse event reporting system data. Biol Pharm Bull 2015; 38:1689–1699. 28. Coupland C, et al. Antidepressant use and risk of suicide and attempted suicide or self harm in people aged 20 to 64: cohort study using a primary care database. BMJ 2015; 350:h517. 29. Hedna K, et al. Antidepressants and suicidal behaviour in late life: a prospective population-based study of use patterns in new users aged 75 and above. Eur J Clin Pharmacol 2018; 74:201–208. 30. Schneeweiss S, et al. Variation in the risk of suicide attempts and completed suicides by antidepressant agent in adults: a propensity score- adjusted analysis of 9 years’ data. Arch Gen Psychiatry 2010; 67:497–506. 31. Isacsson G, et al. The increased use of antidepressants has contributed to the worldwide reduction in suicide rates. Br J Psychiatry 2010; 196:429–433. 32. Gibbons RD, et al. Suicidal thoughts and behavior with antidepressant treatment: reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine. Arch Gen Psychiatry 2012; 69:580–587. 33. Lu CY, et al. Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi- experimental study. BMJ 2014; 348:g3596. 34. Isacsson G, et al. Antidepressant medication prevents suicide in depression. Acta Psychiatr Scand 2010; 122:454–460. 35. Simon GE, et al. Suicide risk during antidepressant treatment. Am J Psychiatry 2006; 163:41–47. 36. Mulder RT, et al. Antidepressant treatment is associated with a reduction in suicidal ideation and suicide attempts. Acta Psychiatr Scand 2008; 118:116–122. 37. Tondo L, et al. Suicidal status during antidepressant treatment in 789 Sardinian patients with major affective disorder. Acta Psychiatr Scand 2008; 118:106–115. 38. Perlis RH, et al. Do suicidal thoughts or behaviors recur during a second antidepressant treatment trial? J Clin Psychiatry 2012; 73:1439–1442. 39. Larsson J. Antidepressants and suicide among young women in Sweden 1999–2013. Int J Risk Saf Med 2017; 29:101–106. 40. Spielmans GI, et al. Duty to warn: antidepressant black box suicidality warning is empirically justified. Front Psychiatry 2020; 11:18. 41. Chen CC, et al. Acute effects of intravenous sub-anesthetic doses of ketamine and intranasal inhaled esketamine on suicidal ideation: a systematic review and meta-analysis. Neuropsychiatr Dis Treat 2023; 19:587–599. 42. Hawton K, et al. Toxicity of antidepressants: rates of suicide relative to prescribing and non-fatal overdose. Br J Psychiatry 2010; 196:354–358. 43. Lewis G, et al. Maintenance or discontinuation of antidepressants in primary care. N Engl J Med 2021; 385:1257–1267. 44. Fava GA. May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance. Ther Adv Psychopharmacol 2020; 10:2045125320970325.

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Hypnotic effect

Depression and anxiety disorders CHAPTER 3 Use in depression Benzodiazepines are not a treatment for major depressive illness. The only meta-analysis conducted found no advantage for benzodiazepines over placebo in depression.20 However, there is some evidence that benzodiazepines may be helpful in preventing relapse of psychotic depression.21 Combining benzodiazepines with antidepressants during the early phase of antidepressant treatment (1–4 weeks) may improve depression to a greater extent than antidepressants alone.22 This improvement is not maintened with longer-term treatment.22 In the UK, the National Service Framework for Mental Health23 at one time emphasised this point by including a requirement that GPs audit the ratio of benzodiazepines to antidepressants prescribed in their practice. NICE suggests that a benzodiazepine may be helpful for up to 2 weeks early in treatment, particularly in combination with an SSRI (to help with sleep and the management of SSRI-induced agitation).7 Use beyond this timeframe is discouraged. Limiting initial supply quantities to short periods (1–7 days) may reduce the risk of patients becoming long-term users of benzodiazepines.24 Use in psychosis Benzodiazepines are commonly used for rapid tranquillisation, either alone or in combination with an antipsychotic.25 However, a Cochrane review concluded that there is no convincing evidence that combining an antipsychotic and a benzodiazepine offers any advantage over the use of antipsychotics or benzodiazepines alone.26 A further Cochrane review in schizophrenia concluded that there are no proven benefits, outside short-term sedation.27 In contrast, another systematic review using different outcome measures found superiority over placebo for global, psychiatric and behavioural outcomes, but inferiority to antipsychotics on longer-term global outcomes.28 A significant minority of patients with established psychotic illness fail to respond adequately to antipsychotics alone, and this can result in benzodiazepines being prescribed on a chronic basis.29 There is, however, no evidence to support benzodiazepine augmentation of antipsychotics in schizophrenia and use should be reserved for the short-term sedation of acutely agitated patients.30 Evidence supporting the use of benzodiazepines in tardive dyskinesia is weak31 but these drugs remain a treatment option in this condition. Adverse effects Headaches, confusion, ataxia, dysarthria, blurred vision, GI disturbances, jaundice and paradoxical excitement are all possible adverse effects. Benzodiazepines impair cognition, and long-term use has been associated with a range of cognitive deficits (e.g. memory, attention and processing speed), which may persist after withdrawal.32,33 The use of benzodiazepines has been associated with at least a 50% increase in the risk of hip fracture in the elderly.34 This is probably because benzodiazepines increase the risk of falls. Benzodiazepines often cause anterograde amnesia and can adversely affect driving performance.35,36 Benzodiazepines can also cause disinhibition (see section on benzodiazepines and disinhibition in this chapter). Benzodiazepines have been linked to aggressive behaviour, although the association is modest and possibly related to dose and personality factors.37

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Use in depression

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Use in psychosis

462 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Epidemiological research has linked benzodiazepine prescribing to serious medical conditions including dementia, infections and cancer.38–41 However, a causal relationship has not been established and evidence is conflicting.39,41 All studies in this area are confounded by the failure to include illicit use of benzodiazepines. Respiratory depression is rare with oral therapy but is possible when parenteral routes are used.25 Buccal and intranasal administration may also cause respiratory depression.42,43 The use of the specific benzodiazepine antagonist flumazenil is effective in reversing respiratory25 depression but is not without risk (e.g. convulsions and arrhythmia, particularly in mixed overdoses with TCAs) so selective use is recommended.44 Flumazenil has a much shorter half-life than many benzodiazepines, making close observation of the patient essential for several hours after administration. Intravenous injections of benzodiazepine can be painful and can lead to thrombophlebitis because of the low water solubility of benzodiazepines, so it is necessary to use solvents in the preparation of injectable forms. Diazepam is available in emulsion form (Diazemuls® in the UK) to overcome these problems. Drug interactions Benzodiazepines do not induce microsomal enzymes and so do not frequently precipitate pharmacokinetic interactions with any other drugs. Most benzodiazepines are metabolised by CYP3A4, which is inhibited by erythromycin, several SSRIs and ketoconazole. It is theoretically possible that co-administration of these drugs will result in higher serum levels of benzodiazepines. Pharmacodynamic interactions (usually increased sedation) can occur. Benzodiazepines are associated with an important interaction with methadone (see Chapter 5) and should be used with caution in patients prescribed clozapine (increased risk of cardiopulmonary depression) and not at all with intramuscular olanzapine. References

Demyttenaere K, et al. Clinical factors influencing the prescription of antidepressants and benzodiazepines: results from the European study of the epidemiology of mental disorders (ESEMeD). J Affect Disord 2008; 110:84–93.
Maust DT, et al. Benzodiazepine use and misuse among adults in the United States. Psychiatr Serv 2019; 70:97–106.
Hirschtritt ME, et al. Balancing the risks and benefits of benzodiazepines. JAMA 2021; 325:347–348.
Slee A, et al. Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis. Lancet 2019; 393:768–777.
Kurko TA, et al. Long-term use of benzodiazepines: definitions, prevalence and usage patterns – a systematic review of register-based studies. Eur Psychiatry 2015; 30:1037–1047.
Brandt J, et al. Prescribing and deprescribing guidance for benzodiazepine and benzodiazepine receptor agonist use in adults with depression, anxiety, and insomnia: an international scoping review. EClinicalMedicine 2024; 70:102507.
National Institute for Health and Care Excellence. Generalised anxiety disorder and panic disorder in adults: management. Clinical guideline [CG113]. 2011 (last updated 2020, last reviewed May 2024); https://www.nice.org.uk/guidance/cg113.
Williams T, et al. Pharmacotherapy for social anxiety disorder (SAnD). Cochrane Database Syst Rev 2017; 10:CD001206.
Guaiana G, et al. Pharmacological treatments in panic disorder in adults: a network meta-analysis. Cochrane Database Syst Rev 2023; 11:CD012729.
Breilmann J, et al. Benzodiazepines versus placebo for panic disorder in adults. Cochrane Database Syst Rev 2019; 3:CD010677.
Bighelli I, et al. Antidepressants and benzodiazepines for panic disorder in adults. Cochrane Database Syst Rev 2016; 9:CD011567.
Campos B, et al. To BDZ or not to BDZ? That is the question! Is there reliable scientific evidence for or against using benzodiazepines in the aftermath of potentially traumatic events for the prevention of PTSD? A systematic review and meta-analysis. J Psychopharmacol 2022; 36:449–459.
Guina J, et al. Benzodiazepines for PTSD: a systematic review and meta-analysis. J Psychiatr Pract 2015; 21:281–303.
Guina J, et al. Benzodiazepines I: upping the care on downers: the evidence of risks, benefits and alternatives. J Clin Med 2018; 7:17.

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Adverse effects

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Drug interactions

Depression and anxiety disorders CHAPTER 3 15. Roehrs T, et al. Drug-related sleep stage changes: functional significance and clinical relevance. Sleep Med Clin 2010; 5:559–570. 16. Yue JL, et al. Efficacy and tolerability of pharmacological treatments for insomnia in adults: a systematic review and network meta-analysis. Sleep Med Rev 2023; 68:101746. 17. Wilson S, et al. British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders: an update. J Psychopharmacol 2019; 33:923–947. 18. Hallahan BP, et al. Benzodiazepine and hypnotic prescribing in an acute adult psychiatric in-patient unit. Psychiatr Bull 2009; 33:12–14. 19. Mahomed R, et al. Prescribing hypnotics in a mental health trust: what consultants say and what they do. Pharmaceutical J 2002; 268:657–659. 20. Benasi G, et al. Benzodiazepines as a monotherapy in depressive disorders: a systematic review. Psychother Psychosom 2018; 87:65–74. 21. Shiwaku H, et al. Benzodiazepines reduce relapse and recurrence rates in patients with psychotic depression. J Clin Med 2020; 9:1938. 22. Ogawa Y, et al. Antidepressants plus benzodiazepines for adults with major depression. Cochrane Database Syst Rev 2019; 6:CD001026. 23. Department of Health and Social Care. A National Service Framework for Mental Health: Modern standards and service models. London: DHSC; 1999 (last accessed February 2025); https://www.gov.uk/government/publications/quality-standards-for-mental-health-services. 24. Bushnell GA, et al. Simultaneous antidepressant and benzodiazepine new use and subsequent long-term benzodiazepine use in adults with depression, United States, 2001–2014. JAMA Psychiatry 2017; 74:747–755. 25. Patel MX, et al. Joint BAP NAPICU evidence-based consensus guidelines for the clinical management of acute disturbance: de-escalation and rapid tranquillisation. J Psychopharmacol 2018; 32:601–640. 26. Zaman H, et al. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev 2017; 12:CD003079. 27. Dold M, et al. Benzodiazepines for schizophrenia. Cochrane Database Syst Rev 2012; 11:CD006391. 28. Sim F, et al. Re-examining the role of benzodiazepines in the treatment of schizophrenia: a systematic review. J Psychopharmacol 2015; 29:212–223. 29. Paton C, et al. Benzodiazepines in schizophrenia. Is there a trend towards long-term prescribing? Psychiatr Bull 2000; 24:113–115. 30. Dold M, et al. Benzodiazepine augmentation of antipsychotic drugs in schizophrenia: a meta-analysis and Cochrane review of randomized controlled trials. Eur Neuropsychopharmacol 2013; 23:1023–1033. 31. Bergman H, et al. Benzodiazepines for antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev 2018; 1:CD000205. 32. Huff C, et al. Enduring neurological sequelae of benzodiazepine use: an Internet survey. Ther Adv Psychopharmacol 2023; 13:20451253221145561. 33. Crowe SF, et al. The residual medium and long-term cognitive effects of benzodiazepine use: an updated meta-analysis. Arch Clin Neuropsychol 2017; 33:901–911. 34. Poly TN, et al. Association between benzodiazepines use and risk of hip fracture in the elderly people: a meta-analysis of observational studies. Joint Bone Spine 2020; 87:241–249. 35. Barbone F, et al. Association of road-traffic accidents with benzodiazepine use. Lancet 1998; 352:1331–1336. 36. Rudisill TM, et al. Medication use and the risk of motor vehicle collisions among licensed drivers: a systematic review. Accid Anal Prev 2016; 96:255–270. 37. Albrecht B, et al. Benzodiazepine use and aggressive behaviour: a systematic review. Aust N Z J Psychiatry 2014; 48:1096–1114. 38. Kim DH, et al. Use of hypnotics and risk of cancer: a meta-analysis of observational studies. Korean J Fam Med 2018; 39:211–218. 39. Brandt J, et al. Benzodiazepines and Z-drugs: an updated review of major adverse outcomes reported on in epidemiologic research. Drugs R D 2017; 17:493–507. 40. Peng TR, et al. Hypnotics and risk of cancer: a meta-analysis of observational studies. Medicina (Kaunas) 2020; 56:513. 41. Wu CC, et al. Benzodiazepine use and the risk of dementia in the elderly population: an umbrella review of meta-analyses. J Pers Med 2023; 13:1485. 42. Mula M. The safety and tolerability of intranasal midazolam in epilepsy. Expert Rev Neurother 2014; 14:735–740. 43. Midazolam oral transmucosal route: an alternative to rectal diazepam for some children. Prescrire Int 2013; 22:173–177. 44. Penninga EI, et al. Adverse events associated with flumazenil treatment for the management of suspected benzodiazepine intoxication: a systematic review with meta-analyses of randomised trials. Basic Clin Pharmacol Toxicol 2016; 118:37–44.

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References

464 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Benzodiazepines, z-drugs and gabapentinoids: dependence, withdrawal effects and discontinuation In most developed countries, the use of benzodiazepines or z-drugs is restricted to a maximum 2–4 weeks.1–3 However, long-term use remains common in the UK, with 300,000 adults taking either a benzodiazepine or z-drug for more than 12 months.4 Most guidelines, including NICE in the UK, recommend that people on long-term benzodiazepines or z-drugs should be advised to stop because of tolerance to these drugs (which can develop after 2–4 weeks) because physical dependence (distinct from addiction) is likely to develop, and because of numerous adverse effects (Box 3.11).5 Gabapentinoids (GABA analogues) can also cause addiction, physical dependence and withdrawal over the same period.6–8 In total, 1.5 million people in England are prescribed gabapentinoids,9 and the number of prescriptions for these medications rose seven-fold between 2010 and 2020.10 Further details on withdrawal effects and safe deprescribing of these drug classes are outlined in the companion to this text, the Maudsley Deprescribing Guidelines: Antidepressants, Benzodiazepines, Gabapentinoids and Z-drugs.11 Physical dependence on these classes of drugs does not require misuse, abuse or addiction but simply repeated exposure.12 The vast majority of people who experience withdrawal effects are taking drugs as prescribed by their physician (so-called ‘iatrogenic dependence’). This is distinct from addiction, which involves craving and compulsion, and can be associated with misuse and abuse, occurring only in 2% of patients.12 Box 3.11 Adverse effects of benzodiazepines Emotional13 Reactions which can be mistaken for a psychiatric disorder14 ■ ■Depression/dysphoria ■ ■Numbness/emotional anaesthesia ■ ■Anxiety/phobias/panic ■ ■Anger/irritability/mood lability ■ ■Excitement/euphoria ■ ■Agitation ■ ■Emotional lability ■ ■Restlessness ■ ■Inter-dose withdrawal Physical13 Cognitive*15–17 ■ ■Motor incoordination/ataxia ■ ■Dizziness ■ ■Slurred speech ■ ■Sensory alterations (tinnitus/strange tastes/ paraesthesia/numbness/burning) ■ ■Rash ■ ■Autonomic dysfunction (tachycardia/bradycardia/ diaphoresis/hypotension/hypertension) ■ ■Deficits in memory ■ ■Deficits in attention ■ ■Increased reaction time ■ ■Motor incoordination ■ ■Drowsiness ■ ■Nightmares/intrusive thoughts ■ ■Impaired judgement ■ ■Perceptual illusions/hallucinations Increased morbidity16,17 Behavioural13 ■ ■Increased risk of motor vehicle accidents ■ ■Higher risk of falls (elderly) ■ ■Delirium (elderly) ■ ■? Dementia ■ ■? Cancer ■ ■? Infections ■ ■Insomnia ■ ■Avoidance/agoraphobia ■ ■Appetite/weight (anorexia, weight gain) ■ ■Impulsivity/disinhibition ■ ■Suicidality ■ ■Aggression * Some of these impairments can persist after discontinuation.

Depression and anxiety disorders CHAPTER 3 Long-term use of benzodiazepines is associated with a number of problems (Box 3.10). Patients may be unaware of problems and may only appreciate the issue after stopping the drug.18 Long-term z-drug use is associated with similar risks.19 Gabapentinoids have been linked to increased risk of suicide, unintentional overdose, road traffic accidents, and head and body injuries,20 suggesting that limitation of their long-term use may be prudent. Withdrawal symptoms Stopping these medications is often difficult (Box 3.12). One study found that 90% of patients experience withdrawal symptoms on stopping benzodiazepines, with 32% of people on long half-life benzodiazepines and 42% of people on short half-life benzodiazepines unable to cease their medication because of withdrawal symptoms.21 Short- acting drugs such as lorazepam are associated with more severe problems on withdrawal than longer-acting drugs such as diazepam.22,23 As these drugs are somewhat ineffective for anxiety and insomnia in the long term, symptoms that arise on stopping are perhaps just as likely to be withdrawal symptoms as opposed to relapse (though symptoms can be similar).24 Mental state often improves after withdrawal symptoms abate.25 Some of the worst consequences of benzodiazepine withdrawal are akathisia and new-onset suicidality, which are poorly recognised and often misdiagnosed.11 Withdrawal symptoms can last days or weeks but, for some people, they can last longer than a year, especially in the case of long-term use,22,25 as highlighted by an FDA black box warning.26 This is called a ‘protracted withdrawal syndrome’.27 The long- lasting effects on the nervous system, months or years after stopping benzodiazepines, have been termed ‘benzodiazepine-induced neural dysfunction’.28 Box 3.12 Withdrawal effects from benzodiazepines29,30 Physical Psychological ■ ■Stiffness ■ ■Fatigue and weakness ■ ■GI disturbance ■ ■Paraesthesia ■ ■Flu-like symptoms ■ ■Visual disturbances ■ ■Sensory hypersensitivity ■ ■Convulsions* ■ ■Cognitive impairment ■ ■Impaired memory ■ ■Tremor ■ ■Dizziness ■ ■Muscle spasms/cramps ■ ■Chest pain ■ ■Hypertension ■ ■Tachycardia ■ ■Photophobia ■ ■Confusion, delirium* ■ ■Akathisia ■ ■Anxiety/insomnia ■ ■Terror/panic attacks ■ ■Nightmares ■ ■Depersonalisation/derealisation ■ ■Delusions and hallucinations ■ ■Depression ■ ■Psychosis* ■ ■Mood instability ■ ■Paranoia ■ ■Obsessive-compulsive symptoms ■ ■Suicidal ideation ■ ■Mania * Usually only from very rapid withdrawal.

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Benzodiazepines, z-drugs and gabapentinoids: dependence, withdrawal effects and discontinuation

466 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Stopping benzodiazepines If the patient is in agreement, benzodiazepines should be withdrawn. Tapering can be difficult and should not be imposed on a patient against their will. A cluster randomised trial supports the effectiveness of a face-to-face educational intervention.31 Continuing support can be required to prepare a patient for withdrawal and to support them through the process (e.g. psychological therapies or self-help groups).32 Dosage reduction (tapering) Gradual reduction of benzodiazepine dose reduces the intensity of withdrawal symptoms by giving time for neural adaptations to the drug to resolve.24 Meta-analysis has confirmed that gradual dose reduction (‘tapering’) improves drug cessation rates compared with routine clinical care.33 Most studies find that a gradual withdrawal over at least 10 weeks is most successful in achieving cessation,34 although many patients will require considerably longer (sometimes several years). Sudden benzodiazepine withdrawal has potentially fatal consequences, so tapering is always advisable. Direct taper or switching to diazepam? Patients who take short- or intermediate-acting benzodiazepines can be tapered off these drugs directly but more than once-a-day dosing might be required. An alternative approach is to switch to an equivalent dose of diazepam, which has a long half-life and therefore might provoke less severe withdrawal.22,29 Some patients report withdrawal symptoms from abrupt switches to diazepam and so a stepwise switch is probably prudent. Cochrane is lukewarm about switching to diazepam.34 Approximate ‘diazepam equivalent’35 doses are shown in Table 3.24. Owing to individual differences some patients may require more or less diazepam to control withdrawal symptoms. The list in Table 3.24 is an approximate guide only and adjustments should be made to manage withdrawal symptoms for the individual.11 Extra precautions apply in Table 3.24 Approximate ‘diazepam equivalent’ doses.35 Drug Dose Chlordiazepoxide 25mg Clonazepam 0.5mg Diazepam 10mg Lorazepam 1mg Lormetazepam 1–2mg Nitrazepam 10mg Oxazepam 20mg Temazepam 20mg

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Withdrawal symptoms

Depression and anxiety disorders CHAPTER 3 patients with hepatic dysfunction, as diazepam and other longer-acting drugs may accumulate to toxic levels. Pattern of tapering The relationship between dose of benzodiazepines and their effect on their principal target, the GABA-A receptor, is hyperbolic, as dictated by the law of mass action, with the following implications: ■ ■Reducing dose by fixed amounts (e.g. 12.5mg in Figure 3.5a) will give rise to increasingly large reductions in GABA-A occupancy. ■ ■This is consistent with clinical observation that withdrawal symptoms are non- linearly related to dose reduction (e.g. a 1mg reduction of diazepam is tolerable from 20mg but intolerable from 5mg).36 ■ ■Reducing the diazepam dose by 5mg from 50mg will cause a reduction of 2.3 percentage points of GABA-A occupancy, but a 5mg reduction from 5mg will cause a reduction of 18.3 percentage points. In order to reduce the dose of benzodiazepines by equal amounts of effect at their major target, hyperbolically reducing doses are required (Figure 3.5b): ■ ■This means that the size of dose reductions should be smaller and smaller as the total dose gets smaller. ■ ■In practice, these reductions can be most easily calculated based on a proportion of the most recent dose (an exponential pattern): for example, reductions of 10% of the most recent dose every month (so that reductions become smaller and smaller as total dose reduces). Final doses before complete cessation may need to be very small (e.g. less than 1mg of diazepam equivalent). (a) (b) GABA-A occupancy (%) 40 0 50 Diazepam dose (mg) 100 GABA-A occupancy (%) 40 0 50 Diazepam dose (mg) Figure 3.5 (a) Linear reductions of dose cause increasingly large reductions in effect on GABA-A receptor occupancy. (b) Reducing effect on GABA-A receptors by even amounts requires hyperbolically reducing doses of diazepam. Note how small the final doses will be required to be to prevent too large a final ‘step down’. Source: Adapted from Brouillet et al. (1991).37

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Stopping benzodiazepines

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Dosage reduction (tapering)

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Recognised minimum effective doses of antidepressants

342 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Recognised minimum effective doses of antidepressants The recommended minimum effective doses of antidepressants are summarised in Table 3.2. Table 3.2 Recommended minimum effective doses of antidepressants. Antidepressant Dose Tricyclics Unclear; at least 75–100mg/day1, possibly 125mg/day2 Lofepramine 140mg/day3 SSRIs Citalopram 20mg/day4 Escitalopram 10mg/day5 Fluoxetine 20mg/day6 Fluvoxamine 50mg/day7 Paroxetine 20mg/day8 Sertraline 50mg/day9 Others Agomelatine 25mg/day10 Bupropion 150mg/day11 Desvenlafaxine 50mg/day12 Dextromethorphan plus bupropion 45/105mg/day13 Duloxetine 60mg/day14,15 Gepirone 20mg/day16 Levomilnacipran 40mg/day17 Mirtazapine 30mg/day (15mg?18) Moclobemide 300mg/day19 Reboxetine 8mg/day20 Trazodone 150mg/day21 Venlafaxine 75mg/day22 Vilazodone 20mg/day17 Vortioxetine 10mg/day17

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Direct taper or switching to diazepam?

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Pattern of tapering

468 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Practical application of these principles Before tapering ■ ■All patients should be informed of the risk of withdrawal symptoms on stopping any benzodiazepine, z-drug or gabapentinoid. ■ ■The patient should be warned not to stop benzodiazepines abruptly, because this can cause seizures and can be fatal, and may be the method most likely to give rise to severe and long-lasting withdrawal symptoms. ■ ■Although stopping benzodiazepines can cause unpleasant symptoms, if tapering is gradual and careful the process can be tolerable. Reassurance may be required for those that have rapidly tapered in the past. ■ ■Most long-term users take months or years to taper. However, rate of reduction should be determined by what is tolerable for the patient, not externally imposed timetables. ■ ■Preparation for benzodiazepine tapering may be required (e.g. lightening work or family duties or bolstering of non-pharmacological coping skills).32,38 ■ ■Gradual dose reduction is the most evidenced approach to cessation, with weaker evidence for adjunctive psychological interventions (relaxation, CBT).33 ■ ■Familiarity with the wide variety of withdrawal symptoms may help to mitigate unnecessary anxiety when symptoms arise. The process of tapering ■ ■Reductions in dosing for patients may be broadly risk stratified: ■ ■for low-risk patients (<6 months’ use, long half-life benzodiazepine, no experience of significant withdrawal in the past), a test reduction could be made of 10–20% ■ ■for high-risk patients (>6 months use, short half-life benzodiazepine, past history of withdrawal symptoms), a test reduction of 5–10% could be recommended. ■ ■Reductions should be made according to a proportion (e.g. 10%) of the last dose. This means that the reductions recommended will become smaller and smaller as the total dose is lowered. Most long-term users will be able to proceed between a rate of about 5–10% of their most recent dose per month (or perhaps more quickly). ■ ■After reduction withdrawal symptoms should be monitored for 2–4 weeks, or until symptoms have resolved. Monitoring may take the form of simple measures of symptoms each day (e.g. out of 10) or using standardised benzodiazepine withdrawal scales. ■ ■Further reduction should be titrated to the tolerability of this experience. Troubleshooting ■ ■If significant withdrawal symptoms emerge at any point, either hold the current dose to allow symptoms to resolve or, if that is intolerable, increase to the last dose at which the symptoms were tolerable and remain there until symptoms resolve. After stabilisation, tapering will need to be more gradual, with reductions being made in smaller amounts. ■ ■The experience of distressing withdrawal symptoms does not necessarily indicate that a patient cannot stop benzodiazepines but that they will need to taper more slowly,

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Practical application of these principles

Depression and anxiety disorders CHAPTER 3 with smaller reductions than they have been undertaking (some need to taper at less than 5% of the most recent dose per month). ■ ■At very small doses, liquid formulations or specially compounded formulations may be required to allow small reductions.11 Off-label options such as crushing and suspending tablets are sometimes used.11 ■ ■Final doses before completely stopping the drug for some people will need to be very small to avoid a larger reduction in effect on the brain (e.g. as low as 0.1mg of diazepam).11 Further details of this process are provided in the Maudsley Deprescribing Guidelines.11 Reduction schedules A guide to diazepam dose reductions: ■ ■Reduce by 5–10mg/day every 2–4 weeks, down to a daily dose of 50mg. ■ ■Reduce by 2–5mg/day every 2–4 weeks, down to a daily dose of 20mg. ■ ■Reduce by 1–2mg/day every 2–4 weeks, down to a daily dose of 10mg. ■ ■Reduce by 0.5–1mg/day every 2–4 weeks, down to a daily dose of 5mg. ■ ■Reduce by 0.25–0.5mg/day every 2–4 weeks, down to a daily dose of 2.5mg. ■ ■Reduce by 0.1–0.25mg/day every 2–4 weeks until stopped. Tapering other drug classes The same principles apply to tapering z-drugs or gabapentinoids. Gabapentinoids can cause severe withdrawal effects, although there is wide inter-individual variation. Tolerance and withdrawal are reported, even after brief or intermittent use for z-drugs as well.39,40 Tapering according to a similar exponential scheme may be required for cessation. Again, specific reduction schedules for all licensed benzodiazepines, gabapentinoids and z-drugs are provided in the Maudsley Deprescribing Guidelines.11 References

National Institute for Health and Care Excellence. British National Formulary. 2024; https://bnf.nice.org.uk.
National Institute for Health and Care Excellence. Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia. Technical Appraisal [TA77]. 2004 (reviewed August 2010, last checked July 2024); https://www.nice.org.uk/guidance/ta77.
National Institute for Health and Care Excellence. Generalised anxiety disorder and panic disorder in adults: management. Clinical guideline [CG113]. 2011 (last updated June 2020, last checked July 2024); https://www.nice.org.uk/guidance/cg113.
Davies J, et al. Long-term benzodiazepine and Z-drugs use in the UK: a survey of general practice. Br J Gen Pract 2017; 67:e609–e613.
National Institute for Health and Care Excellence. Benzodiazepine and z-drug withdrawal. 2024 (last accessed July 2024); https://cks.nice. org.uk/topics/benzodiazepine-z-drug-withdrawal.
Schifano F, et al. An insight into z-drug abuse and dependence: an examination of reports to the European Medicines Agency Database of Suspected Adverse Drug Reactions. Int J Neuropsychopharmacol 2019; 22:270–277.
Evoy KE, et al. Abuse and misuse of pregabalin and gabapentin. Drugs 2017; 77:403–426.
Public Health England. Advice for prescribers on the risk of the misuse of pregabalin and gabapentin. 2014 (last accessed July 2024); https:// assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/385791/PHE-NHS_England_pregabalin_and_ gabapentin_advice_Dec_2014.pdf.
Marsden J, et al. Medicines associated with dependence or withdrawal: a mixed-methods public health review and national database study in England. Lancet Psychiatry 2019; 6:935–950.
Public Health England. Research and Analysis. Prescribed Medicines Review: Report. 2020 (last accessed July 2024); https://www.gov.uk/ government/publications/prescribed-medicines-review-report.

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Troubleshooting

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Reduction schedules

470 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 11. Horowitz M, et al. The Maudsley Deprescribing Guidelines: Antidepressants, Benzodiazepines, Gabapentinoids and Z-drugs. Oxford: Wiley- Blackwell; 2024. 12. Horowitz MA, et al. Addiction and physical dependence are not the same thing. Lancet Psychiatry 2023; 10:e23. 13. Guina J, et al. Benzodiazepines I: upping the care on downers: the evidence of risks, benefits and alternatives. J Clin Med 2018; 7:17. 14. Gutierrez MA, et al. Paradoxical reactions to benzodiazepines. Am J Nurs 2001; 101:34–40. 15. Crowe SF, et al. The residual medium and long-term cognitive effects of benzodiazepine use: an updated meta-analysis. Arch Clin Neuropsychol 2017; 33:901–911. 16. Brandt J, et al. Benzodiazepines and z-drugs: an updated review of major adverse outcomes reported on in epidemiologic research. Drugs R D 2017; 17:493–507. 17. Donnelly K, et al. Benzodiazepines, z-drugs and the risk of hip fracture: a systematic review and meta-analysis. PLoS One 2017; 12:e0174730. 18. Golombok S, et al. Cognitive impairment in long-term benzodiazepine users. Psychol Med 1988; 18:365–374. 19. Finkle WD, et al. Risk of fractures requiring hospitalization after an initial prescription for zolpidem, alprazolam, lorazepam, or diazepam in older adults. J Am Geriatr Soc 2011; 59:1883–1890. 20. Molero Y, et al. Associations between gabapentinoids and suicidal behaviour, unintentional overdoses, injuries, road traffic incidents, and violent crime: population based cohort study in Sweden. BMJ 2019; 365:l2147. 21. Schweizer E, et al. Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper. Arch Gen Psychiatry 1990; 47:908–915. 22. Schweizer E, et al. Benzodiazepine dependence and withdrawal: a review of the syndrome and its clinical management. Acta Psychiatr Scand 1998; 98 Suppl 393:95–101. 23. Uhlenhuth EH, et al. International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: IV. Therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders. J Clin Psychopharmacol 1999; 19:23S–29S. 24. Ashton H. The diagnosis and management of benzodiazepine dependence. Curr Opin Psychiatry 2005; 18:249–255. 25. Ashton H. Benzodiazepine withdrawal: outcome in 50 patients. Br J Addict 1987; 82:665–671. 26. US Food and Drug Administration. FDA requiring boxed warning updated to improve safe use of benzodiazepine drug class: includes potential for abuse, addiction, and other serious risks 2020 (last accessed July 2024); https://www.fda.gov/drugs/drug-safety-and-availability/ fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class#:~:text=FDA. 27. Ashton H. Protracted withdrawal from benzodiazepines: the post-withdrawal syndrome. Psychiatr Ann 1995; 1:174–179. 28. Ritvo AD, et al. Long-term consequences of benzodiazepine-induced neurological dysfunction: a survey. PLoS One 2023; 18:e0285584. 29. Soyka M. Treatment of benzodiazepine dependence. N Engl J Med 2017; 376:1147–1157. 30. Petursson H. The benzodiazepine withdrawal syndrome. Addiction 1994; 89:1455–1459. 31. Tannenbaum C, et al. Reduction of inappropriate benzodiazepine prescriptions among older adults through direct patient education: the EMPOWER cluster randomized trial. JAMA Intern Med 2014; 174:890–898. 32. Guy. A, et al. Guidance for Psychological Therapists: Enabling Conversations with Clients Taking or Withdrawing from Prescribed Psychiatric Drugs. London: APPG for Prescribed Drug Dependence; 2019. 33. Parr JM, et al. Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis. Addiction 2009; 104:13–24. 34. Denis C, et al. Pharmacological interventions for benzodiazepine mono-dependence management in outpatient settings. Cochrane Database Syst Rev 2006; (3):CD005194. 35. Ashton H. Benzodiazepines: How They Work and How to Withdraw. 2002 (last accessed February 2025); http://www.benzo.org.uk/manual/ bzcha01.htm. 36. Ashton H. Benzodiazepine dependence. Adverse syndromes and psychiatric drugs. In: Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. Oxford: Oxford University Press; 2004:239–260. 37. Brouillet E, et al. In vivo bidirectional modulatory effect of benzodiazepine receptor ligands on GABAergic transmission evaluated by positron emission tomography in non-human primates. Brain Res 1991; 557:167–176. 38. Inner Compass Initiative Inc. The Withdrawal Project. 2024; https://withdrawal.theinnercompass.org. 39. Pollmann AS, et al. Deprescribing benzodiazepines and Z-drugs in community-dwelling adults: a scoping review. BMC Pharmacol Toxicol 2015; 16:19. 40. Kales A, et al. Rebound insomnia after only brief and intermittent use of rapidly eliminated benzodiazepines. Clin Pharmacol Ther 1991; 49:468–476.

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Tapering other drug classes

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References

Depression and anxiety disorders CHAPTER 3 Benzodiazepines and disinhibition Unexpected increases in aggressive or impulsive behaviour secondary to drug treatment are usually called disinhibitory or paradoxical reactions. These reactions may include acute excitement, hyperactivity, increased anxiety, vivid dreams, sexual disinhibition, aggression, hostility and rage. Examples of causative agents include amfetamines, methylphenidate, benzodiazepines and alcohol. Paradoxical reactions are an important consideration with benzodiazepines because these drugs are used to sedate and tranquillise – a paradoxical reaction is thus the polar opposite of the desired effect. These reactions are also a major problem in general medicine, where drugs such as midazolam are widely used for conscious sedation. In intensive care medicine, benzodiazepine-related disinhibition can be difficult to distinguish from hyperactive delirium.1 How common are disinhibitory reactions with benzodiazepines? The incidence of disinhibitory reactions varies widely depending on the population studied (see ‘Who is at risk?’ below). For example, a meta-analysis of benzodiazepine RCTs that included many hundreds of patients with a wide range of diagnoses reported an incidence of less than 1% (the same as placebo).2 Similarly, an analysis of behavioural disinhibition frequency in a psychiatric unit found no difference between those treated with benzodiazepines and those not.3 However, a Norwegian study that reported on 415 cases of ‘driving under the influence’, in which flunitrazepam was the sole substance implicated, found that 6% of adverse effects could be described as disinhibitory reactions.4 An RCT that recruited patients with panic disorder reported an incidence of disinhibition of 13%.5 Authors of case series (often describing use in high-risk patients) reported rates of 10–20%,2 and an RCT that included patients with borderline personality disorder reported a rate of 58%.6 Most recently, a study of the use of parenteral midazolam for bronchoscopy found that almost 20% of patients exhibited moderate or severe disinhibition.7 Disinhibition is rather problematic to define, so incident rates are correspondingly difficult to determine. Aggression may be considered to be a disinhibition reaction but not defined as disinhibition per se. Aggression is robustly linked to benzodiazepine use both in the long term and after exposure to a single dose.8,9 Other GABA agonists, particularly zolpidem, have also been linked to disinhibition associated with somnambulism, automatism, amnesia and mania.10–13 Who is at risk? Those at risk include people who have learning disabilities, neurological disorders or CNS degenerative diseases,14 those who are young (children or adolescents) or elderly,14–17 have a history of aggression or poor impulse control,6,18 or are at increased risk of experiencing a disinhibitory reaction. The risk is further increased if the benzodiazepine is a high-potency drug (i.e. is active in doses below 1–2mg), has a short half- life, is given in a high dose or is administered intravenously.14,19–21 Some people may be genetically predisposed to disinhibition reactions.22 Combinations of risk factors are clearly important. Low-risk long-acting benzodiazepines may cause disinhibition in high-risk populations such as children;17 higher-risk,

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Benzodiazepines and disinhibition

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How common are disinhibitory reactions with benzodiazepines?

472 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 short-acting drugs given intravenously are extremely likely to cause disinhibition in personality disorder. What is the mechanism? Various theories of the mechanism have been proposed.19,23–25 First, the anxiolytic and amnesic properties of benzodiazepines may lead to a loss of the restraint that governs normal social behaviour. Second, the sedative and amnesic properties of benzodiazepines may lead to a reduced ability to concentrate on the external social cues that guide appropriate behaviour. Last, benzodiazepine-mediated increases in GABA neurotransmission may lead to a reduction in the restraining influence of the cortex, resulting in untrammelled excitement, anxiety and hostility. Flumazenil is usually used to reverse benzodiazepine sedation and respiratory depression, but it is also effective in treating disinhibition reactions.26 Subjective reports People who take benzodiazepines rate themselves as being more tolerant and friendly, but respond more to provocation than patients treated with placebo.27 People with impulse control problems who take benzodiazepines may self-report feelings of power and overwhelming self-esteem.18 Psychology rating scales demonstrate increased suggestibility, failure to recognise anger in others and reduced ability to recognise social cues. The patient is usually completely unaware that their behaviour is bizarre or that it is the result of drug-induced disinhibition. Clinical implications Benzodiazepines are frequently used in rapid tranquillisation and the short-term management of disturbed behaviour. For the vast majority of treatment episodes, benzodiazepines produce sedation and reductions in anxiety and aggression. It is important to be aware, nonetheless, of their propensity to cause paradoxical disinhibitory reactions. Suspected paradoxical reactions should be clearly documented in the clinical notes. In extreme cases, flumazenil can be used to reverse the reaction although its use is not without its own dangers (agitation, arrythmia, convulsions).28 If the benzodiazepine was prescribed to control acute behavioural disturbance, future episodes should be managed with antipsychotic drugs29 or other non-benzodiazepine sedatives. Paradoxical disinhibitory/aggressive outbursts in the context of benzodiazepine use: ■ ■Rare in the general population but more frequent in people with impulse control problems or central nervous system damage and in the very young or very old. ■ ■Most often associated with high oral doses of high-potency drugs or with any dose of any drug administered parenterally. ■ ■Usually occur in response to (often very mild) provocation, the exact nature of which is not always obvious to others. ■ ■Recognised by others but often not by the sufferers, who often believe that they are friendly and tolerant.

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Who is at risk?

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References

Depression and anxiety disorders CHAPTER 3 References

Furukawa TA, et al. Meta-analysis of effects and side effects of low dosage tricyclic antidepressants in depression: systematic review. BMJ 2002; 325:991.
Donoghue J, et al. Suboptimal use of antidepressants in the treatment of depression. CNS Drugs 2000; 13:365–368.
Lancaster SG, et al. Lofepramine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 1989; 37:123–140.
Montgomery SA, et al. The optimal dosing regimen for citalopram: a meta-analysis of nine placebo-controlled studies. Int Clin Psychopharmacol 1994; 9 Suppl 1:35–40.
Burke WJ, et al. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 2002; 63:331–336.
Altamura AC, et al. The evidence for 20mg a day of fluoxetine as the optimal dose in the treatment of depression. Br J Psychiatry Suppl 1988; (3):109–112.
Walczak DD, et al. The oral dose–effect relationship for fluvoxamine: a fixed-dose comparison against placebo in depressed outpatients. Ann Clin Psychiatry 1996; 8:139–151.
Dunner DL, et al. Optimal dose regimen for paroxetine. J Clin Psychiatry 1992; 53 Suppl:21–26.
Moon CAL, et al. A double-blind comparison of sertraline and clomipramine in the treatment of major depressive disorder and associative anxiety in general practice. J Psychopharmacol 1994; 8:171–176.
Loo H, et al. Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol 2002; 17:239–247.
Hewett K, et al. Eight-week, placebo-controlled, double-blind comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR. J Psychopharmacol 2009; 23:531–538.
Kornstein SG, et al. The effect of desvenlafaxine 50 mg/day on a subpopulation of anxious/depressed patients: a pooled analysis of seven randomized, placebo-controlled studies. Hum Psychopharmacol 2014; 29:492–501.
Iosifescu DV, et al. Efficacy and safety of axs-05 (dextromethorphan-bupropion) in patients with major depressive disorder: a phase 3 randomized clinical trial (GEMINI). J Clin Psychiatry 2022; 83:21m14345.
Goldstein DJ, et al. Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine. J Clin Psychopharmacol 2004; 24:389–399.
Detke MJ, et al. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry 2002; 63:308–315.
Phillips B, et al. Gepirone: A new extended–release oral selective serotonin receptor agonist for major depressive disorder. J Pharm Technol 2024; 40:230–235.
He H, et al. Efficacy and tolerability of different doses of three new antidepressants for treating major depressive disorder: a PRISMA- compliant meta-analysis. J Psychiatr Res 2018; 96:247–259.
Furukawa TA, et al. No benefit from flexible titration above minimum licensed dose in prescribing antidepressants for major depression: systematic review. Acta Psychiatr Scand 2020; 141:401–409.
Priest RG, et al. Moclobemide in the treatment of depression. Rev Contemp Pharmacother 1994; 5:35–43.
Schatzberg AF. Clinical efficacy of reboxetine in major depression. J Clin Psychiatry 2000; 61 Suppl 10:31–38.
Brogden RN, et al. Trazodone: a review of its pharmacological properties and therapeutic use in depression and anxiety. Drugs 1981; 21:401–429.
Feighner JP, et al. Efficacy of once-daily venlafaxine extended release (XR) for symptoms of anxiety in depressed outpatients. J Affect Disord 1998; 47:55–62.

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What is the mechanism?

Depression and anxiety disorders CHAPTER 3 References

Schieveld JNM, et al. On benzodiazepines, paradoxical agitation, hyperactive delirium, and chloride homeostasis. Crit Care Med 2018; 46:1558–1559.
Dietch JT, et al. Aggressive dyscontrol in patients treated with benzodiazepines. J Clin Psychiatry 1988; 49:184–188.
Rothschild AJ, et al. Comparison of the frequency of behavioral disinhibition on alprazolam, clonazepam, or no benzodiazepine in hospitalized psychiatric patients. J Clin Psychopharmacol 2000; 20:7–11.
Bramness JG, et al. Flunitrazepam: psychomotor impairment, agitation and paradoxical reactions. Forensic Sci Int 2006; 159:83–91.
O’Sullivan GH, et al. Safety and side-effects of alprazolam: controlled study in agoraphobia with panic disorder. Br J Psychiatry 1994; 165:79–86.
Gardner DL, et al. Alprazolam-induced dyscontrol in borderline personality disorder. Am J Psychiatry 1985; 142:98–100.
Matsumoto T, et al. Prevalence and characteristics of disinhibition during bronchoscopy with midazolam. Respir Investig 2022; 60:345–354.
Albrecht B, et al. Motivational drive and alprazolam misuse: a recipe for aggression? Psychiatry Res 2016; 240:381–389.
Albrecht B, et al. Benzodiazepine use and aggressive behaviour: a systematic review. Aust N Z J Psychiatry 2014; 48:1096–1114.
Sabe M, et al. Zolpidem stimulant effect: induced mania case report and systematic review of cases. Prog Neuropsychopharmacol Biol Psychiatry 2019; 94:109643.
Poceta JS. Zolpidem ingestion, automatisms, and sleep driving: a clinical and legal case series. J Clin Sleep Med 2011; 7:632–638.
Pressman MR. Sleep driving: sleepwalking variant or misuse of z-drugs? Sleep Med Rev 2011; 15:285–292.
Daley C, et al. ‘I did what?’ Zolpidem and the courts. J Am Acad Psychiatry Law 2011; 39:535–542.
Bond AJ. Drug-induced behavioural disinhibition incidence, mechanisms and therapeutic implications. CNS Drugs 1998; 9:41–57.
Hakimi Y, et al. Paradoxical adverse drug reactions: descriptive analysis of French reports. Euro J Clin Pharmacol 2020; 76:1169–1174.
Hawkridge SM, et al. A risk–benefit assessment of pharmacotherapy for anxiety disorders in children and adolescents. Drug Saf 1998; 19:283–297.
Kandemir H, et al. Behavioral disinhibition, suicidal ideation, and self-mutilation related to clonazepam. J Child Adolesc Psychopharmacol 2008; 18:409.
Daderman AM, et al. Flunitrazepam (Rohypnol) abuse in combination with alcohol causes premeditated, grievous violence in male juvenile offenders. J Am Acad Psychiatry Law 1999; 27:83–99.
van der Bijl P, et al. Disinhibitory reactions to benzodiazepines: a review. J Oral Maxillofac Surg 1991; 49:519–523.
McKenzie WS, et al. Paradoxical reaction following administration of a benzodiazepine. J Oral Maxillofac Surg 2010; 68:3034–3036.
Wilson KE, et al. Complications associated with intravenous midazolam sedation in anxious dental patients. Prim Dent Care 2011; 18:161–166.
Short TG, et al. Paradoxical reactions to benzodiazepines: a genetically determined phenomenon? Anaesth Intensive Care 1987; 15:330–331.
Weisman AM, et al. Effects of clorazepate, diazepam, and oxazepam on a laboratory measurement of aggression in men. Int Clin Psychopharmacol 1998; 13:183–188.
Blair RJ, et al. Selective impairment in the recognition of anger induced by diazepam. Psychopharmacology 1999; 147:335–338.
Wallace PS, et al. Reduction of appeasement-related affect as a concomitant of diazepam-induced aggression: evidence for a link between aggression and the expression of self-conscious emotions. Aggress Behav 2009; 35:203–212.
Tae CH, et al. Paradoxical reaction to midazolam in patients undergoing endoscopy under sedation: incidence, risk factors and the effect of flumazenil. Dig Liver Dis 2014; 46:710–715.
Bond AJ, et al. Behavioural aggression in panic disorder after 8 weeks’ treatment with alprazolam. J Affect Disord 1995; 35:117–123.
Penninga EI, et al. Adverse events associated with flumazenil treatment for the management of suspected benzodiazepine intoxication: a systematic review with meta-analyses of randomised trials. Basic Clin Pharmacol Toxicol 2016; 118:37–44.
Paton C. Benzodiazepines and disinhibition: a review. Psychiatr Bull 2002; 26:460–462.

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Subjective reports

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Clinical implications

474 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Premenstrual syndrome Premenstrual syndrome (PMS) is a collection of mood and physical symptoms occurring during the luteal phase of the menstrual cycle. There are several definitions for PMS, which are differentiated by the severity of symptoms required. Premenstrual dysphoric disorder (PMDD), recently added to ICD-11,1 exists at the more severe end of the diagnostic spectrum (see Craig et al. 20192 for review). Pharmacological management of PMDD The pharmacological management of PMDD can be divided into hormonal and non- hormonal treatments (Figure 3.6). Non-hormonal Guidelines published by the Royal College of Obstetricians and Gynaecologists in the UK3 recommend SSRIs as first-line treatment. This is supported by a meta-analysis, which found similar efficacy between different SSRIs.4 Intermittent, luteal phase dosing of SSRIs has been reported to be as effective as continuous prescribing.5 During intermittent dosing, SSRIs appear to directly promote the conversion of progesterone to allopregnanolone (i.e. an allosteric modulator of the GABA-A receptor).6 Hormonal The combined oral contraceptive pill (COCP) is another first-line treatment. It can be prescribed cyclically or back to back (typically for 3 months) to avoid symptoms associated with hormone withdrawal.7 A 2021 meta-analysis reported that COCPs improved overall premenstrual symptomatology but not premenstrual depressive symptoms.8 There is no evidence of one COCP being more efficacious than any other. Diagnosis of PMDD/severe PMS Non-hormonal Hormonal Choice of treatment governed by patient preference Psychiatric and hormonal treatments may be used in conjunction SSRI (continuous or intermittent dosing) Combined oral contraceptive (cyclical or continuous prescribing) Transdermal estradiol + progestogenic protection if patient has uterus GnRH analogue ± addback hormonal treatment Treatment of any comorbid psychiatric disorder Figure 3.6 The pharmacological management of premenstrual dysphoric disorder.

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References

Depression and anxiety disorders CHAPTER 3 If COCPs are ineffective, not tolerated, or contraindicated, a second-line approach is to prescribe continuous percutaneous bioidentical estradiol (i.e. implants or transdermal preparations).9 In patients with a uterus, combination with a progestogen is required to reduce the risk of endometrial hyperplasia. Gonadotrophin-releasing hormone agonists lead to (reversible) medical menopause. This can be used as a diagnostic test for PMDD and/or to determine the likely benefits of a hysterectomy and oophorectomy. Owing to the adverse effects typically associated with acute menopause, an ‘addback’ regime of estradiol alone or combined with a progestogen is required (i.e. dependent on whether the woman has a uterus). References

World Health Organization. International Classification of Diseases, 11th revision. Geneva: WHO; 2024 (last accessed September 2024); https://icd.who.int/en.
Craig M, et al. Diagnosis and management of premenstrual syndrome. Practitioner 2019; 263:15–19.
Green L, et al. Management of premenstrual syndrome. Green-top Guideline No. 48. BJOG 2017; 124:e73–e105.
Marjoribanks J, et al. Selective serotonin reuptake inhibitors for premenstrual syndrome. Cochrane Database Syst Rev 2013; 2013(6):CD001396.
Reilly TJ, et al. Intermittent selective serotonin reuptake inhibitors for premenstrual syndromes: a systematic review and meta-analysis of randomised trials. J Psychopharmacol 2023; 37:261–267.
Hantsoo L, et al. Allopregnanolone in premenstrual dysphoric disorder (PMDD): evidence for dysregulated sensitivity to GABA-A receptor modulating neuroactive steroids across the menstrual cycle. Neurobiol Stress 2020; 12:100213.
Noachtar IA, et al. Mental health symptoms in oral contraceptive users during short-term hormone withdrawal. JAMA Netw Open 2023; 6:e2335957.
de Wit AE, et al. Efficacy of combined oral contraceptives for depressive symptoms and overall symptomatology in premenstrual syndrome: pairwise and network meta-analysis of randomized trials. Am J Obstet Gynecol 2021; 225:624–633.
Naheed B, et al. Non-contraceptive oestrogen-containing preparations for controlling symptoms of premenstrual syndrome. Cochrane Database Syst Rev 2017; 3:CD010503.

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Drug treatment of depression

344 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Drug treatment of depression Drugs used in the treatment of depression are summarised in Figure 3.1. Discuss choice of drug with the patient No effect No effect Effective Effective Poorly tolerated Poorly tolerated or No effect Include: Potential therapeutic effects Possible adverse effects Likelihood of discontinuation symptoms Likely time to respond (good therapeutic alliance predicts response to medication)1 Suggest SSRI as first choice; mirtazapine if sedation required (see notes) Start antidepressant Titrate (if necessary) to recognised therapeutic dose (see Table 3.2 in previous section) Assess efficacy after 2 weeks (see notes) If possible, increase the dose (see notes) Continue for 6–9 months2–4 at full treatment dose Consider longer-term treatment in recurrent depression2–6 Assess over a further 2 weeks No effect Consider third-choice options – mirtazapine9 (if not already used), vortioxetine,10 agomelatine11 No effect Refer to suggested treatments for refractory depression Switch to a different antidepressant (see notes) Titrate to therapeutic dose Assess efficacy over 4 weeks (increase dose at 2 weeks if no effect) Switch to a different antidepressant7,8 Titrate (if necessary) to therapeutic dose. Assess over 3–4 weeks; increase dose as necessary (see notes) Figure 3.1 Drug treatment for depression.

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17 - Notes

Notes

Depression and anxiety disorders CHAPTER 3 Notes ■ ■Tools such as the Montgomery–Asberg Depression Rating Scale (MADRS)12 and the HAM-D13 are used in trials to assess drug effect. The HAM-D is now somewhat anachronistic and few clinicians are familiar with the MADRS (although it is probably the best scale to measure severity and change). The Patient Health Questionnaire-914 is simple to use and is recommended for assessing symptom change in depression (although it better measures frequency rather than severity of symptoms). All rating scales should be treated with caution: someone with an HAM-D score of 30 is not twice as depressed as someone with a score of 15. That is, these scales are not linear and items are not weighted – on most scales insomnia scores more than a suicide attempt. ■ ■Choice of antidepressant is governed largely by patient and clinician preference, but most authorities recommend an SSRI, or mirtazapine where sedation is required. A large network meta-analysis15 suggested that drugs with effects on both norepinephrine and serotonin uptake are the most effective (five of the top six ranked drugs are dual action) whereas agomelatine and SSRIs have the lowest dropout rates. A 2018 network meta-analysis16 of newer antidepressants suggested few, if any, clear advantages over older drugs for levomilnacipran, vilazodone and vortioxetine. ■ ■Assessment at 2 weeks has some utility in determining eventual outcome.17 Only around 30% of those not reaching accepted symptom score threshold for improvement at 2 weeks will ultimately respond. Even fewer people go on to respond if there is no improvement at all or deterioration at 2 weeks. ■ ■Switching between drug classes in cases of poor tolerability is supported by some studies18 and has a strong theoretical basis. Having said that, in practice, many patients who cannot tolerate one SSRI will readily tolerate another. ■ ■In cases of non-response, there is some evidence that switching within a drug class is effective,8,19–22 but switching between classes is, in practice, the most common option and is supported by some analyses.23 The American Psychiatric Association recommends both options.2 The 2022 NICE guidelines9 suggest that there is little cogent evidence for switching between antidepressants (an observation in another analysis24) and that combining antidepressants or adding a second-generation antipsychotic (SGA) are better-supported options at this stage. The strongest evidence in support of switching after the failure of one treatment is probably for vortioxetine.10 The most compelling evidence for combination antidepressants is for an SSRI plus mirtazapine.25 ■ ■There is minimal evidence to recommend increasing the dose of most SSRIs above the minimum therapeutic dose, at least when severity is measured using total rating scale scores.26 Examining only the mood item on the HAM-D suggests some dose–response relationship for SSRIs.27 Other evidence suggests that increasing the dose of venlafaxine, escitalopram and tricyclics may be helpful.3,28 Generally speaking, gains in efficacy afforded by dose increases are small (SSRIs, venlafaxine) or non-existent (e.g. mirtazapine above 30mg/day) while effects on tolerability are reliably and starkly detrimental.29 ■ ■Switch treatments early (e.g. after 1–2 weeks) if adverse effects are intolerable or if no improvement at all is seen after 2–3 weeks. Opinions on when to switch vary somewhat but it is clear that antidepressants have a fairly prompt onset of action30–32 and that non-response at 2–6 weeks is a good predictor of overall non-response.33–35 The absence of any improvement at all by 2–3 weeks should normally provoke a change

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References

346 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 in treatment (British Association for Psychopharmacology guidelines suggest 4 weeks).3 If there is some improvement at this time, continue and assess for a further 2–3 weeks (see section on general overview of antidepressants in this chapter). ■ ■Our algorithm conveniently dichotomises outcome as response or non-response (effective, not effective). Real-life outcomes include partial response – a positive change that falls short of recovery or remission. In those circumstances there is little evidence to guide practice, but the aim should be to achieve remission by means of dose increase and, if unsuccessful, by changing the antidepressant. ■ ■Adjunctive treatments shown to be effective after the failure of only one antidepressant (early-stage treatment resistance) include (es)ketamine, risperidone, lithium and aripiprazole.36 Dextromethorphan may improve initial outcomes if added to SSRI treatment.37 References

Leuchter AF, et al. Role of pill-taking, expectation and therapeutic alliance in the placebo response in clinical trials for major depression. Br J Psychiatry 2014; 205:443–449.
American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder, 3rd edn. Washington, DC: American Psychiatric Association; 2010.
Anderson IM, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol 2008; 22:343–396.
Crismon ML, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999; 60:142–156.
Kocsis JH, et al. Maintenance therapy for chronic depression: a controlled clinical trial of desipramine. Arch Gen Psychiatry 1996; 53:769–774.
Dekker J, et al. The use of antidepressants after recovery from depression. Eur J Psychiatry 2000; 14:207–212.
Nelson JC. Treatment of antidepressant nonresponders: augmentation or switch? J Clin Psychiatry 1998; 59 Suppl 15:35–41.
Joffe RT. Substitution therapy in patients with major depression. CNS Drugs 1999; 11:175–180.
National Institute for Health and Care Excellence. Depression in adults: treatment and management. NICE guideline [NG222]. 2022 (last reviewed September 2024, last checked November 2024); https://www.nice.org.uk/guidance/ng222.
Montgomery SA, et al. A randomised, double-blind study in adults with major depressive disorder with an inadequate response to a single course of selective serotonin reuptake inhibitor or serotonin-noradrenaline reuptake inhibitor treatment switched to vortioxetine or agomelatine. Human Psychopharmacol 2014; 29:470–482.
Sparshatt A, et al. A naturalistic evaluation and audit database of agomelatine: clinical outcome at 12 weeks. Acta Psychiatr Scand 2013; 128:203–211.
Montgomery SA, et al. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134:382–389.
Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6:278–296.
Kroenke K, et al. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16:606–613.
Cipriani A, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 2018; 391:1357–1366.
Wagner G, et al. Efficacy and safety of levomilnacipran, vilazodone and vortioxetine compared with other second-generation antidepressants for major depressive disorder in adults: a systematic review and network meta-analysis. J Affect Disord 2018; 228:1–12.
de Vries YA, et al. Predicting antidepressant response by monitoring early improvement of individual symptoms of depression: individual patient data meta-analysis. Br J Psychiatry 2019; 214:4–10.
Köhler-Forsberg O, et al. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand 2019; 139:404–419.
Thase ME, et al. Citalopram treatment of fluoxetine nonresponders. J Clin Psychiatry 2001; 62:683–687.
Rush AJ, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006; 354:1231–1242.
Ruhe HG, et al. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review. J Clin Psychiatry 2006; 67:1836–1855.
Brent D, et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. JAMA 2008; 299:901–913.
Papakostas GI, et al. Treatment of SSRI-resistant depression: a meta-analysis comparing within- versus across-class switches. Biol Psychiatry 2008; 63:699–704.
Bschor T, et al. Switching the antidepressant after nonresponse in adults with major depression: a systematic literature search and meta- analysis. J Clin Psychiatry 2018; 79:16r10749.

Depression and anxiety disorders CHAPTER 3 25. Henssler J, et al. Combining antidepressants vs antidepressant monotherapy for treatment of patients with acute depression: a systematic review and meta-analysis. JAMA Psychiatry 2022; 79:300–312. 26. Adli M, et al. Is dose escalation of antidepressants a rational strategy after a medium-dose treatment has failed? A systematic review. Eur Arch Psychiatry Clin Neurosci 2005; 255:387–400. 27. Hieronymus F, et al. A mega-analysis of fixed-dose trials reveals dose-dependency and a rapid onset of action for the antidepressant effect of three selective serotonin reuptake inhibitors. Transl Psychiatry 2016; 6:e834. 28. Zhou S, et al. Efficacy and dose-response relationships of antidepressants in the acute treatment of major depressive disorders: a systematic review and network meta-analysis. Chin Med J (Engl) 2024: doi: 10.1097/CM9.0000000000003138. 29. Furukawa TA, et al. Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose–response meta-analysis. Lancet Psychiatry 2019; 6:601–609. 30. Papakostas GI, et al. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. J Clin Psychopharmacol 2006; 26:56–60. 31. Taylor MJ, et al. Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Arch Gen Psychiatry 2006; 63:1217–1223. 32. Posternak MA, et al. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry 2005; 66:148–158. 33. Szegedi A, et al. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry 2009; 70:344–353. 34. Baldwin DS, et al. How long should a trial of escitalopram treatment be in patients with major depressive disorder, generalised anxiety disorder or social anxiety disorder? An exploration of the randomised controlled trial database. Hum Psychopharmacol 2009; 24:269–275. 35. Nierenberg AA, et al. Early nonresponse to fluoxetine as a predictor of poor 8-week outcome. Am J Psychiatry 1995; 152:1500–1503. 36. Scott F, et al. Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression. J Psychopharmacol 2023; 37:268–278. 37. Maji S, et al. Early augmentation therapy with dextromethorphan in mild to moderate major depressive disorder: a group sequential, response adaptive randomized controlled trial. Psychiatry Res 2024; 342:116257.

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Management of treatment-resistant depression – commonly used treatments

348 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Management of treatment-resistant depression – commonly used treatments Resistant depression is difficult to treat successfully and outcomes are often poor,1–3 especially if evidence-based protocols are not followed.4 Treatment-resistant depression is not a uniform entity but a complex spectrum of severity which can be graded5 and in which outcome is closely linked to grading.6 A significant minority of apparently resistant unipolar depression may in fact be bipolar depression,7,8 which is often unresponsive to standard antidepressants9,10 (see section on bipolar depression in Chapter 2). There has been a move to characterise treatment-resistant depression as ‘difficult to treat’ depression on the basis that the former description implies that depression treatments are normally effective and that non-response is therefore somehow abnormal.11 Others suggest abandoning treatment-resistant depression as a diagnosis (again proposing ‘difficult to treat’ depression) because it propels clinicians to try more and more drugs in increasingly complex regimens rather than managing expectations of recovery to a more realistic level.12 Management of treatment-resistant depression has been informed by the Sequenced Treatment Alternatives to Relieve Depression (STARD) programme. This was a pragmatic effectiveness study, which used remission of symptoms as its main outcome.13 This study and its various subanalyses have now been somewhat discredited, principally because of high dropout rates after the initial treatment stages. Other criticisms of the STARD programme include the absence of a placebo group, the open nature of treatment and some assessments, the failure to account for patients withdrawing after their first visit, the unexplained use of an a priori secondary measure as the main outcome metric, payments made to subjects, and the observation that 93% of 1,518 patients in remission had relapsed or dropped out of the study at 12 months’ follow-up.14,15 In addition to this, reanalysis of original data collected found the overall remission rate to be 35%, as opposed to the claimed rate of 67%.16 Commonly used drugs for refractory depression that are generally well supported by published literature are shown in Table 3.3. Table 3.3 Commonly used treatments, generally well supported by published literature (no preference implied by order). Treatment Advantages Disadvantages Add aripiprazole17–23 (2–20mg/day) to antidepressant (brexpiprazole and cariprazine are also effective)24–26 ■ ■Good evidence base ■ ■Usually well tolerated and safe ■ ■Low doses (2–10mg/day) may be effective ■ ■Supported by meta-analyses24,27,28 ■ ■Akathisia and restlessness common at standard doses (≥10mg/day) ■ ■Insomnia may be problematic Add lithium29 Aim for plasma level of 0.4–0.8mmol/L initially, increasing to up to 1.0mmol/L if suboptimal response ■ ■Well established ■ ■Well supported in the literature ■ ■Recommended by NICE30 ■ ■Supported by meta-analyses27,28 ■ ■Sometimes poorly tolerated at higher plasma levels ■ ■Potentially toxic ■ ■Usually needs specialist referral ■ ■Plasma level monitoring is essential (Continued)

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References

Depression and anxiety disorders CHAPTER 3 References

Dunner DL, et al. Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression. J Clin Psychiatry 2006; 67:688–695.
Wooderson SC, et al. Prospective evaluation of specialist inpatient treatment for refractory affective disorders. J Affect Disord 2011; 131:92–103.
Fekadu A, et al. What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies. J Affect Disord 2009; 116:4–11.
Trivedi MH, et al. Clinical results for patients with major depressive disorder in the Texas Medication Algorithm Project. Arch Gen Psychiatry 2004; 61:669–680.
Fekadu A, et al. A multidimensional tool to quantify treatment resistance in depression: the Maudsley staging method. J Clin Psychiatry 2009; 70:177–184.
Fekadu A, et al. The Maudsley staging method for treatment-resistant depression: prediction of longer-term outcome and persistence of symptoms. J Clin Psychiatry 2009; 70:952–957.
Angst J, et al. Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J Affect Disord 2003; 73:133–146.
Smith DJ, et al. Unrecognised bipolar disorder in primary care patients with depression. British Journal of Psychiatry 2011; 199:49–56.
Sidor MM, et al. Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. J Clin Psychiatry 2011; 72:156–167.
Taylor DM, et al. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis. Acta Psychiatr Scand 2014; 130:452–469.
Cosgrove L, et al. Reconceptualising treatment-resistant depression as difficult-to-treat depression. Lancet Psychiatry 2021; 8:11–13.
Rush AJ, et al. Difficult-to-treat depression: a clinical and research roadmap for when remission is elusive. Aust N Z J Psychiatry 2019; 53:109–118.
Trivedi MH, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STARD: implications for clinical practice. Am J Psychiatry 2006; 163:28–40. Table 3.3 (Continued ) Treatment Advantages Disadvantages Combine olanzapine and fluoxetine31 6.25–12.5mg + 25–50mg daily (US licensed dose) ■ ■Well researched ■ ■Usually well tolerated ■ ■Olanzapine + TCA may also be effective32 ■ ■Olanzapine alone may be effective33,34 ■ ■Risk of weight gain ■ ■Limited clinical experience outside USA ■ ■Most data relate to bipolar depression Add quetiapine25,26 (150mg or 300mg a day) to SSRI/SNRI ■ ■Good evidence base ■ ■Usually well tolerated ■ ■Plausible explanation for antidepressant effect ■ ■Possibly more effective than lithium ■ ■Dry mouth, sedation, constipation can be problematic ■ ■Weight gain risk in the longer term SSRI + bupropion35–40 up to 400mg/day ■ ■Well tolerated ■ ■May improve sexual adverse effects ■ ■Not licensed for depression in the UK SSRI or venlafaxine

mianserin (30mg/day) or mirtazapine40,41 (30–45mg/day) ■ ■Recommended by NICE ■ ■Usually well tolerated ■ ■Widely used ■ ■Theoretical risk of serotonin syndrome (inform patient) ■ ■Risk of blood dyscrasia with mianserin ■ ■Weight gain and sedation with mirtazapine ■ ■One RCT showed no advantage for mirtazapine added to SSRI/SNRIs42 * 5mg + 20mg rising to 10mg + 40mg seems reasonable where combination formulations not available. TCA, tricyclic antidepressant.

350 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 14. Pigott HE, et al. Efficacy and effectiveness of antidepressants: current status of research. Psychother Psychosom 2010; 79:267–279. 15. Pigott HE. The STARD trial: it is time to reexamine the clinical beliefs that guide the treatment of major depression. Can J Psychiatry 2015; 60:9–13. 16. Pigott HE, et al. What are the treatment remission, response and extent of improvement rates after up to four trials of antidepressant therapies in real-world depressed patients? A reanalysis of the STARD study’s patient-level data with fidelity to the original research protocol. BMJ Open 2023; 13:e063095. 17. Marcus RN, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol 2008; 28:156–165. 18. Hellerstein DJ, et al. Aripiprazole as an adjunctive treatment for refractory unipolar depression. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:744–750. 19. Simon JS, et al. Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder. J Clin Psychiatry 2005; 66:1216–1220. 20. Papakostas GI, et al. Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder. J Clin Psychiatry 2005; 66:1326–1330. 21. Berman RM, et al. Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with inadequate response to antidepressants. CNS Spectr 2009; 14:197–206. 22. Fava M, et al. A double-blind, placebo-controlled study of aripiprazole adjunctive to antidepressant therapy among depressed outpatients with inadequate response to prior antidepressant therapy (ADAPT-A Study). Psychother Psychosom 2012; 81:87–97. 23. Jon DI, et al. Augmentation of aripiprazole for depressed patients with an inadequate response to antidepressant treatment: a 6-week prospective, open-label, multicenter study. Clin Neuropharmacol 2013; 36:157–161. 24. Nuñez NA, et al. Augmentation strategies for treatment resistant major depression: a systematic review and network meta-analysis. J Affect Disord 2022; 302:385–400. 25. Kishimoto T, et al. Efficacy and safety/tolerability of antipsychotics in the treatment of adult patients with major depressive disorder: a systematic review and meta-analysis. Psychol Med 2023; 53:4064–4082. 26. Yan Y, et al. Efficacy and acceptability of second-generation antipsychotics with antidepressants in unipolar depression augmentation: a systematic review and network meta-analysis. Psychol Med 2022; 52:2224–2231. 27. Strawbridge R, et al. Augmentation therapies for treatment-resistant depression: systematic review and meta-analysis. Br J Psychiatry 2019; 214:42–51. 28. Terao I, et al. Comparative efficacy, tolerability and acceptability of intravenous racemic ketamine with intranasal esketamine, aripiprazole and lithium as augmentative treatments for treatment-resistant unipolar depression: a systematic review and network meta-analysis. J Affect Disord 2024; 346:49–56. 29. Undurraga J, et al. Lithium treatment for unipolar major depressive disorder: systematic review. J Psychopharmacol 2019; 33:167–176. 30. National Institute for Health and Care Excellence. Depression in adults: treatment and management. NICE guideline [NG222]. 2022 (last reviewed September 2024, last checked November 2024); https://www.nice.org.uk/guidance/ng222. 31. Luan S, et al. Efficacy and safety of olanzapine/fluoxetine combination in the treatment of treatment-resistant depression: a meta-analysis of randomized controlled trials. Neuropsychiatr Dis Treat 2017; 13:609–620. 32. Takahashi H, et al. Augmentation with olanzapine in TCA-refractory depression with melancholic features: a consecutive case series. Hum Psychopharmacol 2008; 23:217–220. 33. Corya SA, et al. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Depress Anxiety 2006; 23:364–372. 34. Thase ME, et al. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment- resistant major depressive disorder. J Clin Psychiatry 2007; 68:224–236. 35. Trivedi MH, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006; 354:1243–1252. 36. Zisook S, et al. Use of bupropion in combination with serotonin reuptake inhibitors. Biol Psychiatry 2006; 59:203–210. 37. Fatemi SH, et al. Venlafaxine and bupropion combination therapy in a case of treatment-resistant depression. Ann Pharmacother 1999; 33:701–703. 38. Lam RW, et al. Citalopram and bupropion-SR: combining versus switching in patients with treatment-resistant depression. J Clin Psychiatry 2004; 65:337–340. 39. Papakostas GI, et al. The combination of duloxetine and bupropion for treatment-resistant major depressive disorder. Depress Anxiety 2006; 23:178–181. 40. Henssler J, et al. Combining antidepressants in acute treatment of depression: a meta-analysis of 38 studies including 4511 patients. Can J Psychiatry 2016; 61:29–43. 41. Ferreri M, et al. Benefits from mianserin augmentation of fluoxetine in patients with major depression non-responders to fluoxetine alone. Acta Psychiatr Scand 2001; 103:66–72. 42. Kessler DS, et al. Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: phase III randomised placebo controlled trial (MIR). BMJ 2018; 363:k4218.

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21 - Management of treatment resistant depression

Management of treatment-resistant depression – other well- supported treatments

Depression and anxiety disorders CHAPTER 3 Management of treatment-resistant depression – other wellsupported treatments Less commonly used treatments for treatment-resistant depression that are generally well supported by published literature are shown in Table 3.4. Table 3.4 Less commonly used treatments, well supported by published evidence (no preference implied by order). Treatment Advantages Disadvantages Add ketamine (0.5mg/kg IV over 40 minutes)1 Intranasal esketamine (licensed in most countries); dose is 28–84mg2 (see section on ketamine in this chapter) Oral ketamine (0.5–1.25mg/kg) effective but no licensed products3 ■ ■Very rapid response (within hours), including effects on suicidality4,5 ■ ■High remission rate6,7 ■ ■Some evidence of maintained response if repeated doses given8 ■ ■Usually well tolerated at this sub-anaesthetic dose ■ ■IV needs to be administered in hospital ■ ■Cognitive effects (confusion, dissociation) and other psychiatric symptoms9 ■ ■Associated with transient increases in BP, tachycardia and arrhythmias. Pretreatment ECG required with IV form10 ■ ■Adverse effects may have been underestimated11 ■ ■Repeated treatment necessary to maintain effect Add lamotrigine (100mg, 200mg and 400mg a day have been used)12 ■ ■Reasonably well researched ■ ■Quite widely used ■ ■Probably the best tolerated augmentation strategy13 ■ ■Slow titration ■ ■Risk of rash ■ ■Optimal dosing unclear ECT14 ■ ■Well established ■ ■Effective ■ ■Well supported in the literature ■ ■Necessitates general anaesthetic ■ ■Needs specialist referral ■ ■Usually reserved for last-line treatment or if rapid response needed ■ ■Usually combined with other treatments Add tri-iodothyronine (20–50mcg/day) Higher doses have been safely used15–21 ■ ■Usually well tolerated ■ ■Good literature support22 ■ ■May be effective in bipolar depression ■ ■Clinical and biochemical TFT monitoring required ■ ■Needs specialist referral ■ ■Some negative studies ■ ■No advantage over antidepressant alone in non-refractory illness23 TFT, thyroid function test.

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References

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Marcantoni WS, et al. A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009 – January 2019. J Affect Disord 2020; 277:831–841.
Papakostas GI, et al. Efficacy of esketamine augmentation in major depressive disorder: a meta-analysis. J Clin Psychiatry 2020; 81:19r12889.
Meshkat S, et al. Oral ketamine for depression: an updated systematic review. World J Biol Psychiatry 2023; 24:545–557.
Wilkinson ST, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry 2018; 175:150–158.
Witt K, et al. Ketamine for suicidal ideation in adults with psychiatric disorders: a systematic review and meta-analysis of treatment trials. Aust N Z J Psychiatry 2020; 54:29–45.
Alnefeesi Y, et al. Real-world effectiveness of ketamine in treatment-resistant depression: a systematic review and meta-analysis. J Psychiatr Res 2022; 151:693–709.
Terao I, et al. Comparative efficacy, tolerability and acceptability of intravenous racemic ketamine with intranasal esketamine, aripiprazole and lithium as augmentative treatments for treatment-resistant unipolar depression: a systematic review and network meta-analysis. J Affect Disord 2024; 346:49–56.
Capuzzi E, et al. Long-term efficacy of intranasal esketamine in treatment-resistant major depression: a systematic review. Int J Mol Sci 2021; 22:9338.
Beck K, et al. Association of ketamine with psychiatric symptoms and implications for its therapeutic use and for understanding schizophrenia: a systematic review and meta-analysis. JAMA Netw Open 2020; 3:e204693.
aan het Rot M, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 2010; 67:139–145.
Short B, et al. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry 2018; 5:65–78.
Goh KK, et al. Lamotrigine augmentation in treatment-resistant unipolar depression: a comprehensive meta-analysis of efficacy and safety. J Psychopharmacol 2019; 33:700–713.
Papadimitropoulou K, et al. Comparative efficacy and tolerability of pharmacological and somatic interventions in adult patients with treatment-resistant depression: a systematic review and network meta-analysis. Curr Med Res Opin 2017; 33:701–711.
Guo Q, et al. Efficacy and safety of eight enhanced therapies for treatment-resistant depression: a systematic review and network meta- analysis of RCTs. Psychiatry Res 2024; 339:116018.
Joffe RT, et al. A comparison of triiodothyronine and thyroxine in the potentiation of tricyclic antidepressants. Psychiatry Res 1990; 32:241–251.
Anderson IM. Drug treatment of depression: reflections on the evidence. Adv Psychiatr Treat 2003; 9:11–20.
Nierenberg AA, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry 2006; 163:1519–1530.
Iosifescu DV, et al. An open study of triiodothyronine augmentation of selective serotonin reuptake inhibitors in treatment-resistant major depressive disorder. J Clin Psychiatry 2005; 66:1038–1042.
Abraham G, et al. T3 augmentation of SSRI resistant depression. J Affect Disord 2006; 91:211–215.
Kelly TF, et al. Long term augmentation with T3 in refractory major depression. J Affect Disord 2009; 115:230–233.
Parmentier T, et al. The use of triiodothyronine (T3) in the treatment of bipolar depression: a review of the literature. J Affect Disord 2018; 229:410–414.
Nuñez NA, et al. Augmentation strategies for treatment resistant major depression: a systematic review and network meta-analysis. J Affect Disord 2022; 302:385–400.
Garlow SJ, et al. The combination of triiodothyronine (T3) and sertraline is not superior to sertraline monotherapy in the treatment of major depressive disorder. J Psychiatr Res 2012; 46:1406–1413.

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Treatment-resistant depression – other reported treatments

Depression and anxiety disorders CHAPTER 3 Treatment-resistant depression – other reported treatments A very wide range of treatments have been investigated as potential therapy for treatment-resistant depression. Table 3.5 briefly describes strategies that have limited support for their use but may be worth trying in exceptional circumstances. Prescribers should familiarise themselves with the primary literature before using these strategies. Table 3.5 Other reported treatments (alphabetical order – no preference implied). Treatment* Comments Ayahuasca1 Effective but specialist use only Buprenorphine2 0.8–2mg/day? Reasonable evidence but obvious contraindications Dexamethasone3,4 3–4 mg/day Limited data Dextromethorphan + quinidine5–7 45/10mg twice a day Promising novel treatment. NMDA antagonist. Quinidine is needed as CYP2D6 inhibitor to prolong action of dextromethorphan8 Folate/methyl folate9 Possible benefit Hyoscine10,11 (scopolomine) (4mcg/kg IV) Growing evidence base of prompt and sizeable effect MAOI and TCA12–14 e.g. trimipramine and phenelzine Formerly very widely used, but great care needed Minocycline 200mg/day Several positive meta-analyses in both animals15 and humans.16,17 Recent failed RCTs.18,19 Modafinil20 100–400mg/day See section on stimulants in depression (this chapter) Naltrexone21,22 100mg/day No studies in non-opiate misusers Nitrous oxide23–25 Short-lived effect Nortriptyline ± lithium26–29 Re-emergent treatment option Oestrogens30 (various regimens) Limited data Omega–3-triglycerides EPA31–33 Many failed trials. Therapeutic dose not defined. Pindolol34–39 5mg three times a day or 7.5mg once daily Well tolerated, can be initiated in primary care. Data mainly relate to acceleration of response. Refractory data somewhat contradictory. Pramipexole40 0.125–5mg/day Probably effective Psilocybin41 10/25mg 1 week apart Effective but specialist use only Risperidone42 0.5–3mg/day to antidepressant Good RCT support as add-on treatment S-adenosyl-l-methionine43–45 400mg/day IM; 1600mg/day oral Limited data in treatment-resistant depression. Use weakly supported by a Cochrane review.46 (Continued)

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References

354 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 References

Gonçalves J, et al. A systematic review on the therapeutic effects of ayahuasca. Plants (Basel) 2023; 12:2573.
Stanciu CN, et al. Use of buprenorphine in treatment of refractory depression: a review of current literature. Asian J Psychiatr 2017; 26:94–98.
Dinan TG, et al. Dexamethasone augmentation in treatment-resistant depression. Acta Psychiatr Scand 1997; 95:58–61.
Bodani M, et al. The use of dexamethasone in elderly patients with antidepressant-resistant depressive illness. J Psychopharmacol 1999; 13:196–197.
Murrough JW, et al. Dextromethorphan/quinidine pharmacotherapy in patients with treatment resistant depression: a proof of concept clinical trial. J Affect Disord 2017; 218:277–283.
Kelly TF, et al. The utility of the combination of dextromethorphan and quinidine in the treatment of bipolar II and bipolar NOS. J Affect Disord 2014; 167:333–335.
Wang PR, et al. An open-label study of adjunctive dextromethorphan/quinidine in treatment-resistant depression. J Clin Psychopharmacol 2023; 43:422–427.
Nofziger JL, et al. Evaluation of dextromethorphan with select antidepressant therapy for the treatment of depression in the acute care psychiatric setting. Ment Health Clin 2019; 9:76–81.
Maruf AA, et al. Systematic review and meta-analysis of l-methylfolate augmentation in depressive disorders. Pharmacopsychiatry 2022; 55:139–147.
Wang X, et al. Group-based symptom trajectory of intramuscular administration of scopolamine augmentation in moderate to severe major depressive disorder: a post-hoc analysis. Neuropsychiatr Dis Treat 2023; 19:1043–1053.
Drevets WC, et al. Antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine: a review. Biol Psychiatry 2013; 73:1156–1163.
White K, et al. The combined use of MAOIs and tricyclics. J Clin Psychiatry 1984; 45:67–69.
Kennedy N, et al. Treatment and response in refractory depression: results from a specialist affective disorders service. J Affect Disord 2004; 81:49–53. Table 3.5 (Continued) Treatment* Comments SSRI + buspirone47,48 Up to 60mg/day Higher doses required poorly tolerated (dizziness common) SSRI + TCA49 Formerly widely used Stimulants amfetamine; methylphenidate Varied outcomes. See section on stimulants in depression in this chapter. TCA – high dose50 Formerly widely used. Cardiac monitoring essential Testosterone gel34,51 Effective in those with low testosterone levels Tianeptine52,53 25–50mg/day Tiny database. Tianeptine not available in many countries. Potential for misuse.54 Tryptophan55–58 2–3g three times a day Long history of successful use Venlafaxine59-62

200mg/day Nausea and vomiting; discontinuation reactions more common. BP monitoring essential. Venlafaxine – very high dose (up to 600mg/day)63 See above. Cardiac monitoring essential. Venlafaxine + IV clomipramine64 Cardiac monitoring essential Zinc65 25mg Zn+/day One RCT (n = 60) showed good results in refractory depression. A few other small studies.66 * Other non-drug treatments are available, including various psychological approaches, rTMS, VNS, deep brain stimulation and psychosurgery. Discussion of these treatments is beyond the scope of this book. CYP, cytochrome P450; EPA, eicosapentaenoic acid; MAOI, monoamine oxidase inhibitor; NMDA, N-methyl-D- aspartate; TCA, tricyclic antidepressant.

Depression and anxiety disorders CHAPTER 3 14. Connolly KR, et al. If at first you don’t succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs 2011; 71:43–64. 15. Reis DJ, et al. The antidepressant impact of minocycline in rodents: a systematic review and meta-analysis. Sci Rep 2019; 9:261. 16. Zazula R, et al. Minocycline as adjunctive treatment for major depressive disorder: pooled data from two randomized controlled trials. Aust N Z J Psychiatry 2020;4867420965697. 17. Strawbridge R, et al. Augmentation therapies for treatment-resistant depression: systematic review and meta-analysis. Br J Psychiatry 2019; 214:42–51. 18. Husain MI, et al. Minocycline and celecoxib as adjunctive treatments for bipolar depression: a multicentre, factorial design randomised controlled trial. Lancet Psychiatry 2020; 7:515–527. 19. Hellmann-Regen J, et al. Effect of minocycline on depressive symptoms in patients with treatment-resistant depression: a randomized clinical trial. JAMA Netw Open 2022; 5:e2230367. 20. Nuñez NA, et al. Augmentation strategies for treatment resistant major depression: a systematic review and network meta-analysis. J Affect Disord 2022; 302:385400. 21. Pettinati HM, et al. A double-blind, placebo-controlled trial combining sertraline and naltrexone for treating co-occurring depression and alcohol dependence. Am J Psychiatry 2010; 167:668–675. 22. Browne CA, et al. Novel targets to treat depression: opioid-based therapeutics. Harvard Rev Psychiatry 2020; 28:40–59. 23. Yan D, et al. Efficacy and safety of nitrous oxide for patients with treatment-resistant depression, a randomized controlled trial. Psychiatry Res 2022; 317:114867. 24. Kim WSH, et al. Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: focus on cerebrovascular target engagement. Bipolar Disord 2023; 25:221–232. 25. Nagele P, et al. A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression. Sci Transl Med 2021; 13:eabe1376. 26. Nierenberg AA, et al. Nortriptyline for treatment-resistant depression. J Clin Psychiatry 2003; 64:35–39. 27. Nierenberg AA, et al. Lithium augmentation of nortriptyline for subjects resistant to multiple antidepressants. J Clin Psychopharmacol 2003; 23:92–95. 28. Fava M, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry 2006; 163:1161–1172. 29. Shelton RC, et al. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry 2005; 66:1289–1297. 30. Stahl SM. Basic psychopharmacology of antidepressants, part 2: oestrogen as an adjunct to antidepressant treatment. J Clin Psychiatry 1998; 59 Suppl 4:15–24. 31. Liao Y, et al. Efficacy of omega-3 PUFAs in depression: a meta-analysis. Transl Psychiatry 2019; 9:190. 32. Mischoulon D, et al. Omega-3 fatty acids for major depressive disorder with high inflammation: a randomized dose-finding clinical trial. J Clin Psychiatry 2022; 83:21m14074. 33. Wu SK, et al. The efficacy of omega-3 fatty acids as the monotherapy for depression: a randomized, double-blind, placebo-controlled pilot study. Nutrients 2024; 16:3688. 34. Kleeblatt J, et al. Efficacy of off-label augmentation in unipolar depression: a systematic review of the evidence. Eur Neuropsychopharmacol 2017; 27:423–441. 35. McAskill R, et al. Pindolol augmentation of antidepressant therapy. Br J Psychiatry 1998; 173:203–208. 36. Rasanen P, et al. Mitchell B. Balter Award 1998. Pindolol and major affective disorders: a three-year follow-up study of 30,485 patients. J Clin Psychopharmacol 1999; 19:297–302. 37. Perry EB, et al. Pindolol augmentation in depressed patients resistant to selective serotonin reuptake inhibitors: a double-blind, randomized, controlled trial. J Clin Psychiatry 2004; 65:238–243. 38. Sokolski KN, et al. Once-daily high-dose pindolol for SSRI-refractory depression. Psychiatry Res 2004; 125:81–86. 39. Whale R, et al. Pindolol augmentation of serotonin reuptake inhibitors for the treatment of depressive disorder: a systematic review. J Psychopharmacol 2010; 24:513–520. 40. Tundo A, et al. Pramipexole augmentation for treatment-resistant unipolar and bipolar depression in the real world: a systematic review and meta-analysis. Life (Basel) 2023; 13:1043. 41. Metaxa AM, et al. Efficacy of psilocybin for treating symptoms of depression: systematic review and meta-analysis. BMJ 2024; 385:e078084. 42. Kishimoto T, et al. Efficacy and safety/tolerability of antipsychotics in the treatment of adult patients with major depressive disorder: a systematic review and meta-analysis. Psychol Med 2023; 53:4064–4082. 43. Pancheri P, et al. A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. Int J Neuropsychopharmacol 2002; 5:287–294. 44. Alpert JE, et al. S-adenosyl-L-methionine (SAMe) as an adjunct for resistant major depressive disorder: an open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine. J Clin Psychopharmacol 2004; 24:661–664. 45. Sharma A, et al. S-adenosylmethionine (SAMe) for neuropsychiatric disorders: a clinician-oriented review of research. J Clin Psychiatry 2017; 78:e656–e667. 46. Galizia I, et al. S-adenosyl methionine (SAMe) for depression in adults. Cochrane Database Syst Rev 2016; 10:CD011286. 47. Trivedi MH, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006; 354:1243–1252. 48. Appelberg BG, et al. Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study. J Clin Psychiatry 2001; 62:448–452. 49. Taylor D. Selective serotonin reuptake inhibitors and tricyclic antidepressants in combination: interactions and therapeutic uses. Br J Psychiatry 1995; 167:575–580.

356 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 50. Malhi GS, et al. Management of resistant depression. Int J Psychiatry Clin Pract 1997; 1:269–276. 51. Pope HG, Jr., et al. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry 2003; 160:105–111. 52. Tobe EH, et al. Possible usefulness of tianeptine in treatment-resistant depression. Int J Psychiatry Clin Pract 2013; 17:313–316. 53. Woo YS, et al. Tianeptine combination for partial or non-response to selective serotonin re-uptake inhibitor monotherapy. Psychiatry Clin Neurosci 2013; 67:219–227. 54. Espiridion ED, et al. A case of ‘Neptune’s fix elixir’: the dangerous consequences of unregulated use of tianeptine in over-the-counter products. Cureus 2024; 16:e55120. 55. Angst J, et al. The treatment of depression with L-5-hydroxytryptophan versus imipramine. Results of two open and one double-blind study. Arch Psychiatr Nervenkr 1977; 224:175–186. 56. Alino JJ, et al. 5-Hydroxytryptophan (5-HTP) and a MAOI (nialamide) in the treatment of depressions: a double-blind controlled study. Int Pharmacopsychiatry 1976; 11:8–15. 57. Hale AS, et al. Clomipramine, tryptophan and lithium in combination for resistant endogenous depression: seven case studies. Br J Psychiatry 1987; 151:213–217. 58. Young SN. Use of tryptophan in combination with other antidepressant treatments: a review. J Psychiatry Neurosci 1991; 16:241–246. 59. Poirier MF, et al. Venlafaxine and paroxetine in treatment-resistant depression: double-blind, randomised comparison. Br J Psychiatry 1999; 175:12–16. 60. Nierenberg AA, et al. Venlafaxine for treatment-resistant unipolar depression. J Clin Psychopharmacol 1994; 14:419–423. 61. Smith D, et al. Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants: a meta-analysis. Br J Psychiatry 2002; 180:396–404. 62. Rush AJ, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006; 354:1231–1242. 63. Harrison CL, et al. Tolerability of high-dose venlafaxine in depressed patients. J Psychopharmacol 2004; 18:200–204. 64. Fountoulakis KN, et al. Combined oral venlafaxine and intravenous clomipramine-A: successful temporary response in a patient with extremely refractory depression. Can J Psychiatry 2004; 49:73–74. 65. Siwek M, et al. Zinc supplementation augments efficacy of imipramine in treatment resistant patients: a double blind, placebo-controlled study. J Affect Disord 2009; 118:187–195. 66. Salari S, et al. Zinc sulphate: a reasonable choice for depression management in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial. Pharmacol Rep 2015; 67:606–609.

08 - Chapter 3 Depression and anxiety disorders

25 - Ketamine

Ketamine

08 - Chapter 3 Depression and anxiety disorders

26 - Background

Background

08 - Chapter 3 Depression and anxiety disorders

27 - Mechanism

Mechanism

08 - Chapter 3 Depression and anxiety disorders

28 - Route of administration

Route of administration

Depression and anxiety disorders CHAPTER 3 Ketamine Background Over the past two decades, ketamine, an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and dissociative anaesthetic, has emerged as a novel and effective rapid-acting antidepressant. In 2000, Berman and colleagues reported findings from a landmark RCT, administering a single subanaesthetic dose of IV ketamine (0.5mg/kg over 40 minutes) to individuals with MDD.1 Ketamine produced a significant antidepressant effect within hours after the infusion that increased progressively up to 3 days after administration. This finding has since been replicated in several trials in both unipolar and bipolar depression (including treatment-resistant individuals).2–6 In addition, perinatal or prenatal ketamine and esketamine reduce the risk of postnatal depression by about 50–75%.7–9 The use of ketamine as anaesthesia may enhance the effect of ECT.10 Ketamine appears to be broadly as effective as ECT.11,12 Ketamine is a racemic mixture composed of equal amounts of the two enantiomers (S)-ketamine and (R)-ketamine (esketamine and arketamine), with esketamine binding more potently to the NMDA receptor. Although racemic ketamine remains an off-label treatment for treatment-resistant depression (TRD), an esketamine nasal spray (Spravato®) is approved for use in TRD (in conjunction with an oral antidepressant) in Europe and the USA. A 2023 trial has shown greater benefit in TRD for augmentation of antidepressants with nasal esketamine than with quetiapine.13 Interestingly, although benefits were evident for both esketamine and quetiapine immediately, the effects continued to build over 32 weeks. The use of the term ‘rapid-acting antidepressant’ might be reconsidered in light of these results. Mechanism At present, the precise mechanisms of action for the antidepressant effects of ketamine and esketamine are not clear, but it has been proposed these effects are mediated via blockade of NMDA receptors on gamma-aminobutyric acid (GABA)ergic interneurons that normally act to suppress glutamate release from glutamatergic neurons.14 This disinhibition results in an acute cortical glutamate surge, activation of post-synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, with downstream effects on synaptogenesis and neuroplastic pathways.14 Route of administration The optimal method for administering ketamine for TRD is not fully established. IV ketamine (0.5mg/kg over 40 minutes) is the gold standard for off-label ketamine administration, with the best supporting evidence for efficacy, and may be more effective than intranasal administration.15,16 Other routes of administration have also been proposed including subcutaneous, intramuscular, oral and sublingual, although further research is needed to qualify the relative efficacy and safety of these routes, as well as the optimal dosing regimen in each case. Each route has its own advantages and challenges in terms of bioavailability, duration of effect, practicality and patient comfort. While no definitive dosing strategy for ketamine has been established across the different routes and

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29 - Adverse effects

Adverse effects

358 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 doses tested, in Table 3.6 we provide a summary of dosing recommendations, considering available evidence and clinical experience. Novel formulations of oral ketamine are under development.17 Adverse effects Ketamine generally leads to significant dissociative symptoms when given at antidepressant doses.18 These symptoms include perceptual distortions and can lead to significant anxiety. As a result, it is necessary that any patients administered ketamine should be observed by a trained clinician during dosing and for 1 hour after administration. Although a rare event, ketamine has also been reported to induce laryngospasm and so the observing clinician should be trained in intermediate or advanced life support. When ketamine is given at lower doses by oral or sublingual routes, it is less likely to induce strong dissociative symptoms so, once a test dose has been given under clinical supervision, it may be possible for administration to take place in a non-clinical (home) setting, although patients should be advised not to drive, operate heavy machinery or partake in other high-risk activities for at least 1 hour after administration. In addition, consideration must be given by the prescribing clinician to the risks of diversion and illegal use. Ketamine can have significant effects on blood pressure and heart rate. Before administration, a physical examination including baseline blood pressure, full blood count, liver function test, thyroid function test plus ECG is recommended. Physical monitoring (blood pressure and heart rate) during and after ketamine administration is also indicated. In longer-term illicit use, ketamine is associated with urinary pain, epithelial bladder barrier damage, reduced bladder capacity, ureter stenosis and kidney failure.19 Although this ketamine-induced cystitis is a recognised complication of recreational use of ketamine, its occurrence in therapeutic use of ketamine in depression has so far not been widely reported but remains a concern.20 Table 3.6 Dosing recommendations for different routes of ketamine administration and intranasal esketamine in treatment-resistant depression. Route Dose Details Frequency Comments IV2–6 ■ ■0.5mg/kg, increasing up to 1.0mg/kg if no response (limited support for doses higher than 0.5mg/ kg16) (titrate from 0.25mg/kg in older people) ■ ■Infuse over 40 minutes ■ ■Induction phase: once or twice a week ■ ■Maintenance phase: according to response, weekly then every 2 weeks, or even monthly (consider supplementing with oral/sublingual doses between IV treatments) ■ ■Must be administered in clinical setting ■ ■Cognitive effects (confusion, dissociation, etc.) do occasionally occur ■ ■Associated with transient increase in BP, tachycardia and arrhythmias. Pretreatment ECG required. Monitor BP before and after infusion. ■ ■Observe during and for 1 hour after infusion (Continued)

Depression and anxiety disorders CHAPTER 3 Route Dose Details Frequency Comments SC21,22 ■ ■0.5mg/kg, increasing up to 1.0mg/kg if no response (titrate from 0.25mg/kg in older people) ■ ■SC bolus injection to appropriate SC site ■ ■As per IV above ■ ■As per IV above ■ ■May be better tolerated than IV or IM routes21 IM23,24 ■ ■0.5mg/kg, increasing up to 1.0mg/kg if no response (titrate from 0.25mg/kg in older people) ■ ■IM bolus injection to appropriate IM site ■ ■As per IV above ■ ■As per IV above Oral25–27 ■ ■0.5–5.0mg/kg depending on dosing strategy ■ ■Oral capsules ■ ■Regular lower doses: ■ ■0.5–2.0mg/kg every 1–3 days ■ ■Intermittent higher doses to supplement IV/SC/IM treatment: ■ ■2.0–5.0mg/kg once or twice a week ■ ■Can be taken at home ■ ■Lower doses show good tolerability, however, antidepressant effects not as rapid as IV/SC/IM ■ ■Higher doses may be practical alternative to maintain response to IV/ SC/IM treatment. Titrate dose according to response/adverse effects. Sublingual27–29 ■ ■0.5–3.0mg/kg depending on dosing strategy ■ ■Ketamine solution (held under tongue for 5 minutes and swallowed) ■ ■Sublingual ketamine lozenges ■ ■Regular lower doses: ■ ■0.5–1.5mg/kg every 1–3 days ■ ■Limited evidence for very low sublingual dosing (10mg every 2–3 days or weekly)30 ■ ■Intermittent higher doses to supplement IV/SC/IM treatment: ■ ■1.5–3.0mg/kg once or twice a week ■ ■Can be taken at home ■ ■Lower doses show good tolerability, however putative antidepressant effects not as rapid as IV/ SC/IM ■ ■Higher doses may be used as practical alternative to maintain response to IV/SC/IM treatment. Titrate dose according to response/ adverse effects. Intranasal esketamine31–34 ■ ■56–84mg (28mg in older people) ■ ■28mg in two sprays (1 spray per nostril) ■ ■Repeat after 5 minutes, depending on total dose required ■ ■Twice weekly, then weekly, then every 2 weeks ■ ■Must be administered in clinical setting ■ ■Cognitive effects (confusion, dissociation, etc.) do occasionally occur ■ ■Associated with transient increase in BP, tachycardia and arrhythmias. Pretreatment ECG recommended. Monitor BP before and after dose. ■ ■Observe for approximately 2 hours after dose Table 3.6 (Continued)

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30 - References

References

360 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 References

Berman RM, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47:351–354.
Zarate CA, Jr., et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006; 63:856–864.
Diazgranados N, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 2010; 67:793–802.
Murrough JW, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013; 170:1134–1142.
Singh JB, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment- resistant depression. Am J Psychiatry 2016; 173:816–826.
Fava M, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry 2020; 25:1592–1603.
Li S, et al. Effects of ketamine and esketamine on preventing postpartum depression after cesarean delivery: a meta-analysis. J Affect Disord 2024; 351:720–728.
Ma S, et al. Association between esketamine interventions and postpartum depression and analgesia following cesarean delivery: a systematic review and meta-analysis. Am J Obstet Gynecol MFM 2024; 6:101241.
Wang S, et al. Efficacy of a single low dose of esketamine after childbirth for mothers with symptoms of prenatal depression: randomised clinical trial. BMJ 2024; 385:e078218.
Ren L, et al. Comparative efficacy and tolerability of different anesthetics in electroconvulsive therapy for major depressive disorder: a systematic review and network meta-analysis. J Psychiatr Res 2024; 171:116–125.
de A Simoes Moreira D, et al. Efficacy and adverse effects of ketamine versus electroconvulsive therapy for major depressive disorder: a systematic review and meta-analysis. J Affect Disord 2023; 330:227–238.
Menon V, et al. Ketamine vs electroconvulsive therapy for major depressive episode: a systematic review and meta-analysis. JAMA Psychiatry 2023; 80:639–642.
Reif A, et al. Esketamine nasal spray versus quetiapine for treatment-resistant depression. N Engl J Med 2023; 389:1298–1309.
Lener MS, et al. Glutamate and gamma-aminobutyric acid systems in the pathophysiology of major depression and antidepressant response to ketamine. Biol Psychiatry 2017; 81:886–897.
Terao I, et al. Comparative efficacy, tolerability and acceptability of intravenous racemic ketamine with intranasal esketamine, aripiprazole and lithium as augmentative treatments for treatment-resistant unipolar depression: a systematic review and network meta-analysis. J Affect Disord 2024; 346:49–56.
Seshadri A, et al. Efficacy of intravenous ketamine and intranasal esketamine with dose escalation for major depression: a systematic review and meta-analysis. J Affect Disord 2024; 356:379–384.
Glue P, et al. Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study. Ther Adv Psychopharmacol 2020; 10:2045125320922474.
Beck K, et al. Association of ketamine with psychiatric symptoms and implications for its therapeutic use and for understanding schizophrenia: a systematic review and meta-analysis. JAMA Netw Open 2020; 3:e204693.
Anderson DJ, et al. Ketamine-induced cystitis: a comprehensive review of the urologic effects of this psychoactive drug. Health Psychol Res 2022; 10:38247.
Chang M, et al. Ketamine cystitis following ketamine therapy for treatment-resistant depression - case report. BMC Psychiatry 2024; 24:9.
Loo CK, et al. Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression. Acta Psychiatr Scand 2016; 134:48–56.
George D, et al. Pilot randomized controlled trial of titrated subcutaneous ketamine in older patients with treatment-resistant depression. Am J Geriatr Psychiatry 2017; 25:1199–1209.
Glue P, et al. Dose- and exposure-response to ketamine in depression. Biol Psychiatry 2011; 70:e9–e10; author reply e11–e12.
Cusin C, et al. Long-term maintenance with intramuscular ketamine for treatment-resistant bipolar II depression. Am J Psychiatry 2012; 169:868–869.
Arabzadeh S, et al. Does oral administration of ketamine accelerate response to treatment in major depressive disorder? Results of a double- blind controlled trial. J Affect Disord 2018; 235:236–241.
Domany Y, et al. Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study. Br J Psychiatry 2019; 214:20–26.
Rosenblat JD, et al. Oral ketamine for depression: a systematic review. J Clin Psychiatry 2019; 80:18r12475.
Swainson J, et al. Sublingual ketamine: an option for increasing accessibility of ketamine treatments for depression? J Clin Psychiatry 2020; 81:19lr13146.
Nguyen L, et al. Off-label use of transmucosal ketamine as a rapid-acting antidepressant: a retrospective chart review. Neuropsychiatr Dis Treat 2015; 11:2667–2673.
Lara DR, et al. Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. Int J Neuropsychopharmacol 2013; 16:2111–2117.

Depression and anxiety disorders CHAPTER 3 31. Canuso CM, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry 2018; 175:620–630. 32. Daly EJ, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry 2018; 75:139–148. 33. Popova V, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment- resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry 2019; 176:428–438. 34. Daly EJ, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry 2019; 76:893–903.

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31 - Psychotic depression

Psychotic depression

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32 - Acute treatment

Acute treatment

362 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Psychotic depression Psychotic depression represents a severe manifestation of depression. It is diagnosed in people experiencing a major depressive illness accompanied by psychotic symptoms such as hallucinations and/or delusions. It can occur in the context of both MDD and bipolar disorder. Psychotic depression has a lifetime prevalence of 1%.1 However, it is often under-diagnosed and is commonly not adequately identified despite requiring a different treatment approach.2,3 When compared with non-psychotic depression, psychotic depression is associated with greater illness severity, impairment and episode duration.4 Once an individual has experienced psychotic symptoms during a depressive episode there is a risk of their recurrence in future episodes.4,5 Furthermore, long-term outcomes are generally poorer for psychotic than non-psychotic depression.6–8 Patients with psychotic depression may also have a poorer response to combined pharmacological and psychological treatment than those with non-psychotic depression.9 People with psychotic depression are much more likely than those with non-psychotic depression to attempt and complete suicide.8,10 Acute treatment While it is important to acknowledge that no treatments have been granted regulatory approval specifically for psychotic depression,11 there is sufficient evidence to guide treatment decisions. Oliva and colleagues12 conducted a systematic review and network meta-analysis of pharmacological treatments for psychotic depression in 2024. This network meta-analysis included 14 randomised controlled trials including patients in the acute phase of their illness. It found that, compared with placebo, the combination of an SSRI and an SGA, particularly fluoxetine and olanzapine, resulted in the highest proportion of participants with a treatment response.12 Overall, this specific combination also showed a good balance between efficacy and tolerability and specifically improved depressive symptom scores compared with placebo.12 The network meta- analysis concluded that this treatment option is the most appropriate choice in people with psychotic depression.12 When different treatment options were compared directly, a combination of antipsychotics and antidepressants was also found to have greater efficacy than monotherapy with either antipsychotic or antidepressant alone.12 Prior meta-analyses support this outcome, although they were not able to provide specific recommendations on individual drugs because of methodological restrictions.13,14 UK NICE guidance from 2022, although written some time before the latest network meta-analysis, also advocates this approach.11,15 The 2024 network meta-analysis also compared monotherapies and found that TCAs (amoxapine and imipramine) were more efficacious than serotonin–noradrenaline reuptake inhibitors (SNRIs; venlafaxine) and noradrenergic and specific serotonergic reuptake inhibitors (mirtazapine) when overall treatment response was assessed.12 It is important to consider that this network meta-analysis only included patients in the acute phase of their illness. Continuation and maintenance studies were excluded. In addition, it only included studies published up to 2013, so drugs used in clinical practice more recently could not be examined.

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33 - Ketamine formulations

Ketamine formulations

08 - Chapter 3 Depression and anxiety disorders

34 - ECT

ECT

08 - Chapter 3 Depression and anxiety disorders

35 - Maintenance treatment

Maintenance treatment

Depression and anxiety disorders CHAPTER 3 Ketamine formulations Many of the more recent studies include ketamine and esketamine, which are increasingly used to treat MDD and bipolar affective disorder,16 and are possibly efficacious for psychotic depression.17 Evidence is limited because people with psychotic depression are usually excluded from clinical trials owing to the concern that these drugs may worsen psychotic symptoms, albeit transiently.17,18 Le et al.17 reviewed the evidence for the use of ketamine in the treatment of psychotic depression. This comprised two case series, three case reports (n = 1), one retrospective chart review (n = 12) and one secondary analysis of a randomised controlled trial (n = 10). Most patients received ketamine 0.5mg/kg IV (fewer received SC), infused over 40 minutes. The number of treatments was very varied, ranging from one to seven over a number of weeks (approximately 3–8 weeks). The patients in the retrospective chart review were given 30–120mg intranasally at intervals of 3–7 days. A 2023 study16 examined the effects of add-on ketamine (0.5mg/kg IV twice a week) in 36 patients and found improvements in all domains. Overall, these lines of evidence indicated that ketamine reduces depressive symptoms and, in a few cases, psychotic symptoms as well. The review did not describe any patients experiencing a worsening of psychotic symptoms. However, all these studies had very small sample sizes. A case series including four patients also provides some limited evidence for the safety and efficacy of esketamine (0.5mg/kg IV or SC) for the treatment of TRD with psychotic features.19 ECT There is a role for ECT in the treatment of psychotic depression, especially where a rapid response is required. Pooled analysis of the two largest sham-controlled ECT trials found a significant improvement in depressive scores with real ECT compared with simulated ECT in patients with depression and delusional features at 4 weeks. However, there was no significant difference between these groups at 6 months.20 ECT is effective in MDD (see section on ECT and psychotropic drugs in this chapter) and a few studies indicate that ECT may be more efficacious in people with depression with psychotic features.21–23 ECT may also be more protective against relapse in psychotic depression than in non-psychotic depression.24,25 One small RCT demonstrated superiority of maintenance ECT plus nortriptyline over nortriptyline alone at 2 years.26 Maintenance treatment Generally, acute treatment should be continued. Evidence from the STOP-PD II (Study of the Pharmacotherapy of Psychotic Depression II) trial suggested that withdrawal of olanzapine from sertraline co-therapy worsens outcomes in the medium term.27,28 Relapse was more than twice as likely in the sertraline placebo group than in the combination group (55% vs 20%) and almost all the excess risk of relapse occurred in the first 2 months. However, one in five patients in the combined group relapsed over 36 weeks from randomisation into the single drug phase of the study (people were on the combination for much longer than this as all patients in the study started on the combination therapy prior to the 8-week remission phase needed prior to randomisation to monotherapy).4 The evidence from this study suggests that combined treatment

08 - Chapter 3 Depression and anxiety disorders

36 - Other treatments

Other treatments

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37 - Summary

Summary

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38 - References

References

364 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 for 4–6 months after remission may be relatively effective at preventing a recurrence in psychotic depression.4 In the UK, NICE15 suggests continuing antipsychotic medication for a number of months after remission, but it is not clear how long combination therapy should be continued past this point. This decision could be based on patient preference and adverse effect profile (e.g. weight gain). Options might include slowly tapering the antipsychotic with reintroduction if psychotic symptoms return or switching to an antipsychotic with different adverse effects. Currently there is no evidence to support the best way to do this. Other treatments Another potential treatment approach is based on glucocorticoid receptor blocking strategies, since hypothalamic–pituitary–adrenal axis hyperactivity is more common in psychotic depression. A combined analysis of data from five double-blind trials (mifepristone n = 833, placebo n = 627) evaluating the efficacy and safety of 7 days’ treatment with mifepristone compared with placebo found that mifepristone reduced psychotic symptoms.29 Patients with a high mifepristone plasma level (≥1637ng/mL) showed a more significant treatment response.29 There is an anecdotal report of the successful use of methylphenidate in a patient who did not respond to robust doses of an antidepressant and antipsychotic combined.30 Other case reports describe successful outcomes with lamotrigine31 and a combination of phenelzine, aripiprazole and quetiapine.32 Minocycline has also shown some effect, albeit in an open study.33 Summary ■ ■In the acute phase of psychotic depression, the combination of an antipsychotic and antidepressant is the best treatment option. The strongest evidence is for a combination of olanzapine and fluoxetine. ■ ■Monotherapy is less effective than combined therapy but if this is the best approach for the patient, TCAs are the drugs of choice. ■ ■If using combined therapy, treat with this combination for at least 4–6 months after remission. After this time, consider slowly tapering the antipsychotic but make a decision based on risk (e.g. metabolic syndrome) and potential benefit (e.g. past history of relapse and psychosis). ■ ■ECT is an effective treatment. Consider when a rapid response is required or where other treatments have failed. ■ ■Ketamine formulations may be effective but are not first-line agents. References

Jääskeläinen E, et al. Epidemiology of psychotic depression: systematic review and meta-analysis. Psychol Med 2018; 48:905–918.
Heslin M, et al. Psychotic major depression: challenges in clinical practice and research. Br J Psychiatry 2018; 212:131–133.
Rothschild AJ, et al. Missed diagnosis of psychotic depression at 4 academic medical centers. J Clin Psychiatry 2008; 69:1293–1296.
Coryell WH. Maintenance treatment for psychotic depressive disorders: progress and remaining challenges. JAMA 2019; 322:615–617.
Tohen M, et al. Two-year outcomes in first-episode psychotic depression the McLean–Harvard First-Episode Project. J Affect Disord 2012; 136:1–8.
Flint AJ, et al. Two-year outcome of psychotic depression in late life. Am J Psychiatry 1998; 155:178–183.

Depression and anxiety disorders CHAPTER 3 7. Maj M, et al. Phenomenology and prognostic significance of delusions in major depressive disorder: a 10-year prospective follow-up study. J Clin Psychiatry 2007; 68:1411–1417. 8. Paljärvi T, et al. Mortality in psychotic depression: 18-year follow-up study. Br J Psychiatry 2023; 222:37-43. 9. Gaudiano BA, et al. Differential response to combined treatment in patients with psychotic versus nonpsychotic major depression. J Nerv Ment Dis 2005; 193:625–628. 10. Gournellis R, et al. Psychotic (delusional) depression and suicidal attempts: a systematic review and meta-analysis. Acta Psychiatr Scand 2018; 137:18–29. 11. Kendrick T, et al. Management of depression in adults: summary of updated NICE guidance. BMJ 2022; 378:o1557. 12. Oliva V, et al. Pharmacological treatments for psychotic depression: a systematic review and network meta-analysis. Lancet Psychiatry 2024; 11:210–220. 13. Kruizinga J, et al. Pharmacological treatment for psychotic depression. Cochrane Database Syst Rev 2021; 12:CD004044. 14. Farahani A, et al. Are antipsychotics or antidepressants needed for psychotic depression? A systematic review and meta-analysis of trials comparing antidepressant or antipsychotic monotherapy with combination treatment. J Clin Psychiatry 2012; 73:486–496. 15. National Institute for Health and Care Excellence. Depression in adults: treatment and management. NICE guideline [NG222]. 2022 (last updated May 2024, last checked May 2024); https://www.nice.org.uk/guidance/ng222. 16. Gałuszko-Wȩgielnik M, et al. Central nervous system-related safety and tolerability of add-on ketamine to standard of care treatment in treatment-resistant psychotic depression in patients with major depressive disorder and bipolar disorder. Front Neurosci 2023; 17:1214972. 17. Le TT, et al. Ketamine for psychotic depression: an overview of the glutamatergic system and ketamine’s mechanisms associated with antidepressant and psychotomimetic effects. Psychiatry Res 2021; 306:114231. 18. Beck K, et al. Association of ketamine with psychiatric symptoms and implications for its therapeutic use and for understanding schizophrenia: a systematic review and meta-analysis. JAMA Netw Open 2020; 3:e204693. 19. Ajub E, et al. Efficacy of esketamine in the treatment of depression with psychotic features: a case series. Biol Psychiatry 2018; 83:e15–e16. 20. Buchan H, et al. Who benefits from electroconvulsive therapy? Combined results of the Leicester and Northwick Park trials. Br J Psychiatry 1992; 160:355–359. 21. Heijnen W, et al. Influence of age on ECT efficacy in depression and the mediating role of psychomotor retardation and psychotic features. J Psychiatr Res 2019; 109:41–-47. 22. Pinna M, et al. Clinical and biological predictors of response to electroconvulsive therapy (ECT): a review. Neurosci Lett 2018; 669:32–42. 23. Spaans HP, et al. Early complete remitters after electroconvulsive therapy: profile and prognosis. J ECT 2016; 32:82–87. 24. Birkenhager TK, et al. One-year outcome of psychotic depression after successful electroconvulsive therapy. J ECT 2005; 21:221–226. 25. Wagenmakers MJ, et al. Psychotic late-life depression less likely to relapse after electroconvulsive therapy. J Affect Disord 2020; 276:984–990. 26. Navarro V, et al. Continuation/maintenance treatment with nortriptyline versus combined nortriptyline and ECT in late-life psychotic depression: a two-year randomized study. Am J Geriatr Psychiatry 2008; 16:498–505. 27. Bingham KS, et al. Stabilization treatment of remitted psychotic depression: the STOP-PD study. Acta Psychiatr Scand 2018; 138:267–273. 28. Flint AJ, et al. Effect of continuing olanzapine vs placebo on relapse among patients with psychotic depression in remission: the STOP-PD II randomized clinical trial. JAMA 2019; 322:622–631. 29. Block T, et al. Mifepristone plasma level and glucocorticoid receptor antagonism associated with response in patients with psychotic depression. J Clin Psychopharmacol 2017; 37:505–511. 30. Huang CC, et al. Adjunctive use of methylphenidate in the treatment of psychotic unipolar depression. Clin Neuropharmacol 2008; 31:245–247. 31. Kajiya T, et al. Effect of lamotrigine in the treatment of bipolar depression with psychotic features: a case report. Ann Gen Psychiatry 2017; 16:31. 32. Meyer JM, et al. Augmentation of phenelzine with aripiprazole and quetiapine in a treatment-resistant patient with psychotic unipolar depression: case report and literature review. CNS Spectr 2017; 22:391–396. 33. Miyaoka T, et al. Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study. Prog Neuropsychopharmacol Biol Psychiatry 2012; 37:222–226.

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Switching antidepressants

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General guidelines

366 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Switching antidepressants General guidelines When changing from one antidepressant to another, abrupt withdrawal of the first drug should be avoided unless there has been a serious adverse event. Cross-tapering is usually preferred – the dose of the ineffective or poorly tolerated drug is slowly reduced while the new drug is slowly introduced. The time taken to withdraw from the first antidepressant is dependent on the drug, the dose, the duration of prior treatment and the drug to which the patient is being switched.1 Example Daily dose Week 1 Week 2 Week 3 Week 4 Withdrawing citalopram 40mg 20mg 10mg 5mg 2.5mg Introducing mirtazapine Nil 15mg 30mg 30mg 45mg (if required) ■ ■The speed of cross-tapering is best judged by patient tolerability. Extended periods of hyperbolic tapering may be necessary to mitigate withdrawal symptoms when they emerge.2 ■ ■Cross-tapering is not always possible. The co-administration of some antidepressants, even when cross-tapering, is absolutely contraindicated. In other cases, theoretical risks or lack of experience preclude recommending cross-tapering. ■ ■The switching strategy depends not only on the reason for switching – inadequate or non-response, poor tolerability or adverse effects – but also on the pharmacokinetic and pharmacodynamic properties of the antidepressants involved.3–5 ■ ■In some cases, cross-tapering may not be necessary. For example, people who have been treated with an antidepressant for less than 3–4 weeks can probably safely stop abruptly and the new antidepressant can be started the next day. Another example is when switching between SSRIs – their effects may be so similar that administration of the second drug is likely to ameliorate withdrawal effects of the first. The use of fluoxetine has been advocated as an abrupt switch treatment to mitigate SSRI discontinuation symptoms6 (but see below). Abrupt cessation may also, albeit rarely, be acceptable when switching to a drug with a similar, but not identical, mode of action.7 Thus, in some cases, abruptly stopping one antidepressant and starting another at the usual dose may not only be well tolerated but may also reduce the risk and severity of discontinuation symptoms. ■ ■It is usually advisable to reduce the first antidepressant to the minimum effective dose before directly switching to the minimum effective dose of the second (see section on recognised minimum effective doses of antidepressants in this chapter).

Depression and anxiety disorders CHAPTER 3 ■ ■Stop–start switching is not always successful, particularly when switching to fluoxetine. The probable reason for this is that plasma levels of fluoxetine and its active metabolite take time to build up to steady state – usually 1–2 weeks. So, even when switching from an apparently equivalent dose (say 20mg paroxetine to 20mg fluoxetine) the plasma levels after one 20mg dose8 of fluoxetine are only 20% of plasma concentration at steady state.9 Thus, this switch is effectively an 80% reduction in drug activity. Withdrawal reactions are almost inevitable. There is more discussion of this and other relevant issues in the Maudsley Deprescribing Guidelines.10 ■ ■Potential dangers of simultaneously administering two antidepressants include pharmacodynamic interactions (serotonin syndrome, hypotension, drowsiness – depending on the drugs involved) and pharmacokinetic interactions (e.g. elevation of the co- administered antidepressant plasma levels by some SSRIs). In the absence of inhibitory pharmacokinetic interactions, it is best to keep the combined percentage maximum dose below 100% (e.g. 50% maximum dose of one drug + 50% maximum dose of another). ■ ■Agomelatine does not seem to be associated with a discontinuation syndrome,11 but slow withdrawal when switching is nonetheless recommended. Given agomelatine’s mode of action (melatonin agonism; 5HT2C antagonism), it is not expected to mitigate discontinuation reactions of other antidepressants. There is no theoretical basis to suggest that pharmacodynamic interactions might occur between agomelatine and other co-administered antidepressants but, in the absence of useful data, caution is advised. Some pharmacokinetic interactions do occur, and agomelatine should not be administered with fluvoxamine or viloxazine. ■ ■Serotonin syndrome can occur with a single serotonergic drug at a therapeutic dose or more commonly in combination of serotonergic drugs or in overdose. Many severe cases of serotonin syndrome involve an MAOI (including moclobemide) plus an SSRI.12,13 Caution is advised when switching strategies call for the combining of serotonergic drugs. Serotonin syndrome – symptoms Increasing severity Severity Symptoms Mild Insomnia, anxiety, nausea, diarrhoea, hypertension, tachycardia, hyper-reﬂexia Moderate Agitation, myoclonus, tremor, mydriasis, ﬂushing, diaphoresis, low fever (<38.5°C) Severe Severe hyperthermia, confusion, rigidity, respiratory failure, coma, death The advice given in Table 3.7 should be treated with caution and patients should be very carefully monitored when switching.

368 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Table 3.7 Antidepressants – swapping and stopping.* To From Agomelatine Bupropion Clomipramine Fluoxetine Fluvoxamine MAOIs Phenelzine Tranylcypromine Selegiline Agomelatinea Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Stop agomelatine then start fluvoxamine Cross-taper cautiously Bupropionb Cross-taper cautiously Cross-taper cautiously with low-dose clomipramine Cross-taper cautiously Cross-taper cautiously Taper and stop then wait for 2 weeks then start MAOIs Clomipramine Cross-taper cautiously Cross-taper cautiously Taper and stop then start fluoxetine at 10mg/ day Taper and stop then start low-dose fluvoxamine Taper and stop then wait for 3 weeks then start MAOIs Fluoxetinec Cross-taper cautiously Stop fluoxetine then wait for 4–7 days then start bupropion Stop fluoxetine then wait for 2 weeks then start low-dose clomipramine Stop fluoxetine then wait for 4–7 days then start fluvoxamine Stop fluoxetine then wait for 5–6 weeks then start MAOIs Fluvoxamined Taper and stop then wait for 4 days Cross-taper cautiously Taper and stop then start low-dose clomipramine Direct switch possible^ Taper and stop then wait for 1 week then start MAOIs MAOIs Phenelzine Tranylcypromine Selegiline Cross-taper cautiously Taper and stop then wait for 2 weeks Taper and stop then wait for 3 weeks Taper and stop then wait for 2 weeks Taper and stop then wait for 2 weeks Taper and stop then wait for 2 weeks Moclobemide Taper and stop then wait for 24 hours Taper and stop then wait for 24 hours Taper and stop then wait for 24 hours Taper and stop then wait for 24 hours Taper and stop then wait for 24 hours Taper and stop then wait for 24 hours then start MAOIs Mirtazapine Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Taper and stop then wait for 2 weeks Reboxetinee Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Taper and stop then wait for 1 week then start MAOIs

370 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 To From Agomelatine Bupropion Clomipramine Fluoxetine Fluvoxamine MAOIs Phenelzine Tranylcypromine Selegiline Trazodone Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously with low-dose clomipramine Cross-taper cautiously Cross-taper cautiously Taper and stop then wait for 1 week Other SSRIsf Vortioxetineg Cross-taper cautiously Cross-taper cautiously Taper and stop then start low-dose clomipramine Direct switch possible^ Direct switch possible Taper and stop then wait for 1 weekh SNRI Duloxetinei Venlafaxine Desvenlafaxine Cross-taper cautiously Cross-taper cautiously Taper and stop then start low-dose clomipramine Direct switch possible^ Direct switch possible Taper and stop then wait for 1 week Tricyclics Cross-taper cautiously Halve dose and add bupropion and then slow withdrawal Direct switch possible Halve dose and add fluoxetine and then slow withdrawal Cross-taper cautiously Taper and stop then wait for 2 weeksj Viloxazinek Taper and stop then wait for 48 hours Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Taper and stop then wait for 2 weeks Table 3.7 (Continued)

Depression and anxiety disorders CHAPTER 3 Moclobemide Mirtazapine Reboxetine Trazodone Other SSRIsf Vortioxetine SNRIs Duloxetine Venlafaxine Desvenla- faxine TCAs (except clomipramine) Viloxazine Taper and stop then wait for 1 week then start moclobemide Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously with low-dose TCA Cross-taper cautiously Taper and stop then wait for 1 week then start moclobemide Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Direct switch possible Direct switch possible Cross-taper cautiously with low-dose TCA Cross-taper cautiously Taper and stop then wait for 1 week then start moclobemide Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Direct switch possible Direct switch possible Cross-taper cautiously with low-dose TCA Cross-taper cautiouslyk Taper and stop then wait for 1 week then start moclobemide Cross-taper cautiously Cross-taper cautiously Halve dose and add trazodone and then slow withdrawal Halve dose and add SSRI and then slow withdrawal Cross-taper cautiously starting with low-dose SNRI Direct switch possible Cross-taper cautiously Taper and stop then wait for 1 week then start moclobemide Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Cross-taper cautiously Notes: * Advice given in this table is partly derived from manufacturers’ information and available published data and partly theoretical. There are several factors that affect individual drug handling and caution is required in every instance. Cross taper cautiously – usually over 2–4 weeks as per example. a Agomelatine has no effect on monoamine uptake and no affinity for α, β adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors. The potential for interactions between agomelatine and other antidepressants is low and it is not expected to mitigate discontinuation reactions of other antidepressants. Some crossover with other antidepressants might be cautiously attempted when switching from agomelatine, as indicated in the table. b Bupropion is licensed for smoking cessation but unlicensed for the treatment of depression in the UK. It is a CYP2D6 inhibitor and particular caution is required when cross-tapering with drugs metabolised by this enzyme. c Beware: interactions with fluoxetine may still occur for 5 weeks after stopping fluoxetine because of its metabolite’s long half-life. d Fluvoxamine is a potent inhibitor of CYP1A2, and to a lesser extent of CYP2C and CYP3A4, and has a high potential for interactions hence extra caution is required. e Switching to reboxetine as antidepressant monotherapy is no longer recommended. f Citalopram, escitalopram, paroxetine and sertraline. g Limited experience with vortioxetine and extra caution is required. Take particular care when switching to or from bupropion and other CYP2D6 inhibitors such as fluoxetine and paroxetine.14 h Wait 3 weeks in the case of vortioxetine.15 i Abrupt switch from SSRIs and venlafaxine to duloxetine is possible, starting at 60mg/day.7 j Wait 3 weeks in the case of imipramine. k Viloxazine is a selective noradrenaline reuptake inhibitor. Now licensed for the treatment of ADHD in the US. Increases in heart rate and diastolic blood pressure have been reported, so caution with SNRIs. ^ Caution when directly switching to fluoxetine. Some overlap (a few days) may be advisable to allow fluoxetine plasma concentration to build up before stopping the first antidepressant. Switching from vortioxetine is a probable exception to this, given its long half-life.

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References

372 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 References

Horowitz MA, et al. Estimating risk of antidepressant withdrawal from a review of published data. CNS Drugs 2023; 37:143–157.
Horowitz MA, et al. Tapering of SSRI treatment to mitigate withdrawal symptoms. Lancet Psychiatry 2019; 6:538–546.
Cleare A, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol 2015; 29:459–525.
Harvey BH, et al. New insights on the antidepressant discontinuation syndrome. Hum Psychopharmacol 2014; 29:503–516.
Malhi GS, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry 2015; 49:1087–1206.
Benazzi F. Fluoxetine for the treatment of SSRI discontinuation syndrome. Int J Neuropsychopharmacol 2008; 11:725-726.
Perahia DG, et al. Switching to duloxetine from selective serotonin reuptake inhibitor antidepressants: a multicenter trial comparing 2 switching techniques. J Clin Psychiatry 2008; 69:95–105.
Díaz-Tufinio CA, et al. Pharmacogenetic variants associated with fluoxetine pharmacokinetics from a bioequivalence study in healthy subjects. Journal of Personalized Medicine 2023; 13:1352.
el-Yazigi A, et al. Steady-state kinetics of fluoxetine and amitriptyline in patients treated with a combination of these drugs as compared with those treated with amitriptyline alone. J Clin Pharmacol 1995; 35:17–21.
Horowitz M, et al. The Maudsley Deprescribing Guidelines: Antidepressants, Benzodiazepines, Gabapentinoids and Z-drugs. Oxford: Wiley-Blackwell; 2024.
Goodwin GM, et al. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2009; 70:1128–1137.
Buckley NA, et al. Serotonin syndrome. BMJ 2014; 348:g1626.
Abadie D, et al. Serotonin syndrome: analysis of cases registered in the French pharmacovigilance database. J Clin Psychopharmacol 2015; 35:382–388.
Chen G, et al. Pharmacokinetic drug interactions involving vortioxetine (Lu AA21004), a multimodal antidepressant. Clin Drug Investig 2013; 33:727–736.
Citrome L. Vortioxetine for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant: what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract 2014; 68:60–82.

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42 - Antidepressant withdrawal symptoms

Antidepressant withdrawal symptoms

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Signs and symptoms

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44 - Incidence and severity

Incidence and severity

Depression and anxiety disorders CHAPTER 3 Antidepressant withdrawal symptoms Signs and symptoms Antidepressant withdrawal symptoms may be entirely new or similar to some of the original symptoms of the illness for which the medication was originally given. Withdrawal symptoms can be distinguished from a relapse or reoccurrence of the underlying disorder by their rapid onset (days, rather than weeks, or within three to five half-lives of the drug),1 the rapid response to reintroduction of the antidepressant (generally within hours, certainly within days), and the presence of somatic and psychological symptoms distinct from the original illness (e.g. brain zaps, dizziness, nausea).2 The wide variety of symptoms reported with SSRIs and related drugs is summarised in Figure 3.2. Symptoms reported with other antidepressants are summarised in Table 3.8. Incidence and severity Antidepressant withdrawal/discontinuation symptoms occur in many patients (Box 3.1). Incidence rates from 14 studies that examined antidepressant withdrawal ranged from 27% to 86%, with a weighted average of 56%.3 Although reported incidence rates vary widely between studies of different drugs and methodologies (9% to 77% for fluoxetine, and from 42% to 100% with paroxetine),3 symptoms are seen to some extent with all antidepressants, with the possible exception of agomelatine.1 Two meta- analyses published in 2024 gave strikingly different estimates of withdrawal incidence.4,5 Sensory symptoms Paresthesia Numbness ‘Shock-like’ or ‘electric zap’ sensations in head or limbs Rushing noises Palinopsia (visual trails) Hyperacusis Unusual taste/smell/visual sensations General somatic symptoms Flu-like symptoms Lethargy/fatigue Headache Tremor Sweating Anorexia Weakness Techycardia Muscle aches/pains Shaking/trembling Affective symptoms Irritability Anxiety/agitation Low mood/depression Tearfulness Dread Panic attacks SSRI withdrawal syndrome Disequilibrium Dizziness (most common) Light-headedness Vertigo Ataxia Gait instability Sleep disturbance Insomnia Nightmares Excessive dreaming Gastrointestinal symptoms Nausea Vomiting Diarrhoea Anorexia Sexual Genital hypersensitivity Premature ejaculation Cognitive Confusion Decreased concentration Amnesia Depersonalisation De-realisation Figure 3.2 Common withdrawal symptoms with SSRIs and similar drugs.

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45 - Time course

Time course

374 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Time course The onset and severity of symptoms are related to the half-life of the antidepressant. Placebo/nocebo effects and loss of therapeutic efficacy may also be important. Short half-life antidepressants like paroxetine and venlafaxine produce symptoms within a day or two, whereas symptoms with fluoxetine can be delayed by 2–6 weeks.2 Symptoms can vary in duration, form and intensity and occur in any combination. While they can be mild and self-limiting, there is substantial variation between individuals and, for some people, symptoms can last much longer than previously reported.6 The perception of symptom severity is probably made worse by the absence of forewarnings. Some symptoms are more likely with individual drugs (see below). Symptoms can be quantified using the Discontinuation–Emergent Signs and Symptoms Scale.7 Box 3.1 Factors influencing the incidence and severity of antidepressant withdrawal symptoms Pharmacological factors: ■ ■Pharmacokinetics ■ ■Drug half-life ■ ■Pharmacodynamics ■ ■Receptor affinities Treatment factors: ■ ■Duration of treatment ■ ■Dose ■ ■Method of tapering Patient-specific factors: ■ ■Prior experience and anticipation effects Other factors: ■ ■Drug half-lives – correlate with the severity and onset of symptoms. Symptoms typically more severe with shorter half-life drugs (e.g. venlafaxine, paroxetine) ■ ■Other pharmacokinetic factors: non-linear pharmacokinetics ■ ■Receptor affinities: higher affinity for the serotonin transporter may confer higher risk of withdrawal symptoms (Continued) Table 3.8 Symptoms reported with other (non-SSRI) antidepressants. Antidepressant type Symptoms Agomelatine Seems to be associated with a very low, if any, risk of discontinuation symptoms1 Bupropion Uncommon, but case reports have described anxiety, headache, insomnia, irritability and myalgias;8,9 single case report of acute dystonia10 Monoamine oxidase inhibitors* Common: agitation, irritability, ataxia, movement disorders, insomnia, somnolence, vivid dreams, cognitive impairment, slowed speech, pressured speech. Occasionally, hallucinations, paranoid delusions. RIMAs: flu-like symptoms reported with moclobemide.11 NaSSAs (e.g. mirtazapine) Panic, anxiety, restlessness, irritability, hypomania, insomnia, dizziness, paraesthesia, nausea, vomiting10

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46 - Clinical relevance14,15

Clinical relevance14,15

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47 - Who is at risk10,1416,18

Who is at risk?10,14–16,18

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48 - How to avoid1416,18

How to avoid14–16,18

Depression and anxiety disorders CHAPTER 3 Clinical relevance14,15 The symptoms of a withdrawal reaction may be mistaken for a relapse of illness or the emergence of a new physical illness,16 leading to unnecessary investigations or reintroduction of the antidepressant. Symptoms may be severe enough to interfere with daily functioning and those who have experienced discontinuation symptoms may reason (perhaps understandably) that antidepressants are ‘addictive’ and not wish to accept treatment. There is also evidence of emergent suicidal thoughts on discontinuation with paroxetine.17 Who is at risk?10,14–16,18 Although anyone can experience discontinuation symptoms, the risk is increased in those prescribed short half-life drugs (e.g. paroxetine, venlafaxine),7 particularly if they do not take them regularly. Two-thirds of patients prescribed antidepressants skip a few doses from time to time,19 and many patients stop their antidepressant abruptly.20 The risk is also increased in those who have been taking antidepressants for 8 weeks or longer,21 those taking antidepressants at higher doses, those who have developed anxiety symptoms at the start of antidepressant therapy (particularly with SSRIs), those receiving other centrally acting medication (e.g. antihypertensives, antihistamines, antipsychotics), children and adolescents,7 younger patients,22 and those who have experienced withdrawal symptoms before. How to avoid14–16,18 Generally, antidepressant therapy should be discontinued gradually.6 The shorter the half-life of the drug, the more important it is that this rule is followed. The end of the taper may need to be slower, as symptoms may not appear until the reduction in the total daily dosage of the antidepressant is (proportionately) substantial. Patients receiving MAOIs may need to be tapered over a longer period. Tranylcypromine may be particularly Table 3.8 (Continued) Antidepressant type Symptoms Serotonin modulators (vortioxetine, vilazodone) None reported,10 although these are relatively new antidepressants with less clinical experience. Shared pharmacological actions with other antidepressants (SSRIs) so possibility of withdrawal symptoms cannot be discounted.10 TCAs General somatic and GI distress, sleep disturbances characterised by initial and middle insomnia or excessively vivid and frightening dreams, akathisia or parkinsonism, hypomania or mania, cardiac arrhythmia10 Trazodone Hypomania, anxiety, restless sleep, nightmares, depersonalisation, formication, headache10 * Tranylcypromine may have amfetamine-like properties at higher doses12 and therefore could be associated with a true ‘withdrawal syndrome’. Delirium may occur.13 NaSSA, noradrenergic and specific serotonergic antidepressant; RIMA, reversible inhibitor of monoamine oxidase A; TCA, tricyclic antidepressant.

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49 - How to treat1416,23

How to treat14–16,23

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50 - References

References

376 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 difficult to stop.13 At-risk patients (see above) may need a slower taper. Agomelatine can probably be stopped abruptly without provoking withdrawal symptoms but should be slowly withdrawn as a matter of principle – all psychotropic drugs should be slowly withdrawn where possible. Many people suffer symptoms despite slow withdrawal and even if they have received adequate education regarding withdrawal symptoms.7,17 This may be because hyperbolic tapering is not employed (see section on stopping antidepressants in this chapter). How to treat14–16,23 There are few systematic studies in this area. Treatment is pragmatic. If symptoms are mild, reassure the patient that these symptoms are common after discontinuing an antidepressant and will pass in a few days or weeks. If symptoms are severe, reintroduce the original antidepressant (or another with a longer half-life from the same class) and taper gradually while monitoring for symptoms.6 Some evidence supports the use of anticholinergic agents in tricyclic withdrawal24 and fluoxetine for symptoms associated with stopping paroxetine,25 sertraline,25 clomipramine26 or venlafaxine27 – fluoxetine, with active metabolites, having a much longer plasma half-life, seems to be associated with a lower incidence of discontinuation symptoms than other similar drugs.7 The use of alternative classes of medications (e.g. shortterm symptomatic use of a benzodiazepine) has been suggested for the treatment of anxiety and insomnia.28 References

Henssler J, et al. Antidepressant withdrawal and rebound phenomena. Dtsch Arztebl Int 2019; 116:355–361.
Horowitz MA, et al. Tapering of SSRI treatment to mitigate withdrawal symptoms. Lancet Psychiatry 2019; 6:538–546.
Davies J, et al. A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: are guidelines evidence- based? Addict Behav 2019; 97:111–121.
Henssler J, et al. Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis. Lancet Psychiatry 2024; 11:526–535.
Zhang MM, et al. Incidence and risk factors of antidepressant withdrawal symptoms: a meta-analysis and systematic review. Mol Psychiatry 2024; doi: 10.1038/s41380-024-02782-4.
National Institute for Health and Care Excellence. Depression in adults: treatment and management. NICE guideline [NG222]. 2022 (last reviewed September 2024, last checked November 2024); https://www.nice.org.uk/guidance/ng222.
Fava GA, et al. Withdrawal symptoms after selective serotonin reuptake inhibitor discontinuation: a systematic review. Psychother Psychosom 2015; 84:72–81.
Berigan TR. Bupropion-associated withdrawal symptoms revisited: a case report. Prim Care Companion J Clin Psychiatry 2002; 4:78.
Berigan TR, et al. Bupropion-associated withdrawal symptoms: a case report. Prim Care Companion J Clin Psychiatry 1999; 1:50–51.
Cosci F, et al. Acute and persistent withdrawal syndromes following discontinuation of psychotropic medications. Psychother Psychosom 2020; 89:283–306.
Curtin F, et al. Moclobemide discontinuation syndrome predominantly presenting with influenza-like symptoms. J Psychopharmacol 2002; 16:271–272.
Ricken R, et al. Tranylcypromine in mind (part II): review of clinical pharmacology and meta-analysis of controlled studies in depression. Eur Neuropsychopharmacol 2017; 27:714–731.
Gahr M, et al. Withdrawal and discontinuation phenomena associated with tranylcypromine: a systematic review. Pharmacopsychiatry 2013; 46:123–129.
Lejoyeux M, et al. Antidepressant withdrawal syndrome: recognition, prevention and management. CNS Drugs 1996; 5:278–292.
Haddad PM, et al. Recognising and managing antidepressant discontinuation symptoms. Adv Psychiatr Treat 2007; 13:447–457.
Haddad PM. Antidepressant discontinuation syndromes. Drug Saf 2001; 24:183–197.
Tint A, et al. The effect of rate of antidepressant tapering on the incidence of discontinuation symptoms: a randomised study. J Psychopharmacol 2008; 22:330–332.
Ogle NR, et al. Guidance for the discontinuation or switching of antidepressant therapies in adults. J Pharm Pract 2013; 26:389–396.

Depression and anxiety disorders CHAPTER 3 19. Meijer WE, et al. Spontaneous lapses in dosing during chronic treatment with selective serotonin reuptake inhibitors. Br J Psychiatry 2001; 179:519–522. 20. van Geffen EC, et al. Discontinuation symptoms in users of selective serotonin reuptake inhibitors in clinical practice: tapering versus abrupt discontinuation. Eur J Clin Pharmacol 2005; 61:303–307. 21. Kramer JC, et al. Withdrawal symptoms following discontinuation of imipramine therapy. Am J Psychiatry 1961; 118:549–550. 22. Read J. How common and severe are six withdrawal effects from, and addiction to, antidepressants? The experiences of a large international sample of patients. Addict Behav 2020; 102:106157. 23. Wilson E, et al. A review of the management of antidepressant discontinuation symptoms. Ther Adv Psychopharmacol 2015; 5:357–368. 24. Dilsaver SC, et al. Antidepressant withdrawal symptoms treated with anticholinergic agents. Am J Psychiatry 1983; 140:249–251. 25. Benazzi F. Re: Selective serotonin reuptake inhibitor discontinuation syndrome: putative mechanisms and prevention strategies. Can J Psychiatry 1999; 44:95–96. 26. Benazzi F. Fluoxetine for clomipramine withdrawal symptoms. Am J Psychiatry 1999; 156:661–662. 27. Giakas WJ, et al. Intractable withdrawal from venlafaxine treated with fluoxetine. Psychiatr Ann 1997; 27:85–93. 28. Fava GA, et al. Understanding and managing withdrawal syndromes after discontinuation of antidepressant drugs. J Clin Psychiatry 2019; 80:19com12794.

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51 - Stopping antidepressants

Stopping antidepressants

08 - Chapter 3 Depression and anxiety disorders

52 - Rate of tapering

Rate of tapering

378 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Stopping antidepressants Up to 50% of patients will experience withdrawal symptoms on reducing or stopping an antidepressant,1,2 but symptoms are less common in shorter-term users.3 For a small proportion of patients, withdrawal symptoms will be severe1,3 or will last for months or years.1,4 Post-acute or protracted withdrawal syndrome (PAWS) is the term used for long-lasting symptoms that last for years and may involve myriad, sometimes debilitating, symptoms.2,5 Alterations to serotonin and hormonal systems after stopping antidepressants are seen in patients and animals and these changes may persist for months and years after long-term antidepressant exposure.2 There are a number of characteristics of antidepressant use that influence the likelihood of withdrawal effects. Patients who have been on antidepressants for longer periods and at higher doses are more likely to have withdrawal effects.2 Antidepressants with short half-lives and anticholinergic or noradrenergic effects tend to be associated with more severe withdrawal. Venlafaxine, desvenlafaxine, duloxetine and paroxetine are the most often implicated.2,6 Patients who stop abruptly or rapidly have more withdrawal effects.7 There are likely to be a range of individual physiological (and psychological) differences, as yet poorly understood, which also determine withdrawal severity.2 Withdrawal symptoms include both physical and psychological symptoms, because antidepressants affect a wide variety of bodily systems.7 Physical symptoms include headache, dizziness, nausea, depersonalisation/derealisation, muscle cramps, brain ‘zaps’ and akathisia. Psychological symptoms include low mood, anxiety, panic attacks, tearfulness, obsessive thinking, impaired concentration and suicidality. Psychological symptoms can easily be mistaken for a relapse of an underlying condition. Timing of onset, symptoms distinct in nature or severity from the underlying condition and response to reinstatement of the drug can help to distinguish withdrawal effects from relapse.8 Further details are provided in the Maudsley Deprescribing Guidelines: Antidepressants, Benzodiazepines, Gabapentinoids and Z-drugs.9 Rate of tapering There is good evidence that tapering slowly can reduce the likelihood of withdrawal symptoms and also of relapse.7,10,11 Meta-regression of discontinuation studies found a highly significant lowering of relapse rate with longer tapering.10 In fact, there was no difference in relapse rate between maintenance treatment and tapering over 6 months.10 While tapering over several months reduces the risk of withdrawal symptoms,7 some patients may take years to withdraw. Clinical experience suggests that long-term users of antidepressants generally take between 3 months and 3 years to withdraw in a tolerable manner.12 In one study, 40% of patients taking antidepressants for more than 1–2 years were able to taper off successfully in approximately 4 months, suggesting that 60% will need longer than this.13

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53 - Pattern of tapering

Pattern of tapering

Depression and anxiety disorders CHAPTER 3 Pattern of tapering Although reducing by linear amounts (e.g. 50mg, 37.5mg, 25mg, 12.5mg, 0 for sertraline) seems intuitively reasonable (and practical, through splitting tablets), because of the hyperbolic relationship between dose of antidepressant and effect on its principal target, the serotonin receptor (SERT) (following the law of mass action),14 this is likely to produce increasingly severe withdrawal symptoms (Figure 3.3a).7 This is consistent with patient reports that reducing at small doses is the most difficult aspect of the process. It makes more sense to reduce the drug in such a way that it produces a fixed reduction in effect on target receptors at each step: this entails hyperbolic dose reductions (Figure 3.3b). This is most easily approximated by exponential (proportional) reductions of dose – for example, reducing by 10–25% of the most recent dose every 2–4 weeks (so that the size of the reductions gets smaller and smaller as the total dose gets lower). The final dose before completely stopping may need to be very small (<1mg) to prevent the reduction to zero being a bigger fall in activity than previously tolerated reductions. This is supported by evidence that tapering down to doses much lower than common therapeutic doses (e.g. 1mg for sertraline) improves the likelihood that people will be able to stop antidepressants,15,16 and remain off them,17 as compared with tapering in a ‘linear’ fashion to minimum therapeutic doses. This approach to tapering is recommended by NICE18,19 and the Royal College of Psychiatrists.20 Further details on how to safely stop antidepressants can be found in the Maudsley Deprescribing Guidelines: Antidepressants, Benzodiazepines, Gabapentinoids and Z-drugs, including specific reduction schedules for all licensed antidepressants.9 (a) (b) SERT occupancy (%) 40 0 50 Sertraline dose (mg) 150 80 SERT occupancy (%) 40 0 50 Sertraline dose (mg) 150 Figure 3.3 (a) Linear reductions of dose cause increasingly large reductions in effect on receptor targets, probably associated with more withdrawal effects. (b) ‘Even’ reductions of effect at target receptors require hyperbolic dose reductions. The final dose before stopping will need to be very small to minimise the destabilisation caused by this reduction.

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54 - Practical application of tapering

Practical application of tapering

380 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Practical application of tapering Before tapering All patients should be informed of the risk of withdrawal symptoms on stopping any antidepressant. Some antidepressants, such as paroxetine and SNRIs, are more commonly associated with severe withdrawal symptoms. Patients should be warned not to stop antidepressants abruptly, because this is the method thought to be most likely to give rise to severe and long-lasting withdrawal symptoms and to an increased risk of relapse. Although stopping antidepressants can cause some unpleasant symptoms, patients should be told that if they taper gradually and carefully, withdrawal symptoms can be maintained at tolerable levels. As patients may have had negative experiences of too- rapid tapering in the past, reassurance may be required. It is difficult to predict the exact period required for an individual to taper off antidepressant medication but most patients who have been taking antidepressants long term take between 3 months and 3 years. This may help to set expectations. Patients’ past experiences of stopping should be explored, as they can be informative for predicting what symptoms may arise again on tapering. Careful consideration of past attempts to stop may detect withdrawal symptoms being misdiagnosed as relapse. Often, patients will require some preparation for antidepressant tapering. This might include arrangements for lightening work or family duties or increased focus on non- pharmacological coping skills (patients have found a wide variety of tools useful, including acceptance, breathing exercises, exercise, hobbies, diary keeping and de- catastrophising).21,22 Psychological interventions to support tapering demonstrated limited effectiveness, probably because physiological factors predominate, and psychological support, while potentially helpful, is not a substitute for gradual, pharmacologically informed tapering.13,23 Both clinicians and patients should be aware that patients can experience negative psychological and physical symptoms during withdrawal that need not indicate that the full dose of the drug is needed (but may indicate that the taper rate needs to be slowed). Familiarity of the patient and the doctor with the wide variety of withdrawal symptoms (Figure 3.3) may help to mitigate unnecessary anxiety when symptoms arise and prevent misdiagnosis of relapse or other physical (such as neurological or psychosomatic conditions) or mental health conditions (such as anxiety, depressive or even psychotic disorders when symptoms are extreme), as often occurs.24 Patients may require more support during the process, professional or otherwise.22 The process of tapering Patients may be broadly risk-stratified (further details are provided in the Maudsley Deprescribing Guidelines):9 ■ ■For low-risk patients (<6 months of use, low-risk antidepressant, no experience of significant withdrawal symptoms in the past), a test reduction could be made (of 25–50%). ■ ■For high-risk patients (>24 months of use, high-risk antidepressant, past history of severe withdrawal symptoms) a test reduction of 5–10% should be recommended. ■ ■Intermediate-risk patients could reduce by 10–20% of their original dose.

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55 - Troubleshooting

Troubleshooting

Depression and anxiety disorders CHAPTER 3 A cautious initial rate of reduction is prudent. The rate of withdrawal can be sped up if symptoms are tolerable. If severe withdrawal symptoms are precipitated by the first step down, then the process may be set to be a difficult one. The first reduction is perhaps the most important. Withdrawal symptoms should be monitored for 2–4 weeks for all patients, or until symptoms have resolved. Monitoring may take the form of simple measures of symptoms each day (e.g. out of 10), which may be more convenient than using long standardised measurement such as the Discontinuation–Emergent Signs and Symptoms scale.25 Further reductions should be titrated against the tolerability of this experience. If the initial reduction was tolerable and withdrawal symptoms were absent or have resolved by the end of this monitoring period, continue reducing dose by the same proportion (worked out on the last dose used; see example regimens in Box 3.2). If symptoms were intolerable, then the taper should proceed at a slower rate. If severe, this may require reinstatement of the previous dose, a period of stabilisation and then a more cautious reduction schedule. Troubleshooting If withdrawal symptoms become intolerable at any point, either hold the current dose for longer to allow them to resolve or, if very unpleasant, increase to the last dose at which the symptoms were tolerable and remain there until symptoms resolve. After stabilisation, tapering will need to be more gradual, with reductions made by smaller amounts. Some patients find they cannot reduce at more than 5% of the last dose per month. If a patient experiences distressing withdrawal symptoms, it does not indicate that they cannot stop antidepressants but that they will need to taper more slowly, with smaller reductions than they have been undertaking. Owing to the long half-life of fluoxetine, withdrawal symptoms can be delayed by weeks, so careful attention should be paid to this. (For reasons that may relate to brain elimination half-lives even shorter-acting antidepressants can present with delayed- onset withdrawal effects.)26 As the withdrawal period is spread over a longer period, larger reductions of fluoxetine may be relatively tolerable,7 but fluoxetine cannot be said to be ‘self-tapering’ for long-term users and so should not be stopped abruptly. Box 3.2 A simplified guide to tapering sertraline according to an exponential pattern The range of reductions provided is equivalent to about 10–25% dose reductions at each step. Some patients may require smaller reductions and others may tolerate larger reductions at a faster rate. ■ ■Reduce dose by 25–50mg every 2–4 weeks until reaching 50mg per day, then ■ ■Reduce by 5–10mg every 2–4 weeks until reaching 15mg per day, then ■ ■Reduce by 1.5–3mg every 2–4 weeks until reaching 6mg per day, then ■ ■Reduce by 0.5–1mg every 2–4 weeks until reaching 2mg per day, then ■ ■Reduce by 0.25–0.5mg every 2–4 weeks until completely stopped. This process normally takes between 3 months and 3 years but in some people can require longer periods.

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56 - References

References

382 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Unfortunately, most current tablet formulations of antidepressants do not permit hyperbolic tapering regimens, so patients will require the use of liquid formulations, as recommended by NICE18 (or compounded smaller dose formulations, e.g. tapering strips).15 Off-label options for making up smaller doses also exist, including crushing and suspending tablets, opening up capsules to count or weigh beads or diluting manufacturers’ liquid preparations, all of which are permissible according to various pharmaceutical authorities.27 Again, further details are provided for licensed and off-label options for hyperbolic tapering in the Maudsley Deprescribing Guidelines: Antidepressants, Benzodiazepines, Gabapentinoids and Z-drugs.9 For many drugs, the final dose before complete stopping will need to be much less than 1mg so that the reduction in effect on target receptors is not greater than the changes previously tolerated. References

Davies J, et al. A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: are guidelines evidence- based? Addict Behav 2019; 97:111–121.
Horowitz MA, et al. Estimating risk of antidepressant withdrawal from a review of published data. CNS Drugs 2023; 37:143-157.
Henssler J, et al. Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis. Lancet Psychiatry 2024; 11:526–535.
Stockmann T, et al. SSRI and SNRI withdrawal symptoms reported on an internet forum. Int J Risk Saf Med 2018; 29:175–180.
Cosci F, et al. Acute and persistent withdrawal syndromes following discontinuation of psychotropic medications. Psychother Psychosom 2020; 89:283–306.
Gastaldon C, et al. Withdrawal syndrome following discontinuation of 28 antidepressants: pharmacovigilance analysis of 31,688 reports from the WHO Spontaneous Reporting Database. Drug Saf 2022; 45:1539–1549.
Horowitz MA, et al. Tapering of SSRI treatment to mitigate withdrawal symptoms. Lancet Psychiatry 2019; 6:538–546.
Horowitz MA, et al. Distinguishing relapse from antidepressant withdrawal: clinical practice and antidepressant discontinuation studies. B J Psych Advances 2022; 28:297–311.
Horowitz M, et al. The Maudsley Deprescribing Guidelines: Antidepressants, Benzodiazepines, Gabapentinoids and Z-drugs. Chichester: Wiley-Blackwell; 2024.
Gøtzsche PC, et al. Interventions to help patients withdraw from depression drugs: a systematic review. Int J Risk Saf Med 2024; 35:103–116.
Baldessarini RJ, et al. Illness risk following rapid versus gradual discontinuation of antidepressants. Am J Psychiatry 2010; 167:934–941.
Cooper RE, et al. ‘Stabilise–reduce, stabilise–reduce’: a survey of the common practices of deprescribing services and recommendations for future services. PLoS One 2023; 18:e0282988.
Kendrick T, et al. Internet and telephone support for discontinuing long-term antidepressants: the REDUCE cluster randomized trial. JAMA Netw Open 2024; 7:e2418383.
Holford N. Pharmacodynamic principles and the time course of delayed and cumulative drug effects. Transl Clin Pharmacol 2018; 26:56–59.
Groot PC, et al. How user knowledge of psychotropic drug withdrawal resulted in the development of person-specific tapering medication. Ther Adv Psychopharmacol 2020; 10:2045125320932452.
Groot PC, et al. Antidepressant tapering strips to help people come off medication more safely. Psychosis 2018; 10:142–145.
Groot PC, et al. Outcome of antidepressant drug discontinuation with taperingstrips after 1–5 years. Ther Adv Psychopharmacol 2020; 10:2045125320954609.
National Institute for Health and Care Excellence. Depression in adults: treatment and management. NICE guideline [NG222]. 2022 (last reviewed September 2024, last checked September 2024); https://www.nice.org.uk/guidance/ng222.
National Institute for Health and Care Excellence. Medicines associated with dependence or withdrawal symptoms: safe prescribing and withdrawal management for adults [NG215]. 2022 (last checked September 2024); https://www.nice.org.uk/guidance/ng215.
Royal College of Psychiatrists. Stopping antidepressants. 2020 (last accessed September 2024); https://www.rcpsych.ac.uk/mental-health/ treatments-and-wellbeing/stopping-antidepressants.
Inner Compass Initiative. The Withdrawal Project; https://withdrawal.theinnercompass.org.
Guy A, et al. Guidance for Psychological Therapists: Enabling conversations with clients taking or withdrawing from prescribed psychiatric drugs. London: APPG for Prescribed Drug Dependence; 2019.
Scholten WD, et al. The efficacy of a group CBT relapse prevention program for remitted anxiety disorder patients who discontinue antidepressant medication: a randomized controlled trial. Psychother Psychosom 2018; 87:240–242.

Depression and anxiety disorders CHAPTER 3 24. Guy A, et al. The ‘patient voice’: patients who experience antidepressant withdrawal symptoms are often dismissed, or misdiagnosed with relapse, or a new medical condition. Ther Adv Psychopharmacol 2020; 10:2045125320967183. 25. Rosenbaum JF, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998; 44:77–87. 26. Sørensen A, et al. The relationship between dose and serotonin transporter occupancy of antidepressants-a systematic review. Mol Psychiatry 2022; 27:192–201. 27. Specialist Pharmacy Service. SSRI suggestions for adults with swallowing difficulties 2021 (last updated July 2024, accessed September 2024); https://www.sps.nhs.uk/articles/selective-serotonin-reuptake-inhibitor-ssri-formulations-suggested-for-adults-with-swallowing-difficulties.

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57 - Electroconvulsive therapy and psychotropic dr

Electroconvulsive therapy and psychotropic drugs

384 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Electroconvulsive therapy and psychotropic drugs Psychotropics are often continued during ECT. Some agents, such as antidepressants,1,2 enhance its efficacy. Table 3.9 summarises the effect of various psychotropics on seizure duration during ECT. There are few well-controlled studies in this area and recommendations should be viewed with this in mind. The choice of anaesthetic agent may profoundly affect seizure duration3,4 as well as the severity of post-ictal confusion and ECT efficacy.5,6 Somewhat against expectation, the use of ketamine or esketamine7,8 as an anaesthetic does not ultimately improve outcome with ECT,9 although ketamine may provide short-term improvement of depressive symptoms at the early stages of ECT.10 Aside from concurrent medication, there are many factors that influence seizure threshold and duration.11 Caffeine reduces seizure threshold and can be used to enable or prolong seizures in ECT.12 Flumazenil has similar effects.13 ECT frequently causes confusion and disorientation. More rarely, it causes an acute confusional state or delirium. Concurrent lithium may increase the risk of delirium.2 Agitation may also occur.14 The use of dexmedetomidine seems to reduce the risk of post-ECT agitation.15 There have been a few reports of serotonin syndrome when serotonergic medications have been used with ECT.16–18 Close observation is essential. Very limited data support the use of thiamine (200mg daily) in reducing post-ECT confusion.19 Some drugs have been investigated for improving the cognitive adverse effects of ECT.20 Supporting evidence is of a low (memantine, liothyronine) or a very low quality (acetylcholinesterase inhibitors, piracetam, melatonin).20 None is recommended. Paracetamol21 or ibuprofen may be used to prevent headache;22 intranasal sumatriptan23 can be used to treat it. Table 3.9 Effect of psychotropic drugs on seizure during electroconvulsive therapy. Drug Effect on ECT seizure duration Comments24–27 Antipsychotics2,28–31 Variable; increased with phenothiazines and clozapine Others; no obvious effect reported Few published data but widely used. Phenothiazines and clozapine are perhaps most likely to prolong seizures. Some suggest withdrawal before ECT. Safe concurrent use has been reported (particularly with clozapine,32,33 which is now usually continued). ECT and antipsychotics appear generally to be a safe combination. Few data on aripiprazole, quetiapine and ziprasidone, but they also appear to be safe. One case series24 suggests that antipsychotics increase post-ictal cognitive dysfunction. Antiseizure medication2,35,36 Reduced If used as a mood stabiliser, continue but be prepared to use higher energy stimulus. Some units omit one or more doses before ECT. If used for epilepsy, their effect is to normalise seizure threshold. Interactions are possible. Valproate may prolong the effect of thiopental and carbamazepine may inhibit neuromuscular blockade. A small RCT found no difference between carbamazepine and valproate in seizure duration, seizure threshold and cognition outcomes. Lamotrigine has been associated with shorter seizure duration and reduced remission rates in one cohort study.37

Depression and anxiety disorders CHAPTER 3 Table 3.9 (Continued) Drug Effect on ECT seizure duration Comments24–27 Barbiturates Reduced All barbiturates reduce seizure duration in ECT but are widely used as sedative anaesthetic agents. Thiopental and methohexital may be associated with cardiac arrhythmia. Benzodiazepines38 Probably reduced. Mixed evidence and clinical implications unclear.37–39 All may raise seizure threshold and so should be avoided where possible. Many are long-acting and may need to be discontinued some days before ECT. Benzodiazepines may also complicate ECT anaesthesia and reduce efficacy of ECT.37 If sedation is required, consider hydroxyzine. If benzodiazepine use is very long term and essential, continue and use higher stimulus, bilaterally. Bupropion2 Possibly increased Epileptogenic in higher doses so could increase seizure duration. In practice, appears to be well tolerated with ECT. Duloxetine40,41 Not known One case report suggests duloxetine does not complicate ECT. Another links its use to ventricular tachycardia. Lithium2,42,43 Possibly increased Conflicting data on lithium and ECT. The combination may be more likely to lead to delirium and confusion. Some authorities suggest discontinuing lithium 48 hours before ECT. In the UK, ECT is often used during lithium therapy but starting with a low stimulus and with very close monitoring. The combination is generally well tolerated. Note that lithium potentiates the effects of non-depolarising neuromuscular blockers such as suxamethonium. Concomitant use of thiopentone or propofol with lithium treatment lowers seizure threshold.44 MAOIs2,45 Minimal effect Data relating to ECT very limited but long history of ECT use during MAOI therapy. MAOIs probably do not affect seizure duration but interactions with sympathomimetics occasionally used in anaesthesia are possible and may lead to hypertensive crisis. Transdermal selegiline seems safe.46 MAOIs may be continued during ECT but the anaesthetist must be informed. Beware hypotension. Mirtazapine47 Minimal effect; small increase Apparently safe in ECT and, like other antidepressants, may enhance ECT efficacy. May reduce post-ECT nausea and headache. SSRIs1,2,48 Minimal effect; small increase possible Generally considered safe to use during ECT. Beware complex pharmacokinetic interactions with anaesthetic agents. Isolated case reports of serotonin syndrome with fluoxetine and paroxetine with ECT.49,50 TCAs51 Possibly increased Few data relevant to ECT but many TCAs lower seizure threshold. TCAs are associated with arrhythmia following ECT and should be avoided in elderly patients and those with cardiac disease. In others, it is preferable to continue TCA treatment during ECT. Close monitoring is essential. Beware hypotension and risk of prolonged seizures. Venlafaxine52 Minimal effect at standard doses Limited data suggest no effect on seizure duration but possibility of increased risk of transient asystole with doses above 300mg/day.2 Clearly epileptogenic in higher doses. ECG advised. MAOI, monoamine oxidase inhibitor; TCA, tricyclic antidepressant.

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References

386 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 References

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Havaki-Kontaxaki BJ, et al. Concurrent administration of clozapine and electroconvulsive therapy in clozapine-resistant schizophrenia. Clin Neuropharmacol 2006; 29:52–56.
Nothdurfter C, et al. The influence of concomitant neuroleptic medication on safety, tolerability and clinical effectiveness of electroconvulsive therapy. World J Biol Psychiatry 2006; 7:162–170.
Gazdag G, et al. The impact of neuroleptic medication on seizure threshold and duration in electroconvulsive therapy. Ideggyogy Sz 2004; 57:385–390.
Oulis P, et al. Corrected QT interval changes during electroconvulsive therapy-antidepressants-atypical antipsychotics coadministration: safety issues. J ECT 2011; 27:e4–e6.
Grover S, et al. Combined use of clozapine and ECT: a review. Acta Neuropsychiatr 2015; 27:131–142.
Flamarique I, et al. Electroconvulsive therapy and clozapine in adolescents with schizophrenia spectrum disorders: is it a safe and effective combination? J Clin Psychopharmacol 2012; 32:756–766.
van Waarde JA, et al. Patient, treatment, and anatomical predictors of outcome in electroconvulsive therapy: a prospective study. J ECT 2013; 29:113–121.
Sienaert P, et al. Concurrent use of lamotrigine and electroconvulsive therapy. J ECT 2011; 27:148–152.

Depression and anxiety disorders CHAPTER 3 36. Jahangard L, et al. Comparing efficacy of ECT with and without concurrent sodium valproate therapy in manic patients. J ECT 2012; 28:118–123. 37. Gillving C, et al. Seizure duration and electroconvulsive therapy in major depressive disorder. JAMA Netw Open 2024; 7:e2422738. 38. Tang VM, et al. Should benzodiazepines and anticonvulsants be used during electroconvulsive therapy? A case study and literature review. J ECT 2017; 237–242. 39. Chiao S, et al. Psychotropic medication effects on seizure threshold and seizure duration during electroconvulsive therapy stimulus titration. J ECT 2020; 36:115–122. 40. Hanretta AT, et al. Combined use of ECT with duloxetine and olanzapine: a case report. J ECT 2006; 22:139–141. 41. Heinz B, et al. Postictal ventricular tachycardia after electroconvulsive therapy treatment associated with a lithium–duloxetine combination. J ECT 2013; 29:e33–e35. 42. Jha AK, et al. Negative interaction between lithium and electroconvulsive therapy: a case-control study. Br J Psychiatry 1996; 168:241–243. 43. Rucker J, et al. A case of prolonged seizure after ECT in a patient treated with clomipramine, lithium, L-tryptophan, quetiapine, and thyroxine for major depression. J ECT 2008; 24:272–274. 44. Galvez V, et al. Predictors of seizure threshold in right unilateral ultrabrief electroconvulsive therapy: role of concomitant medications and anaesthesia used. Brain Stimul 2015; 8:486–492. 45. Dolenc TJ, et al. Electroconvulsive therapy in patients taking monoamine oxidase inhibitors. J ECT 2004; 20:258–261. 46. Horn PJ, et al. Transdermal selegiline in patients receiving electroconvulsive therapy. Psychosomatics 2010; 51:176–178. 47. Li TC, et al. Mirtazapine relieves post-electroconvulsive therapy headaches and nausea: a case series and review of the literature. J ECT 2011; 27:165–167. 48. Masdrakis VG, et al. The safety of the electroconvulsive therapy-escitalopram combination. J ECT 2008; 24:289–291. 49. Okamoto N, et al. Transient serotonin syndrome by concurrent use of electroconvulsive therapy and selective serotonin reuptake inhibitor: a case report and review of the literature. Case Rep Psychiatry 2012; 2012:215214. 50. Klysner R, et al. Transient serotonin toxicity evoked by combination of electroconvulsive therapy and fluoxetine. Case Rep Psychiatry 2014; 2014:162502. 51. Birkenhager TK, et al. Possible synergy between electroconvulsive therapy and imipramine: a case report. J Psychiatr Pract 2016; 22:478–480. 52. Gonzalez-Pinto A, et al. Efficacy and safety of venlafaxine–ECT combination in treatment-resistant depression. J Neuropsychiatry Clin Neurosci 2002; 14:206–209.

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Psychostimulants in depression

388 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Psychostimulants in depression Psychostimulants reduce fatigue, promote wakefulness and can be mood elevating. Amfetamines have been used as treatments for depression since the 1930s1 and more recently modafinil has been evaluated as an adjunct to standard antidepressants. Amfetamines are now rarely used in depression because of their propensity for the development of tolerance and dependence. Prolonged use of high doses is associated with psychosis.2 Methylphenidate is now more widely used than amfetamines but may have similar shortcomings. Modafinil seems not to induce tolerance, dependence or psychosis but lacks the marked euphoric effects of amfetamines. Armodafinil, the longer-acting isomer of modafinil, is available in some countries. Psychostimulants differ importantly from standard antidepressants in that their mood-elevating effects are usually seen within a few hours, but their antidepressant action may be short lived. Amfetamines and methylphenidate may thus be useful where a prompt effect is required and where dependence would not be problematic (e.g. in depression associated with terminal illness), although ketamine might also be considered in these cases. Their use might also be justified in severe, prolonged depression unresponsive to standard treatments (e.g. in those considered for psychosurgery). Modafinil might justifiably be used as an adjunct to antidepressants in a wider range of patients and as a specific treatment for hypersomnia and fatigue.3 Table 3.10 outlines support (or the absence of it) for the use of psychostimulants in various clinical situations. Generally speaking, data relating to stimulants in depression are rather poor and inconclusive.4,5 A network meta-analysis6 concluded that although psychostimulants (particularly methylphenidate) seem to be well tolerated and have some efficacy in depression, the strength of evidence is very low and insufficiently consistent to provide any definitive hierarchy of treatments. Careful consideration should be given to any use of any psychostimulants in depression, since their short- and long-term safety have not been clearly established. Inclusion of individual drugs in Table 3.10 should not in itself be considered a recommendation for their use. (Continued) Table 3.10 Stimulants in depression. Clinical use Regimens evaluated Comments Recommendations Monotherapy in uncomplicated depression Modafinil 100–200mg/day7,8 Case reports only – efficacy unproven Standard antidepressants preferred. Avoid psychostimulants as monotherapy in uncomplicated depression.9 Meta-analysis found adjunctive therapy but not monotherapy to be associated with clinically significant improvements.5 Methylphenidate 20–40mg/day10,11 Minimal efficacy Dexamfetamine 20mg/day10 Minimal efficacy

Depression and anxiety disorders CHAPTER 3 Table 3.10 (Continued) (Continued) Clinical use Regimens evaluated Comments Recommendations Adjunctive therapy to accelerate or improve response SSRI + methylphenidate 10–20mg/day12,13 No clear effect on time to response Psychostimulants in general not recommended, but modafinil may be useful SSRI + modafinil 400mg/day6 Improved response over SSRI alone Tricyclic + methylphenidate 5–15mg/day14 Single open-label trial suggests faster response SSRI or SNRI + lisdexamfetamine 20–70mg/day15 No superiority over placebo Adjunctive treatment of depression with fatigue and hypersomnia SSRI + modafinil 200mg/day6,16 Beneficial effect only on hypersomnia. Modafinil may induce suicidal ideation. Possible effect on fatigue, but weak evidence. An option where fatigue is prominent and otherwise unresponsive. SSRI + methylphenidate 10–40mg/day17 Clear effect on fatigue in hospice patients Adjunctive therapy in treatmentresistant depression SSRI + modafinil 100–400mg/ day5,6,18–21 Effect mainly on fatigue and daytime sleepiness. Meta-analysis of 10 trials suggested clinically significant improvement in depressive symptoms.5 Data limited. Modafinil may be useful for fatigue22 and cognition.23 MAOI + dexamfetamine 7.5–40mg/day24 or lisdexamfetamine 50mg/ day25 Support from single case series and one case report Stimulants an option in refractory illness but other options better supported. One naturalistic study suggests methylphenidate may reduce self-harm or suicide attempts.26 Methylphenidate or dexamfetamine +/– antidepressant27 Large case series (n = 50) suggests benefit in the majority Lisdexamfetamine 20–70mg/ day + antidepressant5,15,28 Two meta-analyses found a small, non-significant effect on depressive symptoms compared with placebo Adjunctive treatment in bipolar depression29,30 Mood stabiliser and/or antidepressants + modafinil 100–200mg/day31 Significantly superior to placebo Possible treatment option where other standard treatments fail. Meta-analysis of trials referenced here found stimulants well tolerated and an overall benefit vs placebo.32 No evidence of treatment- emergent mania.29,32–34 Mood stabiliser + armodafinil 150–200mg/day33 (one case report of 1000mg/day35) Superior to placebo on some measures Mood stabiliser + methylphenidate 10–40mg/ day36 Mixed results, mainly positive Mood stabiliser and/or antipsychotic + lisdexamfetamine 20–70mg/day37 Greater rates of improvement compared with placebo on patient-rated measures

390 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Table 3.10 (Continued) Clinical use Regimens evaluated Comments Recommendations Monotherapy or add-on treatment in late-stage terminal cancer Methylphenidate 5–30mg/ day38–42 Case series and open prospective studies Useful treatment options in those expected to live only for a few weeks Dexamfetamine 2.5–20mg/ day43,44 Beneficial effects seen on mood, fatigue and pain Methylphenidate 20mg/day + mirtazapine 30mg/day45 RCT shows benefit for combination from third day of treatment Methylphenidate 20mg/day + SSRI46 RCT failed to show benefit for combination Modafinil 200mg/day47 Benefit to depression scores only in those also experiencing severe cancer-related fatigue Monotherapy or add-on treatment for depression in the elderly Methylphenidate 1.25–20mg/ day48–50,51 Use supported by four placebo-controlled studies. Rapid effect observed on mood and activity. Recommended only where patients fail to tolerate standard antidepressants or where contraindications apply Methylphenidate 5–40mg + citalopram 20–60mg/day52 Four studies from the same group, two RCTs. Faster rate of response with combination compared with monotherapy with either drug. Significant increase in heart rate seen in one trial Monotherapy in post-stroke depression Methylphenidate 5–40mg/ day53–56 Variable support but including two placebo- controlled trials.53,56 Effect on mood evident after a few days. Standard antidepressants preferred. Further investigation required: stimulants may improve cognition and motor function. Modafinil 100mg/day57 Single case report Monotherapy in depression secondary to medical illness Methylphenidate 5–20mg/ day58 Limited data Psychostimulants not appropriate therapy. Standard antidepressant preferred. Dexamfetamine 2.5–30mg/ day59,60 Monotherapy in depression and fatigue associated with HIV Dexamfetamine 2.5–40mg/ day61,62 Supported by one good, controlled study.62 Beneficial effect on mood and fatigue. Possible treatment option where fatigue is not responsive to standard antidepressants Monotherapy in depression in traumatic brain injury Methylphenidate 5–20mg/ day63 Improves depressive symptoms, daytime sleepiness and cognitive function Appears to outperform antidepressants for this indication, but data are limited to two studies

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60 - References

References

Depression and anxiety disorders CHAPTER 3 References

Satel SL, et al. Stimulants in the treatment of depression: a critical overview. J Clin Psychiatry 1989; 50:241–249.
Warneke L. Psychostimulants in psychiatry. Can J Psychiatry 1990; 35:3–10.
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Candy M, et al. Psychostimulants for depression. Cochrane Database Syst Rev 2008; (2):CD006722.
McIntyre RS, et al. The efficacy of psychostimulants in major depressive episodes: a systematic review and meta-analysis. J Clin Psychopharmacol 2017; 37:412–418.
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Gwirtsman HE, et al. The antidepressant response to tricyclics in major depressives is accelerated with adjunctive use of methylphenidate. Psychopharmacol Bull 1994; 30:157–164.
Giacobbe P, et al. Efficacy and tolerability of lisdexamfetamine as an antidepressant augmentation strategy: a meta-analysis of randomized controlled trials. J Affect Disord 2018; 226:294–300.
Fava M, et al. Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness. Ann Clin Psychiatry 2007; 19:153–159.
Kerr CW, et al. Effects of methylphenidate on fatigue and depression: a randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage 2012; 43:68–77.
Rasmussen NA, et al. Modafinil augmentation in depressed patients with partial response to antidepressants: a pilot study on self-reported symptoms covered by the major depression inventory (MDI) and the symptom checklist (SCL-92). Nord J Psychiatry 2005; 59:173–178.
DeBattista C, et al. A prospective trial of modafinil as an adjunctive treatment of major depression. J Clin Psychopharmacol 2004; 24:87–90.
Markovitz PJ, et al. An open-label trial of modafinil augmentation in patients with partial response to antidepressant therapy. J Clin Psychopharmacol 2003; 23:207–209.
Ravindran AV, et al. Osmotic-release oral system methylphenidate augmentation of antidepressant monotherapy in major depressive disorder: results of a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry 2008; 69:87–94.
Ghanean H, et al. Fatigue in patients with major depressive disorder: prevalence, burden and pharmacological approaches to management. CNS Drugs 2018; 32:65–74.
Vaccarino SR, et al. The potential procognitive effects of modafinil in major depressive disorder: a systematic review. J Clin Psychiatry 2019; 80:19r12767.
Fawcett J, et al. CNS stimulant potentiation of monoamine oxidase inhibitors in treatment refractory depression. J Clin Psychopharmacol 1991; 11:127–132.
Israel JA. Combining stimulants and monoamine oxidase inhibitors: a reexamination of the literature and a report of a new treatment combination. Prim Care Companion CNS Disord 2015; 17:10.4088/PCC.4015br01836.
Rohde C, et al. The use of stimulants in depression: results from a self-controlled register study. Aust N Z J Psychiatry 2020; 54:808–817.
Parker G, et al. Do the old psychostimulant drugs have a role in managing treatment-resistant depression? Acta Psychiatr Scand 2010; 121:308–314.
Richards C, et al. A randomized, double-blind, placebo-controlled, dose-ranging study of lisdexamfetamine dimesylate augmentation for major depressive disorder in adults with inadequate response to antidepressant therapy. J Psychopharmacol 2017; 31:1190–1203.
Szmulewicz AG, et al. Dopaminergic agents in the treatment of bipolar depression: a systematic review and meta-analysis. Acta Psychiatr Scand 2017; 135:527–538.
Perugi G, et al. Use of stimulants in bipolar disorder. Curr Psychiatry Rep 2017; 19:7.
Frye MA, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry 2007; 164:1242–1249.
Tsapakis EM, et al. Adjunctive treatment with psychostimulants and stimulant-like drugs for resistant bipolar depression: a systematic review and meta-analysis. CNS Spectr 2020; doi: 10.1017/S109285292000156X.
Nunez NA, et al. Efficacy and tolerability of adjunctive modafinil/armodafinil in bipolar depression: a meta-analysis of randomized controlled trials. Bipolar Disord 2020; 22:109–120.
Chiorean A, et al. Prescribed psychostimulants and other pro-cognitive medications in bipolar disorder: a systematic review and meta- analysis of recurrence of manic symptoms. Bipolar Disord 2024; 26:418–430.
Kwok WY, et al. High-dose armodafinil in treatment-refractory bipolar depression. Ann Clin Psychiatry 2023; 35:195–198.

392 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 36. Dell’Osso B, et al. Assessing the roles of stimulants/stimulant-like drugs and dopamine-agonists in the treatment of bipolar depression. Curr Psychiatry Rep 2013; 15:378. 37. McElroy SL, et al. Adjunctive lisdexamfetamine in bipolar depression: a preliminary randomized, placebo-controlled trial. Int Clin Psychopharmacol 2015; 30:6–13. 38. Fernandez F, et al. Methylphenidate for depressive disorders in cancer patients. Psychosomatics 1987; 28:455–461. 39. Macleod AD. Methylphenidate in terminal depression. J Pain Symptom Manage 1998; 16:193–198. 40. Homsi J, et al. Methylphenidate for depression in hospice practice. Am J Hospice Palliat Care 2000; 17:393–398. 41. Sarhill N, et al. Methylphenidate for fatigue in advanced cancer: a prospective open-label pilot study. Am J Hosp Palliat Care 2001; 18:187–192. 42. Homsi J, et al. A phase II study of methylphenidate for depression in advanced cancer. Am J Hosp Palliat Care 2001; 18:403–407. 43. Burns MM, et al. Dextroamphetamine treatment for depression in terminally ill patients. Psychosomatics 1994; 35:80–83. 44. Olin J, et al. Psychostimulants for depression in hospitalized cancer patients. Psychosomatics 1996; 37:57–62. 45. Ng CG, et al. Rapid response to methylphenidate as an add-on therapy to mirtazapine in the treatment of major depressive disorder in terminally ill cancer patients: a four-week, randomized, double-blinded, placebo-controlled study. Eur Neuropsychopharmacol 2014; 24:491–498. 46. Sullivan DR, et al. Randomized, double-blind, placebo-controlled study of methylphenidate for the treatment of depression in SSRI-treated cancer patients receiving palliative care. Psychooncology 2017; 26:1763–1769. 47. Conley CC, et al. Modafinil moderates the relationship between cancer-related fatigue and depression in 541 patients receiving chemotherapy. J Clin Psychopharmacol 2016; 36:82–85. 48. Padala PR, et al. Methylphenidate for apathy in community-dwelling older veterans with mild Alzheimer’s disease: a double-blind, randomized, placebo-controlled trial. Am J Psychiatry 2018; 175:159–168. 49. Kaplitz SE. Withdrawn, apathetic geriatric patients responsive to methylphenidate. J Am Geriatr Soc 1975; 23:271–276. 50. Jacobson A. The use of ritalin in psychotherapy of depressions of the aged. Psychiatr Q 1958; 32:474–483. 51. Wallace AE, et al. Double-blind, placebo-controlled trial of methylphenidate in older, depressed, medically ill patients. Am J Psychiatry 1995; 152:929–931. 52. Smith KR, et al. Methylphenidate use in geriatric depression: a systematic review. Int J Geriatr Psychiatry 2021; 36:1304–1312. 53. Grade C, et al. Methylphenidate in early poststroke recovery: a double-blind, placebo-controlled study. Arch Phys Med Rehabil 1998; 79:1047–1050. 54. Lazarus LW, et al. Efficacy and side effects of methylphenidate for poststroke depression. J Clin Psychiatry 1992; 53:447–449. 55. Lingam VR, et al. Methylphenidate in treating poststroke depression. J Clin Psychiatry 1988; 49:151–153. 56. Delbari A, et al. Effect of methylphenidate and/or levodopa combined with physiotherapy on mood and cognition after stroke: a randomized, double-blind, placebo-controlled trial. Eur Neurol 2011; 66:7–13. 57. Sugden SG, et al. Modafinil monotherapy in poststroke depression. Psychosomatics 2004; 45:80–81. 58. Rosenberg PB, et al. Methylphenidate in depressed medically ill patients. J Clin Psychiatry 1991; 52:263–267. 59. Woods SW, et al. Psychostimulant treatment of depressive disorders secondary to medical illness. J Clin Psychiatry 1986; 47:12–15. 60. Kaufmann MW, et al. The use of d-amphetamine in medically ill depressed patients. J Clin Psychiatry 1982; 43:463–464. 61. Wagner GJ, et al. Dexamphetamine as a treatment for depression and low energy in AIDS patients: a pilot study. J Psychosom Res 1997; 42:407–411. 62. Wagner GJ, et al. Effects of dextroamphetamine on depression and fatigue in men with HIV: a double-blind, placebo-controlled trial. J Clin Psychiatry 2000; 61:436–440. 63. Cheng YS, et al. Therapeutic benefits of pharmacologic and nonpharmacologic treatments for depressive symptoms after traumatic brain injury: a systematic review and network meta-analysis. J Psychiatry Neurosci 2021; 46:e196–e207.

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61 - Post stroke depression

Post-stroke depression

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62 - Prophylaxis of post stroke depression

Prophylaxis of post-stroke depression

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63 - Treatment of post stroke depression

Treatment of post-stroke depression

Depression and anxiety disorders CHAPTER 3 Post-stroke depression Depression is a well-established risk factor for stroke.1,2 In addition, depression is seen in at least 30–40% of survivors of stroke3,4 and post-stroke depression is known to slow functional rehabilitation.5 Antidepressants may reduce depressive symptom severity6 and thereby facilitate faster rehabilitation.7 They may also improve global cognitive functioning,8,9 enhance motor recovery10 and even reduce mortality.11 Despite these benefits, post-stroke depression often goes untreated.12 Prophylaxis of post-stroke depression The high incidence of depression after stroke makes prophylaxis worthy of consideration. Pooled data suggest a prophylactic effect for antidepressants.13,14 Nortriptyline, fluoxetine, escitalopram, duloxetine, mirtazapine and sertraline appear to prevent post- stroke depression.13,14 A large cohort study suggested that mirtazapine and venlafaxine may be associated with an increased risk of a new stroke compared with SSRIs or TCAs.15 Mianserin seems ineffective in the treatment of post-stroke depression.16 Amitriptyline17 and duloxetine are effective in treating central post-stroke pain. Routine use of antidepressants for the prevention of post-stroke depression is, however, not recommended.18 A Cochrane review19 suggests that there may be a benefit but regards the supporting evidence as poor. RCTs published since the Cochrane review suggest that the risks of prescribing fluoxetine (bone fractures, falls, seizures) may outweigh uncertain reduction in incident depression.20–22 Prophylactic use may be justified in individual cases. Treatment of post-stroke depression Treatment is complicated by medical comorbidity and by the potential for interaction with other co-prescribed drugs. Antidepressants that enhance serotonin release can be expected to reduce platelet adhesion and increase the risk of bleeding, especially when co-prescribed with aspirin or anticoagulants (see section on SSRIs and bleeding in this chapter). There is also potential for pharmacokinetic interaction between antidepressants and anticoagulants. Overall, contraindication to antidepressant treatment is more likely with tricyclics than with SSRIs.23 Fluoxetine,24,25 citalopram/escitalopram8,26–28 and nortriptyline29,30 are probably the most studied31 and seem to be effective and safe in respect to pharmacokinetic interaction. RCTs also support the use of other antidepressants, including sertraline,27 mirtazapine32 and agomelatine.33 Reboxetine (which, like nortriptyline, does not affect platelet activity) may also be effective and well tolerated,34 although its effects overall are doubtful.35 Vortioxetine may be of particular benefit because of its additional benefits for cognition, independent of any effects on depressive symptoms. It also does not appear to adversely affect cardiovascular parameters or interact with warfarin or aspirin, but data to support its use specifically in post-stroke depression are limited to a single pilot study.36 Despite their anti-platelet effects, SSRIs seem not to increase risk of stroke37,38 (at least post-stroke), although some doubt remains.39,40 Depression itself increases the risk of stroke, so initiation of an antidepressant post-stroke may appear to be associated

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References

394 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 with a heightened risk of stroke recurrence for this reason. Stroke can be embolic or haemorrhagic – SSRIs may protect against the former46,47 and provoke the latter,48,49 although the evidence base for this is rather weak50 (see section on SSRIs and bleeding in this chapter). Other adverse effects may also be problematic; specifically falls, bone fractures and seizures.19,24 Agomelatine is better tolerated than SSRIs or SNRIs in the post-stroke population and seems not to affect clotting parameters.33 Antidepressants are clearly effective in post-stroke depression51 and treatment should not usually be withheld.52 Inadequate treatment of depression increases the risk of stroke.11,53 Two network meta-analyses suggested that paroxetine might be the drug of choice when considering both efficacy and tolerability post-stroke, although small sample sizes and a lack of high-quality studies in this area limit the strength of this recommendation.54,55 Each analysis included only one paroxetine trial, whereas a meta-analysis of four trials of paroxetine found no benefit.56 A 2020 large network meta-analysis of 51 trials ranked mirtazapine first for response rate, followed by venlafaxine and escitalopram, although the studies were limited to Chinese participants and so may lack generalisability.57 Box 3.3 shows recommended drugs for use in post-stroke depression. Where SSRIs are given in any patient treated with anticoagulants or aspirin, consideration should be given to the prescription of a proton-pump inhibitor for gastric protection. Nortriptyline, which does not appear to increase risk of bleeding, is an alternative. References

Murphy RP, et al. Depressive symptoms and risk of acute stroke: INTERSTROKE case-control study. Neurology 2023; 100:e1787–e1798.
Ashraf F, et al. Association between depression and stroke risk in adults: a systematic review and meta-analysis. Front Neurol 2024; 15:1331300.
Gainotti G, et al. Relation between depression after stroke, antidepressant therapy, and functional recovery. J Neurol Neurosurg Psychiatry 2001; 71:258–261.
Hayee MA, et al. Depression after stroke-analysis of 297 stroke patients. Bangladesh Med Res Counc Bull 2001; 27:96–102.
Paolucci S, et al. Post-stroke depression, antidepressant treatment and rehabilitation results: a case-control study. Cerebrovasc Dis 2001; 12:264–271.
Xu XM, et al. Efficacy and feasibility of antidepressant treatment in patients with post-stroke depression. Medicine (Baltimore) 2016; 95:e5349.
Gainotti G, et al. Determinants and consequences of post-stroke depression. Curr Opin Neurol 2002; 15:85–89.
Jorge RE, et al. Escitalopram and enhancement of cognitive recovery following stroke. Arch Gen Psychiatry 2010; 67:187–196.
Gu SC, et al. Early selective serotonin reuptake inhibitors for recovery after stroke: a meta-analysis and trial sequential analysis. J Stroke Cerebrovasc Dis 2018; 27:1178–1189. Box 3.3 Post-stroke depression – recommended drugs ■ ■SSRIs* ■ ■Mirtazapine ■ ■Nortriptyline* *Caution is clearly required if the index stroke was known to be haemorrhagic because SSRIs increase the risk of de novo haemorrhagic stroke (although absolute risk is low), especially when combined with warfarin or other anti- platelet drugs.41,42 If the patient is taking warfarin, suggest citalopram or escitalopram (probably lowest interaction potential43) and use the lowest effective dose.40 Little is known of the pharmacokinetic interaction potential with direct-acting oral anticoagulants (DOACs). Citalopram or escitalopram may again be preferred, as neither drug affects the enzymes associated with DOAC metabolism.44 The pharmacodynamic interaction always remains – SSRIs increase the risk of major bleeding when combined with anticoagulants.45

Depression and anxiety disorders CHAPTER 3 10. Thilarajah S, et al. Factors associated with post-stroke physical activity: a systematic review and meta-analysis. Arch Phys Med Rehabil 2018; 27:1178–1189. 11. Krivoy A, et al. Low adherence to antidepressants is associated with increased mortality following stroke: a large nationally representative cohort study. Eur Neuropsychopharmacol 2017; 27:970–976. 12. El Husseini N, et al. Depression and antidepressant use after stroke and transient ischemic attack. Stroke 2012; 43:1609–1616. 13. Farooq S, et al. Pharmacological interventions for prevention of depression in high risk conditions: systematic review and meta-analysis. J Affect Disord 2020; 269:58–69. 14. Woranush W, et al. Preventive approaches for post-stroke depression: where do we stand? A systematic review. Neuropsychiatr Dis Treat 2021; 17:3359–3377. 15. Coupland C, et al. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ 2011; 343:d4551. 16. Palomaki H, et al. Prevention of poststroke depression: 1 year randomised placebo controlled double blind trial of mianserin with 6 month follow up after therapy. J Neurol Neurosurg Psychiatry 1999; 66:490–494. 17. Lampl C, et al. Amitriptyline in the prophylaxis of central poststroke pain. Preliminary results of 39 patients in a placebo-controlled, long-term study. Stroke 2002; 33:3030–3032. 18. Masuccio FG, et al. Post-stroke depression in older adults: an overview. Drugs Aging 2024; 41:303–318. 19. Legg LA, et al. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Cochrane Database Syst Rev 2021; 11:CD009286. 20. Tay J, et al. Does fluoxetine reduce apathetic and depressive symptoms after stroke? An analysis of the efficacy of fluoxetine – a randomized controlled trial in stroke trial data set. Int J Stroke 2023; 18:285–295. 21. AFFINITY Trial Collaboration. Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2020; 19:651–660. 22. Almeida OP, et al. Depression outcomes among patients treated with fluoxetine for stroke recovery: the AFFINITY randomized clinical trial. JAMA Neurol 2021; 78:1072–1079. 23. Cole MG, et al. Feasibility and effectiveness of treatments for post-stroke depression in elderly inpatients: systematic review. J Geriatr Psychiatry Neurol 2001; 14:37–41. 24. Mead G, et al. Individual patient data meta-analysis of the effects of fluoxetine on functional outcomes after acute stroke. Int J Stroke 2024; 19:798–808. 25. Wu J, et al. The efficacy and safety of fluoxetine versus placebo for stroke recovery: a meta-analysis of randomized controlled trials. Int J Clin Pharm 2023; 45:839–846. 26. Cui M, et al. Efficacy and safety of citalopram for the treatment of poststroke depression: a meta-analysis. J Stroke Cerebrovasc Dis 2018; 27:2905–2918. 27. Yan N, et al. The safety and efficacy of escitalopram and sertraline in post-stroke depression: a randomized controlled trial. BMC Psychiatry 2024; 24:365. 28. Ece Çetin F, et al. Effıcacy of cıtalopram on stroke recurrence: a randomızed clınıcal trıal. J Clin Neurosci 2022; 101:168–174. 29. Robinson RG, et al. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo- controlled, double-blind study. Am J Psychiatry 2000; 157:351–359. 30. Zhang Wh, et al. Nortriptyline protects mitochondria and reduces cerebral ischemia/hypoxia injury. Stroke 2008; 39:455–462. 31. Starkstein SE, et al. Antidepressant therapy in post-stroke depression. Expert Opin Pharmacother 2008; 9:1291–1298. 32. Niedermaier N, et al. Prevention and treatment of poststroke depression with mirtazapine in patients with acute stroke. J Clin Psychiatry 2004; 65:1619–1623. 33. Chen Y, et al. Efficacy and safety of agomelatine versus SSRIs/SNRIs for post-stroke depression: a systematic review and meta-analysis of randomized controlled trials. Int Clin Psychopharmacol 2024; 39:163–173. 34. Rampello L, et al. An evaluation of efficacy and safety of reboxetine in elderly patients affected by ‘retarded’ post-stroke depression: a random, placebo-controlled study. Arch Gerontol Geriatr 2005; 40:275–285. 35. Eyding D, et al. Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. BMJ 2010; 341:c4737. 36. Gamberini G, et al. Safety and efficacy of vortioxetine on depressive symptoms and cognition in post-stroke patients: a pilot study. J Affect Disord 2021; 286:108–109. 37. Broman J, et al. Association of post-stroke-initiated antidepressants with long-term outcomes in young adults with ischaemic stroke. Ann Med 2022; 54:1757–1766. 38. Douglas I, et al. The use of antidepressants and the risk of haemorrhagic stroke: a nested case control study. Br J Clin Pharmacol 2011; 71:116–120. 39. Trajkova S, et al. Use of antidepressants and risk of incident stroke: a systematic review and meta-analysis. Neuroepidemiology 2019; 53:142–151. 40. Kim JH, et al. Major adverse cardiovascular events in antidepressant users within patients with ischemic heart diseases: a nationwide cohort study. J Clin Psychopharmacol 2020; 40:475–481. 41. Jeong HE, et al. Risk of major adverse cardiovascular events associated with concomitant use of antidepressants and non-steroidal anti- inflammatory drugs: a retrospective cohort study. CNS Drugs 2020; 34:1063–1074. 42. Quinn GR, et al. Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin. Am J Cardiol 2014; 114:583–586. 43. Sayal KS, et al. Psychotropic interactions with warfarin. Acta Psychiatr Scand 2000; 102:250–255. 44. Fitzgerald JL, et al. Drug interactions of direct-acting oral anticoagulants. Drug Saf 2016; 39:841–845. 45. Bakker S, et al. Selective serotonin reuptake inhibitor use and risk of major bleeding during treatment with vitamin K antagonists: results of a cohort study. Thromb Haemost 2023; 123:245–254.

396 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 46. He Y, et al. Effect of fluoxetine on three-year recurrence in acute ischemic stroke: a randomized controlled clinical study. Clin Neurol Neurosurg 2018; 168:1–6. 47. Douros A, et al. Degree of serotonin reuptake inhibition of antidepressants and ischemic risk: a cohort study. Neurology 2019; 93:e1010–e1020. 48. Trifiro G, et al. Risk of ischemic stroke associated with antidepressant drug use in elderly persons. J Clin Psychopharmacol 2010; 30:252–258. 49. Wu CS, et al. Association of cerebrovascular events with antidepressant use: a case-crossover study. Am J Psychiatry 2011; 168:511–521. 50. Mortensen JK, et al. Safety of selective serotonin reuptake inhibitor treatment in recovering stroke patients. Expert Opin Drug Saf 2015; 14:911–919. 51. Mead GE, et al. Selective serotonin reuptake inhibitors for stroke recovery. JAMA 2013; 310:1066–1067. 52. Allida SM, et al. Pharmacological, non-invasive brain stimulation and psychological interventions, and their combination, for treating depression after stroke. Cochrane Database Syst Rev 2023; 7:CD003437. 53. Bangalore S, et al. Cardiovascular hazards of insufficient treatment of depression among patients with known cardiovascular disease: a propensity score adjusted analysis. Eur Heart J Qual Care Clin Outcomes 2018; 4:258–266. 54. Sun Y, et al. Comparative efficacy and acceptability of antidepressant treatment in poststroke depression: a multiple-treatments meta- analysis. BMJ Open 2017; 7:e016499. 55. Deng L, et al. Interventions for management of post-stroke depression: a Bayesian network meta-analysis of 23 randomized controlled trials. Sci Rep 2017; 7:16466. 56. Li L, et al. Effectiveness of paroxetine for poststroke depression: a meta-analysis. J Stroke Cerebrovasc Dis 2020; 29:104664. 57. Li X, et al. Comparative efficacy of nine antidepressants in treating Chinese patients with post-stroke depression: a network meta-analysis. J Affect Disord 2020; 266:540–548.

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65 - Antidepressant prophylaxis

Antidepressant prophylaxis

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After first episode

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67 - Recurrent depression

Recurrent depression

Depression and anxiety disorders CHAPTER 3 Antidepressant prophylaxis After first episode A single episode of depression should be treated for at least 6–9 months after full remission.1 If antidepressant therapy is stopped immediately on recovery, 50% of patients experience a return of depressive symptoms within 3–6 months.1 A landmark study of fluoxetine maintenance2 demonstrated that stopping successful treatment at 12 weeks produced the highest relapse rate, followed by withdrawal at 26 weeks, and then withdrawal at 50 weeks (at which point placebo and active treatment did not differ in respect to relapse risk). Another trial suggested that withdrawal should only be attempted when patients had been free of significant symptoms for 16–20 weeks.3 Even non-continuous use of antidepressants during the first 6 months of treatment predicts higher rates of relapse.4 Recurrent depression Major depressive disorder is unremitting in 15% of cases and recurrent in 35%. About 50% of those with a first-onset episode recover and have no further episodes when followed for over 20 years.5 Many factors are known to increase the risk of recurrence, including a family history of depression, recurrent dysthymia, concurrent non-affective psychiatric illness, female gender, long episode duration, degree of treatment resistance,6 chronic medical illness and social factors (e.g. lack of confiding relationships and psychosocial stressors). Some prescription drugs may precipitate depression.6,7 Antidepressants are generally effective in the post-acute maintenance phase – the 6 months after remission.8 Longer-term outcomes have also been examined. Figure 3.4 outlines the risk of recurrence for patients who have multiple episodes of depression. Those recruited to the study had already experienced at least three episodes of depression, with 3 years or less between episodes.9,10 A meta-analysis of antidepressant continuation studies11 concluded that continuing treatment with antidepressants reduces the odds of depressive relapse by around two-thirds 80 40 % of patients remaining well 0 6 24 Time (months) 48 Active drug Placebo after 3 years Placebo Figure 3.4 The risk of recurrence in patients who have several episodes of depression. Patients had experienced at least three episodes of depression with 3 years or fewer between episodes.

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68 - Discontinuation of medium and long term antid

Discontinuation of medium- and long-term antidepressants

398 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 (approximately equal to a halving of the absolute risk). A later meta-analysis of 54 studies suggested that odds of relapse were reduced by 65%.12 The risk of relapse is greatest in the first few months after discontinuation and this holds true irrespective of the duration of prior treatment.13 Benefits persist at 36 months and beyond and seem to be similar across heterogeneous patient groups (first episode, multiple episode and chronic). An RCT of maintenance treatment in elderly patients, many of whom were first episode, found continuation treatment with antidepressants beneficial over 2 years, with a similar effect size to that seen in younger adults.14 One small RCT (n = 22) demonstrated benefit from prophylactic antidepressants in adolescents.15 Many patients who might benefit from maintenance treatment with antidepressants do not receive them.16 Assuring optimal management of long-term depression vastly reduces mortality associated with the condition.17 An alternative view is that the prophylactic effects of antidepressants have been overestimated because of confounding in maintenance trials. Effective drug treatment may be abruptly withdrawn, and it is the manner of this withdrawal (not necessarily the withdrawal itself) which increases the risk of relapse.18,19 Most of the apparent relapse after stopping antidepressants occurs in the first 6 months.20 Abrupt discontinuation increases the risk of relapse and exacerbates withdrawal symptoms (see below). It may be that at least part of the advantage reported for continuation treatment is derived from suboptimal treatment in patients switched to placebo. Some studies employ longer periods (a month or more) of withdrawal from active treatment21 but even this may not be long enough to allow complete abolition of the negative effects of withdrawal.22 There is also a minority school of thought which posits that antidepressants may ultimately worsen the conditions they treat.23 Some tenuous support for this theory comes from the observation that response to antidepressants reduces in line with the number of antidepressants previously prescribed.24 Other disadvantages of long-term antidepressants include an increased risk of GI and cerebral haemorrhage (see section on SSRIs and bleeding in this chapter) and an additional risk of interaction with co-prescribed drugs likely to increase risk of bleeding or hyponatraemia. These observations, alongside awareness that maintenance trials have been conducted largely in those in remission, strongly suggest that antidepressant treatment should be continued only where there is clear evidence of substantial efficacy. This may seem like an obvious point, but clinical experience suggests that long-term, ineffective or partially effective antidepressant treatment is commonplace. The aim of treatment should be the achieving and maintenance of remission. Residual symptoms portend poor outcome and higher risk of relapse.25 Discontinuation of medium- and long-term antidepressants Stopping antidepressants in remitted patients clearly increases the risk of relapse compared with continuing with antidepressants.26 However, as already noted, many studies may be confounded by abrupt discontinuation of active treatment, which worsens risk of relapse27 and increases risk of withdrawal symptoms (which may mimic relapse).28 Two studies have tried to address these confounding influences. In the ANTLER trial, patients who were well after at least 2 years of treatment were randomised to continue

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Dose for prophylaxis

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70 - References

References

Depression and anxiety disorders CHAPTER 3 treatment or to have antidepressants slowly stopped.29 After 1 year, relapse occurred in 56% of stoppers and 39% of continuers. There was clear evidence of withdrawal symptoms despite the slow withdrawal (probably because alternate day dosing was used). In the REDUCE study,30 patients receiving antidepressants for 1 year (first episode) or 2 years (multi-episode) were slowly withdrawn from treatment. Around 43% of patients were able to discontinue treatment without relapse by 6 months. The main finding from these studies, taken together, is that successful withdrawal from long-term antidepressants is possible, but that continued treatment is probably necessary (and somewhat effective) for a substantial proportion of people. Dose for prophylaxis Adults should receive the same dose as used for acute treatment.31 There is some evidence to support the use of lower doses in elderly patients. Dosulepin 75mg/day offers effective prophylaxis32 but is now rarely used and its relevance is dubious. There is no evidence to support the use of lower than standard doses of SSRIs.33 Relapse rates after ECT are similar to those after stopping antidepressants.34 Antidepressant prophylaxis will be required, ideally with a different drug from the one that failed in the first instance, although good data in this area are lacking. Lithium also has some efficacy in the prophylaxis of unipolar depression but efficacy relative to standard antidepressants is unknown.35 Lithium treatment may have the best outcomes of any treatment for unipolar depression.36 In the UK, NICE has recommended that lithium should not be used as the sole prophylactic drug in unipolar depression.37 There is some support for the use of a combination of lithium and nortriptyline.38 Maintenance treatment with lithium protects against suicide.31 References

Cleare A, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol 2015; 29:459–525.
Reimherr FW, et al. Optimal length of continuation therapy in depression: a prospective assessment during long-term fluoxetine treatment. Am J Psychiatry 1998; 155:1247–1253.
Prien RF, et al. Continuation drug therapy for major depressive episodes: how long should it be maintained? Am J Psychiatry 1986; 143:18–23.
Kim KH, et al. The effects of continuous antidepressant treatment during the first 6 months on relapse or recurrence of depression. J Affect Disord 2011; 132:121–129.
Eaton WW, et al. Population-based study of first onset and chronicity in major depressive disorder. Arch Gen Psychiatry 2008; 65:513–520.
National Institute for Health and Care Excellence. Depression in adults with a chronic physical health problem: recognition and management. Clinical guideline [CG91]. 2009 (reviewed May 2024, last checked November 2024); https://www.nice.org.uk/guidance/CG91.
Patten SB, et al. Drug-induced depression. Psychother Psychosom 1997; 66:63–73.
Kishi T, et al. Antidepressants for the treatment of adults with major depressive disorder in the maintenance phase: a systematic review and network meta-analysis. Mol Psychiatry 2023; 28:402–409.
Frank E, et al. Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1990; 47:1093–1099.
Kupfer DJ, et al. Five-year outcome for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1992; 49:769–773.
Geddes JR, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet 2003; 361:653–661.
Glue P, et al. Meta-analysis of relapse prevention antidepressant trials in depressive disorders. Aust N Z J Psychiatry 2010; 44:697–705.
Keller MB, et al. The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) study: outcomes from the 2-year and combined maintenance phases. J Clin Psychiatry 2007; 68:1246–1256.
Reynolds CF, III, et al. Maintenance treatment of major depression in old age. N Engl J Med 2006; 354:1130–1138.
Cheung A, et al. Maintenance study for adolescent depression. J Child Adolesc Psychopharmacol 2008; 18:389–394.
Holma IA, et al. Maintenance pharmacotherapy for recurrent major depressive disorder: 5-year follow-up study. Br J Psychiatry 2008; 193:163–164.

400 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 17. Gallo JJ, et al. Long term effect of depression care management on mortality in older adults: follow-up of cluster randomized clinical trial in primary care. BMJ 2013; 346:f2570. 18. Cohen D, et al. Withdrawal effects confounding in clinical trials: another sign of a needed paradigm shift in psychopharmacology research. Ther Adv Psychopharmacol 2020; 10:2045125320964097. 19. Hengartner MP. Editorial: Antidepressant prescriptions in children and adolescents. Front Psychiatry 2020; 11:600283. 20. Zhou D, et al. Effects of antidepressant medicines on preventing relapse of unipolar depression: a pooled analysis of parametric survival curves. Psychol Med 2022; 52:48–56. 21. DeRubeis RJ, et al. Prevention of recurrence after recovery from a major depressive episode with antidepressant medication alone or in combination with cognitive behavioral therapy: phase 2 of a 2-phase randomized clinical trial. JAMA Psychiatry 2020; 77:237–245. 22. Horowitz MA, et al. Tapering of SSRI treatment to mitigate withdrawal symptoms. Lancet Psychiatry 2019; 6:538–546. 23. Fava GA. May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance. Ther Adv Psychopharmacol 2020; 10:2045125320970325. 24. Amsterdam JD, et al. Prior antidepressant treatment trials may predict a greater risk of depressive relapse during antidepressant maintenance therapy. J Clin Psychopharmacol 2019; 39:344–350. 25. Kennedy N, et al. Residual symptoms at remission from depression: impact on long-term outcome. J Affect Disord 2004; 80:135–144. 26. Kato M, et al. Discontinuation of antidepressants after remission with antidepressant medication in major depressive disorder: a systematic review and meta-analysis. Mol Psychiatry 2021; 26:118–133. 27. Van Leeuwen E, et al. Approaches for discontinuation versus continuation of long-term antidepressant use for depressive and anxiety disorders in adults. Cochrane Database Syst Rev 2021; 4:CD013495. 28. Horowitz MA, et al. Distinguishing relapse from antidepressant withdrawal: clinical practice and antidepressant discontinuation studies. BJPsych Advances 2022; 28:297–311. 29. Lewis G, et al. Maintenance or discontinuation of antidepressants in primary care. N Engl J Med 2021; 385:1257–1267. 30. Kendrick T, et al. Internet and telephone support for discontinuing long-term antidepressants: the REDUCE cluster randomized trial. JAMA Netw Open 2024; 7:e2418383. 31. Anderson IM, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol 2008; 22:343–396. 32. Group OADI. How long should the elderly take antidepressants? A double-blind placebo-controlled study of continuation/prophylaxis therapy with dothiepin. Br J Psychiatry 1993; 162:175–182. 33. Franchini L, et al. Dose-response efficacy of paroxetine in preventing depressive recurrences: a randomized, double-blind study. J Clin Psychiatry 1998; 59:229–232. 34. Nobler MS, et al. Refractory Depression and Electroconvulsive Therapy. Chichester: Wiley; 1994. 35. Cipriani A, et al. Lithium versus antidepressants in the long-term treatment of unipolar affective disorder. Cochrane Database Syst Rev 2006; (4):CD003492. 36. Young AH. Lithium for long-term treatment of unipolar depression. Lancet Psychiatry 2017; 4:511–512. 37. National Institute for Health and Care Excellence. Depression in adults: treatment and management. NICE guideline [NG222]. 2022 (last reviewed September 2024, last checked November 2024); https://www.nice.org.uk/guidance/ng222. 38. Sackeim HA, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA 2001; 285:1299–1307.

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Drug interactions with antidepressants

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Pharmacokinetic interactions

Depression and anxiety disorders CHAPTER 3 Drug interactions with antidepressants Antidepressants are involved in a number of both pharmacokinetic and pharmacodynamic interactions. Pharmacokinetic interactions Pharmacokinetic interactions occur when one drug interferes with the absorption, distribution, metabolism or elimination of another drug. This may result in a subtherapeutic effect or toxicity. The largest group of pharmacokinetic interactions involves drugs that inhibit or induce hepatic CYP enzymes (Tables 3.11 and 3.12). Other enzyme systems include the flavin-containing monooxygenase (FMO) and the uridine diphosphate (UDP)-glucuronosyltransferases (UGT).1 While both these latter enzyme systems are involved in the metabolism of psychotropic drugs, the potential for drugs to inhibit or induce these enzyme systems has been less well studied. The clinical consequences of pharmacokinetic interactions in an individual patient can be difficult to predict. Some could be highly clinically significant; for example, when paroxetine (a potent CYP2D6 inhibitor) is taken with tamoxifen, metabolism to its active metabolite is reduced, possibly increasing the risk of breast cancer recurrence.2 The following factors affect outcome of interactions: the degree of enzyme inhibition or induction, the pharmacokinetic properties of the affected drug and other co-administered drugs, the relationship between plasma level and pharmacodynamic effect for the affected drug, and patient-specific factors such as genetic differences in metabolic enzymes variability3 in the role of primary and secondary metabolic pathways and the presence of comorbid physical illness.4 (Continued) Table 3.11 Summary of antidepressant effects on CYP enzymes.5–7 Antidepressant Substrate for Inhibits SSRIs Citalopram CYP2C19, CYP2D6, CYP3A4 CYP2D6 (weak) Escitalopram CYP2C19, CYP2D6, CYP3A4 CYP2D6 (weak) Fluoxetine CYP2D6, CYP3A4 CYP2D6 (moderate to potent), CYP2C9 (moderate), CYP3A4 (weak) Fluvoxamine CYP2D6; others possibly involved CYP1A2 (potent), CYP2C19 (potent), CYP3A4 (weak), CYP2C9 (weak) Paroxetine CYP2D6 CYP2D6 (potent) Sertraline CYP3A4, CYP2D6 (minor) and possibly other pathways CYP2D6 (weak) SNRIs Desvenlafaxine CYP3A4 CYP2D6 (weak) Duloxetine CYP1A2, CYP2D6 CYP2D6 (moderate) Levomilnacipran CYP3A4, CYP2C8, CYP2C19, CYP2D6 Venlafaxine CYP2D6, CYP3A4 CYP2D6 (weak)

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Pharmacodynamic interactions

402 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Pharmacodynamic interactions Pharmacodynamic interactions arise when the effects of one drug are altered by another drug via mechanisms such as direct competition at receptor sites (e.g. dopamine agonists with dopamine antagonists), augmentation of the same neurotransmitter pathway (e.g. fluoxetine with tramadol or a triptan can lead to serotonin syndrome) or an effect on the physiological functioning of an organ/organ system in different ways (e.g. SSRIs impair clotting and non-steroidal anti-inflammatory drugs [NSAIDs] irritate the gastric Table 3.11 (Continued) Antidepressant Substrate for Inhibits TCAs Amitriptyline CYP1A2, CYP2D6, CYP3A4, CYP2C19 Clomipramine Desipramine CYP2D6 Dosulepin CYP2D6 and possibly other pathways Doxepin CYP2D6, CYP1A2 (minor), CYP3A4 (minor) Imipramine CYP1A2, CYP2D6, CYP3A4, CYP2C19 Lofepramine 2D6 (metabolised to desipramine)8 Not known9 Nortriptyline CYP2D6 Trimipramine CYP2D6 Others Agomelatine CYP1A2 Brexanolone10 Metabolised via non-CYP pathways CYP2C9 Bupropion CYP2B6 CYP2D6 (potent) Dextromethorphan/ bupropion11 CYP2B6, CYP2D6 CYP2D6 (potent) Esketamine CYP3A4, CYP2B6 Mianserin CYP2D6 Mirtazapine CYP1A2, CYP2D6, CYP3A4 CYP2D6 (weak) Phenelzine CYP2C19, CYP3A4 Reboxetine CYP3A4 Tranylcypromine12 CYP2A6, CYP2C19 Trazodone CYP3A4 Vortioxetine CYP2D6, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4 Vilazodone CYP3A4 CYP2C8 CYP enzymes highlighted in bold indicate predominant metabolic enzyme pathway or potent inhibition of enzyme activity.

Depression and anxiety disorders CHAPTER 3 Table 3.12 Pharmacokinetic interactions: a brief summary of important interactions.13,14 CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6 CYP3A4/5/7 Genetic polymorphism. Ultra-rapid metabolisers possible. 2–10% of total hepatic CYP content15 5–10% of people of European descent poor metabolisers ~20% of Asian and 3–5% people of European descent poor metabolisers 3–5% of people of European descent poor metabolisers 60% p450 content Induced by: Induced by: Induced by: Induced by: Induced by: Induced by: carbamazepine charcoal cooking tobacco smoke omeprazole phenobarbital phenytoin carbamazepine efavirenz (chronically)16 lopinavir rifampicin ritonavir phenytoin rifampicin apalutamide artemisinin efavirenz enzalutamide rifampicin carbamazepine phenytoin carbamazepine phenytoin prednisolone rifampicin St John’s wort Inhibited by: Inhibited by: Inhibited by: Inhibited by: Inhibited by: Inhibited by: cimetidine ciprofloxacin erythromycin fluvoxamine clopidogrel efavirenz (acutely)16 ticlopidine voriconazole cimetidine fluoxetine fluvoxamine moclobemide sertraline armodafinil etravirine fluconazole fluoxetine fluvoxamine esomeprazole isoniazid moclobemide modafinil omeprazole voriconazole cimetidine bupropion citalopram chlorpromazine desvenlafaxine duloxetine escitalopram fluoxetine fluphenazine haloperidol paroxetine sertraline tricyclics erythromycin fluoxetine fluvoxamine grapefruit juice ketoconazole norfluoxetine paroxetine sertraline tricyclics Metabolises: Metabolises: Metabolises: Metabolises: Metabolises: Metabolises: agomelatine benzodiazepines caffeine clozapine duloxetine haloperidol mirtazapine olanzapine ramelteon theophylline tizanidine tricyclics warfarin bupropion methadone tramadol agomelatine bupropion citalopram diazepam escitalopram omeprazole phenytoin tricyclics warfarin citalopram diazepam moclobemide aripiprazole atomoxetine brexpiprazole clozapine codeine dextromethorphan donepezil duloxetine haloperidol phenothiazines risperidone tamoxifen tricyclics tramadol trazodone venlafaxine vortioxetine calcium blockers carbamazepine clozapine donepezil erythromycin galantamine levomilnacipran methadone mirtazapine reboxetine risperidone statins tricyclics valproate venlafaxine vilazodone vortioxetine z-hypnotics

404 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 mucosa so, when these drugs are used together, the risk of GI bleeds is increased). Here, we provide a broad summary of these interactions. Up-to-date interaction tables are readily available online and most known interactions are described in an individual product’s literature. Tricyclic antidepressants7,17–19 ■ ■are H1 antagonists (sedative). This effect can be exacerbated by other sedative drugs or alcohol. Beware respiratory depression. ■ ■are anticholinergic (dry mouth, blurred vision, constipation). This effect can be exacerbated by other anticholinergic drugs such as antihistamines or antipsychotics. Also associated with cognitive impairment and GI obstruction. ■ ■are adrenergic α1 blockers (postural hypotension). This effect can be exacerbated by other drugs that block α1 receptors and by antihypertensive drugs in general. As a consequence, falls may be more common. ■ ■are arrhythmogenic. Caution is required with other drugs that can alter cardiac conduction directly or indirectly (see section on antidepressant-induced arrhythmia in this chapter). ■ ■lower the seizure threshold. Caution is required with other proconvulsive drugs (e.g. some antipsychotics) and particularly if the patient is being treated for epilepsy (see section on epilepsy in Chapter 10). ■ ■possess varying degrees of serotonin reuptake inhibition (amitriptyline and clomipramine in particular). There is the potential for these drugs to interact with other serotonergic drugs (e.g. tramadol, SSRIs, MAOIs, triptans) to cause serotonin syndrome. SSRIs/SNRIs7,17,18,20.21 ■ ■increase serotonergic neurotransmission. The main concern when co-prescribed with other serotonergic drugs is serotonin syndrome. ■ ■inhibit platelet aggregation and increase the risk of bleeding, particularly of the upper GI tract. This effect is exacerbated by aspirin and NSAIDs (see section on SSRIs and bleeding in this chapter). ■ ■may be more likely than other antidepressants to cause hyponatraemia (see section on antidepressant-induced hyponatraemia in this chapter). This may exacerbate electrolyte disturbances caused by other drugs such as diuretics. ■ ■are associated with a decrease in bone mineral density. This adds to the negative effects prolactin elevating drugs have on bone mineral density and increases the risks of clinical harm should the patient have a fall. MAOIs12,22,23 ■ ■prevent the metabolism of monoamine neurotransmitters (e.g. serotonin). Co- prescription with serotonergic drugs (in particular, serotonin reuptake inhibitors or releasing agents) risks potentially fatal serotonin syndrome. Examples include SSRI and related antidepressants but also certain over-the-counter medicines (e.g. chlorphenamine, dextromethorphan), opioids (e.g. tramadol, pethidine), antipsychotics

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16. References

Depression and anxiety disorders CHAPTER 3 (lumateperone and ziprasidone) and drugs of misuse such as MDMA (3,4-methylene dioxymethamphetamine). ■ ■prevent the destruction of other monoamine neurotransmitters (e.g. catecholamines). Co-prescription with sympathomimetic drugs that raise blood pressure (e.g. psychostimulants) can cause hypertensive crises. MAOIs also prevent the breakdown of dietary tyramine (high levels present in aged and fermented foods), which acts as a catecholamine-releasing agent leading to similar hypertensive reactions. References

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Lancaster SG, et al. Lofepramine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 1989; 37:123–140.
Edinoff AN, et al. Brexanolone, a GABA(A) modulator, in the treatment of postpartum depression in adults: a comprehensive review. Front Psychiatry 2021; 12:699740.
Keam SJ. Dextromethorphan/bupropion: first approval. CNS Drugs 2022; 36:1229–1238.
Van den Eynde V, et al. The prescriber’s guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression. CNS Spectr 2023; 28:427–440.
Mitchell PB. Drug interactions of clinical significance with selective serotonin reuptake inhibitors. Drug Saf 1997; 17:390–406.
Kelly CM, et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ 2010; 340:c693.
Hedrich WD, et al. Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B 2016; 6:413–425.
Gufford BT, et al. Influence of CYP2B6 pharmacogenetics on stereoselective inhibition and induction of bupropion metabolism by efavirenz in healthy volunteers. J Pharmacol Exp Ther 2022; 382:313–326.
Preskorn SH. Drug–drug interactions (DDIs) in psychiatric practice, part 8: relative receptor binding affinity as a way of understanding the differential pharmacology of currently available antidepressants. J Psychiatr Pract 2020; 26:46–51.
National Institute for Health and Care Excellence. British National Formulary. 2024; https://bnf.nice.org.uk.
Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol 2007; 151:737–748.
Preskorn SH. Drug–drug interactions (DDIs) in psychiatric practice, part 6: pharmacodynamic considerations. J Psychiatr Pract 2019; 25:290–297.
Mercurio M, et al. The use of antidepressants is linked to bone loss: a systematic review and metanalysis. Orthop Rev (Pavia) 2022; 14:38564.
Gillman PK. Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors. J Clin Psychopharmacol 2011; 31:66–74.
Grady MM, et al. Practical guide for prescribing MAOIs: debunking myths and removing barriers. CNS Spectr 2012; 17:2–10.

Cardiac effects of antidepressants – summary The cardiac effects of antidepressants are summarised in Table 3.13. Table 3.13 Cardiac effects of antidepressants. Drug Heart rate Blood pressure QTc Arrhythmia Conduction disturbance Licensed restrictions post-MI Comments Agomelatine1,2 No changes reported No changes reported Single case of QTc prolongation No arrhythmia reported Unclear No specific contra-indication Cautiously recommended Bupropion1,3,4 Slight increase Slight increases in blood pressure but can sometimes be significant. Rarely postural hypotension. QTc shortening, but prolongation has been reported in cases of overdose5 No effect. Rare reports in overdose. None Well tolerated for smoking cessation in post-MI patients Be aware of interaction potential. Monitor blood pressure Brexanolone6–8 One case of tachycardia reported in trials Small reduction in blood pressure possible No effect on QTc interval No arrythmia reported None No specific contraindication Minimal effect on cardiac parameters in trial data Citalopram1,9–12 (assume same for escitalopram) Small decrease in heart rate Slight drop in systolic blood pressure Dose-related increase in QTc Torsade de Pointes reported, mainly in overdose None Caution in patients with recent MI or uncompensated heart failure. But some evidence of safety in CVD. Minor metabolite which increases QTc interval. No clear evidence of increased risk of arrhythmia at any licensed dose. Dextromethorphan

bupropion13 As per bupropion As per bupropion As per bupropion. QTc prolongation in dextromethorphan overdose.14 As per bupropion As per bupropion No specific contraindication As per bupropion Duloxetine1,15–17 Slight increase Important effect (see SPC). Caution in hypertension. Isolated reports of QT prolongation Isolated reports of toxicity Isolated reports of toxicity Caution in patients ‘whose conditions could be compromised by an increased heart rate or by an increase in blood pressure’ Not recommended in cardiac disease

Fluoxetine12,18–20 Small decrease in mean heart rate Minimal effect on blood pressure No effect on QTc interval None None Caution in patients with acute MI or heart failure Evidence of safety post MI Fluvoxamine21,22 Minimal effect on heart rate Small drop in systolic blood pressure No significant effect on QTc None None Caution Limited changes in ECG have been observed Levomilnacipran23–25 Slight increase Small increase No effect on QTc interval* Pre-existing tachyar rhythmias should be treated before initiating treatment None Caution in patients with cardiac disease Monitor heart rate and blood pressure Lofepramine26,27 Modest increase in heart rate Less decrease in postural blood pressure than other TCAs May prolong QTc interval at higher doses May occur at higher doses, but rare Unclear Coronary insufficiency in patients with recent MI Less cardiotoxic than other TCAs. Reasons unclear MAOIs26,28 Decrease in heart rate Postural hypotension. Risk of hypertensive crisis. Unclear but may shorten QTc interval May cause arrhythmia and decrease LVF No clear effect on cardiac conduction Use with caution in patients with CVD Not recommended in CVD Milnacipran1,29 Slight increase in heart rate (c.10bpm) Small increases in systolic and diastolic BP No effect on QTc None None Caution Avoid in hypertension and heart failure Mirtazapine1,30 Minimal change in heart rate Minimal effect on BP No effect on QTc None None Caution in patients with recent MI Evidence of safety post MI. Good alternative to SSRIs. Moclobemide31–33 Marginal decrease in heart rate Minimal effect on blood pressure. Isolated cases of hypertensive episodes. No effect on QTc interval in normal doses. Prolongation in overdose. None None General caution in patients with a history of cardiac disorders Possibly arrhythmogenic in overdose Paroxetine12,34,35 Small decrease in mean heart rate Minimal effect on BP No effect on QTc interval None None General caution in patients with cardiac disease Probably safe post MI Reboxetine36–38 Significant increase in heart rate Marginal increase in both systolic and diastolic BP. Postural decrease at higher doses. No effect on QTc Rhythm abnormalities may occur Atrial and ventricular ectopic beats, especially in the elderly Caution in patients with cardiac disease Probably best avoided in IHD (Continued)

Sertraline12,39–42 Minimal effect on heart rate Minimal effect on BP No effect on QTc interval at standard doses. Small increase (<10ms) at 400mg/day.43 None None Drug of choice post MI but formal labelling acknowledges effect on QT and cautions against use in patients with additional risk factors for QTc prolongation Safe post MI and in heart failure Trazodone26,44–46 Decrease in heart rate more common, although increase can also occur Can cause significant postural hypotension Can prolong QTc interval Several case reports of prolonged QT and arrhythmia Unclear Contraindicated in patients with acute MI May be arrhythmogenic in patients with pre-existing cardiac disease Tricyclics26,47,48 Increase in heart rate Postural hypotension Prolongation of QTc interval† and QRS interval Ventricular arrhythmia common in overdose. Torsade de Pointes reported. Slows cardiac conduction; blocks cardiac Na/K channels Contraindicated in patients with recent MI TCAs affect cardiac contractility. Some TCAs linked to IHD and sudden cardiac death. Avoid in IHD. Venlafaxine15,49–53 (assume same for desvenlafaxine) Marginally increased Some increase in postural blood pressure. At higher doses increase in BP. Possible prolongation in overdose, but very rare Rare reports of cardiac arrhythmia in overdose Rare reports of conduction abnormalities Has not been evaluated in post-MI patients. Caution advised. Evidence for arrhythmogenic potential is slim, but avoid in IHD Vilazodone54–56 Increased in overdose Increased in overdose No effect, even in overdose No reports, even in overdose No effect No specific contraindications Probably no effect on CV function in clinical doses Vortioxetine57–59 No effect No effect No effect No effect No effect No specific contraindications Trial data suggest no effect on QTc or on coagulation parameters * Small increase in QTc reported when using Bazett’s correction formula but not with Fridericia’s. † Possibly the result of overestimation that can occur when using Bazett’s correction formula at high resting heart rates. CV, cardiovascular; CVD, cardiovascular disease; IHD, ischaemic heart disease; LVF, left ventricular function; MI, myocardial infarction; SPC, summary of product characteristics. Table 3.13 (Continued) Drug Heart rate Blood pressure QTc Arrhythmia Conduction disturbance Licensed restrictions post-MI Comments

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Cardiac effects of antidepressants – summary

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References

Depression and anxiety disorders CHAPTER 3 SSRIs are generally recommended in cardiac disease but beware anti-platelet activity and CYP-medicated interactions with co-administered cardiac drugs. Mirtazapine has been suggested as a suitable alternative60 but it is also associated with bleeding disorders.61 SSRIs may protect against myocardial infarction (MI),62,63 and untreated depression worsens prognosis in cardiovascular disease.64 Post MI, SSRIs and mirtazapine have either a neutral or beneficial effect on mortality.65 Treatment of depression with SSRIs should not therefore be withheld post MI. Protective effects of treatment of depression post MI appear to relate to antidepressant administration, possibly because of an anti- coagulant effect or because of indirect reduction in arrhythmia frequency.42,66 CBT may be ineffective in this respect.67,68 Note that the anti-platelet effect of SSRIs may have adverse consequences too (see section on SSRIs and bleeding in this chapter). References

Behlke LM, et al. The cardiovascular effects of newer antidepressants in older adults and those with or at high risk for cardiovascular diseases. CNS Drugs 2020; 34:1133–1147.
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Dwoskin LP, et al. Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent. CNS Drug Rev 2006; 12:178–207.
Castro VM, et al. QT interval and antidepressant use: a cross sectional study of electronic health records. BMJ 2013; 346:f288.
Robinson S. Treatment of status epilepticus and prolonged QT after massive intentional bupropion overdose with lidocaine. Am J Emerg Med 2022; 55:232.e3–232.e4.
Sage Therapeutics. Highlights of prescribing information. ZULRESSO® (brexanolone) injection, for intravenous use. 2019 (last accessed November 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211371lbl.pdf.
Faden J, et al. Intravenous brexanolone for postpartum depression: what it is, how well does it work, and will it be used? Ther Adv Psychopharmacol 2020; 10:2045125320968658.
Center for Drug Evaluation and Research. Risk Evaluation and Mitigation Strategy (REMS) Document ZULRESSO (brexanolone) REMS Program. 2019 (last accessed February 2025); https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211371Orig1s000REMS.pdf.
Catalano G, et al. QTc interval prolongation associated with citalopram overdose: a case report and literature review. Clin Neuropharmacol 2001; 24:158–162.
Astrom-Lilja C, et al. Drug-induced torsades de pointes: a review of the Swedish pharmacovigilance database. Pharmacoepidemiol Drug Saf 2008; 17:587–592.
Zivin K, et al. Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40mg. Am J Psychiatry 2013; 170:642–650.
Calvi A, et al. Antidepressant drugs effects on blood pressure. Front Cardiovasc Med 2021; 8:704281.
Axsome Therapeutics. Highlights of Prescribing Information. AUVELITY (dextromethorphan hydrobromide and bupropion hydrochloride) extended-release tablets for oral use. 2022 (last accessed November 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/2154 30s000lblCorrect3.pdf.
Kaplan B, et al. QTc prolongation due to dextromethorphan. Int J Cardiol 2011; 148:363–364.
Colucci VJ, et al. Heart failure worsening and exacerbation after venlafaxine and duloxetine therapy. Ann Pharmacother 2008; 42:882–887.
Stuhec M. Duloxetine-induced life-threatening long QT syndrome. WienKlinWochenschr 2013; 125:165–166.
Orozco BS, et al. Duloxetine: an uncommon cause of fatal ventricular arrhythmia. Clin Toxicol 2014; 51:672.
Fisch C. Effect of fluoxetine on the electrocardiogram. J Clin Psychiatry 1985; 46:42–44.
Roose SP, et al. Cardiovascular effects of fluoxetine in depressed patients with heart disease. Am J Psychiatry 1998; 155:660–665.
Strik JJ, et al. Efficacy and safety of fluoxetine in the treatment of patients with major depression after first myocardial infarction: findings from a double-blind, placebo-controlled trial. Psychosom Med 2000; 62:783–789.
Strik JJ, et al. Cardiac side-effects of two selective serotonin reuptake inhibitors in middle-aged and elderly depressed patients. Int Clin Psychopharmacol 1998; 13:263–267.
Stirnimann G, et al. Brugada syndrome ECG provoked by the selective serotonin reuptake inhibitor fluvoxamine. Europace 2010; 12:282–283.
Mago R, et al. Safety and tolerability of levomilnacipran ER in major depressive disorder: results from an open-label, 48-week extension study. Clin Drug Investig 2013; 33:761–771.
Allergan USA. Highlights of prescribing information. Fetzima (levomilnacipran) extended-release capsules for oral use. 2019 (last accessed November 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204168s006lbl.pdf.
Huang Q, et al. Efficacy and safety of multiple doses of levomilnacipran extended-release for the treatment of major depressive disorder. Neuropsychiatr Dis Treat 2016; 12:2707–2714.
Warrington SJ, et al. The cardiovascular effects of antidepressants. Psychol Med Monogr Suppl 1989; 16:i–40.
Stern H, et al. Cardiovascular effects of single doses of the antidepressants amitriptyline and lofepramine in healthy subjects. Pharmacopsychiatry 1985; 18:272–277.

410 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 28. Waring WS, et al. Acute myocarditis after massive phenelzine overdose. Eur J Clin Pharmacol 2007; 63:1007–1009. 29. Forest Pharmaceuticals. Highlights of prescribing information. Savella (milnacipran HCl) tablets. 2011 (last accessed November 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022256s011lbl.pdf. 30. Aurobindo Pharma-Milpharm. Summary of product characteristics. Mirtazapine 30mg tablets. 2024 (last accessed November 2024); https:// www.medicines.org.uk/emc/product/535/smpc. 31. Moll E, et al. Safety and efficacy during long-term treatment with moclobemide. Clin Neuropharmacol 1994; 17 Suppl 1:S74–S87. 32. Hilton S, et al. Moclobemide safety: monitoring a newly developed product in the 1990s. J Clin Psychopharmacol 1995; 15:76S–83S. 33. Downes MA, et al. QTc abnormalities in deliberate self-poisoning with moclobemide. Intern Med J 2005; 35:388–391. 34. Kuhs H, et al. Cardiovascular effects of paroxetine. Psychopharmacology 1990; 102:379–382. 35. Roose SP, et al. Comparison of paroxetine and nortriptyline in depressed patients with ischemic heart disease. JAMA 1998; 279:287–291. 36. Mucci M. Reboxetine: a review of antidepressant tolerability. J Psychopharmacol 1997; 11:S33–S37. 37. Holm KJ, et al. Reboxetine: a review of its use in depression. CNS Drugs 1999; 12:65–83. 38. Fleishaker JC, et al. Lack of effect of reboxetine on cardiac repolarization. Clin Pharmacol Ther 2001; 70:261–269. 39. Shapiro PA, et al. An open-label preliminary trial of sertraline for treatment of major depression after acute myocardial infarction (the SADHAT Trial). Sertraline Anti-Depressant Heart Attack Trial. Am Heart J 1999; 137:1100–1106. 40. Glassman AH, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002; 288:701–709. 41. Jiang W, et al. Safety and efficacy of sertraline for depression in patients with CHF (SADHART-CHF): a randomized, double-blind, placebo- controlled trial of sertraline for major depression with congestive heart failure. Am Heart J 2008; 156:437–444. 42. Leftheriotis D, et al. The role of the selective serotonin re-uptake inhibitor sertraline in nondepressive patients with chronic ischemic heart failure: a preliminary study. Pacing Clin Electrophysiol 2010; 33:1217–1223. 43. Abbas R, et al. A thorough QT study to evaluate the effects of a supratherapeutic dose of sertraline on cardiac repolarization in healthy subjects. Clin Pharmacol Drug Dev 2020; 9:307–320. 44. Service JA, et al. QT prolongation and delayed atrioventricular conduction caused by acute ingestion of trazodone. Clin Toxicol (Phila) 2008; 46:71–73. 45. Dattilo PB, et al. Prolonged QT associated with an overdose of trazodone. J Clin Psychiatry 2007; 68:1309–1310. 46. Winkler D, et al. Trazodone-induced cardiac arrhythmias: a report of two cases. Hum Psychopharmacol 2006; 21:61–62. 47. Hippisley-Cox J, et al. Antidepressants as risk factor for ischaemic heart disease: case–control study in primary care. BMJ 2001; 323:666–669. 48. Taylor D, et al. The cardiovascular safety of tricyclic antidepressants in overdose and in clinical use. Ther Adv Psychopharmacol 2024; 14:20451253241243297. 49. Khawaja IS, et al. Cardiovascular effects of selective serotonin reuptake inhibitors and other novel antidepressants. Heart Dis 2003; 5:153–160. 50. Upjohn UK Limited. Summary of product characteristics. Efexor XL 75 mg (venlafaxine hydrochloride) hard prolonged release capsules. 2024 (last accessed November 2024); https://www.medicines.org.uk/emc/product/5474/smpc#gref. 51. Letsas K, et al. QT interval prolongation associated with venlafaxine administration. Int J Cardiol 2006; 109:116–117. 52. Taylor D, et al. Volte-face on venlafaxine: reasons and reflections. J Psychopharmacol 2006; 20:597–601. 53. Cooper JM, et al. Desvenlafaxine overdose and the occurrence of serotonin toxicity, seizures and cardiovascular effects. Clin Toxicol (Phila) 2017; 55:18–24. 54. Edwards J, et al. Vilazodone lacks proarrhythmogenic potential in healthy participants: a thorough ECG study. Int J Clin Pharmacol Ther 2013; 51:456–465. 55. Heise CW, et al. A review of vilazodone exposures with focus on serotonin syndrome effects. Clin Toxicol (Phila) 2017; 55:1004–1007. 56. Gaw CE, et al. Evaluation of dose and outcomes for pediatric vilazodone ingestions. Clin Toxicol (Phila) 2018; 56:113–119. 57. Citrome L. Vortioxetine for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant: what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract 2014; 68:60–82. 58. Takeda Pharmaceuticals America. Highlights of prescribing information. BRINTELLIX (vortioxetine) tablets. 2024 (last accessed February 2025); https://us.trintellix.com. 59. Baldwin DS, et al. The safety and tolerability of vortioxetine: analysis of data from randomized placebo-controlled trials and open-label extension studies. J Psychopharmacol 2016; 30:242–252. 60. Honig A, et al. Treatment of post-myocardial infarction depressive disorder: a randomized, placebo-controlled trial with mirtazapine. Psychosom Med 2007; 69:606–613. 61. Na K-S, et al. Can we recommend mirtazapine and bupropion for patients at risk for bleeding? A systematic review and meta-analysis. J Affect Disord 2018; 225:221–226. 62. Alqdwah-Fattouh R, et al. Differential effects of antidepressant subgroups on risk of acute myocardial infarction: a nested case–control study. Br J Clin Pharmacol 2020; 86:2040–2050. 63. Sauer WH, et al. Selective serotonin reuptake inhibitors and myocardial infarction. Circulation 2001; 104:1894–1898. 64. Davies SJ, et al. Treatment of anxiety and depressive disorders in patients with cardiovascular disease. BMJ 2004; 328:939–943. 65. Taylor D, et al. Pharmacological interventions for people with depression and chronic physical health problems: systematic review and meta- analyses of safety and efficacy. Br J Psychiatry 2011; 198:179–188. 66. Chen S, et al. Serotonin and catecholaminergic polymorphic ventricular tachycardia: a possible therapeutic role for SSRIs? Cardiovasc J Afr 2010; 21:225–228. 67. Berkman LF, et al. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) randomized trial. JAMA 2003; 289:3106–3116. 68. Zambrano J, et al. Psychiatric and psychological interventions for depression in patients with heart disease: a scoping review. J Am Heart Assoc 2020; 9:e018686.

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77 - Antidepressant induced arrhythmia

Antidepressant-induced arrhythmia

Depression and anxiety disorders CHAPTER 3 Antidepressant-induced arrhythmia Depression confers an increased risk of cardiovascular disease1 and sudden cardiac death.2 Possible factors include platelet activation, decreased heart rate variability, reduced physical activity, and an association with an increased risk of diabetes.3 Tricyclic antidepressants have established arrhythmogenic activity, which arises as a result of potent blockade of cardiac sodium channels and variable activity at potassium channels.4 ECG changes produced include PR, QRS and QT prolongation and the Brugada syndrome.5 These actions are very evident in overdose but their effects in clinical doses is unclear. Normal clinical use of nortriptyline has been associated in one study with an increased risk of cardiac arrest,6 although a large cohort study did not confirm this finding.7 Lofepramine, for reasons unknown, seems to lack the overdose arrhythmogenicity of other TCAs, despite its major metabolite, desipramine, being a potent potassium channel blocker.8 Oddly, in one study,9 clinical use of lofepramine was associated with an increased risk of myocardial infarction (MI), whereas other antidepressants were not. Network meta-analysis suggests that TCAs have a very low risk of causing ventricular arrythmia or sudden cardiac death outside overdose or high-dose usage.10 In patients taking tricyclics, ECG monitoring is a more meaningful and useful measure of toxicity than plasma level monitoring. There is limited evidence that venlafaxine is a sodium channel antagonist11 and a weak antagonist at hERG (human ether-a-go-go-related gene) potassium channels. Arrhythmia is a rare occurrence, even after massive overdose,12–15 and ECG changes after overdose are no more common than with SSRIs.16 No ECG changes are seen in therapeutic dosing17 or even at supratherapeutic doses (450mg/day)18 and sudden cardiac death in clinical use is no more common than with fluoxetine or citalopram.7,19 Desvenlafaxine does not appear to prolong QT, even in overdose.20 Moclobemide,21 citalopram,22,23 escitalopram,24 bupropion (amfebutamone),25 trazodone26,27 and sertraline,28 among others,1 have been reported to prolong the QTc interval in overdose but the clinical consequences of this are uncertain. Sertraline prolongs QT by 5–10ms at 400mg a day,29 but QT changes are not usually seen with most SSRIs at normal clinical doses.30,31 Nonetheless, an association between SSRIs (as a group) and QT changes in normal dosing can be shown32 but this seems largely to be driven by the effects of citalopram and escitalopram.33 The effect on QTc is dose related33 but modest.32 Most studies have failed to find any association between citalopram or escitalopram treatment and arrythmia or cardiac mortality in routine clinical practice,7,34,35 although some have reported very small increases in mortality.36 Genetic variation in CYP219 metabolic capacity may explain individual differences in cardiac toxicity, as it determines the serum concentration of citalopram metabolites,37 but whether it is the parent compounds or their metabolites that are responsible for cardiotoxicity is unclear.38 Vortioxetine seems to have no effect on QT.39–41 Similarly, agomelatine has no effect, even at supratherapeutic doses.42 Vilazodone has no effect on cardiac conduction.43 Levomilnacipran44 and milnacipran45 probably have no effect on QT, at least at therapeutic doses.

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Use in at-risk patients

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Relative cardiotoxicity

412 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Use in at-risk patients There is clear evidence for the safety of sertraline46 and mirtazapine47 (and to a lesser extent, citalopram,47 fluoxetine48 and bupropion49) in people at risk of arrhythmia due to recent MI. One trial found that SSRIs and trazodone decrease the risk of MI,50 another suggested no effect in either direction for any antidepressant.51 Citalopram seems to be safe to use in patients with coronary artery disease52 (despite its link to a risk of torsades de pointes).53 Escitalopram did not affect mortality in a trial in patients with heart failure,54 and a later systematic review found no adverse effect on mortality for any SSRIs in heart failure.55 Sertraline may help improve cardiovascular risk factors.56 Recent pharmacovigilance database studies report some association between antidepressants and cardiac arrythmias and cardiovascular death.57,58 Meta-analysis suggests that overall, antidepressants (SSRIs, SNRIs and TCAs) are associated with an increased risk of atrial fibrillation but not ventricular arrythmias or sudden cardiac death.59 Conflicting results are reported in elderly patients, with cohort studies reporting both increased risk of arrythmias60 and no increased risk.61 Relative cardiotoxicity Relative cardiotoxicity of antidepressants is difficult to establish. Surveillance monitoring data suggest that many marketed antidepressants are linked to arrhythmia (ranging from clinically insignificant to life threatening) and sudden cardiac death. For a substantial proportion of drugs, these figures are perhaps more likely to reflect coincidence and/or confounding rather than causation. The Fatal Toxicity Index (FTI) may provide some means for comparison, at least for overdose toxicity. This is a measure of the number of overdose deaths per million (FP10) prescriptions issued. FTI figures suggest high toxicity for all tricyclic drugs (but not lofepramine), medium toxicity for venlafaxine and moclobemide, and low toxicity for SSRIs, mirtazapine and reboxetine.62–66 However, FTI does not necessarily reflect only cardiotoxicity (antidepressants also cause serotonin syndrome, seizures and coma, for example) and is, in any case, open to other influences. This is best evidenced in the change in FTI over time. A good example here is nortriptyline, the FTI of which has been estimated at 0.616 and 39.212 and several values in between.67 This change probably reflects changes in the type of patient prescribed nortriptyline but double counting (nortriptyline is a metabolite of amitriptyline) at post mortem also plays a part. Venlafaxine is relatively more often prescribed to patients with more severe depression and who are relatively more likely to attempt suicide.68–70 This is apt to inflate venlafaxine’s FTI and erroneously suggest greater inherent toxicity. Drugs with consistently low FTIs can probably be assumed to have very low risk of arrhythmias. Citalopram and escitalopram have surprisingly low overdose toxicity, despite QT prolongation occurring in about a third of reported overdoses.71 Standard doses of citalopram may be causally associated with an increased risk of cardiac arrest6 but, as mentioned earlier, other data suggest no increased risk of arrhythmia or death with standard and higher licensed doses of citalopram and escitalopram.34 Citalopram and escitalopram are probably the most cardiotoxic of the SSRIs but their toxicity is modest at worst, and possibly insignificant in respect to risk of adverse outcomes.

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Summary

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References

Depression and anxiety disorders CHAPTER 3 Summary ■ ■Tricyclics (but not lofepramine) have an established link to ion channel blockade and cardiac arrhythmia, especially in overdose. ■ ■Non-tricyclics generally have a very low risk of inducing arrhythmia. ■ ■Sertraline is recommended post MI, but other SSRIs and mirtazapine are also likely to be safe. ■ ■Bupropion, citalopram, escitalopram, moclobemide and venlafaxine should be used with caution or avoided in those at risk of serious arrhythmia (those with heart failure, left ventricular hypertrophy, previous arrhythmia or MI). An ECG should be performed at baseline and 1 week after every increase in dose if any of these drugs are used in at-risk patients. ■ ■TCAs (with the exception of lofepramine) are best avoided completely in patients at risk of serious arrhythmia. If use of a TCA cannot be avoided, an ECG should be performed at baseline, 1 week after each increase in dose and periodically throughout treatment. Frequency will be determined by the stability of the cardiac disorder. Advice from a cardiology specialist should be sought. ■ ■The arrhythmogenic potential of TCAs and other antidepressants is dose related. Consideration should be given to ECG monitoring of all patients prescribed doses towards the top of the licensed range and those who are prescribed other drugs that, through pharmacokinetic (e.g. fluoxetine) or pharmacodynamic (e.g. diuretics) mechanisms, may add to the risk posed by the drug. References

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Feighner JP. Cardiovascular safety in depressed patients: focus on venlafaxine. J Clin Psychiatry 1995; 56:574–579.
Abbas R, et al. Lack of an effect of supratherapeutic dose of venlafaxine on cardiac repolarization in healthy subjects. Clin Pharmacol Drug Dev 2022; 11:100–111.

414 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 19. Martinez C, et al. Use of venlafaxine compared with other antidepressants and the risk of sudden cardiac death or near death: a nested case–control study. BMJ 2010; 340:c249. 20. Cooper JM, et al. Desvenlafaxine overdose and the occurrence of serotonin toxicity, seizures and cardiovascular effects. Clin Toxicol (Phila) 2017; 55:18–24. 21. Downes MA, et al. QTc abnormalities in deliberate self-poisoning with moclobemide. Intern Med J 2005; 35:388–391. 22. Kelly CA, et al. Comparative toxicity of citalopram and the newer antidepressants after overdose. J Toxicol Clin Toxicol 2004; 42:67–71. 23. Grundemar L, et al. Symptoms and signs of severe citalopram overdose. Lancet 1997; 349:1602. 24. Mohammed R, et al. Prolonged QTc interval due to escitalopram overdose. J Miss State Med Assoc 2010; 51:350–353. 25. Isbister GK, et al. Bupropion overdose: QTc prolongation and its clinical significance. Ann Pharmacother 2003; 37:999–1002. 26. Service JA, et al. QT prolongation and delayed atrioventricular conduction caused by acute ingestion of trazodone. Clin Toxicol (Phila) 2008; 46:71–73. 27. Dattilo PB, et al. Prolonged QT associated with an overdose of trazodone. J Clin Psychiatry 2007; 68:1309–1310. 28. de Boer RA, et al. QT interval prolongation after sertraline overdose: a case report. BMC Emerg Med 2005; 5:5. 29. Abbas R, et al. A thorough QT study to evaluate the effects of a supratherapeutic dose of sertraline on cardiac repolarization in healthy subjects. Clin Pharmacol Drug Dev 2020; 9:307–320. 30. Maljuric NM, et al. Use of selective serotonin re-uptake inhibitors and the heart rate corrected QT interval in a real-life setting: the population-based Rotterdam Study. Br J Clin Pharmacol 2015; 80:698–705. 31. van Haelst IM, et al. QT interval prolongation in users of selective serotonin reuptake inhibitors in an elderly surgical population: a cross- sectional study. J Clin Psychiatry 2014; 75:15–21. 32. Beach SR, et al. Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation. J Clin Psychiatry 2014; 75:e441–449. 33. Castro VM, et al. QT interval and antidepressant use: a cross sectional study of electronic health records. BMJ 2013; 346:f288. 34. Zivin K, et al. Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40 mg. Am J Psychiatry 2013; 170:642–650. 35. Ray WA, et al. High-dose citalopram and escitalopram and the risk of out-of-hospital death. J Clin Psychiatry 2017; 78:190–195. 36. Lin YT, et al. Selective serotonin reuptake inhibitor use and risk of arrhythmia: a nationwide, population-based cohort study. Clin Ther 2019; 41:1128–1138.e8. 37. Farhat H, et al. Citalopram and escitalopram: mechanisms of cardiotoxicity, toxicology predisposition and risks of use in geriatric and hemodialysis populations. Glob Cardiol Sci Pract 2024; 2024:e202434. 38. Faraj P, et al. Pro-arrhythmic effect of escitalopram and citalopram at serum concentrations commonly observed in older patients: a study based on a cohort of 19,742 patients. EBioMedicine 2023; 95:104779. 39. Dubovsky SL. Pharmacokinetic evaluation of vortioxetine for the treatment of major depressive disorder. Expert Opin Drug Metab Toxicol 2014; 10:759–766. 40. Alam MY, et al. Safety, tolerability, and efficacy of vortioxetine (Lu AA21004) in major depressive disorder: results of an open-label, flexible- dose, 52-week extension study. Int Clin Psychopharmacol 2014; 29:36–44. 41. Wang Y, et al. Effect of vortioxetine on cardiac repolarization in healthy adult male subjects: results of a thorough QT/QTc study. Clin Pharmacol Drug Dev 2013; 2:298–309. 42. Donazzolo Y, et al. Evaluation of the effects of therapeutic and supra-therapeutic doses of agomelatine on the QT/QTc interval: a phase I, randomised, double-blind, placebo-controlled and positive-controlled, cross-over thorough QT/QTc study conducted in healthy volunteers. J Cardiovasc Pharmacol 2014; 64:440–451. 43. Edwards J, et al. Vilazodone lacks proarrhythmogenic potential in healthy participants: a thorough ECG study. Int J Clin Pharmacol Ther 2013; 51:456–465. 44. Mago R, et al. Safety and tolerability of levomilnacipran ER in major depressive disorder: results from an open-label, 48-week extension study. Clin Drug Investig 2013; 33:761–771. 45. Periclou A, et al. Effects of milnacipran on cardiac repolarization in healthy participants. J Clin Pharmacol 2010; 50:422–433. 46. Glassman AH, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002; 288:701–709. 47. van Melle JP, et al. Effects of antidepressant treatment following myocardial infarction. Br J Psychiatry 2007; 190:460–466. 48. Strik JJ, et al. Efficacy and safety of fluoxetine in the treatment of patients with major depression after first myocardial infarction: findings from a double-blind, placebo-controlled trial. Psychosom Med 2000; 62:783–789. 49. Rigotti NA, et al. Bupropion for smokers hospitalized with acute cardiovascular disease. Am J Med 2006; 119:1080–1087. 50. Alqdwah-Fattouh R, et al. Differential effects of antidepressant subgroups on risk of acute myocardial infarction: a nested case–control study. Br J Clin Pharmacol 2020; 86:2040–2050. 51. Wu CS, et al. Use of antidepressants and risk of hospitalization for acute myocardial infarction: a nationwide case-crossover study. J Psychiatr Res 2017; 94:7–14. 52. Lesperance F, et al. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA 2007; 297:367–379. 53. Astrom-Lilja C, et al. Drug-induced torsades de pointes: a review of the Swedish pharmacovigilance database. Pharmacoepidemiol Drug Saf 2008; 17:587–592. 54. Angermann CE, et al. Effect of escitalopram on all-cause mortality and hospitalization in patients with heart failure and depression: the MOOD-HF randomized clinical trial. JAMA 2016; 315:2683–2693. 55. Hedrick R, et al. The impact of antidepressants on depressive symptom severity, quality of life, morbidity, and mortality in heart failure: a systematic review. Drugs Context 2020; 9:2020-5-4.

Depression and anxiety disorders CHAPTER 3 56. Sherwood A, et al. Effects of exercise and sertraline on measures of coronary heart disease risk in patients with major depression: results from the SMILE-II randomized clinical trial. Psychosom Med 2016; 78:602–609. 57. Wang Z, et al. Exploring the correlation between cardiovascular adverse events and antidepressant use: a retrospective pharmacovigilance analysis based on the FDA Adverse Event Reporting System database. J Affect Disord 2024; 367:96–108. 58. Yokohara S, et al. Psychotherapeutic drug-induced life-threatening arrhythmias: a retrospective analysis using the Japanese adverse drug event report database. J Arrhythm 2023; 39:928–936. 59. Cao Y, et al. Associations of antidepressants with atrial fibrillation and ventricular arrhythmias: a systematic review and meta-analysis. Front Cardiovasc Med 2022; 9:840452. 60. Biffi A, et al. Antidepressants and the risk of arrhythmia in elderly affected by a previous cardiovascular disease: a real-life investigation from Italy. Eur J Clin Pharmacol 2018; 74:119–129. 61. Aakjaer M, et al. Serious arrhythmia in initiators of citalopram, escitalopram, and other selective serotonin reuptake inhibitors: a population- based cohort study in older adults. Clin Transl Sci 2022; 15:2105–2115. 62. Crome P. The toxicity of drugs used for suicide. Acta Psychiatr Scand Suppl 1993; 371:33–37. 63. Cheeta S, et al. Antidepressant-related deaths and antidepressant prescriptions in England and Wales, 1998–2000. Br J Psychiatry 2004; 184:41–47. 64. Buckley NA, et al. Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data. BMJ 2002; 325:1332–1333. 65. Buckley NA, et al. Greater toxicity in overdose of dothiepin than of other tricyclic antidepressants. Lancet 1994; 343:159–162. 66. Morgan O, et al. Fatal toxicity of antidepressants in England and Wales, 1993–2002. Health Stat Q 2004; (23):18–24. 67. Taylor D, et al. The cardiovascular safety of tricyclic antidepressants in overdose and in clinical use. Ther Adv Psychopharmacol 2024; 14:20451253241243297. 68. Egberts ACG, et al. Channeling of three newly introduced antidepressants to patients not responding satisfactorily to previous treatment. J Clin Psychopharmacol 1997; 17:149–155. 69. Mines D, et al. Prevalence of risk factors for suicide in patients prescribed venlafaxine, fluoxetine, and citalopram. Pharmacoepidemiol Drug Saf 2005; 14:367–372. 70. Chan AN, et al. A comparison of venlafaxine and SSRIs in deliberate self-poisoning. J Med Toxicol 2010; 6:116–121. 71. Hasnain M, et al. Escitalopram and QTc prolongation. J Psychiatry Neurosci 2013; 38:E11.

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Antidepressant-induced hyponatraemia

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Which antidepressants?

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Database studies

416 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Antidepressant-induced hyponatraemia Most antidepressants have been associated with hyponatraemia. Onset is usually within 30 days of starting treatment.1–3 The effect appears not to be dose related,1,4 although some case reports suggest otherwise. The most likely mechanism of this adverse effect is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Risk of hospitalisation with hyponatraemia is elevated from 1 in 1,600 in the general population to 1 in 300 for those on any antidepressant.5 Hyponatraemia is a potentially serious adverse effect of antidepressants that demands careful monitoring,6 particularly in those patients at greatest risk. Hyponatraemia of all severities is associated with increased mortality.7 Which antidepressants? No antidepressant has been definitively shown not to be linked with hyponatraemia and almost all have a reported association.8 It has been suggested that serotonergic drugs are relatively more likely than noradrenergic drugs to cause hyponatraemia,9,10 although this is disputed.11 A 2024 meta-analysis suggests that the risk may be highest with SNRIs, followed by SSRIs,12 and lowest with mirtazapine and trazodone. There are notably few reports for MAOIs,13,14 but all marketed antidepressants have some association with hyponatraemia, even more recently introduced drugs such as vortioxetine,15 desvenlafaxine16 and vilazodone.17 Older women who are frail and/or prescribed other medication known to reduce plasma sodium are at greatest risk.15,18 CYP2D6 poor metabolisers may be at increased risk of antidepressant-induced hyponatraemia,19 although evidence is somewhat inconsistent.20 Database studies A 2018 French pharmacovigilance database study found an association of hyponatraemia with agomelatine, a drug not previously reported to cause hyponatraemia.21 Another database study using US Food and Drug Administration (FDA) data found the strongest association between hyponatraemia and antidepressants to be for mirtazapine, in contrast to most other reports,22 and a further French database study found the greatest risk to be with duloxetine.23 A 2022 Japanese study24 found that SSRIs and SNRIs caused, on average, a 1mmol/L fall in plasma sodium, an effect not seen with other antidepressants examined. The effect on sodium was directly linked to a drug’s binding affinity for the SERT transporter. The mean effect of antidepressants on sodium in this study suggests that clinical hyponatraemia might be an extreme of the normal distribution of effects rather than an idiosyncratic effect only seen in certain people. Extrapolating from incident report databases to estimate relative or absolute risk of hyponatraemia is fraught with difficulty. Problems include disproportionate reporting for antidepressants for which the adverse effect is considered to be rare, the inability to adjust for confounding by indication (drugs perceived to be of low risk are more likely to be prescribed to patients at already at high risk of hyponatraemia) and the impact of concomitant prescriptions. Table 3.14 provides a summary of the risk of hyponatraemia with antidepressants.

Depression and anxiety disorders CHAPTER 3 Monitoring1,27,28 All patients taking antidepressants should be informed of and observed for signs of hyponatraemia (dizziness, nausea, lethargy, confusion, cramps, seizures). The risk is highest in the first 4 weeks of starting antidepressants, and diminishes over time until by 3–6 months the risk is the same as for patients who do not take antidepressants.18 Consequently, in patients treated with antidepressants for several months or years, other causes should be assumed in the event of hyponatraemia. Serum sodium should be determined (at baseline and 2 and 4 weeks, and then 3-monthly29) for those at high risk of drug-induced hyponatraemia. This frequency of electrolyte monitoring may not identify all cases as serum sodium may drop precipitously.30 Box 3.4 lists high-risk factors for drug-induced hyponatraemia. Table 3.14 Summary of risk of hyponatraemia with antidepressants5,12,24–26 Drug/drug group Risk of ↓Na Level of supporting evidence SNRIs High Strong SSRIs High Strong Tricyclics Moderate Strong MAOIs Low Weak NaSSas (mirtazapine, mianserin) Low Strong Trazodone Low Strong Bupropion Low Moderate Agomelatine Low Moderate MAOIs, monoamine oxidase inhibitors; NaSSas, noradrenergic and specific serotonergic antidepressants. Box 3.4 High-risk factors for drug-induced hyponatraemia ■ ■Older age ■ ■Female sex ■ ■Major surgery ■ ■History of hyponatraemia or a low baseline sodium concentration ■ ■Co-therapy with other drugs known to be associated with hyponatraemia (e.g. diuretics, NSAIDs, antipsychotics, carbamazepine, cancer chemotherapy, calcium antagonists, angiotensin-converting enzyme inhibitors and laxatives) ■ ■Reduced renal function (glomerular filtration rate <50mL/minute) ■ ■Medical comorbidity (e.g. hypothyroidism, diabetes, chronic obstructive pulmonary disease (COPD), hypertension, head injury, congestive cardiac failure, cardiovascular accident, various cancers) ■ ■Low body weight Age is perhaps the most important risk factor, so for older people (especially women) monitoring is essential.27

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Monitoring1,27,28

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Treatment28

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Restarting treatment

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Other prescribed drugs

418 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Treatment28 The normal range for serum sodium is 136–145mmol/L. It may be possible to manage mild hyponatraemia (>130 mmol/L) with fluid restriction. Some suggest increasing sodium intake,4 although this is likely to be impractical. If symptoms persist, the antidepressant should be discontinued. ■ ■If serum sodium is >125mmol/L – monitor sodium daily until normal. Symptoms include headache, nausea, vomiting, muscle cramps, restlessness, lethargy, confusion and disorientation. Withdraw the offending antidepressant as soon as possible. ■ ■If serum sodium is <125 mmol/L – refer urgently to specialist medical care. The antidepressant should be discontinued immediately. There is an increased risk of life- threatening symptoms such as seizures, coma and respiratory arrest. Over-rapid correction of hyponatraemia may be harmful. Restarting treatment ■ ■Hyponatraemia may recur on rechallenge with the same or a different SSRI, but may be less likely with an antidepressant from another class.27,31 ■ ■Consider withdrawing other drugs associated with hyponatraemia (risk increases exponentially when antidepressants are combined with diuretics, etc.). ■ ■Prescribe a drug from a different class. Consider noradrenergic drugs such as nortriptyline and lofepramine, or mirtazapine, or an MAOI such as moclobemide. Agomelatine or bupropion32 might also be considered. Begin with a low dose, increase slowly and monitor closely. If hyponatraemia recurs and continued antidepressant use is essential, consider water restriction and/or careful use of demeclocycline. ■ ■Consider (es)ketamine or ECT if a standard antidepressant cannot be given. Other prescribed drugs Carbamazepine has a well-known association with SIADH33 and antipsychotic use has been linked to hyponatraemia (see section on hyponatraemia in psychosis in Chapter 1). Other commonly prescribed drugs such as thiazide diuretics, opiates, NSAIDs, tramadol, cytotoxics, omeprazole and trimethoprim can also cause hyponatraemia.2,33 References

Egger C, et al. A review on hyponatremia associated with SSRIs, reboxetine and venlafaxine. Int J Psychiatry Clin Pract 2006; 10:17–26.
Liamis G, et al. A review of drug-induced hyponatremia. Am J Kidney Dis 2008; 52:144–153.
Takeda K, et al. Analysis of the frequency and onset time of hyponatremia/syndrome of inappropriate antidiuretic hormone induced by antidepressants or antipsychotics. Ann Pharmacother 2022; 56:303–308.
Kruger S, et al. Duloxetine and hyponatremia: a report of 5 cases. J Clin Psychopharmacol 2007; 27:101–104.
Gandhi S, et al. Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults. Am J Kidney Dis 2017; 69:87–96.
Mohan S, et al. Prevalence of hyponatremia and association with mortality: results from NHANES. Am J Med 2013; 126:1127–1137.e1.
Selmer C, et al. Hyponatremia, all-cause mortality, and risk of cancer diagnoses in the primary care setting: a large population study. Eur J Intern Med 2016; 36:36–43.
Thomas A, et al. Hyponatraemia and the syndrome of inappropriate antidiuretic hormone secretion associated with drug therapy in psychiatric patients. CNS Drugs 1995; 5:357–369.
Movig KL, et al. Serotonergic antidepressants associated with an increased risk for hyponatraemia in the elderly. Eur J Clin Pharmacol 2002; 58:143–148.

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References

Depression and anxiety disorders CHAPTER 3 10. Movig KL, et al. Association between antidepressant drug use and hyponatraemia: a case-control study. Br J Clin Pharmacol 2002; 53:363–369. 11. Kirby D, et al. Hyponatraemia and selective serotonin re-uptake inhibitors in elderly patients. Int J Geriatr Psychiatry 2001; 16:484–493. 12. Gheysens T, et al. The risk of antidepressant-induced hyponatremia: a meta-analysis of antidepressant classes and compounds. Eur Psychiatry 2024; 67:e20. 13. Mercier S, et al. [Severe hyponatremia induced by moclobemide]. Therapie 1997; 52:82–83. 14. Peterson JC, et al. Inappropriate antidiuretic hormone secondary to a monamine oxidase inhibitor. JAMA 1978; 239:1422–1423. 15. Seifert J, et al. Psychotropic drug-induced hyponatremia: results from a drug surveillance program-an update. J Neural Transm (Vienna) 2021; 128:1249–1264. 16. Liew ED, et al. Syndrome of inappropriate antidiuretic hormone secretion associated with desvenlafaxine. Int J Clin Pharm 2014; 36:253–255. 17. Das S, et al. Dose dependent hyponatremia caused by vilazodone: a case report. Asian J Psychiatr 2019; 43:213. 18. Mannheimer B, et al. Time-dependent association between selective serotonin reuptake inhibitors and hospitalization due to hyponatremia. J Psychopharmacol 2021; 35:928–933. 19. Kwadijk-de GS, et al. Variation in the CYP2D6 gene is associated with a lower serum sodium concentration in patients on antidepressants. Br J Clin Pharmacol 2009; 68:221–225. 20. Stedman CA, et al. Cytochrome P450 2D6 genotype does not predict SSRI (fluoxetine or paroxetine) induced hyponatraemia. Hum Psychopharmacol 2002; 17:187–190. 21. Rochoy M, et al. [Antidepressive agents and hyponatremia: a literature review and a case/non-case study in the French Pharmacovigilance database]. Therapie 2018; 73:389–398. 22. Mazhar F, et al. Association of hyponatraemia and antidepressant drugs: a pharmacovigilance-pharmacodynamic assessment through an analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. CNS Drugs 2019; 33:581–592. 23. Revol R, et al. [Hyponatremia associated with SSRI/NRSI: descriptive and comparative epidemiological study of the incidence rates of the notified cases from the data of the French National Pharmacovigilance Database and the French National Health Insurance]. Encephale 2018; 44:291–296. 24. Nagashima T, et al. Identifying antidepressants less likely to cause hyponatremia: triangulation of retrospective cohort, disproportionality, and pharmacodynamic studies. Clin Pharmacol Ther 2022; 111:1258–1267. 25. Leth-Moller KB, et al. Antidepressants and the risk of hyponatremia: a Danish register-based population study. BMJ Open 2016; 6:e011200. 26. Moscona-Nissan A Sr, et al. Mirtazapine risk of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion in adult and elderly patients: a systematic review. Cureus 2021; 13:e20823. 27. Dirks AC, et al. Recurrent hyponatremia after substitution of citalopram with duloxetine. J Clin Psychopharmacol 2007; 27:313. 28. Pinkhasov A, et al. Management of SIADH-related hyponatremia due to psychotropic medications: an expert consensus from the Association of Medicine and Psychiatry. J Psychosom Res 2021; 151:110654. 29. Arinzon ZH, et al. Delayed recurrent SIADH associated with SSRIs. Ann Pharmacother 2002; 36:1175–1177. 30. Lane NE, et al. Hyponatremia-associated hospital visits are not reduced by early electrolyte testing in older adults starting antidepressants. J Am Geriatr Soc 2024; 72:1770–1780. 31. Bavbek N, et al. Recurrent hyponatremia associated with citalopram and mirtazapine. Am J Kidney Dis 2006; 48:e61–e62. 32. Varela Piñón M, et al. Selective serotonin reuptake inhibitor-induced hyponatremia: clinical implications and therapeutic alternatives. Clin Neuropharmacol 2017; 40:177–179. 33. Shepshelovich D, et al. Medication-induced SIADH: distribution and characterization according to medication class. Br J Clin Pharmacol 2017; 83:1801–1807.

420 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Table 3.15 Reported associations between antidepressants and increased prolactin. Drug/group Prospective studies Case reports/series Agomelatine No mention of prolactin changes in clinical trials8 Melatonin itself may inhibit prolactin production9 None Bupropion Single doses of up to 100mg seem not to affect prolactin10 May decrease prolactin11 None Monoamine oxidase inhibitors Small mean changes observed with phenelzine11 and tranylcypromine12 Very occasional reports of increased prolactin11 Mirtazapine Strong evidence that mirtazapine has no effect on prolactin13 Occasional reports of galactorrhoea14 and gynaecomastia15 SNRIs Clear association observed between venlafaxine and duloxetine and prolactin elevation16–18 Galactorrhoea reported with venlafaxine19,20 and duloxetine.21,22 Duloxetine-linked hyperprolactinaemia has been treated with aripiprazole.16 SSRIs Prospective studies generally show no change in prolactin.23–25 Some evidence from prescription event monitoring that SSRIs are associated with higher risk of non-puerperal lactation.26 In a French study, 1.6% of adverse event reports for SSRIs were of hyperprolactinaemia.3 Galactorrhoea reported with fluoxetine,6,27 paroxetine,28–30 sertraline31 and fluvoxamine30 Euprolactinaemic galactorrhoea and amenorrhoea32 reported with escitalopram33 and fluvoxamine34 Hyperprolactinaemia reported with sertraline7,35 Tricyclics Small mean changes seen in some studies11,36,37 but no changes in others11,38 Symptomatic hyperprolactinaemia reported with imipramine,33 dosulepin39 and clomipramine40,41 Galactorrhoea reported with nortriptyline42 and when trazodone was added to citalopram43 Raised prolactin may be linked to response to amitriptyline36,44 Vortioxetine No mention of prolactin changes in clinical trials45 None One review suggests ‘probable relation between vortioxetine and galactorrhoea’46 Antidepressants and hyperprolactinaemia Prolactin release is controlled by endogenous dopamine but is also indirectly modulated by serotonin via stimulation of 5HT1C and 5HT2 receptors.1,2 Long-standing increased plasma prolactin (with or without symptoms) is very occasionally seen with antidepressant use.3 Where antidepressant-induced hyperprolactinaemia does occur, rises in prolactin are usually small and short-lived,4 so symptoms are very rare. There is no association between SSRI use and breast cancer.5 Routine monitoring of prolactin is not recommended but where symptoms suggest the possibility of hyperprolactinaemia then measurement of plasma prolactin is essential. Where symptomatic hyperprolactinaemia is confirmed, a switch to mirtazapine is recommended (see below), although there is also evidence that switching to an alternative SSRI can resolve symptoms.6,7 Some details of associations between antidepressants and increased prolactin are given in Table 3.15.

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Antidepressants and hyperprolactinaemia

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References

Depression and anxiety disorders CHAPTER 3 References

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Ekinci N, et al. Sertraline-related amenorrhea in an adolescent. Clin Neuropharmacol 2019; 42:99–100.
Fava GA, et al. Prolactin, cortisol, and antidepressant treatment. Am J Psychiatry 1988; 145:358–360.
Orlander H, et al. Imipramine induced elevation of prolactin levels in patients with HIV/AIDS improved their immune status. West Indian Med J 2009; 58:207–213.
Meltzer HY, et al. Lack of effect of tricyclic antidepressants on serum prolactin levels. Psychopharmacology (Berl) 1977; 51:185–187.
Gadd EM, et al. Antidepressants and galactorrhoea. Int Clin Psychopharmacol 1987; 2:361–363.
Anand VS. Clomipramine-induced galactorrhoea and amenorrhoea. Br J Psychiatry 1985; 147:87–88.
Fowlie S, et al. Hyperprolactinaemia and nonpuerperal lactation associated with clomipramine. Scott Med J 1987; 32:52.

422 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 42. Kukreti P, et al. Rising trend of use of antidepressants induced non- puerperal lactation: a case report. J Clin Diagn Res 2016; 10:Vd01–Vd02. 43. Arslan FC, et al. Trazodone induced galactorrhea: a case report. Gen Hosp Psychiatry 2015; 37:373.e1–2. 44. Centner S, et al. Amitriptyline-induced hyperprolactinemia in a pediatric patient. Cureus 2024; 16:e59604. 45. Mahableshwarkar AR, et al. A randomized, double-blind, fixed-dose study comparing the efficacy and tolerability of vortioxetine 2.5 and 10 mg in acute treatment of adults with generalized anxiety disorder. Hum Psychopharmacol 2014; 29:64–72. 46. Verma A, et al. Risks associated with vortioxetine in the established therapeutic indication. Curr Neuropharmacol 2020; 19:711–717.

Depression and anxiety disorders CHAPTER 3 Table 3.16 Effect of antidepressants on glucose homeostasis and weight. Antidepressant class Effect on glucose homeostasis SSRIs7–19 ■ ■Studies indicate that SSRIs have a favourable effect on diabetic parameters in patients with type II diabetes. Insulin requirements may be decreased. ■ ■Fluoxetine has been associated with improvement in HbA1c levels, reduced insulin requirements, weight loss and enhanced insulin sensitivity. Its effect on insulin sensitivity is independent of its effect on weight loss. Sertraline may also reduce HbA1c. ■ ■Escitalopram also seems to improve glycaemic control ■ ■Some evidence that long-term SSRIs may increase the risk of diabetes in general20 and gestational diabetes in particular21 but there is also evidence of no effect either way22 TCAs13,14,23–25 ■ ■TCAs are associated with increased appetite, weight gain and hyperglycaemia ■ ■Nortriptyline improved depression but worsened glycaemic control in diabetic patients in one study. Overall improvement in depression had a beneficial effect on HbA1c. Clomipramine reported to precipitate diabetes. ■ ■Long-term use of TCAs seems to increase risk of diabetes4 MAOIs26,27 ■ ■Irreversible MAOIs have a tendency to cause extreme hypoglycaemic episodes and weight gain ■ ■No known effects with moclobemide SNRIs24,28,29 ■ ■SNRIs do not appear to disrupt glycaemic control and have minimal impact on weight ■ ■Studies of duloxetine in the treatment of diabetic neuropathy show that it has little influence on glycaemic control. No data in depression and diabetes. ■ ■Limited data on venlafaxine but may slightly increase risk of incident diabetes20 ■ ■One report of hyperglycaemia with desvenlafaxine30 Mirtazapine31,32 ■ ■Mirtazapine does not appear to impair glucose tolerance in non-diabetic depressed patients ■ ■Improvement in HbA1c was seen with short-term use but HbA1c worsened during a 1-year follow-up ■ ■Mirtazapine was associated with an increase in body mass index in patients with diabetes both in the short and long term Antidepressants and diabetes mellitus Depression and diabetes Prevalence rates of depression are high in both type I (22%) and type II (19%) diabetes.1 Comorbid depression in type II diabetes is associated with poorer glycaemic control, increased hospital admissions, increased diabetic complications and poorer compliance to diabetes treatments and dietary recommendations.1 The presence of depression has a negative impact on metabolic control and poor metabolic control may worsen depression.2 Considering all of this, the treatment of comorbid depression in patients with diabetes is of vital importance and drug choice should take into account likely effects on metabolic control (Table 3.16). In 2012, Cochrane3 concluded that antidepressants are effective in diabetes and moderately improve glycaemic control. In contrast, there is some evidence that the association between diabetes and depression is in part a reflection of the use of antidepressants. That is, antidepressants as a group may cause diabetes,4,5 although the association may not be present after adjusting for comorbidity.6 Evidence relating to individual drugs is described in Table 3.16. (Continued)

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Antidepressants and diabetes mellitus

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93 - Depression and diabetes

Depression and diabetes

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94 - Recommendations

Recommendations

424 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Recommendations ■ ■All patients with a diagnosis of depression should be screened for diabetes. ■ ■In those who are diabetic: ■ ■use SSRIs first line; data support sertraline, escitalopram and fluoxetine ■ ■SNRIs, bupropion, vortioxetine and agomelatine are also likely to be safe but there are fewer supporting data ■ ■avoid TCAs and MAOIs if possible, because of their effects on weight and glucose homeostasis ■ ■monitor blood glucose and HbA1c carefully when antidepressant treatment is initiated, when the dose is changed and after discontinuation ■ ■metformin may be a preferred diabetes treatment because of its putative beneficial effects on mood in type II diabetes.35,36 References

Berk M, et al. Comorbidity between major depressive disorder and physical diseases: a comprehensive review of epidemiology, mechanisms and management. World Psychiatry 2023; 22:366–387.
Lustman PJ, et al. Depression in diabetic patients: the relationship between mood and glycemic control. J Diabetes Complications 2005; 19:113–122.
Baumeister H, et al. Psychological and pharmacological interventions for depression in patients with diabetes mellitus and depression. Cochrane Database Syst Rev 2012; 12:CD008381.
Wang Y, et al. Antidepressants use and the risk of type 2 diabetes mellitus: a systematic review and meta-analysis. J Affect Disord 2021; 287:41–53.
Movahed F, et al. Incident diabetes in adolescents using antidepressant: a systematic review and meta-analysis. Eur Child Adolesc Psychiatry 2024; doi: 10.1007/s00787-024-02502-x [Online ahead of print].
Kim H, et al. Depression, antidepressant use, and the risk of type 2 diabetes: a nationally representative cohort study. Front Psychiatry 2023; 14:1275984.
Maheux P, et al. Fluoxetine improves insulin sensitivity in obese patients with non-insulin-dependent diabetes mellitus independently of weight loss. Int J Obes Relat Metab Disord 1997; 21:97–102.
Gulseren L, et al. Comparison of fluoxetine and paroxetine in type II diabetes mellitus patients. Arch Med Res 2005; 36:159–165.
Lustman PJ, et al. Sertraline for prevention of depression recurrence in diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry 2006; 63:521–529.
Gray DS, et al. A randomized double-blind clinical trial of fluoxetine in obese diabetics. Int J Obes Relat Metab Disord 1992; 16 Suppl 4:S67–S72.
Knol MJ, et al. Influence of antidepressants on glycaemic control in patients with diabetes mellitus. Pharmacoepidemiol Drug Saf 2008; 17:577–586. Table 3.16 (Continued) Antidepressant class Effect on glucose homeostasis Agomelatine19 ■ ■A few studies suggest agomelatine is effective with some improvement or no worsening of glycaemic parameters ■ ■Agomelatine also demonstrated a minimum effect on body weight Bupropion ■ ■Improved weight and HbA1c in one open study33 Vortioxetine ■ ■No clinically relevant changes in weight or blood in one subgroup analysis of clinical trial data.34 Limited evidence of an improvement in HbA1c.19 Reboxetine, trazodone ■ ■No data in patients with diabetes ■ ■One study revealed 20% increased risk of type 2 diabetes in people prescribed trazodone20 HbA1c, glycated haemoglobin; MAOI, monoamine oxidase inhibitor; TCA, tricyclic antidepressant.

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References

Depression and anxiety disorders CHAPTER 3 12. Briscoe VJ, et al. Effects of a selective serotonin reuptake inhibitor, fluoxetine, on counterregulatory responses to hypoglycemia in healthy individuals. Diabetes 2008; 57:2453–2460. 13. Andersohn F, et al. Long-term use of antidepressants for depressive disorders and the risk of diabetes mellitus. Am J Psychiatry 2009; 166:591–598. 14. Kivimaki M, et al. Antidepressant medication use, weight gain, and risk of type 2 diabetes: a population-based study. Diabetes Care 2010; 33:2611–2616. 15. Rubin RR, et al. Antidepressant medicine use and risk of developing diabetes during the diabetes prevention program and diabetes prevention program outcomes study. Diabetes Care 2010; 33:2549–2551. 16. Echeverry D, et al. Effect of pharmacological treatment of depression on A1C and quality of life in low-income Hispanics and African Americans with diabetes: a randomized, double-blind, placebo-controlled trial. Diabetes Care 2009; 32:2156–2160. 17. Dhavale HS, et al. Depression and diabetes: impact of antidepressant medications on glycaemic control. J Assoc Physicians India 2013; 61:896-899. 18. Mojtabai R. Antidepressant use and glycemic control. Psychopharmacology (Berl) 2013; 227:467–477. 19. Srisurapanont M, et al. Antidepressants for depressed patients with type 2 diabetes mellitus: a systematic review and network meta-analysis of short-term randomized controlled trials. Neurosci Biobehav Rev 2022; 139:104731. 20. Nguyen TTH, et al. Role of serotonin transporter in antidepressant-induced diabetes mellitus: a pharmacoepidemiological-pharmacodynamic study in VigiBase(®). Drug Saf 2018; 41:1087–1096. 21. Dandjinou M, et al. Antidepressant use during pregnancy and the risk of gestational diabetes mellitus: a nested case–control study. BMJ Open 2019; 9:e025908. 22. Kuo HY, et al. Antidepressants and risk of type 2 diabetes mellitus: a population-based nested case-control study. J Clin Psychopharmacol 2020; 40:359–365. 23. Lustman PJ, et al. Effects of nortriptyline on depression and glycemic control in diabetes: results of a double-blind, placebo-controlled trial. Psychosom Med 1997; 59:241–250. 24. McIntyre RS, et al. The effect of antidepressants on glucose homeostasis and insulin sensitivity: synthesis and mechanisms. Expert Opin Drug Saf 2006; 5:157–168. 25. Mumoli N, et al. Clomipramine-induced diabetes. Ann Intern Med 2008; 149:595–596. 26. Goodnick PJ. Use of antidepressants in treatment of comorbid diabetes mellitus and depression as well as in diabetic neuropathy. Ann Clin Psychiatry 2001; 13:31–41. 27. McIntyre RS, et al. Mood and psychotic disorders and type 2 diabetes: a metabolic triad. Can J Diabetes 2005; 29:122–132. 28. Raskin J, et al. Duloxetine versus routine care in the long-term management of diabetic peripheral neuropathic pain. J Palliat Med 2006; 9:29–40. 29. Crucitti A, et al. Duloxetine treatment and glycemic controls in patients with diagnoses other than diabetic peripheral neuropathic pain: a meta-analysis. Curr Med Res Opin 2010; 26:2579–2588. 30. Mekonnen AD, et al. Desvenlafaxine-associated hyperglycemia: a case report and literature review. Ment Health Clin 2020; 10:85–89. 31. Song HR, et al. Does mirtazapine interfere with naturalistic diabetes treatment? J Clin Psychopharmacol 2014; 34:588–594. 32. Song HR, et al. Effects of mirtazapine on patients undergoing naturalistic diabetes treatment: a follow-up study extended from 6 to 12 months. J Clin Psychopharmacol 2015; 35:730–731. 33. Roopan S, et al. Use of antidepressants in patients with depression and comorbid diabetes mellitus: a systematic review. Acta Neuropsychiatr 2017; 29:127–139. 34. Baldwin DS, et al. Efficacy and safety of vortioxetine in treatment of patients with major depressive disorder and common co-morbid physical illness. J Affect Disord 2022; 311:588–594. 35. Zhang Y, et al. Effect of metformin on the risk of depression: a systematic review and meta-regression of observational studies. Asian J Psychiatry 2024; 92:103894. 36. Yang Y, et al. Metformin treatment improves depressive symptoms associated with type 2 diabetes: a 24-week longitudinal study. J Affect Disord 2024; 365:80–86.

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96 - Antidepressants and sexual dysfunction

Antidepressants and sexual dysfunction

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Effects of depression

426 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Antidepressants and sexual dysfunction Sexual dysfunction is common in the general population, although reliable frequency data are lacking.1 Reported prevalence rates vary depending on how sexual dysfunction is defined, assessed and the method of data collection.1 Physical illness, psychiatric illness, substance misuse and prescribed drug treatment can all cause sexual dysfunction.2 People with depression are more likely to have obesity,3 diabetes4 and cardiovascular disease5 than the general population, making them more likely to suffer sexual dysfunction without any influence of depression or antidepressants themselves. Before beginning antidepressants, baseline sexual functioning should be determined to set a baseline against which the effect of antidepressants can be measured. Treatment- emergent sexual dysfunction adversely affects quality of life and may contribute to reduced compliance.6 Questionnaires or rating scales can be useful (for example, the Arizona Sexual Experience Scale).7 If scales are not used then direct questioning should be employed, as it is much more effective than relying on spontaneous patient reporting.8 Complaints of sexual dysfunction may indicate progression or inadequate treatment of underlying medical or psychiatric conditions but may also be the result of drug treatment.6 Effects of depression Both depression and the drugs used to treat depression can cause disorders of desire, arousal and orgasm. The precise nature of the sexual dysfunction may indicate whether depression or treatment is the more likely cause. For example, 40–50% of people with depression report diminished libido and problems regarding sexual arousal in the month before diagnosis (and therefore treatment), but only 15–20% experience orgasm problems before taking an antidepressant.9 The degree of loss of libido appears to correlate with depression severity.10 Although many patients experience treatment-emergent sexual dysfunction while taking antidepressants, in others the reduction in depressive symptoms can be accompanied by improvements in sexual desire and satisfaction.6,11 Improvements are more common among those who respond to antidepressant treatment.6 For example, a post- hoc analysis of data from the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study revealed that sexual dysfunction was problematic in 21% of patients whose depression remitted with citalopram treatment compared with 61% of those whose depression did not remit.12 Effects of antidepressant drugs Antidepressants can cause sedation, hormonal changes, disturbance of cholinergic/ adrenergic balance, peripheral alpha-adrenergic agonism, inhibition of nitric oxide and increased serotonin neurotransmission. Any or all of these actions may result in sexual dysfunction. Sexual dysfunction has been reported as an adverse effect of all antidepressants, although rates vary and some have reported rates similar to or below that of placebo (Table 3.17). Individual susceptibility also varies and may be at least partly genetically determined.13 Not all of the sexual effects of antidepressants are undesirable. Serotonergic antidepressants, including clomipramine, are effective in the treatment of premature ejaculation6,14

Depression and anxiety disorders CHAPTER 3 Table 3.17 Relative frequency of sexual dysfunction (SD) with antidepressants.10,13,15–17 Antidepressant Impact on sexual response Comments13 Sexual desire* Sexual arousal† Orgasm‡ Agomelatine – – – Rates of SD similar to placebo6 Bupropion – +/– – Low rates of SD compared with most antidepressants.18 Good evidence that SD occurs at or below the rate of placebo. Less robust evidence for dextromethorphan-bupropion but rates of SD also appear to be low.19 Duloxetine ++ + ++ Rate of SD similar to some SSRIs and venlafaxine18 Levomilnacipran ? ++ ++ Limited comparative studies with other antidepressants20 so relative frequency of SD is uncertain. Erectile dysfunction and disorders of ejaculation shown in RCTs.21 Monoamine oxidase inhibitors ++ ++ ++ Limited evidence though reported incidence of SD ranges from 20–42%. Rates of SD with transdermal selegiline are comparable to placebo. Mirtazapine + – – Causes less SD than SSRIs22 Moclobemide – – – Consistently shown to have a low risk of SD Reboxetine – + – Probably causes less SD than SSRIs/SNRIs though anti-depressant efficacy has been questioned23 SSRIs ++ ++ ++ High rates of SD with all SSRIs (although reported incidence varies widely).13 Rates of anorgasmia may be lower with fluvoxamine.24 Trazodone – + + Priapism reported in case studies. However, overall reports of SD seem to be low. Early case reports documented increased sexual desire. Tricyclics ++ ++ ++ SD more common with clomipramine (particularly anorgasmia), amitriptyline and imipramine. Less common with secondary amine TCAs (desipramine, nortriptyline, lofepramine). Venlafaxine ++ ++ ++ High rates of SD. Isolated case reports of increased libido, orgasm and spontaneous erections. Vilazodone + + + Rates of SD possibly lower than citalopram and similar to placebo in RCTs. However, a clear advantage over other antidepressants remains uncertain.20 Vortioxetine – + + Rates of SD probably lower than duloxetine and paroxetine,25 and reportedly similar to placebo at doses 10mg/day or less23,26 Key: ++, common; +, may occur; –, absent or rare; ?, unknown/insufficient information. * Or sex drive. † Ease of arousal and ability to achieve lubrication or erections. ‡ Ease of reaching orgasm and orgasm satisfaction.

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Effects of antidepressant drugs

428 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 and may also be beneficial in paraphilias.27 The short-acting SSRI dapoxetine is an effective treatment for premature ejaculation and is licensed for this indication in many countries.6,28 A systematic review of RCTs with trazodone showed benefit for reducing so-called psychogenic erectile dysfunction.6 Sexual adverse effects can be minimised by careful selection of the antidepressant drug. Data mainly come from observational studies as the assessment of sexual adverse effects in early clinical trials was generally inadequate, often relying on spontaneous reports rather than using validated questionnaires and lacking positive controls.29 Where possible, information contained in this section has been obtained from studies where sexual adverse effects are purposefully and directly investigated. Management strategies for people who do develop sexual dysfunction on antidepressants are summarised in Table 3.18. No single approach can be considered ideal,6 so individual assessment is recommended. Post-SSRI sexual dysfunction Sexual dysfunction with antidepressants is largely dose dependent13 and is generally considered to be fully reversible.13 However, there have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRIs.30 The term post-SSRI sexual dysfunction (PSSD) has been used to describe these symptoms. Reported PSSD symptoms include decreased libido, erectile dysfunction, delayed ejaculation, anorgasmia and vaginal dryness.31,32 In men, decreased genital sensation and numbness, pleasureless orgasm and premature ejaculation are also commonly reported symptoms of PSSD.31 The prevalence and pathophysiology of Table 3.18 Management of sexual adverse effects. Strategy Details

Rule out other possible causes33 ■ ■Depressive symptoms are associated with impaired sexual functioning. Compare sexual functioning on antidepressants with sexual functioning before antidepressants, not before the onset of depressive illness. ■ ■Consider other possible contributing causes (e.g. alcohol/substance misuse, diabetes, atherosclerosis, cardiac disease, and central and peripheral nervous system conditions). Other medications could be implicated, including both non-psychotropics (e.g. diuretics, beta-blockers) and other psychotropics.
Switch to a lower-risk antidepressant23 ■ ■Lower-risk antidepressants include agomelatine, bupropion, mirtazapine, vilazodone, vortioxetine and moclobemide.13 Of these, agomelatine, bupropion and vortioxetine34 have the best evidence supporting a more favourable sexual adverse effect profile.13 Non-pharmacological treatment strategies ■ ■Waiting for spontaneous remission: widely used, although least effective method.24 Remission may occur in a small number of people (5–10%) but can take up to 4–6 months.13 Impractical for many patients, although it might be considered in milder cases.30 ■ ■Dose reduction: can be considered in patients who have achieved full remission on an antidepressant6 ■ ■Drug holidays: intermittently missing one or two doses prior to planned sexual activity may possibly help but risks discontinuation symptoms.13,35,36 Not an effective strategy with fluoxetine, owing to its long half-life.13 Lowering doses by a half for two consecutive days prior to sexual activity is another possible strategy.24 (Continued)

Depression and anxiety disorders CHAPTER 3 PSSD remain uncertain.32,45,46 One estimate put the risk at 1 in 216 patients treated.47 Diagnosis relies on taking an accurate history of medications, symptom onset, symptom profile and eliminating other possible causes.31 Healy and co-workers have proposed diagnostic criteria for PSSD.48 Treatment strategies for PSSD remain anecdotal and no definitive treatments exist, although serotonin antagonists, dopaminergic agents and vortioxetine have been used.31 Multidisciplinary management is essential, possibly including urology and endocrinology.31 Table 3.18 (Continued) Strategy Details Pharmacological treatments ■ ■Phosphodiesterase inhibitors: both sildenafil and tadalafil have been shown to improve sexual functioning in men with antidepressant-related erectile dysfunction.23,37 Sildenafil is supported by the most evidence.38 Limited evidence in women, although one RCT found benefits.23 ■ ■Bupropion: may be useful in women at higher doses (300mg/day).37 Lower doses may be ineffective.23 A positive RCT in men39 was later retracted. ■ ■Mirtazapine: evidence is mixed. Open studies suggest some benefit for antidepressant- induced sexual dysfunction, but negative results were reported in one RCT.33 ■ ■Transdermal testosterone: RCTs provide evidence of efficacy in women with SSRI/ SNRI-emergent loss of libido40 and in men who continue to take serotonergic antidepressants with low or low-normal testosterone levels41 ■ ■Others:13 many other agents have been studied; many have little effectiveness. Buspirone was effective in one study for citalopram- or paroxetine-induced sexual dysfunction, but ineffective in another study with fluoxetine. Cyproheptadine has been used successfully in case reports of SSRI-induced sexual dysfunction in men and for anorgasmia in women. Loratadine was effective in a small open study for men with SSRI-induced erectile dysfunction. Amantadine was effective in earlier studies for SSRI-induced sexual dysfunction, but recent results have been negative. Yohimbine may be effective for medication-induced sexual dysfunction and improvements were reported by patients in two small studies (although results were nonsignificant). Bethanechol appears to help with TCA-induced sexual dysfunction when taken before sexual activity. Granisetron has been superficially evaluated. Flibanserin and bremelanotide are approved by the FDA for treatment of hypoactive sexual desire disorder in premenopausal women42 but there are no data to support use for antidepressant-induced sexual dysfunction. Pine bark extract was found to be superior to placebo in one meta-analysis.38 ■ ■Augmenting agents in treatment-resistant depression: some drugs used as an adjunct for treatment-resistant depression have been associated with improvement in sexual functioning in secondary analyses. Aripiprazole improved sexual functioning and desire, though only in women.24 Adjunctive brexpiprazole is associated with modest improvements.43 Pimavanserin, used as an add-on treatment to SSRIs/SNRIs, improved sexual functioning.44 FDA, Food and Drug Administration; TCA, tricyclic antidepressant.

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Post-SSRI sexual dysfunction

09 - Chapter 4 Addictions and substance misuse

01 - Introduction

Introduction

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 4 Introduction Mental and behavioural problems caused by psychoactive substance use are common. The World Health Organization (WHO) in the ICD-111 identifies acute intoxication, harmful use, dependence syndrome, withdrawal state (with or without delirium), substance-induced psychotic disorder, substance-induced amnesic disorder, other mental and behavioural disorders and unspecified mental and behavioural disorders as substance- related disorders. A wide range of psychoactive substances may be problematic including alcohol, opioids, benzodiazepines, gamma-hydroxybutyrate/gamma-butyrolactone (GHB/GBL), stimulants, new psychoactive substances (NPS) (including cathinones, synthetic cannabinoids and phenylethylamines), khat, nitrates, hallucinogens, anabolic steroids, nitazenes and tobacco. Substance misuse is frequently seen in people with severe mental illness (so-called dual diagnosis) and personality disorder. In many adult psychiatry settings, dual diagnosis is the norm rather than the exception. In many parts of the world substance misuse services may be provided separately from general psychiatric services. The model of care in most addiction services means that patients who are not motivated to engage will not be assertively treated and followed up. Dual diagnosis teams are not universally available, resulting in suboptimal treatment of substance misuse for many patients with mental illness.2 According to the ICD-11, dependence syndrome is ‘a cluster of physiological, behavioural, and cognitive phenomena in which the use of a substance or a class of substances takes on a much higher priority for a given individual than other behaviours that once had greater value’. A definite diagnosis of dependence should only be made if at least three of the following have been present together in the last year: ■ ■compulsion to take substance ■ ■difficulties controlling substance-taking behaviour ■ ■physiological withdrawal state Addictions and substance misuse

09 - Chapter 4 Addictions and substance misuse

02 - References

References

478 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 ■ ■evidence of tolerance ■ ■neglect of alternative interests ■ ■persistent use despite harm. Substance use disorders should generally be treated with a combination of psychosocial and pharmacological interventions. This chapter concentrates on pharmacological interventions for alcohol, opioids and nicotine use. Treatments for people misusing benzodiazepines, GHB/GBL and stimulants are discussed briefly. Note that various National Institute for Health and Care Excellence (NICE) guidelines and technology appraisals and Department of Health substance misuse guidelines (the ‘Orange Book’)3 provide a comprehensive overview of treatment options. UK national guidance on the treatment of alcohol-related problems is awaiting publication at the time of writing.4 References

World Health Organization. International Statistical Classification of Diseases and Related Health Problems. 2018 (last accessed September 2024); https://www.who.int/news-room/spotlight/international-classification-of-diseases.
Public Health England. Better care for people with co-occurring mental health and alcohol/drug use conditions. A guide for commissioners and service providers. 2017; https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/625809/Co-occurring_mental_ health_and_alcohol_drug_use_conditions.pdf.
Gov.UK Department of Health and Social Care. Drug misuse and dependence: UK guidelines on clinical management. 2017; https://www. gov.uk/government/publications/drug-misuse-and-dependence-uk-guidelines-on-clinical-management.
Gov.UK Department of Health and Social Care. Closed consultation. UK clinical guidelines for alcohol treatment: consultation document. 2023; https://www.gov.uk/government/consultations/uk-clinical-guidelines-for-alcohol-treatment/uk-clinical-guidelines-for-alcohol-treatment-consultation- document.

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03 - Alcohol dependence

Alcohol dependence

09 - Chapter 4 Addictions and substance misuse

04 - Assessment and brief structured intervention

Assessment and brief structured intervention

Addictions and substance misuse CHAPTER 4 Alcohol dependence In the UK 1 unit of alcohol is 10mL of ethanol or 1L of 1% alcohol. For example, 250mL of wine that is 10% alcohol contains 2.5 units. In the USA, one drink is defined as 14g (17.7mL) of ethanol (1.77 UK units). Other countries use somewhat different definitions based on volume or mass of alcohol. The UK Department of Health has given the following advice and recommendations to minimise the health risks from alcohol consumption:1 ■ ■No more than 14 units should be consumed per week on a regular basis. This applies to both men and women. ■ ■Harm is minimised when these units are spread across 3 or more days. ■ ■Heavy, single-occasion drinking is associated with risk of harm, injury and accidents. ■ ■The consumption of any volume of alcohol is still associated with a number of illnesses such as cancers of the throat, mouth and breast. ■ ■There are no completely safe levels of drinking during pregnancy and precautionary avoidance of alcohol is recommended to reduce risk of harm to the baby. Assessment and brief structured intervention The UK NICE guideline on the diagnosis, assessment and management of harmful drinking and alcohol dependence recommends that staff working in services that might encounter problem drinkers should be competent in identifying and assessing harmful drinking and alcohol dependence.2 The NICE public health guideline on reducing harmful drinking3 recommends a session of brief structured advice based on FRAMES principles (feedback, responsibility, advice, menu, empathy, self- efficacy) as a useful intervention for everyone at increased risk of alcohol-related problems. Where consumption above recommended levels has been identified, a more detailed clinical assessment is required. Depending on the context, this could include the following: ■ ■History of alcohol use, including daily consumption and recent patterns of drinking. ■ ■History of previous episodes of alcohol withdrawal. ■ ■Time of most recent drink. ■ ■Collateral history from a family member or carer. ■ ■Other drug (illicit and prescribed) use. ■ ■Severity of dependence and of withdrawal symptoms. ■ ■Coexisting medical and psychiatric problems. ■ ■Physical examination including cognitive function. ■ ■Breathalyser: absolute breath alcohol level and whether rising or falling (take at least 20 minutes after last drink to avoid falsely high readings from the mouth, and 1 hour later). ■ ■Laboratory investigations: full blood count (FBC), urea and electrolytes (U&E), liver function tests (LFTs), international normalised ratio (INR), prothrombin time (PT) and urinary drug screen.

09 - Chapter 4 Addictions and substance misuse

05 - Alcohol withdrawal

Alcohol withdrawal

480 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 The following structured assessment tools are recommended:2 ■ ■The Alcohol Use Disorders Identification Test (AUDIT)4 questionnaire is a 10-item questionnaire which is useful as a screening tool in those identified as being at increasing risk. Questions 1–3 address the quantity of alcohol consumed, 4–6 the signs and symptoms of dependence and 7–10 the behaviours and symptoms associated with harmful alcohol use. Each question is scored 0–4, giving a maximum total score of 40. A score of 8 or more is suggestive of hazardous or harmful alcohol use. Hazardous drinking = consumption of alcohol likely to cause harm. Harmful drinking = consumption already causing mental or physical health problems. ■ ■The Severity of Alcohol Dependence Questionnaire (SADQ)5 is a more detailed 20-item questionnaire with the score on each item ranging from 0 to 3, giving a maximum total score of 60. Severity of alcohol dependence Mild

SADQ score of 15 or less Moderate

SADQ score 15–30 Severe

SADQ score >30 Alcohol withdrawal In alcohol-dependent drinkers, the central nervous system (CNS) has adjusted to the constant presence of alcohol in the body (neuroadaptation). When the blood alcohol concentration (BAC) is suddenly lowered, the brain remains in a hyper-excited state, resulting in the withdrawal syndrome (Tables 4.1 and 4.2). There is no evidence to support prophylactic use of additional anticonvulsant medication to prevent seizures in high-risk individuals. Table 4.1 Mild alcohol withdrawal. Mild alcohol withdrawal manifestations Usual timing of onset after last drink Other information Agitation/anxiety/irritability Tremor of hands, tongue, eyelids Sweating Nausea/vomiting/diarrhoea Fever Tachycardia Systolic hypertension General malaise Onset at 3–12 hours Peak at 24–48 hours Duration up to 14 days Symptoms are non-specific Absence does not exclude withdrawal May commence before blood alcohol levels reach zero Management ■ ■May be self-limiting but mitigated with adequate benzodiazepine cover and supportive treatment. ■ ■Monitor vital signs. Use a withdrawal assessment scale. ■ ■See Table 4.2 for the various benzodiazepine regimens recommended.

Addictions and substance misuse CHAPTER 4 Table 4.2 Severe alcohol withdrawal. Severe alcohol withdrawal complications Usual timing of onset after last drink Other information Generalised seizures 12–18 hours May commence before blood alcohol levels reach zero Management ■ ■The occurrence of a first seizure during medically assisted withdrawal requires investigation to rule out organic disease or idiopathic epilepsy. ■ ■A meta-analysis of trials assessing the efficacy of drugs preventing alcohol withdrawal seizures demonstrated that benzodiazepines, particularly long-acting preparations such as diazepam, significantly reduced seizures de novo.6,7 ■ ■Long-acting benzodiazepine is recommended as prophylaxis in those with a previous history of seizures.8 ■ ■Some anticonvulsants are as effective as benzodiazepines, with some units recommending carbamazepine loading in patients with untreated epilepsy, or where seizures have occurred despite adequate benzodiazepine loading.6 ■ ■Phenytoin does not prevent alcohol withdrawal-related seizures when used on its own or in combination with benzodiazepines.9 There is no need to continue anticonvulsants long term when used to prevent seizures in alcohol withdrawal.9 Delirium tremens Clouding of consciousness/confusion Vivid hallucinations, particularly in visual and tactile modalities Marked tremor Other clinical features also include: autonomic hyperactivity (tachycardia, hypertension, sweating and fever), paranoid delusions, agitation and insomnia Prodromal symptoms include: night-time insomnia, restlessness, fear and confusion Risk factors: severe alcohol dependence, self-detoxification without medical input, multiple previous admissions for alcohol withdrawal, concurrent medical illness, previous history of delirium tremens and alcohol withdrawal seizures, low potassium, low magnesium, thiamine deficiency, inadequately treated withdrawal Recognition is important because treatment is different from delirium arising from other causes; delirium tremens needs larger doses of benzodiazepines and more caution with antipsychotics 3–4 days (72–96 hours) Develops in 3–5% of those admitted to hospital for alcohol withdrawal A medical emergency Mortality 10–20% if untreated Management ■ ■Delirium tremens is a medical emergency and requires prompt transfer to a general hospital,9 preferably to a high-dependency setting.10,11

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06 - Pharmacologically assisted withdrawal (alcoho

Pharmacologically assisted withdrawal (alcohol detoxification)

482 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Pharmacologically assisted withdrawal (alcohol detoxification) Alcohol withdrawal is associated with significant morbidity and mortality when improperly managed. Pharmacologically assisted withdrawal is likely to be needed when: ■ ■there has been regular consumption of >15 units/day ■ ■AUDIT score >20 ■ ■there is a history of significant withdrawal symptoms. Symptom scales can be helpful in determining the amount of pharmacological support required to manage withdrawal symptoms. The Clinical Institute Withdrawal Assessment of Alcohol Scale Revised (CIWA-Ar)12 (Figure 4.1) and Short Alcohol Withdrawal Scale (SAWS)13 (Table 4.3) are both 10-item scales that can be completed in around 5 minutes. The CIWA-Ar is an objective scale and the SAWS is a self-complete tool. A CIWA-Ar score >10 or a SAWS score >12 should prompt assisted withdrawal. Community detoxification is usually possible when: ■ ■There is a supervising carer, ideally 24 hours a day throughout the duration of the detoxification process. ■ ■The treatment plan has been agreed with the patient, their carer and their GP. ■ ■A contingency plan has been agreed with the patient, their carer and their GP. ■ ■The patient is able to pick up medication daily and be reviewed by professionals regularly throughout the process. ■ ■Out-patient/community-based programmes including psychosocial support are available. Community detoxification should be stopped if the patient resumes drinking or fails to engage with the agreed treatment plan. In-patient detoxification is likely to be required if: ■ ■Regular consumption is >30 units/day. ■ ■SADQ >30 (severe dependence). ■ ■There is a history of seizures or delirium tremens. ■ ■The patient is a minor or an older adult. ■ ■There is current benzodiazepine use in combination with alcohol. ■ ■Substances other than alcohol are also being misused. ■ ■There is comorbid mental or physical illness, learning disability or cognitive impairment. ■ ■The patient is pregnant. ■ ■The patient is homeless or has no social support. ■ ■There is a history of failed community detoxification. In certain situations, there may be a clinical justification for undertaking a community detoxification in these patients, however the reasons must be clear and the decision made by an experienced clinician.

Addictions and substance misuse CHAPTER 4 Patient:__________________________ Date: ________________ Time: _______________ Pulse or heart rate, taken for 1 minute:_________________________ Blood pressure:______ NAUSEA AND VOMITING – Ask ‘Do you feel sick to your stomach? Have you vomited?’ Observation. 0 – no nausea and no vomiting 1 – mild nausea with no vomiting 3 4 – intermittent nausea with dry heaves 6 7 – constant nausea, frequent dry heaves and vomiting TACTILE DISTURBANCES – Ask ‘Have you any itching, pins and (24 hours clock, midnight = 00:00) needles sensations, any burning, any numbness, or do you feel bugs crawling on or under your skin?’ Observation. 0 – none 1 – very mild itching, pins and needles, burning or numbness 2 – mild itching, pins and needles, burning or numbness 3 – moderate itching, pins and needles, burning or numbness 4 – moderately severe hallucinations 5 – severe hallucinations 6 – extremely severe hallucinations 7 – continuous hallucinations TREMOR – Arms extended and ﬁngers spread apart. Observation. 0 – no tremor 1 – not visible, but can be felt ﬁngertip to ﬁngertip 3 4 – moderate, with patient’s arms extended 6 7 – severe, even with arms not extended AUDITORY DISTURBANCES – Ask ‘Are you more aware of sounds around you? Are they harsh? Do they frighten you? Are you hearing anything that is disturbing to you? Are you hearing things you know are not there?’ Observation. 0 – not present 1 – very mild harshness or ability to frighten 2 – mild harshness or ability to frighten 3 – moderate harshness or ability to frighten 4 – moderately severe hallucinations 5 – severe hallucinations 6 – extremely severe hallucinations 7 – continuous hallucinations PAROXYSMAL SWEATS – Observation. 0 – no sweat visible 1 – barely perceptible sweating, palms moist 3 4 – beads of sweat obvious on forehead 6 7 – drenching sweats VISUAL DISTURBANCES – Ask ‘Does the light appear to be too bright? Is its colour different? Does it hurt your eyes? Are you seeing anything that is disturbing to you? Are you seeing things you know are not there?’ Observation. 0 – not present 1 – very mild sensitivity 2 – mild sensitivity 3 – moderate sensitivity 4 – moderately severe hallucinations 5 – severe hallucinations 6 – extremely severe hallucinations 7 – continuous hallucinations ANXIETY – Ask ‘Do you feel nervous?’ Observation. 0 – no anxiety, at ease 1 – mild anxious 3 4 – moderately anxious, or guarded, so anxiety is inferred 6 7 – equivalent to acute panic states as seen in severe delirium or acute schizophrenic reactions HEADACHE, FULLNESS IN HEAD – Ask ‘Does your head feel different? Does it feel like there is a band around your head?’ Do not rate for dizziness or light-headedness. Otherwise, rate severity. 0 – not present 1 – very mild 2 – mild 3 – moderate 4 – moderately severe 5 – severe 6 – very severe 7 – extremely severe AGITATION – Observation. 0 – normal activity 1 – somewhat more than normal activity 3 4 – moderately ﬁdgety and restless 6 7 – paces back and forth during most of the interview, or constantly thrashes about ORIENTATION AND CLOUDING OF SENSORIUM – Ask ‘What day is this? Where are you? Who am I?’ 0 – oriented and can do serial additions 1 – cannot do serial additions or is uncertain about date 2 – disoriented for date by no more than 2 calendar days 3 – disoriented for date by more than 2 calendar days 4 – disoriented for place or person Scores ≤10 – mild withdrawal (do not need additional medication) ≤15 – moderate withdrawal

15 – severe withdrawal Total CIWA-Ar score ______ Rater’s initials ______ Maximum possible score 67 Figure 4.1 Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar).12 The CIWA-Ar is not copyrighted and may be reproduced freely.

484 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Table 4.4 summarises common interventions used in alcohol withdrawal. Benzodiazepines are the treatment of choice for alcohol withdrawal. They exhibit cross- tolerance with alcohol and have anticonvulsant properties. Their use is supported by NICE guidelines,2,14 a Cochrane systematic review7 and British Association for Psychopharmacology guidelines.9 Parenteral thiamine (vitamin B1) and other vitamin Table 4.4 Alcohol withdrawal treatment interventions – a summary. Severity Supportive/ medical care Pharmacotherapy for neuroadaptation reversal Thiamine supplementation Setting Mild CIWA-Ar ≤10 Moderate- to high-level supportive care, little if any medical care required Little to none required Simple remedies only (see below) Oral likely to be sufficient if patient is well nourished Home Moderate CIWA-Ar ≤15 Moderate- to high-level supportive care, little medical care required Little to none required Symptomatic treatment only Intramuscular thiamine should be offered if the patient is malnourished followed by oral supplementation Home or community team Severe CIWA-Ar >15 High-level supportive care plus medical monitoring Symptomatic and substitution treatment (chlordiazepoxide) probably required Intramuscular thiamine should be offered followed by oral supplementation Community team or hospital CIWA-Ar >10 + comorbid alcohol-related medical problems High-level supportive care plus specialist medical care Symptomatic and substitution treatments usually required Intramuscular thiamine followed by oral supplementation Hospital Table 4.3 Short Alcohol Withdrawal Scale (SAWS).13 None (0) Mild (1) Moderate (2) Severe (3) Anxious Sleep disturbance Problems with memory Nausea Restless Tremor (shakes) Feeling confused Sweating Miserable Heart pounding

Addictions and substance misuse CHAPTER 4 replacement is an important adjunctive treatment for the prophylaxis and/or treatment of Wernicke–Korsakoff syndrome and other vitamin-related neuropsychiatric conditions. In the UK, chlordiazepoxide is the benzodiazepine used for most patients in most centres as it is considered to have a relatively low dependence-forming potential. Some centres use diazepam. A short-acting benzodiazepine such as oxazepam or lorazepam may be used in individuals with impaired liver function or those who potentially may metabolise medication more slowly, such as older people. There are three types of assisted withdrawal regimens: fixed-dose reduction (the most common in non-specialist settings), variable-dose reduction (usually results in less benzodiazepine being administered but best reserved for settings where staff have specialist skills in managing alcohol withdrawal) and finally front-loading (infrequently used, and reserved for severe alcohol withdrawal).2,9 Assisted withdrawal regimens should never be started if the blood alcohol concentration is very high or is still rising. Monitor patients for oversedation/respiratory depression. Fixed-dose reduction regimen Fixed-dose regimens can be used in community or non-specialist in-patient/residential settings for uncomplicated patients. Patients should be started on a dose of benzodiazepine selected after an assessment of the severity of alcohol dependence (clinical history, number of units per drinking day and score on the SADQ). With respect to chlordiazepoxide, a general rule of thumb is that the starting dose can be estimated from current alcohol consumption. For example, if 20 units/day are being consumed, the starting dose should be 20mg four times a day. The dose is then tapered to zero over 5–10 days. Alcohol withdrawal symptoms should be monitored using a validated instrument such as the CIWA-Ar12 or SAWS.13 Mild alcohol dependence usually requires very small doses of chlordiazepoxide or else may be managed without medication. For moderate alcohol dependence, a typical regimen might be 10–20mg chlordiazepoxide four times a day, reducing gradually over 5–7 days (Table 4.5). This duration of treatment is usually adequate and longer treatment is rarely helpful or necessary. It is advisable to monitor withdrawal and BAC daily before providing the day’s medication. This may mean that community pharmacologically assisted alcohol withdrawals should start on a Monday and last for 5 days. Table 4.5 Moderate alcohol dependence: example of a fixed-dose chlordiazepoxide treatment regimen. Day Dose Total daily dose (mg) 20mg four times a day 2 15mg four times a day 3 10mg four times a day 4 5mg four times a day 5 5mg twice a day

486 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Severe alcohol dependence usually requires in-patient treatment for assisted withdrawal because of the significant risk of life-threatening complications. However, there are rare occasions where a pragmatic community approach is required. In such situations, the decision to undertake a community-assisted withdrawal must be made by an experienced clinician. Intensive daily monitoring is advised for the first 2–3 days. This may require special arrangements over a weekend. Prescribing should not start if the patient is intoxicated. In such circumstances, they should be reviewed at the earliest opportunity when not intoxicated. The dose of benzodiazepine may need to be reduced over a 7–10-day period in this group (occasionally longer if dependence is very severe or there is a history of complications during previous detoxifications) (Table 4.6). Symptom-triggered regimen This should be reserved for managing assisted withdrawal in specialist alcohol in-patient or residential settings. Regular monitoring is required (e.g. pulse, blood pressure, temperature and level of consciousness). Medication is only given when withdrawal symptoms are observed as determined using CIWA-Ar, SAWS or an alternative validated measure. Symptom-triggered therapy is generally used in patients without a history of complications. A typical symptom-triggered regimen would be chlordiazepoxide 20–30mg hourly as needed. The total dose given each day would be expected to decrease from day 2 onwards. It is common for symptom-triggered treatment to last only 24–48 hours before switching to an individualised fixed-dose reducing schedule. Occasionally (e.g. in delirium tremens) the flexible regimen may need to be prolonged beyond the first 24 hours. Table 4.6 Severe alcohol dependence: example of a fixed-dose chlordiazepoxide regimen. Day Dose Total daily dose (mg) 1 (first 24 hours) 40mg four times a day + 40mg when necessary 2 40mg four times a day 3 30mg four times a day 4 25mg four times a day 5 20mg four times a day 6 15mg four times a day 7 10mg four times a day 8 10mg four times a day 9 5mg four times a day 10 10mg at night Example of a symptom-triggered chlordiazepoxide regimen2 ■ ■Days 1–5: 20–30mg chlordiazepoxide as needed, up to hourly, based on symptoms

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07 - Wernickes encephalopathy

Wernicke’s encephalopathy

Addictions and substance misuse CHAPTER 4 Carbamazepine is an alternative to a benzodiazepine for managing withdrawal in situations where benzodiazepines are not a safe first-line option.15,16 Examples include: ■ ■A history of adverse reaction or allergy to benzodiazepine drugs. ■ ■A preference for carbamazepine because of a history of harmful or dependent use of benzodiazepines. Wernicke’s encephalopathy Wernicke’s encephalopathy is an acute neuropsychiatric condition caused by thiamine deficiency. In alcohol dependence, thiamine deficiency is secondary to both reduced dietary intake and reduced absorption. Risk factors for Wernicke’s encephalopathy in alcohol dependence are:16 ■ ■acute withdrawal ■ ■malnourishment ■ ■decompensated liver disease ■ ■emergency department attendance ■ ■hospitalisation for comorbidity ■ ■homelessness ■ ■memory disturbance ■ ■peripheral neuropathy ■ ■previous history of Wernicke’s encephalopathy. The ‘classic’ triad of ophthalmoplegia, ataxia and confusion is rarely present in Wernicke’s encephalopathy, and the syndrome is much more common than is recognised. A presumptive diagnosis of Wernicke’s encephalopathy should therefore be made in any patient undergoing detoxification who experiences any of the following signs: ■ ■ataxia ■ ■hypothermia ■ ■hypotension ■ ■confusion ■ ■ophthalmoplegia/nystagmus ■ ■memory disturbance ■ ■unconsciousness/coma. Any history of malnutrition, recent weight loss, vomiting or diarrhoea or peripheral neuropathy should also be taken into consideration.17 Prophylactic thiamine Low-risk drinkers without neuropsychiatric complications and with an adequate diet should be offered oral thiamine. The dose should be 300mg daily during assisted alcohol withdrawal and periods of continued alcohol intake.9 As thiamine is required to utilise glucose, a glucose load in a thiamine-deficient patient can precipitate Wernicke’s encephalopathy.

488 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Parenteral thiamine Historically it has been advised that patients undergoing in-patient detoxification should be given parenteral thiamine as prophylaxis against Wernike’s encephalopathy.2,9,18,19 In many countries, there are no licensed forms of parenteral thiamine available. In the UK, NICE20 recommends offering prophylactic parenteral thiamine followed by oral thiamine to those defined as ‘harmful or dependent drinkers’ if they are also known to: ■ ■be malnourished or at risk of malnourishment or ■ ■have decompensated liver disease and in addition: ■ ■they attend an emergency department or ■ ■are admitted to hospital with an acute injury or illness. People at high risk of Wernicke’s encephalopathy can have a range of conditions, including: ■ ■significant weight loss ■ ■poor diet ■ ■low body mass index (BMI) (<18) ■ ■other signs of malnutrition. Consider offering prophylactic parenteral thiamine to people at high risk following the dosing below. If Wernicke’s encephalopathy is suspected the patient should be transferred to a medical unit where intravenous thiamine can be administered. If untreated, Wernicke’s encephalopathy progresses to Korsakoff’s syndrome (permanent memory impairment, confabulation, confusion and personality changes). Treatment of somatic symptoms Somatic complaints are common during assisted withdrawal. Table 4.7 lists some remedies. Community setting doses ■ ■Give intramuscular thiamine 200–300mg once daily for at least 3 days Hospital setting doses ■ ■Give intramuscular or intravenous thiamine 200–300mg once daily for 3–5 days with daily review and monitoring for emergent signs of Wernicke’s encephalopathy

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08 - Relapse prevention

Relapse prevention

Addictions and substance misuse CHAPTER 4 Relapse prevention There is no place for the continued use of benzodiazepines beyond treatment of the acute alcohol withdrawal syndrome. Acamprosate and supervised disulfiram are licensed in some countries for the treatment of alcohol dependence and may be offered in combination with psychosocial treatment.2 Treatment should be initiated by a specialist service. After 12 weeks, transfer of the prescribing to primary care may be appropriate, although specialist care may continue. Naltrexone is also recommended as an adjunct in the treatment of moderate and severe alcohol dependence.2 As it does not have marketing authorisation for the treatment of alcohol dependence in some countries, informed consent should be sought and documented prior to commencing treatment. A large number of new and repurposed agents are undergoing evaluation for the treatment of alcohol use disorder (AUD).21,22 Acamprosate Acamprosate is a synthetic taurine analogue that acts as a functional glutamatergic N-methyl-D-aspartate (NMDA) antagonist and also increases gamma-aminobutyric acid (GABA) function. The number needed to treat (NNT) for the maintenance of abstinence has been calculated as 9–11.9 Acamprosate should be initiated as soon as possible after abstinence has been achieved although the British Association for Psychopharmacology consensus guidelines11 recommend that acamprosate should be started during detoxification because of its potential neuroprotective effect. In the UK, NICE2 recommends that acamprosate should be continued for up to 6 months, with regular (monthly) supervision (Box 4.1). The summary of product characteristics (SPC) recommends that it is given for 1 year. Box 4.1 Acamprosate: NICE Clinical guideline 115 (2011)2,23 Acamprosate should be offered for relapse prevention in moderately to severely dependent drinkers, in combination with psychosocial treatment. It should be prescribed for up to 6 months, or longer for those who perceive benefit and wish to continue taking it. The dose is 1998mg daily (666mg three times per day) for individuals over 60kg. For those under 60kg, the dose is 1332mg daily. Treatment should be stopped in those who continue to drink for 4–6 weeks after starting the drug. Table 4.7 Treatment of somatic symptoms. Symptom Recommended treatment Dehydration Ensure adequate fluid intake in order to maintain hydration and electrolyte balance; dehydration can precipitate life-threatening cardiac arrhythmia Pain Paracetamol (acetaminophen) Nausea and vomiting Metoclopramide 10mg or prochlorperazine 5mg 4–6 hourly Diarrhoea Diphenoxylate and atropine (Lomotil) or loperamide Skin itching Occurs commonly and not only in individuals with alcoholic liver disease: use oral antihistamines

490 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Acamprosate is relatively well tolerated. Adverse effects include diarrhoea, abdominal pain, nausea, vomiting and pruritis.2 It is contraindicated in severe renal or hepatic impairment, thus baseline liver and kidney function tests should be performed before commencing treatment. Acamprosate should be avoided in individuals who are pregnant or breastfeeding. Naltrexone Opioid blockade prevents increased dopaminergic activity after the consumption of alcohol, thus reducing its rewarding effects. Naltrexone, a non-selective opioid receptor antagonist, significantly reduces relapse to heavy drinking.2,24 Although early trials used a dose of 50mg/day, later US studies have used 100mg/day. In the UK the usual dose is 50mg/day with a trial dose of 25mg for 2 days to evaluate for adverse effects (Box 4.2). Naltrexone is well tolerated but adverse effects include nausea (especially in the early stages of treatment), headache, abdominal pain, reduced appetite and tiredness. A comprehensive medical assessment should be carried out prior to commencing naltrexone, together with baseline renal and liver function tests. Naltrexone can be started when patients are still drinking or during medically assisted withdrawal. There is no clear evidence as to the optimal duration of treatment but 6 months appears to be an appropriate period with follow-up, including monitoring liver function.9 Patients on naltrexone should not be given opioid agonist drugs for analgesia, non-opioid analgesics should be used instead. In the event that opioid analgesia is necessary, it can be instituted 48–72 hours after cessation of naltrexone. Hepatotoxicity has been described with high doses of naltrexone, so use should probably be avoided in acute liver failure.25 Long-acting injectable naltrexone has been developed to improve compliance.26 Adverse effects are similar to those seen with the oral preparation.27 In the UK, NICE concluded that the initial evidence was encouraging but not enough to support routine use. Nalmefene Nalmefene is also an opioid antagonist, recommended by NICE as an option for reducing alcohol consumption in people with alcohol dependence.2,24 It has been shown in one meta-analysis to be superior to naltrexone in reducing heavy drinking.28 Box 4.2 Naltrexone: NICE Clinical guideline 115 (2011)2,24 Naltrexone (50mg/day) should be offered for relapse prevention in moderately to severely dependent drinkers in combination with psychosocial treatment. It should be prescribed for up to 6 months, or longer for those who perceive benefit and wish to continue taking it. Treatment should be stopped in those who continue to drink for 4–6 weeks after starting the drug or in those who feel unwell while taking it.

Addictions and substance misuse CHAPTER 4 However, use of nalmefene remains controversial, with another meta-analysis suggesting that nalmefene had only limited efficacy in reducing alcohol consumption and that its value in treating alcohol addiction and relapse prevention is not fully established.29 Nalmefene’s efficacy is better than placebo30 but its place in therapy has yet to be established. Disulfiram (Antabuse) Disulfiram is a second-line treatment for those with moderate or severe alcohol dependence who have successfully completed withdrawal and want to maintain abstinence.31 It acts by inhibiting the enzyme aldehyde dehydrogenase, thus preventing complete metabolism of alcohol in the liver. This results in an accumulation of the toxic intermediate product, acetaldehyde, which causes the alcohol–disulfiram reaction, acting as a deterrent for further alcohol use (Table 4.8). Supervised medication optimises compliance and contributes to effectiveness. The intensity of the intolerance reaction is dose-dependent, with regard to both the amount of alcohol consumed and the dose of disulfiram. However, it is thought that much of the therapeutic effect is mediated by the mental anticipation of the aversive reaction, rather than the pharmacological action itself. Sudden death can occur but is more prevalent at disulfiram doses above 1000mg.31 With this in mind, the value of prescribing higher doses of disulfiram must be carefully considered. The first dose is usually 800mg, reducing to 100–200mg daily for maintenance. In comorbid alcohol and cocaine dependence doses of 500mg daily have been given. Halitosis is a common adverse effect. If there is a sudden onset of jaundice (signalling the rare complication of hepatotoxicity), the patient should stop the drug and seek urgent medical attention. The evidence for disulfiram is weaker than for acamprosate and naltrexone2 although its effect size may be greater.32 In the UK, NICE recommends its use ‘as a second-line option for moderate to severe alcohol dependence for patients who are not suitable for acamprosate or naltrexone or have a specified preference for disulfiram and who aim to stay abstinent from alcohol’ (Box 4.3).2 Table 4.8 The alcohol–disulfiram reaction. Mild alcohol–disulfiram reaction Severe alcohol–disulfiram reaction Contraindications Facial flushing Sweating Nausea Hyperventilation Dyspnea Tachycardia Hypotenision Acute heart failure Myocardial infarction Arrhythmias Bradycardia Respiratory depression Severe hypotension Ingestion of alcohol within the previous 24 hours Cardiac failure Coronary artery disease Hypertension Cerebrovascular disease Pregnancy Breastfeeding Liver disease Peripheral neuropathy Severe mental illness

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09 - Pregnancy and alcohol use

Pregnancy and alcohol use

492 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Baclofen Baclofen is a GABA-B agonist that does not have a licence for use in alcohol dependence but is nevertheless used by some clinicians as second-line treatment for those who have not responded to either naltrexone or acamprosate, or where there are contraindications for first-line treatment. A 2023 Cochrane review suggested that baclofen may help people with AUD in maintaining abstinence, particularly in people who are already detoxified.33 A 2022 meta-analysis32 also suggested baclofen is effective but is associated with higher rates of adverse effects including depression, vertigo, somnolence, numbness and muscle rigidity. Antiseizure medications There is currently insufficient evidence to support the use of antiseizure medications in the treatment of alcohol dependence, although they may reduce the number of drinks per drinking day compared with placebo.34 The majority of the research has been carried out on topiramate. Topiramate acts as a GABA/glutamate modulator that has demonstrated safety and efficacy in reducing heavy drinking in patients without AUD.35 It may as effective as naltrexone in AUD.36 There have been fewer studies on gabapentin,37 valproate and levetiracetam.30 Although these drugs have been used elsewhere in the world, they are not routinely used in the UK owing to lack of evidence and concerns regarding safety profiles for both gabapentin and valproate. Pregnancy and alcohol use Evidence indicates that alcohol consumption during pregnancy may cause harm to the fetus. The Department of Health advises that women should not drink any alcohol at all during pregnancy.1 Drinking even 1–2 units/day during pregnancy can increase the risk of having a preterm, low birthweight or small for gestational age baby. For alcohol-dependent pregnant women who have withdrawal symptoms, pharmacological cover for detoxification should be offered, ideally in an in-patient setting in collaboration with an antenatal team. The timing of detoxification in relation to the trimester of pregnancy should be risk-assessed against continued alcohol consumption and risks to the fetus.9 Chlordiazepoxide has been suggested as being unlikely to pose a substantial risk, however dose-dependent malformations have been observed.11 The UK Teratology Information Service (UKTIS)38 provides national advice for Box 4.3 Disulfiram: NICE Clinical guideline 115 (2011)2 Disulfiram should be considered in combination with a psychological intervention for patients who wish to achieve abstinence, but for whom acamprosate or naltrexone are not suitable. Treatment should be started at least 24 hours after the last drink and should be overseen by a family member or carer. Monitoring is recommended every 2 weeks for the first 2 months, then monthly for the following 4 months. Medical monitoring should be continued at 6-monthly intervals after the first 6 months. Patients must not consume any alcohol while taking disulfiram.

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10 - Children and adolescents

Children and adolescents

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11 - Older adults

Older adults

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12 - Concurrent alcohol and substance use disorder

Concurrent alcohol and substance use disorders

Addictions and substance misuse CHAPTER 4 healthcare professionals and likes to follow up on pregnancies that require alcohol detoxification. Specialist advice should always be sought. (See also Chapter 7.) No relapse prevention medication has been evaluated in pregnancy.9 Children and adolescents The number of young people who are dependent and needing pharmacotherapy is small, but for those who are dependent there should be a lower threshold for admission to hospital. Doses of chlordiazepoxide for medically assisted withdrawal may need to be adjusted, but the general principles of withdrawal management are the same as for adults. All young people should have a full health screen carried out routinely to allow identification of physical and mental health problems. Relapse prevention medications are not licensed in the under 18 population due to lack of evidence. The evidence base for acamprosate, naltrexone and disulfiram in 16–19-year-olds is evolving,9 but naltrexone is best supported in this age group.39–41 Older adults For older adults, there should be a lower threshold for hospital admission for medically assisted alcohol withdrawal.2 Benzodiazepines remain the treatment of choice but they may need to be prescribed in lower doses and in some situations shorter acting drugs may be preferred.9 All older adults with AUD should have full routine health screens to identify physical and mental health problems. The evidence base for pharmacotherapy of AUD in older people is limited.42 Concurrent alcohol and substance use disorders Where alcohol and drug use disorders are comorbid, treat both conditions actively.2 Coexisting alcohol and benzodiazepine dependence This is best managed with one benzodiazepine, either chlordiazepoxide or diazepam. The starting dose should take into account the requirements for medically assisted alcohol withdrawal and the typical daily equivalent dose of the relevant benzodiazepine(s).2,43 In-patient treatment should be carried out over a 2–3-week period, possibly longer.2 Coexisting alcohol dependence and cocaine use In comorbid cocaine/alcohol dependence, naltrexone 150mg/day resulted in reduced cocaine and alcohol use in men but not in women.44 Topiramate seems ineffective.45 Coexisting alcohol and opioid dependence Both conditions should be treated and attention paid to the increased mortality of individuals withdrawing from both drugs.

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13 - Comorbid mental health disorders in AUD

Comorbid mental health disorders in AUD

494 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Coexisting alcohol and nicotine dependence Encourage individuals to stop smoking. Refer for smoking cessation in primary care and other settings. In in-patient settings offer nicotine patches/inhalator during assisted alcohol withdrawal. Always promote vaping as a safer alternative to tobacco smoking. Comorbid mental health disorders in AUD People with AUD often present with other mental health disorders, particularly anxiety and depression. Public Health England has described it as ‘the norm rather than the exception’ and encourages a collaborative, effective and flexible approach between front-line services, stating that it is ‘everyone’s job’ and that there is ‘no wrong door’.46 Substance use disorders, including AUD, should never be a reason to exclude a patient from crisis or specialist psychiatric services after completion of detoxification. Depression in AUD Depressive and anxiety symptoms occur commonly during alcohol withdrawal, but usually diminish by the 3rd or 4th week of abstinence. Meta-analyses suggest that antidepressants with mixed pharmacology (the tricyclics imipramine or trimipramine) perform better than selective serotonin reuptake inhibitors (SSRIs; fluoxetine or sertraline) in reducing depressive symptoms in individuals with AUD, but the antidepressant effect is modest.2,9,47,48 Trazodone may also be effective.49 A greater antidepressant effect was seen if the diagnosis of depression was made after at least 1 week of abstinence, thus excluding those with affective symptoms caused by alcohol withdrawal. There is stronger evidence for depression categorised as independent rather than substance- induced.36 As treatment effects are masked by comparatively large placebo effects, which conceal improvements that would otherwise be attributed to medication, there is a need for larger randomised, placebo-controlled trials. Despite the evidence for tricyclics, they are rarely used in clinical practice because of their potential for cardiotoxicity and toxicity in overdose.50 SSRIs may not be effective in depression in AUD and may worsen drinking behaviour.51 Relapse prevention medication should be considered in combination with anti depressants. Pettinati et al.52 showed that the combination of sertraline (200mg/day) with naltrexone (100mg/day) had superior outcomes – improved drinking outcomes and better mood – compared with placebo and compared with each drug alone. In contrast, citalopram showed no benefit when added to naltrexone.53 Secondary analyses of acamprosate and naltrexone trials suggest that: ■ ■Acamprosate has an indirect modest beneficial effect on depression via increasing abstinence. ■ ■In depressed alcohol-dependent patients, the combination of naltrexone and an antidepressant may be better than either drug alone,9 but findings are not consistent.53 Ketamine is an emerging treatment for AUD54 and may be helpful in comorbid depression.

Addictions and substance misuse CHAPTER 4 Bipolar affective disorder in AUD Bipolar patients tend to use alcohol to reduce symptoms of anxiety and depression, and comorbid AUD is common. Where there is comorbidity, it is important to treat the different phases of bipolar disorder as recommended elsewhere. It may be worth adding sodium valproate to lithium as the combination is associated with better drinking outcomes than lithium alone. However, the combination did not confer any extra benefit than lithium alone in improving mood (see British Association for Psychopharmacology consensus 2012).9 In those who continue to drink, electrolyte imbalance may precipitate lithium toxicity. Lithium is probably best avoided completely in binge drinkers. Adding quetiapine to lithium or valproate has no effect.55 Naltrexone should be offered early to help bipolar patients reduce their alcohol consumption.9 If naltrexone is not effective, then acamprosate should be offered. In the event that both naltrexone and acamprosate fail to promote abstinence, then disulfiram should be considered, and the risks made known to the patient. Anxiety in AUD Anxiety is commonly observed in alcohol-dependent individuals during intoxication, withdrawal and in the early days of abstinence. Alcohol is typically used to self-medicate anxiety disorders, particularly social anxiety. In alcohol-dependent individuals who experience anxiety it is often difficult to determine the extent to which the anxiety is a symptom of the AUD or whether it is an independent disorder. Medically assisted withdrawal and supported abstinence for up to 8 weeks are required before a full assessment can be made. If a medically assisted withdrawal is not possible then treatment of the anxiety disorder should still be attempted, following guidelines for the particular anxiety disorder. The use of benzodiazepines is controversial11 because of the increased risk of benzodiazepine misuse and dependence. Benzodiazepines should only be considered following assessment in a specialist addiction service. Long-term use is generally not recommended.51 One meta-analysis suggested that buspirone is effective in reducing symptoms of anxiety but not alcohol consumption.9,56 Studies have also shown that paroxetine (up to 60mg/day) was superior to placebo in reducing social anxiety in AUD patients although alcohol consumption was not affected.9,56 Either naltrexone or disulfiram, alone or combined, improves drinking outcomes compared with placebo in patients with post-traumatic stress disorder (PTSD) and alcohol dependence.57,58 Both acamprosate and baclofen have shown benefit in reducing anxiety in post hoc analyses of alcohol-dependence trials. It is therefore important to ensure that these patients are enabled to become abstinent and are prescribed relapse prevention medication. Anxiety should then be treated according to the appropriate NICE guidelines. Schizophrenia in AUD Patients with schizophrenia who also have AUD should be assessed and alcohol-specific relapse prevention treatment considered, usually either naltrexone or acamprosate. Disulfiram is contraindicated in psychosis.59 Antipsychotic medication should be

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14 - References

References

496 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 optimised11 and clozapine may be considered. However, there is insufficient evidence to recommend the use of any one antipsychotic medication over another in AUD. Antipsychotics do not improve AUD itself.51 References

Gov.UK Department of Health and Social Care. UK Chief Medical Officers’ low risk drinking guidelines. 2016 (last accessed August 2024); https://www.gov.uk/government/publications/alcohol-consumption-advice-on-low-risk-drinking.
National Institute for Health and Care Excellence. Alcohol-use disorders: diagnosis, assessment and management of harmful drinking (high-risk drinking) and alcohol dependence. Clinical guideline [CG115]. 2011 (last checked July 2019, last accessed August 2024); https://www.nice.org.uk/guidance/cg115.
National Institute for Health and Care Excellence. Alcohol-use disorders: prevention. Public health guideline [PH24]. 2010 (last checked July 2019, last accessed August 2024; updated 2010). https://www.nice.org.uk/guidance/ph24.
Babor T, et al. AUDIT: The Alcohol Use Disorders Identification Test Guidelines for Use in Primary Care, 2nd edn. 2001; https://iris.who. int/handle/10665/67205.
Stockwell T, et al. The severity of alcohol dependence questionnaire: its use, reliability and validity. Br J Addict 1983; 78:145–155.
Minozzi S, et al. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev 2010; 3:CD005064.
Amato L, et al. Efficacy and safety of pharmacological interventions for the treatment of the alcohol withdrawal syndrome. Cochrane Database Syst Rev 2011; 6:CD008537.
Brathen G, et al. EFNS guideline on the diagnosis and management of alcohol-related seizures: report of an EFNS task force. Eur J Neurol 2005; 12:575–581.
Lingford-Hughes AR, et al. Evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP. J Psychopharmacol 2012; 26:899–952.
NSW Government. Clinical guidance for withdrawal from alcohol and other drugs. 2023 (last accessed August 2024); https://www.health. nsw.gov.au/aod/professionals/Pages/clinical-guidance.aspx.
Schuckit MA. Recognition and management of withdrawal delirium (delirium tremens). N Engl J Med 2014; 371:2109–2113.
Sullivan JT, et al. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict 1989; 84:1353–1357.
Gossop M, et al. A Short Alcohol Withdrawal Scale (SAWS): development and psychometric properties. Addict Biol 2002; 7:37–43.
National Institute for Health and Care Excellence. Alcohol-use disorders: diagnosis and management of physical complications. Clinical guideline [CG100]. 2010 (last updated April 2017, last accessed August 2024); https://www.nice.org.uk/guidance/cg100.
Bahji A, et al. Comparative efficacy and safety of pharmacotherapies for alcohol withdrawal: a systematic review and network meta-analysis. Addiction 2022; 117:2591–2601.
Fluyau D, et al. Beyond benzodiazepines: a meta-analysis and narrative synthesis of the efficacy and safety of alternative options for alcohol withdrawal syndrome management. Eur J Clin Pharmacol 2023; 79:1147–1157.
Thomson AD, et al. Time to act on the inadequate management of Wernicke’s encephalopathy in the UK. Alcohol Alcohol 2013; 48:4–8.
Thomson AD, et al. The Royal College of Physicians report on alcohol: guidelines for managing Wernicke’s encephalopathy in the accident and emergency department. Alcohol Alcohol 2002; 37:513–521.
Day E, et al. Thiamine for prevention and treatment of Wernicke-Korsakoff syndrome in people who abuse alcohol. Cochrane Database Syst Rev 2013; 7:CD004033.
National Institute for Health and Care Excellence. CKS: Alcohol – problem drinking: supporting evidence. 2023 (last accessed September 2024); https://cks.nice.org.uk/topics/alcohol-problem-drinking/supporting-evidence.
Burnette EM, et al. Novel agents for the pharmacological treatment of alcohol use disorder. Drugs 2022; 82:251–274.
Köhne S, et al. Emerging drugs in phase II and III clinical development for the treatment of alcohol use disorder. Expert Opin Emerg Drugs 2024; 29:219–232.
Rösner S, et al. Acamprosate for alcohol dependence. Cochrane Database Syst Rev 2010; 9:CD004332.
Rösner S, et al. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev 2010; 12:CD001867.
AOP Orphan Ltd. Summary of product characteristics. Adepend (naltrexone hydrochloride) 50mg filmcoated tablets. 2020 (last accessed August 2024); https://www.medicines.org.uk/emc/product/3559/smpc.
Leighty AE, et al. Treatment outcomes of long-acting injectable naltrexone versus oral naltrexone in alcohol use disorder in veterans. Ment Health Clin 2019; 9:392–396.
Krupitsky E, et al. Injectable extended-release naltrexone (XR-NTX) for opioid dependence: long-term safety and effectiveness. Addiction 2013; 108:1628–1637.
Soyka M, et al. Comparing nalmefene and naltrexone in alcohol dependence: are there any differences? Results from an indirect meta-analysis. Pharmacopsychiatry 2016; 49:66–75.
Palpacuer C, et al. Risks and benefits of nalmefene in the treatment of adult alcohol dependence: a systematic literature review and meta-analysis of published and unpublished double-blind randomized controlled trials. PLoS Med 2015; 12:e1001924.
Kotake K, et al. Efficacy and safety of alcohol reduction pharmacotherapy according to treatment duration in patients with alcohol dependence or alcohol use disorder: a systematic review and network meta-analysis. Addiction 2024; 119:815–832.
Mutschler J, et al. Current findings and mechanisms of action of disulfiram in the treatment of alcohol dependence. Pharmacopsychiatry 2016; 49:137–141.

Addictions and substance misuse CHAPTER 4 32. Bahji A, et al. Pharmacotherapies for adults with alcohol use disorders: a systematic review and network meta-analysis. J Addict Med 2022; 16:630–638. 33. Agabio R, et al. Baclofen for alcohol use disorder. Cochrane Database Syst Rev 2023; 1:CD012557. 34. Pani PP, et al. Anticonvulsants for alcohol dependence. Cochrane Database Syst Rev 2014; 2014:CD008544. 35. Votaw VR, et al. An intensive longitudinal examination of topiramate treatment for alcohol use disorder: a secondary analysis of data from a randomized controlled trial. Addiction 2023; 118:1040–1052. 36. Morley KC, et al. Topiramate versus naltrexone for alcohol use disorder: a genotype-stratified double-blind randomized controlled trial. Am J Psychiatry 2024; 181:403–411. 37. Kranzler HR, et al. A meta-analysis of the efficacy of gabapentin for treating alcohol use disorder. Addiction 2019; 114:1547–1555. 38. UK Teratology Information Service (UKTIS). 2024; www.UKTIS.org. 39. O’Malley SS, et al. Reduction of alcohol drinking in young adults by naltrexone: a double-blind, placebo-controlled, randomized clinical trial of efficacy and safety. J Clin Psychiatry 2015; 76:e207–e213. 40. Miranda R, et al. Effects of naltrexone on adolescent alcohol cue reactivity and sensitivity: an initial randomized trial. Addict Biol 2014; 19:941–954. 41. Roos CR, et al. Reward drinking and naltrexone treatment response among young adult heavy drinkers. Addiction 2021; 116:2360–2371. 42. Joshi P, et al. Evaluation and management of alcohol use disorder among older adults. Curr Geriatr Rep 2021; 10:82–90. 43. Gudin JA, et al. Risks, management, and monitoring of combination opioid, benzodiazepines, and/or alcohol use. Postgrad Med 2013; 125:115–130. 44. Pettinati HM, et al. Gender differences with high-dose naltrexone in patients with co-occurring cocaine and alcohol dependence. J Subst Abuse Treat 2008; 34:378–390. 45. Kampman KM, et al. A double-blind, placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence. Drug Alcohol Depend 2013; 133:94–99. 46. Public Health England. Better care for people with co-occurring mental health and alcohol/drug use conditions. A guide for commissioners and service providers. 2017; https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/625809/Co-occurring_mental_ health_and_alcohol_drug_use_conditions.pdf. 47. Agabio R, et al. Antidepressants for the treatment of people with co-occurring depression and alcohol dependence. Cochrane Database Syst Rev 2018; 4:CD008581. 48. Stokes PRA, et al. Pharmacological treatment of mood disorders and comorbid addictions: a systematic review and meta-analysis: Traitement Pharmacologique des Troubles de L’humeur et des Dépendances Comorbides: une Revue Systématique et une Méta-Analyse. Can J Psychiatry 2020; 65:749–769. 49. Di Nicola M, et al. Update on pharmacological treatment for comorbid major depressive and alcohol use disorders: the role of extended- release trazodone. Curr Neuropharmacol 2023; 21:2195–2205. 50. Taylor D, et al. The cardiovascular safety of tricyclic antidepressants in overdose and in clinical use. Ther Adv Psychopharmacol 2024; 14:20451253241243297. 51. Wood E, et al. Canadian guideline for the clinical management of high-risk drinking and alcohol use disorder. CMAJ 2023; 195:E1364–E1379. 52. Pettinati HM, et al. A double-blind, placebo-controlled trial combining sertraline and naltrexone for treating co-occurring depression and alcohol dependence. Am J Psychiatry 2010; 167:668–675. 53. Adamson SJ, et al. A randomized trial of combined citalopram and naltrexone for nonabstinent outpatients with co-occurring alcohol dependence and major depression. J Clin Psychopharmacol 2015; 35:143–149. 54. Kelson M, et al. Ketamine treatment for alcohol use disorder: a systematic review. Cureus 2023; 15:e38498. 55. Stedman M, et al. A double-blind, placebo-controlled study with quetiapine as adjunct therapy with lithium or divalproex in bipolar I patients with coexisting alcohol dependence. Alcohol Clin Exp Res 2010; 34:1822–1831. 56. Ipser JC, et al. Pharmacotherapy for anxiety and comorbid alcohol use disorders. Cochrane Database Syst Rev 2015; 1:CD007505. 57. Verplaetse TL, et al. Pharmacotherapy for co-occurring alcohol use disorder and post-traumatic stress disorder: targeting the opioidergic, noradrenergic, serotonergic, and GABAergic/glutamatergic systems. Alcohol Res 2018; 39:193–205. 58. Morice CK, et al. Comorbid alcohol use and post-traumatic stress disorders: pharmacotherapy with aldehyde dehydrogenase 2 inhibitors versus current agents. Prog Neuropsychopharmacol Biol Psychiatry 2022; 115:110506. 59. Brown & Burk UK Ltd. Summary of product characteristics. Disulfiram 200mg tablets. 2023 (last accessed August 2024); https://www.medicines. org.uk/emc/product/11168.

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15 - Opioid dependence

Opioid dependence

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16 - Prescribing for opioid dependence

Prescribing for opioid dependence

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17 - Treatment of opioid overdose

Treatment of opioid overdose

498 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Opioid dependence Prescribing for opioid dependence The treatment of opioid dependence is a rapidly changing and dynamic field. A decade or so ago, maintenance treatment with methadone was the dominant approach. The introduction of buprenorphine in different formulations, the positive experience of unsupervised consumption of opioids during the pandemic and the emergence of high-potency opioids in the illicit supply chain have contributed to a sea-change in practice.1,2 The pharmacological interventions used for opioid-dependent people in the UK and most developed countries include: ■ ■Harm minimisation measures, e.g. take-home naloxone. ■ ■Maintenance treatment with opioid substitution treatment (OST) such as methadone or buprenorphine (Box 4.4). ■ ■Naltrexone for relapse prevention (although patient acceptability of this is low). Treatment of opioid overdose Opioid overdose is a preventable cause of death in the opioid-using population. This includes overdose of illicit opioids such as heroin and more potent opioids such as fentanyl and nitazenes, and overdose of prescribed opioids such as methadone or buprenorphine. Opioid overdose is characterised clinically by the presence of: ■ ■unconsciousness ■ ■a low respiratory rate (<12) Box 4.4 Considerations when initiating opioid substitution treatment (OST) ■ ■The aim of treatment is to minimise or abolish withdrawal symptoms without endangering the patient. ■ ■All opioids are respiratory depressants. ■ ■Prescribed opioids such as methadone and buprenorphine have low lethal doses in drug-naïve individuals. ■ ■Even in patients prescribed them long term, tolerance can be lost over a matter of days. ■ ■OST can be fatal, whereas opioid withdrawal is not life-threatening. ■ ■The undoubted risk of opioid toxicity should be weighed against the risk of self-discharge from hospital against medical advice because of intolerable opiate withdrawal. Self-discharge carries risks, with an eightfold increased probability of drug-related death in the 2 days following self-discharge.3 Opioid-dependent patients may also delay seeking care for their physical health problems because of the fear of withdrawal.4 ■ ■Non-specialist doctors should seek guidance either from established local protocols regarding initiation of opioid substitution (opioid agonist) treatment or from specialist drug services before prescribing opioid substitution treatment. ■ ■The key patient safety questions to ask before you prescribe OST are: ■ ■Is OST warranted (i.e. am I confident this patient is currently dependent on opioids)? ■ ■Am I confident that the patient will tolerate the dose of OST I am about to give them? ■ ■It is important to document the reasoning for prescribing or not prescribing.

Addictions and substance misuse CHAPTER 4 ■ ■pin-point pupils ■ ■cyanosis ■ ■cold, clammy skin. Naloxone is an opioid receptor antagonist that can reverse opioid overdose. It is available in pre-loaded syringes to give IM or IV or as a nasal spray.4 For patients who have taken buprenorphine, fentanyl or nitazenes,5,6 repeated naloxone boluses may be necessary to reverse toxicity because of their high affinity for opiate receptors. Naloxone injection Naloxone 400mcg IM/IV should be prescribed ‘as required’ for any in-patient with suspected harmful opioid use or dependence and should be kept in the resuscitation bag on the ward. Anyone can give naloxone to prevent an overdose death. Patients discharged from in-patient wards should be warned about loss of tolerance and they and their family members should be provided with naloxone training and take-home naloxone.8 A summary of what to do in case of opioid overdose is shown in Figure 4.2 and training in take-home naloxone covers these actions. Intranasal naloxone Concentrated intranasal naloxone in doses of 2mg per kit is an alternative to intramuscular naloxone4 with greater ease of use and acceptability to lay people.9 The 2mg dose gives an equivalent time to onset of action to 400mcg IM but produces a longer lasting peak.9,10 Call 999 and ask for an ambulance Give basic life support 30 chest compressions and 2 rescue breaths Give naloxone (either IM naloxone 400mcg OR one dose of nasal naloxone) Give 3 cycles of basic life support (30 chest compressions and 2 rescue breaths) if possible Repeat giving naloxone and 3 cycles of life support until ambulance arrives or patient is breathing normally Figure 4.2 Flowchart for naloxone administration. Adapted from WHO (2014).7

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18 - Opioid substitution treatment (OST)

Opioid substitution treatment (OST)

500 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Opioid substitution treatment (OST) The mainstay of pharmacological management of opioid dependence is OST. OST can be prescribed for detoxification, that is, at a dose to control withdrawal symptoms followed by progressive reduction and discontinuation. Alternatively, OST can be prescribed as ‘maintenance’, which refers to a longer period of months to years on a stable dose of OST. The goals of OST are: ■ ■To reduce or prevent withdrawal symptoms. ■ ■To reduce or eliminate non-prescribed drug use. ■ ■To stabilise drug intake and lifestyle. ■ ■To reduce drug-related harm (particularly injecting drug use). ■ ■To engage and provide an opportunity to work with the patient. Treatment will depend upon: ■ ■What pharmacotherapies and/or other interventions are available. ■ ■Patient’s previous history of drug use and response to treatment. ■ ■Patient’s current drug use and circumstances. ■ ■Physical comorbidity. ■ ■Location/service where treatment is initiated. Most OST prescribing for people with mental health problems should be initiated by specialist addiction services alongside appropriate psychiatric care from mental health services.8,11 Some people with opioid dependence will be admitted to psychiatric or general in-patient wards, and general or liaison psychiatrists will need to take over or initiate prescribing in the immediate term8 (see later in this chapter). Clinicians should take care to ensure that patients are physiologically dependent on opioids before initiating OST. There should be clear clinical evidence of opioid withdrawal and, if possible, a positive urine drug screen and documented recent on-going opioid substitution treatment (e.g. information from drug service or dispensing pharmacy, recently dated and named methadone bottles). Assessment should involve the following: ■ ■Which opioids the person is taking, and in what amounts. ■ ■What other drugs are used, including alcohol and other depressants (e.g. gabapentinoids, benzodiazepines). ■ ■Frequency, quantity and route of administration of all substances used. ■ ■Time of last use. ■ ■Physical comorbidity that may affect prescribing decisions such as chronic obstructive pulmonary disease (COPD) and cardiac conditions. ■ ■Prescribed medication, which can interact with OST – such as respiratory depressants and those that prolong QT interval. ■ ■Previous experience of treatment. ■ ■Previous overdoses and whether these were intentional or accidental. ■ ■Whether or not they have take-home naloxone.

Addictions and substance misuse CHAPTER 4 ■ ■Whether or not there are objective signs of opioid withdrawal using a validated scale such as OOWS or COWS (see below). ■ ■Examination of injection sites if they inject. ■ ■Collateral information from addiction services and/or pharmacy in respect to usual dose of OST and most recently dispensed dose. Timecourse of withdrawal symptoms Withdrawal is dependent on duration of use, degree of dependence and type of opioid used (Table 4.9). Buprenorphine-related withdrawal symptoms tend to be milder than those from full agonist opioids, even when high-dose buprenorphine is abruptly discontinued.12,13 Tapering over 4 weeks before complete discontinuation is associated with considerably less withdrawal than more rapid tapers.14 Early indications are that buprenorphine long-acting injection is not associated with clinically significant withdrawal symptoms.15 Specific opioid withdrawal scales are freely available, such as the Clinical Opiate Withdrawal Scale (COWS)16 or Objective Opiate Withdrawal Scale (OOWS)17 which can be used to help assess withdrawal (Table 4.10). Prescribing OST safely ■ ■Use licensed medications for treatment of heroin dependence (i.e. methadone and buprenorphine). ■ ■Ensure that the patient is dependent on opioids. ■ ■Give a safe initial dose (see later in this chapter) and titrate cautiously. ■ ■Use daily supervised consumption in those patients with a higher risk of overdose during dose initiation. Induction and stabilisation of OST maintenance medication Methadone and buprenorphine are the OST medications recommended by NICE in the UK for maintenance substitute prescribing and are effective in treating withdrawal symptoms and decreasing use of illicit opioids.18 Methadone and buprenorphine are Controlled Drugs with high dependency potential. Methadone in particular has a low lethal dose. For these reasons, there are special documentation requirements, including specifying the patient’s name, date of birth and address on prescriptions and writing the daily dose amount and total amount prescribed in both numbers and words. Instructions such as the requirement for consumption to be supervised should also be specified, for example ‘daily supervised consumption’.8 Table 4.9 Timing of withdrawal symptoms of different opioids. Drug Onset Peak End Heroin 4–6 hours 32–72 hours 5 days Methadone 12–24 hours 4–6 days Up to 40 days19 Buprenorphine (sublingual) 24–48 hours 3–5 days 8–10 days13,20

502 The Maudsley® Prescribing Guidelines in Psychiatry Table 4.10 Clinical Opiate Withdrawal Scale (COWS). Resting pulse rate: _______beats/min Measured after patient is sitting or lying for 1 minute: 0 – pulse rate 80 or below 1 – pulse rate 81–100 2 – pulse rate 101–120 4 – pulse rate greater than 120 Sweating Over past 30 minutes not accounted for by room temperature or patient activity: 0 – no report of chills or flushing 1 – subjective report of chills or flushing 2 – flushed or observable moistness on face 3 – beads of sweat on brow or face 4 – sweat streaming off face Restlessness Observation during assessment: 0 – able to sit still 1 – reports difficulty sitting still, but is able to do so 3 – frequent shifting or extraneous movements of legs/arms 5 – unable to sit still for more than a few seconds CHAPTER 4 Pupil size 0 – pupils pinned or normal size for room light 1 – pupils possibly larger than normal for room light 2 – pupils moderately dilated 5 – pupils so dilated that only the rim of the iris is visible Bone or joint aches If patient was having pain previously, only the additional component attributed to opiates withdrawal is scored: 0 – not present 1 – mild diffuse discomfort 2 – patient reports severe diffuse aching of joints/muscles 4 – patient is rubbing joints or muscles and is unable to sit still because of discomfort Runny nose or tearing Not accounted for by cold symptoms or allergies: 0 – not present 1 – nasal stuffiness or unusually moist eyes 2 – nose running or tearing 4 – nose constantly running or tears streaming down cheeks Scores 5–12: mild withdrawal 13–24: moderate withdrawal 25–36: moderately severe withdrawal More than 36: severe withdrawal GI upset Over last 30 minutes: 0 – no GI symptoms 1 – stomach cramps 2 – nausea or loose stool 3 – vomiting or diarrhoea 5 – multiple episodes of diarrhoea or vomiting Tremor Observation of outstretched hands: 0 – no tremor 1 – tremor can be felt, but not observed 2 – slight tremor observable 4 – gross tremor or muscle twitching Yawning Observation during assessment: 0 – no yawning 1 – yawning once or twice during assessment 2 – yawning three or more times during assessment 4 – yawning several times/minute Anxiety or irritability 0 – none 1 – patient reports increasing irritability or anxiousness 2 – patient obviously irritable or anxious 4 – patient so irritable or anxious that participation in the assessment is difficult Gooseflesh skin: 0 – skin is smooth 3 – piloerection of skin can be felt or hairs standing up on arms 5 – prominent piloerection Total score: ___________ (The total score is the sum of all 11 items)

Addictions and substance misuse CHAPTER 4 The pharmacology of methadone and buprenorphine differs. Methadone is a full agonist at mu opioid receptors while buprenorphine is a partial agonist. This difference in pharmacology dictates the advantages and disadvantages of each drug (Table 4.11). The therapeutic dose (i.e. the dose at which treatment is associated with cessation of heroin use) for methadone is usually 60–100mg per day. The therapeutic dose for buprenorphine is between 12 and 24mg per day. Table 4.11 Choosing between buprenorphine and methadone. Methadone Sublingual buprenorphine Safety Associated with a reduced risk of mortality relative to being out of treatment21 but with increased mortality during induction22 Possible increased methadone-related mortality in those over 4521 Increased risk of drug-related deaths in those with cardiovascular or respiratory comorbidity21 Increased methadone-related death when directly supervised consumption (DSC) is replaced with take-home dosing23 No increased risk during induction22 No increased mortality with age21 Lower drug-related mortality than methadone in cardiovascular or respiratory comorbidity21 No increase in buprenorphine-related deaths above expected trends when DSC replaced with take-home dosing23 Withdrawal syndrome Appears to be more marked and prolonged Has a milder withdrawal syndrome19 Titration Associated with increased mortality during the titration phase22 hence the need for gradual titration over a few weeks to reach therapeutic range (usually 60–100mg a day) Able to reach therapeutic dose (12–16mg a day) within 2–3 days Risk of precipitated withdrawal if patients are not already in withdrawal when buprenorphine is initiated although this is infrequent (<1%)24 and can be mitigated (see below) Differences in retention Greater retention in treatment than buprenorphine25 Associated with greater drop-out from treatment than methadone (applies to both high-dose and low-dose buprenorphine) Differences in adverse effects Risk of QT prolongation26 Less sedating than methadone (can be seen as undesirable by patients)8 Drug interactions Methadone is largely metabolised by CYP3A4 and thus is affected by drugs that inhibit (e.g. cannabis27,28) or induce CYP3A4.29 As for methadone Pregnancy Widely used in pregnancy Buprenorphine is associated with less severe neonatal withdrawal symptoms30 and lower incidence of congenital abnormalities.30 However, buprenorphine should not be initiated in pregnancy even if switching from methadone because of the risk of inducing withdrawal in the fetus. Diversion Patients at greater risk of diversion of medication (e.g. past history of this; treatment in a prison setting)31 may be better served with methadone treatment (although buprenorphine long-acting injection has a low risk of buprenorphine diversion). Sublingual buprenorphine tablets can be more easily diverted with the risk of tablets being injected.32

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19 - Methadone

Methadone

504 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 In rare cases, patients may be allergic to methadone or buprenorphine or to some of the constituents within the formulations. Methadone Initiation in all settings ■ ■Do not prescribe/dispense to a patient who is clinically intoxicated with opioids or other drugs (including alcohol). ■ ■Only prescribe as a 1mg/mL solution. ■ ■Do not prescribe tablets as these can be crushed and injected. ■ ■Describe supervision accurately, for example ‘directly supervised consumption’ or ‘take away three times per week’. Importance of context to methadone titration schedules Methadone is associated with an increased risk of death during titration, because: ■ ■It is a full agonist. ■ ■Assessing dose equivalence with street heroin is difficult. ■ ■There is wide inter-individual pharmacokinetic variation. ■ ■Repeated dosing is associated with substantial accumulation with steady state only reached after about five doses of methadone.33,34 Thus for safety reasons, methadone titration schedules are usually conservative. However, ensuring safe methadone titration is context-dependent, in that the consequences of uncontrolled opioid withdrawal and consequent disengagement need to be considered. Methadone in general hospital settings Fear of inadequate treatment of opioid withdrawal during general hospital admissions has led to people with opioid dependence not seeking help for their physical health problems or seeking help only when desperate.10 There is an elevated (fourfold) risk of drug-related death associated with hospital discharge and even more so for discharge against medical advice (almost eightfold increase).3 The general hospital is also a setting where more doses can be administered within 24 hours (e.g. 4–6 hourly), where respiration and oxygen saturations can be monitored with a greater frequency than in other contexts and more sophisticated respiratory support and sustained naloxone reversal can be provided. All these factors may allow a more aggressive methadone protocol (Table 4.12), with the caveat that a slower protocol may be necessary for those with head injuries, acute respiratory compromise, hepatic or renal failure, or co-prescription of other sedating drugs (e.g. medicated detoxification from alcohol using benzodiazepines). Methadone in psychiatric hospital settings Psychiatric hospital settings are different from general hospital settings in that familiarity with opioids and naloxone is lower, intensive physical health monitoring is less feasible and other sedating medications (antipsychotics, benzodiazepines) are routinely

Addictions and substance misuse CHAPTER 4 given alongside methadone. This does not mean that methadone should be withheld – the risk of drug-related death following psychiatric hospital discharge is too great. All efforts should be directed at (re-)establishing methadone treatment and avoiding loss of tolerance to opioids. Generally, methadone titration in the psychiatric setting is more cautious (Table 4.12). Cautions with methadone Intoxication Methadone should not be given to any patient showing signs of intoxication due to alcohol or other CNS depressant drugs (e.g. benzodiazepines)35,36 as the risk of fatal overdose is greatly enhanced when concurrent methadone is taken.37,38 Concurrent alcohol and both prescribed and illicit drug consumption must be borne in mind when considering subsequent prescribing of methadone. This is because of the increased risk of overdose associated with simultaneous use of several respiratory depressants.39 Severe hepatic/renal dysfunction Metabolism and elimination of methadone may be affected in advanced liver disease.40 The dose or dosing interval should be adjusted accordingly against clinical presentation. Because of extended plasma half-life, the interval between assessments during initial dosing may need to be extended. Around 20% of methadone is eliminated via the renal route. Renal disease does not affect methadone elimination as in such conditions it is excreted exclusively via the biliary route. However, patients with advanced renal disease are more sensitive to sedation caused by methadone. Thus, for those with glomerular filtration rate (GFR) <15mL/min or creatinine >700 mmol/L, a reduction of 50% in methadone dose should be considered.41 Table 4.12 Methadone titration where extent of prior use is unknown or unconfirmed. Setting Procedure General hospital Initial dose of 10–20mg with further doses of 5–10mg every 6 hours if withdrawal persists (according to COWS or OOWS), up to 40mg in 24 hours. In the second 24 hours, the total dose used in the first 24 hours should be given as a split dose. Increase by 10mg every 2 days, monitoring withdrawal, sedation and respiratory depression. Maximum increase from day 1 dose over 1 week is 30mg. Consider split dosing. Psychiatric hospital Initial dose of 10–20mg on day 1. Increase by 10mg every 2 days, monitoring withdrawal, sedation and respiratory depression. Maximum increase from day 1 dose over 1 week is 30mg. Consider split dosing. Community drug service Initially, 10–30mg on day 1. Increase by 10mg every couple of days, monitoring withdrawal, sedation and respiratory depression. Maximum increase from day 1 dose over 1 week is 30mg. Important: All patients starting a methadone treatment programme must be informed of the risks of toxicity and overdose, and the necessity for safe storage of any take-home medication.8 Safe storage is vital, particularly if there are children in the household, as tragic deaths have occurred when children have ingested methadone. Prescribers should consider risks to children in all assessments and treatment plans of drug-using patients.

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Buprenorphine

506 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Methadone overdose In the event of methadone overdose, naloxone should be administered as described in the section on opioid overdose earlier in this chapter. Methadone and risk of torsades de pointes/QT interval prolongation Methadone, either alone or combined with other QT-prolonging agents, may increase the likelihood of QT interval prolongation, which is associated with torsades de pointes and can be fatal.26,42–44 Recommended ECG monitoring There is insufficient evidence to support the effectiveness of QT screening in preventing cardiac death in people prescribed methadone.45 However, in the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) recommends that patients with the following risk factors for QT interval prolongation receive regular electrocardiogram (ECG) monitoring while receiving methadone: ■ ■heart disease ■ ■liver disease ■ ■dose of >100mg per day ■ ■electrolyte abnormalities ■ ■concomitant CYP3A4 inhibitor treatment ■ ■concomitant medication that prolongs QT (e.g. certain antipsychotics and anti depressants, erythromycin). Other factors that may also increase risk of QT prolongation are: ■ ■cocaine use46 ■ ■synthetic cannabinoid receptor agonist (SCRA) use47 ■ ■eating disorder or malnutrition48 ■ ■human immunodeficiency virus (HIV) positive status.48 Individuals with the risk factors listed above should have a baseline ECG and subsequent ECG monitoring. This is especially the case in in-patient settings where ECGs are easily obtained. However, where patients refuse to attend for an ECG, the risk of stopping methadone should be weighed against the risk of continuing without QT data. There is no evidence base guiding frequency following initiation. Annual checks in the absence of cardiac symptomatology would be a reasonable minimum frequency. It is also important to check the actions of any medications being prescribed with methadone for CYP3A4 inhibitory activity, to inform the risk–benefit analysis when commencing methadone. Actions following a finding of prolonged QT interval are summarised in Table 4.13. Buprenorphine Buprenorphine is a synthetic partial opioid agonist with low intrinsic activity and high affinity at mu opioid receptors. This means that it produces less euphoria even at receptor-saturating doses and simultaneously blocks the action of other opioids. It is an effective treatment for heroin and prescribed opioid addiction although no more effective

Addictions and substance misuse CHAPTER 4 than methadone.49 It is associated with lower likelihood of retention in treatment than methadone25 and clinical experience with buprenorphine suggests it can be difficult to initiate using conventional methods because of the need for sufficient withdrawal symptoms to start, but not so much withdrawal that it prevents attendance at the treatment centre. This has been addressed by novel micro- and macro-induction methods (see later). It has also been found to be effective in reducing prescription opioid use and improving treatment adherence in prescription opioid-dependent patients. Sublingual buprenorphine Buprenorphine is absorbed via the sublingual route, and this has long been the most used route of administration.50,51 Each tablet takes approximately 5–10 minutes to disintegrate, dissolve and be absorbed. It is effective in treating opioid dependence because of the following: ■ ■It alleviates/prevents opioid withdrawal and craving. ■ ■It reduces the effects of additional opioid use because of its high receptor affinity – what patients refer to as a ‘blocking’ effect.52,53 ■ ■It is long-acting, allowing daily (or less frequent) dosing. The duration of action is related to the buprenorphine dose administered: low doses (e.g. 2mg) exert effects for up to 12 hours; higher doses (e.g. 16–32mg) exert effects for as long as 48–72 hours, allowing thrice weekly dosing.54 Different brands of oral buprenorphine and bioavailability Espranor is a brand of buprenorphine that is increasingly used in UK community addictions services. Espranor is placed on the tongue, not under it. The pharmacokinetics of Table 4.13 Recommended ECG monitoring for people taking methadone. Borderline prolonged QTc Action Prolonged QTc Action Very prolonged QTc Action Females ≥470ms Repeat ECG Electrolytes Try to modify QT risk factors, e.g. cocaine use, SCRA use, methadone dose, psychotropic medications Regular ECG until normal ≥500ms Repeat ECG Electrolytes Try to modify QT risk factors Seek cardiology and addictions advice Reduce methadone dose If long QTc despite reduction, switch to buprenorphine Regular ECGs until normal ≥550ms Urgent cardiology and addictions advice Repeat ECG Electrolytes Try to modify QT risk factors Reduce methadone and re-evaluate within the week; switch to buprenorphine in in-patient setting Males ≥440ms SCRA, synthetic cannabinoid receptor agonist.

508 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 buprenorphine show quite wide inter-individual variation and this variability is accommodated by titrating people against their personal therapeutic response. Table 4.14 shows the conversion from buprenorphine or other brands of buprenorphine to Espranor, based on clinical experience. Given the uncertainty regarding dose equivalence, it is prudent not to switch between brands without good cause. Conventional buprenorphine induction The same principles apply as for methadone initiation. Proof of recent use is more difficult for buprenorphine because it is not included in standard multiple urine drug testing kits. It is commonly identified using a separate urine drug screen kit, which is not usually available outside addiction services. Therefore, collateral information from the addiction service or the dispensing pharmacy is essential if continuing buprenorphine in a non-specialist setting. Of particular interest with buprenorphine is the phenomenon of precipitated withdrawal. Precipitated withdrawal occurs because buprenorphine is a partial agonist with a high receptor affinity. If it enters the brain when a full agonist (e.g. methadone or heroin) is still present it competes for binding at the opioid receptors and replaces the full agonist. Some receptors previously fully stimulated become partly stimulated. The patient experiences this change as opioid withdrawal. However, if the patient is already in withdrawal, they will experience the addition of a partial agonist as relief of that withdrawal. Patient education is an important factor in reducing the problems during induction. To summarise, buprenorphine is a partial agonist with higher affinity for opioid receptors than pure agonists. If given to someone with high occupancy of opioid receptors by full agonists, the net effect will be a reduction in agonist activity and withdrawal symptoms may result. If receptor occupancy by pure agonists is so low that withdrawal symptoms are already evident, then giving buprenorphine will have the effect of increasing overall opioid receptor stimulation and withdrawal symptoms will abate. When a full agonist is given to someone maintained on buprenorphine, the net effect is usually nothing: buprenorphine cannot be dislodged by lower affinity agonists. This is the ‘blocking effect’ of buprenorphine. Adding a full agonist to buprenorphine does not Table 4.14 Conversion from buprenorphine to Espranor. Buprenorphine sublingual Espranor orodispersible 8mg 6mg 10mg 8mg 12mg 10mg 14/16mg 12mg 18mg 14mg 20/22mg 16mg

26mg 18mg

Addictions and substance misuse CHAPTER 4 (and indeed could not) precipitate withdrawal. This may seem obvious, but the belief that agonists can provoke withdrawal is apparently widely held. The initial dose recommendations are as follows:8 ■ ■Patient in withdrawal and no risk factors: 8mg buprenorphine. ■ ■Patient not experiencing withdrawal and no risk factors: 4mg buprenorphine. ■ ■Patient has concomitant risk factors (e.g. medical condition, polydrug use, low or uncertain severity of dependence, psychiatric medications): 2–4mg buprenorphine. No more than 8mg buprenorphine should be given on the first day in a non-specialist setting. In some cases, 8mg may be sufficient, but this may need to be increased to 12–16mg the following day if there is no evidence of intoxication. The doses can be given in divided doses so that they can be reviewed promptly in the event of any intoxication, although in practice this is difficult in the absence of on-site dispensing. For maintenance, the ‘Orange Book’8 recommends a dose between 12 and 24mg a day. If patients are on other respiratory depressants such as benzodiazepines, the patient should be monitored for intoxication and respiratory depression. Low-dose induction for buprenorphine initiation In North America, the fentanyl epidemic has led to the development of innovations to facilitate initiation of buprenorphine. These include a low-dose induction technique that involves a slower titration of buprenorphine in a patient who is still actively using full opioid agonists and is not in withdrawal.55 The protocols are similar to those discussed later in the section on methadone to buprenorphine transfer. Prolonged-release buprenorphine injection A prolonged-release subcutaneous buprenorphine injection (trade name Buvidal in the UK and EU, Sublocade and others in the USA and Australia) is licensed in the UK in weekly and monthly injectable form (Table 4.15). In Australia, the proportion of patients prescribed buprenorphine in depot form has grown from around 4% in 2019 to around 50% in 202251 and expansion of the use of buprenorphine long-acting injections is part of the 10-year drug strategy in England.50 Table 4.15 Conventional sublingual buprenorphine daily treatment doses and recommended corresponding doses of weekly and monthly Buvidal. Dose of daily sublingual buprenorphine Dose of weekly Buvidal Dose of monthly Buvidal 2–6mg 8mg 8–10mg 16mg 64mg 12–16mg 24mg 96mg 18–24mg 32mg 128mg

510 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Buprenorphine depot injection offers the same benefits as sublingual buprenorphine. It has a sustained release, and some patients find it reduces the noticeable peaks and troughs experienced on sublingual buprenorphine. Contraindications to prolonged- release buprenorphine injection are: ■ ■Hypersensitivity or allergy to active substance or excipients. ■ ■Severe hepatic impairment. ■ ■Alcohol dependence and delirium tremens. Adverse effects relate in the main to the delivery of the medication, with injection site reactions (pain, a lump) being the most common. Long-acting buprenorphine may be more effective than sublingual buprenorphine. While early randomised controlled trials (RCTs) tested non-inferiority to sublingual buprenorphine, a recent trial testing superiority of Sublocade found superior retention, higher odds of early remission from opioid use disorder, reduced or absent craving and better clinician- and patient-reported outcomes for depot buprenorphine.56 Sustained abstinence rates following buprenorphine depot medication were around 70% at 18 months. The longer the period on buprenorphine depot, the greater the proportion of patients who sustained abstinence.57 Transferring from methadone to buprenorphine This should usually be done under the supervision of a specialist prescriber. Patients transferring from methadone are at risk of experiencing precipitated withdrawal symptoms that may continue at some level for 1–2 weeks. Available evidence, albeit of low quality, suggests that conventional methods, which involve stopping methadone either at the stable dose or following a fixed or flexible taper of methadone, are successful in the majority of cases.58 Failure is associated with a methadone dose of

60mg per day. Recently, different techniques have been tried to facilitate transfer without the need for precipitating withdrawal. These include: ■ ■Bridging techniques, using opioids such as oxycodone or non-opioids such as ketamine.59 ■ ■Low-dose induction of buprenorphine, where buprenorphine is slowly titrated to a therapeutic dose while methadone remains at 100% of starting dose, with methadone tapered subsequently.60 Conventional transfer: transferring from methadone dose <40 mg to buprenorphine Methadone should be ceased abruptly, and the first dose of buprenorphine given at least 24 hours after the last methadone dose. The following conversion rates at the start of treatment are recommended but higher buprenorphine doses may be subsequently needed depending on clinical presentation (Table 4.16).

Addictions and substance misuse CHAPTER 4 Transferring from methadone 40–60mg to buprenorphine Either immediately stop methadone and transfer directly to buprenorphine, or taper to 30mg methadone following a fixed or patient-led plan (evidence does not favour one over the other58). The first buprenorphine dose is usually delayed until the patient displays clear signs of withdrawal, generally 48–96 hours after the last dose of methadone. An initial dose of 2–4mg should be given. The patient should then be reviewed 2–3 hours later. If withdrawal has been precipitated or worsened, further symptomatic medication can be prescribed. If there has been no precipitation or worsening of withdrawal, an additional 2–4mg of buprenorphine can be given on the same day. The patient should be reviewed the following day at which point the dose should be increased to between 8 and 12mg. Alternatively, a technique of continuing to increase the buprenorphine on day 1 until withdrawal symptoms subside has also been reported as successful in a case report, but this relies on high levels of trust in the therapeutic relationship.61 Transferring from methadone doses >60mg to buprenorphine Such transfers should not be attempted in an out-patient setting except in exceptional circumstances by an experienced practitioner. Usually, patients would be partially detoxified from methadone and transferred to buprenorphine when the methadone was at or below 30mg daily. However, if transfer from higher dose methadone to buprenorphine is required, a referral to a dedicated addictions in-patient unit should be considered where possible. Transfer from low-dose methadone to buprenorphine Case series of low-dose induction using varying protocols has been reported (Table 4.17). Most are in-patient based, although there is some evidence that it can also be done in the community with remote monitoring.62 Protocols using transdermal buprenorphine patches initially or alongside sublingual buprenorphine have also been published.63 The schedules for reducing methadone following establishment of therapeutic doses of buprenorphine also vary widely, some suggesting a dead stop from 100% original dose and some a rapid reduction (e.g. reduce to 50%, then stop). Few studies report withdrawal phenomena in detail or how these relate to the pharmacokinetics of the two opioids. Table 4.16 Transferring from methadone to oral buprenorphine. Last methadone dose Day 1: initial buprenorphine dose Day 2: buprenorphine dose 20–40mg 4mg 6–8mg 10–20mg 4mg 4–8mg 1–10mg 2mg 2–4mg

512 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Transferring from prescription opioids to buprenorphine Evidence is accruing in the treatment of prescribed opioid dependence with buprenorphine. Buprenorphine improves adherence to drug treatment and reduces prescription opioid misuse.68 In the UK, the ‘Orange Book’ recommends that small divided doses are given to establish the dose required for stabilisation.59 Less than daily dosing with buprenorphine Buprenorphine is licensed in most countries as a medication to be taken daily. International evidence and experience indicate that many clients can be comfortably maintained on one dose every 2–3 days.54,69 This has been considered pertinent for patients in buprenorphine treatment who are considered unsuitable for take-away medication because of the risk of diversion but it may well be replaced by long-acting formulations. The following conversion rate is recommended: ■ ■2-day buprenorphine dose = 2 x daily dose of buprenorphine (to a max. 32mg) ■ ■3-day buprenorphine dose = 3 x daily dose of buprenorphine (to a max. 32mg) In the event of patients being unable to stabilise comfortably on buprenorphine (often those transferring from methadone), the option of transferring to methadone Table 4.17 Example protocols for transition from low-dose methadone to buprenorphine. Daily dose (mg) Study Day 1 3 5 7 9 Terasaki et al. 201964 0.5 0.5 twice daily 1 twice daily 4 twice daily 8+4 Titrate Tay Wee Teck et al. 202162 0.4 0.4 0.8 1.2 1.6 1.6 4 8–12 Weimer et al. 202165 ≈0.5 once daily (buccal 0.225 twice daily) ≈0.5 twice daily (buccal 0.225 twice daily) ≈1 twice daily (buccal 0.45 twice daily) 2 twice daily 4 twice daily 4 three times a day 4–8 twice daily Bhatraju et al. 202266 0.5 once daily 0.5 twice daily 1 twice daily 2 twice daily 4 twice daily 8+4 8 twice daily Anderson et al. 202367 0.5 once daily 0.5 twice daily 1 twice daily 2 twice daily 3 twice daily 4 twice daily 6 twice daily 8 twice daily 12/8 12/8

Addictions and substance misuse CHAPTER 4 should be available. Methadone can be commenced 24 hours after the last buprenorphine dose. Doses should be titrated cautiously according to clinical response, being mindful of the residual ‘blockade’ effect of buprenorphine, which may last for several days, meaning that methadone toxicity can occur in a delayed manner. Cautions with buprenorphine Intoxication Buprenorphine should normally not be given to any patient showing signs of intoxication, especially due to alcohol or other depressant drugs (e.g. benzodiazepines, sedating antipsychotics, pregabalin). Buprenorphine in combination with other sedative drugs can result in respiratory depression, sedation and coma. Nonetheless, buprenorphine is usually preferred to methadone in these clinical situations. Liver function There is some evidence suggesting that high-dose buprenorphine can cause changes in liver function in individuals with a history of liver disease and can rarely cause hepatitis.70,71 Such patients should have LFTs measured before commencing with follow-up investigations conducted 6–12 weeks after commencing buprenorphine. More frequent testing should be considered in patients of particular concern (e.g. with severe liver disease). Elevated liver enzymes in the absence of clinically significant liver disease, however, does not necessarily contraindicate treatment with buprenorphine and if the patient refuses or it is practically difficult to obtain LFTs, the risk of withholding treatment should be weighed against the risk of prescribing without LFTs. Overdose with buprenorphine Buprenorphine (as a single drug in overdose) is generally regarded as safer than methadone and heroin because in experimental studies it causes no respiratory depression at up to 8mg72 and is less likely to be associated with overdose death. However, in combination with other respiratory depressant drugs the effects may be harder to manage.73 Higher than standard doses of naloxone may be needed to reverse buprenorphine overdose, with the optimal dose being between 2 and 4mg and a possible diminishing effect beyond 5mg.6,74 As a consequence, ventilator support is often required in cases where buprenorphine is contributing to respiratory depression (e.g. in polydrug overdose). Buprenorphine with naloxone (Suboxone) Suboxone is a buprenorphine/naloxone combination preparation that may reduce the risk of diversion and injection. The different sublingual and parenteral absorption profiles of buprenorphine and naloxone are the key factor. If used sublingually, the naloxone component will have a negligible effect, but buprenorphine will be absorbed and act as usual. However, if Suboxone is injected, the naloxone will have a substantial antagonist effect and will attenuate the effects of the buprenorphine and is also likely to precipitate withdrawal in opioid-dependent individuals using full opioid agonists.

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Alternative oral opioid preparations

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Injectable diamorphine

514 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Alternative oral opioid preparations Oral methadone and buprenorphine continue to be the mainstay of treatment.8 Other oral options such as slow-release oral morphine (SROM) preparations and dihydrocodeine are not licensed in the UK for the treatment of opiate dependence. These alternatives can be considered in exceptional cases where clients are unable to tolerate methadone or buprenorphine. Note the short half-life, supervision requirements and diversion potential.8 SROM preparations have been shown elsewhere in Europe to be useful as maintenance therapy in those who fail to tolerate methadone, again only for prescribing by specialised clinicians.8 A review of studies on SROM suggested that there was insufficient evidence to assess the effectiveness of this treatment.75 Injectable diamorphine There is compelling evidence supporting the use of injectable diamorphine maintenance for the treatment of patients who fail to benefit from first-line OST.76 Contemporary injectable prescribing differs from the earlier practice of prescribing unsupervised injectable opioids in that the patient must: ■ ■Attend in person for their prescribed injectable opioid maintenance treatment – daily or more frequently, according to the treatment plan. ■ ■Inject their dose under the direct supervision of a competent member of staff. ■ ■Be given no take-away injectable medication. In the UK the prescribing doctor must have a licence from the Home Office to prescribe diamorphine for opioid dependence. Oral OST is prescribed for those days when supervised injectable treatment is not available. This treatment differs from ‘injecting rooms’ – safe places with sterile equipment for people who use intravenous drugs but who are usually not in treatment – in that it is part of a holistic package of care with adjunctive psychosocial interventions. Although its cost-effectiveness has been demonstrated,77 its implementation has been limited by various factors including high set-up costs. At present, people should only be considered for injectable opioid prescribing in combination with psychosocial interventions, as part of a wider package of care. It is an option in cases where the individual has not responded adequately to oral opioid substitution treatment, where it can be supported by the necessary provisions for supervised consumption.8,78 Patients are seen for supervised injecting in a specialist facility twice a day. Doctors caring for patients who are admitted to the acute hospital on diamorphine prescription will need to consult their local policies – ordinarily a documented conversation with the prescribing community addiction psychiatrist is sufficient to continue the prescription. Where withdrawal symptoms occur on stopping OST or other opioids, Table 4.18 gives some advice on the treatment of specific symptoms.

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Prescribing psychotropic medications in patients with opiate dependence

Addictions and substance misuse CHAPTER 4 Prescribing psychotropic medications in patients with opiate dependence General psychiatrists often see and treat patients with addictions and psychiatric comorbidity. Prescribing guidelines regarding the treatment of comorbid psychiatric conditions pharmacologically can be found in the British Association of Psychopharmacology guidelines for substance misuse.79 Some general guidance is as follows: ■ ■Prescribers should be cautious about prescribing sedating medications because of the increased risk of respiratory depression. For example, pregabalin greatly increases the risk of overdose death.37,80 Pregabalin and olanzapine also appear to have an abuse liability in the opioid-dependent population.81,82 ■ ■Patients with opiate dependence suffer disproportionately from depression – about half of those entering treatment will meet the criteria for depression. They may require 20–50% higher doses of methadone than non-depressed patients to stabilise83 but stabilisation may afford remission in a majority of cases.84 There is limited clinical trial evidence of low to moderate quality regarding antidepressant use in opioid dependence which suggests that it is of limited benefit for either mood or drug use.79,84 Positive studies have largely been those using medication with varied pharmacology such as tricyclic antidepressants (TCAs).84 However, TCAs are not recommended in people with comorbid substance misuse because of their cardiotoxicity,79 although lofepramine can probably be used if available.85 The recommended approach to treatment of depression based on the evidence includes stabilising the patient on OST first, then if depression persists trying an SSRI because of their relative safety, but considering mixed pharmacology antidepressants as a second-line should the patient fail to respond.84 Sertraline is probably the drug of choice in OST-treated patients as it has limited interaction potential. Table 4.18 Treatment of withdrawal symptoms in people taking opioids. Adapted from Department of Health and Social Care (2017).8 Symptom Treatment Diarrhoea Loperamide 4mg then 2mg after each loose stool; maximum 16mg daily for up to 5 days Nausea, vomiting Metoclopramide 10mg tds for a maximum of 5 days or prochlorperazine 5mg tds or 12.5mg IM bd Abdominal cramps Mebeverine 135mg tds Agitation, anxiety and insomnia Diazepam up to 5–10mg tds when required or zopiclone 7.5mg nocte for patients with a history of benzodiazepine dependence Muscular pains and headaches Paracetamol, aspirin or non-steroidal anti-inflammatories Topical rubefacients can be helpful in relieving muscle aches from methadone withdrawal.

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Opioid detoxification andÂ reduction regimens

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Opioid withdrawal in a community setting

516 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Opioid detoxification and reduction regimens Opioid maintenance can be continued for a few weeks to almost indefinitely, depending on clinical need. Some patients are keen to detoxify after short periods of stability and other patients may decide to detoxify after longer periods on maintenance prescriptions. All detoxification programmes should be part of a care programme. Given the risk of serious fatal overdose after detoxification, services providing such treatment should educate the patient about these risks and supply them with naloxone and overdose training for emergency use. In the UK, NICE guidelines state ‘dose reduction can take place over anything from a few days to several months, with a higher initial stabilisation dose taking longer to taper’ and indicate that ‘up to 3 months is typical for methadone reduction, while buprenorphine reductions are typically carried out over 14 days to a few weeks’.86 In practice, a detoxification in the community may extend over a longer period if this facilitates the client’s comfort during the process, compliance with the care plan, continued abstinence from illicit use during detoxification and subsequent abstinence following detoxification. Detoxification in an in-patient setting may take place over a shorter time than in the community (e.g. 14–21 days for methadone and 7–14 days for buprenorphine) ‘as the supportive environment helps a service user to tolerate emerging withdrawal symptoms’.87 As in the community, stabilisation on a dose of a substitute opioid is first achieved, followed by gradual dose reduction, with additive medications judiciously prescribed for withdrawal symptoms as needed. Detoxification carries a recognised risk of relapse and fatal overdose. Therefore, if a patient is being detoxified there needs to be adequate aftercare in place, such as a rehabilitation programme and community support. For patients having emergency psychiatric or medical admissions, detoxification is not usually indicated unless with the support of specialist services and where aftercare arrangements are in place. Opioid withdrawal in a community setting Methadone withdrawal Following a period of stabilisation with methadone or a longer period of maintenance, the patient and prescriber may agree a reduction programme as part of a care plan to reduce the daily methadone dose. The usual reduction would be by 5–10mg weekly or every 2 weeks, although there can be variation in the reduction and speed of reduction. In the community setting, patient preference is the most important variable in terms of dose reduction and rate of reduction. The detoxification programme should be reviewed regularly and remain flexible to adjustments and changes, such as relapse to illicit drug use or patient anxieties about speed of reduction. Factors such as an increase in heroin or other drug use or worsening of the patient’s physical, psychological or social well-being may warrant a temporary increase or stabilisation of the dose or a slowing down of the reduction rate. Towards the end of the detoxification, the dose reduction may be slower: 1–2mg per week. A longer length of stability on maintenance treatment and prolonged reduction schedules (up to a year) substantially improve the chances of achieving abstinence.88 Buprenorphine withdrawal The same principles as for methadone apply when planning a buprenorphine detoxification regimen. Dose reduction should be gradual to minimise withdrawal discomfort (Table 4.19).

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Opioid withdrawal in a specialist addiction in-patient setting

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27 - Naltrexone in relapse prevention

Naltrexone in relapse prevention

Addictions and substance misuse CHAPTER 4 Opioid withdrawal in a specialist addiction in-patient setting Methadone Patients should have a starting dose assessment of methadone over 48 hours by a specialist in-patient team. The dose may then be reduced following a linear regimen over up to 4 weeks.86 Buprenorphine Buprenorphine can be used effectively for short-term in-patient detoxifications following the same principles as for methadone. Naltrexone in relapse prevention Trial evidence for the effectiveness of either oral or sustained-release naltrexone as a treatment for relapse prevention in opioid misusers has been inconclusive.89,90 Naltrexone was found by NICE to be a cost-effective treatment strategy in aiding abstinence from opioid misuse for those who prefer an abstinence programme, are fully informed of the potential adverse effects and benefits of treatment, are highly motivated to remain on treatment, and have a partner supporting concordance.91 Subsequently, Australian data indicated a threefold risk of mortality relative to methadone treatment following naltrexone cessation.92 Almost all of the excess mortality was associated with overdose deaths after stopping naltrexone. Close monitoring is particularly important when naltrexone is initiated because of the higher risk of fatal overdose at this and other times. Discontinuation of naltrexone is also associated with an increase in inadvertent overdose from illicit opioids. Postmortem data from Australia found that only 15.8% of those prescribed oral naltrexone had any naltrexone detected.93 Thus, supervision of naltrexone administration and careful choice of who is prescribed it (those who are abstinence-focused and motivated) are very important. Although there have been concerns about people taking naltrexone experiencing adverse effects of unease (dysphoria), depression and insomnia, potentially leading to relapse to illicit opioid use or failure to continue on treatment, real-world evidence is mixed, with two studies finding no effect of naltrexone on mood and sleep94,95 and one finding higher insomnia and distress in those patients who discontinued naltrexone.96 Initiating naltrexone Naltrexone has the propensity to cause a severe withdrawal reaction in patients who are either currently taking opioid drugs or who were previously taking opioid drugs and in whom there has not been a sufficient wash-out period before administering naltrexone. Table 4.19 A suggested reduction regimen for buprenorphine. Daily buprenorphine dose Reduction rate Above 16mg 4mg every 1–2 weeks 8–16mg 2–4mg every 1–2 weeks 2–8mg 2mg per week or fortnight Below 2mg 0.4–0.8mg per week

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28 - Pain control in patients on OST

Pain control in patients on OST

518 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 The minimum recommended interval between stopping the opioid and starting naltrexone depends on the opioid used, duration of use and the amount taken as a last dose. Opioid agonists with long half-lives such as methadone will require a wash-out period of up to 10 days, whereas shorter acting opioids such as heroin, morphine or fentanyl may only require up to 7 days. Experience with buprenorphine indicates that a wash-out period of up to 7 days is sufficient if the final buprenorphine dose is >2mg and duration of use >2 weeks. In some cases naltrexone may be started within 2–3 days of a patient stopping (e.g. if final buprenorphine dose <2mg and duration of use <2 weeks). A test dose of naloxone (0.2–0.8mg) (which has a much shorter half-life than naltrexone) may be given to the patient as an IM dose before starting naltrexone treatment. Any withdrawal symptoms precipitated will be of shorter duration than if precipitated by naltrexone. Patients must be advised of the risk of withdrawal before giving the dose (Box 4.5). It is worth thoroughly questioning the patient as to whether they have taken any opioid-containing preparation unknowingly (e.g. over-the-counter analgesic). Dose of naltrexone An initial dose of 25mg naltrexone should be administered after a suitable opioid-free interval (and naloxone challenge if appropriate). The patient should be monitored for 4 hours after the first dose for symptoms of opioid withdrawal. Symptomatic medication for withdrawal should be available for use, if necessary, on the first day of naltrexone dosing (withdrawal symptoms may last up to 4–8 hours). Once the patient has tolerated this low naltrexone dose, subsequent doses can be increased to 50mg daily as a maintenance dose. Naltrexone is contraindicated in patients with hepatic dysfunction and liver function tests should be monitored during treatment. Pain control in patients on OST Analgesia for methadone-prescribed patients Non-opioid analgesics should be used in preference (e.g. paracetamol, non-steroidal anti-inflammatory drugs [NSAIDs]) initially where appropriate. If opioid analgesia (e.g. codeine, dihydrocodeine, morphine) is indicated due to the type and severity of Box 4.5 Important points regarding prescribing naltrexone ■ ■Ensure the recipient is fully informed of the increased risk of fatal opioid overdose. ■ ■Following detoxification and any period of abstinence, an individual’s tolerance to opioids will decrease markedly. At such a time, using opioids puts the individual at greatly increased risk of overdose. ■ ■Discontinuation of naltrexone may also be associated with an increase in inadvertent overdose from illicit opioids, emphasising the need for close monitoring and support of the client at this time.

Addictions and substance misuse CHAPTER 4 the pain then this should be titrated accordingly for pain relief in line with usual analgesic protocols. If an opioid analgesic is appropriate, a non-methadone opioid may be co-prescribed, i.e. it is not necessary to ‘rationalise’ the patient’s entire opioid requirements to one drug.97 Analgesia for buprenorphine-prescribed patients Patients taking buprenorphine will have a reduced effect of opioids including those prescribed for analgesia. While there are case reports detailing resolution of acute pain, or easier management of it, following buprenorphine discontinuation, head-to-head comparisons of stopping buprenorphine versus continuing buprenorphine show no superiority of one strategy over the other and there is no expert consensus. The British Peri-operative Pain and Addiction Interdisciplinary Network (PAIN) guidelines state that buprenorphine should be continued during periods of acute pain, for example perioperatively.98 If a patient on buprenorphine requires treatment for acute pain, non- opioid analgesia and regional anaesthetic techniques should be used and an additional opioid added if needed.98 The Australian guidelines include an option to use a more potent opioid (e.g. fentanyl) with the rationale that it may displace buprenorphine.99 The PAIN guidelines state that there is insufficient evidence to choose one full agonist over another. If standard pain approaches do not cause a resolution of the pain, consider reducing the dose of buprenorphine. The Australian guidelines state that second-line adjuvant non-opioid analgesia can also be considered such as ketamine as a potential third step.99 If buprenorphine is stopped during the period when acute pain relief is required, use of low-dose induction to re-establish buprenorphine treatment has been described as acceptable and tolerable.100,101 From an implementation perspective, it is a practical option in the acute hospital as it does not rely on careful monitoring of withdrawal severity and awareness of medications prescribed on the ‘prn’ side, both of which can be missed on a busy ward. The primary objectives during the period of acute pain are to manage the pain and avoid the consequences of withdrawal (e.g. discharge against medical advice), so it is important to maintain sufficient background medication to achieve both. Liaison with both the in-patient pain team and the local addictions services, as well as collaborative discussion with the patient, is important. In palliative care, the principles of providing analgesia in substance misusers are no different from those for other adult patients needing palliative care, although increased liaison with substance misuse services is essential. Those who are opioid-dependent may receive maintenance therapy from a substance misuse service. For the purposes of palliative care, this should be regarded as a separate prescription from that for analgesia when attending a pain clinic. During admission all medication would usually be received from the in-patient unit, but there should be a clear plan for separate follow- ups for substance misuse and symptom palliation.97 Pregabalin may be used for pain relief but there have been concerns regarding both the abuse potential of the drug81 and the potential for co-prescription of pregabalin and opioids to increase the potential for fatal overdose.102

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29 - References

References

520 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 References

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522 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 69. Amass L, et al. Alternate-day buprenorphine dosing is preferred to daily dosing by opioid-dependent humans. Psychopharmacology 1998; 136:217–225. 70. Kothadia JP, et al. Acute hepatitis after oral buprenorphine use in a heroin addict: 1838. Am J Gastroenterol 2016; 111:S881. 71. Berson A, et al. Hepatitis after intravenous buprenorphine misuse in heroin addicts. J Hepatol 2001; 34:346–350. 72. Comer SD, et al. Abuse liability of prescription opioids compared to heroin in morphine-maintained heroin abusers. Neuropsychopharmacology 2008; 33:1179–1191. 73. Hickman M, et al. The impact of buprenorphine and methadone on mortality: a primary care cohort study in the United Kingdom. Addiction 2018; 113:1461–1476. 74. Sarton E, et al. Naloxone reversal of opioid-induced respiratory depression with special emphasis on the partial agonist/antagonist buprenorphine. Adv Exp Med Biol 2008; 605:486–491. 75. Ferri M, et al. 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Nicotine and smoking cessation

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31 - Nicotine replacement therapy (NRT)

Nicotine replacement therapy (NRT)

Addictions and substance misuse CHAPTER 4 Nicotine and smoking cessation Tobacco smoking is the leading preventable cause of illness and premature death worldwide. Smoking cessation interventions are clinically and cost effective for people with and without a mental illness. In the UK, NICE recommends that every person who smokes, including those receiving community and in-patient mental healthcare, should be offered support to stop smoking. For those people who feel unable or who are unwilling to give up, they should be provided with treatment to temporarily abstain from smoking.1 NICE recommends that bupropion, nicotine replacement therapy (NRT), varenicline and nicotine-containing vaping devices should be accessible to adults who smoke.1 It advises that when combined with behavioural support, varenicline, a combination of short-acting (e.g. mouth spray, lozenges) and long-acting (e.g. skin patches) NRT, or nicotine-containing vaping devices are more likely to help people successfully stop smoking, whereas behavioural support combined with either bupropion or single NRT is less likely to help people stop smoking. A component network mental analysis to assess the comparative benefits and harms of vaping and different licensed smoking cessation pharmacotherapies found the most effective interventions were nicotine vaping devices (odds ratio [OR] 2.37), varenicline (OR 2.33), cytisine (OR 2.21) and combination NRT (OR 1.93).2 The effectiveness of smoking cessation treatments appears not to be reduced in patients with a variety of mental health problems.3 Smoking induces CYP1A2, and so stopping smoking may result in increased plasma levels of CYP1A2 substrates. See ‘Smoking and psychotropic drugs’ in Chapter 11. Nicotine replacement therapy (NRT) In the UK, NRT is licensed for smokers over the age of 12 years to help those who want to stop smoking, to reduce before stopping or during a temporary period of enforced abstinence when a person is unable to smoke. NRT is also indicated for pregnant and breastfeeding women attempting to stop smoking. Clinical guidelines in other countries recommend NRT as first-line treatment for people seeking pharmacological help to stop smoking. In recent years, vaping has become the most often used alternative to tobacco smoking in many countries. The aim of NRT in those stopping smoking is to assist the transition from cigarette smoking to complete abstinence. It may also be used for those who wish to stop vaping. This is achieved by temporarily replacing some of the nicotine obtained from tobacco cigarettes with NRT products and minimising nicotine withdrawal symptoms and the motivation to smoke. People who have stopped smoking can safely use NRT if they wish to continue using nicotine recreationally or to prevent relapse back to smoking. There are eight licensed NRT products in the UK: transdermal patches, lozenges, gum, sublingual tablets, inhalator, nasal spray, mouth spray and oral strips. All these products are General Sales List medicines and can be bought over the counter in the UK. NRT is formulated for systemic absorption through either the skin in the case of patches or the oral or nasal mucosa in the case of all the other products. This means that absorption of nicotine from NRT is much slower than nicotine from inhaling tobacco smoke and the risk of becoming addicted to NRT is lower.4

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32 - Varenicline

Varenicline

524 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Clinical effectiveness A Cochrane review of NRT suggests combination NRT (i.e. two formulations such as a patch and an oral/nasal product) is associated with higher long-term abstinence rates than using a single NRT product (risk ratio [RR] 1.27).5 Higher dose nicotine patches (25mg patches worn for 16 hours, or 21mg patches worn for 24 hours) are more likely to help people stop smoking compared with using lower dose patches (15mg patches worn for 16 hours, or 14mg patches worn for 24 hours).5 Studies with smokers from the general population suggest that each cigarette provides a smoker with approximately 1–2.9mg of nicotine, depending on the frequency and intensity of smoking.6 Findings from studies in people with schizophrenia who smoke suggest they take more frequent puffs over a shorter period of time and, as a result, extract more nicotine from cigarettes compared with those without a mental health condition.7 It is therefore plausible that these smokers may require higher doses of nicotine replacement. However, in general population studies, there is no clear evidence of superiority for higher dose NRT patches (42/44mg) over 21/22mg (24-hour) patches.5 The nicotine from oral products has to be absorbed through the cheeks, gums and back of the lips. The correct technique is to chew the gum/suck the lozenge until the taste becomes strong and then rest it between the cheek and gum. When the taste starts to fade, it is advised to repeat this process for about 20–30 minutes. Many gum users press the gum down against the (buccal) gum to increase the surface area of contact and hence the rate of nicotine absorption. Lozenges also allow sublingual absorption of nicotine but their physical size usually precludes this method unless the lozenge is broken into smaller pieces. Sublingual tablets are much smaller in size. Drinking coffee and carbonated drinks may block the absorption of nicotine from oral nicotine products.8 Preparations and dose Table 4.20 details preparations and doses of different types of NRT. Adverse effects Adverse effects from using NRT are related to the type of product and include skin irritation from patches and irritation to the inside of the mouth and coughs from oral products. Nausea may occur if the patient is still smoking. Some sleep disturbance can be expected in the early days of treatment, though this is also a symptom of nicotine withdrawal. NRT has no known pharmacokinetic interactions with psychotropic medication. Overdosing on nicotine is very rare (and usually intentional). Initial signs include nausea, vomiting, headache and diarrhoea. It has been estimated that the lower limit for causing a fatal outcome is 0.5–1g of ingested nicotine.9 Varenicline Varenicline is a selective nicotinic acetylcholine receptor partial agonist. It mimics the action of nicotine and causes a sustained release of dopamine in the mesolimbic pathway. It also blocks dopamine release resulting from subsequent nicotine intake.

Addictions and substance misuse CHAPTER 4 This means if it is taken as prescribed, any attempt to smoke a cigarette will be less pharmacologically rewarding and feel less satisfying to a smoker. Varenicline is indicated for smokers over the age of 18 who are motivated to stop smoking. It should be avoided in pregnancy and breastfeeding. In 2021, Pfizer recalled varenicline because it exceeded acceptable intake limits of a nitrosamine impurity (N-nitroso-varenicline). Generic versions of varenicline are available in some countries (e.g. USA). Clinical effectiveness A 2023 Cochrane review10 found high-certainty evidence that varenicline is more effective than placebo (RR 2.32), bupropion (RR 1.36) and single-product NRT (RR 1.25), and is similarly effective to combination NRT.11,12 Varenicline is more effective than placebo among patients with cardiovascular disease, COPD, severe mental illness, depression and HIV.10 In smokers with serious mental illness, varenicline improved the odds of stopping smoking by 4–5 times compared with placebo.13,14 There is inconclusive evidence for its effectiveness compared with placebo among people with asthma, substance use disorder and alcohol dependence.10 Table 4.20 Nicotine preparations and doses. Smoking <20 cigarettes/day Smoking >20 cigarettes/day or people who smoke within 30 minutes of waking up Topical patch 24-hour formulation (21mg, 14mg, 7mg) 16-hour formulation (25mg, 15mg, 10mg) If smoking >20 cigarettes/day use 21mg (24-hour) or 25mg (16-hour) patch. There is no difference in efficacy between 16-hour and 24-hour formulations. The 16-hour patch should be removed at bedtime. Nasal spray (0.5mg/spray) One spray in each nostril when craving; no more than twice per hour; maximum 64 sprays/day Oral spray (1mg/spray) 1–2 sprays when craving; no more than 2 sprays per episode; no more than 4 sprays/h; maximum 64 sprays/day Lozenge (1mg, 2mg, 4mg) One 1mg lozenge hourly to prevent craving One 2mg or 4mg lozenge hourly to prevent craving; usually no more than 15 lozenges/day Gum (2mg, 4mg, 6mg) One piece of 2mg hourly to prevent craving One piece of 4mg or 6mg hourly to prevent craving; no more than 15 pieces 4mg/day Inhalator (15mg) No more than 6 cartridges of 15mg/day Sublingual tablet 1–2 tablets hourly to prevent craving 2 tablets hourly to prevent craving; no more than 40 tablets/day Mouth strips (2.5mg) One strip hourly to prevent craving One strip hourly to prevent craving; no more than 15 strips/day

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33 - Cytisine

Cytisine

526 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Preparations and dose People who smoke should set a target stopping date between 1 and 2 weeks after starting varenicline treatment. Those who are not willing or able to set a target date within 1–2 weeks can start treatment and then choose their own stopping date within 5 weeks. Dosage regimens can be found in the treatment algorithm for those people making an attempt to stop smoking at the end of this section (Table 4.21). Adverse effects Very common adverse effects include nausea, strange dreams, sleep disturbance and headache, all occurring in more than 1 in 10 people. Varenicline has no known pharmacokinetic interaction with psychotropic medication. Varenicline does not significantly increase the risk of neuropsychiatric adverse events (including anxiety, depression, aggression, psychosis and suicidal behaviour) when compared with placebo or nicotine patches in patients with or without a history of psychiatric disorders.10,15 Cytisine Cytisine has a similar mechanism of action as varenicline and although it has been available as a smoking cessation aid in Eastern Europe since the 1960s, it has only latterly received marketing approval in the UK and other countries. It is indicated for smokers over the age of 18 who are motivated to stop smoking. It is contraindicated during pregnancy and breastfeeding. Clinical effectiveness A Cochrane review10 found moderate-certainty evidence that cytisine is more effective than placebo (RR 1.30) or NRT (RR 1.43). Pooled results from two studies that compared cytisine with varenicline found no significant difference between the two drugs. The review did not identify studies among people with mental illness. Preparations and dose A course of treatment lasts 25 days, which is shorter than the recommended length of treatment for NRT, varenicline and bupropion with a multiple dosing regimen. A stopping date no later than the fifth day of treatment should be aimed for. Dosage regimens can be found in the treatment algorithm for those people making an attempt to stop smoking at the end of this section (Table 4.21). Adverse effects Very common adverse effects include increased appetite, weight gain, dizziness, irritability, mood changes, anxiety, drowsiness, fatigue, abnormal dreams, tachycardia, hypertension, dry mouth and nausea, although the latter may be less common than in patients taking varenicline and more common than in those using NRT. The SPC states that cytisine should not be used with antituberculous drugs.

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Bupropion

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35 - Electronic nicotine vaping devices and vaping

Electronic nicotine vaping devices and vaping

Addictions and substance misuse CHAPTER 4 Bupropion Bupropion is an antidepressant with dopaminergic and adrenergic actions and is additionally an antagonist at the nicotinic acetylcholine receptor. It is indicated for smokers over the age of 18 who are motivated to stop smoking. Clinical effectiveness A Cochrane review16 found high-certainty evidence that bupropion is more effective than placebo (RR 1.60). Bupropion was of similar efficacy to single-product NRT and less effective for quitting compared with varenicline and combination NRT. In smokers with serious mental illness, bupropion improved the odds of stopping by 3–4 times compared with placebo.13,14 Preparations and dose People who smoke should set a target stopping date in the first 2 weeks of starting bupropion treatment. Dosage regimens can be found in the treatment algorithm for those people making an attempt to stop smoking at the end of this section (Table 4.21). Adverse effects Bupropion is contraindicated in those with seizure disorders, eating disorders and alcohol dependence. Clinicians should be cautious of the potential for manic switch in patients with bipolar affective disorder (very low risk but it can occur17). Common adverse effects include dizziness, taste changes, gastrointestinal disturbance and insomnia, which can be reduced by avoiding a dose close to bedtime. Unlike NRT and varenicline, bupropion is known to interact with psychotropic medicines. It is metabolised by the cytochrome CYP2B6. Caution is advised when bupropion is co-administered with medicines known to induce (e.g. carbamazepine, phenytoin) or inhibit (e.g. valproate) its metabolism as this may affect the efficacy of bupropion or increase the risk of adverse effects. Bupropion and its main metabolite (hydroxybupropion) are inhibitors of the CYP2D6 enzyme. It has been shown to increase the levels of medicines metabolised by CY2D6 (e.g. imipramine, risperidone, haloperidol) and so caution is required particularly with narrow therapeutic index drugs (lower starting doses are recommended). Electronic nicotine vaping devices and vaping Also referred to as vapes (formerly known as electronic cigarettes or e-cigarettes), electronic nicotine vaping devices produce an inhalable aerosol (vapour) which is formed by heating an e-liquid using a battery-powered heating coil. Vaping devices are activated by a switch or by suction as the user draws on the device’s mouthpiece. They do not contain tobacco, are not combusted and do not produce smoke or sidestream vapour. Regulation of vaping devices varies across different countries and states, ranging from total bans to the absence of regulation. In the UK and European Union there are controls on quality standards (e.g. ingredients, packaging and advertising) and manufacturers have to notify the competent authority in each country (the MHRA in the UK) of the ingredients in nicotine vaping devices before they are placed on the market. Notified nicotine-containing vaping devices can only be sold to people over the age of 18 in the UK. Vaping devices

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Treatment algorithms

528 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 that do not contain nicotine are regulated by Trading Standards in the UK. The Office for Health Improvement and Disparities, NHS England and the Care Quality Commission (CQC) support the use of vaping devices in mental health in-patient settings.18–20 Clinical effectiveness Since 2013, electronic devices have been the most popular quitting aid in England. A Cochrane review of the effect of e-cigarettes for smoking cessation found high-certainty evidence that nicotine-containing vaping devices were more effective than NRT (RR 1.59) and moderate-certainty evidence that they were more effective than vaping devices without nicotine (RR 1.46).2 There is a small evidence base that they are also effective for helping people with a mental health condition reduce smoking.21 Preparations and dose The e-liquid is made up of nicotine, flavourings, propylene glycol (PG) and vegetable glycerine (VG). Single-use devices, prefilled cartridges or pods, and bottles of e-liquids are labelled with how many milligrams (mg) of nicotine there are per millilitre (mL), or as the percentage weight per volume (%w/v). In the UK, and several other countries, nicotine content ranges from zero (0%) to a maximum of 20mg/mL (or 2%). Nicotine is incorporated as freebase or nicotine salts; the latter has a lower pH than freebase nicotine, enabling a smoother throat-hit. Additionally, nicotine salts allow vaporisation at a lower temperature and enable higher nicotine levels to be inhaled,21 which may help with switching from smoking to vaping. Access to a variety of flavours can encourage the uptake of vaping as an aid to stopping smoking and vaping non-tobacco flavours is associated with increased smoking cessation in adults.22 The label on the vaping product packaging includes the ratio of VG to PG (VG/PG). PG is the carrier for the flavourings and nicotine and is also responsible for the throat-hit. VG has a natural sweetness and is responsible for the majority of aerosol (vapour). A 50/50 ratio is the most common. For smokers who miss the throat-hit or harsh feeling at the back of the throat from tobacco smoking, an e-liquid with a high PG ratio may be preferable (e.g. PG 70/VG 30). If big vapour clouds are preferred, then a high VG ratio needs to be used (e.g. PG 30/VG 70), though this is best suited to particular vaping devices (modular). Adverse effects Mouth and throat irritation, cough, headache and nausea are the most commonly reported symptoms of vaping and these subside over time. The Royal College of Physicians,23 Office for Health Improvement and Disparities22 and Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment24 advise that regulated vaping devices are a much less harmful alternative to tobacco smoking for dependent smokers and bystanders. Concurrent smoking and vaping (dual use) may not reduce the risk of adverse health effects, and people who vape should be encouraged to stop smoking completely, whereas people who have never smoked should be encouraged not to smoke or vape.22,24 Treatment algorithms Tables 4.21 and 4.22 outline treatment algorithms for people making an attempt to stop smoking and those wanting to abstain or reduce their smoking level.

Addictions and substance misuse CHAPTER 4 Table 4.21 Treatment algorithm for people making an attempt to stop smoking. First-line pharmacological treatment is combination NRT or varenicline or a nicotine-containing vaping device1 weekly by a trained tobacco-dependence treatment advisor for the duration of the attempt at stopping and for at least 4 weeks after discharge from hospital. Combination NRT Varenicline For people who smoke more than 20 cigarettes/day or who smoke within 30 minutes of waking up: Start 21mg (24-hour) or 25mg (16-hour) patch and an oral/nasal NRT product of the person’s choice Continue patch use for up to 12 weeks, aiming to reduce patch dosage every 4 weeks Continue oral/nasal product use while experiencing craving. Set target stopping date between 1 and 2 weeks of starting varenicline treatment. Start 0.5mg PO varenicline once daily on days 1–3. Increase to 0.5mg PO varenicline twice daily on days 4–7. Increase to 1mg PO varenicline twice daily on days 8–84. Consider 1mg varenicline PO twice daily for an additional 12 weeks for maintenance of abstinence in people who have successfully stopped smoking at the end of the initial 12 week course of varenicline. For people who smoke less than 20 cigarettes/day and do not smoke within 30 minutes of waking up: Start 14mg (24-hour) or 15mg (16-hour) patch and/or an oral/nasal NRT product of the person’s choice Continue patch use for up to 12 weeks, aiming to reduce patch dosage every 4 weeks Continue oral/nasal product use while experiencing craving. People who want to use a nicotine vaping device to quit should generally set a stopping date and use the device to stop in one go by replacing all their tobacco cigarettes with it as soon as possible. Alternatively, they can gradually reduce the amount of tobacco they smoke over several weeks and increase the use of the vape until they have completely switched. Similar to the use of NRT, advise the service user to start with a higher strength of nicotine. There is no contraindication to using NRT and a nicotine vaping device simultaneously (if people find this beneficial). Cytisine Set target stopping date within 5 days of starting cytisine treatment Days of treatment Recommended dosing Maximum daily dose Days 1–3 1.5mg (1 tablet) every 2 hours 9mg (6 tablets) Days 4–12 1.5mg (1 tablet) every 2.5 hours 7.5mg (5 tablets) Days 13–16 1.5mg (1 tablet) every 3 hours 6mg (4 tablets) Days 17–20 1.5mg (1 tablet) every 5 hours 4.5mg (3 tablets) Days 21–25 1.5–3mg (1–2 tablets) a day 3mg (2 tablets) Bupropion Bupropion could be considered second line or where people who smoke express a preference for bupropion therapy. Set target stopping date between 1 and 2 weeks of bupropion treatment. Start 150mg PO bupropion daily on days 1–6. Increase to 150mg PO bupropion twice daily on days 7–49 (with an interval of at least 8 hours between doses, and avoiding bedtime dosing to reduce risk of insomnia). Maintain dose at 150mg PO bupropion on days 50–63 (otherwise discontinue if person has not stopped).

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References

530 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 References

National Institute for Health and Care Excellence. Tobacco: preventing uptake, promoting quitting and treating dependence. NICE guideline [NG209]. 2021 (last updated 2023, last accessed March 2024); https://www.nice.org.uk/guidance/ng209.
Lindson N, et al. Pharmacological and electronic cigarette interventions for smoking cessation in adults: component network meta-analyses. Cochrane Database Syst Rev 2023; 9:CD015226.
Tidey JW, et al. Smoking cessation and reduction in people with chronic mental illness. BMJ 2015; 351:h4065.
Hajek P, et al. Dependence potential of nicotine replacement treatments: effects of product type, patient characteristics, and cost to user. Prev Med 2007; 44:230–234.
Theodoulou A, et al. Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2023; 6:CD013308.
Henningfield JE, et al. Pharmacotherapy for nicotine dependence. CA Cancer J Clin 2005; 55:281–299; quiz 322–323, 325.
Williams JM, et al. Increased nicotine and cotinine levels in smokers with schizophrenia and schizoaffective disorder is not a metabolic effect. Schizophr Res 2005; 79:323–335.
Henningfield JE, et al. Drinking coffee and carbonated beverages blocks absorption of nicotine from nicotine polacrilex gum. JAMA 1990; 264:1560–1564.
Mayer B. How much nicotine kills a human? Tracing back the generally accepted lethal dose to dubious self-experiments in the nineteenth century. Arch Toxicol 2014; 88:5–7.
Livingstone-Banks J, et al. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2023; 5:CD006103.
Cahill K, et al. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2016:CD006103.
Howes S, et al. Antidepressants for smoking cessation. Cochrane Database Syst Rev 2020; 4:CD000031.
Roberts E, et al. Efficacy and tolerability of pharmacotherapy for smoking cessation in adults with serious mental illness: a systematic review and network meta-analysis. Addiction 2016; 111:599–612.
Siskind DJ, et al. Pharmacological interventions for smoking cessation among people with schizophrenia spectrum disorders: a systematic review, meta-analysis, and network meta-analysis. Lancet Psychiatry 2020; 7:762–774. Table 4.22 Treatment algorithm for people not making an attempt to stop, i.e. those people temporarily abstaining or aiming to reduce their cigarette consumption. Those who are unwilling or feel unable to quit should be encouraged to minimise harm and substitute nicotine from tobacco cigarettes with either combination NRT or a vaping device Combination NRT Vaping devices For people who smoke more than 20 cigarettes/day or who smoke within 30 minutes of waking up: Start 21mg (24-hour) or 25mg (16-hour) patch and an oral/nasal NRT product of the person’s choice Continue to offer NRT products even if met with initial refusal Smokers should have fingertip control over NRT products at times of craving. The dose of nicotine a vaper extracts from a vaping device varies depending on the device, the volume of e-liquid, other ingredients in the liquid and the frequency, size and depth of inhalation. The more dependent a smoker is, the higher the strength of nicotine is recommended. A rough guide is that smokers of 20 tobacco cigarettes/ day may require up to 20mg of nicotine/day. Smokers should have fingertip control over their vaping device at times of craving. Similar to NRT, people who smoke should be encouraged to regularly use a vaping device between smoking episodes to promote smoke-free intervals. For people who smoke less than 20 cigarettes/day and do not smoke within 30 minutes of waking up: Start 14mg (24-hour) or 15mg (16-hour) patch and/or an oral/nasal NRT product of the person’s choice Continue to offer NRT products even if met with initial refusal Smokers should have fingertip control over NRT products at times of craving. There are currently no medicinally licensed nicotine vaping devices and therefore it is not possible to prescribe them in most countries. Practitioners should consult local smoke-free policies to establish which type of vaping device is permitted in individual mental health in-patient settings and how to access them.

Addictions and substance misuse CHAPTER 4 15. Anthenelli RM, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet 2016; 387:2507–2520. 16. Hajizadeh A, et al. Antidepressants for smoking cessation. Cochrane Database Syst Rev 2023; 5:CD000031. 17. Giasson-Gariepy K, et al. A case of hypomania during nicotine cessation treatment with bupropion. Addict Sci Clin Pract 2013; 8:22. 18. Care Quality Commission. Brief guide: the use of ‘blanket restrictions’ in mental health wards. 2020; https://www.cqc.org.uk/sites/default/ files/20191125_900767_briefguide-blanket_restrictions_mental_health_wards_v3.pdf. 19. Health and Social Care. Using electronic cigarettes in NHS mental health organisations. 2020; https://www.gov.uk/government/publications/ e-cigarettes-use-by-patients-in-nhs-mental-health-organisations/using-electronic-cigarettes-in-nhs-mental-health-organisations. 20. NHS England. Long term plan. 2019; https://www.longtermplan.nhs.uk/wp-content/uploads/2019/08/nhs-long-term-plan-version-1.2.pdf. 21. McNeill A, et al. Vaping in England: an evidence update including mental health and pregnancy, March 2020: a report commissioned by Public Health England. London: Public Health England. 2020; https://assets.publishing.service.gov.uk/government/uploads/system/uploads/ attachment_data/file/869401/Vaping_in_England_evidence_update_March_2020.pdf. 22. Gov.UK. Research and analysis. Nicotine vaping in England: 2022 evidence update main findings. 2022; https://www.gov.uk/government/ publications/nicotine-vaping-in-england-2022-evidence-update/nicotine-vaping-in-england-2022-evidence-update-main-findings. 23. Royal College of Physicians. Nicotine without smoke: tobacco harm reduction. A report by the Tobacco Advisory Group of the Royal College of Physicians. 2016; https://www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-tobacco-harm-reduction-0. 24. Committee on Toxicity of Chemicals in Food Consumer Products and the Environment (COT). Statement on the potential toxicological risks from electronic nicotine (and non-nicotine) delivery systems (E(N)NDS – e-cigarettes). 2020; https://cot.food.gov.uk/sites/default/files/2020- 09/COT%20E%28N%29NDS%20statement%202020-04.pdf.

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Stimulant use disorder (SUD)

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39 - Overview of treatment

Overview of treatment

532 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Stimulant use disorder (SUD) Stimulants, as a group, encompass a wide range of synthetics (amfetamine, methamphetamine, methylphenidate, mephedrone) and naturally derived substances (cocaine and crack, ephedrine, khat) broadly described as sympathomimetic. Ingestion creates characteristic euphoric effects thought to be mediated by release of the monoamines norepinephrine, serotonin and dopamine.1 Cocaine and amfetamine use are the most common with a global prevalence rate of 0.4% and 0.7%, respectively. It is estimated that dependence will develop in 16% of people using cocaine and 11% of those who use amfetamines.2 Acute intoxication and chronic use of these substances can present with cardiovascular symptoms, movement disorders and a range of psychiatric symptoms including agitation, enhanced anxiety, paranoia, panic attacks and psychosis. Associations with violent behaviour, high-risk sexual activity and the injecting of stimulants further underline the implications of stimulant use at the public health level.2–4 Tolerance and dependence can be expected to develop following regular, long-term use. For patients dependent on stimulants, a withdrawal syndrome of approximately 1 week’s duration marked by craving, fatigue, agitation, insomnia and increased appetite can follow on from abstinence.5,6 Recreationally, patterns of SUD vary from use of a single stimulant, several different stimulants and simultaneous or sequential use of drugs from different classes. Combinations of different drugs may be explored by patients as a means of shaping the overall psychoactive experience.3 Stimulant use among people with opiate use disorder is common and linked to poor engagement with opiate agonist therapy and the increased risk of overdose that follows.7,8 Overview of treatment After decades of research there are, at the time of writing, no pharmacological agents approved in the treatment of SUD.9–12 It is worth mentioning explicitly that there is also limited evidence to support the prescribing of stimulants themselves (so-called agonist replacement therapy) for patients with SUD.10,13 There is a need for rigorous, high-quality clinical trials that can overcome the historical methodological challenges.11 Stimulant use for many will be self-limiting without treatment beyond the provision of harm minimisation advice and psychoeducation. For those who use stimulants in combination with alcohol, heroin or GBL, effective treatment of the co-occurring dependency may enable reductions in stimulant use. Successful care of patients dependent on stimulants should involve a comprehensive treatment approach that includes psychosocial interventions that reflect the complexity of factors behind SUD. While a range of therapeutic modalities are recommended, there is particularly good evidence for contingency management.2,11 For many the route to abstinence is through mutual aid and peer support such as Cocaine Anonymous, Crystal Meth Anonymous or Rational Recovery. Further information on the treatment of cocaine dependence can be found in UK clinical guidelines.14 The limited effective interventions available for SUD have prompted the exploring of other treatment modalities.

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Cocaine

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Amfetamines

Addictions and substance misuse CHAPTER 4 There is a small developing evidence base for the potential of interventions based on neuromodulation such as transcranial magnetic stimulation (tMS) in SUD. This is an area of research in its early stages, without consensus on an appropriate cortical target or optimal frequency of TMS.15 An important area of consideration is the management of patients with SUD and suspected or verified attention deficit hyperactivity disorder (ADHD). As might be expected, ADHD is more common in patients with substance use disorder.16 There is limited guidance to support clinicians in making a definitive diagnosis of ADHD in this group of patients or to navigate the risk–benefit balance of commencing treatment with stimulants compared with second-line non-stimulant-based alternatives.17,18 Cocaine Cocaine is a naturally derived compound found in the coca plant. Aside from application as a topical anaesthetic, it is primarily used recreationally. Once extracted, cocaine’s properties are enhanced when processed into cocaine hydrochloride, a powdered form that is commonly insufflated (snorted). Removal of the hydrochloride creates a water- insoluble base form (freebase) known as ‘crack’ that can be smoked. Both forms of cocaine can be injected although as a freebase it must first be dissolved in an acid. An epidemiological study from 2023 suggests an increase in rates of crack injection in both England and Wales.19 Detoxification Symptoms of withdrawal include depressed mood, agitation and insomnia. These are usually self-limiting. It should be noted that given cocaine’s short half-life and the binge nature of cocaine use, many patients essentially detoxify themselves regularly, with no pharmacological therapy. Symptomatic relief such as the short-term use of hypnotics may be helpful in some, but these agents may become agents of dependence themselves for some patients.14 Substitution treatment There is little evidence for substitution therapy for the treatment of cocaine misuse and it should not usually be prescribed.1,9,11 Amfetamines Amfetamine-type substances were first synthesised in the early 20th century initially having a wide range of applications. Currently, their clinical use is restricted to the treatment of ADHD and narcolepsy.20 Amfetamine as a salt, usually amfetamine sulphate, the cathinone mephedrone and the more potent, long-acting methamphetamine are most commonly associated with significant misuse. Within a recreational context, amfetamine sulphate is known as ‘speed’ and mephedrone as ‘drone’ or ‘meow meow’; names for methamphetamine include ‘meth’, ‘crystal’ or ‘tina’. These substances can be ingested as tablets or ‘pills’, insufflated as powders and, less commonly, injected or ‘slammed’. Methamphetamine, when in its crystalline form ‘ice’, can also be inhaled.

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Polysubstance abuse

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43 - Psychosis associated with stimulant drugs

Psychosis associated with stimulant drugs

534 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Detoxification and dependence A withdrawal syndrome is common in those who are dependent. Treatment should focus on symptomatic relief, although many symptoms of amfetamine withdrawal (low mood, listlessness, agitation, irritability, fatigue, etc.) are short-lived and may not be amenable to pharmacological treatment. Insomnia can be treated with short courses of hypnotics, again noting the risk of dependence on these agents.1,9,11 A 2022 systemic review and meta-analysis observed that mirtazapine may reduce the amount of methamphetamine consumed by patients with methamphetamine use disorder.21 Polysubstance abuse In those who are dependent on opioids and cocaine, the provision of effective substitution therapy for treatment of the opioid dependence with either methadone or buprenorphine can lead to a reduction in cocaine use.14 Psychosis associated with stimulant drugs Psychotic symptoms in association with methamphetamine are related to frequency of use and severity of methamphetamine dependence.22 In many, perhaps most, cases psychotic symptoms can resolve with the resolution of intoxication – i.e. over the course of a day or so. The majority of patients attending an emergency setting with acute psychotic symptoms in the context of very recent methamphetamine use can be managed with simple sedation (e.g. diazepam 5–10mg as needed 4–6 hourly for agitation) and therapeutic rest.23 Some patients, however, may need more intensive treatment in line with the treatment of acute psychosis in Chapter 2. It should be noted that psychotic symptoms in the context of stimulant use are progressive with continued use – they tend to start earlier in each binge and to last longer. A median of 25% of patients report on-going symptoms 1 month after methamphetamine consumption.24 Psychosis in the context of intoxication is associated with persecutory delusions and tactile hallucinations, while more persistent methamphetamine-associated psychosis is characterised by delusions of persecution and auditory hallucinations and is largely indistinguishable from a primary psychotic disorder.24 In the emergency department it can be difficult to make a clear diagnosis. Between 16% and 38% of patients initially diagnosed with methamphetamine psychosis are later diagnosed as having schizophrenia.24 In the acute setting, another important differential diagnosis in methamphetamine users presenting with agitated psychosis is GBL withdrawal delirium (where stimulant/ GBL polysubstance use is prevalent). There is symptomatic overlap between stimulant intoxication – autonomic hyperactivity, agitation, hallucinations – and GBL withdrawal delirium. The latter requires higher doses of benzodiazepines and more prolonged treatment (see ‘GHB and GBL dependence’ later in this chapter). As already stated, in the emergency setting, simple sedation with benzodiazepines for agitation is often sufficient initially. If antipsychotics are indicated, the fourfold increased odds of developing extrapyramidal side effects (EPSEs) in patients who use methamphetamine should be borne in mind.25 Agents with a low propensity to cause EPSEs should be used and there is evidence for efficacy of olanzapine. Aripiprazole may be preferred for rapid tranquillisation as olanzapine and benzodiazepines

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Stimulant-associated depression

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45 - References

References

Addictions and substance misuse CHAPTER 4 cannot be co-administered. Haloperidol should not be used because of the risk of dystonia. Early review regarding continuation is important as for most patients their symptoms resolve within 2 or 3 weeks, and there is no evidence to support the benefit of prophylactic prescription of antipsychotics in methamphetamine-related psychosis.26 Stimulant-associated depression Anhedonia can be profound in early abstinence from stimulants. For many, low mood will resolve in line with duration of abstinence and supportive psychosocial interventions.19 For those in whom it endures psychological treatments are effective but may be difficult for addiction patients to access because of institutional barriers.2 Antidepressants have primarily been evaluated as treatment for the substance dependence itself, with depression as a secondary outcome. There is some evidence for TCAs in reducing depressive symptoms.27 However, TCAs are not recommended in those with on-going comorbid substance misuse because of their cardiotoxicity.28 There is no evidence to support the use of SSRIs and indeed these are associated with significant interactions with stimulants19 and increased disengagement.2 References

Murnane KS, et al. Selective serotonin 2A receptor antagonism attenuates the effects of amphetamine on arousal and dopamine overflow in non-human primates. J Sleep Res 2013; 22:581–588.
Farrell M, et al. Responding to global stimulant use: challenges and opportunities. Lancet 2019; 394:1652–1667.
United Nations Office on Drugs and Crime. Treatment of stimulant use disorders: current practices and promising perspectives. United Nations Office on Drugs and Crime Vienna, Austria. 2019 (last checked May 2024); https://www.unodc.org/documents/drug-prevention- and-treatment/Treatment_of_PSUD_for_website_24.05.19.pdf.
Moradi S, et al. The association between methamphetamine use and number of sexual partners in men who have sex with men: a systematic review and meta-analysis. Subst Abuse Treat Prevention Policy 2022; 17:27.
Substance Abuse and Mental Health Services Administration (SAMHSA). Treatment of stimulant use disorders. SAMSHA publication PEP 20-06-01-001. 2020; https://store.samhsa.gov/sites/default/files/pep20-06-01-001.pdf.
McGregor C, et al. The nature, time course and severity of methamphetamine withdrawal. Addiction 2005; 100:1320–1329.
Mintz CM, et al. Analysis of stimulant prescriptions and drug-related poisoning risk among persons receiving buprenorphine treatment for opioid use disorder. JAMA Netw Open 2022; 5:e2211634.
Cicero TJ, et al. Polysubstance use: a broader understanding of substance use during the opioid crisis. Am J Public Health 2020; 110:244–250.
Siefried KJ, et al. Pharmacological treatment of methamphetamine/amphetamine dependence: a systematic review. CNS Drugs 2020; 34:337–365.
Bahji A, et al. Navigating evidence, challenges, and caution in the treatment of stimulant use disorders. Brain Sci 2023; 13:1416.
Ronsley C, et al. Treatment of stimulant use disorder: a systematic review of reviews. PLoS One 2020; 15:e0234809.
Liu MT. Pharmacotherapy treatment of stimulant use disorder. Ment Health Clin 2021; 11:347–357.
Stoops WW, et al. Agonist replacement for stimulant dependence: a review of clinical research. Curr Pharm Des 2013; 19:7026–7035.
Department of Health and Social Care. Drug misuse and dependence: UK guidelines on clinical management. 2017; https://www.gov.uk/ government/publications/drug-misuse-and-dependence-uk-guidelines-on-clinical-management.
Edinoff AN, et al. Transcranial stimulation for the treatment of stimulant use disorder. Neurol Int 2023; 15:325–338.
Rohner H, et al. Prevalence of attention deficit hyperactivity disorder (ADHD) among substance use disorder (SUD) populations: meta- analysis. Int J Environ Res Public Health 2023; 20:1275.
Ward B, et al. Managing adult attention-deficit/hyperactivity disorder with comorbid substance use disorder. Can J Addict 2023; 13:6–12.
Levin FR. Diagnosing attention-deficit/hyperactivity disorder in patients with substance use disorders. J Clin Psychiatry 2007; 68 Suppl 11:9–14.
Edmundson C, et al. Recent increases in crack injection and associated risk factors among people who inject psychoactive drugs in England and Wales. Int J Drug Policy 2023:104262.
Heal DJ, et al. Amphetamine, past and present – a pharmacological and clinical perspective. J Psychopharmacol 2013; 27:479–496.
Naji L, et al. Mirtazapine for the treatment of amphetamine and methamphetamine use disorder: a systematic review and meta-analysis. Drug Alcohol Depend 2022; 232:109295.
Arunogiri S, et al. A systematic review of risk factors for methamphetamine-associated psychosis. Aust NZ J Psychiatry 2018; 52:514–529.

536 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 23. Isoardi KZ, et al. Methamphetamine presentations to an emergency department: management and complications. Emerg Med Australas 2019; 31:593–599. 24. Voce A, et al. A systematic review of the symptom profile and course of methamphetamine-associated psychosis(substance use and misuse). Subst Use Misuse 2019; 54:549–559. 25. Temmingh HS, et al. Methamphetamine use and antipsychotic-related extrapyramidal side-effects in patients with psychotic disorders. J Dual Diagn 2020; 16:208–217. 26. Shoptaw SJ, et al. Treatment for amphetamine psychosis. Cochrane Database Syst Rev 2009; 1:CD003026. 27. Pani PP, et al. Antidepressants for cocaine dependence and problematic cocaine use. Cochrane Database Syst Rev 2011; 12:CD002950. 28. Lingford-Hughes AR, et al. BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP. J Psychopharmacol 2012; 26:899–952.

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GHB and GBL dependence

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47 - The withdrawal syndrome1,2

The withdrawal syndrome1,2

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48 - Withdrawal management

Withdrawal management

Addictions and substance misuse CHAPTER 4 GHB and GBL dependence Gamma-hydroxybutyrate (GHB) and gamma-butyrolactone (GBL, a pro-drug of GHB) are colloquially often referred to as ‘G’. They reduce anxiety and produce disinhibition and sedation, primarily through actions at the GABA-B receptor. These drugs are used recreationally for socialising and occasionally to aid sleep. Among men who have sex with men (MSM) they can be used, often alongside stimulants such as mephedrone and crystal methamphetamine, to facilitate sex in the context of potential high-risk sexual behaviour (‘chemsex’). Both GHB and GBL have a narrow therapeutic index and overdose is not uncommon. Dependence is rare, but in dependent users withdrawal has a rapid onset and can produce severe delirium with paranoid delusions and life-threatening complications.1 The withdrawal syndrome1,2 Dependent users take doses ‘round the clock’ (consuming doses day and night, typically every 1–3 hours). The onset of withdrawal symptoms occurs a few hours following the last dose. This withdrawal syndrome is similar to alcohol withdrawal and may include symptoms such as tachycardia, insomnia, anxiety, sweating and fine tremors.1 Untreated, it can progress to agitated delirium, often with psychotic features (including paranoid delusions and hallucinations) later followed by severe tremors, muscle rigidity and seizures.1 Muscle rigidity may be so severe as to produce fever, rhabdomyolysis and acute renal failure. The requirement for medication to manage symptoms eases over 4–6 days, although there are case reports of more prolonged withdrawal. Withdrawal management The evidence base for detoxification is limited. The core principle of managing withdrawal is to treat early and so prevent the development of delirium and other complications. Once established, delirium can be difficult to control.3 Early treatment with benzodiazepines is required, and baclofen (a GABA-B agonist) and phenobarbital have also been used effectively as adjunctive medications.1,4 Antispychotic drugs are used in some countries.5 Baclofen is freely available online and may be obtained by users for unsupervised withdrawal,6 something which, given the dangers involved in withdrawal, should be unequivocally discouraged. There is as yet no validated screening tool to determine when patients should receive pharmacological treatment for withdrawal symptoms. However, two case reports suggest that the CIWA-Ar scale can be used in the assessment of patients withdrawing from GHB.7,8 GHB itself has also been successfully used to aid withdrawal9 with reducing doses given every 3 hours over up to 2 weeks. Pharmaceutical GHB may be more effective than benzodiazepines in managing withdrawal.10 GHB and GBL misuse is uncommon but medically important because, in dependent users, withdrawal can proceed rapidly to life-threatening agitated delirium. Complications include seizures, bradycardia, cardiac arrest and renal failure. Professionals in acute and psychiatric hospitals need to be able to recognise and manage acute withdrawal.

538 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Box 4.7 Management of planned elective withdrawal Setting ■ ■All patients undergoing planned withdrawal should be medically supervised ■ ■Ambulatory community detoxification should be attempted only where there is no history of delirium or psychosis. A responsible third party should be at home who is able to monitor and support the withdrawal process. There should be the option of transferring the patient to an in-patient unit if symptoms are not well controlled For up-to-date guidance on the management of GHB/GBL withdrawal, it is recommended in the UK that information be sought from the National Poisons Information Service (NPIS),11 specifically the NPIS 24-hour telephone service and the poisons information database TOXBASE.12 The two scenarios with which clinicians should be conversant are unplanned acute withdrawal (Box 4.6) and planned elective withdrawal (Box 4.7). Box 4.6 Management of unplanned acute withdrawal Setting ■ ■Acute unplanned withdrawal is a medical emergency and should be managed in the acute hospital inpatient setting ■ ■Severe withdrawal may require admission to ICU Initial pharmacotherapy ■ ■Initiate diazepam 20mg PO as soon as withdrawal symptoms are observed ■ ■Diazepam can be repeated at 30 minutes to 4-hourly intervals until symptoms are controlled ■ ■Most cases of GBL withdrawal require 60–80mg diazepam in the first 24 hours ■ ■Higher daily dosages of up to 300mg PO diazepam may be necessary ■ ■If on assessment the patient is drowsy, withhold diazepam dose, monitor respiratory signs and review once sedation attenuates ■ ■One-to-one nursing care may assist in managing severe cases ■ ■If there are concerns about the level of drowsiness from treatment with benzodiazepines then early discussion with anaesthetics/ICU team is advised to consider need for airway support ■ ■From day 2 a tapering regimen of diazepam is started based on the total diazepam administered in the first 24 hours Ajunctive pharmacotherapy ■ ■Initiate baclofen 10mg PO tds in combination with benzodiazepine withdrawal regimen where benzodiazepines prove inadequate ■ ■This can be titrated to 20mg PO tds in cases of continued anxiety and agitation ■ ■In cases of severe withdrawal consider addition of phenobarbital in doses of 150–450mg/day oral or IV* (ICU only)13 ■ ■In cases where severe withdrawal remains uncontrolled, IV anaesthetics such as propofol* may be required (ICU only) ■ ■Thiopental* coma has also been used in severe resistant withdrawal10 *The respiratory depressant effects of phenobarbital, thiopental and propofol cannot be reversed; facilities for mechanical ventilation should be available. GBL, gamma-butyrolactone; ICU, intensive care unit; PO, by mouth; tds, three times a day.

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References

Addictions and substance misuse CHAPTER 4 References

Kamal RM, et al. Pharmacological treatment in gamma-hydroxybutyrate (GHB) and gamma-butyrolactone (GBL) dependence: detoxification and relapse prevention. CNS Drugs 2017; 31:51–64.
Bell J, et al. Gamma-butyrolactone (GBL) dependence and withdrawal. Addiction 2011; 106:442–447.
Abdulrahim D, et al. Textbook of Clinical Management of Club Drugs and Novel Psychoactive Substances: NEPTUNE Clinical Guidance. Cambridge: Cambridge University Press; 2022.
LeTourneau JL, et al. Baclofen and gamma-hydroxybutyrate withdrawal. Neurocrit Care 2008; 8:430–433.
Siefried KJ, et al. Inpatient GHB withdrawal management in an inner-city hospital in Sydney, Australia: a retrospective medical record review. Psychopharmacology (Berl) 2023; 240:127–135.
Floyd CN, et al. Baclofen in gamma-hydroxybutyrate withdrawal: patterns of use and online availability. Eur J Clin Pharmacol 2018; 74:349–356.
Liao PC, et al. Clinical management of gamma-hydroxybutyrate (GHB) withdrawal delirium with CIWA-Ar protocol. J Formos Med Assoc 2018; 117:1124–1127.
Habibian S, et al. Successful management of gamma-hydroxybutyrate (GHB) withdrawal using baclofen as a standalone therapy: a case report. J Addict Med 2019; 13:415–417.
Dijkstra BA, et al. Detoxification with titration and tapering in gamma-hydroxybutyrate (GHB) dependent patients: the Dutch GHB monitor project. Drug Alcohol Depend 2017; 170:164–173.
Beurmanjer H, et al. Tapering with pharmaceutical GHB or benzodiazepines for detoxification in GHB-dependent patients: a matched- subject observational study of treatment-as-usual in Belgium and the Netherlands. CNS Drugs 2020; 34:651–659.
National Poisons Information Service. 2024; https://www.npis.org.
TOXBASE®. 2024; https://www.toxbase.org.
Freeman G, et al. Phenobarbital to manage severe gamma-hydroxybutyrate withdrawal: a case series. Drug Alcohol Rev 2023; 42:27–32. Pre-withdrawal ■ ■Discuss treatment plan with the patient and person who will be supporting them ■ ■Encourage patient to keep a week-long diary of GBL use including dose frequency and quantity ■ ■Encourage patient to cease ‘on-top’ drug use such as mephedrone and crystal methamphetamine before elective withdrawal ■ ■Start baclofen 10mg PO tds 3–7 days before target withdrawal date ■ ■Encourage patients to reduce GBL dose as much as tolerable either by reducing each dose by 0.1mL every 1–2 days or increasing the time period between doses Withdrawal ■ ■On day 1 of planned ambulatory withdrawal, ask patient to attend having used no GBL for a minimum of 2 hours, and advise them to dispose of their remaining supplies of GBL ■ ■Advise patients they will need to stay at the clinic for up to 4 hours on day 1, that they cannot drive motor vehicles during withdrawal, and should not drink alcohol or take other sedatives during withdrawal ■ ■Increase baclofen to 20mg PO tds ■ ■Initiate benzodiazepine treatment once signs and symptoms of withdrawal develop – tachycardia, sweaty palms, fine tremor and anxiety. Start diazepam 20mg, review after 2 hours and monitor for anxiety/sedation/respiratory depression. Repeat up to 20mg PO diazepam if indicated ■ ■Once 6 hours have passed since last GBL usage the patient may be given up to a further 40mg diazepam, and then seen daily on the following 2 days ■ ■At each daily visit, review diazepam dosage and titrate to symptoms. Diazepam is seldom needed beyond 7 days. Typical initial daily doses of diazepam are around 40–60mg/day Post-withdrawal ■ ■Continue baclofen 20mg PO tds following benzodiazepine withdrawal, reducing over 4–6 weeks. One of the few trials in this area successfully used 45–60mg a day for 3 months for relapse prevention11 ■ ■After withdrawal, persisting anxiety and insomnia are common, and there is a high risk of relapse. Before initiating elective withdrawal management, a plan should be in place to monitor and support patients for a minimum of 4 weeks to minimise risk of relapse GBL, gamma-butyrolactone; PO, by mouth; tds, three times a day.

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50 - Benzodiazepine misuse

Benzodiazepine misuse

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51 - Withdrawal management

Withdrawal management

540 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Benzodiazepine misuse Benzodiazepine prescribing reached its peak during the 1960s and 1970s. Prescriptions that were originally started for disorders such as anxiety, depression and insomnia were often continued long term and led to the development of dependence. Benzodiazepines are still widely used in the USA: 5.2% of adults were prescribed a benzodiazepine in 2008,1 just over 4% in 2018 and just less than 4% in 2021.2 There are a growing number of novel or ‘designer’ illicit benzodiazepines (e.g. diclazepam, etizolam, flualprazolam, flunitrazolam and norfludiazepam). There is limited information available about the health consequences and social harms of these substances, but they are likely to be similar to or worse than the established benzodiazepines.3 As well as being prescribed, benzodiazepines can be acquired via the illicit market, diversion of prescriptions and internet purchasing (thought to be a rising trend).4,5 Benzodiazepine dependence can be thought of as either iatrogenic (low daily doses prescribed over many years) or non-iatrogenic (high doses, illicitly obtained, often consumed intermittently). Withdrawal management The UK NICE guideline on safe prescribing and withdrawal management of medicines associated with dependence recommends a shared decision-making approach with the individual.6 Detailed information regarding benefits of discontinuation, the withdrawal process and possible symptoms should be discussed over the course of regular scheduled reviews. Withdrawal from benzodiazepines usually involves conversion to an equivalent dose of diazepam because its long duration of action may mitigate withdrawal symptoms. Dose reduction recommendations include: ■ ■Gradual reduction rather than abrupt discontinuation.6 ■ ■‘Slow, step-wise rate of reduction proportionate to the existing dose, so that decrements become smaller as the dose is lowered’ (unless there is clinical risk and rapid withdrawal is needed).6 ■ ■Individualise according to the drug, dose, duration of treatment, history of dependence, withdrawal symptoms and re-emergence of underlying conditions (such as anxiety or insomnia). ■ ■Withdrawal over a period of less than 6 months is appropriate for some patients.7 ■ ■Some guidelines suggest a reduction of about one-eighth of the daily dose every 2 weeks.8 ■ ■If reduction is unsuccessful aim to review regularly, stop further escalation in dose and consider reduction again later. Additional interventions are given in Table 4.23.

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52 - Polysubstance use

Polysubstance use

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53 - Pregnancy and benzodiazepine misuse

Pregnancy and benzodiazepine misuse

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54 - Summary

Summary

Addictions and substance misuse CHAPTER 4 Polysubstance use Illicit benzodiazepines are often used in addition to a primary substance of abuse. People with non-iatrogenic benzodiazepine dependence often consume doses greater than 100mg diazepam equivalent a day. There is no evidence that substitute prescribing of benzodiazepines ultimately reduces benzodiazepine misuse. Benzodiazepine dependence as part of polysubstance dependence should also be treated by a gradual withdrawal of the medication. Benzodiazepines prescribed at greater than 30mg diazepam equivalent per day may cause harm8 and so this should be avoided if at all possible. Pregnancy and benzodiazepine misuse Benzodiazepines are not major human teratogens but should ideally be gradually discontinued before a planned pregnancy. If a woman is prescribed benzodiazepines and found to be pregnant, the prescription should be gradually withdrawn over as short a time as possible, being mindful of the risk of withdrawal seizures and the potential consequences for the pregnant woman and fetus. A risk–benefit analysis should be undertaken and specialist advice sought (see pregnancy section in Chapter 7). As for all patients, it may be appropriate for a woman dependent on benzodiazepines to be stabilised on diazepam before any dose reduction.8 Summary ■ ■Benzodiazepines should be withdrawn using a hyperbolic tapering schedule (Table 4.24). ■ ■Discontinuation can sometimes be completed within 6 months. ■ ■Switching to an equivalent dose of diazepam before withdrawal is commonplace but not always effective. Table 4.23 Psychosocial and pharmacological interventions in benzodiazepine withdrawal. Psychosocial Pharmacological Contingency management and patient education have had some success at reducing benzodiazepine use A Cochrane review found evidence that supported the use of cognitive behavioural therapy (CBT) alongside dose reduction9 Evidence suggests targeted interventions with non-pharmacological supportive therapies are more likely to result in successful deprescription10 Multifaceted prescribing interventions (usually including psychological interventions/support) are recommended for older patients11 A 2018 Cochrane review could find no pharmaceutical add-on that could help facilitate the withdrawal process12 Withdrawal symptoms should not be treated with another dependence-forming medicine or sodium valproate or buspirone6

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References

542 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 ■ ■Benzodiazepine misuse is frequently seen in multisubstance misuse where opioids may be the primary drug of dependence. ■ ■Consider cognitive behavioural therapy (CBT) when withdrawing from benzodiazepines. More detailed information on benzodiazepine withdrawal is given in The Maudsley Deprescribing Guidelines.13 References

Olfson M, et al. Benzodiazepine use in the United States. JAMA Psychiatry 2015; 72:136–142.
Milani SA, et al. Trends in the use of benzodiazepines, Z-hypnotics, and serotonergic drugs among US women and men before and during the COVID-19 pandemic. JAMA Netw Open 2021; 4:e2131012.
Advisory Council on the Misuse of Drugs (ACMD). A review of the evidence of use and harms of novel benzodiazepines. London: Home Office. 2020; https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/881969/ACMD_report_-_ a_review_of_the_evidence_of_use_and_harms_of_novel_benzodiazepines.pdf.
Manchester KR, et al. The emergence of new psychoactive substance (NPS) benzodiazepines: a review. Drug Test Anal 2018; 10:392–393.
Sarker A, et al. Evidence of the emergence of illicit benzodiazepines from online drug forums. Eur J Public Health 2022; 32:939–941.
National Institute for Health and Care Excellence. Medicines associated with dependence or withdrawal symptoms: safe prescribing and withdrawal management for adults. NICE guideline [NG215]. 2022 (last checked April 2024); https://www.nice.org.uk/guidance/ng215.
Lader M, et al. Withdrawing benzodiazepines in primary care. CNS Drugs 2009; 23:19–34.
Department of Health. Drug misuse and dependence: UK guidelines on clinical management. London: Department of Health. 2017; https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/673978/clinical_guidelines_2017.pdf.
Darker CD, et al. Psychosocial interventions for benzodiazepine harmful use, abuse or dependence. Cochrane Database Syst Rev 2015; 5:CD009652.
Soni A, et al. Feasibility and effectiveness of deprescribing benzodiazepines and Z-drugs: systematic review and meta-analysis. Addiction 2023; 118:7–16.
Gould RL, et al. Interventions for reducing benzodiazepine use in older people: meta-analysis of randomised controlled trials. Br J Psychiatry 2014; 204:98–107.
Baandrup L, et al. Pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users. Cochrane Database Syst Rev 2018; 3:CD011481.
Horowitz M, et al. The Maudsley Deprescribing Guidelines: Antidepressants, Benzodiazepines, Gabapentinoids and Z-drugs. Oxford: Wiley-Blackwell; 2024. Table 4.24 Typical diazepam withdrawal schedule for iatrogenic dependence. Week Dose Baseline 30mg/day Week 2 25mg/day Week 4 20mg/day Week 6 18mg/day Week 8 16mg/day Week 10 14mg/day Week 12 12mg/day Week 14 10mg/day Then reduce by 2mg/day every 2 weeks if tolerated.

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56 - Drug induced excited state

Drug-induced excited state

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57 - Pathophysiology

Pathophysiology

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58 - Identification

Identification

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59 - Management

Management

Addictions and substance misuse CHAPTER 4 Drug-induced excited state A drug-induced excited state is an under-recognised and potentially life-threatening syndrome of agitation, aggression and dysregulated physiological responses.1 Illicit drugs are the most common cause, notably cocaine and New Psychoactive Substances including synthetic cannabinoids and stimulants such as mephedrone. There are also other causes of a drug-induced excited state.2 This section draws attention to the approach required for people whose behaviour presents a danger to themselves or others because of the acute effect of illicit substances, and who are at significant risk of physiological harm. The terms ‘acute behavioural disturbance’ or ‘excited delirium’ are not used because they are not recognised diagnoses and because they are highly controversial terms that are suspected of being misused in respect to deaths in police custody.3–5 Early intervention and de-escalation are crucial to effective and safe treatment. It cannot be overemphasised that physical restraint should be avoided whenever possible because of the substantial risk to life presented by restraint in these patients. Where restraint cannot be avoided, it should be used carefully and safely: avoiding restraint in the prone position and employing it for the briefest possible time (i.e. for seconds, not minutes). Pathophysiology Various components of the drug-induced excited state and its treatment (including restraint) lead to disorientation and a ‘fight or flight’ response. The physical exertion employed to ‘escape’ results in hyperthermia and catecholamine release.6 Hyperthermia in turn leads to rhabdomyolysis (with raised creatine kinase)7 as well as worsening delirium.8 Excess sympathetic catecholamines prolong the cardiac QT interval and may adversely affect myocardial function.9 Excess muscle activity, raised catecholamines, hyperthermia and dehydration contribute to a metabolic acidosis and the production of carbon dioxide. This manifests with tachypnoea and may herald pending cardiovascular collapse. It cannot be overemphasised that restraint grossly exacerbates risks in this cascade of events, especially if restraint is prolonged. Identification A drug-induced excited state is not a distinct diagnosis, but a term used to encapsulate a range of situations in which a person experiences distress, displays agitation or aggression and is at risk of physiological dysregulation. Perhaps the most common symptoms are violent behaviour, increased pain tolerance and constant activity.10 Rapid breathing, a lack of fatigue, hyperpyrexia and tactile hyperthermia are also frequently observed.11 A cascade of events may develop and may be provoked or worsened by restraint, leading to increased fear, then protracted physical struggle, hypoxia due to restraint, catecholamine release, lactic acidosis, and so on. Management Verbally de-escalate and try to ensure environmental safety for the individual and others. It bears repeating that restraint may exacerbate hyperthermia and catecholamine release, worsening outcomes.12 Sedation is important to calm aggression and to reduce

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60 - Outcomes

Outcomes

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61 - References

References

544 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 heat generation and catecholamine release. There is evidence to support intramuscular use of benzodiazepines (including lorazepam and midazolam13), antipsychotics (including haloperidol, droperidol, olanzapine and chlorpromazine13,14) and their combination.15 Caution is required with antipsychotics because of the risk of acute dystonia and neuroleptic malignant syndrome. Record pulse, blood pressure and temperature where and when safe to do so. Basic urinary drug screens have limited validity for New Psychoactive Substances but many clinical laboratories can identify potentially causative compounds (albeit with a time lag). An ECG is desirable but unlikely to be possible until individuals have been sedated. Full assessment and treatment require urgent ambulance transfer to an emergency department.16 Psychiatric nursing personnel might be required to contain and support the individual. In the emergency department, intramuscular ketamine is the preferred sedative, with a predictable dose–response effect at 2–4mg/kg.17 Antipyretics are ineffective cooling agents. Cooled intravenous fluids, water sprays and ice to the whole body may be required. Outcomes Mortality rates are not known, with the only source of data available being uncontrolled observations.18 Risk of death is related to the duration of hyperthermia and peak temperature reached – body temperatures over 42°C usually have very poor outcomes. A body mass index of more than 25kg/m2 is also associated with worse outcome. In non-fatal instances, most cases of drug-induced excited state are brief and fully resolve within 48 hours. Longer-term cardiac, renal and hepatic damage can occasionally occur. References

Stevenson R, et al. Acute behavioural disturbance: a physical emergency psychiatrists need to understand. BJPsych Advances 2021; 27:333–342.
Kennedy DB, et al. Delayed in-custody death involving excited delirium. J Correct Health Care 2018; 24:43–51.
Tracy DK. Acute behavioural disturbance: what’s in a name? BJPsych Open 2024; 10:e38.
Polling C, et al. Use of ‘acute behavioural disturbance’ in mental health records: differences over time and by ethnicity. BJPsych Open 2023; 9:e133.
Humphries C, et al. Consensus on acute behavioural disturbance in the UK: a multidisciplinary modified Delphi study to determine what it is and how it should be managed. Emerg Med J 2023; 41:4–12.
Bunai Y, et al. Fatal hyperthermia associated with excited delirium during an arrest. Leg Med (Tokyo) 2008; 10:306–309.
Borek HA, et al. Hyperthermia and multiorgan failure after abuse of ‘bath salts’ containing 3,4-methylenedioxypyrovalerone. Ann Emerg Med 2012; 60:103–105.
Otahbachi M, et al. Excited delirium, restraints, and unexpected death: a review of pathogenesis. Am J Forensic Med Pathol 2010; 31:107–112.
Wittstein IS, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005; 352:539–548.
Hall CA, et al. Frequency of signs of excited delirium syndrome in subjects undergoing police use of force: descriptive evaluation of a prospective, consecutive cohort. J Forensic Leg Med 2013; 20:102–107.
Baldwin S, et al. Distinguishing features of excited delirium syndrome in non-fatal use of force encounters. J Forensic Leg Med 2016; 41:21–27.
Stratton SJ, et al. Factors associated with sudden death of individuals requiring restraint for excited delirium. Am J Emerg Med 2001; 19:187–191.
Isbister GK, et al. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med 2010; 56:392–401 e391.
Page CB, et al. A prospective study of the safety and effectiveness of droperidol in children for prehospital acute behavioral disturbance. Prehosp Emerg Care 2019; 23:519–526.
O’Connor N, et al. Pharmacological management of acute severe behavioural disturbance: a survey of current protocols. Australas Psychiatry 2017; 25:395–398.
Wetli CV, et al. Cocaine-associated agitated delirium and the neuroleptic malignant syndrome. Am J Emerg Med 1996; 14:425–428.
Li M, et al. Evaluation of ketamine for excited delirium syndrome in the adult emergency department. J Emerg Med 2020; 58:100–105.
Baldwin S, et al. Excited delirium syndrome (ExDS): situational factors and risks to officer safety in non-fatal use of force encounters. Int J Law Psychiatry 2018; 60:26–34.

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62 - Interactions between illicit drugs and prescr

Interactions between illicit drugs and prescribed psychotropic drugs

Addictions and substance misuse CHAPTER 4 Interactions between illicit drugs and prescribed psychotropic drugs Interactions between drugs of misuse and prescribed psychotropics are common, not least because of the high rates of psychotropic prescribing in such patients.1 Information on adverse interactions is derived largely from case reports and theoretical assumptions and rarely from systematic investigation. A summary of major interactions can be found in Table 4.25. In all patients who misuse illicit drugs: ■ ■Infection with hepatitis B and C is more common. The associated liver damage may lead to a reduced ability to metabolise other drugs and increased sensitivity to adverse effects. ■ ■Infection with HIV is relatively common.2,3 Antiretroviral drugs are involved in pharmacokinetic interactions with a number of prescribed and non-prescribed drugs.4 For example, ritonavir can decrease the metabolism of ecstasy and precipitate toxicity, and a number of antiretrovirals can increase or decrease methadone metabolism.5 ■ ■Prescribed drugs may be used in the same way as illicit drugs (i.e. erratically and not as intended). Large quantities of prescribed drugs should not be given to out-patients. ■ ■Additive or synergistic effects of respiratory depressants may play a contributory role in deaths from overdose with methadone or other opioid agonists.6 Caution is needed in prescribing sedative medicines such as benzodiazepines and gabapentinoids.

Table 4.25 Interactions between illicit drugs and psychotropics. Cannabis Heroin/methadone6 Cocaine, amfetamines, ecstasy, MDA, 6-APD Alcohol Ketamine7 General considerations ■ ■Usually smoked in cigarettes (induces CYP1A2) ■ ■Can be sedative ■ ■Dose-related tachycardia ■ ■THC/CBD inhibit CYP3A4, CYP2C19 and CYP2D68,9 ■ ■Can produce sedation/ respiratory depression ■ ■QTc prolongation with methadone (see section on methadone earlier in this chapter) ■ ■Stimulants (cocaine can be sedative in higher doses) ■ ■Arrhythmia possible ■ ■Cerebral/cardiac ischaemia with cocaine – may be fatal ■ ■MDMA inhibits CYP2D6/CYP3A4 ■ ■Hyperthermia/dehydration with ecstasy10 ■ ■Sedative ■ ■Liver damage possible ■ ■Induces various enzymes ■ ■Sedative readily causes unconciousness ■ ■Onset of effects may be rapid if snorted or injected Older antipsychotics ■ ■Antipsychotics reduce the psychotropic effects of almost all drugs of abuse by blocking dopamine receptors (dopamine is the neurotransmitter responsible for ‘reward’) (e.g. haloperidol and MDMA11) ■ ■Patients prescribed antipsychotics may increase their consumption of illicit substances to compensate ■ ■Patients who have taken ecstasy may be more prone to EPSEs ■ ■Cardiotoxic or very sedative antipsychotics are best avoided, at least initially. Sulpiride is a reasonably safe first choice ■ ■Methamphetamines increase risk of EPSEs with haloperidol12 Second- generation antipsychotics ■ ■Risk of additive sedation ■ ■Cannabis smoking in tobacco can reduce plasma levels of olanzapine and clozapine via induction of CYP1A213 ■ ■Clozapine might reduce cannabis and alcohol consumption14 ■ ■Outcome of THC/CBD inhibition of CYP1A2 unknown ■ ■Risk of additive sedation ■ ■Case report of methadone withdrawal being precipitated by risperidone15 ■ ■Isolated report of quetiapine increasing methadone levels, especially in those with slowed CYP2D6 hepatic metabolism16 ■ ■Antipsychotics may reduce craving and cocaine-induced euphoria17–21 ■ ■Olanzapine may worsen cocaine dependency22 ■ ■Clozapine may increase cocaine levels but diminish subjective response23 ■ ■Increased risk of hypotension with olanzapine (and possibly other beta-blockers) ■ ■Increased sedation ■ ■Possible interaction between risperidone and ketamine24

Antidepressants ■ ■Tachycardia has been reported (monitor pulse and take care with TCAs25) ■ ■Complex, unpredictable effects of CYP induction (tobacco) and CYP inhibition (THC/CBD) ■ ■Avoid very sedative antidepressants ■ ■Some SSRIs can increase methadone plasma levels26 (citalopram is SSRI of choice but note the small risk of additive QTc prolongation) ■ ■Case report of serotonin syndrome occurring when sertraline prescribed with methadone for a palliative care patient27 ■ ■Avoid TCAs (arrhythmia risk) ■ ■MAOIs contraindicated (hypertension) ■ ■Combining moclobemide and MDMA can be fatal28 ■ ■SSRIs may increase plasma concentrations of MDMA29 but reduce subjective effects30 ■ ■Risk of SSRIs increasing cocaine levels, especially fluoxetine31 ■ ■Concomitant use of SSRIs or aripiprazole and lamotrigine with cocaine or other stimulants (especially MDA and 6-APD) could precipitate a serotonin syndrome32,33 ■ ■SSRIs may enhance subjective reaction to cocaine34 ■ ■Avoid very sedative antidepressants ■ ■Avoid antidepressants that are toxic in overdose ■ ■Impaired psychomotor skills (not SSRIs) ■ ■Inhibitors of CYP3A4 (e.g. fluoxetine/ paroxetine) will lengthen ketamine half-life ■ ■Beware hypertension with SNRIs and reboxetine Anticholinergics ■ ■Misuse is likely. Try to avoid if at all possible (by using a second-generation drug if an antipsychotic is required) ■ ■Can cause hallucinations, elation and cognitive impairment Lithium ■ ■Very toxic if taken erratically ■ ■Always consider the effects of dehydration (particularly problematic with alcohol or ecstasy) Carbamazepine/ valproate ■ ■Carbamazepine may decrease THC concentrations via induction of CYP3A435 ■ ■Carbamazepine decreases methadone levels36 (danger if carbamazepine stopped suddenly) ■ ■Valproate seems less likely to interact ■ ■Monitor LFTs ■ ■Carbamazepine decreases ketamine plasma concentrations via CYP3A4 induction Benzodiazepines ■ ■Monitor level of sedation ■ ■Oversedation (and respiratory depression possible) ■ ■Concomitant use can lead to accidental overdose ■ ■Possible pharmacokinetic interaction (increased methadone levels) ■ ■Oversedation (if high doses of cocaine have been taken) ■ ■Widely used after cocaine intoxication ■ ■Future misuse possible ■ ■Oversedation (and respiratory depression) possible ■ ■Widely used in alcohol detoxification ■ ■Oversedation and respiratory depression Gabapentinoids ■ ■Monitor level of sedation ■ ■Large increase in risk of death in overdose37,38 ■ ■Does not reduce cocaine use39 ■ ■Oversedation and respiratory depression possible ■ ■No interaction reported24 6-APD, 6-(2-aminopropyl)benzofuran; CBD, cannabidiol; EPSEs, extrapyramidal side effects; MAOIs, monoamine oxidase inhibitors, MDA, 3,4-methylenedioxyamphetamine; MDMA, 3,4-methylene dioxymethamphetamine; TCAs, tricyclic antidepressants; THC, tetrahydrocannabiniol.

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References

548 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 References

Zapelini do Nascimento D, et al. Potential psychotropic drug interactions among drug-dependent people. J Psychoactive Drugs 2021; 53:168–176.
Vocci FJ, et al. Medication development for addictive disorders: the state of the science. Am J Psychiatry 2005; 162:1432–1440.
Tsuang J, et al. Pharmacological treatment of patients with schizophrenia and substance abuse disorders. Addict Disord Treat 2005; 4:127–137.
Bracchi M, et al. Increasing use of ‘party drugs’ in people living with HIV on antiretrovirals: a concern for patient safety. Aids 2015; 29:1585–1592.
Gruber VA, et al. Methadone, buprenorphine, and street drug interactions with antiretroviral medications. Curr HIV/AIDS Rep 2010; 7:152–160.
Department of Health and Social Care. Drug misuse and dependence: UK guidelines on clinical management. 2017; https://www.gov.uk/ government/publications/drug-misuse-and-dependence-uk-guidelines-on-clinical-management.
Pfizer Ltd. Summary of product characteristics. Ketalar (ketamine hydrochloride) 10mg/ml injection. 2024 (last accessed July 2024); https://www.medicines.org.uk/emc/medicine/12939.
Arellano AL, et al. Neuropsychiatric and general interactions of natural and synthetic cannabinoids with drugs of abuse and medicines. CNS Neurol Disord Drug Targets 2017; 16:554–566.
Abbott KL, et al. Adverse pharmacokinetic interactions between illicit substances and clinical drugs. Drug Metab Rev 2020; 52:44–65.
Gowing LR, et al. The health effects of ecstasy: a literature review. Drug Alcohol Rev 2002; 21:53–63.
Liechti ME, et al. Acute psychological and physiological effects of MDMA (‘Ecstasy’) after haloperidol pretreatment in healthy humans. Eur Neuropsychopharmacol 2000; 10:289–295.
Matthew BJ, et al. Drug-induced parkinsonism following chronic methamphetamine use by a patient on haloperidol decanoate. Int J Psychiatry Med 2015; 50:405–411.
Zullino DF, et al. Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. Int Clin Psychopharmacol 2002; 17:141–143.
Green AI, et al. Alcohol and cannabis use in schizophrenia: effects of clozapine vs. risperidone. Schizophr Res 2003; 60:81–85.
Wines JD, Jr., et al. Opioid withdrawal during risperidone treatment. J Clin Psychopharmacol 1999; 19:265–267.
Uehlinger C, et al. Increased (R)-methadone plasma concentrations by quetiapine in cytochrome P450s and ABCB1 genotyped patients. J Clin Psychopharmacol 2007; 27:273–278.
Poling J, et al. Risperidone for substance dependent psychotic patients. Addict Disord Treat 2005; 4:1–3.
Albanese MJ, et al. Risperidone in cocaine-dependent patients with comorbid psychiatric disorders. J Psychiatr Pract 2006; 12:306–311.
Sattar SP, et al. Potential benefits of quetiapine in the treatment of substance dependence disorders. J Psychiatry Neurosci 2004; 29:452–457.
Grabowski J, et al. Risperidone for the treatment of cocaine dependence: randomized, double-blind trial. J Clin Psychopharmacol 2000; 20:305–310.
Kishi T, et al. Antipsychotics for cocaine or psychostimulant dependence: systematic review and meta-analysis of randomized, placebo- controlled trials. J Clin Psychiatry 2013; 74:e1169–e1180.
Kampman KM, et al. A pilot trial of olanzapine for the treatment of cocaine dependence. Drug Alcohol Depend 2003; 70:265–273.
Farren CK, et al. Significant interaction between clozapine and cocaine in cocaine addicts. Drug Alcohol Depend 2000; 59:153–163.
Veraart JKE, et al. Pharmacodynamic interactions between ketamine and psychiatric medications used in the treatment of depression: a systematic review. Int J Neuropsychopharmacol 2021; 24:808–831.
Benowitz NL, et al. Effects of delta-9-tetrahydrocannabinol on drug distribution and metabolism. Antipyrine, pentobarbital, and ethanol. Clin Pharmacol Ther 1977; 22:259–268.
Hemeryck A, et al. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab 2002; 3:13–37.
Bush E, et al. A case of serotonin syndrome and mutism associated with methadone. J Palliat Med 2006; 9:1257–1259.
Vuori E, et al. Death following ingestion of MDMA (ecstasy) and moclobemide. Addiction 2003; 98:365–368.
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Papaseit E, et al. MDMA interactions with pharmaceuticals and drugs of abuse. Expert Opin Drug Metab Toxicol 2020; 16:357–369.
Fletcher PJ, et al. Fluoxetine, but not sertraline or citalopram, potentiates the locomotor stimulant effect of cocaine: possible pharmacokinetic effects. Psychopharmacology (Berl) 2004; 174:406–413.
Silins E, et al. Qualitative review of serotonin syndrome, ecstasy (MDMA) and the use of other serotonergic substances: hierarchy of risk. Aust NZ J Psychiatry 2007; 41:649–655.
Kotwal A, et al. Serotonin syndrome in the setting of lamotrigine, aripiprazole, and cocaine use. Case Rep Med 2015; 2015:769531.
Soto PL, et al. Citalopram enhances cocaine’s subjective effects in rats. Behav Pharmacol 2009; 20:759–762.
GW Pharma Ltd. Summary of product characteristics. Sativex (delta-9-tetrahydrocannabinol, cannabidiol) oromucosal spray. 2022 (last accessed July 2024); https://www.medicines.org.uk/emc/product/602.
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Kalk NJ, et al. Fatalities associated with gabapentinoids in England (2004–2020). Br J Clin Pharmacol 2022; 88:3911–3917.
Bonnet U, et al. Gabapentinoid-related deaths: an alarming global trend or just a special challenge within the long tail of the giant opioid epidemic? Lancet Reg Health Am 2022; 11:100309.
Quintero Garzola GC. Reviewing treatments for cocaine consume problems: the gabapentinoid alternative. Open Access J Clin Trials 2021; 13:45–60.

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Drugs of misuse – a summary

Addictions and substance misuse CHAPTER 4 Drugs of misuse – a summary Urine testing for illicit drugs is routine on many psychiatric wards and in out-patient settings and doctors’ offices. It is important to be aware of the duration of ability to detect drugs in urine and of other commonly used substances and of drugs that can give a false positive result. Some false positives are unpredictable (i.e. not related to chemical similarity), for example amisulpride can give a false positive for buprenorphine.1 False positive results are most likely with point-of-care immunoassay kits. If a positive result has implications for a patient’s liberty, and the patient denies use of substances, a second sample should be sent to the laboratory for definitive testing by liquid chromatography and mass spectrometry (LC-MS). Table 4.26 gives a basic summary of the features of drugs of misuse.

Table 4.26 Summary of drugs of misuse. Most common mental state changes2 Withdrawal symptoms Duration of withdrawal Physical signs/ symptoms of intoxication Drug Amfetamine-type stimulants8 Tachycardia, increased BP; anorexia, tremor, restlessness Fatigue, hunger, depression, irritability, craving, social withdrawal Visual/tactile/olfactory/ auditory hallucinations, paranoia, elation Benzodiazepines Sedation, disinhibition Relaxation, visual hallucinations, disorientation, sleep disturbance Anxiety, insomnia, delirium, seizures, visual/tactile/ olfactory/auditory hallucinations, psychosis Cannabis10–16 Tachycardia, lack of co-ordination, red eyes, postural hypotension Restlessness, irritability, insomnia, anxiety Elation, psychosis, perceptual distortions, disturbance of memory/judgement, twofold increase in risk of developing schizophrenia Cocaine Tachycardia/tachypnoea, increased BP/headache, respiratory depression, chest pain Fatigue, hunger, depression, irritability, craving, social withdrawal Euphoria, paranoid psychosis, panic attacks, anxiety, insomnia, excitement Duration of detection in the urine3,4 Other substances that give a positive urine test result5–7 Cough and decongestant preparations, bupropion, chloroquine, chlorpromazine, labetalol, promethazine, ranitidine, selegiline, large quantities of tyramine, tranylcypromine, trazodone and many others Depends on half-life, mostly 48–72 hours Peaks 7–34 hours, lasts maximum of 5 days Desvenlafaxine may give a positive result for PCP9 Nefopam, sertraline, zopiclone, efavirenz Up to 28 days depending on half-life of drug taken Usually short-lived but may last weeks to months Passive ‘smoking’ of cannabis Single use: 3 days Uncertain, probably less than 1 month (longer in heavy users) Efavirenz, ibuprofen, naproxen Chronic heavy use: up to 30 days 12–18 hours Up to 96 hours Food/tea containing coco leaves, codeine, ephedrine/ pseudoephedrine

GHB/GBL Drowsiness, coma, disinhibition Sociability, confidence Tremor, tachycardia, paranoia, delirium, psychosis, visual/ tactile/olfactory/ auditory hallucinations Heroin (diamorphine) Pinpoint pupils, clammy skin, respiratory depression Drowsiness, euphoria, hallucinations Dilated pupils, nausea, diarrhoea, generalised pains, gooseflesh, runny nose/eyes Ketamine19–22 Increased HR, increased BP, palpitations, dizziness, abdominal discomfort, lower urinary tract symptoms, ataxia Fatigue, poor appetite, drowsiness, craving, anxiety, dysphoria, restlessness, palpitations, tremor, sweating Impaired consciousness, dissociation, hallucinations, ego diffusion LSD23 Variable Euphoria, introspection, illusions, pseudo-hallucinations, altered sense of time, altered thought processes, altered perception of body, vivid recollections of significant memories Dilated pupils, moderate increase in HR and BP, flushing, sweating, hypersalivation, increased tendon reflexes 3–4 days 8–10 hours17 Not known Usually (and reliably) measured by LC-MS18 Peaks after 36–72 hours Up to 72 hours Diphenoxylate, naltrexone, naloxone, opiate analgesics, food/ tea containing poppy seed, amisulpride, diphenhydramine, 4-quinolones, tramadol Quetiapine 48 hours Ketamine: up to 2 days Norketamine: up to 14 days None N/A Up to 4 days Ambroxol, amitriptyline, brompheniramine, bupropion, buspirone, cephadrine, chlorpromazine, desipramine, diltiazem, doxepin, ergonovine, fentanyl, fluoxetine, haloperidol, imipramine, labetalol, lysergol, methylphenidate, metoclopramide, prochlorperaxine, risperidone, sertraline, thioridazine, trazodone, verapamil (Continued )

Methadone Pinpoint pupils, respiratory depression, pulmonary oedema As for heroin As for heroin but milder and longer lasting Peaks after 4–6 days, can last 6 weeks Up to 7 days with chronic use Quetiapine Other opioids such as nitazenes, fentanyls and oxycodone24,25 As for heroin, higher potency than heroin, faster onset of action, overdose common, seen as adulterants to street heroin As for heroin As for heroin As for heroin, faster peak Fentanyl: up to 72 hours Oxycodone: 2–4 days Nitazenes: variable Fentanyls – ascorbic acid Synthetic cannabinoid receptor agonists (SCRAs) Tachycardia, hypertension, red eyes, agitation Anxiety, agitation, aggression, psychotic symptoms, clouded consciousness Anxiety, sleep disturbance, headache Uncertain Difficult to detect using conventional screening methods because of chemical heterogeneity Too chemically diverse for urine screens, e.g. AB-fubinaca, ADB-fubinaca, AB-chminaca 3-methyl-butanoic acid, ADB- chminaca and 5-flouro-PB-22 are all classed as SCRAs Best detected and measured by LC-MS26* Xylazine27 Bradycardia, hypotension, sedation, respiratory depression Rarely taken alone – usually an adulterant of opioids Sedation, muscle relaxation Hypertension, anxiety, irritability Unclear Unclear; probably a few hours Urine testing not common Unclear LC-MS testing available28* *For more detail on cross-reacting substances in urine testing, see Moeller et al. (2017).29 GBL/GHB, gamma-hydroxybutyrate/gamma-butyrolactone; HR, heart rate; LC-MS, liquid chromatography and mass spectrometry; LSD, lysergic acid diethylamide; N/A, not applicable; PCP, phencyclidine. Table 4.26 (Continued) Drug Physical signs/ symptoms of intoxication Most common mental state changes2 Withdrawal symptoms Duration of withdrawal Duration of detection in the urine3,4 Other substances that give a positive urine test result5–7

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References

Addictions and substance misuse CHAPTER 4 References

Couchman L, et al. Amisulpride and sulpiride interfere in the CEDIA DAU buprenorphine test. Ann Clin Psychiatry 2008; 45 Suppl 1.
Merative US L.P. Micromedex. 2024; https://www.micromedexsolutions.com/home/dispatch/.
Substance Abuse and Mental Health Services Administration (US). Substance Abuse: Clinical Issues in Intensive Outpatient Treatment. Treatment Improvement Protocol (TIP) Series, No. 47. 2006.
Vandevenne M, et al. Detection time of drugs of abuse in urine. Acta Clin Belg 2000; 55:323–333.
Brahm NC, et al. Commonly prescribed medications and potential false-positive urine drug screens. Am J Health Syst Pharm 2010; 67:1344–1350.
Saitman A, et al. False-positive interferences of common urine drug screen immunoassays: a review. J Anal Toxicol 2014; 38:387–396.
Liu CH, et al. False positive ketamine urine immunoassay screen result induced by quetiapine: a case report. J Formos Med Assoc 2017; 116:720–722.
Shoptaw SJ, et al. Treatment for amphetamine psychosis. Cochrane Database Syst Rev 2009; 1:CD003026.
Farley TM, et al. False-positive phencyclidine (PCP) on urine drug screen attributed to desvenlafaxine (Pristiq) use. BMJ Case Rep 2017; 2017:bcr-2017-222106.
Johns A. Psychiatric effects of cannabis. Br J Psychiatry 2001; 178:116–122.
Hall W, et al. Long-term cannabis use and mental health. Br J Psychiatry 1997; 171:107–108.
Murray RM, et al. Traditional marijuana, high-potency cannabis and synthetic cannabinoids: increasing risk for psychosis. World Psychiatry 2016; 15:195–204.
Marconi A, et al. Meta-analysis of the association between the level of cannabis use and risk of psychosis. Schizophr Bull 2016; 42:1262–1269.
Arseneault L, et al. Causal association between cannabis and psychosis: examination of the evidence. Br J Psychiatry 2004; 184:110–117.
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Bonnet U, et al. The cannabis withdrawal syndrome: current insights. Subst Abuse Rehabil 2017; 8:9–37.
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Gov.UK Advisory Council on Misuse of Drugs. Research and analysis: ACMD advice on 2-benzyl benzimidazole and piperidine benzimidazolone opioids (accessible version). 2024; https://www.gov.uk/government/publications/acmd-advice-on-2-benzyl-benzimidazole-and-piperidine- benzimidazolone-opioids/acmd-advice-on-2-benzyl-benzimidazole-and-piperidine-benzimidazolone-opioids-accessible-version.
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Substance misuse in pregnancy

554 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Substance misuse in pregnancy Substance misuse in pregnancy has a wide range of adverse obstetric and fetal outcomes (Table 4.27). The overall quality of evidence is poor and based on small-scale observational studies. In the UK, the two main sources of information are the UK Teratology Information Service1 and NICE guidance for pregnancy and complex social factors.2 Outside the UK, WHO guidelines are available.3

Table 4.27 Risks and management of various drugs in pregnancy. Substance Associated risks Management Alcohol Alcohol is a teratogen, even 1–2 units can increase the risk of having a preterm, low birthweight or small for gestational age baby.4 In utero exposure can cause fetal alcohol spectrum disorders (FASDs) which include neurodevelopmental impairment, facial dysmorphology, congenital abnormalities and poor growth. These are dependent on dose, pattern timing, duration of exposure, fetal and maternal genetics, maternal nutrition, concurrent substance use and epigenetic response.5 Neonates can experience withdrawal symptoms, including hyperactivity, crying, irritability, poor sucking, tremors, seizures, poor sleeping pattern hyperphagia and diaphoresis.6 Breastfeeding Pregnant patients should be encouraged to cease alcohol consumption. Medically assisted withdrawal ■ ■Those who experience withdrawal symptoms should have benzodiazepine-assisted withdrawal.3 ■ ■The timing of detoxification in relation to the trimester of pregnancy should be risk-assessed against continued alcohol consumption and risks to the fetus.7 ■ ■Benzodiazepines are not known to be major teratogens and the duration of their use in medically assisted alcohol withdrawal is short. Diazepam and chlordiazepoxide are the benzodiazepines of choice.8 ■ ■Specialist advice should usually be sought. Relapse prevention medications ■ ■No relapse prevention medications are advised in pregnancy, owing to the lack of safety data. However, given the teratogenicity of alcohol, there is debate over whether the benefit might outweigh the risk in certain circumstances.9 ■ ■Acamprosate – fetal malformation and increased stillbirth are observed in animal studies with greater doses than in human therapy. One retrospective cohort study did not find an increased rate of congenital malformation, preterm delivery, low birthweight or neonatal complications. A small sample (n = 32) of unpublished data has observed congenital malformations, miscarriage and neurodevelopmental impacts; the results are confounded by maternal alcohol use and therefore cannot be reliably interpreted.1 ■ ■Naltrexone – in animal studies it was not found to be teratogenic, however increased early fetal loss was observed at higher than recommended therapeutic doses. Clinical data relate to naltrexone use in opioid use disorder (OUD), and therefore are difficult to apply to alcohol use disorder. One study identified increased rates of pregnancy and labour complications for those with a naltrexone implant, compared with women without OUD, although this may be related to their OUD.9 ■ ■Disulfiram – very limited data. There are concerns over the autonomic instability caused by the disulfiram- alcohol reaction.1 Animal studies have not demonstrated the safety of disulfiram in pregnancy.9 ■ ■Alcohol is excreted in breast milk in similar concentrations to those in maternal blood. Alcohol is at its highest concentration in breast milk 30–60 minutes after ingestion and declines at the same rate as in maternal blood. Therefore, pregnant patients are advised to wait before breastfeeding. One study demonstrated that alcohol decreased lactation.10 The safest option is to not drink alcohol, but if an individual chooses to drink, then they should drink no more than the recommended weekly intake and spread the drinks across the week.11 (Continued )

Tobacco Miscarriage, low birthweight, prematurity and stillbirth7 Patients should be encouraged to cease smoking completely. Pharmacological treatment ■ ■Nicotine replacement therapy (NRT) probably does not have adverse effects on the fetus or infant.12 NRT should be offered at the earliest opportunity and provided if desired throughout the pregnancy.13 ■ ■Vaping may be preferred but its effect on the fetus has not been established, with few studies available. There is some evidence that vaping has no impact on birthweight.14 ■ ■NRT should be offered alongside behavioural support.13 ■ ■Bupropion and varenicline are not recommended.13 Bupropion, when used to treat depression, may be continued after a risk–benefit analysis. Available human pregnancy exposure data have not indicated an increased risk of miscarriage, major congenital malformations, intrauterine death, impaired fetal growth or preterm delivery for bupropion or varenicline. One single case–control study of bupropion has suggested possible associations with cardiac malformations, but this has not been replicated.1 Opioids Heroin dependence: sixfold increase in maternal obstetric complications and increased risk of neonatal complications including low birthweight, neonatal abstinence syndrome (NAS) and sudden infant death syndrome.15 Dependence on other opioids: low birthweight, toxaemia, third trimester bleeding, malpresentation, puerperal morbidity, fetal distress, meconium aspiration, NAS, postnatal growth deficiency, microcephaly, neurobiological problems, increased neonatal mortality, increased sudden infant death syndrome (74-fold increase).15 Treatment should take place within a multidisciplinary team (including obstetric team, anaesthetists, neonatologists and addiction specialists) delivering a holistic package of care. Opioid substitution treatment (OST) ■ ■It is advised that methadone/buprenorphine (OST) be commenced or continued in pregnancy. It carries a significantly lower risk than continued illicit use despite the known risks of these medications.3 ■ ■Buprenorphine is associated with a lower risk of NAS than methadone.16 ■ ■Buprenorphine and methadone increase the risk of preterm delivery, small for gestational age and low birthweight. Buprenorphine carries a relatively lower risk of these.16 ■ ■Buprenorphine has been associated with a lower risk of congenital malformations than methadone.17 ■ ■Buprenorphine and methadone have the same rates of severe maternal complications and caesarean sections.16 ■ ■Methadone-exposed babies have a higher rate of mortality in the first 2 years when compared with buprenorphine and naltrexone exposed babies.18 ■ ■A Cochrane review found no difference in treatment retention between methadone and buprenorphine during pregnancy.15 However, a larger systematic review and meta-analysis not focused on pregnancy found greater treatment retention for methadone.19 ■ ■Pregnant patients are not advised to switch from methadone to buprenorphine because of the risk of withdrawal.3 Table 4.27 (Continued) Substance Associated risks Management

Detoxification Naltrexone Other considerations Breastfeeding ■ ■In the past, guidelines recommended that patients who take buprenorphine-naloxone (e.g. Suboxone) be switched to buprenorphine owing to there being inadequate safety data for the former.20 However, a 2020 systematic review and meta-analysis identified no difference in outcomes for pregnant patients receiving buprenorphine-naloxone and that neonates were less likely to require treatment for NAS.21 A 2023 systematic review confirmed that Suboxone was no less safe than buprenorphine alone (or methadone).22 ■ ■Metabolism of methadone is increased in the third trimester so it may be necessary to split the dose to twice daily or increase the dose.4 ■ ■Pregnancy increases the metabolism of buprenorphine. Increased frequency of dosing is required to maintain plasma levels, reducing the risk of withdrawals and increasing adherence to treatment.23 ■ ■Buvidal (long-acting buprenorphine injection) – there are very limited safety data available, and any benefits of use should be balanced with possible risks.24 ■ ■Detoxification is associated with a higher rate of relapse and mortality.3 It should be driven by informed patient choice. If desired, detoxification is safest in the second trimester, as in the first it is associated with spontaneous abortion and in the third with preterm delivery, fetal distress and stillbirth.4 ■ ■Detoxification medications should be employed in small, frequent decrements, e.g. 2–3mg of methadone every 3–5 days.4 ■ ■Cycling between abstinence, relapse and intoxication results in fluctuating opioid concentrations, which increases the risk of maternal, obstetric, fetal and neonatal complications.25 ■ ■There are limited human data that suggest similar findings with regard to safety as for methadone and buprenorphine.18 ■ ■It is useful to anticipate potential problems in pain management for pregnant patients prescribed opioids who are likely to require opioid pain relief. Such patients should be managed in specialist antenatal clinics due to the increased associated risks. ■ ■Antenatal assessment by anaesthetists is recommended to anticipate any anaesthetic risks, analgesic requirements and problems with venous access. ■ ■Patients prescribed methadone or buprenorphine should be encouraged to breastfeed even if they continue to use illicit opioids.1 The level of buprenorphine and methadone in breast milk is low.18 ■ ■Breastfeeding brings general health benefits to mother and infant, low concentrations of methadone and buprenorphine are transferred to infant, and it reduces admission length and need for intervention in NAS. ■ ■Patients should be advised to discontinue breastfeeding gradually as abrupt cessation can cause a delayed NAS.26 (Continued )

Table 4.27 (Continued) Substance Associated risks Management Cannabis Associations with stillbirth, fetal growth restriction, impaired fetal neurodevelopment, preterm delivery, neonatal intensive care unit admissions and small for gestational age infants, neonatal withdrawal-like syndrome, increased aggressive behaviour and attention deficits.27 Breastfeeding Benzodiazepines No conclusive evidence of congenital defects. Associations have been found with increased risk of spontaneous abortion and preterm labour.28 Prolonged use of benzodiazepines in the near-term period, especially high doses, is associated with a neonatal withdrawal syndrome and ‘floppy baby syndrome’.1 Breastfeeding Stimulants Increased risk of miscarriage, placental abruption, preterm birth, decreased birthweight, disturbed neurobehaviour at birth, poorer medical/ behavioural/cognitive and motor problems.29 Breastfeeding Abstinence should be encouraged. CBT, motivational enhancement therapy and abstinence-based incentives can be used. There are no pharmacological treatments currently available.27 ■ ■There are limited data. Avoid or reduce use during breastfeeding.27 Ideally, benzodiazepines should be discontinued before pregnancy. Abrupt withdrawal of benzodiazepines is not advised because of the possibility of destabilisation, and the risk that it could lead to alcohol being substituted, which could pose a considerable risk to the fetus.1 The consensus is that those dependent on illicit benzodiazepines should be stabilised on long-acting benzodiazepines (e.g. diazepam) at the lowest dose possible to prevent withdrawal symptoms. The dose should be gradually reduced, as long as it does not result in illicit use.4 ■ ■People taking high doses of benzodiazepines should not breastfeed.4 There are no effective pharmacological interventions and detoxification is the primary aim. ■ ■Breastfeeding is not advised.3

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67 - References

References

Addictions and substance misuse CHAPTER 4 References

UK Health Security Agency. UK Teratology Information Service. 2024; https://uktis.org.
National Institute for Health and Care Excellence. Pregnancy and complex social factors: a model for service provision for pregnant women with complex social factors. Clinical guideline [CG110]. 2010 (last checked March 2024); https://www.nice.org.uk/guidance/CG110.
World Health Organization. Guidelines for the Identification and Management of Substance Use and Substance Use Disorders in Pregnancy. Geneva: World Health Organization; 2014.
Department of Health. Drug misuse and dependence: UK guidelines on clinical management. London: Department of Health. 2017; https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/673978/clinical_guidelines_2017.pdf.
Popova S, et al. Fetal alcohol spectrum disorders. Nat Rev Dis Primers 2023; 9:11.
Hudak ML, et al. Neonatal drug withdrawal. Pediatrics 2012; 129:e540–e560.
Lingford-Hughes AR, et al. Evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP. J Psychopharmacol 2012; 26:899–952.
McAllister-Williams RH, et al. British Association for Psychopharmacology consensus guidance on the use of psychotropic medication preconception, in pregnancy and postpartum 2017. J Psychopharmacol 2017; 31:519–552.
Kelty E, et al. Pharmacotherapies for the treatment of alcohol use disorders during pregnancy: time to reconsider? Drugs 2021; 81:739–748.
Haastrup MB, et al. Alcohol and breastfeeding. Basic Clin Pharmacol Toxicol 2014; 114:168–173.
Royal College of Obstetricians and Gynaeocologists. Alcohol and pregnancy. 2018 (last accessed March 2024); https://www.rcog.org.uk/ for-the-public/browse-our-patient-information/alcohol-and-pregnancy.
Taylor L, et al. Fetal safety of nicotine replacement therapy in pregnancy: systematic review and meta-analysis. Addiction 2021; 116:239–277.
National Institute for Health and Care Excellence. Tobacco: preventing uptake, promoting quitting and treating dependence. NICE guideline [NG209]. 2021 (last updated 2023, last accessed March 2024); https://www.nice.org.uk/guidance/ng209.
Calder R, et al. Vaping in pregnancy: a systematic review. Nicotine Tob Res 2021; 23:1451–1458.
Minozzi S, et al. Maintenance agonist treatments for opiate-dependent pregnant women. Cochrane Database Syst Rev 2020; 11:CD006318.
HalesMeds.com. Hale’s medications and mothers’ milk. 2024; https://www.halesmeds.com.
Suarez EA, et al. First trimester use of buprenorphine or methadone and the risk of congenital malformations. JAMA Intern Med 2024; 184:242–251.
Suarez EA, et al. Buprenorphine versus methadone for opioid use disorder in pregnancy. N Engl J Med 2022; 387:2033–2044.
Degenhardt L, et al. Buprenorphine versus methadone for the treatment of opioid dependence: a systematic review and meta-analysis of randomised and observational studies. Lancet Psychiatry 2023; 10:386–402.
Edge R, et al. Buprenorphine for Opioid Use Disorders during Pregnancy: a Review of Comparative Clinical Effectiveness, Safety, Cost- Effectiveness, and Guidelines. CADTH Rapid Response Reports. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2019.
Link HM, et al. Buprenorphine-naloxone use in pregnancy: a systematic review and metaanalysis. Am J Obstet Gynecol MFM 2020; 2:100179.
Ordean A, et al. Safety and efficacy of buprenorphine-naloxone in pregnancy: a systematic review of the literature. Pathophysiology 2023; 30:27–36.
Caritis SN, et al. An evidence-based recommendation to increase the dosing frequency of buprenorphine during pregnancy. Am J Obstet Gynecol 2017; 217:459.e451–459.e456.
Camurus Ltd. Buvidal in pregnancy and breastfeeding. Personal communication, 2024.
Rausgaard NLK, et al. Management and monitoring of opioid use in pregnancy. Acta Obstet Gynecol Scand 2020; 99:7–15.
Holmes AP, et al. Breastfeeding considerations for mothers of infants with neonatal abstinence syndrome. Pharmacotherapy 2017; 37:861–869.
Hayer S, et al. Cannabis and pregnancy: a review. Obstet Gynecol Surv 2023; 78:411–428.
Shyken JM, et al. Benzodiazepines in pregnancy. Clin Obstet Gynecol 2019; 62:156–167.
Wouldes TA, et al. Stimulants: how big is the problem and what are the effects of prenatal exposure? Semin Fetal Neonatal Med 2019; 24:155–160.

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68 - Gambling disorder

Gambling disorder

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References

560 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 4 Gambling disorder At the time of writing, no medicines are licensed for the treatment of problem gambling. However, international guidelines and draft NICE guidance recommend naltrexone off-label to reduce gambling severity in people with gambling problems.1,2 A 2017 meta-analysis demonstrated that when people receiving psychological therapy for problem gambling were given naltrexone there was a greater reduction in gambling than with those given placebo.3 Naltrexone is the only drug with likely effectiveness in problem gambling. Other drugs that have been evaluated include nalmefene, serotonin reuptake inhibitors, glutamatergic agents (e.g. N-acetylcysteine, acamprosate, memantine), mood stabilisers (e.g. topiramate, carbamazepine, lithium) and modafinil, olanzapine, haloperidol, tolcapone and bupropion.4 Naltrexone should only be initiated in specialist gambling clinics following a discussion of efficacy and adverse effects. Patients should be told about the interaction with concomitant opioids. Following baseline biochemistry analysis to exclude severe renal or hepatic impairment, naltrexone should be initiated at a dose of 25mg, increasing to 50mg with a review of efficacy at 4–6 weeks. Prescriptions could then be transferred to primary care with continuation for as long as the person continues to report benefit, alongside 6-monthly monitoring of renal and liver function. Clinicians should be aware of the known risks of developing or worsening of impulse control disorders with dopaminergic agents and aripiprazole (and probably other dopamine partial agonists),5–7 particularly in individuals at increased risk for problem gambling.8 References

National Institute for Health and Care Excellence. Harmful gambling: identification, assessment and management. In development [GID-NG10210]. https://www.nice.org.uk/guidance/indevelopment/gid-ng10210.
Thomas SA, et al. Australian guideline for treatment of problem gambling: an abridged outline. Med J Aust 2011; 195:664–665.
Mouaffak F, et al. Naltrexone in the treatment of broadly defined behavioral addictions: a review and meta-analysis of randomized controlled trials. Eur Addict Res 2017; 23:204–210.
Mestre-Bach G, et al. Pharmacological management of gambling disorder: an update of the literature. Expert Rev Neurother 2024; 24:391–407.
Akbari M, et al. Aripiprazole and its adverse effects in the form of impulsive-compulsive behaviors: a systematic review of case reports. Psychopharmacology (Berl) 2024; 241:209–223.
Wolfschlag M, et al. Drug-induced gambling disorder: epidemiology, neurobiology, and management. Pharmaceut Med 2023; 37:37–52.
Williams BD, et al. Aripiprazole and other third-generation antipsychotics as a risk factor for impulse control disorders: a systematic review and meta-analysis. J Clin Psychopharmacol 2024; 44:39–48.
Medicines and Healthcare products Regulatory Agency. Aripiprazole (Abilify): reminder on known risk of gambling disorder. 2023; https://www.gov.uk/government/news/aripiprazole-abilify-reminder-on-known-risk-of-gambling-disorder.

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01 - Principles of prescribing practice in childho

Principles of prescribing practice in childhood and adolescence

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 5 Principles of prescribing practice in childhood and adolescence Diagnosis can be difficult in children and comorbidity is very common. Treatment should generally target key symptoms rather than specific conditions. While a working diagnosis is beneficial to frame expectations and help communication with patients and parents, it should be kept in mind that it could take some time for the illness to evolve.1 Differences in pharmacokinetics and pharmacodynamics compared with adults can explain the more pronounced or unforeseen adverse reactions to medication in the young, as well as the differences in dose–effect relationships compared with those in adults.2 ■ ■Start low, go slow and monitor Depending on the age, dose starts lower than in adults or may be calculated in mg/kg per day terms.1,2 Titration of dose should proceed slowly, aiming for the minimum dose that adequately controls symptoms and has minimum adverse reactions. Regular reviewing of efficacy and tolerability should guide if treatment is necessary and requires continuation. ■ ■Polypharmacy in the severely ill Monotherapy is ideal. However, childhood-onset illness can be severe and may require treatment with psychosocial approaches in combination with more than one medication.1 Co-prescribing of medication for different disorders or symptoms is common. This complicates the interpretation of efficacy of each medicine1 and requires care with drug interactions and dose adjustments. ■ ■Adequate treatment duration Children are generally relatively more ill than their adult counterparts and will often require longer periods of treatment before responding. An adequate trial of treatment for those who are admitted for in-patient care may well be 8 weeks or more for depression or schizophrenia. Prescribing in children and adolescents

562 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 ■ ■Change one drug at a time Ideally changes should be made to one drug at a time and, if possible, remove a drug when adding a new one. ■ ■Monitor outcome in more than one setting For symptomatic treatments (such as stimulants for attention deficit hyperactivity or ADHD), bear in mind that the expression of problems may be different in different settings (e.g. home and school). For example, a dose titrated against parent reports may be too high for the daytime at school. ■ ■Educate the child and parents on the treatment For some, the need for medication will be life-long. The first experiences with medications are crucial to long-term outcomes and adherence. Education regarding the target symptoms of the medication, likely adverse reactions and medication adherence should be addressed. Provide information on the monitoring required and how to identify adverse reactions. Patients and their guardians should be encouraged to ask for changes to their treatment regimen where they consider them ineffective or poorly tolerated. ■ ■Review long-term treatment As children develop and grow through adolescence, dose changes may be required and adverse reactions may emerge or wane. ■ ■Transition from paediatric to adult services It is essential that continuity of care is not lost when moving from paediatric to adult services as this can be distressing and increase the risk of relapse. Planning and co-ordination should start at an early stage to achieve a smooth transition.3 ■ ■Technical aspects of paediatric prescribing Most psychotropic drugs used in adults are not licensed for use in children or adolescents.4 The Medicines Act 1968 and European legislation make provision for doctors to use medicines in an off-label or out-of-licence capacity or to use unlicensed medicines. Where possible a licensed preparation should be prescribed (Table 5.1), however it is recognised that the informed use of unlicensed medicines, or of licensed medicines in an ‘off-label’ way, is often necessary in paediatric practice. Individual prescribers are always responsible for ensuring that there is adequate information to support the quality, efficacy, safety and intended use of a drug before prescribing it.5 When writing a prescription in most countries, inclusion of age is a legal requirement in the case of prescription-only medicines for children under 12 years of age, but it is preferable to state the age for all prescriptions for children.

Prescribing in children and adolescents CHAPTER 5 Table 5.1 Psychotropic medications approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA), European Medicines Agency and the US Food and Drug Administration for children and adolescents (January 2024).6–9 Condition UK MHRA approval only; age (years) European Medicine Agency;* age (years) US Food and Drug Administration; age (years) ADHD Amfetamine–dexamfetamine mixed salts – – 3+ Amfetamine–dexamfetamine mixed salts extended release – – 6+ Atomoxetine 6+ 6+ 6+ Clonidine extended release – – 6–17 Dexamfetamine 6–17 6–17 3–16 Dexamfetamine sustained release – – 6–16 Dexmethylphenidate – – 6+ Guanfacine extended release 6–17 6–17 6–17 Lisdexamfetamine 6+ 6+ 6–17 Methamfetamine – – 6–17 Methylphenidate 6+ 6–18 6+ Viloxazine – – 6+ Anxiety disorders Duloxetine – – GAD 7+ Escitalopram – – GAD 7+ Autism spectrum disorder (irritability) Aripiprazole – – 6–17 Risperidone – – 5–17 Bipolar disorder (depressive episodes) Lurasidone – – 10+ Olanzapine–fluoxetine combination – – 10+ Bipolar disorder (manic or mixed episodes) Aripiprazole Manic episodes 13+ Manic episodes 13+ Manic or mixed episodes 10+ Asenapine – – 10+ Lithium – – 7+ Lithium extended release – – 12+ Olanzapine – – 13+ Quetiapine extended release – – 10+ (Continued )

564 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Condition UK MHRA approval only; age (years) European Medicine Agency;* age (years) US Food and Drug Administration; age (years) Risperidone – – 10+ Ziprasidone – 10+ – Conduct disorder Risperidone 5–18 5–18 – Depressive disorder Amitriptyline – – 12+ Escitalopram – – 12+ Fluoxetine 8+ 8+ 8+ Enuresis Amitriptyline 6–17 6–17 – Imipramine 6–17 5–18 6–17 Insomnia (in autism spectrum disorder or Smith Magenis syndrome) Melatonin extended release 6–17 2–18 – Insomnia (in ADHD) Melatonin immediate release 6–17 – – Insomnia (short term) Promethazine 5+ – – Obsessive compulsive disorder Clomipramine – – 10+ Fluoxetine – – 7+ Fluvoxamine 8+ 8+ 8+ Sertraline 6+ 6+ 6+ Schizophrenia Aripiprazole 15+ 15+ 13+ Brexpiprazole – – 13+ Lurasidone 13+ – 13+ Olanzapine – – 13+ Paliperidone 15+ 15+ 12+ Quetiapine – – 13+ Risperidone – – 13+ Sulpiride 14+ 6+ – Tourette’s disorder Aripiprazole – – 6–18 *Approvals may differ in individual countries. GAD, generalised anxiety disorder. Table 5.1 (Continued)

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02 - References

References

Prescribing in children and adolescents CHAPTER 5 References

Gerlach M, et al. Psychiatric Drugs in Children and Adolescents. Basic Pharmacology and Practical Applications. Vienna: Springer-Verlag;
Turner M, et al. Prescribing Medicines for Children: From drug development to practical administration. London: Pharmaceutical Press. Royal Pharmaceutical Society; 2019.
Paediatric Formulary Committee. BNF for Children (online). London: BMJ, Pharmaceutical Press, and RCPCH Publications; http://www. medicinescomplete.com.
Smogur M, et al. Psychotropic drug prescription in children and adolescents: approved medications in European countries and the United States. J Child Adolesc Psychopharmacol 2022; 32:80–88.
Sharma AN, et al. BAP position statement: off-label prescribing of psychotropic medication to children and adolescents. J Psychopharmacol 2016; 30:416–421.
Cortese S, et al. Psychopharmacology in children and adolescents: unmet needs and opportunities. Lancet Psychiatry 2023; 11:143–154.
EMC. Summaries of Product Characteristics. 2024; https://www.medicines.org.uk/emc/.
IBM Watson Health. IBM Micromedex Solutions. 2024; https://www.ibm.com/watson-health/about/micromedex.
Gelbe Liste Pharmindex. Gelbe Liste Online. News, Infos und Datenbanken für Ärzte, Apotheker und Fachpersonal aus Medizin und Pharmazie. 2024; https://www.gelbe-liste.de/.

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03 - Depression in children and adolescents

Depression in children and adolescents

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04 - Diagnostic issues

Diagnostic issues

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05 - Clinical guidance

Clinical guidance

566 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Depression in children and adolescents Diagnostic issues Approximately 15% of young people experience depression by age 18 years and these young people often have significant functional impairment and risk of harm.1 Compared with depressed adults, young people with depression tend to experience more irritability, loss of energy, insomnia and weight change, and less anhedonia and concentration problems.2 These symptoms can overlap with and appear similar to other disorders or can be minimised and incorrectly attributed to typical teenage development, making diagnosis challenging. Assessments should therefore be undertaken by clinicians who understand developmental variations and can accurately identify depression in young people.3 Clinical guidance For mild depression in children and adolescents, the UK National Institute for Health and Care Excellence (NICE) guidelines4 and American Academy of Child and Adolescent Psychiatry (AACAP) practice parameter3 recommend that supportive care or psychological intervention should be considered as first-line treatment, and that antidepressant medication should not be prescribed. For moderate to severe depression in young people, these same guidelines recommend offering psychological therapy, either alone or in combination with antidepressant medication. In addition, the AACAP practice parameter recommends that antidepressant medication alone could be considered, particularly if the presentation is severe and the patient is unable to engage in talking therapy, if psychological interventions are not available or if this is the patient’s and family’s preference. These guidelines were informed by research evidence for the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in treating depression in young people. For example, a seminal large UK National Institute of Mental Health (NIMH) funded randomised controlled trial (RCT) – the Treatment of Adolescents With Depression Study (TADS)5 – found a fluoxetine response rate of 61% over the acute (12-week) phase, which was significantly higher than the placebo response rate of 35%, giving a number needed to treat (NNT) of 4.5 Subsequent systematic reviews and meta-analyses, which include this trial and others, have provided further evidence demonstrating that SSRIs are effective at improving symptoms and functioning, and are largely acceptable treatments for depression in young people. However, several individual studies and systematic reviews studies report less certain effects6–10 and a 2021 Cochrane review described antidepressant effects as ‘small and unimportant’.11 The current evidence base is unclear about whether SSRI medications alone, psychological therapy alone or combined treatment is most effective for treating depression in children and adolescents. TADS found that fluoxetine alone or in combination with cognitive behavioural therapy (CBT) might accelerate treatment response, and that adding CBT might decrease adverse effects including suicidality, so enhancing the safety of fluoxetine.5,12 However, other studies have not replicated this finding,13,14 including the Adolescent Depression Antidepressants and Psychotherapy Trial (ADAPT), which found no benefit in combining fluoxetine with CBT over fluoxetine alone.15 A network

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06 - Prescribing for depression in children and ad

Prescribing for depression in children and adolescents

Prescribing in children and adolescents CHAPTER 5 meta-analysis comparing several treatments for depression in children and adolescents also found that combined fluoxetine and CBT was no more effective than fluoxetine alone but found that this combination was more effective than CBT alone.16 Prescribing for depression in children and adolescents Before prescribing ■ ■Undertake a comprehensive assessment: Establish a clinical diagnosis of depression. Exclude differential diagnoses, including psychiatric disorders (such as bipolar affective disorder), medical disorders (such as endocrine disorders) and medication-related effects (such as steroid adverse effects). Identify any comorbid psychiatric or medical conditions. Consider contraindications to SSRIs and potential interactions. Assess risk of harm to self and others. Formulate considering factors that could predispose, precipitate and perpetuate depression, such as family history of psychiatric disorders (including depression and bipolar affective disorder) and environmental stressors (including victimisation and other adverse experiences). If any co-occurring problems are identified, these should be addressed and prioritised based on a comprehensive formulation. ■ ■Measure baseline severity: Measures of depression symptoms include the clinician- administered Children’s Depression Rating Scale-Revised (CDRS-R)17,18 and the childand parent-reported Mood and Feelings Questionnaire (MFQ)19 or Revised Children’s Anxiety and Depression Scale (RCADS).20 Measures of functional impairment include the Children’s Global Assessment Scale (CGAS).21 ■ ■Obtain informed consent: Discuss the nature, course and treatment of depression, potential adverse effects of medication, delay in onset of treatment effects, plan for monitoring and maintenance of medication and potential discontinuation effects. ■ ■Develop a safety plan: In all but exceptional circumstances, a parent or carer should be responsible for the secure storage of medication for a child or adolescent. Advise the young person and their parent/carer of professionals or services they should contact if they experience significant adverse effects, risk of harm or worsening symptoms. What to prescribe ■ ■Fluoxetine is the recommended first-line medication for depression in children and adolescents.3,4 It has the strongest current evidence for efficacy,6,9,11,16,22,23 showing moderate effects in reducing depression symptoms versus placebo (standardised mean difference = 0.51).16 In the UK, NICE states that fluoxetine is the only antidepressant for which clinical trial evidence shows that benefits outweigh risks.4 Fluoxetine should be started at a dose of 10mg daily which can be increased after 1 week to the minimum therapeutic dose of 20mg daily. Higher doses (up to 40–60mg daily) may be considered, particularly in older children of higher body weight or when, in severe illness, an early clinical response is considered a priority.4,5,15,24 The long half-life of fluoxetine may be beneficial for adolescents because it confers a reduced risk of discontinuation effects or relapse if doses are delayed or missed.25 Fluoxetine is approved for treatment of depression in patients aged 8 years and over by the US Food and

568 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Drug Administration (FDA), and by the European Medicines Agency and the UK Medicines and Healthcare products Regulatory Agency (MHRA) if the young person has moderate to severe depression and has not responded to psychological therapy.26 ■ ■Sertraline and escitalopram have also been found to be more effective than placebo for treating depression in young people6,22 and should be considered as alternatives if fluoxetine is not tolerated. Sertraline and escitalopram should also be started at low doses (25–50mg daily and 5–10mg daily, respectively) and titrated to therapeutic doses (50–200mg daily and 10–20mg daily, respectively). The half-lives of sertraline, escitalopram and some other antidepressants may be shorter in young people than adults, so twice daily dosing could be considered to prevent discontinuation symptoms.27 Escitalopram is approved by the FDA for treatment of depression in patients aged 12 years and over. ■ ■Duloxetine and venlafaxine may be effective but are relatively poorly tolerated.28 ■ ■Agomelatine was more effective than placebo in children aged 7–11 years and showed similar efficacy to fluoxetine. A dose of 10mg seems to be effective. Agomelatine is extremely well tolerated but not licensed for children or adolescents. Liver function test (LFT) changes occurred in 1% of participants.29 Vortioxetine was no more effective than placebo in a large study of 12–17-year-old children.30 ■ ■For children and adolescents who have significant depressive symptoms resulting in distress or impairment despite an adequate trial of an SSRI alone, consider combination SSRI and psychological therapy. There is some limited evidence that combination treatment may be more beneficial than SSRI alone for some young people.6,31–33 ■ ■For children and adolescents who have significant depressive symptoms resulting in distress or impairment despite adequate trials of an SSRI (fluoxetine) and psychological therapy, consider a switch to a different SSRI (sertraline, escitalopram).4,31 This guidance is largely based on the Treatment of Resistant Depression in Adolescents (TORDIA) trial,24 the only RCT that has examined the comparative efficacy of different treatment strategies for SSRI-resistant depression in young people.24 This trial found that many participants improved when switched to another SSRI or venlafaxine (response rate 47% and 48%, respectively) and improved even more when this medication switch was combined with starting concurrent CBT (response rate 55% vs 41% without CBT) after 12 weeks of treatment. A switch to an SSRI was just as efficacious as a switch to venlafaxine but had less frequent and severe side effects, so an SSRI switch is preferred. ■ ■If limited response despite adequate trials of these medications and psychological therapy, consider augmenting SSRI treatment with another medication such as a second-generation antipsychotic or lithium. (Also consider augmentation if there has been partial response to an SSRI.31) Alternatively, consider switching to an antidepressant from a different class, for example mirtazapine34 – especially if poor sleep is a problem. There are no RCTs testing the effectiveness of these strategies in children or adolescents, and so this guidance is largely based on evidence from studies of adults with treatment-resistant depression, in addition to very limited follow-up of TORDIA participants receiving open-label treatment.31,35 ■ ■Finally, if still no response to these medications and the young person’s depression is very severe, ketamine, repetitive transcranial magnetic stimulation (rTMS) or electroconvulsive therapy can be considered. These interventions have an evidence base and

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07 - After prescribing

After prescribing

Prescribing in children and adolescents CHAPTER 5 are approved for use in adults with treatment-resistant depression, but there is no substantial evidence in children and adolescents.31 With regard to ketamine, or its enantiomer esketamine, emerging evidence suggests that it may be effective and adequately tolerated in adolescents with treatment-resistant depression based on a small number of studies, including two small RCTs.36–38 Considering rTMS, initial evidence suggested that it may be effective, again based on a small number of studies and a small RCT, but a larger RCT found no evidence of effectiveness.39 Electroconvulsive therapy (ECT) has limited evidence of effectiveness in young people, although one randomised trial in adolescents showed good effect against both depression and suicide.40 Therefore, these treatments’ unknown potential effects on the developing brain need to be considered carefully and weighed up against the risks of not attempting these treatments.41 Further research is greatly needed to inform clinical decisions.42 ■ ■NICE warns against prescribing paroxetine, venlafaxine, tricyclic antidepressants or St John’s wort for depression in young people, because of potential adverse effects and interactions.4 Table 5.2 summarises medication treatment for depression in children and adolescents. After prescribing Acute phase ■ ■Monitor for adverse effects regularly, for example weekly for the first 4 weeks. Children and adolescents generally tolerate SSRIs well. Potential adverse effects include those experienced by adults, described in Chapter 3. Additionally, young people taking SSRIs have a small increased risk of suicidality and switch to mania, as well as activation effects (see ‘Specific issues’ later in this chapter). Therefore, risk of harm, mood and behaviour should be monitored closely and addressed.3,4,6,31 ■ ■After 4 weeks of SSRI treatment at a therapeutic dose, assess response including depression severity using the measures completed at baseline. Most therapeutic effects appear by 4 weeks.43 ■ ■If partial or non-response, consider the possibility of poor treatment adherence, inaccurate diagnosis, comorbidity or modifiable maintaining factors. Table 5.2 Summary of pharmacotherapy for depression in children and adolescents.3,4,6,31 Medication Starting dose Therapeutic dose range First line Fluoxetine 10mg/day 20–60mg/day Second line Sertraline Escitalopram Citalopram* 25–50mg/day 5–10mg/day 10mg/day 50–200mg/day 10–20mg/day 20–40mg/day Subsequently Consider augmentation of antidepressant with second-generation antipsychotic or lithium.† Consider switching to an antidepressant from a different class, such as mirtazapine. *Caution advised in cardiac or hepatic disease. †No randomised controlled trials available in young people (but there is evidence from adult trials).

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08 - Specific issues

Specific issues

570 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 ■ ■If none of these factors explains the continued depressive symptoms and the young person does not have adverse effects, consider increasing the dose. Reassess every 4 weeks.3,31 This recommendation is largely based on evidence from adult depression trials, which have demonstrated small but significant improvements in depression symptoms with higher doses of SSRIs,44 as there has been only limited research on this topic in children and adolescents.45 ■ ■If adverse effects develop, consider reducing the dose to the highest tolerated dose. ■ ■If partial or non-response after 8 weeks of the maximum recommended (or highest tolerated) therapeutic dose of an SSRI, consider the medication changes outlined earlier.31 Maintenance phase Continue medication for 6–12 months after remission to reduce the risk of relapse. Consider a longer maintenance phase if depressive episodes were recurrent or chronic.3,4,6,31 Again, this recommendation is largely based on evidence from adult depression trials, in addition to very limited research in children and adolescents.46,47 Discontinuation phase Discontinuation may be considered after the maintenance phase. This is best undertaken during a period of low stress. Taper medications slowly and hyperbolically (see Chapter 3) to minimise the risk of discontinuation symptoms.3,4,6,31 Specific issues ■ ■Age The evidence base for these recommendations is stronger for adolescents than for children, so caution should be higher when considering prescribing for children. There has been no research investigating antidepressant medication use in pre-school children, and medications are not recommended for this age group.4,22 ■ ■Suicidality Antidepressant medication has been linked to an increased risk of suicidality in young people, which led to warnings issued by the US FDA, the European Medicines Agency and the UK MHRA in 2003–2005. Subsequent meta-analyses have also found evidence of this association with reported suicidality,11,22,48 particularly for venlafaxine,16,23 as well as a link with aggression.49 A meta-analysis of reported suicidal thoughts or attempts in depression trials found a pooled absolute rate in antidepressant-treated young people of 3% and in those receiving placebo of 2%, giving a number needed to harm (NNH) of 112 (note these rates are low, probably because those with high risk of suicidality were often excluded from trials).50 Concern has also been expressed about emergent suicidality with escitalopram.51 To date, there has been no link between antidepressant use and completed suicides, but extreme care should be exercised. Untreated depression is a significant risk factor for suicidality. After the FDA warning on antidepressant use in children and adolescents, antidepressant use declined, untreated depression increased and suicide rates increased.52,53 Given the risks of untreated depression, including completed suicide and impaired functioning, and that many more patients benefit from SSRIs than those who experience these serious adverse events, it is thought that the benefits of antidepressants, particularly fluoxetine, are

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09 - References

References

Prescribing in children and adolescents CHAPTER 5 likely to outweigh these risks in moderate to severe depression. Nonetheless, it bears repeating that the risk of suicide should be very carefully monitored.3,4,6,31 ■ ■Activation and manic switch Activation adverse effects of antidepressant medication – including increased activity, restlessness and agitation – occur more commonly in children than in adolescents or adults. These effects, including mild symptoms, may occur in about 10% of children with depression taking SSRIs.54,55 They are usually a transient response to starting medication or increasing dose and should be differentiated from manic switch. Conversion to mania is rarer but is observed more often in young people taking antidepressants than in adults.56,57 However, there is no clear evidence that this switch is caused by antidepressants. References

Avenevoli S, et al. Major depression in the national comorbidity survey-adolescent supplement: prevalence, correlates, and treatment. J Am Acad Child Adolesc Psychiatry 2015; 54:37–44.e32.
Rice F, et al. Adolescent and adult differences in major depression symptom profiles. J Affect Disord 2019; 243:175–181.
Birmaher B, et al. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry 2007; 46:1503–1526.
National Institute for Health and Care Excellence (NICE). Depression in children and young people: identification and management. NICE Guideline [NG134]. 2019 (last checked December 2023). www.nice.org.uk/guidance/ng134.
March J, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. JAMA 2004; 292:807–820.
Goodyer IM, et al. Practitioner Review: Therapeutics of unipolar major depressions in adolescents. J Child Psychol Psychiatry 2019; 60:232–243.
Locher C, et al. Efficacy and safety of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and placebo for common psychiatric disorders among children and adolescents: a systematic review and meta-analysis. JAMA Psychiatry 2017; 74:1011–1020.
Teng T, et al. Effect of antidepressants on functioning and quality of life outcomes in children and adolescents with major depressive disorder: a systematic review and meta-analysis. Transl Psychiatry 2022; 12:183.
Vitiello B, et al. Pharmacological treatment of children and adolescents with depression. Expert Opin Pharmacother 2016; 17:2273–2279.
Walkup JT. Antidepressant efficacy for depression in children and adolescents: industry- and NIMH-funded studies. Am J Psychiatry 2017; 174:430–437.
Hetrick SE, et al. New generation antidepressants for depression in children and adolescents: a network meta-analysis. Cochrane Database Syst Rev 2021; 5:CD013674.
Treatment for Adolescents With Depression Study (TADS) Team. The Treatment for Adolescents With Depression Study (TADS): long-term effectiveness and safety outcomes. Arch Gen Psychiatry 2007; 64:1132–1143.
Cox GR, et al. Psychological therapies versus antidepressant medication, alone and in combination for depression in children and adolescents. Cochrane Database Syst Rev 2014; 11:CD008324.
Dubicka B, et al. Combined treatment with cognitive-behavioural therapy in adolescent depression: meta-analysis. Br J Psychiatry 2010; 197:433–440.
Goodyer I, et al. Selective serotonin reuptake inhibitors (SSRIs) and routine specialist care with and without cognitive behaviour therapy in adolescents with major depression: randomised controlled trial. BMJ 2007; 335:142.
Zhou X, et al. Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis. Lancet Psychiatry 2020; 7:581–601.
Poznanski EO, et al. Children’s Depression Rating Scale, Revised (CDRS-R). Los Angeles: Western Psychological Services; 1996.
Mayes TL, et al. Psychometric properties of the Children’s Depression Rating Scale-Revised in adolescents. J Child Adolesc Psychopharmacol 2010; 20:513–516.
Angold A, et al. Development of a short questionnaire for use in epidemiological studies of depression in children and adolescents. Int J Methods Psychiatr Res 1995; 5:237–249.
Chorpita BF, et al. Assessment of symptoms of DSM-IV anxiety and depression in children: a revised child anxiety and depression scale. Behav Res Ther 2000; 38:835–855.
Shaffer D, et al. A children’s global assessment scale (CGAS). Arch Gen Psychiatry 1983; 40:1228–1231.
Hetrick SE, et al. Newer generation antidepressants for depressive disorders in children and adolescents. Cochrane Database Syst Rev 2012; 11:CD004851.
Cipriani A, et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. Lancet 2016; 388:881–890.
Brent D, et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA Randomized Controlled Trial. JAMA 2008; 299:901–913.
Wilens TE, et al. Fluoxetine pharmacokinetics in pediatric patients. J Clin Psychopharmacol 2002; 22:568–575.

572 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 26. Aurobindo Pharma – Milpharm Ltd. Summary of product characteristics. Fluoxetine 20mg capsules. 2020 (last checked December 2023); https://www.medicines.org.uk/emc/product/11909/smpc#gref. 27. Findling RL, et al. The relevance of pharmacokinetic studies in designing efficacy trials in juvenile major depression. J Child Adolesc Psychopharmacol 2006; 16:131–145. 28. Rao Y, et al. Efficacy and tolerability of antidepressant drugs in treatment of depression in children and adolescents: a network meta-analysis. Zhejiang Da Xue Xue Bao Yi Xue Ban 2022; 51:480–490. 29. Arango C, et al. Safety and efficacy of agomelatine in children and adolescents with major depressive disorder receiving psychosocial counselling: a double-blind, randomised, controlled, phase 3 trial in nine countries. Lancet Psychiatry 2022; 9:113–124. 30. Findling RL, et al. Vortioxetine for major depressive disorder in adolescents: 12-week randomized, placebo-controlled, fluoxetine-referenced, fixed-dose study. J Am Acad Child Adolesc Psychiatry 2022; 61:1106–1118.e1102. 31. Dwyer JB, et al. Annual research review: defining and treating pediatric treatment-resistant depression. J Child Psychol Psychiatry 2020; 61:312–332. 32. Asarnow JR, et al. Treatment of selective serotonin reuptake inhibitor-resistant depression in adolescents: predictors and moderators of treatment response. J Am Acad Child Adolesc Psychiatry 2009; 48:330–339. 33. Curry J, et al. Predictors and moderators of acute outcome in the Treatment for Adolescents with Depression Study (TADS). J Am Acad Child Adolesc Psychiatry 2006; 45:1427–1439. 34. Haapasalo-Pesu KM, et al. Mirtazapine in the treatment of adolescents with major depression: an open-label, multicenter pilot study. J Child Adolesc Psychopharmacol 2004; 14:175–184. 35. Emslie GJ, et al. Treatment of Resistant Depression in Adolescents (TORDIA): week 24 outcomes. Am J Psychiatry 2010; 167:782–791. 36. Dwyer JB, et al. Efficacy of intravenous ketamine in adolescent treatment-resistant depression: a randomized midazolam-controlled trial. Am J Psychiatry 2021; 178:352–362. 37. Di Vincenzo JD, et al. The effectiveness, safety and tolerability of ketamine for depression in adolescents and older adults: a systematic review. J Psychiatr Res 2021; 137:232–241. 38. Zhou Y, et al. Effect of repeated intravenous esketamine on adolescents with major depressive disorder and suicidal ideation: a randomized active-placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 2024; 63:507–518. 39. Sigrist C, et al. Transcranial magnetic stimulation in the treatment of adolescent depression: a systematic review and meta-analysis of aggregated and individual-patient data from uncontrolled studies. Eur Child Adolesc Psychiatry 2022; 31:1501–1525. 40. Cai H, et al. Suicidal ideation and electroconvulsive therapy: outcomes in adolescents with major depressive disorder. J ECT 2023; 39:166–172. 41. Zimmermann KS, et al. Esketamine as a treatment for paediatric depression: questions of safety and efficacy. Lancet Psychiatry 2020; 7:827–829. 42. Ayvaci ER, et al. Special populations: treatment-resistant depression in children and adolescents. Psychiatr Clin North Am 2023; 46:359–370. 43. Varigonda AL, et al. Systematic review and meta-analysis: early treatment responses of selective serotonin reuptake inhibitors in pediatric major depressive disorder. J Am Acad Child Adolesc Psychiatry 2015; 54:557–564. 44. Jakubovski E, et al. Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry 2016; 173:174–183. 45. Heiligenstein JH, et al. Fluoxetine 40-60 mg versus fluoxetine 20 mg in the treatment of children and adolescents with a less-than-complete response to nine-week treatment with fluoxetine 10-20 mg: a pilot study. J Child Adolesc Psychopharmacol 2006; 16:207–217. 46. Emslie GJ, et al. Fluoxetine treatment for prevention of relapse of depression in children and adolescents: a double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry 2004; 43:1397–1405. 47. Emslie GJ, et al. Fluoxetine versus placebo in preventing relapse of major depression in children and adolescents. Am J Psychiatry 2008; 165:459–467. 48. Li K, et al. Risk of suicidal behaviors and antidepressant exposure among children and adolescents: a meta-analysis of observational studies. Front Psychiatry 2022; 13:880496. 49. Sharma T, et al. Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports. BMJ 2016; 352:i65. 50. Bridge JA, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta- analysis of randomized controlled trials. JAMA 2007; 297:1683–1696. 51. Plöderl M, et al. Re: “A multicenter double-blind, placebo-controlled trial of escitalopram in children and adolescents with generalized anxiety disorder” by Strawn et al. – Concerning harm-benefit ratio in a recent trial about escitalopram for generalized anxiety disorder. J Child Adolesc Psychopharmacol 2023; 33:295–296. 52. Gibbons RD, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry 2007; 164:1356–1363. 53. Libby AM, et al. Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs. Am J Psychiatry 2007; 164:884–891. 54. Offidani E, et al. Excessive mood elevation and behavioral activation with antidepressant treatment of juvenile depressive and anxiety disorders: a systematic review. Psychother Psychosom 2013; 82:132–141. 55. Safer DJ, et al. Treatment-emergent adverse events from selective serotonin reuptake inhibitors by age group: children versus adolescents. J Child Adolesc Psychopharmacol 2006; 16:159–169. 56. Baldessarini RJ, et al. Antidepressant-associated mood-switching and transition from unipolar major depression to bipolar disorder: a review. J Affect Disord 2013; 148:129–135. 57. Virtanen S, et al. Antidepressant use and risk of manic episodes in children and adolescents with unipolar depression. JAMA Psychiatry 2024; 81:25–33.

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10 - Bipolar disorder in children and adolescents

Bipolar disorder in children and adolescents

10 - Chapter 5 Prescribing in children and adolescents

11 - Clinical guidance

Clinical guidance

Prescribing in children and adolescents CHAPTER 5 Bipolar disorder in children and adolescents Clinical guidance Before prescribing ■ ■Establish clinical diagnosis informed by structured instrument assessment if possible. Symptom checklists should be avoided, especially in primary care. Try to monitor symptom patterns prospectively with mood or sleep diaries. If in doubt, seek specialist advice early on. ■ ■Explain the diagnosis to the patient and family and invest time and effort in psycho education. This is likely to improve adherence and help children and adolescents and their families appreciate early warning signs of a relapse. Furthermore, there is evidence that such approaches reduce relapse rates, at least in adults.1 ■ ■Measure baseline symptoms of mania (e.g. Young Mania Rating Scale2 [YMRS] and the parent YMRS3), depression (e.g. Children’s Depression Rating Scale4 [CDRS]) and impairment (e.g. Clinical Global Impression – BD version5). Use these to set clear and realistic treatment goals. ■ ■Measure baseline height, weight, waist and hip circumference, pulse, blood pressure and electrocardiogram (ECG) and obtain baseline bloods as appropriate (fasting blood glucose, HbA1c, fasting lipid profile, full blood count [FBC], urea and electrolytes [U&E], creatine kinase, LFTs, prolactin and thyroid function). What to prescribe ■ ■Tables 5.3, 5.4, 5.5 and 5.6 summarise medication use in bipolar mania and depression and acute mania. ■ ■For the treatment of mania and hypomania in children and adolescents, UK NICE guidelines suggest following the same recommendations as for adults – second- generation antipsychotics (SGAs) may be used as first-line treatment, and mood stabilisers (MS) can be added after a failure of two trials of SGAs.6 The difference in comparison with adult guidelines is that NICE recommends that SGAs should not be routinely offered for more than 12 weeks. This information should be shared with the child or adolescent and their family. ■ ■SGAs seem to show greater short-term efficacy (effect size [ES] = 0.65 compared with placebo) than MS (ES = 0.20 compared with placebo) in youth, according to a 2010 meta-analysis.7 ■ ■SGAs produce significantly greater weight gain (particularly olanzapine) and somnolence in children and adolescents compared with adults,7 although weight gain assessment is made complicated by normal growth at this time of life. ■ ■Valproate should be completely avoided in all adolescents. ■ ■Adherence to lithium cannot be assumed and blood level testing may be difficult in adolescents. ■ ■Overall, we recommend the use of SGAs as first line for the acute treatment of mania in children and adolescents (Tables 5.3 and 5.5). ■ ■It is helpful to document family history of response and non-response to pharmacological treatment as there is evidence to suggest that pharmacological response, at least for lithium, runs in families.8

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12 - Other treatments

Other treatments

574 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 After prescribing ■ ■Assess and measure symptoms on a regular basis to establish effectiveness. ■ ■Monitor weight, height and waist to hip circumference at each visit and repeat all fasting bloods at 3 months (then every 6 months). Offer advice on healthy lifestyle and exercise. ■ ■The duration of most medication trials is 3–5 weeks – this is the period over which most improvement is anticipated to occur. This should guide decisions about how long to try a single drug in a patient. A complete absence of response at 2 weeks should prompt consideration of a switch to another SGA (or a dose increase where labelling allows). ■ ■If there is no response, check adherence, measure blood levels where possible and consider increasing the dose. Consider concurrent use of an SGA and MS. ■ ■Judicious extrapolation of the evidence from adults9 is required because of the very limited evidence base in youths with bipolar disorder. This includes treatment duration and prophylaxis.6,7,10 Maintenance treatment should follow adult guidelines. Consider the use of lithium early in the course of treatment, either by switching to lithium monotherapy prophylaxis or as an adjunct to a successful acute medication. Lithium has therapeutic advantages over other options in adults but should only be used where adherence is assured. Specific issues ■ ■Bipolar depression is a common clinical challenge and its treatment has been studied much less in youths than in adults (Tables 5.4 and 5.6). Antidepressants should be used rarely and with care for the minimum duration possible and only in the presence of an antimanic agent.6 There is limited evidence for the benefit of antidepressants in bipolar depression in adults.11 Because of the dearth of trials in youth, we are compelled to extrapolate from adult studies,6 which suggest use of the olanzapine/fluoxetine combination as the most effective treatment, along with lurasidone, which is supported by evidence from several trials in children aged 10–17 years.12–14 The metabolic effects of olanzapine arguably make it a second-line choice after lurasidone. ■ ■The exact relationship between ADHD and bipolar depression is still debated. Some evidence suggests that stimulants in children with ADHD and manic symptoms may be well tolerated15 and that they may be safe and effective to use after mood stabilisation.15 Caution and experience with prescribing these drugs are required. ■ ■The DSM-5 category of disruptive mood dysregulation disorder (DMDD) includes severely irritable children (who were commonly misdiagnosed as having bipolar depression in the USA). There is no established treatment for DMDD. Lithium is ineffective16 but SSRIs and psychological treatment options, such as parenting interventions, may be considered.17 Other treatments ■ ■Adjunct treatments including psychoeducation, CBT and especially family-focused interventions can enhance treatment and reduce depression relapse rates in bipolar disorder.18

Prescribing in children and adolescents CHAPTER 5 ■ ■There is emerging evidence that a combination of omega-3 fatty acids with inositol is effective in mania and hypomania in children aged 5–12 years.19 Confirmatory trials are needed. ■ ■Cariprazine may be effective in young people but evidence is limited.20 ■ ■The use of high-frequency rTMS in adolescents with treatment-resistant unipolar depression is only supported by open-label studies21 and no RCT has been done in youth with either unipolar or bipolar depression. Therefore, its use is still considered experimental. One randomised sham-controlled study found rTMS ineffective in treating acute mania in youth (as an add-on to standard pharmacotherapy).22 ■ ■One small trial supported the adjunctive use of melatonin (6mg/day) in adults with mania.23 Evidence is not yet sufficient to recommend its use in children. Table 5.3 Pharmacological treatments of mania in children and adolescents. Medication Comment Lithium Lithium is cleared relatively quickly in children so twice daily dosing will be required, especially when using liquid or non-modified-release preparations.24 One double-blind placebo-controlled randomised trial25 showed significant reductions in substance use and clinical ratings after 6 weeks in adolescents with bipolar disorder and comorbid substance misuse. In a double-blind placebo- controlled discontinuation trial (N = 40) over 2 weeks, no significant difference in relapse rates were found between lithium and placebo.26 A later double-blind placebo-controlled study (N = 81), over 8 weeks, demonstrated a significantly larger change in YMRS score in lithium-treated youths. There was a significant increase in thyrotropin with lithium, but no difference in weight gain.27 Lithium and divalproex did not differ in an 18-month maintenance trial in youths (N = 60) who initially stabilised on combination pharmacotherapy of lithium and divalproex.28 However, given the compelling evidence for lithium maintenance and prophylaxis in adults, we recommend that clinicians consider its use in adolescents in preference to valproate. Valproate should be avoided in adolescents in any case. A meta-analysis29 found lithium to be ‘clearly inferior’ to risperidone in mania. Lithium may also be inferior to quetiapine in the treatment of mania in children and adolescents.30 One small 6-month study found higher relapse rates in those who discontinued lithium compared with those who continued.31 Another naturalistic 8-month study showed lithium to be effective and well tolerated.32 Valproate In an RCT (N = 150)33 divalproex ER (titrated to clinical response or 80–125mg/L) did not lead to significant differences in mean YMRS compared with placebo at 4 weeks. (Also see risperidone and quetiapine sections below.) Valproate should be avoided in all peri- and post-pubertal children and adolescents. Oxcarbazepine A double-blind placebo-controlled study (N = 116) did not show significant differences between placebo and oxcarbazepine (mean dose 1515mg/day) in reducing mania rating at 7 weeks.34 (Continued )

576 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Medication Comment Olanzapine A double-blind placebo-controlled study (N = 161)35 showed olanzapine (5–20mg/day) to be significantly more effective than placebo over a period of 3 weeks. There was greater weight gain in the treatment group (weight gain was 3.7kg for olanzapine vs 0.3kg for placebo) and associated significantly increased fasting glucose, total cholesterol, AST, ALT and uric acid. The addition of topiramate reduces weight gain by more than a half.36 Risperidone A double-blind placebo-controlled study (N = 169) showed risperidone (at doses 0.5–2.5 or 3–6mg) to be more effective than placebo in YMRS mean score reduction in a 3-week follow-up.37 The lower dose led to the same benefits at a lower risk of adverse effects. Sleepiness and fatigue were common. Mean weight increase in treatment groups was 0.7kg vs 1.7kg for the low-dose arm and 1.4kg for the high-dose arm. In the Treatment of Early Age Mania (TEAM) study, higher response rates (and metabolic side effects) occurred with risperidone (mean dose 2.57mg) than with lithium (mean level 1.09mmol/L) and divalproex sodium (mean level 113.6mg/L).38 A randomised follow-up of this study showed again the superiority of risperidone as an alternative treatment for non-responders to lithium and divalproex sodium, and as an add-on treatment to partial responders to the two drugs.39 These results need to be interpreted with caution as the definition of mania was broader than that used in some countries. The same caveat applies when considering another double-blind placebo-controlled trial showing significantly better results for risperidone (mean dose 0.5mg) than for valproic acid (mean level 81mg/L) in 3–7-year-old children supposedly diagnosed with mania.40 Quetiapine A double-blind placebo-controlled study (N = 277)41 showed quetiapine (at doses of 400 or 600mg/day) to be significantly better than placebo in reducing mean YMRS scores at 3 weeks. The most common side effects included somnolence and sedation. Weight gain was 1.7kg in the quetiapine group and 0.4kg for placebo. Quetiapine is effective as an adjunct to valproate compared with valproate alone (N = 30, 6 weeks)42 and was as effective as valproate in a double-blind trial (N = 50, 4 weeks).43 Aripiprazole A double-blind placebo-controlled study44,45 showed aripiprazole (at doses 10 or 30mg/day) to be significantly better than placebo at both 4 weeks (N = 296)44 and 30 weeks (N = 210).45 There was a higher incidence of extrapyramidal side effects in the treatment groups (especially the higher dose). Weight gain was significantly more common in the treatment groups compared with placebo (3.0kg for placebo; 6.5kg for the low-dose arm and 6.6kg for the high-dose arm) at week 30. Ziprasidone A double-blind placebo-controlled trial (N = 237)46 showed ziprasidone (at flexible doses 40–160mg) to be more effective than placebo in reducing mean YMRS scores at 4 weeks. Sedation and somnolence were the most common side effects, while it demonstrated a neutral metabolic profile and no QTc prolongation. A second RCT of 171 participants showed broadly similar outcomes.47 Asenapine A 3-week double-blind placebo-controlled study (N = 350) demonstrated statistical superiority of asenapine over placebo for each of the doses used (2.5, 5 or 10mg BD), with significant difference as early as day 4. However, many side effects were reported, including weight gain of more than 7% of baseline in 8–12% of the asenapine group vs 1.1% in the placebo group, metabolic changes (increase in insulin, lipids, glucose), as well as somnolence, sedation, oral hypoaesthesia and paraesthesia.48 ALT, alanine transaminase; AST, aspartate aminotransferase; ER, extended release; MS, mood stabilisers; YMRS, Young Mania Rating Scale. Table 5.3 (Continued)

Prescribing in children and adolescents CHAPTER 5 Table 5.4 Pharmacological treatments of bipolar depression in children and adolescents. Medication Comment Olanzapine/ fluoxetine combination A large study (N = 255) of the olanzapine/fluoxetine combination (either 6/25 or 12/50mg daily) for 8 weeks49 showed an advantage for the combination. Most frequent side effects were weight gain (4.4kg for olanzapine/fluoxetine and 0.5kg for placebo), somnolence and hyperlipidaemia. The olanzapine/fluoxetine combination is recommended by UK NICE guidelines,6 along with quetiapine, as first-line treatment for bipolar depression in children and adolescents, as in adults. Although the olanzapine/fluoxetine combination is not currently available as a single preparation in the UK or European Union, its effects can be achieved by combining olanzapine and fluoxetine (e.g. 5/20 or 10/40mg). Lurasidone Lurasidone has been shown to be effective in bipolar depression in adults50–52 and it does not seem to cause weight gain and other metabolic disturbances. It is also safe and effective in treating schizophrenia in adolescents.53 Lurasidone was effective in bipolar depression in children (10–17 years) both acutely12 and in a 2-year follow-up study.14 Dose ranged from 18.5mg (20mg) to 74mg (80mg). Lurasidone may be the preferred antipsychotic in children on account of its good tolerability.54 In fact, a 2022 network meta-analysis14 considered lurasidone to be the optimal treatment for bipolar depression in youths. Quetiapine A small study in 32 adolescents,55 followed by a larger RCT (N = 193),56 failed to show effectiveness. The second study had a very high placebo response, which is not usually seen in adult quetiapine studies57 and which may reflect issues in diagnosing mood disorders in multisite studies.58 A 2022 meta-analysis suggested quetiapine was ineffective in bipolar depression in young people.14 Lamotrigine Lamotrigine has only modest, if any, effects in adult bipolar depression59 and it has not been studied in RCTs for the treatment of acute bipolar depression in children and adolescents and is, therefore, not recommended as a first-line drug. Moreover, a placebo-controlled randomised withdrawal study of adjunctive lamotrigine for bipolar disorder in youth, lasting over 36 weeks, failed to show any benefit in preventing time to occurrence of a bipolar event.60 Table 5.6 Recommended first-line treatments for bipolar depression.* Lurasidone 18.5mg (20mg) to 74mg (80mg) daily Olanzapine/fluoxetine 6/25mg to 12/50mg daily Continue acutely effective dosing regimen as prophylaxis and consider need for lithium if not already prescribed. Table 5.5 Recommended first-line treatments for acute mania. Aripiprazole 10mg daily Risperidone 0.5–2.5mg daily Olanzapine 5–20mg daily Quetiapine Up to 400mg daily Asenapine 2.5–10mg twice daily *Continue acutely effective dosing regimen as prophylaxis and consider need for lithium if not already prescribed.

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References

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Gracious BL, et al. Discriminative validity of a parent version of the Young Mania Rating Scale. J Am Acad Child Adolesc Psychiatry 2002; 41:1350–1359.
Poznanski EO, et al. Preliminary studies of the reliability and validity of the children’s depression rating scale. J Am Acad Child Psychiatry 1984; 23:191–197.
Spearing MK, et al. Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP. Psychiatry Res 1997; 73:159–171.
National Institute for Health and Care Excellence. Bipolar disorder: assessment and management. Clinical Guidance [CG185]. 2014 (last updated December 2023); https://www.nice.org.uk/guidance/cg185.
Correll CU, et al. Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trials. Bipolar Disord 2010; 12:116–141.
Duffy A, et al. A prospective study of the offspring of bipolar parents responsive and nonresponsive to lithium treatment. J Clin Psychiatry 2002; 63:1171–1178.
Geddes JR, et al. Treatment of bipolar disorder. Lancet 2013; 381:1672–1682.
Diaz-Caneja CM, et al. Practitioner review: long-term pharmacological treatment of pediatric bipolar disorder. J Child Psychol Psychiatry 2014; 55:959–980.
Pacchiarotti I, et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry 2013; 170:1249–1262.
DelBello MP, et al. Efficacy and safety of lurasidone in children and adolescents with bipolar I depression: a double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry 2017; 56:1015–1025.
Singh MK, et al. Lurasidone in children and adolescents with bipolar depression presenting with mixed (subsyndromal hypomanic) features: post hoc analysis of a randomized placebo-controlled trial. J Child Adolesc Psychopharmacol 2020; 30:590–598.
DelBello MP, et al. Tolerability, safety, and effectiveness of two years treatment with lurasidone in children and adolescents with bipolar depression. J Am Acad Child Adolesc Psychiatry 2021; 31:494–503.
Goldsmith M, et al. Antidepressants and psychostimulants in pediatric populations: is there an association with mania? Paediatr Drugs 2011; 13:225–243.
Dickstein DP, et al. Randomized double-blind placebo-controlled trial of lithium in youths with severe mood dysregulation. J Child Adolesc Psychopharmacol 2009; 19:61–73.
Vidal-Ribas P, et al. The status of irritability in psychiatry: a conceptual and quantitative review. J Am Acad Child Adolesc Psychiatry 2016; 55:556–570.
Miklowitz DJ. Evidence-based family interventions for adolescents and young adults with bipolar disorder. J Clin Psychiatry 2016; 77 Suppl E1:e5.
Wozniak J, et al. A randomized, double-blind, controlled clinical trial of omega-3 fatty acids and inositol as monotherapies and in combination for the treatment of pediatric bipolar spectrum disorder in children age 5-12. Psychopharmacol Bull 2022; 52:31–51.
Riccobene T, et al. Pharmacokinetics, safety, and tolerability of cariprazine in pediatric patients with bipolar I disorder or schizophrenia. J Child Adolesc Psychopharmacol 2022; 32:434–443.
Wall CA, et al. Magnetic resonance imaging-guided, open-label, high-frequency repetitive transcranial magnetic stimulation for adolescents with major depressive disorder. J Child Adolesc Psychopharmacol 2016; 26:582–589.
Pathak V, et al. Efficacy of adjunctive high frequency repetitive transcranial magnetic stimulation of right prefrontal cortex in adolescent mania: a randomized sham-controlled study. Clin Psychopharmacol Neurosci 2015; 13:245–249.
Moghaddam HS, et al. Efficacy of melatonin as an adjunct in the treatment of acute mania: a double-blind and placebo-controlled trial. Int Clin Psychopharmacol 2020; 35:81–88.
Grant B, et al. Using lithium in children and adolescents with bipolar disorder: efficacy, tolerability, and practical considerations. Paediatr Drugs 2018; 20:303–314.
Geller B, et al. Double-blind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency. J Am Acad Child Adolesc Psychiatry 1998; 37:171–178.
Kafantaris V, et al. Lithium treatment of acute mania in adolescents: a placebo-controlled discontinuation study. J Am Acad Child Adolesc Psychiatry 2004; 43:984–993.
Findling RL, et al. Lithium in the acute treatment of bipolar I disorder: a double-blind, placebo-controlled study. Pediatrics 2015; 136:885–894.
Findling RL, et al. Double-blind 18-month trial of lithium versus divalproex maintenance treatment in pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005; 44:409–417.
Duffy A, et al. Efficacy and tolerability of lithium for the treatment of acute mania in children with bipolar disorder: a systematic review: a report from the ISBD-IGSLi joint task force on lithium treatment. Bipolar Disord 2018; 20:583–593.
Patino LR, et al. A randomized, double-blind, controlled trial of lithium versus quetiapine for the treatment of acute mania in youth with early course bipolar disorder. J Child Adolesc Psychopharmacol 2021; 31:485–493.
Findling RL, et al. Lithium for the maintenance treatment of bipolar I disorder: a double-blind, placebo-controlled discontinuation study. J Am Acad Child Adolesc Psychiatry 2019; 58:287–296.e284.

Prescribing in children and adolescents CHAPTER 5 32. Masi G, et al. Lithium treatment in bipolar adolescents: a follow-up naturalistic study. Neuropsychiatr Dis Treat 2018; 14:2749–2753. 33. Wagner KD, et al. A double-blind, randomized, placebo-controlled trial of divalproex extended-release in the treatment of bipolar disorder in children and adolescents. J Am Acad Child Adolesc Psychiatry 2009; 48:519–532. 34. Wagner KD, et al. A double-blind, randomized, placebo-controlled trial of oxcarbazepine in the treatment of bipolar disorder in children and adolescents. Am J Psychiatry 2006; 163:1179–1186. 35. Tohen M, et al. Olanzapine versus placebo in the treatment of adolescents with bipolar mania. Am J Psychiatry 2007; 164:1547–1556. 36. DelBello MP, et al. A double-blind placebo-controlled pilot study of topiramate in manic adolescents treated with olanzapine. J Child Adolesc Psychopharmacol 2023; 33:126–133. 37. Haas M, et al. Risperidone for the treatment of acute mania in children and adolescents with bipolar disorder: a randomized, double-blind, placebo-controlled study. Bipolar Disord 2009; 11:687–700. 38. Geller B, et al. A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. Arch Gen Psychiatry 2012; 69:515–528. 39. Walkup JT, et al. Treatment of early-age mania: outcomes for partial and nonresponders to initial treatment. J Am Acad Child Adolesc Psychiatry 2015; 54:1008–1019. 40. Kowatch RA, et al. Placebo-controlled trial of valproic acid versus risperidone in children 3-7 years of age with bipolar I disorder. J Child Adolesc Psychopharmacol 2015; 25:306–313. 41. Pathak S, et al. Efficacy and safety of quetiapine in children and adolescents with mania associated with bipolar I disorder: a 3-week, double- blind, placebo-controlled trial. J Clin Psychiatry 2013; 74:e100–e109. 42. Delbello MP, et al. A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry 2002; 41:1216–1223. 43. Delbello MP, et al. A double-blind randomized pilot study comparing quetiapine and divalproex for adolescent mania. J Am Acad Child Adolesc Psychiatry 2006; 45:305–313. 44. Findling RL, et al. Acute treatment of pediatric bipolar I disorder, manic or mixed episode, with aripiprazole: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2009; 70:1441–1451. 45. Findling RL, et al. Aripiprazole for the treatment of pediatric bipolar I disorder: a 30-week, randomized, placebo-controlled study. Bipolar Disord 2013; 15:138–149. 46. Findling RL, et al. Ziprasidone in adolescents with schizophrenia: results from a placebo-controlled efficacy and long-term open-extension study. J Child Adolesc Psychopharmacol 2013; 23:531–544. 47. Findling RL, et al. Efficacy, safety, and tolerability of flexibly dosed ziprasidone in children and adolescents with mania in bipolar I disorder: a randomized placebo-controlled replication study. J Child Adolesc Psychopharmacol 2022; 32:143–152. 48. Findling RL, et al. Asenapine for the acute treatment of pediatric manic or mixed episode of bipolar I disorder. J Am Acad Child Adolesc Psychiatry 2015; 54:1032–1041. 49. Detke HC, et al. Olanzapine/fluoxetine combination in children and adolescents with bipolar I depression: a randomized, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 2015; 54:217–224. 50. Loebel A, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry 2014; 171:160–168. 51. Suppes T, et al. Lurasidone adjunctive with lithium or valproate for bipolar depression: a placebo-controlled trial utilizing prospective and retrospective enrolment cohorts. J Psychiatr Res 2016; 78:86–93. 52. Suppes T, et al. Lurasidone for the treatment of major depressive disorder with mixed features: a randomized, double-blind, placebo- controlled study. Am J Psychiatry 2016; 173:400–407. 53. Goldman R, et al. Efficacy and safety of lurasidone in adolescents with schizophrenia: a 6-week, randomized placebo-controlled study. J Child Adolesc Psychopharmacol 2017; 27:516–525. 54. Solmi M, et al. Safety of 80 antidepressants, antipsychotics, anti-attention-deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta-review of 78 adverse effects. World Psychiatry 2020; 19:214–232. 55. Delbello MP, et al. A double-blind, placebo-controlled pilot study of quetiapine for depressed adolescents with bipolar disorder. Bipolar Disord 2009; 11:483–493. 56. Findling RL, et al. Efficacy and safety of extended-release quetiapine fumarate in youth with bipolar depression: an 8 week, double-blind, placebo-controlled trial. J Child Adolesc Psychopharmacol 2014; 24:325–335. 57. Suttajit S, et al. Quetiapine for acute bipolar depression: a systematic review and meta-analysis. Drug Des Devel Ther 2014; 8:827–838. 58. Bridge JA, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta- analysis of randomized controlled trials. JAMA 2007; 297:1683–1696. 59. Calabrese JR, et al. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord 2008; 10:323–333. 60. Findling RL, et al. Adjunctive maintenance lamotrigine for pediatric bipolar I disorder: a placebo-controlled, randomized withdrawal study. J Am Acad Child Adolesc Psychiatry 2015; 54:1020–1031.e1023.

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Psychosis in children and adolescents

580 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Psychosis in children and adolescents Schizophrenia is rare in children, but the incidence increases rapidly in adolescence. A detailed developmental and physical assessment is always needed before the diagnosis is made.1,2 Early-onset schizophrenia spectrum (EOSS) disorder is often chronic and in the majority of cases requires long-term treatment with antipsychotic medication.3 However, there is very limited RCT evidence for maintenance treatment with antipsychotics beyond 8 weeks,4 although there are supportive open-label studies.5 There have been several RCTs of first-generation antipsychotics, many of them using very high doses and all of them showing high rates of extrapyramidal side effects (EPSEs) and significant sedation.5 Treatment-emergent dyskinesias can also be problematic6 even when smaller doses are used.7 First-generation antipsychotics should be avoided in children and adolescents. There have also been a number of RCTs of SGAs in EOSS disorder. Olanzapine,8–10 risperidone,8,9,11,12 aripiprazole,13,14 quetiapine,14,15 paliperidone16 and lurasidone17 have all been shown to be effective in the treatment of psychosis in younger people. There is meta-analytical evidence suggesting broadly comparable efficacy of individual SGAs, with the exception of ziprasidone and asenapine which are relatively less effective.18,19 Importantly, neither aripiprazole nor lurasidone seems to have an effect on QT in adolescents.20,21 At the time of writing there is no RCT evidence supporting any additional benefit for long-acting antipsychotic injections in younger people, although advantages observed in adults might be assumed to be relevant in younger people. Indeed, a 2023 review of 119 reported adolescent cases suggested good outcomes.22 Children and adolescents are at greater risk than adults for adverse effects such as extrapyramidal symptoms, raised prolactin, sedation (even with aripiprazole14), weight gain and metabolic effects.23 Metformin has RCT evidence for the reduction of antipsychotic-related overweight/obesity in children and adolescents with EOSS disorder, while healthy lifestyle education alone does not.24 There is evidence that clozapine is effective in treatment-resistant psychosis in adolescents, although this population may be somewhat more prone to neutropenia and seizures than adults.25–29 Based on data obtained from the treatment of younger adults, olanzapine should probably be tried before moving to clozapine30 because there is a palpable chance that it will be effective, although clozapine is clearly more effective than olanzapine in adolescents.26,27 Overall, algorithms for treating psychosis in children and adolescents are the same as those for adult patients. In the UK, NICE31 recommends oral antipsychotics in conjunction with family interventions, individual CBT and art therapy. Starting doses should be at the lower end of, or below, the adult range. Antipsychotics should not be offered with the aim of decreasing the risk of developing psychosis;31–33 they are indicated only in the treatment of psychosis. When prescribing antipsychotics in children and adolescents always measure baseline parameters and monitor as outlined in the guidance in the chapter on schizophrenia (see Chapter 1). For children and adolescents also include waist and hip circumference, assessment of any movement disorders and assessment of nutritional status, diet and level of physical activity.31

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References

Prescribing in children and adolescents CHAPTER 5 References

Pina-Camacho L, et al. Autism spectrum disorder and schizophrenia: boundaries and uncertainties. BJPsych Advances 2016; 22:316–324.
Hayes D, et al. Dilemmas in the treatment of early-onset first-episode psychosis. Ther Adv Psychopharmacol 2018; 8:231–239.
Kumra S, et al. Efficacy and tolerability of second-generation antipsychotics in children and adolescents with schizophrenia. Schizophr Bull 2008; 34:60–71.
Singappuli P, et al. Antipsychotic long-term treatment in children and young people: a systematic review and meta-analysis of efficacy and tolerability across mental health and neurodevelopmental conditions. CNS Spectr 2022; 27:570–587.
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Connor DF, et al. Neuroleptic-related dyskinesias in children and adolescents. J Clin Psychiatry 2001; 62:967–974.
Campbell M, et al. Neuroleptic-related dyskinesias in autistic children: a prospective, longitudinal study. J Am Acad Child Adolesc Psychiatry 1997; 36:835–843.
Sikich L, et al. A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial. Neuropsychopharmacology 2004; 29:133–145.
Sikich L, et al. Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry 2008; 165:1420–1431.
Kryzhanovskaya L, et al. Olanzapine versus placebo in adolescents with schizophrenia: a 6-week, randomized, double-blind, placebo- controlled trial. J Am Acad Child Adolesc Psychiatry 2009; 48:60–70.
Haas M, et al. A 6-week, randomized, double-blind, placebo-controlled study of the efficacy and safety of risperidone in adolescents with schizophrenia. J Child Adolesc Psychopharmacol 2009; 19:611–621.
Haas M, et al. Efficacy, safety and tolerability of two dosing regimens in adolescent schizophrenia: double-blind study. Br J Psychiatry 2009; 194:158–164.
Findling RL, et al. A multiple-center, randomized, double-blind, placebo-controlled study of oral aripiprazole for treatment of adolescents with schizophrenia. Am J Psychiatry 2008; 165:1432–1441.
Pagsberg AK, et al. Quetiapine extended release versus aripiprazole in children and adolescents with first-episode psychosis: the multicentre, double-blind, randomised tolerability and efficacy of antipsychotics (TEA) trial. Lancet Psychiatry 2017; 4:605–618.
Findling RL, et al. Efficacy and safety of quetiapine in adolescents with schizophrenia investigated in a 6-week, double-blind, placebo- controlled trial. J Child Adolesc Psychopharmacol 2012; 22:327–342.
Singh J, et al. A randomized, double-blind study of paliperidone extended-release in treatment of acute schizophrenia in adolescents. Biol Psychiatry 2011; 70:1179–1187.
Arango C, et al. Lurasidone compared to other atypical antipsychotic monotherapies for adolescent schizophrenia: a systematic literature review and network meta-analysis. Eur Child Adolesc Psychiatry 2019; 29:1195–1205.
Pagsberg AK, et al. Acute antipsychotic treatment of children and adolescents with schizophrenia-spectrum disorders: a systematic review and network meta-analysis. J Am Acad Child Adolesc Psychiatry 2017; 56:191–202.
Lopez-Morinigo JD, et al. Pharmacological treatment of early-onset schizophrenia: a critical review, evidence-based clinical guidance and unmet needs. Pharmacopsychiatry 2022; 55:233–245.
Jensen KG, et al. Change and dispersion of QT interval during treatment with quetiapine extended release versus aripiprazole in children and adolescents with first-episode psychosis: results from the TEA trial. Psychopharmacology (Berl) 2018; 235:681–693.
Goldman R, et al. Efficacy and safety of lurasidone in adolescents with schizophrenia: a 6-week, randomized placebo-controlled study. J Child Adolesc Psychopharmacol 2017; 27:516–525.
Baeza I, et al. What role for long-acting injectable antipsychotics in managing schizophrenia spectrum disorders in children and adolescents? A systematic review. Paediatr Drugs 2023; 25:135–149.
Sunshine A, et al. Practitioner review: psychosis in children and adolescents. J Child Psychol Psychiatry 2023; 64:980–988.
Correll CU, et al. Metformin add-on vs. antipsychotic switch vs. continued antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness: results from the IMPACT trial. World Psychiatry 2020; 19:69–80.
Kumra S, et al. Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry 1996; 53:1090–1097.
Shaw P, et al. Childhood-onset schizophrenia: a double-blind, randomized clozapine-olanzapine comparison. Arch Gen Psychiatry 2006; 63:721–730.
Kumra S, et al. Clozapine and ‘high-dose’ olanzapine in refractory early-onset schizophrenia: a 12-week randomized and double-blind comparison. Biol Psychiatry 2008; 63:524–529.
Schneider C, et al. Systematic review of the efficacy and tolerability of clozapine in the treatment of youth with early onset schizophrenia. Eur Psychiatry 2014; 29:1–10.
Adnan M, et al. Clozapine for management of childhood and adolescent-onset schizophrenia: a systematic review and meta-analysis. J Child Adolesc Psychopharmacol 2022; 32:2–11.
Agid O, et al. An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry 2011; 72:1439–1444.
National Institute for Health and Care Excellence. Psychosis and schizophrenia in children and young people: recognition and management. Clinical Guidance [CG155]. 2013 (last updated October 2016, last checked October 2023); https://www.nice.org.uk/guidance/cg155.
Catalan A, et al. Annual research review: prevention of psychosis in adolescents – systematic review and meta-analysis of advances in detection, prognosis and intervention. J Child Psychol Psychiatry 2021; 62:657–673.
Lång U, et al. Systematic review and meta-analysis: psychosis risk in children and adolescents with an at-risk mental state. J Am Acad Child Adolesc Psychiatry 2022; 61:615–625.

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16 - Anxiety disorders in children and adolescents

Anxiety disorders in children and adolescents

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17 - Diagnostic issues

Diagnostic issues

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18 - Clinical guidance

Clinical guidance

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19 - Prescribing for anxiety disorders in children

Prescribing for anxiety disorders in children and adolescents

582 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Anxiety disorders in children and adolescents Diagnostic issues Fear and worry are common in children and they are part of normal development. At the same time, anxiety disorders often begin in childhood and adolescence1 and they are the most common psychiatric disorders in this age group, with overall prevalence between 8% and 30% depending on the impairment cut-offs used.2 Anxiety disorders may be even more common in children with neurodevelopmental disorders.3 In children, the more obvious clinical presentation with distress and avoidance may be masked by prominent behavioural symptoms (e.g. irritability and angry outbursts linked to avoidance). Therefore, the assessment and treatment of anxiety disorders in children need to be undertaken by clinicians who can discriminate normal, developmentally appropriate worries, fears and shyness from anxiety disorders that significantly impair a child’s functioning, and who can appreciate developmental variations in the presentation of symptoms. Clinical guidance Anxiety symptoms in children and adolescents often improve with age, presumably in parallel to the development of the prefrontal cortex and, in particular, executive function. However, anxiety disorders are distressing and impairing conditions that need to be treated promptly. Chronic stress mediators may have significant impact on brain development4 and functional impairment linked to anxiety symptoms may prevent young people from accessing normative experiences that are critical for social, emotional and cognitive development. Finally, early and effective treatment may prevent continuity of psychopathology into adulthood: for example, young people with anxiety disorders are three times more likely to have anxiety and depression in adult life compared with non-anxious youth.5 Guidelines for the treatment of anxiety disorders in children and adolescents have been made available in the UK and the USA. NICE guidelines focus on the treatment of social anxiety disorder in children and adolescents, suggesting the use of cognitive behavioural therapy and cautioning against the routine use of pharmacological treatment for social anxiety in this age group.6 Guidelines from AACAP cover the treatment of all anxiety disorders except post-traumatic stress disorder (PTSD) and obsessive compulsive disorder (OCD) (which are classified separately according to DSM).7 AACAP guidelines suggest multimodal treatment including psychoeducation, psychotherapy (e.g. a 12-session course of exposure-based CBT) and pharmacotherapy. Drug treatment is endorsed for moderate-to-severe anxiety symptoms, when impairment makes participation in psychotherapy difficult, or when psychotherapy leads to only partial response. Prescribing for anxiety disorders in children and adolescents Before prescribing ■ ■Exclude other diagnoses: Anxiety symptoms can be mimicked by a range of psychiatric disorders including depression (inattention, sleep problems), bipolar disorder (irritability, sleep problems, restlessness), oppositional-defiant disorder (irritability,

Prescribing in children and adolescents CHAPTER 5 oppositional behaviour), psychotic disorders (social withdrawal, restlessness), ADHD (inattention, restlessness), autism spectrum disorder (social withdrawal, poor social skills, repetitive behaviours and routines) and learning disabilities. They may also be mimicked by a range of endocrine (hyperthyroidism, hypoglycaemia, phaeochromocytoma), neurological (migraine, seizures, delirium, brain tumours), cardiovascular (cardiac arrhythmias) and respiratory (asthma) conditions and lead intoxication. Anxiety-like symptoms can be observed in response to several drugs and substances including anti-asthma medications, sympathomimetics, steroids, SSRIs, antipsychotics (akathisia), diet pills, cold medicines, caffeine and energy drinks. ■ ■Beware contraindications to SSRIs and potential interactions. ■ ■Measure baseline severity: Use structured interviews including the Anxiety Disorders Interview Schedule (ADIS) and the Kiddie-Schedule for Affective Disorders and Schizophrenia (Kiddie-SADS); questionnaires including the Revised Children’s Anxiety and Depression Scale (RCADS), Screen for Child Anxiety and Related Emotional Disorders (SCARED) or the Multidimensional Anxiety Scale for Children (MASC); and measures of functional impairment including the Children’s Global Assessment Scale (CGAS). ■ ■Obtain consent: Discuss treatment with the young person and the family (e.g. name of medication, starting/estimated ending dose, titration timeline, possible side effects and strategies to monitor/minimise them, strategies to monitor progress, interventions for treatment-resistant cases). Document consent in writing. What to prescribe ■ ■SSRIs: These are the medications of choice for the treatment of anxiety disorders in children and adolescents. SSRI treatment is at least as effective as non-drug treatments.8 A 2019 meta-analysis identified seven short-term RCTs (<16 weeks; n treatment = 446, n control = 386) testing the efficacy of SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline) on changes in severity of anxiety in young people (Clinical Global Impression I [CGI-I] scale). The odds ratio (vs placebo) of overall treatment response was 4.6 (95%CI = 3.1–7.5) and, in anxiety symptoms specifically, 5.2 (95%CI = 2.8–8.8).9 The Childhood Anxiety Multimodal Study (CAMS) showed that monotherapy with sertraline (55% response) is as effective as CBT for anxiety (60% response) and better than placebo (24% response), and that combined therapy with sertraline and CBT is most likely to be successful (81% response).10 A 2017 network meta-analysis found that SSRIs significantly reduce clinician-reported and parent-reported (but not child-reported) anxiety symptoms and increased rates of remission.11 Another network meta-analysis found that the likelihood of treatment response was higher for SSRI compared with the following other medications;9 a standard meta-analysis showed that clinically significant treatment effects typically emerge by week 6 of treatment, and that SSRIs are associated with more rapid and greater improvement than these other medications.12 The most recent meta-analysis (11 studies, 2122 participants [2023])13 suggests broadly similar efficacy for SSRIs/ serotonin–noradrenaline reuptake inhibitors (SNRIs). With regard to tolerability, SSRIs are the best tolerated class of medications, particularly escitalopram and fluoxetine.14

584 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Sertraline, fluoxetine and fluvoxamine have been approved by the US FDA for treatment of paediatric OCD, and fluoxetine and escitalopram have been approved for treatment of paediatric depression. The FDA issued in 2004 a black box warning for concerns related to worsening of depression, agitation and suicidal ideation linked to SSRIs. These concerns were based on a review of studies of adolescents with depression rather than young people with anxiety. ■ ■SNRIs: Venlafaxine was tested in two short-term RCTs (n treatment = 294, n control = 311), duloxetine was tested in one short-term RCT (n treatment = 135, n control = 137) and atomoxetine was tested in one short-term RCT. The overall odds ratio of treatment response for SNRIs was 2.4 (95%CI = 1.7–3.6) over placebo.9 However, SNRIs did not show statistically significant effects on improvement in anxiety symptoms over placebo.9 The network meta-analysis mentioned earlier found that SNRIs significantly reduce clinician-reported (but not parent-reported or child-reported) anxiety symptoms.11 SSRIs are more effective and better tolerated9 so SNRIs could be considered a third-line treatment for anxiety disorders when two trials with different SSRIs prove ineffective. ■ ■Others: The 5HT1A agonist buspirone has been examined in one short-term RCT (n treatment = 334, n control = 225) and found not to be effective.15 The alpha2 agonist guanfacine was evaluated in one short-term RCT (n treatment = 62, n control = 21) and found to be associated with an increased odds ratio for treatment response (5.6 [95%CI = 1.4–26.8]) but not for improvement in anxiety symptoms.16 ■ ■Neither benzodiazepine nor tricyclic antidepressant use is supported by controlled trials in children.9 Benzodiazepine may also lead to paradoxical disinhibition in some children. Nevertheless, use of longer-acting benzodiazepines is at times considered in clinical practice either to alleviate disabling anxiety during initial titration of SSRIs or for rapid tranquillisation. Table 5.7 lists the doses for treating anxiety disorders in children and adolescents. After prescribing Acute phase ■ ■Start at the lowest available dose. ■ ■Monitor side effects. SSRIs are generally well tolerated during treatment for anxiety disorders in young people. Psychological side effects include worsening of anxiety symptoms, agitation and disinhibition. Physical side effects including gastrointestinal symptoms (e.g. nausea, vomiting, dyspepsia, abdominal pain, diarrhoea, constipation), headache, increased motor activity and insomnia may occur, often in mild and transient form. ■ ■After 1 week of treatment with SSRIs (2 weeks for SNRIs) when the child is compliant with medications and does not manifest more than minimal side effects, titrate incrementally with weekly intervals to the minimal therapeutic dose. ■ ■Monitor side effects and response (e.g. RCADS, SCARED, MASC, CGAS, CGI-I) frequently and systematically. ■ ■Dosage for treatment with SSRIs is often similar to dosage in adults because of faster metabolism in children. ■ ■Therapeutic effect should appear by 6–8 weeks of treatment. It is important to communicate this to families. ■ ■If partial or non-response, consider accuracy of diagnosis, adequacy of medication trial and compliance of patient.

Prescribing in children and adolescents CHAPTER 5 ■ ■To improve response, consider adding CBT, changing medication (e.g. switch SSRIs, other classes) or combining medications (e.g. for comorbidities, to treat side effects, to potentiate action). Augmentation strategies with buspirone, benzodiazepines, atypical antipsychotics and stimulant medications have been proposed but lack empirical support.7 Maintenance phase ■ ■Continue maintenance treatment for at least 1 year of stable improvement. ■ ■Monitor response and side effects regularly. Discontinuation phase ■ ■Because of lack of information on long-term safety and possible improvement in symptoms with age and learning, consider discontinuing treatment after a period of stable improvement. A trial of medication withdrawal should be started at a period of low stress/demands. Discontinuation should also be considered if the medication is no longer working or the side effects are too severe. Taper SSRIs slowly (e.g. 25% of previous dose weekly) to minimise the risk of discontinuation symptoms. Monitor closely for recurrence of symptoms/relapse and, if deterioration is noted, consider restarting medication. Table 5.7 Typical dosage of medications for treatment of anxiety disorders in children and adolescents. Medication Starting dose (mg) Dose range (mg/day) SSRI Sertraline 12.5–25 25–200 Fluoxetine 5–10 10–60 Fluvoxamine 12.5–25 50–200 (bd if >50) Paroxetine 5–10 10–40 Citalopram* 5–10 10–40 SNRI Venlafaxine XR 37.5 37.5–225 Duloxetine 30–120 Alpha2 agonist Guanfacine 1–6 5HT1A partial agonist Buspirone* 5 tds 15–60 Benzodiazepine (prn) Clonazepam* 0.25–0.5 – Lorazepam* 0.5–1 – Note: always check dose with latest formal guidance, e.g. British National Formulary for Children (in the UK). *Treatments not supported by randomised controlled trial evidence. bd, twice daily; prn, as required; tds, three times daily.

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References

586 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Pre-school children Treatment of anxiety disorders in pre-school children must routinely focus on psychotherapy. In rare cases when a very young child has extreme ongoing symptoms and impairment, clinicians should reconsider diagnosis and case formulation, and reassess the adequacy of the psychotherapy trial. There are no RCTs of pharmacological interventions for anxiety in pre-school children, but case reports suggest a potential benefit of fluoxetine and buspirone.17 Any prescription in pre-school children is off-label.18 References

Kessler RC, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62:593–602.
Merikangas KR, et al. Lifetime prevalence of mental disorders in U.S. adolescents: results from the National Comorbidity Survey Replication – Adolescent Supplement (NCS-A). J Am Acad Child Adolesc Psychiatry 2010; 49:980–989.
Simonoff E, et al. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry 2008; 47:921–929.
Danese A, et al. Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiol Behav 2012; 106:29–39.
Pine DS, et al. The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disorders. Arch Gen Psychiatry 1998; 55:56–64.
National Institute for Health and Clinical Excellence. Social anxiety disorder: recognition, assessment and treatment. Clinical Guidance [CG159]. 2013 (last updated 2017, last checked December 2023); https://www.nice.org.uk/guidance/cg159.
Connolly SD, et al. Practice parameter for the assessment and treatment of children and adolescents with anxiety disorders. J Am Acad Child Adolesc Psychiatry 2007; 46:267–283.
Arnardóttir A, et al. Comparative effectiveness of cognitive behavioral treatment, serotonin, and serotonin noradrenaline reuptake inhibitors for anxiety in children and adolescents: a network meta-analysis. Nord J Psychiatry 2023; 77:118–126.
Dobson ET, et al. Efficacy and tolerability of pharmacotherapy for pediatric anxiety disorders: a network meta-analysis. J Clin Psychiatry 2019; 80:17r12064.
Walkup JT, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med 2008; 359:2753–2766.
Wang Z, et al. Comparative effectiveness and safety of cognitive behavioral therapy and pharmacotherapy for childhood anxiety disorders: a systematic review and meta-analysis. JAMA Pediatrics 2017; 171:1049–1056.
Strawn JR, et al. The impact of antidepressant dose and class on treatment response in pediatric anxiety disorders: a meta-analysis. J Am Acad Child Adolesc Psychiatry 2018; 57:235–244.e232.
Stefánsdóttir ÍH, et al. Efficacy and safety of serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors (SNRI) for children and adolescents with anxiety disorders: a systematic review and meta-analysis. Nord J Psychiatry 2023; 77:137–146.
Solmi M, et al. Safety of 80 antidepressants, antipsychotics, anti-attention-deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta-review of 78 adverse effects. World Psychiatry 2020; 19:214–232.
Strawn JR, et al. Buspirone in children and adolescents with anxiety: a review and Bayesian analysis of abandoned randomized controlled trials. J Child Adolesc Psychopharmacol 2018; 28:2–9.
Strawn JR, et al. Extended release guanfacine in pediatric anxiety disorders: a pilot, randomized, placebo-controlled trial. J Child Adolesc Psychopharmacol 2017; 27:29–37.
Gleason MM, et al. Psychopharmacological treatment for very young children: contexts and guidelines. J Am Acad Child Adolesc Psychiatry 2007; 46:1532–1572.
Mohatt J, et al. Treatment of separation, generalized, and social anxiety disorders in youths. Am J Psychiatry 2014; 171:741–748.

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21 - Obsessive compulsive disorder (OCD) and body

Obsessive compulsive disorder (OCD) and body dysmorphic disorder (BDD) in children and adolescents

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22 - Drug treatment in obsessive compulsive disord

Drug treatment in obsessive compulsive disorder (OCD)

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23 - Drug treatment in body dysmorphic disorder (B

Drug treatment in body dysmorphic disorder (BDD)

Prescribing in children and adolescents CHAPTER 5 Obsessive compulsive disorder (OCD) and body dysmorphic disorder (BDD) in children and adolescents The treatment of OCD and BDD in children and young people largely follows the same principles as those for adults.1 BDD is recognised by both DSM-5 and ICD-11 as one of the obsessive compulsive disorders. Cognitive behavioural therapy is effective for both conditions in this age group and is recommended in the UK by NICE as the first-choice treatment, although it may be combined with medication for optimal effect.2 While CBT is the mainstay of treatment for OCD and BDD, medication alone may be the only viable therapeutic option in some cases. Some children are reluctant to engage with CBT, some may find it difficult to access or they may have very poor insight. This last situation may arise in the autism spectrum disorder alongside comorbid OCD or BDD. Insight in BDD is characteristically poorer than in OCD, with up to 50% of cases having beliefs about their appearance which are of delusional intensity. This too can affect motivation to engage with psychological therapy. Where medication is being used as the only evidence-based treatment, it is essential that this remains under review so that motivation and ability to engage with CBT are regularly revisited. Drug treatment in obsessive compulsive disorder (OCD) Sertraline (from age 6 years) and fluvoxamine (from age 8 years) are the SSRIs licensed in the UK for the treatment of OCD in young people. Studies have established the efficacy of SSRIs in the child and adolescent population in several placebo-controlled trials.3–5 SSRIs have a medium to large effect size in the treatment of OCD in children and young people.6 A meta-analysis of 12 RCTs of pharmacotherapy in young people under 19 years of age showed that medication is consistently more effective than placebo. Fluoxetine is the most efficacious SSRI for treatment of depression.7 Many young people presenting with OCD have a diagnosis of comorbid depression, so fluoxetine could be considered as an alternative SSRI to sertraline or fluvoxamine in these cases. Paroxetine is not recommended for use in children and young people. Clomipramine remains a useful drug for some individuals and is debatably more efficacious than the SSRIs in treating OCD in children and young people.8 However, clomipramine’s side effect profile (sedation, dry mouth, potential for cardiac side effects) tends to limit its use in this age group and, as a consequence, SSRIs remain the first-line choice in OCD. SNRIs are not recommended for treatment of OCD in children and young people, with no clear evidence of efficacy and poorer tolerability than SSRIs. Drug treatment in body dysmorphic disorder (BDD) No treatment is licensed in the UK for either adults or children with BDD. However, evidence shows significant improvements with SSRIs, both in terms of BDD symptoms, suicidality and often comorbid depressive symptoms (80–90% of people with BDD also have a comorbid diagnosis of depression9). In the UK, NICE recommends fluoxetine as the SSRI of choice for treating BDD in children. Although BDD cases have delusional intensity beliefs about their appearance, antipsychotics are not effective and are

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24 - Prescribing SSRIs in children

Prescribing SSRIs in children

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25 - NICE guidelines for the assessment and treatm

NICE guidelines for the assessment and treatment of OCD and BDD

588 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 not recommended. Research in adult patients shows that BDD patients with delusional intensity appearance beliefs are as likely to respond to SSRI monotherapy as are non- delusional patients.9 Prescribing SSRIs in children In 2004, the UK MHRA cautioned against the use of SSRIs in children and young people owing to a possible increased risk of suicidal ideation.10 Careful re-analysis of treatment data suggests that SSRIs are clearly more efficacious in OCD than they are in moderate depressive episodes in children and young people.6 Investigators concluded that within the paediatric OCD group, the pooled risk for suicidal ideation and attempts was less than 1% across all studies. This of course is an important risk and should be explained and carefully monitored. Nonetheless, the naturalistic course of untreated OCD and BDD is that patients tend not to spontaneously remit, and they have tremendous associated morbidity. It is also known that untreated OCD and BDD are associated with a 10-fold increased risk of completed suicide compared with the general population in OCD.9,11 The risk of suicide in BDD is higher, with roughly one in three patients with BDD attempting suicide.12 These factors need to be carefully considered and discussed with the patient and their carers or family in making informed choices about treatment. On occasion, medications other than sertraline and fluvoxamine may be used ‘off-label’ with the appropriate and suitable cautions. NICE guidance13 for the treatment of OCD recommends the use of maximum tolerated dose strategies of two SSRIs before the use of clomipramine, owing to the latter drug’s greater propensity for side effects and need for cardiac monitoring. The alternative to clomipramine is augmentation with a low-dose antipsychotic. Factors guiding the choice of other medications may include issues such as the presence of other disorders; response to a certain drug in other family members; and cost and availability. Compliance with medication can be an issue with some young people, which can guide the choice of preparation. For instance, young people with poor compliance may be better suited to treatment with fluoxetine considering its long half-life compared with other SSRIs. A 2020 meta-analysis showed fluoxetine and sertraline to be more effective in OCD treatment than fluvoxamine.8 Some children can find tablets or capsules hard to swallow and the availability of licensed liquid formulations is limited in most countries. NICE guidelines for the assessment and treatment of OCD and BDD NICE published guidelines in 2005 on evidence-based treatment options for OCD and BDD for young people and adults.13 NICE recommends a ‘stepped care’ model, with increasing intensity of treatment according to clinical severity and complexity.13 Assessment of the severity and impact of OCD or BDD can be aided by the use of the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) or BDD-YBOCS questionnaires, respectively, or other quantitative measures, both at baseline and as a helpful monitoring tool.14 The summary treatment algorithm from the NICE guideline is shown in Figure 5.1.

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26 - Initiation of treatment with medication

Initiation of treatment with medication

Prescribing in children and adolescents CHAPTER 5 Initiation of treatment with medication Clomipramine and SSRIs show a similar incremental effect on obsessions and compulsions from as early as 1–2 weeks after initiation and placebo-referenced improvements continue for at least 24 weeks. In some cases, a positive impact on mood may be seen before the initial changes in OCD symptoms.16 In the UK, NICE therefore recommends two treatment trials of SSRIs for OCD and BDD of 3 months and increasing towards the maximum tolerated effective dosage. Carefully explaining these temporal effects to patients can be important in sustaining compliance. In addition, the earliest signs of improvement may be apparent to an informant before the patient. Use of an observer- rated quantitative measure such as the CY-BOCS or BDD-YBOCS may therefore be helpful to monitor progress in clinical settings.17 Expert consensus typically suggests starting at the lowest dose known to be effective, titrating upwards and waiting for up to 12 weeks before evaluating effectiveness.18 Careful dose titration is particularly recommended if there is insufficient clinical response. In clinical practice a balance must clearly be struck between tolerability and the rate of dosage increase. It is worth noting that the majority of young people with OCD will require a higher dose of SSRI, and as such it may well be clinically indicated to increase the dose more quickly after starting an SSRI. Mild functional impairment Moderate or severe functional impairment Consider guided self-help support and information for family/carers Ineffective or refused Ineffective or refused Consider an SSRI (with careful monitoring) Multidisciplinary review Consider either (especially if previous good response to): Different SSRI Clomipramine SSRI + ongoing CBT (including ERP): Consider use in 8–11-year age group Offer to 12–18-year age group Carefully monitor for adverse events, especially at start of treatment Offer CBT (+ERP); involve family/carers (individual or group formats) Figure 5.1 Treatment options for children and young people with obsessive compulsive disorder. CBT, cognitive behaviour therapy; ERP, exposure and response prevention. Adapted from NICE guidance.13 Reprinted with permission.15

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27 - Treatment refractory OCD and BDD in children

Treatment-refractory OCD and BDD in children

590 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Treatment-refractory OCD and BDD in children Evidence from randomised trials suggests that up to three-quarters of medicated patients have an adequate response to treatment. About a quarter of children and young people with OCD will therefore fail to respond to an initial SSRI, administered for at least 12 weeks at the maximum tolerated dose, in combination with an adequate trial of CBT and exposure and response prevention (ERP). These children should be reassessed and compliance clarified, and it should be ensured that clinical comorbidities are not being missed. In such cases, children and young people should usually have additional trials of at least one other SSRI. Research suggests that approximately 40% respond to a second SSRI in both OCD and BDD.19 Following this, if the response is limited, consideration should be given to referral to a specialist centre. In OCD, trials of clomipramine may be considered and/or augmentation with a low dose of risperidone or aripiprazole.13,20 Augmentation with antipsychotics is not recommended in the treatment of BDD. The combination of fluvoxamine and clomipramine has been used in refractory cases21,22 but, given the dangers of serotonin syndrome, these regimens should be reserved for specialist centres. Improved efficacy seems to be linked to the altering of the metabolism of clomipramine by fluvoxamine. There is evidence that low-dose antipsychotic augmentation of SSRI treatment as an off-label therapy can benefit patients whose response to treatment has been inadequate despite at least 3 months of two maximal tolerated separate SSRIs. There is a more robust evidence base in adult cohorts than in younger people. Only a third of treatment- resistant adult cases of OCD showed a meaningful response to this augmentation strategy. Small studies conducted on children and young people showed a clinical improvement for OCD, with a larger evidence base available for aripiprazole compared with risperidone.23–25 A 6–8-week trial of low-dose antipsychotic augmentation is typically sufficient to assess efficacy. In practice, doses no larger than aripiprazole 2.5–5mg daily or risperidone 0.5mg daily should be used. It is important to discontinue the anti psychotic if no response is noted after this trial of SSRI augmentation. Antipsychotics alone are not efficacious treatments for obsessive compulsive disorders. Often children and young people whose OCD or BDD has been difficult to treat have comorbidities such as autism spectrum disorder, ADHD or tic disorders. The response to medication can be differentially affected by these comorbidities. For instance, patients with tic disorders may benefit somewhat more from augmentation with second- generation antipsychotics.26 Untreated ADHD can also commonly interfere with engagement with CBT due to poor focus. Very often efforts to address ADHD with appropriate treatments including medication can dramatically improve engagement with CBT. However, caution is required with regard to stimulant use, particularly for young people who are not ‘fighting back’ against compulsions. In this group, one can see an increase in compulsions as concentration improves. Careful clinical review and reformulation are important in treatment-resistant OCD and BDD. Comorbidities and wider psychosocial factors need to be considered for their impact on the treatment response overall. The evidence base around systemic factors and their application in OCD is poor. Very often clinical experience shows that it can be vital to support families and carers during treatment. Alternative experimental and adult treatments are given in Tables 5.8 and 5.9.

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28 - Duration of treatment and long term follow up

Duration of treatment and long-term follow-up

Prescribing in children and adolescents CHAPTER 5 Duration of treatment and long-term follow-up Untreated OCD runs a chronic course. A series of adult studies have shown that discontinuation of medication tends to result in a varying degree of symptomatic relapse.27 Some authors have suggested that those with comorbidities are at the greatest risk of relapse.28 Given that studies frequently exclude cases with additional comorbidities, it is likely that the relapse rates have been underestimated. In the UK, NICE guidelines recommend that if a young person has responded to medication, treatment for OCD or BDD should continue for at least 6 months after remission. This recommendation was based on clinical consensus rather than the product of carefully conducted research trials. Clinical experience would also suggest that when discontinuation of treatment is attempted it should be done slowly, cautiously and in a transparent manner with the patient and their family. Once again, the careful use of clinical outcome measures should be considered when stopping medication. There is a considerable evidence base and expert clinical consensus suggesting that discontinuing medication is associated with a deterioration in symptoms of either OCD or BDD. Increasingly adults and young people are being counselled to consider whether they wish to remain on SSRI medication longer term to mitigate the substantial risk of relapse of OCD or BDD symptoms. Thoughtful and honest discussion about the potential risks of stopping medication should be an active part of any care plan in OCD. Individuals with developmental disabilities often struggle to generalise the lessons taken from successful CBT. They also have a higher propensity for adverse effects such as activation syndromes with SSRIs, therefore titration may need to be slower.29 It is important that throughout childhood, adolescence and into adult life individuals with OCD or BDD should have rapid access to healthcare professionals, treatment opportunities and other support as needed. NICE recommends that if relapse occurs, people with OCD or BDD should be seen as soon as possible rather than placed on a routine waiting list because of the propensity for rapid deterioration of symptoms. Table 5.8 Alternative and experimental treatment of OCD in children and young people. Treatment Comment Aripiprazole augmentation of SSRI Evidence of clinical improvement in children and young people with OCD23,24,26,30 No evidence base for use in BDD Risperidone augmentation of SSRI Fewer studies than aripiprazole augmentation in children and young people25 Fluvoxamine with low-dose clomipramine Better tolerated than clomipramine monotherapy31 N-acetylcysteine (NAC) Limited evidence suggests children and adolescents with OCD refractory to SSRIs or CBT may benefit from NAC augmentation.32 Memantine Limited evidence suggests potential benefit.33–35 Lamotrigine Case studies have reported response.36 BDD, body dysmorphic disorder; CBT, cognitive behavioural therapy; OCD, obsessive compulsive disorder.

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References

592 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 References

Bandelow B, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders – version 3. Part II: OCD and PTSD. World J Biol Psychiatry 2023; 24:118–134.
Tao Y, et al. Comparing the efficacy of pharmacological and psychological treatment, alone and in combination, in children and adolescents with obsessive-compulsive disorder: a network meta-analysis. J Psychiatr Res 2022; 148:95–102.
Pediatric OCD Treatment Study Team (POTS). Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA 2004; 292:1969–1976.
Geller DA, et al. Which SSRI? A meta-analysis of pharmacotherapy trials in pediatric obsessive-compulsive disorder. Am J Psychiatry 2003; 160:1919–1928.
March JS, et al. Treatment benefit and the risk of suicidality in multicenter, randomized, controlled trials of sertraline in children and adolescents. J Child Adolesc Psychopharmacol 2006; 16:91–102.
Garland J, et al. Update on the use of SSRIs and SNRIs with children and adolescents in clinical practice. J Can Acad Child Adolesc Psychiatry 2016; 25:4–10.
National Institute for Clinical Excellence. Depression in children and young people: identification and management. NICE Guideline [NG134]. 2019 (last checked December 2023); https://www.nice.org.uk/guidance/ng134.
Boaden K, et al. Antidepressants in children and adolescents: meta-review of efficacy, tolerability and suicidality in acute treatment. Front Psychiatry 2020; 11:717.
Phillips KA, et al. Treating body dysmorphic disorder with medication: evidence, misconceptions, and a suggested approach. Body Image 2008; 5:13–27.
Weller IVD, et al. Report of the CSM expert working group on the safety of selective serotonin reuptake inhibitor antidepressants. 2005; https://www.neuroscience.ox.ac.uk/publications/474047.
Fernández de la Cruz L, et al. Suicide in obsessive-compulsive disorder: a population-based study of 36 788 Swedish patients. Mol Psychiatry 2017; 22:1626–1632.
Pellegrini L, et al. Suicidality in patients with obsessive-compulsive and related disorders (OCRDs): a meta-analysis. Compr Psychiatry 2021; 108:152246. Table 5.9 Treatments of OCD used in adults that may be effective in children. Treatment Comment Topiramate augmentation of SSRI Case studies suggest this may be beneficial and one RCT showed an effect for compulsions but not obsessions.37,38 Other trials have not found it to be effective.39 Not to be used in female adolescents. High-dose SSRI (with ECG monitoring) Higher than licensed maximum dose SSRI associated with clinical improvement and well tolerated in a retrospective case note survey, double-blind trial and open-label study40–42 SNRIs Duloxetine shown to be as effective as sertraline in a small RCT, and an open-label trial suggested it could reduce symptoms of OCD43,44 Mirtazapine Superior to placebo in an open trial45 Pregabalin Augmentation of sertraline was more effective than augmentation with placebo.46 5HT3 antagonists Ondansetron is effective as add-on treatment.47 Note risk of QT prolongation Ketamine IV Case report showed rapid resolution of symptoms48 Tolcapone (catechol-Omethyltransferase inhibitor) One small trial showed benefit over placebo.49 Methylphenidate Small study showed some benefit for OCD in combination with fluvoxamine50 Deep brain stimulation Could be effective treatment for resistant OCD.51 Transcranial magnetic stimulation (TMS) Meta-analysis showed that TMS can reduce the severity of OCD.52

Prescribing in children and adolescents CHAPTER 5 13. National Institute for Clinical Excellence. Obsessive-compulsive disorder and body dysmorphic disorder: treatment. Clinical Guideline [CG31]. 2005 (last checked December 2023); https://www.nice.org.uk/guidance/cg31. 14. Fernández de la Cruz L, et al. Suicide in obsessive-compulsive disorder: a population-based study of 36 788 Swedish patients. Mol Psychiatry 2017; 22:1626–1632. 15. Heyman I, et al. Obsessive-compulsive disorder. BMJ 2006; 333:424–429. 16. Scahill L, et al. Children’s Yale-Brown Obsessive Compulsive Scale: reliability and validity. J Am Acad Child Adolesc Psychiatry 1997; 36:844–852. 17. Baldwin DS, et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol 2014; 28:403–439. 18. Bloch MH, et al. Assessment and management of treatment-refractory obsessive-compulsive disorder in children. J Am Acad Child Adolesc Psychiatry 2015; 54:251–262. 19. Grados M, et al. Pharmacotherapy in children and adolescents with obsessive-compulsive disorder. Child Adolesc Psychiatr Clin N Am 1999; 8:617–634, x. 20. Bloch MH, et al. A systematic review: antipsychotic augmentation with treatment refractory obsessive-compulsive disorder. Mol Psychiatry 2006; 11:622–632. 21. Fung R, et al. Retrospective review of fluvoxamine-clomipramine combination therapy in obsessive-compulsive disorder in children and adolescents. J Can Acad Child Adolesc Psychiatry 2021; 30:150–155. 22. Hardy NE, et al. Clomipramine in combination with fluvoxamine: a potent medication combination for severe or refractory pediatric OCD. J Can Acad Child Adolesc Psychiatry 2021; 30:273–277. 23. Masi G, et al. Aripiprazole augmentation in 39 adolescents with medication-resistant obsessive-compulsive disorder. J Clin Psychopharmacol 2010; 30:688–693. 24. Ardic UA, et al. Successful treatment response with aripiprazole augmentation of SSRIs in refractory obsessive–compulsive disorder in childhood. Child Psychiatry Hum Dev 2017; 48:699–704. 25. Simeon J, et al. A retrospective chart review of risperidone use in treatment-resistant children and adolescents with psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26:267–275. 26. Masi G, et al. Antipsychotic augmentation of selective serotonin reuptake inhibitors in resistant tic-related obsessive-compulsive disorder in children and adolescents: a naturalistic comparative study. J Psychiatr Res 2013; 47:1007–1012. 27. Fineberg NA, et al. Sustained response versus relapse: the pharmacotherapeutic goal for obsessive-compulsive disorder. Int Clin Psychopharmacol 2007; 22:313–322. 28. Fineberg NA, et al. Pharmacotherapy of obsessive-compulsive disorder: evidence-based treatment and beyond. Austr N Z J Psychiatry 2013; 47:121–141. 29. Kolevzon A, et al. Selective serotonin reuptake inhibitors in autism: a review of efficacy and tolerability. J Clin Psychiatry 2006; 67:407–414. 30. Ercan ES, et al. A promising preliminary study of aripiprazole for treatment-resistant childhood obsessive-compulsive disorder. J Child Adolesc Psychopharmacol 2015; 25:580–584. 31. Fung R, et al. Retrospective review of fluvoxamine-clomipramine combination therapy in obsessive-compulsive disorder in children and adolescents. J Can Acad Child Adolesc Psychiatry 2021; 30:150–155. 32. Parli GM, et al. N-acetylcysteine for obsessive-compulsive and related disorders in children and adolescents: a review. Ann Pharmacother 2023; 57:847–854. 33. Hosenbocus S, et al. Memantine: a review of possible uses in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry 2013; 22:166–171. 34. Häge A, et al. Glutamatergic medication in the treatment of obsessive compulsive disorder (OCD) and autism spectrum disorder (ASD) – study protocol for a randomised controlled trial. Trials 2016; 17:141. 35. Niemeyer L, et al. Memantine as treatment for compulsivity in child and adolescent psychiatry: descriptive findings from an incompleted randomized, double-blind, placebo-controlled trial. Contemp Clin Trials Commun 2022; 29:100982. 36. Naguy A, et al. Lamotrigine augmentation in treatment-resistant pediatric obsessive-compulsive disorder with a 16 month follow-up. J Child Adolesc Psychopharmacol 2016; 26:769–772. 37. Berlin HA, et al. Double-blind, placebo-controlled trial of topiramate augmentation in treatment-resistant obsessive-compulsive disorder. J Clin Psychiatry 2011; 72:716–721. 38. Van Ameringen M, et al. Topiramate augmentation in treatment-resistant obsessive-compulsive disorder: a retrospective, open-label case series. Depress Anxiety 2006; 23:1–5. 39. Afshar H, et al. Topiramate augmentation in refractory obsessive-compulsive disorder: a randomized, double-blind, placebo-controlled trial. J Res Med Sci 2014; 19:976–981. 40. Pampaloni I, et al. High-dose selective serotonin reuptake inhibitors in OCD: a systematic retrospective case notes survey. J Psychopharmacol 2010; 24:1439–1445. 41. Ninan PT, et al. High-dose sertraline strategy for nonresponders to acute treatment for obsessive-compulsive disorder: a multicenter double- blind trial. J Clin Psychiatry 2006; 67:15–22. 42. Rabinowitz I, et al. High-dose escitalopram for the treatment of obsessive–compulsive disorder. Int Clin Psychopharmacol 2008; 23:49–53. 43. Mowla A, et al. Duloxetine augmentation in resistant obsessive-compulsive disorder: a double-blind controlled clinical trial. J Clin Psychopharmacol 2016; 36:720–723.

594 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 44. Dougherty DD, et al. Open-label study of duloxetine for the treatment of obsessive-compulsive disorder. Int J Neuropsychopharmacol 2015; 18:pyu062. 45. Koran LM, et al. Mirtazapine for obsessive-compulsive disorder: an open trial followed by double-blind discontinuation. J Clin Psychiatry 2005; 66:515–520. 46. Mowla A, et al. Pregabalin augmentation for resistant obsessive-compulsive disorder: a double-blind placebo-controlled clinical trial. CNS Spectr 2020; 25:552–556. 47. Eissazade N, et al. Efficacy and safety of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists in augmentation with selective serotonin reuptake inhibitors (SSRIs) in the treatment of moderate to severe obsessive-compulsive disorder: a systematic review and meta-analysis of randomized clinical trials. Sci Rep 2023; 13:20837. 48. Rodriguez CI, et al. Rapid resolution of obsessions after an infusion of intravenous ketamine in a patient with treatment-resistant obsessive- compulsive disorder. J Clin Psychiatry 2011; 72:567–569. 49. Grant JE, et al. Tolcapone in obsessive-compulsive disorder: a randomized double-blind placebo-controlled crossover trial. Int Clin Psychopharmacol 2021; 36:225–229. 50. Zheng H, et al. Combined fluvoxamine and extended-release methylphenidate improved treatment response compared to fluvoxamine alone in patients with treatment-refractory obsessive-compulsive disorder: a randomized double-blind, placebo-controlled study. Eur Neuropsychopharmacol 2019; 29:397–404. 51. Abdelnaim MA, et al. Deep brain stimulation for treatment resistant obsessive compulsive disorder; an observational study with ten patients under real-life conditions. Front Psychiatry 2023; 14:1242566. 52. Patel S, et al. Effectiveness of repetitive transcranial magnetic stimulation in depression, schizophrenia, and obsessive-compulsive disorder: an umbrella meta-analysis. Prim Care Companion CNS Disord 2023; 25:22r03423.

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30 - Post traumatic stress disorder (PTSD) in chil

Post-traumatic stress disorder (PTSD) in children and adolescents

Prescribing in children and adolescents CHAPTER 5 Post-traumatic stress disorder (PTSD) in children and adolescents Diagnostic issues Traumatic events and PTSD are common in young people. One in three children experiences traumatic events1 and about 1 in 13 children develops PTSD before age 18.1 The prevalence of PTSD in adolescents can be much higher in at-risk groups, for example those attending emergency departments, in forensic settings or among refugee/asylum seekers. Young people with PTSD are at high risk of self-harm (nearly 50%) and suicide attempt (20%) and are often functionally impaired, for example not being in education, employment or education (NEET) (more than 25%).1 Of note, more than three out of four young people with PTSD have comorbid psychiatric diagnoses, most commonly depression, conduct disorder, alcohol dependence or generalised anxiety disorder.1 Furthermore, PTSD is not the most common diagnosis in trauma-exposed young people – disorders that are most prevalent in the general population (e.g. depression, conduct disorder, alcohol dependence) are also more prevalent in trauma-exposed young people.1 A diagnosis of PTSD is based on the triad of intrusive re-experiencing, avoidance of stimuli associated with the trauma and hyper-arousal after trauma exposure. Because of the abnormal processing of traumatic memories, young people with PTSD may suffer persistent re-experiencing of the traumatic event(s) through nightmares or unwanted and distressing memories, which are often experienced as if they were happening in the ‘here and now’ and often do not appear as frank dissociative symptoms or flashbacks. In order to minimise re-experiencing symptoms, young people with PTSD often develop overt or covert avoidance strategies, keeping themselves busy or distracted or staying away from people or places that remind them of the traumatic event. As a result of the symptoms, young people with PTSD often feel under continued threat and, therefore, display physiological hyper-arousal, appearing alert and vigilant for danger, irritable and struggling to concentrate on daily tasks. Because of the varied clinical manifestations, the assessment and treatment of PTSD in children and adolescents should be undertaken by clinicians who have expertise in the clinical presentations seen in trauma- exposed children and can appreciate developmental variations in the manifestation of symptoms. Clinical guidance The UK NICE guidelines2 advise that treatment of PTSD in young people should focus on psychotherapy, with 12 sessions of trauma-focused CBT (TF-CBT) for PTSD resulting from a single traumatic event or longer for chronic or recurrent events. If TF-CBT is not effective, or based on the young person’s preference, treatment may also include eye movement desensitisation and reprocessing (EMDR). Based on the current evidence in NICE guidelines,2 the AACAP3 and the International Society for Traumatic Stress Studies (ISTSS),4 pharmacotherapy is not recommended for treatment of PTSD in young people. The evidence for efficacy of pharmacotherapy (SSRIs and SGAs) in adults is also somewhat limited at present.5,6 However, because of the high rates of comorbidity,1 pharmacotherapy may be needed to target co-occurring psychiatric disorders. In adult PTSD, the best supported treatments are fluoxetine, paroxetine and

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References

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Diagnostic issues

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33 - Clinical guidance

Clinical guidance

596 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 venlafaxine.7 3,4-Methylenedioxymethamphetamine (MDMA),8 ketamine9 and psychedelic drugs10 also show promise. Prazosin appears to be effective in reducing PTSD-related nightmares in children aged 4–18 years.11 None of these agents is currently used to any extent in children and adolescents. References

Lewis SJ, et al. The epidemiology of trauma and post-traumatic stress disorder in a representative cohort of young people in England and Wales. Lancet Psychiatry 2019; 6:247–256.
National Institute for Clinical Excellence. Post-traumatic stress disorder. NICE Guideline [NG116]. 2018 (last checked December 2023); https://www.nice.org.uk/guidance/NG116.
Cohen JA, et al. Practice parameter for the assessment and treatment of children and adolescents with posttraumatic stress disorder. J Am Acad Child Adolesc Psychiatry 2010; 49:414–430.
International Society for Traumatic Stress Studies (ISTSS). Posttraumatic stress disorder prevention and treatment guidelines: methodology and recommendations. 2019; https://istss.org/getattachment/Treating-Trauma/New-ISTSS-Prevention-and-Treatment-Guidelines/ISTSS_ PreventionTreatmentGuidelines_FNL-March-19-2019.pdf.aspx.
Cipriani A, et al. Comparative efficacy and acceptability of pharmacological treatments for post-traumatic stress disorder in adults: a network meta-analysis. Psychol Med 2018; 48:1975–1984.
Huang ZD, et al. Comparative efficacy and acceptability of pharmaceutical management for adults with post-traumatic stress disorder: a systematic review and meta-analysis. Front Pharmacol 2020; 11:559.
Ehret M. Treatment of posttraumatic stress disorder: focus on pharmacotherapy. Ment Health Clin 2019; 9:373–382.
Jerome L, et al. Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials. Psychopharmacology (Berl) 2020; 237:2485–2497.
Fremont R, et al. Ketamine for treatment of posttraumatic stress disorder: state of the field. Focus (Am Psychiatr Publ) 2023; 21:257–265.
Krediet E, et al. Reviewing the potential of psychedelics for the treatment of PTSD. Int J Neuropsychopharmacol 2020; 23:385–400.
Hudson N, et al. Evaluation of low dose prazosin for PTSD-associated nightmares in children and adolescents. Ment Health Clin 2021; 11:45–49.

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Attention deficit hyperactivity disorder (ADHD) in children and adolescents

Prescribing in children and adolescents CHAPTER 5 Attention deficit hyperactivity disorder (ADHD) in children and adolescents ■ ■A diagnosis of ADHD should be made only after a comprehensive assessment by a specialist with expertise in ADHD.1 Appropriate psychological, psychosocial and behavioural interventions should be put in place. Drug treatments should be only a part of the overall treatment plan. ■ ■The indication for drug treatment is the presence of impairment resulting from ADHD despite environmental modifications, parent training (if appropriate), advice on parenting strategies and liaison with school. ■ ■Methylphenidate is the first-line treatment when medication is indicated. It is a central nervous system (CNS) stimulant with a large evidence base from trials. Most common adverse effects include insomnia, appetite suppression, raised blood pressure, raised pulse rate and growth deceleration. These adverse effects can usually be managed by treatment breaks or dose reduction, depending on the side effect. Long-term use in children is associated with lower height and weight.2 In the UK and elsewhere, there are several modified-release preparations with different release profiles available, including generic options. ■ ■Dexamfetamine is an alternative CNS stimulant. Effects and adverse reactions are broadly similar to methylphenidate, but there is somewhat less evidence for efficacy and safety than exists for methylphenidate. Dexamfetamine is probably more likely to be diverted and misused. Both methylphenidate and dexamfetamine are Controlled Drugs in most countries. This makes prescribing and dispensing more complex. ■ ■Lisdexamfetamine is a pro-drug – dexamfetamine is complexed with the amino acid lysine and in this form is inactive. It is broken down in red blood cells so that dexamfetamine is gradually made available. It therefore has a similar practical role to extended-release preparations of methylphenidate and, like them, is unlikely to be abused for recreational or dependency-driven purposes. Several RCTs have established it as superior to placebo in children3,4 and adolescents.5 Effect size from preliminary research appears to be at least as great as that of osmotic-controlled release oral delivery system (OROS)-methylphenidate4 and it seems to have a similar range of adverse effects.6,7 Network meta-analyses found lisdexamfetamine to be more effective than methylphenidate8,9 and long-term data suggest that it can be considered as an alternative to extended-release methylphenidate.10 Lisdexamfetamine is also effective in pre-school children11 although it is not licensed for this age group. ■ ■Atomoxetine is a non-stimulant alternative.12–15 It may be particularly useful for children who do not respond to stimulants, where stimulant diversion is a problem or when ‘dopaminergic’ adverse effects (such as tics, anxiety and stereotypies) become problematic on stimulants. Parents should be warned of the possibilities of suicidal thinking and emerging liver disease and advised of the possible features that they might notice. Atomexetine is less effective than stimulants.9,13,16,17

598 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 ■ ■A licensed modified-release preparation of guanfacine is approved in the UK and elsewhere for use in children with ADHD. Guanfacine is an α2 agonist medication and can be considered as an alternative non-stimulant medication to atomoxetine.18 It is broadly as effective as atomoxetine.19 Although not licensed for adults in most countries, children started on guanfacine should probably continue as adults. ■ ■Another non-stimulant medication with evidence of effectiveness in the treatment for ADHD is the α2 agonist clonidine.20 Extended-release clonidine is widely used for ADHD in the USA but not licensed in most countries. ■ ■There is some evidence supporting the efficacy of tricyclic antidepressants21,22 but these are not recommended in clinical practice. ■ ■Bupropion9,23,24 seems to be efficacious and well tolerated. Modafinil also appears to have useful activity in children but not in adults with ADHD.9,25,26 Evidence supporting the use of these drugs is somewhat limited compared with standard treatments.9 Viloxazine is also effective27 and approved in the USA. ■ ■The use of second-generation antipsychotics28,29 for ADHD is not recommended.28,29 These may reduce hyperactivity in autism spectrum disorders30 but should not be prescribed for this indication. ■ ■Emerging ADHD pharmacotherapies31 include the SNRIs venlafaxine and duloxetine, agomelatine, dasotraline (a serotonin, noradrenaline and dopamine reuptake inhibitor) and tipepidine (potassium channel inhibitor). ■ ■Comorbid psychiatric illness is common in children with ADHD. Stimulants are often helpful overall but are unlikely to be appropriate for children who have a psychotic illness. Problems with substance misuse should be managed in their own right alongside ADHD treatment32 and treatments need to be chosen carefully. ■ ■Combinations of stimulants and atomoxetine have been used, but there are few trials and no clear evidence for improved efficacy.33 ■ ■Combinations of stimulants and guanfacine are approved in some countries. There is some evidence that the combination might have additive effects on symptoms control.34 ■ ■Once stimulant treatment has been established, it is appropriate for repeat prescriptions to be supplied through general practitioners1 with reviews at least once a year by a healthcare professional with training and expertise in managing ADHD. Box 5.1 summarises the NICE guidelines for treating children with ADHD and Table 5.10 summarises prescribing in ADHD.

Prescribing in children and adolescents CHAPTER 5 Box 5.1 Summary of UK NICE guidance for ADHD in children1 ■ ■Drug treatment should only be initiated by a specialist and only after comprehensive assessment of mental and physical health and social influences. In children under 5 years, medication should be initiated after a second specialist opinion from an ADHD service with expertise in managing ADHD in younger children (ideally a tertiary service) ■ ■An ADHD-focused group parent-training programme should be offered for parents or carers of children aged less than 5 years with ADHD. Environmental modifications need to be implemented in all cases. If ADHD symptoms are still causing a persistent significant impairment in at least one domain despite environmental modifications, medication can be offered following a baseline assessment ■ ■Methylphenidate, lisdexamfetamine, dexamfetamine, atomoxetine and guanfacine are recommended within their licensed indications ■ ■Methylphenidate (either short or long acting) is the first choice of medication ■ ■Consider switching to lisdexamfetamine for children aged 5 years and over and young people who have had a 6-week trial of methylphenidate at an adequate dose and not derived enough benefit in terms of reduced ADHD symptoms and associated impairment ■ ■Consider dexamfetamine for children aged 5 years and over and young people whose ADHD symptoms are responding to lisdexamfetamine but who cannot tolerate the longer effect profile ■ ■Offer atomoxetine or guanfacine to children aged 5 years and over and young people if they cannot tolerate methylphenidate or lisdexamfetamine or their symptoms have not responded to separate 6-week trials of lisdexamfetamine and methylphenidate, having considered alternative preparations and adequate doses ■ ■Monitoring should include measurement of height and weight (with entry on growth charts) and recording of blood pressure and heart rate. An electrocardiogram is not needed before starting stimulants* atomoxetine or guanfacine unless the person has any of the following: ■ ■History of congenital heart disease or previous cardiac surgery ■ ■history of sudden death in a first-degree relative under 40 years suggesting a cardiac disease ■ ■shortness of breath on exertion compared with peers ■ ■fainting on exertion or in response to fright or noise ■ ■palpitations that are rapid, regular and start and stop suddenly ■ ■chest pain suggesting cardiac origin ■ ■signs of heart failure ■ ■a murmur heard on cardiac examination ■ ■blood pressure that is classified as hypertensive for adults ■ ■a coexisting condition that is being treated with a medicine that may pose an increased cardiac risk A cardiology opinion should be sought if any of the above apply *The cardiovascular toxicity of stimulants remains poorly quantified. Some analyses show no adverse effect35 while population studies suggest increased risk of hypertension and other adverse outcomes.36

CHAPTER 5 Table 5.10 Prescribing in attention deficit hyperactivity disorder (ADHD). Medication Onset and duration of action Dose Notes Recommended monitoring/general notes Methylphenidate immediate release Branded products (Ritalin, Medikinet, Tranquilyn) and various generic preparations available37–39 Onset: 20–60 minutes Duration: 2–4 hours Initially 5–10mg daily titrated up in weekly increments of 5–10mg, to a maximum of 2.1mg/ kg/day in divided doses. Licensed maximum dose 60mg daily (or after specialist review up to 90mg daily)1 Methylphenidate usually first-line treatment in ADHD. Generally well tolerated40 For methylphenidate, dexamfetamine and lisdexamfetamine Monitor: ■ ■Blood pressure41 ■ ■Pulse ■ ■Height ■ ■Weight Monitor for insomnia, mood and appetite change and the development of tics,42 although some evidence suggests tics are not associated with psychostimulants43 Discontinue if no benefits seen in 1 month Controlled Drugs Methylphenidate modified release* An afternoon dose of immediate-release methylphenidate may be necessary in some children to optimise treatment. Concerta XL37,38,44–46 Bioequivalent versions: Affenid XL, Xaggitin XL, Matoride XL, Xenidate XL, Delmosart modified release Onset: 0.5 –2 hours Duration: 12 hours Initially 18mg in the morning, titrated up to a licensed maximum dose of 54mg daily (or after specialist review up to 108mg daily; NB unlicensed) 18mg = 15mg methylphenidate immediate release Consists of an immediate-release component (22% of the dose) and a modified- release component (78% of the dose). Equasym XL47,48 Onset: 20–60 minutes Duration: 8 hours Initially 10mg in the morning, titrated up to a licensed maximum dose of 60mg daily Consists of an immediate- release component (30% of the dose) and a modified-release component (70% of the dose). Capsules can be opened and sprinkled. Medikinet XL Bioequivalent versions: Metyrol XL and Meflynate Onset: 20–60 minutes Duration: up to 8 hours Dose as for Equasym XL Consists of an immediate- release component (50% of the dose) and a modified-release component (50% of the dose). Capsules can be opened and sprinkled.49

Table 5.10 (Continued) Onset and duration of action Dose Notes Medication Ritalin XL50 Onset: 60 minutes Duration: 8–12 hours Dexamfetamine immediate release40,51 Initially 2.5–10mg daily, titrated up in weekly increments of 2.5–5mg, to a maximum of 20mg daily in divided doses (occasionally up to 40mg daily is necessary) Onset: 20–60 minutes Duration: 3–6 hours Lisdexamfetamine (Elvanse)3–5 Onset: 20–60 minutes Duration: 13+ hours Initially 20 or 30mg in the morning, titrated up to a licensed maximum dose of 70mg daily Atomoxetine53,54 Approximately 4–6 weeks (atomoxetine is a noradrenaline reuptake inhibitor) When switching from a stimulant, continue stimulant for first 4 weeks of therapy. For children <70kg: Initially 0.5mg/kg/day for 7 days, then increase according to response. Recommended maintenance dose 1.2mg/kg/day (in single or divided doses) and up to 1.8mg/kg/day, to a maximum of 120mg daily if necessary1 For children >70kg: Initially 40mg daily for 7 days, then increase according to response. Recommended maintenance dose 80mg daily Prescribing in children and adolescents Recommended monitoring/general notes Dose as for Equasym XL Consists of an immediate-release component (50% of the dose) and a modified- release component (50% of the dose). Considered to be less well tolerated than methylphenidate.40 Pro-drug, gradually hydrolysed to dexamfetamine Capsules can be opened and sprinkled.52 Licensed in adults CHAPTER 5 Less effective than stimulants (see text).13,17 Monitor: ■ ■Blood pressure56 ■ ■Pulse May be useful where stimulant diversion is a problem.55 ■ ■Height ■ ■Weight Monitor for insomnia, mood and appetite change and the development of tics. Licensed in adults Monitor young people and adults with ADHD for sexual dysfunction (that is, erectile and ejaculatory dysfunction) as potential adverse effects of atomoxetine. Not a Controlled Drug (Continued )

602 The Maudsley® Prescribing Guidelines in Psychiatry Table 5.10 (Continued) Onset and duration of action Dose Notes Medication Guanfacine modified release9,57 Approximately 1– 5 weeks58 (guanfacine is a central alpha2Aadrenergic receptor agonist) For child 6–12 years (body weight 25kg and above): Initially 1mg once daily; adjusted in steps of 1mg every week if necessary and if tolerated; maintenance 0.05–0.12mg/kg once daily (max. per dose 4mg) For child 13–17 years (body weight 34–41.4kg): Initially 1mg once daily; adjusted in steps of 1mg every week if necessary and if tolerated; maintenance 0.05–0.12mg/kg once daily (max. per dose 4mg) For child 13–17 years (body weight 41.5–49.4kg): Initially 1mg once daily; adjusted in steps of 1mg every week if necessary and if tolerated; maintenance 0.05–0.12mg/kg once daily (max. per dose 5mg) CHAPTER 5 For child 13–17 years (body weight 49.5–58.4kg): Initially 1mg once daily; adjusted in steps of 1mg every week if necessary and if tolerated; maintenance 0.05–0.12mg/kg once daily (max. per dose 6mg) For child 13–17 years (body weight 58.5kg and above): Initially 1mg once daily; adjusted in steps of 1mg every week if necessary and if tolerated; maintenance 0.05–0.12mg/kg once daily (max. per dose 7mg) *For details of other preparations available outside the UK, see Cortese et al., 2017.59 Recommended monitoring/general notes Efficacy and tolerability data should be interpreted with caution.9 Similar monitoring to other medication for ADHD.

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References

Prescribing in children and adolescents CHAPTER 5 References

National Institute for Health and Clinical Excellence. Attention deficit hyperactivity disorder: diagnosis and management. NICE Guideline [NG87]. 2018 (last updated September 2019, last accessed December 2023); https://www.nice.org.uk/guidance/NG87.
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Coghill D, et al. European, randomized, phase 3 study of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/ hyperactivity disorder. Eur Neuropsychopharmacol 2013; 23:1208–1218.
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Connor DF, et al. A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1999; 38:1551–1559.
Hazell P. Tricyclic antidepressants in children: is there a rationale for use? CNS Drugs 1996; 5:233–239.
Otasowie J, et al. Tricyclic antidepressants for attention deficit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database Syst Rev 2014; 9:CD006997.
Gorman DA, et al. Canadian guidelines on pharmacotherapy for disruptive and aggressive behaviour in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, or conduct disorder. Can J Psychiatry 2015; 60:62–76.
Ng QX. A systematic review of the use of bupropion for attention-deficit/hyperactivity disorder in children and adolescents. J Child Adolesc Psychopharmacol 2017; 27:112–116.
Biederman J, et al. A comparison of once-daily and divided doses of modafinil in children with attention-deficit/hyperactivity disorder: a randomized, double-blind, and placebo-controlled study. J Clin Psychiatry 2006; 67:727–735.
Wang SM, et al. Modafinil for the treatment of attention-deficit/hyperactivity disorder: a meta-analysis. J Psychiatr Res 2017; 84:292–300.
Nasser A, et al. A phase III, randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of viloxazine extended-release capsules in adults with attention-deficit/hyperactivity disorder. CNS Drugs 2022; 36:897–915.
Einarson TR, et al. Novel Antipsychotics for Patients with Attention-Deficit Hyperactivity Disorder: a Systematic Review. Technology Report No. 17. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 2001.
Pringsheim T, et al. The pharmacological management of oppositional behaviour, conduct problems, and aggression in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder: a systematic review and meta-analysis. Part 2: antipsychotics and traditional mood stabilizers. Can J Psychiatry 2015; 60:52–61.
Ji N, et al. An update on pharmacotherapy for autism spectrum disorder in children and adolescents. Curr Opin Psychiatry 2015; 28:91–101.
Pozzi M, et al. Emerging drugs for the treatment of attention-deficit hyperactivity disorder (ADHD). Expert Opin Emerg Drugs 2020; 25:395–407.
Humphreys KL, et al. Stimulant medication and substance use outcomes: a meta-analysis. JAMA Psychiatry 2013; 70:740–749.

604 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 33. Treuer T, et al. A systematic review of combination therapy with stimulants and atomoxetine for attention-deficit/hyperactivity disorder, including patient characteristics, treatment strategies, effectiveness, and tolerability. J Child Adolesc Psychopharmacol 2013; 23:179–193. 34. McCracken JT, et al. Combined stimulant and guanfacine administration in attention-deficit/hyperactivity disorder: a controlled, comparative study. J Am Acad Child Adolesc Psychiatry 2016; 55:657–666.e651. 35. Zhang L, et al. Risk of cardiovascular diseases associated with medications used in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. JAMA Network Open 2022; 5:e2243597. 36. Zhang L, et al. Attention-deficit/hyperactivity disorder medications and long-term risk of cardiovascular diseases. JAMA Psychiatry 2024; 81:178–187. 37. Wolraich ML, et al. Pharmacokinetic considerations in the treatment of attention-deficit hyperactivity disorder with methylphenidate. CNS Drugs 2004; 18:243–250. 38. Joint Formulary Committee. British National Formulary (online). London: BMJ and Pharmaceutical Press; http://www.medicinescomplete.com. 39. Janssen-Cilag Ltd. Summary of product characteristics. Concerta XL 18mg, 27mg, 36mg and 54mg prolonged-release tablets. 2023; https://www.medicines.org.uk/emc/product/6872/smpc. 40. Efron D, et al. Side effects of methylphenidate and dexamphetamine in children with attention deficit hyperactivity disorder: a double-blind, crossover trial. Pediatrics 1997; 100:662–666. 41. Hennissen L, et al. Cardiovascular effects of stimulant and non-stimulant medication for children and adolescents with ADHD: a systematic review and meta-analysis of trials of methylphenidate, amphetamines and atomoxetine. CNS Drugs 2017; 31:199–215. 42. Gadow KD, et al. Efficacy of methylphenidate for attention-deficit hyperactivity disorder in children with tic disorder. Arch Gen Psychiatry 1995; 52:444–455. 43. Cohen SC, et al. Meta-analysis: risk of tics associated with psychostimulant use in randomized, placebo-controlled trials. J Am Acad Child Adolesc Psychiatry 2015; 54:728–736. 44. Hoare P, et al. 12-month efficacy and safety of OROS MPH in children and adolescents with attention-deficit/hyperactivity disorder switched from MPH. Eur Child Adolesc Psychiatry 2005; 14:305–309. 45. Remschmidt H, et al. Symptom control in children and adolescents with attention-deficit/hyperactivity disorder on switching from immediate- release MPH to OROS MPH. Results of a 3-week open-label study. Eur Child Adolesc Psychiatry 2005; 14:297–304. 46. Wolraich ML, et al. Randomized, controlled trial of OROS methylphenidate once a day in children with attention-deficit/hyperactivity disorder. Pediatrics 2001; 108:883–892. 47. Findling RL, et al. Comparison of the clinical efficacy of twice-daily Ritalin and once-daily Equasym XL with placebo in children with attention deficit/hyperactivity disorder. Eur Child Adolesc Psychiatry 2006; 15:450–459. 48. Anderson VR, et al. Spotlight on methylphenidate controlled-delivery capsules (Equasym XLTM) in the treatment of children and adolescents with attention-deficit hyperactivity disorder. CNS Drugs 2007; 21:173–175. 49. Flynn Pharma Ltd. Summary of product characteristics. Medikinet XL 5mg, 10mg, 20mg, 30mg, 40mg, 50mg and 60mg modified release capsules (methylphenidate hydrochloride). 2023; https://www.medicines.org.uk/emc/product/313/smpc. 50. Medicines and Healthcare products Regulatory Agency. Public assessment report. Ritalin XL 10mg, 20mg, 30mg, 40mg, 60mg modified- release hard capsules (last updated March 2014); https://mhraproductsproduction.blob.core.windows.net/docs/4781baf366b1fafd0ea20396 2ccb54faadcdcfcc. 51. Cyr M, et al. Current drug therapy recommendations for the treatment of attention deficit hyperactivity disorder. Drugs 1998; 56:215–223. 52. Takeda UK Ltd. Summary of product characteristics. Elvanse 20mg, 30mg, 40mg, 50mg, 60mg and 70mg capsules, hard (lisdexafetamine). 2023; https://www.medicines.org.uk/emc/product/14091/smpc. 53. Kelsey DK, et al. Once-daily atomoxetine treatment for children with attention-deficit/hyperactivity disorder, including an assessment of evening and morning behavior: a double-blind, placebo-controlled trial. Pediatrics 2004; 114:e1–e8. 54. Wernicke JF, et al. Cardiovascular effects of atomoxetine in children, adolescents, and adults. Drug Saf 2003; 26:729–740. 55. Heil SH, et al. Comparison of the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate in light drug users. Drug Alcohol Depend 2002; 67:149–156. 56. Reed VA, et al. The safety of atomoxetine for the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a comprehensive review of over a decade of research. CNS Drugs 2016; 30:603–628. 57. Childress A, et al. Evaluation of the current data on guanfacine extended release for the treatment of ADHD in children and adolescents. Expert Opin Pharmacother 2020; 21:417–426. 58. Takeda UK Ltd. Guanfacine modified-release. Personal communication, 2020. 59. Cortese S, et al. New formulations of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: pharmacokinetics, efficacy, and tolerability. CNS Drugs 2017; 31:149–160.

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36 - Autism spectrum disorder (ASD) in children an

Autism spectrum disorder (ASD) in children and adolescents

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37 - Pharmacological treatment of core ASD symptom

Pharmacological treatment of core ASD symptoms

Prescribing in children and adolescents CHAPTER 5 Autism spectrum disorder (ASD) in children and adolescents Autism spectrum disorder is a complex condition characterised by core deficits in social communication development and behaviour (stereotypies and/or restricted and unusual patterns of interests) as well as sensory difficulties. ICD-11 now matches DSM-5 in removing the subtypes of autism (e.g. the term Asperger’s syndrome has been discontinued). In addition, ICD-11 distinguishes between ASD with or without intellectual development. DSM-5 recommends recording whether or not there is accompanying intellectual impairment. The heterogeneity of ASD poses assessment and treatment challenges. Co-occurring mental health conditions are highly prevalent in ASD1 with 69–79% of individuals experiencing at least one in their lifetime.2,3 These include attention deficit hyperactivity disorder (ADHD), disruptive behavioural disorders, anxiety and obsessive compulsive and mood disorders. Other associated problems include intellectual disability, epilepsy, sleep disturbance, self-harm, irritability and aggression towards others. Associated neurodevelopmental, medical and psychiatric disorders complicate the symptom profile and affect overall outcome. Evaluating and optimally treating co-occurring conditions and/or associated problem behaviours are, therefore, essential. Currently there are no validated or licensed pharmacological treatments that alleviate core ASD symptoms.4,5 Targeting problem behaviours and comorbid psychiatric conditions with pharmacological interventions is, however, common practice. Pharmacotherapies are commonly used in individuals with ASD as adjuncts to psychological interventions. The evidence to date4,6 shows reasonable efficacy of risperidone and aripiprazole for irritability and aggression; supports the use of methylphenidate, atomoxetine and guanfacine for ADHD and melatonin for sleep problems; but shows limited efficacy of SSRIs for anxiety, depression and repetitive behaviours. The evidence for antiepileptics remains inconsistent. There is a potential role for α2 agonists, cholinergic agonists, glutamatergic agents, gamma-aminobutyric acid (GABA) agonists and oxytocin but these require further investigation.4,6 Individuals with ASD are likely to experience more severe adverse effects than typically developing individuals.4–6 Therefore, achieving an effective dose with minimum adverse effects can be a challenging task. Treatment should be initiated in small doses and increased about every five half-lives of the drug, and it may take 4–6 weeks of titration to determine the therapeutic dose for each individual case.7 Excluding any medical conditions, the presence of pain or any other physical discomfort such as gastro-esophageal reflux must be a priority before managing problem behaviour with psychotropic drugs. A comprehensive physical examination should be part of standard practice. The efficacy and adverse effects associated with pharmacotherapy in individuals with ASD should be systematically monitored in view of their impaired communication and the increased propensity for more adverse effects. Standardised behaviour rating scales and adverse effect checklists are essential tools in monitoring progress.8 Pharmacological treatment of core ASD symptoms Evidence from clinical trials to date has not demonstrated clear efficacy of any psychotropic agent in routinely treating core symptoms of ASD.4,6

606 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Restricted repetitive behaviours and interests (RRBIs) RRBIs are distressing and disruptive to functioning and therefore an important treatment target to improve overall outcomes in ASD.9 Behavioural therapies should be used as first line. When RRBIs are severe with significant impact on functioning and/or pose risks to others or self then pharmacotherapy can be considered. A Cochrane review (last updated in 2013) found ‘no evidence of effect of SSRIs on reducing RRBIs in children and emerging evidence of harm’ although there are data that support their use in adults.10 A 2022 meta-analysis of 16 studies demonstrated a small effect size for antidepressants in treating restricted and repetitive behaviours. Subgroup analyses indicated that clomipramine had a higher efficacy than SSRIs and adults had a better response than adolescents and children.11 Risperidone is probably effective in reducing RRBIs in children who have high levels of irritability or aggression12 (any specific efficacy for repetitive behaviours is doubtful). Reductions in stereotypical behaviours have also been reported13–16 albeit in studies with methodological limitations.6 A 2020 meta-analysis of studies on a wide range of currently available pharmacological agents showed evidence supporting only antipsychotic medication,17 whereas another recent meta-analysis of nine studies found no evidence for any pharmacological agent in reducing RRBIs.18 Overall, given the profile of adverse effects of dopamine-blocking agents, consensus guidance from the British Association for Psychopharmacology6 rightly cautions against their routine use for the treatment of RRBIs. If they are used, they should be prescribed in small doses and as part of a carefully considered, time-limited and monitored overall treatment plan. Social and communication impairment Currently, no drug has been consistently shown to improve the core social and communication impairments in ASD.7 Risperidone may have a secondary effect through improvement in irritability.19 Analysis of data from two multicentre trials suggested that risperidone was effective for the treatment of social disability in children with ASD.20 Glutamatergic drugs and oxytocin looked promising.21 However, two meta-analyses and two recent double-blind placebo-controlled trials suggested that oxytocin has no significant effect on social communication.22–25 Larger studies with better methodology are needed.23,26 Sulforaphane has shown mixed results with both positive and negative trials.27–29 Insulin growth factor 1 (IGF-1)30 awaits further work to prove its efficacy in modifying ASD core symptoms, as do glutamatergic agents.31–33 Acetylcysteine34 is probably not effective. Three small double-blind placebo-controlled trials using folinic acid for language impairment look encouraging.35 There is growing but inconsistent evidence for dietary interventions reducing ASD core symptoms.36,37 The targeting of the gut microbiome, including probiotic treatment and faecal microbiota transplants, has drawn much interest.38 However, there is little evidence to support the use of nutritional supplements or dietary therapies for children with ASD36 or indeed any relationship between maternal food intake and child’s diet and the development of ASD/symptoms severity.37

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38 - Pharmacological treatment of co occurring dis

Pharmacological treatment of co-occurring disorders and problem behaviours in ASD

Prescribing in children and adolescents CHAPTER 5 Pharmacological treatment of co-occurring disorders and problem behaviours in ASD Inattention, overactivity and impulsiveness in ASD (symptoms of ADHD) Individuals with ASD have high rates of inattention, overactivity and impulsiveness and in around a third of patients these symptoms merit the diagnosis of ADHD.1,39 The largest controlled trial to date has been with methylphenidate, conducted by the Research Units on Paediatric Psychopharmacology (RUPP) Autism Network.40,41 In a previous retrospective and prospective study of children with ASD, Santosh and colleagues42 reported positive benefits of treatment with methylphenidate. In general, methylphenidate produces highly variable responses in children with ASD and ADHD symptoms, ranging from marked improvement with few adverse effects to poor response with or without problematic adverse effects. A large double-blind placebo- controlled trial of methylphenidate in children with intellectual disability and ADHD showed that optimal dosing with methylphenidate was effective in some.43 Adverse effects are more commonly reported than in children with ADHD alone.44–46 However, where ADHD symptoms are severe and/or disabling, it is reasonable to proceed with a treatment trial of methylphenidate. It is advisable to warn parents of the lower likelihood of response and the potential adverse effects and to proceed with low initial doses (around 0.125mg/kg three times daily, depending on the preparation) increasing by small increments. Treatment should be stopped immediately if behaviour deteriorates or there are unacceptable adverse effects. A systematic review6 confirms that, although effective, the efficacy of methylphenidate for treatment of ADHD in ASD is less than in ADHD alone and that more adverse effects (decreased appetite, sleeping difficulties, abdominal discomfort, social withdrawal, irritability and emotional outbursts) should be expected in ASD. A 2021 meta-analysis supports the efficacy of methylphenidate and atomoxetine.47 There are no published data on the efficacy of amfetamines in children with ASD even though they have been used to treat ADHD in these patients as well as in typically developed children. Lisdexamfetamine (a pro-drug containing d-amfetamine bound to amino acid lysine) has been found to have efficacy and tolerability in treating ADHD in children and young people48 but with no specific data about those with ASD. Atomoxetine is a noradrenergic reuptake inhibitor licensed to treat ADHD with similar efficacy to methylphenidate.6 Preliminary evidence from small open-label trials and a handful of randomised double-blind trials49,50 showed that it may be useful in children with ASD, with the most common adverse effects being nausea, fatigue and sleep difficulties. These studies were followed by a larger trial that confirmed that atomoxetine (alone and combined with parent training) significantly reduced ADHD symptoms.51 In a 24-week extension of the same study, atomoxetine combined with parent training was superior in reducing ADHD symptoms to atomoxetine alone.52 There is evidence that α2 agonists (clonidine and guanfacine) can be used as alternative treatments. A multisite RCT of extended-release guanfacine compared with placebo in children with ASD (mean age 8.5 years) over a period of 8 weeks showed that it is safe and effective in managing hyperactivity in this group.53 No serious adverse events except for drowsiness, fatigue and decreased appetite were reported.

608 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 There are reports from controlled studies supporting the use of risperidone or aripiprazole for ADHD symptoms. However, these were not primary outcomes of the studies and therefore need further investigation. Irritability (aggression, self-injurious behaviour, severe disruptive behaviours) Aggression towards others and self, frequently underlined by irritability, is a common problem in ASD. Although behavioural and environmental approaches should be first- line treatments, more severe and dangerous behaviours usually necessitate pharmacotherapy.54 The duration of recommended treatment is difficult to derive from published evidence but treatment appears to be beneficial for up to 6–12 months.55 Efforts to reduce and possibly discontinue such treatment at the end of this period should be strongly considered.54,55 SGAs are the first-line pharmacological treatment for children and adolescents with ASD and associated irritability.55–58 Risperidone59,60 and aripiprazole61 have been reliably shown to help with irritability and associated disruptive behaviours5 in ASD and have been approved for this use by the US FDA. In a meta-analysis of data from 46 RCTs62 comparing efficacy of risperidone, aripiprazole and other compounds with placebo, risperidone and aripiprazole were the most effective, with moderate to large effect sizes. Another meta- analysis of short-term (8 weeks) aripiprazole in the treatment of irritability in ASD children aged 6–17 years63 found similar results when compared with placebo. The most recent Cochrane review64 concluded that aripiprazole and risperidone probably reduce both irritability and self-injury with a large effect size. However, no effect was shown for aggression. The usual recommended dose of aripiprazole for maintenance is between 5 and 15mg daily.55 The starting dose is 2mg/day. The dosing of risperidone is rather more complicated – FDA-recommended dosages for risperidone are outlined in Box 5.2. Despite their promising efficacy, adverse effects such as weight gain and metabolic changes, increased appetite and somnolence (even with aripiprazole) can be problematic.16,65–68 Research is underway to determine if therapeutic drug monitoring of risperidone and aripiprazole will help in optimising treatment while minimising weight gain.69 One long-term placebo discontinuation study found that relapse rates did not differ between those who stayed on aripiprazole versus those randomised to switch to only placebo, suggesting that re-evaluation of aripiprazole use after a period of stabilisation in irritability symptoms is warranted.70 There is only one study that makes a direct head-to-head comparison71 showing similar tolerability and efficacy profiles for risperidone and aripiprazole. Risperidone usually causes hyperprolactinaemia which, although it may be asymptomatic, may have longer-term effects, therefore necessitating close monitoring. Aripiprazole has no effect on prolactin, which makes it a preferred option. Aripiprazole may on the other hand be ineffective for self-injurious behaviours.6 Lurasidone, in fixed doses of 20 or 60mg/day, has been shown to be ineffective in a randomised double-blind trial over 6 weeks.72 The effectiveness of other SGAs such as olanzapine,73 quetiapine, ziprasidone and clozapine has not been tested in adequately powered RCTs. While controlled studies support the use of mood stabilisers such as lithium74,75 and sodium valproate76 in the treatment of persistent aggression in children they are not as effective as SGAs for the treatment of irritability in ASD.77 Limited data support the combination of risperidone and topiramate being better than risperidone alone.78 Further RCTs are probably warranted of brain-derived neurotrophic factor stimulators such as loxapine and amitriptyline.79

Prescribing in children and adolescents CHAPTER 5 Use of risperidone in children and adolescents Box 5.2 US Food and Drug Administration guidance for risperidone dosing in children and adolescents80 ■ ■Risperidone is indicated for the treatment of irritability associated with autistic spectrum disorder (ASD) in children (aged 5 years and over) and adolescents in the UK/EU and USA ■ ■The dosage of risperidone should be individualised according to the response of the patient Doses of risperidone in paediatric patients with autism spectrum disorders (by total mg/day) Weight categories Days 1–3 Days 4–18 Increments if dose increases are needed Dose range <20kg* 0.25mg 0.5mg +0.25mg at ≥2-week intervals 0.5–3mg† ≥20kg 0.5mg 1.0mg +0.5mg at ≥2-week intervals 1.0–3mg‡ *Caution should be exercised for children <15kg – no dosing data available †Therapeutic effect plateaus at 1mg/day ‡Those weighing >45kg may require higher doses – therapeutic effect plateaus at 3mg General considerations ■ ■Risperidone can be administered once daily or twice daily ■ ■Patients experiencing somnolence may benefit from taking the whole daily dose at bedtime ■ ■Once sufficient clinical response has been achieved and maintained, consideration may be given to gradually lowering the dose to achieve the optimal balance of efficacy and safety ■ ■There is insufficient evidence from controlled trials to indicate how long treatment should continue Adverse effects ■ ■Weight gain, somnolence and hyperglycaemia require monitoring ■ ■Long-term safety of risperidone in children and adolescents with ASD remains to be fully determined Using benzodiazepines to manage irritability and aggression in ASD is not recommended. However, it may be necessary to manage acute aggression with a benzodiazepine. The possibility of behavioural disinhibition that may worsen aggression must be borne in mind. The use of minocycline, arbaclofen or amantadine for irritability is not recommended unless better evidence from double-blind RCTs is available.6 Sleep disturbance Children with ASD have significant sleep problems,81 with sleep-onset insomnia, sleep-maintenance insomnia and irregularities of the sleep–wake cycle being the typical problems encountered. It is essential to understand the aetiology of the sleep problem before embarking on a course of treatment. Abnormalities in the melatonin system have received some attention.82

610 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Melatonin has been shown in 17 studies to be beneficial in children with ASD.83 A meta-analysis of five studies showed good efficacy with doses ranging from 1mg to 10mg and treatment lasting from 14 days to over 4 years.84 Melatonin is usually very well tolerated.84,85 One RCT showed that, while melatonin improved sleep onset, the child’s behaviour during the day did not improve.86 There is also evidence that melatonin combined with CBT is superior to melatonin only, CBT only and placebo in reducing symptoms of insomnia.87 Risperidone may benefit sleep difficulties in those with extreme irritability. In the anxious or depressed child, antidepressants may be beneficial. Insomnia due to hyper arousal may benefit from clonidine or clonazepam.88 Anxiety, OCD and depression SSRIs have yet to show specific efficacy in ASD. Preliminary data from a randomised placebo-blind clinical trial showed beneficial effects of fluoxetine in reducing OCD symptoms in children with ASD, although confounding factors precluded firm conclusions.89 In a systematic review,6 although risperidone was reported by several studies to reduce OCD and anxiety symptoms in young people with ASD, the selection of participants with high levels of irritability did not allow firm conclusions to be drawn about specific effects of risperidone on OCD and anxiety. There is little or no evidence for treating anxiety or OCD symptoms with risperidone, clomipramine or an SSRI. There are some data on buspirone effectively targeting anxiety in ASD90 and propranolol showing positive cognitive effects in ASD.91 However, further evaluation is needed. Guidance on doses of fluoxetine can be found in Box 5.3. Use of fluoxetine in children and adolescents When using fluoxetine to treat repetitive behaviours in ASD patients, doses much lower than those used to treat depression are normally required. It is advisable to use a liquid preparation and begin at the lowest possible dose, monitoring for adverse effects. A suitable regimen is outlined in Box 5.3. Box 5.3 Use of fluoxetine in children and adolescents ■ ■Liquid fluoxetine (as hydrochloride): 20mg/5mL ■ ■2.5mg/day a day for 1 week; note that 2.5mg = 0.625mL, which is difficult to measure accurately ■ ■Follow with a flexible titration schedule based on weight, tolerability and adverse effects up to a maximum dose of 0.8mg/kg/day (0.3mg/kg/day for week 2, 0.5mg/kg/day for week 3 and 0.8mg/kg/day subsequently) ■ ■Reduction may be indicated if adverse effects are problematic Adverse effects ■ ■Monitor for treatment-emergent suicidal behaviour, self-harm and hostility, particularly at the beginning of treatment ■ ■Hyponatraemia is also possible – see Chapter 3

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39 - References

References

Prescribing in children and adolescents CHAPTER 5 References

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612 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 37. Peretti S, et al. Diet: the keystone of autism spectrum disorder? Nutr Neurosci 2019; 22:825–839. 38. Yang Y, et al. Targeting gut microbiome: a novel and potential therapy for autism. Life Sci 2018; 194:111–119. 39. Lee YJ, et al. Advanced pharmacotherapy evidenced by pathogenesis of autism spectrum disorder. Clin Psychopharmacol Neurosci 2014; 12:19–30. 40. Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Arch Gen Psychiatry 2005; 62:1266–1274. 41. Posey DJ, et al. Positive effects of methylphenidate on inattention and hyperactivity in pervasive developmental disorders: an analysis of secondary measures. Biol Psychiatry 2007; 61:538–544. 42. Santosh PJ, et al. Impact of comorbid autism spectrum disorders on stimulant response in children with attention deficit hyperactivity disorder: a retrospective and prospective effectiveness study. Child Care Health Dev 2006; 32:575–583. 43. Simonoff E, et al. Randomized controlled double-blind trial of optimal dose methylphenidate in children and adolescents with severe attention deficit hyperactivity disorder and intellectual disability. J Child Psychol Psychiatry 2013; 54:527–535. 44. Sung M, et al. What’s in the pipeline? Drugs in development for autism spectrum disorder. Neuropsychiatr Dis Treat 2014; 10:371–381. 45. Siegel M, et al. Psychotropic medications in children with autism spectrum disorders: a systematic review and synthesis for evidence-based practice. J Autism Dev Disord 2012; 42:1592–1605. 46. Williamson ED, et al. Psychotropic medications in autism: practical considerations for parents. J Autism Dev Disord 2012; 42:1249–1255. 47. Rodrigues R, et al. Practitioner review: pharmacological treatment of attention-deficit/hyperactivity disorder symptoms in children and youth with autism spectrum disorder: a systematic review and meta-analysis. J Child Psychol Psychiatry 2021; 62:680–700. 48. Coghill D, et al. European, randomized, phase 3 study of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/ hyperactivity disorder. Eur Neuropsychopharmacol 2013; 23:1208–1218. 49. Arnold LE, et al. Atomoxetine for hyperactivity in autism spectrum disorders: placebo-controlled crossover pilot trial. J Am Acad Child Adolesc Psychiatry 2006; 45:1196–1205. 50. Harfterkamp M, et al. A randomized double-blind study of atomoxetine versus placebo for attention-deficit/hyperactivity disorder symptoms in children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry 2012; 51:733–741. 51. Handen BL, et al. Atomoxetine, parent training, and their combination in children with autism spectrum disorder and attention-deficit/ hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2015; 54:905–915. 52. Smith T, et al. Atomoxetine and parent training for children with autism and attention-deficit/hyperactivity disorder: a 24-week extension study. J Am Acad Child Adolesc Psychiatry 2016; 55:868–876.e862. 53. Scahill L, et al. Extended-release guanfacine for hyperactivity in children with autism spectrum disorder. Am J Psychiatry 2015; 172:1197–1206. 54. National Institute for Health and Care Excellence. Autism spectrum disorder in under 19s: support and management. Clinical Guidance 170 [CG170]. 2013 (last updated June 2021, last checked February 2024); https://www.nice.org.uk/guidance/CG170. 55. Kaplan G, et al. Psychopharmacology of autism spectrum disorders. Pediatr Clin North Am 2012; 59:175–187, xii. 56. McDougle CJ, et al. Atypical antipsychotics in children and adolescents with autistic and other pervasive developmental disorders. J Clin Psychiatry 2008; 69 Suppl 4:15–20. 57. Parikh MS, et al. Psychopharmacology of aggression in children and adolescents with autism: a critical review of efficacy and tolerability. J Child Adolesc Psychopharmacol 2008; 18:157–178. 58. DeVane CL, et al. Pharmacotherapy of autism spectrum disorder: results from the randomized BAART clinical trial. Pharmacotherapy 2019; 39:626–635. 59. Jesner OS, et al. Risperidone for autism spectrum disorder. Cochrane Database Syst Rev 2007; 2007:CD005040. 60. Scahill L, et al. Risperidone approved for the treatment of serious behavioral problems in children with autism. J Child Adolesc Psychiatr Nurs 2007; 20:188–190. 61. Curran MP. Aripiprazole: in the treatment of irritability associated with autistic disorder in pediatric patients. PaediatrDrugs 2011; 13:197–204. 62. Fung LK, et al. Pharmacologic treatment of severe irritability and problem behaviors in autism: a systematic review and meta-analysis. Pediatrics 2016; 137 Suppl 2:S124–S135. 63. Douglas-Hall P, et al. Aripiprazole: a review of its use in the treatment of irritability associated with autistic disorder patients aged 6-17. J Cent Nerv Syst Dis 2011; 3:1–11. 64. Iffland M, et al. Pharmacological intervention for irritability, aggression, and self-injury in autism spectrum disorder (ASD). Cochrane Database Syst Rev 2023; 10:CD011769. 65. Caccia S. Safety and pharmacokinetics of atypical antipsychotics in children and adolescents. Paediatr Drugs 2013; 15:217–233. 66. Sharma A, et al. Efficacy of risperidone in managing maladaptive behaviors for children with autistic spectrum disorder: a meta-analysis. J Pediatr Health Care 2012; 26:291–299. 67. Kent JM, et al. Risperidone dosing in children and adolescents with autistic disorder: a double-blind, placebo-controlled study. J Autism Dev Disord 2013; 43:1773–1783. 68. Maayan L, et al. Weight gain and metabolic risks associated with antipsychotic medications in children and adolescents. J Child Adolesc Psychopharmacol 2011; 21:517–535. 69. Hermans RA, et al. The effect of therapeutic drug monitoring of risperidone and aripiprazole on weight gain in children and adolescents: the SPACe 2: STAR (trial) protocol of an international multicentre randomised controlled trial. BMC Psychiatry 2022; 22:814. 70. Hirsch LE, et al. Aripiprazole for autism spectrum disorders (ASD). Cochrane Database Syst Rev 2016; 2016:CD009043. 71. Ghanizadeh A, et al. A head-to-head comparison of aripiprazole and risperidone for safety and treating autistic disorders, a randomized double blind clinical trial. Child Psychiatry Hum Dev 2014; 45:185–192.

Prescribing in children and adolescents CHAPTER 5 72. Loebel A, et al. Lurasidone for the treatment of irritability associated with autistic disorder. J Autism Dev Disord 2016; 46:1153–1163. 73. Hollander E, et al. A double-blind placebo-controlled pilot study of olanzapine in childhood/adolescent pervasive developmental disorder. J Child Adolesc Psychopharmacol 2006; 16:541–548. 74. Campbell M, et al. Lithium in hospitalized aggressive children with conduct disorder: a double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry 1995; 34:445–453. 75. Malone RP, et al. A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder. Arch Gen Psychiatry 2000; 57:649–654. 76. Donovan SJ, et al. Divalproex treatment for youth with explosive temper and mood lability: a double-blind, placebo-controlled crossover design. Am J Psychiatry 2000; 157:818–820. 77. Stigler KA, et al. Pharmacotherapy of irritability in pervasive developmental disorders. Child Adolesc Psychiatr Clin N Am 2008; 17:739–752. 78. Rezaei V, et al. Double-blind, placebo-controlled trial of risperidone plus topiramate in children with autistic disorder. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:1269–1272. 79. Hellings JA, et al. Dopamine antagonists for treatment resistance in autism spectrum disorders: review and focus on BDNF stimulators loxapine and amitriptyline. Expert Opin Pharmacother 2017; 18:581–588. 80. Janssen Pharmaceutical Companies. Highlights of prescribing information. Risperdal® (risperidone) tablets, for oral use, Risperdal® (risperidone) oral solution, Risperdal® M-TAB® (risperidone) orally disintegrating tablets. 2019; https://www.accessdata.fda.gov/drugsatfda_ docs/label/2019/020272s082,020588s070,021444s056lbl.pdf. 81. Krakowiak P, et al. Sleep problems in children with autism spectrum disorders, developmental delays, and typical development: a population- based study. J Sleep Res 2008; 17:197–206. 82. Sanchez-Barcelo EJ, et al. Clinical uses of melatonin in pediatrics. Int J Pediatr 2011; 2011:892624. 83. Doyen C, et al. Melatonin in children with autistic spectrum disorders: recent and practical data. Eur Child Adolesc Psychiatry 2011; 20:231–239. 84. Rossignol DA, et al. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev Med Child Neurol 2011; 53:783–792. 85. Andersen IM, et al. Melatonin for insomnia in children with autism spectrum disorders. J Child Neurol 2008; 23:482–485. 86. Gringras P, et al. Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial. BMJ 2012; 345:e6664. 87. Cortesi F, et al. Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial. J Sleep Res 2012; 21:700–709. 88. Johnson KP, et al. Sleep in children with autism spectrum disorders. Curr Treat Options Neurol 2008; 10:350–359. 89. Reddihough DS, et al. Effect of fluoxetine on obsessive-compulsive behaviors in children and adolescents with autism spectrum disorders: a randomized clinical trial. JAMA 2019; 322:1561–1569. 90. Buitelaar JK, et al. Buspirone in the management of anxiety and irritability in children with pervasive developmental disorders: results of an open-label study. J Clin Psychiatry 1998; 59:56–59. 91. Narayanan A, et al. Effect of propranolol on functional connectivity in autism spectrum disorder – a pilot study. Brain Imaging Behav 2010; 4:189–197.

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40 - Tics and Tourettes syndrome in children and a

Tics and Tourette’s syndrome in children and adolescents

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41 - Detection and treatment of comorbidity

Detection and treatment of comorbidity

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42 - Education and behavioural treatments

Education andÂ behavioural treatments

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Pharmacological treatments

614 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Tics and Tourette’s syndrome in children and adolescents Transient tics occur in 5–20% of children. Tourette’s syndrome (TS) occurs in about 0.7% of children and adolescents and is defined by persistent motor and vocal tics. As many as 65% of individuals with TS will have no tics or only very mild tics by adult life. Tics wax and wane over time and are variably exacerbated by external factors such as stress, inactivity and fatigue, depending on the individual. Tics are about two to three times more common in boys than girls.1 Functional tic disorders (involuntary physical movements, often related to anxiety) have also been described in recent years.2 These are typically seen in teenage girls. Detection and treatment of comorbidity Comorbid OCD, ADHD, ASD, depression, anxiety and behavioural problems are more prevalent than would be expected by chance, and often cause the major impairment in people with tic disorders.3 These comorbid conditions are usually treated first before assessing the level of disability caused by the tics. Education and behavioural treatments Most people with tics do not require pharmacological treatment. Education is crucial for the individual with tics, their family and the people they interact with, especially at school (Figure 5.2). Treatment aimed primarily at reducing tics is warranted if the tics cause distress to the patient or are functionally disabling. Behavioural interventions have been found to be effective with similar effect sizes to antipsychotic medication.4,5 Habit reversal, comprehensive behavioural intervention for tics and exposure and response prevention are the behavioural treatments of choice.6 Pharmacological treatments Studies of pharmacological interventions in TS are difficult to interpret for several reasons: ■ ■There is a large inter-individual variation in tic frequency and severity. Small, randomised studies may include patients who are very different at baseline. ■ ■The severity of tics in a given individual varies markedly over time, making it difficult to separate drug effect from natural variation. ■ ■The bulk of the literature consists of case reports, case series, open studies and underpowered, randomised studies. Publication bias is also likely to be an issue. ■ ■A high proportion of patients have comorbid psychiatric illness. It can be difficult to disentangle any direct effect on tics from an effect on the comorbid illness. This makes it difficult to interpret studies that report improvements in global functioning rather than specific reductions in tics. ■ ■Large numbers of individuals attending clinics with TS appear to use complementary or alternative therapies, with the majority reporting benefits and up to half finding

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Adrenergic 2 agonists

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Antipsychotics

Prescribing in children and adolescents CHAPTER 5 these more helpful compared with medication.7 Robust research about the use of complementary or alternative therapies, their efficacy and potential adverse effects is lacking8 and certainty of evidence for their use is very low.9 Adrenergic α2 agonists Clonidine has been shown in open studies to reduce the severity and frequency of tics but in one study this effect did not seem to be convincingly larger than placebo.10 Other studies have shown more substantial reductions in tics.11–14 Therapeutic doses of clonidine are in the order of 3–5mcg/kg, and the dose should be built up gradually. A transdermal patch has also shown effectiveness.15 The main adverse effects are sedation, postural hypotension and depression. Patients and their families should be informed not to stop clonidine suddenly because of the risk of rebound hypertension. Guanfacine also has some evidence of effectiveness in the treatment of tics.16,17 The efficacy of clonidine (but not of guanfacine) was demonstrated in a 2023 systematic review and network meta-analysis of double-blind RCTs in TS which included children, adolescents and adults.9 Adrenergic α2 agonists may also be used in children with ADHD whose tics deteriorate with stimulant medication.18 Antipsychotics Adverse effects of antipsychotics may outweigh their beneficial effects in the treatment of tics so it is recommended that clonidine or guanfacine is generally tried first (Figure 5.2). Antipsychotics may, however, be more effective than adrenergic α2 agonists in alleviating tics.9 A number of first-generation antipsychotics have been used in TS. In a Cochrane review, pimozide demonstrated robust efficacy in a meta-analysis of six trials.19 In these trials, pimozide was compared with haloperidol (one trial), placebo (one trial), haloperidol and placebo (two trials) and risperidone (two trials) and was found to be more effective than placebo, as effective as risperidone and slightly less effective than haloperidol in reducing tics. It was associated with less severe adverse effects than haloperidol but did not differ from risperidone in that respect. ECG monitoring is essential for pimozide and haloperidol. Haloperidol is often poorly tolerated. Tiapride may also be effective, but evidence may not be generalisable and it has limited availability.9 SGAs, in particular aripiprazole, have in recent years been used more commonly for the treatment of TS.20 Aripiprazole is an effective and well-tolerated treatment of children with TS (and also tics21). A 10-week multicentre double-blind randomised placebo- controlled trial (N = 61) demonstrated the efficacy of aripiprazole in tic reduction in TS. Treatment was associated with significantly decreased serum prolactin concentration, increased mean body weight (by 1.6kg), body mass index and waist circumference.22 Aripiprazole was also found to be effective in another randomised double-blind placebo-controlled trial (N = 133) comparing low-dose aripiprazole (5mg/day if <50kg; 10mg/day if ≥50kg), high-dose aripiprazole (10mg/day if <50kg; 20mg/day if ≥50kg) or placebo for 8 weeks.23 At week 8, tics were reduced in both the high-dose group and the low-dose group, with 69% of patients in the low-dose group and 74% in the high- dose group being very much improved or much improved, compared with 38% in the

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Other drugs

616 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 placebo group. Surprisingly, a higher proportion of children in the low-dose group (18.2%) compared with the high-dose group (9.3%) and placebo group (9.1%) gained clinically significant weight (≥7%) which may have been related to a lower average baseline weight in this group. Several case series also support the use of aripiprazole.24–27 A study evaluating the metabolic side effects of aripiprazole (N = 25) and pimozide (N = 25) in TS over a 24-month period demonstrated that treatment was not associated with significant increase in body mass index. However, pimozide treatment was associated with increases in blood glucose that did not plateau from 12 to 24 months, aripiprazole treatment was associated with increased cholesterol and both medications were associated with increased triglycerides.28 Two meta-analyses support the efficacy of aripiprazole.29,30 One study31 suggests twice-weekly administration may be better tolerated than daily dosing. A small RCT (N = 24) comparing aripiprazole with sodium valproate in children with TS demonstrated a statistically significant difference in tic reduction favouring aripiprazole.32 Risperidone has, in addition to the studies mentioned, also been shown to be more effective than placebo in a small (N = 34) randomised study.33 Fatigue and increased appetite were problematic in the risperidone arm and a mean weight gain of 2.8kg over 8 weeks was reported. One small RCT found risperidone and clonidine to be equally effective.34 A small double-blind crossover study suggested that olanzapine35 may be more effective than pimozide. Sulpiride has been shown to be effective and relatively well tolerated,36 as has ziprasidone.37 Open studies support the efficacy of quetiapine38 and olanzapine.39,40 One very small crossover study (N = 7) found no effect for clozapine.41 Antipsychotic medications may not differ from each other in terms of efficacy for tics, with low to very low certainty of evidence for this comparison.9 Overall, metabolic side effects and weight gain are common with second-generation antipsychotics, even aripiprazole, so benefit/risk ratios need careful discussion.42 Other drugs A small, double-blind placebo-controlled crossover trial of baclofen was suggestive of beneficial effects in overall impairment rather than a specific effect on tics.43 The numerical benefits shown in this study did not reach statistical significance. Similarly, a double-blind placebo-controlled trial of nicotine augmentation of haloperidol found beneficial effects in overall impairment rather than a specific effect on tics.44 These benefits persisted for several weeks after nicotine (in the form of patches) was withdrawn. Nicotine patches were associated with a high prevalence of nausea and vomiting (71% and 40%, respectively). The authors suggest that use as required may be appropriate. Flutamide, an antiandrogen, has been the subject of a small RCT in adults with TS. Modest, short-lived effects were seen in motor but not phonic tics.45 A small RCT showed significant advantages for metoclopramide over placebo46 and for topiramate over placebo. A meta-analysis identified 14 RCTs (all from China) comparing topiramate with haloperidol or tiapride. It concluded that owing to the overall low quality of the study designs, there is not enough evidence to support the routine use of topiramate in clinical practice.47 Tetrabenazine may be useful as an add-on treatment.48 Ecopipam, a D1 receptor antagonist, was also found to be effective in the treatment of tics in a

Prescribing in children and adolescents CHAPTER 5 randomised placebo-controlled crossover study including children and adolescents with TS.49 A second trial (n = 153)50 confirmed the efficacy of ecopipam. The monoamine depleting agents deutetrabenazine and valbenazine, the selective serotonin 5-HT3 receptor antagonist ondansetron and pergolide, a D1-D2-D3 agonist, are probably not effective.9,51 Case reports or case series describing positive effects have been published for clomiphene,52 tramadol,53 ketanserin,54 cyproterone,55 levetiracetam,56 pregabalin57 and cannabis.58 A Cochrane review of cannabinoids concluded that there was little if any current evidence for efficacy59 and, despite a strong biological rationale for use, their overall efficacy and safety remain largely unknown.60 Many other drugs have been reported to be effective in single case reports. Patients in these reports all had comorbid psychiatric illness, making it difficult to determine the effect of these drugs on TS alone. Botulinum toxin has been used to treat bothersome or painful focal motor tics, particularly those affecting neck muscles.42 However, a 2018 Cochrane review expressed uncertainty about its place in the treatment of tics owing to the low quality of available evidence.61 There may be a subgroup of children who develop tics and/or OCD in association with streptococcal or other infections or triggers. This group has been given (in the case of Streptococcus) the acronym PANDAS (paediatric autoimmune neuropsychiatric disorder associated with Streptococcus)62 or, more broadly, PANS (paediatric acute- onset neuropsychiatric syndrome).63 This is thought to be an autoimmune-mediated effect, and there have been trials of immune-modulatory therapy in these children as well as treatment with antibiotics for active infections and also as preventative treatment. More research in this area is warranted. It is extremely rare in practice to get to this point – almost all cases can be effectively treated by recommendations above this point. Not fully effective Poorly tolerated Not effective Educational and behavioural treatment Clonidine or guanfacine Antipsychotic treatment, e.g. aripiprazole or risperidone Consider older or more experimental treatments (see text) Not fully effective Figure 5.2 Summary of recommendations for the treatment of tics and Tourette’s syndrome.

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47 - References

References

618 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 References

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Tao D, et al. Randomized controlled clinical trial comparing the efficacy and tolerability of aripiprazole and sodium valproate in the treatment of Tourette syndrome. Ann Gen Psychiatry 2019; 18:24.
Scahill L, et al. A placebo-controlled trial of risperidone in Tourette syndrome. Neurology 2003; 60:1130–1135.

Prescribing in children and adolescents CHAPTER 5 34. Gaffney GR, et al. Risperidone versus clonidine in the treatment of children and adolescents with Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 2002; 41:330–336. 35. Onofrj M, et al. Olanzapine in severe Gilles de la Tourette syndrome: a 52-week double-blind cross-over study vs. low-dose pimozide. J Neurol 2000; 247:443–446. 36. Robertson MM, et al. Management of Gilles de la Tourette syndrome using sulpiride. Clin Neuropharmacol 1990; 13:229–235. 37. Sallee FR, et al. Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry 2000; 39:292–299. 38. Mukaddes NM, et al. Quetiapine treatment of children and adolescents with Tourette’s disorder. J Child Adolesc Psychopharmacol 2003; 13:295–299. 39. Budman CL, et al. An open-label study of the treatment efficacy of olanzapine for Tourette’s disorder. J Clin Psychiatry 2001; 62:290–294. 40. McCracken JT, et al. Effectiveness and tolerability of open label olanzapine in children and adolescents with Tourette syndrome. J Child Adolesc Psychopharmacol 2008; 18:501–508. 41. Caine ED, et al. The trial use of clozapine for abnormal involuntary movement disorders. Am J Psychiatry 1979; 136:317–320. 42. Roessner V, et al. Pharmacological treatment of tic disorders and Tourette syndrome. Neuropharmacology 2013; 68:143–149. 43. Singer HS, et al. Baclofen treatment in Tourette syndrome: a double-blind, placebo-controlled, crossover trial. Neurology 2001; 56:599–604. 44. Silver AA, et al. Transdermal nicotine and haloperidol in Tourette’s disorder: a double-blind placebo-controlled study. J Clin Psychiatry 2001; 62:707–714. 45. Peterson BS, et al. A double-blind, placebo-controlled, crossover trial of an antiandrogen in the treatment of Tourette’s syndrome. J Clin Psychopharmacol 1998; 18:324–331. 46. Nicolson R, et al. A randomized, double-blind, placebo-controlled trial of metoclopramide for the treatment of Tourette’s disorder. J Am Acad Child Adolesc Psychiatry 2005; 44:640–646. 47. Yang CS, et al. Topiramate for Tourette’s syndrome in children: a meta-analysis. Pediatr Neurol 2013; 49:344–350. 48. Porta M, et al. Tourette’s syndrome and role of tetrabenazine: review and personal experience. Clin Drug Invest 2008; 28:443–459. 49. Gilbert DL, et al. Ecopipam, a D1 receptor antagonist, for treatment of Tourette syndrome in children: a randomized, placebo-controlled crossover study. Mov Disord 2018; 33:1272–1280. 50. Gilbert DL, et al. Ecopipam for Tourette syndrome: a randomized trial. Pediatrics 2023; 151:e2022059574. 51. Chou CY, et al. Emerging therapies and recent advances for Tourette syndrome. Heliyon 2023; 9:e12874. 52. Sandyk R. Clomiphene citrate in Tourette’s syndrome. Int J Neurosci 1988; 43:103–106. 53. Shapira NA, et al. Novel use of tramadol hydrochloride in the treatment of Tourette’s syndrome. J Clin Psychiatry 1997; 58:174–175. 54. Bonnier C, et al. Ketanserin treatment of Tourette’s syndrome in children. Am J Psychiatry 1999; 156:1122–1123. 55. Izmir M, et al. Cyproterone acetate treatment of Tourette’s syndrome. Can J Psychiatry 1999; 44:710–711. 56. Awaad Y, et al. Use of levetiracetam to treat tics in children and adolescents with Tourette syndrome. Mov Disord 2005; 20:714–718. 57. Hienert M, et al. Pregabalin in Tourette’s syndrome: a case series. Am J Psychiatry 2016; 173:1242–1243. 58. Sandyk R, et al. Marijuana and Tourette’s syndrome. J Clin Psychopharmacol 1988; 8:444–445. 59. Curtis A, et al. Cannabinoids for Tourette’s syndrome. Cochrane Database Syst Rev 2009; 2009:CD006565. 60. Artukoglu BB, et al. The potential of cannabinoid-based treatments in Tourette syndrome. CNS Drugs 2019; 33:417–430. 61. Pandey S, et al. Botulinum toxin for motor and phonic tics in Tourette’s syndrome. Cochrane Database Syst Rev 2018; 1:CD012285. 62. Martino D, et al. The PANDAS subgroup of tic disorders and childhood-onset obsessive-compulsive disorder. J Psychosom Res 2009; 67:547–557. 63. Chang K, et al. Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome (PANS): recommendations from the 2013 PANS Consensus Conference. J Child Adolesc Psychopharmacol 2015; 25:3–13.

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48 - Melatonin in the treatment of insomnia in chi

Melatonin in the treatment of insomnia in children and adolescents

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49 - Efficacy

Efficacy

620 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Melatonin in the treatment of insomnia in children and adolescents Insomnia is a common symptom in childhood. Underlying causes may be behavioural (inappropriate sleep associations or bedtime resistance), physiological (delayed sleep phase syndrome) or related to underlying mood disorders (anxiety, depression and bipolar disorder). All forms of insomnia are more common in children with learning difficulties, autism, ADHD and sensory impairments (particularly visual). Although behavioural interventions should be the primary intervention and have a robust evidence base, exogenous melatonin is now the first-line medication prescribed for childhood insomnia (Figure 5.3).1 Melatonin is a hormone that is produced by the pineal gland in a circadian manner. The evening rise in melatonin, enabled by darkness, precedes the onset of natural sleep by about 2 hours.2 Melatonin is involved in the induction of sleep and in synchronisation of the circadian system. There is a wide variety of unlicensed fast-release, slow-release and liquid preparations of melatonin. Many products rely on food grade rather than pharmaceutical grade melatonin and some are expensive. In 2018 the European Medicines Agency and UK MHRA approved Slenyto, a paediatric-appropriate prolonged-release melatonin minitablet, for children with autism and insomnia. This approval was on the basis of a phase III multicentre randomised placebo-controlled study of children with autism. Results of the study included clinically significant improvement in caregivers’ diary-reported sleep latency, total sleep time and longest sleep period.3 Effects were maintained in the long term. The medication was well tolerated and no unexpected safety issues were reported. The study was the only ‘class 1’ rated study in the 2020 America Academy of Neurology practice guideline on the treatment for insomnia and disrupted sleep behaviour in children and adolescents with ASD.4 Secondary outcomes showed improvements in children’s social functioning and behaviour, and caregivers’ well-being. A meta-analysis of melatonin in ASD came to similar, positive conclusions.5 Two RCTs6,7 showed melatonin had comparable benefits when used to treat children with ADHD and insomnia. On this basis, the MHRA in the UK has approved various immediate-release (tablet, e.g. Adaflex) and liquid (e.g. Colonis, Ceyesto) melatonin preparations for the management of sleep-onset insomnia in children with ADHD. There is less evidence (and clinical consensus) for the use of melatonin in typically developing children, although a 2023 meta-analysis provided a conditional recommendation ‘for use of melatonin in children and adolescents 2–20 years, who despite optimisation of sleep hygiene practices, continue to present with difficulties in daily functioning, due to chronic insomnia attributed to an underlying disorder’.8 Efficacy A meta-analysis that included adult and paediatric studies of melatonin in primary sleep disorders demonstrated that melatonin modestly decreases sleep-onset latency, increases total sleep time and improves overall sleep quality; effects that appear not to dissipate with continued melatonin use.9 A more recent (2022) analysis confirmed benefits only for sleep latency and sleep duration.10

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50 - Adverse effects

Adverse effects

10 - Chapter 5 Prescribing in children and adolescents

51 - Dose

Dose

Prescribing in children and adolescents CHAPTER 5 Adverse effects Many of the children who have received melatonin in RCTs and published case series had developmental problems and/or sensory deficits. The scope for detecting subtle adverse effects in this population is limited. Screening for adverse effects was not routine in all studies. In early published accounts, melatonin was reported to worsen seizures11 and exacerbate asthma.12,13 Other reported adverse effects included headache, depression, restlessness, confusion, nausea, tachycardia and pruritis.14,15 However, in more recent and larger placebo-controlled studies involving children with learning difficulty, autism and epilepsy,3,16–18 there were no excess adverse effects in the treatment group over placebo and, in particular, seizures were not worsened. A Cochrane review also found no worsening of seizure frequency in patients with epilepsy who were given melatonin.19 Melatonin has no detectable impact on puberty.20 Dose The cut-off point between physiological and pharmacological doses in children is less than 500mcg. Physiological doses (i.e. <500mcg) of melatonin may result in very high receptor occupancy. The doses used in RCTs and published case series vary hugely with between 500mcg and 5mg doses usually being used, although much lower and higher doses have been studied. In one large RCT, 18% of children seemed to respond to a 500mcg dose but others seemed to require much higher doses (12mg).18 Increasing doses above 5mg is likely to provoke the direct sedative effects of melatonin rather than its sleep phase-shifting properties. This might be necessary and helpful for some children with severe and bilateral brain injury. No response to 6–10mg Response Sleep hygiene Parent-led sleep behavioural interventions Melatonin: Use licensed product 2–5mg Consider use of 6–10mg if response poor Discontinue melatonin Identify and treat secondary causes Not effective Childhood insomnia in association with ASD or ADHD Continue at minimum effective dose Figure 5.3 Summary of recommendations in the treatment of insomnia.

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References

622 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 References

Gringras P. When to use drugs to help sleep. Arch Dis Child 2008; 93:976–981.
Macchi MM, et al. Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol 2004; 25:177–195.
Gringras P, et al. Efficacy and safety of pediatric prolonged-release melatonin for insomnia in children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry 2017; 56:948–957.e944.
Williams Buckley A, et al. Practice guideline: treatment for insomnia and disrupted sleep behavior in children and adolescents with autism spectrum disorder: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 2020; 94:392–404.
Xiong M, et al. Efficacy of melatonin for insomnia in children with autism spectrum disorder: a meta-analysis. Neuropediatrics 2023; 54:167–173.
Van der Heijden KB, et al. Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia. J Am Acad Child Adolesc Psychiatry 2007; 46:233–241.
Weiss MD, et al. Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia. J Am Acad Child Adolesc Psychiatry 2006; 45:512–519.
Edemann-Callesen H, et al. Use of melatonin for children and adolescents with chronic insomnia attributable to disorders beyond indication: a systematic review, meta-analysis and clinical recommendation. EClinicalMedicine 2023; 61:102049.
Ferracioli-Oda E, et al. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One 2013; 8:e63773.
Salanitro M, et al. Efficacy on sleep parameters and tolerability of melatonin in individuals with sleep or mental disorders: a systematic review and meta-analysis. Neurosci Biobehav Rev 2022; 139:104723.
Sheldon SH. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet 1998; 351:1254.
Maestroni GJ. The immunoneuroendocrine role of melatonin. J Pineal Res 1993; 14:1–10.
Sutherland ER, et al. Elevated serum melatonin is associated with the nocturnal worsening of asthma. J Allergy Clin Immunol 2003; 112:513–517.
Chase JE, et al. Melatonin: therapeutic use in sleep disorders. Ann Pharmacother 1997; 31:1218–1226.
Jan JE, et al. Melatonin treatment of sleep-wake cycle disorders in children and adolescents. Dev Med Child Neurol 1999; 41:491–500.
Coppola G, et al. Melatonin in wake-sleep disorders in children, adolescents and young adults with mental retardation with or without epilepsy: a double-blind, cross-over, placebo-controlled trial. Brain Dev 2004; 26:373–376.
Garstang J, et al. Randomized controlled trial of melatonin for children with autistic spectrum disorders and sleep problems. Child Care Health Dev 2006; 32:585–589.
Gringras P, et al. Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial. BMJ 2012; 345:e6664.
Brigo F, et al. Melatonin as add-on treatment for epilepsy. Cochrane Database Syst Rev 2016; 2016:CD006967.
Malow BA, et al. Sleep, growth, and puberty after 2 years of prolonged-release melatonin in children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry 2012; 60:252–261.e3.

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53 - Rapid tranquillisation (RT) in children and a

Rapid tranquillisation (RT) in children and adolescents

Prescribing in children and adolescents CHAPTER 5 Rapid tranquillisation (RT) in children and adolescents As in adults, a comprehensive assessment and effective treatment plan undertaken by staff skilled in the use of de-escalation techniques and appropriate placement of the patient are key to minimising the need for enforced parenteral medication. The differential diagnoses for agitated or challenging behaviour can be broad, but there is concern that RT may be disproportionately used in a neurodiverse population where other strategies may be more appropriate and the outcome more predictable.1,2 Healthcare professionals undertaking RT and/or restraint in children and adolescents should be trained and competent in undertaking these procedures in this population and should be clear about the legal context for any restrictive practices they employ. Be particularly cautious when considering high-potency antipsychotic medication (e.g. haloperidol) especially for those who are neuroleptic naïve, because of the increased risk of acute dystonic reactions in this age group.3 Children are particularly prone to acute extrapyramidal effects of psychotropic and physical medication.4 In the UK, NICE recommends using intramuscular lorazepam (and recommends no other drug).5 Evidence suggests that lorazepam is effective (at a median dose of 1mg) and rarely causes respiratory depression resulting in oxygen desaturation.1 Reviews support the use of a range of SGA drugs6 with the most frequently used agent being olanzapine, which has evidence of its safety and efficacy.7 A wide dose range is given here for medication used in RT. This is partly a consequence of the wide range of body mass in individuals aged from under 10 to 18 years. Caution is required, especially for younger children, but in older adolescents consider the use of adult doses, especially in those who are not drug naïve and where doses at the lower end of the quoted dose range have proved ineffective. A summary is given in Table 5.11. Table 5.11 Recommended drugs for rapid tranquillisation if the oral route is refused or has proven ineffective. Medication Dose Onset of action Comment Olanzapine IM8,9 2.5–10mg 15–30 minutes Possibly increased risk of respiratory depression when administered with benzodiazepines, particularly if alcohol has been consumed. Separate administration by at least 1 hour. Haloperidol IM10 0.025–0.075mg/kg/dose (max. 2.5mg) IM Adolescents >12 years can receive the adult dose (2.5–5mg) 20–30 minutes Must have parenteral anticholinergics present in case of laryngeal spasm or other dystonia (young people more vulnerable to severe dystonia). Adult data suggest co-administration of promethazine may reduce EPS risk.11 ECG is essential Lorazepam* IM12 <12 years: 0.5–1mg;

12 years: 0.5-2mg 20–40 minutes Slower onset of action than midazolam Only treatment recommended by NICE Flumazenil is the reversing agent for all benzodiazepines. (Continued )

624 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Oral medication should always be offered (and repeated if necessary if the young person is willing to take it) before resorting to parenteral treatment. Oral alternatives such as buccal midazolam14 and inhaled loxapine20 have not been widely investigated in children in RT and have limited availability. Buccal midazolam is commonly used for seizures in children. Monitoring after RT is the same as in adults (see Chapter 3). Medication Dose Onset of action Comment Midazolam* IM, IV or buccal12 0.1–0.15mg/kg IM Buccal midazolam 300–500mcg/kg or 6–10 years = 7.5mg;

10 years = 10mg 10–20 min IM (1–3 min IV) Quicker onset and shorter duration of action than lorazepam or diazepam IV administration should only be used (usually as a last resort) with extreme caution and where resuscitation facilities are available. Quicker onset and shorter duration of action than haloperidol When given as buccal liquid, onset of action is 15–30 minutes.13 There are some published data of its use in mental health but only in adults;14 buccal liquid is unlicensed for this use. Diazepam* IV (not for IM administration)15 0.1mg/kg/dose by slow IV injection Max. 40mg total daily dose <12 years and 60mg >12 years 1–3 minutes Long half-life that does not correlate with length of sedation Possibility of accumulation Never give as IM injection. Ziprasidone IM16,17 10–20mg 15–30 minutes IM Apparently effective QT prolongation is of concern in this patient group. ECG is essential. Aripiprazole IM18,19 9.75mg 15–30 minutes Evidence of effectiveness in adults but no clinical trial data for children and adolescents Promethazine IM <12 years: 5–25mg (max. 50mg/day) 12 years: 25–50mg (max. 100mg/day) Up to 60 minutes An effective sedative, although has a slow onset of action. Useful if the cause of behavioural disturbance is unknown and there is concern about the use of antipsychotic medication in a child or young person. *Note that young people are particularly vulnerable to disinhibitory reactions with benzodiazepines. EPS, extrapyramidal symptoms. Table 5.11 (Continued)

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References

Prescribing in children and adolescents CHAPTER 5 References

Kendrick JG, et al. Pharmacologic management of agitation and aggression in a pediatric emergency department – a retrospective cohort study. J Pediatric Pharmacol Therapeutics 2018; 23:455–459.
Wolpert KH, et al. Behavioral management of children with autism in the emergency department. Pediatr Emerg Care 2023; 39:45–50.
National Institute for Health and Care Excellence. Psychosis and schizophrenia in children and young people: recognition and management. Clinical Guidance [CG155]. 2013 (last updated October 2016, last checked October 2023); https://www.nice.org.uk/guidance/cg155.
Chang MY, et al. Drug-induced extrapyramidal symptoms at the pediatric emergency department. Pediatr Emerg Care 2020; 36:468–472.
National Institute for Health and Care Excellence. Violence and aggression: short-term management in mental health, health and community settings. NICE Guideline [NG10]. 2015 (last checked October 2023); https://www.nice.org.uk/guidance/ng10.
Rudolf F, et al. A retrospective review of antipsychotic medications administered to psychiatric patients in a tertiary care pediatric emergency department. J Pediatric Pharmacol Therapeutics 2019; 24:234–237.
Cole JB, et al. The use, safety, and efficacy of olanzapine in a level I pediatric trauma center emergency department over a 10-year period. Pediatr Emerg Care 2020; 36:70–76.
Breier A, et al. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry 2002; 59:441–448.
Lindborg SR, et al. Effects of intramuscular olanzapine vs. haloperidol and placebo on QTc intervals in acutely agitated patients. Psychiatry Res 2003; 119:113–123.
Powney MJ, et al. Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation). Cochrane Database Syst Rev 2012; 11:CD009377.
TREC Collaborative Group. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine. BMJ 2003; 327:708–713.
Nobay F, et al. A prospective, double-blind, randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of violent and severely agitated patients. Acad Emerg Med 2004; 11:744–749.
Schwagmeier R, et al. Midazolam pharmacokinetics following intravenous and buccal administration. Br J Clin Pharmacol 1998; 46:203–206.
Taylor D, et al. Buccal midazolam for agitation on psychiatric intensive care wards. Int J Psychiatry Clin Pract 2008; 12:309–311.
Nunn K, et al. Medication table. In: Nunn KP, Dey C, eds. The Clinician’s Guide to Psychotropic Prescribing in Children and Adolescents, 1st edn. Sydney: Glad Publishing 2003:383–452.
Khan SS, et al. A naturalistic evaluation of intramuscular ziprasidone versus intramuscular olanzapine for the management of acute agitation and aggression in children and adolescents. J Child Adolesc Psychopharmacol 2006; 16:671–677.
Staller JA. Intramuscular ziprasidone in youth: a retrospective chart review. J Child Adolesc Psychopharmacol 2004; 14:590–592.
Sanford M, et al. Intramuscular aripiprazole: a review of its use in the management of agitation in schizophrenia and bipolar I disorder. CNS Drugs 2008; 22:335–352.
National Institute for Health and Clinical Excellence. Aripiprazole for schizophrenia in people aged 15 to 17 years. Technology Appraisal [TA213]. 2011 (last checked October 2023); https://www.nice.org.uk/guidance/ta213.
Lesem MD, et al. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry 2011; 198:51–58.

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55 - Doses of commonly used psychotropic drugs in

Doses of commonly used psychotropic drugs in children and adolescents

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56 - References

References

626 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 5 Doses of commonly used psychotropic drugs in children and adolescents Commonly used psychotropic drugs are presented in Table 5.12. References

Paediatric Formulary Committee. BNF for Children (online). London: BMJ, Pharmaceutical Press, and RCPCH Publications; http://www. medicinescomplete.com.
Merative US LP. Micromedex. 2024; https://www.micromedexsolutions.com/home/dispatch/.
Gov.UK. Guidance: Valproate use by women and girls. 2018 (last updated January 2024); https://www.gov.uk/guidance/valproate-use-by- women-and-girls. Table 5.12 Starting doses of commonly used psychotropic drugs in children and adolescents.1,2 Drug Starting dose* Comment Antipsychotics Aripiprazole 2mg Adjust dose according to response and adverse effects. Clozapine 6.25–12.5mg Use plasma levels to determine maintenance dose. Lurasidone 18.5mg (20mg) to 37mg (40mg) Adjust dose according to response and adverse effects. Olanzapine 2.5–5mg Adjust dose according to response and adverse effects. Quetiapine 25mg Effective dose usually in the range 150–200mg daily. Risperidone 0.25–2mg Adjust dose according to response and adverse effects. Antidepressants Citalopram 10mg daily Effective dose 10–40mg (note QT effects) Escitalopram 5mg/day Effective dose 10–20mg (note QT effects) Fluoxetine 5–10mg/day Adjust dose according to response and adverse effects. Sertraline 25mg daily Effective dose usually in the range 50–100mg daily. Other drugs Lithium 100–200mg/day lithium carbonate Use plasma levels to determine maintenance dose. Melatonin 1–2mg at night Effective dose 2–10mg Valproate 10–20mg/kg/day in divided doses Use plasma levels to determine maintenance dose. Do not offer valproate to girls or young women of child-bearing potential unless there is a pregnancy prevention programme (PPP) in place.1,3 *Suggested approximate oral starting doses (see primary literature for doses in individual indications). Lower dose in suggested range is for children weighing less than 25kg.

11 - Chapter 6 Prescribing in older people

01 - General principles in prescribing in older ad

General principles in prescribing in older adults

11 - Chapter 6 Prescribing in older people

02 - General principles

General principles

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. General principles in prescribing in older adults General principles The pharmacokinetics and pharmacodynamics of most drugs are altered to an important extent in older people. These changes in drug handling and action must be taken into account if treatment is to be effective and adverse effects minimised. Older people often have a number of concurrent illnesses and may require treatment with several drugs. This leads to a greater chance of problems arising because of drug interactions and a higher rate of drug-induced problems in general.1 It is reasonable to assume that all drugs are more likely to cause adverse effects in older patients than in younger patients (Box 6.1). How drugs affect the ageing body (altered pharmacodynamics) As we age, control over reflex actions such as blood pressure and temperature regulation is reduced. Receptors may become more sensitive. This results in an increased incidence and severity of adverse effects. For example, drugs that decrease gut motility are more likely to cause constipation (e.g. anticholinergics and opioids) and drugs that affect blood pressure are more likely to cause falls (e.g. tricyclic antidepressants [TCAs] Chapter 6 Prescribing in older people Box 6.1 Reducing drug-related risk in older people Adherence to the following principles will reduce drug-related morbidity and mortality: ■ ■Use drugs only when absolutely necessary ■ ■Avoid, if possible, drugs that block α1 adrenoceptors, have anticholinergic adverse effects, are very sedative, have a long half-life or are potent inhibitors of hepatic metabolising enzymes ■ ■Start with a low dose and increase slowly but do not undertreat. Some drugs still require the full adult dose ■ ■Try not to treat the adverse effects of one drug with another drug. Find a better-tolerated alternative ■ ■Keep therapy simple; that is, once-daily administration whenever possible

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03 - Drug interactions

Drug interactions

628 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 and diuretics). Older people demonstrate an exaggerated response to central nervous system (CNS)-active drugs such as benzodiazepines and opioids. This is partly because of an age-related decline in CNS function and partly due to increased pharmacodynamic sensitivity to these drugs (due to increased blood–brain barrier permeability).2,3 Therapeutic response to medication can also be delayed; for example, older adults may take longer to respond to antidepressants than younger adults.4 Older people may be more prone to developing serious adverse effects such as agranulocytosis5 and neutropenia6 with clozapine, stroke with antipsychotic drugs7 and bleeding with selective serotonin reuptake inhibitors (SSRIs).8 How ageing affects drug therapy (altered pharmacokinetics)9,10 Absorption Gut motility decreases with age, as does secretion of gastric acid. This leads to drugs being absorbed more slowly, resulting in a slower onset of action. In general, the same amount of drug is absorbed as in a younger adult, but the rate of absorption is slower. Distribution Older adults have more body fat, less body water and less albumin than younger adults. This leads to an increased volume of distribution and a longer duration of action for some fat-soluble drugs (e.g. diazepam), higher concentrations of some drugs at the site of action (e.g. digoxin) and a reduction in the amount of drug bound to albumin (increased amounts of active ‘free drug’; e.g. warfarin, phenytoin). Metabolism The majority of drugs are hepatically metabolised. Liver size is reduced in the elderly, but in the absence of hepatic disease or significantly reduced hepatic blood flow, there is no significant reduction in metabolic capacity. The magnitude of pharmacokinetic interactions is unlikely to be altered but the pharmacodynamic consequences of these interactions may be amplified. Excretion Renal function declines with age: 35% of function is lost by the age of 65 years and 50% by the age of 80. More function is lost if there are concurrent medical problems such as heart disease, diabetes or hypertension. Measurement of serum creatinine or urea can be misleading in the elderly because muscle mass is reduced, so less creatinine is produced. It is particularly important that estimated glomerular filtration rate (eGFR)11 is used as a measure of renal function in this age group. It is best to assume that all elderly patients have at most two-thirds of normal renal function. Most drugs are eventually (after metabolism) excreted by the kidney. A few do not undergo biotransformation first. Lithium and sulpiride are important examples. Drugs primarily excreted via the kidney will accumulate in the elderly, leading to toxicity and adverse effects. Dosage reduction is likely to be required (see Chapter 8). Drug interactions Some drugs have a narrow therapeutic index (a small increase in dose can cause toxicity and a small reduction in dose can cause a loss of therapeutic action). The most commonly prescribed ones are digoxin, warfarin, theophylline, phenytoin and lithium.

11 - Chapter 6 Prescribing in older people

04 - Administering medicines in foodstuffs1316

Administering medicines in foodstuffs13–16

11 - Chapter 6 Prescribing in older people

05 - References

References

Prescribing in older people CHAPTER 6 Changes in the way these drugs are handled in older people and the greater chance of interaction with other drugs mean that toxicity and therapeutic failure are more likely. These drugs can be used safely but extra care must be taken and blood concentrations should be measured where possible. Some drugs inhibit or induce hepatic metabolising enzymes. Important examples include some SSRIs, erythromycin and carbamazepine. This may lead to the metabolism of another drug being altered. Many drug interactions occur through this mechanism. Details of individual interactions and their consequences can be found in the British National Formulary (BNF) online for individual drugs.12 Most can be predicted by a sound knowledge of pharmacology. Administering medicines in foodstuffs13–16 Sometimes patients refuse treatment with medicines, even when such treatment is thought to be in their best interests. In the UK, where the patient has a mental illness or has capacity, the Mental Health Act should be used, but if the patient lacks capacity this option may not be desirable. Medicines should never be administered covertly to older patients with dementia without a full discussion with the multidisciplinary team (MDT) and the patient’s relatives. The outcome of this discussion should be clearly documented in the patient’s clinical notes. Medicines should be administered covertly only if the clear and express purpose is to reduce suffering for the patient. (For further information, see ‘Covert administration of medicines within food and drink’ later in this chapter.) For advice on dosing of psychotropics in older people, see ‘A guide to medication doses of commonly used psychotropics in older adults’ later in this chapter. References

Royal College of Physicians. Medication for older people. Summary and recommendations of a report of a working party of The Royal College of Physicians. J R Coll Physicians Lond 1997; 31:254–257.
Bowie MW, et al. Pharmacodynamics in older adults: a review. Am J Geriatr Pharmacother 2007; 5:263–303.
Cleare A, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol 2015; 29:459–525.
Baldwin R, et al. Management of depression in later life. Adv Psychiatr Treat 2004; 10:131–139.
Munro J, et al. Active monitoring of 12,760 clozapine recipients in the UK and Ireland. Beyond pharmacovigilance. Br J Psychiatry 1999; 175:576–580.
O’Connor DW, et al. The safety and tolerability of clozapine in aged patients: a retrospective clinical file review. World J Biol Psychiatry 2010; 11:788–791.
Douglas IJ, et al. Exposure to antipsychotics and risk of stroke: self controlled case series study. BMJ 2008; 337:a1227.
Paton C, et al. SSRIs and gastrointestinal bleeding. BMJ 2005; 331:529–530.
Mayersohn M. Special pharmacokinetic considerations in the elderly. In: Evans W, Schentage J, Jusko J, eds. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. Vancouver, WA: Applied Therapeutics Inc; 1992.
Dening T, Thomas A, Stewart R, Taylor JP, eds. Oxford Textbook of Old Age Psychiatry. Oxford: Oxford University Press; 2020.
Morriss R, et al. Lithium and eGFR: a new routinely available tool for the prevention of chronic kidney disease. Br J Psychiatry 2008; 193:93–95.
Joint Formulary Committee. British National Formulary (online). London: BMJ and Pharmaceutical Press; http://www.medicinescomplete.com.
Royal College of Psychiatrists. College statement on covert administration of medicines. Psychiatric Bull 2004; 28:385–386.
Haw C, et al. Administration of medicines in food and drink: a study of older inpatients with severe mental illness. Int Psychogeriatr 2010; 22:409–416.
Haw C, et al. Covert administration of medication to older adults: a review of the literature and published studies. J Psychiatr Ment Health Nurs 2010; 17:761–768.
Specialist Pharmacy Service. Covert administration of medicines in adults: pharmaceutical issues 2022 (last updated June 2023); https://www.sps. nhs.uk/articles/covert-administration-of-medicines-in-adults-pharmaceutical-issues/.

11 - Chapter 6 Prescribing in older people

06 - Dementia

Dementia

11 - Chapter 6 Prescribing in older people

07 - Alzheimers disease (AD)

Alzheimer’s disease (AD)

630 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Dementia Dementia is a progressive syndrome affecting around 5% of those aged over 65 years, rising to 20% in the over 80s. The disorder is characterised by cognitive decline, impaired memory and thinking and a gradual loss of skills needed to carry out activities of daily living (ADL). Changes in mood, personality and social behaviour are frequent.1 The various types of dementia are classified according to the different disease processes affecting the brain. The most common cause of dementia is Alzheimer’s disease (AD), accounting for around 60% of all cases. Vascular dementia (VaD) and dementia with Lewy bodies (DLB) are responsible for most other cases. AD and VaD may coexist and are often difficult to separate clinically. Dementia is also encountered in about 30–70% of patients with Parkinson’s disease1 (see Chapter 10). Alzheimer’s disease (AD) Mechanism of action of cognitive enhancers used in AD Acetylcholinesterase (AChE) inhibitors The cholinergic hypothesis of AD is predicated on the observation that the cognitive deterioration associated with the disease results from progressive loss of cholinergic neurons and decreasing levels of acetylcholine (ACh) in the brain.2 However, it is no longer widely believed that cholinergic depletion alone is responsible for the symptoms of AD.3 Three inhibitors of AChE are currently licensed in the UK and elsewhere for the treatment of mild to moderate dementia in AD: donepezil, rivastigmine and galantamine. These three drugs are also recommended in severe AD. In addition, rivastigmine is licensed in some countries for the treatment of mild to moderate dementia associated with Parkinson’s disease. Both AChE and butyrylcholinesterase (BuChE) have been found to play an important role in the degradation of ACh.4 Cholinesterase inhibitors differ in pharmacological action: donepezil selectively inhibits AChE, rivastigmine affects both AChE and BuChE and galantamine selectively inhibits AChE and also has nicotinic receptor agonist properties.5 To date, these differences have not been shown to result in important differences in efficacy or tolerability (see Table 6.1 for a comparison of AChE inhibitors). Memantine Memantine is licensed in the UK and elsewhere for the treatment of moderate to severe dementia in AD. It is believed to exert its therapeutic effect by acting as a low to moderate affinity, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that binds preferentially to open NMDA receptor-operated calcium channels. This activity- dependent binding blocks NMDA-mediated ion flux and is thought to mitigate the effects of sustained and pathologically elevated levels of glutamate (and this excitotoxicity) that may lead to neuronal dysfunction (Table 6.1).6

Prescribing in older people CHAPTER 6 Table 6.1 Characteristics of cognitive enhancers.7–14 Characteristic Donepezil Rivastigmine Galantamine Memantine Primary mechanism AChE-I (selective and reversible) AChE-I (reversible, non- competitive inhibitor) AChE-I (competitive and reversible) Glutamate receptor antagonist Other mechanism None BuChE-I Nicotine receptor agonist 5HT3 receptor antagonist Starting dose 5mg daily 1.5mg bd (oral) (or 4.6mg/24 hours patch) 8mg XL daily (or 4mg bd solution) (immediate-release tablets largely discontinued) 5mg daily Usual treatment dose 10mg daily 3–6mg bd (oral) (or 9.5mg/24 hours patch) 16–24mg XL daily (or 8–12mg bd solution) 20mg daily (or 10mg bd) Recommended minimum interval between dose increases 4 weeks (increase by 5mg daily) 2 weeks for oral (increase by 1.5mg twice a day) 4 weeks for patch (increase to 9.5mg/24 hours) Consider increase to 13.3mg/24 hours after 6 months 4 weeks (increase by 8mg XL daily or by 4mg bd for solution) 1 week (increase by 5mg weekly) Adverse effects7–13 (very common: ≥1/10 and common: ≥1/100) Diarrhoea, nausea,* headache,* common cold, anorexia, hallucinations, agitation, aggressive behaviour, abnormal dreams and nightmares, syncope, dizziness, insomnia, vomiting, rash, pruritis, muscle cramps, urinary incontinence, fatigue, pain, falls Anorexia,* dizziness,* nausea,* vomiting,* diarrhoea,* decreased appetite, nightmares, agitation, confusion, anxiety, headache, somnolence, tremor, abdominal pain and dyspepsia, sweating, fatigue and asthenia, malaise, weight loss (frequency of adverse effects with the patch may differ) Nausea,* vomiting,* decreased appetite, hallucination, depression, syncope, dizziness, tremor, headache, somnolence, lethargy, bradycardia, hypertension, abdominal pain and discomfort, diarrhoea, dyspepsia, muscle spasms, fatigue, asthenia, malaise, weight loss, fall, laceration Drug hypersensitivity, somnolence, dizziness, balance disorders, hypertension, dyspnoea, constipation, elevated liver function test, headache Half-life (hours) ~70 ~1 (oral) 3.4 (patch) 7–8 (oral solution) 8–10 (XL capsules) 60–100 Metabolism CYP3A4 CYP2D6 (minor) Minimal involvement of CYP isoenzymes CYP3A4 CYP2D6 Primarily non-hepatic Drug–drug interactions Yes (see Table 6.2) Interactions unlikely Yes (see Table 6.2) Yes (see Table 6.2) Effect of food on absorption None Delays rate and extent of absorption Delays rate but not extent of absorption None AChE-I, acetylcholinesterase inhibitor; bd, twice a day; BuChE, butyrylcholinesterase.

632 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Efficacy of cognitive enhancers used in AD Currently, no treatments exist that unequivocally reverse disease progression in dementia. Therapeutic interventions are therefore targeted at specific symptoms or at improving or slowing the decline in cognitive function. AChE inhibitors (AChE-Is) may provide some modest cognitive, functional and global benefits in mild to moderate AD.15 The three AChE-Is seem to have broadly similar clinical effects; estimates of the number needed to treat (NNT) (for an improvement of >4 points in the AD Assessment Scale – cognitive subscale [ADAS-cog]) range from 4 to 12.16 An analysis of memantine studies found estimated NNT ranged from 3 to 817 for improved cognitive function. A Cochrane review of memantine in dementia confirmed that there was a small clinical benefit of memantine in people with moderate to severe AD, which occurs irrespective of whether they are also taking a cholinesterase inhibitor, but no benefit in people with mild AD.17 A 2021 study18 investigated the ‘real world’ effectiveness of cholinesterase inhibitors and memantine. The study found that, in general, the initial decline in Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores occurred approximately 2 years before medication was eventually initiated. Medication stabilised cognitive performance for the ensuing 2–5 months. The effect was enhanced in more cognitively impaired cases and attenuated in those taking antipsychotics. Importantly, patients who were switched between agents at least once tended to continue to decline at their pre-medication rate (i.e. did not benefit from pharmacological interventions). Those who remained on the same agent tended to respond better and to stabilise in respect to cognitive changes for a period once the medication was prescribed. Of course, switching might be more common in non-responders, so the act of switching itself may not be detrimental to outcome. Overall, 68% of individuals experienced a period of cognitive stabilisation before continuing to decline at the pre- treatment rate. Other studies have found similar benefits alongside evidence that AChE-Is may reduce overall mortality.19 Switching between drugs used in dementia The benefits of treatment with AChE-Is are rapidly lost when drug administration is interrupted20 and may not be fully regained when drug treatment is reinitiated.21 Poor tolerability with one agent does not rule out good tolerability with another.22 The British Association for Psychopharmacology (BAP) guidelines for dementia confirm that previous comparative trials have failed to consistently demonstrate any significant differences in efficacy between the three AChE-Is, the main differences found being in frequency and type of adverse events. As a result, their recommendation remains valid that a significant proportion of patients (up to 50%) appear to both tolerate and benefit from switching between AChE-Is if they cannot tolerate one.23 Several cases of discontinuation syndrome upon stopping donepezil have been published24,25 suggesting that a gradual withdrawal should be carried out where possible. However, a study comparing abrupt versus stepwise switching from donepezil to memantine found no clinically relevant differences in adverse effects despite patients in

Prescribing in older people CHAPTER 6 the abrupt group experiencing more frequent adverse effects than the stepwise discontinuation group (46% vs 32%, respectively).26 (For switching to rivastigmine patch see ‘Tolerability’ later in this chapter.) Following a systematic review of the literature,27 a practical approach to switching between AChE-Is has been proposed. In the case of intolerance, switching to another agent should be done only after complete resolution of side effects following discontinuation of the initial agent. In the case of lack of efficacy, switching can be done overnight, with a quicker titration scheme thereafter. Switching to another AChE-I is not recommended in individuals who show loss of benefit several years after initiation of therapy. Other effects AChE-Is may also affect non-cognitive aspects of AD and other dementias. For more information about the management of these symptoms, see ‘Management of behavioural and psychological symptoms of dementia (BPSD)’ later in this chapter. Dosing and formulations For dosing information see Table 6.1 and up-to-date manufacturers’ literature. Rivastigmine transdermal patches (9.5mg/24 hours) have been shown to be as effective as the highest doses of capsules but with a superior tolerability profile in a 6-month double-blind placebo-controlled randomised controlled (RCT).28 This has been confirmed in a Chinese study.29 A nasal spray has also been developed.30 The US Food and Drug Administration (FDA) has approved a higher daily dose of donepezil sustained release (23mg) for moderate to severe AD. In the approval trial there was a small statistically significant improvement in cognition (a 2.2 improvement over the 10mg dose on the Severe Impairment Battery [SIB] scale) but no difference in global functioning (a 0.06 improvement on the Clinician’s Interview-Based Impression of Change plus caregiver input [CIBIC-plus] scale). Furthermore, the higher dose was not superior on either of the prespecified secondary outcome measures and the rate of gastrointestinal adverse effects was over three times higher (21%) in the first month in the group receiving donepezil 23mg than in the 10mg group (5.9%).31 The memantine extended release (ER) 28mg once-daily capsule formulation was approved in the USA in 2010. Its efficacy was demonstrated in a large, multinational, phase III trial which showed that the addition of memantine ER to ongoing cholinesterase inhibitors improved key outcomes compared with cholinesterase inhibitor monotherapy, including measures of cognition and global status. The most common adverse events were headache, diarrhoea and dizziness.32 While the FDA chose to approve memantine ER based on efficacy data from this study, the European Medicines Agency decided against approval. It questioned the clinical relevance of the drug given the small differences on the co-primary endpoints and the non-significant differences on the functional measure. In addition, since no comparison studies were performed between memantine immediate release (IR) and memantine ER, the risk–benefit ratio could not be fully evaluated.33

634 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 These high doses of donepezil and memantine have not yet been approved in the UK and many other countries. In addition, most older people seen in practice with AD are likely to be frailer and have more comorbidities than patients in clinical trials and may therefore be less likely to tolerate the higher doses. Combination treatment Guidelines and the UK’s National Institute for Health and Care Excellence (NICE)1 recommend the use of a combination of AChE-I plus memantine rather than AChE-I alone in patients with moderate to severe AD. A network meta-analysis of 54 trials found that memantine plus donepezil showed superior outcomes for cognition, global assessment, daily activities and neuropsychiatric symptoms, but lower acceptability than monotherapy and placebo. A 2022 analysis observed broadly similar outcomes.34 Combination therapy may be more cost-effective because memantine slows the progression of AD.35 A Cochrane review has confirmed these recommendations for combined therapy.36 Studies have also shown that there are no pharmacokinetic or pharmacodynamic interactions between AChE-Is and memantine.37,38 Drug tolerability Drug tolerability may differ between AChE-Is, but, in the absence of sufficient direct comparisons, it is difficult to draw conclusions. Overall tolerability can be broadly evaluated by reference to the numbers withdrawing from clinical trials. Withdrawal rates in trials of donepezil39,40 ranged from 4% to 16% (placebo 1–7%), 7% to 29% (placebo 7%) with rivastigmine41,42 and 7% to 23% (placebo 7–9%) with galantamine.43–45 These figures relate to withdrawals specifically associated with adverse effects. The number needed to harm (NNH) has been reported to be 12.16 A study of the French pharmacovigilance database identified age and the use of antipsychotic drugs, antihypertensives and drugs targeting the alimentary tract and metabolism as factors associated with serious reactions to AChE-Is.46 It has also been suggested that donepezil and rivastigmine are active centrally (CNS events, extrapyramidal symptoms, sleep disturbances and cardiorespiratory events), in contrast to galantamine, which is more active peripherally (muscle cramps and weakness, cardiorespiratory events and urinary incontinence).47 Tolerability seems to be affected by the speed of titration and, perhaps less clearly, by dose. Most adverse effects occurred in trials during titration, and slower titration schedules are recommended in clinical use. This may mean that these drugs are equally well tolerated in practice. Rivastigmine patches offer convenience and a superior tolerability profile to rivastigmine capsules.28,29 Data from three trials found that rivastigmine patches were better tolerated than the capsules with fewer gastrointestinal adverse effects and fewer discontinuations due to these adverse effects.48 Data support recommendations for patients on high doses of rivastigmine capsules (>6mg/day) to switch directly to the 9.5mg/24 hours patch, while those on lower doses (≤6mg/day) should start on 4.6mg/hour patch for 4 weeks before increasing to the 9.5mg/hour patch. This latter switch is also recommended for patients switching from other oral cholinesterase inhibitors to the

Prescribing in older people CHAPTER 6 rivastigmine patch (with a 1-week washout period in patients sensitive to adverse effects or who have very low body weight or a history of bradycardia).49 It is possible to consider increasing the dose to 13.3mg/24 hours after 6 months on 9.5mg/24 hours if tolerated and cognitive or functional decline occurs on the lower dose. A 48-week RCT found the higher-strength patch (13.3mg) significantly reduced deterioration in instrumental activities of daily living (IADL) compared with the 9.5mg/24 hours patch and was well tolerated.50 Patients and caregivers should be instructed on important administration details for the rivastigmine patch:9 ■ ■The transdermal patch should not be applied to skin that is red, irritated or cut. ■ ■Reapplication to the exact same skin location within 14 days should be avoided to minimise the potential risk of skin irritation. ■ ■The previous day’s patch must be removed before applying a new one every day. ■ ■Only one patch should be worn at a time. ■ ■The patch should not be cut into pieces. The following cautions exist for the use of AChE-Is: asthma, chronic obstructive pulmonary disease (COPD), sick sinus syndrome, supraventricular conduction abnormalities, susceptibility to peptic ulcers, history of seizures, bladder (or gastrointestinal) outflow obstruction, cardiac disease, congestive heart failure, unstable angina, electrolyte disturbances; and for rivastigmine patches: risk of fatal overdose with patch administration errors.7 Memantine appears to be well tolerated51,52 and the only conditions associated with warnings include severe hepatic impairment and epilepsy/seizures.53 (See BNF or equivalent for required dosage adjustments in renal impairment.) Isolated cases of international normalised ratio (INR) increases have been reported when memantine is co-administered with warfarin. Adverse effects of drugs Cholinesterase inhibitors When adverse effects occur with AChE-Is they are largely predictable: excess cholinergic stimulation leads to nausea, vomiting, dizziness, insomnia and diarrhoea.54 Such effects are most likely to occur at the start of therapy or when the dose is increased. They are dose related and tend to be transient. Urinary incontinence has also been reported.55 A network meta-analysis56 compared efficacy and safety with these agents and found the following hierarchy in terms of tolerability: ■ ■Withdrawals from studies due to adverse effects: donepezil > galantamine > rivastigmine patch > rivastigmine (meaning donepezil is best tolerated and so on). ■ ■Nausea: rivastigmine patch > donepezil > galantamine > rivastigmine. ■ ■Vomiting: donepezil > rivastigmine patch > galantamine > rivastigmine. ■ ■Diarrhoea: galantamine > rivastigmine > rivastigmine patch > donepezil. ■ ■Dizziness: rivastigmine patch > galantamine > donepezil > rivastigmine.

636 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 An analysis of 16 years of individual case safety reports from VigiBase found that the most common adverse effects reported with AChE-Is were neuropsychiatric symptoms (31.4%), gastrointestinal disorders (15.9%) and general disorders and administration site conditions (11.9%). Cardiovascular adverse drug reactions (ADRs) accounted for 11.7% of ADRs.57 In view of their pharmacological action, AChE-Is can be expected to have vagotonic effects on the heart rate (i.e. bradycardia). The potential for this action may be of particular importance in patients with sick sinus syndrome or other supraventricular cardiac conduction disturbances, such as sinoatrial or atrioventricular block.7–12 Concerns over the potential cardiac adverse effects associated with AChE-Is were raised following findings from controlled trials of galantamine in mild cognitive impairment (MCI) in which increased mortality was associated with galantamine compared with placebo (1.5% vs 0.5%).58 Although no specific cause of death was dominant, half the deaths reported were due to cardiovascular disorders. As a result, the FDA issued a warning restricting galantamine in patients with MCI. The relevance to AD remains unclear.59 The most prominent cardiovascular adverse effects of AChE-Is are bradycardia and syncope, which can result in serious outcomes such as falls, fractures and other trauma as well as necessitate pacemaker placement. If these adverse effects are experienced, patients should undergo a thorough history/evaluation, including a medication review, rhythm monitoring, consideration of neurological symptoms, lowering the doses of other medications that might contribute to bradycardia, stopping or reducing the AChE-I dose or even pacemaker placement. Many of these factors should be considered before the initiation of these medications and periodically thereafter to optimise patient care and mitigate possible adverse events60,61 (Figure 6.1). There are also a few reports that they may occasionally be associated with QT prolongation and torsades de pointes.62 It seems that patients with DLB are more susceptible to the bradyarrhythmic adverse effects of these drugs owing to the autonomic insufficiency associated with the disease.63 The manufacturers of all three agents advise that the drugs should be used with caution in patients with cardiovascular disease or in those taking concurrent medicines that reduce heart rate (e.g. digoxin or β blockers). Although a pre-treatment mandatory electrocardiogram (ECG) has been suggested,59 a review of published evidence showed that the incidence of cardiovascular side effects is low and that serious adverse effects are rare. In addition, the value of pre-treatment screening and routine ECGs is questionable and is not currently recommended by NICE. However, in patients with a history of cardiovascular disease or who are prescribed concomitant negative chronotropic drugs with AChE-Is, an ECG is advised.60 Memantine Although little is known about the cardiovascular effects of memantine, there have been reports of bradycardia and reduced cardiovascular survival associated with its use.64 An analysis of pooled prospective data for memantine revealed that the most frequently reported adverse effects in placebo-controlled trials included agitation

Prescribing in older people CHAPTER 6 (7.5% memantine vs 12% placebo), falls (6.8% vs 7.1%), dizziness (6.3% vs 5.7%), accidental injury (6.0% vs 7.2%), influenza-like symptoms (6.0% vs 5.8%), headache (5.2% vs 3.7%) and diarrhoea (5.0% vs 5.6%).65 Given the higher or similar rates seen with placebo, few conclusions can be drawn. The French pharmacovigilance database compared adverse effects reported with donepezil with memantine. The most frequent ADRs with donepezil alone and memantine alone were respectively bradycardia (10% vs 7%), weakness (5% vs 6%) and convulsions (4% vs 3%). Although it is well known that donepezil is often associated with bradycardia and memantine associated with seizures, this analysis suggested that memantine can also induce bradycardia and donepezil seizures, thus highlighting the care required when treating patients with dementia who have a history of bradycardia or epilepsy.66 Drug interactions Potential for interaction may also differentiate currently available cholinesterase inhibitors. Donepezil67 and galantamine68 are metabolised by cytochromes 2D6 and 3A4 so drug levels may be altered by other drugs affecting the function of these enzymes.

Routine pulse checks should be carried out at baseline, at monthly intervals during titration and at 6-monthly intervals thereafter Symptomatic (e.g. syncope, ‘funny turns’) Asymptomatic Asymptomatic Under 50bpm 50–60bpm Pulse check* Remains asymptomatic • Start/continue drug • Review pulse and symptoms after 1 week • Withhold/stop drug and seek GP or specialist review for underlying cause • If cause is found to be unrelated to drug, or a pacemaker is fitted, consider retrial of drug • Continue drug • Pulse check 1 week after any increase in drug dose • Start/continue drug • Carry out routine pulse checks • Withhold/stop drug and seek GP or specialist review for underlying cause • If cause is found to be unrelated to the drug, or a pacemaker is fitted, consider retrial of drug Over 60bpm Figure 6.1 Suggested guidelines for managing cardiovascular risk prior to and during treatment with acetylcholinesterase inhibitors (AChE-Is) in Alzheimer’s disease.60,61 bpm, beats per minute. Reproduced with permission from Rowland et al. 2007, © 2007 by The Royal College of Psychiatrists.

638 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Cholinesterase inhibitors themselves may also interfere with the metabolism of other drugs, although this is perhaps a theoretical consideration. Rivastigmine has almost no potential for interaction since it is metabolised at the site of action and does not affect hepatic cytochromes. A prospective pharmacodynamic analysis of potential drug interactions between rivastigmine and other medications (22 different therapeutic classes) commonly prescribed in the elderly population compared adverse effects odds ratios between rivastigmine and placebo. Rivastigmine was not associated with any significant pattern of increase in adverse effects that would indicate a drug interaction compared with placebo.69 Rivastigmine thus appears to be least likely to cause problematic drug interactions, a factor that may be important in an elderly population subject to polypharmacy (Table 6.2). Analysis of the French pharmacovigilance database found that the majority of reported drug interactions concerning AChE-Is were pharmacodynamic in nature and most frequently involved the combination of AChE-I and bradycardic drugs (β blockers, digoxin, amiodarone, calcium channel antagonists). Almost a third of these interactions resulted in cardiovascular ADRs such as bradycardia, atrioventricular block and arterial hypotension. The second most frequent drug interaction reported was the combination of AChE-I with anticholinergic drugs leading to pharmacological antagonism.70 The pharmacodynamics, pharmacokinetic and pharmacogenetic aspects of drugs used in dementia have been summarised in two comprehensive reviews.71,72 Table 6.2 Drug–drug interactions.8–12,73,74 Drug Metabolism Plasma levels increased by Plasma levels decreased by Pharmacodynamic interactions Donepezil (Aricept®) Substrate at 3A4 and 2D6 Ketoconazole Itraconazole Erythromycin Quinidine Fluoxetine Paroxetine Rifampicin Phenytoin Carbamazepine Alcohol Antagonistic with anticholinergic drugs and competitive neuromuscular blockers (e.g. tubocurarine). Potential for synergistic activity with cholinomimetics such as depolarising neuromuscular blocking agents (e.g. succinylcholine), cholinergic agonists and peripherally acting cholinesterase inhibitors (e.g. neostigmine). Beta blockers, amiodarone or calcium channel blockers may have additive effects on cardiac conduction. Caution with concomitant use of drugs known to induce QT prolongation and/or torsades de pointes. Movement disorders and neuroleptic malignant syndrome have occurred with concomitant use of antipsychotics and cholinesterase inhibitors. Concurrent use with seizure lowering agents may result in reduced seizure threshold.

Prescribing in older people CHAPTER 6 (Continued ) Drug Metabolism Plasma levels increased by Plasma levels decreased by Pharmacodynamic interactions Rivastigmine (Exelon®) Non-hepatic metabolism Metabolic interactions appear unlikely Smoking tobacco increases the clearance of rivastigmine Antagonistic effects with anticholinergic and competitive neuromuscular blockers (e.g. tubocurarine). Potential for synergistic activity with cholinomimetics such as depolarising neuromuscular blocking agents (e.g. succinylcholine), cholinergic agonists (e.g. bethanecol) or peripherally acting cholinesterase inhibitors (e.g. neostigmine). Synergistic effects on cardiac conduction with β blockers, amiodarone and calcium channel blockers. Caution with concomitant use of drugs known to induce QT prolongation and/or torsades de pointes. Movement disorders and neuroleptic malignant syndrome have occurred with concomitant use of antipsychotics and cholinesterase inhibitors. Concurrent use with metoclopramide may result in increased risk of EPSEs. Galantamine (Reminyl®) Substrate at 3A4 and 2D6 Ketoconazole Erythromycin Ritonavir Quinidine Paroxetine Fluoxetine Fluvoxamine Amitriptyline None known Antagonistic effects with anticholinergic and competitive neuromuscular blockers (e.g. tubocurarine). Potential for synergistic activity with cholinomimetics such as depolarising neuromuscular blocking agents (e.g. succinylcholine), cholinergic agonists and peripherally acting cholinesterase inhibitors (e.g. neostigmine). Possible interaction with agents that significantly reduce heart rate such as digoxin, β blockers, certain calcium channel blockers and amiodarone. Caution with concomitant use of drugs known to induce QT prolongation and/or torsades de pointes (manufacturer recommends ECG in such cases). Movement disorders and neuroleptic malignant syndrome have occurred with concomitant use of antipsychotics and cholinesterase inhibitors. Table 6.2 (Continued)

640 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 When to stop treatment A large multicentre study75 of community-dwelling patients with moderate or severe AD investigated the long-term effects of donepezil over 12 months compared with stopping donepezil after 3 months, switching to memantine or combining donepezil with memantine. Continued treatment with donepezil was associated with continued cognitive benefits, and patients with an MMSE score as low as 3 also benefitted from treatment. This suggests that patients should continue treatment with AChE-Is for as long as possible and there should not be a cut-off MMSE score where treatment is stopped automatically. Moreover, secondary and post-hoc analyses of this study found that withdrawal of donepezil in patients with moderate to severe AD increased the risk of nursing home placement during 12 months of treatment but made no difference during the following 3 years of follow-up. This highlights the point that decisions to stop or Table 6.2 (Continued ) Drug Metabolism Plasma levels increased by Plasma levels decreased by Pharmacodynamic interactions Memantine (Exiba®) Primarily non-hepatic metabolism Renally eliminated Cimetidine Ranitidine Procainamide Quinidine Quinine Nicotine Trimethoprim Isolated cases of INR increases reported with concomitant warfarin (close monitoring of prothrombin time or INR advisable) Drugs that alkalinise urine (pH ~8) may reduce renal elimination of memantine, e.g. carbonic anhydrase inhibitors, sodium bicarbonate None known (Possibility of reduced serum level of hydrochlorothiazide when co-administered with memantine) Effects of L-dopa, dopaminergic agonists, selegiline and anticholinergics may be enhanced. Effects of barbiturates and antipsychotics may be reduced. Avoid concomitant use with amantadine, ketamine and dextromethorphan – increased risk of CNS toxicity. One published case report on possible risk for phenytoin and memantine combination. Dosage adjustment may be necessary for antispasmodic agents, dantrolene or baclofen when administered with memantine. A single case report of myoclonus and confusion when co-administered with co-trimoxazole or trimethoprim NB This list is not exhaustive. Take caution with other drugs that are also inhibitors or enhancers of CYP3A4 and CYP2D6 enzymes. EPSEs, extrapyramidal side effects; INR, international normalised ratio.

Prescribing in older people CHAPTER 6 continue treatment should be informed by potential risks of withdrawal, even if the perceived benefits of continued treatment are not clear.76 A 2021 Cochrane review came to similar conclusions.36 The consensus opinion is that if the drug is well tolerated and the patient’s physical health is stable, then it is probably best to continue the drug. The risks of discontinuation of dementia medication should be balanced against the adverse effects.77 In addition to this, a meta-analysis evaluating the efficacy of the three AChE-Is and memantine in relation to the severity of AD found that the efficacy of all drugs except memantine was independent of dementia severity in all domains. The effect of memantine on functional impairment was actually better in patients with more severe AD. This suggests that the severity of a patient’s illness should not preclude treatment with these drugs.78 Guidance for discontinuation of dementia medication in clinical practice is summarised here.79 Reasons for stopping treatment ■ ■When the patient/caregiver decides to stop (after being advised on the risks and benefits of stopping treatment). ■ ■When the patient refuses to take the medication (but see ‘Covert administration of medicines within food and drink’ later in this chapter). ■ ■When there are problems with patient compliance which cannot be reasonably resolved. ■ ■When the patient’s cognitive, functional or behavioural decline is worsened by treatment. ■ ■When there are intolerable adverse effects. ■ ■When comorbidities make treatment risky or futile (e.g. terminal illness). ■ ■Where there is no clinically meaningful benefit to continuing therapy (clinical judgement should be used here rather than ceasing treatment when a patient reaches a certain score on a cognitive outcome or when they are institutionalised). ■ ■When dementia has progressed to a severely impaired stage (Global Deterioration Scale stage 7: development of swallowing difficulties). When a decision is made to stop therapy (for reasons other than lack of tolerability), tapering of the dose and monitoring the patient for evidence of significant decline during the next 1–3 months are advised. If such decline occurs, reinstatement of therapy should be considered. NICE recommendations NICE guidance on dementia80 was last updated in June 2018 (Box 6.2). Other treatments (where the evidence remains less certain) A 2009 Cochrane review81 concluded that Ginkgo biloba appears to be safe in use with no excess adverse effects compared with placebo, but the evidence that it has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unreliable. In contrast, a 2015 systematic review and meta-analysis82

CHAPTER 6 Box 6.2 Summary of NICE guidance for the treatment of AD80,83 ■ ■The three AChE-Is donepezil, galantamine and rivastigmine are recommended for managing mild to moderate AD ■ ■Memantine is recommended for managing moderate AD for people who are intolerant of or have a contraindication to AChE-Is or for managing severe AD ■ ■For people with an established diagnosis of AD who are already taking an AChE-I: ■ ■consider memantine in addition to an AChE-I if they have moderate disease ■ ■offer memantine in addition to an AChE-I if they have severe disease ■ ■For people who are not taking an AChE-I or memantine, prescribers should only start treatment with these on the advice of a clinician who has the necessary knowledge and skills. This could include: ■ ■secondary care medical specialists such as psychiatrists, geriatricians and neurologists ■ ■other healthcare professionals (such as GPs, nurse consultants and advanced nurse practitioners) if they have specialist expertise in diagnosing and treating AD ■ ■Once a decision has been made to start an AChE-I or memantine, the first prescription may be made in primary care ■ ■For people with an established diagnosis of AD who are already taking an AChE-I, primary care prescribers may start treatment with memantine without taking advice from a specialist clinician ■ ■Ensure that local arrangements for prescribing, supply and treatment review follow the NICE guideline on medicines optimisation84 ■ ■Do not stop AChE-Is in people with AD because of disease severity alone ■ ■Therapy with an AChE-I should be initiated with a drug with the lowest acquisition cost (taking into account required daily dose and the price per dose once shared care has started). An alternative may be considered on the basis of adverse effects profile, expectations about adherence, medical comorbidity, possibility of drug interactions and dosing profiles Summary of NICE guidance for the treatment of non-AD dementia80,83 ■ ■Offer donepezil or rivastigmine to people with mild to moderate DLB ■ ■Only consider galantamine for people with mild to moderate DLB if donepezil and rivastigmine are not tolerated ■ ■Consider donepezil or rivastigmine for people with severe DLB ■ ■Consider memantine for people with DLB if AChE-Is are not tolerated or are contraindicated ■ ■Only consider AChE-Is or memantine for people with VaD if they have suspected comorbid AD, Parkinson’s disease dementia or DLB ■ ■Do not offer AChE-Is or memantine to people with frontotemporal dementia ■ ■Do not offer AChE-Is or memantine to people with cognitive impairment caused by multiple sclerosis ■ ■For guidance on pharmacological management of Parkinson’s disease dementia, see Parkinson’s disease dementia in the NICE guideline on Parkinson’s disease Medicines that may cause cognitive impairment1 ■ ■Be aware that some commonly prescribed medicines are associated with increased anticholinergic burden, and therefore cognitive impairment ■ ■Consider minimising the use of medicines associated with increased anticholinergic burden, and if possible look for alternatives: ■ ■when assessing whether to refer a person with suspected dementia for diagnosis ■ ■during medication reviews with people living with dementia ■ ■Be aware that there are validated tools for assessing anticholinergic burden but there is insufficient evidence to recommend one over the others (see ‘Safer prescribing for physical conditions in dementia’ later in this chapter). ■ ■For guidance on carrying out medication reviews, see the medication review in the NICE guideline on medicines optimisation84 NB The Anticholinergic Effect on Cognition (AEC) scale can be accessed at www.medichec.com. AChE-I, acetylcholinesterase inhibitors; AD, Alzheimer’s disease; DLB, dementia with Lewy bodies; VaD, vascular dementia.

Prescribing in older people CHAPTER 6 found that Ginkgo biloba 240mg/day was able to stabilise or slow decline in cognition, function, behaviour and global change at 22–26 weeks in patients with cognitive impairment and dementia, especially for patients with neuropsychiatric symptoms. A 2022 umbrella review confirmed the efficacy of Ginkgo.85 Several reports have noted that Ginkgo may increase the risk of bleeding.86 The findings of a systematic review87 suggest that supplementation of B complex vitamins, especially folic acid, may have a positive effect on delaying and preventing the risk of cognitive decline. Ascorbic acid and a high dose of vitamin E, when given separately, also showed positive effects on cognitive performance, but there is not sufficient evidence to support their use. The results of vitamin D supplementation trials are not conclusive in assessing the potential benefits that vitamin D might have on cognition. A Cochrane review of omega-3 fatty acids for the treatment of dementia (632 people with mild to moderate AD) found that taking omega-3 polyunsaturated fatty acid supplements for 6 months had no effect on cognition (learning and understanding), everyday functioning, quality of life or mental health. The trials did not report side effects very well, but none of the studies described significant harmful effects on health.88 A systematic review and meta-analysis including four RCTs involving 259 participants suggested that the effects of ginseng on AD remain unproven.89 Natural hirudin, isolated from the salivary gland of the medicinal leech, is a direct thrombin inhibitor and has been used for many years in China. A small 20-week open- label RCT of 84 patients receiving donepezil or donepezil plus hirudin (3g/day) found that patients on the combination showed significant decrease in ADAS-cog scores and significant increase in ADL scores compared with donepezil alone. However, haemorrhage and hypersensitivity reactions were more common in the combination group than in the donepezil group (11.9% and 7.1% vs 2.4% and 2.4%, respectively).77 The potential haemorrhagic effects of hirudin need further exploration before it can be considered for clinical use. Huperzine A, an alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly selective, reversible AChE-I used for treating AD since 1994 in China and available as a nutraceutical in the USA. Despite its promising effects on cognition and ADLs, there is insufficient evidence to support its use in dementia90 or MCI90,91 due to the high heterogeneity of reviews and low quality of primary studies. High-quality, large, multicentre RCTs with long-term follow-up in different settings are warranted but no studies have been published since 2020. A Cochrane review of huperzine A in VaD found no convincing evidence for its value in VaD.92 There is increasing evidence to suggest possible efficacy of Crocus sativus (saffron) in the management of AD. A systematic review and meta-analysis of RCTs revealed that saffron significantly improves cognitive function measured by ADAS-cog and the Clinical Dementia Rating Scale – Sums of Boxes (CDR-SB) compared with placebo groups. In addition, there was no difference between saffron and conventional medicines (donepezil, memantine). No serious adverse events were reported in the included studies. Saffron may be beneficial in improving cognitive function in patients with MCI and AD, however no evidence was found to support its effects on other types of dementia. More high-quality randomised placebo-controlled trials are needed to further confirm the efficacy and safety of saffron for MCI and dementia.93 Cerebrolysin is a parenterally administered, porcine brain-derived peptide preparation that has pharmacodynamic properties similar to those of endogenous neurotrophic

644 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 factors. A meta-analysis included six RCTs comparing cerebrolysin 30mg/day with placebo in mild to moderate AD. Cerebrolysin was more effective than placebo at 4 weeks regarding cognitive function and at 4 weeks and 6 months regarding global clinical change and ’global benefit’. Its safety was comparable with placebo. In addition, a large 28-week RCT comparing cerebrolysin, donepezil or combination therapy showed (i) higher improvements in global outcome for cerebrolysin and the combination therapy than for donepezil alone at study endpoint; (ii) a lack of significant group differences in cognitive, functional and behavioural domains at the endpoint; and (iii) best scores of cognitive improvement in the combination therapy group at all study visits.94 This therapeutic option requires further investigation in large trials. A Cochrane review assessing cerebrolysin in VaD found that intravenous courses improved cognition and general function in people living with VaD, with no suggestion of adverse effects. However, these data are not definitive. The analyses were limited by heterogeneity, and studies had high risk of bias. If there are benefits, the effects may be too small to be clinically meaningful. Cerebrolysin continues to be used and promoted as a treatment for VaD, but the supporting evidence base is weak. The most commonly reported non-serious adverse events were headache, aesthenia, dizziness, hypertension and hypotension.95 For information on statins see ‘Safer prescribing for physical conditions in dementia’ later in this chapter. A longitudinal prospective study examined the relationship between chocolate consumption and cognitive decline in an elderly cognitively healthy population. A total of 531 participants aged ≥65 years with normal MMSE scores were followed for a median of 48 months. Dietary habits were evaluated at baseline and the MMSE was used to assess global cognitive function at baseline and at follow-up. After adjustment for confounders, chocolate intake was associated with a 41% lower risk of cognitive decline. This protective effect was observed only among subjects with an average daily consumption of caffeine lower than 75mg.96 Souvenaid is a medical food for the dietary management of early AD. A Cochrane review97 concluded that it probably does not reduce the risk of progression to dementia, there is no convincing evidence that it affects other outcomes important to people with AD (in the prodromal stage or mild to moderate stages) and its effects in more severe AD remain unclear. Idalopirdine is a 5HT6 receptor antagonist. The 5HT6 receptor is expressed in areas of the CNS involved with memory and there is evidence suggesting that blocking of these receptors induces acetylcholine release and could restore ACh levels in a deteriorated cholinergic system.98 A systematic review and meta-analysis analysed four RCTs with 2803 patients with AD. Idalopirdine was not shown to be effective for AD patients and is associated with a risk of elevated liver enzymes and vomiting. Although idalopirdine might be more effective at high doses and in moderate AD subgroups, the effect size is small.99 A large number of RCTs of anti-inflammatory drugs in AD have failed to reach primary outcomes. Large-scale studies of non-steroidal anti-inflammatory drugs (NSAIDs) including indomethacin, naproxen and rofecoxib in AD have been unsuccessful. RCTs with a range of other anti-inflammatory drugs including prednisolone, hydroxychloroquine, simvastatin, atorvastatin, aspirin and rosiglitazone have also shown no clinically significant changes in primary cognitive outcomes in patients with AD.23 A 2020 Cochrane review evaluated aspirin and other NSAIDs for the prevention of dementia

Prescribing in older people CHAPTER 6 and found no evidence to support the use of low-dose aspirin or other NSAIDs of any class (celecoxib, rofecoxib, naproxen) for the prevention of dementia. There was, however, evidence of harm including higher rates of death and major bleeding compared with placebo with aspirin, and in one of the studies more people developed dementia in the NSAID group. More stomach bleeding and other stomach problems, such as pain, nausea and gastritis, were also reported with NSAIDs.100 Two existing compounds, trazodone and dibenzoylmethane, were found to be markedly neuroprotective in mouse models of neurodegeneration, using clinically relevant doses over a prolonged period of time, without systemic toxicity. Trazodone, a serotonin antagonist and reuptake antidepressant with additional anxiolytic and hypnotic effects, was associated with delayed cognitive decline in a small retrospective study examining its long-term use. Trazodone non-users had a 2.6-fold faster decline in MMSE (primary outcome) assessment than trazodone users.101 However, a study of UK population- based electronic health records found no association between trazodone use and a reduced risk of dementia compared with other antidepressants. These results suggest that the clinical use of trazodone is not associated with a reduced risk of dementia.102 Similarly, three identical naturalistic cohort studies using UK clinical registers found no evidence of cognitive benefit from trazodone compared with other antidepressants in people with dementia.104 Despite pre-clinical evidence, trazodone should not be prescribed for cognition in dementia.103 There are no observational data suggesting trazodone reduces risk of dementia but some data that suggest important adverse outcomes in older people.104 Dibenzoylmethane (DBM) is a minor constituent of liquorice that has been found to have antineoplastic effects, with efficacy against prostate and mammary tumours. In prion-diseased mice, both trazodone and DBM treatment restored memory deficits, abrogated the development of neurological signs, prevented neurodegeneration and significantly prolonged survival. In tauopathy-frontotemporal dementia mice, both drugs were neuroprotective, rescued memory deficits and reduced hippocampal atrophy. Further, trazodone reduced p-tau burden.105 KarXT (xanomeline plus trospium (Cobenfy)) is an investigational treatment that has shown early promise in the treatment of positive and negative symptoms of schizophrenia. Unlike all currently approved treatments for schizophrenia, KarXT does not directly bind to dopamine receptors; instead, the therapeutic effects of KarXT appear to be mediated through direct agonism of muscarinic acetylcholine receptors. To mitigate the cholinomimetic effects of xanomeline (e.g. vomiting), trospium is combined with xanomeline. Findings suggest that KarXT may have a separable and meaningful impact on cognition, particularly among patients with cognitive impairment.106 Quercetin is a flavonoid widely distributed among plants and found commonly in our daily diet (fruits and vegetables). It has beneficial properties against general mechanisms of AD aetiology; it protects neuronal cells by attenuating oxidative stress and neuro inflammation. Quercetin inhibits β-amyloid (Aβ) aggregation and tau phosphorylation and restores acetylcholine levels through the inhibition of hydrolysis of acetylcholine by AChE enzyme. Although showing neuroprotective efficacy in several in vitro and animal models, in vivo studies have reported that it is extensively metabolised upon absorption from the gut, affecting its bioavailability, and has low blood–brain barrier penetrability, thus limiting its efficacy in combating neurodegenerative disorders. Therefore, future clinical trials must improve its bioavailability, developing related molecules with greater gut and brain penetrability, which will likely improve clinical efficacy.107

646 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Novel treatments Amyloid plaques are composed of β-amyloid (Aβ) in the extracellular space. Aβ is derived from the amyloid precursor protein (APP), a transmembrane protein. Β secretase and γ secretase cleave the APP and generate pathological Aβ, and accumulation of Aβ results in neurotoxicity. Reducing the accumulation of Aβ has become a therapeutic purpose of AD. Antiamyloid therapy consists of three strategies: secretase inhibitors, Aβ aggregation inhibitors and Aβ immunotherapy.108 Aducanumab is an antibody that works by targeting Aβ and preferentially binds to the aggregated Aβ. Through this interaction, aducanumab could reduce the build-up of Aβ and therefore the number of amyloid plaques present in the brain, thus potentially slowing neurodegeneration and disease progression. Although in early 2019 the manufacturers (Biogen) announced that aducanumab failed futility analyses in two identically designed phase III AD trials and discontinued its development, later in the year they made the announcement that they were applying for US FDA marketing approval. They explained they had reanalysed data from the trials to include patients who had continued in the studies after the cut-off date for the futility analyses and stated that one trial showed significant findings and a subset from the second trial supports these positive findings.109 One concern with aducanumab was the frequency of adverse effects, particularly amyloid-related imaging abnormalities (ARIAs). In June 2021, the FDA made the decision to grant conditional accelerated approval for aducanumab to treat AD patients. Aducanumab was not approved in Europe. The phase III trial of lecanemab (Clarity-AD trial) was more encouraging. Lecanemab lowers brain Aβ plaque burden through binding to soluble Aβ protofibrils as well as (to a variable extent) other forms of Aβ. The study included 1795 participants with MCI or early AD plus evidence of amyloid on a positron emission tomography (PET) scan or by cerebrospinal fluid testing. They were randomly assigned to receive 10mg/kg body weight of lecanemab via intravenous infusion every 2 weeks or matched placebo. After 18 months, lecanemab reduced cognitive decline, as measured by CDR-SB, which quantifies symptom severity across a range of cognitive and functional domains, by 27% compared with placebo; an absolute difference of 0.45 points (change from baseline 1.21 for lecanemab vs 1.66 with placebo, p <0.001). All key secondary endpoints were also met. The incidence of ARIAs, which manifest as oedema or microhaemorrhages, was 21% of the lecanemab group. Most cases were asymptomatic and detected incidentally. However, reports of deaths in the open-label extension phase of the study (possibly linked to co-administration of the thrombolytic drug alteplase) have heightened concerns about lecanemab’s safety in patients taking thrombolytic drugs.110,111 Lecanemab has been approved by the FDA and was undergoing a full evaluation by the European Medicines Agency at the time of writing.112 Donanemab is another high-potency antiamyloid drug infused intravenously every 4 weeks. In 2022, results were announced for the phase III trial (TRAILBLAZER-ALZ 2 trial) which included 1736 participants with early symptomatic AD (MCI/mild dementia) with amyloid and low/medium or high tau pathology based on PET imaging. Compared with placebo, donanemab treatment over 18 months resulted in slowing of cognitive and functional decline by approximately 35% in the primary target population studied. In addition, 52% of treated participants converted to amyloid PET-negative status by 12 months. ARIA-E (with oedema) and ARIA-H (with microhaemorrhage/haemosiderosis) occurred in

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08 - Vascular dementia (VaD)

Vascular dementia (VaD)

Prescribing in older people CHAPTER 6 24.0% and 31.4% of treated individuals, respectively.113,114 Donanemab is, at the time of writing, undergoing a full evaluation by the FDA and NICE. The development of three monoclonal antibodies, gosuranemab, tilavonemab and zagotenemab, was terminated due to negative results. A phase II study of semorinemab, an anti-tau monoclonal antibody, was negative. While semorinemab had a significant effect on cognition measured by the ADAS-Cog11, this effect did not extend to improved functional or global outcomes.115 Further exploration is required. Clinical trials of anti-tau vaccines are underway. In addition to the above, results of recent trials of solanezumab, crenezumab and gantenerumab were all negative. Vascular dementia (VaD) Vascular dementia comprises 10–50% of dementia cases and is the second most common type of dementia after AD. It is caused by ischaemic damage to the brain and is associated with cognitive impairment and behavioural disturbances. The management options are currently very limited and focus on controlling the underlying risk factors for cerebrovascular disease.116 Note that it is impossible to diagnose with certainty vascular or Alzheimer’s dementia and much dementia has mixed causation. This might explain why certain AChE-Is do not always provide consistent results in probable VaD and the data indicating efficacy in cognitive outcomes were derived from older patients, who were therefore likely to have concomitant AD pathology.117 None of the currently available drugs is formally licensed in the UK for VaD. The management of VaD has been summarised.118,119 Unlike the situation with stroke, there is no conclusive evidence that treatment of hyperlipidaemia with statins or treatment of blood clotting abnormalities with acetylsalicylic acid has an effect on VaD incidence or disease progression.120 Similarly, a Cochrane review found that there were no studies supporting the role of statins in the treatment of VaD.121 A Cochrane review of cholinesterase inhibitors for VaD and other vascular cognitive impairments found moderate- to high-certainty evidence that donepezil 5mg, donepezil 10mg and galantamine 16–24mg have a slight beneficial effect on cognition in people with vascular cognitive impairment, although the size of the change is unlikely to be clinically important. Donepezil 10mg and galantamine 16–24mg are probably associated with more adverse events than placebo. The evidence for rivastigmine was less certain. Data suggest that donepezil 10mg has the greatest effect on cognition, but at the cost of adverse effects. The effect is modest, but in the absence of any other treatments, these agents may be considered in people living with vascular cognitive impairments. Further research into rivastigmine is needed, including the use of transdermal patches.122 A meta-analysis of RCTs found that cholinesterase inhibitors and memantine produce small benefits in cognition of uncertain clinical significance and concluded that data were insufficient to support widespread use of these agents in VaD; the effect is lower than that seen in AD, although no direct comparison has been made.116 A systematic review and Bayesian network meta-analysis comparing the efficacy and safety of cognitive enhancers for treating vascular cognitive impairment found significant efficacy for donepezil, galantamine and memantine on cognition. Memantine was found to provide significant efficacy in global status. They were all safe and well tolerated.123

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09 - Dementia with Lewy bodies (DLB)

Dementia with Lewy bodies (DLB)

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10 - Mild cognitive impairment (MCI)

Mild cognitive impairment (MCI)

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11 - Other dementias

Other dementias

648 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Dementia with Lewy bodies (DLB) DLB may account for 15–25% of cases of dementia. Characteristic symptoms are dementia with fluctuation of cognitive ability, early and persistent visual hallucinations and spontaneous motor features of parkinsonism. Falls, syncope, transient disturbances of consciousness, neuroleptic sensitivity and hallucinations in other modalities are also common.124 There are significant complexities in managing an individual with DLB. Presentation varies between patients and can vary over time within an individual. Treatments can address one symptom but worsen another, which makes disease management difficult. Symptoms are often managed in isolation and by different specialists, which makes high-quality care difficult to accomplish. Clinical trials and meta-analyses now provide an evidence base for the treatment of cognitive, neuropsychiatric and motor symptoms in patients with DLB.125 In summary, robust evidence exists for the efficacy of rivastigmine and donepezil in the treatment of cognitive symptoms in patients with DLB, but high-quality RCTs of galantamine are needed. Memantine could have some benefits, but further studies with larger numbers of patients are also needed to determine whether there is an improvement and, if so, which specific symptoms are improved. Whether memantine should be used as a monotherapy or whether it should be combined with cholinesterase inhibitors is also unclear.125,126 For a helpful guide on the management of specific symptoms in DLB see the management of DLB summary sheets.127 The 2018 update of the NICE guidelines1 recommends the use of AChE-Is and memantine (if AChE-Is are not tolerated) in DLB and Parkinson’s disease dementia (see Box 6.2). Mild cognitive impairment (MCI) Mild cognitive impairment is hypothesised to represent a pre-clinical stage of dementia but forms a heterogeneous group with variable prognosis. A Cochrane review assessing the safety and efficacy of AChE-Is in MCI found there was very little evidence that they affect progression to dementia or cognitive test scores. This weak evidence was countered by the increased risk of adverse effects, particularly gastrointestinal effects, meaning that AChE-Is could not be recommended in MCI.128 A systematic review129 found that there was no replicated evidence that any intervention was effective for MCI including AChE-Is and the NSAID rofecoxib. A further systematic review and meta-analysis found that although AChE-Is have a slight efficacy in the treatment of MCI, there are many safety issues, therefore they are difficult to recommend for MCI.130 Experts from several different countries have reviewed the available evidence for the pharmacological and non-pharmacological treatment for MCI.131,132 Other dementias A systemic review of RCTs for frontotemporal dementias showed that certain drugs may be effective in reducing behavioural symptoms (e.g. SSRIs, trazodone) but none of these had an effect on cognition.133 Due to new techniques in neuroimaging,

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12 - Summary of clinical practice guidance for use

Summary of clinical practice guidance for use of anti-dementia drugs

Prescribing in older people CHAPTER 6 genetics and biomarker analysis, much has been discovered about the phenomena underlying frontotemporal lobar degeneration. This has allowed the design of new molecule-based therapies that are still in the early stages of research but may show promise.134 A Cochrane review assessed the efficacy and safety of AChE-Is for rare dementias associated with neurological conditions. The sample sizes of most trials were very small and efficacy on cognitive function was found to be unclear, although AChE-Is were associated with more gastrointestinal adverse effects than placebo.135 Summary of clinical practice guidance for use of anti-dementia drugs AChE-Is and memantine are effective in AD of a broad range of severity. Other drugs including statins, anti-inflammatory drugs, vitamin E, nutritional supplements and Gingko cannot be recommended either for the treatment or prevention of AD. Neither AChE-Is nor memantine are effective in MCI. AChE-Is are not effective in frontotemporal dementia and may cause agitation. AChE-Is may be used for people with Lewy body dementia (both Parkinson’s disease dementia and DLB), and memantine may be helpful. No drugs are clearly effective in VaD, though AChE-Is are beneficial in mixed dementia. Early evidence suggests multifactorial interventions may have the potential to prevent or delay the onset of dementia. Many novel pharmacological approaches involving strategies to reduce amyloid and/or tau deposition in those with or at high risk of AD are in progress. Although results of pivotal studies in early (prodromal/ mild) AD are awaited, results to date in more established (mild to moderate) AD have been equivocal and no disease-modifying agents are either licensed or can be currently recommended for clinical use. Table 6.3 summarises the clinical practice guidelines from BAP.23 Table 6.3 Summary of British Association for Psychopharmacology recommendations. First choice Second choice Alzheimer’s disease AChE-Is Memantine Vascular dementia None (some benefit with donepezil 10mg – but risk of adverse effects) None Mixed dementia AChE-Is Memantine Dementia with Lewy bodies AChE-Is Memantine Mild cognitive impairment None None Dementia with Parkinson’s disease AChE-Is Memantine Frontotemporal dementia None None AChE-Is, acetylcholinesterase inhibitors.

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13 - References

References

650 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 References

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Farlow MR, et al. Effective pharmacologic management of Alzheimer’s disease. Am J Med 2007; 120:388–397.
O’Brien JT, et al. Clinical practice with anti-dementia drugs: a revised (third) consensus statement from the British Association for Psychopharmacology. J Psychopharmacol 2017; 31:147–168.
Singh S, et al. Discontinuation syndrome following donepezil cessation. Int J Geriatr Psychiatry 2003; 18:282–284.
Bidzan L, et al. Withdrawal syndrome after donepezil cessation in a patient with dementia. Neurol Sci 2012; 33:1459–1461.
Waldemar G, et al. Tolerability of switching from donepezil to memantine treatment in patients with moderate to severe Alzheimer’s disease. Int J Geriatr Psychiatry 2008; 23:979–981.
Massoud F, et al. Switching cholinesterase inhibitors in older adults with dementia. Int Psychogeriatr 2011; 23:372–378.
Winblad B, et al. A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer’s disease – rivastigmine patch versus capsule. Int J Geriatr Psychiatry 2007; 22:456–467.
Zhang ZX, et al. Rivastigmine patch in Chinese patients with probable Alzheimer’s disease: a 24-week, randomized, double-blind parallel-group study comparing rivastigmine patch (9.5 mg/24 h) with capsule (6 mg twice daily). CNS Neurosci Ther 2016; 22:488–496.
Morgan TM, et al. Absolute bioavailability and safety of a novel rivastigmine nasal spray in healthy elderly individuals. Br J Clin Pharmacol 2017; 83:510–516.
Knopman DS. Donepezil 23 mg: an empty suit. Neurol Clin Pract 2012; 2:352–355.
Plosker GL. Memantine extended release (28 mg once daily): a review of its use in Alzheimer’s disease. Drugs 2015; 75:887–897.
Deardorff WJ, et al. A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer’s disease. Drug Des Devel Ther 2016; 10:3267–3279.
Veroniki AA, et al. Comparative safety and efficacy of cognitive enhancers for Alzheimer’s dementia: a systematic review with individual patient data network meta-analysis. BMJ Open 2022; 12:e053012.
Guo J, et al. Memantine, donepezil, or combination therapy – what is the best therapy for Alzheimer’s disease? A network meta-analysis. Brain Behav 2020; 10:e01831.
Parsons C, et al. Withdrawal or continuation of cholinesterase inhibitors or memantine or both, in people with dementia. Cochrane Database Syst Rev 2021; 2:CD009081.
Periclou AP, et al. Lack of pharmacokinetic or pharmacodynamic interaction between memantine and donepezil. Ann Pharmacother 2004; 38:1389–1394.

Prescribing in older people CHAPTER 6 38. Grossberg GT, et al. Rationale for combination therapy with galantamine and memantine in Alzheimer’s disease. J Clin Pharmacol 2006; 46:17S–26S. 39. Rogers SL, et al. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med 1998; 158:1021–1031. 40. Rogers SL, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology 1998; 50:136–145. 41. Corey-Bloom J, et al. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer’s disease. Int J Geriatr Psychopharmacol 1998; 1:55–64. 42. Rosler M, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ 1999; 318:633–638. 43. Tariot PN, et al. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology 2000; 54:2269–2276. 44. Raskind MA, et al. Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology 2000; 54:2261–2268. 45. Wilcock GK, et al. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. BMJ 2000; 321:1445–1449. 46. Pariente A, et al. Factors associated with serious adverse reactions to cholinesterase inhibitors: a study of spontaneous reporting. CNS Drugs 2010; 24:55–63. 47. Inglis F. The tolerability and safety of cholinesterase inhibitors in the treatment of dementia. Int J Clin Pract Suppl 2002; 127:45–63. 48. Sadowsky CH, et al. Safety and tolerability of rivastigmine transdermal patch compared with rivastigmine capsules in patients switched from donepezil: data from three clinical trials. Int J Clin Pract 2010; 64:188–193. 49. Sadowsky C, et al. Switching from oral cholinesterase inhibitors to the rivastigmine transdermal patch. CNS Neurosci Ther 2010; 16:51–60. 50. Cummings J, et al. Randomized, double-blind, parallel-group, 48-week study for efficacy and safety of a higher-dose rivastigmine patch (15 vs. 10 cm2) in Alzheimer’s disease. Dement Geriatr Cogn Disord 2012; 33:341–353. 51. Parsons CG, et al. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist – a review of preclinical data. Neuropharmacology 1999; 38:735–767. 52. Reisberg B, et al. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003; 348:1333–1341. 53. Jones RW. A review comparing the safety and tolerability of memantine with the acetylcholinesterase inhibitors. Int J Geriatr Psychiatry 2010; 25:547–553. 54. Dunn NR, et al. Adverse effects associated with the use of donepezil in general practice in England. J Psychopharmacol 2000; 14:406–408. 55. Hashimoto M, et al. Urinary incontinence: an unrecognised adverse effect with donepezil. Lancet 2000; 356:568. 56. Kobayashi H, et al. The comparative efficacy and safety of cholinesterase inhibitors in patients with mild-to-moderate Alzheimer’s disease: a Bayesian network meta-analysis. Int J Geriatr Psychiatry 2016; 31:892–904. 57. Kroger E, et al. Adverse drug reactions reported with cholinesterase inhibitors: an analysis of 16 years of individual case safety reports from VigiBase. Ann Pharmacother 2015; 49:1197–1206. 58. FDA Alert for Healthcare Professionals. Galantamine hydrobromide (marketed as Razadyne, formerly Reminyl). 2005; https://www.fda.gov/ Drugs/DrugSafety/ucm109350.htm. 59. Malone DM, et al. Cholinesterase inhibitors and cardiovascular disease: a survey of old age psychiatrists’ practice. Age Ageing 2007; 36:331–333. 60. NHS Yorkshire and Humber Clinical Networks. The assessment of cardiac status before prescribing acetyl cholinesterase inhibitors for dementia. Version 1. 2016; http://www.yhscn.nhs.uk/media/PDFs/mhdn/Dementia/ECG%20Documents/ACHEIGuidance%20V1_Final.pdf. 61. Rowland JP, et al. Cardiovascular monitoring with acetylcholinesterase inhibitors: a clinical protocol. Adv Psychiatric Treat 2007; 13:178–184. 62. Young S, et al. Cardiovascular complications of acetylcholinesterase inhibitors in patients with Alzheimer’s disease: a narrative review. Ann Geriatr Med Res 2021; 25:170–177. 63. Rosenbloom MH, et al. Donepezil-associated bradyarrhythmia in a patient with dementia with Lewy bodies (DLB). Alzheimer Dis Assoc Disord 2010; 24:209–211. 64. Howes LG. Cardiovascular effects of drugs used to treat Alzheimer’s disease. Drug Saf 2014; 37:391–395. 65. Farlow MR, et al. Memantine for the treatment of Alzheimer’s disease: tolerability and safety data from clinical trials. Drug Saf 2008; 31:577–585. 66. Babai S, et al. Comparison of adverse drug reactions with donepezil versus memantine: analysis of the French pharmacovigilance database. Therapie 2010; 65:255–259. 67. Dooley M, et al. Donepezil: a review of its use in Alzheimer’s disease. Drugs Aging 2000; 16:199–226. 68. Scott LJ, et al. Galantamine: a review of its use in Alzheimer’s disease. Drugs 2000; 60:1095–1122. 69. Grossberg GT, et al. Lack of adverse pharmacodynamic drug interactions with rivastigmine and twenty-two classes of medications. Int J Geriatr Psychiatry 2000; 15:242–247. 70. Tavassoli N, et al. Drug interactions with cholinesterase inhibitors: an analysis of the French pharmacovigilance database and a comparison of two national drug formularies (Vidal, British National Formulary). Drug Saf 2007; 30:1063–1071. 71. Noetzli M, et al. Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer’s disease. Clin Pharmacokinet 2013; 52:225–241. 72. Pasqualetti G, et al. Potential drug-drug interactions in Alzheimer patients with behavioral symptoms. Clin Interv Aging 2015; 10:1457–1466.

652 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 73. Medicines Complete. Stockley’s drug interactions. 2023; https://www.medicinescomplete.com/. 74. Merative US LP. Micromedex. 2023; https://www.micromedexsolutions.com/home/dispatch/. 75. Howard R, et al. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. N Engl J Med 2012; 366:893–903. 76. Howard R, et al. Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease (DOMINO-AD) trial: secondary and post-hoc analyses. Lancet Neurol 2015; 14:1171–1181. 77. Li DQ, et al. Donepezil combined with natural hirudin improves the clinical symptoms of patients with mild-to-moderate Alzheimer’s disease: a 20-week open-label pilot study. Int J Med Sci 2012; 9:248–255. 78. Di Santo SG, et al. A meta-analysis of the efficacy of donepezil, rivastigmine, galantamine, and memantine in relation to severity of Alzheimer’s disease. J Alzheimers Dis 2013; 35:349–361. 79. Parsons C. Withdrawal of antidementia drugs in older people: who, when and how? Drugs Aging 2016; 33:545–556. 80. National Institute for Health and Care Excellence. Dementia: assessment, management and support for people living with dementia and their carers. NICE Guideline [NG97]. 2018 (checked September 2023, last accessed December 2023); https://www.nice.org.uk/guidance/ ng97. 81. Birks J, et al. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2009; 2:CD003120. 82. Tan MS, et al. Efficacy and adverse effects of ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis. J Alzheimers Dis 2015; 43:589–603. 83. National Institute for Health and Clinical Excellence. Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease. Technology Appraisal [TA217]. 2011 (last updated June 2018, last accessed December 2023); https://www.nice.org.uk/guidance/ ta217. 84. National Institute for Health and Clinical Excellence. Medicines optimisation: the safe and effective use of medicines to enable the best possible outcomes. NICE Guideline [NG5]. 2015 (checked March 2019, last accessed January 2024); https://www.nice.org.uk/guidance/ ng52015. 85. Fan F, et al. The efficacy and safety of Alzheimer’s disease therapies: an updated umbrella review. J Alzheimers Dis 2022; 85:1195–1204. 86. Bent S, et al. Spontaneous bleeding associated with ginkgo biloba: a case report and systematic review of the literature: a case report and systematic review of the literature. J Gen Intern Med 2005; 20:657–661. 87. Gil Martínez V, et al. Vitamin supplementation and dementia: a systematic review. Nutrients 2022; 14:1033. 88. Burckhardt M, et al. Omega-3 fatty acids for the treatment of dementia. Cochrane Database Syst Rev 2016; 4:CD009002. 89. Wang Y, et al. Ginseng for Alzheimer’s disease: a systematic review and meta-analysis of randomized controlled trials. Curr Top Med Chem 2016; 16:529–536. 90. Ghassab-Abdollahi N, et al. The effects of Huperzine A on dementia and mild cognitive impairment: an overview of systematic reviews. Phytother Res 2021; 35:4971–4987. 91. Yue J, et al. Huperzine A for mild cognitive impairment. Cochrane Database Syst Rev 2012; 12:CD008827. 92. Hao Z, et al. Huperzine A for vascular dementia. Cochrane Database Syst Rev 2009; 2:CD007365. 93. Ayati Z, et al. Saffron for mild cognitive impairment and dementia: a systematic review and meta-analysis of randomised clinical trials. BMC Complement Med Ther 2020; 20:333. 94. Gavrilova SI, et al. Cerebrolysin in the therapy of mild cognitive impairment and dementia due to Alzheimer’s disease: 30 years of clinical use. Med Res Rev 2021; 41:2775–2803. 95. Cui S, et al. Cerebrolysin for vascular dementia. Cochrane Database Syst Rev 2019; 11:CD008900. 96. Moreira A, et al. Chocolate consumption is associated with a lower risk of cognitive decline. J Alzheimers Dis 2016; 53:85–93. 97. Burckhardt M, et al. Souvenaid for Alzheimer’s disease. Cochrane Database Syst Rev 2020; 12:CD011679. 98. Galimberti D, et al. Idalopirdine as a treatment for Alzheimer’s disease. Expert Opin Investig Drugs 2015; 24:981–987. 99. Matsunaga S, et al. Efficacy and safety of idalopirdine for Alzheimer’s disease: a systematic review and meta-analysis. Int Psychogeriatr 2019; 31:1627–1633. 100. Jordan F, et al. Aspirin and other non-steroidal anti-inflammatory drugs for the prevention of dementia. Cochrane Database Syst Rev 2020; 4:CD011459. 101. La AL, et al. Long-term trazodone use and cognition: a potential therapeutic role for slow-wave sleep enhancers. J Alzheimers Dis 2019; 67:911–921. 102. Brauer R, et al. Trazodone use and risk of dementia: a population-based cohort study. PLoS Med 2019; 16:e1002728. 103. Sommerlad A, et al. Effect of trazodone on cognitive decline in people with dementia: cohort study using UK routinely collected data. Int J Geriatr Psychiatry 2021; 37:doi: 10.1002/gps.5625. 104. Coupland C, et al. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ 2011; 343:d4551. 105. Halliday M, et al. Repurposed drugs targeting eIF2alpha-P-mediated translational repression prevent neurodegeneration in mice. Brain 2017; 140:1768–1783. 106. Sauder C, et al. Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study. Transl Psychiatry 2022; 12:491. 107. Khan H, et al. Neuroprotective effects of quercetin in Alzheimer’s disease. Biomolecules 2019; 10:59. 108. Yu TW, et al. Novel therapeutic approaches for Alzheimer’s disease: an updated review. Int JMol Sci 2021; 22:8208. 109. Schneider L. A resurrection of aducanumab for Alzheimer’s disease. Lancet Neurol 2020; 19:111–112. 110. The Lancet. Lecanemab for Alzheimer’s disease: tempering hype and hope. Lancet 2022; 400:1899. 111. Van Dyck CH, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med 2023; 388:9–21. 112. Jönsson L, et al. The affordability of lecanemab, an amyloid-targeting therapy for Alzheimer’s disease: an EADC-EC viewpoint. Lancet Reg Health Eur 2023; 29:100657.

Prescribing in older people CHAPTER 6 113. Sims JR, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA 2023; 330:512–527. 114. Ramanan VK, et al. Antiamyloid monoclonal antibody therapy for Alzheimer disease: emerging issues in neurology. Neurology 2023; 101:842–852. 115. Monteiro C, et al. Randomized phase II study of the safety and efficacy of semorinemab in participants with mild-to-moderate Alzheimer disease: Lauriet. Neurology 2023; 101:e1391–e1401. 116. Kavirajan H, et al. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials. Lancet Neurol 2007; 6:782–792. 117. Wang J, et al. Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment. Acta Pharmacol Sin 2009; 30:879–888. 118. Bocti C, et al. Management of dementia with a cerebrovascular component. Alzheimers Dementia 2007; 3:398–403. 119. Demaerschalk BM, et al. Treatment of vascular dementia and vascular cognitive impairment. Neurologist 2007; 13:37–41. 120. Baskys A, et al. Pharmacological prevention and treatment of vascular dementia: approaches and perspectives. Exp Gerontol 2012; 47:887–891. 121. McGuinness B, et al. Statins for the prevention of dementia. Cochrane Database Syst Rev 2016; 1:CD003160. 122. Battle CE, et al. Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments: a network meta-analysis. Cochrane Database Syst Rev 2021; 2:CD013306. 123. Jin BR, et al. Comparative efficacy and safety of cognitive enhancers for treating vascular cognitive impairment: systematic review and Bayesian network meta-analysis. Neural Regen Res 2019; 14:805–816. 124. Wild R, et al. Cholinesterase inhibitors for dementia with Lewy bodies. Cochrane Database Syst Rev 2003; 3:CD003672. 125. Taylor JP, et al. New evidence on the management of Lewy body dementia. Lancet Neurol 2020; 19:157–169. 126. McKeith IG, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology 2017; 89:88–100. 127. Newcastle University. Management of Lewy body dementia summary sheet. Diamond Lewy. 2019; https://research.ncl.ac.uk/media/sites/ researchwebsites/diamond-lewy/One%20page%20symptom%20LBD%20management%20summaries.pdf. 128. Russ TC, et al. Cholinesterase inhibitors for mild cognitive impairment. Cochrane Database Syst Rev 2012; 9:CD009132. 129. Cooper C, et al. Treatment for mild cognitive impairment: systematic review. Br J Psychiatry 2013; 203:255–264. 130. Matsunaga S, et al. Efficacy and safety of cholinesterase inhibitors for mild cognitive impairment: a systematic review and meta-analysis. J Alzheimers Dis 2019; 71:513–523. 131. Kasper S, et al. Management of mild cognitive impairment (MCI): the need for national and international guidelines. World J Biol Psychiatry 2020; 21:579–594. 132. Petersen RC, et al. Practice guideline update summary: mild cognitive impairment. Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology 2018; 90:126–135. 133. Nardell M, et al. Pharmacological treatments for frontotemporal dementias: a systematic review of randomized controlled trials. Am J Alzheimers Dis Other Demen 2014; 29:123–132. 134. Boeve BF, et al. Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations. Lancet Neurol 2022; 21:258–272. 135. Li Y, et al. Cholinesterase inhibitors for rarer dementias associated with neurological conditions. Cochrane Database Syst Rev 2015; 3:CD009444.

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Safer prescribing for physical conditions in dementia

11 - Chapter 6 Prescribing in older people

15 - Anticholinergic drugs

Anticholinergic drugs

654 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Safer prescribing for physical conditions in dementia People with dementia are susceptible to cognitive adverse effects of drugs. Drugs may affect cognition through their action on cholinergic, histaminergic, opioid or other neurotransmitter pathways. Some medications may also interact with cognitive-enhancing medication. Anticholinergic drugs Anticholinergic drugs reduce the efficacy of acetylcholinesterase inhibitors1 and cause sedation, delirium and falls.2 These effects are more severe in older patients with dementia.3 A high anticholinergic burden is associated with cognitive decline4 and increased hospitalisation and mortality.4,5 The Anticholinergic Effect on Cognition (AEC)6 scale can be used to calculate the anticholinergic burden of drugs in patients. Table 6.4 lists the AEC scores of drugs commonly prescribed for older adults in the UK.6 Combining several drugs with anticholinergic activity increases the total anticholinergic burden for an individual. It is good practice to keep the anticholinergic burden to a minimum in older people and those with dementia. Where possible, drugs with no anticholinergic action and an equivalent therapeutic effect should be used. If this is not possible, the prescription of a drug with low anticholinergic activity or high specificity to the site of action (and thus minimal central activity) should be encouraged. Anticholinergic drugs that do not cross the blood–brain barrier (BBB) have less profound effects on cognitive function.7 The AEC takes all of these factors into account. The following are recommendations for using AEC scores:6 ■ ■All individual drugs with an AEC score of 2 or 3 in older people presenting with symptoms of cognitive impairment, dementia or delirium should either be: ■ ■stopped, or ■ ■switched to an alternative drug with a lower AEC score (preferably 0). ■ ■In patients who are not receiving any individual drug with an AEC score of 2 or 3 but who have a total AEC score of 3 or above, a patient–clinician review should take place. ■ ■If withdrawal of the drug is deemed appropriate, this should be gradual (where possible) to avoid rebound (nausea, sweating, urinary frequency, diarrhoea).

Table 6.4 Anticholinergic Effect on Cognition (AEC) scale scores (Adapted from [6]).* Adcal – 0 Clarithromycin – NK Gabapentin – 0 Naproxen – 0 Sitagliptin – 0 Agomelatine – 0 Clemastine – 3 Galantamine – 0 Nifedipine – 0 Solifenacin – 1 Alendronic acid (alendronate) – 0 Clomipramine – 3 Gaviscon – 0 Nimodipine – 0 Sotalol – 0 Alfuzosin – 0 Clonazepam – NK Gliclazide – 0 Nitrofurantoin – NK Spironolactone – NK Alimemazine (trimeprazine) – 3 Clonidine – NK Granisetron – 0 Nortriptyline – 3 Sulphasalazine – 0 Allopurinol – NK Clopidogrel – 0 Haloperidol – 0 Olanzapine – 2 Sulpiride – 0 Alprazolam – 0 Clozapine – 3 Heparin – 0 Omeprazole – 0 Tamoxifen – NK Alverine – 0 Co-beneldopa – 0 Hydrochlorothiazide – 0 Ondansetron – 0 Tamsulosin – 0 Amantadine – 2 Co-careldopa – 0 Hydrocodone – NK Orlistat – 0 Temazepam – 1 Amiloride – 0 Codeine – NK Hydrocortisone – NK Orphenadrine – 3 Tetracycline – 0 Aminophylline – 0 Colchicine – NK Hydroxyzine – 1 Oxcarbazepine – NK Theophylline – 0 Amiodarone – 1 Co-tenidone – 0 Hyoscine butylbromide (buscopan) – 1 Oxybutynin – 3 Thiamine – 0 Amisulpride – 0 Cyclizine – 1 Hyoscine hydrobromide – 3 Oxycodone – NK Tiotropium bromide (inhalation) – 0 Amitriptyline – 3 Cyproheptadine – 3 Ibuprofen – 0 Paliperidone – 1 Tizanidine – NK Amlodipine – 0 Dabigatran – NK Iloperidone – 1 Pantoprazole – 0 Tolcapone – 0 Amoxicillin – 0 Darifenacin – 0 Imipramine – 3 Paracetamol – 0 Tolterodine – 2 Anastrozole – NK Desipramine – 2 Indapamide – 0 Paroxetine – 2 Topiramate – NK Apixaban – NK Dexamethasone – NK Insulin – 0 Penicillin – 0 Tramadol – 0 Apomorphine – 0 Dexamfetamine – 0 Ipratropium bromide – 0 Peppermint oil – 0 Tranylcypromine – 0 Aripiprazole – 1 Dextropropoxyphene – NK Irbesartan – NK Pergolide – 0 Trazodone – 0 Asenapine – 1 Diazepam – 1 Isocarboxazid – 1 Perindopril – 0 Trifluoperazine – 2 Aspirin – 0 Diclofenac – 0 Isosorbide dinitrate – 0 Perphenazine – 1 Trihexyphenidyl (benzhexol) – 3 (Continued )

Atenolol – 0 Dicycloverine (dicyclomine) – 2 Isosorbide mononitrate – 0 Pethidine – 2 Trimethoprim – 0 Atomoxetine – 0 Digoxin – NK Ketorolac – 0 Phenelzine – 1 Trimipramine – 3 Atorvastatin – 0 Dihydrocodeine – NK Labetalol – 0 Phenytoin – NK Trospium – 0 Atropine – 3 Diltiazem – 0 Lactulose – 0 Pimozide – 2 Valproate – 0 Atropine eye drops – 1 Dimenhydrinate – 2 Lamotrigine – 0 Pirenzepine – 1 Venlafaxine – 0 Azathioprine – 0 Diphenhydramine – 2 Lansoprazole – NK Pravastatin – 0 Verapamil – NK Baclofen – NK Dipyridamole – 0 Lercanidipine – 0 Prazosin – 0 Vitamin B12 – 0 Beclometasone dipropionate (inhaler) – 0 Disopyramide – 2 Levetiracetam – NK Prednisolone – 1 Vitamins – 0 Bendroflumethiazide – 0 Docusate sodium – 0 Levodopa – 0 Pregabalin – NK Vortioxetine – 0 Benztropine – 3 Domperidone – 1 Levomepromazine (methotrimeprazine) – 2 Prochlorperazine – 2 Warfarin – 0 Betahistine – 0 Donepezil – 0 Levothyroxine (thyroxine) – 0 Procyclidine – 3 Ziprasidone – 0 Bezafibrate – 0 Dothiepin (dosulepin) – 3 Liraglutide – 0 Promazine – 2 Zolpidem – 0 Bisacodyl – 0 Doxazosin – 0 Lisinopril – 0 Promethazine – 3 Zopiclone – NK Bisoprolol – NK Doxepin – 3 Lithium – 1 Propantheline – 2 Zotepine – 2 Bromocriptine – 1 Doxycycline – 0 Lofepramine – 3 Propranolol – 0 Zuclopentixol (zuclopenthixol) – 1 Budesonide (inhaler) – 0 Dulaglutide – 0 Loperamide – 0 Quetiapine – 2 Bumetanide – NK Duloxetine – 0 Loratadine – 0 Quinidine – 1 Buprenorphine – 0 Escitalopram – 1 Lorazepam – 0 Quinine – 1 Bupropion – 0 Enalapril – 0 Losartan – 0 Rabeprazole – 0 Buspirone – 1 Enoxaparin – 0 Lovastatin – 0 Ramipril – NK Cabergoline – 0 Entacapone – 0 Lurasidone – 0 Ranitidine – 0 Table 6.4 (Continued )

Calcium – 0 Erythromycin – NK Macrogol – 0 Rasagiline – 0 Calcium and vitamin D – 0 Exanatide – 0 Magnesium – 0 Reboxetine – 0 Candersartan – 0 Ezetimibe – 0 Mebeverine – 0 Risedronate – 0 Captopril – NK Felodipine – 0 Melatonin – 0 Risperidone – 0 Carbachol – 0 Fentanyl – 1 Meloxicam – 0 Rivaroxaban – NK Carbamazepine – 1 Ferrous sulphate – 0 Memantine – 0 Rivastigmine – 0 Carbimazole – NK Fesoterodine – 0 Mesalazine – 0 Ropinirole – 0 Carbocisteine – 0 Fexofenadine – 0 Metformin – NK Rosiglitazone – 0 Cariprazine– 0 Finasteride – 0 Methocarbamol – NK Rosuvastatin – NK Carvedilol – NK Flavoxate – NK Methotrexate – NK Salbutamol – 0 Cefalexin (cephalexin) – 0 Flecainide – 0 Metoclopramide – 0 Salmeterol (inhaler) – 0 Cetirizine – 0 Flucloxacillin – 0 Metoprolol – 0 Selegiline – 0 Chloral hydrate – NK Fludrocortisone – NK Mianserin – 2 Senna – 0 Chlordiazepoxide – 0 Fluoxetine – 1 Midazolam – 1 Sertindole – 1 Chlorphenamine – 2 Flupentixol (flupenthixol) – 1 Minocycline – 0 Sertraline – 1 Chlorpromazine – 3 Fluphenazine – 1 Mirabegron – 0 Sildenafil – 0 Chlortalidone – NK Fluvoxamine – 0 Mirtazapine – 1 Simvastatin – 0 Cimetidine – 0 Folic acid – 0 Moclobemide – 0 Cinnarizine – 1 Furosemide – 0 Morphine – 0 Ciprofloxacin – 0 Citalopram – 1 *The AEC scale is available as a regularly updated web-based app. Please go to www.medichec.com. This site has been updated to include the identification of medications that are reported to cause dizziness and drowsiness since these adverse effects can add to cognitive impairment and confusion in older people and can increase the risk of falls. Medichec also identifies medications that are reported to cause QTc prolongation, hyponatraemia, bleeding risk and constipation. 1–3, scores 1 to 3; NK, not known.

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Safety of physical health medication prescribed in dementia

658 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Safety of physical health medication prescribed in dementia Anticholinergic drugs used in urinary incontinence Oxybutynin penetrates the CNS and is associated with cognitive decline. Although studies of tolterodine found no adverse CNS effects,8 case reports have described memory loss, hallucinations and delirium.9–11 Darifenacin, an M3 selective receptor antagonist, has shown no effects on cognitive function tests compared with placebo,12,13 although studies in dementia are lacking. Solifenacin may cause memory impairment14 although it did not affect cognition in patients with a stroke.15 Trospium16–18 and fesoterodine19 do not seem to cause cognitive changes.17,18,20,21 Tertiary amine drugs (i.e. oxybutynin, tolterodine, solifenacin, fesoterodine, darifenacin) are metabolised by cytochrome P450 (CYP) enzymes. Increasing age or co-administration of drugs that inhibit these enzymes (e.g. erythromycin, fluoxetine) can lead to higher serum levels and increased adverse effects. The metabolism of trospium is unknown, although metabolism via the CYP system does not occur, meaning that pharmacokinetic drug interactions are unlikely with this drug.8 Alpha blockers for urinary retention Alpha blockers such as tamsulosin, alfuzosin and prazosin cause drowsiness, dizziness and depression.22 There is no published literature reporting their effects on cognition, but α blockers are not thought to have any anticholinergic action. Drugs used in gastrointestinal disorders Loperamide Although loperamide may have some anticholinergic activity, there are no data to suggest that it can worsen cognitive function in patients with dementia. It may add to the anticholinergic cognitive burden if used in conjunction with other anticholinergic drugs. Laxatives Laxatives do not have any negative impact on cognitive function. In fact, since constipation can lead to delirium and behavioural and psychological symptoms of dementia, treating it may improve these symptoms. Antiemetics Cyclizine is a first-generation histamine antagonist and can impair cognitive and psychomotor performance (see ‘Antihistamines’ later in this chapter).23 Metoclopramide has little anticholinergic action, but the D2 receptor antagonism of both metoclopramide and prochlorperazine can produce movement disorders and so these drugs must be used with caution in people with dementia. Domperidone is a dopamine D2 receptor antagonist that does not usually cross the BBB. However, since BBB alterations can occur in dementia, CNS penetration of domperidone and resulting adverse effects can occur.24 There is a small increased risk of serious cardiac adverse effects with domperidone, especially in older people. Domperidone is now contraindicated in those with underlying cardiac conditions or

Prescribing in older people CHAPTER 6 severe hepatic impairment and in patients receiving other medications known to prolong QT interval or potent CYP3A4 inhibitors; treatment should not exceed 1 week.25 Serotonin 5HT3 receptor antagonists, used for treating chemotherapy-induced nausea and vomiting, do not have adverse effects on cognition, and may have some cognitive-enhancing action.26 These drugs should be used cautiously in patients with cardiac comorbidities or taking concomitant arrhythmogenic drugs or drugs known to prolong QT interval. Granisetron can be administered once daily, which is preferable in people with dementia or swallowing difficulties. Granisetron is metabolised exclusively via a single CYP family (CYP3A4), and thus has a lower propensity for drug interactions.27 Antispasmodics Hyoscine hydrobromide (scopolamine) is a centrally acting lipophilic anticholinergic which penetrates the BBB. It impairs memory, speed of processing and attention. Older patients suffer these symptoms at lower doses and are more vulnerable to confusion and hallucinations.28 People with Alzheimer’s disease experience clinically significant cognitive impairment at lower doses compared with healthy, aged-matched controls.3 The effect that hyoscine has on cognition is so significant that it is used in trials to produce memory deficits similar to those seen in dementia (the scopolamine challenge test).29 There is rarely a good reason to use this drug in people with dementia. Hyoscine butylbromide (Buscopan) exerts topical spasmolytic action on smooth muscle of the gastrointestinal tract. Hyoscine butylbromide is not thought to enter the CNS, so central anticholinergic adverse effects are rare.30 Alverine, mebeverine and peppermint oil are relaxants of intestinal smooth muscle with no effect on cognition. Bronchodilators Beta agonists In patients with Parkinson’s disease or essential tremor, tremor induced by β agonists may result in misdiagnosis and over-treatment of Parkinson’s disease.31 Tremor is a common adverse effect of cholinesterase inhibitors so caution should be exercised when used with β agonists. Anticholinergic bronchodilators Inhaled anticholinergic drugs have few systemic side effects.31 A placebo-controlled comparison of ipratropium and theophylline treatment was unable to detect a negative effect with either drug on the cognitive function of older patients. This suggests that treatment with inhaled ipratropium is not associated with significant cognitive impairment in older people.32 Theophylline As with cholinesterase inhibitors, nausea and vomiting are common adverse effects of theophylline. Neurological effects such as headaches, anxiety, behavioural disturbances, depression and seizures can occur in 50% of patients on theophylline. Although seizures are rare, they are much more likely in older people. Theophylline does not cause significant cognitive impairment.32

660 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Hypersalivation Oral anticholinergic agents used for hypersalivation (e.g. hyoscine hydrobromide) should be avoided in older people because of the risk of cognitive impairment, delirium and constipation (see ‘Anticholinergic drugs’ and ‘Antispasmodics’ earlier in this chapter). Pirenzepine is a relatively selective M1 and M4 muscarinic receptor antagonist which is not thought to cross the BBB and therefore has little CNS penetration.33 Atropine solution given sublingually or used as a mouthwash is sometimes used to manage hypersalivation. There are no data available on the extent of penetration through the BBB when atropine is administered by this route. Myasthenia gravis Unlike acetylcholinesterase inhibitors used in Alzheimer’s disease (donepezil, rivastigmine, galantamine), those used in myasthenia gravis (pyridostigmine, neostigmine) act peripherally and do not cross the BBB.34 Combining peripheral and central acetylcholinesterase inhibitors may add to the cholinomimetic adverse effect burden (e.g. nausea, vomiting, diarrhoea, abdominal cramps, increased salivation). Memantine may be an alternative to cholinesterase inhibitors in cases where the combined cholinomimetic effects of drugs used for myasthenia gravis and Alzheimer’s disease are not tolerated. Analgesics NSAIDs and paracetamol Paracetamol (acetaminophen) does not cause cognitive impairment other than in overdose, when it may cause delirium.35 There is some evidence that the chronic use of aspirin can cause confusional states.36 Case reports implicate NSAIDs in causing delirium and psychosis37 although clinical trials have not demonstrated significant adverse effects on cognition with naproxen38 or indomethacin.39 NSAIDs are difficult to use in older people due to their cardiovascular risk and risk of gastrointestinal bleeding.40 It is good practice to prescribe gastroprotection with these drugs or consider using topical NSAIDs (if clinically appropriate) to reduce the risk of gastrointestinal bleeding. Opiates Sedation is a potential problem with all opiates.41 Delirium induced by opioids may be associated with agitation, hallucinations or delusions.41 Pethidine is associated with a high risk of cognitive impairment as its metabolites have anticholinergic properties and accumulate rapidly if renal function is impaired.42 Codeine may increase the risk of falls, and both tramadol and codeine have a high risk of drug–drug interactions as well as considerable variation in response and adverse effects.43 Fentanyl patches should not be used to initiate opioid analgesia in frail older people44 because of their long duration of action even after the patch is removed, making the treatment of adverse effects more difficult.43 Morphine is an effective analgesic but is likely to cause cognitive problems and other adverse effects in older patients.45 Oxycodone has a

Prescribing in older people CHAPTER 6 short half-life (at least in non-modified-release tablets), few drug–drug interactions and more predictable dose–response relationships than other opiates. It is therefore, theoretically, a good candidate for oral analgesia in dementia.43 Caution, however, should be used owing to its addictive potential. Buprenorphine transdermal patches probably have less severe adverse effects than many other opiates. Antihistamines First-generation H1 antihistamines include chlorpheniramine, hydroxyzine, cyclizine and promethazine. They are non-selective, have anticholinergic activity and readily penetrate the BBB. They can impair cognitive performance and can trigger seizures, dyskinesia, dystonia and hallucinations. The second-generation H1 antihistamines (such as loratadine, cetirizine and fexofenadine) penetrate poorly into the CNS and should be the preferred choice because of their lack of sedative, cognitive and psychomotor impairment and anticholinergic adverse effects. Statins A Cochrane review assessed the clinical efficacy and tolerability of statins in the treatment of dementia46 and showed that there was no significant benefit from statins in terms of cognitive function, but equally no evidence that statins were detrimental to cognition. Earlier case reports had highlighted subjective complaints of memory loss associated with the use of statins.47 These tended to occur within 2 months of starting the drug and were most commonly associated with simvastatin. If cognitive problems occur on simvastatin, it may be worth first stopping the drug, and if the complaint resolves, try atorvastatin or pravastatin instead as these drugs are less likely to cross the BBB. However, in a large prospective cohort study of patients without dementia, baseline statin use was not associated with incident dementia or MCI, nor was statin use associated with decline in cognitive function over time and results did not differ by statin lipophilicity.48 Another Cochrane review49 assessed the efficacy of statins in the prevention of dementia and concluded that there was no evidence that statins given in late life to people at risk of vascular disease prevented cognitive decline or dementia. A meta-analysis of observational studies found that similar risks were observed for lipophilic and hydrophilic statins for both dementia and Alzheimer’s disease, while high- potency statins showed a 20% reduction of dementia risk compared with a 16% risk reduction associated with low-potency statins, suggesting a greater efficacy of the former. While evidence has been mixed, it suggests that statins are unlikely to cause dementia or cognitive decline, but they may not prevent it either. Nevertheless, indications for statin treatment to prevent cardiovascular events remain.50 Antihypertensives Mid-life hypertension has negative effects on cognition and increases the risk of a person developing dementia.51 There is no evidence that antihypertensive treatment worsens cognition; it appears to have a positive effect on global cognition and long-term treatment of hypertension can reduce the risk of dementia.52,53

662 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Anticoagulants Several systematic reviews concluded that oral anticoagulation reduced significantly the incidence of cognitive impairment and dementia in patients with atrial fibrillation, probably due to the reduction of ischaemic cerebrovascular events. It appears that direct oral anticoagulant therapy is associated with a significant decrease in the risk of dementia when compared with vitamin K antagonist therapy, however further studies are needed to confirm these findings.54 Other cardiac drugs Digoxin has been associated with acute confusional states at therapeutic drug concentrations.55 It has also been reported to cause nightmares.56 However, one study showed the treatment of cardiac failure with digoxin improved cognitive performance in 25% of patients treated (and in 23% of patients treated who did not have cardiac failure).57 There are some case reports of amiodarone being associated with delirium.58,59 H2 antagonists and proton pump inhibitors (PPIs) Histamine-2 receptor antagonists (e.g. cimetidine, ranitidine, famotidine) are rarely used nowadays. Cimetidine causes several pharmacokinetic interactions, and ranitidine products have been recalled due to possible contamination with N-nitrosodimethylamine, identified as a potential risk factor in the development of certain cancers. Famotidine remains in use. CNS reactions to these drugs have been reported, especially with cimetidine.60 A study looking at observational data on PPIs found an association between PPI use and incident dementia. This is supported by pharmacoepidemiological analyses on primary data and is in line with animal studies in which the use of PPIs increased the levels of β-amyloid in the brains of mice.61 Randomised prospective clinical trials are needed to confirm this association. Many patients on PPIs have Helicobacter pylori- infected gastric mucosa. As Helicobacter has been reported to be associated with cognitive deterioration, this could be the mechanism behind the apparent link between PPI drugs and dementia. Furthermore, this association was not replicated in other studies.62,63 Despite reports that PPIs are associated with an increased risk of developing dementia,61,64 data collected in a large-scale real-world setting using linked national health data in the UK were unable to confirm this association. This suggests that previously reported links may be associated with confounders of people using PPIs, such as increased risk of cardiovascular disease and/or depression and their associated medications.65 Antibiotics There are reports of many antibiotics being associated with delirium66,67 but there is no consistent pattern of them causing cognitive impairment. Given the importance of treating infection in dementia the most appropriate antibiotic for the infection being treated should be used. Antituberculous therapy, particularly isoniazid, has attracted some case reports of adverse psychiatric reactions.68 Table 6.5 lists drugs that are recommended for use in dementia and those that should be avoided.

Prescribing in older people CHAPTER 6 Table 6.5 Recommended drugs and drugs to avoid in dementia. Adapted with permission.69 Condition Drug class or drug name Drugs to avoid in dementia Recommended drugs in dementia Allergic conditions Antihistamines Chlorphenamine Promethazine Hydroxyzine Cyproheptadine Cyclizine (and other first-generation antihistamines) Cetirizine Loratadine Fexofenadine (and other second- generation antihistamines) Asthma/COPD Bronchodilators Beta agonists Inhaled anticholinergics (have not been reported to affect cognition) Theophylline Constipation Laxatives No evidence to suggest that laxatives have any negative impact on cognitive function. Constipation itself may worsen cognition Diarrhoea Loperamide Low-potency anticholinergic. Not known to have effects on cognitive function, however may add to the anticholinergic cognitive burden if used in combination with other anticholinergics Hyperlipidaemia Statins All are safe but atorvastatin and pravastatin are less likely to cross the BBB. Hypersalivation Anticholinergics Hyoscine hydrobromide Pirenzepine Atropine (sublingually) Hypertension Antihypertensives Beta blockers (avoidance may not always be possible) Calcium channel blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may all improve cognitive function. Infections Antibiotics Delirium reported mostly with quinolone and macrolide antibiotics. But given the importance of treating infections, the most appropriate antibiotic for the infection should be used. Myasthenia gravis Peripheral acetylcholinesterase inhibitors, e.g. neostigmine and pyridostigmine May add to the cholinergic adverse effects of central acetylcholinesterase inhibitors (e.g. donepezil) in patients with dementia, e.g. increased risk of nausea/vomiting. Nausea/vomiting Antiemetics Cyclizine Metoclopramide Prochlorperazine Domperidone (see main text for restrictions) Serotonin 5HT3 receptor antagonists (Continued )

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17 - References

References

664 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 References

Sink KM, et al. Dual use of bladder anticholinergics and cholinesterase inhibitors: long-term functional and cognitive outcomes. J Am Geriatr Soc 2008; 56:847–853.
Ruxton K, et al. Drugs with anticholinergic effects and cognitive impairment, falls and all-cause mortality in older adults: a systematic review and meta-analysis. Br J Clin Pharmacol 2015; 80:209–220.
Sunderland T, et al. Anticholinergic sensitivity in patients with dementia of the Alzheimer type and age-matched controls. A dose-response study. Arch Gen Psychiatry 1987; 44:418–426.
Fox C, et al. Anticholinergic medication use and cognitive impairment in the older population: the Medical Research Council Cognitive Function and Ageing Study. J Am Geriatr Soc 2011; 59:1477–1483.
Bishara D, et al. The anticholinergic effect on cognition (AEC) scale – associations with mortality, hospitalisation and cognitive decline following dementia diagnosis. Int J Geriatr Psychiatry 2020; 35:1069–1077.
Bishara D, et al. Anticholinergic effect on cognition (AEC) of drugs commonly used in older people. Int J Geriatr Psychiatry 2017; 32:650–656.
Wagg A. The cognitive burden of anticholinergics in the elderly – implications for the treatment of overactive bladder. Eur Urol Rev 2012; 7:42–49.
Pagoria D, et al. Antimuscarinic drugs: review of the cognitive impact when used to treat overactive bladder in elderly patients. Curr Urol Rep 2011; 12:351–357.
Womack KB, et al. Tolterodine and memory: dry but forgetful. Arch Neurol 2003; 60:771–773.
Tsao JW, et al. Transient memory impairment and hallucinations associated with tolterodine use. N Engl J Med 2003; 349:2274–2275. Table 6.5 (Continued ) Condition Drug class or drug name Drugs to avoid in dementia Recommended drugs in dementia Other GI conditions Antispasmodics Atropine sulphate Dicycloverine hydrochloride Alverine, mebeverine, peppermint oil Hyoscine-n-butylbromide Propantheline bromide Pain Analgesics Pethidine Pentazocine Dextropropoxyphene Codeine Tramadol Methadone Paracetamol Oxycodone Buprenorphine Topical NSAIDs (where appropriate) Fentanyl patches (caution in opioid-naïve patients) Morphine (may be indicated in treatment-resistant pain or palliative care; use cautiously due to associated cognitive and other adverse effects) Urinary frequency Anticholinergic drugs used in overactive bladder Oxybutynin Tolterodine Fesoterodine Darifenacin Trospium Solifenacin (use if others are not available; some reports of cognitive adverse effects) Data for fesoterodine are still lacking; it is non-selective, has high central anticholinergic activity but theoretically has very low ability to cross the BBB. Urinary retention Alpha blockers Not known to have effects on cognitive function. BBB, blood–brain barrier; COPD, chronic obstructive pulmonary disease; GI, gastrointestinal.

Prescribing in older people CHAPTER 6 11. Edwards KR, et al. Risk of delirium with concomitant use of tolterodine and acetylcholinesterase inhibitors. J Am Geriatr Soc 2002; 50:1165–1166. 12. Kay G, et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol 2006; 50:317–326. 13. Lipton RB, et al. Assessment of cognitive function of the elderly population: effects of darifenacin. J Urol 2005; 173:493–498. 14. Chancellor MB, et al. Blood-brain barrier permeation and efflux exclusion of anticholinergics used in the treatment of overactive bladder. Drugs Aging 2012; 29:259–273. 15. Park JW. The effect of solifenacin on cognitive function following stroke. Dement Geriatr Cogn Dis Extra 2013; 3:143–147. 16. Liabeuf S, et al. Trospium chloride for overactive bladder may induce central nervous system adverse events. Eur Geriatr Med 2014; 5:220–224. 17. Isik AT, et al. Trospium and cognition in patients with late onset Alzheimer disease. J Nutr Health Aging 2009; 13:672–676. 18. Geller EJ, et al. Effect of trospium chloride on cognitive function in women aged 50 and older: a randomized trial. Female Pelvic Med Reconstr Surg 2017; 23:118–123. 19. Heesakkers J, et al. Safety and tolerability of fesoterodine in older adult patients with overactive bladder. Can Geriatr J 2022; 25:72–78. 20. Wagg A. Fesoterodine fumarate for the treatment of overactive bladder in the elderly – a review of the latest clinical data. Clin Investig 2012; 2:825–833. 21. Yonguc T, et al. Randomized, controlled trial of fesoterodine fumarate for overactive bladder in Parkinson’s disease. World J Urol 2020; 38:2013–2019. 22. Joint Formulary Committee. British National Formulary (online). London: BMJ and Pharmaceutical Press; http://www.medicinescomplete.com. 23. Mahdy AM, et al. Histamine and antihistamines. Anaesth Intens Care Med 2011; 12:324–329. 24. Roy-Desruisseaux J, et al. Domperidone-induced tardive dyskinesia and withdrawal psychosis in an elderly woman with dementia. Ann Pharmacother 2011; 45:e51. 25. Medicines and Healthcare products Regulatory Agency. Domperidone: risks of cardiac side effects – indication restricted to nausea and vomiting, new contraindications, and reduced dose and duration of use. 2014; http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/ CON418518. 26. Bentley KR, et al. Therapeutic potential of serotonin 5-HT3 antagonists in neuropsychiatric disorders. CNS Drugs 1995; 3:363–392. 27. Gridelli C. Same old story? Do we need to modify our supportive care treatment of elderly cancer patients? Focus on antiemetics. Drugs Aging 2004; 21:825–832. 28. Flicker C, et al. Hypersensitivity to scopolamine in the elderly. Psychopharmacology (Berl) 1992; 107:437–441. 29. Ebert U, et al. Scopolamine model of dementia: electroencephalogram findings and cognitive performance. Eur J Clin Invest 1998; 28:944–949. 30. Sanofi. Summary of product characteristics. Buscopan 10 mg tablets. 2020 (last updated November 2021); https://www.medicines.org.uk/ emc/medicine/30089. 31. Gupta P, et al. Potential adverse effects of bronchodilators in the treatment of airways obstruction in older people: recommendations for prescribing. Drugs Aging 2008; 25:415–443. 32. Ramsdell JW, et al. Effects of theophylline and ipratropium on cognition in elderly patients with chronic obstructive pulmonary disease. Ann Allergy Asthma Immunol 1996; 76:335–340. 33. Fritze J, et al. Pirenzepine for clozapine-induced hypersalivation. Lancet 1995; 346:1034. 34. Pohanka M. Acetylcholinesterase inhibitors: a patent review (2008 – present). Expert Opin Ther Pat 2012; 22:871–886. 35. Gray SL, et al. Drug-induced cognition disorders in the elderly: incidence, prevention and management. Drug Saf 1999; 21:101–122. 36. Bailey RB, et al. Chronic salicylate intoxication. A common cause of morbidity in the elderly. J Am Geriatr Soc 1989; 37:556–561. 37. Hoppmann RA, et al. Central nervous system side effects of nonsteroidal anti-inflammatory drugs. Aseptic meningitis, psychosis, and cognitive dysfunction. Arch Intern Med 1991; 151:1309–1313. 38. Wysenbeek AJ, et al. Assessment of cognitive function in elderly patients treated with naproxen. A prospective study. Clin Exp Rheumatol 1988; 6:399–400. 39. Bruce-Jones PN, et al. Indomethacin and cognitive function in healthy elderly volunteers. Br J Clin Pharmacol 1994; 38:45–51. 40. Barber JB, et al. Treatment of chronic non-malignant pain in the elderly: safety considerations. Drug Saf 2009; 32:457–474. 41. Ripamonti C, et al. CNS adverse effects of opioids in cancer patients. CNS Drugs 1997; 8:21–37. 42. Alagiakrishnan K, et al. An approach to drug induced delirium in the elderly. Postgrad Med J 2004; 80:388–393. 43. McLachlan AJ, et al. Clinical pharmacology of analgesic medicines in older people: impact of frailty and cognitive impairment. Br J Clin Pharmacol 2011; 71:351–364. 44. Dosa DM, et al. Frequency of long-acting opioid analgesic initiation in opioid-naive nursing home residents. J Pain Symptom Manage 2009; 38:515–521. 45. Tannenbaum C, et al. A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs. Drugs Aging 2012; 29:639–658. 46. McGuinness B, et al. Statins for the treatment of dementia. Cochrane Database Syst Rev 2014; 7:CD007514. 47. Wagstaff LR, et al. Statin-associated memory loss: analysis of 60 case reports and review of the literature. Pharmacotherapy 2003; 23:871–880. 48. Zhou Z, et al. Effect of statin therapy on cognitive decline and incident dementia in older adults. J Am Coll Cardiol 2021; 77:3145–3156. 49. McGuinness B, et al. Statins for the prevention of dementia. Cochrane Database Syst Rev 2016; 1:CD003160. 50. Olmastroni E, et al. Statin use and risk of dementia or Alzheimer’s disease: a systematic review and meta-analysis of observational studies. Eur J Prev Cardiol 2022; 29:804–814.

666 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 51. Qiu C, et al. The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol 2005; 4:487–499. 52. Wändell P, et al. Antihypertensive drugs and relevant cardiovascular pharmacotherapies and the risk of incident dementia in patients with atrial fibrillation. Int J Cardiol 2018; 272:149–154. 53. Levi MN, et al. Antihypertensive classes, cognitive decline and incidence of dementia: a network meta-analysis. J Hypertens 2013; 31:1073–1082. 54. Branco DR, et al. Direct oral anticoagulants vs vitamin K antagonist on dementia risk in atrial fibrillation: systematic review with meta-analysis. J Thromb Thrombolysis 2023; 56:474–484. 55. Eisendrath SJ, et al. Toxic neuropsychiatric effects of digoxin at therapeutic serum concentrations. Am J Psychiatry 1987; 144:506–507. 56. Brezis M, et al. Nightmares from digoxin. Ann Intern Med 1980; 93:639–640. 57. Laudisio A, et al. Digoxin and cognitive performance in patients with heart failure: a cohort, pharmacoepidemiological survey. Drugs Aging 2009; 26:103–112. 58. Athwal H, et al. Amiodarone-induced delirium. Am J Geriatr Psychiatry 2003; 11:696–697. 59. Foley KT, et al. Separate episodes of delirium associated with levetiracetam and amiodarone treatment in an elderly woman. Am J Geriatr Pharmacother 2010; 8:170–174. 60. Cantu TG, et al. Central nervous system reactions to histamine-2 receptor blockers. Ann Intern Med 1991; 114:1027–1034. 61. Gomm W, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neuroly 2016; 73:410–416. 62. Goldstein FC, et al. Proton pump inhibitors and risk of mild cognitive impairment and dementia. J Am Geriatr Soc 2017; 65:1969–1974. 63. Lochhead P, et al. Association between proton pump inhibitor use and cognitive function in women. Gastroenterology 2017; 153:971–979.e974. 64. Haenisch B, et al. Risk of dementia in elderly patients with the use of proton pump inhibitors. Eur Arch Psychiatry Clin Neurosci 2015; 265:419–428. 65. Cooksey R, et al. Proton pump inhibitors and dementia risk: evidence from a cohort study using linked routinely collected national health data in Wales, UK. PLoS One 2020; 15:e0237676. 66. Grahl JJ, et al. Antimicrobial exposure and the risk of delirium in critically ill patients. Crit Care 2018; 22:337. 67. Bhattacharyya S, et al. Antibiotic-associated encephalopathy. Neurology 2016; 86:963–971. 68. Kass JS, et al. Nervous system effects of antituberculosis therapy. CNS Drugs 2010; 24:655–667. 69. Bishara D, et al. Safe prescribing of physical health medication in patients with dementia. Int J Geriatr Psychiatry 2014; 29:1230–1241.

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Management of behavioural and psychological symptoms of dementia (BPSD)

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Non-drug measures

Prescribing in older people CHAPTER 6 Management of behavioural and psychological symptoms of dementia (BPSD) Behavioural and psychological symptoms of dementia (BPSD) cover a range of difficulties including aggression, agitation, vocalisation, distress during care, disinhibition, hallucinations, delusions, apathy, low mood and anxiety.1 Such symptoms occur in over 90% of patients to varying degrees.2 Drug treatment of BPSD is not well supported by evidence3 and many of the drugs used in BPSD have serious adverse effects. Non-drug measures Since the publication in the UK of Time for Action, a report which highlighted the risks of antipsychotic use in dementia,4 there has been a drive to formulate and employ non- pharmacological treatment for BPSD. Systematic reviews have been completed,5 new models of care developed6,7 and guidance documents written.8 The key themes include:

An individualised approach rather than the application of more generalised therapies.
Ensuring contributory physical factors are addressed as a first step. These factors include pain (see following section), infection, constipation and medication adverse effects (see ‘Safer prescribing for physical conditions in dementia’ earlier in this chapter).
The importance of understanding and reframing ‘problem behaviours’ as an expression of distress and unmet need.6,7
Use of life history, direct observation of care and data collection (e.g. sleep, pain and ABC charts) to uncover unmet needs and to inform treatment.8
Formulation meetings to develop a model of the factors contributing to the behaviour.
Clear care plans developed with carers to address unmet needs.
Care plans reviewed and adjusted according to effectiveness of the interventions tried. Some structured psychosocial interventions for BPSD9 are supported by research.10 These can be useful to consider within an individualised care plan and are better if implemented by supporting caregivers. Behavioural management techniques and caregiver psychoeducation centred on an individual patient’s behaviour have been found to be generally successful and the effects can last for months.11 A 2017 systematic review of systematic reviews12 provided a comprehensive summary of the evidence for non-pharmacological interventions in BPSD. Among sensory stimulation interventions, the only convincingly effective intervention (reducing agitation and aggressive behaviour) was music therapy.12,13 Multicomponent interventions that use a comprehensive, integrated multidisciplinary approach combining medical, psychiatric and nursing interventions may be more effective at reducing severe behavioural problems in nursing home patients.12 Animal-assisted therapy has shown a significant reduction in BPSD, especially depression.14 Doll therapy has been shown to reduce agitation, aggressiveness as well as dysphoria, wandering, apathy, professional caregiver burden and delirium.15 Increasing light exposure and bright light therapy may be beneficial in BPSD and sundowning.16,17 A systematic review suggested that aerobic exercise might be effective in reducing neuropsychiatric symptoms.18 A 2020 Cochrane

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Pharmacological measures

668 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 review of aromatherapy (13 studies with 708 participants) found no evidence that it is beneficial for people with dementia although there are many limitations to the existing data.19 Clinicians have limited time to develop non-drug interventions, but in essence they are no more than good clinical practice: taking a clear history to understand factors contributing to behaviours and drawing up a care plan to address these factors. Given drug therapy has such a limited evidence base in this area, there is a duty to do this before even considering prescribing. Pharmacological measures Analgesics Pain in people with dementia may cause agitation and the treatment of pain may reduce agitation.13,20 An RCT investigating the effects of a stepwise protocol of treatment with analgesics noted significant improvement in agitation, overall neuropsychiatric symptoms and pain. Most patients received only paracetamol (acetaminophen). Education of nursing staff on the link between pain and behaviour may be as effective as an algorithm-based pain management intervention.21 A Cochrane review investigated the efficacy and safety of opioids for agitation in people with dementia.22 RCTs of opioids compared with placebo were assessed but there was insufficient evidence to establish any benefit. Antipsychotics Antipsychotic drugs were once widely used in BPSD23 but their use is now discouraged.24,25 Their effect size is small,26–29 tolerability is poor29–31 and they increase mortality.32 Despite this, antipsychotic medications have been the subject of the largest number of studies of any intervention for BPSD. Typical antipsychotics (with the exception of haloperidol) show no efficacy in BPSD, but SGAs do have some efficacy. A comparative effectiveness review found the most effective antipsychotics include risperidone (psychosis, agitation, overall BPSD), olanzapine (agitation) and aripiprazole (overall BPSD). Though commonly used, quetiapine has failed to show effectiveness for BPSD, except at doses (100–200mg/day) that may not be well tolerated.33 A 2006 Cochrane review34 of atypical antipsychotics for aggression and psychosis in AD concluded that risperidone and olanzapine can diminish aggression and that Recommendation: The first-line treatments for BPSD are personalised, multicomponent non-drug measures, which involve working closely with caregivers. Recommendation: The assessment and effective treatment of pain in people with BPSD are important. Even in people without overt pain, a trial of analgesics (usually paracetamol) may be worthwhile.

Prescribing in older people CHAPTER 6 risperidone reduces psychotic symptoms. However, because of modest efficacy and significant increase in adverse effects, neither drug should be used to treat BPSD unless there is severe distress or a serious risk of physical harm to those living or working with the patient. Brexpiprazole is a relatively newly introduced dopamine D2 receptor partial agonist, like aripiprazole. It has a lower intrinsic activity at D2 and D3 than aripiprazole and so has a lower risk for akathisia and extrapyramidal side effects (EPSEs).35 Brexpiprazole’s efficacy and tolerability in the treatment of agitation in AD were investigated in a 12- week RCT. A dose of 2 or 3mg/day showed a statistically significant improvement versus placebo in agitation over 12 weeks and it was generally well tolerated.36 Brexpiprazole is the only drug that is FDA approved for agitation associated with dementia due to AD.37 It is not available in the UK. Increased mortality with antipsychotics in dementia Following analysis of published and unpublished data in 2004, warnings were issued in the UK and USA regarding increased mortality in patients with dementia taking certain atypical antipsychotics.38–40 Warnings now apply to all antipsychotics40,41 and a warning about a possible risk of cerebrovascular events has been added to product labelling for all antipsychotics when used in dementia. Whether mortality risk varies between antipsychotics has been investigated in several studies.42–45 In general, haloperidol led to an increased mortality whereas quetiapine users had a decreased risk. No clinically meaningful differences were observed for olanzapine, aripiprazole and ziprasidone42 (or valproic acid43). The effects were strongest shortly after the start of treatment and remained after adjustment for dose. There was a dose–response relationship for all drugs except quetiapine42 (the higher the dose, the greater the mortality risk). In a 2019 network meta-analysis of 17 studies (5373 patients), no significant differences were found across measures of effectiveness and safety among aripiprazole, olanzapine, quetiapine and risperidone.46,47 Clinical information for antipsychotic use in dementia Antipsychotics should not be used routinely to treat agitation and aggression in people with dementia.48 Risperidone and haloperidol are the only drugs licensed in the UK for the management of BPSD. Owing to the dangers of haloperidol, risperidone is the agent of choice. It is specifically indicated for short-term treatment (up to 6 weeks) of persistent aggression in moderate to severe AD unresponsive to non-pharmacological approaches and when there is a risk of harm to self or others.49 Risperidone is licensed up to 1mg twice a day50 although the optimal dose in dementia is 500mcg twice a day (1mg daily).51 Alternative antipsychotic drugs may be used (off-licence) if risperidone is contraindicated or not tolerated (e.g. because of extrapyramidal symptoms or hyperprolactinaemia). Olanzapine has some positive efficacy data for reducing aggression in dementia,34 Recommendation: Risperidone is licensed for persistent aggression in Alzheimer’s disease. An alternative agent may be justified if risperidone is contraindicated, not tolerated or not effective. Effect is modest at best. When prescribed, regular review is recommended.

670 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 aripiprazole has shown modest efficacy for BPSD47 and both are less likely to cause Parkinsonian effects. Quetiapine is often considered in patients with Parkinson’s disease or DLB (at very small doses) because of its low propensity for causing movement disorders, however it was found to have limited efficacy in dementia so low-dose alternatives (including clozapine) may be required.52 Always consider anticholinergic burden when selecting an antipsychotic drug in dementia (see ‘Safer prescribing for physical conditions in dementia’ earlier in this chapter). Only prescribe antipsychotics after: ■ ■Treating any physical illness, pain or constipation. ■ ■Addressing sensory deficits (find and clean the person’s glasses, get a battery for the hearing aid). ■ ■Trying person-centred non-pharmacological options. ■ ■Only use antipsychotics for psychosis or aggression. Other BPSD need different approaches. ■ ■Assess if the antipsychotic drug is safe to use. Assess fall risk and risk factors for stroke. ■ ■Discussing possible risks and benefits with carer (and patient if they have capacity). ■ ■Clear documentation of the above points.48 ■ ■Review appropriateness of treatment regularly so that an ineffective drug is not continued unnecessarily. ■ ■Monitor for adverse effects. Guidance on the monitoring of antipsychotic use in dementia is limited. See Appropriate Prescribing of Antipsychotic Medication in Dementia Toolkit (https://www.england.nhs.uk/london/wp-content/uploads/sites/8/2022/10/ Antipsychotic-Prescribing-Toolkit-for-Dementia.pdf). Ideally, patients prescribed antipsychotics for longer than a few weeks (and who are not terminally ill) should have the following tests at baseline, at 3 months and annually (or as appropriate), if possible, and if it does not lead to unnecessary distress.

Blood pressure and pulse.
Weight (ideally also monitor monthly for the first 3 months).
Blood tests: a. fasting glucose or HbA1c b. urea and electrolytes (U&Es) including eGFR c. full blood count (FBC) d. lipids (if possible fasting) e. liver function tests (LFTs) f. prolactin levels.
ECG (repeat at between 4 weeks and 3 months or when clinically indicated). ■ ■In-patients or physically frail patients may need more frequent physical health monitoring. ■ ■Review of the antipsychotic drug needs to be done at 4–6 weeks (maybe earlier for in- patients), then at 3 months and then every 6 months if physically stable and there are no adverse effects. Consider stopping the antipsychotic at each review, where appropriate.

Prescribing in older people CHAPTER 6 ■ ■Several deprescribing studies have shown that antipsychotics53–55 (and other psychotropics)55,56 can be deprescribed successfully (Table 6.6) as the reductions in psychotropic drug use did not negatively affect BPSD, while ADL improved.55 Other pharmacological agents in BPSD Cognitive enhancers Acetylcholinesterase inhibitors and memantine have a modest effect on BPSD.13 According to a meta-analysis59 and systematic review,60 the effect of AChE-Is on BPSD is at least statistically significant. Overall, cholinesterase inhibitors are more effective for depression, dysphoria, apathy and anxiety than for agitation or aggression. Memantine can help to improve agitation, aggression and delusions. Benzodiazepines Benzodiazepines61,62 are widely used but their use is poorly supported. Benzodiazepines increase the rate of cognitive decline,61 risk of dementia,63 risk of pneumonia64 and increase all-cause mortality.65 They may contribute to the increased frequency of falls and hip fractures62,66 in older people. Table 6.6 Reduction or discontinuation regimen for antipsychotic drugs in BPSD – a guide.57,58 Antipsychotic Usual dose range in dementia Suggested regimen for reduction/discontinuation (generally over 4 weeks if possible)* Amisulpride 25–50mg/day Reduce by 12.5–25mg every 1–2 weeks (depending on dose) then stop Aripiprazole 5–15mg/day Reduce by 5mg every 1–2 weeks (depending on dose) then stop (if patient is on 5mg daily, reduce to 2.5mg for 2 weeks) Haloperidol Not recommended in older people with dementia (except in delirium) Reduce by 0.25–0.5mg every 1–2 weeks (depending on dose) then stop Olanzapine 2.5–10mg/day Reduce by 2.5mg every 1–2 weeks (depending on dose) then stop Quetiapine 12.5–300mg/day For doses 12.5–100mg/day – reduce by 12.5–25mg every 1–2 weeks (depending on dose) then stop For doses >100–300mg/day – reduce by 25–50mg every 1–2 weeks (depending on dose) then stop If dose is 300mg/day – reduce to 150–200mg/day for 1 week then by 50mg/week then stop Risperidone 0.25–2mg/day Reduce by 0.25–0.5mg every 1–2 weeks (depending on dose) then stop *Duration of taper should not normally exceed the duration of treatment. NB If serious adverse effects occur, stop the antipsychotic drug immediately. BPSD, behavioural and psychological symptoms of dementia. Recommendation: AChE-Is or memantine can help with mild BPSD and are worth considering if a patient is not already on one of these drugs.

672 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Antidepressants Depression is a risk factor and consequence of AD. The prevalence of depression and AD comorbidity is estimated to be 30–50%.67 As with other BPSD, non-pharmacological approaches such as reminiscence, cognitive stimulation/rehabilitation, therapeutic approaches, music-based approaches and education/training have the potential to reduce symptoms of depression in dementia.68 If you can, try simple measures to improve quality of life as the first-line intervention in mild to moderate depression in dementia. The evidence for efficacy of antidepressants in BPSD is mixed and limited, showing that antidepressants are most helpful for treating agitation and less useful for depression, apathy, anxiety or psychosis in dementia.33 Citalopram has the strongest evidence for efficacy in agitation, with the CitAD trial69 showing that a high dose (30mg) of citalopram daily had a positive effect on agitation in dementia; unfortunately this study also confirmed a risk of QT prolongation with citalopram. The maximum dose of citalopram in older people is limited to 20mg a day because of the drug’s effect on cardiac QT interval. Although there is less evidence, escitalopram may also be effective in BPSD. The evidence for efficacy of sertraline is mixed, though its cardiac safety is compelling.33 One Cochrane review of trazodone for agitation in dementia70 found insufficient evidence from RCTs to support its use in dementia, but another Cochrane review found trazodone 50mg at bedtime was well tolerated and improved sleep for people with dementia and insomnia.71 Additionally, trazodone 150–300mg/day was found effective in reducing BPSD in frontotemporal dementia.72 Although mirtazapine is frequently used to treat older adults with depression, a pilot study showed no significant therapeutic effect of 15mg mirtazapine on Alzheimer’s patients with sleep disorders and in fact found worsening of daytime sleep patterns.73 A study of mirtazapine for agitation in dementia randomly assigned patients to receive either mirtazapine (titrated to 45mg) or placebo, and found no benefit of mirtazapine and a potentially higher mortality in patients who received it.74 Bupropion has not been studied in controlled trials in dementia.33 Vortioxetine has multimodal activity and potential effects on cognitive function through its mechanisms on glutamate neurotransmission and neuroplasticity in the prefrontal cortex, which may be useful in dementia. In a 12-month open-label observational study of 108 patients with mild AD and depressive symptoms, vortioxetine had a beneficial effect on cognition and mood and was well tolerated.75 However, a 12-week placebo-controlled RCT of 100 patients with AD and depression found no statistically significant difference between the two groups in terms of depressive symptoms, cognitive functions and ADL. The percentage of adverse events and drug discontinuation was similar between groups.76 A possible explanation for the divergent results is that the second study included patients with more severe cognitive impairment and depressive symptoms. An open-label prospective study in patients with Parkinson’s disease and major depression showed that vortioxetine was well tolerated and improved depressive symptoms as well as cognitive function, apathy, fatigue and quality of life 3 months after starting the drug.77 Recommendation: Avoid benzodiazepines other than as a single use for emergency sedation.

Prescribing in older people CHAPTER 6 Tricyclic antidepressants are best avoided in patients with dementia. They can cause falls, via orthostatic hypotension, and worsen cognition owing to their anticholinergic adverse effect.78 While some studies have found that antidepressant use in older people may be associated with an increased risk of dementia,79 it is important to keep in mind that previous studies have shown that late-life depression is associated with an increased risk for dementia. Hence any comparisons of antidepressant users with non-depressed non- users are subject to indication bias as the increased dementia risk could be due to depression, not the medication. Mood stabilisers/antiseizure medications Randomised controlled trials of mood stabilisers in BPSD have been completed for oxcarbazepine,80 carbamazepine81 and valproate.82 Gabapentin, lamotrigine and topiramate have also been used.83 Of the mood stabilisers, carbamazepine has the most robust evidence of efficacy in non-cognitive symptoms.84 However, its serious adverse effects (especially Stevens-Johnson syndrome, ataxia and hyponatraemia) and its potential for drug interactions limit its use. One RCT of valproate found it to be ineffective in controlling BPSD symptoms.85 A Cochrane review of valproate for the treatment of agitation in dementia concluded that it was ineffective and associated with a higher rate of adverse effects, and possibly of serious ones.86 Valproate does not delay emergence of agitation in dementia.87 Literature reviews of anticonvulsants in non-cognitive symptoms of dementia found that valproate, oxcarbazepine and lithium showed low or no evidence of efficacy and that more RCTs are needed to strengthen the evidence for gabapentin, topiramate and lamotrigine.84 Preliminary low-grade evidence based on case series and case reviews suggests a possible benefit of gabapentin and pregabalin in patients with BPSD in AD. Evidence in frontotemporal dementia is lacking.88 In a small case series, gabapentin reduced aggression among seven patients with vascular dementia or mixed vascular/AD, using daily doses ranging from 200 to 600mg daily. Three of the seven patients were able to discontinue antipsychotics after gabapentin initiation; thus, it may be useful in patients with cardiac conditions where antipsychotics are inappropriate. Caution should be noted about the use of gabapentin in DLB. Dramatic worsening of neuropsychiatric symptoms has been reported after its use to treat behavioural symptoms.89 There is inadequate evidence to support the use of levetiracetam for BPSD, with concerns regarding tolerability.90 Although clearly beneficial in some patients, anticonvulsants/mood stabilisers cannot be recommended for routine use in the treatment of the neuropsychiatric symptoms in dementia at present.83 Recommendation: Although evidence is weak, use of antidepressants is justified in people with dementia who have clear symptoms of moderate or severe depression, especially if non-pharmacological approaches have been ineffective. Recommendation: Limited evidence to support use; use may be justified where other treatments are contraindicated or ineffective. Valproate is best avoided.

674 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Management of sleep disturbances in dementia Non-pharmacological management of sleep disturbances using established sleep hygiene methods should be the first-line treatment for insomnia in dementia.91,92 A 2020 Cochrane review93 of pharmacotherapies for sleep disturbances in dementia found a distinct lack of evidence to guide decisions about drug treatment of sleep problems in dementia. There were no RCTs for the many widely prescribed drugs (including benzodiazepine and non-benzodiazepine hypnotics), despite considerable uncertainty about the balance of benefits and risks for these common treatments. The authors found no evidence for beneficial effects of melatonin (up to 10mg) or a melatonin receptor agonist. There was evidence of some beneficial effects on sleep outcomes from trazodone and orexin antagonists (suvorexant and lemborexant; two studies, n = 323) and no evidence of harmful effects in these small trials, although larger trials are needed. Of note, melatonin (at 2mg and occasionally up to 10mg/day modified release) is used in patients with dementia with good effects. In one study, melatonin 9mg resulted in improvement in subjective sleep, reduction of sundowning behaviour and lack of decline in cognitive function testing over a period of 22–35 months. Several other case reports and small open-label trials described benefits on subjective sleep characteristics and cognitive function, but data quality is limiting.94 An expert review92 also deduced that non-pharmacological interventions are generally preferred as the first-line approach to improve sleep-related symptoms in AD; however, when non-pharmacological interventions alone are insufficient, a range of pharmacological agents can be considered. Trazodone and melatonin are commonly used as adjunctive therapies, while Z-drugs including zopiclone and zolpidem are specifically employed to treat insomnia in patients with late-onset AD. Furthermore, dual orexin receptor antagonists have emerged and gained approval for improving sleep onset and maintenance in AD patients. The review proposed a stepwise algorithm for the management of sleep disturbances in AD.92 Sedating antihistamines Promethazine is frequently used in BPSD for its sedative effects. It has strong anticholinergic effects and readily penetrates the BBB, potentially causing significant cognitive impairment.95 Miscellaneous agents96,97 A meta-analysis of RCTs for Gingko biloba (240mg daily, 22–24-week treatment) showed improvement in BPSD (except psychotic-like features) and in caregiver distress caused by such symptoms.98 Recommendation: Despite limited evidence for the efficacy of melatonin, it is safe to use and may be justified in cases where benefits are seen. Non-pharmacological management of sleep disturbances should be tried first. Recommendation: Promethazine should be avoided.

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Electroconvulsive therapy (ECT)

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Summary

Prescribing in older people CHAPTER 6 Pimavanserin (inverse agonist and antagonist at 5HT2A receptors) is approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. One RCT evaluated its use for the treatment of psychosis in AD and showed improved psychotic symptoms when compared with placebo and a lower risk of relapse with continuation. Headache, constipation, urinary tract infection and asymptomatic QT prolongation occurred with pimavanserin.99 It has also shown improvement of depressive symptoms in patients with Parkinson’s disease.100 A recent phase III, randomised double-blind placebo-controlled multicentre study investigating the efficacy of lumateperone (a potent antagonist at 5HT2A receptors, and a serotonin reuptake inhibitor) in reducing dementia-related agitation failed to show any benefit.101 Other agents being investigated for BPSD include dextromethorphan/quinidine (one RCT found it decreased agitation and was well tolerated),102 bupropion/dextromethorphan103 and methylphenidate (one RCT found it to be effective for apathy in AD in individuals who were not anxious or agitated).103,104 Prazosin (a centrally acting α1 adrenoceptor antagonist) appears to benefit individuals with dementia and agitation and aggression. When compared with other treatments for BPSD, the data for its use in BPSD are limited to just one good-quality RCT. Given these limitations, its routine use for the management of BPSD cannot be recommended at this time; however, it may be used when other medications (e.g. acetylcholinesterase inhibitors, memantine, antidepressants and/or atypical antipsychotics) have been ineffective or not tolerated.47,105 A Cochrane review (4 small studies, 110 participants) found low-certainty evidence suggesting there may be little or no clinically important effect of cannabinoids on overall BPSD assessed with the Neuropsychiatric Inventory.106 Electroconvulsive therapy (ECT) Electroconvulsive therapy may have a place in the treatment of severe and refractory BPSD. A review (20 published reports, 172 individuals with dementia; 40% AD) found that over 90% of the individuals responded to ECT treatment. Adverse effects were infrequent, mild and transient. The most common adverse event noted was postictal confusion/ memory impairment that was seen in approximately 15% of the individuals.47 However, ECT would not be recommended as a common intervention given limited evidence, and the considerable practical aspects of transporting patients to the ECT clinic and difficulty with obtaining consent. Summary The evidence base available to guide treatment in this area is insufficient to allow specific recommendations on appropriate management and drug choice. The basic approach is to exclude physical illness and try non-drug measures before resorting to the use of psychotropics. When using pharmacological treatments, there should be clearly documented treatment aims and prescribing should cease if these aims are not met within a specified timeframe. Recommendation: There is insufficient evidence to recommend ECT use in BPSD. Caution: It can cause significant cognitive adverse effects.

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References

676 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 References

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Lancet Neurol 2009; 8:151–157. 55. Gedde MH, et al. Less is more: the impact of deprescribing psychotropic drugs on behavioral and psychological symptoms and daily functioning in nursing home patients. results from the cluster-randomized controlled COSMOS Trial. Am J Geriatr Psychiatry 2021; 29:304–315. 56. Cossette B, et al. Optimizing practices, use, care, and services-antipsychotics (OPUS-AP) in long-term care centers in Quebec, Canada: a successful scale-up. J Am Med Dir Assoc 2022; 23:1084–1089. 57. NHS PrescQIPP. T7: reducing antipsychotic prescribing in dementia. 2014; https://www.prescqipp.info/our-resources/bulletins/t7-reducing- antipsychotic-prescribing-in-dementia/. 58. Bjerre LM, et al. Deprescribing antipsychotics for behavioural and psychological symptoms of dementia and insomnia: evidence-based clinical practice guideline. Can Fam Physician 2018; 64:17–27. 59. Campbell N, et al. Impact of cholinesterase inhibitors on behavioral and psychological symptoms of Alzheimer’s disease: a meta-analysis. Clin Interv Aging 2008; 3:719–728. 60. Seibert M, et al. Efficacy and safety of pharmacotherapy for Alzheimer’s disease and for behavioural and psychological symptoms of dementia in older patients with moderate and severe functional impairments: a systematic review of controlled trials. Alzheimers Res Ther 2021; 13:131. 61. Verdoux H, et al. Is benzodiazepine use a risk factor for cognitive decline and dementia? A literature review of epidemiological studies. Psychol Med 2005; 35:307–315. 62. Lagnaoui R, et al. Benzodiazepine utilization patterns in Alzheimer’s disease patients. Pharmacoepidemiol Drug Saf 2003; 12:511–515. 63. Billioti de Gage S, et al. Benzodiazepine use and risk of dementia: prospective population based study. BMJ 2012; 345:e6231. 64. Taipale H, et al. Risk of pneumonia associated with incident benzodiazepine use among community-dwelling adults with Alzheimer disease. CMAJ 2017; 189:e519–e529. 65. Palmaro A, et al. Benzodiazepines and risk of death: results from two large cohort studies in France and UK. Eur Neuropsychopharmacol 2015; 25:1566–1577. 66. Chang CM, et al. Benzodiazepine and risk of hip fractures in older people: a nested case-control study in Taiwan. Am J Geriatr Psychiatry 2008; 16:686–692.

678 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 67. Aboukhatwa M, et al. Antidepressants are a rational complementary therapy for the treatment of Alzheimer’s disease. Mol Neurodegener 2010; 5:10. 68. Burley CV, et al. Nonpharmacological approaches reduce symptoms of depression in dementia: a systematic review and meta-analysis. Ageing Res Rev 2022; 79:101669. 69. Porsteinsson AP, et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA 2014; 311:682–691. 70. Martinon-Torres G, et al. Trazodone for agitation in dementia. Cochrane Database Syst Rev 2004; 4:CD004990. 71. McCleery J, et al. Pharmacotherapies for sleep disturbances in dementia. Cochrane Database Syst Rev 2016; 11:CD009178. 72. Trieu C, et al. Effectiveness of pharmacological interventions for symptoms of behavioral variant frontotemporal dementia: a systematic review. Cogn Behav Neurol 2020; 33:1–15. 73. Scoralick FM, et al. Mirtazapine does not improve sleep disorders in Alzheimer’s disease: results from a double-blind, placebo-controlled pilot study. Psychogeriatrics 2017; 17:89–96. 74. Banerjee S, et al. Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial. Lancet 2021; 398:1487–1497. 75. Cumbo E, et al. Treatment effects of vortioxetine on cognitive functions in mild Alzheimer’s disease patients with depressive symptoms: a 12 month, open-label, observational study. J Prev Alzheimers Dis 2019; 6:192–197. 76. Jeong HW, et al. Vortioxetine treatment for depression in Alzheimer’s disease: a randomized, double-blind, placebo-controlled study. Clin Psychopharmacol Neurosci 2022; 20:311–319. 77. Santos García D, et al. Vortioxetine improves depressive symptoms and cognition in Parkinson’s disease patients with major depression: an open-label prospective study. Brain Sci 2022; 12:1466. 78. Ballard C, et al. Management of neuropsychiatric symptoms in people with dementia. CNS Drugs 2010; 24:729–739. 79. Wang YC, et al. Increased risk of dementia in patients with antidepressants: a meta-analysis of observational studies. Behav Neurol 2018; 2018:5315098. 80. Sommer OH, et al. Effect of oxcarbazepine in the treatment of agitation and aggression in severe dementia. Dement Geriatr Cogn Disord 2009; 27:155–163. 81. Tariot PN, et al. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry 1998; 155:54–61. 82. Lonergan E, et al. Valproate preparations for agitation in dementia. Cochrane Database Syst Rev 2009; 3:CD003945. 83. Konovalov S, et al. Anticonvulsants for the treatment of behavioral and psychological symptoms of dementia: a literature review. Int Psychogeriatr 2008; 20:293–308. 84. Yeh YC, et al. Mood stabilizers for the treatment of behavioral and psychological symptoms of dementia: an update review. Kaohsiung J Med Sci 2012; 28:185–193. 85. Sival RC, et al. Sodium valproate in aggressive behaviour in dementia: a twelve-week open label follow-up study. Int J Geriatr Psychiatry 2004; 19:305–312. 86. Baillon SF, et al. Valproate preparations for agitation in dementia. Cochrane Database Syst Rev 2018; 10:CD003945. 87. Tariot PN, et al. Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch Gen Psychiatry 2011; 68:853–861. 88. Supasitthumrong T, et al. Gabapentin and pregabalin to treat aggressivity in dementia: a systematic review and illustrative case report. Br J Clin Pharmacol 2019; 85:690–703. 89. Cooney C, et al. Use of low-dose gabapentin for aggressive behavior in vascular and mixed vascular/Alzheimer dementia. J Neuropsychiatry Clin Neurosci 2013; 25:120–125. 90. Gallagher D, et al. Antiepileptic drugs for the treatment of agitation and aggression in dementia: do they have a place in therapy? Drugs 2014; 74:1747–1755. 91. David R, et al. Non-pharmacologic management of sleep disturbance in Alzheimer’s disease. J Nutr Health Aging 2010; 14:203–206. 92. Javed B, et al. Pharmacological and non-pharmacological treatment options for sleep disturbances in Alzheimer’s disease. Expert Rev Neurother 2023; 23:501–514. 93. McCleery J, et al. Pharmacotherapies for sleep disturbances in dementia. Cochrane Database Syst Rev 2020; 11:CD009178. 94. Roland JP, et al. Impact of pharmacotherapy on insomnia in patients with Alzheimer’s disease. Drugs Aging 2021; 38:951–966. 95. Bishara D, et al. Anticholinergic effect on cognition (AEC) of drugs commonly used in older people. Int J Geriatr Psychiatry 2017; 32:650–656. 96. Porsteinsson AP, et al. An update on the advancements in the treatment of agitation in Alzheimer’s disease. Expert Opin Pharmacother 2017; 18:611–620. 97. Carrarini C, et al. Agitation and dementia: prevention and treatment strategies in acute and chronic conditions. Front Neurol 2021; 12:644317. 98. Savaskan E, et al. Treatment effects of Ginkgo biloba extract EGb 761® on the spectrum of behavioral and psychological symptoms of dementia: meta-analysis of randomized controlled trials. Int Psychogeriatr 2018; 30:285–293. 99. Tariot PN, et al. Trial of pimavanserin in dementia-related psychosis. N Engl J Med 2021; 385:309–319. 100. DeKarske D, et al. An open-label, 8-week study of safety and efficacy of pimavanserin treatment in adults with Parkinson’s disease and depression. J Parkinsons Dis 2020; 10:1751–1761. 101. ClinicalTrials.gov. ITI-007 for the treatment of agitation in patients with dementia, including Alzheimer’s disease [NCT02817906]. 2021; https://clinicaltrials.gov/study/NCT02817906.

Prescribing in older people CHAPTER 6 102. Tampi RR, et al. Evidence for using dextromethorphan-quinidine for the treatment of agitation in dementia. World J Psychiatry 2020; 10:29–33. 103. Ahmed M, et al. Current agents in development for treating behavioral and psychological symptoms associated with dementia. Drugs Aging 2019; 36:589–605. 104. Lanctôt KL, et al. Heterogeneity of response to methylphenidate in apathetic patients in the ADMET 2 Trial. Am J Geriatr Psychiatry 2023; 31:1077–1087. 105. Chen A, et al. The Psychopharmacology Algorithm Project at the Harvard South Shore Program: an update on management of behavioral and psychological symptoms in dementia. Psychiatry Res 2021; 295:113641. 106. Bosnjak Kuharic D, et al. Cannabinoids for the treatment of dementia. Cochrane Database Syst Rev 2021; 9:CD012820.

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Management of inappropriate sexual behaviour in older adults

680 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Management of inappropriate sexual behaviour in older adults This section deals with sexual behaviours that are causing distress either to the person with dementia or to other people. Sexually inappropriate behaviours have been reported in between 1.8% and 25.9% of patients with neurocognitive disorders,1 and in people with dementia the prevalence rate is 2–17%, occurring with about equal frequency in men and women.2 Sexual symptoms are more prevalent in frontal lobe disorders (most commonly stroke and behavioural variant frontotemporal dementia) and in Parkinson’s (adverse effects of dopaminergic drugs), but can occur in any dementia subtype.1 These symptoms present a challenge for patients, carers and healthcare workers. Assessment of the behaviours, the contexts in which they arise and their risks is essential. It is important to manage the environment and to educate and discuss the behaviour with carers and families. Behavioural measures are probably helpful, although no specific intervention has been shown to be effective in this area. Several classes of drug may help to control aberrant sexual behaviours, but owing to the lack of large-scale studies there is no gold standard treatment. No treatments are licensed for hypersexuality in this population and the medications used are all potentially harmful.2 A thorough history should be taken before starting any drug therapy to obtain the relevant medical, psychiatric, medication and sexual history. Changes in sexual behaviour can be caused by urinary or genital conditions, delirium or a medication side effect. Benzodiazepines, dopamine-receptor agonists (e.g. apomorphine, pramipexole, rotigotine) and L-dopa can cause hypersexuality.2 Non-pharmacological treatment, such as distraction/diversion of the patient when inappropriate sexual behaviours occur,1 is recommended as first-line therapy (Box 6.3). Antidepressants Box 6.3 Non-pharmacological measures1 ■ ■Identify and treat medical causes for behaviour, e.g. urinary retention and genital disorders causing the patient to touch their genitals due to discomfort. Delirium can cause sexual disinhibition ■ ■Identify and treat any psychiatric disorder that may cause inappropriate sexual behaviour, e.g. mania or depression ■ ■If possible, stop or reduce dose of medication that may be causing the behaviour, e.g. benzodiazepines, dopamine agonists and high-dose L-dopa ■ ■Prevention: fulfil the need for intimacy/connection in other ways such as having meals in groups, conversation among peers and activities such as walking or exercise ■ ■Discussion with patient, caregivers and relatives to better understand the behaviour and explore attitudes to sexuality, which may inform therapy ■ ■Distraction or diversion, redirect behaviour, engage patients in activities that involve the hands and reduce sexual stimulation (e.g. iPads, magazines, TV) ■ ■Provide sensory and environmental stimulation (e.g. aromatherapy, music therapy, multisensory therapy, pet therapy). ■ ■Behavioural/cognitive behavioural therapy if available (though evidence is limited)

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Management

Prescribing in older people CHAPTER 6 have been recommended as the first line of pharmacological treatment after attempting non-pharmacological interventions. Several other categories of pharmacological interventions are listed in Table 6.7. Management To inform the management of inappropriate sexual behaviour, evaluation should include a medical history, physical examination, sexual history and medication review. The history should cover specifics of the demonstrated behaviour, such as potential precipitants and consequences including the frequencies of episodes, when and where they occur and with whom.3 Sometimes normal sexual behaviour, such as a patient masturbating in their bedroom, can be labelled as ‘disinhibition’, particularly in care home settings. In these cases, a discussion with staff and relatives about simple measures (e.g. a care plan to allow the resident periods of privacy in their room at set times each day) can avoid normal behaviours being pathologised. Non- pharmacological treatments should be tried first to prevent unnecessary prescription of psychotropics. Because of the complex nature of sexual disinhibition and varying origins of this behaviour, treatment will be most successful when tailored to the patient’s specific presentation.1 Studies on the pharmacological treatment of sexual disinhibition are limited and larger studies are necessary to establish a preferred medication regimen. In addition, there are few data available on treating these symptoms in women.1 A systematic review4 concluded that when treating patients with Alzheimer’s disease, vascular dementia or unspecified dementia, serotonergic agents including SSRIs and TCAs are recommended as a first-line treatment, followed by antiandrogens as a second line, and luteinising hormone-releasing hormone agonists and oestrogens as a third line. A literature review5 determined SSRIs to be the first line of treatment, antipsychotics to be the second line and hormonal modulators to be the third line (owing to cost and adverse effects).

Table 6.7 Pharmacological options in inappropriate sexual behaviour in older adults.1,6–8 Medication Drug Dose Mechanism of action Adverse effects Cautions/additional information Antiandrogens Cyproterone acetate Low dose 10mg/day9 High dose 50–100mg/day10 Cyproterone is licensed in the UK for hypersexuality in males: 50mg bd11 Reduction in serum testosterone level by inhibiting LH and FSH1 Gynaecomastia, galactorrhoea, elevated blood glucose, depression, osteoporosis1 Cyproterone acetate has been associated with risk of meningioma. Monitor patients for meningiomas and discontinue treatment if diagnosed. Surgical implantation of hormonal therapy to reduce male sex drive is subject to the conditions of Section 57 of the UK MHA and requires patient consent and a second medical opinion.12 Medroxyprogesterone acetate (MPA) Oral 5mg/day7 Oral 100–400mg/ day13 IM 100–300mg/week every 2 weeks14 Reduction in testosterone1 Sedation, weight gain, hot flushes, depression, elevated blood glucose1 Finasteride (for men who have benign prostatic hyperplasia) 5mg/day7 Reduction in testosterone1 Gynaecomastia, testicular pain, depression1 Antidepressants SSRIs usually first-line treatment Citalopram 20mg/day15 Decreased libido and antiobsessive effects Insomnia, somnolence, nausea, diarrhoea, headache, anorexia1 SSRIs cited as best first-line treatment Escitalopram 10–20mg/day Paroxetine 20mg/day16 Clomipramine 150–175mg/day16 Decreased libido1 Postural hypotension, anticholinergic effects including constipation, dry mouth, urinary retention and memory impairment1 Anticholinergic activity less than ideal in this group of patients Trazodone 100–500mg/day16 Decreased libido1 Day-time sedation, orthostatic hypotension, priapism, falls and fractures, delirium1 Mirtazapine 30mg/day16 Unknown Appetite increase, arthralgia, confusion, constipation, diarrhoea, dizziness, drowsiness, dry mouth, fatigue

Anticonvulsants Gabapentin 300–1800mg/day17 Increased GABA1 GI upset, skin reactions, confusion, nystagmus, dizziness, drowsiness6 Carbamazepine 200–800mg/day16 May help lower testosterone levels leading to decreased libido1 Dizziness, ataxia, drowsiness, diplopia, hyponatraemia, blood dyscrasias, severe skin reaction6 Potent enzyme inducer with many interactions Oxcarbazepine Starting dose 150mg/ day, titrated by 150mg/day in two divided doses. Average effective dose 600–750mg/ day in two divided doses18 May help lower testosterone levels leading to decreased libido1 Abdominal pain, alopecia, asthenia, ataxia, concentration impaired, depression, dizziness, drowsiness, hyponatraemia, nausea, nystagmus, skin reactions, vertigo, vision disorders, leucopenia Valproate Dose not specified but 50–200mg/day has been used Unknown Abdominal pain, tremor, agitation, alopecia (regrowth may be curly), anaemia, confusion, deafness, diarrhoea, drowsiness, haemorrhage, hallucination, headache, hepatic disorders Valproate causes serious harm in pregnancy and in children of men taking valproate (see Chapter 7). (Continued )

Antipsychotics Haloperidol 1.5–3mg/day16 Blocks dopamine receptors to decrease libido1 Cognitive decline, extrapyramidal symptoms, sedation, gait disturbances, falls, tardive dyskinesia, delirium, QT prolongation, increases in UTI and respiratory infections1 Increased risk of stroke and mortality in dementia. Extrapyramidal symptoms First-line treatment in cases where patients present with pathological irritability or unstable mood1 Olanzapine 2.5–15mg/day7 Arrhythmias, constipation, dizziness, drowsiness, dry mouth, erectile dysfunction, fatigue, galactorrhoea, gynaecomastia, hyperglycaemia, weight increase11 Quetiapine 25–75mg/day16 Appetite increased, asthenia, dysarthria, dyspepsia, dyspnoea, fever, headache, irritability, palpitations, peripheral oedema11 Zuclopenthixol 50mg IM monthly6 Tardive dyskinesia, delirium, QT prolongation, increases in UTI and respiratory infections, peripheral oedema, extrapyramidal effects1 Beta blockers Pindolol 5–40mg/day6,16 Decreased adrenergic drive1 Dizziness, sleep disturbance, headache, weakness, fatigue, GI upset Buspirone 10–60mg/day16,19 Unknown Abdominal pain, cold sweat, confusion, depression, dizziness, drowsiness, dry mouth, laryngeal pain, movement disorders, musculoskeletal pain, paraesthesia, skin reactions, tachycardia Table 6.7 (Continued ) Medication Drug Dose Mechanism of action Adverse effects Cautions/additional information

Cimetidine 600–1600mg/day14 Antiandrogen actions1 Worsening cognition, dizziness, nausea, arthralgia, headache1 A small study (n = 20) on elderly patients exhibiting hypersexual behaviours with dementia. This study found that 14 patients improved with cimetidine alone while six patients improved with a combination of cimetidine with ketoconazole or spironolactone.1 Ketoconazole 100–200mg/day20 Antiandrogen actions1 Sedation, headache, rash, photosensitivity, pruritus, hepatotoxicity, GI upset1 Gonadotropin and luteinising hormone- releasing hormone (GnRH and LHRH) agonists Leuprolide 7.5mg IM monthly6 Triptorelin is licensed in the UK for male hypersexuality: 11.25 mg IM every 12 weeks Decrease testosterone and decrease libido1 Hot flushes, decreased erectile dysfunction1 Caution: risk factors for osteoporosis L-tryptophan supplementation Dose not specified Increases 5HT synthesis in brain, stimulating 5HT release and function1 High blood glucose, increased risk of bladder cancer, eosinophilia-myalgia syndrome1 Naltrexone 100–150mg/day21 Unknown Abdominal pain, anxiety, appetite abnormal, arthralgia, asthenia, chest pain, dizziness, eye disorders, headache, hyperhidrosis, myalgia, nausea, palpitations, sexual dysfunction, skin reactions, sleep disorders, tachycardia, thirst Naltrexone is used after establishing normal liver and kidney function tests. (Continued )

Oestrogens Conjugated oestrogens Diethylstilbestrol 0.625mg once daily 0.05–0.1mg/day transdermal patch8 1mg once to twice daily7 Decreased testosterone and decreased libido Weight gain, gynaecomastia, venous thromboembolism, risk of cardiovascular adverse effects, fluid retention, GI effects1 Rivastigmine Up to 4.5mg bd (oral)22 4.6–9.5mg/day (patch) Reduces behavioural symptoms by improving cognitive functioning1 Nausea, diarrhoea, urinary incontinence, syncope1 Conflicting evidence. Rivastigmine has been shown to help many patients with sexual disinhibition while donepezil may exacerbate these symptoms.1 Spironolactone 12.58–75mg/day20 Antiandrogen actions1 Hyperkalaemia, gynaecomastia, GI ulcers1 bd, twice a day; FSH, follicle-stimulating hormone; GABA, gamma-aminobutyric acid; GI, gastrointestinal; LH, luteinising hormone; MHA, Mental Health Act; UTI, urinary tract infection. Table 6.7 (Continued ) Medication Drug Dose Mechanism of action Adverse effects Cautions/additional information

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References

Prescribing in older people CHAPTER 6 References

Sarangi A, et al. Treatment and management of sexual disinhibition in elderly patients with neurocognitive disorders. Cureus 2021; 13:e18463.
Dégano P, et al. Hypersexuality in dementia. Adv Psychiatr Treat 2005; 11:424–431.
Cipriani G, et al. Sexual disinhibition and dementia. Psychogeriatrics 2016; 16:145–153.
Guay DRP. Inappropriate sexual behaviors in cognitively impaired older individuals. Am J Geriatr Pharmacother 2008; 6:269–288.
Ibrahim C, et al. Hypersexuality in neurocognitive disorders in elderly people – a comprehensive review of the literature and case study. Psychiatr Danub 2014; 26 Suppl 1:36–40.
Tucker I. Management of inappropriate sexual behaviors in dementia: a literature review. Int Psychogeriatr 2010; 22:683–692.
Kindrat A, et al. Pharmacologic management of inappropriate sexual behaviour in long-term care residents. Can Fam Physician 2023; 69:687–689.
Joller P, et al. Approach to inappropriate sexual behaviour in people with dementia. Can Fam Physician 2013; 59:255–260.
Haussermann P, et al. Low-dose cyproterone acetate treatment of sexual acting out in men with dementia. Int Psychogeriatr 2003; 15:181–186.
Tavares A, et al. Cyproterone for treatment of hypersexuality in an elderly Huntington’s disease patient. Progr Neuropsychopharmacol Biol Psychiatry 2008; 32:1994–1995.
Joint Formulary Committee. British National Formulary (online). London: BMJ and Pharmaceutical Press; http://www.medicinescomplete.com.
Department of Health. Code of practice: Mental Health Act 1983 (last updated October 2017); https://www.gov.uk/government/publications/ code-of-practice-mental-health-act-1983#history.
Cross BS, et al. High-dose oral medroxyprogesterone for inappropriate hypersexuality in elderly men with dementia: a case series. Ann Pharmacother 2013; 47:e1.
Ozkan B, et al. Pharmacotherapy for inappropriate sexual behaviors in dementia: a systematic review of literature. Am J Alzheimers Dis Other Demen 2008; 23:344–354.
Mania I, et al. Citalopram treatment for inappropriate sexual behavior in a cognitively impaired patient. Prim Care Companion J Clin Psychiatry 2006; 8:106.
De Giorgi R, et al. Treatment of inappropriate sexual behavior in dementia. Curr Treat Options Neurol 2016; 18:41.
Alkhalil C, et al. Can gabapentin be a safe alternative to hormonal therapy in the treatment of inappropriate sexual behavior in demented patients? Int Urol Nephrol 2003; 35:299–302.
Shua-Haim JR, et al. P1–446: safety and efficacy of oxcarbazepine in the treatment of hypersexuality in Alzheimer’s disease patients residing in a special care unit in an assisted living facility. Alzheimers Dement 2006; 2:S228–S229.
Plantier D, et al. Drugs for behavior disorders after traumatic brain injury: systematic review and expert consensus leading to French recommendations for good practice. Ann Phys Rehabil Med 2016; 59:42–57.
Wiseman SV, et al. Hypersexuality in patients with dementia: possible response to cimetidine. Neurology 2000; 54:2024.
Sultana T, et al. Compulsive sexual behavior and alcohol use disorder treated with naltrexone: a case report and literature review. Cureus 2022; 14:e25804.
Canevelli M, et al. Rivastigmine in the treatment of hypersexuality in Alzheimer disease. Alzheimer Dis Assoc Disord 2013; 27:287–288.

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Depression in older adults

688 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Depression in older adults The prevalence of most physical illnesses increases with age and physical problems such as cardiovascular disease, chronic pain, diabetes and Parkinson’s disease are associated with a high risk of depressive illness.1,2 The morbidity and mortality associated with depression are increased in older adults3 as older people are more likely to be physically frail and therefore vulnerable to serious consequences from self-neglect (e.g. life- threatening dehydration or hypothermia) and immobility (e.g. venous stasis). Suicide is relatively more common in older people.4 Mortality is reduced by effective treatment of depression.5 A meta-analysis of placebo-controlled and antidepressant-controlled studies found a response rate of 51% in older patients,6 similar to that for the adult population.7 There is a common perception that older patients do not respond as well or as quickly to antidepressants as their younger counterparts,8 perhaps because of structural brain changes or higher rates of physical comorbidity.9 It may be that biological age is more relevant than chronological age.10 The presence of physical illness, as well as baseline anxiety and reduced executive functioning, is also associated with poorer treatment outcomes.11 Nonetheless, even in older people, it may still be possible to identify non- responders as early as 4 weeks into treatment.12,13 A Cochrane review examined the efficacy and associated withdrawal rates of different classes of antidepressants in older people and found that SSRIs and tricyclics have similar efficacy, but TCAs are associated with higher withdrawal rates.14 A 2022 population study found non-TCA antidepressants to have broadly similar effectiveness.15 In the UK, NICE guidance for depression in adults recommends starting with an SSRI in the first instance (sertraline is commonly used first line in older people). When switching to another antidepressant, NICE recommends switching initially to a different SSRI or a better tolerated newer-generation antidepressant (this effectively indicates mirtazapine). Subsequently, an antidepressant of a different pharmacological class that may be less well tolerated is recommended, for example venlafaxine or lofepramine.16 The OTIMUM trial17 found that augmenting with aripiprazole or bupropion was better than switching to bupropion in ‘treatment- resistant geriatric depression’. Network meta-analysis suggests that quetiapine, duloxetine, agomelatine, imipramine and vortioxetine have the highest efficacy in major depressive disorder in older people, although individual data are somewhat inconsistent.18 Two studies have found that, in older people who had recovered from an episode of depression and had received antidepressants for 2 years, over 60% relapsed within 2 years if antidepressant treatment was withdrawn.19,20 Some of this relapse may have been a result of the speed and method of antidepressant discontinuation.21 Deprescribing antidepressants in older people presents a particular conundrum. Effective treatment should usually be continued, especially if depression was severe or recurrent. Ineffective treatment (i.e. was never effective or has become ineffective) should usually be withdrawn owing to the risk of adverse effects and interaction with polypharmacy regimens.22

Prescribing in older people CHAPTER 6 There is no ideal antidepressant in older people; all are associated with problems. TCAs are broadly considered to be agents of last resort owing to the increased risk of cardiac conduction abnormalities and because of anticholinergic effects. Although SSRIs are generally better tolerated than TCAs14 they do, however, increase the risk of gastrointestinal bleeds, particularly in the very old and those with established risk factors such as a history of bleeds or who are on treatment with an NSAID, steroid or warfarin. The risk of other types of bleed such as haemorrhagic stroke may also be increased23,24 (see Chapter 3). In older people, this increase in risk of stroke may persist after cessation of antidepressants.25 Older people are also particularly prone to develop hyponatraemia26 when starting SSRIs and most other antidepressants (see Chapter 3), as well as postural hypotension and falls27 (the clinical consequences of which may be increased by SSRI-induced osteopenia28). TCAs may also increase fracture risk.29 Table 6.8 summarises the use of antidepressants in older adults. Trazodone was once widely used in elderly populations30 but sedation and postural hypotension may be dose limiting. It retains some utility in depression occurring in dementia.31 Agomelatine is effective in older patients, is well tolerated and has not been linked to hyponatraemia.32,33 Its use is limited by the need for frequent blood sampling to check LFTs. Vortioxetine and duloxetine have also been shown to be effective and reasonably well tolerated in the older person34 but the caveats related to SSRIs are relevant here. A general practice database study found that, compared with SSRIs, ‘other antidepressants’ (venlafaxine, mirtazapine, etc.) were associated with a greater risk of a number of potentially serious adverse effects in the old (stroke/transient ischaemic attack [TIA], fracture, seizures, attempted suicide/self-harm) as well as increased all- cause mortality.26 However, SSRIs showed the highest risk for falls and hyponatraemia. All classes of antidepressant were associated with an increased risk of a range of adverse outcomes compared with no use. The study was observational and so could not separate the effect of antidepressants from any increased risk inherent in the group of patients treated with these antidepressants. Polysaturated fatty acids (fish oils) may be helpful in mild to moderate depression (compared with placebo),35 as may memantine.36 Methylphenidate seems effective in older people37 and may be useful where a rapid onset of action is required. There is some evidence that esketamine and ketamine are rapidly effective in people over 65 (without worsening cognition).38,39 The effect of antidepressants on cognition in later life is still debated – some studies find antidepressants to worsen cognitive outcomes,40–42 others find no effect.43 The choice of antidepressant may affect the risk – highly anticholinergic medicines undoubtedly worsen cognition and are known to increase the likelihood of developing dementia.44 Depression in dementia is probably best treated by cognitive or physical therapies rather than antidepressants.45 Antidepressants are of doubtful benefit.45–48 The same might be said for their use in the treatment of MCI in older people.49 Ultimately, choice is determined by the individual clinical circumstances of each patient, particularly physical comorbidity and concomitant medication (both prescribed and ‘over the counter’).

Table 6.8 Antidepressants and older people. Anticholinergic side effects (urinary retention, dry mouth, blurred vision, constipation) Postural hypotension Sedation Weight gain Safety in overdose Other side effects Drug interactions Older tricyclics50 Moderate to severe with all TCAs All can also cause central anticholinergic effects (confusion, impaired cognition) All can cause postural hypotension Dosage titration is required Variable: from moderate with imipramine to profound with amitriptyline All tricyclics can cause weight gain All are toxic in overdose (seizures, cardiac arrhythmia) Seizures, anticholinergic-induced cognitive impairment Increased risk of bleeds with serotonergic drugs Mainly pharmacodynamic: increased sedation with benzodiazepines, increased hypotension with diuretics, increased constipation with other anticholinergic drugs, etc. Lofepramine Moderate, although constipation/sweating can be severe Can be a problem but generally better tolerated than older tricyclics Minimal Few data, but lack of spontaneous reports may indicate less potential than older tricyclics Relatively safe Raised LFTs Less likely to cause hyponatraemia than other TCAs and SSRIs SSRIs50,51 Dry mouth with paroxetine – probably best avoided in older people Unlikely, but an increased risk of falls is documented with SSRIs Sometimes seen with paroxetine and fluvoxamine Unlikely with the other SSRIs Paroxetine and possibly citalopram may cause weight gain Others are weight neutral Safe with the possible exceptions of citalopram and escitalopram which have the greatest effect on QT. Still much less toxic than TCAs GI effects and headaches, hyponatraemia, increased risk of bleeds in the older person (add gastroprotection if also on an NSAID or aspirin), orofacial dyskinesia with paroxetine, cognitive impairment,41 interstitial lung disease52,53 Fluvoxamine, fluoxetine and paroxetine are potent inhibitors of several hepatic cytochrome enzymes (see Chapter 3). Sertraline is safer and citalopram, escitalopram and vortioxetine are safest.

Mirtazapine, mianserin and trazodone are sedative with significant hangover in older people Venlafaxine, duloxetine have neutral effects Agomelatine aids sleep Venlafaxine and duloxetine can cause hypotension at lower doses, but usually increase BP at higher doses Occasional postural hypotension with trazodone Dizziness common with agomelatine Others54,55 Minimal with mirtazapine, trazodone and venlafaxine* Can be observed with reboxetine* Duloxetine* – few effects Agomelatine has no anticholinergic potential *Noradrenergic drugs may produce ‘anticholinergic’ effects via norepinephrine reuptake inhibition. GI, gastrointestinal; TCA, tricyclic antidepressant. Insomnia and hypokalaemia with reboxetine Nausea with venlafaxine and duloxetine Weight loss and nausea with duloxetine Possibly hepatotoxicity with agomelatine – monitor LFTs Cognitive impairment reported with trazodone41 but may be no worse than other antidepressants56 Venlafaxine is more toxic in overdose than SSRIs, but safer than TCAs Others are relatively safe Highest risk with mirtazapine, although older people are not particularly prone to weight gain Low incidence with agomelatine Duloxetine inhibits CYP2D6 Moclobemide and venlafaxine inhibit CYP450 enzymes. Check for potential interactions. Reboxetine has a low interaction potential. Agomelatine should be avoided in patients who take potent CYP1A2 inhibitors. Interstitial lung disease with SNRIs53

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28 - References

References

692 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 References

Katona C, et al. Impact of screening old people with physical illness for depression? Lancet 2000; 356:91–92.
Lyketsos CG. Depression and diabetes: more on what the relationship might be. Am J Psychiatry 2010; 167:496–497.
Gallo JJ, et al. Long term effect of depression care management on mortality in older adults: follow-up of cluster randomized clinical trial in primary care. BMJ 2013; 346:f2570.
Naghavi M. Global, regional, and national burden of suicide mortality 1990 to 2016: systematic analysis for the Global Burden of Disease Study 2016. BMJ 2019; 364:l94.
Ryan J, et al. Late-life depression and mortality: influence of gender and antidepressant use. Br J Psychiatry 2008; 192:12–18.
Gutsmiedl K, et al. How well do elderly patients with major depressive disorder respond to antidepressants: a systematic review and single- group meta-analysis. BMC Psychiatry 2020; 20:102.
Cipriani A, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet 2018; 391:1357–1366.
Paykel ES, et al. Residual symptoms after partial remission: an important outcome in depression. Psychol Med 1995; 25:1171–1180.
Iosifescu DV, et al. Brain white-matter hyperintensities and treatment outcome in major depressive disorder. Br J Psychiatry 2006; 188:180–185.
Brown PJ, et al. Biological age, not chronological age, is associated with late-life depression. J Gerontol A Biol Sci Med Sci 2018; 73:1370–1376.
Tunvirachaisakul C, et al. Predictors of treatment outcome in depression in later life: a systematic review and meta-analysis. J Affect Disord 2018; 227:164–182.
Zilcha-Mano S, et al. Early symptom trajectories as predictors of treatment outcome for citalopram versus placebo. Am J Geriatr Psychiatry 2017; 25:654–661.
Mulsant BH, et al. What is the optimal duration of a short-term antidepressant trial when treating geriatric depression? J Clin Psychopharmacol 2006; 26:113–120.
Mottram P, et al. Antidepressants for depressed elderly. Cochrane Database Syst Rev 2006; 1:CD003491.
Hsu CW, et al. Comparative effectiveness of antidepressants on geriatric depression: real-world evidence from a population-based study. J Affect Disord 2022; 296:609–615.
National Institute for Health and Care Excellence. Depression in adults: treatment and management. NICE Guideline [NG222]. 2022 (last accessed December 2023); https://www.nice.org.uk/guidance/ng222.
Lenze EJ, et al. Antidepressant augmentation versus switch in treatment-resistant geriatric depression. N Engl J Med 2023; 388:1067–1079.
Krause M, et al. Efficacy and tolerability of pharmacological and non-pharmacological interventions in older patients with major depressive disorder: a systematic review, pairwise and network meta-analysis. Eur Neuropsychopharmacol 2019; 29:1003–1022.
Flint AJ, et al. Recurrence of first-episode geriatric depression after discontinuation of maintenance antidepressants. Am J Psychiatry 1999; 156:943–945.
Reynolds CF, III, et al. Maintenance treatment of major depression in old age. N Engl J Med 2006; 354:1130–1138.
Horowitz MA, et al. Distinguishing relapse from antidepressant withdrawal: clinical practice and antidepressant discontinuation studies. BJPsych Advances 2022; 28:297–311.
Romdhani A, et al. Discontinuation of antidepressants in older adults: a literature review. Ther Clin Risk Manag 2023; 19:291–299.
Smoller JW, et al. Antidepressant use and risk of incident cardiovascular morbidity and mortality among postmenopausal women in the Women’s Health Initiative study. Arch Intern Med 2009; 169:2128–2139.
Laporte S, et al. Bleeding risk under selective serotonin reuptake inhibitor (SSRI) antidepressants: a meta-analysis of observational studies. Pharmacol Res 2017; 118:19–32.
Ön BI, et al. Antidepressant use and stroke or mortality risk in the elderly. Eur J Neurol 2022; 29:469–477.
Coupland C, et al. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ 2011; 343:d4551.
Haddad YK, et al. A comparative analysis of selective serotonin reuptake inhibitors and fall risk in older adults. J Am Geriatr Soc 2022; 70:1450–1460.
Williams LJ, et al. Selective serotonin reuptake inhibitor use and bone mineral density in women with a history of depression. Int Clin Psychopharmacol 2008; 23:84–87.
Power C, et al. Bones of contention: a comprehensive literature review of non-SSRI antidepressant use and bone health. J Geriatr Psychiatry Neurol 2019; 33:340–352.
Fagiolini A, et al. Rediscovering trazodone for the treatment of major depressive disorder. CNS Drugs 2012; 26:1033–1049.
Fagiolini A, et al. Trazodone in the management of major depression among elderly patients with dementia: a narrative review and clinical insights. Neuropsychiatr Dis Treat 2023; 19:2817–2831.
Heun R, et al. The efficacy of agomelatine in elderly patients with recurrent major depressive disorder: a placebo-controlled study. J Clin Psychiatry 2013; 74:587–594.
Laux G. The antidepressant efficacy of agomelatine in daily practice: Results of the non-interventional study VIVALDI. Eur Psychiatry 2011; 26 Suppl 1:647.
Katona C, et al. A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int Clin Psychopharmacol 2012; 27:215–223.
Bae JH, et al. Systematic review and meta-analysis of omega-3-fatty acids in elderly patients with depression. Nutr Res 2018; 50:1–9.
Hsu TW, et al. The efficacy and tolerability of memantine for depressive symptoms in major mental diseases: a systematic review and updated meta-analysis of double-blind randomized controlled trials. J Affect Disord 2022; 306:182–189.

Prescribing in older people CHAPTER 6 37. Smith KR, et al. Methylphenidate use in geriatric depression: a systematic review. Int J Geriatr Psychiatry 2021; 36:1304–1312. 38. Ochs-Ross R, et al. Comparison of long-term efficacy and safety of esketamine nasal spray plus oral antidepressant in younger versus older patients with treatment-resistant depression: post-hoc analysis of SUSTAIN-2, a long-term open-label phase 3 safety and efficacy study. Am J Geriatr Psychiatry 2022; 30:541–556. 39. Subramanian S, et al. Ketamine for depression in older adults. Am J Geriatr Psychiatry 2021; 29:914–916. 40. Moraros J, et al. The association of antidepressant drug usage with cognitive impairment or dementia, including Alzheimer disease: a systematic review and meta-analysis. Depress Anxiety 2017; 34:217–226. 41. Leng Y, et al. Antidepressant use and cognitive outcomes in very old women. J Gerontol A Biol Sci Med Sci 2018; 73:1390–1395. 42. Chan JYC, et al. Depression and antidepressants as potential risk factors in dementia: a systematic review and meta-analysis of 18 longitudinal studies. J Am Med Dir Assoc 2019; 20:279–286.e271. 43. Carriere I, et al. Antidepressant use and cognitive decline in community-dwelling elderly people – the Three-City Cohort. BMC Med 2017; 15:81. 44. Wang YC, et al. Increased risk of dementia in patients with antidepressants: a meta-analysis of observational studies. Behav Neurol 2018; 2018:5315098. 45. Watt JA, et al. Comparative efficacy of interventions for reducing symptoms of depression in people with dementia: systematic review and network meta-analysis. BMJ 2021; 372:n532. 46. Jeong HW, et al. Vortioxetine treatment for depression in Alzheimer’s disease: a randomized, double-blind, placebo-controlled study. Clin Psychopharmacol Neurosci 2022; 20:311–319. 47. Leong C. Antidepressants for depression in patients with dementia: a review of the literature. Consult Pharm 2014; 29:254–263. 48. Costello H, et al. Antidepressant medications in dementia: evidence and potential mechanisms of treatment-resistance. Psychol Med 2023; 53:654–667. 49. Jin B, et al. Comparative efficacy and acceptability of treatments for depressive symptoms in cognitive impairment: a systematic review and Bayesian network meta-analysis. Front Aging Neurosci 2022; 14:1037414. 50. Draper B, et al. Tolerability of selective serotonin reuptake inhibitors: issues relevant to the elderly. Drugs Aging 2008; 25:501–519. 51. Bose A, et al. Escitalopram in the acute treatment of depressed patients aged 60 years or older. Am J Geriatr Psychiatry 2008; 16:14–20. 52. Deidda A, et al. Interstitial lung disease induced by fluoxetine: systematic review of literature and analysis of Vigiaccess, Eudravigilance and a national pharmacovigilance database. Pharmacol Res 2017; 120:294–301. 53. Rosenberg T, et al. The relationship of SSRI and SNRI usage with interstitial lung disease and bronchiectasis in an elderly population: a case- control study. Clin Interv Aging 2017; 12:1977–1984. 54. Raskin J, et al. Safety and tolerability of duloxetine at 60 mg once daily in elderly patients with major depressive disorder. J Clin Psychopharmacol 2008; 28:32–38. 55. Johnson EM, et al. Cardiovascular changes associated with venlafaxine in the treatment of late-life depression. Am J Geriatr Psychiatry 2006; 14:796–802. 56. Gonçalo AMG, et al. The effects of trazodone on human cognition: a systematic review. Eur J Clin Pharmacol 2021; 77:1623–1637.

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29 - Covert administration of medicines within foo

Covert administration of medicines within food and drink

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30 - Assessment of mental capacity4,6,7

Assessment of mental capacity4,6,7

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31 - Guidance on covert administration

Guidance on covert administration

694 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Covert administration of medicines within food and drink This section deals with covert medication administration within UK law only. Other countries may have different laws pertaining to this area, or indeed no laws or official guidance.1 In mental health settings it is common for patients to refuse medication. People with psychiatric disorders may lack capacity to make an informed choice about whether medication will be beneficial to them or not. In these cases, the clinical team may consider whether it would be in the patient’s best interests to administer medication covertly. This practice is known as covert administration of medicines. Guidance from the Royal Pharmaceutical Society and Royal College of Nursing2 and the Royal College of Psychiatrists3 has been published in order to protect patients from the unlawful and inappropriate administration of medication in this way. In the UK, the legal framework for such interventions is either the Mental Capacity Act (MCA)4 or, more rarely, the Mental Health Act (MHA).5 Assessment of mental capacity4,6,7 The assessment of capacity regarding medication is primarily a matter for the prescriber, usually a doctor treating the patient,4,6 or less commonly a pharmacist or nurse. Nurses and allied health professionals who are not prescribers will also have to be mindful of their own codes of professional practice and should be satisfied that the doctor’s assessment is reasonable. The assessment must be made in relation to the particular treatment proposed as part of a covert medication care plan. Capacity can vary over time and the assessment should be made at the time of the proposed treatment. The assessment should be documented in the patient’s notes and recorded in the care plan. Assessment of capacity should be conducted in line with the MCA code of practice. Guidance on covert administration If a patient has the capacity to give a valid refusal to medication and is not detainable under the MHA, their refusal should be respected. If a patient has the capacity to give a valid refusal and is either being treated under the MHA or is legally detainable under the Act, the provisions of the MHA with regard to treatment will apply (which are outside the scope of this chapter). The administration of medicines to patients who lack the capacity to consent and who are unable to appreciate that they are taking medication (e.g. unconscious patients) should not need to be carried out covertly. However, some patients who lack the capacity to consent would be aware of receiving medication if they were not deceived into thinking otherwise,7 for example a patient with moderate dementia who has no insight and does not believe they need to take medication but will take liquid medication if this is mixed with their tea without being aware of this. It is this group to whom this guidance applies. Treatment may be given to people who lack capacity if the treatment is in the patient’s best interests (Section 5, MCA4) and is proportionate to the harm to be avoided (Chapter 6.41, MCA Code of Practice7). So, there should be a clear expectation that the

Prescribing in older people CHAPTER 6 patient will benefit from covert administration, and that this will avoid significant harm (either mental or physical) to the patient or others. The treatment must be necessary to save the patient’s life, to prevent deterioration in health or to ensure an improvement in physical or mental health.4,7 Covert administration must be the least restrictive option after trying all other options. An assessment should be carried out to understand why the person is refusing to take their medicines. Alternative methods of administration (e.g. liquid formulation) and trial of different approaches in nursing care (e.g. explaining to the patient about the medicines at the time they are administered or changing the time of administration to a time of day when the patient is more alert or less distressed) should be considered.8 The decision to administer medication covertly should not be made by a single individual but through discussion with the multidisciplinary team caring for the patient and the patient’s relatives or informal carers. A Best Interests meeting should be held, except in urgent situations if the decision cannot wait, in which case a less formal decision can take place with a view to arranging a Best Interests meeting as soon as practicably possible. If it were determined at this meeting that the provision of covert medication would amount to a deprivation of liberty (where previously there was none), then an application for Deprivation of Liberty Safeguards (DoLS) authorisation should be made. Decisions regarding covert administration of medication should be carefully documented in the patient’s medical records with a clear management plan, including details of how the covert medication plan will be reviewed. This documentation must be easily accessible on viewing the person’s records and the decision should be subject to regular review. It is not necessary to have a new Best Interests meeting each time there is a change in medication. However, when covert medication is first considered, healthcare professionals should consider what types of changes in medication may be anticipated in future and should agree on the thresholds of what changes may require a new Best Interests meeting. This management plan should be recorded in the patient’s notes. If significant changes that could cause adverse effects are envisaged, then a new meeting should be held before changes are made. In deciding how often capacity assessments should be repeated, clinicians should follow the guidance within the practical guide to the MCA.6 If there is any evidence that the patient has regained capacity with regard to administration of their medication, an immediate capacity assessment must be done. Decisions in the patient’s best interest can no longer be made if they are under a DoLS authorisation for reasons including the administration of medication covertly; this part of the DoLS authorisation will no longer be valid and covert administration of medication must cease immediately. Case law9,10 has dealt with the relationship between the use of covert medication and the need for a DoLS authorisation. A person is deprived of their liberty when they are under continuous supervision and control and are not free to leave. The administration of covert medication will only in itself lead to a deprivation of liberty where that covert medication affects the person’s behaviour, mental health or it acts as a sedative to such an extent that it will deprive the person of their liberty. The use of covert medication within a care plan must be clearly identified within the DoLS assessment and authorisation.

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32 - Summary of process

Summary of process

696 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 When considering covert use of psychiatric medication the following must be considered:11

If the patient meets the criteria for the MHA, this must be used in preference to the MCA.
The MCA might be used to provide authority for covert medication for physical health whether or not the patient is detained under the MHA. The MCA can be used as authority for covert use of psychiatric medication in patients not under the MHA if the medication is necessary to prevent deterioration or ensure an improvement in the patient’s mental health and it is in the person’s best interest to receive the drug. The usual procedures for covert medication, including documentation of capacity assessment, Best Interests meeting and pharmacist’s review, should be followed.
Caution is needed in the use of medication that may sedate or reduce a patient’s physical mobility, as use of such drugs may constitute a deprivation of liberty and require the patient to be under the DoLS framework. Documentation of whether the proposed use of a covert psychiatric drug constitutes a deprivation of liberty is important. Note that if a patient is found to lack capacity to consent to the admission and does not meet the criteria for detention under the MHA, DoLS should be used, so most in-patients who lack capacity to consent to medication will already be under the MHA or DoLS, although there may be some who can consent to admission but not to medication. However, even if the patient is already under the MHA or MCA as part of their admission, there still needs to be the same approach and considerations as documented here with regard to medication being given covertly. Summary of process The process for covert administration of medicines should include: ■ ■The assurance that all efforts have been made to give medication openly in its normal form before considering covert administration. ■ ■Assessment of capacity of the patient to make a decision regarding their treatment with medication. If the patient has capacity their wishes should be respected and covert medication not administered. ■ ■A record of the examination of the patient’s capacity must be made in the clinical notes, and evidence for incapacity documented. ■ ■If the patient lacks capacity there should be a Best Interests meeting which should be attended by relevant health professionals and a person who can communicate the views and interests of the patient (family member, friend or independent mental capacity advocate). These meetings can be held virtually. If the patient has an attorney appointed under the MCA for health and welfare decisions then this person should be present at the meeting. ■ ■Those attending the meeting should ascertain whether the patient has made an ‘advance decision’ refusing a particular medication or treatment which can be used to guide decision-making.

Prescribing in older people CHAPTER 6 ■ ■The Best Interests meeting should consider whether a formal legal procedure such as the MHA or DoLS is appropriate. Discussion of the indications and use of this legislation in the context of covert medication is outside the scope of this guidance but specialist psychiatric and/or legal opinion should be sought in individual circumstances if necessary. However, the other considerations given here – including the involvement of pharmacy, the recording of medication being given covertly on the drug chart, the dispensing nurse ensuring the covert medication is taken by the patient and regular reviews – apply for all patients, whichever legal framework is being used to give medication covertly. ■ ■Medication should not be administered covertly until a Best Interests meeting has been held. If the situation is urgent, it is acceptable for a less formal discussion to occur between carer/nursing staff, prescriber and family/advocate in order to make an urgent decision, but a formal meeting should be arranged as soon as possible. ■ ■After the meeting, there should be clear documentation of the outcome of the meeting. If the decision is to use covert administration of medication, a check should be made with the pharmacy to determine whether the properties of the medications are likely to be affected by crushing and/or being mixed with food or drink.12 The medication chart and electronic prescribing and medicines administration record should be amended to describe how the medication is to be administered. ■ ■When the medication is administered in foodstuffs, it is the responsibility of the dispensing nurse to ensure that the medication is taken. This can be facilitated by direct observation or by nominating another member of the clinical team to observe the patient taking the medication. ■ ■A plan should be made to review on a regular basis the need for continued covert administration of medicines. Additional information ■ ■For patients in care homes, the NICE guideline ‘Managing medicines in care homes’ should be referred to.13,14 The basic principles of this NICE guidance are the same as the policy discussed in this section. Mental health practitioners have a duty to inform the care home manager if they suspect the correct procedures are not being followed as regards covert medication, and to discuss with their team leader possible safeguarding referral if the home manager does not act on their advice. The role of mental health teams supporting care homes is to support the care homes and prescriber (usually GP) in carrying out this guidance. For patients with complex mental health needs, it may be appropriate that they attend or contribute to the Best Interests meeting. However, it should be the prescriber (usually the GP), care home staff and care home pharmacist who manage the process. ■ ■There are no specific restrictions to state that relatives or other informal carers cannot give medication covertly and in certain cases it may be acceptable as long as they have been advised to do so by a health professional (e.g. GP) and all standards of the policy have been met. Figure 6.2 provides an algorithm for determining whether or not to administer medicines covertly.

698 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Consider second opinion or ethics forum or legal advice Is there agreement at ‘Best Interest’ discussion? Reason established and resolved Give medication as normal DO NOT GIVE: Seek alternative preparation Unable to resolve USE ALTERNATIVE No No No No No No Yes Yes Yes Yes Yes Yes Establish why the patient does not want to take medication Is medication essential? Is there a viable alternative? Does the patient have mental capacity? Yes Is there a Lasting Power of Attorney (LPA)* or Advance Decision to Refuse Treatment (ADRT)? DO NOT GIVE DO NOT GIVE DO NOT GIVE Does attorney or ADRT prevent or conflict with treatment plan medication? Have pharmacy confirmed how to give covertly? Give medication covertly (ensure covert medication care plan is in place) Document and review regularly *LPA covering health and welfare decisions. NB Any deprivation of liberty would need to be authorised by a legal framework, e.g. Mental Health Act, Deprivation of Liberty Safeguards or Court of Protection, as appropriate. No Figure 6.2 Flow chart for the use of covert medication.

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33 - References

References

Prescribing in older people CHAPTER 6 References

Wikipedia. Covert medication. 2023; https://en.wikipedia.org/wiki/covert_medication.
Royal Pharmaceutical Society and Royal College of Nursing. Professional guidance on the administration of medicines in healthcare settings. 2019; https://www.rpharms.com/Portals/0/RPS%20document%20library/Open%20access/Professional%20standards/SSHM%20and%20 Admin/Admin%20of%20Meds%20prof%20guidance.pdf?ver=2019-01-23-145026-567.
Royal College of Psychiatrists. College statement on covert administration of medicines. Psychiatric Bull 2004; 28:385–386.
Office of Public Sector Information. Mental Capacity Act 2005 – Chapter 9. 2005; http://www.legislation.gov.uk/ukpga/2005/9/pdfs/ ukpga_20050009_en.pdf.
The National Archives. Mental Health Act 2007. 2007; http://www.legislation.gov.uk/ukpga/2007/12/contents.
British Medical Association and the Law Society. Assessment of Mental Capacity. A Practical Guide for Doctors and Lawyers, 4th edn. London: Law Society Publishing; 2015.
Gov.uk. Office of the Public Guardian. Mental Capacity Act Code of Practice. 2013 (last updated October 2020); https://www.gov.uk/ government/publications/mental-capacity-act-code-of-practice.
Care Quality Commission. Covert administration of medicines. 2020; https://www.cqc.org.uk/guidance-providers/adult-social-care/ covert-administration-medicines.
Medication Training Company. Covert administration of medicines. Recent Court of Protection ruling on covert medication – 6th July 2016. 2016; https://medicationtraining.co.uk/covert-administration-medicines/.
Doughty Street Chambers. Covert medication of persons lacking capacity. What guidance is there? 2023; https://insights.doughtystreet.co.uk/ post/102i743/covert-medication-of-persons-lacking-capacity-what-guidance-is-there.
Care Quality Commission. Brief guide: covert medication in mental health services. 2018 (reviewed 2019); https://www.cqc.org.uk/sites/ default/files/20180406_9001398_briefguide-covert_medication_mental_health_v2.pdf.
Specialist Pharmacy Service. Covert administration of medicines in adults: pharmaceutical issues. 2022 (last updated June 2023); https:// www.sps.nhs.uk/articles/covert-administration-of-medicines-in-adults-pharmaceutical-issues/.
National Institute for Health and Care Excellence. Managing medicines in care homes. Social Care Guideline [SC1]. 2014 (last updated 2020); https://www.nice.org.uk/guidance/sc1.
PrescQIPP. Bulletin 101. Best practice guidance in covert administration of medication. 2015; https://www.prescqipp.info/umbraco/surface/ authorisedmediasurface/index?url=%2fmedia%2f1174%2fb101-covert-administration-21.pdf.

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34 - A guide to medication doses of commonly used

A guide to medication doses of commonly used psychotropics in older adults, [1] / National Institute for Health and Care Excellence (NICE).

700 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 A guide to medication doses of commonly used psychotropics in older adults, [1] / National Institute for Health and Care Excellence (NICE). Drug Specific indication/ additional notes Starting dose Usual maintenance dose Maximum dose in elderly Antidepressants Agomelatine Depression Monitor LFTs Data suggest agomelatine is not effective in patients

75 years 25mg nocte 25–50mg daily 50mg nocte Bupropion2 Depression Immediate release tablets: 100mg bd2 Sustained release tablets (SR): 150mg once daily2 Extended-release tablets (XL): 150mg once daily2 May increase to 100mg tds after 3 days2 May increase dose to 150mg SR twice daily after 3 days2 May increase dose to 300mg XL once daily after at least 4 days2 300mg/day* Consider reduced dosage and/or dosage frequency in patients with a CrCl <90mL/min2 Bupropion and dextromethorphan3 Depression Each tablet contains 45mg dextromethorphan hydrobromide (equivalent to 32.98mg dextromethorphan base) in an immediate-release formulation and 105mg bupropion hydrochloride (equivalent to 91.14mg bupropion base) in an XL formulation.3 1 tablet mane3 1 tablet bd (at least 8 hours apart; dose can be increased to bd after 3 days)3 Reduced dosage of 1 tablet mane is recommended for patients with moderate kidney impairment (eGFR 30–59mL/ min/1.73m2), those known to be poor CYP2D6 metabolisers and when co-administered with strong CYP2D6 inhibitors. Concomitant use with strong CYP2B6 inducers should be avoided. 1 tablet bd3 Citalopram Depression/anxiety disorder 10mg mane 10–20mg mane 20mg mane Clomipramine Depression/phobic and obsessional states 10mg nocte (dose increases should be cautious) 30–75mg daily4 should be reached after about 10 days. 75mg daily4

Prescribing in older people CHAPTER 6 Drug Specific indication/ additional notes Starting dose Usual maintenance dose Maximum dose in elderly Desvenlafaxine5 Major depression No formal recommendations are available for dosing in older adults.5 However, possible reduced renal clearance of desvenlafaxine should be considered when determining an appropriate dose. 50mg daily Dosage in renal impairment: CrCl 50–80mL/ min: no dosage adjustment needed CrCl 30–50mL/ min: 50mg daily is recommended daily and max. dose CrCl <30mL/min or ESRD: 50mg every other day is recommended daily and max. dose 50mg daily Usual dose 50mg/ day Max. dose 400mg daily5 however no additional benefit was demonstrated at doses >50mg/ day and adverse reactions and discontinuations were more frequent at higher doses. Duloxetine Depression/anxiety disorder 30mg daily* 60mg daily 120mg daily6 (caution as limited data in elderly for this dose) Escitalopram Depression/anxiety disorder 5mg mane 5–10mg mane 10mg mane Fluoxetine Depression/anxiety disorder Caution as long half-life and inhibitor of several CYP enzymes 20mg mane 20mg mane 40mg mane usually (but 60mg can be used) Lofepramine Depression 35mg nocte* 70mg nocte* 140mg nocte or in divided doses* (occasionally 210mg nocte required) Mirtazapine Depression 7.5mg nocte or usually 15mg nocte* 15–30mg nocte 45mg nocte Sertraline Depression/anxiety disorder 25–50mg mane (25mg can be increased to 50mg mane after 1 week) 50–100mg mane* 100mg (occasionally up to 150mg mane)* Trazodone Depression 100mg daily in divided doses or as a single night time dose7 100–200mg daily* 300mg daily7 (Continued )

702 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Drug Specific indication/ additional notes Starting dose Usual maintenance dose Maximum dose in elderly Agitation in dementia Avoid single doses

100mg 25mg bd* 25–100mg daily* 200mg daily* (in divided doses) Venlafaxine Depression/anxiety disorder Monitor BP on initiation 37.5mg mane (increased to 75mg XL mane after 1 week)* 75–150mg (XL) mane* 150mg daily (occasionally 225mg daily is necessary)* Vortioxetine8 Major depressive disorder Vortioxetine is extensively metabolised in the liver, primarily by CYP2D6 and to a minor extent by CYP3A4/5 and CYP2C9. Co-administration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. 5mg daily 5–10mg daily 10mg daily Caution advised in ≥65 years with doses >10mg daily for which data are limited8 Antipsychotics† Amisulpride Chronic schizophrenia 50mg daily* 100–200mg daily* 400mg daily9 (caution >200mg daily)* Late life psychosis 25–50mg daily* 50–100mg daily* (increase in 25mg steps) 200mg daily10 (caution >100mg daily)* Agitation/psychosis in dementia Caution QTc prolongation 25mg nocte11 25–50mg daily11 50mg daily11 Aripiprazole Schizophrenia, mania (oral) 5mg mane* 5-15mg daily* 20mg mane* Control of agitation (IM injection) 5.25mg* 5.25–9.75mg* 15mg daily* (combined oral + IM) Brexpiprazole12 Schizophrenia12 Metabolism is primarily mediated by CYP3A4 and CYP2D6. Co-administration of certain drugs may need to be avoided or dosage adjustments may be necessary. 0.5mg once daily On day 5 may increase to 1mg once daily On day 8 may further increase to 2mg daily 4mg daily Max. 3mg/day if CrCl <60mL/min, including ESRD12

Prescribing in older people CHAPTER 6 Drug Specific indication/ additional notes Starting dose Usual maintenance dose Maximum dose in elderly Further titration may be made weekly in 1mg increments based on response and tolerability. Recommended range: 2–4mg once daily12 Depression (adjunctive treatment) 0.5 once daily12 Target dose 2mg once daily. Titrate dosage at weekly intervals based on response and tolerability.12 3mg/day12 Max. 2mg/day if CrCl <60mL/min, including ESRD12 Agitation in Alzheimer’s disease 0.5mg once daily12 On day 8 increase dose to 1mg once daily for an additional 7 days. On day 15 increase to 2mg po once daily, the recommended target dose. May increase to 3mg once daily after at least 14 more days based on clinical response and tolerability.12 3mg/day12 Max. 2mg/day if CrCl <60mL/min, including ESRD12 Cariprazine13 Schizophrenia Cariprazine and its major active metabolites are highly protein bound and extensively metabolised by CYP3A4 and, to a lesser extent, by CYP2D6. Co-administration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. 1.5mg once daily13 May increase to 3mg once daily on day 2 Make further dose adjustments in 1.5mg increments based on response and tolerability.13 Effective range: 1.5–6mg po once daily14 6mg/day14 (Continued )

704 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Drug Specific indication/ additional notes Starting dose Usual maintenance dose Maximum dose in elderly Mania or mixed episodes of bipolar disorder 1.5mg once daily14 May increase to 3mg once daily on day 2 Adjust dose by 1.5–3mg/day based on clinical response and tolerability Usual dose: 3–6mg/day14 6mg/day for acute mania14 Bipolar depression and adjunctive treatment of major depressive disorder 1.5mg once daily14 May increase dose to 3mg/day after 2 weeks based on clinical response and tolerability14 3mg/day14 BPSD Dose not yet established14 Clozapine Schizophrenia 6.25–12.5mg daily,15,16 increased by no more than 6.25–12.5mg once or twice a week15 50–100mg daily15,16 100mg daily15,16 Parkinson’s related psychosis 6.25mg daily17 25–37.5mg daily17 50mg daily17 IM injection The oral bioavailability of clozapine is about half that of the IM injection (e.g. 50mg daily of the IM injection is roughly equivalent to 100mg daily of the tablets/oral solution). After each injection has been given the patient must be observed every 15 minutes for the first 2 hours to check for excess sedation. NB If IM lorazepam is required, leave at least 1 HOUR between administration of IM clozapine and IM lorazepam. Iloperidone No formal recommendations are available for dosing in older adults18 Lumateperone19 Schizophrenia 42mg daily (equivalent to 60mg lumateperone tosylate) Dose titration not required 42mg daily 42mg daily Lurasidone Schizophrenia 37mg once daily (or 18.5mg daily when given with concomitant moderate CYP3A4 inhibitors, max. dose 74mg once daily) 18.5–111mg daily20 Limited data on higher doses used in older adults. No data are available in elderly people treated with 148mg. Caution should be exercised when treating patients ≥65 years of age with higher doses.20

Prescribing in older people CHAPTER 6 Drug Specific indication/ additional notes Starting dose Usual maintenance dose Maximum dose in elderly Dosing for elderly with normal renal function (CrCl ≥80mL/min) is the same as for adults with normal renal function. In diminished renal function, dose adjustments may be required according to their renal function status.20 Olanzapine Schizophrenia 2.5mg nocte* 5–10mg daily* 15mg nocte16 Agitation/psychosis in dementia 2.5mg nocte* 2.5–10mg daily* 10mg nocte* (optimal dose is 5mg daily)16 Olanzapine and samidorphan No formal recommendations are available for dosing in older adults.21 Pimavanserin22,23 Treatment of hallucinations and delusions associated with Parkinson’s disease psychosis 34mg daily (or 10mg daily if co-administered with strong CYP3A4 inhibitors) Dose titration not required 34mg daily (or 10mg daily if co- administered with strong CYP3A4 inhibitors) 34mg daily (or 10mg daily if co-administered with strong CYP3A4 inhibitors) Monitor patients for reduced efficacy if used concomitantly with strong CYP3A4 inducers. Quetiapine Schizophrenia 12.5–25mg daily16 75–125mg daily15 200–300mg daily16 Agitation/psychosis in dementia 12.5–25mg daily* 50–100mg daily* 100–300mg daily16 Risperidone Psychosis 0.5mg bd (0.25–0.5mg daily in some cases)16 1–2.5mg daily15 4mg daily Late-onset psychosis 0.5mg daily* 1mg daily* 2mg daily* (optimal dose is 1mg daily) Agitation/psychosis in dementia 0.25mg daily* or bd 0.5mg bd 2mg daily (optimal dose is 1mg daily)16 (Continued )

706 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Drug Specific indication/ additional notes Starting dose Usual maintenance dose Maximum dose in elderly Haloperidol Psychosis/mania associated with bipolar disorder/delirium 0.25–0.5mg daily15 1–3.5mg daily15 Caution >3.5mg – assess tolerability and ECG Max. 5mg/day (oral) Max. 5mg/day (IM) Doses >5mg/day should only be considered in patients who have tolerated higher doses and after reassessment of the patient’s individual benefit–risk profile Agitation Avoid in older adults (except in delirium) owing to risk of QTc prolongation. 0.25–0.5mg daily* 0.5–1.5mg daily or bd Long-acting conventional antipsychotic drugs† Flupentixol decanoate Test dose: 5–10mg After at least 7 days of test dose: 10–20mg every 2–4 weeks* Dose increased gradually according to response and tolerability in steps of 5–10mg every 2 weeks* 40mg every 2 weeks* (extend frequency to every 3-–4 weeks if EPSE develop) Occasionally up to 50 or 60mg every 2 weeks* may be used if tolerated Fluphenazine decanoate Caution – high risk of EPSE Test dose: 6.25mg After 4–7 days of test dose: 12.5–25mg every 2-4 weeks Dose increased gradually according to response and tolerability in steps of 12.5mg every 2–4 weeks* 50mg every 4 weeks* Haloperidol decanoate Risk of EPSE and QTc prolongation No test dose 12.5–25mg every 4 weeks 12.5–25mg every 4 weeks 50mg every 4 weeks* Pipotiazine palmitate Test dose: 5–10mg 25–100mg every 4 weeks 100mg every 4 weeks* Zuclopenthixol decanoate Test dose: 25–50mg After at least 7 days of test dose: 50–200mg every 2–4 weeks* 200mg every 2 weeks*

Prescribing in older people CHAPTER 6 Drug Specific indication/ additional notes Starting dose Usual maintenance dose Maximum dose in elderly Long-acting atypical antipsychotic drugs† Aripiprazole (long-acting injection24) One injection start No detectable effect of age on pharmacokinetics24 One injection of 400mg and continue treatment with oral dose 10–20mg/day for 14 days One injection of 300mg in frail individuals or poor metabolisers of CYP2D6 (and continue with prescribed oral dose for 14 days) One injection of 200mg used for patients known to be CYP2D6 poor metabolisers or concomitantly use a strong CYP3A4 inhibitor (and continue with prescribed oral dose for 14 days) 400mg monthly (reduce to 300mg/ month if adverse effects) 300mg monthly in frail individuals or poor metabolisers of CYP2D6 400mg monthly (reduce to 300mg/ month if adverse effects) 300mg monthly in frail individuals or poor metabolisers of CYP2D6 Two injection start (two injection start not to be used in patients who are known to be CYP2D6 poor metabolisers and concomitantly use a strong CYP3A4 inhibitor) Two separate injections of 400mg at separate injection sites along with one 10–20mg dose of oral aripiprazole Two injections of 300mg in frail individuals or poor metabolisers of CYP2D6 (along with one single dose of the previous prescribed dose of oral aripiprazole) 400mg monthly (reduce to 300mg/ month if adverse effects) 300mg monthly in frail individuals or poor metabolisers of CYP2D6 400mg monthly (reduce to 300mg/ month if adverse effects) 300mg monthly in frail individuals or poor metabolisers of CYP2D6 (Continued )

708 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Drug Specific indication/ additional notes Starting dose Usual maintenance dose Maximum dose in elderly Olanzapine pamoate25 Has not been systematically studied in elderly patients (>65 years). Not recommended for treatment in the elderly population unless a well-tolerated and effective dose regimen using oral olanzapine has been established. A lower starting dose (150mg/4 weeks) is not routinely indicated but should be considered for those 65 and over when clinical factors warrant. Not recommended to be started in patients >75 years. Paliperidone palmitate Dose based on renal function Because elderly patients may have diminished renal function, they are dosed as in mild renal impairment even if tests show normal renal function.* Loading doses: day 1: 100mg day 8: 75mg (lower loading doses may be appropriate in some)* 25–100mg monthly* 100mg monthly* Paliperidone palmitate 3-monthly injection Dose based on renal function Because elderly patients may have diminished renal function, they are dosed as in mild renal impairment even if tests show normal renal function.* If the last dose of 1-monthly paliperidone palmitate injectable is: 50mg 75mg 100mg Initiate the 3-monthly injection at the following doses: 175mg 263mg 350mg (There is no equivalent dose for the 25mg dose of 1-monthly paliperidone palmitate injection).26 350mg 3-monthly* Paliperidone palmitate 6-monthly injection27 Dose based on renal function Because elderly patients may have diminished renal function, they are dosed as in mild renal impairment even if tests show normal renal function.* Patients adequately treated with 1-monthly paliperidone palmitate injection 100mg (preferably for 4 months or more) or 3-monthly paliperidone palmitate injection at 350mg (for at least one injection cycle) may be transitioned to 6-monthly paliperidone palmitate injection 700mg 700mg every 6 months* There are no equivalent doses of 6-monthly paliperidone palmitate for the 25, 50 or 75mg doses of 1-monthly injection, nor for the 175 or 263 mg 3-monthly injection. 700mg every 6 months*

Prescribing in older people CHAPTER 6 Drug Specific indication/ additional notes Starting dose Usual maintenance dose Maximum dose in elderly Risperidone long-acting injection Monitor renal function 25mg every 2 weeks 25mg every 2 weeks 25mg every 2 weeks Consider 37.5mg every 2 weeks in patients treated with oral risperidone doses

4mg/day28 Mood stabilisers Carbamazepine Bipolar disorder Caution – drug interactions Check LFTs, FBC and U Es; consider checking plasma levels. 50mg bd or 100mg bd* 200–400mg/day* 600–800mg/day* Lamotrigine Bipolar disorder (titration as in young adults) Check for interactions and make appropriate dose alterations (see BNF). 25mg daily (monotherapy) Increase by 25mg steps every 14 days 200mg/day* 25mg on alternate days (if with valproate) Increase by 25mg steps every 14 days 100mg/day* 50mg daily (if with carbamazepine) Increase by 50mg steps every 14 days 100mg bd* Lithium carbonate modified release Bipolar disorder Mania/depression Caution – drug interactions Check renal and thyroid function and regularly monitor plasma levels. 100–200mg nocte* 200–600mg daily* 600–1200mg daily (aim for plasma levels 0.4–0.7mmol/L in elderly)29 Sodium valproate Bipolar disorder Check LFTs and consider checking plasma levels. Sodium valproate: 100–200mg bd* Semi-sodium valproate: 250mg daily or bd* Sodium valproate: 200–400mg bd* Semi-sodium valproate: 500mg to 1g daily* Sodium valproate: 400mg bd* Semi-sodium valproate: 1g daily* Agitation in dementia (not licensed and not recommended) Check response, tolerability and plasma levels for guide. Sodium valproate: 50mg bd (liquid) or 100mg bd* Sodium valproate: 100–200mg bd* Sodium valproate: 200mg bd* (Continued )

710 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 Drug Specific indication/ additional notes Starting dose Usual maintenance dose Maximum dose in elderly Anxiolytics/hypnotics Clonazepam Agitation 0.5mg daily 1–2mg/day* 4mg/day* Daridorexant30 Insomnia Taken within 30 minutes before going to bed, with at least 7 hours remaining prior to planned awakening 25mg nocte 25–50mg nocte 50mg nocte Diazepam Agitation 1mg tds 1mg tds* 7.5–15mg/day in divided doses (for anxiety) Lemborexant31 Insomnia 5mg nocte (take no more than once per night, immediately before bed) 5–10mg nocte 10mg nocte Elderly are at a higher risk of falls. Caution when using doses >5mg in patients ≥65 years old The maximum recommended dose is 5mg nocte when co-administered with weak CYP3A inhibitors or in moderate hepatic impairment (avoid in severe hepatic impairment). Lorazepam PRN only – avoid regular use due to short half-life and risk of dependence 0.5mg daily 0.5–2mg daily* 2mg/day Melatonin Insomnia – short-term use (up to 13 weeks) 2mg (modified release) once daily (1–2 hours before bedtime) 2mg once daily Occasionally 10mg/day (modified release) has been used successfully in dementia Pregabalin Generalised anxiety disorder Dose adjustment based on renal function (see product information)32 Usually 25mg bd (increase by 25mg bd weekly) Up to 75mg bd (if healthy and normal renal function) Usually 150mg daily* Up to 150mg bd (if healthy and normal renal function) 150–300mg/day*

11 - Chapter 6 Prescribing in older people

35 - References

References

Prescribing in older people CHAPTER 6 Drug Specific indication/ additional notes Starting dose Usual maintenance dose Maximum dose in elderly Zolpidem Insomnia (short-term use – up to 4 weeks) 5mg nocte 5mg nocte 5mg nocte Zopiclone Insomnia (short-term use – up to 4 weeks) 3.75mg nocte 3.75–7.5mg nocte 7.5mg nocte Where no references were given the British National Formulary (BNF) October 20231 was used. *There is no specific information available in the literature for these drug doses in elderly patients. The doses stated are a guide only. Where there are no data, the maximum doses are conservative and may be exceeded if the drug is well tolerated and following clinician’s assessment. †NB All antipsychotic drugs contain warnings for increased mortality in elderly patients with dementia. bd, twice a day; BPSD, behavioural and psychological symptoms of dementia; CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; EPSE, extrapyramidal side effects; ESRD, end-stage renal disease; mane, in the morning; nocte, at night; po, by mouth; prn, as required; tds, three times a day. References

Joint Formulary Committee. British National Formulary (online). London: BMJ and Pharmaceutical Press; http://www.medicinescomplete.com.
Prescribers’ Digital Reference (PDR) by Connective Rx®. Bupropion – drug summary. 2023 (last assessed October 2023); https://www.pdr.net/ drug-summary/?drugLabelId=237.
Keam SJ. Dextromethorphan/bupropion: first approval. CNS Drugs 2022; 36:1229–1238.
Mylan. Summary of product characteristics. Clomipramine 25mg capsules, hard. 2021 (last checked December 2023); https://www.medicines. org.uk/emc/medicine/33260.
Prescribers’ Digital Reference (PDR) by Connective Rx®. Desvenlafaxine – drug summary. 2023 (last accessed October 2023); https://www. pdr.net/drug-summary/?drugLabelId=3333.
Eli Lilly and Company Ltd. Summary of product characteristics. Cymbalta 30mg, 60mg hard gastro-resistant capsules. 2023; https://www. medicines.org.uk/emc/medicine/15694.
Zentiva. Summary of product characteristics. Molipaxin 100mg/trazodone 100mg capsules. 2021 (last checked December 2023); https://www.medicines.org.uk/emc/medicine/26734.
Lundbeck Ltd. Summary of product characteristics. Brintellix 10mg film-coated tablets (vortioxetine). 2023; https://www.medicines.org.uk/ emc/product/10441/smpc;%202022.
Muller MJ, et al. Amisulpride doses and plasma levels in different age groups of patients with schizophrenia or schizoaffective disorder. J Psychopharmacol 2009; 23:278–286.
Psarros C, et al. Amisulpride for the treatment of very-late-onset schizophrenia-like psychosis. Int J Geriatr Psychiatry 2009; 24:518–522.
Clark-Papasavas C, et al. Towards a therapeutic window of D2/3 occupancy for treatment of psychosis in Alzheimer’s disease, with [18F] fallypride positron emission tomography. Int J Geriatr Psychiatry 2014; 29:1001–1009.
Prescribers’ Digital Reference (PDR) by Connective Rx®. Brexpiprazole – drug summary. 2023 (last accessed October 2023); https://www. pdr.net/drug-summary/?drugLabelId=3759.
Prescribers’ Digital Reference (PDR) by Connective Rx®. Cariprazine – drug summary. 2023 (last accessed October 2023); https://www.pdr. net/drug-summary/?drugLabelId=3792.
Szatmári B, et al. Cariprazine safety in adolescents and the elderly: analyses of clinical study data. Front Psychiatry 2020; 11:61.
Jeste DV, et al. Conventional vs. newer antipsychotics in elderly patients. Am J Geriatr Psychiatry 1999; 7:70–76.
Karim S, et al. Treatment of psychosis in elderly people. Adv Psychiatr Treat 2005; 11:286–296.
Parkinson Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. N Engl J Med 1999; 340:757–763.
Caccia S, et al. New atypical antipsychotics for schizophrenia: iloperidone. Drug Des Devel Ther 2010; 4:33–48.
Intra-Cellular Therapies, Inc. Highlights of prescribing information. CAPLYTA (lumateperone) capsules, for oral use. 2019; https://www. accessdata.fda.gov/drugsatfda_docs/label/2019/209500s000lbl.pdf.
CNX Therapeutics Ltd (formerly Sunovion Pharmaceuticals Europe). Summary of product characteristics. Latuda 18.5mg, 37mg and 74mg film-coated tablets. 2022 (last checked December 2023); https://www.medicines.org.uk/emc/product/3299/smpc.
Alkermes, Inc. Highlights of prescribing information. LYBALVI® (olanzapine and samidorphan) tablets, for oral use. 2023; https://www. lybalvi.com/lybalvi-prescribing-information.pdf.
ACADIA Pharmaceuticals, Inc. Highlights of prescribing information. Nuplazid (pimavanserin) tablets for oral use. 2016; https://www. accessdata.fda.gov/drugsatfda_docs/label/2016/207318lbl.pdf.
Prescribers’ Digital Reference (PDR) by Connective Rx®. Pimavanserin – drug summary. 2023 (last accessed October 2023); https://www. pdr.net/drug-summary/?drugLabelId=3909#dosing-considerations.

712 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 6 24. Otsuka Pharmaceuticals (UK) Ltd. Summary of product characteristics. Abilify Maintena 300mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe (aripiprazole). 2022 (last checked December 2023); https://www.medicines.org.uk/emc/ product/12955/smpc%202022. 25. Eli Lily and Company Ltd. Summary of product characteristics. Zypadhera 210mg powder and solvent for prolonged release suspension for injection (olanzapine). 2023; https://www.medicines.org.uk/emc/product/6429/smpc. 26. Janssen-Cilag Ltd. Summary of product characteristics. TREVICTA 175mg, 263mg, 350mg, 525mg prolonged release suspension for injection (paliperidone). 2023; https://www.medicines.org.uk/emc/medicine/32050. 27. Janssen-Cilag Ltd. Summary of product characteristics. Byannli 700mg prolonged-release suspension for injection in pre-filled syringe (paliperidone). 2023; https://www.medicines.org.uk/emc/product/13307/smpc. 28. Janssen-Cilag Ltd. Summary of product characteristics. RISPERDAL CONSTA 25mg powder and solvent for prolonged-release suspension for intramuscular injection (risperidone). 2022 (last checked December 2023); https://www.medicines.org.uk/emc/medicine/9939. 29. Essential Pharma Ltd. Summary of product characteristics. Camcolit 400mg controlled release lithium carbonate. 2023; https://www.medicines. org.uk/emc/product/10829/smpc. 30. Idorsia Pharmaceuticals US, Inc. Highlights of prescribing information. QUVIVIQ (daridorexant) tablets, for oral use (controlled substance schedule pending). 2022 (last checked December 2023); https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214985s000lbl.pdf. 31. Eisai, Inc. Medication guide. DAYVIGO™ (lemborexant) tablets, for oral use (controlled substance schedule pending). 2019; https://www. accessdata.fda.gov/drugsatfda_docs/label/2019/212028s000lbl.pdf#page=21. 32. Upjohn UK Ltd. Summary of product characteristics. Lyrica (pregabalin) 25mg, 50mg, 75mg, 100mg, 150mg, 200mg, 225mg, 300mg capsules. 2023; https://www.medicines.org.uk/emc/product/10303/smpc.

12 - Chapter 7 Prescribing in pregnancy and breastfeedi

01 - Drug choice in pregnancy

Drug choice in pregnancy

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 7 Drug choice in pregnancy A ‘normal’ outcome to pregnancy can never be guaranteed. The spontaneous abortion rate in confirmed early pregnancy is 10–20%, and the risk of major malformation in the newborn is 2–3% (approximately 1 in 40 pregnancies).1 Lifestyle factors, such as smoking cigarettes, poor diet and drinking alcohol during pregnancy, can have adverse consequences for the fetus. Pre-pregnancy obesity increases the risk of neural tube defects and is associated with risk factors for the mother. Psychiatric illness during pregnancy is an independent risk factor for congenital malformations, stillbirths and neonatal deaths2 and perinatal mental disorders are associated with a broad range of negative child outcomes, many of which can persist into late adolescence.3 Severe mental illness is also associated with increased risk of obstetric near misses (life-threatening obstetric complications).4 The safety of psychotropics in pregnancy cannot be clearly established because robust, prospective trials are unethical and long-term observational studies are challenging to undertake. Data are derived from database studies (many of which fail to control for confounders such as the impact of maternal mental illness, use of illicit drugs and alcohol, smoking, obesity and other medications), limited prospective data from teratology information centres and published case reports. For many drugs, the perceived association or otherwise with adverse outcomes changes over time, as more information is gathered and analysed. The patient’s view of risks and benefits has paramount importance and needs to be informed by up-to-date evidence. Clinicians should be aware of the importance of prescribing medication to women with a severe mental illness. Perinatal suicides are notable for being associated with lack of active treatment, specifically the lack of treatment with psychotropic medication.5 The American College of Obstetricians and Gynecologists (ACOG) warns against withholding or discontinuing medications for mental health conditions because of pregnancy or lactation status alone.6 Box 7.1 provides a brief summary of the relevant issues and evidence available in early 2024. Prescribing in pregnancy and breastfeeding

714 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 Box 7.1 General principles of prescribing in pregnancy In all women of child-bearing potential ■ ■Always discuss the possibility of pregnancy – half of all pregnancies are unplanned7 ■ ■Avoid using drugs that are contraindicated during pregnancy (notably valproate, topiramate and carbamazepine). If use of these drugs is unavoidable then women should be made fully aware of their teratogenic properties even if not planning pregnancy. In addition, the prescriber should confirm the presence of an effective and stable long-term contraceptive plan If mental illness is newly diagnosed in a pregnant woman ■ ■Consider non-pharmacological interventions ■ ■Try to avoid all drugs in the first trimester (when major organs are being formed) unless benefits clearly outweigh risks (i.e. if non-drug treatments are not effective/appropriate) ■ ■Use an established drug and use the lowest effective dose ■ ■Review current medication regimen to ensure there is a clear indication for each drug and that ineffective drugs are stopped If a woman taking psychotopic drugs is planning a pregnancy ■ ■Consideration should be given to discontinuing treatment if the woman is well and at low risk of relapse, after a careful review of her history ■ ■Discontinuation of treatment for women with severe mental illness (SMI) and at a high risk of relapse is generally unwise but consideration should be given to switching to a low-risk drug. However, be aware that switching drugs may increase the risk of relapse. Any changes must be made with caution and considered in the context of the woman’s illness history and previous response to treatment ■ ■Drug-induced hyperprolactinaemia may prevent pregnancy. Consider switching to an alternative drug if hyperprolactinaemia occurs and a pregnancy is planned ■ ■For women with SMI, pre-conception advice from a perinatal psychiatrist should be sought to ensure that women are aware of their risk of relapse in the perinatal period and are able to discuss a prospective perinatal care plan If a woman taking psychotropic medication discovers that she is pregnant ■ ■Abrupt discontinuation of treatment post-conception is unwise for women with SMI and at a high risk of relapse. Relapse may ultimately be more harmful to the mother and child than continued, effective drug therapy ■ ■Consider continuing with current (effective) medication rather than switching, to minimise the risk of relapse and the number of drugs to which the fetus is exposed ■ ■Valproate (if prescribed as a mood stabiliser) must be stopped immediately ■ ■Early pregnancy can be associated with noticeable changes in mood, therefore it may be necessary to review the medication plan at this stage to ensure symptoms are well controlled If the patient smokes (smoking is more common in pregnant women with psychiatric illness8) ■ ■Smoking has been associated with the greatest proportion of excess risk of poor pregnancy outcomes9 ■ ■Always encourage switching to nicotine replacement therapy. Referral to smoking cessation services is mandated by NICE in the UK ■ ■Vaping is probably safer than tobacco smoking but is not without risk. Nicotine replacement is probably safer than vaping10 ■ ■Stopping smoking can increase plasma levels of certain drugs (e.g. clozapine)

12 - Chapter 7 Prescribing in pregnancy and breastfeedi

02 - Psychosis during pregnancy and postpartum

Psychosis during pregnancy and postpartum

Prescribing in pregnancy and breastfeeding CHAPTER 7 Psychosis during pregnancy and postpartum Pregnancy does not protect against psychotic relapse and psychosis during pregnancy predicts postpartum psychosis.13 The incidence of postpartum psychosis is 0.1–0.25% in the general population (around 1–2 psychiatric hospitalisations per 1000 births). Women with bipolar disorder have an increased risk of postpartum psychosis with around one in five experiencing a psychotic relapse postpartum.14 There is a high risk of relapse in women with a family history of postpartum psychosis or a personal history of postpartum psychosis.15 The risk of postpartum psychosis for women with a previous episode of illness, a diagnosis of bipolar disorder type 1 or schizoaffective disorder, and genetic loading for postpartum psychosis, bipolar 1 or schizoaffective disorder, can be as high as 50%. The mental health of the mother in the perinatal period influences fetal well-being, obstetric outcome and child development. The risks of not treating psychosis include harm to the mother and harm to the fetus or neonate (ranging from neglect to infanticide). First-generation antipsychotics ■ ■Some specific malformations have been reported with individual agents. However, first-generation antipsychotics (FGAs) are unlikely to be major teratogens.16 ■ ■Most initial data originated from studies that included primarily women with hyperemesis gravidarum (a condition associated with an increased risk of congenital malformations) treated with low doses of phenothiazines. The modest increase in risk identified in some of these studies, along with the absence of clear clustering of congenital abnormalities, suggested that the condition being treated may be responsible rather than drug treatment. ■ ■In a large American study including over a million women, no meaningful increase in the risk of major malformations or cardiac malformations was seen in 733 women prescribed an FGA.17 A 2023 study of nearly 6.5 million women (6371 prescribed an FGA) in the USA and Nordic countries found that antipsychotics were not major In all pregnant women ■ ■Ensure that parents are as involved as possible in all decisions ■ ■Prescribe as few drugs as possible (both simultaneously and in sequence) and use the lowest effective dose ■ ■Be prepared to adjust doses as pregnancy progresses and drug handling is altered. Dose increases are frequently required in the third trimester11 when blood volume expands by around 30%. Plasma level monitoring may be helpful, where available. Hepatic enzyme activity also changes markedly during pregnancy. CYP2D6 activity is increased by almost 50% by the end of pregnancy while the activity of CYP1A2 is reduced by up to 70%12 ■ ■For patients with SMI, discuss with the patient a referral to specialist perinatal services ■ ■Ensure adequate fetal screening by liaison with obstetric services ■ ■Be aware of potential problems with individual drugs around the time of delivery ■ ■Inform the obstetric team of psychotropic use and possible complications and where appropriate liaise with the neonatology team ■ ■Monitor the neonate for withdrawal effects after birth ■ ■Document all decisions (including the plan for medication)

716 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 teratogens. In the same study, the authors reported an observed increased risk of cardiac malformations with (the rarely used) chlorprothixene, which the authors suggest should be viewed as a safety signal for further study.18 ■ ■There may be an association between haloperidol and limb defects (based on a small number of cases) but, if real, the risk is likely to be extremely low and it has not been replicated in larger studies. ■ ■An increased risk of gestational diabetes19 and possibly preterm birth20 has been reported. A prospective study that included 284 women who took an FGA during pregnancy concluded that preterm birth and low birth weight were more common with FGAs than second-generation antipsychotics (SGAs) (or no antipsychotic exposure).21 In addition to this, 20% of neonates exposed to an FGA in the last week of gestation experienced early somnolence and jitteriness. ■ ■A higher risk of postpartum bleeding in vaginal delivery and a higher placenta to birth weight ratio has been reported.22 ■ ■Neonatal dyskinesia has been reported with FGAs.23 ■ ■Neonatal jaundice has been reported with phenothiazines.24 ■ ■An increased risk (greater in late pregnancy exposure) of neonatal withdrawal symptoms, neurological disorders and persistent pulmonary hypertension has been reported. The absolute risk is low, and the effects appear to be predominantly mild and transient.25 Prolonged neonatal hospital stay after birth has been reported.22 Second-generation antipsychotics ■ ■Some specific malformations have been reported with individual agents. However, SGAs are unlikely to be major teratogens.16 ■ ■In a large American study, no meaningful increase in the risk of major malformations or cardiac malformations was seen in 9258 women prescribed an SGA. In this same study a small increase in absolute risk of malformations was seen with risperidone. The authors suggested that this particular finding should be interpreted with caution and be seen as a possible safety signal that requires further investigation.17 In a separate study of 214 women taking an SGA, the absolute risk of major malformation was estimated to be 1.4% (1.1% in the control group).17 Another American study which analysed data from the National Birth Defects Prevention Study reported an association between SGA use in early pregnancy and conotruncal heart defects, tetralogy of Fallot, anorectal atresia/stenosis and gastroschisis. The study included over 22,000 cases and over 11,000 controls. Notably (and this may explain the findings in relation to SGAs), women exposed to SGAs were more likely to report pre-pregnancy obesity, illicit drug use, smoking and alcohol use and use of other psychiatric medications during pregnancy.26 A 2023 study of nearly 6.5 million women (21,751 prescribed an SGA) in the USA and Nordic countries reported that antipsychotics were not major teratogens. In the same study there was an observed increased risk of oral clefts with olanzapine and gastroschisis and brain anomalies with all SGAs, which the authors suggested should be viewed only as safety signals for further study.18 ■ ■A prospective study of 561 women who took an SGA during pregnancy concluded that SGA exposure was associated with increased birth weight, a modestly increased risk of cardiac septal defects (possibly due to screening bias or co-exposure to selective

Prescribing in pregnancy and breastfeeding CHAPTER 7 serotonin reuptake inhibitors [SSRIs]) and, as with FGAs, withdrawal effects in 15% of neonates.20 ■ ■Available data do not suggest that lurasidone is a major teratogen.27 ■ ■Olanzapine has been associated with lower birth weight and increased risk of intensive care admission,28 a large head circumference29 and macrosomia30 (the last of these is consistent with the reported increase in the risk of gestational diabetes24,29,31,32). ■ ■Neonatal seizures may be more likely to occur with clozapine31 than with other SGAs. There is a single case report of maternal overdose resulting in fetal death24 and there are theoretical concerns about the risk of agranulocytosis in the fetus/ neonate.24 Overall, pharmacovigilance data do not indicate that clozapine is less safe in pregnancy than other antipsychotics.33 Clozapine is included by the UK National Institute for Health and Care Excellence (NICE) in medications that may be prescribed in pregnancy. Lower mean adaptive behaviour scores have been reported in infants exposed to clozapine in utero compared with risperidone, quetiapine or olanzapine. A higher rate of disturbed sleep and lability were reported in clozapine- exposed infants in the same study.34 On the balance of evidence available, clozapine should usually be continued during pregnancy. Clozapine plasma level monitoring may be beneficial,35 especially if there are changes in smoking habits. ■ ■An increased risk of gestational diabetes has been reported for SGAs19 and possibly preterm birth,20 low birth weight36 and postpartum bleeding in vaginal delivery. The risk of gestational diabetes may be greatest with clozapine, olanzapine and quetiapine,37 and aripiprazole may not be associated with an increased risk.38 In a population- based study of over a million women, an increased risk of caesarean section, large for gestational age and preterm birth were reported in women prescribed an SGA compared with no antipsychotic. The risk of caesarean section and large for gestational age was higher with SGAs than with FGAs.39 Maternal mental illness and lifestyle may also be important factors in the risk for gestational diabetes.40,41 A lower risk with SGAs compared with FGAs has also been reported19 and other studies did not report increased risk of metabolic complications.36 ■ ■An increased risk (greater in late pregnancy exposure) of neonatal withdrawal symptoms, neurological disorders and persistent pulmonary hypertension has been reported. The absolute risk is low, and the effects appear to be predominantly mild and transient.37 ■ ■Quetiapine has a relative low rate of placental passage.42,43 One study of antipsychotic use in Finland showed a higher risk of increased postpartum bleeding in vaginal delivery, prolonged neonatal hospitalisation stay and a higher placenta to birth weight ratio with antipsychotics use. Quetiapine was the most commonly used antipsychotic in this study.22 ■ ■The manufacturers of cariprazine have advised against its use in pregnancy because of an increased risk of malformations noted in animal studies. It should probably be avoided. Antipsychotic use and longer-term neurodevelopment The effect of antipsychotics on longer-term neurodevelopment is unclear.44 A small prospective case–control study reported that babies who were exposed to SGAs in utero had delayed cognitive, motor and social–emotional development at 2 and 6 months old but

718 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 not at 12 months.45 The clinical significance of this finding is unclear. No significant adverse effect on IQ or neurodevelopmental functioning was shown in a small study of school-aged children following exposure to antipsychotics during pregnancy.46 A cohort study of 667,517 children did not show an association between maternal antipsychotic prescription and poorer standardised test performance in language and mathematics in schoolchildren.47 Two large cohort studies have reported increased risk of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) associated with maternal mental illness but not with prenatal antipsychotic exposure.20,48 A smaller study reported no increased risk of psychiatric disorders in children born to women who continued antipsychotics in pregnancy.49 A 2022 birth cohort study found antipsychotics to not be causally associated with neurodevelopmental disorders although there was a safety signal for aripiprazole, which requires further study.50 Recommendations for psychosis in pregnancy are outlined in Box 7.2. Box 7.2 Recommendations – psychosis in pregnancy ■ ■Overall, the data do not allow an assessment of relative risks associated with different agents and certainly do not confirm absolutely the safety of any particular drug. However, the high risk of adverse outcomes for the mother and child associated with untreated maternal illness should be noted ■ ■Patients with a history of psychosis who are maintained on antipsychotic medication should be advised to discuss a planned pregnancy as early as possible ■ ■Women should be supported to minimise the risks in pregnancy from smoking and alcohol and drug misuse. Women should be referred to appropriate services such as smoking cessation clinics and addictions services ■ ■Drug-induced hyperprolactinaemia may prevent pregnancy. Consider switching to an alternative drug if hyperprolactinaemia occurs and a pregnancy is planned ■ ■If a pregnant woman is stable on an antipsychotic and likely to relapse without medication, advise her to continue the antipsychotic.51 Switching medication is generally not advised owing to the risk of relapse ■ ■When initiating an antipsychotic consider using the antipsychotic that has previously worked best for the woman, after discussion of benefits and risks.43 This may minimise fetal exposure by avoiding the need for higher doses and/or multiple drugs should relapse occur ■ ■Be clear of the indication for each drug, use the lowest effective dose and prescribe as few drugs as possible both simultaneously and in sequence. Do not continue medication that is not effective ■ ■Advise pregnant women taking antipsychotic medication about diet and monitor for excessive weight gain ■ ■Women taking an antipsychotic during pregnancy should be monitored for gestational diabetes. In the UK, NICE recommends women are offered an oral glucose tolerance test ■ ■In the UK, NICE recommends avoiding depot preparations in a woman who is planning a pregnancy, pregnant or considering breastfeeding, unless she is responding well to a depot and has a previous history of non-adherence with oral medication51 ■ ■The Australian Centre of Perinatal Excellence (COPE) recommends a 13- or 18–20-week ultrasound for women taking antipsychotics in the first trimester52 ■ ■Antipsychotic discontinuation symptoms can occur in the neonate (e.g. crying, agitation, increased suckling). This is thought to be a class effect.53 When antipsychotics are taken in pregnancy it is recommended that the woman gives birth in a unit that has access to paediatric intensive care facilities.21 Some centres used mixed (breast/bottle) feeding to minimise withdrawal symptoms ■ ■Document all decisions

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03 - Depression during pregnancy and postpartum545

Depression during pregnancy and postpartum54–56

Prescribing in pregnancy and breastfeeding CHAPTER 7 Depression during pregnancy and postpartum54–56 Approximately 10% of pregnant women develop or have a pre-existing depressive illness. Around a third of cases of postpartum depression begin before birth and there is a significant increase in new psychiatric episodes in the first 3 months after delivery. At least 80% of these are mood disorders, particularly severe depression. Women who have had a previous episode of depressive illness (postpartum or not) are at higher risk of further episodes during pregnancy and postpartum. The risk is highest in women with bipolar illness who are also at risk of mania or mixed affective episodes. There is some evidence that depression increases the risk of spontaneous abortion (miscarriage),57 having a low birth weight or small for gestational age baby, or of preterm delivery, although effects are small.3,58,59 The mental health of the mother influences fetal well-being, obstetric outcome and child development. The risks of not treating depression include harm to the mother through poor self-care, lack of obstetric care or self-harm and harm to the fetus or neonate (ranging from neglect to infanticide). Antidepressants Relapse rates are higher in those with a history of depression who discontinue medication compared with those who continue. One study found that 68% of women who were well on antidepressant treatment and stopped during pregnancy relapsed, compared with 26% who continued antidepressants.54 Risk is likely to be highest for women with a history of severe and/or recurrent depression.60 The rate of antidepressant withdrawal will also influence the risk of depressive relapse. Available data do not suggest an association between prenatal antidepressant use and neurodevelopmental disorders (after controlling for maternal illness and other confounders).61 There is also some evidence that successful antidepressant use can be beneficial for child behavioural outcomes. A Danish study found that adverse outcomes were relatively more likely in depressed women not taking antidepressants.62 However, antidepressant exposure in pregnancy may be an important marker of the need for early screening and intervention. Tricyclic antidepressants ■ ■Fetal exposure to tricyclics (via the umbilicus and amniotic fluid) is high.63,64 ■ ■Tricyclic antidepressants (TCAs) have been widely used throughout pregnancy without apparent detriment to the fetus.65–67 ■ ■A weak association between clomipramine use and cardiovascular defects cannot be excluded68 and the European summary of product characteristics (SPC) for Anafranil states: ‘Neonates whose mothers had taken tricyclic antidepressants until delivery have developed dyspnoea, lethargy, colic, irritability, hypotension or hypertension, tremor or spasms, during the first few hours or days. Studies in animals have shown reproductive toxicity. Anafranil (i.e. branded clomipramine) is not recommended during pregnancy and in women of child-bearing potential not using contraception.’ The labels for other TCAs also contain a caution about withdrawal effects in neonates. One case of neonatal QT prolongation and torsades de pointes has been reported following maternal clomipramine use69 and one case of Timothy syndrome

720 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 (a disorder characterised by severe QT prolongation) in a newborn whose mother took amitriptyline in early pregnancy.70 ■ ■TCA use during pregnancy is associated with an increased risk of preterm delivery.65,66,71 ■ ■Use of TCAs in the third trimester is well known to produce neonatal withdrawal effects, such as agitation, irritability, seizures, respiratory distress and endocrine and metabolic disturbances.65 These are usually mild and self-limiting. ■ ■Little is known of the early developmental effects of prenatal exposure to tricyclics, although one small study detected no adverse consequences.72 Limited data suggest in utero exposure to tricyclics has no effects on later development.72,73 The authors of a study that reported an association between maternal antidepressant use and an increased risk of affective disorders in offspring74 suggested the observed associations may be attributable to underlying parental psychopathology. There are no convincing data suggesting an association between prenatal antidepressant use and neurodevelopmental disorders61 or ASD diagnoses or traits.75 Selective serotonin reuptake inhibitors (SSRIs) ■ ■SSRIs appear not to be major teratogens.65,67,76–78 An association between prenatal SSRI use and congenital heart defects has been reported, with some studies reporting a higher risk with fluoxetine and paroxetine.79 However, other studies have found no association between any SSRI and an increased risk of cardiac septal defects80–82 nor any other heart defects83–87 and it is suggested that mood disorders alone may be the cause of any increased risk of congenital heart defects.78 ■ ■One database study reported that fetal alcohol disorders were 10 times more common in those exposed to SSRIs in utero than in controls,88 and that alcohol use during pregnancy (which may be used as self-medication for depression) is associated with an increased risk of cardiac defects in the fetus.68 ■ ■Sertraline appears to result in the least placental exposure.89 ■ ■There may be a small increased risk of preterm birth and low birth weight and lower Apgar scores and admission to neonatal intensive care units with SSRIs.78 Maternal depression itself increases these risks.90,91 Poor neonatal adaptation (including withdrawal symptoms) has been reported and risk may be increased with prematurity92 and increasing dose, and may be higher with other SSRIs than sertraline.93 ■ ■SSRIs may increase the risk for persistent pulmonary hypertension of the newborn. The absolute risk appears to be small and more modest than previously estimated.94 The risk may exist only in late pregnancy exposure95 and may be lower with sertraline.96 ■ ■Gestational hypertension, pre-eclampsia, placental abnormalities and postpartum haemorrhage have been reported with SSRI use. The risks appear to be small and it should be noted that maternal depression itself increases the risk of these outcomes.78 The UK Medicines and Healthcare products Regulatory Agency (MHRA) advises that healthcare professionals need to be aware of the small increased risk of postpartum haemorrhage with SSRI/serotonin–noradrenaline reuptake inhibitor (SNRI) antidepressant use during the month before delivery. ■ ■Data relating to neurodevelopmental outcome of fetal exposure to SSRIs are less than conclusive.72,73,97–100 Depression itself may have more obvious adverse effects on development.72,101 Some studies have reported a small increased risk of ASD.102–104

Prescribing in pregnancy and breastfeeding CHAPTER 7 However, larger studies have either failed to show this association after accounting for maternal illness and other demographic confounders75,105–107 or have found it to be no longer statistically significant.108,109 A large cohort study in 2022 reported that antidepressant use in pregnancy itself does not appear to increase the risk of neurodevelopmental disorders in children.61 There is no reliable evidence indicating an increased risk of ADHD.91 Poorer cognitive and gross motor development110 and problems with speech and language,111–113 behaviour114,115 and fine motor control have been reported116 but it is not clear whether or not this is a result of confounding. Authors of two separate studies, one reporting an association between antidepressant exposure in pregnancy and increased risk in the offspring of affective disorders74 and the other describing higher rates of emotional disorders and antidepressant medication prescriptions,117 have suggested the observed associations may be attributable to underlying parental psychopathology rather than direct exposure in utero. A 2023 study reported changes in brain morphology associated with SSRI exposure during pregnancy, some of which persisted into adolescence. The study did not assess clinical outcomes in the children and as such the significance of these findings is unclear.118 Other antidepressants ■ ■Despite a previous reported association between venlafaxine and increased risk of specific birth defects111 including cardiac defects, anencephaly and cleft palate,119 a 2022 meta-analysis concluded that available data do not indicate any SNRIs to be major teratogens.120 An earlier observational study of 281 venlafaxine-exposed pregnancies did not find conclusive evidence that venlafaxine increased the risk of adverse pregnancy or fetal outcomes.121 However, venlafaxine has been associated with neonatal withdrawal and poor neonatal adaptation syndrome,122 babies being born small for gestational age123 and postpartum haemorrhage.124 The UK MHRA advises that healthcare professionals need to be aware of the small increased risk of postpartum haemorrhage with SSRI/SNRI antidepressant use during the month before delivery. SNRIs may be associated with an increased risk for persistent pulmonary hypertension of the newborn. The absolute risk appears to be low.96 ■ ■A large cohort study using propensity scores and several sensitivity analyses found duloxetine use in pregnancy may be associated with a small increase in the risk of postpartum hemorrhage,124 and a case of suspected withdrawal syndrome in the newborn requiring hospitalisation has been reported.125 However, no specific risks were identified with duloxetine in a study that prospectively followed 233 women through pregnancy and delivery.126 A population-based observational study from Sweden and Denmark did not show an increased risk of major or minor congenital malformations or stillbirth with duloxetine.127 ■ ■Trazodone, bupropion (amfebutamone) and mirtazapine have few data supporting their safety.122,128,129 A 2023 observational study did not find a significant difference in the risk of major congenital anomalies after first-trimester exposure to trazodone compared with SSRI exposure.130 Available data suggest that both bupropion and mirtazapine are not associated with malformations but, like SSRIs, may be linked to an increased rate of spontaneous abortion;131–133 however this might be attri butable to underlying psychiatric disease. A 2022 Danish study did not observe an

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04 - Bipolar illness during pregnancy and postpart

Bipolar illness during pregnancy and postpartum

722 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 association between mirtazapine use and major congenital malformations, spontaneous abortion, stillbirth or neonatal death.134 ■ ■First-trimester exposure to bupropion may be associated with a slightly elevated risk of ventricular septal defects.135 Bupropion exposure in utero has been associated with an increased risk of ADHD in young children.136,137 Rather limited data suggest the absence of teratogenic potential with moclobemide138 and reboxetine.139 ■ ■Monamine oxidase inhibitors should be avoided in pregnancy because of a suspected increased risk of congenital malformations and because of the risk of hypertensive crisis.140 ■ ■There is no evidence to suggest that electroconvulsive therapy (ECT) causes harm to either the mother or fetus during pregnancy141 although general anaesthesia is of course not without risks. NICE recommends ECT for pregnant women with severe depression, severe mixed affective states or mania, or catatonia, whose physical health or that of the fetus is at serious risk. Box 7.3 summarises recommendations for treating depression in pregnancy. Bipolar illness during pregnancy and postpartum The risk of relapse during pregnancy if mood-stabilising medication is discontinued is high143 and the risk of relapse after delivery is hugely increased. The mental health of the mother influences fetal well-being, obstetric outcome and child development. The risks of not stabilising mood include harm to the mother through poor self-care, lack of obstetric care, the need for hospital admission and harm to the fetus or neonate (ranging from neglect to infanticide). Box 7.3 Recommendations – depression in pregnancy ■ ■Patients who are already receiving antidepressants and are at high risk of relapse are best maintained on the same antidepressant (assuming it is effective and well tolerated) during and after pregnancy ■ ■Those who develop a moderate to severe or severe depressive illness during pregnancy should be treated with antidepressant drugs. If initiating an antidepressant during pregnancy or for a woman considering pregnancy, previous response to treatment must be taken into account. The antidepressant which has previously proved to be effective should be considered. For previously untreated patients, sertraline may be considered. ACOG recommends selective serotonin reuptake inhibitors (SSRIs) first line (with serotonin–noradrenaline reuptake inhibitors [SNRIs] a reasonable alternative) and if there is no pharmacotherapy history, sertraline or escitalopram is a reasonable first-line medication. COPE recommends SSRIs first line ■ ■For moderate to severe perinatal depression with onset in the third trimester, ACOG recommends consideration of brexanolone ■ ■Screen for alcohol use and be vigilant for the development of hypertension and pre-eclampsia ■ ■Women who take SSRIs or SNRIs late in pregnancy may be at increased risk of postpartum haemorrhage ■ ■When taken in late pregnancy, SSRIs may increase the risk of persistent pulmonary hypertension of the newborn. The absolute risk is very low ■ ■The neonate may experience poor neonatal adaptation syndrome or discontinuation symptoms ■ ■NICE in the UK142 advises additional monitoring of the newborn of women who have taken an SRRI or SNRI antidepressant during pregnancy

Prescribing in pregnancy and breastfeeding CHAPTER 7 Mood stabilisers (non-antipsychotics) ■ ■Lithium completely equilibrates across the placenta.144 Lithium exposure during pregnancy has been associated with an increased risk of congenital anomalies.145 The risk is higher in the first trimester146 and may be greater at higher doses.145 Although the overall risk of major malformations in infants exposed in utero has probably been overestimated in the past, lithium should be avoided in pregnancy if possible. However, if lithium is the best drug for the woman and the drug most likely to keep her well, she should be advised of the increased risk but supported to stay on lithium. If discontinuation is planned, slow discontinuation before conception is the preferred course of action31,147 because abrupt discontinuation worsens the risk of relapse. The relapse rate postpartum may be as high as 70% in women who discontinued lithium before conception.148 ■ ■Lithium use during pregnancy has a well-known association with the cardiac malformation Ebstein’s anomaly. However, more recent data suggest that the magnitude of the effect is much smaller than previously estimated.149,150 Furthermore, a large surveillance study of 5.6 million births found an association of Ebstein’s anomaly with maternal mental health problems generally rather than specifically with lithium.151 The period of maximum risk to the fetus is 2–6 weeks after conception,152 before many women know that they are pregnant. The risk of atrial and ventricular septal defects may also be increased.28 If lithium is continued during pregnancy, high- resolution ultrasound and echocardiography should be performed in liaison with fetal medicine obstetric services. ■ ■In the third trimester, the use of lithium may be problematic because of changing pharmacokinetics. An increasing dose of lithium is required to maintain the lithium level during pregnancy as total body water increases, but the requirements return abruptly to pre-pregnancy levels immediately after delivery.153 Women taking lithium should deliver in hospital where fluid balance can be monitored and maintained. ■ ■Lithium use in pregnancy has been associated with an increased risk of spontaneous preterm birth and large for gestational age neonates.154 However, a large cohort study reported that lithium was not associated with placenta-mediated complications or preterm birth.155 Lithium use may increase the risk of neonatal readmission within 4 weeks postpartum,146 although a later study failed to replicate this finding.156 Neonatal goitre, hypotonia, lethargy, cardiac arrhythmia, respiratory symptoms157 and low Apgar scores158 have been reported. ■ ■Lithium probably does not affect neonatal brain development.159 ■ ■Most data relating to carbamazepine, valproate and lamotrigine come from studies in epilepsy, a condition associated with increased neonatal malformation. These data may not be precisely relevant to use in mental illness. Both carbamazepine and valproate have a clear causal link with increased risk of a variety of fetal abnormalities, particularly neural tube defects including spina bifida.160 Both drugs should be avoided, and an antipsychotic prescribed instead. Valproate confers a higher risk (around 10% for major malformations) than carbamazapine161–163 and should not be used in women of child-bearing age except where all other treatment has failed and when there is a long-term effective contraception plan. There is no evidence that folate protects against anticonvulsant-induced neural tube defects if given during pregnancy,164 but it may do so if given prior to conception (the neural tube is essentially

724 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 formed by 8 weeks of pregnancy165 before many women realise they are pregnant). However, folate supplementation may be beneficial with regard to early neurodevelopment and so should always be offered.164 Valproate monotherapy has also been associated with an increased relative risk of atrial septal defects, cleft palate, hypospadias, polydactyly and craniosynostosis, although absolute risks are low.166 Valproate is also associated with a reduced head circumference in the neonate.167 ■ ■There appears to be a clear causal association between valproate use in pregnancy and motor and neurodevelopmental problems in exposed children. A review of studies by the European Medicines Agency showed that up to 40% of pre-school children exposed to valproate in utero experienced some form of developmental delay, including delayed walking and talking, memory problems, difficulty with speech and language and a lower intellectual ability. Poorer outcomes have been shown in language functioning, attention, memory, executive functioning and adaptive behaviour compared with carbamazepine and lamotrigine exposure. Lower IQs and an increased diagnosis rate of ASD are also reported.168,169 Processing, working memory and learning deficits appear to be dose-related.170 Decreased school performance has been associated with valproate use compared with children unexposed to anticonvulsants and with children exposed to lamotrigine.171 ■ ■Valproate use may increase risk of pre-eclampsia.172 ■ ■Where continued use of carbamazepine is deemed essential, low-dose (but effective) monotherapy is strongly recommended as the teratogenic effect is probably dose related.173,174 Use of carbamazepine in the third trimester may necessitate maternal vitamin K. ■ ■There is growing evidence that lamotrigine is safer in pregnancy than carbamazepine or valproate across a range of outcomes.164,168,175–177 The risk of major malformations appears to be in the range reported for children not exposed to anticonvulsants.178 Clearance of lamotrigine seems to increase radically during pregnancy179,180 and then reduces postpartum181 so frequent lamotrigine levels are necessary. ■ ■Behaviour problems have been reported by parents of children exposed to lamotrigine in pregnancy.182 Lamotrigine may be associated with an increased risk of autism.183 However, available data suggest the effect of lamotrigine on neurodevelopment appears to not be significant.184 ■ ■Lower Apgar scores at birth have been reported with carbamazepine, valproate and topiramate. If an association exists, the absolute risk is low.185 ■ ■Major malformations,186 specifically orofacial clefts, have been reported with topiramate.187 The risk of oral clefts may be higher in women with epilepsy who use higher doses of the drug.188 A large population study reported an increased risk of neurodevelopmental disorders, small for gestational age and congenital malformations189 with prenatal topiramate exposure. Topiramate should not be used in pregnant women, and women of child-bearing age should take precautions to avoid getting pregnant.190 ■ ■The data for oxcarbazepine are not clear. A 2022 meta-analysis reported a small but not statistically significant increased risk of malformations in children exposed to oxcarbazepine.191 Three studies in the same analysis reported an association with fetal/perinatal deaths. Because of some notable limitations in the studies incuded in this analysis, it is difficult to draw firm conclusions. ■ ■Similarly, data for pregabalin are not clear.192 However, based on a Nordic study193 that showed a small increased risk of major malformations (compared with

Prescribing in pregnancy and breastfeeding CHAPTER 7 lamotrigine and duloxetine) the UK MHRA194 and the manufacturers of pregabalin advise that women taking pregabalin be made aware of this risk and advised to use effective contraception. ■ ■A large cohort study reported that anticonvulsant mood stabilisers were not associated with placenta-mediated complications or preterm birth.170 Recommendations for the treatment of bipolar disorder in pregnancy are outlined in Box 7.4. Box 7.4 Recommendations – bipolar disorder in pregnancy ■ ■For women who have had a long period without relapse, the possibility of switching to a safer drug (antipsychotic) or withdrawing treatment completely before conception and for at least the first trimester should be considered ■ ■For women with a severe mental illness, discuss referral to perinatal services for pre-conception advice ■ ■The risk of relapse both pre- and postpartum is very high if medication is discontinued abruptly ■ ■No mood stabiliser is clearly safe. In the UK, NICE recommends the use of mood-stabilising antipsychotics as a preferable alternative to continuation with a mood stabiliser ■ ■Women with severe illness or who are known to relapse quickly after discontinuation of a mood-stabilising agent should be advised to continue their medication, following discussion of the risks. (This advice does not apply to valproate.) NICE recommends that if a woman taking lithium becomes pregnant, consider stopping lithium gradually over 4 weeks if she is well. Explain to her that there is a risk of relapse, particularly in the postnatal period, if she has bipolar disorder. If a woman taking lithium becomes pregnant and is not well or is at high risk of relapse, consider switching gradually to an antipsychotic or stopping lithium and restarting it in the second trimester (if the woman is not planning to breastfeed and her symptoms have responded better to lithium than to other drugs in the past) or continuing with lithium if she is at high risk of relapse and an antipsychotic is unlikely to be effective. If lithium is considered essential in a woman planning pregnancy, the woman should be informed of the risk of fetal heart malformations when lithium is taken in the first trimester and the risk of toxicity in the baby if lithium is continued during breastfeeding. In the UK, NICE recommends checking the plasma lithium levels every 4 weeks, then weekly from the 36th week, and to adjust the dose to keep plasma lithium levels in the woman’s therapeutic range, ensuring the woman maintains an adequate fluid balance. The woman should give birth in hospital and be monitored by the obstetric team when labour starts, including checking plasma lithium levels and fluid balance because of the risk of dehydration and lithium toxicity. Lithium should be stopped during labour and plasma lithium levels checked 12 hours after the mother’s last dose. ACOG recommends that pregnant patients taking lithium in the first trimester receive a detailed ultrasound examination in the second trimester to evaluate the fetal anatomy with a particular focus on cardiac anatomy. COPE recommends a 13- or 18–20-week ultrasound for women taking lithium or anticonvulsants in the first trimester ■ ■Women prescribed lithium should undergo appropriate monitoring of the fetus in liaison with fetal medicine obstetric services to screen for Ebstein’s anomaly ■ ■NICE, ACOG and COPE strongly advise against the use of valproate in pregnancy. Valproate should be discontinued before a woman becomes pregnant. Women taking valproate who are planning a pregnancy should be strongly advised to gradually stop the drug because of the high risk of fetal malformations and adverse neurodevelopmental outcomes after any exposure in pregnancy. COPE recommends once the decision to conceive is made to stop valproate over 2–4 weeks, while adding in high-dose folic acid (5mg/day), which should continue for the first trimester.52 In the UK, valproate may not be initiated in patients under 55 or continued in women of child-bearing potential unless two specialists agree and document that there is no other effective or tolerated treatment195

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05 - Anxiety and insomnia during pregnancy and pos

Anxiety and insomnia during pregnancy and postpartum

726 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 Anxiety and insomnia during pregnancy and postpartum Anxiety disorders and insomnia are commonly seen in pregnancy.196 Preferred treatments are cognitive behavioural therapy (CBT) and sleep-hygiene measures, respectively. Sedatives ■ ■First-trimester exposure to benzodiazepines has been associated with specific malformations197 such as oral clefts in newborns,198 although other studies198–202 have failed to confirm this association. Benzodiazepine use in pregnancy may be a marker for cardiac and total malformation risk.203 ■ ■Benzodiazepine use in pregnancy has been associated with caesarean delivery, spontaneous abortion, neonatal intensive care admission, neonatal ventilatory support, low birth weight, preterm delivery, small head circumference and small for gestational age babies.199,204–208 Third-trimester use is commonly associated with neonatal difficulties (floppy baby syndrome).209 A Taiwanese population-based study which accounted for confounding factors such as indication reported that benzodiazepine or Z drug use in early pregnancy was not associated with a substantial increase in the risk of stillbirth and preterm birth but there was an increased risk of small for gestational age. Exposure during late pregnancy was found to be associated with a substantially elevated risk of stillbirth and preterm birth.210 ■ ■Note that, in the UK, NICE advises that benzodiazepines are not offered to women in pregnancy and the postnatal period except for the short-term treatment of severe anxiety and agitation. It also suggests gradually stopping benzodiazepines in women who are planning a pregnancy, pregnant or considering breastfeeding.51 ACOG recommends that benzodiazepines be avoided or prescribed sparingly as a treatment for perinatal anxiety. ■ ■Promethazine has been used in hyperemesis gravidarum and appears not to be teratogenic, although data are limited. ■ ■If valproate is the only drug that works for a particular woman, and this is seen as the only option for her during pregnancy, then the patient should be given a clear briefing of the risks and give written consent confirming that she understands the risk of malformations and developmental delays. Having said this, it is difficult to imagine any situation where the benefits of valproate outweigh the huge risks presented by using valproate in pregnancy ■ ■NICE advises that carbamazepine not be offered to treat a mental health problem in women who are planning a pregnancy, pregnant or considering breastfeeding. NICE advises discussing the possibility of stopping carbamazepine if a woman is planning a pregnancy or becomes pregnant. If carbamazepine is used, prophylactic vitamin K should be administered to the mother and neonate after delivery. ACOG recommends against discontinuing mood stabilisers (except for valproate) during pregnancy due to the risk of recurrence or exacerbation of mood symptoms ■ ■NICE advises if a woman is taking lamotrigine to check lamotrigine levels frequently during pregnancy and into the postnatal period because they vary substantially at these times ■ ■In acute mania in pregnancy use an antipsychotic and, if ineffective, consider electroconvulsive therapy ■ ■In bipolar depression during pregnancy use cognitive behavioural therapy for moderate depression and a selective serotonin reuptake inhibitor for more severe depression. Lamotrigine is also an option

12 - Chapter 7 Prescribing in pregnancy and breastfeedi

06 - Attention deficit hyperactivity disorder (ADH

Attention deficit hyperactivity disorder (ADHD) in pregnancy

12 - Chapter 7 Prescribing in pregnancy and breastfeedi

07 - References

References

Prescribing in pregnancy and breastfeeding CHAPTER 7 ■ ■Hypnotic benzodiazepine receptor agonists (Z drugs) are probably not associated with an increased risk of congenital malformations,211,212 but an increased risk of premature birth, low birth weight and small for gestational age has been reported.211 ■ ■Zolpidem may be associated with an increased likelihood of caesarean section.213 ■ ■Available data do not appear to show an association between in utero benzodiazepine and/or Z drug exposure and neurodevelopmental disorders.214–216 Attention deficit hyperactivity disorder (ADHD) in pregnancy Methylphenidate and amfetamines are probably not major teratogens.217,218 A small increased risk of cardiac malformations has been reported with methylphenidate but is not seen with amfetamines.219 There may be a small increased risk of spontaneous abortion with methylphenidate and a small increased risk of premature birth and low birth weight with amfetamines.218 Modafinil may be associated with an increased risk of congenital malformations (including congenital heart defects, hypospadias and orofacial clefts).220,221 In the UK, the MHRA advises that modafinil should not be used during pregnancy.220 Women of child-bearing age must understand the risk of taking modafinil in pregnancy and should be advised to use effective contraception during treatment with modafinil and for 2 months after discontinuing treatment.220 Available data do not show an increased risk of neurodevelopmental disorders in children exposed to ADHD medications in utero.222,223 References

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Neonatal admission after lithium use in pregnant women with bipolar disorders: a retrospective cohort study. Int J Bipolar Disord 2023; 11:24. 157. Torfs M, et al. Early postnatal outcome and care after in utero exposure to lithium: a single center analysis of a Belgian tertiary university hospital. Int J Environ Res Public Health 2022; 19:10111. 158. Sagué-Vilavella M, et al. Obstetric outcomes regarding the use of lithium in pregnant women with bipolar disorders: a prospective cohort study. Arch Womens Ment Health 2022; 25:729–737. 159. Poels EMP, et al. Brain development after intrauterine exposure to lithium: a magnetic resonance imaging study in school-age children. Bipolar Disord 2023; 25:181–190. 160. James L, et al. Informing patients of the teratogenic potential of mood stabilising drugs: a case note review of the practice of psychiatrists. J Psychopharmacol 2007; 21:815–819. 161. Wide K, et al. Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study. Acta Paediatr 2004; 93:174–176.

732 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 162. Wyszynski DF, et al. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 2005; 64:961–965. 163. Weston J, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev 2016; 11:CD010224. 164. Campbell E, et al. Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers. J Neurol Neurosurg Psychiatry 2014; 85:1029–1034. 165. Bestwick JP, et al. Prevention of neural tube defects: a cross-sectional study of the uptake of folic acid supplementation in nearly half a million women. PLoS One 2014; 9:e89354. 166. Jentink J, et al. Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med 2010; 362:2185–2193. 167. Tomson T, et al. Teratogenic effects of antiepileptic drugs. Lancet Neurol 2012; 11:803–813. 168. Bromley R, et al. Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child. Cochrane Database Syst Rev 2014; 10:CD010236. 169. Bromley RL, et al. Fetal antiepileptic drug exposure and cognitive outcomes. Seizure 2017; 44:225–231. 170. Cohen MJ, et al. Fetal antiepileptic drug exposure and learning and memory functioning at 6 years of age: the NEAD prospective observational study. Epilepsy Behav 2019; 92:154–164. 171. Elkjær LS, et al. Association between prenatal valproate exposure and performance on standardized language and mathematics tests in school-aged children. JAMA Neurol 2018; 75:663–671. 172. Danielsson KC, et al. Hypertensive pregnancy complications in women with epilepsy and antiepileptic drugs: a population-based cohort study of first pregnancies in Norway. BMJ Open 2018; 8:e020998. 173. Vajda FJ, et al. Critical relationship between sodium valproate dose and human teratogenicity: results of the Australian register of anti- epileptic drugs in pregnancy. J Clin Neurosci 2004; 11:854–858. 174. Vajda FJ, et al. Maternal valproate dosage and foetal malformations. Acta Neurol Scand 2005; 112:137–143. 175. Tomson T, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol 2011; 10:609–617. 176. Molgaard-Nielsen D, et al. Newer-generation antiepileptic drugs and the risk of major birth defects. JAMA 2011; 305:1996–2002. 177. Vajda FJE, et al. Antiepileptic drugs and foetal malformation: analysis of 20 years of data in a pregnancy register. Seizure 2019; 65:6–11. 178. Tomson T, et al. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol 2018; 17:530–538. 179. De Haan GJ, et al. Gestation-induced changes in lamotrigine pharmacokinetics: a monotherapy study. Neurology 2004; 63:571–573. 180. Karanam A, et al. Lamotrigine clearance increases by 5 weeks gestational age: relationship to estradiol concentrations and gestational age. Ann Neurol 2018; 84:556–563. 181. Clark CT, et al. Lamotrigine dosing for pregnant patients with bipolar disorder. Am J Psychiatry 2013; 170:1240–1247. 182. Huber-Mollema Y, et al. Neurocognition after prenatal levetiracetam, lamotrigine, carbamazepine or valproate exposure. J Neurol 2020; 267:1724–1736. 183. Veroniki AA, et al. Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis. BMJ Open 2017; 7:e017248. 184. Knight R, et al. Neurodevelopmental outcomes in children exposed to newer antiseizure medications: a systematic review. Epilepsia 2021; 62:1765–1779. 185. Christensen J, et al. Apgar-score in children prenatally exposed to antiepileptic drugs: a population-based cohort study. BMJ Open 2015; 5:e007425. 186. Cohen JM, et al. Comparative safety of antiseizure medication monotherapy for major malformations. Ann Neurol 2023; 93:551–562. 187. Bromley RL, et al. Cognition in school-age children exposed to levetiracetam, topiramate, or sodium valproate. Neurology 2016; 87:1943–1953. 188. Hernandez-Diaz S, et al. Topiramate use early in pregnancy and the risk of oral clefts: a pregnancy cohort study. Neurology 2018; 90:e342–e351. 189. Bjørk MH, et al. Association of prenatal exposure to antiseizure medication with risk of autism and intellectual disability. JAMA Neurol 2022; 79:672–681. 190. European Medicines Agency. Topiramate. New measures to avoid topiramate exposure in pregnancy. 2023; https://www.ema.europa.eu/en/ medicines/human/referrals/topiramate. 191. Athar F, et al. Adverse fetal and neonatal outcomes following in-utero exposure to oxcarbazepine: a systematic review and meta-analysis. Br J Clin Pharmacol 2022; 88:3600–3609. 192. Richardson JL, et al. A critical appraisal of controlled studies investigating malformation risks following pregabalin use in early pregnancy. Br J Clin Pharmacol 2023; 89:630–640. 193. Dudukina E, et al. Prenatal exposure to pregabalin, birth outcomes and neurodevelopment – a population-based cohort study in four Nordic countries. Drug Saf 2023; 46:661–675. 194. Medicines and Healthcare products Regulatory Agency. Pregabalin and risks in pregnancy. 2022; https://www.gov.uk/government/ publications/pregabalin-and-risks-in-pregnancy. 195. Medicines and Healthcare products Regulatory Agency. Valproate: review of safety data and expert advice on management of risks. 2023; https://www.gov.uk/government/publications/valproate-review-of-safety-data-and-expert-advice-on-management-of-risks. 196. Ross LE, et al. Anxiety disorders during pregnancy and the postpartum period: a systematic review. J Clin Psychiatry 2006; 67:1285–1298. 197. Noh Y, et al. First-trimester exposure to benzodiazepines and risk of congenital malformations in offspring: a population-based cohort study in South Korea. PLoS Med 2022; 19:e1003945.

Prescribing in pregnancy and breastfeeding CHAPTER 7 198. Dolovich LR, et al. Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies. BMJ 1998; 317:839–843. 199. Wikner BN, et al. Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and congenital malformations. Pharmacoepidemiol Drug Saf 2007; 16:1203–1210. 200. Reis M, et al. Combined use of selective serotonin reuptake inhibitors and sedatives/hypnotics during pregnancy: risk of relatively severe congenital malformations or cardiac defects. A register study. BMJ Open 2013; 3(2):e002166. 201. Tinker SC, et al. Use of benzodiazepine medications during pregnancy and potential risk for birth defects, National Birth Defects Prevention Study, 1997–2011. Birth Defects Res 2019; 111:613–620. 202. Grigoriadis S, et al. Benzodiazepine use during pregnancy alone or in combination with an antidepressant and congenital malformations: systematic review and meta-analysis. J Clin Psychiatry 2019; 80:18r12412. 203. Andrade C. Gestational exposure to benzodiazepines, 2: the risk of congenital malformations examined through the prism of compatibility intervals. J Clin Psychiatry 2019; 80:19f13081. 204. Calderon-Margalit R, et al. Risk of preterm delivery and other adverse perinatal outcomes in relation to maternal use of psychotropic medications during pregnancy. Am J Obstet Gynecol 2009; 201:579–578. 205. Okun ML, et al. A review of sleep-promoting medications used in pregnancy. Am J Obstet Gynecol 2015; 212:428–441. 206. Yonkers KA, et al. Maternal antidepressant use and pregnancy outcomes. JAMA 2017; 318:665–666. 207. Freeman MP, et al. Obstetrical and neonatal outcomes after benzodiazepine exposure during pregnancy: results from a prospective registry of women with psychiatric disorders. Gen Hosp Psychiatry 2018; 53:73–79. 208. Sheehy O, et al. Association between incident exposure to benzodiazepines in early pregnancy and risk of spontaneous abortion. JAMA Psychiatry 2019; 76:948–957. 209. McElhatton PR. The effects of benzodiazepine use during pregnancy and lactation. Reprod Toxicol 1994; 8:461–475. 210. Meng LC, et al. Association between maternal benzodiazepine or Z-hypnotic use in early pregnancy and the risk of stillbirth, preterm birth, and small for gestational age: a nationwide, population-based cohort study in Taiwan. Lancet Psychiatry 2023; 10:499–508. 211. Grigoriadis S, et al. Hypnotic benzodiazepine receptor agonist exposure during pregnancy and the risk of congenital malformations and other adverse pregnancy outcomes: a systematic review and meta-analysis. Acta Psychiatr Scand 2022; 146:312–324. 212. Wikner BN, et al. Are hypnotic benzodiazepine receptor agonists teratogenic in humans? J Clin Psychopharmacol 2011; 31:356–359. 213. Wang LH, et al. Increased risk of adverse pregnancy outcomes in women receiving zolpidem during pregnancy. Clin Pharmacol Ther 2010; 88:369–374. 214. Chen VC, et al. Association of prenatal exposure to benzodiazepines with development of autism spectrum and attention-deficit/hyperactivity disorders. JAMA Network Open 2022; 5:e2243282. 215. Sundbakk LM, et al. Association of prenatal exposure to benzodiazepines and Z-hypnotics with risk of attention-deficit/hyperactivity disorder in childhood. JAMA Network Open 2022; 5:e2246889. 216. Chan AYL, et al. Maternal benzodiazepines and Z-drugs use during pregnancy and adverse birth and neurodevelopmental outcomes in offspring: a population-based cohort study. Psychother Psychosom 2023; 92:113–123. 217. Pottegard A, et al. First-trimester exposure to methylphenidate: a population-based cohort study. J Clin Psychiatry 2014; 75:e88–e93. 218. Ornoy A, et al. Neurotropic drugs in pregnancy and lactation from the point of view of the clinical teratologist. Curr Neuropharmacol 2021; 19:1792–1793. 219. Huybrechts KF, et al. Association between methylphenidate and amphetamine use in pregnancy and risk of congenital malformations: a cohort study from the International Pregnancy Safety Study Consortium. JAMA Psychiatry 2018; 75:167–175. 220. Gov.UK. Modafinil (Provigil): increased risk of congenital malformations if used during pregnancy. 2020; https://www.gov.uk/drug-safety- update/modafinil-provigil-increased-risk-of-congenital-malformations-if-used-during-pregnancy?utm_source=e-shot&utm_medium= email&utm_campaign=DSU_November2020split1. 221. Damkier P, et al. First-trimester pregnancy exposure to modafinil and risk of congenital malformations. JAMA 2020; 323:374–376. 222. Bang Madsen K, et al. In utero exposure to ADHD medication and long-term offspring outcomes. Mol Psychiatry 2023; 28:1739–1746. 223. Suarez EA, et al. Prescription stimulant use during pregnancy and risk of neurodevelopmental disorders in children. JAMA Psychiatry 2024; 81:477–488.

12 - Chapter 7 Prescribing in pregnancy and breastfeedi

08 - Drug choice in breastfeeding

Drug choice in breastfeeding

12 - Chapter 7 Prescribing in pregnancy and breastfeedi

09 - Infant exposure

Infant exposure

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10 - General principles of prescribing psychotropi

General principles of prescribing psychotropics in breastfeeding

734 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 Drug choice in breastfeeding The long-term benefits of breastfeeding on a child’s physical health and cognitive development are well known. Women are generally encouraged to breastfeed for at least 6 months. One factor that may influence a mother’s decision to breastfeed is the safety of a drug taken while breastfeeding. With some notable exceptions, most psychotropic drugs should be continued in breastfeeding women because of the benefits of breastfeeding and the lack of evidence of harm for most drugs. However, current evidence suggests that for a few drugs the woman should be advised not to breastfeed if such medications are the best and only option for her care. Data on the safety of psychotropic medication in breastfeeding are largely derived from small studies or case reports and case series. Reported infant and neonatal outcomes in most cases are limited to short-term acute adverse effects. Long-term safety cannot therefore be guaranteed for the psychotropics mentioned here. The information presented must be interpreted with caution with respect to the limits of the data from which it is derived and the need for such information to be regularly updated. There are two distinct clinical scenarios. In the first, the mother will have been taking the psychotropic drug(s) during pregnancy and often up until birth. In these people, the same psychotropic(s) should be continued during breastfeeding to mitigate withdrawal symptoms in the neonate (but see exceptions later). In the second, the mother is newly prescribed a psychotropic after the child has been born but wishes to breastfeed. Decisions in this scenario are rather more complex and the reader is referred to the tables in this section. Infant exposure All psychotropics are excreted in breast milk to varying degrees. The most direct measure of infant exposure is, of course, infant plasma levels but these data are rarely available. Instead, many publications report only drug concentrations in breast milk and in maternal plasma. Maternal plasma levels of antipsychotics may be a useful estimate of infant exposure.1 Breast milk drug concentrations can be used to estimate the daily infant dose (by assuming a milk intake of 150mL/kg/day). The infant weight-adjusted dose when expressed as a proportion of the maternal weight-adjusted dose is known as the relative infant dose (RID). The RID should be used as a guide only, as values are estimates and these estimates vary widely in the literature for individual drugs. Drugs with an RID below 10% are usually regarded as safe in breastfeeding. Where measured, infant plasma levels below 10% of average maternal plasma levels have also been proposed as being safe in breastfeeding.2 General principles of prescribing psychotropics in breastfeeding ■ ■The safety of individual drugs in breastfeeding should be taken into account when prescribing psychotropic medication for women considering pregnancy. ■ ■Discussions about the safety of drugs in breastfeeding should be held as early as possible – ideally before conception or early in pregnancy. Decisions about the use of drugs in pregnancy should include the discussion about breastfeeding. Switching drugs at the end of pregnancy or in the days after birth is not advisable because of the high risk of relapse.

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11 - Antidepressants in breastfeeding

Antidepressants in breastfeeding

Prescribing in pregnancy and breastfeeding CHAPTER 7 ■ ■Where a mother has taken a particular psychotropic during pregnancy and until delivery, continuation with the drug while breastfeeding will usually be appropriate (but see notable exceptions later), as this may minimise withdrawal symptoms in the infant. ■ ■In each case the benefits of breastfeeding to the mother and infant must be weighed against the risk of drug exposure in the infant. Consider the infant’s general health and gestational age at birth.3 ■ ■It is usually inappropriate to stop breastfeeding unless the currently prescribed drug is absolutely contraindicated in breastfeeding. As treatment of maternal mental illness is the priority, in such cases treatment should not be withheld but the mother should be advised to bottle feed with formula milk. ■ ■When initiating a drug postpartum it is: ■ ■important to consider the mother’s previous response to treatment ■ ■best to avoid a psychotropic with high reported infant plasma levels or a high RID ■ ■important to consider the half-lives of the drugs: drugs with a long half-life can accumulate in breast milk and the infant. ■ ■Neonates and infants do not have the same capacity for drug clearance as adults. Premature infants and infants with renal, hepatic, cardiac or neurological impairment are at a greater risk from exposure to drugs. ■ ■Infants should be monitored for any specific adverse effects of the drugs as well as for abnormalities in feeding patterns and growth and development. ■ ■Infant plasma levels should be monitored if adverse effects are noted or toxicity is suspected. ■ ■Women receiving sedating medication should be strongly advised to not breastfeed in bed as they may fall asleep and roll onto the baby, with a potential risk of hypoxia to the baby. ■ ■Sedation may affect women’s ability to interact with their children. Women receiving sedating drugs should be monitored for this effect. ■ ■Wherever possible: ■ ■use the lowest effective dose ■ ■avoid polypharmacy ■ ■continue the regimen prescribed during pregnancy. Table 7.1 outlines recommendations for treatment with psychotropics in breastfeeding. Antidepressants in breastfeeding Table 7.2 provides information on individual drugs in breastfeeding based on available published data in late 2023. Manufacturers’ formal advice on drugs in breastfeeding is available in the formal product literature or European Public Assessment Report for individual drugs. Table 7.2 does not include this advice (which is often uninformative), but instead uses primary reference sources. It is worth repeating that it is usually advisable to continue the antidepressant prescribed during pregnancy. Switching drugs postpartum for the purpose of breastfeeding is usually not sensible. Table 7.2 should be used as a guide when initiating treatment postpartum. In each case previous response (and lack of response) to treatment must be considered.

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12 - Antipsychotics in breastfeeding

Antipsychotics in breastfeeding

12 - Chapter 7 Prescribing in pregnancy and breastfeedi

13 - Mood stabilisers in breastfeeding

Mood stabilisers in breastfeeding

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14 - Hypnotics in breastfeeding

Hypnotics in breastfeeding

736 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 Antipsychotics in breastfeeding Table 7.3 provides information on individual drugs in breastfeeding based on available published data in mid-2024. Manufacturers’ formal advice on drugs in breastfeeding is available in the SPC or European Public Assessment Report for individual drugs. Table 7.3 does not include this advice (which is often uninformative), but instead uses primary reference sources. It is usually advisable to continue the antipsychotic prescribed during pregnancy. Switching drugs postpartum for the purpose of breastfeeding is usually not sensible. The exception to this is clozapine; clozapine should continue but breastfeeding should be avoided. Table 7.3 should be used as a guide when initiating treatment postpartum. In each case the previous response (and lack of response) to treatment must be considered. Mood stabilisers in breastfeeding Table 7.4 provides information on individual drugs in breastfeeding based on available published data in mid-2024. Manufacturers’ formal advice on drugs in breastfeeding is available in the SPC or European Public Assessment Report for individual drugs. Table 7.4 does not include this advice (which is often uninformative), but instead uses primary reference sources. It is usually advisable to continue the mood stabiliser prescribed during pregnancy. Switching drugs postpartum for the purpose of breastfeeding is usually not sensible. The exception to this is lithium. Lithium should be continued but breastfeeding should not be permitted. Table 7.4 should be used as a guide when initiating treatment postpartum. In each case the previous response (and lack of response) to treatment must be considered. Hypnotics in breastfeeding Table 7.5 provides information on individual drugs in breastfeeding based on available published data in mid-2024. Manufacturers’ formal advice on drugs in breastfeeding is available in the SPC or European Public Assessment Report for individual drugs. Table 7.5 does not include this advice (which is often uninformative), but instead uses primary reference sources. Table 7.1 Summary of recommendations. It is usually advisable to continue whichever drug has been used during pregnancy. When initiating a drug postpartum, previous response and tolerability should be considered Drug group Recommended drugs Antidepressants When initiating an antidepressant postpartum, sertraline may be considered. Other drugs may be used. See Table 7.2. Antipsychotics Women taking clozapine should be advised against breastfeeding and clozapine should be continued When initiating an antipsychotic postpartum, olanzapine or quetiapine may be considered. Other drugs may be used. See Table 7.3. Mood stabilisers Women taking lithium should be advised against breastfeeding and lithium should be continued When initiating a mood stabiliser postpartum, a mood-stabilising antipsychotic such as olanzapine or quetiapine may be considered. Other drugs may be used. See Table 7.4. Sedatives Best avoided. Use a drug with a short half-life. See Table 7.5.

Table 7.2 Antidepressants in breastfeeding. Drug Infant plasma concentrations Relative infant dose (RID) Reported acute adverse effects in infant Reported developmental effects in infant Agomelatine4,5 Not assessed Not available None reported but not studied None reported but not studied Brexanolone6 Not assessed 1–2% None reported but not studied None reported but not studied Bupropion5,7–14 Undetectable or low 0.2–2% Two reports of seizure-like activity in 6-month-olds. In one of the cases the infant experienced sleep disturbance, severe emesis and somnolence. The infant plasma levels were below the level required for quantification. The mother was also taking escitalopram. None reported but not studied Citalopram2,5,12,15–24 Undetectable to up to 10% of maternal plasma levels Higher than for fluvoxamine, sertraline, paroxetine and escitalopram, but lower than for fluoxetine 3.56–5.37%5 Sleep disturbance (which resolved on halving maternal dose), colic, decreased feeding, irritability and restlessness One case of irregular breathing, sleep disorder and hypo- and hypertonia; the Infant was exposed to citalopram in utero. Symptoms were attributed to withdrawal syndrome despite the mother continuing citalopram postpartum. None reported In a study of 78 infants of mothers taking an SSRI or venlafaxine, no difference in weight was noted at 6 months compared with the ‘normative’ weight. In a study of 11 infants, normal neurodevelopment was observed up to 1 year. One of the children was unable to walk at 1 year, However, neurological status of the child was deemed normal 6 months later. Duloxetine5,12,25–28 <1% of maternal plasma levels <1% Dizziness, nausea and fatigue None reported but not assessed (Continued)

Drug Infant plasma concentrations Relative infant dose (RID) Reported acute adverse effects in infant Reported developmental effects in infant Escitalopram5,12,14,29–34 Undetectable or low 3–8.3% Necrotising enterocolitis in 5-day-old infant (necessitating intensive care admission and intravenous antibiotic treatment). Infant was exposed to escitalopram in utero. Symptoms were lethargy, decreased oral intake and blood in the stools. Seizure-like activity, sleep disturbance, severe emesis and somnolence in 6-monthold. Mother was also taking bupropion. None reported but not studied Fluoxetine2,5,12,15,24,35–46 Variable: can be >10% of maternal plasma levels. Highest reported levels of SSRIs 1.6–14.6% Colic, excessive crying, decreased sleep, diarrhoea, vomiting, somnolence, decreased feeding, hypotonia, moaning, grunting and hyperactivity One case of seizure activity at 3 weeks, 4 months and then 5 months. Mother was also taking carbamazepine. One case of tachypnoea, jitteriness, irritability, fever and compensated metabolic acidosis. Infant plasma levels were in the adult therapeutic range. The authors diagnosed serotonin syndrome. Mother was taking fluoxetine 60mg. Normal weight gain and neurological development have been reported for many infants. One retrospective study found lower growth curves compared with non- exposed infants. One case of a reduction in platelet serotonin Fluvoxamine5,12,15,47–54 Undetectable to up to half the maternal plasma level 1–2% Neonatal jaundice, severe diarrhoea, mild vomiting, decreased sleep and agitation None reported In a study of 78 infants of mothers taking an SSRI or venlafaxine, no difference in weight was noted at 6 months compared with the ‘normative’ weight. MAOIs55,56 No published data available at the time of writing Isoniazid = 1.2–18% None reported None reported but not assessed Table 7.2 (Continued)

Drug Infant plasma concentrations Relative infant dose (RID) Reported acute adverse effects in infant Reported developmental effects in infant Mianserin5,57 Not assessed Not assessed None reported None reported but not studied Mirtazapine5,12,58,59 Undetectable or low. There was one case of higher mirtazapine plasma levels. Elimination rates may differ between individual infants 0.5–4.4% In a study of 54 infants exposed to mirtazapine in utero, the incidence of poor neonatal adaptation syndrome was significantly diminished in those who were breastfed. None reported In a study of eight infants, weights for three were observed to be between the 10th to 25th percentiles; all three were noted to also have a low birth weight. Moclobemide5,60,61 Low 3.4% None reported None reported but not studied Paroxetine2,5,12,15,24,39,47,62–71 Undetectable or low 0.5–2.8% Vomiting and irritability which were attributed to severe hyponatraemia In a study of 72 infants, adverse effects were noted in nine infants. Insomnia, restlessness and constant crying were most commonly reported. None reported In a study of 78 infants of mothers taking an SSRI or venlafaxine, no difference in weight was noted at 6 months compared with the ‘normative’ weight. Breastfed infants of 27 women taking paroxetine reached the usual developmental milestones at 3, 6 and 12 months, similar to a control group. Reboxetine5,12,72 Undetectable or low 1–3% None reported In a study of four infants, three reached normal milestones. The fourth had developmental problems thought not to be related to reboxetine. Sertraline5,12,24,39,66,73–81 Undetectable or low. There was one report of an unusually high infant serum level (half maternal serum level). The infant was reported to be ‘clinically thriving’ 0.5–3% Serotonergic overstimulation reported in preterm infant also exposed to sertraline in utero. Symptoms included hyperthermia, shivering, myoclonus, tremor, irritability, high-pitched crying, decreased suckling reflex and reactivity Withdrawal symptoms (agitation, restlessness, insomnia and an enhanced startle reaction) developed in a breastfed neonate, after abrupt withdrawal of maternal sertraline. The neonate was exposed to sertraline in utero. None reported In a study of 78 infants of mothers taking an SSRI or venlafaxine, no difference in weight was noted at 6 months compared with the ‘normative’ weight. (Continued)

Drug Infant plasma concentrations Relative infant dose (RID) Reported acute adverse effects in infant Reported developmental effects in infant Trazodone5,82,83 Not assessed 2.8% None reported None reported Tricyclic antidepressants (TCAs)5,15,84–92 Undetectable or low Nortriptyline Amitriptyline 1–3% Clomipramine Adverse effects have not been reported in infants exposed to nortriptyline, clomipramine, imipramine, dosulepin and desipramine through breast milk. Severe sedation and poor feeding reported with amitriptyline Poor suckling, muscle hypotonia, drowsiness and respiratory depression reported with doxepin None reported A study of 15 children did not show a negative outcome in regard to cognitive development in breastfed children 3–5 years postpartum. Venlafaxine5,12,24,39,66,93–100 Undetectable to up to 37% of maternal plasma levels 6–9% (>10% reported in one case)101 Lethargy, jitteriness, rapid breathing, poor suckling and dehydration in an infant also exposed in utero. Symptoms subsided over a week on breastfeeding. Authors suggested that breastfeeding may have helped manage infant withdrawal symptoms postpartum. None reported In a study of 78 infants of mothers taking an SSRI or venlafaxine, no difference in weight was noted at 6 months compared with the ‘normative’ weight. Vortioxetine 1.1 –1.7%102 1.1–1.8% None reported None reported but not studied MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor. Table 7.2 (Continued)

Table 7.3 Antipsychotics in breastfeeding. Drug Infant plasma concentration Estimated daily infant dose as proportion of maternal dose (RID) Acute adverse effects in infant Developmental effects in infant Amisulpride5,96,103–105 10.5% of maternal plasma concentration* 4.7–10.7% None reported None reported Aripiprazole5,106–111 (may lead to reduced milk supply)112,113 4% of maternal plasma concentration* 0.9–8.3% None reported None reported Asenapine No published data available at the time of writing Brexpiprazole (may lead to reduced milk supply)112 No published data available at the time of writing Butyrophenones5,15,39,84,104,114–117 Not reported Haloperidol = 0.2–12% One case of hypersomnia, poor feeding and slowing in motor movements. Mother was also taking risperidone. The effects were noted when haloperidol dose was increased. Delayed development was noted in three infants exposed to a combination of haloperidol and chlorpromazine in breast milk. Normal development has also been reported. Cariprazine No published data available at the time of writing Clozapine5,15,39,84,115,118–121 NB avoid 6.5% of maternal plasma concentration* 1.4% Sedation, agranulocytosis, decreased sucking reflex, irritability, seizures and cardiovascular instability There is one report of delayed speech acquisition. The infant was also exposed to clozapine in utero. Iloperidone No published data available at the time of writing Lurasidone No published data available at the time of writing (Continued)

Drug Infant plasma concentration Estimated daily infant dose as proportion of maternal dose (RID) Acute adverse effects in infant Developmental effects in infant Lumateperone Published data not available Olanzapine5,15,39,104,122–134 Undetectable or low One case of plasma levels decreasing over 5 months. The authors proposed that an infant’s capacity to metabolise olanzapine ‘developed rapidly’ around the age of 4 months 1.0–1.6% Somnolence, drowsiness, irritability, tremor, insomnia, lethargy, poor suckling and shaking One case of jaundice and sedation. Infant was exposed in utero and had cardiomegaly. One case of lower developmental age than chronological age. Mother was taking additional psychotropic medication. One case of speech delay and one of motor developmental delay Two cases of failure to gain weight Normal development has also been reported. Paliperidone No specific data available (see risperidone) Phenothiazines5,15,84,114–116 Variable Chlorpromazine = 0.3% Lethargy Delayed development in three infants exposed to a combination of chlorpromazine and haloperidol Pimavanserin No published data available at the time of writing Quetiapine5,97,131,135–144 Undetectable 0.09–0.1% Excessive sleep. Mother was also taking mirtazapine and a benzodiazepine. In a small study of quetiapine augmentation of maternal antidepressant, there were two cases of mild developmental delays, thought not to be related to quetiapine. Table 7.3 (Continued)

Drug Infant plasma concentration Estimated daily infant dose as proportion of maternal dose (RID) Acute adverse effects in infant Developmental effects in infant Risperidone5,117,145–149 Risperidone undetectable 9-hydoxyrisperidone low Risperidone = 2.8–9.1% 9-hydoxyrisperidone = 3.46–4.7% One case of hypersomnia, poor feeding and slowing in motor movements. Mother was also taking haloperidol. The effects were noted when haloperidol dose was increased. None reported Sertindole No published data available at the time of writing Sulpiride5,150–154 Not reported 2.7–20.7% None reported None reported but not assessed Thioxanthenes5,15,116,155–157 Not reported Zuclopenthixol = 0.4–0.9% Flupentixol = 0.7–1.75% None reported None reported for flupentixol Not assessed for zuclopenthixol Ziprasidone5,23,116,158 Not reported 0.07–1.2% None reported None reported *A proportion of the drug detected may have been due to placental transfer following in utero exposure. RID, relative infant dose.

Table 7.4 Mood stabilisers in breastfeeding. Drug Infant plasma concentration 1.1–7.3% Adverse effects have not been reported for a number of infants. One case of cholestatic hepatitis, one of transient hepatic dysfunction with hyperbilirubinaemia and elevated GGT. Adverse effects in the first case resolved after discontinuation of breastfeeding and the second resolved despite continued feeding. One case of seizure-like activity, drowsiness, irritability and high-pitched crying. Mother was taking multiple agents. Poor suckling, poor feeding and two cases of hyperexcitability Carbamazepine5,15,159–169 Generally low although one report of an infant plasma level within adult therapeutic range Lamotrigine5,162,167,170–181 Up to 48% of maternal plasma levels182 9.2–18.3% No adverse effects have been reported in a number of infants. Seven cases of thrombocytosis One case of a severe cyanotic episode (preceded by mild episodes of apnoea) requiring resuscitation. Neonatal serum concentration was in the upper therapeutic range. The infant was exposed in utero and the mother was taking a high dose (850mg/ day). One case of normocytic normochromic anaemia and asymptomatic neutropenia.183 In Australia, the Centre for Perinatal Excellence (COPE) recommends close monitoring of the infant and a specialist neonatologist consultation where possible3 Estimated daily infant dose as proportion of maternal dose (RID) Acute adverse effects in infant Developmental effects in infant None reported A prospective study of children of women with epilepsy found no adverse development at ages 6–36 months. The study assessed outcomes in children exposed to anticonvulsants in utero who were subsequently breastfed compared with those who were not. A study of 199 infants exposed to antiepileptic medications in utero and through breast milk failed to show a difference in IQ between breastfed and non- breastfed infants at the age of 3 years. A study of 181 children concluded that IQ was not adversely affected by anticonvulsant exposure through breast milk. No abnormalities reported A prospective study of children of women with epilepsy found that breastfeeding while taking an anticonvulsant was not associated with adverse development of infants at ages 6–36 months. The study assessed outcomes in children exposed to anticonvulsants in utero who were subsequently breastfed compared with those who were not. A study of 199 infants exposed to antiepileptic medications during breastfeeding failed to show a difference in IQ between breastfed and non-breastfed infants at the age of 3 years. The infants were exposed to antiepileptic medications in utero. A study of 181 children concluded that IQ was not adversely affected by anticonvulsant exposure in breast milk. Three cases of rash. In one case the rash was attributed to eczema, and to soy allergy in another. The third case resolved spontaneously.

Drug Infant plasma concentration Estimated daily infant dose as proportion of maternal dose (RID) Acute adverse effects in infant Developmental effects in infant Lithium184 NB avoid Up to 57% of maternal plasma levels 12–30.1% Early feeding problems, increased urea, raised creatinine and non-specific signs of toxicity One case of elevated TSH. In utero exposure. One case of cyanosis, lethargy, hypothermia, hypotonia and a heart murmur. In utero exposure No adverse effects have been reported in others. None reported Topiramate185,186 Undetectable to 20% of maternal plasma levels 3– 35% Diarrhoea None reported but not assessed Valproate5,15,159–162,167,187,188 <2% of maternal plasma levels 1.4–1.7% Thrombocytopenia and anaemia which reversed on stopping breastfeeding. In utero exposure A prospective study of children of women with epilepsy found that breastfeeding while taking an anticonvulsant was not associated with adverse development of infants at ages 6–36 months. The study assessed outcomes in children exposed to anticonvulsants in utero who were subsequently breastfed compared with those who were not. A study of 199 infants exposed to antiepileptic medications during breastfeeding failed to show a difference in IQ between breastfed and non-breastfed infants at the age of 3 years. The infants were exposed to antiepileptic medications in utero. A study of 181 children concluded that IQ was not adversely affected by anticonvulsant exposure through breast milk. GGT, gamma-glutamyl transferase; RID, relative infant dose; TSH, thyroid-stimulating hormone.

Table 7.5 Hypnotics in breastfeeding. Drug Infant plasma concentration Estimated daily infant dose as proportion of maternal dose (RID) Acute adverse effects in infant Developmental effects in infant Benzodiazepines5,15,39,189–196 Clonazepam: undetectable to 10% of maternal plasma levels197 Clonazepam = 2.8% Diazepam = 0.88–7.1% Lorazepam = 2.6–2.9% Oxazepam = 0.28–1% Sedation, lethargy, weight loss and mild jaundice One case of persistent apnoea with clonazepam Restlessness and mild drowsiness with alprazolam In a telephone survey of 124 women two reported CNS depression in their breastfeeding neonates. One of the children was exposed to benzodiazepines in utero. No adverse effects have been reported in others. None reported but not studied Promethazine No published data available at the time of writing Zopiclone, zolpidem and zaleplon5,198–200 Zolpidem: undetectable201 Zopiclone and zaleplon: not reported Zaleplon = 1.5% Zopiclone = 1.5% Zolpidem = 0.02–0.18% None reported None reported but not studied RID, relative infant dose.

12 - Chapter 7 Prescribing in pregnancy and breastfeedi

15 - Stimulants in breastfeeding

Stimulants in breastfeeding

12 - Chapter 7 Prescribing in pregnancy and breastfeedi

16 - References

References

Prescribing in pregnancy and breastfeeding CHAPTER 7 Stimulants in breastfeeding Table 7.6 provides information on individual drugs in breastfeeding based on available published data in mid-2024. Manufacturers’ formal advice on drugs in breastfeeding is available in the SPC or European Public Assessment Report for individual drugs. Table 7.6 does not include this advice (which is often uninformative), but instead uses primary reference sources. It is usually advisable to continue the drug prescribed during pregnancy. Switching drugs postpartum for the purpose of breastfeeding is usually not sensible. Table 7.6 should be used as a guide when initiating treatment postpartum. In each case the previous response (and lack of response) to treatment must be considered. References

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COPE (Centre of Perinatal Excellence). 2023 National Perinatal Mental Health Guideline. 2023; https://www.cope.org.au/health- professionals/review-of-new-perinatal-mental-health-guidelines/.
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Baab SW, et al. Serum bupropion levels in 2 breastfeeding mother-infant pairs. J Clin Psychiatry 2002; 63:910–911. Table 7.6 Stimulants in breastfeeding. Drug Infant plasma concentration Estimated daily infant dose as proportion of maternal dose (RID) Acute adverse effects in infant Developmental effects in infant Atomoxetine No published data available at the time of writing Dexamfetamine202 Undetectable to 14% of maternal plasma level 2.4 –10.6% None reported None reported but not assessed Lisdexamfetamine No published data available at the time of writing Methylphenidate28,203–205 Undetectable 0.16–0.7% None reported None reported Modafinil206,207 Armodafanil = 1.5%208 Modafanil not reported Armodafanil = 4.85%208 Modafanil = 5.3% None reported None reported but not assessed RID, relative infant dose.

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Gentile S. Quetiapine-fluvoxamine combination during pregnancy and while breastfeeding (Letter). Arch Womens Ment Health 2006; 9:158–159. 137. Seppala J. Quetiapine (Seroquel) is effective and well tolerated in the treatment of psychotic depression during breast feeding. Eur Neuropsychopharmacol 2004; 7 Suppl 1:S245. 138. Kruninger U, et al. Pregnancy and lactation under treatment with quetiapine. Psychiatr Prax 2007; 34 Suppl 1:S75–S76. 139. Ritz S. Quetiapine monotherapy in post-partum onset bipolar disorder with a mixed affective state. Eur Neuropsychopharmacol 2005; 15 Suppl 3:S407. 140. Rampono J, et al. Quetiapine and breast feeding. Ann Pharmacother 2007; 41:711–714. 141. Tanoshima R, et al. Quetiapine in human breast milk – population PK analysis of milk levels and simulated infant exposure. J Popul Ther Clin Pharmacol 2012; 19:e259–e298. 142. Yazdani-Brojeni P, et al. Quetiapine in human milk and simulation-based assessment of infant exposure. Clin Pharmacol Ther 2010; 87 Suppl 1:S3–S4. 143. Var L, et al. Management of postpartum manic episode without cessation of breastfeeding: a longitudinal follow up of drug excretion into breast milk. Eur Neuropsychopharmacol 2013; 23 Suppl 2:S382.

Prescribing in pregnancy and breastfeeding CHAPTER 7 144. Van Boekholt AA, et al. Quetiapine concentrations during exclusive breastfeeding and maternal quetiapine use. Ann Pharmacother 2015; 49:743–744. 145. Hill RC, et al. Risperidone distribution and excretion into human milk: case report and estimated infant exposure during breast-feeding. J Clin Psychopharmacol 2000; 20:285–286. 146. Aichhorn W, et al. Risperidone and breast-feeding. J Psychopharmacol 2005; 19:211–213. 147. Ilett KF, et al. Transfer of risperidone and 9-hydroxyrisperidone into human milk. Ann Pharmacother 2004; 38:273–276. 148. Ratnayake T, et al. No complications with risperidone treatment before and throughout pregnancy and during the nursing period. J Clin Psychiatry 2002; 63:76–77. 149. Weggelaar NM, et al. A case report of risperidone distribution and excretion into human milk: how to give good advice if you have not enough data available. J Clin Psychopharmacol 2011; 31:129–131. 150. Ylikorkala O, et al. Treatment of inadequate lactation with oral sulpiride and buccal oxytocin. Obstet Gynecol 1984; 63:57–60. 151. Ylikorkala O, et al. Sulpiride improves inadequate lactation. BMJ 1982; 285:249–251. 152. Aono T, et al. Augmentation of puerperal lactation by oral administration of sulpiride. J Clin Endocrinol Metab 1970; 48:478–482. 153. Polatti F. Sulpiride isomers and milk secretion in puerperium. Clin Exp Obstet Gynecol 1982; 9:144–147. 154. Aono T, et al. Effect of sulpiride on poor puerperal lactation. Am J Obstet Gynecol 1982; 143:927–932. 155. Matheson I, et al. Milk concentrations of flupenthixol, nortriptyline and zuclopenthixol and between-breast differences in two patients. Eur J Clin Pharmacol 1988; 35:217–220. 156. Kirk L, et al. Concentrations of Cis(Z)-flupentixol in maternal serum, amniotic fluid, umbilical cord serum, and milk. Psychopharmacology (Berl) 1980; 72:107–108. 157. Aes-Jorgensen T, et al. Zuclopenthixol levels in serum and breast milk. Psychopharmacology (Berl) 1986; 90:417–418. 158. Schlotterbeck P, et al. Low concentration of ziprasidone in human milk: a case report. Int J Neuropsychopharmacol 2009; 12:437–438. 159. Chaudron LH, et al. Mood stabilizers during breastfeeding: a review. J Clin Psychiatry 2000; 61:79–90. 160. Wisner KL, et al. Serum levels of valproate and carbamazepine in breastfeeding mother-infant pairs. J Clin Psychopharmacol 1998; 18:167–169. 161. Ernst CL, et al. The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-spectrum psychotropics. J Clin Psychiatry 2002; 63 Suppl 4:42–55. 162. Meador KJ, et al. Effects of breastfeeding in children of women taking antiepileptic drugs. Neurology 2010; 75:1954–1960. 163. Zhao M, et al. [A case report of monitoring on carbamazepine in breast feeding woman]. Beijing Da Xue Xue Bao 2010; 42:602–603. 164. Froescher W, et al. Carbamazepine levels in breast milk. Ther Drug Monit 1984; 6:266–271. 165. Frey B, et al. Transient cholestatic hepatitis in a neonate associated with carbamazepine exposure during pregnancy and breast-feeding. Eur J Pediatr 1990; 150:136–138. 166. Merlob P, et al. Transient hepatic dysfunction in an infant of an epileptic mother treated with carbamazepine during pregnancy and breastfeeding. Ann Pharmacother 1992; 26:1563–1565. 167. Veiby G, et al. Early child development and exposure to antiepileptic drugs prenatally and through breastfeeding: a prospective cohort study on children of women with epilepsy. JAMA Neurol 2013; 70:1367–1374. 168. Pynnonen S, et al. Carbamazepine and mother’s milk (Letter). Lancet 1975; 2:563. 169. Meador KJ, et al. Breastfeeding in children of women taking antiepileptic drugs: cognitive outcomes at age 6 years. JAMA Pediatr 2014; 168:729–736. 170. Ohman I, et al. Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation. Epilepsia 2000; 41:709–713. 171. Liporace J, et al. Concerns regarding lamotrigine and breast-feeding. Epilepsy Behav 2004; 5:102–105. 172. Gentile S. Lamotrigine in pregnancy and lactation (Letter). Arch Womens Ment Health 2005; 8:57–58. 173. Page-Sharp M, et al. Transfer of lamotrigine into breast milk (Letter). Ann Pharmacother 2006; 40:1470–1471. 174. Rambeck B, et al. Concentrations of lamotrigine in a mother on lamotrigine treatment and her newborn child. Eur J Clin Pharmacol 1997; 51:481–484. 175. Tomson T, et al. Lamotrigine in pregnancy and lactation: a case report. Epilepsia 1997; 38:1039–1041. 176. Newport DJ, et al. Lamotrigine in breast milk and nursing infants: determination of exposure. Pediatrics 2008; 122:e223–e231. 177. Fotopoulou C, et al. Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period. Epilepsy Res 2009; 85:60–64. 178. Nordmo E, et al. Severe apnea in an infant exposed to lamotrigine in breast milk. Ann Pharmacother 2009; 43:1893–1897. 179. Wakil L, et al. Neonatal outcomes with the use of lamotrigine for bipolar disorder in pregnancy and breastfeeding: a case series and review of the literature. Psychopharmacol Bull 2009; 42:91–98. 180. Birnbaum AK, et al. Antiepileptic drug exposure in infants of breastfeeding mothers with epilepsy. JAMA Neurol 2020; 77:441–450. 181. Kacirova I, et al. A short communication: lamotrigine levels in milk, mothers, and breastfed infants during the first postnatal month. Ther Drug Monit 2019; 41:401–404. 182. Kacirova I, et al. Monitoring of lamotrigine concentrations in mothers, colostrum, and breastfed newborns during the early postpartum period. Biomed Pharmacother 2022; 151:113167. 183. Bedussi F, et al. Normocytic normochromic anaemia and asymptomatic neutropenia in a 40-day-old infant breastfed by an epileptic mother treated with lamotrigine: infant’s adverse drug reaction. J Paediatr Child Health 2018; 54:104–105. 184. Newmark RL, et al. Risk-benefit assessment of infant exposure to lithium through breast milk: a systematic review of the literature. Int Rev Psychiatry 2019; 31:295–304.

752 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 7 185. Westergren T, et al. Probable topiramate-induced diarrhea in a 2-month-old breast-fed child – a case report. Epilepsy Behav Case Rep 2014; 2:22–23. 186. Gentile S. Topiramate in pregnancy and breastfeeding. Clin Drug Investig 2009; 29:139–141. 187. Piontek CM, et al. Serum valproate levels in 6 breastfeeding mother-infant pairs. J Clin Psychiatry 2000; 61:170–172. 188. Bjornsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scand 2008; 118:281–290. 189. Spigset O, et al. Excretion of psychotropic drugs into breast milk: pharmacokinetic overview and therapeutic implications. CNS Drugs 1998; 9:111–134. 190. Hagg S, et al. Anticonvulsant use during lactation. Drug Saf 2000; 22:425–440. 191. Iqbal MM, et al. Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant. Psychiatr Serv 2002; 53:39–49. 192. Buist A, et al. Breastfeeding and the use of psychotropic medication: a review. J Affect Disord 1990; 19:197–206. 193. Fisher JB, et al. Neonatal apnea associated with maternal clonazepam therapy: a case report. Obstet Gynecol 1985; 66:34S–35S. 194. Davanzo R, et al. Benzodiazepine e allattamento materno. Med Bambino 2008; 27:109–114. 195. Kelly LE, et al. Neonatal benzodiazepines exposure during breastfeeding. J Pediatr 2012; 161:448–451. 196. Birnbaum CS, et al. Serum concentrations of antidepressants and benzodiazepines in nursing infants: a case series. Pediatrics 1999; 104:e11. 197. Tomson T, et al. Breastfeeding while on treatment with antiseizure medications: a systematic review from the ILAE Women Task Force. Epileptic Disord 2022; 24:1020–1032. 198. Darwish M, et al. Rapid disappearance of zaleplon from breast milk after oral administration to lactating women. J Clin Pharmacol 1999; 39:670–674. 199. Pons G, et al. Excretion of psychoactive drugs into breast milk. Pharmacokinetic principles and recommendations. Clin Pharmacokinet 1994; 27:270–289. 200. Matheson I, et al. The excretion of zopiclone into breast milk. Br J Clin Pharmacol 1990; 30:267–271. 201. Saito J, et al. Presence of hypnotics in the cord blood and breast milk, with no adverse effects in the infant: a case report. Breastfeed Med 2022; 17:349–352. 202. Ilett KF, et al. Transfer of dexamphetamine into breast milk during treatment for attention deficit hyperactivity disorder. Br J Clin Pharmacol 2007; 63:371–375. 203. Hackett LP, et al. Methylphenidate and breast-feeding. Ann Pharmacother 2006; 40:1890–1891. 204. Bolea-Alamanac BM, et al. Methylphenidate use in pregnancy and lactation: a systematic review of evidence. Br J Clin Pharmacol 2014; 77:96–101. 205. Marchese M, et al. Is it safe to breastfeed while taking methylphenidate? Can Fam Physician 2015; 61:765–766. 206. Aurora S, et al. Evaluating transfer of modafinil into human milk during lactation: a case report. J Clin Sleep Med 2018; 14:2087–2089. 207. Calvo-Ferrandiz E, et al. Narcolepsy with cataplexy and pregnancy: a case-control study. J Sleep Res 2018; 27:268–272. 208. Leggett C, et al. Infant exposure to armodafinil through human milk following maternal use of modafinil. J Hum Lact 2023; 39:218–222.

13 - Chapter 8 Prescribing in hepatic and renal impairm

01 - Hepatic impairment

Hepatic impairment

13 - Chapter 8 Prescribing in hepatic and renal impairm

02 - General principles of prescribing in hepatic

General principles of prescribing in hepatic impairment

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 8 Hepatic impairment Patients with hepatic impairment may have the following: ■ ■Reduced capacity to metabolise biological waste products, dietary proteins and foreign substances such as drugs. Clinical consequences include hepatic encephalopathy and increased dose-related adverse effects from drugs. ■ ■Reduced ability to synthesise plasma proteins and vitamin K-dependent clotting factors. Clinical consequences include hypoalbuminaemia, leading in extreme cases to ascites. Increased toxicity from highly protein-bound drugs should be anticipated. There is also an increased risk of bleeding from gastrointestinal irritant drugs and with selective serotonin reuptake inhibitors (SSRIs). ■ ■Reduced hepatic blood flow. Clinical consequences include oesophageal varices and elevated plasma levels of drugs that are subject to first-pass metabolism. General principles of prescribing in hepatic impairment Liver function tests (LFTs) are a poor marker of hepatic metabolising capacity. Many patients with chronic liver disease are asymptomatic or have fluctuating clinical symptoms. LFTs help evaluate hepatic damage but tell us little about hepatic function. There are few clinical studies relating to the use of psychotropic drugs in people with hepatic disease. The following principles should be adhered to:

Prescribe as few drugs as possible.
Use lower starting doses, particularly of drugs that are highly protein bound. Tricyclic antidepressants (TCAs), SSRIs (except citalopram), trazodone and Prescribing in hepatic and renal impairment

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03 - Antipsychotics in hepatic impairment2

Antipsychotics in hepatic impairment2

754 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 antipsychotics may have increased free plasma levels, at least initially. This will not be reflected in measured (total) plasma levels. Use lower doses of drugs known to be subject to extensive first-pass metabolism. Examples include TCAs and haloperidol. 3. Be cautious with drugs that are extensively hepatically metabolised (most psychotropic drugs). Lower doses may be required. Exceptions are sulpiride, amisulpride, lithium and gabapentin, which all undergo no or minimal hepatic metabolism. 4. Leave longer intervals between dosage increases. The half-life of most drugs is prolonged in hepatic impairment and the duration of action is longer. Accumulation is more likely. Time to steady state is prolonged. 5. If albumin is reduced, consider the implications for drugs that are highly protein bound, and if ascites is present, consider the increased volume of distribution for water-soluble drugs. 6. Avoid medicines with a very long half-life or those that need to be metabolised to render them active (pro-drugs). 7. Always monitor carefully for adverse effects, which may be delayed. 8. Avoid drugs that are very sedative because of the risk of precipitating hepatic encephalopathy. 9. Avoid drugs that are very constipating because of the risk of precipitating hepatic encephalopathy. 10. Avoid drugs that are known to be hepatotoxic in their own right (e.g. monoamine oxidase inhibitors [MAOIs], chlorpromazine). Pre-existing liver disease does not increase the risk of drug-induced hepatotoxicity, but it may be more catastrophic if it does occur. 11. Choose a low-risk drug (see the tables in this section) and monitor LFTs weekly, at least initially. If LFTs deteriorate after a new drug is introduced, consider switching to another drug. Note that cross-hepatotoxicity between drugs is possible, especially if they are structurally related.1 These rules should always be observed in severe liver disease (low albumin, increased clotting time, ascites, jaundice, encephalopathy, etc.). The information here and following should be interpreted in the context of the patient’s clinical presentation. Antipsychotics in hepatic impairment2 One-third of patients who are prescribed antipsychotic medication have at least one abnormal LFT and in 4% at least one LFT is elevated three times above the upper limit of normal.3 Transaminases are most often affected and this generally occurs within 1–6 weeks of treatment initiation.3 Only rarely does clinically significant hepatic damage result.3 Later in the treatment, the development of metabolic syndrome (obesity, insulin resistance) may be linked to the emergence of non-alcoholic fatty liver disease.4,5 Table 8.1 summarises antipsychotic medications used in hepatic impairment.

Prescribing in hepatic and renal impairment CHAPTER 8 Table 8.1 Antipsychotics in hepatic impairment. Drug Comments Amisulpride6–8 Predominantly renally excreted, so dosage reduction should not be necessary as long as renal function is normal. Uncommonly associated with rises in transaminases and rarely hepatocellular injury.9 Aripiprazole6,7,10,11 Extensively hepatically metabolised. Limited data that hepatic impairment has minimal effect on pharmacokinetics. Manufacturer states no dosage reduction required in mild to moderate hepatic impairment, but caution required in severe impairment. Small number of reports of hepatotoxicity, increased LFTs, hepatitis and jaundice.3,9,12–14 Asenapine6,7,11 Hepatically metabolised. Manufacturer advises to avoid use in severe hepatic disease (sevenfold increase in asenapine exposure). No dose adjustment required in mild to moderate disease,15 but be aware of the possibility of increased plasma levels in patients with moderate impairment. Transient, asymptomatic rises in transaminases, AST and ALT are common, especially early in treatment. Single case report of mild cholestatic liver injury that resolved on stopping treatment.16 Brexpiprazole7,17 Little information. Use no more than 3mg/day (schizophrenia) or 2mg/day (depression or agitation in Alzheimer’s disease) in moderate or severe hepatic failure. Long half-life (~90 hours). Cariprazine7,18 Occasional, non-clinically relevant increases in ALT and AST. No dosage adjustment is required in patients with mild or moderate hepatic failure; not advised in severe hepatic disease (has not been evaluated). Long half-life (~2–4 days). Hepatitis has been reported. Clozapine1,6,7,19,20 Very sedative and constipating. Contraindicated in active liver disease (associated with nausea, anorexia or jaundice), progressive liver disease or hepatic failure. In less severe disease, start with 12.5mg and increase slowly, using plasma levels to gauge metabolising capacity and guide dosage adjustment. More frequently associated with changes in liver enzymes than other antipsychotics. Transient elevations in AST, ALT and GGT to over twice the normal range occur in up to a third of people, resolving spontaneously in 6–12 weeks.21 Clozapine-induced hepatitis, jaundice, cholestasis and liver failure have been reported. Clozapine should be discontinued if these develop. Successful rechallenge following hepatitis has been described.22,23 Flupentixol/ zuclopenthixol6,7,24,25 Both are extensively hepatically metabolised. Abnormal LFTs and (rarely) jaundice have been reported with flupentixol.6 Small, transient elevations in transaminases, cholestatic hepatitis and jaundice6 have been reported in some patients treated with zuclopenthixol. One report of flupentixol-induced hepatitis.26 No other literature reports of use or harm.27 Reduce doses by 50% in patients with compromised hepatic function. Depot preparations are best avoided, as altered pharmacokinetics will make dosage adjustment difficult and adverse effects from accumulation more likely. Haloperidol6 Extensively hepatically metabolised. Halve initial doses, adjust dose with smaller increments and at longer intervals. Transient and asymptomatic elevations in LFTs reported in 20% of patients.28 Isolated reports of cholestasis, acute hepatic failure, hepatitis and abnormal LFTs.6,7 Iloperidone7,11,29 Hepatically metabolised. Reduce dose in moderate impairment (twofold increase in active metabolites) and avoid completely in severe hepatic impairment (no studies done). No dose reduction necessary in mild impairment. Infrequent reports of cholelithiasis. Lumateperone30,31 Hepatically metabolised to active metabolites. No dose adjustment required in mild impairment. Increased exposure to lumateperone in moderate and severe impairment; manufacturer recommends dose of 21mg daily. Increases in transaminases reported in licensing trials. (Continued )

756 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Table 8.1 (Continued) Drug Comments Lurasidone6,7,11 Hepatically metabolised. No dose adjustment is required in mild hepatic impairment. Manufacturer recommends a starting dose of 18.5mg (20mg) in moderate or severe hepatic impairment, and a maximum dose of 74mg (80mg)/day in moderate impairment (1.7-fold increase in exposure) and of 37mg (40mg)/day in severe impairment (threefold increase in exposure). Increases in ALT reported infrequently. Olanzapine1,6,7,11 Although extensively hepatically metabolised, the pharmacokinetics of olanzapine seem to change little in severe hepatic impairment. It is sedative and anticholinergic (can cause constipation) so caution is advised. Start with 5mg/day in moderate or severe impairment and consider using plasma levels to guide dosage (aim for 20–40mcg/L). Dose-related, transient, asymptomatic elevations in ALT and AST are very common in physically healthy adults, particularly early in treatment. Along with clozapine, more often associated with drug-induced liver injury than other antipsychotics.32,33 Paliperidone6,7,11 Mainly excreted unchanged so no dosage adjustment required for mild to moderate impairment. May be a good choice for patients with pre-existing hepatic disease.34–37 However, no data are available with respect to severe hepatic impairment, so caution required. Rises in transaminases and GGT reported, and some cases of jaundice and hepatic steatosis.38 One case report of hepatotoxicity with risperidone that did not remit on switching to paliperidone – it is possible that paliperidone may cause hepatotoxicity.39 Phenothiazines6,7,32 All cause sedation and constipation. Transient abnormalities in LFTs reported. Associated with cholestasis and some reports of fulminant hepatic cirrhosis. Best avoided completely in hepatic impairment, some phenothiazines are actively contraindicated. Chlorpromazine is particularly hepatotoxic and is also associated with rare cases of immune-mediated obstructive jaundice which may progress to liver disease. Pimavanserin7 Active metabolite has a very long half-life (200 hours) but hepatic impairment does not appear to affect plasma concentrations. Manufacturer advises that no dose adjustment is required. No reports of hepatotoxicity. Quetiapine6,7,11,40 Extensively hepatically metabolised but short half-life. Clearance reduced by a mean of 30% in hepatic impairment so start at 25mg/day (IR preparation) or 50mg/day (XL preparation) and increase in 25–50mg/day increments. Can cause sedation and constipation. Transient rises in AST, ALT and GGT reported, as well as jaundice and hepatitis.41 Severe hepatic toxicity probably more common with quetiapine (1.65% of patients) than other SGAs.41 Several cases of fatal hepatic failure and of hepatocellular damage reported. A number of studies describe safe use in patients with alcohol dependence.42–44 Risperidone1,6,7,11 Extensively hepatically metabolised and highly protein bound. Those with severe impairment should start at 0.5mg bd and increase by 0.5mg bd at a maximum rate of weekly for doses above 1.5mg bd. Risperidone Consta can be started at 12.5mg, or 25mg every 2 weeks if 2mg daily oral dosing has been tolerated. Okedi should be started at 75mg, after confirming tolerability of 3mg oral risperidone. Perseris can be given at 90mg monthly if 3mg oral risperidone is tolerated, and Uzedy at 50mg monthly if 2mg oral is tolerated. Transient, asymptomatic elevations in LFTs, cholestatic hepatitis, jaundice and rare cases of hepatic failure have been reported. Cross-hepatotoxicity with paliperidone has been reported.39 Steatohepatitis may arise as a result of weight gain.45 Sulpiride6,7 Almost completely renally excreted with a low potential to cause sedation or constipation. Dosage reduction should not be required. Rises in hepatic enzymes are common. Isolated case reports of cholestatic jaundice and primary biliary cirrhosis. ALT, alanine aminotransferase; AST, aspartate aminotransferase; bd, twice a day; GGT, gamma-glutamyl transferase.

13 - Chapter 8 Prescribing in hepatic and renal impairm

04 - Antidepressants in hepatic impairment2

Antidepressants in hepatic impairment2

Prescribing in hepatic and renal impairment CHAPTER 8 Antidepressants in hepatic impairment2 Of those treated with antidepressants, 0.5–3% develop asymptomatic mild elevation of hepatic transaminases.46 Onset is normally between several days and 6 months of treatment initiation and the elderly are more vulnerable.46 Frank, clinically significant liver damage however is rare and mostly idiosyncratic (unpredictable and not related to dose). Cross-toxicity within class has been described.46 Table 8.2 lists antidepressants commonly used in hepatic impairment. Table 8.2 Antidepressants in hepatic impairment. Drug Comments Agomelatine6,7,46–48 Liver injury including hepatic failure, liver enzyme increases more than 10 x ULN, and hepatitis reported, most commonly in first months of treatment. Contraindicated in hepatic impairment, including cirrhosis and active liver disease. Dose-related increase in transaminases reported; perform LFTs at baseline, 3, 6, 12 and 24 weeks during initiation and at each dose increase, and thereafter where clinically indicated. Stop treatment if transaminases rise more than 3 x ULN. Use cautiously where other risk factors for hepatic disease are present. Under current monitoring restrictions, risk of liver injury is no higher than for other antidepressants.49,50 Almost all reactions are reversible on stopping agomelatine.47 Brexanolone7,28 No dose adjustment required in hepatic impairment. Does not appear to be hepatotoxic, although experience is limited. Citalopram7,51,52 Hepatically metabolised and accumulates in chronic dosing. Dosage reduction required in renal impairment because of the extended half-life of citalopram in renal impairment which results in steady-state concentrations at a given dose to be about twice as high as those found in patients with normal renal function. Greater risk of QT interval prolongation because of higher drug exposure. Restrict the maximum daily dose to 20mg in hepatic impairment. Exercise caution due to the increased risk of bleeding seen with all SSRIs. Duloxetine6,7,53–57 Hepatically metabolised. Clearance markedly reduced even in mild impairment. Reports of hepatocellular injury (liver enzyme increases more than 10 x ULN) and, less commonly, jaundice. Hepatic failure, sometimes fatal, has been reported. Contraindicated in hepatic impairment. Escitalopram7,58,59 Hepatically metabolised and accumulates in chronic dosing. Longer half-life and 60% higher exposure in mild to moderate impairment. Initiate the dose at 5mg daily for the first 2 weeks, maximum dose 10mg daily. Careful dose titration in severe hepatic impairment. Be aware of increased risk of bleeding and QT prolongation. Fluoxetine6,7,60–64 Extensively hepatically metabolised with a long half-life (further increased in hepatic insufficiency). Kinetic studies demonstrate accumulation in compensated cirrhosis. Dose reduction (of at least 50%) or alternate-day dosing is recommended. Attainment of steady state is delayed. Asymptomatic increases in LFTs found in 0.5% of healthy adults. Rare cases of hepatitis reported. Fluvoxamine7,28,65 Hepatically metabolised and accumulates in chronic dosing. Dose adjustments are necessary in hepatic impairment. Low risk of hepatotoxicity. Raised LFTs rarely reported and do not require dose change or fluvoxamine discontinuation. Be mindful of increased risk of bleeding. Levomilnacipran, milnacipran7,28 No dose adjustment required in hepatic impairment, although the manufacturers of milnacipran advise avoiding in chronic liver disease, alcohol use or severe hepatic dysfunction. Increased liver enzymes have been reported, and hepatitis with milnacipran. Discontinue use if jaundice or liver dysfunction occurs. (Continued )

758 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Table 8.2 (Continued) Drug Comments MAOIs6,7,66 Rare cases of fatal hepatic necrosis, hepatotoxicity and jaundice with phenelzine. Rarely hepatitis is reported with tranylcypromine, and one isolated case of fatal hepatotoxicity with moclobemide. Doses of moclobemide should be reduced to half or one-third in hepatic impairment. Selegiline has not been associated with liver injury, although one study reported serum enzyme elevations in 41% of patients (other studies found no changes). Transdermal doses do not need to be adjusted in mild or moderate impairment (no data for severe impairment).67 Selegiline orodispersible tablets should be started at 1.25mg/day in mild to moderate impairment and are contraindicated in severe disease. Non-selective MAOIs are contraindicated in patients with hepatic impairment. Mirtazapine6,7,68 Hepatically metabolised and sedative. 50% dose reduction recommended based on kinetic data. Mild, asymptomatic increases in LFTs seen in healthy adults (ALT

3 times the upper limit of normal in 2%). Few cases of cholestatic and hepatocellular damage reported. Has been used safely in patients with primary biliary cholangitis.69 Paroxetine70–72 Hepatically metabolised and accumulates in chronic dosing. Dose adjustments are necessary in hepatic impairment. Raised LFTs and rare cases of hepatitis, with or without jaundice, including chronic active hepatitis, have been reported. Paroxetine has demonstrated mild to moderate antipruritic effects in cholestatic pruritus. Be aware of increased risk of bleeding. Reboxetine6,7,73 50% reduction in starting dose advised. Does not seem to be associated with hepatotoxicity. Sertraline7,28,72,74 Hepatically metabolised and accumulates in chronic dosing. Use a low or less frequent dose in mild hepatic impairment. Avoid in patients with moderate (Child–Pugh score 7–10) or severe hepatic impairment (Child–Pugh score 10–15). Rare instances of acute liver injury, with or without jaundice, have been described. Sertraline is used in the management of cholestatic pruritus. Be aware of increased risk of bleeding. Tricyclics6,7,75 All are hepatically metabolised, highly protein bound and will accumulate. They vary in their propensity to cause sedation and constipation. All are associated with raised LFTs and rare cases of hepatitis. Sedative TCAs such as trimipramine, imipramine, dothiepin (dosulepin) and amitriptyline are best avoided. Venlafaxine/ desvenlafaxine6,7,76,77 Dosage reduction of 50% advised in mild and moderate hepatic impairment. Rare cases of hepatitis reported. Vilazodone7 No dose adjustment required in hepatic impairment. Does not appear to affect liver enzymes and no cases of hepatotoxicity, but data are limited, and all other SSRIs have been linked to liver toxicity. Vortioxetine6,78,79 Extensively metabolised in the liver. Little experience in hepatic impairment, but pharmacokinetic studies suggest no dose reduction is required. Does not seem to be associated with hepatotoxicity, but experience is limited and all other SSRIs are implicated in rare instances of liver toxicity. ALT, alanine aminotransferase; LFTs, liver function tests; MAOIs, monoamine oxidase inhibitors; TCAs, tricyclic antidepressants; ULN, upper limit of normal.

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05 - Mood stabilisers in hepatic impairment6,7,80

Mood stabilisers in hepatic impairment6,7,80

Prescribing in hepatic and renal impairment CHAPTER 8 Mood stabilisers in hepatic impairment6,7,80 Recommendations for the use of mood-stabilising medications in hepatic impairment are summarised in Table 8.3. Table 8.3 Mood stabilisers in hepatic impairment. Drug Comments Carbamazepine6,7,80 Extensively hepatically metabolised and potent inducer of CYP450 enzymes (this can cause modest elevations in gamma-glutamyl transferase and alkaline phosphatase, which in themselves are not an indication for stopping6). In chronic stable disease, caution is advised. Associated with hepatitis, cholangitis, cholestatic and hepatocellular jaundice, and hepatic failure (rare). Adverse hepatic effects are most common in the first 2 months of treatment.80 Hepatocellular damage is often associated with a poor outcome. Vulnerability to carbamazepine-induced hepatic damage may be genetically determined.80 Avoid use in acute liver disease. In chronic liver disease reduce starting dose by 50%7 and titrate up slowly, using plasma levels to guide dosage. Stop if liver function tests (LFTs) deteriorate. Lamotrigine28 Manufacturers advise 50% reduction in initial dose, dose escalation and maintenance dose in moderate hepatic impairment and 75% reduction of these parameters in severe hepatic impairment. Discontinue if there is lamotrigine-induced rash (which can be serious). Elevated LFTs and hepatitis reported. Women, children and patients taking valproate appear to be at increased risk of lamotrigine-related hepatotoxicity. Lithium7 Not metabolised so dosage reduction not required as long as renal function is normal. Use serum levels to guide dosage and monitor more frequently if ascites status changes (volume of distribution will change). Asymptomatic and transient LFT abnormalities reported in small proportion of patients on long-term therapy.28 One case of ascites and one of hyperbilirubinaemia reported over many decades of lithium use worldwide. Valproate81 Highly protein bound and hepatically metabolised. Reduce doses and closely monitor LFTs in hepatic impairment. Use plasma levels (measure free levels; total concentrations may appear to be normal) to guide dosage. Contraindicated in severe and/or active hepatic impairment or family history of severe impairment. Impairment of usual metabolic pathway can lead to generation of hepatotoxic metabolites via alternative pathway. Risk of liver toxicity is increased in people with hepatic insufficiency if salicylates are used concomitantly. Associated with elevated LFTs and serious hepatotoxicity including fulminant hepatic failure (sometimes fatal). Mitochondrial disease, learning disability, polypharmacy, metabolic disorders and underlying hepatic disease may be risk factors. Particularly hepatotoxic in very young children. The greatest risk is in the first 3 months of treatment.

13 - Chapter 8 Prescribing in hepatic and renal impairm

06 - Stimulants in hepatic impairment6,7,82

Stimulants in hepatic impairment6,7,82

13 - Chapter 8 Prescribing in hepatic and renal impairm

07 - Sedatives in hepatic impairment

Sedatives in hepatic impairment

760 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Stimulants in hepatic impairment6,7,82 Recommendations for the use of stimulant medications in hepatic impairment are outlined in Table 8.4. Sedatives in hepatic impairment Table 8.5 summarises recommended sedatives in hepatic impairment. Table 8.5 Sedatives in hepatic impairment. Drug Comments Benzodiazepines Extensively hepatically metabolised. Prolonged duration of effect particularly for drugs with active metabolites (diazepam, midazolam, clonazepam). Lorazepam, oxazepam and temazepam do not have active metabolites and are preferred. Lorazepam is considered the best tolerated in advanced liver disease28 and is commonly used in alcohol withdrawal. Liver enzyme elevations are uncommon and liver injury very rare.28 Melatonin7,89 Complex handling of melatonin in liver impairment. Reduced clearance and prolonged half-life contribute to higher circulating levels of endogenous melatonin in daytime hours; negative feedback and accumulation of toxic products results in reduced endogenous production. Relevance to dosing of exogenous melatonin is unclear, although toxicity of melatonin is minimal. Manufacturer advises avoiding in moderate or severe liver disease. Rarely associated with changes in liver function tests (LFTs). Promethazine7 Extensive hepatic metabolism. Manufacturers advise caution in liver impairment. Jaundice reported with high doses. Despite widespread use, no reports of LFT abnormalities or toxicity with lower doses.28 Z drugs7,90,91 Hepatically metabolised, but all have a relatively short half-life. Reduce initial doses in mild to moderate impairment (use zopiclone 3.75mg, zolpidem 5mg, zaleplon 5mg). Avoid in severe impairment. Manufacturers warn that benzodiazepines as a class may precipitate encephalopathy. Zaleplon is subject to significant first-pass metabolism and zolpidem plasma concentrations and half-life are significantly increased in hepatic impairment. These agents should be used with caution.92 Although zopiclone has the longer half-life, this may not be clinically relevant except in severe disease.90 Zopiclone and zaleplon have not been associated with hepatotoxicity. There are rare reports of abnormal LFTs and a single case of liver injury with zolpidem.28 There is one case of acute liver injury with eszopiclone (a zopiclone isomer).93 Table 8.4 Stimulants in hepatic impairment. Drug Comments Atomoxetine83 Reduce initial and target dose by 50% in moderate impairment, and by 75% in severe impairment. Very rare reports of liver toxicity, manifested by elevated hepatic enzymes, and raised bilirubin with jaundice. Manufacturer states ‘discontinue in patients with jaundice or laboratory evidence of liver injury, and do not restart’. Dexamfetamine/ lisdexamfetamine84,85 Little experience in liver disease. Manufacturers recommend cautious dose titration. Very rarely associated with abnormal liver function, two case reports of hepatotoxicity.86,87 Methylphenidate88 Mild and transient elevations in liver enzymes have been reported. Rare reports of liver dysfunction and hypersensitivity reactions. Limited experience in liver disease.

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08 - Other psychotropics in hepatic impairment

Other psychotropics in hepatic impairment

13 - Chapter 8 Prescribing in hepatic and renal impairm

09 - Summary of recommended psychotropics in hepat

Summary of recommended psychotropics in hepatic impairment

Prescribing in hepatic and renal impairment CHAPTER 8 Other psychotropics in hepatic impairment Table 8.6 gives a summary of other psychotropics recommended in hepatic impairment. Summary of recommended psychotropics in hepatic impairment Table 8.7 gives an outline of the drug groups of psychotropics recommended for use in hepatic impairment. Table 8.6 Other psychotropics in hepatic impairment. Drug Comments Bremelanotide7 No dose adjustment required in mild to moderate hepatic impairment. Use with caution in severe impairment; adverse effects more likely.30 One case of acute hepatitis reported. Deutetrabenazine6,28 Not studied in hepatic impairment but, based on experience with tetrabenazine, use is contraindicated. Limited information available but clinically relevant hepatotoxicity not reported. Occasional asymptomatic rises in ALT. Gabapentin Largely renally excreted but occasional cases of liver toxicity reported.94,95 Lemborexant, daridorexant, suvorexant7,30 No dose adjustments in mild or moderate impairment required for suvorexant. For lemorexant and daridorexant, no dose adjustment in mild impairment (risk of increased somnolence). In moderate impairment, starting and maximum dose of 5mg for lemborexant, 25mg for daridorexant. None is recommended in severe impairment. Little experience but hepatotoxicity not reported.96 Pitolisant6,30 Extensively hepatically metabolised. No dose adjustment in mild impairment. In moderate impairment the half-life is doubled; daily dose can be increased 2 weeks after initiation, daily maximum 17.8mg. Manufacturers recommend monitoring patients with hepatic impairment for increased QTc. Contraindicated in severe impairment. Hepatic enzyme increases are uncommon. No reports of liver injury. Pregabalin Not metabolised and largely renally excreted.97 Rare cases of hepatoxicity.98,99 Solriamfetol6 Not metabolised. No known problems in liver impairment, no reports of liver injury. Valbenazine7,28 Hepatically metabolised pro-drug of α-dihydrotetrabenazine. Unlike deutetrabenazine, valbenazine is not contraindicated in liver disease, but maximum dose of 40mg in moderate to severe impairment. Few data, but no reports of clinically relevant liver injury other than a single report of reactivation of pre-existing hepatitis C. ALT, alanine aminotransferase. Table 8.7 Psychotropic drug groups in hepatic impairment. Drug group Recommended drugs Antipsychotics Sulpiride/amisulpride: no dosage reduction required if renal function is normal Paliperidone: if depot required. Antidepressants Paroxetine, sertraline, citalopram, escitalopram or vortioxetine: start at low dose. Titrate slowly (if required) as above. Mood stabilisers Lithium: use plasma levels to guide dosage. Care needed if ascites status changes. Sedatives Lorazepam, oxazepam, temazepam: short half-life with no active metabolites. Use low doses with caution, as sedative drugs used in severe disease can precipitate hepatic encephalopathy. Zopiclone: 3.75mg with care in moderate hepatic impairment.

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10 - Drug induced hepatic damage

Drug-induced hepatic damage

762 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Drug-induced hepatic damage Hy’s rule is defined as alanine aminotransferase (ALT) more than three times the upper limit of normal combined with serum bilirubin more than two times the upper limit of normal. This is recommended by the US Food and Drug Administration (FDA) to assess the hepatotoxicity of new drugs.80 Drug-induced hepatic damage can be due to: ■ ■Direct dose-related hepatotoxicity (type 1 adverse drug reaction). A small number of drugs fall into this category (e.g. paracetamol, alcohol). ■ ■Hypersensitivity reactions (type 2 adverse drug reaction). These can present with rash, fever and eosinophilia. Almost all drugs have been associated with cases of hepatotoxicity; the frequency varies. Almost any type of liver damage can occur, ranging from mild transient asymptomatic increases in LFTs to fulminant hepatic failure. See Tables 8.1–8.6 for details of the hepatotoxic potential of individual drugs. Risk factors for drug-induced hepatotoxicity include:100 ■ ■Increasing age. ■ ■Female gender. ■ ■Alcohol consumption. ■ ■Co-prescription of enzyme-inducing drugs. ■ ■Genetic predisposition. ■ ■Obesity. ■ ■Pre-existing liver disease (small effect). When interpreting LFTs, remember that:101 ■ ■About 12% of the healthy adult population have one LFT outside (above or below) the normal reference range. ■ ■Up to 10% of patients with clinically significant hepatic disease have normal LFTs. ■ ■Individual LFTs lack specificity for the liver, but more than one abnormal test greatly increases the likelihood of liver pathology. ■ ■The absolute values of LFTs are a poor indicator of disease severity. When monitoring LFTs consider the following: ■ ■Ideally LFTs should be measured before treatment starts so that ‘baseline’ values are available. ■ ■LFT elevations of over two times the upper limit of the normal reference range are rarely clinically significant. ■ ■Most drug-related LFT elevations occur early in treatment (first month) and are transient. They may indicate adaptation of the liver to the drug rather than damage per se. Transient LFT elevations may also occur during periods of weight gain.102 ■ ■If LFTs are persistently elevated more than threefold, continuing to rise or accompanied by clinical symptoms, the suspected drugs should be withdrawn. ■ ■When tracking change, >20% change in liver enzymes is required to exclude bio logical or analytical variation.

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11 - References

References

Prescribing in hepatic and renal impairment CHAPTER 8 References

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Gunther M, et al. Antipsychotic safety in liver disease: a narrative review and practical guide for the clinician. J Acad Consult Liaison Psychiatry 2023; 64:73–82.
Amatniek J, et al. Safety of paliperidone extended-release in patients with schizophrenia or schizoaffective disorder and hepatic disease. Clin Schizophr Relat Psychoses 2014; 8:8–20.
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Chang CH, et al. Paliperidone is associated with reduced risk of severe hepatic outcome in patients with schizophrenia and viral hepatitis: a nationwide population-based cohort study. Psychiatry Res 2019; 281:112597.
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Braude MR, et al. Liver disease prevalence and severity in people with serious mental illness: a cross-sectional analysis using non-invasive diagnostic tools. Hepatol Int 2021; 15:812–820.
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764 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 41. Ko S, et al. Investigation of hepatic adverse events due to quetiapine by using the common data model. Pharmacoepidemiol Drug Saf 2023; 32:1341–1349. 42. Monnelly EP, et al. Quetiapine for treatment of alcohol dependence. J Clin Psychopharmacol 2004; 24:532–535. 43. Brown ES, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in patients with bipolar disorder, mixed or depressed phase, and alcohol dependence. Alcohol Clin Exp Res 2014; 38:2113–2118. 44. Vatsalya V, et al. Safety assessment of liver injury with quetiapine fumarate XR management in very heavy drinking alcohol-dependent patients. Clin Drug Investig 2016; 36:935–944. 45. Holtmann M, et al. Risperidone-associated steatohepatitis and excessive weight-gain. Pharmacopsychiatry 2003; 36:206–207. 46. Voican CS, et al. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry 2014; 171:404–415. 47. Freiesleben SD, et al. A systematic review of agomelatine-induced liver injury. J Mol Psychiatry 2015; 3:4. 48. Gahr M, et al. Safety and tolerability of agomelatine: focus on hepatotoxicity. Curr Drug Metab 2014; 15:694–702. 49. Billioti de Gage S, et al. Antidepressants and hepatotoxicity: a cohort study among 5 million individuals registered in the French National Health Insurance Database. CNS Drugs 2018; 32:673–684. 50. Pladevall-Vila M, et al. Risk of acute liver injury in agomelatine and other antidepressant users in four European countries: a cohort and nested case-control study using automated health data sources. CNS Drugs 2019; 33:383–395. 51. Lundbeck Limited. Summary of product characteristics. Citalopram 20mg film-coated tablets. 2023; https://www.medicines.org.uk/emc/ product/992/smpc. 52. Lopez-Torres E, et al. Hepatotoxicity related to citalopram (Letter). Am J Psychiatry 2004; 161:923–924. 53. Hanje AJ, et al. Case report: fulminant hepatic failure involving duloxetine hydrochloride. Clin Gastroenterol Hepatol 2006; 4:912–917. 54. Vuppalanchi R, et al. Duloxetine hepatotoxicity: a case-series from the drug-induced liver injury network. Aliment Pharmacol Ther 2010; 32:1174–1183. 55. Lin ND, et al. Hepatic outcomes among adults taking duloxetine: a retrospective cohort study in a US health care claims database. BMC Gastroenterol 2015; 15:134. 56. McIntyre RS, et al. The hepatic safety profile of duloxetine: a review. Expert Opin Drug Metab Toxicol 2008; 4:281–285. 57. Bunchorntavakul C, et al. Drug hepatotoxicity: newer agents. Clin Liver Dis 2017; 21:115–134. 58. Lundbeck Limited. Summary of product characteristics. Escitalopram 10mg film-coated tablets. 2023; https://www.medicines.org.uk/emc/ product/7718/smpc. 59. Rao N. The clinical pharmacokinetics of escitalopram. Clin Pharmacokinet 2007; 46:281–290. 60. Schenker S, et al. Fluoxetine disposition and elimination in cirrhosis. Clin Pharmacol Ther 1988; 44:353–359. 61. Cai Q, et al. Acute hepatitis due to fluoxetine therapy. Mayo Clin Proc 1999; 74:692–694. 62. Friedenberg FK, et al. Hepatitis secondary to fluoxetine treatment. Am J Psychiatry 1996; 153:580. 63. Johnston DE, et al. Chronic hepatitis related to use of fluoxetine. Am J Gastroenterol 1997; 92:1225–1226. 64. Hale AS. New antidepressants: use in high-risk patients. J Clin Psychiatry 1993; 54 Suppl:61–70. 65. Mylan. Summary of product characteristics. Fluvoxamine 100mg film-coated tablets. 2023; https://www.medicines.org.uk/emc/product/6603/ smpc. 66. Stoeckel K, et al. Absorption and disposition of moclobemide in patients with advanced age or reduced liver or kidney function. Acta Psychiatr Scand Suppl 1990; 360:94–97. 67. Mylan Specialty LP. Highlights of prescribing information. EMSAM® (selegiline transdermal system) 2014; https://www.accessdata.fda.gov/ drugsatfda_docs/label/2014/021336s005s010,021708s000lbl.pdf. 68. Thomas E, et al. Mirtazapine-induced steatosis. Int J Clin Pharmacol Ther 2017; 55:630–632. 69. Shaheen AA, et al. The impact of depression and antidepressant usage on primary biliary cholangitis clinical outcomes. PLoS One 2018; 13:e0194839. 70. Sandoz Limited. Summary of product characteristics. Paroxetine 20mg tablets. 2024; https://www.medicines.org.uk/emc/product/4168/smpc. 71. Colakoglu O, et al. Toxic hepatitis associated with paroxetine. Int J Clin Pract 2005; 59:861–862. 72. Düll MM, et al. Evaluation and management of pruritus in primary biliary cholangitis. Clin Liver Dis 2022; 26:727–745. 73. Tran A, et al. Pharmacokinetics of reboxetine in volunteers with hepatic impairment. Clin Drug Investig 2000; 19:473–477. 74. Mylan. Summary of product characteristics. Setraline 100mg tablets. 2023; https://www.medicines.org.uk/emc/product/10586/smpc. 75. Committee on Safety of Medicines. Lofepramine (Gamanil) and abnormal blood tests of liver function. Curr Problems 1988; 23:371. 76. Archer DF, et al. Cardiovascular, cerebrovascular, and hepatic safety of desvenlafaxine for 1 year in women with vasomotor symptoms associated with menopause. Menopause 2013; 20:47–56. 77. Baird-Bellaire S, et al. An open-label, single-dose, parallel-group study of the effects of chronic hepatic impairment on the safety and pharmacokinetics of desvenlafaxine. Clin Ther 2013; 35:782–794. 78. Ryan PB, et al. Atypical antipsychotics and the risks of acute kidney injury and related outcomes among older adults: a replication analysis and an evaluation of adapted confounding control strategies. Drugs Aging 2017; 34:211–219. 79. Chen G, et al. Vortioxetine: clinical pharmacokinetics and drug interactions. Clin Pharmacokinet 2018; 57:673–686. 80. Bjornsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scand 2008; 118:281–290. 81. Guo HL, et al. Valproic acid and the liver injury in patients with epilepsy: an update. Curr Pharm Des 2019; 25:343–351. 82. Panei P, et al. Safety of psychotropic drug prescribed for attention-deficit/hyperactivity disorder in Italy. Adv Drug Reaction Bull 2010; 260:999–1002. 83. Reed VA, et al. The safety of atomoxetine for the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a comprehensive review of over a decade of research. CNS Drugs 2016; 30:603–628.

Prescribing in hepatic and renal impairment CHAPTER 8 84. Shire Pharmaceuticals Limited. Summary of product characteristics. Elvanse 20mg, 30mg, 40mg, 50mg, 60mg, 70mg hard capsules. 2023; https://www.medicines.org.uk/emc/search?q=%22Elvanse%22. 85. Medice UK Ltd. Summary of product characteristics. Amfexa 5mg, 10mg, 20mg tablets. 2023; https://www.medicines.org.uk/emc/ search?q=amfexa. 86. Vanga RR, et al. Adderall induced acute liver injury: a rare case and review of the literature. Case Rep Gastrointest Med 2013; 2013:902892. 87. Hood B, et al. Eosinophilic hepatitis in an adolescent during lisdexamfetamine dimesylate treatment for ADHD. Pediatrics 2010; 125:e1510–1513. 88. Tong HY, et al. Liver transplant in a patient under methylphenidate therapy: a case report and review of the literature. Case Rep Pediatr 2015; 2015:437298. 89. Flynn Pharma Ltd. Summary of product characteristics. Circadin 2mg prolonged-release tablets. 2021; https://www.medicines.org.uk/emc/ product/2809/smpc. 90. SANOFI. Summary of product characteristics. Zimovane 7.5mg and 3.75mg LS film-coated tablets. 2023; https://www.medicines.org.uk/ emc/product/2855/smpc. 91. Zentiva. Summary of product characteristics. Zolpidem tartrate 5mg, 10mg tablets. 2021; https://www.medicines.org.uk/emc/ search?q=zolpidem. 92. Gunja N. The clinical and forensic toxicology of Z-drugs. J Med Toxicol 2013; 9:155–162. 93. Wu T, et al. Case report of acute liver injury caused by the eszopiclone in a patient with chronic liver disease. Medicine (Baltimore) 2021; 100:e26243. 94. Jackson CD, et al. Hold the gaba: a case of gabapentin-induced hepatotoxicity. Cureus 2018; 10:e2269. 95. Chahal J, et al. Gabapentin-induced liver toxicity. Am J Ther 2022; 29:e751–e752. 96. Kärppä M, et al. Long-term efficacy and tolerability of lemborexant compared with placebo in adults with insomnia disorder: results from the phase 3 randomized clinical trial SUNRISE 2. Sleep 2020; 43:zsaa123. 97. Upjohn UK Limited. Summary of product characteristics. Lyrica (pregabalin) 25mg, 50mg, 75mg, 100mg, 150mg, 200mg, 225mg, 300mg capsules. 2024; https://www.medicines.org.uk/emc/product/10303/smpc. 98. Sendra JM, et al. Pregabalin-induced hepatotoxicity. Ann Pharmacother 2011; 45:e32. 99. Düzenli T, et al. Pregabaline as a rare cause of hepatotoxicity. Pain Med 2017; 18:1407–1408. 100. Grattagliano I, et al. Biochemical mechanisms in drug-induced liver injury: certainties and doubts. World J Gastroenterol 2009; 15:4865–4876. 101. Rosalki SB, et al. Liver function profiles and their interpretation. Br J Hosp Med 1994; 51:181–186. 102. Rettenbacher MA, et al. Association between antipsychotic-induced elevation of liver enzymes and weight gain: a prospective study. J Clin Psychopharmacol 2006; 26:500–503.

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12 - Renal impairment

Renal impairment

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13 - General principles of prescribing in renal im

General principles of prescribing in renal impairment

766 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Renal impairment Using drugs in patients with renal impairment needs careful consideration. This is partly because some drugs are nephrotoxic but principally because the pharmacokinetics (absorption, distribution, metabolism, excretion) of drugs are altered in renal impairment. In particular, patients with renal impairment have a reduced capacity to excrete drugs and their metabolites. General principles of prescribing in renal impairment ■ ■Estimate the excretory capacity of the kidney. Laboratories usually report renal function based on the estimated glomerular filtration rate (eGFR). This is derived from either the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula or the Modification of Diet in Renal Disease (MDRD) formula. The CKD-EPI formula is more accurate than the MDRD and is preferred, but note that these estimates are still less than perfect when compared with directly measured GFR.1 ■ ■Check proteinuria by measuring urinary albumin and calculate the albumin : creatinine ratio. This is because proteinuria is a significant risk factor for progression to end stage disease.1 ■ ■For most drugs and most adult patients of average build and height, eGFR (calculated using the CKD-EPI formula, Box 8.1) can be used to determine dose adjustments. ■ ■For nephrotoxic drugs, elderly patients (75 years and over) and patients at both extremes of muscle mass (body mass index [BMI] <18 or >40kg/m2), calculate creatinine clearance (CrCl) to determine dose adjustments. In addition, the Medicines Healthcare products Regulatory Agency (MHRA) advises that CrCl should be used as an estimate of renal function for direct-acting oral anticoagulants (DOACs) and drugs with a narrow therapeutic index that are mainly renally excreted (e.g. lithium) (UK Kidney Association, https://ukkidney.org). The Cockroft and Gault equation should be used to calculate CrCl (Box 8.2). Box 8.1 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula This replaces the previously used modification of diet in renal disease (MDRD) equation)2 although some pathology departments still use MDRD. GFR S k,1 S k,1 0.993 1.018 if cr cr 1.209 Age

min ( ) max [ ( ) / /

female 1.159 if black ] [ ]

Where Scr is serum creatinine in mg/dL κ is 0.7 for females and 0.9 for males α is -0.329 for females and -0.411 for males min indicates the minimum of Scr/κ or 1 max indicates the maximum of Scr/κ or 1 ■ ■Online calculator available at https://www.kidney.org/professionals/kdoqi/gfr_calculator

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14 - Stage of renal impairment

Stage of renal impairment

Prescribing in hepatic and renal impairment CHAPTER 8 Stage of renal impairment Figure 8.1 indicates how to classify the stage of renal impairment.2 Box 8.2 Cockroft and Gault equation* CrCl ml/ F age in years ideal body weight kg Ser ( min) ( ( )) ( ) um creatinine mol/L ( )

Where F = 1.23 (men) and 1.04 (women) Ideal body weight should be used for patients at extremes of body weight or else the result of the calculation is a poor estimate For men, ideal body weight (kg) = 50kg + 2.3kg per inch over 5 feet For women, ideal body weight (kg) = 45.5kg + 2.3kg per inch over 5 feet ■ ■Online calculator available at https://www.nuh.nhs.uk/staff-area/antibiotics/creatinine-clearance- calculator * This equation is not accurate if plasma creatinine is unstable (e.g. acute renal failure), in obesity, in pregnant women, in children or in diseases causing the production of abnormal amounts of creatinine. It has only been validated in white patients. Creatinine clearance is not the same as GFR and is relatively less representative of GFR in severe renal failure. ACR categories (mg/mmol) Description and range GFR categories (mL/min/1.73m2) Description and range A1 A2 A3 Normal to mildly increased Moderately increased Severely increased <3 ≥90 60–89 45–59 30–44 15–29 <15 Normal and high Mild reduction related to normal range for a young adult Mild–moderate reduction Moderate–severe reduction Severe reduction Kidney failure G1 G2 G3a G3b G4 G5 No CKD in the absence of markers of kidney damage Refer for specialist assessment 3–30 Refer for specialist assessment if the person has: • a sustained decrease in GFR of 25% or more and a change in GFR category or sustained decrease in GFR of 15 mL/min/1.73 m2 or more within 12 months • hypertension that remains poorly controlled despite the use of at least 4 antihypertensive drugs at therapeutic doses (see also ‘Hypertension’ NICE clinical guideline 127) • known or suspected rare or genetic causes of CKD • suspected renal artery stenosis Refer for specialist assessment if the person has any of the criteria in A2, or: • ACR 70mg/mmol or more, unless known to be caused by diabetes and already appropriately treated • haematuria Manage in primary care according to recommendations

30 Figure 8.1 Classification of renal impairment. ACR, albumin : creatinine ratio; CKD, chronic kidney disease; GFR, glomerular filtration rate.

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15 - Notes

Notes

768 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Notes ■ ■Monitor decline in renal function over a considerable period as a 30% change over 2 years is associated with a fivefold increase in risk of end stage renal disease. Chronic kidney disease (CKD) progression is often non-linear.1 ■ ■Monitor risk of moving from CKD stage 3–5 (eGFR 10–59) to dialysis/transplantation using the Tangri score at https://qxmd.com/calculate/calculator_125/kidney-failure- risk-equation-8-variable. The four (age, sex, eGFR, urine albumin : creatinine ratio) and eight (previous four items plus serum calcium, phosphorus, bicarbonate, albumin) variable equations accurately predict the 2- and 5-year probability of treated kidney failure (dialysis or transplantation) for a potential patient with CKD stage 3–5.3 ■ ■In general, renal function significantly affects overall drug elimination so the amount of drug excreted unchanged in urine should be 30% or more of the dose.4 ■ ■Older adults (>65 years) should be assumed to have at least mild renal impairment. Their serum creatinine may not be raised because they have a smaller muscle mass. ■ ■Avoid drugs that are nephrotoxic (e.g. lithium, non-steroidal anti-inflammatory drugs) where renal reserve is limited. ■ ■Be cautious when using drugs that are extensively renally cleared (e.g. sulpiride, amisulpride, lithium). ■ ■Elimination of drugs metabolised hepatically can be reduced in kidney disease possibly by inhibition of enzymatic activity caused by uraemia.5 ■ ■Start at a low dose and increase slowly because, in renal impairment, the half-life of a drug and the time for it to reach steady state (amount absorbed is the same as cleared when the drug is given continuously) are often prolonged. Plasma level monitoring may be useful for some drugs. ■ ■Try to avoid long-acting drugs (e.g. depot preparations). Their dose and frequency cannot be easily adjusted should renal function change. ■ ■Prescribe as few drugs as possible. Patients with renal failure take many medications requiring regular review. Interactions and adverse effects can be avoided if fewer drugs are used. ■ ■Monitor patient for adverse effects. Patients with renal impairment are more likely to experience adverse effects and they may take longer to develop than in healthy patients. Adverse effects such as sedation, confusion and postural hypotension can be more common. ■ ■Be cautious when using drugs with anticholinergic effects, since they may cause urinary retention. ■ ■There are few clinical studies of the use of psychotropic drugs in people with renal impairment. Advice about drug use in renal impairment is often based on knowledge of the drug’s pharmacokinetics in healthy patients. ■ ■The effect of renal replacement therapies (e.g. dialysis) on drugs is difficult to predict. See Tables 8.8–8.14. Seek specialist advice. ■ ■Try to avoid drugs known to prolong the QTc interval. In established renal failure electrolyte changes are common so it is probably best to avoid antipsychotics with the greatest risk of QTc prolongation (see section on ECG changes – QT prolongation in Chapter 1). ■ ■Monitor weight carefully. Weight gain predisposes to diabetes which can contribute to rhabdomyolysis6 and renal failure. Psychotropic medications commonly cause weight gain.

Prescribing in hepatic and renal impairment CHAPTER 8 ■ ■Be vigilant for serotonin syndrome with antidepressants, dystonias and neuroleptic malignant syndrome (NMS) with antipsychotics. The resulting rhabdomyolysis can cause renal failure. There are case reports of rhabdomyolysis occurring with antipsychotics without other symptoms of NMS.7–9 ■ ■Depression is common in CKD but evidence for effectiveness of antidepressants in this condition is lacking.10,11 In CKD starting some antidepressants at a higher versus lower dose reduces mortality risk.12 Depression is poorly treated in patients on haemodialysis.13 In common with other chronic physical illnesses, depression in end stage renal disease may be associated with increased mortality,14–16 and the degree of risk may be linked to the severity of the depression.17 Non-drug treatment such as cognitive behavioural therapy, exercise or relaxation techniques probably reduces depressive symptoms for adults on dialysis.18 SSRIs are associated with hip fracture in patients on haemodialysis (adjusted odds ratio 1.25; 95% confidence interval [CI] 1.17, 1.35).19 ■ ■Both schizophrenia and bipolar disorder are associated with an increased risk of CKD.20,21 ■ ■Antipsychotics (e.g. olanzapine, quetiapine) may be associated with acute kidney injury22 possibly via their effects on blood pressure and urinary retention but studies are conflicting.23 ■ ■Mood-stabilising anticonvulsants used in bipolar disorder are associated with an increased rate of CKD.21 Table 8.8 Antipsychotic medications in renal impairment. Drug Comments Amisulpride24–27 Primarily renally excreted. 50% excreted unchanged in urine. Limited experience in renal disease, one study in Chinese patients showing more than twofold increase in AUC, trough and peak plasma concentrations with GFR 30mL/min.28 Manufacturer states no data with doses of >50mg but recommends following dosing: 50% of dose if GFR 30–60mL/min; 33% of dose if GFR is 10–30mL/min; no recommendations for GFR <10mL/min so best avoided in established renal failure. Aripiprazole24,25,27,29–32 Less than 1% of unchanged aripiprazole renally excreted. Manufacturer states no dose adjustment required in renal failure as pharmacokinetics are similar in healthy and severely renally diseased patients. There is one case report of safe use of oral aripiprazole 5mg in an 83-year-old man having haemodialysis. Avoid depot formulation where possible although there is a case report of aripiprazole 400mg depot use in a 64-year-old man on haemodialysis. Asenapine25,27,33 Extensively hepatically metabolised. Manufacturer states no dose adjustment required for patients with renal impairment but no experience with use if GFR <15mL/min. A 5mg single-dose study suggests that no dose adjustment is needed with any degree of renal impairment. Chlorpromazine24,27,34–36 Less than 1% excreted unchanged in urine. Caution required in severe impairment because of the risk of accumulation. No dose adjustment required for GFR >10mL/ min. For GFR <10mL/min, start with small doses and monitor for anticholinergic, sedative and hypotensive adverse effects. (Continued )

770 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Table 8.8 (Continued) Drug Comments Clozapine25,27,37–41 Contraindicated by manufacturer in severe renal disease, but only trace amounts of unchanged clozapine are excreted in urine. No dose adjustment required in GFR

10mL/min, titrate cautiously in very severe impairment. Nocturnal enuresis and urinary retention are common adverse effects. Anticholinergic, sedative and hypotensive adverse effects are more frequent in patients with renal disease. May cause and aggravate diabetes, a common cause of renal disease. Rare case reports of interstitial nephritis and acute renal failure, but also successful continuation after renal transplantation.42 Flupentixol24,25,27 Negligible renal excretion of unchanged flupentixol. Dosing: GFR 10–50mL/min dose as in normal renal function; GFR <10mL/min start with quarter to half of normal dose and titrate slowly. May cause hypotension and sedation in renal impairment and can accumulate. Manufacturer advises caution in renal failure because of increased cerebral sensitivity to antipsychotics. Avoid depot preparations in renal impairment. Haloperidol8,24,25,27,43,44 Less than 1% excreted unchanged in the urine. Manufacturer advises caution in renal failure. Dosing: GFR 10–50mL/min dose as in normal renal function; GFR <10mL/min start with a lower dose as can accumulate with repeated dosing. A case report of haloperidol use in renal failure suggests starting at a low dose and increasing slowly. Has been used to treat uraemia-associated nausea in renal failure. Avoid depot preparations in renal impairment. Lumateperone45,46 <1% excreted unchanged in urine. Manufacturer advises no dose adjustment needed in renal impairment. Lurasidone24 9% excreted unchanged in the urine. Serum concentrations are increased by 1.5-, 1.9- and 2.0-fold in mild, moderate and severe impairment, respectively. Manufacturer advises a starting dose of 18.75mg (20mg) and maximum dose of 74mg (80mg) per day if GFR <50mL/min. Avoid in GFR <15mL/min unless benefits outweigh risks (no data to support use). Renal failure has been reported rarely. Olanzapine7,25,27,34,44,47 57% of olanzapine is excreted mainly as metabolites (7% excreted unchanged) in urine. Dosing: UK manufacturers recommend GFR <50mL/min initially 5mg daily and titrate as necessary. Avoid long-acting preparations in renal impairment unless the oral dose is well tolerated and effective. UK manufacturer recommends a lower long-acting injection starting dose of 150mg, 4-weekly in patients with renal impairment. US manufacturers state that no dose adjustment is required for oral or depot preparation. May cause and aggravate diabetes, a common cause of renal disease. Hypothermia has been reported when used in renal failure. Paliperidone25,27,34 Paliperidone is a metabolite of risperidone. 59% excreted unchanged in urine. Dosing: GFR 50–80mL/min, 3mg daily and increase according to response to max. of 6mg daily; GFR 10–50mL/min, 3mg alternate days (or 1.5mg daily) increasing to 3mg daily according to response. Use with caution as clearance is reduced by 71% in severe kidney disease. Manufacturer contraindicates oral form if GFR <10mL/min due to lack of experience, and monthly, 3-monthly and 6-monthly depot preparations if GFR <50mL/min (reduced loading and maintenance doses if GFR >50mL/min). Two case reports of successful paliperidone monthly injection use in patients with renal failure undergoing haemodialysis.48,49

Prescribing in hepatic and renal impairment CHAPTER 8 Drug Comments Pimavanserin45,50 <1% excreted unchanged in urine. Manufacturer states no dose adjustment needed in GFR ≥30mL/min but advises to avoid if GFR <30mL/min due to lack of data. Pimozide24,25,27 <1% of pimozide excreted unchanged in the urine; dose reductions not usually needed in renal impairment. Dosing: GFR 10–50mL/min dose as in normal renal function; GFR <10mL/min start at a low dose and increase according to response. Manufacturer cautions in renal failure. Quetiapine24,25,27,51–53 <5% of quetiapine excreted unchanged in the urine. Plasma clearance reduced by an average of 25% in patients with a GFR <30mL/min but manufacturer states no dose adjustment is necessary. Case reports (thrombotic thrombocytopenic purpura, DRESS and non-NMS rhabdomyolysis) resulting in acute renal failure with quetiapine have been published. Risperidone24,25,27,44,54–57 Clearance of risperidone and the active metabolite of risperidone (9-OH-) is reduced by 60% in patients with moderate to severe renal disease. Dosing: GFR <50mL/min 0.5mg twice daily for at least 1 week then increasing by 0.5mg twice daily to 1–2mg bd. The long-acting injection should only be used after titration with oral risperidone as described above. If 2mg orally is tolerated, 25mg intramuscularly every 2 weeks (Risperdal Consta®) can be administered. Manufacturers of the Okedi® monthly injection do not recommend use in GFR <60mL/min. Risvan® 75mg monthly or PerserisTM (subcutaneous) 90mg monthly can be used if 3mg oral is tolerated. UzedyTM can be given 50mg monthly if 2mg oral is tolerated. There are two case reports of successful use of risperidone long-acting injection in haemodialysis at a dose of 50mg 2 weekly in one patient and 37.5mg then 25mg in an older adult. Another describes the successful use of risperidone in a child with steroid-induced psychosis and nephrotic syndrome. Sulpiride6,24,25,27,58 Almost totally renally excreted, with 95% excreted in urine and faeces as unchanged sulpiride. Dosing regimen: GFR 30–60mL/min give 70% of normal dose; GFR 10–30mL/min give 50% of normal dose; GFR <10mL/min give 34% of normal dose. Alternately, the dosing interval can be prolonged by a factor of 1.5, 2 and 3, respectively. There is a case report of renal failure with sulpiride due to diabetic coma and rhabdomyolysis. Probably best avoided in renal impairment. Trifluoperazine27 Less than 1% excreted unchanged in the urine. Dose GFR <10–50mL/min as for normal renal function – start with a low dose. Very limited data. Ziprasidone24,44,59,60 <1% renally excreted unchanged. No dose adjustment needed for GFR >10mL/min but care needed with using the injection as it contains a renally eliminated excipient (cyclodextrin sodium). Case report of 80mg twice daily dose used in a patient on haemodialysis who then developed agranulocytosis.61 Zuclopenthixol24,27 10–20% of unchanged drug and metabolites excreted unchanged in urine. Manufacturer cautions use in renal disease as can accumulate. Dosing: 10–50mL/min dose as in normal renal function; GFR <10mL/min start with 50% of the dose and titrate slowly. Avoid both intramuscular preparations (acetate and decanoate) in renal impairment. If use is essential, follow the same dosing guidance as for oral. AUC, area under the curve; bd, twice a day; DRESS, drug reaction with eosinophilia and systemic symptoms; GFR, glomerular filtration rate. Table 8.8 (Continued)

772 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Table 8.9 Antidepressants in renal impairment.10 Drug Comments Agomelatine25 Negligible renal excretion of unchanged agomelatine. No data on use in renal disease. Manufacturer says pharmacokinetics unchanged in small study of 25mg dose in severe renal impairment but cautions use in moderate or severe renal disease. A growing number of studies demonstrate nephroprotective effects in rats. Amitriptyline24,25,27,36,44,62–64 <2% excreted unchanged in urine; no dose adjustment needed in renal failure. Dose as in normal renal function but start at a low dose and increase slowly. Monitor patient for urinary retention, confusion, sedation and postural hypotension. Has been used to treat pain in those with renal disease. Associated with acute kidney injury.64 Brexanolone45,65 <1% excreted unchanged in urine. Manufacturer states no dosage adjustment is recommended in patients with GFR 15–60mL/min; avoid use in patients with GFR of <15mL/min because of the potential accumulation of the injection solubilising agent, betadex sulfobutyl ether sodium. Bupropion24,25,27,36,44,66–68 (amfebutamone) 0.5% excreted unchanged in urine but in patients with renal impairment, plasma concentrations are higher, elimination half-life is longer and oral clearance is significantly lower. Metabolites may accumulate, increasing the risk of seizures. In renal impairment, reduce dose to 150mg once daily and/or reduce frequency of dosing. A single-dose study in haemodialysis patients (stage 5 disease) recommended a dose of 150mg every 3 days. Has been used to treat sexual dysfunction in mild to moderately depressed patients with chronic kidney disease. Citalopram24,25,27,44,69–75 <13% of citalopram excreted unchanged in urine. Single-dose studies in mild and moderate renal impairment show no change in the pharmacokinetics of citalopram. Dosing is as for normal renal function; however, use with caution if GFR <10mL/min due to reduced clearance. The manufacturer does not advise use if GFR <20mL/min. Renal failure has been reported with citalopram overdose. Citalopram can treat depression in chronic renal failure and improve quality of life but use of citalopram (or escitalopram) is associated with a higher risk of sudden cardiac death vs other SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline) when used in patients on haemodialysis (adjusted hazard ratio 1.18; 95%CI 1.05, 1.31). Concurrent PPI use may increase the risk in haemodialysis;76 minimising the serum-to-dialystate potassium gradient may attenuate it.77 A case report of hyponatraemia has been reported in a renal transplant patient on citalopram. Clomipramine25,27,34,36,78 2% of unchanged clomipramine excreted in urine. Dosing: GFR 20–50mL/min dose as for normal renal function; GFR <20mL/min, effects unknown, start at a low dose and monitor patient for urinary retention, confusion, sedation and postural hypotension as accumulation can occur. There is a case report of clomipramine- induced interstitial nephritis and reversible acute renal failure. Desvenlafaxine10,34,79,80 45% of desvenlafaxine excreted unchanged in urine. Manufacturer recommends GFR 30–50mL/min 50mg/day; GFR <30mL/min 25mg/day or 50mg on alternate days. Half-life is prolonged and desvenlafaxine accumulates as GFR decreases. Urinary retention, delay when starting to pass urine and proteinuria have been reported as adverse effects. Dosulepin27,34,81 (dothiepin) 56% of mainly active metabolites renally excreted. They have a long half-life and may accumulate, resulting in excessive sedation. Dosing: GFR 20–50mL/min dose as for normal renal function; GFR <20mL/min start with a small dose and titrate to response. Monitor patient for urinary retention, confusion, sedation and postural hypotension. Doxepin25,27,34,36,82 <1% excreted unchanged in urine. Dosing: GFR 10–50mL/min as in normal renal function but monitor patient for urinary retention, confusion, sedation and postural hypotension; GFR <10mL/min start with a small dose and increase slowly. Manufacturer advises using with caution. Haemolytic anaemia with renal failure has been reported with doxepin. Used topically to treat pruritis in chronic renal failure.

Prescribing in hepatic and renal impairment CHAPTER 8 Drug Comments Duloxetine27,34,83–85 <1% excreted unchanged in urine. Manufacturer states no dose adjustment is necessary for GFR >30mL/min; however, starting at a low dose and increasing slowly are advised. Duloxetine is contraindicated in patients with a GFR <30mL/min as it can accumulate in chronic kidney disease. Two case reports of acute renal failure with duloxetine have been reported. Serotonin syndrome was reported in a patient with chronic kidney disease on trazodone and duloxetine.86 Escitalopram27,34,75,87–89 8% excreted unchanged in urine. The manufacturer states dosage adjustment is not necessary in patients with mild or moderate renal impairment, but caution is advised if GFR <30mL/min so start with a low dose and increase slowly. A case study of reversible renal tubular defects and another of renal failure have been reported with escitalopram. One study says effective vs placebo in end stage renal disease. Use of escitalopram (or citalopram) is associated with a higher risk of sudden cardiac death vs other SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline) when used in patients on haemodialysis (adjusted hazard ratio 1.18; 95%CI 1.05, 1.31). Concurrent PPI use may increase the risk in haemodialysis;76 minimising the serum-to-dialystate potassium gradient may attenuate it.77 Fluoxetine11,25,27,34,36,44,90–93 2.5–5% of fluoxetine and 10% of the active metabolite norfluoxetine are excreted unchanged in urine. Dosing: GFR 20–50mL/min dose as normal renal function; GFR <20mL/min consider using a low dose or on alternate days and increase according to response. Plasma levels after 2 months’ treatment with 20mg (in patients on dialysis with GFR <10mL/min) are similar to those with normal renal function. Efficacy studies of fluoxetine in depression and renal disease are conflicting. One small placebo-controlled study of fluoxetine in patients on chronic dialysis found no significant differences in depression scores between the two groups after 8 weeks of treatment. Another found fluoxetine effective. A case series (n = 4) of once-weekly fluoxetine 90mg or 180mg use in depressed patients on haemodialysis describes efficacious use with better tolerability at 90mg dose. Fluvoxamine27,34,36,44,94 2% excreted unchanged in urine. Renal impairment does not appear to affect the pharmacokinetics of fluvoxamine, but the UK manufacturer recommends starting at a low dose. Acute renal failure has been reported. Variations in albumin levels might affect serum concentrations of fluvoxamine in haemodialysis. Imipramine25,27,34,36,62 <5% excreted unchanged in urine. No specific dose adjustment necessary in renal impairment. Monitor patient for urinary retention, confusion, sedation and postural hypotension. Renal impairment with imipramine has been reported and manufacturer advises caution in severe renal impairment. Renal damage reported rarely. Lofepramine25,27,34,95 There is little information about the use of lofepramine in renal impairment. <5% excreted unchanged in urine. Dosing: GFR 10–50mL/min dose as in normal renal function; GFR <10mL/min start with a small dose and titrate slowly. Manufacturer contraindicates in severe renal impairment. Mirtazapine25,27,34,96 75% excreted unchanged in urine. Clearance is reduced by 30% in patients with GFR of 11–39mL/min and by 50% in patients with GFR <10mL/min. Dosing advice: GFR 10–40mL/min dose as for normal renal function but monitor for adverse effects; GFR <10mL/min start at a low dose and monitor closely. Mirtazapine has been used to treat pruritis caused by renal failure97 and appetite loss in chronic kidney disease.98,99 Rarely associated with kidney calculus formation. Moclobemide25,27,34,100,101 <1% of parent drug excreted unchanged in urine; an active metabolite was found to be raised in patients with renal impairment but this does not appear to be clinically significant. Dose adjustments are not required in renal impairment. Table 8.9 (Continued) (Continued )

774 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Drug Comments Nortriptyline27,34,36,44,62,102 <5% excreted unchanged in urine. If GFR 10–50mL/min dose as in normal renal function; if GFR <10mL/min start at a low dose. Plasma level monitoring recommended at doses of >100mg/day, as plasma concentrations of active metabolites are raised in renal impairment. Worsening of GFR in elderly patients has also been reported. Paroxetine25,27,34,36,103–106 <2% of oral dose excreted unchanged in urine. Single-dose studies show increased plasma concentrations of paroxetine when GFR <30mL/min. Dosing advice differs: GFR 30–50mL/min dose as normal renal function; GFR <10–30mL/min start at 10mg/ day (other source says start at 20mg) and increase dose according to response in 10mg increments/week, max. dose 40mg/day. Extended release paroxetine should be started at 12.5mg/day in severe renal impairment, max. dose 50mg/day in depression or panic disorder, 37.5mg/day in social anxiety disorder. Paroxetine 10mg daily has been used to treat depression in patients on haemodialysis. Rarely associated with Fanconi syndrome and acute renal failure. Phenelzine27,34 Approximately 1% excreted unchanged in urine. No dose adjustment required in renal failure. Reboxetine25,27,34,107,108 Approximately 10% of unchanged drug excreted unchanged in urine. Dosing: GFR <80mL/min, 2mg twice daily, adjusting dose according to response. Half-life is prolonged and plasma concentration increased as renal function decreases. Sertraline25,27,34,36,109–113 <0.2% of unchanged sertraline excreted in urine. Pharmacokinetics in renal impairment are unchanged in single-dose studies but no published data on multiple dosing. Dosing is as for normal renal function. Sertraline has been used to treat dialysis-associated hypotension114 and uraemic pruritis;115 however acute renal failure has been reported so it should be used with caution. Overall, studies of sertraline in patients with depression and chronic kidney disease fail to show efficacy. The CAST study, an RCT of sertraline (median dose 150mg) vs placebo in chronic non-dialysis- dependent kidney disease, found no difference in change in depressive symptoms.113 The ASCEND trial of sertraline vs CBT in patients on haemodialysis with depression found no significant differences between sertraline (to 200mg) and CBT in response and remission rates but QIDS-C depression scores at 12 weeks were lower for sertraline than CBT.116 Another small RCT (ASSertID study) in patients with depression on haemodialysis reported no difference between sertraline and placebo.117 Has been associated with serotonin syndrome when used in patents on haemodialysis. Case report of neutropenia when used in end stage renal disease.118 May reduce CRP in patients on haemodialysis with depression119 and a high CRP may predict response to sertraline (not placebo) in depression with chronic kidney disease.120 Trazodone25,27,34,121 <5% excreted unchanged in urine but care needed as approximately 70% of active metabolite also excreted. Dosing: GFR 20–50mL/min dose as normal renal function; GFR <20mL/min start with small dose and increase gradually; serotonin syndrome reported in a patient with chronic kidney disease on trazodone and duloxetine.86 Has been trialled (unsuccessfully) for insomnia in haemodialysis, incidence of adverse events was higher with trazodone vs placebo.122 Long-term use may be associated with an increased risk of chronic kidney disease.123 Trimipramine27,34,36,62,124,125 No dose reduction required in renal impairment; however, elevated urea, acute renal failure and interstitial nephritis have been reported. As with all tricyclic antidepressants in renal impairment, monitor patient for urinary retention, confusion, sedation and postural hypotension. Table 8.9 (Continued)

Prescribing in hepatic and renal impairment CHAPTER 8 Drug Comments Venlafaxine25,34,36,126–128 1–10% excreted unchanged in urine (30% as the active metabolite). Clearance is decreased and half-life prolonged in renal impairment. Dosing: GFR 30–90mL/min reduce by 25–50%; GFR <30mL/min reduce dose by at least 50%, consider alternate day dosing. Rhabdomyolyisis129 and renal failure have been reported rarely with venlafaxine. Has been used to treat peripheral diabetic neuropathy in haemodialysis patients. High doses may cause hypertension. Vortioxetine25,130 Negligible amounts are excreted unchanged in urine. Manufacturer advises that no dose adjustment is needed in renal impairment and end stage disease but advises caution due to a lack of data. CBT, cognitive behavioural therapy; CRP, C-reactive protein; GFR, glomerular filtration rate; PPIs, proton pump inhibitors. Table 8.9 (Continued) Table 8.10 Mood stabilisers in renal impairment. Drug Comments Carbamazepine25,27,34,131–134 2–3% of dose excreted unchanged in urine. Dose reduction not necessary in renal disease, although cases of renal failure, tubular necrosis and tubulointerstitial nephritis have been reported rarely and metabolites may accumulate. Can cause Stevens–Johnson syndrome and toxic epidermal necrolysis, which may result in acute renal failure. Maintenance therapy in bipolar disorder is associated with an increased rate of chronic kidney disease.21 Lamotrigine25,27,34,135–139 <10% of lamotrigine excreted unchanged in urine. Single-dose studies in renal failure show pharmacokinetics are little affected; however, inactive metabolites can accumulate (effects unknown) and half-life can be prolonged. Renal failure and interstitial nephritis have also been reported. Dosing: GFR <10–50mL/min use cautiously, start with a low dose, increase slowly and monitor closely. One source suggests in GFR <10mL/min use 100mg every other day. Lithium25,27,34,36,140,141 Lithium is nephrotoxic and contraindicated in severe renal impairment; 95% excreted unchanged in urine. Long-term treatment may result in impaired renal function in about a quarter of patients142 (‘creatinine creep’), permanent changes in kidney histology, microcysts, oncocytoma and collecting duct renal carcinoma, nephrogenic diabetes insipidus, nephrotic syndrome and both reversible and irreversible kidney damage.143,144 However shorter studies in younger populations do not show declining GFR145 or the development of end stage renal disease.21,146,147 These differences may be due to methodology, improved monitoring and targeting recommended maintenance serum levels (0.6–0.8mmol/L in BPAD). Prevent nephrotoxicity by using once daily dosing, tightly adhering to recommended plasma levels, avoiding intoxication, assertively treating comorbidities and actively monitoring kidney function. Collaboration is vital between psychiatrist, nephrologist and patient in decision-making if chronic kidney disease occurs.148 Risk factors for lithium-induced nephrotoxicity include increasing age, duration of treatment, cumulative dose, lower initial eGFR, female gender, hypertension and diabetes, concomitant nephrotoxic drugs, nephrogenic diabetes insipidus and previous lithium toxicity.149 If lithium is used in renal impairment, toxicity is more likely and lithium toxicity increases the risk of renal impairment. Renal damage is more likely with chronic toxicity than acute. The manufacturer contraindicates lithium in severe renal impairment. Dosing: GFR 10–50mL/min avoid or reduce dose (50–75% of normal dose) and monitor levels; GFR <10mL/min avoid if possible, however if used it is essential to reduce dose (25–50% of normal dose). Lithium can be used successfully during haemodialysis.150 (Continued )

776 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Table 8.11 Anxiolytics and hypnotics in renal impairment. Drug Comments Buspirone25,27,34,36 <1% excreted unchanged; however, active metabolite is renally excreted. Dosing advice contradictory, suggests GFR 20–50mL/min start at a low dose and give twice daily; GFR <20mL/min avoid if possible due to accumulation of active metabolites; if essential, reduce dose by 25–50% if patient is anuric. Manufacturer contraindicates in severe renal impairment (GFR <20mL/min). Chlordiazepoxide25,27,36 1–2% excreted unchanged but chlordiazepoxide has a long-acting active metabolite that can accumulate. Dosing: GFR 10–50mL/min dose as normal renal function; GFR <10mL/min reduce dose by 50%. Monitor for excessive sedation. Manufacturer cautions in chronic renal disease. Long-term use may be associated with an increased risk of CKD.123 Clomethiazole25,27,34,160 (chlormethiazole) 0.1–5% of drug excreted unchanged in urine. Dose as in normal renal function but monitor for excessive sedation. Manufacturer recommends caution in renal disease. Clonazepam25,27,34,161 <0.5% of clonazepam excreted unchanged in urine. Dose adjustment not required in impaired renal function; however with long-term administration, active metabolites may accumulate so start at a low dose and increase according to response. Monitor for excessive sedation. Has been used for insomnia in patients on haemodialysis. Long-term use may be associated with an increased risk of CKD.123 Diazepam27,34,36,162 <0.5% is excreted unchanged. Dosing: GFR 20–50mL/min dose as in normal renal function; GFR <20mL/min use small doses and titrate to response. Long-acting, active metabolites accumulate in renal impairment; monitor patients for excessive sedation and encephalopathy. One case of interstitial nephritis with diazepam has been reported in a patient with chronic renal failure. Long-term use may be associated with an increased risk of CKD.123 Eszopiclone163 <10% excreted unchanged in urine. No dose adjustment is needed in renal impairment. Gabapentin 100% excreted unchanged in urine, clearance is reduced in renal impairment resulting in higher plasma concentrations and longer elimination half-lives.164 As expected this may result in toxicity in renal impairment if doses are not reduced.165 Acute renal failure has been reported,166 as has myoclonus,167 altered mental status, fall and fracture when used in patients on haemodialysis for restless legs, itch and neuropathic pain.168,169 Has been used to treat pruritis, muscle cramps and restless legs syndrome in haemodialysis patients in RCTs.170–172 Dosing advice differs: GFR 15–60mL/min start low and increase according to response; GFR <15mL/min 300mg alternate days36,166 or 100mg at night then increase according to tolerability27,173 but check for toxicity as described above. Manufacturer has table of very specific dosing in renal impairment in SMPC.166 Drug Comments Valproate25,27,34,151–155 Approximately 2% excreted unchanged. Dose adjustment usually not required in renal impairment; however free valproate levels may be increased. Renal impairment, interstitial nephritis, Fanconi syndrome, renal tubular acidosis and renal failure have been reported. Risk factors for renal tubular dysfunction include being bedbound and low serum carnitine and phosphorus levels.156 Dose as in normal renal function, however in severe impairment (GFR <10mL/min) it may be necessary to alter doses according to free (unbound) valproate levels. Possibly less likely than lithum to cause chronic kidney disease in patients with bipolar disorder157,158 but data are conflicting.159 BPAD, bipolar affective disorder; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate. Table 8.10 (Continued)

Prescribing in hepatic and renal impairment CHAPTER 8 Drug Comments Lemborexant,45,174 suvorexant, daridorexant <1% excreted unchanged in urine. Manufacturers state no dose adjustment needed in renal impairment. Exposure to lemborexant may increase during severe renal impairment with a potential increased risk of somnolence.175 Lorazepam25,27,34,36,176–181 <1% excreted unchanged in urine, dose as in normal renal function but carefully according to response as some may need lower doses. Monitor for excessive sedation. Impaired elimination reported in two patients with severe renal impairment and also reports of propylene glycol in lorazepam injection causing renal impairment and acute tubular necrosis. However, lorazepam injection has been successfully used to treat catatonia in two patients with renal failure, and it is the drug of choice in status epilepticus for patients with renal disease.182 Melatonin <1% excreted unchanged in urine. Manufacturers state limited information on use in renal impairment, but numerous studies suggest melatonin may be renoprotective in acute kidney injury and chronic renal disease183,184 and beneficial for sleep in haemodialysis patients.185,186 Dose as for normal renal function but monitor for oversedation in severe impairment. Nitrazepam25,27 <5% excreted unchanged in urine. Dosing: GFR 10–50mL/min dose as in normal renal function; GFR <10mL/min start with small dose and increase slowly. Manufacturer advises reducing dose in renal impairment. Monitor patient for sedation and unsteadiness. Long-term use may be associated with an increased risk of CKD.123 Pregabalin Up to 99% excreted unchanged in urine. Acute renal failure reported.187 Associated with altered mental status and falls when used in patients on haemodialysis168 and myoclonus.188 Case report of seizure on abrupt cessation in patient with CKD.189 Used to treat uraemic pruritis and neuropathic pain in patients on haemodialysis190–192 and restless legs syndrome in CKD.193 Dosing advice differs; titrate dosing by tolerability and response for all GFRs; initial dose for GFR 30–60mL/min 75mg daily and max. 300mg daily; GFR 15–30mL/min 25–50mg daily and max. 150mg daily; GFR <15mL/min 25mg daily and max. 75mg daily. Manufacturer has table of very specific dosing in renal impairment in SMPC.187 Oxazepam27,34,36,194 <1% excreted unchanged in urine. Dose adjustment may be needed in severe renal impairment. Oxazepam may take longer to reach steady state in patients with renal impairment. Dosing: GFR 10–50mL/min dose as in normal renal function; GFR <10mL/min start at a low dose and increase according to response. Monitor for excessive sedation. Promethazine25,27,34,36,195 Dose reduction usually not necessary; however, promethazine has a long half-life so monitor for excessive sedative effects in patients with renal impairment. Manufacturer advises caution in renal impairment. There is a case report of interstitial nephritis in a patient who was a poor metaboliser of promethazine. Temazepam25,27,34,36 <2% excreted unchanged in urine. In renal impairment the inactive metabolite can accumulate. Monitor for excessive sedative effects. Dosing: GFR 20–50mL/min dose as normal renal function; GFR <20mL/min dose as in normal renal function but start with 5mg. Zolpidem25,27,34,161,196 Clearance moderately reduced in renal impairment. No dose adjustment required in renal impairment. Zolpidem 1mg has been used to treat insomnia in patients on haemodialysis. One trial of use as a sleep aid in haemodialysis patients with pruritis.197 Associated with acute pyelonephritis in women.198 Long-term use may be associated with an increased risk of CKD.123 Zopiclone25,27,34,199,200 <5% excreted unchanged in urine. Manufacturer states no accumulation of zopiclone in renal impairment but suggests starting at 3.75mg. Dosing: GFR <10mL/ min start with lower dose. Interstitial nephritis reported rarely. Long-term use may be associated with an increased risk of CKD.123 CKD, chronic kidney disease; GFR, glomerular filtration rate; SMPC, summary of product characteristics. Table 8.11 (Continued)

778 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Table 8.12 Anti-dementia drugs in renal impairment. Drug Comments Donepezil25,27,201–203 17% excreted unchanged in urine. Dosing is as in normal renal function for GFR ≤10–50mL/min. Manufacturer states that clearance not affected by renal impairment. Single-dose studies find similar pharmacokinetics in moderate and severe renal impairment compared with healthy controls. Has been used at a dose of 3mg/day in an elderly patient with Alzheimer’s dementia on dialysis. Single case of rhabdomyolysis causing acute renal failure204 and one of donepezil-induced parkinsonism in end stage renal disease.205 Galantamine25,27 18–22% excreted unchanged in urine. Dose as in normal renal function for GFR 9–50mL/min and at GFR <9mL/min start at a low dose and increase slowly. Maximum 16mg/day in moderate impairment. Manufacturer contraindicates use in GFR <9mL/ min. Plasma levels may be increased in patients with moderate and severe renal impairment. Memantine25,34,206 Manufacturers recommend a 10mg immediate release dose if GFR 5–29mL/min; 10mg daily for 7 days then increased to 20mg daily if tolerated for GFR 30–49mL/min; no dose adjustment required for GFR >50mL/min. Extended release dose is 14mg daily for GFR 5–29mL/min. Renal tubular acidosis, severe urinary tract infections and alkalisation of urine (e.g. by drastic dietary changes, such as switching from carnivore to vegetarian diet) can increase plasma levels of memantine. Acute renal failure has been reported, and one case of encephalopathy in chronic kidney disease.207 Rivastigmine25,27 0% excreted unchanged in urine but manufacturer states caution is required for patients with renal disease because of an increased risk of adverse effects. Dosing advice for GFR <50mL/min start at a low dose and gradually increase. Steady-state plasma concentrations are not affected by renal function.208 GFR, glomerular filtration rate. Table 8.13 Other psychotropic drugs in renal impairment. Drug Comments Bremelanotide45,209 64.8% excreted unchanged in urine. Manufacturer states GFR 30–89mL/min no dosage adjustment necessary; caution for GFR <30mL/min as increased adverse effects (nausea and vomiting). Exposure is increased in renal impairment. Case report of Melotan II (bremelanotide is a variation of Melotan II) and rhabdomyolysis and renal dysfunction.210 Deutetrabenazine211 No clinical studies in renal impairment. Data limited, no specific dosing advice. Pitolisant45,212 <2% excreted unchanged in urine. Dosing: GFR 15–59mL/min 8.9mg daily, increase after 7 days to max. 17.8mg once daily;213 GFR <15mL/min not recommended.213 Peak concentrations and exposure increased in all stages of renal impairment. Solriamfetol45,214 95% excreted unchanged in urine. Dosing: GFR 60–89mL/min no dose adjustment is required; GFR 30–59mL/min 37.5mg once daily, increased to max. of 75mg once daily after 5 days; GFR 15–29mL/min 37.5mg once daily; GFR <15mL/min not recommended. In moderate or severe renal impairment risk of increased blood pressure and heart rate because of the prolonged half-life. Increased exposure and t1/2 in all stages of renal impairment particularly end stage renal disease.215 Valbenazine45 <2% excreted unchanged in urine. No adjustment is necessary. Urinary retention reported as adverse effect in clinical trials. GFR, glomerular filtration rate.

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16 - Summary of recommended psychotropics in renal

Summary of recommended psychotropics in renal impairment

Prescribing in hepatic and renal impairment CHAPTER 8 Summary of recommended psychotropics in renal impairment Where renal function declines while on existing drug treatment, rule out existing drugs as a cause of reduced function and continue at a dose suggested in Tables 8.9–8.14. Where new drug treatment is required follow the suggestions in Table 8.15. Table 8.14 Attention deficit hyperactivity disorder (ADHD) drugs in renal impairment. Drug Comments Atomoxetine24,216 No dose adjustment required. Atomoxetine may exacerbate hypertension in patients with end stage renal disease. Dexamfetamine24,217 30–40% excreted unchanged in normal urine pH (renal elimination is decreased under alkaline conditions, increased under acidic conditions). Limited data in renal disease, manufacturers state that peak plasma levels could be higher and elimination prolonged. For the transdermal patch: GFR 15–30mL/min max. dose 13.5mg/ 9 hours; GFR <15mL/min max. dose 9mg/9 hours. For oral dosing: start at low doses and increase cautiously. Lisdexamfetamine24,218 Reduced clearance in patients with severe renal insufficiency. GFR 15–30mL/min max. dose 50mg/day; GFR <15mL/min max. dose 30mg/day.219 Methylphenidate24,220 <1% excreted unchanged in urine. Limited data in renal disease, but pharmacokinetics suggest dose adjustment is unlikely to be necessary. Two case reports (one in a patient undergoing peritoneal dialysis) suggest no change in clearance of methylphenidate in end stage renal disease.221 One case report of use in polycystic kidney disease.222 GFR, glomerular filtration rate. Table 8.15 Recommended psychotropics in renal impairment. Drug group Recommended drugs Antipsychotics No agent clearly preferred to another, however: ■ ■Avoid sulpiride and amisulpride ■ ■Avoid highly anticholinergic agents because they can contribute to urinary retention ■ ■First-generation antipsychotic – suggest haloperidol 2–6mg a day ■ ■Second-generation antipsychotic – suggest olanzapine 5mg a day Antidepressants223 No agent clearly preferred to another, however reasonable choices are: ■ ■Sertraline but poor efficacy data in renal disease ■ ■Citalopram (NB QTc-prolonging effects and greater risk of sudden death in those on haemodialysis vs other selective serotonin reuptake inhibitors) ■ ■Fluoxetine but consider long half-life and need for alternate day dosing at lower GFRs Mood stabilisers No agent clearly preferred to another, however: ■ ■Avoid lithium if possible ■ ■Suggest start one of the following at a low dose and increase slowly, monitor for adverse effects: valproate or lamotrigine Anxiolytics and hypnotics No agent clearly preferred to another, however: ■ ■Excessive sedation is more likely to occur in patients with renal impairment, so monitor all patients carefully ■ ■Lorazepam and zopiclone are suggested as reasonable choices Anti-dementia drugs No agent clearly preferred to another, however: ■ ■Rivastigmine is a reasonable choice GFR, glomerular filtration rate.

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17 - References

References

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Serotonin syndrome in chronic kidney disease patient after given a dose of duloxetine while on trazodone: a case report. PM&R 2014; 6 Suppl:S214–S215. 87. Miriyala K, et al. Renal failure in a depressed adolescent on escitalopram. J Child Adolesc Psychopharmacol 2008; 18:405–408. 88. Adiga GU, et al. Renal tubular defects from antidepressant use in an older adult: an uncommon but reversible adverse drug effect. Clin Drug Invest 2006; 26:607–610. 89. Yazici AE, et al. Efficacy and tolerability of escitalopram in depressed patients with end stage renal disease: an open placebo-controlled study. Bull Clin Psychopharmacol 2012; 22:23–30. 90. Bergstrom RF, et al. The effects of renal and hepatic disease on the pharmacokinetics, renal tolerance, and risk-benefit profile of fluoxetine. Int Clin Psychopharmacol 1993; 8:261–266. 91. Blumenfield M, et al. Fluoxetine in depressed patients on dialysis. Int J Psychiatry Med 1997; 27:71–80. 92. Levy NB, et al. Fluoxetine in depressed patients with renal failure and in depressed patients with normal kidney function. Gen Hosp Psychiatry 1996; 18:8–13. 93. Kauffman KM, et al. Higher dose weekly fluoxetine in hemodialysis patients: a case series report. Int J Psychiatry Med 2021; 56:3–13. 94. Constantino JL, et al. Pharmacokinetics of antidepressants in patients undergoing hemodialysis: a narrative literature review. Braz J Psychiatry 2019; 41:441–446. 95. Lancaster SG, et al. Lofepramine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 1989; 37:123–140. 96. Davis MP, et al. Mirtazapine for pruritus. J Pain Symptom Manage 2003; 25:288–291. 97. Fawaz B, et al. Defining the role of mirtazapine in the treatment of refractory pruritus. J Dermatolog Treat 2021; 32:132–136. 98. Liles AM, et al. Appetite stimulants for treatment of protein energy wasting of chronic kidney disease. Nephrol Nurs J 2021; 48:267–273. 99. Shibata K, et al. SP704 The effect of mirtazapine in dialysis patient with appetite loss. Nephrol Dial Transplant 2015; 30 Suppl 3:iii611. 100. Schoerlin MP, et al. Disposition kinetics of moclobemide, a new MAO-A inhibitor, in subjects with impaired renal function. J Clin Pharmacol 1990; 30:272–284. 101. Stoeckel K, et al. Absorption and disposition of moclobemide in patients with advanced age or reduced liver or kidney function. Acta Psychiatr Scand Suppl 1990; 360:94–97. 102. Pollock BG, et al. Metabolic and physiologic consequences of nortriptyline treatment in the elderly. Psychopharmacol Bull 1994; 30:145–150. 103. Doyle GD, et al. The pharmacokinetics of paroxetine in renal impairment. Acta Psychiatr Scand Suppl 1989; 350:89–90. 104. Ishii T, et al. A rare case of combined syndrome of inappropriate antidiuretic hormone secretion and Fanconi syndrome in an elderly woman. Am J Kidney Dis 2006; 48:155–158. 105. Kaye CM, et al. A review of the metabolism and pharmacokinetics of paroxetine in man. Acta Psychiatr Scand Suppl 1989; 350:60–75. 106. Koo JR, et al. Treatment of depression and effect of antidepression treatment on nutritional status in chronic hemodialysis patients. Am J Med Sci 2005; 329:1–5. 107. Coulomb F, et al. Pharmacokinetics of single-dose reboxetine in volunteers with renal insufficiency. J Clin Pharmacol 2000; 40:482–487. 108. Dostert P, et al. Review of the pharmacokinetics and metabolism of reboxetine, a selective noradrenaline reuptake inhibitor. Eur Neuropsychopharmacol 1997; 7 Suppl 1:S23–S35. 109. Brewster UC, et al. Addition of sertraline to other therapies to reduce dialysis-associated hypotension. Nephrology (Carlton) 2003; 8:296–301. 110. Chan KY, et al. Use of sertraline for antihistamine-refractory uremic pruritus in renal palliative care patients. J Palliat Med 2013; 16:966–970. 111. Chander WP, et al. Serotonin syndrome in maintenance haemodialysis patients following sertraline treatment for depression. J Indian Med Assoc 2011; 109:36–37. 112. Jain N, et al. Rationale and design of the Chronic Kidney Disease Antidepressant Sertraline Trial (CAST). Contemp Clin Trials 2013; 34:136–144.

Prescribing in hepatic and renal impairment CHAPTER 8 113. Hedayati SS, et al. Effect of sertraline on depressive symptoms in patients with chronic kidney disease without dialysis dependence: the CAST randomized clinical trial. JAMA 2017; 318:1876–1890. 114. Razeghi E, et al. A randomized crossover clinical trial of sertraline for intradialytic hypotension. Iran J Kidney Dis 2015; 9:323–330. 115. Elsayed MM, et al. The effectiveness of sertraline in alleviating uremic pruritus in hemodialysis patients: a randomized clinical trial. BMC Nephrol 2023; 24:155. 116. Mehrotra R, et al. Comparative efficacy of therapies for treatment of depression for patients undergoing maintenance hemodialysis: a randomized clinical trial. Ann Intern Med 2019; 170:369–379. 117. Friedli K, et al. Sertraline versus placebo in patients with major depressive disorder undergoing hemodialysis: a randomized, controlled feasibility trial. Clin J Am Soc Nephrol 2017; 12:280–286. 118. Chien CW, et al. Sertraline-induced neutropenia and fatigue in a patient with end-stage renal disease. Am J Ther 2020; 29:e101–e103. 119. Zahed NS, et al. Impact of sertraline on serum concentration of CRP in hemodialysis patients with depression. J Ren Injury Prevent 2017; 6:65–69. 120. Gregg LP, et al. Inflammation and response to sertraline treatment in patients with CKD and major depression. Am J Kidney Dis 2020; 75:457–460. 121. Catanese B, et al. A comparative study of trazodone serum concentrations in patients with normal or impaired renal function. Boll Chim Farm 1978; 117:424–427. 122. Mehrotra R, et al. Effectiveness of existing insomnia therapies for patients undergoing hemodialysis: a randomized clinical trial. Ann Intern Med 2024; 177:177–188. 123. Liao CY, et al. Taking sleeping pills and the risk of chronic kidney disease: a nationwide population-based retrospective cohort study. Front Pharmacol 2021; 11:524113. 124. Leighton JD, et al. Trimipramine-induced acute renal failure (Letter). NZ Med J 1986; 99:248. 125. Simpson GM, et al. A preliminary study of trimipramine in chronic schizophrenia. Curr Ther Res Clin Exp 1966; 99:248. 126. Troy SM, et al. The effect of renal disease on the disposition of venlafaxine. Clin Pharmacol Ther 1994; 56:14–21. 127. Guldiken S, et al. Complete relief of pain in acute painful diabetic neuropathy of rapid glycaemic control (insulin neuritis) with venlafaxine HCL. Diabetes Nutr Metab 2004; 17:247–249. 128. Pascale P, et al. Severe rhabdomyolysis following venlafaxine overdose. Ther Drug Monit 2005; 27:562–564. 129. Ren J, et al. Venlafaxine-associated rhabdomyolysis: a literature review. J Clin Psychopharmacol 2024; 44:297–301. 130. Takeda Pharmaceuticals America Inc. Highlights of prescribing information. BRINTELLIX (vortioxetine) tablets 2023 (last accessed May 2024); www.us.brintellix.com. 131. Hegarty J, et al. Carbamazepine-induced acute granulomatous interstitial nephritis. Clin Nephrol 2002; 57:310–313. 132. Tutor-Crespo MJ, et al. Relative proportions of serum carbamazepine and its pharmacologically active 10,11-epoxy derivative: effect of polytherapy and renal insufficiency. Ups J Med Sci 2008; 113:171–180. 133. Verrotti A, et al. Renal tubular function in patients receiving anticonvulsant therapy: a long-term study. Epilepsia 2000; 41:1432–1435. 134. Hung CC, et al. Acute renal failure and its risk factors in Stevens-Johnson syndrome and toxic epidermal necrolysis. Am J Nephrol 2009; 29:633–638. 135. Fervenza FC, et al. Acute granulomatous interstitial nephritis and colitis in anticonvulsant hypersensitivity syndrome associated with lamotrigine treatment. Am J Kidney Dis 2000; 36:1034–1040. 136. Fillastre JP, et al. Pharmacokinetics of lamotrigine in patients with renal impairment: influence of haemodialysis. Drugs Exp Clin Res 1993; 19:25–32. 137. Schaub JE, et al. Multisystem adverse reaction to lamotrigine. Lancet 1994; 344:481. 138. Wootton R, et al. Comparison of the pharmacokinetics of lamotrigine in patients with chronic renal failure and healthy volunteers. Br J Clin Pharmacol 1997; 43:23–27. 139. Bansal AD, et al. Use of antiepileptic drugs in patients with chronic kidney disease and end stage renal disease. Semin Dial 2015; 28:404–412. 140. Gitlin M. Lithium and the kidney: an updated review. Drug Saf 1999; 20:231–243. 141. Lepkifker E, et al. Renal insufficiency in long-term lithium treatment. J Clin Psychiatry 2004; 65:850–856. 142. Schoretsanitis G, et al. Prevalence of impaired kidney function in patients with long-term lithium treatment: a systematic review and meta- analysis. Bipolar Disord 2022; 24:264–274. 143. McKnight RF, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet 2012; 379:721–728. 144. Shine B, et al. Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet 2015; 386:461–468. 145. Clos S, et al. Long-term effect of lithium maintenance therapy on estimated glomerular filtration rate in patients with affective disorders: a population-based cohort study. Lancet Psychiatry 2015; 2:1075–1083. 146. Kessing LV, et al. Lithium versus anticonvulsants and the risk of physical disorders – results from a comprehensive long-term nation-wide population-based study emulating a target trial. Eur Neuropsychopharmacol 2024; 84:48–56. 147. Bosi A, et al. Absolute and relative risks of kidney outcomes associated with lithium vs valproate use in Sweden. JAMA Network Open 2023; 6:e2322056. 148. Schoot TS, et al. Systematic review and practical guideline for the prevention and management of the renal side effects of lithium therapy. Eur Neuropsychopharmacol 2020; 31:16–32. 149. Davis J, et al. Lithium and nephrotoxicity: a literature review of approaches to clinical management and risk stratification. BMC Nephrol 2018; 19:305. 150. Kuiper WJ, et al. Concurrent lithium and haemodialysis treatment: clinical recommendations based on the literature and a multicentre survey. Bipolar Disord 2024; 26:335–347.

784 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 151. Smith GC, et al. Anticonvulsants as a cause of Fanconi syndrome. Nephrol Dial Transplant 1995; 10:543–545. 152. Fukuda Y, et al. Immunologically mediated chronic tubulo-interstitial nephritis caused by valproate therapy. Nephron 1996; 72:328–329. 153. Watanabe T, et al. Secondary renal Fanconi syndrome caused by valproate therapy. Pediatr Nephrol 2005; 20:814–817. 154. Tanaka H, et al. Distal type of renal tubular acidosis after anti-epileptic therapy in a girl with infantile spasms. Clin Exp Nephrol 1999; 3:311–313. 155. Rahman MH, et al. Acute hemolysis with acute renal failure in a patient with valproic acid poisoning treated with charcoal hemoperfusion. Hemodial Int 2006; 10:256–259. 156. Koga S, et al. Risk factors for sodium valproate-induced renal tubular dysfunction. Clin Exp Nephrol 2018; 22:420–425. 157. Hayes JF, et al. Adverse renal, endocrine, hepatic, and metabolic events during maintenance mood stabilizer treatment for bipolar disorder: a population-based cohort study. PLoS Med 2016; 13:e1002058. 158. Damba JJ, et al. Psychotropic drugs and adverse kidney effects: a systematic review of the past decade of research. CNS Drugs 2022; 36:1049–1077. 159. Kessing LV, et al. Continuation of lithium after a diagnosis of chronic kidney disease. Acta Psychiatr Scand 2017; 136:615–622. 160. Pentikainen PJ, et al. Pharmacokinetics of chlormethiazole in healthy volunteers and patients with cirrhosis of the liver. Eur J Clin Pharmacol 1980; 17:275–284. 161. Dashti-Khavidaki S, et al. Comparing effects of clonazepam and zolpidem on sleep quality of patients on maintenance hemodialysis. Iran J Kidney Dis 2011; 5:404–409. 162. Sadjadi SA, et al. Allergic interstitial nephritis due to diazepam. Arch Intern Med 1987; 147:579. 163. Sunovion Pharmaceuticals Inc. Highlights of prescribing information. LUNESTA® (eszopiclone) tablets, for oral use. 2014 (last accessed May 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021476s030lbl.pdf. 164. Blum RA, et al. Pharmacokinetics of gabapentin in subjects with various degrees of renal function. Clin Pharmacol Ther 1994; 56:154–159. 165. Miller A, et al. Gabapentin toxicity in renal failure: the importance of dose adjustment. Pain Med 2009; 10:190–192. 166. Upjohn UK Limited. Summary of product characteristics. Neurontin (gabapentin) 600mg film-coated tablets. 2023 (last accessed May 2024); https://www.medicines.org.uk/emc/product/3197/smpc. 167. Yeddi A, et al. Myoclonus and altered mental status induced by single dose of gabapentin in a patient with end-stage renal disease: a case report and literature review. Am J Ther 2019; 26:e768–e770. 168. Ishida JH, et al. Gabapentin and pregabalin use and association with adverse outcomes among hemodialysis patients. J Am Soc Nephrol 2018; 29:1970–1978. 169. Gobo-Oliveira M, et al. Gabapentin versus dexchlorpheniramine as treatment for uremic pruritus: a randomised controlled trial. Eur J Dermatol 2018; 28:488–495. 170. Gunal AI, et al. Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial. Nephrol Dial Transplant 2004; 19:3137–3139. 171. Beladi Mousavi SS, et al. The effect of gabapentin on muscle cramps during hemodialysis: a double-blind clinical trial. Saudi J Kidney Dis Transpl 2015; 26:1142–1148. 172. Razazian N, et al. Gabapentin versus levodopa-c for the treatment of restless legs syndrome in hemodialysis patients: a randomized clinical trial. Saudi J Kidney Dis Transpl 2015; 26:271–278. 173. Rossi GM, et al. Randomized trial of two after-dialysis gabapentin regimens for severe uremic pruritus in hemodialysis patients. Intern Emerg Med 2019; 14:1341–1346. 174. Eisai Inc. Highlights of prescribing information. Dayvigo (lemborexant) tablets for oral use [controlled substance schedule pending]. 2019 (last accessed May 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212028s000lbl.pdf. 175. Landry I, et al. Effect of severe renal impairment on pharmacokinetics, safety, and tolerability of lemborexant. Pharmacol Res Perspect 2021; 9:e00734. 176. Huang CE, et al. Intramuscular lorazepam in catatonia in patients with acute renal failure: a report of two cases. Chang Gung Med J 2010; 33:106–109. 177. Reynolds HN, et al. Hyperlactatemia, increased osmolar gap, and renal dysfunction during continuous lorazepam infusion. Crit Care Med 2000; 28:1631–1634. 178. Verbeeck RK, et al. Impaired elimination of lorazepam following subchronic administration in two patients with renal failure. Br J Clin Pharmacol 1981; 12:749–751. 179. Yaucher NE, et al. Propylene glycol-associated renal toxicity from lorazepam infusion. Pharmacotherapy 2003; 23:1094–1099. 180. Zar T, et al. Acute kidney injury, hyperosmolality and metabolic acidosis associated with lorazepam. Nat Clin Pract Nephrol 2007; 3:515–520. 181. Hayman M, et al. Acute tubular necrosis associated with propylene glycol from concomitant administration of intravenous lorazepam and trimethoprim-sulfamethoxazole. Pharmacotherapy 2003; 23:1190–1194. 182. Mastroianni G, et al. Management of status epilepticus in patients with liver or kidney disease: a narrative review. Expert Rev Neurother 2021; 21:1251–1264. 183. Markowska M, et al. Melatonin treatment in kidney diseases. Cells 2023; 12:838. 184. Yang J, et al. Effects of melatonin against acute kidney injury: a systematic review and meta-analysis. Int Immunopharmacol 2023; 120:110372. 185. Aperis G, et al. The role of melatonin in patients with chronic kidney disease undergoing haemodialysis. J Ren Care 2012; 38:86–92. 186. Russcher M, et al. The role of melatonin treatment in chronic kidney disease. Front Biosci (Landmark Ed) 2012; 17:2644–2656. 187. Upjohn UK Limited. Lyrica (pregabalin) 25mg, 50mg, 75mg, 100mg, 150mg, 200mg, 225mg and 300mg hard capsules. 2024 (last accessed May 2024); https://www.medicines.org.uk/emc/product/10303/smpc.

Prescribing in hepatic and renal impairment CHAPTER 8 188. Desai A, et al. Gabapentin or pregabalin induced myoclonus: a case series and literature review. J Clin Neurosci 2019; 61:225–234. 189. Du YT, et al. Seizure induced by sudden cessation of pregabalin in a patient with chronic kidney disease. BMJ Case Rep 2017; 2017:bcr2016219158. 190. Foroutan N, et al. Comparison of pregabalin with doxepin in the management of uremic pruritus: a randomized single blind clinical trial. Hemodial Int 2017; 21:63–71. 191. Otsuki T, et al. Efficacy and safety of pregabalin for the treatment of neuropathic pain in patients undergoing hemodialysis. Clin Drug Investig 2017; 37:95–102. 192. Khan NJ, et al. Comparing the efficacy and safety of pregabalin vs gabapentin in uremic pruritus in patients of chronic kidney injury undergoing haemodialysis. J Ayub Med Coll Abbottabad 2022; 34:524–527. 193. Safarpour Y, et al. Restless legs syndrome in chronic kidney disease – a systematic review. Tremor Other Hyperkinet Mov (NY) 2023; 13:10. 194. Murray TG, et al. Renal disease, age, and oxazepam kinetics. Clin Pharmacol Ther 1981; 30:805–809. 195. Leung N, et al. Acute kidney injury in patients with inactive cytochrome P450 polymorphisms. Ren Fail 2009; 31:749–752. 196. Drover DR. Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone. Clin Pharmacokinet 2004; 43:227–238. 197. Rehman IU, et al. Effectiveness and safety profiling of zolpidem and acupressure in CKD associated pruritus: an interventional study. Medicine (Baltimore) 2021; 100:e25995. 198. Hsu FG, et al. Use of zolpidem and risk of acute pyelonephritis in women: a population-based case-control study in Taiwan. J Clin Pharmacol 2017; 57:376–381. 199. Goa KL, et al. Zopiclone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy as an hypnotic. Drugs 1986; 32:48–65. 200. Hussain N, et al. Zopiclone-induced acute interstitial nephritis. Am J Kidney Dis 2003; 41:E17. 201. Suwata J, et al. New acetylcholinesterase inhibitor (donepezil) treatment for Alzheimer’s disease in a chronic dialysis patient. Nephron 2002; 91:330–332. 202. Nagy CF, et al. Steady-state pharmacokinetics and safety of donepezil HCl in subjects with moderately impaired renal function. Br J Clin Pharmacol 2004; 58 Suppl 1:18–24. 203. Tiseo PJ, et al. An evaluation of the pharmacokinetics of donepezil HCl in patients with moderately to severely impaired renal function. Br J Clin Pharmacol 1998; 46 Suppl 1:56–60. 204. Sahin OZ, et al. A rare case of acute renal failure secondary to rhabdomyolysis probably induced by donepezil. Case Rep Nephrol 2014; 2014:214359. 205. Wang HM, et al. Letter to the editor: Donepezil-induced parkinsonism in end-stage renal disease. Neurol Sci 2021; 42:4809–4812. 206. Periclou A, et al. Pharmacokinetic study of memantine in healthy and renally impaired subjects. Clin Pharmacol Ther 2006; 79:134–143. 207. Prasad P, et al. Memantine induced encephalopathy in chronic kidney disease: a case report. Postgrad Med J 2023; 99:498–499. 208. Lefevre G, et al. Effects of renal impairment on steady-state plasma concentrations of rivastigmine: a population pharmacokinetic analysis of capsule and patch formulations in patients with Alzheimer’s disease. Drugs Aging 2016; 33:725–736. 209. AMAG Pharmaceutical Inc. Highlights of prescribing information. Vyleesi (bremelanotide injection) for subcutaneous use. 2019 (last accessed May 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210557s000lbl.pdf. 210. Nelson ME, et al. Melanotan II injection resulting in systemic toxicity and rhabdomyolysis. Clin Toxicol (Phila) 2012; 50:1169–1173. 211. Teva Pharmaceuticals USA Inc. Highlights of prescribing information. Austedo (deutetrabenazine) tablets for oral use. 2017 (last accessed May 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209885lbl.pdf. 212. Lincoln Medical Limited. Wakix 4.5mg/18mg film-coated tablets. 2023 (last accessed May 2024); https://www.medicines.org.uk/emc/ product/7402. 213. Bioprojet Pharma. Highlights of prescribing information. Wakix (pitolisant) tablets for oral use. 2019 (last accessed May 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211150s000lbl.pdf. 214. Atnahs Pharma UK Ltd. Sunosi (solriamfetol) 75mg and 140mg film-coated tablets. 2023 (last accessed May 2024); https://www.medicines. org.uk/emc/product/14978/pil#gref. 215. Zomorodi K, et al. Single-dose pharmacokinetics and safety of solriamfetol in participants with normal or impaired renal function and with end-stage renal disease requiring hemodialysis. J Clin Pharmacol 2019; 59:1120–1129. 216. Genus Pharmaceuticals. Summary of product characteristics. Atomoxetine 40 mg hard capsules. 2020 (last accessed April 2024); https://www.medicines.org.uk/emc/product/11126/smpc. 217. Medice UK Ltd. Summary of product characteristics. Amfexa 5mg, 10mg, 20mg tablets. 2023 (last accessed May 2024); https://www. medicines.org.uk/emc/search?q=amfexa. 218. Takeda UK Limited. Summary of product characteristics. Elvanse 20mg, 30mg, 40mg, 50mg, 60mg and 70mg capsules, hard (lisdexafetamine). 2023 (last accessed May 2024); https://www.medicines.org.uk/emc/product/14091/smpc. 219. Ermer J, et al. A single-dose, open-label study of the pharmacokinetics, safety, and tolerability of lisdexamfetamine dimesylate in individuals with normal and impaired renal function. Ther Drug Monit 2016; 38:546–555. 220. Janssen-Cilag Ltd. Summary of product characteristics. Concerta XL 18 mg, 27 mg, 36 mg, 54 mg prolonged-release tablets. 2023 (last accessed April 2024); https://www.medicines.org.uk/emc/product/6872/smpc. 221. Stiebel VG. Methylphenidate plasma levels in depressed patients with renal failure. Psychosomatics 1994; 35:498–500. 222. Kasahara S, et al. Case report: guanfacine and methylphenidate improved chronic lower back pain in autosomal dominant polycystic kidney disease with comorbid attention deficit hyperactivity disorder and autism spectrum disorder. Front Pediatr 2023; 11:1283823. 223. Gregg LP, et al. Pharmacologic and psychological interventions for depression treatment in patients with kidney disease. Curr Opin Nephrol Hypertens 2020; 29:457–464.

14 - Chapter 9 Drug treatment of other psychiatric cond

01 - Borderline personality disorder (BPD)

Borderline personality disorder (BPD)

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 9 Borderline personality disorder (BPD) Borderline personality disorder (BPD) is common in psychiatric settings, affecting 2% of individuals living in the community,1 over 10% of community mental health patients and 20% of in-patients.2 People diagnosed with BPD on average have higher prevalence of a wide range of other comorbid mental health conditions including mood disorders (both unipolar and bipolar affective disorder), anxiety disorders, eating disorders, post-traumatic stress disorder (PTSD) and substance use disorders. Concurrent mental health conditions will affect successful treatment of BPD and should be treated prior to BPD, according to usual guidance for the particular condition, irrespective of any coexisting BPD diagnosis. More than 75% of people with BPD attempt suicide with 2–5% of patients dying from suicide.2,3 A high proportion of people with BPD are prescribed psychotropic drugs, often in polypharmacy regimens.4 A survey of prescribing practice in England found that over 90% of patients with BPD had been prescribed psychotropic medication, most commonly antidepressants or antipsychotics, particularly for affective instability.5 Individuals with BPD appear to be just as likely to be prescribed antipsychotics, antidepressants and mood stabilisers, whether or not they have a clear and documented comorbid diagnosis of schizophrenia, depression or bipolar disorder.4,5 This suggests that medicines are sometimes prescribed for the treatment of BPD per se (for which there is very limited support) rather than for specific comorbid conditions. No medicine is specifically licensed for the treatment of BPD, or indeed any aspect of BPD. Psychological treatments such as Dialectical Behaviour Therapy (DBT) have garnered much better evidence – a Cochrane review noted 75 randomised controlled trials (RCTs) of psychological treatments in 20206 and a 2023 network meta-analysis included 43 studies.7 Drug treatment of other psychiatric conditions

14 - Chapter 9 Drug treatment of other psychiatric cond

02 - Drug treatments of BPD

Drug treatments of BPD

788 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 9 In 2009 the UK National Institute for Health and Care Excellence (NICE)8 recommended that: ■ ■Drug treatment should not be used routinely for BPD or for the individual symptoms or behaviour associated with the disorder (e.g. repeated self-harm, marked emotional instability, risk-taking behaviour and transient psychotic symptoms). ■ ■Drug treatment may be considered in the overall treatment of comorbid conditions. ■ ■Short-term use of sedative medication may be considered as part of the overall treatment plan for people with BPD in a crisis. The duration of treatment should be agreed with the patient but should be no longer than 1 week. Owing to changes in the latest revision of ICD-11, which now defines all personality disorders as a single condition classified by severity, the current UK NICE guidelines are under review.8 A number of systematic reviews have been completed since the initial publication of the NICE guideline, concluding that evidence does not support the use of medicines alone, although when coupled with psychotherapy significant improvements in mood and behaviour can be anticipated.9,10 A 2022 Cochrane review11 concluded that medication has little or no effect on BPD symptom severity, self-harm, suicide-related outcomes and psychosocial functioning compared with placebo but may slightly reduce interpersonal problems. However, the evidence considered by the Cochrane review was rated as very low or low certainty and reporting on adverse events was poor and mostly non-standardised. It is clear that further research of good quality is required in this area. Drug treatments of BPD Antipsychotics A systematic review of RCTs evaluating the efficacy of second-generation antipsychotics (SGAs) in a number of aspects of BPD found that there was no overall improvement in BPD or in functioning.10 A beneficial effect of aripiprazole on anger and of quetiapine on aggression were shown, but a number of trials were rated as having moderate or high risk of bias and most of the evidence was deemed to be of low certainty.10 Olanzapine may have the best supported effectiveness in treating some BPD symptoms, along with depressive and anxiety symptoms, although it has not been shown to improve self-harm or aggression.10 Furthermore, olanzapine’s propensity for inducing metabolic syndrome means that patients must be fully informed of the risks of this before commencing off-label treatment with this agent and it should only be considered an option of ‘last resort’ for individuals with distressing symptoms that cannot be managed psychologically. Quetiapine is perhaps the most widely used antipsychotic in BPD. Its use is supported by small studies that reported modest improvement in a number of symptoms, but not impulsivity.12,13 In general, SGAs appear to improve general psychopathology, although this may be a reflection of improvement in comorbid conditions. There is some evidence to support the use of clozapine to improve psychotic symptoms, aggression, impulsivity, self-harming behaviour and overall functioning (with associated reduced hospital use) in those with severe treatment-refractory BPD, high suicide risk and frequent hospitalisations.9,14 A placebo-controlled RCT of lumateperone is underway at the time of writing.15

Drug treatment of other psychiatric conditions CHAPTER 9 Antidepressants Several open studies and small RCTs have investigated the use of selective serotonin reuptake inhibitors (SSRIs), serotonin–noradrenaline reuptake inhibitors (SNRIs) and flupentixol in BPD. Fluoxetine has been noted to improve symptoms of BPD including impulsivity, self-harm, anger and mood instability, but one RCT comparing DBT or supportive therapy alone or in combination with fluoxetine showed higher rates of suicide attempts in those given fluoxetine.16 Duloxetine has been reported to improve overall psychopathology, depression, impulsivity and affective dysregulation17 and venlafaxine reduced somatic symptoms and self-injurious behaviour.18 In an open study, antidepressant doses of flupentixol showed significant improvements in general psychopathology and impulsivity symptoms but no further studies have been published to confirm this effect.9,19 Lastly, in a large database review of patients with BPD, bupropion decreased the risk of psychiatric re-hospitalisation.20 Overall, evidence supporting the use of antidepressants is weak and any beneficial effects are modest at best. Mood stabilisers and anticonvulsants There is some evidence in BPD that valproate and topiramate may improve anger.10 Valproate may reduce aggression and irritability and gabapentin may improve anxiety, affective instability and depressive symptoms.9 Obviously, given the risk of teratogenicity associated with valproate, it should never be prescribed to people of child-bearing age. Lithium is licensed for the control of aggressive behaviour or intentional self-harm, although its use in BPD has declined owing to concerns over long- term toxicity.21 Small studies have suggested lamotrigine may improve anger and reduce aggression, impulsivity and affective lability, though a large RCT found it had no effect at all on any symptom domain.9,10 Carbamazepine9 and mifepristone are likewise ineffective.22 Lisdexamfetamine and methylphenidate In a large database review of patients with BPD, lisdexamfetamine and methylphenidate decreased the risk of all hospitalisations, death and psychiatric re-hospitalisation.20 This probably reflects prescribing for attention deficit hyperactivity disorder (ADHD) in the context of BPD. Memantine An RCT of 33 subjects found adjunctive memantine 20mg a day to be more effective than placebo and well tolerated. More trials are needed.9 Opioid antagonists Very limited evidence supports the efficacy of naltrexone in reducing dissociative symptoms, but there have been no definitive trials supporting the effectiveness of naltrexone in the treatment of patients with BPD.9

14 - Chapter 9 Drug treatment of other psychiatric cond

03 - Management of crisis

Management of crisis

790 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 9 Ketamine A small RCT investigating the effects of one infusion of ketamine (vs midazolam) found more improvement in socio-occupational functioning in the ketamine group at day 14.23 However, the apparent improvement in BPD may well reflect changes in underlying mood rather than change in BPD psychopathology. In treatment-resistant depression with comorbid BPD, ketamine was shown significantly to improve both depressive and borderline symptoms.24 A case report of BPD and treatment-resistant depression that was managed with citalopram and esketamine nasal spray resulted in improvement in depression, anxiety and behavioural symptoms.25 Clearly, further studies are required. Omega-3 fatty acids A 2021 meta-analysis concluded that marine omega-3 fatty acids improve symptoms of BPD, particularly impulsive behaviour and affective dysregulation, and that they could be considered as an add-on therapy.26 Botulinum toxin In an RCT comparing glabellar botulinum toxin with acupuncture, both groups showed significant reductions in symptoms, but findings did not support the superiority of any particular treatment.27 Management of crisis Medications are often used during periods of crisis when symptoms can be severe, distressing and potentially life-threatening. In BPD these symptoms can be expected to fluctuate.28 Consequently, pharmacological therapy may then be required intermittently, and with each episode the decision to prescribe needs to be informed by a careful consideration of the relative harms and benefits of medication. It is generally easy to see when treatment is required, but much more difficult to decide when modest gains are worthwhile and whether or not continuation is likely to be necessary. The use of psychotropic drugs is not without harm, so treatment should always take the form of a rigorously evaluated short-term trial. In the UK, NICE8 recommends that during periods of crisis, time-limited treatment with a sedative drug may be helpful. The anticipated side effect profile and potential toxicity in overdose should guide choice. For example, benzodiazepines (particularly short-acting drugs) can cause disinhibition in this group of patients,29 ultimately compounding problems. Sedative antipsychotics can cause extrapyramidal side effects (EPSEs) and/or considerable weight gain, and tricyclic antidepressants are particularly toxic in overdose. A sedative antihistamine such as promethazine (25–50mg) is usually well tolerated and may be a helpful short-term treatment when used as part of a coordinated care plan (although there is no study evidence to support this assumption). Its adverse effects (dry mouth, constipation), deleterious effects on sleep architecture and lack of clear anxiolytic effects militate against longer-term use.

14 - Chapter 9 Drug treatment of other psychiatric cond

04 - References

References

Drug treatment of other psychiatric conditions CHAPTER 9 References

Winsper C, et al. The prevalence of personality disorders in the community: a global systematic review and meta-analysis. Br J Psychiatry 2020; 216:69–78.
Leichsenring F, et al. Borderline personality disorder: a review. JAMA 2023; 329:670–679.
Pascual JC, et al. Pharmacological management of borderline personality disorder and common comorbidities. CNS Drugs 2023; 37:489–497.
Riffer F, et al. Psychopharmacological treatment of patients with borderline personality disorder: comparing data from routine clinical care with recommended guidelines. Int J Psychiatry Clin Pract 2019; 23:178–188.
Paton C, et al. The use of psychotropic medication in patients with emotionally unstable personality disorder under the care of UK mental health services. J Clin Psychiatry 2015; 76:e512–e518.
Storebø OJ, et al. Psychological therapies for people with borderline personality disorder. Cochrane Database Syst Rev 2020; 5:CD012955.
Setkowski K, et al. Which psychotherapy is most effective and acceptable in the treatment of adults with a (sub)clinical borderline personality disorder? A systematic review and network meta-analysis. Psychol Med 2023; 53:3261–3280.
National Institute for Clinical Excellence. Borderline personality disorder: recognition and management. Clinical Guideline [CG78]. 2009 (last checked April 2022, last accessed January 2024); https://www.nice.org.uk/guidance/CG78.
Del Casale A, et al. Current clinical psychopharmacology in borderline personality disorder. Curr Neuropharmacol 2021; 19:1760–1779.
Gartlehner G, et al. Pharmacological treatments for borderline personality disorder: a systematic review and meta-analysis. CNS Drugs 2021; 35:1053–1067.
Stoffers-Winterling JM, et al. Pharmacological interventions for people with borderline personality disorder. Cochrane Database Syst Rev 2022; 11:CD012956.
ClinicalTrials.gov. Seroquel extended release (XR) for the management of borderline personality disorder (BPD). NCT00880919. 2017; https://clinicaltrials.gov/study/NCT00880919?tab=results.
Black DW, et al. Comparison of low and moderate dosages of extended-release quetiapine in borderline personality disorder: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2014; 171:1174–1182.
Han J, et al. A systematic review of the role of clozapine for severe borderline personality disorder. Psychopharmacology (Berl) 2023; 240:2015–2031.
ClinicalTrials.gov. Caplyta in borderline personality disorder. NCT05356013. 2023; https://clinicaltrials.gov/study/NCT05356013? cond=Borderline%20Personality%20Disorder&page=2&rank=11.
ClinicalTrials.gov. Treating suicidal behavior and self-mutilation in people with borderline personality disorder. NCT00533117. 2024; https://clinicaltrials.gov/ct2/show/results/NCT00533117.
Bellino S, et al. Efficacy and tolerability of duloxetine in the treatment of patients with borderline personality disorder: a pilot study. J Psychopharmacol 2010; 24:333–339.
Markovitz PJ, et al. Venlafaxine in the treatment of borderline personality disorder. Psychopharmacol Bull 1995; 31:773–777.
Kutcher S, et al. The successful pharmacological treatment of adolescents and young adults with borderline personality disorder: a preliminary open trial of flupenthixol. J Psychiatry Neurosci 1995; 20:113–118.
Lieslehto J, et al. Association of pharmacological treatments and real-world outcomes in borderline personality disorder. Acta Psychiatr Scand 2023; 147:603–613.
Essential Pharma Ltd. Summary of product characteristics. Camcolit 400mg prolonged release lithium carbonate. 2023; https://www.medicines. org.uk/emc/product/10829/smpc.
ClinicalTrials.gov. Preliminary trial of the effect of glucocorticoid receptor antagonist on borderline personality disorder (BPD). NCT01212588. 2019; https://clinicaltrials.gov/ct2/show/NCT01212588.
Fineberg SK, et al. A pilot randomized controlled trial of ketamine in borderline personality disorder. Neuropsychopharmacology 2023; 48:991–999.
Danayan K, et al. Real world effectiveness of repeated ketamine infusions for treatment-resistant depression with comorbid borderline personality disorder. Psychiatry Res 2023; 323:115133.
Nandan NK, et al. ‘Esketamine’ in borderline personality disorder: a look beyond suicidality. Cureus 2022; 14:e24632.
Karaszewska DM, et al. Marine omega-3 fatty acid supplementation for borderline personality disorder: a meta-analysis. J Clin Psychiatry 2021; 82:20r13613.
Wollmer MA, et al. Clinical effects of glabellar botulinum toxin injections on borderline personality disorder: a randomized controlled trial. J Psychopharmacol 2022; 36:159–169.
Links PS, et al. Prospective follow-up study of borderline personality disorder: prognosis, prediction of outcome, and axis II comorbidity. Can J Psychiatry 1998; 43:265–270.
Gardner DL, et al. Alprazolam-induced dyscontrol in borderline personality disorder. Am J Psychiatry 1985; 142:98–100.

14 - Chapter 9 Drug treatment of other psychiatric cond

05 - Eating disorders

Eating disorders

14 - Chapter 9 Drug treatment of other psychiatric cond

06 - Anorexia nervosa (AN)

Anorexia nervosa (AN)

792 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 9 Eating disorders The incidence of eating disorders continues to increase.1 Lifetime risk of any eating disorder is 8.4% in women and 2.2% in men.2 Those with eating disorders may misuse medication and substances to manage their weight (e.g. laxatives, diuretics, ADHD stimulants, slimming pills, semaglutide and caffeine).3,4 Other psychiatric conditions (particularly anxiety, depression and obsessive compulsive disorder [OCD]) often coexist with eating disorders, and this may in part explain the benefit sometimes seen with medication. Any medicine prescribed should be accompanied by close monitoring to check for possible adverse reactions, and the timing of medicine administration should be considered in the context of purging. Anorexia nervosa (AN) General guidance Medicines have limited efficacy in AN and none is currently licensed for this condition.5 Prompt weight restoration to a safe weight, family therapy and structured psychotherapy are the main interventions.6,7 The aim of (physical) treatment is to improve nutritional health through re-feeding and there is very limited evidence to support the use of any pharmacological interventions other than those used to correct metabolic deficiencies. Medicines may be used to treat comorbid conditions which should be managed according to usual guidance for the particular condition. These may need to be treated before addressing AN, depending on the severity.6 Weight restoration Medicines have a limited role in weight restoration.8–10 Olanzapine has shown a positive effect on weight in AN in seven RCTs.11 One of these12 showed that 87.5% of patients given olanzapine achieved weight restoration (vs 55.6% on placebo), although olanzapine use was limited by poor tolerance and low patient acceptability. There is also some non-RCT evidence to support the use of aripiprazole.13,14 One RCT with risperidone showed no benefit on weight.15 Early data for quetiapine were encouraging16 but were not replicated in a later RCT.17 A 2023 review and guideline concluded that amitriptyline, clomipramine, fluoxetine, citalopram and sertraline do not restore weight and are not recommended.15 Two case reports with mirtazapine suggest it may improve weight18,19 although a small case–control study was negative.20 Benzodiazepines or antihistamines (e.g. promethazine) are not usually recommended for the promotion of weight gain.6 Metreleptin, a recombinant human leptin analogue, shows some promise with five cases reported of weight gain and improvement in hyperactivity and psychological symptoms associated with eating disorders.15 Dronabinol, a synthetic cannabinoid agonist, has some limited evidence supporting significant weight gain,21 but in the absence of any improvements in symptoms or psychological features. Adverse effects (particularly dysphoria) are common, and this may limit its usefulness.

Drug treatment of other psychiatric conditions CHAPTER 9 Treatment of psychological symptoms Antidepressants A Cochrane review found no evidence from four placebo-controlled trials that antidepressants improved eating disorder or associated psychopathology.22 It has been suggested that neurochemical abnormalities in starvation may partially explain this non-response.22 Co-prescribing nutritional supplementation (including tryptophan) with fluoxetine has not been shown to increase efficacy.23 In the UK, NICE found little evidence to support the use of antidepressants.6 Naturalistic studies suggest an important risk of switch to mania.24 Since 2021 case studies in adults with AN have shown that ketamine reduces depression scores and suicidality while improving psychological features of eating disorders.25,26 Psilocybin is hypothesised to alleviate neurobiological and behavioural features associated with AN, and several trials are underway.27 Other psychotropic medicines Antipsychotics, benzodiazepines or antihistamines (e.g. promethazine) are often used to reduce the high levels of anxiety associated with AN. A 2023 expert guideline noted that a number of RCTs suggest olanzapine may reduce agitation, pre-meal anxiety and obsessional or abnormal beliefs, while there is relatively limited evidence that aripiprazole reduces eating-specific anxiety and one RCT with risperidone showed no benefit for body image or psychological symptoms.15 Quetiapine may improve psychological symptoms but there are few data.16 If antipsychotics are used, only prolactin-sparing antipsychotics should be considered owing to the risk of osteoporosis (i.e. avoid risperidone, amisulpride and sulpiride). Many other medications15 have been investigated in small placebo-controlled trials of varying quality and success. These include lithium, zinc, naltrexone and cyproheptadine. None is currently widely used in practice. Case reports15 have shown a potential role for valproate and growth hormone-releasing peptide-2. Relamorelin (a ghrelin agonist), oxytocin, growth hormone and testosterone are probably not effective.15 An RCT is to be conducted to assess short-chain fatty acids (acetate, propionate, butyrate) in AN.28 Healthcare professionals should be aware of the risk of medicines that prolong the QT interval. All patients with a diagnosis of AN should have an alert placed in their prescribing record noting that they are at increased risk of arrhythmias secondary to electrolyte disturbances and potential cardiac complications associated with inadequate nutrition. Electrocardiogram (ECG) monitoring should be undertaken if the prescription of any medicine that may compromise cardiac functioning is essential.6 Treatment of physical aspects Vitamins and minerals Treatment with a multivitamin and multimineral supplement in oral form is recommended during both in-patient and out-patient weight restoration.6 Vitamin D supplementation may also be required.29 Electrolytes Electrolyte disturbances (e.g. hypokalaemia) may be asymptomatic and develop slowly. Life-threatening medical complications can result. Caution is required because electrolyte disturbances often resolve with re-feeding, but rapid correction may be hazardous

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07 - Bulimia nervosa (BN) and binge eating disorde

Bulimia nervosa (BN) and binge eating disorder (BED)

794 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 9 and result in re-feeding-precipitated hypophosphataemia. Oral supplementation is used to prevent serious sequelae rather than to restore normal levels. If supplements are used, urea and electrolytes (U&Es), bicarbonate, calcium, phosphorus and magnesium need to be monitored and an ECG needs to be performed.30 Osteoporosis Bone loss is an important complication of AN with serious consequences. There is limited and conflicting evidence regarding the use of oestrogen, dehydroepiandrosterone (DHEA), combined oral contraceptives and bisphosphonates to improve bone density in AN. For those who have long-term low body weight and low bone mineral density, 17β-estradiol (with cyclic progesterone) or oestrogen (in young women aged 13–17 years) and bisphosphonates (for women over 18 years) can be used. Antipsychotics that raise prolactin levels can further increase the risk of bone loss and osteoporosis6 and should be avoided. Relapse prevention A 2018 review suggested that fluoxetine, citalopram, sertraline or mirtazapine may have a role to play in relapse prevention and improving symptoms in weight-restored patients.31 Evidence for this is very weak and since this review an RCT of fluoxetine has been published showing no effect.32 SSRIs can sometimes elevate prolactin so monitoring is recommended. Comorbid disorders Second-generation antidepressants are often used to treat comorbid major depression, anxiety and OCD. However, caution is necessary because depressive symptoms that are a consequence of self-starvation are only likely to improve with weight restoration. As weight loss is a frequent side effect of bupropion, this antidepressant is contraindicated for the treatment of comorbid depression in AN.33 Mania and psychosis occurring in the context of AN is probably best treated with olanzapine, and bipolar depression with olanzapine plus fluoxetine.33 Bulimia nervosa (BN) and binge eating disorder (BED) Medicines should not be offered as the sole treatment for BN or BED.6 Fluoxetine is the only SSRI to hold a product licence for BN, and adults with BN and BED may be offered a trial of fluoxetine. The effective dose of fluoxetine is 60mg daily.34 Patients should be informed that fluoxetine can reduce the frequency of binge eating and purging but long-term effects are unknown.35 Early response (at 3 weeks) is a strong predictor of response overall.36 Sertraline has also shown a reduction in binge eating and purging in both BN and BED, whereas citalopram showed improvement only in BED.15 Antidepressants may sometimes be used for the treatment of BN in adolescents, but they are not licensed for this age group and there is little evidence for this practice. They should not be considered as a first-line treatment in adolescent BN.6 There is some reasonable evidence that topiramate15 reduces the frequency of binge eating although topiramate is contraindicated in pregnancy and in women of child- bearing potential (if not using a highly effective method of contraception). There is rather limited evidence for the usefulness of aripiprazole, bupropion, duloxetine,

14 - Chapter 9 Drug treatment of other psychiatric cond

08 - Other atypical eating disorders

Other atypical eating disorders

Drug treatment of other psychiatric conditions CHAPTER 9 reboxetine, lamotrigine, liraglutide, methylphenidate, zonisamide and sodium oxybate in BN/BED or both.15 Bupropion is not recommended due to a high risk of seizures in BN.15 Acamprosate37 also has limited evidence in BED. Systematic reviews35,38 confirm the modest efficacy of SSRIs and also suggest benefit for lisdexamfetamine (based on one high-quality RCT39). Lisdexamfetamine is approved for BED in the USA.40 Some limited evidence supports the use of a slow-release combination of phentermine and topiramate, however this combination was refused marketing authorisation owing to serious adverse effects.15 The noradrenaline/dopamine reuptake inhibitor dasotraline may also be effective41 but its development appears to have ceased in 2020. Comorbid depression Depression is a frequent comorbidity in BN and BED. Citalopram has been shown to be more effective than fluoxetine for depressive symptoms in BN patients.42 As weight gain is a frequent side effect of mirtazapine, this antidepressant should be avoided or used with caution for the treatment of comorbid depression in BED.33 Other atypical eating disorders There have been very few useful studies of the use of medicines to treat atypical eating disorders other than AN, BN and BED.6,43 Evidence for avoidant restrictive food intake disorder based on case reports/series and chart reviews suggests some benefit for mirtazapine, SSRIs (fluoxetine, sertraline), olanzapine and cyproheptadine.15 In the absence of evidence to guide the management of other atypical eating disorders (also known as ‘eating disorders not otherwise specified’), it is recommended that the clinician considers following the guidance of the eating disorder that most closely resembles the individual patient’s eating disorder (Box 9.1).6 Box 9.1 Summary of UK NICE guidance on eating disorders6 Anorexia nervosa ■ ■Psychological interventions are the treatments of choice and should be accompanied by psychoeducation and monitoring of the patient’s weight, mental and physical health and any risk factors ■ ■Do not offer medication as the sole treatment for anorexia nervosa Bulimia nervosa ■ ■An evidence-based self-help programme or cognitive behaviour therapy for bulimia nervosa should be the first choice of treatment followed by other psychological therapies ■ ■A trial of fluoxetine may be offered in combination with other treatments. Do not offer medication as the sole treatment for bulimia nervosa Binge eating disorder ■ ■An evidence-based self-help programme of cognitive behavioural therapy for binge eating disorder should be the first choice of treatment followed by cognitive behavioural therapy ■ ■A trial of a selective serotonin reuptake inhibitor can be considered in combination with other treatments. Do not offer medication as the sole treatment for binge eating disorder ■ ■Lisdexamfetamine is also an option

14 - Chapter 9 Drug treatment of other psychiatric cond

09 - References

References

796 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 9 References

Martínez-González L, et al. Incidence of anorexia nervosa in women: a systematic review and meta-analysis. Int J Environ Res Public Health 2020; 17:3824.
Galmiche M, et al. Prevalence of eating disorders over the 2000–2018 period: a systematic literature review. Am J Clin Nutr 2019; 109:1402–1413.
Nitsch A, et al. Medical complications of bulimia nervosa. Cleve Clin J Med 2021; 88:333–343.
Chiappini S, et al. Exploring the nexus of binge eating disorder (BED), new psychoactive substances (NPS), and misuse of pharmaceuticals: charting a path forward. Expert Opin Pharmacother 2023; 24:1915–1918.
Frank GKW. Pharmacotherapeutic strategies for the treatment of anorexia nervosa – too much for one drug? Expert Opin Pharmacother 2020; 21:1045–1058.
National Institute for Health and Care Excellence. Eating disorders: recognition and treatment. NICE Guideline [NG69]. 2017 (last updated March 2020); https://www.nice.org.uk/guidance/ng69.
American Psychiatric Association. Treatment of patients with eating disorders, third edition. Am J Psychiatry 2006; 163:4–54.
Frank B, et al. Antipsychotic effects on anthropometric outcomes in anorexia nervosa: a retrospective chart review of hospitalized children and adolescents. J Eat Disord 2023; 11:151.
Costandache GI, et al. An overview of the treatment of eating disorders in adults and adolescents: pharmacology and psychotherapy. Postep Psychiatr Neurol 2023; 32:40–48.
Bauschka M, et al. Atypical antipsychotic use does not impact weight gain for individuals with extreme anorexia nervosa: a retrospective case-control study. J Eat Disord 2023; 11:215.
Thorey S, et al. Efficacy and tolerance of second-generation antipsychotics in anorexia nervosa: a systematic scoping review. PLoS One 2023; 18:e0278189.
Bissada H, et al. Olanzapine in the treatment of low body weight and obsessive thinking in women with anorexia nervosa: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2008; 165:1281–1288.
Tahıllıoğlu A, et al. Is aripiprazole a key to unlock anorexia nervosa? A case series. Clin Case Rep 2020; 8:2827–2834.
Frank GK, et al. The partial dopamine D2 receptor agonist aripiprazole is associated with weight gain in adolescent anorexia nervosa. Int J Eat Disord 2017; 50:447–450.
Himmerich H, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines update 2023 on the pharmacological treatment of eating disorders. World J Biol Psychiatry 2023; 1–64.
Court A, et al. Investigating the effectiveness, safety and tolerability of quetiapine in the treatment of anorexia nervosa in young people: a pilot study. J Psychiatr Res 2010; 44:1027–1034.
Powers PS, et al. Double-blind placebo-controlled trial of quetiapine in anorexia nervosa. Eur Eat Disord Rev 2012; 20:331–334.
Naguy A, et al. An adolescent male with anorexia nervosa favorably responded to mirtazapine. Am J Ther 2018; 25:e675–e676.
Safer DL, et al. Use of mirtazapine in an adult with refractory anorexia nervosa and comorbid depression: a case report. Int J Eat Disord 2011; 44:178–181.
Hrdlicka M, et al. Mirtazapine in the treatment of adolescent anorexia nervosa. Case-control study. Eur Child Adolesc Psychiatry 2008; 17:187–189.
Andries A, et al. Dronabinol in severe, enduring anorexia nervosa: a randomized controlled trial. Int J Eat Disord 2014; 47:18–23.
Claudino AM, et al. Antidepressants for anorexia nervosa. Cochrane Database Syst Rev 2006; 1:CD004365.
Barbarich NC, et al. Use of nutritional supplements to increase the efficacy of fluoxetine in the treatment of anorexia nervosa. Int J Eat Disord 2004; 35:10–15.
Rossi G, et al. Pharmacological treatment of anorexia nervosa: a retrospective study in preadolescents and adolescents. Clin Pediatr (Phila) 2007; 46:806–811.
Keeler JL, et al. Ketamine as a treatment for anorexia nervosa: a narrative review. Nutrients 2021; 13:4158.
Keeler JL, et al. Case report: intramuscular ketamine or intranasal esketamine as a treatment in four patients with major depressive disorder and comorbid anorexia nervosa. Front Psychiatry 2023; 14:1181447.
Keeler JL, et al. Novel treatments for anorexia nervosa: insights from neuroplasticity research. Eur Eat Disord Rev 2024; 32:1069–1084.
Quagebeur R, et al. The role of short-chain fatty acids (SCFAs) in regulating stress responses, eating behavior, and nutritional state in anorexia nervosa: protocol for a randomized controlled trial. J Eat Disord 2023; 11:191.
Nagata JM, et al. Assessment of vitamin D among male adolescents and young adults hospitalized with eating disorders. J Eat Disord 2022; 10:104.
Royal College of Psychiatrists. Medical emergencies in eating disorders (MEED). Guidance on recognition and management. College Report [CR233]. 2022; https://www.rcpsych.ac.uk/improving-care/campaigning-for-better-mental-health-policy/college-reports/2022-collegereports/cr233.
Marvanova M, et al. Role of antidepressants in the treatment of adults with anorexia nervosa. Ment Health Clin 2018; 8:127–137.
Walsh BT, et al. Time course of relapse following acute treatment for anorexia nervosa. Am J Psychiatry 2021; 178:848–853.
Himmerich H, et al. Pharmacological treatment of eating disorders, comorbid mental health problems, malnutrition and physical health consequences. Pharmacol Ther 2020; 217:107667.
Bacaltchuk J, et al. Antidepressants versus placebo for people with bulimia nervosa. Cochrane Database Syst Rev 2003; 4:CD003391.
Ghaderi A, et al. Psychological, pharmacological, and combined treatments for binge eating disorder: a systematic review and meta-analysis. Peer J 2018; 6:e5113.
Sysko R, et al. Early response to antidepressant treatment in bulimia nervosa. Psychol Med 2010; 40:999–1005.

Drug treatment of other psychiatric conditions CHAPTER 9 37. McElroy SL, et al. Acamprosate in the treatment of binge eating disorder: a placebo-controlled trial. Int J Eat Disord 2011; 44:81–90. 38. Hilbert A, et al. Meta-analysis on the long-term effectiveness of psychological and medical treatments for binge-eating disorder. Int J Eat Disord 2020; 53:1353–1376. 39. McElroy SL, et al. Efficacy and safety of lisdexamfetamine for treatment of adults with moderate to severe binge-eating disorder: a randomized clinical trial. JAMA Psychiatry 2015; 72:235–246. 40. Citrome L. Lisdexamfetamine for binge eating disorder in adults: a systematic review of the efficacy and safety profile for this newly approved indication – what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract 2015; 69:410–421. 41. Grilo CM, et al. Efficacy and safety of dasotraline in adults with binge-eating disorder: a randomized, placebo-controlled, fixed-dose clinical trial. CNS Spectr 2021; 26:481–490. 42. Leombruni P, et al. Citalopram versus fluoxetine for the treatment of patients with bulimia nervosa: a single-blind randomized controlled trial. Adv Ther 2006; 23:481–494. 43. Leombruni P, et al. A 12 to 24 weeks pilot study of sertraline treatment in obese women binge eaters. Hum Psychopharmacol 2006; 21:181–188.

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10 - Attention deficit hyperactivity disorder (ADH

Attention deficit hyperactivity disorder (ADHD) in adults

798 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 9 Attention deficit hyperactivity disorder (ADHD) in adults While globally ADHD may still be under-recognised and under-treated, rates of ADHD diagnoses and psychostimulant use have been rapidly rising over the past two decades in many countries, including the UK.1–3 Increased awareness about this often life-long and disabling condition has also fuelled societal debates on ‘pathologising’ a condition that many interpret as indissoluble from their identity, with relevant implications on the appropriateness of potentially life-long pharmacological treatment. A first-time diagnosis of ADHD in an adult is compatible with both ICD-11 and DSM-5 and should only be made after a comprehensive assessment by a healthcare professional with training and expertise in diagnosing and managing ADHD. Whenever possible, this should include information from other informants and from adults who knew the patient as a child. It is recommended to establish the symptoms and impairments of ADHD using a validated diagnostic interview assessment such as the Diagnostic Interview for ADHD in Adults (DIVA-5), based on the DSM-5 adult ADHD criteria.4 Evaluation of innovative technology in addition to routine clinical assessment to diagnose ADHD and evaluate different treatments is underway.5 People with untreated ADHD might have poorer long-term outcomes in several life domains compared with people without ADHD and people with treated ADHD.6 However, assumptions of efficacy, tolerability or better functional outcomes from long- term ADHD medication use are currently unsubstantiated due to the scarcity of data from randomised placebo-controlled trials of ADHD treatment lasting more than 52 weeks. Short-term trials have consistently found that ADHD medications improved inattentiveness and restlessness more than quality-of-life measures. There is inadequate direct comparative evidence to guide clinical practice on choice of ADHD medications or augmentation regimens. Moreover, the strength of the evidence for efficacy of the most frequently used pharmacological treatments for ADHD in adults is ‘low’ or ‘very low’.7–9 To some extent, adult ADHD clinical guidelines and consensus documents do not reflect this uncertainty and recommend medications as first-line treatment in adults with ADHD whose symptom severity cannot be sufficiently reduced by environmental modifications. Daily intake of ADHD medication is usually advised, although ad hoc trial periods of stopping medication, medication off-days or reducing the dose should be considered to minimise any possible adverse outcomes. Doubts remain about the long-term cardiovascular effects of stimulant drugs. A 2022 meta- analysis suggested no adverse effect, but a 2024 population study found increased (and dose- related) risk of cardiovascular disease.10,11 Clinicians should regularly and consistently monitor cardiovascular signs and symptoms throughout the course of treatment. A healthcare professional with training and expertise in managing ADHD should review ADHD medication at least once a year and discuss with the person (and their family and carers as appropriate) whether medication should be continued.12 Additional considerations in adults (as opposed to children) include a diagnosis of bipolar or psychosis (ADHD medication may worsen these conditions13) and the need to reduce the opportunity for diversion or misuse (prescribe modified-release [MR] preparations or non-stimulants). Medications for the treatment of adult ADHD belong to two broad categories:

Psychostimulants (i.e. methylphenidate, dexamfetamine, lisdexamfetamine [Controlled Drugs in most countries]).
Non-stimulants14 (i.e. atomoxetine or other non-controlled drugs).

Drug treatment of other psychiatric conditions CHAPTER 9 The enhancement of dopaminergic and noradrenergic neurotransmission in the prefrontal cortex is the probable mechanism of ADHD drugs.15 Evidence largely supports amfetamines in adults as the preferred first-choice medication for the short-term treatment of ADHD, followed by methylphenidate preparations.16 Lisdexamfetamine or methylphenidate is considered first-line choice of medication in adults.12 Lisdexamfetamine is associated with improved outcomes in persons with ADHD and co-occurring amfetamine or methamfetamine use disorders.17 Atomoxetine might be an appropriate alternative for patients who did not tolerate or have contraindications to stimulants, or in cases of concern of medication misuse or diversion. Stimulant medication response may lessen over longer durations of treatment in a significant percentage of patients.18 MR stimulant preparations are generally preferred to immediate-release (IR) tablets because of the higher liability to tolerance, misuse and diversion (for recreational use, cognitive enhancement or appetite suppression) of IR stimulant preparations, and the convenience of a once-daily intake (compared with twice or three times daily). It is possible that several formulations will need to be tried before one is found that suits an individual. While all long-acting methylphenidate preparations include an IR component as well as an MR component, the biphasic release profiles of these products are not equivalent and contain different IR/MR proportions. The different time–action profiles provided by long-acting formulations facilitate individualisation of ADHD treatment. Transferring to another formulation can result in changes in symptom management at key time periods during the day. Patient preference should guide clinicians’ decisions on any medication change, which, during worldwide ADHD medication supply disruptions at the time of writing, is frequently the only alternative to discontinuation. For adults with ADHD and drug or alcohol addiction disorders, there should be close liaison between the professional considering prescribing ADHD medication and an addiction specialist. As with any prescription of controlled substances, the clinician must weigh the risk of misuse/diversion against the stimulant’s potential therapeutic benefit.19 In the UK, atomoxetine, lisdexamfetamine and two MR capsule formulations of methylphenidate (Medikinet XL, Ritalin XL) are licensed for first-time use in adults with ADHD, while most MR tablet formulations of methylphenidate are licensed for children and for continued treatment when initiated before the age of 18 years. In some cases, starting drug-naïve adults with ADHD on formulations prescribed off-licence might be appropriate. Guanfacine is also effective and well tolerated in adults. A 2023 meta-analysis of 12 studies showed a response rate of around 60% (placebo 30%).20 Viloxazine also appears to be effective21 as is bupropion22 but data are limited compared with guanfacine. Prescribers should be familiar with the national and international requirements of Controlled Drug legislation governing the prescription and supply of stimulants.23,24 Generally, for Controlled Drugs or medicines that are liable to abuse, overuse or misuse or when there is a risk of addiction and monitoring is important, prescribing should be considered only when it is possible to access relevant information from the patient’s medical records.25 Box 9.2 summarises UK NICE guidelines and Table 9.1 lists the advantages and disadvantages of different medications for the treatment of ADHD in adults. See Chapter 5 for details of products available in the UK (see also local and national prescribing information).

800 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 9 Box 9.2 Summary of NICE guidance for the treatment of ADHD in adults12 ■ ■Drug treatment should only be initiated by a specialist and only after comprehensive assessment of mental and physical health and social influences ■ ■Medication for ADHD should be offered to adults if their ADHD symptoms are still causing a significant impairment in at least one domain after environmental modifications have been implemented and reviewed ■ ■Non-pharmacological options (supportive therapy, cognitive behavioural therapy, regular reviews) can be considered depending on choice, difficulties with adherence or intolerable adverse effects. Combination of medication with non-pharmacological options can also be considered in partial response to medication treatment ■ ■Methylphenidate or lisdexamfetamine is recommended for use in adults with ADHD as first-line treatment. Switching between the two could be considered after a 6-week trial of an adequate dose with suboptimal response ■ ■Atomoxetine could be offered to adults if: ■ ■they cannot tolerate lisdexamfetamine or methylphenidate, or ■ ■their symptoms have not responded to separate 6-week trials of lisdexamfetamine and methylphenidate, having considered alternative preparations and adequate doses ■ ■Monitoring should include measurement of weight, blood pressure and heart rate ■ ■For atomoxetine, monitoring for symptoms of liver dysfunction and suicidal thinking is advised ■ ■An ECG is not needed before starting stimulants, atomoxetine or guanfacine if cardiovascular history and examination are normal and the person is not on medicine that poses an increased cardiovascular risk Table 9.1 The advantages and disadvantages of medications indicated for treating ADHD in adults. Drug group Drug Advantages Disadvantages ADHD stimulants Immediate release: ■ ■Methylphenidate ■ ■Dexamfetamine Quick onset of effect Allows for flexible dosing regimens, or during initial titration to determine correct dosing levels May be associated with euphoric effects, misuse/diversion and adverse effects Higher effect size compared with non- stimulants Generally well tolerated and safe short term Modified or prolonged release: ■ ■Lisdexamfetamine ■ ■Methylphenidate Convenient once-daily regimen Less risk of misuse and diversion compared with IR stimulants Less flexible dose titration and regimen compared with IR stimulants In the UK some preparations are not licensed for initiation in adults. Caution when switching between apparently bioequivalent preparations owing to differences in dosing frequency, requirements for administration with food, differences in the MR component and overall clinical effect Tablet and capsule preparations might be difficult to swallow.

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11 - References

References

Drug treatment of other psychiatric conditions CHAPTER 9 References

Raman SR, et al. Trends in attention-deficit hyperactivity disorder medication use: a retrospective observational study using population-based databases. Lancet Psychiatry 2018; 5:824–835.
Piper BJ, et al. Trends in use of prescription stimulants in the United States and Territories, 2006 to 2016. PLoS One 2018; 13:e0206100.
NHS Business Services Authority. Medicines used in mental health – England – 2015/16 to 2022/23. 2023; https://www.nhsbsa.nhs.uk/ statistical-collections/medicines-used-mental-health-england/medicines-used-mental-health-england-201516-202223.
DIVA Foundation. DIVA-5: Diagnostic Interview for ADHD in adults (DIVA). 2019 (last accessed December 2023); https://www.divacenter. eu/DIVA.aspx?id=461.
National Institute for Health and Care Excellence. QbTest for the assessment of attention deficit hyperactivity disorder (ADHD). Medtech Innovation Briefing [MIB318]. 2023; https://www.nice.org.uk/advice/mib318.
Shaw M, et al. A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment. BMC Med 2012; 10:99.
Boesen K, et al. Extended-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst Rev 2022; 2:CD012857.
Cândido RCF, et al. Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst Rev 2021; 1:CD013011.
Castells X, et al. Amphetamines for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst Rev 2018; 8:CD007813.
Zhang L, et al. Risk of cardiovascular diseases associated with medications used in attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. JAMA Network Open 2022; 5:e2243597.
Zhang L, et al. Attention-deficit/hyperactivity disorder medications and long-term risk of cardiovascular diseases. JAMA Psychiatry 2024; 81:178–187.
National Institute for Health and Care Excellence. Attention deficit hyperactivity disorder: diagnosis and management. NICE Guideline [NG87]. 2018 (last updated September 2019, last accessed December 2023); https://www.nice.org.uk/guidance/NG87.
Viktorin A, et al. The risk of treatment-emergent mania with methylphenidate in bipolar disorder. Am J Psychiatry 2017; 174:341–348.
Radonjić NV, et al. Nonstimulant medications for attention-deficit/hyperactivity disorder (ADHD) in adults: systematic review and meta-analysis. CNS Drugs 2023; 37:381–397. Drug group Drug Advantages Disadvantages Non- stimulants Atomoxetine (NE reuptake inhibitor) Not Controlled Drugs – less restrictive prescribing regulations Can help when stimulants are not indicated or not tolerated (e.g. tic disorders, active substance use disorders, others) Might be considered by specialists in case of refractory ADHD or as an alternative to stimulants Require weeks to attain full effect Higher risk of interactions (metabolised by CYP2D6) and effect variability due to genotype – might require dose adjustments26 Lower effect size than stimulants Guanfacine (α2A-adrenoceptor agonist) In many countries off-label (unlicensed) for ADHD in adults Off-label prescribing may restrict opportunities to transfer to primary care. Viloxazine (5HT- and NE-modulating agent) USA only Bupropion (dopamine and NE reuptake inhibitor) Limited evidence base 5HT, 5-hydroxytryptamine; NE, norepinephrine. Table 9.1 (Continued )

802 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 9 15. Bolea-Alamañac B, et al. Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: update on recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2014; 28:179–203. 16. Cortese S, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry 2018; 5:727–738. 17. Heikkinen M, et al. Association of pharmacological treatments and hospitalization and death in individuals with amphetamine use disorders in a Swedish nationwide cohort of 13 965 patients. JAMA Psychiatry 2023; 80:31–39. 18. Cunill R, et al. Efficacy, safety and variability in pharmacotherapy for adults with attention deficit hyperactivity disorder: a meta-analysis and meta-regression in over 9000 patients. Psychopharmacology (Berl) 2016; 233:187–197. 19. Crunelle CL, et al. International consensus statement on screening, diagnosis and treatment of substance use disorder patients with comorbid attention deficit/hyperactivity disorder. Eur Addict Res 2018; 24:43–51. 20. Yu S, et al. Guanfacine for the treatment of attention-deficit hyperactivity disorder: an updated systematic review and meta-analysis. J Child Adolesc Psychopharmacol 2023; 33:40–50. 21. Nasser A, et al. A phase III, randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of viloxazine extended-release capsules in adults with attention-deficit/hyperactivity disorder. CNS Drugs 2022; 36:897–915. 22. Verbeeck W, et al. Bupropion for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst Rev 2017; 10:CD009504. 23. National Institute for Health and Care Excellence. Controlled drugs: safe use and management. NICE Guideline [NG46]. 2016 (last checked December 2023); https://www.nice.org.uk/guidance/ng46/chapter/context. 24. Gallagher CT, et al. Doctor or drug dealer? International legal provisions for the legitimate handling of drugs of abuse. Drug Sci Policy Law 2020; 6:2050324519900070. 25. General Medical Council. Controlled drugs and other medicines where additional safeguards are needed. 2021; https://www.gmc-uk.org/ ethical-guidance/ethical-guidance-for-doctors/good-practice-in-prescribing-and-managing-medicines-and-devices/controlled- drugs-and-other-medicines-where-additional-safeguards-are-needed. 26. Clinical Pharmacogenetics Implementation Consortium (CPIC). CPIC® guideline for atomoxetine based on CYP2D6 genotype. 2019 (last checked December 2023); https://cpicpgx.org/guidelines/cpic-guideline-for-atomoxetine-based-on-cyp2d6-genotype/.

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01 - Prescribing in human immunodeficiency virus (

Prescribing in human immunodeficiency virus (HIV)

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 10 Prescribing in human immunodeficiency virus (HIV) People living with human immunodeficiency virus (PLWH) may experience symptoms of mental illness because of a variety of factors (Box 10.1). In practice, several of these factors may coexist within an individual.1 When prescribing psychotropics, the following principles should be adhered to: ■ ■Start with a low dose and titrate according to tolerability and response. ■ ■Select the simplest dosing regimen possible. (Remember that the patient’s drug regimen is likely to be complex already.) ■ ■Select an agent with the fewest adverse effects. Consider drug interactions, medical comorbidities and any ongoing substance misuse. ■ ■Ensure that management is conducted in close co-operation with the HIV specialists and the rest of the multidisciplinary team. Drug treatment of psychiatric symptoms occurring in the context of other conditions Box 10.1 Factors contributing to the development of psychiatric symptoms in people living with HIV ■ ■Primary (or pre-existing) psychiatric disorders ■ ■Neurobiological changes caused by HIV in the CNS ■ ■Other infections or CNS tumours ■ ■Antiretroviral drugs and other medical treatments ■ ■Alcohol or substance misuse (particularly crystal methamfetamine and GHB/GBL) ■ ■Adverse psychosocial factors (e.g. stigma, social isolation) ■ ■Awareness of a chronic disease requiring strict adherence to medication CNS, central nervous system; GHB/GBL, gamma hydroxybutyrate/gamma butyrolactone.

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02 - HIV treatment advances and mental health

HIV treatment advances and mental health

15 - Chapter 10 Drug treatment of psychiatric symptoms

03 - Psychotic illness

Psychotic illness

15 - Chapter 10 Drug treatment of psychiatric symptoms

04 - Depression

Depression

804 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Although most psychotropic agents are thought to be safe in PLWH, definitive data are lacking in many cases. PLWH may be more sensitive to higher doses, adverse effects and to interactions.2 Patients with advanced HIV disease are particularly more likely to suffer exaggerated adverse reactions to psychotropic medication. HIV treatment advances and mental health Treatment of HIV infection has evolved in recent years to include long-acting injectable antiretroviral therapy (ART) (e.g. cabotegravir/rilpivirine)3 aiming to improve adherence to and persistence with treatment.3 Ensuring continuous ART is crucial for a number of reasons including the fact that inflammation associated with untreated HIV can worsen pre-existing cognitive decline in people with psychosis. Successful treatment with ART is associated with a lower risk of mental health disorders.4 In those at high risk of psychiatric relapse and poor compliance with medicines, long-acting injections of both antipsychotics and antiretrovirals are available and could be used concurrently. Psychotic illness For most PLWH and comorbid psychosis, treatment is similar to that used in people without HIV5 but with some specific considerations. PLWH are more susceptible to extrapyramidal side effects (EPSEs) because HIV, a neurotropic virus, enters the brain and replicates in the basal ganglia leading to dopaminergic neuronal loss.6 In addition to this, both HIV and ART are implicated in metabolic abnormalities, hyperlipidaemia, weight gain and insulin resistance.7 Use of second-generation antipsychotics (SGAs) in PLWH has been shown to increase the cardiovascular risk and metabolic complications compared with those not on SGAs.8 Likewise, QT interval prolongation can be a complication of HIV progression, HIV comorbidities and use of antiretrovirals as well as antipsychotics.9 Pharmacokinetic interactions should be considered and are discussed further in this section. SGAs are clearly first-line options for the treatment of psychosis in PLWH although close physical health monitoring is essential, as is the use of preventative measures if required. Clozapine is a treatment option in PLWH10–12 and comorbid treatment-resistant schizophrenia. Haematological abnormalities, including leukopenia, neutropenia, lymphopenia, thrombocytopenia and anaemias, are frequent complications of HIV13 as well as ART. Clozapine treatment may be erroneously interrupted if these are considered as clozapine-induced, with detrimental consequences for the treatment of both HIV and psychosis. The safe and effective management of the additive haematological, metabolic and cardiovascular effects of clozapine and ART and complex pharmacokinetic interactions require the close collaboration of specialist medical teams and pharmacists. Clozapine may also be helpful in the treatment of individuals with HIV-associated psychosis with drug-induced parkinsonism.14 Depression Depression is the most common mental health disorder in PLWH, with prevalence estimated to be between 14% and 78%.1 Depressive symptoms can be a consequence of HIV infection or ART or of a pre-existing disorder. Untreated depression in PLWH is associated with reduced viral suppression and faster HIV illness progression.15 Antidepressants

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05 - Bipolar affective disorder

Bipolar affective disorder

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06 - Secondary mania (HIV mania)

Secondary mania (‘HIV mania’)

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07 - Anxiety disorders

Anxiety disorders

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 are more effective than placebo in the treatment of depression in PLWH16 and may improve adherence to ART.17 Selective serotonin reuptake inhibitors (SSRIs) are preferred as first-line agents. Escitalopram/citalopram18,19 probably have lower risk of pharmacokinetic interactions, although one study found no difference between the efficacy of escitalopram and placebo, possibly because of a large placebo response.20 Electrocardiogram (ECG) monitoring is recommended when citalopram/escitalopram is co-administered with ART that prolongs the QT interval.9,21 Mirtazapine is effective22,23 and may be beneficial in coexisting HIV wasting and depression24 or in reducing methamfetamine use among active users.25 The serotonin–noradrenaline reuptake inhibitors (SNRIs) duloxetine and venlafaxine were found to be as effective as SSRIs for depressive symptoms in PLWH.26 Bupropion was effective with similar tolerability to SSRIs in a 6-week open-label study in a small number of HIV-positive, depressed out-patients.27 The adverse effect burden of tricyclic antidepressants (TCAs) may limit efficacy and compliance, although their use may be appropriate, particularly in patients troubled with insomnia, irritable bowel disease or painful neuropathy related to HIV or ART. Constipation and dry mouth are frequently reported in PLWH on TCAs.16 Monoamine oxidase inhibitors (MAOIs) are not recommended in PLWH. Bipolar affective disorder Mania in PLWH can be primary (pre-existing bipolar affective disorder) or, rarely, secondary (‘HIV mania’ associated with late-stage HIV infection). Treatment of bipolar disorder in HIV is similar to that in the general population.27 Lithium is renally excreted and so cytochrome P450 (CYP) interactions are unlikely. However, its use can be problematic in renal impairment, something which is often seen in PLWH. Lithium may be used cautiously in PLWH for primary bipolar disorder with close monitoring to avoid development of toxicity. Carbamazepine should be avoided because of significant drug interactions with ART and the risk of blood dyscrasias.28 Valproate is a known teratogen and should not be used in women of childbearing age.29 Its use is also best avoided with other hepatotoxic drugs (e.g. nevirapine, rifampicin)28 and where there is infection involving the liver (e.g. hepatitis C, mycobacterium avium complex30). Mood-stabilising antipsychotics such as risperidone, quetiapine, aripiprazole and olanzapine may be preferred. Secondary mania (‘HIV mania’) Secondary mania may infrequently be seen in advanced illness in the context of HIV- associated neurocognitive disorders or central nervous system (CNS) opportunistic infections. The primary aim is to identify and treat the potential underlying cause (infections, substance misuse, alcohol withdrawal, metabolic abnormalities). Secondary mania may respond to quetiapine, olanzapine, aripiprazole or ziprasidone31 but their efficacy has not been demonstrated in clinical trials. Anxiety disorders Anxiety disorders, including generalised anxiety disorder, obsessive compulsive disorder, panic disorder and post-traumatic stress disorder (PTSD), are highly prevalent in PLWH.32 Treatment follows standard guidelines for the management of anxiety disorders, with

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08 - HIV associated neurocognitive disorders (HAND

HIV-associated neurocognitive disorders (HAND)

15 - Chapter 10 Drug treatment of psychiatric symptoms

09 - Delirium

Delirium

15 - Chapter 10 Drug treatment of psychiatric symptoms

10 - Substance use disorders

Substance use disorders

806 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 SSRIs being the first-line options. Benzodiazepines may have some utility in the acute treatment of anxiety but require caution because of potential misuse, possible drug interactions and a higher risk of sedative and neurocognitive adverse effects in PLWH.33 Lorazepam is metabolised by non-CYP pathways, and so has a lower risk of interactions. Clonazepam has no active metabolites and so it may be a preferred short-term option for PLWH.34,35 Buspirone may also be helpful.34 HIV-associated neurocognitive disorders (HAND) HAND encompasses three sub-disorders, ranging from the more common asymptomatic neurocognitive impairment (ANI) to a mild neurocognitive disorder (MND) and the more severe but less common HIV-associated dementia (HAD). Screening for cognitive impairment is recommended in PLWH using scales such as the MoCA or the three-item Cognitive Concerns Questionnaire.36 In 2023, the International HIV-Cognition Working Group published recommendations to better define the cognitive impairment in HIV.37 Treatment involves the use of ART with high CNS penetration effectiveness (e.g. raltegravir), aiming to achieve therapeutic levels in the CNS with minimal drug-related neurotoxicity. Cognitive rehabilitation is an essential treatment component. Effective treatment of depression is essential as is management of substance use disorders and physical health comorbidities. Psychostimulants, modafinil, memantine, lithium and valproate have been studied but there is currently no licensed treatment for HAND.38 Delirium Delirium in HIV can be difficult to differentiate from HAND, although onset of delirium is more acute and its severity may fluctuate. Organic causes should be identified and treated. Antipsychotics are probably not effective in treating delirium and so should only be used as a last resort in severe cases and when non-pharmacological measures fail.27 Early studies document the efficacy of haloperidol, but the lowest possible dose should be used given the high incidence of EPSEs, particularly in those with advanced HIV (e.g. doses used in delirium in palliative care may be considered).27 Benzodiazepines should be used cautiously as they may worsen delirium except when alcohol or benzodiazepine withdrawal is the precipitating factor.27 Substance use disorders Substance use disorders are highly prevalent in PLWH. Commonly used substances include alcohol, stimulants (including cocaine and methamfetamine), benzodiazepines, opioids and cannabinoids. The potential for interactions between drug use and prescribed medicines should be considered. Treatment should be offered to PLWH with comorbid substance use disorders. Naltrexone is safe and effective for alcohol relapse prevention in PLWH,39 while acamprosate has not been studied in this population and has a high tablet burden. Methadone and buprenorphine are possible evidence-based options for opioid use disorder but care is required with ART drug interactions.27,40

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11 - Interactions between antiretroviral drugs and

Interactions between antiretroviral drugs and psychotropics

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Interactions between antiretroviral drugs and psychotropics Pharmacokinetic interactions between antiretroviral drugs and psychotropics occur frequently and can be clinically significant. Potential interactions should be investigated for all patients receiving antiretrovirals and psychotropics concomitantly and include current prescribed medication, alternative/herbal treatments, recreational drugs and other non-prescribed medicines. Interactions are numerous and complex. Readers are directed to regularly updated online resources for information about individual pharmacokinetic interactions such as www.hiv-druginteractions.org (also available as an app). Pharmacodynamic interactions may also occur, usually through overlapping adverse effects. Potential pharmacodynamic interactions are shown in Table 10.1. Table 10.1 Potential pharmacodynamic interactions with antiretrovirals.40,41 Potential adverse effect Implicated antiretroviral drug(s)21,42,43 Implications for psychotropic prescribing Bone marrow suppression Zidovudine (anaemia, neutropenia) Concurrent use with certain psychotropics (e.g. clozapine) may increase the risk of myelosuppression/neutropenia Bone mineral density (BMD) reduction Tenofovir disoproxil fumarate (TDF) (tenofovir alafenamide has smaller decline of BMD) NNRTIs, PIs, INSTIs: decreases in BMD following any regimen May compound the reductions in BMD possible with prolactin elevating antipsychotics Creatine kinase (CK) elevations Dolutegravir, emtricitabine, raltegravir May be important to acknowledge associated link if diagnosis of NMS is being considered ECG changes Efavirenz, rilpivirine, saquinavir/ ritonavir: QT prolongation Atazanavir, lopinavir saquinavir: PR prolongation May increase risk of arrhythmias associated with certain psychotropic drugs Cardiovascular effects Abacavir, darunavir/ritonavir, lopinavir/ritonavir Cardiovascular events (e.g. myocardial infarction) occurred in some cohorts Renal effects TDF (risk increased if used with ritonavir) Tenofovir alafenamide: less impact on renal function versus TDF Atazanavir (kidney stones, tubo-interstitial nephritis) Proteinuria, hypophosphataemia, glycosuria, hypokalaemia, renal tubular Gastrointestinal disturbances Atazanavir, darunavir, dolutegravir, didanosine, elvitegravir/cobicistat, fosamprenavir, indinavir, lopinavir, nelfinavir, raltegravir, saquinavir, tipranavir, zidovudine May compound gastrointestinal disturbances associated with certain psychotropics (e.g. SSRIs) (Continued )

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12 - Adverse psychiatric effects of antiretroviral

Adverse psychiatric effects of antiretroviral drugs

808 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Table 10.2 Summary of psychiatric adverse drug reactions (ADRs) with antiretroviral drugs.21,40–45 Drug Adverse psychiatric effects/comments Nucleoside reverse transcriptase inhibitors Abacavir Depression, anxiety, nightmares, labile mood, mania, psychosis. Very few cases reported. In all reported cases, the patient rapidly returned to baseline after discontinuing drug. Didanosine Lethargy, nervousness, anxiety, confusion, sleep disturbance, mood disorders, psychosis, mania. Very rare. Emtricitabine Confusion, irritability, insomnia Tenofovir alafenamide Insomnia Zidovudine Sleep disturbance, vivid dreams, agitation, mania, depression, psychosis, delirium. Psychiatric ADRs are usually dose-related. Onset varies widely, from <24 hours to 7 months. Non-nucleoside reverse transcriptase inhibitors Efavirenz Somnolence, insomnia, abnormal dreams, impaired concentration, depression, psychosis, suicidal ideation. Symptoms usually subside or diminish after 2–4 weeks. However, subtler long-term neuropsychiatric effects may occur. Can exacerbate psychiatric symptoms; avoid in patients with a history of psychiatric illness. Adverse psychiatric effects of antiretroviral drugs Psychiatric adverse events have been reported with most antiretroviral drugs, but a causal relationship remains uncertain for many. Efavirenz has been most commonly implicated, and HIV guidelines suggest avoiding its use in patients with psychiatric comorbidity. Table 10.2 summarises the most important psychiatric adverse effects of antiretroviral drugs. Note that this is not an exhaustive list and readers are directed to the summaries of product characteristics/product labelling for greater detail. Potential adverse effect Implicated antiretroviral drug(s)21,42,43 Implications for psychotropic prescribing Seizure(s) Darunavir, efavirenz, maraviroc, ritonavir, saquinavir, zidovudine May increase seizure risk associated with certain psychotropic drugs (e.g. clozapine) Metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia All combination antiretroviral therapy Raltegravir, elvitegravir, dolutegravir: greater risk of weight gain May compound risk of metabolic adverse effects associated with certain psychotropic drugs (particularly SGAs) INSTIs, integrase strand transfer inhibitors; NMS, neuroleptic malignant syndrome; NNRTIs, non-nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors. Table 10.1 (Continued )

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13 - References

References

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 A 2023 systematic review concluded that dolutegravir-based regimens led to higher discontinuation rates due to neuropsychiatric adverse effects compared with those treated with bictegravir, emtricitabine and tenofovir alafenamide. Antiretroviral regimen choice should evidently take into account the individual’s risk factors for developing neuropsychiatric adverse effects.46 References

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Ferrara M, et al. The concomitant use of second-generation antipsychotics and long-term antiretroviral therapy may be associated with increased cardiovascular risk. Psychiatry Res 2014; 218:201–208.
Liu J, et al. QT prolongation in HIV-positive patients: review article. Indian Heart J 2019; 71:434–439.
Nejad SH, et al. Clozapine use in HIV-infected schizophrenia patients: a case-based discussion and review. Psychosomatics 2009; 50:626–632.
Sanz-Cortés S, et al. A case report of schizophrenia and HIV: HAART in association with clozapine. J Psychiatric Intensive Care 2009; 5:47–49.
Whiskey E, et al. Clozapine, HIV and neutropenia: a case report. Ther Adv Psychopharmacol 2018; 8:365–369.
Duguma N, et al. Hematological parameters abnormalities and associated factors in HIV-positive adults before and after highly active antiretroviral treatment in Goba Referral Hospital, southeast Ethiopia: a cross-sectional study. SAGE Open Med 2021; 9:20503121211020175.
Lera G, et al. Pilot study with clozapine in patients with HIV-associated psychosis and drug-induced parkinsonism. Mov Disord 1999; 14:128–131.
Lesko CR, et al. Depression and HIV viral nonsuppression among people engaged in HIV care in an urban clinic, 2014–2019. AIDS 2021; 35:2017–2024. Table 10.2 (Continued ) Drug Adverse psychiatric effects/comments Etravirine Sleep disturbance Nevirapine Visual hallucinations, persecutory delusions, mood changes, nightmares and vivid dreams, depression. A handful of cases have been reported. Onset of symptoms was within the first couple of weeks. Symptoms all resolved on discontinuation of nevirapine. Rilpivirine Depression, suicidality, sleep disturbances. A similar adverse effect profile to efavirenz but a lower incidence of each event. May exacerbate psychiatric symptoms; consider avoiding in patients with a history of psychiatric illness. Integrase strand transfer inhibitors Dolutegravir, elvitegravir, raltegravir Insomnia, depression, suicidal ideation (particularly with dolutegravir and symptoms may appear within first months of treatment) Bictegravir Depression incidence similar to dolutegravir (though suicidality greater for dolutegravir) but further data required Cabotegravir Limited data but incidence appears low – also long acting and so effects may be prolonged

810 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 16. Eshun-Wilson I, et al. Antidepressants for depression in adults with HIV infection. Cochrane Database Syst Rev 2018; 1:CD008525. 17. Gokhale RH, et al. Depression prevalence, antidepressant treatment status, and association with sustained HIV viral suppression among adults living with HIV in care in the United States, 2009–2014. AIDS Behav 2019; 23:3452–3459. 18. Currier MB, et al. Citalopram treatment of major depressive disorder in Hispanic HIV and AIDS patients: a prospective study. Psychosomatics 2004; 45:210–216. 19. Freudenreich O, et al. Psychiatric treatment of persons with HIV/AIDS: an HIV-psychiatry consensus survey of current practices. Psychosomatics 2010; 51:480–488. 20. Hoare J, et al. Escitalopram treatment of depression in human immunodeficiency virus/acquired immunodeficiency syndrome: a randomized, double-blind, placebo-controlled study. J Nerv Ment Dis 2014; 202:133–137. 21. European AIDS Clinical Society. Guidelines version 10.1 October 2020. 2020 (last accessed May 2024); https://www.eacsociety.org/media/ guidelines-10.1_finaljan2021_1.pdf. 22. Patel S, et al. Escitalopram and mirtazapine for the treatment of depression in HIV patients: a randomized controlled open label trial. ASEAN J Psychiatry 2013; 14:3139. 23. Elliott AJ, et al. Mirtazapine for depression in patients with human immunodeficiency virus. J Clin Psychopharmacol 2000; 20:265–267. 24. Badowski M, et al. Pharmacologic management of human immunodeficiency virus wasting syndrome. Pharmacotherapy 2014; 34:868–881. 25. Coffin PO, et al. Effects of mirtazapine for methamphetamine use disorder among cisgender men and transgender women who have sex with men: a placebo-controlled randomized clinical trial. JAMA Psychiatry 2020; 77:246–255. 26. Mills JC, et al. Comparative effectiveness of dual-action versus single-action antidepressants for the treatment of depression in people living with HIV/AIDS. J Affect Disord 2017; 215:179–186. 27. Hirsch CH, et al. HIV-associated neurocognitive disorders and delirium. In: Bourgeois JA, Cohen MAA, Makurumidze G (eds.) HIV Psychiatry: A Practical Guide for Clinicians. Cham: Springer Nature; 2022:181–233. 28. Gallego L, et al. Psychopharmacological treatments in HIV patients under antiretroviral therapy. AIDS Rev 2012; 14:101–111. 29. Medicines and Healthcare Products Regulatory Agency. New valproate safety measures apply from 31 January 2024; https://www.gov.uk/ government/news/new-valproate-safety-measures-apply-from-31-january. 30. Pieper AA, et al. Depression, mania, and schizophrenia in HIV-infected patients. 2021 (last accessed May 2024); https://pro.uptodatefree.ir/ Show/4864. 31. Spiegel DR, et al. The successful treatment of mania due to acquired immunodeficiency syndrome using ziprasidone: a case series. J Neuropsychiatry Clin Neurosci 2010; 22:111–114. 32. Armoon B, et al. HIV related stigma associated with social support, alcohol use disorders, depression, anxiety, and suicidal ideation among people living with HIV: a systematic review and meta-analysis. Int J Ment Health Syst 2022; 16:17. 33. Saloner R, et al. Benzodiazepine use is associated with an increased risk of neurocognitive impairment in people living with HIV. J Acquir Immune Defic Syndr 2019; 82:475–482. 34. Brogan K, et al. Management of common psychiatric conditions in the HIV-positive population. Curr HIV/AIDS Rep 2009; 6:108–115. 35. Bourgeois J, et al. HIV Psychiatry. Cham: Springer; 2022. 36. Wang Y, et al. Global prevalence and burden of HIV-associated neurocognitive disorder. Neurology 2020; 95:e2610–e2621. 37. Nightingale S, et al. Cognitive impairment in people living with HIV: consensus recommendations for a new approach. Nat Rev Neurol 2023; 19:424–433. 38. Elendu C, et al. HIV-related neurocognitive disorders: diagnosis, treatment, and mental health implications: a review. Medicine (Baltimore) 2023; 102:e35652. 39. Farhadian N, et al. Effectiveness of naltrexone treatment for alcohol use disorders in HIV: a systematic review. Subst Abuse Treat Prev Policy 2020; 15:24. 40. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. 2024 (last accessed May 2024); https://clinicalinfo.hiv.gov/sites/default/files/guidelines/ documents/adult-adolescent-arv/guidelines-adult-adolescent-arv.pdf. 41. Waters L, et al. BHIVA guidelines on antiretroviral treatment for adults living with HIV-1 2022. HIV Med 2022; 23 Suppl 5:3–115. 42. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Department of Health and Human Services. 2017 (last accessed August 2024); https://clinicalinfo.hiv.gov/en/guidelines/hivclinical-guidelines-adult-and-adolescent-arv/whats-new. 43. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach, 2nd edn. 2016; http://www.who.int/hiv/pub/arv/arv-2016/en. 44. Parker C. Psychiatric effects of drugs for other disorders. Medicine 2016; 44:768–774. 45. Préta LH, et al. Association of depression and suicidal behaviour reporting with HIV integrase inhibitors: a global pharmacovigilance study. J Antimicrob Chemother 2023; 78:1944–1947. 46. Pérez-Valero I, et al. Real-world discontinuations due to neuropsychiatric symptoms in people living with HIV treated with second-generation integrase inhibitors: a systematic review. Expert Rev Anti Infect Ther 2023; 21:655–665.

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14 - Epilepsy

Epilepsy

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15 - Psychiatric comorbidities in epilepsy

Psychiatric comorbidities in epilepsy

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Epilepsy Psychiatric comorbidities in epilepsy People with epilepsy (PWE) have an elevated prevalence of several psychiatric disorders including depression (13–37%), anxiety (20%) and psychosis (5%).1,2 Suicide is threefold higher in PWE compared with the general population3 and is an important cause of premature mortality.4 The link between epilepsy and mental illness is bidirectional as patients with depression, anxiety and psychosis have an increased risk of developing new-onset epilepsy.5,6 Suicide attempts are also associated with the development of epilepsy.7 This bidirectional relationship might be explained by a common underlying pathology between mental illness and epilepsy. Disturbances in neurotransmission, neuroinflammation and the hypothalamic–pituitary–adrenal (HPA) axis have all been suggested8 to be the shared pathology. Interictal psychiatric disorders (with symptoms occurring independently of seizures) are likely to require treatment with psychotropics.9–11 When prescribing psychotropics to people with epilepsy, the following general principles12,13 should be adhered to: ■ ■First, rule out other possible causes of psychiatric symptoms (both peri-ictal and iatrogenic – Table 10.3). ■ ■Optimise the treatment of epilepsy (ideally before prescribing psychotropics). ■ ■Consider using psychotropics with known antiseizure properties (e.g. antiseizure medications in bipolar disorder). ■ ■Check for interactions with antiseizure medications. ■ ■Start with a low dose and titrate according to tolerability and response (proconvulsive effects are dose-related). ■ ■If seizures do occur, consider changing the psychotropic drug or optimising the antiseizure medication. Table 10.3 Possible causes of psychiatric symptoms in people with epilepsy (PWE) and their management.5 Cause of symptoms Description Management Interictal psychiatric disorders Symptoms occurring independently of seizures. Although common in PWE, other causes and relatedness to seizures should be ruled out first. Likely to require treatment with psychotropics. See Table 10.5 for more information about the use of specific psychotropics in PWE. Peri-ictal symptoms PWE may experience psychiatric symptoms that are temporally related to seizures. All peri-ictal psychiatric symptoms (pre-ictal, postictal and ictal) are initially treated by optimising antiseizure medications.12 Peri-ictal depressive symptoms do not appear to respond to treatment with antidepressants.14,15 Postictal psychosis can remit spontaneously or respond to treatment with low doses of antipsychotics.16 Short-term symptomatic treatment with a benzodiazepine or antipsychotic is recommended for up to 3 months.17 Taper off carefully after symptom resolution.15 There is no evidence that psychotropics can prevent ictal symptoms.18 Pre-ictal symptoms Typically presents as a dysphoric mood preceding a seizure by a period of 30 minutes to hours to 2 or 3 days. Postictal symptoms Typically presents between several hours to 7 days following a seizure (depression, anxiety, suicidal ideation and psychosis reported) PWE and interictal psychiatric disorders may experience worsening of symptoms previously in remission (breakthrough symptoms). Ictal symptoms May present as ictal fear/panic (most commonly), depressive symptoms or, rarely, psychosis. (Continued )

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16 - Psychiatric side effects of antiseizure medic

Psychiatric side effects of antiseizure medications

812 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Psychiatric side effects of antiseizure medications Virtually all antiseizure medications are known to have psychotropic effects. These effects can be both helpful and unhelpful. The adverse and beneficial psychiatric side effects of antiseizure medications are summarised in Table 10.4. Cause of symptoms Description Management Para-ictal episodes ‘forced normalisation’ (psychiatric symptoms emerging as a result of a reduction in seizure frequency) Psychotic or, less commonly, severe affective symptoms following seizure remission in PWE Rapid medication titration schedules, rapid seizure control, previously medication-resistant epilepsy, and temporal lobe epilepsy may be risk factors.16 A decision should be made on how to proceed with antiseizure medications and psychotropics through a process of shared decision-making with carers.15 Symptomatic treatment with antipsychotics or antidepressants may be indicated. Iatrogenic psychiatric symptoms Changes in treatments for seizures could result in psychiatric symptoms as a result of: Starting antiseizure medications with known negative psychotropic properties (particularly in those with a psychiatric history). Stopping antiseizure medications with beneficial psychotropic properties (e.g. mood stabilisation). Starting antiseizure medications with enzyme-inducing properties in people stable on psychotropics. Surgery for epilepsy: de novo postsurgical episodes of depression, anxiety and, rarely, psychosis have been reported. Exacerbation of pre-existing conditions more common. Symptoms are managed by resolving the underlying cause in the first instance. Consider switching antiseizure medications with known negative psychotropic properties to better tolerated antiseizure medications (see Table 10.4). Antiseizure medications can lower folate levels which may affect mood. Folate levels should be checked and low levels remedied if necessary. If changing antiseizure medications is not suitable, antidepressants can be considered for iatrogenic depressive symptoms.19 Postsurgical neuropsychiatric symptoms may be treated successfully with psychotropics.18 Table 10.3 (Continued ) Table 10.4 Adverse and beneficial psychiatric side effects of antiseizure medications.5,20,21 Antiseizure medication Adverse psychiatric symptoms Psychiatric benefits Barbiturates, primidone Behavioural disturbance/ADHD symptoms, depression, cognitive impairment Anxiolytic, hypnotic Benzodiazepines Brivaracetam Depression, aggression, rage, suicidality None reported Carbamazepine, eslicarbazepine, oxcarbazepine Insomnia Mood stabilising, anti-manic

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17 - Interactions of antiseizure medications22

Interactions of antiseizure medications22

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Interactions of antiseizure medications22 Pharmacokinetic interactions Important pharmacokinetic interactions occur in both directions between antiseizure medications and psychotropics, primarily mediated through cytochrome enzymes.9,23 Psychotropics with enzyme-inhibiting effects (e.g. fluoxetine, fluvoxamine, paroxetine and, at higher doses, sertraline) may increase antiseizure plasma levels. This is especially relevant to antiseizure medications with a narrow therapeutic index (e.g. carbamazepine and phenytoin). Plasma levels should be monitored, and dosage adjustment may be required. Citalopram and escitalopram are very weak inhibitors of CYP1A2 and CYP2D6, and so may be preferred in some cases. Some antiseizure medications are potent enzyme inducers (e.g. phenytoin, carbamazepine, phenobarbital, primidone) and others are weak inducers (e.g. oxcarbazepine at doses ≥900mg/day, topiramate at doses ≥400mg/day). These drugs can lower plasma levels of many psychotropics, leading to treatment failure. Antiseizure medication Adverse psychiatric symptoms Psychiatric benefits Ethosuximide Behavioural disturbance, depression, psychosis None reported Felbamate Anxiety, depression None reported Gabapentin, pregabalin Depression and anxiety on cessation Anxiolytic Lacosamide None reported None reported Lamotrigine Anxiogenic in some. Behavioural disturbance in cognitive impairment Antidepressant, mood stabilising Levetiracetam Anxiety, behavioural disturbance, depression, suicidality None confirmed Perampanel Behavioural disturbance, depression, psychosis None reported Phenytoin Behavioural disturbance, depression Anti-manic Rufinamide Anxiety, insomnia None reported Tiagabine Behavioural disturbance, depression Anxiolytic Topiramate Anxiety, behavioural disturbance, depression, psychosis Unclear. Possible anti-manic/antipsychotic Valproate Behavioural disturbance (at high doses in children) Mood stabilising, anti-manic, anti-panic Vigabatrin Behavioural disturbance/ADHD symptoms, depression, psychosis None reported Zonisamide Behavioural disturbance, depression None confirmed Table 10.4 (Continued)

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18 - Psychotropics and the risk of seizures in peo

Psychotropics and the risk of seizures in people with epilepsy

814 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Pharmacodynamic interactions14 Adverse effects with antiseizure medications that may overlap with psychotropic adverse effects include: ■ ■Weight gain: caused by some antiseizure medications (e.g. carbamazepine, gabapentin, pregabalin, valproate). ■ ■Sexual adverse effects: with phenobarbital and primidone but possible with all enzyme-inducing antiseizure medications. ■ ■Hyponatraemia: with carbamazepine and oxcarbazepine (note, if severe, can provoke seizures). ■ ■Osteoporosis and osteopenia: reported with long-term use of enzyme-inducing antiseizure medications. ■ ■Blood dyscrasias: reported with valproate, carbamazepine11 and especially with felbamate. Psychotropics and the risk of seizures in people with epilepsy In the general population, the annual incidence of unprovoked seizures is about 50 per 100,000 persons.24,25 It is notable that the incidence of unprovoked seizures in the placebo arms of randomised controlled trials of antidepressants and antipsychotics is approximately 15-fold higher, suggesting that both depression and psychosis are risk factors for seizures.26 A bidirectional relationship between epilepsy and several psychiatric illnesses has been demonstrated, whereby not only do PWE have a higher risk of developing a psychiatric illness, but people with psychiatric illness have a higher risk of developing epilepsy.5,6 This bidirectional relationship exists for depression, anxiety, psychosis and suicidality.5–7 Thus, the occurrence of seizures may, in some cases, be the expression of the natural progression of a psychiatric illness and be unrelated to the use of psychotropics. Reports of seizures associated with psychotropics must factor in this bidirectional relationship between psychiatric illness and epilepsy. For example, although observational studies have reported an association between antidepressant treatment and seizures,27 a similar association is also found with non-drug treatments for depression (counselling, for example).28 These findings are consistent with depression itself being the main risk factor for seizures. In fact, one analysis of controlled studies with psychotropics showed that the incidence of seizures was substantially lower among patients receiving most antidepressants (e.g. SSRIs) in comparison with those randomised to placebo.26 Nonetheless, definitive data are lacking in PWE29,30 and certain psychotropics have a dose-related risk of seizures within usual dose ranges. Most can cause seizures in overdose. Note also that almost all antidepressants and antipsychotics have been associated with hyponatraemia (see sections on hyponatraemia in Chapters 1 and 3) and seizures may occur if this is severe.18,31 General guidance on the safety of psychotropics in PWE is summarised in Table 10.5. Electroconvulsive therapy (ECT) has anticonvulsive properties and is worth considering in the treatment of depression in patients with unstable epilepsy.9,18,23 ECT does not appear to cause or worsen epilepsy.18,32

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Table 10.5 Psychotropics in epilepsy. Safety in epilepsy Drug Comments Antidepressants Low risk – good choices33 SSRIs Recommended in PWE.15,19 SSRIs may be anticonvulsant at therapeutic doses14 but proconvulsant in overdose.34 SSRIs with the lowest risk of interactions with antiseizure medications are generally preferred (citalopram/escitalopram, followed by sertraline).15,19,35,36 Escitalopram is preferred over citalopram in PWE (lower risk of seizures in overdose).37 Others have low risk of seizures (e.g. fluoxetine37) but drug interactions with antiseizure medications should be considered.15,19 Fluoxetine may be less likely to provoke seizures in older people than escitalopram or citalopram.38 Some evidence that sertraline is safe and effective in PWE.39 Mirtazapine Recommended in PWE.19,40 Not known to be proconvulsive.26 Duloxetine Recommended for PWE.12,19 Risk of seizures is probably negligible.37,38 Probably low risk – use with caution (limited evidence) Agomelatine Not known to be proconvulsive.41 Anticonvulsant in animal models.37 MAOIs Not known to be proconvulsive at therapeutic doses.37 Low risk of seizures in overdose.18 Moclobemide Not known to be proconvulsive.37 Anticonvulsant in animal models.37 Reboxetine Small open-label study suggests no problems in PWE.42 Vortioxetine Not known to be proconvulsive.37,43 One report of successful use of vortioxetine in three PWE.44 Moderate risk – care required Lithium Low risk of seizures.37 Anticonvulsant in animal models.37 However, limited data showing both increases and decreases in seizures frequency in PWE.37 At standard plasma levels lithium is probably not proconvulsive.45 For bipolar, consider anticonvulsant mood stabilisers.46 Trazodone Limited data suggest some risk of seizures.37,47 Venlafaxine Effective in PWE12 and has been recommended19 but mixed evidence on seizure risk.37 Vilazodone Limited data. Seizure exacerbation in a patient with epilepsy has been reported.37 Higher risk – avoid (proconvulsive at therapeutic doses14) Amoxapine Several reports of seizures at therapeutic doses47 Bupropion Dose-related risk of seizures (particularly with immediate-release formulations).37 Risk is less with slow-release formulations at doses under 300mg/day.37 At least one study found no increased risk with bupropion.48 Maprotiline Several reports of seizures at therapeutic doses.47 TCAs Most TCAs are epileptogenic at higher doses (particularly clomipramine and amitriptyline11,26,47). Doxepin possibly lower risk (one small study in PWE).37 SNRIs are preferred over TCAs in PWE18 (Continued )

816 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Table 10.5 (Continued) Safety in epilepsy Drug Comments Antipsychotics Low risk – good choices Amisulpride/sulpiride Considered to be safe in PWE.49 Renally excreted, so low risk of pharmacokinetic interactions with antiseizure medications. Seizures uncommon in overdose.50 Aripiprazole Rarely lowers seizure threshold.5 Incidence of seizures similar to placebo in RCTs.26 Ziprasidone High-potency FGAs e.g. fluphenazine, haloperidol, trifluoperazine, flupentixol. Low risk of lowering the seizure threshold.5 Risperidone Unlikely to lower the seizure threshold.5 Incidence of seizures similar to placebo in RCTs.26 Has been recommended for PWE.35,51 Evidence of safety in a case series of adolescents with epilepsy.52 Probably low risk – use with caution (limited evidence) Asenapine Seizure rate similar to placebo in RCTs.53 Data and clinical experience of use in PWE is extremely limited. Brexpiprazole Cariprazine Lurasidone Moderate risk – care required Olanzapine Olanzapine and quetiapine both associated with seizures in RCTs.26 Overall risk of reducing the seizure threshold is considered to be low5 and olanzapine has been recommended by some for PWE.35 Data relating to olanzapine are difficult to interpret. EEG changes are seen in some but not all studies54 and it has been reported to be both anticonvulsant55 and proconvulsant.56 Quetiapine has a high risk of drug interaction in PWE.51 Quetiapine Higher risk – care required Clozapine Most proconvulsive antipsychotic.35 However, has been used successfully in PWE stable on antiseizure medications without worsening seizures57 and even in treatment-resistant epilepsy.58 Note, should not be used with carbamazepine (risk of blood dyscrasias and reduced clozapine levels). Lamotrigine is the antiseizure medication of choice. Higher risk – avoid Low-potency FGAs (e.g. chlorpromazine) Best avoided in PWE.34 Doses of chlorpromazine above 1g/day have a 9% incidence of seizures. Loxapine Highest rate of seizures among the FGAs.59 Depot antipsychotics None of the depot preparations currently available is thought to be epileptogenic, however the kinetics of depots are complex (seizures may be delayed). If seizures do occur, the offending drug may not be easily withdrawn. Depots should be used with extreme care. Zotepine Has established dose-related proconvulsive effect50 Drugs for ADHD Low risk Methylphenidate Three RCTs support safety and efficacy in children with epilepsy at therapeutic doses (0.3–1mg/kg/day).11 Two single-dose RCTs and one open-label extension study demonstrated no effect on seizures in adults.60,61 A large case–control study found an increased rate of seizures after the start of methylphenidate but not in the longer term.62 This is difficult to interpret but suggests caution would be appropriate. May be a higher risk of seizures at higher doses.63

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19 - Epilepsy and driving

Epilepsy and driving

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20 - References

References

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Epilepsy and driving In the UK, people with epilepsy may not drive a car if they have had a seizure while awake in the previous year. However, they may be eligible to drive if seizures occur only during sleep and this has been an established nocturnal pattern for at least 3 years. The consequences of inducing seizure with antidepressants or antipsychotics can therefore be significant. For further information see https://www.gov.uk/epilepsy-and-driving. Other countries have different rules, but most require a seizure-free period of between 6 and 36 months.71 References

Scott AJ, et al. Anxiety and depressive disorders in people with epilepsy: a meta-analysis. Epilepsia 2017; 58:973–982.
Clancy MJ, et al. The prevalence of psychosis in epilepsy; a systematic review and meta-analysis. BMC Psychiatry 2014; 14:75.
Wang H, et al. Suicidality and epilepsy: a systematic review and meta-analysis. Front Psychiatry 2023; 14:1097516.
Thurman DJ, et al. The burden of premature mortality of epilepsy in high-income countries: a systematic review from the Mortality Task Force of the International League Against Epilepsy. Epilepsia 2017; 58:17–26.
Kanner AM. Management of psychiatric and neurological comorbidities in epilepsy. Nat Rev Neurol 2016; 12:106–116.
Hesdorffer DC. Comorbidity between neurological illness and psychiatric disorders. CNS Spectr 2016; 21:230–238.
Hesdorffer DC, et al. Occurrence and recurrence of attempted suicide among people with epilepsy. JAMA Psychiatry 2016; 73:80–86.
Kanner AM. Can neurochemical changes of mood disorders explain the increase risk of epilepsy or its worse seizure control? Neurochem Res 2017; 42:2071–2076.
Curran S, et al. Selecting an antidepressant for use in a patient with epilepsy. Safety considerations. Drug Saf 1998; 18:125–133.
Blumer D, et al. Treatment of the interictal psychoses. J Clin Psychiatry 2000; 61:110–122.
Mula M. The pharmacological management of psychiatric comorbidities in patients with epilepsy. Pharmacol Res 2016; 107:147–153.
Elger CE, et al. Diagnosing and treating depression in epilepsy. Seizure 2017; 44:184–193.
Anbarasan D. Psychoactive medications and seizures—challenges and pitfalls. Neurol Rep 2016; 9:24–27.
Kanner AM. Most antidepressant drugs are safe for patients with epilepsy at therapeutic doses: a review of the evidence. Epilepsy Behav 2016; 61:282–286.
Kerr MP, et al. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy. Epilepsia 2011; 52:2133–2138.
Josephson CB, et al. Psychiatric comorbidities in epilepsy. Int Rev Psychiatry 2017; 29:409–424.
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Mula M. Neuropsychiatric Symptoms of Epilepsy. Basel: Springer International Publishing; 2016.
Villanueva V, et al. Proposed recommendations for the management of depression in adults with epilepsy: an expert consensus. Neurol Ther 2023; 12:479–503. Table 10.5 (Continued) Safety in epilepsy Drug Comments Probably low risk64,65 – use with caution (limited data) Amfetamines Data are limited to one small retrospective study in PWE.11 No patients who had well-controlled epilepsy experienced an increase in seizure frequency.66 Dexamfetamine was historically used as an adjunctive antiseizure agent.67 Atomoxetine Data are limited to one small retrospective study in PWE.11 Discontinuation rates were high (though none due to seizure exacerbation68). Seizure rate similar to placebo for patients without epilepsy.69 Low risk Acetylcholinesterase inhibitors: donepezil/ rivastigmine/ galantamine No increased risk of seizures has been observed.70 This table contains information about the proconvulsive effects of antidepressants and antipsychotics when used in therapeutic doses. See Chapter 13 for information about supratherapeutic doses. EEG, electroencephalogram; MAOIs, monoamine oxidase inhibitors; PWE, people with epilepsy; TCAs, tricyclic antidepressants.

818 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 20. Schmidt D, et al. Drug treatment of epilepsy in adults. BMJ 2014; 348:g254. 21. Piedad J, et al. Beneficial and adverse psychotropic effects of antiepileptic drugs in patients with epilepsy: a summary of prevalence, underlying mechanisms and data limitations. CNS Drugs 2012; 26:319–335. 22. Spina E, et al. Clinically significant pharmacokinetic drug interactions of antiepileptic drugs with new antidepressants and new antipsychotics. Pharmacol Res 2016; 106:72–86. 23. Harden CL, et al. Mood disorders in patients with epilepsy: epidemiology and management. CNS Drugs 2002; 16:291–302. 24. Ngugi AK, et al. Incidence of epilepsy: a systematic review and meta-analysis. Neurology 2011; 77:1005–1012. 25. Wigglesworth S, et al. The incidence and prevalence of epilepsy in the United Kingdom 2013–2018: a retrospective cohort study of UK primary care data. Seizure 2023; 105:37–42. 26. Alper K, et al. Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biol Psychiatry 2007; 62:345–354. 27. Wu CS, et al. Seizure risk associated with antidepressant treatment among patients with depressive disorders: a population-based case- crossover study. J Clin Psychiatry 2017; 78:e1226–e1232. 28. Josephson CB, et al. Association of depression and treated depression with epilepsy and seizure outcomes: a multicohort analysis. JAMA Neurol 2017; 74:533–539. 29. Farooq S, et al. Interventions for psychotic symptoms concomitant with epilepsy. Cochrane Database Syst Rev 2015; 12:CD006118. 30. Maguire MJ, et al. Antidepressants for people with epilepsy and depression. Cochrane Database Syst Rev 2014; 4:CD010682. 31. Maramattom BV. Duloxetine-induced syndrome of inappropriate antidiuretic hormone secretion and seizures. Neurology 2006; 66:773–774. 32. Ray AK. Does electroconvulsive therapy cause epilepsy? J ECT 2013; 29:201–205. 33. Tallarico M, et al. Antidepressant drugs for seizures and epilepsy: where do we stand? Curr Neuropharmacol 2023; 21:1691–1713. 34. Steinert T, et al. [Epileptic seizures during treatment with antidepressants and neuroleptics]. Fortschr Neurol Psychiatr 2011; 79:138–143. 35. Mula M. Epilepsy and psychiatric comorbidities: drug selection. Curr Treat Options Neurol 2017; 19:44. 36. National Institute for Health and Care Excellence. Depression in adults with a chronic physical health problem: recognition and management. Clinical Guidance [CG91] 2009 (last updated and checked May 2024); http://www.nice.org.uk/CG91. 37. Steinert T, et al. Epileptic seizures under antidepressive drug treatment: systematic review. Pharmacopsychiatry 2018; 51:121–135. 38. Finkelstein Y, et al. Second-generation anti-depressants and risk of new-onset seizures in the elderly. Clin Toxicol (Phila) 2018; 56:1179–1184. 39. Gilliam FG, et al. A trial of sertraline or cognitive behavior therapy for depression in epilepsy. Ann Neurol 2019; 86:552–560. 40. Craig DP, et al. Risk of seizures with antidepressants: what is the evidence? Drug Ther Bull 2020; 58:137–140. 41. Servier Laboratories Limited. Summary of product characteristics. Valdoxan (agomelatine). 2021 (last accessed May 2024); https://www. medicines.org.uk/emc/medicine/21830. 42. Kuhn KU, et al. Antidepressive treatment in patients with temporal lobe epilepsy and major depression: a prospective study with three different antidepressants. Epilepsy Behav 2003; 4:674–679. 43. Lundbeck Limited. Summary of product characteristics. Brintellix (vortioxetine) tablets 5, 10 and 20mg. 2024 (last checked May 2024); https://www.medicines.org.uk/emc/medicine/30904. 44. Siwek M, et al. Case report: vortioxetine in the treatment of depressive symptoms in patients with epilepsy – case series. Front Pharmacol 2022; 13:852042. 45. Bojja SL, et al. What is the role of lithium in epilepsy? Curr Neuropharmacol 2022; 20:1850–1864. 46. Knott S, et al. Epilepsy and bipolar disorder. Epilepsy Behav 2015; 52:267–274. 47. Johannessen Landmark C, et al. Proconvulsant effects of antidepressants – what is the current evidence? Epilepsy Behav 2016; 61:287–291. 48. Chu C-S, et al. Antidepressant drugs use and epilepsy risk: a nationwide nested case-control study. Epilepsy Behav 2023; 140:109102. 49. Elnazer H, et al. Managing aggression in epilepsy. BJPsych Advances 2017; 23:253. 50. Steinert T, et al. Seizures. In: Manu P, Flanagan RJ, Donaldson K, eds. Life-threatening Effects of Antipscyhotic Drugs. San Diego, CA: Academic Press; 2016:207–222. 51. Agrawal N, et al. Treatment of psychoses in patients with epilepsy: an update. Ther Adv Psychopharmacol 2019; 9:2045125319862968. 52. Gonzalez-Heydrich J, et al. No seizure exacerbation from risperidone in youth with comorbid epilepsy and psychiatric disorders: a case series. J Child Adolesc Psychopharmacol 2004; 14:295–310. 53. IBM Watson Health. IBM micromedex solutions. 2024; https://www.ibm.com/watson-health/about/micromedex. 54. Jackson A, et al. EEG changes in patients on antipsychotic therapy: a systematic review. Epilepsy Behav 2019; 95:1–9. 55. Qiu X, et al. Antiepileptic effect of olanzapine in epilepsy patients with atypical depressive comorbidity. Epileptic Disord 2018; 20:225–231. 56. Mansoor M, et al. Generalised tonic-clonic seizures on the subtherapeutic dose of olanzapine. BMJ Case Rep 2019; 12:e230018. 57. Langosch JM, et al. Epilepsy, psychosis and clozapine. Hum Psychopharmacol 2002; 17:115–119. 58. Jette Pomerleau V, et al. Clozapine safety and efficacy for interictal psychotic disorder in pharmacoresistant epilepsy. Cogn Behav Neurol 2017; 30:73–76. 59. Habibi M, et al. The impact of psychoactive drugs on seizures and antiepileptic drugs. Curr Neurol Neurosci Rep 2016; 16:71. 60. Adams J, et al. Methylphenidate, cognition, and epilepsy: a 1-month open-label trial. Epilepsia 2017; 58:2124–2132. 61. Adams J, et al. Methylphenidate, cognition, and epilepsy: a double-blind, placebo-controlled, single-dose study. Neurology 2017; 88:470–476.

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 62. Man KKC, et al. Association between methylphenidate treatment and risk of seizure: a population-based, self-controlled case-series study. Lancet Child Adolesc Health 2020; 4:435–443. 63. Eaton C, et al. Stimulant and non-stimulant drug therapy for people with attention deficit hyperactivity disorder and epilepsy. Cochrane Database Syst Rev 2022; 7:CD013136. 64. Besag F, et al. Psychiatric and behavioural disorders in children with epilepsy (ILAE Task Force Report): epilepsy and ADHD. Epileptic Disord 2016; 18:S8–S15. 65. Besag F, et al. Psychiatric and behavioural disorders in children with epilepsy (ILAE Task Force Report): when should pharmacotherapy for psychiatric/behavioural disorders in children with epilepsy be prescribed? Epileptic Disord 2016; 18:S77–S86. 66. Gonzalez-Heydrich J, et al. Comparing stimulant effects in youth with ADHD symptoms and epilepsy. Epilepsy Behav 2014; 36:102–107. 67. Schubert R. Attention deficit disorder and epilepsy. Pediatr Neurol 2005; 32:1–10. 68. Torres A, et al. Tolerability of atomoxetine for treatment of pediatric attention-deficit/hyperactivity disorder in the context of epilepsy. Epilepsy Behav 2011; 20:95–102. 69. Williams AE, et al. Epilepsy and attention-deficit hyperactivity disorder: links, risks, and challenges. Neuropsychiatr Dis Treat 2016; 12:287–296. 70. Ha J, et al. Association of cognitive enhancers and incident seizure risk in dementia: a population-based study. BMC Geriatr 2022; 22:480. 71. Ooi WW, et al. International regulations for automobile driving and epilepsy. J Travel Med 2006; 7:1–4.

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21 - 22q11.2 deletion syndrome

22q11.2 deletion syndrome

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22 - Clinical features

Clinical features

820 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 22q11.2 deletion syndrome Clinical features 22q11.2 deletion syndrome (22q11.2DS), the most common microdeletion syndrome in humans, is a multisystem disorder with a heterogenous presentation which varies greatly in severity between affected individuals.1 Prevalence is estimated at 1 in 2148 live births.1,2 The syndrome has been known by many names (including velocardiofacial syndrome and DiGeorge syndrome) in part because of its broad phenotypic range of clinical features (Table 10.6). Table 10.6 Selected clinical features and risks in people with 22q11.2 deletion syndrome.1,3 Clinical risks Cognitive and adaptive functioning Intellectual disabilities Deficits in adaptive functioning Endocrinological Hypocalcaemia and hypoparathyroidism Hypomagnesaemia Thyroid disease (usually hypothyroidism) Obesity and type 2 diabetes mellitus Gastroenterology General gastrointestinal symptoms (constipation, dysphagia) GERD Fatty liver Psychiatric disorders Anxiety Psychosis Autism spectrum disorder ADHD Cardiovascular Congenital cardiac defects Hypertension, arrhythmia, heart failure, aortic root dilation Genitourinary Congenital anomalies, renal cysts, renal failure Menstrual disorders (e.g. dysmenorrhoea) Neurology Seizures, often secondary (e.g. to hypocalcaemia) Early-onset Parkinson’s disease Other motor disorders (e.g. dystonia, myoclonus) Sleep Sleep pattern disruptions Obstructive sleep apnoea Haematology Mild to moderate thrombocytopenia, mild cytopenias Immune thrombocytopenia Impaired haemostasis (e.g. epistaxis, menorrhagia) GERD, gastro-esophageal reflux disease.

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23 - Psychiatric disorders in people with 22q11.2D

Psychiatric disorders in people with 22q11.2DS

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Psychiatric disorders in people with 22q11.2DS Around 60% of people with 22q11.2DS meet diagnostic criteria for some type of psychiatric disorder during their lives.4 Children with 22q11.2DS have an elevated prevalence of anxiety, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders.2 Anxiety disorders are profoundly increased in adults, with about 2–3 times the expected population prevalence.1 Schizophrenia is diagnosed in approximately one in every four to five adults with 22q11.2DS.1 Box 10.2 summarises the general principles of prescribing in 22q11.2DS. Few studies have evaluated the safety and efficacy of psychotropics in people with 22q11.2DS. However, standard pharmacological (and non-pharmacological) treatments for ADHD, anxiety, mood disorders and schizophrenia appear to be effective and treatment protocols used in the general population should be followed.1,5 Current evidence and opinion on the treatment of psychiatric disorders in people with 22q11.2DS are summarised in Table 10.7. Box 10.2 General principles of prescribing in 22q11.2 deletion syndrome6,7 ■ ■22q11.2DS confers an increased risk of treatable psychiatric disorders ■ ■Standard pharmacological treatment protocols should be followed ■ ■Consider the individual patient comorbidities and clinical features (Table 10.6) that may increase the propensity to adverse effects from psychotropics (e.g. arrhythmias, seizures, weight gain, EPSEs) ■ ■Endocrine abnormalities (e.g. hypoparathyroidism and hypothyroidism) should be corrected before starting psychotropics because they can mimic psychiatric symptoms and complicate treatment with psychotropics4,5 DS, deletion syndrome; EPSEs, extrapyramidal side effects. Table 10.7 Management of psychiatric disorders in people with 22q11.2 deletion syndrome.8 Psychiatric disorder Treatments ADHD There is a theoretical risk of psychosis with psychostimulants in people with 22q11.2DS but standard treatment protocols are advised.4 In those with congenital heart disease, cardiology advice should be sought before initiating stimulant medications.9 Three studies support the efficacy of methylphenidate in children with 22q11.2DS.4,10 Treatment was generally well tolerated. A comprehensive cardiovascular assessment before and during treatment is recommended. Depression and anxiety Both depression and anxiety appear to respond favourably to SSRIs.4 Further management after treatment failure follows standard protocols. Caution should be exercised with drugs that lower the seizure threshold (e.g. bupropion).7 Obsessive compulsive disorder One study of four people with OCD and 22q11.2DS found a mean rate of improvement of 35% in symptom score after treatment with fluoxetine (30–60mg/day). Treatment was well tolerated.11 (Continued )

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References

822 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 References

Boot E, et al. Updated clinical practice recommendations for managing adults with 22q11.2 deletion syndrome. Genet Med 2023; 25:100344.
McDonald-McGinn DM, et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers 2015; 1:15071.
Bayat M, et al. Neurological manifestation of 22q11.2 deletion syndrome. Neurol Sci 2022; 43:1695–1700.
Mosheva M, et al. Effectiveness and side effects of psychopharmacotherapy in individuals with 22q11.2 deletion syndrome with comorbid psychiatric disorders: a systematic review. Eur Child Adolesc Psychiatry 2020; 29:1035–1048.
Fung WL, et al. Practical guidelines for managing adults with 22q11.2 deletion syndrome. Genet Med 2015; 17:599–609.
Tanham M, et al. The effectiveness and tolerability of pharmacotherapy for psychosis in 22q11.2 deletion syndrome: a systematic review. Aust NZ J Psychiatry 2024; 58:393–403.
Van L, et al. Mental health in adults with 22q11. 2 deletion syndrome. In: McDonald-McGinn DM, ed. The Chromosome 22q11. 2 Deletion Syndrome. London: Academic Press; 2022:322–337.
Baker K, et al. Psychiatric illness. Consensus document on 22q11 deletion syndrome (22q11DS) MaxAppeal. 2017; https://www.maxappeal.org. uk/library-consensus-document.
Chung LM, et al. Safety of stimulant medications for attention deficit hyperactivity disorder in paediatric congenital heart disease. J Paediatr Child Health 2023; 59:580–588. Psychiatric disorder Treatments Schizophrenia Standard treatment protocols are generally recommended.1,5 People with 22q11.2DS may be more susceptible to seizures and EPSEs with antipsychotics.7,8 EPSEs must be distinguished from motor problems that may be a direct effect of the 22q11.2DS (diagnosis of Parkinson’s disease may be delayed if misattributed to antipsychotics).7 Specialist neurological opinion and neuroimaging have been recommended to distinguish Parkinson’s disease from antipsychotic-induced parkinsonism.6 There is a significantly elevated risk of obesity in 22q11.2DS so metabolic adverse effects should be closely monitored.12 Those with cardiac abnormalities have an increased risk of QTc prolongation.8 Close ECG monitoring is recommended.8 Antipsychotics with a low effect on the QT interval are preferred8 (note that hypocalcaemia can also prolong the QT interval7). Low starting doses and slow dose titrations are recommended.8 Case reports have described the successful use of various antipsychotics, with remission of psychosis in 41% of published reports.6 Treatment resistance has been described in 19% of case series and 8% of case reports (although treatment failure was due to adverse effects rather than inefficacy in some).6 Clozapine was found to be effective in one retrospective study of 20 patients with 22q11.2DS.4 Compared with matched controls, lower doses were needed (a median of 250mg/day vs 450mg/ day). However, half of the 22q11.2DS group experienced at least one serious adverse effect from clozapine, primarily seizures, but also myocarditis and neutropenia. Several case reports further support the efficacy of clozapine at low doses (median of 200mg/day) for people with 22q11.2DS, while highlighting the risk of both seizures (generalised or myoclonic) and thrombocytopenia.12 Overall, clozapine appears to have demonstrable efficacy at lower than usual doses, but the risk of rare serious adverse events appears to be relatively high.4 Adjunctive anticonvulsants should be considered12 to mitigate the increased seizure risk when prescribing clozapine.1 Several authors advocate the use of lower starting doses and slower titrations.6 Seizures with other antipsychotics: investigate low calcium and magnesium levels in all cases and ensure adequate treatment.13 Adjunctive anticonvulsants can be considered1 although they should not be prescribed routinely as many do not experience seizures.6 Other agents: drugs that act directly against catecholamine excess may also be effective. Metyrosine, used as a monotherapy or as an adjunctive agent, was found to be effective in 22 of 29 patients in one study.14 An additional positive case report has been published15 but there are no further recent studies. There is a single case study where methyldopa was used successfully.16 DS, deletion syndrome; EPSEs, extrapyramidal side effects; OCD, obsessive compulsive disorder. Table 10.7 (Continued)

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 10. Maeder J, et al. Selective effects of methylphenidate on attention and inhibition in 22q11.2 deletion syndrome: results from a clinical trial. Int J Neuropsychopharmacol 2022; 25:215–225. 11. Gothelf D, et al. Obsessive-compulsive disorder in patients with velocardiofacial (22q11 deletion) syndrome. Am J Med Genet B Neuropsychiatr Genet 2004; 126b:99–105. 12. De Boer J, et al. Adverse effects of antipsychotic medication in patients with 22q11.2 deletion syndrome: a systematic review. Am J Med Genet A 2019; 179:2292–2306. 13. Bassett AS, et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr 2011; 159:332–339. 14. Faedda GL, et al. 4.19 Treatment of velo-cardio-facial syndrome-related psychosis with metyrosine. J Am Acad Child Adolesc Psychiatry 2016; 55:S169. 15. Engebretsen MH, et al. Metyrosine treatment in a woman with chromosome 22q11.2 deletion syndrome and psychosis: a case study. Int J Dev Disabil 2019; 65:116–121. 16. O’Hanlon JF, et al. Replacement of antipsychotic and antiepileptic medication by L-alpha-methyldopa in a woman with velocardiofacial syndrome. Int Clin Psychopharmacol 2003; 18:117–119.

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25 - Learning disabilities

Learning disabilities

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26 - General considerations1

General considerations1

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27 - Key practice areas

Key practice areas

824 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Learning disabilities General considerations1 Prescribing psychotropic medications for people with learning disabilities (LD) is a challenging and controversial area of psychiatric practice.2,3 There are concerns that psychotropic drugs of all kinds (antipsychotics, antidepressants, benzodiazepines [both regular and as required] and antiepileptics as mood stabilisers) are overprescribed with poor review and assessment of their benefit. The LD field is notable in having only a small therapeutics research base of its own, with particular ethical and practical considerations regarding how emotional and behavioural disturbances are classified and treated. Although prescribing for individuals with mild or borderline intellectual impairment may be undertaken by mainstream mental health services, the assessment and treatment of behavioural and emotional disorders in people with more marked (or, as in the case of autism, atypical) patterns of significant cognitive impairment should be undertaken in the first instance by, or at least in consultation with, specialist clinicians. The term ‘dual diagnosis’ in this context refers to the co-occurrence of an identifiable psychiatric disorder (mental illness, personality disorder) and LD. ‘Diagnostic overshadowing’ is the misattribution of emotional or behavioural problems to LD itself rather than a comorbid condition. LD is an important risk factor for all psychiatric disorders (including dementia, particularly for individuals with Down’s syndrome).4 Where it is possible to diagnose a mental illness using conventional or modified criteria then drug treatment in the first instance should, in general, be similar to that in the population at large. Most treatment guidelines are increasingly stating their intended applicability to people with LD. Mental illness may present in unusual ways in LD, for example depression as self- injurious behaviour, or persecutory ideation as complaints of being ‘picked on’. Conversely, behaviours such as self-talk may be normal in some individuals but mistakenly identified as a disorder such as psychosis. In general, diagnosis becomes increasingly complex with increasing severity of disability and associated communication impairment. Comorbid autistic spectrum disorder has special assessment considerations and in its own right is an important risk factor for psychiatric disorder, in particular anxiety and depression, bipolar spectrum disorder, severe obsessional behaviour, anger disorders and psychosis-like episodes that may not meet criteria for schizophrenia but nonetheless require treatment. Autistic traits are common among patients using LD services. Guidance on the treatment of mental health problems in autism can be found in Chapter 5. Key practice areas Capacity and consent It is uncommon for patients in LD services (who often represent a subpopulation of those identified with special educational needs in childhood) to have sufficient understanding of their treatment in order to be able to take truly informed decisions. There is inevitably an increased onus on the clinician to bear the weight of decision-making. The patient’s decision-making capacity, depending on the severity of intellectual

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 impairment, may be improved through appropriate verbal and written communication. The involvement of carers in this process is generally essential. Physical comorbidity, especially epilepsy Epilepsy is over-represented in LD populations, becoming more prevalent as severity increases, with approximately one-third of affected individuals developing a seizure disorder by early adulthood. Special consideration is needed when considering the use of medications that may lower seizure threshold or interact with drugs used for epilepsy. Assessment of care environments Behavioural and emotional disturbance may sometimes be a reflection of problems or failings in the care environment. Different staff in a care home may have different thresholds of tolerance (or make different attributions) for these difficulties which can lead to varied reports of their significance and impact. Allowing for a period of prospective assessment and using simple assessment tools (e.g. simple ABC or sleep charts) can be very helpful to the clinician in making judgements about recommending medication. If medication is used in a care home, staff may need special education in its use and anticipated adverse effects and, for ‘as required’ medications, clear guidelines for its use. This may make it difficult to initiate certain treatments in the community. Adverse effect sensitivity It is widely thought that people with LD are especially sensitive to adverse effects of psychotropics and more at risk of long-term effects such as the metabolic syndrome. However, we only know of one study that has given support to this view. A cohort study extracting information from a large UK primary care database compared the incidence of EPSEs of antipsychotics in adults with LD with that in adults without LD. The incidence of EPSEs was 30% higher in people with LD than in those without LD.5 It is good practice to start at lower doses and increase more slowly than might be usual in general psychiatric practice. Notable adverse effects include worsening of seizures, sedation, extrapyramidal reactions (including with risperidone at normal doses, especially in individuals who already have mobility problems), problems with swallowing (with clozapine and other antipsychotics) and worsening of cognitive function with anticholinergic medications (see Chapter 6). Psychological interventions In the absence of an identifiable mental illness (including atypical presentations) with clear treatment implications, psychological interventions such as functional behavioural analysis should be considered as first-line intervention for all but the most serious or intractable presentations of behavioural disturbance (Table 10.8). In studies where it has been possible to infer the severity of challenging behaviour, treatment response is generally associated with more severe problems at baseline.

826 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Table 10.8 Some notes on currently and historically used medications for behaviour disorder. Drug class Clinical applications Notes Antipsychotics6 Use in psychosis with LD is justified Used across a broad range of behavioural disturbances7 May be useful for aggression and irritability The most widely used8,9 yet most controversial medication for behavioural problems.10,11 Although an RCT12 casts doubt on their efficacy for this indication the study was not without its problems and there is a significant body of other evidence supporting their use, including a number of small RCTs in children with LD. Discontinuation studies in long-term treatment commonly (but not always) show re-emergence of problem behaviours. NICE suggests considering slow withdrawal of antipsychotics in all those who do not have psychotic symptoms.13 The UK STOMP programme promotes deprescribing of antipsychotics.14 It has been successful, but antipsychotics are often replaced by other psychotropics.15 A 2022 analysis of UK NHS data suggests antidepressants now replace antipsychotics as the most widely prescribed psychotropic.16 Before the advent of SGAs the best evidence was for haloperidol17 in the context of autism and for zuclopenthixol for behavioural disturbance.18 Zuclopenthixol may reduce aggression and challenging behaviour.19 Among SGAs the best evidence is for risperidone20,21 at low dose (0.5–2mcg) for aggression and mood instability, particularly with associated autism though also in non-autistic cases. Aripiprazole has a US FDA licence for behavioural disturbance in young people with autism.22,23 Some evidence to support olanzapine24 and case reports of clozapine25 for very severe cases of aggression, though not widely used and unlikely to be used outside highly specialist (in-patient) settings. In 2015, Cochrane uncovered 38 case reports and chart reviews but found no RCT evidence for the use of clozapine in psychosis in LD.26 Results for quetiapine are modest at best.27 SSRIs Helpful for severe anxiety and obsessionality in autistic spectrum disorder. Use here is off-licence unless an additional diagnosis of anxiety disorder or OCD is made Also used as a first-line alternative to antipsychotics for aggression and impulsivity Commonly used in combination with antipsychotics though limited evidence base for combination treatment. Effectiveness in absence of mood or anxiety spectrum disorder is unclear, however, and a 2013 Cochrane review was pessimistic28 about the evidence for their effectiveness for behaviour disorder in autistic children (who may be at heightened risk of adverse effects) though a little more encouraging for use in adults. Some good evidence for fluoxetine in OCD in LD/autism although the drop-out rate is high.29 Generally, quality of trials is poor and effects may be exaggerated by use in less severe cases.30 Caution needed because of the risk of precipitation of hypomania in this population.31 As with antipsychotics, there are major concerns about overprescribing.32 Venlafaxine is probably not effective.33

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References

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 References

Deb S. The use of medications for the management of problem (challenging) behaviours in adults who have intellectual disabilities. University of Hertfordshire. 2012 (revised 2018, last accessed July 2024); https://www.intellectualdisability.info/mental-health/articles/the-use-of- medications-for-the-management-of-problem-behaviours-in-adults-who-have-intellectual-disabilities.
Sheehan R, et al. Psychotropic prescribing in people with intellectual disability and challenging behaviour. BMJ 2017; 358:j3896.
Ji NY, et al. Pharmacotherapy for mental health problems in people with intellectual disability. Curr Opin Psychiatry 2016; 29:103–125.
Cooper SA, et al. Mental ill-health in adults with intellectual disabilities: prevalence and associated factors. Br J Psychiatry 2007; 190:27–35.
Sheehan R, et al. Movement side effects of antipsychotic drugs in adults with and without intellectual disability: UK population-based cohort study. BMJ Open 2017; 7:e017406.
Antochi R, et al. Psychopharmacological treatments in persons with dual diagnosis of psychiatric disorders and developmental disabilities. Postgrad Med J 2003; 79:139–146. Drug class Clinical applications Notes Anticonvulsants34 Aggression and self-injury Some uncontrolled studies supporting sodium valproate35 in LD populations though evidence is not strong and research findings are contradictory. However, valproate remains best supported of the anticonvulsants for mood lability and aggression, partly because of positive studies in non-LD groups.36 Limited studies of lamotrigine, mostly in children, suggest no effect, at least in autism and in the absence of affective instability.27 Data for carbamazepine also unconvincing, but it is still widely used.37 Lithium38 Licensed for the treatment of self-injurious behaviour and aggression Some RCT evidence39 for LD but there have been no studies in this population for many years,3 although there has been one fairly recent positive RCT for its use in aggression in adolescents without developmental impairment.40 Experience suggests it can be very helpful in individual cases where other treatments have failed and is possibly underused, though adverse effects can be problematic. Perhaps best considered where there is a sub-syndromal or non-specific ‘affective component’. Some authorities suggest that, on close examination, challenging behaviour may occur in the context of very rapid cycling bipolar disorder in some individuals with severe and profound LD and that the diagnosis is easily missed. Some RCT evidence that short-term use is reasonably well tolerated (at 6mg/kg).41 Methylphenidate Effective in ADHD associated with LD NICE13 conducted a meta-analysis and found clear benefit for methylphenidate (and risperidone and clonidine) in ADHD in the context of LD. Insomnia is common. Naltrexone42 Has been used for severe self-injurious behaviour43 Evidence not strong and results are inconsistent. Use may still be an option in severe and intractable cases. One case of successful treatment of kleptomania.44 Overall, clinical use has declined of late.45 FDA, Food and Drug Administration; LD, learning disability; OCD, obsessive compulsive disorder. Table 10.8 (Continued)

828 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 7. Lunsky Y, et al. Antipsychotic use with and without comorbid psychiatric diagnosis among adults with intellectual and developmental disabilities. Can J Psychiatry 2017; 63:361–369. 8. Deb S, et al. Characteristics and the trajectory of psychotropic medication use in general and antipsychotics in particular among adults with an intellectual disability who exhibit aggressive behaviour. J Intellect Disabil Res 2015; 59:11–25. 9. Sheehan R, et al. Mental illness, challenging behaviour, and psychotropic drug prescribing in people with intellectual disability: UK population based cohort study. BMJ 2015; 351:h4326. 10. Deb S, et al. The effectiveness of antipsychotic medication in the management of behaviour problems in adults with intellectual disabilities. J Intellect Disabil Res 2007; 51:766–777. 11. Roy D, et al. Pharmacologic management of aggression in adults with intellectual disability. J Intellect Disabil Res 2013; 1:28–43. 12. Tyrer P, et al. Risperidone, haloperidol, and placebo in the treatment of aggressive challenging behaviour in patients with intellectual disability: a randomised controlled trial. Lancet 2008; 371:57–63. 13. National Institute of Health and Care Excellence. Mental health problems in people with learning disabilities: prevention, assessment and management. NICE Guideline [NG54]. 2016 (last checked November 2020, last accessed March 2024); https://www.nice.org.uk/Guidance/ NG54. 14. Shankar R, et al. Stopping, rationalising or optimising antipsychotic drug treatment in people with intellectual disability and/or autism. Drug Ther Bull 2019; 57:10–13. 15. Deb S, et al. UK psychiatrists’ experience of withdrawal of antipsychotics prescribed for challenging behaviours in adults with intellectual disabilities and/or autism. Br J Psych Open 2020; 6:e112. 16. Branford D, et al. Antidepressant prescribing for adult people with an intellectual disability living in England. Br J Psychiatry 2022; 221:488–493. 17. Malone RP, et al. The role of antipsychotics in the management of behavioural symptoms in children and adolescents with autism. Drugs 2009; 69:535–548. 18. Malt UF, et al. Effectiveness of zuclopenthixol compared with haloperidol in the treatment of behavioural disturbances in learning disabled patients. Br J Psychiatry 1995; 166:374–377. 19. Hassler F, et al. Treatment of aggressive behavior problems in boys with intellectual disabilities using zuclopenthixol. J Child Adolesc Psychopharmacol 2014; 24:579–581. 20. Nagaraj R, et al. Risperidone in children with autism: randomized, placebo-controlled, double-blind study. J Child Neurol 2006; 21:450–455. 21. Pandina GJ, et al. Risperidone improves behavioral symptoms in children with autism in a randomized, double-blind, placebo-controlled trial. J Autism Dev Disord 2007; 37:367–373. 22. Owen R, et al. Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics 2009; 124:1533–1540. 23. Marcus RN, et al. A placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder. J Am Acad Child Adolesc Psychiatry 2009; 48:1110–1119. 24. Fido A, et al. Olanzapine in the treatment of behavioral problems associated with autism: an open-label trial in Kuwait. Med Princ Pract 2008; 17:415–418. 25. Zuddas A, et al. Clinical effects of clozapine on autistic disorder. Am J Psychiatry 1996; 153:738. 26. Ayub M, et al. Clozapine for psychotic disorders in adults with intellectual disabilities. Cochrane Database Syst Rev 2015; 9:CD010625. 27. Stigler KA, et al. Pharmacotherapy of irritability in pervasive developmental disorders. Child Adolesc Psychiatr Clin N Am 2008; 17:739–752. 28. Williams K, et al. Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Syst Rev 2013; 8:CD004677. 29. Reddihough DS, et al. Effect of fluoxetine on obsessive-compulsive behaviors in children and adolescents with autism spectrum disorders: a randomized clinical trial. JAMA 2019; 322:1561–1569. 30. Myers SM. Citalopram not effective for repetitive behaviour in autistic spectrum disorders. Evid Based Ment Health 2010; 13:22. 31. Cook Jr, EH, et al. Fluoxetine treatment of children and adults with autistic disorder and mental retardation. J Am Acad Child Adolesc Psychiatry 1992; 31:739–745. 32. Oswald DP, et al. Medication use among children with autism spectrum disorders. J Child Adolesc Psychopharmacol 2007; 17:348–355. 33. Carminati GG, et al. Using venlafaxine to treat behavioral disorders in patients with autism spectrum disorder. Prog Neuropsychopharmacol Biol Psychiatry 2016; 65:85–95. 34. Deb S, et al. The effectiveness of mood stabilizers and antiepileptic medication for the management of behaviour problems in adults with intellectual disability: a systematic review. J Intellect Disabil Res 2008; 52:107–113. 35. Ruedrich S, et al. Effect of divalproex sodium on aggression and self-injurious behaviour in adults with intellectual disability: a retrospective review. J Intellect Disabil Res 1999; 43 Pt 2:105–111. 36. Donovan SJ, et al. Divalproex treatment for youth with explosive temper and mood lability: a double-blind, placebo-controlled crossover design. Am J Psychiatry 2000; 157:818–820. 37. Unwin GL, et al. Use of medication for the management of behavior problems among adults with intellectual disabilities: a clinicians’ consensus survey. Am J Ment Retard 2008; 113:19–31. 38. Pary RJ. Towards defining adequate lithium trials for individuals with mental retardation and mental illness. Am J Ment Retard 1991; 95:681–691. 39. Craft M, et al. Lithium in the treatment of aggression in mentally handicapped patients. A double-blind trial. Br J Psychiatry 1987; 150:685–689.

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 40. Malone RP, et al. A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder. Arch Gen Psychiatry 2000; 57:649–654. 41. Yuan J, et al. Lithium treatment is safe in children with intellectual disability. Front Mol Neurosci 2018; 11:425. 42. Campbell M, et al. Naltrexone in autistic children: an acute open dose range tolerance trial. J Am Acad Child Adolesc Psychiatry 1989; 28:200–206. 43. Barrett RP, et al. Effects of naloxone and naltrexone on self-injury: a double-blind, placebo-controlled analysis. Am J Ment Retard 1989; 93:644–651. 44. Mouaffak F, et al. Kleptomania treated with naltrexone in a patient with intellectual disability. J Psychiatry Neurosci 2020; 45:71–72. 45. Sabus A, et al. Management of self-injurious behaviors in children with neurodevelopmental disorders: a pharmacotherapy overview. Pharmacotherapy 2019; 39:645–664.

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29 - Huntingtons disease

Huntington’s disease

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30 - Motor symptoms

Motor symptoms

830 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Huntington’s disease Huntington’s disease (HD) is a genetic neurodegenerative disease with an estimated prevalence of 4.88 individuals per 100,000 worldwide, and a higher incidence in Europe and North America.1 The mutant Huntington protein causes neuronal dysfunction and death through several mechanisms, resulting in a triad of motor, cognitive and neuropsychiatric symptoms.2 There are currently no disease-modifying treatments3,4 so symptomatic therapies are used to improve quality of life (Box 10.3). There are few controlled studies to guide practice in this area,3 although some direction can be drawn from published expert opinion and clinical experience. A summary of the available literature is given in this section. Readers are directed to the reports cited for details of dosage regimens and further information about tolerability. Clinicians who treat patients with HD are encouraged to publish reports of both positive and negative outcomes to increase the primary literature base. Motor symptoms Motor disturbances follow a biphasic course – an initial hyperkinetic phase with prominent chorea which tends to plateau over time, and a later hypokinetic phase characterised by bradykinesia, dystonia, balance and gait disturbance.7 With regard to chorea, the goal of treatment is not to obliterate movements but to reduce their severity to achieve better tolerability.5 Treatment pathways are available to guide management.8 First-line treatments include tetrabenazine (licensed) or SGAs (unlicensed) (Table 10.9).8 Monotherapy is preferred to prevent an increased risk of adverse effects and complicating the management of non-motor symptoms.8 Box 10.3 General principles of pharmacological symptom management in Huntington’s disease5,6 ■ ■Tailor management to the needs of the individual patient (treatment is typically initiated when symptoms become bothersome, interfering or socially stigmatising) ■ ■Check whether existing medications are causing or exacerbating symptoms before commencing new treatments ■ ■Prioritise treatment to target the most troublesome symptoms first, with consideration of comorbid features ■ ■Balance therapeutic benefit with the potential for adverse effects ■ ■Start with a low dose and titrate according to tolerability and response (patients are relatively more sensitive to cognitive and motor adverse effects which may also be difficult to distinguish from disease progression) ■ ■Regularly follow up with patients to address changes in treatment (because symptomology evolves with disease progression)

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31 - Mental and behavioural symptoms

Mental and behavioural symptoms

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Mental and behavioural symptoms A wide variety of mental and behavioural symptoms occur in HD, including anxiety, depression, suicidality, preservation, disinhibition, irritability, apathy and, rarely, psychosis.13 Mental and behavioural symptoms can emerge before motor disturbances and reduce quality of life substantially.13 In comparison with other HD features, psychiatric symptoms are perhaps the most amenable to pharmacotherapy.6 In general, psychiatric treatment choices are selected as they would be in other conditions5 although patients are relatively more sensitive to adverse effects.5 The most commonly prescribed psychotropics are summarised in Tables 10.10 and 10.11 (mostly based on low-quality evidence).13 Table 10.9 Evidence and experience regarding the pharmacological treatment of motor symptoms in Huntington’s disease (HD). Symptoms Treatment Chorea Tetrabenazine: unlike antipsychotics, tetrabenazine’s effectiveness is well established.2,3,8 However, adverse effects including sedation, depression and parkinsonism may limit its clinical benefit. In clinical practice, many prefer to use tetrabenazine first line in patients without depressive symptoms and suicidal behaviour.8 Compliance with a multiple daily dosing regimen (e.g. three times a day) is needed. Other VMAT2 inhibitors: deutetrabenazine and valbenazine are licensed in the USA for the treatment of chorea in HD.2,4,9 Where available, they may be preferred over tetrabenazine owing to an improved pharmacokinetic and adverse effect profile,2,9 although direct comparisons are lacking.4 Antipsychotics: considered first-line treatment in clinical practice, particularly in the presence of depression, aggression, psychosis or when poor drug compliance is suspected5,8,10 despite a lack of data from RCTs.2 SGAs such as aripiprazole, risperidone or olanzapine are used most commonly.8,11 Potentially limiting adverse effects include dyskinesia, parkinsonism and metabolic syndrome.5 FGAs have been used successfully but are less popular in clinical practice because of the risk of EPSEs.10 LAI antipsychotics have been used in some published case reports, in cases of non- compliance or motor fluctuations with oral antipsychotics.12 For severe chorea, antipsychotics and VMAT2 inhibitors have been used in combination.8 Note that VMAT2 inhibitors have the potential for QT prolongation, as do most antipsychotics. Hypokinetic rigidity Levodopa may provide partial and temporary relief of symptoms.8 Note the potential for such drugs to exacerbate behavioural disturbances. Rigidity may be caused/worsened by antipsychotics or tetrabenazine; dose reduction or discontinuation should be considered in the first instance, after weighing any derived benefits against symptom severity.8 Positive case reports exist for amantadine and dopamine agonists (although guidelines do not make recommendations on their use).8 Myoclonus Valproate or clonazepam has been suggested, used alone or combination.8 Levetiracetam is a therapeutic alternative.8 Dystonia Low-dose tetrabenazine has been suggested11 and a 2022 review concluded that deutetrabenazine is likely also to be effective.2 Botulinum toxin injections have been suggested for focal dystonia;8 clonazepam or baclofen has been suggested for non-focal dystonia.5 EPSEs, extrapyramidal side effects; LAI, long-acting injectable; VMAT2, vesicular monoamine transporter 2.

832 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Table 10.10 Pharmacological treatment of mental and behavioural symptoms in Huntington’s disease (HD). Symptoms Treatment Anxiety Reported 16.7–24% lifetime prevalence in HD.13 There are no RCTs to guide choice; however, olanzapine 5mg/day substantially improved anxiety symptoms in one small open-label pilot study.13 SSRIs and SNRIs have been suggested as first-line treatment.5,8 Some guidelines have recommended considering SGAs (quetiapine8, risperidone or olanzapine) for anxiety associated with personality or behavioural disturbances14 or when other treatments fail.8 Anxiolytics such as benzodiazepines or buspirone may also be useful.11,14 Depression Reported 30–70% prevalence in HD.15 Treatment is typically required because depression is linked to a lower quality of life in HD and increases the risk of suicide.13,15 There are almost no RCTs to guide choice.11,16 However, most experts agree that depression in HD responds well to antidepressants. SSRIs are the preferred first-line treatment5,8 but this is based on a less than perfect literature base.17 SSRIs: two controlled trials examined the effects of fluoxetine and citalopram in non-depressed patients with HD. Despite excluding depressed patients, both showed near significant improvements in depressive symptoms.16 Note that VMAT2 inhibitors are metabolised by CYP2D6; so inhibitors of this enzyme (e.g. fluoxetine, paroxetine) are predicted to increase exposure to active metabolites. SNRIs: venlafaxine was effective in an uncontrolled study;16 however, one in five developed adverse effects such as nausea and irritability.13 TCAs: beneficial effects reported in some cases18 but generally their use should be avoided or limited. Anticholinergic properties of TCAs may worsen hyperkinesias and cognition.11,18 Toxicity in overdose may also make them less suitable choices (suicidality is increased in HD13). Others: Mirtazapine was used successfully in one case report of severe depression.5 In a case registry study it was one of the most frequently prescribed treatments for depression in HD.13 Bupropion and SSRIs were found to be superior to SNRIs in one analysis of an observational study.19 Lithium produced improvements in suicidality in a small case series16 but experience is very limited, and tolerability may be poor. MAOIs have been used in earlier case studies;18 a lack of recent experience and important interactions with VMAT2 inhibitors make these less suitable. ECT can be used safely and effectively and may be considered in life-threatening cases.8,20 Obsessive compulsive behaviours or perseveration There are no RCTs.21 International consensus supports the use of SSRIs first line;8 use of clomipramine is also supported13 but tolerability may be poor. Case studies document the successful use of fluoxetine, paroxetine and sertraline.5 One study of two patients with perseveration and aggression reported beneficial effects with buspirone.13 For ideational perseveration, consensus also supports the use of olanzapine or risperidone (particularly if associated with irritability).8 Irritability or agitation22 Reported prevalence of 38–73% in HD. Initial management is non-pharmacological (e.g. by addressing possible triggers such as pain or akathisia and using behavioural/psychological approaches). No medications are approved specifically, but expert consensus supports the use of SSRIs as preferred first-line agents, with antipsychotics being the next most favoured alternative monotherapy. Clinical features influence treatment choice. For example, SGAs (e.g. olanzapine, risperidone, quetiapine) may be preferred in the presence of chorea, acute irritability, aggression or impulsivity. Benzodiazepines are a widely used adjunctive therapy. Guidelines have also recommended mirtazapine or mianserin in patients not benefitting from maximum doses of SSRIs, especially in those with a comorbid sleep disorder. In cases non-responsive to antidepressants and/or antipsychotics, adjunctive mood stabilisers have also been recommended.8 The effect of dextromethorphan/quinidine for irritability in HD is, at the time of writing, being studied in a phase III RCT.4 Aggressive behaviours: a wide variety of psychotropics have been used with reported beneficial effects (e.g. antipsychotics, lithium, valproate, propranolol, medroxyprogesterone, SSRIs, buspirone).18,23 Antipsychotics have been used most commonly. The evidence base is too limited to make specific treatment recommendations23 but low-dose antipsychotics can be considered.5 ECT was helpful in a few case reports of agitation refractory to pharmacotherapy.20

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Symptoms Treatment Apathy Common in HD and appears to worsen with disease progression.13 Some sedative medications (e.g. antipsychotics, benzodiazepines, tetrabenazine) may contribute, so dose reduction or withdrawal should be considered.8 In one small open study of 16 participants, cariprazine was associated with improvements in apathy, depressive symptoms and cognitive test scores.11 Bupropion was studied in one multicentre RCT and found to be ineffective.11 Other agents, including methylphenidate, atomoxetine, modafinil, amantadine and bromocriptine, have been trialled with little success.13 Psychosis One of the least prevalent psychiatric manifestations of HD, perhaps because of the use of antidopaminergics for motor symptoms.13 There are no RCTs to guide choice11 – treatment is empirical. Note that antipsychotic drugs may exacerbate any underlying movement disorder. VMAT2 inhibitors may have antipsychotic activity24 but they are not drugs of choice for psychosis in HD. SGAs: olanzapine and risperidone are used most frequently.13 Low starting doses are recommended.5 Case reports support the efficacy of risperidone, quetiapine, aripiprazole and amisulpride.18 Clozapine may be considered in refractory cases6,18 or akinetic forms of HD with debilitating parkinsonian symptoms.8,11 FGAs: used less frequently due to the risk of dystonia and parkinsonism; however, haloperidol has been used when chorea is also problematic to the patient.18 MAOIs, monoamine oxidase inhibitors; TCAs, tricyclic antidepressants; VMAT2, vesicular monoamine transporter 2. Table 10.10 (Continued) Table 10.11 Summary of treatments for mental state and behavioural changes in Huntington’s disease.6,8,13 Symptoms Most commonly prescribed pharmacological treatments Alternatives Anxiety SSRIs, mirtazapine, pregabalin, venlafaxine Olanzapine, risperidone, quetiapine, benzodiazepines, propranolol, buspirone Depression or suicidality SSRIs, bupropion, mirtazapine, venlafaxine TCAs; ECT in refractory cases Obsessive compulsive behaviours SSRIs Clomipramine Irritability or agitation SSRIs, SGAs (olanzapine, risperidone, sulpiride), tiapride, benzodiazepines Anticonvulsants (lamotrigine, carbamazepine, valproate), TCAs, buspirone, propranolol; consider trial of an analgesic Apathy None None Psychosis Olanzapine, risperidone, haloperidol, sulpiride, tiapride, LAI antipsychotics Clozapine, quetiapine LAI, long-acting injectable; TCAs, tricyclic antidepressants.

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32 - Cognitive symptoms

Cognitive symptoms

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33 - References

References

834 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Cognitive symptoms Cognitive disturbances may emerge many years before motor disturbances.7 The progression of cognitive decline is gradual25 and dementia is inevitable in late stages. Although a wide variety of agents have been studied,2,11 none has become established treatment and the benefit of most remains unclear.26 There is insufficient evidence to support the use of acetylcholinesterase inhibitors27 and no evidence to support any other medications to treat dementia in HD.11,28 References

Medina A, et al. Prevalence and incidence of Huntington’s disease: an updated systematic review and meta-analysis. Mov Disord 2022; 37:2327–2335.
Ferreira JJ, et al. An MDS evidence-based review on treatments for Huntington’s disease. Mov Disord 2022; 37:25–35.
Mestre T, et al. Therapeutic interventions for disease progression in Huntington’s disease. Cochrane Database Syst Rev 2009; 2009:CD006455.
Van de Roovaart HJ, et al. Huntington’s disease drug development: a phase 3 pipeline analysis. Pharmaceuticals (Basel) 2023; 16:1513.
Killoran A, et al. Current therapeutic options for Huntington’s disease: good clinical practice versus evidence-based approaches? Mov Disord 2014; 29:1404–1413.
Anderson KE, et al. Clinical management of neuropsychiatric symptoms of Huntington disease: expert-based consensus guidelines on agitation, anxiety, apathy, psychosis and sleep disorders. J Huntingtons Dis 2018; 7:355–366.
McColgan P, et al. Huntington’s disease: a clinical review. Eur J Neurol 2018; 25:24–34.
Bachoud-Lévi AC, et al. International guidelines for the treatment of Huntington’s disease. Front Neurol 2019; 10:710.
Furr Stimming E, et al. Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington’s disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2023; 22:494–504.
Unti E, et al. Antipsychotic drugs in Huntington’s disease. Expert Rev Neurother 2017; 17:227–237.
Saft C, et al. Symptomatic treatment options for Huntington’s disease (guidelines of the German Neurological Society). Neurol Res Pract 2023; 5:61.
Javelot H, et al. Benefit of long-acting paliperidone in Huntington’s disease: a case report. Int Clin Psychopharmacol 2021; 36:101–103.
Eddy CM, et al. Changes in mental state and behaviour in Huntington’s disease. Lancet Psychiatry 2016; 3:1079–1086.
Desamericq G, et al. Guidelines for clinical pharmacological practices in Huntington’s disease. Rev Neurol (Paris) 2016; 172:423–432.
Jellinger KA. The pathobiology of depression in Huntington’s disease: an unresolved puzzle. J Neural Transm 2024; doi: 10.1007/ s00702-024-02750-w.
Moulton CD, et al. Systematic review of pharmacological treatments for depressive symptoms in Huntington’s disease. Mov Disord 2014; 29:1556–1561.
Zadegan SA, et al. Treatment of depression in Huntington’s disease: a systematic review. J Neuropsychiatry Clin Neurosci 2024; doi: 10.1176/ appi.neuropsych.20230120.
van Duijn E. Medical treatment of behavioral manifestations of Huntington disease. Handb Clin Neurol 2017; 144:129–139.
McLauchlan DJ, et al. Different depression: motivational anhedonia governs antidepressant efficacy in Huntington’s disease. Brain Commun 2022; 4:fcac278.
Yahya A, et al. Electroconvulsive therapy in Huntington’s disease. Prog Neurol Psychiatry 2021; 25:33–38.
Oosterloo M, et al. Obsessive-compulsive and perseverative behaviors in Huntington’s disease. J Huntingtons Dis 2019; 8:1–7.
Karagas NE, et al. Irritability in Huntington’s disease. J Huntingtons Dis 2020; 9:107–113.
Fisher CA, et al. Aggression in Huntington’s disease: a systematic review of rates of aggression and treatment methods. J Huntingtons Dis 2014; 3:319–332.
Connolly A, et al. Meta-analysis and systematic review of vesicular monoamine transporter (VMAT-2) inhibitors in schizophrenia and psychosis. Psychopharmacology (Berl) 2024; 241:225–241.
Ross CA, et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol 2014; 10:204–216.
Van der Vaart T, et al. Treatment of cognitive deficits in genetic disorders: a systematic review of clinical trials of diet and drug treatments. JAMA Neurol 2015; 72:1052–1060.
Li Y, et al. Cholinesterase inhibitors for rarer dementias associated with neurological conditions. Cochrane Database Syst Rev 2015; 3:CD009444.
O’Brien JT, et al. Clinical practice with anti-dementia drugs: a revised (third) consensus statement from the British Association for Psychopharmacology. J Psychopharmacol 2017; 31:147–168.

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34 - Multiple sclerosis

Multiple sclerosis

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35 - Depression

Depression

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Multiple sclerosis Individuals with multiple sclerosis (MS) experience a variety of psychiatric and neurological disorders. These include depression, anxiety, pathological laughter and crying (pseudobulbar affect, PBA), mania, euphoria, psychosis, bipolar disorder, fatigue and cognitive impairment. Psychiatric disorders result from a variety of factors – the psychological impact of MS diagnosis and its prognosis, perceived lack of social support or unhelpful coping styles, increased stress, iatrogenic effects of treatments used with MS and MS-related inflammation and damage to neuronal pathways.1 Depression In people with MS, depression is common with a point prevalence of 14–31%2,3 and lifetime prevalence of up to 50%.4,5 Suicide rates are 2–7.5 times higher than the general population6 and suicidality is seen in more than a fifth of people with MS.7 Depression in MS is often associated with fatigue and pain, although the relationship direction is unclear.8 Overlapping symptoms of depression, PBA and MS can complicate diagnosis and so co-operation between neurologists and psychiatrists is essential to ensure optimal treatment. Depression in MS may result from structural changes in the brain related to MS pathology and, as such, it may differ fundamentally from non-MS depression.9,10 Suggested treatments are described in Table 10.12. Table 10.12 Recommendations for treatment for depression in multiple sclerosis (MS). Step Intervention Screen for depression with PHQ-9 HADS/BDI11/CES-D.12 Exclude or treat any organic causes. Consider iatrogenic effects of medications as potential cause of depression. Ensure there is no past history of mania or bipolar disorder. People with mild depression should be considered for CBT13 or self-help.14 Guidelines recommend SSRIs as first-line treatment12,15,16 but have been criticised for the dearth of MS-specific data.17 Sertraline was as effective as CBT in one trial18 but paroxetine was equivalent to placebo in another.19 Fluoxetine was effective in MS-related depression in a small case series.20 For those with comorbid pain, consideration should be given to treating with an SNRI such as duloxetine21 or venlafaxine.22 One RCT of desipramine showed it was more effective than placebo but tricyclics in general are often poorly tolerated.23 In 2011, a Cochrane review was not convinced by many of the studies cited here,24 but there is little reason to suppose that antidepressants are any less effective in depression associated with physical illness.25 In 2023, bupropion was shown to be effective in a small RCT.26 Vortioxetine may also improve both depression and anxiety.27 CBT is the most appropriate psychological intervention with best efficacy in comparison with supportive therapy or usual care, and should be used in conjunction with medication for those who are moderately to severely depressed.18,28,29 Mindfulness training may also help.30 Omega-3 fatty acids are ineffective.31 Because of reduced tolerability of adverse effects in this patient group, medications should be titrated from an initial half dose. Many MS patients are prescribed low-dose TCAs for pain/bladder disturbance, so SSRIs should be used with caution and patients should be observed for serotonin syndrome. If SSRIs are not tolerated or there is no response, there are limited data that moclobemide is effective and well tolerated.32,33 There are no published trials on venlafaxine, duloxetine and mirtazapine but these are used widely. Mirtazapine may worsen fatigue, at least initially. Venlafaxine and duloxetine are used for pain management in MS.34 ECT could be considered for people who are actively suicidal or severely depressed and at high risk, but it may trigger an exacerbation of MS symptoms, although some studies suggest that no neurological disturbance occurs.35 CBT, cognitive behaviour therapy; TCAs, tricyclic antidepressants.

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36 - Anxiety

Anxiety

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37 - Pseudobulbar affect

Pseudobulbar affect

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38 - Bipolar disorder

Bipolar disorder

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39 - Psychosis

Psychosis

836 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Anxiety Anxiety affects many people with MS, with a point prevalence of up to 50%36 and lifetime incidence of 35–37%.37 Elevated rates in comparison with the general population are seen for generalised anxiety disorder, panic disorder, obsessive compulsive disorder37 and social anxiety. The uncertainty of prognosis is a major cause of anxiety in MS.38 There are no published trials for the drug treatment of anxiety in MS, but SSRIs can be used and, in non-responsive cases, venlafaxine might be considered (based on practice in non-MS patients). Bupropion may also be effective.26 Benzodiazepines may be used for acute and severe anxiety but only for a maximum of 4 weeks and should not be prescribed in the long term. Buspirone and beta-blockers could also be considered although there is no demonstrated efficacy in MS. Pregabalin is also licensed for anxiety and may be useful in this population group especially where pain relief is required.39,40 People with MS may also respond to cognitive behaviour therapy (CBT). Generally, treatment is as for non-MS anxiety disorders. Pseudobulbar affect Around 25% of individuals with MS experience pathological laughing or crying or other incongruence of affect.41 It is more common in the advanced stages of the disease and is associated with cognitive impairment.37 There have been a few open-label trials recommending the use of small doses of TCAs such as amitriptyline or SSRIs such as fluoxetine42,43 in MS. Citalopram,44 nortriptyline45 and sertraline46 have been investigated in people with post-stroke pathological laughing or crying and have shown reasonable efficacy and rapid response. Valproic acid may be effective.47 The combination of dextromethorphan and low-dose quinidine (DMq) is effective.48 Dextromethorphan plus fluoxetine may show similar effects.49 In these combinations, dextromethorphan (an analgesic and cough suppressant) is the active ingredient and quinidine/fluoxetine the metabolic inhibitor. DMq is approved by the US Food and Drug Administration (FDA) as Nuedexta and once held approval in the EU but is not marketed there. Bipolar disorder The lifetime prevalence of bipolar disorder in MS is just less than 10%.50 Lithium can cause diuresis and thus lead to increased difficulties with tolerance in people with MS- related bladder disorder. Mania accompanied by psychosis could be treated with low- dose antipsychotics such as risperidone, olanzapine51 or ziprasidone.52 Patients requiring psychiatric treatment for steroid-induced mania with psychosis have been shown to respond to olanzapine.53 Psychosis Psychosis is relatively uncommon compared with other psychiatric disorders.52 A 2015 meta-analysis estimated the prevalence of psychosis to be 4.3%.1 In a very few cases, psychosis is the presenting complaint of MS.54 There have been few

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40 - Cognitive impairment

Cognitive impairment

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41 - Fatigue

Fatigue

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 published trials, but risperidone or clozapine has been recommended because of the low risk of extrapyramidal symptoms.55 On this basis, olanzapine, aripiprazole and quetiapine might also, in theory at least, be possible options. ECT has been used in refractory cases.56 Risperidone, quetiapine, olanzapine and, particularly, clozapine may have beneficial immunomodulatory properties.57 Psychosis may rarely be the presentation of an MS relapse in which case steroids may be beneficial but would need to be given under close supervision. Note also the small risk of psychotic reactions in patients receiving tetrahydrocannabinol (THC)-containing formulations.58,59 Cognitive impairment Cognitive impairment occurs in at least 40–65% of people with MS. Some of the medications commonly prescribed can worsen cognition, such as tizanidine, diazepam and gabapentin.60 Although there are no published trials, evidence from clinical case studies suggests that the treatment of sleep difficulties, depression and fatigue can enhance cognitive function.60 There have been two small trials with donepezil for people with mild to moderate cognitive impairment showing moderate efficacy.61,62 A larger study found no effect.63 Similarly, data supporting the use of memantine are weak.64 Overall, no treatment has proven worthwhile efficacy65 and disease-modifying agents offer greater promise.66 Fatigue Fatigue is a common symptom in MS, with up to 80% of people affected.67 The aetiology of fatigue is unclear but there have been suggestions that disruption of neuronal networks,68 depression or psychological reactions,55 sleep disturbances, inflammation69 or medication may play a role in its development. Pharmacological and non- pharmacological strategies67 should be used in a treatment strategy. Non-pharmacological strategies include reviewing history for any possible contributing factors, assessment and treatment of underlying depression if present, medication, pacing activities and appropriate exercise. One trial suggests that CBT reduces fatigue scores.70 Pharmacological strategies include the use of amantadine71 or modafinil. In the UK, National Institute for Health and Care Excellence (NICE) guidelines suggest no medicine should be used routinely but that amantadine could have a small benefit and should be offered.72 A Cochrane review of amantadine in people with MS suggested that the quality and outcomes of the amantadine trials are inconsistent and that therefore efficacy remains unclear.71 A meta-analysis of 11 RCTs found supporting data for amantadine73 and a later (2020) meta-analysis confirmed its value.74 Modafinil has mixed results in clinical trials, but a meta-analysis of five RCTs75 found clear benefit. Despite doubts over its efficacy, modafinil is widely used in MS.76 A 2023 meta-analysis of five studies suggested benefit for vitamin D supplementation.77

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References

838 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 References

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Baghbanian SM, et al. The effects of bupropion on sexual dysfunction in female patients with multiple sclerosis: a double-blind randomized clinical trial. Mult Scler Relat Disord 2023; 69:104399.
Gil-Sanchez A, et al. Effects of vortioxetine on cognition and fatigue in patients with multiple sclerosis and depression: a case series study. CNS Neurol Disord Drug Targets 2024; 23:395–401.
Siegert RJ, et al. Depression in multiple sclerosis: a review. J Neurol Neurosurg Psychiatry 2005; 76:469–475.
Larcombe NA, et al. An evaluation of cognitive-behaviour therapy for depression in patients with multiple sclerosis. Br J Psychiatry 1984; 145:366–371.
Grossman P, et al. MS quality of life, depression, and fatigue improve after mindfulness training: a randomized trial. Neurology 2010; 75:1141–1149.
Shinto L, et al. Omega-3 fatty acids for depression in multiple sclerosis: a randomized pilot study. PLoS One 2016; 11:e0147195.
Schiffer RB, et al. Antidepressant pharmacotherapy of depression associated with multiple sclerosis. Am J Psychiatry 1990; 147:1493–1497.
Barak Y, et al. Moclobemide treatment in multiple sclerosis patients with comorbid depression: an open-label safety trial. J Neuropsychiatry Clin Neurosci 1999; 11:271–273.
Shkodina AD, et al. Pharmacological and non-pharmacological approaches for the management of neuropathic pain in multiple sclerosis. CNS Drugs 2024; 38:205–224.
Rasmussen KG, et al. Electroconvulsive therapy in patients with multiple sclerosis. J ECT 2007; 23:179–180.
Jones KH, et al. A large-scale study of anxiety and depression in people with multiple sclerosis: a survey via the web portal of the UK MS Register. PLoS One 2012; 7:e41910.
Korostil M, et al. Anxiety disorders and their clinical correlates in multiple sclerosis patients. Mult Scler 2007; 13:67–72.
Butler E, et al. ‘It’s the unknown’ – understanding anxiety: from the perspective of people with multiple sclerosis. Psychol Health 2019; 34:368–383.

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 39. Solaro C, et al. Pregabalin for treating paroxysmal painful symptoms in multiple sclerosis: a pilot study. J Neurol 2009; 256:1773–1774. 40. Bittner S, et al. [Pregabalin and gabapentin in multiple sclerosis: clinical experiences and therapeutic implications]. Nervenarzt 2011; 82:1273–1280. 41. Nabizadeh F, et al. Pseudobulbar affect in neurodegenerative diseases: a systematic review and meta-analysis. J Clin Neurosci 2022; 100:100–107. 42. Feinstein A, et al. The effects of anxiety on psychiatric morbidity in patients with multiple sclerosis. Mult Scler 1999; 5:323–326. 43. Feinstein A, et al. Prevalence and neurobehavioral correlates of pathological laughing and crying in multiple sclerosis. Arch Neurol 1997; 54:1116–1121. 44. Andersen G, et al. Citalopram for post-stroke pathological crying. Lancet 1993; 342:837–839. 45. Robinson RG, et al. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 1993; 150:286–293. 46. Burns A, et al. Sertraline in stroke-associated lability of mood. Int J Geriatr Psychiatry 1999; 14:681–685. 47. Johnson B, et al. Crying and suicidal, but not depressed. Pseudobulbar affect in multiple sclerosis successfully treated with valproic acid: case report and literature review. Palliat Support Care 2015; 13:1797–1801. 48. Pioro EP, et al. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann Neurol 2010; 68:693–702. 49. McGrane I, et al. Treatment of pseudobulbar affect with fluoxetine and dextromethorphan in a woman with multiple sclerosis. Ann Pharmacother 2017; 51:1035–1036. 50. Joseph B, et al. Prevalence of bipolar disorder in multiple sclerosis: a systematic review and meta-analysis. Evid Based Ment Health 2021; 24:88–94. 51. Patten SB, et al. Biopsychosocial correlates of lifetime major depression in a multiple sclerosis population. Mult Scler 2000; 6:115–120. 52. Davids E, et al. Antipsychotic treatment of psychosis associated with multiple sclerosis. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28:743–744. 53. Budur K, et al. Olanzapine for corticosteroid-induced mood disorders. Psychosomatics 2003; 44:353. 54. Camara-Lemarroy CR, et al. The varieties of psychosis in multiple sclerosis: a systematic review of cases. Mult Scler Relat Disord 2017; 12:9–14. 55. Jefferies K. The neuropsychiatry of multiple sclerosis. Adv Psychiatric Treat 2006; 12:214–220. 56. Narita Z, et al. Possible effects of electroconvulsive therapy on refractory psychosis in primary progressive multiple sclerosis: a case report. Neuropsychopharmacol Rep 2018; 38:92–94. 57. Stamoula Ε, et al. Atypical antipsychotics in multiple sclerosis: a review of their in vivo immunomodulatory effects. Mult Scler Relat Disord 2022; 58:103522. 58. Aragona M, et al. Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: a double-blind, placebo controlled, crossover study. Clin Neuropharmacol 2009; 32:41–47. 59. Black N, et al. Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis. Lancet Psychiatry 2019; 6:995–1010. 60. Pierson SH, et al. Treatment of cognitive impairment in multiple sclerosis. Behav Neurol 2006; 17:53–67. 61. Krupp LB, et al. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology 2004; 63:1579–1585. 62. Greene YM, et al. A 12-week, open trial of donepezil hydrochloride in patients with multiple sclerosis and associated cognitive impairments. J Clin Psychopharmacol 2000; 20:350–356. 63. Krupp LB, et al. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis. Neurology 2011; 76:1500–1507. 64. Lovera JF, et al. Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. Mult Scler 2010; 16:715–723. 65. Chen MH, et al. Cognitive efficacy of pharmacologic treatments in multiple sclerosis: a systematic review. CNS Drugs 2020; 34:599–628. 66. Patti F. Treatment of cognitive impairment in patients with multiple sclerosis. Expert Opin Investig Drugs 2012; 21:1679–1699. 67. Bakshi R. Fatigue associated with multiple sclerosis: diagnosis, impact and management. Mult Scler 2003; 9:219–227. 68. Sepulcre J, et al. Fatigue in multiple sclerosis is associated with the disruption of frontal and parietal pathways. Mult Scler 2009; 15:337–344. 69. Ormstad H, et al. Chronic fatigue and depression due to multiple sclerosis: immune-inflammatory pathways, tryptophan catabolites and the gut-brain axis as possible shared pathways. Mult Scler Relat Disord 2020; 46:102533. 70. Van KK, et al. A randomized controlled trial of cognitive behavior therapy for multiple sclerosis fatigue. Psychosom Med 2008; 70:205–213. 71. Pucci E, et al. Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst Rev 2007; 1:CD002818. 72. National Institute for Health and Care Excellence. Multiple sclerosis in adults: management. NICE guideline [NG220]. 2022 (last checked May 2024); https://www.nice.org.uk/guidance/ng220. 73. Yang TT, et al. Pharmacological treatments for fatigue in patients with multiple sclerosis: a systematic review and meta-analysis. J Neurol Sci 2017; 380:256–261. 74. Perez DQ, et al. Efficacy and safety of amantadine for the treatment of fatigue in multiple sclerosis: a systematic review and meta-analysis. Neurodegener Dis Manag 2020; 10:383–395. 75. Shangyan H, et al. Meta-analysis of the efficacy of modafinil versus placebo in the treatment of multiple sclerosis fatigue. Mult Scler Relat Disord 2018; 19:85–89. 76. Davies M, et al. Safety profile of modafinil across a range of prescribing indications, including off-label use, in a primary care setting in England: results of a modified prescription-event monitoring study. Drug Saf 2013; 36:237–246. 77. López-Muñoz P, et al. Effect of vitamin D supplementation on fatigue in multiple sclerosis: a systematic review and meta-analysis. Nutrients 2023; 15:2861.

15 - Chapter 10 Drug treatment of psychiatric symptoms

43 - Parkinsons disease

Parkinson’s disease

15 - Chapter 10 Drug treatment of psychiatric symptoms

44 - Depression

Depression

840 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Parkinson’s disease Psychiatric comorbidity is common in Parkinson’s disease (PD). Approximately 25% of PD patients will suffer from major depression, a further 25% from milder forms of depression, 25% from anxiety spectrum disorders and 25% from psychosis.1–3 The risk of developing dementia is 3.5–6-fold higher, depending on definition, than in age- and gender-matched controls.4 Depression and anxiety often precede PD diagnosis. Anti-parkinsonian treatment is likely to increase psychiatric comorbidity. Indeed treatment-linked prolonged cognitive processing may be a harbinger of more disabling morbidity, like deficits in attention, multitasking and difficulties in sequencing and planning.5 While depression and anxiety can occur at any time in the course of PD, psychosis, dementia and delirium are more prevalent in the later stages of the illness. Close co-operation between the psychiatrist and prescriber of anti-parkinsonian medication is often required to optimise treatment for this group of patients. Depression Depression in PD predicts greater cognitive decline, deterioration in functioning and progression of motor symptoms,6 possibly reflecting more advanced and widespread neurodegeneration involving a variety of neurotransmitter pathways7 and/or inability/ disinclination to seek or comply with remedial therapies. Depression may also occur after the withdrawal of dopamine agonists.8 Similarly, cyclical mood changes follow the on/off fluctuations associated with the levodopa dosage cycle. Suggested treatments are described in Table 10.13. Table 10.13 Recommendations for treatment of depression in Parkinson’s disease (PD). Step Intervention Exclude/treat organic causes such as hypothyroidism (the prevalence of which is relatively high in PD6). SSRIs are considered to be first-line treatment although the effect size is modest.9–11 Some patients may experience a worsening of motor symptoms,12,13 in particular tremor. Sertraline is the preferred SSRI in PD.14 Care must be taken when combining SSRIs with selegiline (or rasagiline), as the risk of serotonin syndrome is increased.6 The SNRIs venlafaxine15 and duloxetine16 also appear to have some effect although venlafaxine may modestly worsen motor symptoms.15 TCAs are generally poorly tolerated because of their anticholinergic (can worsen cognitive problems and constipation) and alpha-blocking effects (can worsen symptoms of autonomic dysfunction). A 2022 network meta-analysis17 showed that dopamine agonists and SSRIs have the highest efficacy and acceptability. Limited evidence supports the safe and effective use of agomelatine,18,19 bupropion20 and vortioxetine.21 Consider augmentation with dopamine agonists/releasers such as pramiprexole.22 Note though that these drugs increase the risk of impulse control disorders.23,24 They have also rarely been associated with the development of psychosis.25 Dopamine agonists are effective antidepressants when used as a single agent.26 Consider ECT. Depression and motor symptoms generally respond well6 but the risk of inducing delirium is high,27 particularly in patients with pre-existing cognitive impairment. Follow the algorithm for treatment-resistant depression (see ’Drug treatment of depression’ in Chapter 3) from this point. Be aware of the increased propensity for adverse effects and drug interactions in this patient group. TCAs, tricyclic antidepressants.

15 - Chapter 10 Drug treatment of psychiatric symptoms

45 - Psychosis

Psychosis

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Psychosis Psychosis in PD is often characterised by visual hallucinations.28 Auditory hallucinations and delusions occur far less frequently,29 and usually in younger patients.30 Psychosis and dementia frequently coexist. Having one predicts the development of the other.31 Sleep disorders are also an established risk factor for the development of psychosis.32 The exact aetiology of PD psychosis is poorly understood. In the majority of patients, psychotic symptoms are thought to be secondary to dopaminergic medication rather than part of PD itself. Psychosis secondary to medication may be determined at least in part through polymorphisms of the ACE gene.33 From the limited data available, anticholinergics and dopamine agonists seem to be associated with a higher risk of inducing psychosis than levodopa or catechol-O-methyltransferase (COMT) inhibitors.29,34 Psychosis is a major contributor to caregiver distress and a risk factor for institutionalisation and early death.31 Suggested treatments are described in Table 10.14. Table 10.14 Recommendations for treatment of psychosis in Parkinson’s disease (PD). Step Intervention Exclude organic causes (delirium). Optimise the environment to maximise orientation and minimise problems due to poor caregiver–patient interactions. If the patient has insight and hallucinations are infrequent and not troubling, do not treat. Consider reducing or stopping anticholinergics and dopamine agonists. Monitor for signs of motor deterioration. Be prepared to restart/increase the dose of these drugs again to achieve the best balance between psychosis and mobility. Consider an atypical antipsychotic. The efficacy of clozapine (see step 7) is unequivocally supported by placebo-controlled RCTs.28 In contrast, there are several negative placebo-controlled trials for quetiapine and olanzapine.28 Low-dose quetiapine (25–200mg a day) is the least badly tolerated and may have marginal efficacy.35 It is probably reasonable to try quetiapine36 before clozapine but the success rate is minimal. Olanzapine, ziprasidone and aripiprazole are likely to all have greater adverse effects on motor function than quetiapine and have no proven therapeutic effect. Risperidone and conventional antipsychotics should be avoided completely. All antipsychotics may be relatively less effective in managing psychotic symptoms in patients with dementia, and such patients may be more prone to developing motor and cognitive adverse effects.37 Antipsychotics have been associated with an increased risk of vascular events in the elderly. In PD all antipsychotics are linked to increased mortality38 although the effect of clozapine is not known. Consider a cholinesterase inhibitor, particularly if the patient has comorbid dementia.39 Cholinesterase inhibitors may also reduce the risk of falls.40 Early use of these drugs does not prevent or reduce episodes of psychosis although there is some benefit on cognition.41,42 Try clozapine. Clozapine is highly effective in PD psychosis but widely underused.43 It also has useful anti-tremor properties equivalent to benztropine.44 A 2023 European study45 reported that only 1% of PD psychosis patients received clozapine (72% received quetiapine). Start at 6.25mg – usual dose 25–35mg/day.28,46 Usually safe but neuroleptic malignant syndrome has been reported.47 Monitor as for clozapine in schizophrenia. Older people are more prone to develop serious blood dyscrasia. A case of aplastic anaemia has been reported.48 Overall, clozapine is safer than other antipsychotics in PD psychosis.49 Consider ECT.50 Psychotic and motor symptoms usually respond well51 but the risk of inducing delirium is high,27 particularly in patients with pre-existing cognitive impairment.

15 - Chapter 10 Drug treatment of psychiatric symptoms

46 - Pimavanserin

Pimavanserin

15 - Chapter 10 Drug treatment of psychiatric symptoms

47 - Cholinesterase inhibitors

Cholinesterase inhibitors

15 - Chapter 10 Drug treatment of psychiatric symptoms

48 - Other treatments

Other treatments

842 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Pimavanserin Pimavanserin is a 5-HT2A receptor inverse agonist available in the USA and some other countries. It is effective in PD psychosis but has no dopamine receptor activity and does not worsen PD movement disorder or seem to increase mortality.52,53 It is more effective and better tolerated than quetiapine54 and olanzapine.35 Its therapeutic effects seem to increase with the age of the patient.55 Pimavanserin and clozapine are the only drugs unreservedly recommended for PD psychosis.56 A network meta-analysis suggested only these two drugs had efficacy in PD, while having minimal effect on motor function.49 Clozapine may be effective in pimavanserin non-responders.57 Cholinesterase inhibitors Cholinesterase inhibitors have been shown to improve cognition, delusions and hallucinations in patients with Lewy body dementia (which has many similarities to PD). Motor function may deteriorate.58,59 Improvements in cognitive functioning are modest.60–62 A Cochrane review and some large RCTs61,63,64 concluded that there is evidence that cholinesterase inhibitors lead to improvements in global functioning, cognition, behavioural disturbance and activities of daily living in PD. Again, motor function may deteriorate64,65 with particular increase in tremor.62 Evidence for memantine is mixed.66,67 Discontinuation of anticholinergic drugs should improve cognition and psychosis – PD patients often have a very high anticholinergic burden, some of this unrelated to the treatment of PD itself.68 Where confounding by indication is removed (where dementia risk could be better explained by indication than a medicine), the classes of medicine with anti-cholinergic properties indicated in dementia are reduced somewhat.69 RCTs are needed to compare deprescribing of maintenance medicines with their continuation in diseases with dementia.5 Other treatments Many patients with PD use complementary therapies, some of which may be modestly beneficial; see Zesiewicz et al.70 Caffeine (and perhaps nicotine)71 may offer a protective effect against the development of PD and also modestly improve motor function in established disease.72 Box 10.4 summarises the treatment of PD. Box 10.4 Simplified summary of treatment in Parkinson’s disease Depression in PD Sertraline is first choice. Venlafaxine and duloxetine are next option. Consider agomelatine or bupropion. Pramipexole is an option in those not already on a dopamine agonist. Psychosis in PD Try low-dose quetiapine but withdraw if ineffective. Clozapine is the drug of choice for PD psychosis. Pimavanserin may be used where available. Electroconvulsive therapy is a last resort.

15 - Chapter 10 Drug treatment of psychiatric symptoms

49 - References

References

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 References

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Åström DO, et al. High risk of developing dementia in Parkinson’s disease: a Swedish registry-based study. Sci Rep 2022; 12:16759.
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Richard IH, et al. A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease. Neurology 2012; 78:1229–1236.
Bonuccelli U, et al. A non-comparative assessment of tolerability and efficacy of duloxetine in the treatment of depressed patients with Parkinson’s disease. Expert Opin Pharmacother 2012; 13:2269–2280.
Wang XL, et al. Comparative efficacy and acceptability of drug treatments for Parkinson’s disease with depression: a systematic review with network meta-analysis. Eur J Pharmacol 2022; 927:175070.
Avila A, et al. Agomelatine for depression in Parkinson disease: additional effect on sleep and motor dysfunction. J Clin Psychopharmacol 2015; 35:719–723.
De Berardis D, et al. Agomelatine treatment of major depressive disorder in Parkinson’s disease: a case series. J Neuropsychiatry Clin Neurosci 2013; 25:343–345.
Vismara M, et al. Clinical uses of bupropion in patients with Parkinson’s disease and comorbid depressive or neuropsychiatric symptoms: a scoping review. BMC Neurol 2022; 22:169.
Santos García D, et al. Vortioxetine improves depressive symptoms and cognition in Parkinson’s disease patients with major depression: an open-label prospective study. Brain Sci 2022; 12:1466.
Barone P, et al. Pramipexole versus sertraline in the treatment of depression in Parkinson’s disease: a national multicenter parallel-group randomized study. J Neurol 2006; 253:601–607.
Antonini A, et al. A reassessment of risks and benefits of dopamine agonists in Parkinson’s disease. Lancet Neurol 2009; 8:929–937.
Weintraub D, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol 2010; 67:589–595.
Li CT, et al. Pramipexole-induced psychosis in Parkinson’s disease. Psychiatry Clin Neurosci 2008; 62:245.
Ziaei E, et al. Comparison of pramipexole and citalopram in the treatment of depression in Parkinson’s disease: a randomized parallel-group trial. J Res Med Sci 2022; 27:55.
Figiel GS, et al. ECT-induced delirium in depressed patients with Parkinson’s disease. J Neuropsychiatry Clin Neurosci 1991; 3:405–411.
Friedman JH. Parkinson’s disease psychosis 2010: a review article. Parkinsonism Relat Disord 2010; 16:553–560.
Ismail MS, et al. A reality test: How well do we understand psychosis in Parkinson’s disease? J Neuropsychiatry Clin Neurosci 2004; 16:8–18.
Kiziltan G, et al. Relationship between age and subtypes of psychotic symptoms in Parkinson’s disease. J Neurol 2007; 254:448–452.
Factor SA, et al. Longitudinal outcome of Parkinson’s disease patients with psychosis. Neurology 2003; 60:1756–1761.
Reich SG, et al. Ten most commonly asked questions about the psychiatric aspects of Parkinson’s disease. Neurologist 2003; 9:50–56.
Lin JJ, et al. Genetic polymorphism of the angiotensin converting enzyme and L-dopa-induced adverse effects in Parkinson’s disease. J Neurol Sci 2007; 252:130–134.
Stowe RL, et al. Dopamine agonist therapy in early Parkinson’s disease. Cochrane Database Syst Rev 2008; 2:CD006564.
Yunusa I, et al. Comparative efficacy, safety, and acceptability of pimavanserin and other atypical antipsychotics for Parkinson’s disease psychosis: systematic review and network meta-analysis. J Geriatr Psychiatry Neurol 2023; 36:417–432.
Divac N, et al. The efficacy and safety of antipsychotic medications in the treatment of psychosis in patients with Parkinson’s disease. Behav Neurol 2016; 2016:4938154.

844 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 37. Prohorov T, et al. The effect of quetiapine in psychotic Parkinsonian patients with and without dementia. An open-labeled study utilizing a structured interview. J Neurol 2006; 253:171–175. 38. Weintraub D, et al. Association of antipsychotic use with mortality risk in patients with Parkinson disease. JAMA Neurol 2016; 73:535–541. 39. D’Angremont E, et al. Cholinesterase inhibitors for treatment of psychotic symptoms in Alzheimer disease and Parkinson disease: a meta- analysis. JAMA Neurol 2023; 180:813–823. 40. Chung KA, et al. Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease. Neurology 2010; 75:1263–1269. 41. Sawada H, et al. Early use of donepezil against psychosis and cognitive decline in Parkinson’s disease: a randomised controlled trial for 2 years. J Neurol Neurosurg Psychiatry 2018; 89:1332–1340. 42. Van Mierlo TJM, et al. Rivastigmine for minor visual hallucinations in Parkinson’s disease: a randomized controlled trial with 24 months follow-up. Brain Behav 2021; 11:e2257. 43. Friedman JH. Clozapine is severely underused in Parkinson’s disease patients. Mov Disord Clin Pract 2022; 9:1021–1024. 44. Friedman JH, et al. Benztropine versus clozapine for the treatment of tremor in Parkinson’s disease. Neurology 1997; 48:1077–1081. 45. Pirttilä A, et al. Hospitalization and the risk of initiation of antipsychotics in persons with Parkinson’s disease. J Am Med Dir Assoc 2023; 24:1290–1296.e4. 46. Pintor L, et al. Ziprasidone versus clozapine in the treatment of psychotic symptoms in Parkinson disease: a randomized open clinical trial. Clin Neuropharmacol 2012; 35:61–66. 47. Mesquita J, et al. Fatal neuroleptic malignant syndrome induced by clozapine in Parkinson’s psychosis. J Neuropsychiatry Clin Neurosci 2014; 26:E34. 48. Ziegenbein M, et al. Clozapine-induced aplastic anemia in a patient with Parkinson’s disease. Can J Psychiatry 2003; 48:352. 49. Iketani R, et al. Efficacy and safety of atypical antipsychotics for psychosis in Parkinson’s disease: a systematic review and Bayesian network meta-analysis. Parkinsonism Relat Disord 2020; 78:82–90. 50. Factor SA, et al. Combined clozapine and electroconvulsive therapy for the treatment of drug-induced psychosis in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 1995; 7:304–307. 51. Martin BA. ECT for Parkinson’s? CMAJ 2003; 168:1391–1392. 52. Sarva H, et al. Evidence for the use of pimavanserin in the treatment of Parkinson’s disease psychosis. Ther Adv Neurol Disord 2016; 9:462–473. 53. Rissardo JP, et al. Pimavanserin and Parkinson’s disease psychosis: a narrative review. Brain Sci 2022; 12:1286. 54. Alipour-Haris G, et al. Comparison of pimavanserin versus quetiapine for hospitalization and mortality risk among medicare beneficiaries with Parkinson’s disease psychosis. Mov Disord Clin Pract 2023; 10:406–414. 55. Mansuri Z, et al. Pimavanserin in the treatment of Parkinson’s disease psychosis: meta-analysis and meta-regression of randomized clinical trials. Innov Clin Neurosci 2022; 19:46–51. 56. Wilby KJ, et al. Evidence-based review of pharmacotherapy used for Parkinson’s disease psychosis. Ann Pharmacother 2017; 51:682–695. 57. Thames BH, et al. Clozapine: efficacy for Parkinson disease psychosis in patients refractory to pimavanserin. Parkinsonism Relat Disord 2023; 109:105356. 58. Richard IH, et al. Rivastigmine-induced worsening of motor function and mood in a patient with Parkinson’s disease. Mov Disord 2001; 16 Suppl 1:33–34. 59. McKeith I, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000; 356:2031–2036. 60. Emre M, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 2004; 351:2509–2518. 61. Aarsland D, et al. Donepezil for cognitive impairment in Parkinson’s disease: a randomised controlled study. J Neurol Neurosurg Psychiatry 2002; 72:708–712. 62. Pagano G, et al. Cholinesterase inhibitors for Parkinson’s disease: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2015; 86:767–773. 63. Rolinski M, et al. Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson’s disease dementia and cognitive impairment in Parkinson’s disease. Cochrane Database Syst Rev 2012; 3:CD006504. 64. Dubois B, et al. Donepezil in Parkinson’s disease dementia: a randomized, double-blind efficacy and safety study. Mov Disord 2012; 27:1230–1238. 65. Connolly BS, et al. Pharmacological treatment of Parkinson disease: a review. JAMA 2014; 311:1670–1683. 66. Emre M, et al. Memantine for patients with Parkinson’s disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010; 9:969–977. 67. Seppi K, et al. The Movement Disorder Society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson’s disease. Mov Disord 2011; 26 Suppl 3:S42–S80. 68. Nawaz H, et al. Anticholinergic medication burden in Parkinson’s disease outpatients. J Parkinsons Dis 2022; 12:599–606. 69. Mur J, et al. Association between anticholinergic burden and dementia in UK Biobank. Alzheimers Dement (NY) 2022; 8: e12290. 70. Zesiewicz TA, et al. Potential influences of complementary therapy on motor and non-motor complications in Parkinson’s disease. CNS Drugs 2009; 23:817–835. 71. Biswas S, et al. Study of the effects of nicotine and caffeine for the treatment of Parkinson’s disease. Appl Biochem Biotechnol 2023; 195:639–654. 72. Postuma RB, et al. Caffeine for treatment of Parkinson disease: a randomized controlled trial. Neurology 2012; 79:651–658.

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50 - Atrial fibrillation

Atrial fibrillation

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Atrial fibrillation Atrial fibrillation (AF) is the most common cardiac arrhythmia. It particularly affects older people but may occur in an important proportion of people aged less than 40 years. Risk factors include anxiety, obesity, diabetes, hypertension, long-standing aerobic exercise and high alcohol consumption.1–3 AF itself is not usually life-threatening but stasis of blood in the atria during fibrillation predisposes to clot formation and substantially increases the risk of stroke.4 The use of warfarin or direct-acting oral anticoagulants is therefore essential.3 AF can be defined as ‘lone’ or paroxysmal (occurring infrequently, and spontaneously reverting to sinus rhythm), persistent (repeated and prolonged [>1 week] episodes usually, if temporarily, responsive to treatment) or permanent (unresponsive). Risk of stroke is increased in all three conditions.3 Treatment may involve DC conversion, rhythm control (usually flecainide, propafenone or amiodarone) or rate control (with diltiazem, verapamil or sotalol). With rhythm control the aim is to maintain sinus rhythm, although this is not always achieved. With rate control, AF is allowed to continue but ventricular response is controlled and the ventricles are filled passively. Many people with paroxysmal or persistent AF can be effectively cured of the condition by catheter or cryoablation of aberrant electrical pathways,5,6 now a routine and effective procedure.7 AF is commonly encountered in psychiatry not least because of the high rates of obesity, diabetes and alcohol misuse seen in mental health patients. The onset of AF also provokes prescription of antidepressants, anxiolytics and hypnotics.8 When considering the use of psychotropics several factors need to be taken into account: ■ ■Interactions between psychotropics and anticoagulant therapy. ■ ■Arrhythmogenicity of psychotropics prescribed. AF usually results from cardiovascular disease, and drugs affecting cardiac ion channels may increase mortality in these patients, especially those with ischaemic disease.9,10 Drugs that prolong the QT interval may also increase the risk of incident AF11 although their effect on established AF is not known. ■ ■Effect on ventricular rate: some drugs induce reflex tachycardia via postural hypotension, others (clozapine, quetiapine) directly increase heart rate. ■ ■Reported association between individual psychotropics and AF (Table 10.15). ■ ■Risk of interaction with co-prescribed antiarrhythmics or rate-controlling drugs. ■ ■Whether AF is paroxysmal (aim to avoid precipitating AF), persistent (aim to avoid prolonging AF) or permanent (aim to avoid increasing ventricular rate).

846 The Maudsley® Prescribing Guidelines in Psychiatry Table 10.15 Recommendations for using psychotropics in atrial fibrillation (AF). CHAPTER 10 Condition Suggested drugs Drugs to avoid Schizophrenia/ schizoaffective disorder The condition itself may be associated with an increased risk of AF12 In paroxysmal or persistent AF, cariprazine, brexpiprazole or lurasidone may be appropriate choices. In permanent AF with rate control, drug choice is less crucial but probably best to avoid drugs with potent effects on the ECG (ziprasidone, pimozide, etc.) and those that increase heart rate. One case–control study suggested antipsychotics increase risk of AF by 17%13 All antipsychotics appear to increase the risk of bleeding when combined with DOACs in AF.14 Bipolar disorder Valproate Lithium Carbamazepine Depression Untreated depression predicts recurrence of AF27 SSRIs but beware interaction with warfarin and other anticoagulants29 as severe bleeding risk is increased.30 Presence of AF increases risk of depression and anxiety28 Animal studies suggest an antiarrhythmic effect for SSRIs.31,32 Paroxetine improved paroxysmal AF in a series of non-depressed patients.33 Venlafaxine does not directly affect atrial conduction34 and may cardiovert paroxysmal AF.35 One study suggested no increased risk of bleeding when combined with DOACs,36 another suggested a particular risk of bleeding when SNRIs are combined with apixaban.37 Mirtazapine and trazodone may increase bleeding risk when combined with DOACs in AF.37 AF incidence falls after starting antidepressant treatment.38,39 No evidence that agomelatine affects cardiac conduction or clotting. AF reported with clozapine,15,16 olanzapine,17,18 aripiprazole19,20 and paliperidone.21 Causation not clearly established but avoid use in lone, paroxysmal or persistent AF. Avoid QT-prolonging drugs in ischaemic heart disease (see section on QT prolongation in Chapter 1). Association of antipsychotics with AF13 may be linked to metabolic disturbance22 although some studies suggest no link between antipsychotics and AF.23 Mood stabilisers appear not to affect risk of AF. Valproate may cause AV conduction block.24 One case of AF following lithium overdose25 and one in chronic toxicity.26 Avoid tricyclics in coronary disease.40 Tricyclics may provoke AF41,42 but do not increase risk of haemorrhage when combined with warfarin29 or DOACs.37 One database study suggested antidepressants in general do not increase risk of AF43 although another suggested both depression and antidepressant use are linked to incident AF.44

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51 - References

References

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 References

Chen LY, et al. Epidemiology of atrial fibrillation: a current perspective. Heart Rhythm 2007; 4:S1–S6.
Tully PJ, et al. Anxiety, depression, and stress as risk factors for atrial fibrillation after cardiac surgery. Heart Lung 2011; 40:4–11.
National Institute for Health and Care Excellence. Atrial fibrillation: diagnosis and management. NICE guideline [NG196]. 2021 (last accessed August 2024); https://www.nice.org.uk/guidance/ng196.
Lakshminarayan K, et al. Clinical epidemiology of atrial fibrillation and related cerebrovascular events in the United States. Neurologist 2008; 14:143–150.
Rodgers M, et al. Curative catheter ablation in atrial fibrillation and typical atrial flutter: systematic review and economic evaluation. Health Technol Assess 2008; 12:iii–iv, xi–xiii, 1–198.
Latchamsetty R, et al. Catheter ablation of atrial fibrillation. Cardiol Clin 2014; 32:551–561.
Saglietto A, et al. Impact of atrial fibrillation catheter ablation on mortality, stroke, and heart failure hospitalizations: a meta-analysis. J Cardiovasc Electrophysiol 2020; 31:1040–1047.
Hagengaard L, et al. Incident atrial fibrillation and risk of psychoactive drug redemptions and psychiatric hospital contacts: a Danish Nationwide Register-based Follow-up Study. Eur Heart J Qual Care Clin Outcomes 2021; 7:76–82.
Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med 1992; 327:227–233.
Epstein AE, et al. Mortality following ventricular arrhythmia suppression by encainide, flecainide, and moricizine after myocardial infarction. The original design concept of the Cardiac Arrhythmia Suppression Trial (CAST). JAMA 1993; 270:2451–2455.
Zhang N, et al. Prolonged corrected QT interval in predicting atrial fibrillation: a systematic review and meta-analysis. Pacing Clin Electrophysiol 2018; 41:321–327.
Emul M, et al. P wave and QT changes among inpatients with schizophrenia after parenteral ziprasidone administration. Pharmacol Res 2009; 60:369–372.
Chou RH, et al. Antipsychotic treatment is associated with risk of atrial fibrillation: a nationwide nested case-control study. Int J Cardiol 2017; 227:134–140.
Chen CM, et al. Major bleeding risk in atrial fibrillation patients co-medicated with non-vitamin K oral anticoagulants and antipsychotics. Front Pharmacol 2022; 13:819878.
Cam B, et al. [Clozapine and olanzapine associated atrial fibrillation: a case report]. Turk Psikiyatri Dergisi 2015; 26:221–226.
Low Jr, RA, et al. Clozapine induced atrial fibrillation. J Clin Psychopharmacol 1998; 18:170.
Waters BM, et al. Olanzapine-associated new-onset atrial fibrillation. J Clin Psychopharmacol 2008; 28:354–355.
Yaylaci S, et al. Atrial fibrillation due to olanzapine overdose. Clin Toxicol (Phila) 2011; 49:440. Condition Suggested drugs Drugs to avoid Anxiety disorders (anxiety symptoms increase risk of AF)45 Benzodiazepines (although a 2022 cohort study found a hugely increased risk of incident AF in benzodiazepine users46) SSRIs (see above) Tricyclics (see above) Several reported cases of pregabalin- and gabapentin-associated AF47,48 and one cohort study suggested increased risk of AF49 with both drugs Promethazine may increase the risk of being hospitalised with AF50 Alzheimer’s disease Acetylcholinesterase inhibitors (but beware bradycardic effects in patients with paroxysmal ’vagal’ AF [paroxysmal AF provoked by low heart rate]) Rivastigmine has least interaction potential Memantine may be able to prevent and terminate AF51 Avoid cholinesterase inhibitors in paroxysmal ‘vagal’ AF AV, atrioventricular; DOACs, direct-acting oral anticoagulants. Table 10.15 (Continued)

848 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 19. D’Urso G, et al. Aripiprazole-induced atrial fibrillation in a patient with concomitant risk factors. Exp Clin Psychopharmacol 2018; 26:509–513. 20. Stefatos A, et al. Atrial fibrillation and injected aripiprazole: a case report. Innov Clin Neurosci 2018; 15:43–45. 21. Schneider RA, et al. Apparent seizure and atrial fibrillation associated with paliperidone. Am J Health Syst Pharm 2008; 65:2122–2125. 22. Zeng J, et al. Metabolic disorder caused by antipsychotic treatment may facilitate the development of atrial fibrillation. Int J Cardiol 2017; 239:14. 23. Polcwiartek C, et al. Electrocardiogram characteristics and their association with psychotropic drugs among patients with schizophrenia. Schizophr Bull 2020; 46:354–362. 24. Davutoglu V, et al. Valproic acid as a cause of transient atrio-ventricular conduction block episodes. J Atr Fibrillation 2017; 9:1520. 25. Kalcik MDM, et al. Acute atrial fibrillation as an unusual form of cardiotoxicity in chronic lithium overdose. J Atr Fibrillation 2014; 6:1009. 26. Acharya S, et al. Lithium-induced cardiotoxicity: a rare clinical entity. Cureus 2020; 12:e7286. 27. Lange HW, et al. Depressive symptoms predict recurrence of atrial fibrillation after cardioversion. J Psychosom Res 2007; 63:509–513. 28. Patel D, et al. A systematic review of depression and anxiety in patients with atrial fibrillation: the mind-heart link. Cardiovasc Psychiatry Neurol 2013; 2013:159850. 29. Quinn GR, et al. Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin. Am J Cardiol 2014; 114:583–586. 30. Komen JJ, et al. Concomitant anticoagulant and antidepressant therapy in atrial fibrillation patients and risk of stroke and bleeding. Clin Pharmacol Ther 2020; 107:287–294. 31. Pousti A, et al. Effect of sertraline on ouabain-induced arrhythmia in isolated guinea-pig atria. Depress Anxiety 2009; 26:E106–E110. 32. Pousti A, et al. Effect of citalopram on ouabain-induced arrhythmia in isolated guinea-pig atria. Hum Psychopharmacol 2003; 18:121–124. 33. Shirayama T, et al. Usefulness of paroxetine in depressed men with paroxysmal atrial fibrillation. Am J Cardiol 2006; 97:1749–1751. 34. Emul M, et al. The influences of depression and venlafaxine use at therapeutic doses on atrial conduction. J Psychopharmacol 2009; 23:163–167. 35. Finch SJ, et al. Cardioversion of persistent atrial arrhythmia after treatment with venlafaxine in successful management of major depression and posttraumatic stress disorder. Psychosomatics 2006; 47:533–536. 36. Shao IY, et al. Association of type of antidepressant initiation with bleeding risk in atrial fibrillation patients taking oral anticoagulants. Drugs Real World Outcomes 2021; 8:383–391. 37. Chang KH, et al. Major bleeding risk in patients with non-valvular atrial fibrillation concurrently taking direct oral anticoagulants and antidepressants. Front Aging Neurosci 2022; 14:791285. 38. Andrade C. Antidepressants and atrial fibrillation: the importance of resourceful statistical approaches to address confounding by indication. J Clin Psychiatry 2019; 80:19f12729. 39. Fenger-Grøn M, et al. Depression, antidepressants, and the risk of non-valvular atrial fibrillation: a nationwide Danish matched cohort study. Eur J Prevent Cardiol 2019; 26:187–195. 40. Taylor D. Antidepressant drugs and cardiovascular pathology: a clinical overview of effectiveness and safety. Acta Psychiatr Scand 2008; 118:434–442. 41. Moorehead CN, et al. Imipramine-induced auricular fibrillation. Am J Psychiatry 1965; 122:216–217. 42. Rosen BH. Case report of auricular fibrillation following the use of imipramine (Tofranil). J Mt Sinai Hosp NY 1960; 27:609–611. 43. Lapi F, et al. The use of antidepressants and the risk of chronic atrial fibrillation. J Clin Pharmacol 2015; 55:423–430. 44. Fu Y, et al. Association of depression, antidepressants with atrial fibrillation risk: a systemic review and meta-analysis. Front Cardiovasc Med 2022; 9:897622. 45. Eaker ED, et al. Tension and anxiety and the prediction of the 10-year incidence of coronary heart disease, atrial fibrillation, and total mortality: the Framingham Offspring Study. Psychosom Med 2005; 67:692–696. 46. Hu X, et al. Hypnotics use is associated with elevated incident atrial fibrillation: a propensity-score matched analysis of cohort study. J Pers Med 2022; 12:1645. 47. Chilkoti G, et al. Could pregabalin premedication predispose to perioperative atrial fibrillation in patients with sepsis? Saudi J Anaesth 2014; 8 Suppl 1:S115–S116. 48. Park SH, et al. Atrial fibrillation induced by gabapentin: a case report. J Med Case Rep 2023; 17:236. 49. Ortiz de Landaluce L, et al. Gabapentin and pregabalin and risk of atrial fibrillation in the elderly: a population-based cohort study in an electronic prescription database. Drug Saf 2018; 41:1325–1331. 50. Sessa M, et al. The risk of fractures, acute myocardial infarction, atrial fibrillation and ventricular arrhythmia in geriatric patients exposed to promethazine. Expert Opin Drug Saf 2020; 19:349–357. 51. Xie D, et al. Memantine targets glutamate receptors in atrial cardiomyocytes to prevent and treat atrial fibrillation. Cell Discov 2022; 8:76.

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52 - Bariatric surgery

Bariatric surgery

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Pharmacokinetic changes following bariatric surgery

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54 - Medication formulations5,6

Medication formulations5,6

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Bariatric surgery Psychiatric illness is relatively common in patients who have undergone bariatric surgery.1 Over a third of those seeking bariatric surgery are prescribed psychotropics.2 Bariatric surgery can be associated with clinically important changes in drug pharmacokinetics, although it is difficult to predict exactly how psychotropics will be affected because of interindividual differences and rather limited data. There is clearly a need for close treatment monitoring and the ongoing monitoring of symptoms after bariatric surgery.3 Surgical procedures can be classified as: ■ ■Predominantly restrictive: sleeve gastrectomy and gastric banding. ■ ■Predominantly malabsorptive: biliopancreatic diversion and jejunoileal bypass. ■ ■Mixed restrictive/malabsorptive: Roux-en-Y gastric bypass (RYGB) and gastric reduction duodenal switch (GRDS). Absorption following bariatric surgery is drug-specific and shows high variability among individuals. It can be affected by many factors including route of administration, dosage form, patient-specific factors, pharmacokinetic/pharmacodynamic considerations and type of surgery; it can be temporary or permanent.4,5 Malabsorptive procedures (including RYGB and GRDS) have a relatively greater potential to alter drug absorption. Most data are derived from studies of patients undergoing RYGB. It is not clear how these data relate to the consequences of other procedures. Pharmacokinetic changes following bariatric surgery All procedures may alter the following: ■ ■Tablet disintegration and dissolution times via changes in gastric pH and mixing. ■ ■Area for drug absorption (reduced gastric and/or functional intestinal surface area). ■ ■Rate of absorption via changes in the gastric emptying rate. ■ ■Drug distribution via loss of adipose tissue (especially lipid-soluble drugs) and altered protein binding. ■ ■Drug metabolism owing to improvements in hepatic function after weight loss. ■ ■Drug excretion via changes in renal function after weight loss. Malabsorptive surgical procedures may further lead to: ■ ■Changes in the availability of certain enzymes and transporters. ■ ■Altered lipophilic drug solubilisation (bypassing proximal small intestine bile salts). ■ ■Reduced intestinal wall drug metabolism via decreased intestinal length. Medication formulations5,6 Any formulation that prolongs drug disintegration or dissolution can potentially impair drug absorption following bariatric surgery. Switching to immediate-release formulations before surgery is generally recommended. Orodispersible and liquid preparations do not go through a disintegration phase, and may be preferred if reduced absorption from solid tablets is suspected.7 Very large tablets (e.g. over 10mm in diameter) should be avoided as passage may be impeded by restrictive procedures.

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55 - Antidepressants

Antidepressants

850 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Antidepressants Table 10.16 summarises the use of antidepressants in bariatric surgery. Table 10.16 Antidepressants in bariatric surgery. Medication Specific evidence and considerations SSRIs4,8,9 Evidence demonstrates that plasma levels may be significantly reduced following RYGB or sleeve gastrectomy. The concentration of SSRIs may drop initially and then rebound within a few months; dose adjustments occurring in the immediate postoperative period might be temporary. Malabsorption has been implicated in cases of discontinuation symptoms and loss of efficacy. Sertraline and vortioxetine absorption appear to be the most affected and fluoxetine the least. SNRIs9–11 Suggest avoid duloxetine owing to significant reduction in levels and risk of discontinuation syndrome. The absorption of venlafaxine MR capsules seems not to be altered by RYGB Mirtazapine9,12–14 Plasma levels may be significantly reduced following RYGB or sleeve gastrectomy. Dose increase is often needed. Increased appetite and weight gain are possible. TCAs15,16 Single case report suggests therapeutic plasma levels can be achieved within usual dose range after RYGB. Plasma levels may be increased after significant weight loss. Consider monitoring levels and reducing dose. Agomelatine No data available on absorption after bariatric surgery. Follow general recommendations. Dextromethorphan and bupropion There are no studies of the combined formulation after bariatric surgery No pharmacokinetic changes after bariatric surgery were reported for dextromethorphan liquid in the short or long term.5,17 In an in vitro model bupropion was found to have a significantly higher dissolution after RYGB which may lead to increased bioavailability.18 Esketamine nasal spray19 Primarily absorbed via nasal mucosa. Problems after bariatric surgery are not expected. General summary ■ ■Antidepressants are the best-studied psychotropics in the bariatric population. Current evidence suggests that antidepressant absorption is reduced after surgery (though studies are mostly limited to SSRIs after RYGB). ■ ■Signs of reduced absorption may include the rapid development of discontinuation symptoms and later loss of efficacy. Patients should be made aware of discontinuation symptoms and signs of relapse and seek medical advice if they occur. ■ ■Patients require close monitoring as those at risk of reduced absorption cannot be reliably predicted. ■ ■The risk of gastric bleeds with bariatric surgery will probably be increased by serotonergic antidepressants. MR, modified release; RYGB, Roux-en-Y gastric bypass; TCAs, tricyclic antidepressants.

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Antipsychotics

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Antipsychotics Table 10.17 summarises the use of antipsychotics in bariatric surgery. Table 10.17 Antipsychotics in bariatric surgery. Medication Specific evidence and considerations Aripiprazole20 One case report of subtherapeutic levels post RYGB using aripiprazole tablets that became therapeutic on switching to suspension. Available as an LAI. Asenapine21 Primarily absorbed via oral mucosa. Problems after bariatric surgery are not expected One case report of successful use after RYGB. Brexpiprazole No data available on absorption after bariatric surgery Cariprazine No data available on absorption after bariatric surgery The absorption of oral contraceptives may be reduced after bariatric surgery.22 Therefore, to ensure highly effective contraception for women prescribed cariprazine, non-oral methods are recommended. Clozapine23–25 Two case reports of relapse after RYGB26 Take drug plasma levels before surgery and regularly monitor after. Constipation is common after surgery; the manufacturer recommends close monitoring and active treatment. Check smoking status (quitting before surgery is encouraged); adjust dose accordingly. Haloperidol27 Single case report suggests levels after RYGB are similar to those generally reported in the literature. Iloperidone No data available on absorption after bariatric surgery Lumateperone No data available on absorption after bariatric surgery Lurasidone Risk of reduced absorption with reduced or inconsistent calorific intake perioperatively. Must be taken with food for absorption (350kcal). One case report of relapse following GRDS. Significant reduction in bioavailability and peak serum concentration.28 One case report post-RYGB showed significant reduction in plasma concentration with no worsening of psychotic symptoms.29 Consider switching to alternatives before surgery. Olanzapine One report of reduction in dose-adjusted drug concentration following bariatric surgery30 One case report following RYGB of continued efficacy with no dose adjustment required31 In an in vitro model olanzapine was found to have a significantly lower dissolution after RYGB which may lead to decreased bioavailability.32 Follow general recommendations. Quetiapine7,30,33 Dose-adjusted concentrations decreased following bariatric surgery. Switching to immediate-release preparation and dividing doses above 300mg has been recommended. Risperidone34 Consider switching stable patients to an equivalent dose of paliperidone LAI. Risperidone LAI has been used successfully when oral treatment was not tolerated after bariatric surgery. Ziprasidone35 Must be taken with food for absorption (500kcal); risk of reduced absorption with reduced/inconsistent calorific intake perioperatively. Consider switching to alternatives before surgery. (Continued )

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Mood stabilisers

852 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Mood stabilisers Table 10.18 summarises the use of mood stabilisers in bariatric surgery. General summary ■ ■Antipsychotics are not well studied in bariatric surgery. Data are limited to case reports or theoretical concerns. ■ ■Monitor for decreased efficacy. Adjust dose accordingly or consider switching to another antipsychotic. ■ ■Depot antipsychotics avoid the risk of reduced absorption after surgery. Given the limited data on pharmacokinetic changes after surgery and interindividual variability, routinely switching to depot antipsychotics before surgery may not be justified.7 However, depot preparations remain an option for those stabilised on treatment available as a depot or in patients demonstrating signs of reduced bioavailability after surgery. ■ ■Bariatric surgery may contribute additional cardiac stressors to patients with QT prolongation.36 ECG monitoring before and after surgery is recommended. GRDS, gastric reduction duodenal switch; LAI, long-acting injection; RYGB, Roux-en-Y gastric bypass. Table 10.17 (Continued) Table 10.18 Mood stabilisers in bariatric surgery. Medication Summary of evidence and considerations Carbamazepine Carbamazepine CR levels have been observed to both increase and decrease following bariatric surgery.37 In a case series of eight following sleeve gastrectomy, levels were found to be reduced in half the cases, with two resulting in deterioration of previously well-controlled illness. One case had increased levels.38 Single case report of agranulocytosis possibly related to increased plasma levels after sleeve gastrectomy.38 Baseline plasma carbamazepine levels, FBC, renal function and LFTs with ongoing monitoring recommended.38 Lamotrigine38 Increased, decreased or unchanged lamotrigine levels after bariatric surgery are all possible; monitor for adverse effects and loss of efficacy. Lithium39,40 (see below) Cases of lithium toxicity following RYGB and sleeve gastrectomy have been reported. Switch to an equivalent dose of lithium citrate solution in divided doses. In the preoperative period, plasma levels may be affected by prescribed dietary changes. In the postoperative period, plasma levels may be affected by malabsorption (mainly absorbed via small intestine), fluid shifts and weight loss (lithium clearance increased in obesity). Valproate7,41,42 Single case report suggests that absorption may be significantly reduced after malabsorptive procedures; no data on restrictive procedures. Dose reductions may be necessary after weight loss (plasma levels related to body weight). Switch to liquid preparation before surgery or if malabsorption suspected on enteric-coated tablets. Avoid CR preparations. Baseline plasma valproate levels, FBC and LFTs with ongoing monitoring recommended. Monitor for clinical signs of poor tolerability, possibly occurring at normal plasma levels. General summary ■ ■The literature on mood stabilisers after bariatric surgery is limited to a few case reports; the use of lithium requires particular care owing to its narrow therapeutic index. ■ ■The absorption of oral contraceptives may be reduced after bariatric surgery.22 In patients prescribed teratogenic mood stabilisers, non-oral methods of contraception are recommended. CR, controlled release; FBC, full blood count; LFTs, liver function tests; RYGB, Roux-en-Y gastric bypass.

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Lithium around the time of bariatric surgery

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59 - Other medicines

Other medicines

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Lithium around the time of bariatric surgery The continued use of lithium throughout the perioperative phases of bariatric surgery requires particularly close monitoring. The following guidance is based on available case reports and expert opinion.40 ■ ■Monitor lithium plasma levels preoperatively and perform a scale-based clinical assessment of mood. ■ ■Educate the patient preoperatively on the importance of drinking 2.5–3 litres of fluid per day (including liquid meal replacement). ■ ■Postoperatively assess for toxicity by monitoring lithium plasma levels and renal function weekly for 6 weeks (as fluid intake gradually increases), 2-weekly for 6 months and monthly thereafter. Resume usual lithium monitoring 1 year post- bariatric surgery. ■ ■If plasma levels increase by >25% or approach 1.2mmol/L consider decreasing the lithium dose. ■ ■Withhold lithium if signs of toxicity are present and review the dose. ■ ■To prevent dehydration, counsel the patient to alert their physician or psychiatrist in case of any changes in food or fluid intake or severe vomiting. ■ ■Monitor mental state periodically, using formal rating scales if possible. Other medicines Table 10.19 summarises the use of other medicines in bariatric surgery. Table 10.19 Miscellaneous agents in bariatric surgery. Medication Summary of evidence and considerations Antimuscarinics No data available on absorption after bariatric surgery Benzodiazepines43–46 Bioavailability probably unaffected, shorter time to peak concentration Lisdexamfetamine47 A single-dose case–control study found no significant differences in lisdexamfetamine and active metabolite d-amfetamine following RYGB compared to non-surgical controls. Due to potential for interindividual differences, monitor for adverse effects and loss of efficacy. Methadone48 Substantial increase in bioavailability after sleeve gastrectomy in one case report, possibly related increased rate of gastric emptying; consider plasma level and QT monitoring Methylphenidate49,50 Conflicting limited data; one case report of reduced treatment efficacy after RYGB that resolved after switching to transdermal patch suggesting reduced oral bioavailability; another reported signs of toxicity Modafinil No data available on absorption after bariatric surgery Orexin antagonists No data available on absorption after bariatric surgery Pregabalin17 Increased levels shortly after surgery and decreased values in the long term post-surgery; monitor for adverse effects and loss of efficacy Solriamfetol No data available on absorption after bariatric surgery Zolpidem In an in vitro model found to have non-significant lower dissolution after RYGB.32 Food delays the onset of effect; take on an empty stomach.51 RYGB, Roux-en-Y gastric bypass.

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60 - General recommendations

General recommendations

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61 - Psychotropics with a risk of weight gain afte

Psychotropics with a risk of weight gain after bariatric surgery

854 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 General recommendations Box 10.5 outlines the general recommendations for prescribing in bariatric surgery, while Box 10.6 summarises the strategies used in patients who show signs of reduced bioavailability. Psychotropics with a risk of weight gain after bariatric surgery Around 70% of patients regain a significant amount of weight (more than 10% of lowest postoperative weight) within 5 years of bariatric surgery.52 There has been conflicting information on how psychotropics affect weight loss outcomes after surgery. One study reported no significant differences in total weight loss 1 year post-surgery between those on psychotropics and those not.2 Another reported that treatment with antidepressants, particularly SNRIs and TCAs, was associated with reduced weight loss after gastric bypass surgery53 and another found that those on obesogenic medications lost statistically significantly less excess weight than controls.54 Medicines with a high risk of weight gain should be avoided where possible. Binge eating disorder, problematic alcohol use and depressive symptoms are associated with postoperative weight gain.52 Box 10.6 General management strategies for patients demonstrating signs of reduced bioavailability ■ ■Consider non-oral routes of administration where available (e.g. depots for patients stable on antipsychotics) ■ ■Dividing doses may improve malabsorption related to a reduced stomach capacity after surgery ■ ■Switching modified/prolonged/delayed-release to immediate-release formulations ■ ■Switching solid tablets to liquid or orodispersible preparations to bypass disintegration phase ■ ■Switching large tablets to smaller ones ■ ■In cases where doses have been increased to account for reduced bioavailability, monitor for emergent adverse effects as bioavailability may normalise over time Box 10.5 General recommendations for prescribing in bariatric surgery7,14 Before surgery ■ ■Do not routinely increase doses; clinically relevant malabsorption cannot be reliably predicted ■ ■Assess mental state before surgery using validated scales and consider measuring baseline drug plasma levels ■ ■Switch modified-release/ enteric-coated preparations to immediate-release tablets or to liquid preparations After surgery (0–6 weeks) ■ ■Assess mental state using validated scales ■ ■Closely monitor for signs of adverse effects and drug malabsorption (symptom re-emergence, discontinuation symptoms) ■ ■Regularly monitor drug plasma levels if clinically indicated ■ ■If malabsorption suspected consider the recommended strategies ■ ■If medication toxicity suspected withhold and reassess dose After surgery (>6 weeks after) ■ ■Continue regular monitoring for the first year postoperatively using validated scales, although frequency can be reduced if stable ■ ■Monitor for an increase in adverse effects, especially if doses were increased in the acute postoperative period ■ ■Consider returning to pre-surgical treatment regimen after 1 year (depending on clinical history)

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62 - Alcohol55,56

Alcohol55,56

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63 - Wider considerations14,57

Wider considerations14,57

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64 - References

References

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Alcohol55,56 Gastric bypass surgery is associated with accelerated alcohol absorption, higher maximum alcohol concentrations and a longer time to elimination. There is also an increased risk of alcohol misuse disorders after gastric bypass. Data are less clear for sleeve gastrectomy and there is no evidence that gastric banding leads to any changes. Wider considerations14,57 Despite severe mental illness often being considered a contraindication for bariatric surgery it has been shown to be effective in those with schizophrenia and bipolar affective disorder. Because of the variability of pharmacokinetic changes of psychiatric medicines, it is important to monitor patients closely for adverse effects and loss of efficacy, and medicines should be adjusted accordingly if required. Significant improvements in mental health are well documented following surgery, however deterioration can also occur. Depression and/or eating disorders may persist, re-emerge or newly develop and there is an increased risk of self-harm, suicide, alcohol disorder and opioid misuse following bariatric surgery. References

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Gondek W. Psychiatric suitability assessment for bariatric surgery. In: Sockalingam S, Hawa R, eds. Psychiatric Care in Severe Obesity: An Interdisciplinary Guide to Integrated Care. Cham: Springer International Publishing; 2017:173–186.
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Bingham KS, et al. Psychopharmacology in bariatric surgery patients. In: Sockalingam S, Hawa R, eds. Psychiatric Care in Severe Obesity: An Interdisciplinary Guide to Integrated Care. Cham: Springer International Publishing; 2017:313–333.
Pasi P, et al. Plasma concentrations of SSRI/SNRI after bariatric surgery and the effects on depressive symptoms. Front Psychiatry 2023; 14:1132112.
Maass D, et al. Changes in serum concentration of antidepressants after bariatric surgery and recommendations for postbariatric surgery antidepressant therapy. J Acad Consult Liaison Psychiatry 2024; 65:261–270.
Roerig JL, et al. A comparison of duloxetine plasma levels in postbariatric surgery patients versus matched nonsurgical control subjects. J Clin Psychopharmacol 2013; 33:479–484.
Hamad GG, et al. The effect of gastric bypass on the pharmacokinetics of serotonin reuptake inhibitors. Am J Psychiatry 2012; 169:256–263.
Teixeira FV, et al. Mirtazapine (Remeron) as treatment for non-mechanical vomiting after gastric bypass. Obes Surg 2005; 15:707–709.
Huerta S, et al. Intractable nausea and vomiting following Roux-en-Y gastric bypass: role of mirtazapine. Obes Surg 2006; 16:1399.
Coughlin JW, et al. Psychotropic medications in metabolic and bariatric surgery: research updates and clinical considerations. Curr Psychiatry Rep 2022; 24:89–98.
Broyles JE, et al. Nortriptyline absorption in short bowel syndrome. J Parenter Enteral Nutr 1990; 14:326–327.
Jobson K, et al. Weight loss and a concomitant change in plasma tricyclic levels. Am J Psychiatry 1978; 135:237–238.
Lau C, et al. Impact of bariatric surgery in the short and long term: a need for time-dependent dosing of drugs. Obes Surg 2023; 33:3266–3302.
Konstantinidou SK, et al. The effects of bariatric surgery on pharmacokinetics of drugs: a review of current evidence. Curr Nutr Rep 2023; 12:695–708.
Jannsen-Cilag Ltd. Summary of product characteristics. Spravato 28mg nasal spray, solution. 2024 (last accessed August 2024); https://www. medicines.org.uk/emc/product/10977/smpc.
Kuzin M, et al. Switching from aripiprazole tablets to oral suspension in a patient with Roux-en-Y gastric bypass: a case report. J Clin Psychopharmacol 2023; 43:300–302.
Tabaac BJ, et al. Pica patient, status post gastric bypass, improves with change in medication regimen. Ther Adv Psychopharmacol 2015; 5:38–42.
Merhi ZO. Challenging oral contraception after weight loss by bariatric surgery. Gynecol Obstet Investig 2007; 64:100–102.

856 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 23. Kaltsounis J, et al. Intravenous valproate treatment of severe manic symptoms after gastric bypass surgery: a case report. Psychosomatics 2000; 41:454–456. 24. Afshar S, et al. The effects of bariatric procedures on bowel habit. Obes Surg 2016; 26:2348–2354. 25. Leyden Delta BV. Summary of product characteristics. Zaponex 100mg tablets. 2020 (last accessed August 2024); https://www.medicines.org. uk/emc/product/7715/smpc. 26. Mahgoub Y, et al. Schizoaffective exacerbation in a Roux-en-Y gastric bypass patient maintained on clozapine. Prim Care Companion CNS Disord 2019; 21:19l02462. 27. Fuller AK, et al. Haloperidol pharmacokinetics following gastric bypass surgery. J Clin Psychopharmacol 1986; 6:376–378. 28. Ward HB, et al. Lurasidone malabsorption following bariatric surgery: a case report. J Psychiatr Pract 2019; 25:313–317. 29. McGrane IR, et al. Roux-en-Y gastric bypass and antipsychotic therapeutic drug monitoring: two cases. J Pharm Pract 2021; 34:503–506. 30. Wallerstedt SM, et al. Serum concentrations of antidepressants, antipsychotics, and antiepileptics over the bariatric surgery procedure. Eur J Clin Pharmacol 2021; 77:1875–1885. 31. Brito ME, et al. Patients with schizophrenia undergoing gastric bypass surgery: a case series study. Obes Surg 2020; 30:3813–3821. 32. Seaman JS, et al. Dissolution of common psychiatric medications in a Roux-en-Y gastric bypass model. Psychosomatics 2005; 46:250–253. 33. Miller AD, et al. Medication and nutrient administration considerations after bariatric surgery. Am J Health Syst Pharm 2006; 63:1852–1857. 34. Brietzke E, et al. Long-acting injectable risperidone in a bipolar patient submitted to bariatric surgery and intolerant to conventional mood stabilizers. Psychiatry Clin Neurosci 2011; 65:205. 35. Gandelman K, et al. The impact of calories and fat content of meals on oral ziprasidone absorption: a randomized, open-label, crossover trial. J Clin Psychiatry 2009; 70:58–62. 36. Woodard G, et al. Cardiac arrest during laparoscopic Roux-en-Y gastric bypass in a bariatric patient with drug-associated long QT syndrome. Obes Surg 2011; 21:134–137. 37. Triplett JD, et al. The effect of weight reduction surgery on the efficacy and tolerability of epilepsy pharmacotherapy. Epilepsy Behav 2021; 124:108307. 38. Porat D, et al. Carbamazepine therapy after bariatric surgery: eight sleeve gastrectomy cases and review of the literature. 2022; 32:3481–3486. 39. Bingham KS, et al. Perioperative lithium use in bariatric surgery: a case series and literature review. Psychosomatics 2016; 57:638–644. 40. Ayub S, et al. Lithium toxicity following Roux-en-Y gastric bypass: mini review and illustrative case. Ment Health Clin 2022; 12:214–218. 41. Dahan A, et al. Lithium toxicity with severe bradycardia post sleeve gastrectomy: a case report and review of the literature. Obes Surg 2019; 29:735–738. 42. Brown CS, et al. Antiseizure medication use in gastric bypass patients and other post-surgical malabsorptive states. Epilepsy Behav Rep 2021; 16:100439. 43. Tandra S, et al. Pharmacokinetic and pharmacodynamic alterations in the Roux-en-Y gastric bypass recipients. Ann Surg 2013; 258:262–269. 44. Chan LN, et al. Proximal Roux-en-Y gastric bypass alters drug absorption pattern but not systemic exposure of CYP3A4 and P-glycoprotein substrates. Pharmacotherapy 2015; 35:361–369. 45. Brill MJ, et al. The pharmacokinetics of the CYP3A substrate midazolam in morbidly obese patients before and one year after bariatric surgery. Pharm Res 2015; 32:3927–3936. 46. Ochs HR, et al. Diazepam absorption: effects of age, sex, and Billroth gastrectomy. Dig Dis Sci 1982; 27:225–230. 47. Steffen KJ, et al. Lisdexamfetamine pharmacokinetic comparison between patients who underwent Roux-en-Y gastric bypass and nonsurgical controls. Obes Surg 2021; 31:4289–4294. 48. Strømmen M, et al. Bioavailability of methadone after sleeve gastrectomy: a planned case observation. Clin Ther 2016; 38:1532–1536. 49. Azran C, et al. Impaired oral absorption of methylphenidate after Roux-en-Y gastric bypass. Surg Obes Relat Dis 2017; 13:1245–1247. 50. Ludvigsson M, et al. Methylphenidate toxicity after Roux-en-Y gastric bypass. Surg Obes Relat Dis 2016; 12:e55–e57. 51. Greenblatt DJ, et al. Influence of food on pharmacokinetics of zolpidem from fast dissolving sublingual zolpidem tartrate tablets. J Clin Pharmacol 2013; 53:1194–1198. 52. Noria SF, et al. Weight regain after bariatric surgery: scope of the problem, causes, prevention, and treatment. Curr Diab Rep 2023; 23:31–42. 53. Plaeke P, et al. Postoperative continuation of antidepressant therapy is associated with reduced short-term weight loss following Roux-en-Y gastric bypass surgery. Langenbecks Arch Surg 2019; 404:621–631. 54. Leggett CB, et al. The effects of provider-prescribed obesogenic drugs on post-laparoscopic sleeve gastrectomy outcomes: a retrospective cohort study. Int J Obes 2019; 43:1154–1163. 55. Ivezaj V, et al. Changes in alcohol use after metabolic and bariatric surgery: predictors and mechanisms. Curr Psychiatry Rep 2019; 21:85. 56. Parikh M, et al. ASMBS position statement on alcohol use before and after bariatric surgery. Surg Obes Relat Dis 2016; 12:225–230. 57. Stogios N, et al. Antipsychotic-induced weight gain in severe mental illness: risk factors and special considerations. Curr Psychiatry Rep 2023; 25:707–721.

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65 - Menopause

Menopause

15 - Chapter 10 Drug treatment of psychiatric symptoms

66 - Diagnosis

Diagnosis

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Menopause The menopause transition is a phase in a woman’s reproductive life where ovarian function declines, menstruation stops and production of the female reproductive hormones oestrogen, progesterone and testosterone significantly declines. The menopause signifies a date in time 12 months after a women’s last menstrual period (LMP). The normal age range for the menopause is 45–55 years. The perimenopause is the phase leading up to a women’s LMP characterised by erratic ovarian function and fluctuations in hormones. Perimenopausal symptoms typically arise 2–7 years prior to the LMP. About 75% of women experience menopausal symptoms (Table 10.20), 25% of women experience severe menopausal symptoms and 20% of women experience life- long symptoms.1,2 Symptoms associated with the menopause should be considered in women older than 40. However, women may experience an early menopause before 45 years of age, or premature ovarian insufficiency (POI) below 40 years of age, so symptoms may present earlier. Diagnosis Clinical diagnosis using the Greene Climacteric questionnaire is sufficient in most women older than 40 years presenting with typical symptoms. In women younger than 45 years, two raised follicle-stimulating hormone (FSH) levels >30mIU/mL, taken 6 weeks apart, tested on days 2–5 of the menstrual cycle may help confirm a diagnosis if clinical symptoms are not conclusive.1,3 Table 10.20 Menopause symptoms. Vasomotor Physical Genitourinary Psychological Hot flushes/flashes Sleep disturbance Urinary frequency Anxiety Night sweats Muscular aches and pains Nocturia Low mood Excessive sweating Period changes – flow, duration, frequency Vaginal dryness/irritation Loss of motivation Cold chills Headaches/migraines Weight gain Tinnitus Breast tenderness Heart palpitations Acne Fatigue and low energy Vulval itching and irritation Frequent UTIs Low libido Loss of sexual pleasure Vaginal discomfort Mood swings Tearfulness Increased PMS Poor concentration and focus Brain fog Poor word-finding and short-term memory Irritability PMS, premenstrual syndrome; UTIs, urinary tract infections.

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67 - Psychological symptoms of the menopause

Psychological symptoms of the menopause

858 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Psychological symptoms of the menopause Depression and anxiety The impact of the menopause on mental well-being is significant. Suicidal ideation is present in around 6% of women experiencing menopause-related psychological symptoms. There is a 2–5-fold increase in the risk of depression during the perimenopause.4 Hormone replacement therapy (HRT) is first-line treatment for menopausal insomnia, anxiety and depression.1 Psychosis The decline in production of protective oestrogens is thought to be the reason that women show an increased risk of psychosis later in life (particularly at menopause) that is not observed in men, with one study suggesting that first hospital admission rates for psychosis are twice as high in women (21%) than in men (10%) after the age of 40. Pharmacodynamics Oestrogen is thought to have complex effects on dopamine transmission and receptor sensitivity, as well as antipsychotic binding. Human positron emission tomography (PET) studies have revealed that women have more D2 receptors in the brain compared with men. As oestrogen is thought to enhance antipsychotic binding affinity to these receptors, declining oestrogen levels in menopause serve to reduce antipsychotic activity.5–7 Consequently, many women require higher doses of antipsychotic medication after menopause to maintain previous effect.8 Pharmacokinetics Gender variations in the pharmacokinetics of psychotropic drugs are often not considered but may play an important role in drug efficacy and adverse effects. Factors such as gastrointestinal transit time, drug distribution of lipophilic drugs (e.g. antipsychotics) and drug elimination can vary with age and with hormonal changes seen during and after menopause.9 Oestrogen and progesterone can decrease levels of glycoproteins responsible for binding to antipsychotic drugs. Declining levels of these hormones may therefore result in less free drug entering the brain.9 Oestrogens are also thought to influence the activity and expression of some of the enzymes responsible for the hepatic metabolism of antipsychotics, i.e. oestrogens can induce and inhibit CYP isoenzymes (Table 10.21).9 Alternative treatments and drug interactions Polypharmacy in menopausal women is common, with many women using alternative treatments (such as herbal remedies) to address menopausal symptoms. It is important that drug interactions are ruled out when prescribing antipsychotic medication.10 The use of several medications, for example for sleep, pain and depression, may also affect protein binding of concurrent antipsychotics leading to changes in the ability for certain drugs to enter the brain.5

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Long-acting injections (LAIs) Switching to an antipsychotic depot may improve levels of drugs that are mainly hepatically metabolised by CYP enzymes, as first-pass metabolism is avoided.6 The use of antipsychotic depot injections should be considered if oral medications appear to lose efficacy in menopause.10 Longer dosage intervals for LAIs may be beneficial in menopause as older women tend to eliminate drugs more slowly than their male counterparts.12 Risk of adverse effects Increasing age coupled with oestrogen loss in menopause can make women more vulnerable to antipsychotic-related adverse effects. Older women are more vulnerable to QTc prolongation and motor symptoms (parkinsonism, akathisia and tardive dyskinesia) and therefore it is best to avoid antipsychotic drugs that may worsen these adverse effects.8 Increased adiposity in menopause may be associated with a heightened risk for Table 10.21 Summary of antipsychotic/oestrogen interactions.5,8,11 Isoenzyme Substrates Effect of oestrogen on enzyme activity Recommendations CYP1A2 Clozapine, olanzapine Inhibits Oestrogen is thought to inhibit/reduce CYP1A2 activity and thus doses of antipsychotics that are mainly metabolised by this isoenzyme may need to be increased at menopause. Extra care should be given to antipsychotic dosing in menopausal women who smoke. CYP3A4 Aripiprazole, quetiapine, lurasidone Induces Women generally have a higher expression of CYP3A4 enzyme than men, and menopause may cause reduced expression of this enzyme. High levels of oestrogen in pregnancy are thought to increase the metabolism via CYP3A4, further suggesting that oestrogen (and progesterone) play a role in rate of hepatic drug metabolism. Lower doses of CYP3A4-metabolised antipsychotics may be required in menopause, particularly if onset of menopause causes an increase in adverse effects. CYP2D6 Aripiprazole, haloperidol, risperidone, zuclopenthixol Possibly induces CYP2D6 activity is generally higher in women than men. The clinical relevance of increased activity may be small, particularly as there may be genetic variations in the CYP2D6 gene. Some evidence suggests that doses of aripiprazole may require lowering at menopause (this may also be because it is metabolised by CYP3A4). CYP2C19 Clozapine (minor route) Possibly inhibits Females reportedly have a 40% lower enzyme activity than men. This difference is thought to be most pronounced from 18 to 40 years (generally prior to onset of menopause). As stated previously, clozapine doses may need to be higher in menopausal women, however this needs to be balanced against risk of adverse effects. More regular therapeutic drug monitoring may be required.

860 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 adverse effects such as insulin resistance, diabetes, sleep apnoea, cardiovascular disease and hypertriglyceridaemia.13 Prolactin levels Persistently high prolactin levels may cause hypo-oestrogenic states and subsequently induce iatrogenic menopause.12 This may worsen psychotic symptoms and cognition5 as well as further increase the risk of osteoporosis in an already vulnerable group.8,13 There is some evidence to suggest that high prolactin levels can also increase the risk of breast cancer.13 Genitourinary problems and sexual dysfunction (including diminished libido) are issues that can be troublesome due to menopause and can be further worsened by hyperprolactinaemia.12 It is important to note that hormones other than prolactin and oestrogen (e.g. progesterone) may play a potentially key role when considering antipsychotic use in menopause, although further research is required in this area.5 Oestrogen augmentation for psychosis Treatment with adjunct oestrogenic medications may be beneficial in helping to relieve menopausal symptoms as well as improving psychotic symptoms and increasing the efficacy of antipsychotic drugs.8 Recent meta-analyses have shown that selective oestrogen receptor modulators (SERMs) such as raloxifene (60–120mg/day) are a safe and effective adjunct for treating schizophrenia in menopausal women.14 Raloxifene may be more suitable for long-term use than HRT as it has oestrogenic effects on the brain and bone tissue but anti-oestrogenic effects on other tissues such as the breast and uterus (therefore reducing the risk of breast and uterine cancer).8,15 Both HRT and SERMs may increase the risk of venous thromboembolism (VTE)16 and so potential risks and benefits of using these drugs as oestrogen-augmenting agents should be balanced individually, for example oestrogen replacement therapy may not be appropriate for those with a history of thromboembolic conditions.8 The preferred options for treating menopausal women with antipsychotic medications are summarised in Box 10.7. Box 10.7 Summary of preferred antipsychotic options for menopausal women8,12 First option(s): aripiprazole, lurasidone Second option(s): olanzapine, quetiapine, clozapine Avoid where possible: amisulpride, risperidone, paliperidone and FGAs Monitor: weight, bone mineral density, blood pressure, blood glucose, cholesterol and prolactin levels (especially if using prolactin-raising antipsychotics); therapeutic drug monitoring – due to hormonal fluctuations17 ■ ■Consider augmentation with raloxifene or HRT at an early stage, i.e. at the beginning of menopause/perimenopausal stage, where appropriate15,18 ■ ■If the efficacy of previously effective antipsychotic doses wanes at menopause, review the drug dose ■ ■Be mindful of the risk of dose-related adverse effects such as weight gain and cardiovascular and cerebrovascular events6 ■ ■Switching to prolactin-sparing medications can benefit both mental and physical health13 ■ ■Consider adding anti-diabetic drugs (where appropriate) such as metformin which may help to prevent excess weight gain19 ■ ■Consider using LAIs as an option if oral medication becomes ineffective6 HRT, hormone replacement therapy; LAIs, long-acting injections.

15 - Chapter 10 Drug treatment of psychiatric symptoms

68 - Elderly care

Elderly care

15 - Chapter 10 Drug treatment of psychiatric symptoms

69 - Use of HRT

Use of HRT

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Elderly care Genitourinary symptoms of menopause (GSM) may be a factor in agitation and aggression in elderly care. Consider vaginal atrophy and localised vaginal oestrogen or ospemifene use in women presenting with GSM symptoms, recurrent urinary tract infections, recurrent candida, urinary leakage and vaginal discomfort.20,21 Use of HRT For most women, HRT is a very safe and effective first-line option for treatment of menopausal symptoms, reducing osteoporosis and cardiovascular disease risk,21–23 although there are some contraindications and precautions to its use (Table 10.22). Treatment options 1 Perimenopause: sequential combined HRT (oestrogen + progesterone cover in luteal phase for 12–14 days of cycle) ± localised vaginal oestrogen, and testosterone (Table 10.23). 2 Post menopause: continuous combined HRT (oestrogen + progesterone) ± local vaginal oestrogen, and testosterone (Table 10.23). Combined HRT – oestrogen and progesterone – is required in all women except those who have had a total hysterectomy who may have oestrogen-only treatment. Oral oestrogen imposes a small increase in thrombus risk and therefore transdermal oestrogen is preferred when there is an increased risk of VTE or stroke.1,23 Table 10.22 Summary of the risks of using hormone replacement therapy (HRT). Contraindications to HRT use Precautions for HRT use Risks Oestrogen-dependent malignant tumours Undiagnosed vaginal bleeding Pregnancy Active liver disease with abnormal LFTs Active or recent thromboembolic disorder (angina/MI) Active or idiopathic VTE untreated Untreated endometrial hyperplasia Symptomatic fibroids Untreated hypertension Migraine with aura – clot risk Epilepsy – lamotrigine interaction Endometriosis – choice of HRT important VTE/stroke – choice of HRT important Heart disease – choice of HRT important Endometrial hyperplasia and cancer Clot risk – dependent on type of HRT Breast cancer risk – small increased risk for women over 50 years. Use patient counselling aided by WHC Irregular bleeding – see Table 10.25 Adverse effects – see Table 10.25 MI, myocardial infarction; VTE, venous thromboembolism; WHC, Women’s Health Concern.

862 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Local treatment options with GSM Additional topical treatment options when GSM symptoms are prominent are given in Table 10.24. Table 10.23 Hormone replacement therapy (HRT) products and regimens. Estradiol Progesterone Sequential combined HRT – perimenopause (prescribe by brand name) Patch: 25–100mcg twice weekly Micronised progesterone 200mg on, days 15–28 of cycle Estradiol gel 0.6mg/g: 1–4 pumps daily Progesterone 200mg on, days 15–28 of cycle Estradiol gel sachets: 0.5–1.5mg daily Medroxyprogesterone acetate 10mg od, days 16–27 of cycle Estradiol 1.53mg/spray: 1–3 sprays daily Levonorgestrel 52mg IUD Estradiol hemihydrate/valerate tablets: 1–2mg daily Combined products: ■ ■Estradiol hemihydrate 50mcg/24h and norethisterone acetate 11.2mg combined patch, used for 14/28 days, and estradiol 50mcg patch used for 14/28 days. Applied twice weekly ■ ■Estradiol 1mg/2mg with dydrogesterone 10mg tablets – calendar pack one daily ■ ■Estradiol 1mg/2mg with norethisterone 1mg tablets – calendar pack one daily Continuous combined HRT – post menopause (prescribe by brand name) Estradiol patch: 25–100mcg twice weekly Micronised progesterone 100mg on Estradiol gel 0.6mg/g: 1–4 pumps daily Progesterone 100mg on Estradiol gel sachets: 0.5–1.5mg daily Medroxyprogesterone acetate 2.5–5mg od Estradiol 1.53mg/spray: 1–3 sprays daily Levonorgestrel 52mg IUD Estradiol hemihydrate/valerate tablets: 1–2mg daily Combined products: ■ ■Estradiol hemihydrate 50mcg/24h and norethisterone acetate 11.2mg combined patch, applied twice weekly ■ ■Estradiol 0.5/1mg with 2.5/5mg dydrogesterone tablets: 1 od ■ ■Estradiol 2mg with 1mg norethisterone tablets: 1 od IUD, intrauterine device; od, once a day; on, every night. Table 10.24 Topical vaginal oestrogen or GSM treatment. Drug Dose Estradiol 10mcg vaginal tablets One pv daily for 14 days and then twice weekly Estriol 0.03mg pessary One pv daily for 21 days and then twice weekly Estriol 1mg cream 1 applicator daily for 4 weeks and then twice weekly Prasterone 6.5mg pessary One daily Ospemifene 60mg oral One daily with food GSM, genitorurinary symptoms of menopause; pv, per vagina.

15 - Chapter 10 Drug treatment of psychiatric symptoms

70 - References

References

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Starting treatment Start HRT at 25–50mcg estradiol patch dose equivalents (1mg estradiol tablet/1–2 pumps estradiol 0.6mg/g gel). Increase after 6–8 weeks if symptomatic. Higher doses of estradiol may require additional progesterone for endometrial protection.24 HRT is not a contraceptive. Management of adverse effects Table 10.25 outlines the management of the possible adverse effects of HRT. References

National Institute for Health and Care Excellence. Menopause: diagnosis and management. NICE guideline [NG23]. 2015 (last updated December 2019, last checked December 2023); https://www.nice.org.uk/guidance/ng23.
Avis NE, et al. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med 2015; 175:531–539.
Greene JG. Constructing a standard climacteric scale. Maturitas 1998; 29:25–31.
El Khoudary SR, et al. The menopause transition and women’s health at midlife: a progress report from the Study of Women’s Health Across the Nation (SWAN). Menopause 2019; 26:1213–1227.
González-Rodríguez A, et al. The association between hormones and antipsychotic use: a focus on postpartum and menopausal women. Ther Adv Psychopharmacol 2019; 9:2045125319859973.
González-Rodríguez A, et al. The effect of menopause on antipsychotic response. Brain Sci 2022; 12:1342.
Brand BA, et al. Estrogens in schizophrenia: progress, current challenges and opportunities. Curr Opin Psychiatry 2021; 34:228–237.
Brand BA, et al. Antipsychotic medication for women with schizophrenia spectrum disorders. Psychol Med 2022; 52:649–663.
Seeman MV. Men and women respond differently to antipsychotic drugs. Neuropharmacology 2020; 163:107631.
Seeman MV. Treating schizophrenia at the time of menopause. Maturitas 2012; 72:117–120.
Choi SY, et al. Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos 2013; 41:263–269.
Lange B, et al. How gender affects the pharmacotherapeutic approach to treating psychosis – a systematic review. Expert Opin Pharmacother 2017; 18:351–362.
Brand BA, et al. Towards better care for women with schizophrenia-spectrum disorders. Lancet Psychiatry 2022; 9:330–336.
Li Z, et al. Estradiol and raloxifene as adjunctive treatment for women with schizophrenia: a meta-analysis of randomized, double-blind, placebo-controlled trials. Acta Psychiatr Scand 2023; 147:360–372.
Sommer IE, et al. Women with schizophrenia-spectrum disorders after menopause: a vulnerable group for relapse. Schizophr Bull 2022; 49:136–143. Table 10.25 Management of adverse effects of hormone replacement therapy (HRT). Adverse effect Comments Breast tenderness Bloating Spotting Common within first 3–6 months, or on dose adjustment, normally transient. Headaches Nausea Common in first 3 months of starting or dose increase. May need slower titration. Mood swings Increase in PMS symptoms Increased anxiety/agitation Often common when starting for first month, then transient. Consider progesterone intolerance if beyond 1 month or severe. Irregular bleeding Common for the first 3 months. Refer for investigation if after 4–6 months it has not settled or patient has been on HRT for a while and it is a new presentation. PMS, premenstrual syndrome.

864 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 16. González-Rodríguez A, et al. Women with schizophrenia over the life span: health promotion, treatment and outcomes. Int J Environ Res Public Health 2020; 17:5594. 17. Brand BA, et al. Evidence-based recommendations for the pharmacological treatment of women with schizophrenia spectrum disorders. Curr Psychiatry Rep 2023; 25:723–733. 18. Culbert KM, et al. Risk for midlife psychosis in women: critical gaps and opportunities in exploring perimenopause and ovarian hormones as mechanisms of risk. Psychol Med 2022; 52:1612–1620. 19. Seeman MV. Selecting the right treatment plan for schizophrenia in postmenopausal women: an update of the literature. Expert Rev Neurother 2023; 23:515–523. 20. Hamoda H, et al. The British Menopause Society and Women’s Health Concern 2020 recommendations on hormone replacement therapy in menopausal women. Post Reprod Health 2020; 26:181–209. 21. Chakrabarti R, et al. Prescribing hormone replacement therapy: key considerations for primary care physicians. Br J Gen Pract 2023; 73:330–332. 22. Weiss SR, et al. A randomized controlled trial of four doses of transdermal estradiol for preventing postmenopausal bone loss. Transdermal Estradiol Investigator Group. Obstet Gynecol 1999; 94:330–336. 23. Boardman HM, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev 2015; 2015:CD002229. 24. British Menopause Society (BMS). Progestogens and endometrial protection. BMS consensus statement. 2021; https://thebms.org.uk/wp- content/uploads/2021/10/14-BMS-TfC-Progestogens-and-endometrial-protection-01H.pdf.

16 - Chapter 11 Pharmacokinetics

01 - Plasma level monitoring of psychotropic drugs

Plasma level monitoring of psychotropic drugs

16 - Chapter 11 Pharmacokinetics

02 - First order pharmacokinetics

First-order pharmacokinetics

16 - Chapter 11 Pharmacokinetics

03 - Steady state

Steady state

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 11 Plasma level monitoring of psychotropic drugs The measurement of blood or plasma drug concentrations is widely known as therapeutic drug monitoring or TDM. It is often used in psychiatry but not always well used. The interpretation of drug concentrations (drug ‘levels’) is a complex process that requires a thorough understanding of pharmacokinetics. Some principles are outlined here. First-order pharmacokinetics The metabolism and excretion of most drugs follow first-order elimination kinetics. The key feature of this model is that clearance of a drug is constant when expressed in volume per unit time – usually L/h. The mass of drug cleared (metabolised or excreted) increases as blood concentration increases. For example, if clearance of a drug is 10L/h and the concentration is 5mg/L then 50mg (10×50mg) will be cleared in an hour. If the concentration increases to 10mg/L then 100mg will be cleared in an hour. The concept of first-order pharmacokinetics is important to the understanding of steady state. Steady state Repeated dosing of any drug that is not completely removed within the dosing interval will inevitably lead to accumulation. That is, the second dose will add to what remains of the first and the third dose will add to what remains of the first and second doses. As the drug concentration in the blood increases, the mass of the drug cleared will also rise, according to first-order principles. Eventually, a point is reached where blood levels remain stable within a specific peak-to-trough range – this is steady state. It is important Pharmacokinetics

16 - Chapter 11 Pharmacokinetics

04 - Timing of sampling

Timing of sampling

866 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 11 to know when a drug is or is not at steady state but there are two concepts connected to steady state that are often misunderstood. ■ ■Time to reach steady state follows a logarithmic pattern The time taken to reach steady state is dependent on the drug half-life – the time taken for concentration to fall by 50%. This table shows the rise to steady state. Number of half-lives % of steady state reached 75% 87.5% 94% 97% Most people know the adage that it takes four to five half-lives to reach steady state. In fact, three half-lives are sufficient for an approximation of steady state concentrations. ■ ■Steady state is not always related to therapeutic activity Blood levels at steady state are determined by dose and drug half-life. The concentration at which therapeutic activity occurs is fixed (see later) and, during therapeutic dosing, is often exceeded before steady state is reached. Loading doses are sometimes used to achieve therapeutic concentrations as quickly as possible. Loading doses do not hasten the achievement of steady state levels. Timing of sampling Sampling time is vitally important for many but not all drugs. If the recommended sampling time is, say, 12 hours post-dose, then the sample should be taken 11–13 hours post-dose if possible; 10–14 hours post-dose, if absolutely necessary. A study of clozapine samples taken 1 and 2 hours before and after the 12-hour scheduled sample time showed a mean variation of clozapine blood concentration of less than 10%, but some individuals’ levels varied by over 50%.1 So, if a sample is not taken within 1–2 hours of the required time, it has the potential to mislead rather than inform. Always try to take samples as close to the scheduled time as possible. Obviously, if toxicity is suspected, take a sample straightaway, ignoring any scheduled timings. For trough or ‘pre-dose’ samples, take the blood sample immediately before the next dose is due. Do not, under any circumstances, withhold the next dose for more than 1 or possibly 2 hours until the sample is taken. Withholding for longer than this will inevitably give a misleading result (it will give a lower result than that ever seen in the usual, regular dosing), and this may lead to an inappropriate dose increase. Sampling time is less critical with drugs with a long half-life (e.g. olanzapine, aripiprazole) but, as an absolute minimum, prescribers should always record the time of sampling and time of last dose. This cannot be emphasised enough, and is worth repeating in bold. Always record the time of sampling and the time of the last dose.

16 - Chapter 11 Pharmacokinetics

05 - Interpretation of results

Interpretation ofÂ results

16 - Chapter 11 Pharmacokinetics

06 - Target ranges

Target ranges

Pharmacokinetics CHAPTER 11 Interpretation of results Is there a target range of plasma levels? If so, then plasma levels (from samples taken at the right time) will usefully guide dosing. If there is not an accepted target range, plasma levels can only indicate adherence or potential toxicity. However, if the sample is being used to check compliance, then bear in mind that a plasma level of zero indicates only that the drug has not been taken in the past several days. Plasma levels above zero may indicate erratic compliance, full compliance or even long-standing non-compliance disguised by recent taking of prescribed doses. Note also that target ranges have their limitations – patients may respond to lower levels than the quoted range and tolerate levels above the range. Also, ranges quoted by different laboratories vary sometimes widely, often without explanation. This is discussed further later. The basic rule for sample level interpretation is to act upon assay results only in conjunction with reliable clinical observation (‘treat the patient, not the level’). For example, if a patient is responding adequately to a drug but has a plasma level below the accepted target range, then the dose should not normally be increased. If a patient has intolerable adverse effects but a plasma level within the target range, then a dose decrease may be appropriate. Where a plasma level result is substantially different from previous results, a repeat sample is usually advised. Check the dose, the timing of dose and recent compliance but ensure, in particular, the correct timing of the sample, or at the very least that the timing of sampling is known. Many anomalous results are the consequence of changes in sample timing. Target ranges In psychiatry, target ranges for psychotropic drug concentrations should be treated with some caution. Establishing a range of concentrations associated with response is made difficult by the presence in trials of non-responders (who show no response whatever the blood concentration) and by the presence of placebo responders and spontaneous remitters (who respond at any blood concentration). Establishing a target range based on adverse effects is made difficult by the development of tolerance over time. Thus, most studies aimed at determining target ranges have as much ‘noise’ as ‘signal’ and results ultimately represent broad approximations. Interestingly, drug concentrations associated with response in clinical practice show a fairly close correlation to published target ranges.2 The lower quartile (25th percentile) of drug concentrations is usually close to the lower end of the target range and the upper quartile (75th percentile) is around the value of, but usually less than, the upper limit. Broadly speaking, this means that around 25% of patients respond below the target range and up to 25% tolerate blood concentrations above the target range. The simplicity of published target ranges disguises considerable complexity. For most drugs, the concentration at which therapeutic activity appears is fairly constant across a population. This is called the therapeutic threshold – above it, full effect is seen, but below it, activity is lost. A good example here is risperidone where the threshold concentration of active moiety is 20mcg/L. Risperidone and paliperidone could reasonably be considered to have a target concentration rather than a target range of

868 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 11 concentrations. This concept of a therapeutic threshold is supported by neuroimaging studies. A concentration of 20mcg/L of active moiety is associated with a dopamine occupancy of 65–70%3 – the degree of pharmacological activity associated with response for most antipsychotics.4 Increasing dopamine occupancy above this level does not improve efficacy or likelihood of response but does make adverse effects more likely.3 Clozapine is completely different. For clozapine, the target range represents concentrations usually associated with both response and good tolerability. However, perhaps 10% of responders will improve with clozapine concentrations below the target range and as many as 20% of responders will only respond at concentrations above the target range. There is also a so-called point of futility – the concentration above which no additional responders will be uncovered. Responders to clozapine will have blood concentrations between 250 and 1000mcg/L5 – a much wider range than the accepted target range. Unlike risperidone and many other drugs, the threshold concentration is not fixed across populations. This subject is eloquently covered in much more detail in The Clinical Use of Antipsychotic Plasma Levels by Jonathan Meyer and Stephen Stahl (Cambridge University Press, 2021). Table 11.1 discusses the interpretation of sample results for various drugs. Table 11.1 Interpreting sample results for drugs with established target ranges. Drug Target range Sample timing Time to steady state Comments Amisulpride 200–320mcg/L 20–60mcg/L (elderly) Trough 3 days See text Aripiprazole 100–210mcg/L Trough 15–16 days See text Carbamazepine6–8

7mg/L Bipolar disorder Trough 2 weeks Carbamazepine induces its own metabolism. Time to steady state dependent on auto-induction Clozapine 350–600mcg/L Trough 2–3 days See text Lamotrigine9–11 Not established but suggest 2.5–15mg/L Trough 5 days Auto-induction is thought to occur, so time to steady state may be longer Some debate over utility of lamotrigine levels, especially in bipolar disorder. In treatment- resistant unipolar depression, plasma levels of above 12.7μmol/L (3.3mg/L) are associated with response.12,13 Toxicity may be increased above 15mg/L but is normally well tolerated Lithium14–18 0.6–1.0mmol/L (0.4mmol may be sufficient for some patients/indications; 1.0mmol/L required for mania) 12 hours 5 days post-dose Well-established target range, albeit derived from ancient data sources. A fairly recent study19 suggested 0.6mmol/L was the minimum level for a prophylactic effect

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07 - Amisulpride

Amisulpride

Pharmacokinetics CHAPTER 11 Amisulpride Amisulpride plasma levels are closely related to dose with insufficient variation to make routine plasma level monitoring prudent. Higher levels observed in women27–29 seem to have little significant clinical implication for either therapeutic response or adverse effects. A (trough) threshold for clinical response has been suggested to be approximately 100mcg/L30 and mean levels of 367mcg/L29 have been noted in responders. Adverse effects (notably extrapyramidal side effects [EPSEs]) occur at mean levels of 336mcg/L,27 377mcg/L30 and 395mcg/L.28 A plasma level threshold of below 320mcg/L has been found to predict avoidance of EPSEs.30 One review31 has suggested an approximate range of 200–320mcg/L for optimal clinical response and avoidance of adverse effects but a more recent consensus statement32 suggested a target range of 100–320mcg/L. A dose of 200mg a day is sufficient to give a blood level of 100mcg/L33 so this lower threshold is probably too low for a reliable therapeutic effect. In older patients with Drug Target range Sample timing Time to steady state Comments Olanzapine 20–40mcg/L 12 hours 1 week See text Paliperidone20 20–60mcg/L (9-OH risperidone) Trough 2–3 days oral 2 months depot Target range is the same as that established for risperidone.21 As with risperidone, routine plasma level monitoring is not recommended. Phenytoin7 10–20mg/L Trough Variable Follows zero-order kinetics. Free levels may be useful in some circumstances. Quetiapine Around 50–100mcg/L? Trough? 2–3 days oral Target range poorly defined. Plasma level monitoring not recommended. See text. Risperidone 20–60mcg/L (active moiety – risperidone + 9-OH risperidone) Trough 2–3 days oral 6–8 weeks injection Routine plasma level monitoring is not recommended. See text. Tricyclics22 Nortriptyline 50–150mcg/L Amitriptyline 100–200mcg/L Trough 2–3 days Rarely used and of dubious benefit. Use ECG to assess toxicity. Valproate6,7,23–25 50–100mg/L Epilepsy and bipolar Trough 2–3 days Some doubt over value of levels in epilepsy and in bipolar disorder. Some evidence that, in mania, levels up to 125mg/L are tolerated and more effective than lower concentrations. Valproate plasma levels are linearly related to plasma ammonia.26 Table 11.1 (Continued )

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08 - Aripiprazole

Aripiprazole

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09 - Clozapine

Clozapine

870 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 11 psychosis, studies suggest plasma concentrations of 20–60mcg/L may give optimal D2 occupancy and clinical response.34,35 In practice, only a minority of treated patients have ‘therapeutic’ plasma levels (probably because of poor adherence36) so plasma monitoring may be of some benefit. However, amisulpride plasma level monitoring is rarely undertaken and few laboratories offer amisulpride assays. The dose–response relationship is sufficiently robust (in trials, at least) to obviate the need for plasma sampling within the licensed dose range (although in older patients, doses of 50–100mg a day may be sufficient) and adverse effects are usually well managed by dose adjustment alone. Plasma level monitoring is best reserved for those in whom clinical response is poor, adherence is questioned or in whom drug interactions or physical illness may make adverse effects more likely. Aripiprazole Plasma level monitoring of aripiprazole is sometimes undertaken in practice. The dose– response relationship for aripiprazole is well established with a plateau in clinical response and D2 dopamine occupancy seen in doses above approximately 10mg/day.37 Plasma levels of aripiprazole, its metabolite and the total moiety (parent plus metabolite) strongly relate linearly to dose, making it possible to predict, with some certainty, an approximate plasma level for a given dose.38 Target plasma level ranges for optimal clinical response have been suggested as 146–254mcg/L39 and 150–300mcg/L,40 with adverse effects more frequent above 210mcg/L.40 Inter-individual variation in aripiprazole plasma levels has been observed but not fully investigated, although gender appears to have little influence.41,42 Age, metabolic enzyme genotype and interacting medications seem likely causes of variation.40–43 A putative range of between 150 and 210mcg/L38 has been suggested as a target for patients taking aripiprazole and these are broadly the concentrations seen in patients receiving depot aripiprazole at 300 and 400mg monthly.44 Some authorities suggest a lower threshold for clinical effect of 100mcg/L32 – a plasma level usually afforded by an oral dose of 10mg a day33,45 and around the minimum level reached during treatment with 2-monthly depot.46 Clozapine Clozapine plasma levels are broadly related to daily dose47 but there is sufficient variation to make impossible any precise prediction of plasma level. Plasma levels are generally lower in younger patients, males48 and smokers49 and higher in Asians.50 Much lower doses of clozapine are required in East Asians,51,52 Indians53 and Bangladeshis.54 The prevalence of clozapine poor metabolisers is also higher in East Asians.55,56 A series of algorithms has been developed for the approximate prediction of clozapine levels according to patient factors and these are recommended.57 Dose prediction using genetic analysis is more accurate that algorithm prediction.58 Neither method can account for other influences on clozapine plasma levels such as changes in adherence, inflammation59 and infection.60,61 The plasma level threshold for acute response to clozapine has been suggested to be 200mcg/L,62 350mcg/L,63–65 370mcg/L,66 420mcg/L,67 504mcg/L68 and 550mcg/L.69 Limited data suggest a level of at least 200mcg/L is required to prevent relapse.70 Substantial variation in clozapine plasma level may also predict relapse.71 Changes in

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10 - Olanzapine

Olanzapine

Pharmacokinetics CHAPTER 11 an individual’s clozapine plasma levels are common with a tendency for concentrations to slightly decrease over time,72 although one study suggests a decrease only in norclozapine concentrations.73 Despite these somewhat varied estimates of response threshold, plasma levels can be useful in optimising treatment. In those not responding to clozapine, the dose should be adjusted to give plasma levels in the range 350–600mcg/L (a range reflecting a consensus of the above findings32). Those not tolerating clozapine may benefit from a reduction to a dose giving plasma levels in this range. An upper limit to the clozapine target range has not been defined. Any upper limit must take into account two components: the level above which no therapeutic advantage is gained and the level at which toxicity/ tolerability is unacceptable. Plasma levels do seem to predict EEG changes74,75 and seizures occur more frequently in patients with levels above 1000mcg/L,76 so levels should probably be kept well below this. Other non-neurological clozapine-related adverse effects also seem to be plasma-level related77 as might be expected. An upper limit of concentrations around 600–800mcg/L has been proposed,78 although a level of 1000mcg/L may be the point of futility.79,80 Placing an upper limit on the target range for clozapine levels may discourage potentially worthwhile dose increases within the licensed dose range. Before plasma levels were widely used, clozapine was sometimes given in doses up to 900mg/day, with valproate being added when the dose reached 600mg/day. It remains unclear whether using these high doses can benefit patients with plasma levels already above the accepted threshold. Nonetheless, it is prudent to use an antiseizure agent as prophylaxis against seizures and myoclonus when plasma levels are above 600mcg/L (a level based more on repeated recommendation than on being a clear evidence-based threshold78) and certainly when levels approach 1000μmcg/L. Norclozapine is the major metabolite of clozapine. The ratio of clozapine to norclozapine averages 1.25 in populations81 but may differ markedly for individuals.82 In chronic dosing, the ratio should remain the same for a given patient. A decrease in ratio may suggest enzyme induction, an increase suggests enzyme inhibition, a non-trough sample or recent missed doses. Time of sampling radically alters the clozapine/norclozapine ratio as clozapine is relatively high in early samples and norclozapine is higher in late samples.1 Clozapine metabolism may become saturated at higher doses: the ratio of clozapine to norclozapine increases with increasing plasma levels, suggesting saturation.83–85 The effect of fluvoxamine also suggests that metabolism via CYP1A2 to norclozapine can be overwhelmed.86 Ultimately, changes in the clozapine/norclozapine ratio may be impossible to interpret. A systematic review concluded that knowledge of clozapine/norclozapine ratio had no clinical utility.87 Olanzapine Plasma levels of olanzapine are linearly related to daily dose88 but there is substantial variation,89 with higher levels seen in women,68 non-smokers90 and those on enzyme- inhibiting drugs.90,91 With once-daily dosing, the threshold level for response in schizophrenia has been suggested to be 9.3mcg/L (trough sample),92 23.2mcg/L (12-hour post-dose sample)68 and 23mcg/L at a mean of 13.5 hours post-dose.93 There is evidence to suggest that levels greater than around 40mcg/L (12-hour sampling) produce no

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11 - Quetiapine

Quetiapine

872 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 11 further therapeutic benefit than lower levels.94 Severe toxicity is uncommon but may be associated with levels above 100mcg/L, and death is occasionally seen at levels above 160mcg/L95 (albeit when other drugs or physical factors are relevant). A target range for therapeutic use of 20–40mcg/L (12-hour post-dose sample) has been proposed96 for schizophrenia; the range for mania is probably similar.97 This target range was for a time widened to 20–80mcg/L98,99 but the reasons for this were not clear. A 2023 systematic review suggests a target range of 20–40mcg/L for 12-hour samples.100 Significant weight gain seems most likely to occur in those with plasma levels above 20mcg/L.101 Constipation, dry mouth and tachycardia also seem to be related to plasma level.102 In practice, the dose of olanzapine should be largely governed by response and tolerability. However, a survey of UK sample assay results suggested that around 20% of patients on 20mg a day will have sub-therapeutic plasma levels and more than 40% have levels above 40mcg/L.103 Plasma level determinations might then be useful for those suspected of non-adherence, those showing poor tolerability or those not responding to the maximum licensed dose. Where there is poor response and plasma levels are below 20mcg/L, dose may then be adjusted to give 12-hour plasma levels of 20–40mcg/ L; where there is good response and poor tolerability, the dose should be tentatively reduced to give plasma levels below 40mcg/L. Changes in dose give proportionate changes in plasma levels.104 A case might be made to increase the dose to give blood levels in the range 40–80mcg/L but only where no other options remain. Quetiapine Doses of quetiapine are weakly related to trough plasma samples.105 Mean levels reported within the dose range 150–800mg/day vary from 27 to 387mcg/L,106–111 although the highest and lowest levels are not necessarily found at the lowest and highest doses. Age, gender and co-medication may contribute to the significant inter- individual variance observed in TDM studies, with female gender,111,112 older age110,111 and CYP3A4-inhibiting drugs106,110,111 likely to increase quetiapine concentration. Reports of these effects are conflicting112 and not sufficient to support the routine use of plasma level monitoring based on these factors alone. Despite the substantial variation in plasma levels at each dose, there is insufficient evidence to suggest a target therapeutic range to aim for (although a target range of 100–500mcg/L has been proposed113), thus plasma level monitoring is likely to have little value. Moreover, the metabolites of quetiapine have major therapeutic effects and their concentrations are only loosely associated with parent drug levels.114 Most current reports of quetiapine concentration associations are derived from the analysis of trough samples. Because of the short half-life of quetiapine, trough levels tend to drop to within a relatively small range regardless of dose and previous peak level. Peak plasma levels may be more closely related to dose and clinical response,105 although monitoring of such is not currently justified in the absence of an established peak plasma target range. Interestingly, a study of quetiapine in patients with borderline personality disorder or drug-induced psychosis showed a linear relationship between response and 12-hour plasma levels.112 Peak to trough variation is greater for immediate-release formulations (roughly a maximum of 4000mcg/L to zero) than for slow-release preparations (roughly a maximum of 3000mcg/L to around 100mcg/L).45

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12 - Risperidone

Risperidone

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13 - Target ranges for other psychotropics

Target ranges for other psychotropics

Pharmacokinetics CHAPTER 11 Quetiapine has an established dose–response relationship, and appears to be well tolerated at doses well beyond the licensed dose range.115 In practice, dose adjustment should be based on patient response and tolerability. Risperidone The therapeutic range for risperidone is generally agreed to be 20–60mcg/L of the active moiety (risperidone + 9-OH-risperidone)98,116,117 although other ranges (25–150mcg/L and 25–80mcg/L) have been proposed.118 Plasma levels of 20–60mcg/L are usually afforded by oral doses of between 3mg and 6mg a day.116,119–121 Occupancy of striatal dopamine D2 receptors has been shown to be around 65% (the minimum required for acute therapeutic effect) at plasma levels of approximately 20mcg/L.117,122 Limited data for paliperidone palmitate 1-monthly long-acting injection (LAI) suggest that standard loading doses give plasma levels of 25–45mcg/L; while at steady state, plasma levels ranged from 10 to 25mcg/L for 100mg/month and 15 to 35mcg/L for 150mg/month.123 Plasma concentrations may gradually rise in the first year of treatment to around 35mcg/L (mean dose 138mg/month)124 and remain stable thereafter.125 For the 3-monthly injection, steady state plasma concentrations range from 30 to 55mcg/L for 525mg every 3 months, 25 to 55mcg/L for 350mg every 3 months and 20 to 35mcg/L for 263mg every 3 months.126,127 Six-monthly paliperidone, available as 700 and 1000mg injections, provides similar plasma concentrations to those achieved by the corresponding doses of 3-monthly injections.128 Plasma concentrations of risperidone ISM® remain above 20mcg/L throughout the dosing interval.129 Target ranges for other psychotropics The target ranges listed in Table 11.2 have somewhat dubious usefulness and, in some cases, merely represent the range of values seen in clinical use. Assays for these drugs are likely to be available only in specialist units. Table 11.2 Target ranges for other psychotropics.32,98,130 Target range (mcg/L) Antipsychotics Asenapine 1–5 Brexpiprazole 40–140 Cariprazine 10–20 Chlorpromazine 30–300 Flupentixol 0.5–5 (cis-isomer) Fluphenazine 1–10 Haloperidol 1–10 (Continued )

874 The Maudsley® Prescribing Guidelines in Psychiatry Table 11.2 (Continued ) Iloperidone 5–10 Lurasidone 15–40 Melperone 30–100 CHAPTER 11 Sulpiride 200–1000 Ziprasidone 50–200 Zuclopenthixol 4–50 Antidepressants Agomelatine 7–300 Citalopram 50–110 Desvenlafaxine 100–400 Dosulepin 45–100 Duloxetine 30–120 Escitalopram 15–80 Fluoxetine (+ norfluoxetine) 120–500 Fluvoxamine 60–230 Levomilnacipran 80–120 Mianserin 15–70 Milnacipram 100–150 Mirtazapine 30–80 Moclobemide 300–1000 Paroxetine 20–65 Reboxetine 60–350 Sertraline 10–150 Trazodone 700–1000 Venlafaxine (+ O-desmethylvenlafaxine) 100–400 Vilazodone 30–70 Vortioxetine 15–60 Target range (mcg/L)

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14 - References

References

Pharmacokinetics CHAPTER 11 References

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Serious respiratory infections can increase clozapine levels and contribute to side effects: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27:1059–1063. 61. Espnes KA, et al. A puzzling case of increased serum clozapine levels in a patient with inflammation and infection. Ther Drug Monit 2012; 34:489–492. 62. VanderZwaag C, et al. Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges. Am J Psychiatry 1996; 153:1579–1584. 63. Perry PJ, et al. Clozapine and norclozapine plasma concentrations and clinical response of treatment refractory schizophrenic patients. Am J Psychiatry 1991; 148:231–235. 64. Miller DD. Effect of phenytoin on plasma clozapine concentrations in two patients. J Clin Psychiatry 1991; 52:23–25. 65. Spina E, et al. Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics. Psychopharmacology 2000; 148:83–89. 66. Hasegawa M, et al. Relationship between clinical efficacy and clozapine concentrations in plasma in schizophrenia: effect of smoking. J Clin Psychopharmacol 1993; 13:383–390. 67. Potkin SG, et al. Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia. J Clin Psychiatry 1994; 55 Suppl B:133–136. 68. Perry PJ. Therapeutic drug monitoring of antipsychotics. Psychopharmacol Bull 2001; 35:19–29. 69. Llorca PM, et al. Effectiveness of clozapine in neuroleptic-resistant schizophrenia: clinical response and plasma concentrations. J Psychiatry Neurosci 2002; 27:30–37. 70. Xiang YQ, et al. Serum concentrations of clozapine and norclozapine in the prediction of relapse of patients with schizophrenia. Schizophr Res 2006; 83:201–210.

Pharmacokinetics CHAPTER 11 71. Stieffenhofer V, et al. Clozapine plasma level monitoring for prediction of rehospitalization schizophrenic outpatients. Pharmacopsychiatry 2011; 44:55–59. 72. Lee J, et al. Quantifying intraindividual variations in plasma clozapine levels: a population pharmacokinetic approach. J Clin Psychiatry 2016; 77:681–687. 73. Turrion MC, et al. Intra-individual variation of clozapine and norclozapine plasma levels in clinical practice. Rev Psiquiatr Salud Ment 2020; 13:31–35. 74. Khan AY, et al. Examining concentration-dependent toxicity of clozapine: role of therapeutic drug monitoring. J Psychiatr Pract 2005; 11:289–301. 75. Varma S, et al. Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Ther Adv Psychopharmacol 2011; 1:47–66. 76. Greenwood-Smith C, et al. Serum clozapine levels: a review of their clinical utility. J Psychopharmacol 2003; 17:234–238. 77. Yusufi B, et al. Prevalence and nature of side effects during clozapine maintenance treatment and the relationship with clozapine dose and plasma concentration. Int Clin Psychopharmacol 2007; 22:238–243. 78. Remington G, et al. Clozapine and therapeutic drug monitoring: is there sufficient evidence for an upper threshold? Psychopharmacology (Berl) 2013; 225:505–518. 79. Bogers J, et al. Feasibility and effect of increasing clozapine plasma levels in long-stay patients with treatment-resistant schizophrenia. J Clin Psychopharmacol 2023; 43:97–105. 80. Northwood K, et al. Optimising plasma clozapine levels to improve treatment response: an individual patient data meta-analysis and receiver operating characteristic curve analysis. Br J Psychiatry 2023; 222:241–245. 81. Couchman L, et al. Plasma clozapine, norclozapine, and the clozapine:norclozapine ratio in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1993–2007. Ther Drug Monit 2010; 32:438–447. 82. Wickramarachchi P, et al. Biological variation in clozapine and metabolite reporting during therapeutic drug monitoring. Clin Chim Acta 2022; 531:183–187. 83. Volpicelli SA, et al. Determination of clozapine, norclozapine, and clozapine-N-oxide in serum by liquid chromatography. Clin Chem 1993; 39:1656–1659. 84. Guitton C, et al. Clozapine and metabolite concentrations during treatment of patients with chronic schizophrenia. J Clin Pharmacol 1999; 39:721–728. 85. Palego L, et al. Clozapine, norclozapine plasma levels, their sum and ratio in 50 psychotic patients: influence of patient-related variables. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26:473–480. 86. Wang CY, et al. The differential effects of steady-state fluvoxamine on the pharmacokinetics of olanzapine and clozapine in healthy volunteers. J Clin Pharmacol 2004; 44:785–792. 87. Schoretsanitis G, et al. A comprehensive review of the clinical utility of and a combined analysis of the clozapine/norclozapine ratio in therapeutic drug monitoring for adult patients. Expert Rev Clin Pharmacol 2019; 12:603–621. 88. Bishara D, et al. Olanzapine: a systematic review and meta-regression of the relationships between dose, plasma concentration, receptor occupancy, and response. J Clin Psychopharmacol 2013; 33:329–335. 89. Aravagiri M, et al. Plasma level monitoring of olanzapine in patients with schizophrenia: determination by high-performance liquid chromatography with electrochemical detection. Ther Drug Monit 1997; 19:307–313. 90. Gex-Fabry M, et al. Therapeutic drug monitoring of olanzapine: the combined effect of age, gender, smoking, and comedication. Ther Drug Monit 2003; 25:46–53. 91. Bergemann N, et al. Olanzapine plasma concentration, average daily dose, and interaction with co-medication in schizophrenic patients. Pharmacopsychiatry 2004; 37:63–68. 92. Perry PJ, et al. Olanzapine plasma concentrations and clinical response in acutely ill schizophrenic patients. J Clin Psychopharmacol 1997; 17:472–477. 93. Fellows L, et al. Investigation of target plasma concentration–effect relationships for olanzapine in schizophrenia. Ther Drug Monit 2003; 25:682–689. 94. Mauri MC, et al. Clinical outcome and olanzapine plasma levels in acute schizophrenia. Eur Psychiatry 2005; 20:55–60. 95. Rao ML, et al. Olanzapine: pharmacology, pharmacokinetics and therapeutic drug monitoring. Fortschr Neurol Psychiatr 2001; 69:510–517. 96. Robertson MD, et al. Olanzapine concentrations in clinical serum and postmortem blood specimens – when does therapeutic become toxic? J Forensic Sci 2000; 45:418–421. 97. Bech P, et al. Olanzapine plasma level in relation to antimanic effect in the acute therapy of manic states. Nord J Psychiatry 2006; 60:181–182. 98. Schoretsanitis G, et al. Blood levels to optimize antipsychotic treatment in clinical practice: a joint consensus statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie. J Clin Psychiatry 2020; 81:19cs13169. 99. Noel C. A review of a recently published guidelines’ ‘strong recommendation’ for therapeutic drug monitoring of olanzapine, haloperidol, perphenazine, and fluphenazine. Ment Health Clin 2019; 9:287–293. 100. Wesner K, et al. Therapeutic reference range for olanzapine in schizophrenia: systematic review on blood concentrations, clinical effects, and dopamine receptor occupancy. J Clin Psychiatry 2023; 84:22r14626. 101. Perry PJ, et al. The association of weight gain and olanzapine plasma concentrations. J Clin Psychopharmacol 2005; 25:250–254. 102. Kelly DL, et al. Plasma concentrations of high-dose olanzapine in a double-blind crossover study. Hum Psychopharmacol 2006; 21:393–398.

878 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 11 103. Patel MX, et al. Plasma olanzapine in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1999–2009. J Clin Psychopharmacol 2011; 31:411–417. 104. Tsuboi T, et al. Predicting plasma olanzapine concentration following a change in dosage: a population pharmacokinetic study. Pharmacopsychiatry 2015; 48:286–291. 105. Sparshatt A, et al. Relationship between daily dose, plasma concentrations, dopamine receptor occupancy, and clinical response to quetiapine: a review. J Clin Psychiatry 2011; 72:1108–1123. 106. Hasselstrom J, et al. Quetiapine serum concentrations in psychiatric patients: the influence of comedication. Ther Drug Monit 2004; 26:486–491. 107. Winter HR, et al. Steady-state pharmacokinetic, safety, and tolerability profiles of quetiapine, norquetiapine, and other quetiapine metabolites in pediatric and adult patients with psychotic disorders. J Child Adolesc Psychopharmacol 2008; 18:81–98. 108. Li KY, et al. Multiple dose pharmacokinetics of quetiapine and some of its metabolites in Chinese suffering from schizophrenia. Acta Pharmacol Sin 2004; 25:390–394. 109. McConville BJ, et al. Pharmacokinetics, tolerability, and clinical effectiveness of quetiapine fumarate: an open-label trial in adolescents with psychotic disorders. J Clin Psychiatry 2000; 61:252–260. 110. Castberg I, et al. Quetiapine and drug interactions: evidence from a routine therapeutic drug monitoring service. J Clin Psychiatry 2007; 68:1540–1545. 111. Aichhorn W, et al. Influence of age, gender, body weight and valproate comedication on quetiapine plasma concentrations. Int Clin Psychopharmacol 2006; 21:81–85. 112. Mauri MC, et al. Two weeks’ quetiapine treatment for schizophrenia, drug-induced psychosis and borderline personality disorder: a naturalistic study with drug plasma levels. Expert Opin Pharmacother 2007; 8:2207–2213. 113. Patteet L, et al. Therapeutic drug monitoring of common antipsychotics. Ther Drug Monit 2012; 34:629–651. 114. Fisher DS, et al. Plasma concentrations of quetiapine, N-desalkylquetiapine, o-desalkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide in relation to quetiapine dose, formulation, and other factors. Ther Drug Monit 2012; 34:415–421. 115. Sparshatt A, et al. Quetiapine: dose-response relationship in schizophrenia. CNS Drugs 2008; 22:49–68. 116. Olesen OV, et al. Serum concentrations and side effects in psychiatric patients during risperidone therapy. Ther Drug Monit 1998; 20:380–384. 117. Remington G, et al. A PET study evaluating dopamine D2 receptor occupancy for long-acting injectable risperidone. Am J Psychiatry 2006; 163:396–401. 118. Seto K, et al. Risperidone in schizophrenia: is there a role for therapeutic drug monitoring? Ther Drug Monit 2011; 33:275–283. 119. Lane HY, et al. Risperidone in acutely exacerbated schizophrenia: dosing strategies and plasma levels. J Clin Psychiatry 2000; 61:209–214. 120. Taylor D. Risperidone long-acting injection in practice – more questions than answers? Acta Psychiatr Scand 2006; 114:1–2. 121. Nyberg S, et al. Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2A receptor occupancy in schizophrenic patients. Am J Psychiatry 1999; 156:869–875. 122. Uchida H, et al. Predicting dopamine D receptor occupancy from plasma levels of antipsychotic drugs: a systematic review and pooled analysis. J Clin Psychopharmacol 2011; 31:318–325. 123. Pandina GJ, et al. A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. J Clin Psychopharmacol 2010; 30:235–244. 124. Mauri MC, et al. Paliperidone long-acting plasma level monitoring and a new method of evaluation of clinical stability. Pharmacopsychiatry 2017; 50:145–151. 125. Paletta S, et al. Two years of maintenance therapy with paliperidone long-acting in schizophrenia and schizoaffective disorder: a study with plasma levels. Eur Neuropsychopharmacol 2016; 26:S556–S557. 126. Berwaerts J, et al. Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clinical trial. JAMA Psychiatry 2015; 72:830–839. 127. Magnusson MO, et al. Dosing and switching strategies for paliperidone palmitate 3-month formulation in patients with schizophrenia based on population pharmacokinetic modeling and simulation, and clinical trial data. CNS Drugs 2017; 31:273–288. 128. T’Jollyn H, et al. Model-informed clinical development of once-every-6-month injection of paliperidone palmitate in patients with schizophrenia: a pharmacometric bridging approach (Part I). Eur J Drug Metab Pharmacokinet 2024; 49:477–489. 129. Álamo C. Risperidone ISM as a new option in the clinical management of schizophrenia: a narrative review. Adv Ther 2022; 39:4875–4891. 130. Biso L, et al. Therapeutic drug monitoring in psychiatry: enhancing treatment precision and patient outcomes. Pharmaceuticals (Basel) 2024; 17:642.

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Interpreting postmortem blood concentrations

Pharmacokinetics CHAPTER 11 Interpreting postmortem blood concentrations Much is known about the distribution of drugs in the body during life but relatively little about these same parameters after death. A great many drugs are subject to postmortem distribution changes but, for obvious practical reasons, research into the mechanisms and extent of these effects is very limited. The best that can be said is that a drug plasma concentration measured during life may be very different from the concentration measured at some time after death (usually in whole blood from the femoral artery). A number of processes are responsible for these changes. In life, active mechanisms serve to concentrate some drugs in certain organs or tissues. After death, passive diffusion occurs as cell membranes break down and this will mean that postmortem blood samples will, for some drugs, show higher concentrations than were seen during life. This is known as postmortem redistribution (PMR). In addition, central blood vessels surrounding major organs often demonstrate much higher drug concentrations than relatively distant peripheral samples.1 PMR and other processes are temperature- and time-dependent so time since death and conditions of storage are important determinants of blood concentration changes.2 PMR tends to be greater with drugs with a large volume of distribution (i.e. those for which tissue concentrations in life vastly exceed blood concentrations) especially when given over a long period during life. Other processes of importance3 include the postmortem synthesis of certain compounds. For example, the body is able to generate gamma-hydroxybutyrate. Trauma may allow the introduction of yeasts that metabolise glucose to alcohol. Another phenomenon is the degradation of drugs by bacteria (e.g. clonazepam and nitrazepam) or fungi. Also, the metabolism of some drugs (cocaine, for example) appears to continue after death (although this may be simple chemical instability of the parent compound). All of the processes described here contribute to an overall direction of change of concentration postmortem. Antidepressant concentrations tend to increase in postmortem samples whereas those of benzodiazepines invariably decrease.4 Mirtazapine concentrations also appear to decrease.5,6 Antipsychotic concentrations both increase and decrease depending on the drug.4 Thus, when an isolated postmortem concentration is considered (i.e. one which cannot be compared with a concentration measured in life), it can only be said that the in-life concentration would have been higher or lower.7 Table 11.3 lists some of the factors relevant to drug concentration changes after death and the possible consequences of these processes. Generally speaking, an isolated postmortem blood concentration cannot be sensibly interpreted. Even where in-life levels are available, for most drugs in most circumstances, interpretation of blood levels after death is near impossible. High postmortem concentrations should certainly not be taken, in the absence of other evidence, to indicate death by overdose, for example. Two valuable reference sources for interpretation of postmortem sample analysis are the systematic reviews of Ketola and Kriikku8 and Ketola and Ojanperä.9 Expert advice should always be sought when considering the role of medication in a death.10

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References

880 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 11 References

Ferner RE. Post-mortem clinical pharmacology. Br J Clin Pharmacol 2008; 66:430–443.
Flanagan RJ, et al. Analytical toxicology: guidelines for sample collection postmortem. Toxicol Rev 2005; 24:63–71.
Kennedy MC. Post-mortem drug concentrations. Intern Med J 2010; 40:183–187.
Mantinieks D, et al. Postmortem drug redistribution: a compilation of postmortem/antemortem drug concentration ratios. J Anal Toxicol 2021; 45:368–377.
Brockbals L, et al. Time- and site-dependent postmortem redistribution of antidepressants and neuroleptics in blood and alternative matrices. J Anal Toxicol 2021; 45:356–367.
Brockbals L, et al. Postmortem metabolomics: strategies to assess time-dependent postmortem changes of diazepam, nordiazepam, morphine, codeine, mirtazapine and citalopram. Metabolites 2021; 11:643.
Maskell PD. Just say no to postmortem drug dose calculations. J Forensic Sci 2021; 66:1862–1870.
Ketola RA, et al. Drug concentrations in post-mortem specimens. Drug Test Anal 2019; 11:1338–1357.
Ketola RA, et al. Summary statistics for drug concentrations in post-mortem femoral blood representing all causes of death. Drug Test Anal 2019; 11:1326–1337.
Flanagan RJ. Poisoning: fact or fiction? Med Leg J 2012; 80:127–148.
Flanagan RJ, et al. Effect of post-mortem changes on peripheral and central whole blood and tissue clozapine and norclozapine concentrations in the domestic pig (Sus scrofa). Forensic Sci Int 2003; 132:9–17.
Flanagan RJ, et al. Suspected clozapine poisoning in the UK/Eire, 1992–2003. Forensic Sci Int 2005; 155:91–99.
Saar E, et al. The time-dependant post-mortem redistribution of antipsychotic drugs. Forensic Sci Int 2012; 222:223–227.
Caplehorn JR, et al. Methadone dose and post-mortem blood concentration. Drug Alcohol Rev 2002; 21:329–333.
Lewis RJ, et al. Paroxetine in postmortem fluids and tissues from nine aviation accident victims. J Anal Toxicol 2015; 39:637–641.
Launiainen T, et al. Drug concentrations in post-mortem femoral blood compared with therapeutic concentrations in plasma. Drug Test Anal 2014; 6:308–316.
Soderberg C, et al. Reference values of lithium in postmortem femoral blood. Forensic Sci Int 2017; 277:207–214.
Linnet K, et al. Postmortem femoral blood concentrations of risperidone. J Anal Toxicol 2014; 38:57–60.
Skov L, et al. Postmortem femoral blood reference concentrations of aripiprazole, chlorprothixene, and quetiapine. J Anal Toxicol 2015; 39:41–44.
Rodda KE, et al. The redistribution of selected psychiatric drugs in post-mortem cases. Forensic Sci Int 2006; 164:235–239.
Scanlon KA, et al. Comprehensive duloxetine analysis in a fatal overdose. J Anal Toxicol 2016; 40:167–170.
Breivik H, et al. Post mortem tissue distribution of quetiapine in forensic autopsies. Forensic Sci Int 2020; 315:110413.
Butzbach DM, et al. Bacterial degradation of risperidone and paliperidone in decomposing blood. J Forensic Sci 2013; 58:90–100.
Martinez-Ramirez JA, et al. Search for fungi-specific metabolites of four model drugs in postmortem blood as potential indicators of postmortem fungal metabolism. Forensic Sci Int 2016; 262:173–178.
Martinez-Ramirez JA, et al. Studies on drug metabolism by fungi colonizing decomposing human cadavers. Part II: biotransformation of five model drugs by fungi isolated from post-mortem material. Drug Test Anal 2015; 7:265–279. Table 11.3 Factors affecting postmortem blood concentrations. Factor Examples Consequences Redistribution of drug from tissues to blood compartment Most drugs with large volume of distribution, e.g. clozapine,11,12 olanzapine,13 methadone,14 SSRIs,15 TCAs, mirtazapine,16 lithium17 May not occur to any significant effect with risperidone,4,18 aripiprazole19 or quetiapine4,19 Postmortem levels up to 10× higher than in-life levels, sometimes higher still9 Uneven distribution of drugs in the blood compartment and in organs (i.e. site of blood collection affects concentration) Most drugs,8,20 e.g. clozapine, TCAs, SSRIs, duloxetine,21 benzodiazepines, quetiapine22 Concentrations may vary several-fold according to site of collection at postmortem, e.g. femoral blood vs heart blood Decay of drugs in postmortem tissue (usually by bacterial degradation) Not widely studied but known to occur with olanzapine, risperidone23 and some benzodiazepines. Fungi can metabolise amitriptyline, mirtazapine and zolpidem.24,25 Postmortem levels may be lower than in-life levels Postmortem metabolism/ degradation Cocaine metabolised/degraded postmortem. Many other drugs are unstable in postmortem samples. Yeasts may produce ethanol following trauma.3 Postmortem levels may be lower (cocaine) or higher (alcohol) than in-life levels TCAs, tricyclic antidepressants.

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17 - Acting on clozapine plasma concentration resu

Acting on clozapine plasma concentration results

Pharmacokinetics CHAPTER 11 Acting on clozapine plasma concentration results In most developed countries, clozapine blood concentration monitoring is widely used. Table 11.4 gives some general advice about actions that should be taken when clozapine levels are within a certain range. The ranges shown are somewhat arbitrary and convenient – the concentration at which a particular patient might respond cannot be known without a trial of clozapine. Most adverse effects are linearly or exponentially related to dose or plasma level. That is, there is no step-change in the risk of seizures, for example, at a particular dose or plasma concentration.1 The same is broadly true of therapeutic effects. The likelihood of response in an individual increases from concentrations below the accepted therapeutic range up to around 1000mcg/L.2–4 Table 11.4 should be considered more an aid to decision-making rather than a rigorous, unbending evidence-based instruction. Note also the effect of tolerance to adverse effects – many patients have a significant adverse effect burden before therapeutic concentrations are reached,5 reducing over time as tolerance develops. Table 11.4 Recommended actions in response to clozapine concentrations.* Plasma concentration Response status Tolerability status Suggested action <350mcg/L Poor Poor Increase dose very slowly to give level of 350mcg/L Poor Good Increase dose to give level of 350mcg/L Good Poor Maintain dose. Consider cautious dose reduction if tolerability does not improve. Good Good Continue to monitor. No action required. 350–500mcg/L Poor Poor Increase dose slowly, according to tolerability, to give level of >500mcg/L. Consider prophylactic anticonvulsant.† If no improvement, consider augmentation. Poor Good Increase dose slowly, according to tolerability, to give level of >500mcg/L (up to 1000mcg/mL if tolerated). Consider prophylactic anticonvulsant.† If no improvement, consider augmentation. Good Poor Maintain dose to see if tolerability improves. Consider cautious dose reduction to give plasma level of around 350mcg/L. Good Good Continue to monitor. No action required. 500–1000mcg/L Poor Poor Consider use of prophylactic antiseizure drug.† Consider augmentation. Attempt dose reduction if augmentation successful. Poor Good Consider use of prophylactic antiseizure drug.† Slowly increase dose (up towards 1000mcg/mL if tolerated). Also consider augmentation. Good Poor Attempt slow dose reduction to give plasma level of 350–500mcg/L unless there is known non-response at lower level. If this is the case, maintain dose and consider adding anticonvulsant.† Optimise treatment of adverse effects. Good Good Consider use of prophylactic antiseizure drug.† Maintain dose if good tolerability continues. (Continued )

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References

882 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 11 References

Varma S, et al. Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Ther Adv Psychopharmacol 2011; 1:47–66.
Northwood K, et al. Optimising plasma clozapine levels to improve treatment response: an individual patient data meta-analysis and receiver operating characteristic curve analysis. Br J Psychiatry 2023; 222:241–245.
Tralongo F, et al. Association between clozapine plasma concentrations and treatment response: a systematic review, meta-analysis and individual participant data meta-analysis. Clin Pharmacokinet 2023; 62:807–818.
Bogers J, et al. Feasibility and effect of increasing clozapine plasma levels in long-stay patients with treatment-resistant schizophrenia. J Clin Psychopharmacol 2023; 43:97–105.
Yusufi B, et al. Prevalence and nature of side effects during clozapine maintenance treatment and the relationship with clozapine dose and plasma concentration. Int Clin Psychopharmacol 2007; 22:238–243.
Malik S, et al. Sodium valproate and clozapine induced neutropenia: a case control study using register data. Schizophr Res 2018; 195:267–273. Table 11.4 (Continued ) Plasma concentration Response status Tolerability status Suggested action

1000mcg/L Poor Poor Add antiseizure drug. Attempt augmentation. Reduce dose to give level of <1000mcg/L. Consider abandoning clozapine treatment. Poor Good Add antiseizure drug. Attempt augmentation. If augmentation successful, reduce dose to give level <1000mcg/L. If unsuccessful, consider abandoning clozapine treatment. Good Poor Add antiseizure drug. Attempt slow dose reduction to give plasma level <1000mcg/L. Good Good Add antiseizure drug. Monitor closely; attempt dose reduction only if tolerability declines. Notes Poor response No response or unsatisfactory response to clozapine. For example, not sufficiently well to be discharged. Good response Obvious positive changes related to use of clozapine. Patient likely to be suitable for discharge to either supported or unsupported care in the community. Poor tolerability Dose constrained by adverse effects such as tachycardia, sedation, hypersalivation, hypotension, etc. (see Chapter 1 for suggestions of treatment for adverse effects). Good tolerability Patient tolerates treatment well and there are no signs of serious toxicity. Augmentation Adding another antipsychotic or mood stabiliser (see Chapter 1). In all situations, ensure adequate treatment for clozapine-induced constipation. Constipation is dose-related. Ensure regular bowel movements and record bowel function. Stimulant laxatives such as senna are required (see Chapter 1). Seizures are dose- and plasma level-dependent. Suitable antiseizure agents are valproate, lamotrigine and, rarely, topiramate. Use lamotrigine if response is poor; valproate if affective symptoms are present (see Chapter 2). Note that use of valproate increases risk of neutropenia with clozapine.6 Both valproate and topiramate are contraindicated in women of child-bearing age. *This table applies to results for patients on a stable clozapine dose with confirmed good adherence. †Antiseizure drugs should usually be used in patients whose plasma level exceeds 600mcg/L, unless EEG is normal, and in those with lower plasma levels who experience clozapine-induced seizures.

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19 - Psychotropic drugs and cytochrome (CYP) funct

Psychotropic drugs and cytochrome (CYP) function

Pharmacokinetics CHAPTER 11 Psychotropic drugs and cytochrome (CYP) function Information on the effect of drugs on CYP function helps predict or confirm suspected interactions that may not have been uncovered in regulatory trials or in clinical use. In addition to the effect of co-administered drugs on CYP function, genetic polymorphism associated with some enzymes may also account for inter-individual variations in the metabolism of certain drugs. Genetic variation influences both likelihood of response and tolerability (see later in this section for more information on genetic variation).1,2 The effects of polymorphism and pharmacokinetic interaction are difficult to predict because some drugs are metabolised by more than one enzyme and an alternative pathway(s) may compensate if other enzyme pathways are inhibited. A further complication is that CYPs are active in sites other than the liver (e.g. gut, brain). The effect of psychotropics on brain CYPs can be markedly different from hepatic CYPs.3 The function of CYPs is not the only consideration. P-glycoprotein (P-gp) is a drug transporter protein found in the gut wall. P-gp can eject (active process) drugs that diffuse (passive process) across the gut wall. P-gp is also found in testes and in the blood– brain barrier. Drugs that inhibit P-gp are anticipated to increase the uptake of other drugs (that are substrates for P-gp), and drugs that induce P-gp are anticipated to reduce the uptake of other drugs (that are substrates for P-gp). Many drugs that are substrates for CYP3A4 have also been found to be substrates for P-gp. Uridine diphosphate (UDP)-glucuronosyltransferase (UGT) has been identified as an enzyme that is responsible for phase II (conjugation) reactions. Valproate is a potent inhibitor of UGT, hence its interaction with lamotrigine, a drug which is primarily metabolised by UGT. UGT enzymes are also involved in the metabolism of lumateperone, olanzapine, topiramate and trifluoperazine. In Table 11.5, drugs highlighted in bold indicate: ■ ■Predominant metabolic enzyme pathway, or ■ ■Predominant enzyme activity (inhibition or induction). Drugs annotated with * are known to be a minor metabolic enzyme pathway or activity (i.e. not demonstrated to be clinically significant). Drugs in normal font (not bold and without *) indicate metabolic enzyme pathway(s) or activity where significance is unclear or unknown. Table 11.5 does not include details of the effects of non-psychotropics on CYP function.

884 The Maudsley® Prescribing Guidelines in Psychiatry Table 11.5 Effects of psychotropics on CYP function. CYP1A2 Substrates Inhibitors Inducers Asenapine4 Agomelatine Amitriptyline* Bupropion* Caffeine Chlorpromazine Clomipramine* Clozapine Duloxetine Fluphenazine Fluvoxamine Haloperidol Imipramine* Levomepromazine Lumateperone Melatonin Mirtazapine* Olanzapine Perphenazine Pimozide* Ramelteon Zolpidem* CHAPTER 11 Moclobemide Perphenazine CYP2A6 Substrates Inhibitors Inducers Bupropion* Caffeine Nicotine CYP2B6 Substrates Inhibitors Inducers Bupropion Methadone* Nicotine Sertraline* Fluoxetine* Fluvoxamine Memantine Paroxetine* Sertraline* CYP2B7 Substrates Inhibitors Inducers Buprenorphine* Not known Not known ‘Barbiturates’ Carbamazepine Modafinil* Phenobarbital Phenytoin Fluvoxamine Iloperidone Levomepromazine Melatonin5 Tranylcypromine Phenobarbital Carbamazepine* Modafinil* Phenobarbital Phenytoin

Table 11.5 (Continued ) CYP2C8 Substrates Inhibitors Inducers Lumateperone Zopiclone* Not known Not known CYP2C9 Substrates Inhibitors Inducers Fluoxetine* Fluvoxamine Modafinil Valproate Agomelatine* Amitriptyline Bupropion* Doxepin Fluoxetine* Lamotrigine Phenobarbital Phenytoin Sertraline* Valproate CYP2C19 Substrates Inhibitors Inducers Escitalopram* Fluoxetine Fluvoxamine Iloperidone Melatonin5 Agomelatine* Amitriptyline Atomoxetine Carbamazepine* Citalopram Clomipramine* Diazepam Escitalopram Fluoxetine* Imipramine* Melatonin Methadone Moclobemide Phenytoin Sertraline* Suvorexant Trimipramine* Valproate Moclobemide Modafinil Topiramate Pharmacokinetics CHAPTER 11 Carbamazepine SJW Carbamazepine SJW (Continued )

886 The Maudsley® Prescribing Guidelines in Psychiatry Table 11.5 (Continued ) CYP2D6 Substrates Inhibitors Inducers ‘Amfetamines’ Amitriptyline Aripiprazole Atomoxetine CHAPTER 11 Brexpiprazole Cariprazine Chlorpromazine Citalopram Clomipramine Clozapine* Deutetrabenazine Donepezil* Doxepin Duloxetine Escitalopram Fluoxetine Fluphenazine Fluvoxamine Galantamine Haloperidol Iloperidone Imipramine Methadone* Mianserin Mirtazapine* Moclobemide Nortriptyline Olanzapine Paroxetine Perphenazine Pimavanserin Pimozide* Quetiapine* Risperidone Sertindole Sertraline Trazodone* Trimipramine Valbenazine Venlafaxine Vortioxetine Zuclopenthixol CYP2E1 Substrates Inhibitors Inducers Bupropion Ethanol Disulfiram Paracetamol Ethanol Amitriptyline Asenapine4 Not known Bupropion Chlorpromazine Citalopram* Clomipramine Clozapine Doxepin Duloxetine Escitalopram Fluoxetine Fluphenazine Fluvoxamine* Haloperidol Iloperidone Levomepromazine Methadone* Moclobemide Paroxetine Perphenazine Reboxetine* Risperidone Sertraline* Venlafaxine* Ziprasidone*

Table 11.5 (Continued ) CYP3A4 Substrates Inhibitors Inducers Alfentanyl Alprazolam Amitriptyline Aripiprazole Atomoxetine* Fluoxetine Fluvoxamine Iloperidone Blonaserin Brexipiprazole Buprenorphine Bupropion* Buspirone Carbamazepine Cariprazine Chlorpromazine Citalopram Clomipramine* Clonazepam Clozapine* Diazepam Donepezil Dosulepin Escitalopram* Fentanyl Fluoxetine* ?Flurazepam Galantamine Haloperidol Imipramine Lemborexant Levomepromazine Lumateperone Lurasidone Methadone Midazolam Mirtazapine Modafinil Nitrazepam Paliperidone Perphenazine Pimavanserin Pimozide Quetiapine Reboxetine Risperidone* Sertindole Sertraline* Suvorexant Trazodone Trimipramine* Valbenazine Venlafaxine Vilazodone Zaleplon Ziprasidone Zolpidem Zopiclone Zuclopenthixol Levomepromazine Paroxetine Perphenazine Reboxetine* Ziprasidone* Note: information on CYP function is derived from individual SPCs and US labelling (accessed August 2024), from systematic reviews7,8 and the Flockhart table.9 SJW, St John’s wort; SPC, summary of product characteristics. Asenapine? Carbamazepine Clozapine6 Levomepromazine6 Modafinil Phenobarbital ‘and probably other barbituates’ Phenytoin SJW Topiramate CHAPTER 11

16 - Chapter 11 Pharmacokinetics

20 - Genetics of cytochrome function

Genetics of cytochrome function

888 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 11 Genetics of cytochrome function The function of CYPs is under genetic control. Each individual’s CYP function is determined by heredity and is often, but not always, linked to ethnicity. Phenotypes are usually described as poor metabolisers, intermediate metabolisers, normal metabolisers and rapid or ultrarapid metabolisers. Table 11.6 gives the approximate distribution of phenotypes across nine ethnicities. Awareness of differences in phenotype frequencies can help predict and understand drug metabolism differences. As an example, CYP1A2 ultrarapid metaboliser phenotypes are most often seen in African Americans and so we might expect a higher rate of clozapine failure (or at least low plasma levels) in this population.

Table 11.6 Estimated phenotype frequency by ancestry for CYP1A2, CYP2D6, CYP2C19, CYP2C9 and CYP3A4.10–22 Genotype-predicted phenotypes African10,11 African American12,13 European ancestry + North American14 Near Eastern East Asian South/Central Asian Americas Latino15 Oceanian CYP1A2 Ultrarapid metaboliser 10–20% 15–30% 1–4% 5–10% 1–5% 3–8% 5–10% 7–12% 5–10% Normal metaboliser 55–70% 50–60% 70–80% 65–75% 65–75% 60–70% 60–70% 65–75% 65–75% Intermediate metaboliser 10–20% 10–15% 10–15% 10–15% 10–20% 10–15% 10–15% 10–15% 10–15% Poor metaboliser 5–10% 5–10% 5–10% 5–10% 10–15% 10–15% 5–10% 5–10% 5–10% CYP2D6 Ultrarapid metaboliser 4% 5% 3% 10% 1% 2% 6% 4% 20% Normal metaboliser 43% 56% 51% 55% 52% 62% 64% 59% 67% Intermediate metaboliser 44% 36% 39% 30% 39% 30% 24% 29% 10% Poor metaboliser 2% 2% 7% 2% 1% 2% 2% 3% 0% CYP2C19 Ultrarapid metaboliser 3% 4% 5% 4% 0% 3% 1% 3% 0% Rapid metaboliser 19% 24% 27% 26% 3% 19% 14% 24% 2% Normal metaboliser 30% 33% 40% 45% 38% 30% 63% 53% 4% Intermediate metaboliser 36% 31% 26% 24% 46% 41% 21% 19% 37% Likely intermediate metaboliser 4% 3% 0% 0% 0% 0% 0% 0% 0% Poor metaboliser 6% 4% 2% 2% 13% 8% 2% 1% 57% Likely poor metaboliser 1% 1% 0% 0% 0% 0% 0% 0% 0% CYP2C9 Normal metaboliser 73% 76% 63% 61% 84% 60% 83% 75% 91% (Continued )

Table 11.6 (Continued ) Genotype-predicted phenotypes African10,11 African American12,13 European ancestry + North American14 Near Eastern East Asian South/Central Asian Americas Latino15 Oceanian Intermediate metaboliser 26% 24% 35% 36% 15% 36% 16% 25% 9% Poor metaboliser 1% 1% 3% 3% 1% 4% 0% 1% 0% CYP3A4 Ultrarapid metaboliser 7–15% 10–15% 1–5% 5–10% 1–4% 2–6% 4–9% 3–8% 4–10% Normal metaboliser 50–65% 55–70% 65–75% 60–70% 60–75% 60–70% 55–65% 60–70% 60–70% Intermediate metaboliser 15–25% 10–20% 15–20% 15–20% 15–25% 15–20% 15–20% 15–20% 15–20% Poor metaboliser 5–10% 5–10% 5–10% 5–10% 5–10% 5–10% 5–10% 5–10% 5–10%

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References

Pharmacokinetics CHAPTER 11 References

Baldacci A, et al. Pharmacogenetic guidelines for psychotropic drugs: optimizing prescriptions in clinical practice. Pharmaceutics 2023; 15:2540.
Cojocaru A, et al. The implications of cytochrome P450 2D6/CYP2D6 polymorphism in the therapeutic response of atypical antipsychotics in adolescents with psychosis – a prospective study. Biomedicines 2024; 12:494.
Daniel WA, et al. The mechanisms of interactions of psychotropic drugs with liver and brain cytochrome P450 and their significance for drug effect and drug-drug interactions. Biochem Pharmacol 2022; 199:115006.
Wójcikowski J, et al. In vitro inhibition of human cytochrome P450 enzymes by the novel atypical antipsychotic drug asenapine: a prediction of possible drug-drug interactions. Pharmacol Rep 2020; 72:612–621.
Matura JM, et al. Dietary supplements, cytochrome metabolism, and pharmacogenetic considerations. Ir J Med Sci 2022; 191:2357–2365.
Danek PJ, et al. Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4. Pharmacol Rep 2021; 73:303–308.
Hart XM, et al. Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: focus on antipsychotics. World J Biol Psychiatry 2024:1–123.
Schoretsanitis G, et al. TDM in psychiatry and neurology: a comprehensive summary of the consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology, update 2017; a tool for clinicians. World J Biol Psychiatry 2018; 19:162–174.
Indiana University School of Medicine. Drug Interactions Flockhart Table™ 2024 (last accessed August 2024); https://drug-interactions. medicine.iu.edu/MainTable.aspx.
Masimirembwa CM, et al. Genetic polymorphism of drug metabolising enzymes in African populations: implications for the use of neuroleptics and antidepressants. Brain Res Bull 1997; 44:561–571.
Aklillu E, et al. Genetic polymorphism of CYP1A2 in Ethiopians affecting induction and expression: characterization of novel haplotypes with single-nucleotide polymorphisms in intron 1. Mol Pharmacol 2003; 64:659.
Muscat JE, et al. Comparison of CYP1A2 and NAT2 phenotypes between black and white smokers. Biochem Pharmacol 2008; 76:929–937.
Wrighton SA, et al. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol 1992; 22:1–21.
Rasmussen BB, et al. The interindividual differences in the 3-demthylation of caffeine alias CYP1A2 is determined by both genetic and environmental factors. Pharmacogenetics 2002; 12:473–478.
Ingelman-Sundberg M, et al. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 2007; 116:496–526.
Stanford University. PharmGKB. 2024 (last accessed August 2024); https://www.pharmgkb.org.
Zhou SF, et al. Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2. AAPS J 2009; 11:481–494.
Myriad Genetics. Genesight. 2024 (last accessed August 2024); https://www.genesight.com.
Enoch MA, et al. Using ancestry-informative markers to define populations and detect population stratification. J Psychopharmacol 2006; 20:19–26.
Genetic Lifehacks. 2024 (last accessed August 2024); https://www.geneticlifehacks.com.
Guttman Y, et al. Polymorphism in cytochrome P450 3A4 is ethnicity related. Front Genet 2019; 10:224.
Darney K, et al. Inter-ethnic differences in CYP3A4 metabolism: a Bayesian meta-analysis for the refinement of uncertainty factors in chemical risk assessment. Computational Toxicol 2019; 12:100092.

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22 - Smoking and psychotropic drugs

Smoking and psychotropic drugs

892 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 11 Smoking and psychotropic drugs Tobacco smoke contains polycyclic aromatic hydrocarbons that induce certain hepatic enzymes (CYP1A2 in particular).1 Other enzymes that may be induced by smoking are CYP2C19 and, possibly, CYP3A4 and some variants of UGT (glycosyltransferases).2 The extent of enzyme induction is determined by the number and type of cigarettes smoked and by the degree of smoke inhalation.3 For some drugs used in psychiatry, smoking significantly reduces drug plasma levels and higher doses are required than in non-smokers. Smoking may also affect alcohol metabolism by inducing CYP2E1.3 When people stop smoking, enzyme activity halves roughly every 2 days.4 It is very important to appreciate that nicotine replacement and vaping have no effect on this process (they do not contain polycyclic aromatic hydrocarbons). Plasma levels of affected drugs will then rise, sometimes substantially. Dose reduction will usually be necessary. If smoking is restarted, enzyme activity increases, plasma levels fall and dose increases are then required. The process is complicated, and effects are difficult to predict. Of course, few people manage to give up smoking completely, so additional complexity is introduced by intermittent smoking and repeated attempts at stopping completely. Close monitoring of plasma levels (where useful), clinical progress and adverse effect severity are essential. Table 11.7 gives details of psychotropic drugs known to be affected by smoking status. Table 11.7 Effect of smoking on psychotropic drugs. Drug Effect of smoking Action to be taken on stopping smoking Action to be taken on restarting smoking Agomelatine5 Plasma levels reduced Monitor closely. Dose may need to be reduced. Consider reintroducing previous smoking dose. Benzodiazepines3,6 Plasma levels reduced by 0–50% (depends on drug and smoking status) Monitor closely. Consider reducing dose by up to 25% over 1 week. Monitor closely. Consider restarting ‘normal’ smoking dose. Carbamazepine3 Unclear, but smoking may reduce carbamazepine plasma levels to a small extent. Monitor for changes in severity of adverse effects. Monitor plasma levels. Chlorpromazine3,6,7 Plasma levels reduced. Varied estimates of exact effect. Monitor closely. Consider dose reduction. Monitor closely. Consider restarting previous smoking dose. Clozapine8–10 Reduces plasma levels by up to 50%. Effect may be maximal at as few as 2–5 cigarettes a day.11 Plasma level reduction and risk of relapse may be greater in those receiving valproate.12 Effect is reversed by co-administered fluvoxamine.13 Take plasma level before stopping. On stopping, reduce dose gradually (over a week) until around 75% of original dose is reached (i.e. reduce by 25%). Repeat plasma level 1 week after stopping. Anticipate further dose reductions. Take plasma level before restarting. Increase dose to previous smoking dose over 1 week. Repeat plasma level. Deterioration is common if dose increases allow a fall in blood levels.14 Duloxetine15,16 Plasma levels may be reduced by up to 50%. Monitor closely. Dose may need to be reduced. Consider reintroducing previous smoking dose.

Pharmacokinetics CHAPTER 11 Table 11.7 (Continued ) Drug Effect of smoking Action to be taken on stopping smoking Action to be taken on restarting smoking Escitalopram17 In practice, smokers have lower blood levels despite being given higher doses. Reduction in levels may be up to 50% (possibly via induction of CYP2C19). Monitor closely. Consider 25% dose reduction. Monitor closely. Reinstate smoking dose. Fluphenazine18 Reduces plasma levels by up to 50% On stopping, reduce dose by 25%. Monitor carefully over following 4–8 weeks. Consider further dose reductions. On restarting, increase dose to previous smoking dose. Fluvoxamine19 Plasma levels decreased by around a third Monitor closely. Dose may need to be reduced. Dose may need to be increased to previous level. Haloperidol20,21 Reduces plasma levels by around 25–50% Reduce dose by around 25%. Monitor carefully. Consider further dose reductions. On restarting, increase dose to previous smoking dose. Loxapine22 (inhaled) Half-life reduced from 15.7 to 13.6 hours Monitor Monitor Mirtazapine23 Unclear, but effect probably minimal Monitor Monitor Olanzapine10,24–26 Reduces plasma levels by up to 50%. Effect increases with number of cigarettes smoked.26 Take plasma level before stopping. On stopping, reduce dose by 25%. After 1 week, repeat plasma level. Consider further dose reductions. Take plasma level before restarting. Increase dose to previous smoking dose over 1 week. Repeat plasma level. Risperidone2,27 Active moiety concentrations probably lower in smokers. Minor effect (possibly via induction of CYP3A4). Smoking may not affect paliperidone concentrations.28 Monitor closely Monitor closely Trazodone29 Around 25% reduction Monitor for increased sedation. Consider dose reduction. Monitor closely. Consider increasing dose. Tricyclic antidepressants3,6,30 Plasma levels reduced by 25–50%. Some studies suggest more limited effect.2,31 Monitor closely. Consider reducing dose by 10–25% over 1 week. Consider further dose reductions. Monitor closely. Consider restarting previous smoking dose. Zuclopenthixol32,33 Unclear, but effect probably minimal Monitor Monitor Note (again: it bears repeating): only tobacco smoking induces hepatic enzymes in the manner described above. This includes cigarettes and cannabis/tobacco ‘joints’. Nicotine replacement, vaping devices and electronic cigarettes (which do not contain polycyclic aromatic compounds) have no effect on enzyme activity.34,35

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References

894 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 11 References

Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm 2007; 64:1917–1921.
Scherf-Clavel M, et al. Analysis of smoking behavior on the pharmacokinetics of antidepressants and antipsychotics: evidence for the role of alternative pathways apart from CYP1A2. Int Clin Psychopharmacol 2019; 34:93–100.
Desai HD, et al. Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. CNS Drugs 2001; 15:469–494.
Faber MS, et al. Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clin Pharmacol Ther 2004; 76:178–184.
Servier Laboratories Limited. Summary of product characteristics. Valdoxan (agomelatine). 2021; https://www.medicines.org.uk/emc/ medicine/21830.
Miller LG. Recent developments in the study of the effects of cigarette smoking on clinical pharmacokinetics and clinical pharmacodynamics. Clin Pharmacokinet 1989; 17:90–108.
Goff DC, et al. Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects. Am J Psychiatry 1992; 149:1189–1194.
Haring C, et al. Influence of patient-related variables on clozapine plasma levels. Am J Psychiatry 1990; 147:1471–1475.
Diaz FJ, et al. Estimating the size of the effects of co-medications on plasma clozapine concentrations using a model that controls for clozapine doses and confounding variables. Pharmacopsychiatry 2008; 41:81–91.
Tsuda Y, et al. Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine. BMJ Open 2014; 4:e004216.
Flanagan RJ, et al. Effect of cigarette smoking on clozapine dose and on plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in clinical practice. J Clin Psychopharmacol 2023; 43:514–519.
Tsukahara M, et al. Effect of smoking habits and concomitant valproic acid use on relapse in patients with treatment-resistant schizophrenia receiving clozapine: a 1-year retrospective cohort study. Acta Psychiatr Scand 2023; 148:437–446.
Augustin M, et al. Effect of fluvoxamine augmentation and smoking on clozapine serum concentrations. Schizophr Res 2019; 210:143–148.
Qurashi I, et al. Changes in smoking status, mental state and plasma clozapine concentration: retrospective cohort evaluation. BJPsych Bull 2019; 43:271–274.
Fric M, et al. The influence of smoking on the serum level of duloxetine. Pharmacopsychiatry 2008; 41:151–155.
Augustin M, et al. Differences in duloxetine dosing strategies in smoking and nonsmoking patients: therapeutic drug monitoring uncovers the impact on drug metabolism. J Clin Psychiatry 2018; 79:17m12086.
Scherf-Clavel M, et al. Smoking is associated with lower dose-corrected serum concentrations of escitalopram. J Clin Psychopharmacol 2019; 39:485–488.
Ereshefsky L, et al. Effects of smoking on fluphenazine clearance in psychiatric inpatients. Biol Psychiatry 1985; 20:329–332.
Spigset O, et al. Effect of cigarette smoking on fluvoxamine pharmacokinetics in humans. Clin Pharmacol Ther 1995; 58:399–403.
Jann MW, et al. Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance. Psychopharmacology (Berl) 1986; 90:468–470.
Shimoda K, et al. Lower plasma levels of haloperidol in smoking than in nonsmoking schizophrenic patients. Ther Drug Monit 1999; 21:293–296.
Takahashi LH, et al. Effect of smoking on the pharmacokinetics of inhaled loxapine. Ther Drug Monit 2014; 36:618–623.
Grasmader K, et al. Population pharmacokinetic analysis of mirtazapine. Eur J Clin Pharmacol 2004; 60:473–480.
Carrillo JA, et al. Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol 2003; 23:119–127.
Lowe EJ, et al. Impact of tobacco smoking cessation on stable clozapine or olanzapine treatment. Ann Pharmacother 2010; 44:727–732.
Horvat M, et al. Association of smoking cigarettes, age, and sex with serum concentrations of olanzapine in patients with schizophrenia. Biochem Med (Zagreb) 2023; 33:030702.
Schoretsanitis G, et al. Effect of smoking on risperidone pharmacokinetics – a multifactorial approach to better predict the influence on drug metabolism. Schizophr Res 2017; 185:51–57.
Schoretsanitis G, et al. Lack of smoking effects on pharmacokinetics of oral paliperidone—analysis of a naturalistic therapeutic drug monitoring sample. Pharmacopsychiatry 2021; 54:31–35.
Ishida M, et al. Effects of various factors on steady state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine. Int Clin Psychopharmacol 1995; 10:143–146.
Ereshefsky L, et al. Pharmacokinetic factors affecting antidepressant drug clearance and clinical effect: evaluation of doxepin and imipramine – new data and review. Clin Chem 1988; 34:863–880.
Lundstrøm NH, et al. The effect of smoking on the plasma concentration of tricyclic antidepressants: a systematic review. Acta Neuropsychiatr 2022; 34:1–9.
Jann MW, et al. Clinical pharmacokinetics of the depot antipsychotics. Clin Pharmacokinet 1985; 10:315–333.
Jorgensen A, et al. Zuclopenthixol decanoate in schizophrenia: serum levels and clinical state. Psychopharmacology (Berl) 1985; 87:364–367.
Blacker CJ. Clinical issues to consider for clozapine patients who vape: a case illustration. Focus (Am Psychiatr Publ) 2020; 18:55–57.
Montville DJ, et al. Fluctuation between cigarette smoking and use of electronic nicotine delivery systems: impact on clozapine concentrations and clinical effect. Ment Health Clin 2021; 11:365–368.

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Drug interactions with alcohol

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25 - Pharmacokinetic interactions14

Pharmacokinetic interactions1–4

Pharmacokinetics CHAPTER 11 Drug interactions with alcohol Drug interactions with alcohol are complex. Many patient-related and drug-related factors need to be considered. It can be difficult to predict outcomes accurately because a number of processes may occur simultaneously or consecutively. Pharmacokinetic interactions1–4 Alcohol (ethanol) is absorbed from the gastrointestinal tract and distributed in body water. The volume of distribution is smaller in women and the elderly where plasma levels of alcohol will be higher than in young males for a given intake of alcohol. Ingested alcohol is subject to metabolism by alcohol dehydrogenase (ADH). A small proportion of alcohol is metabolised by ADH in the stomach. The remainder is metabolised in the liver by ADH, and by CYP2E1. At low alcohol concentrations only ADH is active; CYP2E1 only begins to contribute when concentrations approach the legal driving limit of many countries (0.08%).5 CYP2E1 plays a minor role in occasional drinkers but is an important and inducible metabolic route in chronic, heavy drinkers. The induction of CYP2E1 accounts for the apparent tolerance of alcohol in heavy drinkers.6 CYP1A2, CYP3A4 and many other CYP enzymes also play a minor role in the metabolism of ethanol.7,8 CYP2E1 and ADH convert alcohol to acetaldehyde. This is both the toxic substance responsible for the unpleasant symptoms of the ‘Antabuse reaction’ (e.g. flushing, headache, nausea, malaise) and the compound implicated in hepatic damage. It may have psychotropic effects – ethanol is metabolised to acetaldehyde by CYP2E1 in the brain.9 The enzyme catalase is also known to metabolise alcohol to acetaldehyde in the brain and elsewhere.10 Acetaldehyde is further metabolised by aldehyde dehydrogenase to acetic acid and then to carbon dioxide and water (Figure 11.1).

This is a minor route in occasional drinkers, and a major route in heavy drinkers and at higher blood alcohol concentration. The ubiquitous enzyme catalase is also able to metabolise ethanol but its overall contribution is not known. Alcohol dehydrogenase (ADH) CYP2E1* Aldehyde dehydrogenase Ethanol Acetaldehyde Ethanoic acid CYP3A4 CYP1A2 Water + CO2 CYP2B6 Figure 11.1 Metabolism of alcohol.

896 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 11 All of the enzymes involved in the metabolism of alcohol exhibit genetic polymorphism. For example, the majority of people of north Asian origin are poor metabolisers via aldehyde dehydrogenase.11 Enzyme function can change in response to alcohol. Chronic consumption of alcohol induces CYP2E1 and CYP3A4. The effects of alcohol on other hepatic metabolising enzymes have been poorly studied. Table 11.8 lists drugs that inhibit ADH and aldehyde dehydrogenase. Interactions are difficult to predict in alcohol misusers because two opposing processes may be at work: competition for enzymatic sites during periods of consumption/ intoxication (increasing drug plasma levels) and enzyme induction prevailing during periods of sobriety (reducing drug plasma levels10). In chronic drinkers, particularly those who binge-drink, blood levels of prescribed drugs may reach toxic levels during periods of intoxication with alcohol and then be sub-therapeutic when the patient is sober. Even in non-intoxicated individuals there is some evidence that co-administered alcohol confers competitive inhibition of CYP3A4, leading to increased exposure to drugs metabolised by this enzyme (Table 11.9).15 This makes it very difficult to optimise treatment of physical or mental illness. Table 11.8 Drugs that inhibit alcohol dehydrogenase and aldehyde dehydrogenase. Enzyme Inhibited by Potential consequences Alcohol dehydrogenase Aspirin H2 antagonists Reduced metabolism of alcohol resulting in higher plasma levels for longer periods of time Aldehyde dehydrogenase Chlorpropamide Disulfiram Griseofulvin Isoniazid Isosorbide dinitrate Metronidazole* Nitrofurantoin Sulphamethoxazole Tolbutamide Reduced ability to metabolise acetaldehyde leading to ‘Antabuse’ type reaction: facial flushing, headache, tachycardia, nausea and vomiting, arrhythmias and hypotension *Evidence that metronidazole has any effect on aldehyde dehydrogenase is surprisingly weak.12–14 Table 11.9 Co-administration of alcohol and substrates for CYP2E1 and CYP3A4.5,6,16 Substrates for enzyme (note: this is not an exhaustive list) Effects in an intoxicated patient Effects in a chronic, sober drinker CYP2E1 Isoniazid Paracetamol Phenobarbitone Warfarin Zopiclone Competition between alcohol and drug leading to reduced rates of metabolism of both compounds. Increased plasma levels may lead to toxicity Activity of CYP2E1 is increased up 10-fold Increased metabolism of drugs potentially leading to therapeutic failure

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26 - Pharmacodynamic interactions24

Pharmacodynamic interactions2–4

Pharmacokinetics CHAPTER 11 Interactions of uncertain aetiology include increased blood alcohol concentrations in people who take verapamil and decreased metabolism of methylphenidate in people who consume alcohol. Alcohol may also, via various routes, impair the function of slow-release tablet mechanisms causing dose-dumping.17 Pharmacodynamic interactions2–4 Alcohol enhances inhibitory neurotransmission at gamma-aminobutyric acid A (GABA-A) receptors and reduces excitatory neurotransmission at glutamate N-methyl-D-aspartate (NMDA) receptors. It also increases dopamine release in the mesolimbic pathway and may have some effects on serotonin and opiate pathways. Given these actions, alcohol would be expected to cause sedation, amnesia and ataxia (Table 11.10) and give rise to feelings of pleasure (and/or worsen psychotic symptoms in vulnerable individuals). Table 11.9 (Continued ) Substrates for enzyme (note: this is not an exhaustive list) Effects in an intoxicated patient Effects in a chronic, sober drinker CYP3A4 Alprazolam Aripiprazole Benzodiazepines Carbamazepine Clozapine Donepezil Galantamine Haloperidol Methadone Mirtazapine Quetiapine Risperidone Sildenafil Tricyclics Valproate Venlafaxine Z-hypnotics Competition between alcohol and drug leading to reduced rates of metabolism of both compounds. Increased plasma levels may lead to toxicity Increased rate of drug metabolism potentially leading to therapeutic failure Enzyme induction can last for several weeks after alcohol consumption ceases Table 11.10 Pharmacodynamic interactions with alcohol. Effect of alcohol Effect exacerbated by Potential consequences Sedation Other sedative drugs, e.g.: Antihistamines Antipsychotics Baclofen Benzodiazepines Lofexidine Opiates Tizanidine Tricyclics Z-hypnotics Increased CNS depression ranging from increased propensity to be involved in accidents through to respiratory depression and death (Continued )

898 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 11 Alcohol can cause or worsen psychotic symptoms by increasing dopamine release in mesolimbic pathways. The effect of antipsychotic drugs may be competitively antagonised, rendering them less effective. Electrolyte disturbances secondary to alcohol-related dehydration can be exacerbated by other drugs that cause electrolyte disturbances (e.g. diuretics). Heavy alcohol consumption can lead to hypoglycaemia in people with diabetes who take insulin or oral hypoglycaemics. Theoretically there is an increased risk of lactic acidosis in patients who take metformin with alcohol. Alcohol can also increase blood pressure. Chronic alcohol drinkers are particularly susceptible to the gastrointestinal irritant effects of aspirin and non-steroidal anti-inflammatory drugs. In the presence of pharmacokinetic interactions, pharmacodynamic interactions may be more marked. For example, in a chronic heavy drinker who is sober, enzyme induction will increase the metabolism of diazepam, which may lead to increased levels of anxiety (treatment failure). If the same patient becomes intoxicated with alcohol, the metabolism of diazepam will be greatly reduced as it will have to compete with alcohol for the metabolic capacity of CYP3A4. Plasma levels of alcohol and diazepam will rise (toxicity). As both alcohol and diazepam are sedative (via GABA-A affinity), loss of consciousness and respiratory depression may occur. Table 11.11 lists drugs that are safe and those that should be avoided in patients who continue drinking. Table 11.10 (Continued ) Effect of alcohol Effect exacerbated by Potential consequences Amnesia Other amnesic drugs, e.g.: Barbiturates Benzodiazepines Z-hypnotics Increased amnesic effects ranging from mild memory loss to total amnesia. Usually anterograde amnesia: loss of memory of events after the effects of alcohol begin Ataxia ACE inhibitors Beta-blockers Calcium channel blockers Nitrates Adrenergic alpha receptor antagonists, e.g.: Clozapine Risperidone Tricyclics Increased unsteadiness and falls ACE, angiotensin-converting enzyme; CNS, central nervous system.

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References

Pharmacokinetics CHAPTER 11 References

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Williams CS, et al. Do ethanol and metronidazole interact to produce a disulfiram-like reaction? Ann Pharmacother 2000; 34:255–257.
Visapää JP, et al. Lack of disulfiram-like reaction with metronidazole and ethanol. Ann Pharmacother 2002; 36:971–974.
Mergenhagen KA, et al. Fact versus fiction: a review of the evidence behind alcohol and antibiotic interactions. Antimicrob Agents Chemother 2020; 64:e02167–02119.
Huang Z, et al. Influence of ethanol on the metabolism of alprazolam. Expert Opin Drug Metab Toxicol 2018; 14:551–559.
Traccis F, et al. Alcohol-medication interactions: a systematic review and meta-analysis of placebo-controlled trials. Neurosci Biobehav Rev 2022; 132:519–541.
Lennernäs H. Ethanol-drug absorption interaction: potential for a significant effect on the plasma pharmacokinetics of ethanol vulnerable formulations. Mol Pharm 2009; 6:1429–1440. Table 11.11 Psychotropic drugs: choice in patients who continue to drink. Safest choice Best avoided Antipsychotics Sulpiride and amisulpride Paliperidone, if depot required (non-sedative and renally excreted) Very sedative antipsychotics such as chlorpromazine and clozapine Antidepressants SSRIs – citalopram, sertraline Potent inhibitors of CYP3A4 (fluoxetine, paroxetine) may decrease alcohol metabolism in chronic drinkers TCAs, because impairment of metabolism by alcohol (while intoxicated) can lead to increased plasma levels and consequent signs and symptoms of overdose (profound hypotension, seizures, arrhythmias and coma) Cardiac effects can be exacerbated by electrolyte disturbances Combinations of TCAs and alcohol profoundly impair psychomotor skills Mirtazapine – often very sedative MAOIs, as can cause profound hypotension. Also potential interaction with tyramine-containing drinks which can lead to hypertensive crisis Mood stabilisers Valproate (where regulations allow) Carbamazepine Higher plasma levels achieved during periods of alcohol intoxication may be poorly tolerated Lithium, because it has a narrow therapeutic index and alcohol-related dehydration and electrolyte disturbance can precipitate lithium toxicity Note: be aware of the possibility of hepatic failure or reduced hepatic function in chronic alcohol misusers. See ‘Hepatic impairment’ in Chapter 8. Also note the risk of hepatic toxicity with some recommended drugs (e.g. valproate). MAOIs, monoamine oxidase inhibitors; TCAs, tricyclic antidepressants.

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01 - Caffeine

Caffeine

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 12 Caffeine Caffeine is probably the most used psychoactive substance in the world. Mean daily consumption in the UK is 350–620mg.1 A quarter of the general population and half of those with psychiatric illness regularly consume over 500mg caffeine per day.2 Consumption of caffeine should be routinely discussed with an individual to assess its effect on their symptoms and presentation.3 Both caffeine intake and caffeine withdrawal can have a marked effect on mental and physical health. Most caffeine intake is in the form of coffee and tea but increasingly in the form of energy drinks (Table 12.1). Caffeine is also a constituent of chocolate and hundreds of over-the-counter medicines where it is often included as a co-analgesic. Other substances Table 12.1 Typical caffeine content of drinks. Drink Caffeine content Brewed coffee4 100mg/cup (around 100mg per espresso shot) Red Bull 80mg/can (other energy drinks may contain substantially more; volume of cans varies substantially) Instant coffee 60mg/cup Black tea 45mg/cup Soft drinks (sodas) 25–50mg/can Green tea 20–30mg/cup Decaffeinated coffee 3–16mg5

17 - Chapter 12 Other substances

02 - General effects of caffeine

General effects of caffeine

17 - Chapter 12 Other substances

03 - Psychotropic effects of caffeine

Psychotropic effects of caffeine

902 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 12 General effects of caffeine ■ ■Acute use can increase systolic and diastolic blood pressure (BP) by up to 10mmHg for up to 4 hours.3 Chronic moderate use probably has little effect on BP.9 ■ ■May enhance reinforcing effects of nicotine and possibly other drugs of misuse.10,11 ■ ■Caffeine has important psychotropic effects (Table 12.2), may worsen existing psychiatric illness and may interact with psychotropic drugs. ■ ■Caffeine is an antagonist at adenosine A1 and A2A receptors, thus stimulating dopamine pathways. Psychotropic effects of caffeine Withdrawal An established withdrawal syndrome exists; symptoms include headache, depressed mood, anxiety, fatigue, irritability, nausea, dysphoria and craving.12 Pharmacokinetics ■ ■Absorption: Rapid after oral administration, especially in liquid form. ■ ■Metabolism: ■ ■Half-life of 2.5–4.5 hours. ■ ■Metabolised by CYP1A2, a hepatic cytochrome enzyme that exhibits genetic polymorphism. This may account for the large interindividual differences that are seen in the ability to tolerate caffeine.13 Note that CYP1A2 is induced by smoking and inhibited by a number of drugs such as fluvoxamine. ■ ■This metabolic pathway may become saturated at higher doses.14 ■ ■Interactions (Table 12.3): ■ ■Caffeine competitively inhibits CYP1A2. Chronic caffeine use may increase plasma levels of drugs metabolised by CYP1A2. Plasma levels of some drugs may be reduced if caffeine is withdrawn. Table 12.2 Dose and psychotropic effects of caffeine. Dose Psychotropic effect Generally Central nervous system stimulation Increase catecholamine release, particularly dopamine6 Low to moderate dose2,7 Elation Impulsivity Peacefulness Large doses >600mg/day8 (sensitive [non-tolerant] individuals may experience effects at lower doses; tolerance develops in long-term users) Anxiety Insomnia Psychomotor agitation Excitement Rambling speech Delirium Psychosis

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04 - Caffeine intoxication

Caffeine intoxication

Other substances CHAPTER 12 ■ ■The potential effects of caffeine on the metabolism of other drugs, as well as the potential to induce a caffeine withdrawal syndrome, should always be considered before substituting caffeine-free drinks. Caffeine intoxication The DSM-519 defines caffeine intoxication as the recent consumption of caffeine, usually in excess of 250mg, accompanied by five or more of the symptoms in Box 12.1. In caffeine intoxication, these symptoms cause significant distress or impairment in social, occupational or other important areas of functioning and are not due to a general medical condition or better accounted for by another mental disorder (e.g. an anxiety disorder). Caffeine abuse or dependence as a clinical syndrome has been reported3 and caffeine use disorder and caffeine withdrawal are both DSM-5 diagnoses. Table 12.3 Interactions with caffeine. Interacting substance Effect Comments CYP1A2 inhibitors: Oestrogens Cimetidine Fluvoxamine (may decrease caffeine clearance by 80%)15 Disulfiram Reduce caffeine clearance Effects of caffeine may be prolonged or increased Adverse effects may be increased May precipitate caffeine toxicity Cigarette smoke* CYP1A2 inducer – increased caffeine metabolism6 Smokers may require higher doses of caffeine to gain desired effects6 Lithium High doses of caffeine may reduce lithium levels Caffeine withdrawal may cause a lithium level rise16 MAOIs May enhance stimulant CNS effects Clozapine Caffeine may increase clozapine plasma concentrations by up to 60%17 Thought to be via competitive inhibition of CYP1A2. Other drugs affected by caffeine-induced inhibition of the enzyme include olanzapine, imipramine and clomipramine. SSRIs Large doses of caffeine may increase risk of serotonin syndrome18 Benzodiazepines Caffeine may act as an antagonist Caffeine reduces the efficacy of benzodiazepines8 * Vaping has no effect on CYP1A2 function. CNS, central nervous system; MAOIs, monoamine oxidase inhibitors.

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05 - Energy drinks

Energy drinks

17 - Chapter 12 Other substances

06 - Effects of caffeine on different disorders

Effects of caffeine on different disorders

904 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 12 Energy drinks So-called energy drinks contain large amounts of caffeine along with sugar, vitamins and a number of other ingredients such as guarana and taurine. There is some evidence that these drinks can improve attention and short-term memory.20 Marketing is targeted at adolescents and young adults, some of whom consume large volumes of these drinks and seem to be particularly vulnerable to developing signs and symptoms of caffeine intoxication. Symptoms of anxiety and depression, frank suicidal behaviour and seizures have been associated with use of these products by young people.21–23 When combined with alcohol, aggressive behaviour may result.24 Excessive intake may lead to acute psychosis25,26 or mania.27 Effects of caffeine on different disorders Schizophrenia ■ ■Patients with schizophrenia often consume large amounts of caffeine-containing drinks1 and they are twice as likely as controls to consume >200mg caffeine/day.6 ■ ■Caffeine-containing drinks may be used to relieve dry mouth (as an adverse effect of some antipsychotic drugs), for the stimulant effects of caffeine (to relieve dysphoria/ sedation/negative symptoms)6 or simply because coffee/tea drinking structures the day or relieves boredom. ■ ■Schizophrenia may increase sensitivity to drug-related cues.6 ■ ■Moderate caffeine intake may improve cognitive and negative symptoms in schizophrenia.28,29 ■ ■Large doses of caffeine can worsen psychotic symptoms6,30 (in particular elation and conceptual disorganisation) and result in the prescription of larger doses of antipsychotic drugs. ■ ■The removal of caffeine from the diets of chronically disturbed (challenging behaviour) patients may ultimately lead to decreased levels of hostility, irritability and suspiciousness31 although this may not hold true in less disturbed populations.32 ■ ■Caffeine cessation may be of benefit in clozapine-resistant schizophrenia.33 Box 12.1 Symptoms of caffeine intoxication ■ ■Restlessness ■ ■Gastrointestinal disturbance ■ ■Nervousness ■ ■Muscle twitching ■ ■Excitement ■ ■Rambling flow of thought and speech ■ ■Insomnia ■ ■Tachycardia or cardiac arrhythmia ■ ■Flushed face ■ ■Periods of inexhaustibility ■ ■Diuresis ■ ■Psychomotor agitation

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07 - Summary

Summary

Other substances CHAPTER 12 Mood disorders ■ ■Caffeine may elevate mood through increasing noradrenaline release34 and modest caffeine consumption may protect against depression in those who do not have a pre- existing mood disorder.35 ■ ■People with mood disorders are more likely to consume caffeine, particularly when depressed.16,36 ■ ■Depressed patients may be more sensitive to the anxiogenic effects of caffeine.37,38 ■ ■Excessive consumption of caffeine may precipitate mania.38,39 ■ ■Caffeine can increase cortisol secretion (gives a false positive in the dexamethasone- suppression test),40 increase seizure length during electroconvulsive therapy41 and increase the clearance of lithium by promoting diuresis.42 Anxiety disorders ■ ■Caffeine increases vigilance, decreases reaction times, increases sleep latency and worsens sleep quality; effects that may be more marked in poor metabolisers. ■ ■May precipitate or worsen generalised anxiety and panic attacks;43 vulnerability to these effects may be genetically determined.11 ■ ■Effects are so marked that caffeine intoxication should always be considered when patients complain of anxiety symptoms or insomnia. ■ ■Symptoms may diminish considerably or even abate completely if caffeine is avoided.44 ■ ■Patients with panic disorder consume much more caffeine than controls45 but the reasons for this are not clear. Greater consumption triggers panic attacks in those with panic disorder but not in other populations.46 Other disorders Weak evidence supports the benefit of caffeine in attention deficit hyperactivity disorder (ADHD)47 and that high caffeine consumption may protect against late-life cognitive decline.48 Summary ■ ■Caffeine is present in high quantities in coffee and some soft drinks, particularly energy drinks. ■ ■The intake of caffeine may worsen psychosis and anxiety. Young people may be particularly vulnerable. ■ ■Caffeine inhibits clozapine metabolism. ■ ■Caffeine intoxication is characterised by psychomotor agitation and rambling speech. ■ ■Caffeine may be associated with toxicity when co-administered with CYP1A2 inhibitors such as fluvoxamine. ■ ■Caffeine can enhance the reinforcing effects of nicotine and possibly other drugs of misuse.

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08 - References

References

906 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 12 References

Rihs M, et al. Caffeine consumption in hospitalized psychiatric patients. Eur Arch Psychiatry Clin Neurosci 1996; 246:83–92.
Clementz GL, et al. Psychotropic effects of caffeine. Am Fam Physician 1988; 37:167–172.
Ogawa N, et al. Clinical importance of caffeine dependence and abuse. Psychiatry Clin Neurosci 2007; 61:263–268.
Desbrow B, et al. An examination of consumer exposure to caffeine from retail coffee outlets. Food Chem Toxicol 2007; 45:1588–1592.
McCusker RR, et al. Caffeine content of decaffeinated coffee. J Anal Toxicol 2006; 30:611–613.
Adolfo AB, et al. Effects of smoking cues on caffeine urges in heavy smokers and caffeine consumers with and without schizophrenia. Schizophr Res 2009; 107:192–197.
Grant JE, et al. Caffeine’s influence on gambling behavior and other types of impulsivity. Addict Behav 2018; 76:156–160.
Sawynok J. Pharmacological rationale for the clinical use of caffeine. Drugs 1995; 49:37–50.
O’Keefe JH, et al. Effects of habitual coffee consumption on cardiometabolic disease, cardiovascular health, and all-cause mortality. J Am Coll Cardiol 2013; 62:1043–1051.
Pharmaceutical Press. Martindale: The Complete Drug Reference. 2024; www.medicinescomplete.com.
Bergin JE, et al. Common psychiatric disorders and caffeine use, tolerance, and withdrawal: an examination of shared genetic and environmental effects. Twin Res Hum Genet 2012; 15:473–482.
Silverman K, et al. Withdrawal syndrome after the double-blind cessation of caffeine consumption. N Engl J Med 1992; 327:1109–1114.
Butler MA, et al. Determination of CYP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites. Pharmacogenetics 1992; 2:116–127.
Kaplan GB, et al. Dose-dependent pharmacokinetics and psychomotor effects of caffeine in humans. J Clin Pharmacol 1997; 37:693–703.
Pharmaceutical Press. Medicines Complete: Stockley’s Drug Interactions. 2024; www.medicinescomplete.com.
Baethge C, et al. Coffee and cigarette use: association with suicidal acts in 352 Sardinian bipolar disorder patients. Bipolar Disord 2009; 11:494–503.
Carrillo JA, et al. Effects of caffeine withdrawal from the diet on the metabolism of clozapine in schizophrenic patients. J Clin Psychopharmacol 1998; 18:311–316.
Ohta R, et al. Serotonin syndrome triggered by overuse of caffeine and complicated with neuroleptic malignant syndrome: a case report. Cureus 2022; 14:e22468.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th edn (DSM-5). Arlington, VA: American Psychiatric Association; 2013.
Wesnes KA, et al. An evaluation of the cognitive and mood effects of an energy shot over a 6h period in volunteers: a randomized, double- blind, placebo controlled, cross-over study. Appetite 2013; 67:105–113.
Szpak A, et al. A case of acute suicidality following excessive caffeine intake. J Psychopharmacol 2012; 26:1502–1510.
Trapp GS, et al. Energy drink consumption among young Australian adults: associations with alcohol and illicit drug use. Drug Alcohol Depend 2014; 134:30–37.
Pennington N, et al. Energy drinks: a new health hazard for adolescents. J Sch Nurs 2010; 26:352–359.
Sheehan BE, et al. Caffeinated and non-caffeinated alcohol use and indirect aggression: the impact of self-regulation. Addict Behav 2016; 58:53–59.
Görgülü Y, et al. A case of acute psychosis following energy drink consumption. Noro Psikiyatri Arsivi 2014; 51:79–81.
Kelsey D, et al. A case of psychosis and renal failure associated with excessive energy drink consumption. Case Rep Psychiatry 2019; 2019:3954161.
Rodrigues Cordeiro C, et al. Triggers for acute mood episodes in bipolar disorder: a systematic review. J Psychiatr Res 2023; 161:237–260.
Szoke A, et al. Clinical and pharmacological correlates of caffeine consumption in subjects with schizophrenia – data from the FACE-SZ cohort. J Psychiatr Res 2023; 161:206–212.
Han Almis B, et al. Is there a relationship between caffeine intake and smoking and positive and negative symptom severity in schizophrenia? Psychiatr Danub 2023; 35:56–61.
Wang HR, et al. Caffeine-induced psychiatric manifestations: a review. Int Clin Psychopharmacol 2015; 30:179–182.
De Freitas B, et al. Effects of caffeine in chronic psychiatric patients. Am J Psychiatry 1979; 136:1337–1338.
Koczapski A, et al. Effects of caffeine on behavior of schizophrenic inpatients. Schizophr Bull 1989; 15:339–344.
Dratcu L, et al. Clozapine-resistant psychosis, smoking, and caffeine: managing the neglected effects of substances that our patients consume every day. Am J Ther 2007; 14:314–318.
Achor MB, et al. Diet aids, mania, and affective illness. Am J Psychiatry 1981; 138:392.
Wang L, et al. Coffee and caffeine consumption and depression: a meta-analysis of observational studies. Aust NZ J Psychiatry 2016; 50:228–242.
Maremmani I, et al. Are “social drugs” (tobacco, coffee and chocolate) related to the bipolar spectrum? J Affect Disord 2011; 133:227–233.
Lee MA, et al. Anxiogenic effects of caffeine on panic and depressed patients. Am J Psychiatry 1988; 145:632–635.
Rizkallah E, et al. Could the use of energy drinks induce manic or depressive relapse among abstinent substance use disorder patients with comorbid bipolar spectrum disorder? Bipolar Disord 2011; 13:578–580.
Machado-Vieira R, et al. Mania associated with an energy drink: the possible role of caffeine, taurine, and inositol. Can J Psychiatry 2001; 46:454–455.
Uhde TW, et al. Caffeine-induced escape from dexamethasone suppression. Arch Gen Psychiatry 1985; 42:737–738.
Cantu TG, et al. Caffeine in electroconvulsive therapy. Ann Pharmacother 1991; 25:1079–1080.

Other substances CHAPTER 12 42. Mester R, et al. Caffeine withdrawal increases lithium blood levels. Biol Psychiatry 1995; 37:348–350. 43. Bruce MS. The anxiogenic effects of caffeine. Postgrad Med J 1990; 66 Suppl 2:S18–S24. 44. Bruce MS, et al. Caffeine abstention in the management of anxiety disorders. Psychol Med 1989; 19:211–214. 45. Santos VA, et al. Panic disorder and chronic caffeine use: a case-control study. Clin Pract Epidemiol Ment Health 2019; 15:120–125. 46. Klevebrant L, et al. Effects of caffeine on anxiety and panic attacks in patients with panic disorder: a systematic review and meta-analysis. Gen Hosp Psychiatry 2022; 74:22–31. 47. Ioannidis K, et al. Ostracising caffeine from the pharmacological arsenal for attention-deficit hyperactivity disorder – was this a correct decision? A literature review. J Psychopharmacol 2014; 28:830–836. 48. Panza F, et al. Coffee, tea, and caffeine consumption and prevention of late-life cognitive decline and dementia: a systematic review. J Nutr Health Aging 2015; 19:313–328.

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09 - Nicotine

Nicotine

17 - Chapter 12 Other substances

10 - Psychotropic effects

Psychotropic effects

17 - Chapter 12 Other substances

11 - Effects of nicotine on different disorders

Effects of nicotine on different disorders

908 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 12 Nicotine Nicotine is consumed by vaping or tobacco smoking and causes peripheral vasoconstriction, tachycardia and increased blood pressure.1 People with schizophrenia who smoke are more likely to develop the metabolic syndrome compared with those who do not smoke.2 Alongside nicotine, cigarettes also contain tar (a complex mixture of organic molecules, many carcinogenic), a cause of cancers of the respiratory tract, chronic bronchitis and emphysema.3 Electronic cigarettes and vaping devices contain only nicotine (along with some necessary excipients), which has very limited toxicity and is not thought to be carcinogenic. Vaping is thus preferred for all smokers, albeit with some reservations in regard to quality control of content and the so-called re-normalisation of smoking. Vaping is not without risk but this is a complex area beyond the scope of this book. Nicotine is highly addictive and vulnerability to nicotine addiction may be genetically determined.4 People with mental illness are 2–3 times more likely than the general population to develop and maintain a nicotine addiction.5 Chronic smoking contributes to the increased morbidity and mortality from respiratory and cardiovascular disease that is seen in this patient group. Nicotine also has psychotropic effects. Smoking can affect the metabolism (and therefore the efficacy and toxicity) of drugs prescribed to treat psychiatric illness6 (see ‘Smoking and psychotropic drugs’ in Chapter 11). Nicotine use may be a gateway drug to experimenting with other psychoactive substances. Psychotropic effects Nicotine is highly lipid-soluble and rapidly enters the brain after inhalation. Nicotine receptors are found on dopaminergic cell bodies and stimulation of these receptors leads to dopamine release.5 Nicotine may be used by people with mental health problems as a form of ‘self-medication’ (e.g. to alleviate the negative symptoms of schizophrenia or antipsychotic-induced dysphoria or for its anxiolytic effect7). Drugs that increase the release of dopamine reduce craving for nicotine. They may also, of course, worsen psychotic illness. Nicotine improves concentration and vigilance,5 probably by enhancing the effects of glutamate, acetylcholine and serotonin.7 Effects of nicotine on different disorders Schizophrenia Before the introduction of vaping, 70–80% of people with schizophrenia regularly smoked cigarettes.8 Now both tobacco use and vaping are more common among people with psychosis.9,10 A 2024 study in the USA11 found that 28% of people with a first episode of psychosis used nicotine in one form or another – roughly double the rate of age-matched controls. In people with longer-standing psychosis in 2023, tobacco use was seen in just over 40% but use of any nicotine product was reported in around 70–80% (i.e. a prevalence no different from before the availability of vaping devices).12

Other substances CHAPTER 12 This increased tendency to use nicotine predates the onset of psychiatric symptoms13 and smoking might actually be a causal factor in schizophrenia.14 Possible explanations are as follows:15 (i) smoking causes dopamine release, leading to feelings of well-being and a reduction in negative symptoms;7 (ii) smoking alleviates some of the adverse effects of antipsychotics such as drowsiness and extrapyramidal side effects (EPSEs)5 and cognitive slowing;16,17 (iii) smoking serves as a means of structuring the day (a behavioural filler); (iv) smoking arises as a result of a familial vulnerability;18 or (v) smoking may be used as a means of alleviating the deficit in auditory gaiting that is found in schizophrenia.19 Nicotine may also improve working memory and attentional deficits.20–22 Nicotinic receptor agonists may have beneficial effects on neurocognition,23,24 although none is licensed for this purpose. Note though that cholinergic agonists may exacerbate nicotine dependence.25 Interestingly, the greater the occupancy of striatal D2 receptors by antipsychotic drugs, the more likely the patient is to smoke.26 This may partly explain the clinical observation that smoking cessation may be more achievable when clozapine (a weak dopamine antagonist) is prescribed in place of a conventional antipsychotic. It has been suggested that people with schizophrenia find it particularly difficult to tolerate nicotine withdrawal symptoms6 (although some certainly can stop27). Switching to nicotine replacement therapy or vaping may thus be the preferred option.28,29 A switch from tobacco smoking to vaping has been shown to be well tolerated even in severe mental illness.30 Depression and anxiety Moderate consumption of nicotine is associated with pleasure and a decrease in anxiety and feelings of anger.31 The mechanism of this anxiolytic effect is not understood. People who suffer from anxiety and/or depression are more likely to smoke32 and find it more difficult to stop.31,33 Nicotine itself might have antidepressant activity.34 Nicotine withdrawal can precipitate or exacerbate depression in those with a history of the illness,31 but cigarette smoking may directly increase the risk of depression.35 A 2020 study suggested nicotine addiction and depression are independently linked.36 Some studies suggest that stopping smoking ultimately improves depression and anxiety.37,38 A 2020 Cochrane review39 suggests smoking cessation is achievable in depressed smokers, but a later twin study found that depression made smoking cessation much less likely.40 Patients with depression are at increased risk of cardiovascular disease. By directly causing tachycardia and hypertension,1 nicotine may, in theory, exacerbate this problem. More importantly, smoking tobacco is a well-known independent risk factor for cardiovascular disease, probably because it hastens atherosclerosis. Vaping, while not carcinogenic, increases risk of cardiovascular disease.41 Attention deficit hyperactivity disorder (ADHD) People with ADHD are relatively more likely to use nicotine products.42 Tobacco smoke contains monoamine oxidase inhibitors which may benefit ADHD symptoms.43 There is ample evidence of complex pharmacodynamic interactions between nicotine and stimulant drugs.44

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12 - Drug interactions

Drug interactions

17 - Chapter 12 Other substances

13 - Smoking cessation and withdrawal symptoms

Smoking cessation and withdrawal symptoms

17 - Chapter 12 Other substances

14 - References

References

910 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 12 Movement disorders and Parkinson’s disease By increasing dopaminergic neurotransmission, nicotine is thought to provide a protective effect against both drug-induced EPSEs and idiopathic Parkinson’s disease. Smokers are less likely to suffer from antipsychotic-induced movement disorders than non-smokers5 and use anticholinergic drugs less often.6 Parkinson’s disease occurs less frequently in smokers than in non-smokers and the onset of clinical symptoms is delayed.5,45 This may reflect the inverse association between Parkinson’s disease and sensation-seeking behavioural traits, rather than a direct effect of nicotine.46 The protective effect may not be related to nicotine at all but rather to other compounds in tobacco smoke.47 Drug interactions Polycyclic hydrocarbons in tobacco smoke are known to stimulate the hepatic microsomal enzyme system, particularly CYP1A2,7 the enzyme responsible for the metabolism of many psychotropic drugs. Smoking can lower the blood levels of some drugs by more than 50%.7 This can both affect efficacy and influence adverse effects and needs to be taken into account when making clinical decisions. The drugs most likely to be affected are clozapine,48 fluphenazine, haloperidol, chlorpromazine, olanzapine, many tricyclic antidepressants, mirtazapine, fluvoxamine and propranolol. Vaping has no effect on hepatic enzyme function. See ‘Smoking and psychotropic drugs’ in Chapter 11. Smoking cessation and withdrawal symptoms Withdrawal symptoms occur within 6–12 hours of stopping smoking and include intense craving, depressed mood, insomnia, anxiety, restlessness, irritability, difficulty in concentrating and increased appetite. Nicotine withdrawal can be misdiagnosed as depression, anxiety, sleep disorders and mania.49 Withdrawal can also exacerbate the symptoms of schizophrenia.6 See also ‘Nicotine and smoking cessation’ in Chapter 4. References

Benowitz NL, et al. Cardiovascular effects of nasal and transdermal nicotine and cigarette smoking. Hypertension 2002; 39:1107–1112.
Yevtushenko OO, et al. Influence of 5-HT2C receptor and leptin gene polymorphisms, smoking and drug treatment on metabolic disturbances in patients with schizophrenia. Br J Psychiatry 2008; 192:424–428.
Anderson JE, et al. Treating tobacco use and dependence: an evidence-based clinical practice guideline for tobacco cessation. Chest 2002; 121:932–941.
Berrettini W. Nicotine addiction. Am J Psychiatry 2008; 165:1089–1092.
Goff DC, et al. Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects. Am J Psychiatry 1992; 149:1189–1194.
Ziedonis DM, et al. Schizophrenia and nicotine use: report of a pilot smoking cessation program and review of neurobiological and clinical issues. Schizophr Bull 1997; 23:247–254.
Lyon ER. A review of the effects of nicotine on schizophrenia and antipsychotic medications. Psychiatr Serv 1999; 50:1346–1350.
Winterer G. Why do patients with schizophrenia smoke? Curr OpinPsychiatry 2010; 23:112–119.
Sharma R, et al. Motivations and limitations associated with vaping among people with mental illness: a qualitative analysis of Reddit discussions. Int J Environ Res Public Health 2016; 14:7.
Bianco CL. Rates of electronic cigarette use among adults with a chronic mental illness. Addict Behav 2019; 89:1–4.
Bennett ME, et al. Tobacco smoking and nicotine vaping in persons with first episode psychosis. Schizophr Res 2024; 267:141–149.
Han B, et al. Tobacco use, nicotine dependence, and cessation methods in US adults with psychosis. JAMA Network Open 2023; 6:e234995.
Weiser M, et al. Higher rates of cigarette smoking in male adolescents before the onset of schizophrenia: a historical-prospective cohort study. Am J Psychiatry 2004; 161:1219–1223.
Hunter A, et al. The effects of tobacco smoking, and prenatal tobacco smoke exposure, on risk of schizophrenia: a systematic review and meta-analysis. Nicotine Tob Res 2020; 22:3–10.

Other substances CHAPTER 12 15. Caponnetto P, et al. Tobacco smoking, related harm and motivation to quit smoking in people with schizophrenia spectrum disorders. Health Psychol Res 2020; 8:9042. 16. Harris JG, et al. Effects of nicotine on cognitive deficits in schizophrenia. Neuropsychopharmacology 2004; 29:1378–1385. 17. Gupta T, et al. Nicotine usage is associated with elevated processing speed, spatial working memory, and visual learning performance in youth at ultra high-risk for psychosis. Psychiatry Res 2014; 220:687–690. 18. Ferchiou A, et al. Exploring the relationships between tobacco smoking and schizophrenia in first-degree relatives. Psychiatry Res 2012; 200:674–678. 19. McEvoy JP, et al. Smoking and therapeutic response to clozapine in patients with schizophrenia. Biol Psychiatry 1999; 46:125–129. 20. Jacobsen LK, et al. Nicotine effects on brain function and functional connectivity in schizophrenia. Biol Psychiatry 2004; 55:850–858. 21. Sacco KA, et al. Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch Gen Psychiatry 2005; 62:649–659. 22. Smith RC, et al. Effects of nicotine nasal spray on cognitive function in schizophrenia. Neuropsychopharmacology 2006; 31:637–643. 23. Olincy A, et al. Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 2006; 63:630–638. 24. Lieberman JA, et al. Cholinergic agonists as novel treatments for schizophrenia: the promise of rational drug development for psychiatry. Am J Psychiatry 2008; 165:931–936. 25. Kelly DL, et al. Lack of beneficial galantamine effect for smoking behavior: a double-blind randomized trial in people with schizophrenia. Schizophr Res 2008; 103:161–168. 26. De Haan L, et al. Occupancy of dopamine D2 receptors by antipsychotic drugs is related to nicotine addiction in young patients with schizophrenia. Psychopharmacology (Berl) 2006; 183:500–505. 27. Gilbody S, et al. Smoking cessation for people with severe mental illness (SCIMITAR+): a pragmatic randomised controlled trial. Lancet Psychiatry 2019; 6:379–390. 28. Caponnetto P, et al. Impact of an electronic cigarette on smoking reduction and cessation in schizophrenic smokers: a prospective 12-month pilot study. Int J Environ Res Public Health 2013; 10:446–461. 29. Kozak K, et al. Pharmacotherapy for smoking cessation in schizophrenia: a systematic review. Expert Opin Pharmacother 2020; 21:581–590. 30. Hickling LM, et al. A pre-post pilot study of electronic cigarettes to reduce smoking in people with severe mental illness. Psychol Med 2019; 49:1033–1040. 31. Glassman AH. Cigarette smoking: implications for psychiatric illness. Am J Psychiatry 1993; 150:546–553. 32. Cai J, et al. E-cigarette use or dual use of E-cigarette and combustible cigarette and mental health and cognitive impairment: findings from the National Health Interview Survey, 2020–2021. J Affect Disord 2024; 351:878–887. 33. Wilhelm K, et al. Clinical aspects of nicotine dependence and depression. Med Today 2004; 5:40–47. 34. Gandelman JA, et al. Transdermal nicotine for the treatment of mood and cognitive symptoms in nonsmokers with late-life depression. J Clin Psychiatry 2018; 79:18m12137. 35. Boden JM, et al. Cigarette smoking and depression: tests of causal linkages using a longitudinal birth cohort. Br J Psychiatry 2010; 196:440–446. 36. Bainter T, et al. A key indicator of nicotine dependence is associated with greater depression symptoms, after accounting for smoking behavior. PLoS One 2020; 15:e0233656. 37. Taylor G, et al. Change in mental health after smoking cessation: systematic review and meta-analysis. BMJ 2014; 348:g1151. 38. Cather C, et al. Improved depressive symptoms in adults with schizophrenia during a smoking cessation attempt with varenicline and behavioral therapy. J Dual Diagn 2017; 13:168–178. 39. Van der Meer RM, et al. Smoking cessation interventions for smokers with current or past depression. Cochrane Database Syst Rev 2013; 8:CD006102. 40. Ranjit A, et al. Depressive symptoms predict smoking cessation in a 20-year longitudinal study of adult twins. Addict Behav 2020; 108:106427. 41. Zong H, et al. Electronic cigarettes and cardiovascular disease: epidemiological and biological links. Pflugers Arch 2024; 476:875–888. 42. Xu G, et al. Association of attention-deficit/hyperactivity disorder with E-cigarette use. Am J Prev Med 2021; 60:488–496. 43. Taylor MR, et al. Tobacco and ADHD: a role of MAO-inhibition in nicotine dependence and alleviation of ADHD symptoms. Front Neurosci 2022; 16:845646. 44. McNealy KR, et al. The co-use of nicotine and prescription psychostimulants: a review of their behavioral and neuropharmacological interactions. Drug Alcohol Depend 2023; 248:109906. 45. Scott WK, et al. Family-based case-control study of cigarette smoking and Parkinson disease. Neurology 2005; 64:442–447. 46. Evans AH, et al. Relationship between impulsive sensation seeking traits, smoking, alcohol and caffeine intake, and Parkinson’s disease. J Neurol Neurosurg Psychiatry 2006; 77:317–321. 47. Rose KN, et al. Clearing the smoke: what protects smokers from Parkinson’s disease? Mov Disord 2024; 39:267–272. 48. Derenne JL, et al. Clozapine toxicity associated with smoking cessation: case report. Am J Ther 2005; 12:469–471. 49. Conti AA, et al. Severity of negative mood and anxiety symptoms occurring during acute abstinence from tobacco: a systematic review and meta-analysis. Neurosci Biobehav Rev 2020; 115:48–63.

18 - Chapter 13 Psychotropic drugs in special condition

01 - Psychotropics in overdose

Psychotropics in overdose

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 13 Psychotropics in overdose Suicide attempts and suicidal gestures are frequently encountered in psychiatric and general practice, and psychotropic drugs are often taken in overdose (Table 13.1). This section gives brief details of the toxicity in overdose of commonly used psychotropics. It is intended to help guide drug choice in those thought to be at risk of suicide, to give some indication of safe quantities to prescribe and to help identify symptoms of overdose. This section gives no information on the treatment of psychotropic overdose and readers are directed to specialist poisons centres. In all cases of suspected overdose, urgent referral to acute medical facilities is, of course, strongly advised. Psychotropic drugs in special conditions Table 13.1 Psychotropic drugs in overdose. Drug or drug group Toxicity in overdose* Smallest dose likely to cause death Signs and symptoms of overdose Antidepressants Agomelatine1,2 Low No deaths reported. In early trials, 800mg was maximum tolerated dose. EU SPC reports no serious effects from 2.45g overdose. A mixed overdose of 7.5g caused only drowsiness and mild tachycardia. Sedation, agitation, stomach pains, dizziness Brexanolone3 Not known No deaths reported. Two cases of accidental overdose due to pump malfunction. Sudden loss of consciousness (Continued )

914 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 13 Table 13.1 (Continued ) Drug or drug group Toxicity in overdose* Smallest dose likely to cause death Signs and symptoms of overdose Bupropion4–7 Moderate Around 4.5g, although largest overdose of 15g was not fatal.3,8 Tachycardia, seizures, QRS prolongation, QT prolongation, arrhythmia. Agitation and toxic psychosis also reported. Fatal serotonin syndrome may occur if taken with venlafaxine.9 Dextromethorphan and bupropion3 Probably moderate Unclear. Bupropion inhibits metabolism of the dextromethorphan which may result in more severe/persistent overdose. Bupropion: as above Dextromethorphan: nausea, vomiting, stupor, coma, respiratory depression, seizures, tachycardia, hyperexcitability, toxic psychosis Duloxetine10–13 Low Unclear – no deaths from single overdose reported but involved in numerous mixed overdose deaths. Drowsiness, bradycardia, hypotension May be asymptomatic Esketamine14 Not known Unclear. No deaths reported. Predicted to mirror ketamine overdose including sedation, hypertension, tachycardia, respiratory depression.15 Ketamine16 Moderate Iatrogenic overdoses of up to 50mg/kg IV are not usually fatal if prompt treatment is given. Mechanical ventilation may be required. Illicit overdose is rarely fatal unless other drugs present.15 Sedation, respiratory depression, hypertension, tachycardia Lofepramine17,18 Low Unclear. Fatality unlikely if lofepramine taken alone. Sedation, coma, tachycardia, hypotension MAOIs17,19–21 (not moclobemide) High Phenelzine – 400mg Tranylcypromine – 200mg Tremor, weakness, confusion, sweating, tachycardia, hypertension Mianserin22–24 Low Unclear but probably more than 1000mg. Fatality unlikely if mianserin taken alone. Sedation, coma, hypotension, hypertension, tachycardia, possible QT prolongation Mirtazapine4,25–28 Low Fatality unlikely in overdose of mirtazapine alone. One death reported following overdose with 990mg.29 Sedation. Even large overdose may be asymptomatic. Tachycardia/ hypertension sometimes seen. Agitation. Moclobemide30,31 Low Unclear, but probably more than 8g. Fatality unlikely if moclobemide taken alone. Vomiting, sedation, disorientation Reboxetine4,32 Low Not known. Fatality unlikely in overdose of reboxetine alone. Sweating, tachycardia, changes in blood pressure SSRIs18,33–36 Low Unclear. Probably above 1–2g. Fatality unlikely if SSRI taken alone. Vomiting, tremor, drowsiness, tachycardia, ST depression. Seizures and QT prolongation possible. Citalopram most toxic of SSRIs in overdose28,37 (coma, seizures, arrhythmia); escitalopram is less toxic.38,39

Psychotropic drugs in special conditions CHAPTER 13 Table 13.1 (Continued ) Drug or drug group Toxicity in overdose* Smallest dose likely to cause death Signs and symptoms of overdose Trazodone11,40–43 Low Unclear but probably more than 10g. Fatality unlikely in overdose of trazodone alone. Mortality rate about 1 in 10,000 overdose exposures.28 Drowsiness, nausea, hypotension, dizziness. Rarely QT prolongation, arrhythmia. Tricyclics17,19,20,44 (not lofepramine) High Around 500mg. Doses over 50mg/kg usually fatal. Sedation, coma, tachycardia, arrhythmia (QRS, QT prolongation), hypotension, seizures Venlafaxine4,45–48 (desvenlafaxine causes similar effects but may be less toxic49) Moderate Probably above 5g, but seizures may occur after ingestion of 1g Vomiting, sedation, tachycardia, hypertension, seizures, acidosis, hypoglycaemia. Rarely QT prolongation, arrhythmia, rhabdomyolysis. Very rarely cardiac arrest/MI, heart failure. Vilazodone50,51 Low Doses below 300mg are not fatal. No fatalities recorded in 714 overdose exposures.28 Drowsiness, agitation, vomiting, seizures Vortioxetine52 Low Unclear. An overdose of 250mg caused no symptoms. Nausea, somnolence, diarrhoea, pruritis Antipsychotics Amisulpride53–55 Moderate Around 16g QT prolongation, arrhythmia, cardiac arrest Aripiprazole56–58 Low Unclear. Fatality unlikely when taken alone. Sedation, lethargy, GI disturbance, drooling Asenapine59 Probably low Unclear. No deaths from overdose reported. Oral absorption very limited. Sedation, confusion, facial dystonia, benign ECG changes Brexpiprazole3 Probably low No information available Presumably agitation and nausea Butyrophenones60–62 (e.g. haloperidol) Moderate Haloperidol – probably above 500mg. Arrhythmia may occur at 300mg. Sedation, coma, dystonia, NMS, QT prolongation, arrhythmia Cariprazine63 Low EU SPC reports one (non-fatal) overdose of 48mg Sedation, low blood pressure Clozapine64,65 Moderate Around 2g, but very much lower in those not tolerant to its effects66 Lethargy, coma, tachycardia, hypotension, hypersalivation, pneumonia, seizures Iloperidone67–69 Probably moderate Unclear but probably more than 500mg. Potent effect on QT interval. Sedation, tachycardia, respiratory depression, hypotension likely Lumateperone70 Probably low No overdoses reported Presumably sedation and dizziness (Continued )

916 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 13 Table 13.1 (Continued) Drug or drug group Toxicity in overdose* Smallest dose likely to cause death Signs and symptoms of overdose Lurasidone71 Low Unclear. An overdose of 1360mg was not fatal.72 One study reported no deaths in 821 overdose exposures.28 Very limited information. Minimal effect on QT interval. Olanzapine64,73–76 Moderate Unclear. Fatal outcomes have been reported for acute overdoses as low as 450mg. Lethargy, confusion, myoclonus, myopathy, hypotension, tachycardia, delirium. Possibly QT prolongation. Olanzapine and samidorphan3 Moderate Unclear. An overdose of 110mg/110mg was not fatal. Possible altered risk of fatality in opioid overdose due to opioid blockade. As for olanzapine Phenothiazines60,77–79 (e.g. chlorpromazine, fluphenazine) Moderate Chlorpromazine 5–10g Sedation, coma, tachycardia, arrhythmia, pulmonary oedema, hypotension, QT prolongation, seizures, dystonia, NMS Pimavanserin80 Not known No overdoses reported but pimavanserin prolongs QT interval in clinical doses. Probably QT prolongation and arrhythmia. ?Nausea, vomiting, confusion.81 Quetiapine28,64,82,83 Moderate Unclear. Probably more than 5g. Fatalities can occur in single substance overdose. Lethargy, delirium, tachycardia, QT prolongation, respiratory depression, hypotension, rhabdomyolysis, NMS Risperidone64,84,85 (assume the same for paliperidone) Low Unclear. Fatality rare in those taking risperidone or paliperidone alone. Lethargy, dystonia, tachycardia, changes in blood pressure, QT prolongation. Renal failure with paliperidone. Ziprasidone86–91 Low Around 10g. Fatality unlikely when taken alone. Drowsiness, lethargy, QT prolongation, Torsades de pointes Mood stabilisers Carbamazepine92–94 Moderate Around 20g, but seizures may occur at around 5g; an overdose of 44g was not fatal. Somnolence, coma, respiratory depression, ataxia, seizures, tachycardia, arrhythmia, electrolyte disturbance Lamotrigine95,96 Low At least 4g. Two deaths reported – one after 4g, the other after 7.5g, but overdoses of >40g have not proved fatal. Drowsiness, vomiting, ataxia, seizures, tachycardia, dyskinesia, QT prolongation Lithium97–99 Moderate Chronic toxicity probably more dangerous but single overdose is occasionally fatal. Six acute overdose deaths recorded in UK 2005–2012.100 Nausea, diarrhoea, tremor, confusion, weakness, lethargy, seizures, coma, cardiovascular collapse, bradycardia, arrhythmia, heart block, renal failure Valproate101–105 Moderate Unclear but probably more than 20g. Doses over 400mg/kg cause severe toxicity. Somnolence, coma, cerebral oedema, respiratory depression, blood dyscrasia, hypotension, hypothermia, seizures, electrolyte disturbance (hyperammonaemia)

Psychotropic drugs in special conditions CHAPTER 13 Table 13.1 (Continued) Drug or drug group Toxicity in overdose* Smallest dose likely to cause death Signs and symptoms of overdose Others Benzodiazepines106–108 Low Probably more than 100mg diazepam equivalents. Often involved in fatal mixed overdose but can be fatal when taken alone. Alprazolam is most toxic. Drowsiness, ataxia, nystagmus, respiratory dysarthria, depression, coma Buspirone28 Low Limited data. Deaths not reported. Not known Daridorexant3 Not known No overdoses reported. In trials, 200mg was maximum dose. Not known. Likely increased somnolence, muscle weakness, cataplexy-like symptoms, headache. Lemborexant3 Not known No overdoses reported. In trials, 75mg was maximum dose. Not known. Likely increased somnolence. Methadone109–111 High 20–50mg may be fatal in non-users. Co-ingestion of benzodiazepines increases toxicity. Drowsiness, nausea, hypotension, respiratory depression, coma, pulmonary oedema, constricted pupils, rhabdomyolysis Modafinil112–114 Low Unclear, but no fatalities reported. Overdoses of >6g have not caused death. Tachycardia, insomnia, agitation, anxiety, nausea, hypertension, dystonia Pitolisant115 Not known No overdoses reported. In trials, 216mg was maximum dose. Probably QT prolongation, headache, insomnia, irritability, nausea, abdominal pain Pregabalin116–118 Low Often involved in fatal mixed overdose (e.g. with opiates) but can be fatal when taken alone. One overdose of 8.4g caused unconsciousness and coma. May be asymptomatic. Sedation and coma may occur Solriamfetol3 Not known No overdoses reported. In trials, 1200mg was maximum dose. Probably hypertension, tachycardia, QT prolongation Suvorexant114,119 Low Unclear. No deaths reported. An overdose of 100mg caused enhanced sedation. Sedation, vomiting Zolpidem120–122 Low Unclear. Probably >200mg, but an overdose of 9g was not fatal. Fatality rare in those taking zolpidem alone. Drowsiness, agitation, respiratory depression, tachycardia, coma, absent brainstem reflexes Zopiclone106,123,124 Low Unclear. Probably >100mg. Fatality rare in those taking zopiclone alone. Ataxia, nausea, diplopia, drowsiness, coma * High = less than 1 week’s supply likely to cause serious toxicity or death. Moderate = 1–4 weeks’ supply likely to cause serious toxicity or death. Low = death or serious toxicity unlikely even if more than 1 month’s supply taken. GI, gastrointestinal; IV, intravenous; MAOIs, monoamine oxidase inhibitors; MI, myocardial infarction; NMS, neuroleptic malignant syndrome; SPC, summary of product characteristics.

18 - Chapter 13 Psychotropic drugs in special condition

02 - References

References

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Pharmacokinetics, tolerability, and safety of ACP-103 following single or multiple oral dose administration in healthy volunteers. J Clin Pharmacol 2007; 47:704–714. 82. Ngo A, et al. Acute quetiapine overdose in adults: a 5-year retrospective case series. Ann Emerg Med 2008; 52:541–547. 83. Bertol E, et al. Overdose of quetiapine – a case report with QT prolongation. Toxics 2021; 9:339. 84. Liang CS, et al. Acute renal failure after paliperidone overdose: a case report. J Clin Psychopharmacol 2012; 32:128. 85. Lapid MI, et al. Acute dystonia associated with paliperidone overdose. Psychosomatics 2011; 52:291–294. 86. Gomez-Criado MS, et al. Ziprasidone overdose: cases recorded in the database of Pfizer-Spain and literature review. Pharmacotherapy 2005; 25:1660–1665. 87. Arbuck DM. 12,800-mg ziprasidone overdose without significant ECG changes. Gen Hosp Psychiatry 2005; 27:222–223. 88. Insa Gomez FJ, et al. Ziprasidone overdose: cardiac safety. Actas Esp Psiquiatr 2005; 33:398–400. 89. Klein-Schwartz W, et al. Prospective observational multi-poison center study of ziprasidone exposures. Clin Toxicol (Phila) 2007; 45:782–786. 90. Tan HH, et al. A systematic review of cardiovascular effects after atypical antipsychotic medication overdose. Am J Emerg Med 2009; 27:607–616. 91. Alipour A, et al. Torsade de pointes after ziprasidone overdose with coingestants. J Clin Psychopharmacol 2010; 30:76–77.

920 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 13 92. Spiller HA. Management of carbamazepine overdose. Pediatr Emerg Care 2001; 17:452–456. 93. Schmidt S, et al. Signs and symptoms of carbamazepine overdose. J Neurol 1995; 242:169–173. 94. Pap C, et al. Severe carbamazepine overdose associated with shock, repeated seizures and extreme high serum concentrations treated by extended intermittent hemodiafiltration. 42nd International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 24–27 May 2022, Tallinn, Estonia. Clin Toxicol 2022; 60:abstract 145. 95. Alabi A, et al. Safety profile of lamotrigine in overdose. Ther Adv Psychopharmacol 2016; 6:369–381. 96. Alyahya B, et al. Acute lamotrigine overdose: a systematic review of published adult and pediatric cases. Clin Toxicol (Phila) 2018; 56:81–89. 97. Tuohy K, et al. Acute lithium intoxication. Dial Transplant 2003; 32:478–481. 98. Chen KP, et al. Implication of serum concentration monitoring in patients with lithium intoxication. Psychiatry Clin Neurosci 2004; 58:25–29. 99. Offerman SR, et al. Hospitalized lithium overdose cases reported to the California Poison Control System. Clin Toxicol (Phila) 2010; 48:443–448. 100. Ferrey AE, et al. Relative toxicity of mood stabilisers and antipsychotics: case fatality and fatal toxicity associated with self-poisoning. BMC Psychiatry 2018; 18:399. 101. Isbister GK, et al. Valproate overdose: a comparative cohort study of self poisonings. Br J Clin Pharmacol 2003; 55:398–404. 102. Spiller HA, et al. Multicenter case series of valproic acid ingestion: serum concentrations and toxicity. J Toxicol Clin Toxicol 2000; 38:755–760. 103. Sztajnkrycer MD. Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol 2002; 40:789–801. 104. Eyer F, et al. Acute valproate poisoning: pharmacokinetics, alteration in fatty acid metabolism, and changes during therapy. J Clin Psychopharmacol 2005; 25:376–380. 105. Robinson P, et al. Severe hypothermia in association with sodium valproate overdose. NZ Med J 2005; 118:U1681. 106. Reith DM, et al. Comparison of the fatal toxicity index of zopiclone with benzodiazepines. J Toxicol Clin Toxicol 2003; 41:975–980. 107. Isbister GK, et al. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin Pharmacol 2004; 58:88–95. 108. Kleinman RA, et al. Benzodiazepine-involved overdose deaths in the USA: 2000–2019. J Gen Intern Med 2022; 37:2103–2109. 109. Gable RS. Comparison of acute lethal toxicity of commonly abused psychoactive substances. Addiction 2004; 99:686–696. 110. Caplehorn JR, et al. Fatal methadone toxicity: signs and circumstances, and the role of benzodiazepines. Aust NZ J Public Health 2002; 26:358–362. 111. Martindale Pharma an Ethypharm Group Company. Summary of product characteristics. Methadone 5mg tablets. 2023; (last accessed August 2024) https://www.medicines.org.uk/emc/product/11838/smpc. 112. Spiller HA, et al. Toxicity from modafinil ingestion. Clin Toxicol (Phila) 2009; 47:153–156. 113. Carstairs SD, et al. A retrospective review of supratherapeutic modafinil exposures. J Med Toxicol 2010; 6:307–310. 114. Russell J, et al. Retrospective assessment of toxicity following exposure to Orexin pathway modulators modafinil and suvorexant. Toxicol Commun 2019; 3:33–36. 115. Bioprojet UK Limited. Summary of product characteristics. Wakix 18 mg film-coated tablets (pitolisant). 2023; https://www.medicines.org. uk/emc/product/14454/smpc. 116. Miljevic C, et al. A case of pregabalin intoxication. Psychiatriki 2012; 23:162–165. 117. Wood DM, et al. Significant pregabalin toxicity managed with supportive care alone. J Med Toxicol 2010; 6:435–437. 118. Kriikku P, et al. Pregabalin and gabapentin in non-opioid poisoning deaths. Forensic Sci Int 2021; 324:110830. 119. Trautman W, et al. Orexin antagonist overdose should not keep you up at night: mild toxicity in a large suvorexant overdose. Clinical Toxicology 2023; 61 Suppl 2: abstract 205. http://doi.org/10.1080/15563650.2023.2233835. 120. Gock SB, et al. Acute zolpidem overdose – report of two cases. J Anal Toxicol 1999; 23:559–562. 121. Garnier R, et al. Acute zolpidem poisoning – analysis of 344 cases. J Toxicol Clin Toxicol 1994; 32:391–404. 122. De Donatis D, et al. Extremely high-dosage zolpidem poisoning with favorable outcome. J Clin Psychopharmacol 2021; 41:222–223. 123. Pounder D, et al. Zopiclone poisoning. J Anal Toxicol 1996; 20:273–274. 124. Bramness JG, et al. Fatal overdose of zopiclone in an elderly woman with bronchogenic carcinoma. J Forensic Sci 2001; 46:1247–1249.

18 - Chapter 13 Psychotropic drugs in special condition

03 - Driving and psychotropic medicines

Driving and psychotropic medicines

18 - Chapter 13 Psychotropic drugs in special condition

04 - Effects of mental illness

Effects of mental illness

18 - Chapter 13 Psychotropic drugs in special condition

05 - Psychiatric medicines, driving and UK law

Psychiatric medicines, driving and UK law

Psychotropic drugs in special conditions CHAPTER 13 Driving and psychotropic medicines Everyone has a legal duty to drive safely and in almost all countries drivers are legally responsible for accidents they cause, whether or not they are under the influence of drugs or alcohol.1 Many factors have been shown to affect driving performance. These include age, gender, personality, physical and mental state and being under the influence of alcohol, prescribed medicines, street drugs or over-the-counter medicines.2,3 Studying the effects of any of these individual factors in isolation is extremely difficult. Some studies have attempted to categorise medicinal drugs according to how they affect driving performance,4 and some have assessed the effect of medication on tests such as response time and attention,5 but these tests do not directly measure ability to drive. As many as 10% of people killed or injured in road traffic accidents (RTAs) are taking psychotropic medication (Table 13.2).5 Patients with personality disorders and alcoholism have the highest rates of motoring offences and are more likely to be involved in accidents.5 In most countries, people whose driving ability may be impaired through their illness or prescribed medication are required to inform their motor insurer. Failure to do so is considered to be ‘withholding a material fact’ and may render the insurance policy void. Effects of mental illness In the UK, severe mental disorder is a so-called ‘prescribed disability’ for the purposes of the Road Traffic Act 1988.6 Regulations define mental disorder as including mental illness, arrested or incomplete development of the mind, psychopathic disorder or severe impairment of intelligence or social functioning. There is an assessing fitness to drive guide.7 Among physical conditions commonly seen in mental illness, licence restrictions may also apply to people with diabetes, particularly if treated with insulin or if there are established micro- or macrovascular complications. In the USA, regulations related to driving and mental health disorders vary somewhat from state to state (see US Department of Motor Vehicles website [www.dmvusa.com] for each state). Many people with early dementia are capable of driving safely.8,9 In the UK, all drivers with new diagnoses of Alzheimer’s disease and other dementias must notify the Driver and Vehicle Licensing Agency (DVLA).8 The doctor may need to make an immediate decision on safety to drive and ensure that the DVLA is notified.10 There are no data to support ongoing driving assessments as a way of maintaining driving ability or improving road safety of drivers with dementia.11,12 In the USA, some states mandate that doctors report a diagnosis of dementia but in others the issue may only arise on licence renewal. Interestingly, states in which reporting is mandatory have a relatively lower rate of dementia diagnosis.13 Psychiatric medicines, driving and UK law Most countries prohibit the use of a range of illicit substances when driving. In the UK drug–driving law gives threshold blood concentration for eight drugs associated with illicit use (with a zero tolerance approach – the threshold is set to reveal any recent use) and eight medicinal drugs.14 For the latter group, Table 13.3 gives the legal limit and expected plasma concentrations in clinical use.

922 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 13 Table 13.2 Psychotropics and driving. Drug group Effect Alcohol Alcohol causes sedation and impaired co-ordination, vision, attention and information processing. Alcohol-dependent drivers are twice as likely to be involved in RTAs and offences than licensed drivers as a whole,5 and a third of all fatal RTAs involve alcohol-dependent drivers.5 Young drivers who use alcohol in combination with illicit drugs are particularly high risk.15,16 Antiseizure medications Initial, dose-related adverse effects may affect driving ability (e.g. diplopia, ataxia and sedation). In most countries there are strict rules regarding epilepsy and driving that over-ride considerations of medication effects. Carbamazepine has minor adverse effects on driving.17,18 Lamotrigine may have limited effects on driving ability.19 Valproate may not increase the risk of RTAs.20 Antidepressants People who are prescribed an antidepressant have an increased risk of being involved in an RTA.21 SSRIs may have some advantages over TCAs but driving ability is still diminished compared with healthy individuals,22 suggesting that depression itself may make a major contribution.23,24 SSRIs tend not to impair driving in healthy volunteers.25–27 In remitted patients on SSRIs, driving performance may likewise not be impaired.28 Initiation effects caused by mirtazapine diminish to an extent when it is given as a single dose at night but many people experience substantial hangover which can impair driving.29 Effects may disappear in chronic treatment.30 Trazodone also appears to impair driving ability31 – a review of 27 studies suggested that only trazodone among antidepressants afforded an increased risk of RTAs.32 Agomelatine and venlafaxine may actually improve driving performance.33 Vortioxetine has no effect.30 Intranasal esketamine seems to have no effect on driving ability 8 hours post-dose34 or the day after.35 Antipsychotics Sedation and EPSEs can impair co-ordination and response time.2 A high proportion of patients treated with antipsychotics may have an impaired ability to drive.36,37 One study found patients with schizophrenia taking atypical antipsychotics or clozapine performed better in tests of skills related to car driving ability than patients with schizophrenia taking FGAs,38 but 25% of all patients were severely impaired with respect to driving skills. SGAs seem to cause less impairment than FGAs39 and are preferred. Hypnotics and anxiolytics Benzodiazepines cause sedation and impairment of attention, information processing, memory and motor co-ordination, and along with opiates are the medicines most frequently implicated in RTAs.32,40 When used as anxiolytics and hypnotics, benzodiazepines, zopiclone and zolpidem are associated with an increased risk of RTAs.40 There is some gender variation in the pharmacokinetics of zolpidem with females having higher drug plasma concentrations than males for any given dose; the driving ability of females may therefore be particularly impaired.3 Zolpidem may additionally be associated with automatism and ‘sleep driving’.41 Zaleplon and the newer hypnotics acting at melatonin or serotonin receptors have not been found to have any negative residual effects on driving ability.42,43 Orexin receptor antagonists (suvorexant and lemborexant), available in some countries, appear not to impair driving the day after being taken.44,45 There is some evidence that daridorexant impairs driving ability during the first few days of use.46 Lithium Lithium may impair visual adaptation to the dark2 but the implications for driving safety are unknown. Many patients treated with lithium can be shown to be unfit to drive19 although the exact contribution of lithium is difficult to determine. Elderly people who take lithium may be at increased risk of being involved in an injurious RTA.47 Lithium causes a greater degree of driving impairment than lamotrigine.39 Methylphenidate Some studies have demonstrated that reaction time is longer in patients with ADHD, which may in turn be associated with increased driving risks.48 Other studies have found that methylphenidate improved driving performance in adults with ADHD,49 again suggesting that illness may make a bigger contribution to fitness to drive than the specific pharmacology of the treatment.49 Opioids Opioids have major adverse effect on the risk of RTAs.50 Buprenorphine and methadone reduce driving ability at low doses in non-addicts.51 EPSEs, extrapyramidal side effects; RTAs, road traffic accidents; TCAs, tricyclic antidepressants.

18 - Chapter 13 Psychotropic drugs in special condition

06 - Other medicines

Other medicines

18 - Chapter 13 Psychotropic drugs in special condition

07 - UK DVLA

UK DVLA

Psychotropic drugs in special conditions CHAPTER 13 In regards to methadone, doses of up to 80mg a day generally give plasma levels below the UK legal limit.61 The legal limits listed here apply only to those who are lawfully prescribed the drug in question – the driver may be subject to prosecution if it can be proved the drugs were taken illicitly. Other medicines Many psychotropics can impair alertness, concentration and driving performance. Medicines that block H1, α1-adrenergic or cholinergic receptors may be particularly problematic. Sedative antihistamines used in mental health conditions (promethazine, diphenhydramine) very probably impair driving ability.62 Effects are particularly marked at the start of treatment and after increasing the dose. Drivers must be made aware of any potential for impairment and are advised to evaluate their driving performance at these times. They must stop driving if adversely affected.63 The use of alcohol will further increase any impairment. Some antipsychotics and antidepressants lower the seizure threshold. In the UK, the DVLA advises this is taken into consideration when prescribing for a driver. Medication-induced sedation Many psychotropics are sedating. The more sedating a medicine is, the more likely it is to impair driving ability. Other medicines, either prescribed or bought over the counter, may also be sedative and/or affect driving ability (e.g. antihistamines5). One study found that 89% of patients taking other psychotropics in addition to antidepressants failed a battery of ‘fitness to drive’ tests.64 Since the degree of sedation any individual will experience is very difficult to predict, patients prescribed sedating medicines should be advised not to drive if they feel sedated. In the UK it is the responsibility of the driver to ensure they are fit to drive. UK DVLA Duty of the driver In the UK it is the legal responsibility of the licence holder or applicant to notify the DVLA of any medical condition that may affect safe driving. A list of relevant medical conditions can be found in the DVLA assessing fitness to drive guide.65 Table 13.3 Benzodiazepines concentration in normal dosing and the UK legal limit. Drug/daily dose Range of concentrations reported Legal limit Clonazepam 0.5–6.0mg52,53 5–80mcg/L 50mcg/L Diazepam 5–30mg54 50–1000mcg/L 550mcg/L Flunitrazepam 0.5–2.0mg55,56 10–20mcg/L 300mcg/L Lorazepam 1–4mg57,58 10–70mcg/L 100mcg/L Oxazepam 15–30mg59 250–600mcg/L 300mcg/L Temazepam 10–20mg60 200–900mcg/L 1000mcg/L

18 - Chapter 13 Psychotropic drugs in special condition

08 - UK General Medical Council guidelines for pre

UK General Medical Council guidelines for prescribers66

18 - Chapter 13 Psychotropic drugs in special condition

09 - References

References

924 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 13 Duty of the prescriber Make sure the patient understands that their condition may impair their ability to drive. If the patient is incapable of understanding, notify the DVLA immediately. Explain to the patient that they have a legal duty to inform the DVLA. Note that the DVLA guidance specifies that patients under Section 17 of the 1983 Mental Health Act must be able to satisfy the standards of fitness for their respective conditions and be free from any effects of medication that would affect driving adversely, before resuming driving. Very few patients will fulfil these criteria. UK General Medical Council guidelines for prescribers66 ■ ■Patients who disagree with the diagnosis or the effect of the condition on their ability to drive should seek a second opinion and refrain from driving until this has been obtained. ■ ■If the patient continues to drive while unfit, you should make every reasonable effort to persuade them to stop. This may include telling their next of kin if they agree you may do so. ■ ■If they continue to drive, inform the DVLA. Tell the patient you are going to do this and write to the patient to confirm you have done so. Document the advice given clearly in the patient’s notes. References

Annas GJ. Doctors, drugs, and driving – tort liability for patient-caused accidents. N Engl J Med 2008; 359:521–525.
Metzner JL, et al. Impairment in driving and psychiatric illness. J Neuropsychiatry Clin Neurosci 1993; 5:211–220.
Farkas RH, et al. Zolpidem and driving impairment – identifying persons at risk. N Engl J Med 2013; 369:689–691.
Ravera S, et al. A European approach to categorizing medicines for fitness to drive: outcomes of the DRUID project. Br J Clin Pharmacol 2012; 74:920–931.
Noyes R, Jr. Motor vehicle accidents related to psychiatric impairment. Psychosomatics 1985; 26:569–580.
The National Archives. Road Traffic Act 1991. 1991; http://www.legislation.gov.uk/ukpga/1991/40/contents.
Driver and Vehicle Licensing Agency. Guidance: assessing fitness to drive: a guide for medical professionals. 2016 (last updated February 2024, last checked May 2024); https://www.gov.uk/government/publications/assessing-fitness-to-drive-a-guide-for-medical-professionals.
Driver and Vehicle Licensing Agency. Assessing fitness to drive – a guide for medical professionals. 2016 (last updated 2018, last accessed May 2024). https://www.gov.uk/dvla/fitnesstodrive.
Piersma D, et al. Prediction of fitness to drive in patients with Alzheimer’s dementia. PLoS One 2016; 11:e0149566.
Breen DA, et al. Driving and dementia. BMJ 2007; 334:1365–1369.
Martin AJ, et al. Driving assessment for maintaining mobility and safety in drivers with dementia. Cochrane Database Syst Rev 2013; 8:CD006222.
Toups R, et al. Driving performance in older adults: current measures, findings, and implications for roadway safety. Innov Aging 2022; 6:igab051.
Jun H, et al. State Department of Motor Vehicles reporting mandates of dementia diagnoses and dementia underdiagnosis. JAMA Network Open 2024; 7:e248889.
Department for Transport. Changes to drug driving law. 2013 (last updated August 2017, last accessed May 2024); https://www.gov.uk/ government/collections/drug-driving.
Biecheler MB, et al. SAM survey on ‘drugs and fatal accidents’: search of substances consumed and comparison between drivers involved under the influence of alcohol or cannabis. Traffic Inj Prev 2008; 9:11–21.
Oyefeso A, et al. Fatal injuries while under the influence of psychoactive drugs: a cross-sectional exploratory study in England. BMC Public Health 2006; 6:148.
Kaussner Y, et al. Effects of oxcarbazepine and carbamazepine on driving ability: a double-blind, randomized crossover trial with healthy volunteers. Psychopharmacology (Berl) 2010; 210:53–63.
Ramaekers G, et al. A comparative study of the effects of carbamazepine and the NMDA receptor antagonist remacemide on road tracking and car-following performance in actual traffic. Psychopharmacology (Berl) 2002; 159:203–210.
Segmiller FM, et al. Driving ability according to German guidelines in stabilized bipolar I and II outpatients receiving lithium or lamotrigine. J Clin Pharmacol 2013; 53:459–462.

Psychotropic drugs in special conditions CHAPTER 13 20. Bramness JG, et al. An increased risk of road traffic accidents after prescriptions of lithium or valproate? Pharmacoepidemiol Drug Saf 2009; 18:492–496. 21. Olesen AV, et al. Use of psychotropic medication and risk of road traffic crashes: a registry-based case–control study in Denmark, 1996–2018. Psychopharmacology (Berl) 2022; 239:2537–2546. 22. Brunnauer A, et al. The effects of most commonly prescribed second generation antidepressants on driving ability: a systematic review: 70th birthday Prof. Riederer. J Neural Transm 2013; 120:225–232. 23. Bramness JG, et al. Minor increase in risk of road traffic accidents after prescriptions of antidepressants: a study of population registry data in Norway. J Clin Psychiatry 2008; 69:1099–1103. 24. Verster JC, et al. Psychoactive medication and traffic safety. Int J Environ Res Public Health 2009; 6:1041–1054. 25. Iwamoto K, et al. The effects of acute treatment with paroxetine, amitriptyline, and placebo on driving performance and cognitive function in healthy Japanese subjects: a double-blind crossover trial. Hum Psychopharmacol 2008; 23:399–407. 26. Ridout F, et al. A placebo controlled investigation into the effects of paroxetine and mirtazapine on measures related to car driving performance. Hum Psychopharmacol 2003; 18:261–269. 27. Wingen M, et al. Actual driving performance and psychomotor function in healthy subjects after acute and subchronic treatment with escitalopram, mirtazapine, and placebo: a crossover trial. J Clin Psychiatry 2005; 66:436–443. 28. Miyata A, et al. Driving performance of stable outpatients with depression undergoing real-world treatment. Psychiatry Clin Neurosci 2018; 72:399–408. 29. Verster JC, et al. Mirtazapine as positive control drug in studies examining the effects of antidepressants on driving ability. Eur J Pharmacol 2015; 753:252–256. 30. Theunissen EL, et al. A randomized trial on the acute and steady-state effects of a new antidepressant, vortioxetine (Lu AA21004), on actual driving and cognition. Clin Pharmacol Ther 2013; 93:493–501. 31. Ip EJ, et al. The effect of trazodone on standardized field sobriety tests. Pharmacotherapy 2013; 33:369–374. 32. Rudisill TM, et al. Medication use and the risk of motor vehicle collisions among licensed drivers: a systematic review. Accid Anal Prev 2016; 96:255–270. 33. Brunnauer A, et al. Driving performance and psychomotor function in depressed patients treated with agomelatine or venlafaxine. Pharmacopsychiatry 2015; 48:65–71. 34. Van de Loo A, et al. The effects of intranasal esketamine (84 mg) and oral mirtazapine (30 mg) on on-road driving performance: a double- blind, placebo-controlled study. Psychopharmacology (Berl) 2017; 234:3175–3183. 35. Dijkstra FM, et al. The effects of intranasal esketamine on on-road driving performance in patients with major depressive disorder or persistent depressive disorder. J Psychopharmacol 2022; 36:614–625. 36. Grabe HJ, et al. The influence of clozapine and typical neuroleptics on information processing of the central nervous system under clinical conditions in schizophrenic disorders: implications for fitness to drive. Neuropsychobiology 1999; 40:196–201. 37. Wylie KR, et al. Effects of depot neuroleptics on driving performance in chronic schizophrenic patients. J Neurol Neurosurg Psychiatry 1993; 56:910–913. 38. Brunnauer A, et al. The impact of antipsychotics on psychomotor performance with regards to car driving skills. J Clin Psychopharmacol 2004; 24:155–160. 39. Brunnauer A, et al. Driving performance under treatment of most frequently prescribed drugs for mental disorders: a systematic review of patient studies. Int J Neuropsychopharmacol 2021; 24:679–693. 40. Dassanayake T, et al. Effects of benzodiazepines, antidepressants and opioids on driving: a systematic review and meta-analysis of epidemiological and experimental evidence. Drug Saf 2011; 34:125–156. 41. Poceta JS. Zolpidem ingestion, automatisms, and sleep driving: a clinical and legal case series. J Clin Sleep Med 2011; 7:632–638. 42. Verster JC, et al. Hypnotics and driving safety: meta-analyses of randomized controlled trials applying the on-the-road driving test. Curr Drug Saf 2006; 1:63–71. 43. Torres R, et al. Simulated driving performance in healthy adults after night-time administration of 20 mg tasimelteon. J Sleep Res 2022; 31:e13430. 44. Vermeeren A, et al. On-the-road driving performance the morning after bedtime administration of lemborexant in healthy adult and elderly volunteers. Sleep 2019; 42:zsy260. 45. Vermeeren A, et al. On-the-road driving performance the morning after bedtime use of suvorexant 15 and 30 mg in healthy elderly. Psychopharmacology (Berl) 2016; 233:3341–3351. 46. Muehlan C, et al. Driving performance after bedtime administration of daridorexant, assessed in a sensitive simulator. Clin Pharmacol Ther 2022; 111:1334–1342. 47. Etminan M, et al. Use of lithium and the risk of injurious motor vehicle crash in elderly adults: case-control study nested within a cohort. BMJ 2004; 328:558–559. 48. Hashemian F, et al. A comparison of the effects of reboxetine and placebo on reaction time in adults with attention deficit-hyperactivity disorder (ADHD). Daru 2011; 19:231–235. 49. Classen S, et al. Evidence-based review on interventions and determinants of driving performance in teens with attention deficit hyperactivity disorder or autism spectrum disorder. Traffic Inj Prev 2013; 14:188–193. 50. Hetland A, et al. Medications and impaired driving. Ann Pharmacother 2014; 48:494–506. 51. Strand MC, et al. Pharmacokinetics of single doses of methadone and buprenorphine in blood and oral fluid in healthy volunteers and correlation with effects on psychomotor and cognitive functions. J Clin Psychopharmacol 2019; 39:489–493. 52. Sjo O, et al. Pharmacokinetics and side-effects of clonazepam and its 7-amino-metabolite in man. Eur J Clin Pharmacol 1975; 8:249–254.

926 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 13 53. Berlin A, et al. Pharmacokinetics of the anticonvulsant drug clonazepam evaluated from single oral and intravenous doses and by repeated oral administration. Eur J Clin Pharmacol 1975; 9:155–159. 54. Rutherford DM, et al. Plasma concentrations of diazepam and desmethyldiazepam during chronic diazepam therapy. Br J Clin Pharmacol 1978; 6:69–73. 55. Wickstrom E, et al. Pharmacokinetic and clinical observations on prolonged administration of flunitrazepam. Eur J Clin Pharmacol 1980; 17:189–196. 56. Mattila MA, et al. Flunitrazepam: a review of its pharmacological properties and therapeutic use. Drugs 1980; 20:353–374. 57. Greenblatt DJ, et al. Single- and multiple-dose kinetics of oral lorazepam in humans: the predictability of accumulation. J Pharmacokinet Biopharm 1979; 7:159–179. 58. Greenblatt DJ, et al. Pharmacokinetic comparison of sublingual lorazepam with intravenous, intramuscular, and oral lorazepam. J Pharm Sci 1982; 71:248–252. 59. Smink BE, et al. The concentration of oxazepam and oxazepam glucuronide in oral fluid, blood and serum after controlled administration of 15 and 30 mg oxazepam. Br J Clin Pharmacol 2008; 66:556–560. 60. Greenblatt DJ, et al. Clinical pharmacokinetics of the newer benzodiazepines. Clin Pharmacokinet 1983; 8:233–252. 61. Ferrari A, et al. Methadone – metabolism, pharmacokinetics and interactions. Pharmacol Res 2004; 50:551–559. 62. European Monitoring Centre for Drugs and Drug Addiction. Drug use, impaired driving and traffic accidents. 2014 (last accessed May 2024); http://bookshop.europa.eu/uri?target=EUB:NOTICE:TDXD14016:EN:HTML. 63. Department of Transport. Medication and road safety: a scoping study. Road Safety Research Report No. 116. 2010 (last accessed May 2024); https://webarchive.nationalarchives.gov.uk/20101007211118/http://www.dft.gov.uk/pgr/roadsafety/research/rsrr/theme3/report16 findings.pdf. 64. Grabe HJ, et al. The influence of polypharmacological antidepressive treatment on central nervous information processing of depressed patients: implications for fitness to drive. Neuropsychobiology 1998; 37:200–204. 65. Driver and Vehicle Licensing Agency. At a glance guide to the current medical standards of fitness to drive. 2013 (last updated February 2024, last checked May 2024); https://www.gov.uk/government/publications/at-a-glance. 66. General Medical Council. Good practice in prescribing and managing medicines and devices. 2021 (last accessed May 2024); https://www. gmc-uk.org/guidance/ethical_guidance/14316.asp.

19 - Chapter 14 Prescribing psychotropics

01 - Working towards adherence

Working towards adherence

19 - Chapter 14 Prescribing psychotropics

02 - What is adherence

What is adherence?

19 - Chapter 14 Prescribing psychotropics

03 - How common is non adherence

How common is non-adherence?

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 14 Working towards adherence What is adherence? The first clear statement about adherence comes from Hippocrates (460–377 bc), who vividly described non-adherence and linked it with poor outcomes. The World Health Organization (WHO) has described adherence as ‘the extent to which a person’s behaviour – taking medication, following a diet, and/or executing lifestyle changes – corresponds with agreed recommendations from a healthcare provider’.1 In the UK, the National Institute for Health and Care Excellence (NICE) has, more succinctly, defined adherence as ‘the extent to which the patient’s action matches the agreed recommendations’.2 The more traditional notion of the patient ‘complying’ with the doctor’s orders seems patronising and to deny the agency of the patient.3 ‘Concordance’ is another term that has been used, which seems to refer to an agreement between the patient and the doctor. This is part of the notion of informed consent and is essential for a ‘prescribing partnership’ with patients.4 But, as we know, agreement about a course of action does not necessarily guarantee that the action will happen. Thus ‘adherence’ will be used in this section to refer to the development of behaviours that will, it is hoped, result in better outcomes for our patients. How common is non-adherence? Large numbers of people, in most areas of medicine, do not seem to take their tablets very regularly – and so can be said to be partly or fully non-adherent. This is a phenomenon that arises in other clinical areas as well, such as psychological therapies. For people referred to psychotherapy services in the north of England, 34% did not attend for their first assessment session and, of those who did, only 57% subsequently attended the first treatment session.5 Prescribing psychotropics

19 - Chapter 14 Prescribing psychotropics

04 - Impact of non adherence

Impact of non-adherence

928 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 For chronic physical and mental disorders, the picture is not much better. Although 76% of patients with several conditions reported adhering to medication, electronic monitoring suggested that, in fact, only 44% did so.6 Consistent with previous findings, a 2020 meta-analysis suggested that, overall, about 50% of people with mental health problems do not take their medication as prescribed.7 This, however, may be an oversimplification. It is probable that a small proportion of patients are fully adherent, the majority are partially adherent to varying degrees, and a few never take any medication at all (of their own volition).8 These findings are not only characteristic of western medical culture, they are reflected in other parts of the world.9 Adherence rates also vary both over time and across settings. For example, 10 days after discharge from hospital, up to 25% of patients with schizophrenia are partially or completely non-adherent with oral treatment and this figure rises to 50% at 1 year and to 75% by 2 years.10 Other studies have reported 25.8% complete discontinuation of medication within 1 year of discharge from hospital.11 In some mental healthcare settings, the rate of non-adherence may be as high as 90%.12 Diagnosis may also be significant. An Austrian study found that significantly more patients with schizophrenia (66%) did not take their medication as prescribed, compared with patients with affective disorders (47%) or those with other psychiatric diagnoses (41%).13 A major issue is that poor adherence almost always occurs without the knowledge of the prescriber. In one study, prescribers identified only half of those who were non- adherent.14 In another, 35% of patients referred for treatment of (apparently) refractory schizophrenia had sub-therapeutic plasma concentrations and many of them had plasma levels of zero.15 Impact of non-adherence Medicines are only effective if taken at a therapeutic dose. And they are effective. A 20- year follow-up study of 62 250 patients with schizophrenia reported a significantly lower suicide mortality during antipsychotic use compared with non-use.16 Antipsychotic use also decreased overall mortality. Poor adherence to medication is a major risk factor for worse outcomes including relapse in people with schizophrenia,17–19 bipolar disorder20 and depression.21 Wider health benefits are also lost. Depressed patients who do not take an antidepressant have a 20% increased risk of an incident myocardial infarction compared with those who do.22 The serious consequences of non-adherence with medication may be mitigated by implementing routine monitoring. Data were collected as part of the National Confidential Inquiry into Suicide and Homicide by People with Mental Illness.23 This revealed that healthcare providers who had a policy regarding how to manage patients who are not taking their medication as prescribed had 20% fewer suicides than providers who did not have such a policy.23 Another reason that poorly adherent individuals do worse is that they may stop their medication abruptly and without monitoring (and without telling anyone). Abrupt cessation of almost all psychotropic drugs tends to worsen prognosis (see The Maudsley Deprescribing Guidelines). One of the findings that clearly illustrate the benefits of adherence is the example of depot antipsychotic medications. They do not differ pharmacologically from their oral equivalents but have consistently been shown to result in lower rates of readmission to

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05 - Factors affecting adherence7,28

Factors affecting adherence7,28

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06 - Assessing adherence29,30

Assessing adherence29,30

Prescribing psychotropics CHAPTER 14 hospital. The only difference is that with the depot preparations, adherence is, for a while at least, assured (and known about) – something which cannot be said for oral medications. Improving adherence offers substantial possibilities for improving the outcomes from treatments. WHO comments that ‘increasing the effectiveness of adherence interventions may have far greater impact on the health of the population than any improvements in specific medical treatments’.1 We must also remember that medication is not the only effective treatment for psychosis. Although a meta-analysis24 and systematic review25 of such psychodynamic interventions (which included studies in unmedicated patients) confirmed the superiority of treatment with antipsychotics, the most recent systematic review of psychosocial interventions for psychotic patients (with no or low-dose antipsychotics) found the effect of such interventions to be equal to treatment with antipsychotics.26 Cognitive behavioural therapy (CBT) for psychosis has been demonstrated to reduce certain symptoms, although its effect on quality of life does not seem to be significant.27 So – we certainly need better drugs, but we need also to improve adherence. Factors affecting adherence7,28 Table 14.1 lists many of the factors that might affect adherence. Clearly, not all of these factors necessarily fit into a single category. For example, poor understanding by the patient can either be due to poor health literacy and/or numeracy or can be due to deficiencies in communication by the doctor. Assessing adherence29,30 Table 14.2 outlines methods of assessing medication adherence. For some antipsychotics such as clozapine, olanzapine, aripiprazole and risperidone, blood tests can be used to directly assess plasma levels. However, the plasma levels of these drugs attained with a fixed dose do vary, as do the therapeutic effects in individuals. It is therefore not possible to accurately determine partial non-adherence. That is to say, total non-adherence will be readily revealed (plasma level = zero) but partial and full adherence may be difficult to tell apart. Table 14.1 Factors affecting adherence. Illness-related Treatment-related Clinician-related Patient-related Environmental Lack of motivation Poor insight Grandiose delusions Cognitive deficit Thought disorder Forgetfulness Disorganisation Adverse effects Dysfunctional beliefs Inappropriate medication preparation or packaging Dosing schedules31,32 Poor therapeutic alliance Lack of follow-up Limited consultation time Poor provision of information and explanation Denial Poor insight Comorbidities Physical impairments Poor literacy Poor health literacy33 Poor understanding of treatment options Disorganised environment Family’s beliefs Religious beliefs Health beliefs

930 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 Table 14.2 Assessing adherence. Method Variables measured Advantages Disadvantages Direct Blood test Drug/metabolite plasma levels Accurate Invasive Costly Inter-individual variations (e.g. fast and slow metabolisers) Not reliable for all drugs (see text) Only a result of zero can be definitively interpreted Information only relevant for a very limited timeframe No information about the patterns of medication-taking behaviour, levels of adherence or factors that may change adherence Indirect Pill count Number of missing tablets/ missed prescriptions Simple to use (useful in clinical trials) Labour-intensive in clinical practice Substantial evidence that pill counts underestimate levels of non-adherence Electronic database: clinical/pharmacy records History of non-adherence (but generally with very little detail or formal assessment) Pharmacy dispensing and collection records (e.g. medication possession ratio – MPR) Readily accessible Easy to identify non-adherent patients Inexpensive Non-invasive Not reliable – only provides evidence for collection and possession of medication Self-report Validated assessment scales (questionnaires) (e.g. Medication Adherence Rating Scale – MARS) Easy to use Inexpensive Subject to reporting bias Tendency to please clinicians Massively overestimates adherence Subjective Electronic monitoring devices (e.g. Medication Event Monitoring System – MEMS) Number of times medication container has been opened and (assumed) percentage of doses removed Among the most accurate methods Objective Provides additional information on medication-taking behaviour Expensive Bulky containers Not evidence for ingestion of medication – only of container opening Patient feels under surveillance

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07 - Monitoring adherence and assessing attitudes

Monitoring adherence and assessing attitudes to medication

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08 - Enhancing medication adherence

Enhancing medication adherence

Prescribing psychotropics CHAPTER 14 Monitoring adherence and assessing attitudes to medication Psychiatrists generally prefer to use direct questioning over the use of more intrusive/ objective and elaborate methods of assessing adherence. Partly as a result non-adherence may go undetected.34 NICE recommends that the patient should be asked in a non- judgemental way if they have missed any doses over a specific time period such as the previous week.35 Issues of forgetfulness aside, whether the patient takes medication or not will be, to a significant extent, determined by their views about medication and its perceived effect on their life and condition. Rating scales and checklists can help the clinician to guide and structure a discussion of what the patient thinks and feels about medication. The most widely used is the Drug Attitude Inventory (DAI),36 which consists of a mix of positive and negative statements about medication; 30 statements in its full form and 10 in its short form. The patient completes it by simply agreeing or disagreeing with each statement. The total score is an indicator of the patient’s overall perception of the balance between the benefits and harms associated with taking medication, and therefore likely adherence. Attitudes to medication as measured in this way have been shown to be a useful predictor of adherence over time.37 Other checklists include the Rating of Medication Influences (ROMI) scale,38 the Beliefs about Medicines Questionnaire39 and the Medication Adherence Rating Scale (MARS).19 Enhancing medication adherence Adherence to medication requires collaboration between the patient and the prescriber. NICE recommends that, as long as the patient has capacity to consent, their right not to take medication should be respected. If the prescriber considers that this decision may lead to harm, the reasons for the patient’s decision and the prescriber’s concerns should be recorded. Adherence is a complex behaviour that is influenced by malleable underlying factors. Consequently, determinants of non-adherence can be modified through patient-specific and factor-focused interventions (Table 14.3). However, most adherence-enhancing interventions are not based on a sound theoretical framework and lack methodological rigour.40 Low-quality studies and their outcomes are often not duplicated in different settings. This phenomenon was also highlighted by the most recent Cochrane review of adherence interventions when they reported that only 11 studies out of 182 included papers had the lowest risk of bias.41 Strategies for improving adherence Systematic reviews suggest that patient-specific interventions are more likely to enhance adherence in patients with serious mental disorders.42 NICE has reviewed the evidence for adherence over a range of health conditions and concluded that no specific intervention can be recommended for all patients. Note that few studies in this area specifically recruited non-adherent patients (the refusal rate in such patients is likely to be high) and the specific barriers to adherence are rarely identified. The small effect size seen in many studies may simply be a consequence of this unfocused approach. An intervention mapping framework43 provides a way to connect determinants of non-adherence to evidence-based interventions.

932 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 Medication-taking aids ‘Compliance aids’ are boxes that contain compartments that can accommodate up to four doses of multiple medicines each day. These may be helpful in patients who are clearly motivated to take medication but who are disorganised or who have cognitive deficits. But only 10% of non-adherent patients say that they simply forgot to take medication, so medication-taking aids are not a substitute for lack of insight or lack of motivation. Moreover, some medicines are unstable when removed from blister packaging and placed in a compliance aid. These include oro-dispersible formulations which are often prescribed for non-adherent patients. In addition, medication-taking aids are labour-intensive (expensive) to fill, it can be difficult to change prescriptions at short notice and the process of filling of these devices is particularly error-prone.46 More sophisticated programmes of practical support, both electronic and in-person, have been shown to be effective.47 Depot/long-acting antipsychotics Meta-analyses of clinical trials have shown that the relative and absolute risks of relapse with depot maintenance treatment were 30% and 10% lower, respectively, than with oral treatment.48,49 NICE recommends that depots are an option in patients who are known to be non-adherent to oral treatment and/or those who prefer this method of administration. However, it is worth remembering that switching a non- adherent patient from oral antipsychotics to a long-acting injectable formulation does not address the underlying reasons driving that non-adherence. This has been highlighted by a recent systematic review that reported a rate of discontinuation of above 50% in those who had been prescribed second-generation depots.50 So long-acting antipsychotics do not stop non-adherence but they do prevent sudden cessation of medication and its consequences (all depots provide a slow decline in plasma levels). Table 14.3 Interventions for non-adherence.44 Intentional non-adherence Unintentional non-adherence Psychoeducation is the foundation for all adherence interventions, but without behaviour-changing components it is not overwhelmingly effective. Provides both verbal and written information. Motivational interviewing for goal-setting Adherence therapy for exploring dysfunctional beliefs about medication or the illness, providing information and goal setting. It requires more time and multiple sessions. Cognitive behavioural therapy to eradicate or control the residual symptoms that prevent adherence. To address dysfunctional beliefs about treatment. Cognitive remediation to help with cognitive deficit in psychotic patients and thought disorder Mindfulness to help with symptoms Monitor adverse effects regularly and periodically Therapeutic alliance – a non-judgemental clinician allows patients to honestly disclose their thoughts and beliefs about medication Family intervention – psychoeducation and family therapy Simplify dose regimen – reduce number of medications and/or frequency of administration Dispensing interventions – medication-taking aids EAM (electronic adherence monitoring) – evidence for this is weak45 Pairing-up medication – taking with a daily activity (e.g. having breakfast, brushing teeth or before bedtime) Use technology – messaging service, email and telephone reminders Pharmacy interventions for those with physical impairment (e.g. opening bottles)

Prescribing psychotropics CHAPTER 14 Their use can also provide certainty about the level of adherence (the injection is either given or it is not). Depots are probably underused, for example a US study found that depot preparations were prescribed for fewer than one in five patients with a recent episode of non-adherence.51 An alternative to depots is the use of long-acting oral antipsychotics such as penfluridol, which can be given weekly.52 Supervised administration obviates the need for injections but does not provide the same level of certainty over compliance given the facility that patients have demonstrated for disguising the taking of oral medication. In the USA, Abilify MyCite is approved for use.53 This is a version of aripiprazole with a transmitting sensor embedded in the formulation which is able to confirm that a tablet has been taken. Evidence for its effectiveness is slim.54 Financial incentives Controlled trials in a number of disease areas support the offer of financial incentives to enhance medication adherence. Paying people to take their medication is extremely controversial, though some clinicians have found this strategy to be effective. The effect could not be maintained in a randomised controlled trial (RCT) at 6- and 24-month follow-up after payments were stopped, and complete adherence was achieved in only 28% of patients receiving the incentives.55 Other RCTs also have demonstrated a significant increase in adherence during the trial and a decline at follow-up when payments had stopped.56 Offering financial incentives did not reduce patients’ motivation for treatment.57 A systematic review of acceptability of financial incentives for health- related behaviours has raised concerns about the validity and reliability of these interventions given their methodological limitations.58 Psychological interventions In physical medicine, medication adherence has been found to be associated with health beliefs and psychological variables, such as self-efficacy and locus of control.59 Family support is also positively related to medication adherence. It is likely to be the same in psychiatry – but what can be done? One such intervention – called, at the time, ‘compliance therapy’ – was evaluated at the Maudsley Hospital.60 This was a pilot of a mixed intervention, consisting of active listening, cognitive behavioural techniques, motivational interviewing and the provision of information and explanation. This showed promising results in terms of increased adherence and reduced admission rates over the next 6 months. However, training for staff and supervision render it time-consuming. A subsequent replication did not show the same improvements,61 but also did not appear to have incorporated a training or supervisory element for those delivering the therapy. However, a trial of training in compliance therapy did seem to have an effect on the junior doctors involved, who felt that they were more aware of the drivers of non-adherence and of the importance of empathic listening and more able to understand why a patient might not take medication.62 One prerequisite for successful adherence to a treatment regimen should be that the patient understands the objectives of treatment, the options on offer and the rationale behind them. However, many – perhaps most – doctors have had no specific training in how to convey information and understanding to patients. Difficulties have been noted

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09 - Conclusion

Conclusion

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10 - References

References

934 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 to arise in cancer medicine regarding the benefits and risks of anti-cancer medications.63 One must assume that we are likely to meet the same difficulties in psychiatry. We also need to consider that our patients may have a very different explanatory model for what is happening to them. For example, not so long ago, only just over a third of white English patients viewed schizophrenia as having a substantially biological origin.64 So our explanations for a person’s psychosis may not be as convincing to them – and their families – as we might imagine. One simple step that might help is to encourage patients with a serious medical illness to read their own notes; one study reported that this helped such patients to better understand why they were prescribed medications.65 However, this begs the question of why they did not understand in the first place. The range of practical interventions described in Table 14.3 – and, to a great extent, the psychological interventions contained in the original model of compliance therapy – will need to be tailored to the needs of the individual patient. But this assumes that clinicians have an awareness of the issue, the requisite skills and the time available to use them. The current RCPsych curricula, although they refer to some of the psychological skills modalities mentioned, do not include the management of adherence as an issue in either the core curriculum or the general psychiatry curriculum.66 Conclusion Establishing and maintaining adherence is a quintessentially biopsychosocial activity. It is central to the practice of medicine and, hence, to psychiatry. It demands both an awareness of the problem, a knowledge of practical strategies for its improvement and a repertoire of psychological skills. The neglect of this area of therapeutics in training should not deter prescribers from recognising non-adherence and taking active steps to manage it. An initial gambit might be, at the end of any first prescription, to ask ourselves ‘What have I done to help this patient take this medication?’ and to record this answer as part of the care plan, as a reminder to ourselves and our colleagues that this issue needs our conscious, structured and regular attention. References

World Health Organization. Adherence to long-term therapies: evidence for action. 2003; https://apps.who.int/iris/bitstream/handle/ 10665/42682/9241545992.pdf.
National Institute for Health and Care Excellence. Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. Clinical guideline [CG76]. 2009 (last checked August 2023); https://www.nice.org.uk/guidance/cg76.
Piatkowska O, et al. Medication — compliance or alliance? A client-centred approach to increasing adherence. In: Kavanagh DJ, ed. Schizophrenia: An Overview and Practical Handbook. Boston, MA: Springer US; 1992:339–355.
Bond C, et al. Prescribing and partnership with patients. Br J Clin Pharmacol 2012; 74:581–588.
Sweetman J, et al. Risk factors for initial appointment non-attendance at Improving Access to Psychological Therapy (IAPT) services: a retrospective analysis. Psychother Res 2023; 33:535–550.
Foley L, et al. Prevalence and predictors of medication non-adherence among people living with multimorbidity: a systematic review and meta-analysis. BMJ Open 2021; 11:e0987.
Semahegn A, et al. Psychotropic medication non-adherence and its associated factors among patients with major psychiatric disorders: a systematic review and meta-analysis. Syst Rev 2020; 9:17.
Masand PS, et al. Partial adherence to antipsychotic medication impacts the course of illness in patients with schizophrenia: a review. Prim Care Companion J Clin Psychiatry 2009; 11:147–154.
Alosaimi K, et al. Medication adherence among patients with chronic diseases in Saudi Arabia. Int J Environ Res Public Health 2022; 19:10053.
Leucht S, et al. Epidemiology, clinical consequences, and psychosocial treatment of nonadherence in schizophrenia. J Clin Psychiatry 2006; 67 Suppl 5:3–8.

Prescribing psychotropics CHAPTER 14 11. Zhou Y, et al. Factors associated with complete discontinuation of medication among patients with schizophrenia in the year after hospital discharge. Psychiatry Res 2017; 250:129–135. 12. Cramer JA, et al. Compliance with medication regimens for mental and physical disorders. Psychiatr Serv 1998; 49:196–201. 13. Geretsegger C, et al. Non-adherence to psychotropic medication assessed by plasma level in newly admitted psychiatric patients: prevalence before acute admission. Psychiatry Clin Neurosci 2019; 73:175–178. 14. Remington G, et al. The use of electronic monitoring (MEMS) to evaluate antipsychotic compliance in outpatients with schizophrenia. Schizophr Res 2007; 90:229–237. 15. McCutcheon R, et al. Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia. Acta Psychiatr Scand 2018; 137:39–46. 16. Taipale H, et al. 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20). World Psychiatry 2020; 19:61–68. 17. Morken G, et al. Non-adherence to antipsychotic medication, relapse and rehospitalisation in recent-onset schizophrenia. BMC Psychiatry 2008; 8:32. 18. Knapp M, et al. Non-adherence to antipsychotic medication regimens: associations with resource use and costs. Br J Psychiatry 2004; 184:509–516. 19. Jaeger S, et al. Adherence styles of schizophrenia patients identified by a latent class analysis of the Medication Adherence Rating Scale (MARS): a six-month follow-up study. Psychiatry Res 2012; 200:83–88. 20. Lang K, et al. Predictors of medication nonadherence and hospitalization in Medicaid patients with bipolar I disorder given long-acting or oral antipsychotics. J Med Econ 2011; 14:217–226. 21. Mitchell AJ, et al. Why don’t patients take their medicine? Reasons and solutions in psychiatry. Adv Psychiatric Treat 2007; 13:336–346. 22. Scherrer JF, et al. Antidepressant drug compliance: reduced risk of MI and mortality in depressed patients. Am J Med 2011; 124:318–324. 23. Appleby L, et al. National Confidential Inquiry into Suicide and Homicide by People with Mental Illness. 2013; http://www.bbmh.manchester. ac.uk/cmhr/research/centreforsuicideprevention/nci/. 24. Malmberg L, et al. Individual psychodynamic psychotherapy and psychoanalysis for schizophrenia and severe mental illness. Cochrane Database Syst Rev 2001; 3:CD001360. 25. Mueser KT, et al. Psychodynamic treatment of schizophrenia: is there a future? Psychol Med 1990; 20:253–262. 26. Cooper RE, et al. Psychosocial interventions for people with schizophrenia or psychosis on minimal or no antipsychotic medication: a systematic review. Schizophr Res 2019; 225:15–30. 27. Health Quality Ontario. Cognitive behavioural therapy for psychosis: a health technology assessment. Ont Health Technol Assess Ser 2018; 18:1–141. 28. Pedley R, et al. Qualitative systematic review of barriers and facilitators to patient-involved antipsychotic prescribing. BJPsych Open 2018; 4:5–14. 29. Forbes CA, et al. A systematic literature review comparing methods for the measurement of patient persistence and adherence. Curr Med Res Opin 2018; 34:1613–1625. 30. Anghel LA, et al. An overview of the common methods used to measure treatment adherence. Med Pharmacy Rep 2019; 92:117–122. 31. Greenberg RN. Overview of patient compliance with medication dosing: a literature review. Clin Ther 1984; 6:592–599. 32. Saini SD, et al. Effect of medication dosing frequency on adherence in chronic diseases. Am J Manag Care 2009; 15:e22–33. 33. Miller TA. Health literacy and adherence to medical treatment in chronic and acute illness: a meta-analysis. Patient Educ Couns 2016; 99:1079–1086. 34. Vieta E, et al. Psychiatrists’ perceptions of potential reasons for non- and partial adherence to medication: results of a survey in bipolar disorder from eight European countries. J Affect Disord 2012; 143:125–130. 35. National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management. Clinical guideline [CG178]. 2014 (last checked August 2023); https://www.nice.org.uk/guidance/cg178. 36. Hogan TP, et al. A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative validity. Psychol Med 1983; 13:177–183. 37. Perkins DO. Predictors of noncompliance in patients with schizophrenia. J Clin Psychiatry 2002; 63:1121–1128. 38. Weiden P, et al. Rating of medication influences (ROMI) scale in schizophrenia. Schizophr Bull 1994; 20:297–310. 39. Horne R, et al. The beliefs about medicines questionnaire: the development and evaluation of a new method for assessing the cognitive representation of medication. Psychol Health 1999; 14:1–24. 40. Zullig LL, et al. Moving from the trial to the real world: improving medication adherence using insights of implementation science. Annu Rev Pharmacol Toxicol 2019; 59:423–445. 41. Nieuwlaat R, et al. Interventions for enhancing medication adherence. Cochrane Database Syst Rev 2014; 11:CD000011. 42. Nosè M, et al. [Systemic review of clinical interventions for reducing treatment non-adherence in psychosis]. Epidemiol Psichiatr Soc 2003; 12:272–286. 43. Kok G, et al. A taxonomy of behaviour change methods: an intervention mapping approach. Health Psychol Rev 2016; 10:297–312. 44. Hartung D, et al. Interventions to improve pharmacological adherence among adults with psychotic spectrum disorders and bipolar disorder: a systematic review. Psychosomatics 2017; 58:101–112. 45. Chan AHY, et al. Effect of electronic adherence monitoring on adherence and outcomes in chronic conditions: a systematic review and meta-analysis. PLoS One 2022; 17:e0265715. 46. Barber ND, et al. Care homes’ use of medicines study: prevalence, causes and potential harm of medication errors in care homes for older people. Qual Safety Health Care 2009; 18:341–346.

936 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 47. Velligan D, et al. A randomized trial comparing in person and electronic interventions for improving adherence to oral medications in schizophrenia. SchizophrBull 2013; 39:999–1007. 48. Leucht C, et al. Oral versus depot antipsychotic drugs for schizophrenia – a critical systematic review and meta-analysis of randomised long-term trials. Schizophr Res 2011; 127:83–92. 49. Leucht S, et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012; 379:2063–2071. 50. Gentile S. Discontinuation rates during long-term, second-generation antipsychotic long-acting injection treatment: a systematic review. Psychiatry Clin Neurosci 2019; 73:216–230. 51. West JC, et al. Use of depot antipsychotic medications for medication nonadherence in schizophrenia. Schizophr Bull 2008; 34:995–1001. 52. Soares BG, et al. Penfluridol for schizophrenia. Cochrane Database Syst Rev 2006; 2:CD002923. 53. Otsuka Pharmaceutical Co. Ltd. Highlights of prescribing information. Abilify Mycite (aripiprazole with sensor) for oral use 2017. https:// www.accessdata.fda.gov/drugsatfda_docs/label/2017/207202lbl.pdf. 54. Cosgrove L, et al. Digital aripiprazole or digital evergreening? A systematic review of the evidence and its dissemination in the scientific literature and in the media. BMJ Evid Based Med 2019; 24:231–238. 55. Priebe S, et al. Financial incentives to improve adherence to antipsychotic maintenance medication in non-adherent patients: a cluster randomised controlled trial. Health Technol Assess 2016; 20:1–122. 56. Noordraven EL, et al. Financial incentives for improving adherence to maintenance treatment in patients with psychotic disorders (Money for Medication): a multicentre, open-label, randomised controlled trial. Lancet Psychiatry 2017; 4:199–207. 57. Noordraven EL, et al. The effect of financial incentives on patients’ motivation for treatment: results of ‘Money for Medication,’ a randomised controlled trial. BMC Psychiatry 2018; 18:144. 58. Hoskins K, et al. Acceptability of financial incentives for health-related behavior change: an updated systematic review. Prev Med 2019; 126:105762. 59. Marrero RJ, et al. Psychological factors involved in psychopharmacological medication adherence in mental health patients: a systematic review. Patient Educ Couns 2020; 103:2116–2131. 60. Kemp R, et al. Compliance therapy in psychotic patients: randomised controlled trial. BMJ 1996; 312:345–349. 61. O’Donnell C, et al. Compliance therapy: a randomised controlled trial in schizophrenia. BMJ 2003; 327:834. 62. Surguladze S, et al. Teaching psychiatric trainees ‘compliance therapy’. Psychiatric Bull 2002; 26:12–15. 63. Davis C, et al. Communication of anticancer drug benefits and related uncertainties to patients and clinicians: document analysis of regulated information on prescription drugs in Europe. BMJ 2023; 380:e073711. 64. McCabe R, et al. Explanatory models of illness in schizophrenia: comparison of four ethnic groups. Br J Psychiatry 2004; 185:25–30. 65. Blease C, et al. Association of patients reading clinical notes with perception of medication adherence among persons with serious mental illness. JAMA Netw Open 2021; 4:e212823. 66. Royal College of Psychiatrists. Curricula documents and resources. 2022; https://www.rcpsych.ac.uk/training/curricula-and-guidance/ curricula-implementation/curricula-documents-and-resources.

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11 - Restarting psychotropic medications after a p

Restarting psychotropic medications after a period of non-compliance

Prescribing psychotropics CHAPTER 14 Restarting psychotropic medications after a period of non-compliance When a patient is admitted to hospital it is often because they have been non-compliant with their medications for some time before admission. The clinical question of whether to restart the medication and at which dose is a complex one. The risk of withdrawal symptoms and relapse must be balanced against the risk of adverse drug reactions when medications are reintroduced too quickly. There is little published evidence on this area, with most guidance (often of undeclared provenance) coming from manufacturers. The guidance below should be followed with caution. Summaries of product characteristics (SPCs) and other formal, regulatory documents tend not to deal with the issue of restarting medication. Official patient information leaflets sometimes give detailed advice. These leaflets are unanimous in advising that on no account should a double dose be given to make up for a missed dose. However, the vast majority of leaflets advise only on what to do if a single dose has been missed. Some leaflets advise taking the missed dose later (providing it is not too close to the next dose), whereas others recommend skipping the missed dose altogether and starting again with the next dose. In the event that more than one dose has been missed, the first question to ask is whether or not this is the appropriate drug for a patient to be taking. Poor compliance often indicates some dissatisfaction on the part of the patient. If it is a drug with a short half-life or one that requires lengthy re-titration, it may not be appropriate to restart prescribing for a patient who is frequently non-compliant. Similarly, if a patient is intoxicated with alcohol or drugs, it may not be sensible to restart medication at that time. Efforts should be made to find out if there are any particular reasons for non- compliance. Where poor adherence is a result of factors other than tolerability, consider the use of a long-acting injection (although these are only used, officially at least, in schizophrenia and schizoaffective disorder). When considering whether to restart the drug at the same dose as before or to re-titrate from a lower dose, the time since the last dose is vitally important. If more than a week or two has passed, then all drugs will probably need to be restarted as if it is new treatment (although for many drugs that do not require titration this might mean starting back on the same dose as before). Exceptions include long-acting depot formulations and oral drugs with long half-lives such as aripiprazole, cariprazine and penfluridol. With these, there is a need to reload if the gap in treatment is very long, although shorter gaps (<2 weeks) might be managed by giving the usual dose and then reverting to the original dosing schedule. Lamotrigine must be considered separately from all other psychotropics because it has been associated with life-threatening cutaneous reactions, especially with high initial doses. The manufacturer’s product information advises that if five half-lives have elapsed since the last lamotrigine dose was given, lamotrigine should be titrated as if for the first time. The half-life in healthy subjects on no other medication is around 33 hours. This is affected by other medications and is approximately 14 hours when given with glucuronidation-inducing drugs such as carbamazepine or phenytoin. The half-life is increased to approximately 70 hours when given with valproate. This means that the time before complete re-titration is necessary varies between 3 and 7 days, depending on other drugs co-prescribed.1 Table 14.4 summarises some very general recommendations. The drugs in the first column have specific safety issues that mean they require re-titration after the specified

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12 - References

References

938 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 length of time. The drugs in the middle column are thought to be safe because the maximum dose is usually no higher than the highest recommended starting dose. The drugs in the right-hand column are thought to be safe to restart at the prior dose because a similar drug appears in the middle column, because clinical experience suggests they are safe or because the risks associated with giving untitrated high doses are thought to be low. Some suggestions are obtained from EU regulatory documents (SPCs),2 while others are mere suggestions based on clinical experience. If the gap in oral treatment is longer than 2 weeks, start as if it is new treatment (noting the exceptions listed earlier). References

Aurobindo Pharma-Milpharm Ltd. Summary of product characteristics. Lamotrigine 25mg tablets. 2024 (last accessed September 2024); https://www.medicines.org.uk/emc/product/4736/smpc.
EMC. Summaries of Product Characteristics. 2024 (last accessed September 2024); https://www.medicines.org.uk/emc/. Table 14.4 Restarting medication up to 2 weeks after stopping oral treatment. Drugs that require re-titration Drugs that are usually safe for restarting at the previous dose Drugs that are possibly safe for restarting at the previous dose Drug Time after which re-titration must be performed Further guidance Clozapine 48 hours See section in Chapter 1 Acamprosate Asenapine Fluoxetine Haloperidol Isocarboxazid Lofepramine Methylphenidate Phenelzine Sulpiride Tranylcypromine Valproate Antipsychotics (exceptions in column 1) Carbamazepine (beware loss on enzyme induction) Cholinesterase inhibitors CNS stimulants Disulfiram Lithium (titration advised if renal function has changed) MAOIs Memantine Naltrexone Pregabalin SSRIs Lamotrigine 3–7 days See text Methadone, buprenorphine 3 days See section in Chapter 4 Paliperidone long-acting injection Depends on formulation See section in Chapter 1 Aripiprazole long-acting injection Depends on formulation See section in Chapter 1 Quetiapine Suggest 1 week Tolerance to sedative and hypotensive effects may be lost Risperidone Suggest 1 week Tolerance to hypotensive effects may be lost Tricyclics Suggest 1 week Tolerance to sedative and hypotensive effects may be lost MAOIs, monoamine oxidase inhibitors.

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13 - Relational aspects of prescribing practice

Relational aspects of prescribing practice

19 - Chapter 14 Prescribing psychotropics

14 - Object relations

Object relations

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15 - Memory

Memory

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16 - Treatment framework

Treatment framework

Prescribing psychotropics CHAPTER 14 Relational aspects of prescribing practice This section provides clinicians with practically useful advice in the relational aspects of prescribing. Evidence exists for the importance of the doctor–patient relationship in improving treatment outcomes.1–3 The key factors that help develop, maintain and deepen the relationship include instilling trust and regard.4 Three concepts are important here: object relations, memory and the treatment framework. Object relations This means how the individual views themselves and others around them. This view then influences how they process incoming data (e.g. what is happening in an interaction). This view of themselves has been determined from early experience. In essence it means that the present interaction may be experienced inaccurately through the prism of the past (another way to think of this experience is that this is the transference). This has implications for both the patient and the clinician. For example, if the patient has had early experience of uncaring parents, they will have greater difficulty in trusting the clinician. In turn, if the clinician’s early experience is of demanding parents who expected them to always get it right, a treatment-resistant patient may be a particular challenge for them. This object relations approach allows one to be aware of factors regarding the patient, the clinician and the clinician– patient relationship. Memory Up to 95% of our goal-directed activities are executed unconsciously.5 Thus, the clinician’s prescribing may be more influenced by procedural memory than their subjective view that they are using working memory (i.e. there is an illusion of the application of active thinking to solve the specificity of the present problem). By definition, procedural memory and the action flowing from this may not be best suited for a particular clinical situation. Acknowledging the unconscious influence on the present may help bring the conscious mind into play. Treatment framework This is using knowledge of the clinician’s usual way of working (e.g. following this edition of The Maudsley Prescribing Guidelines), and a knowledge of how they tend to personally apply these guidelines. Straying from the guidelines may be based on good clinical judgement but also it may indicate that there is some psychological factor influencing decision-making. Given this psychological factor may be unconscious, the ability to review ‘what one usually does’ is then a useful check on what may be happening in prescribing. For example, if the prescriber is able to think ‘I do not usually prescribe such a high dose of antipsychotic as a starting dose’ they may then be able to pose the question ‘Am I feeling very anxious to satisfy the demands of this patient?’ In effect they may then be able to catch themselves acting out (i.e. replacing thinking with behaviour) in the countertransference (in this case their great anxiety to satisfy the patient).

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17 - Factors that may influence the patients use o

Factors that may influence the patient’s use of and adherence to medication

940 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 Factors that may influence the patient’s use of and adherence to medication How the individual views themselves, and others, will influence many aspects of a person’s behaviour. These issues include their personal and cultural beliefs, readiness to change, ambivalence, expectations of treatment, attachment style and treatment preference. In addition, patients might use medication in countertherapeutic ways. We address each of these in turn in terms of their practical implications.6,7 Personal and cultural beliefs The religious, cultural and socioeconomic contexts shape our beliefs around concepts of illness, health and disability.8 Adherence to treatments is affected by the patient’s subjective beliefs and averages roughly 50% in almost all conditions.9 Recommendation: When it comes to prescribing within a culturally diverse population, prescribers need to reflect on their own cultural biases, enquire about the patient’s cultural beliefs, and work collaboratively with communities and families.10 Readiness to change Patients’ motivation and readiness to change can affect treatment outcomes. Beitman et al.11 examined stages of change and response to medication in patients with panic disorder and found that readiness to change was associated with better outcomes. The transtheoretical model12 proposes that people move through different stages of change and that interventions must match the stage of readiness. This model can also be useful for the treatment of other mental health conditions including personality disorder.13 Recommendation: The clinician’s appreciation of the stages of change, and the work involved in lasting change, can increase compassion and avoid wrongly timed interventions (including wrongly timed prescribing). A recovery-focused and patient-centred approach may help patients to understand entrenched patterns of behaviour, and to actively participate in behavioural change. Ambivalence Patients may worry about the safety of psychotropics, and mistrust clinicians. Further, symptoms may have an adaptive and protective function thus making them harder for the patient to relinquish. For example, a patient who has elicited care might be ambivalent about getting better and losing this care. Recovery might portend, for example, confronting a difficult relationship or working through an intolerable loss.14 Recent advances in the field of neuropsychoanalysis suggest that unpleasurable feelings at a biological level indicate that the patient’s underlying emotional needs are not being satisfied, serving as homeostatic ‘error signals’. It is not a surprise then that symptoms (associated with feelings states) can be stubbornly resistant to symptom-focused treatments when the patient’s basic emotional needs continue to be unmet.15 Recommendation: Exploring patients’ ambivalence towards medication and healthcare professionals, and their previous experiences of care, can deepen the therapeutic relationship and is crucial in understanding patients’ concerns. Understanding the

Prescribing psychotropics CHAPTER 14 patient’s (often unconscious) underlying conflicts and motivations can explain symptom perseverance despite pharmacological endeavours. Acknowledgement of the patient’s ambivalence during the recovery process may help validate their experience, facilitate rapport and enable conversations that the patient might otherwise be reluctant to approach. Expectations of treatment: placebo and nocebo effect Expectations of improvement or harm when taking medication exert a significant impact on treatment responses. The powerful ‘placebo’ response has been well described in medicine as a genuine psychobiological event.16 Conversely, expectations of harm are associated with negative treatment outcomes known as the ‘nocebo’ effect. Patients often expect harm from taking antidepressants, fearing dependence and loss of control of their emotions.17 Interestingly, patients who discussed adverse effects of antidepressants with their doctors were reported less likely to discontinue therapy than patients who did not discuss them.18 Recommendation: These findings emphasise the need to use all the elements of the therapeutic relationship in the care of patients.19 Clinical management of the nocebo effect includes awareness and recognition, focusing on the treatment alliance, carefully naming and working through mistrust, and careful disclosure of potential drug-related adverse effects, while remaining honest and clear.20 Attachment style Healthcare staff often represent attachment figures21 as they treat patients in times of need and distress. The attachment is particularly important when it comes to the management of long-term conditions. In one study, diabetic patients with dismissive attachment had significantly worse glucose control than patients with preoccupied or secure attachment style, but the effect was mitigated by improved communication between doctors and patients.22,23 Concerns about rejection, abandonment, control and intimacy24 are likely to affect patients’ use of their medication. Patients with a dismissive attachment style may fear dependence on medication and services and not adhere to the prescribed interventions. Patients with a fearful-anxious attachment might need regular reassurance, while patients with a disorganised attachment might evoke disorganised and chaotic responses from healthcare staff. Recommendation: Consider attachment patterns when prescribing. Particular attention and consistency are needed to deliver coherent and reliable care alongside pharmacological interventions. Treatment preference The chronic illness model encourages consideration of the patient’s treatment preferences. Research suggests that matching treatment to preference might improve outcomes for patients with depression.25 An RCT matching patients to treatment preference for major depressive disorder concluded that patients had better outcomes on their preferred treatment.26 These observations might apply to other conditions.

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18 - Summary a checklist when prescribing

Summary – a checklist when prescribing

942 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 Recommendation: Consider treatment preference as one of the decision factors when prescribing. Countertherapeutic use of medication Medication (including overdose) may be used as a way of signalling submission, anger or helplessness. This is especially true in people who lack an emotional vocabulary and secure internal representations of benign care. Medication may become a way of self- management, replacing more developmental coping strategies and relationships. Recommendation: The clinician should consider the meaning of the emotional communication and be curious about alliance ruptures and system failures (and therefore reflect on the clinician’s possible contributions to the rupture). Summary – a checklist when prescribing When faced with complex prescribing decisions, a checklist considering the discussed issues from the perspective of the patient, the clinician and the clinician–patient relationship may be helpful. The patient factor Q: ‘What is my patient’s story? What is my patient trying to communicate using words or, as important, through their actions in the here and now?’ Recommendation: A formulation of the patient’s underlying psychological difficulties may help. This may include: ■ ■Predominant relational pattern(s) – attachment style and relationship to care/ authority. ■ ■Ambivalence about symptoms – underlying psychological investment in status quo. ■ ■Meaning attached to medication and overall use of medication (including countertherapeutic use of medication). The clinician factor Q: ‘How do I feel in response to my patient and how does that influence the action I am considering taking (e.g. do I feel helpless, frustrated, incompetent, guilty in the face of the patient’s symptoms)? Am I prescribing to avoid unwanted feelings in my relationship with my patient?’ Recommendation: 1 The first step in identifying countertransference pressure is to recognise and accept it, without always resorting to immediate action. 2 Self-review of practice. The clinician may ask: ■ ■Am I working within relevant guidelines? ■ ■Am I doing what I normally do (if not, am I being overly influenced by my countertransference)? ■ ■Do I have strong feelings about this patient? Do I have no feelings about this patient? (Which would be also worth considering.)

Prescribing psychotropics CHAPTER 14 ■ ■Are any circumstances different, for example do I have managers or other colleagues or the patient’s family scrutinising me with this particular patient? 3 Seek support. Use supervision with colleagues and ask support from other members of the multidisciplinary team. It is important to work closely with colleagues (including pharmacists) to triangulate decisions when in complex prescribing dilemmas. Choosing to discuss a problem in supervision and outside of the heat of the consulting room can clarify thinking. The clinician–patient relationship Q: ‘What might prescribing a medication – or not prescribing – come to represent in my relationship with my patient?’ Limited consultation time and cancelled clinics might reinforce feelings of rejection and abandonment. Non-adherence to medication or overdose of prescribed medication might be a sign of a rupture in the clinician–patient relationship and further exploration can promote useful insights for patient and clinician. Recommendation: Consider the meaning of medication in the context of the patient, the clinician and the clinician–patient relationship. Cultivate a pharmacotherapeutic partnership and set limits:24 ■ ■Reframe prescribing as a partnership, rather than a one-directional activity of the doctor. ■ ■Provide, as much as possible, a stable and consistent consultation setting. ■ ■Set therapeutic limits, confronting unrealistic expectations of care. (This includes maintaining a realistic humility around the limitations of psychopharmacology, and psychoeducating patients regarding what medications can and cannot achieve and their place in the overall journey to recovery and development.) ■ ■Endorse a stance that can promote the pharmacotherapeutic alliance, characterised by emotional presence and warmth, good and honest communication, and support of the patient’s autonomy and agency. This includes shared decision-making and respect for the patient’s treatment preferences, when clinically indicated. ■ ■Openly discuss overall recovery goals, target symptoms, duration of treatment and potential adverse effects, and address any associated anxieties. ■ ■A clear agreement on treatment objectives, consistent with the overall care plan, and the respective responsibilities of doctor and patient can promote agency and strengthen the pharmacotherapeutic partnership. ■ ■Collaborative crisis planning should be part of this, especially when there are risk concerns.

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19 - References

References

944 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 References

Olaisen RH, et al. Assessing the longitudinal impact of physician-patient relationship on functional health. Ann Fam Med 2020; 18:422–429.
McKay KM, et al. Psychiatrist effects in the psychopharmacological treatment of depression. J Affect Disord 2006; 92:287–290.
Kelley JM, et al. The influence of the patient-clinician relationship on healthcare outcomes: a systematic review and meta-analysis of randomized controlled trials. PLoS One 2014; 9:e94207.
Ridd M, et al. The patient-doctor relationship: a synthesis of the qualitative literature on patients’ perspectives. Br J Gen Pract 2009; 59:e116–e133.
Bargh JA, et al. The unbearable automaticity of being. Am Psychol 1999; 54:462.
Mintz DL, et al. How (not what) to prescribe: nonpharmacologic aspects of psychopharmacology. Psychiatr Clin North Am 2012; 35:143–163.
Konstantinidou H, et al. Will this tablet make me happy again? The contribution of relational prescribing in providing a pragmatic and psychodynamic framework for prescribers. BJPsych Advances 2023; 29:265–273.
Ravindran N, et al. Cultural influences on perceptions of health, illness, and disability: a review and focus on autism. J Child Fam Studies 2012; 21:311–319.
Lam WY, et al. Medication adherence measures: an overview. BioMed Res Int 2015; 2015:217047.
Brooks LA, et al. Culturally sensitive communication in healthcare: a concept analysis. Collegian 2019; 26:383–391.
Beitman BD, et al. Patient stage of change predicts outcome in a panic disorder medication trial. Anxiety 1994; 1:64–69.
Prochaska JO, et al. Stages and processes of self-change of smoking: toward an integrative model of change. J Consult Clin Psychol 1983; 51:390–395.
Roughley M, et al. Referral of patients with emotionally unstable personality disorder for specialist psychological therapy: why, when and how? BJPsych Bull 2021; 45:52–58.
Gibbons R. The mourning process and its importance in mental illness: a psychoanalytic understanding of psychiatric diagnosis and classification. BJPsych Advances 2024; 30:80–88.
Lee T, et al. Managing the clinical encounter with patients with personality disorder in a general psychiatry setting: key contributions from neuropsychoanalysis. BJPsych Advances 2023; doi:10.1192/bja.2023.43.
Finniss DG, et al. Biological, clinical, and ethical advances of placebo effects. Lancet 2010; 375:686–695.
Piguet V, et al. Patients’ representations of antidepressants: a clue to nonadherence? Clin J Pain 2007; 23:669–675.
Bull SA, et al. Discontinuation of use and switching of antidepressants: influence of patient-physician communication. JAMA 2002; 288:1403–1409.
Benedetti F. Placebo and the new physiology of the doctor-patient relationship. Physiol Rev 2013; 93:1207–1246.
Data-Franco J, et al. The nocebo effect: a clinicians guide. Aust NZ J Psychiatry 2013; 47:617–623.
Adshead G. Psychiatric staff as attachment figures. Understanding management problems in psychiatric services in the light of attachment theory. Br J Psychiatry 1998; 172:64–69.
Ciechanowski PS, et al. The patient-provider relationship: attachment theory and adherence to treatment in diabetes. Am J Psychiatry 2001; 158:29–35.
Ciechanowski PS, et al. The association of patient relationship style and outcomes in collaborative care treatment for depression in patients with diabetes. Med Care 2006; 44:283–291.
Mintz D. Psychodynamic Psychopharmacology: Caring for the Treatment-Resistant Patient. Washington, DC: American Psychiatric Association Publishing; 2022.
Lin P, et al. The influence of patient preference on depression treatment in primary care. Ann Behav Med 2005; 30:164–173.
Kocsis JH, et al. Patient preference as a moderator of outcome for chronic forms of major depressive disorder treated with nefazodone, cognitive behavioral analysis system of psychotherapy, or their combination. J Clin Psychiatry 2009; 70:354–361.

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20 - Prescribing drugs outside their licensed indi

Prescribing drugs outside their licensed indications (‘off-label’ prescribing)

Prescribing psychotropics CHAPTER 14 Prescribing drugs outside their licensed indications (‘off-label’ prescribing) A Product Licence is granted when regulatory authorities are satisfied that the drug in question has proven efficacy in the treatment of a specified disorder, along with an acceptable adverse effect profile, relative to the severity of the disorder being treated and other available treatments. Licensed indications are preparation- specific, outlined in the SPCs, and may be different for branded and generic formulations of the same drug.1 In the USA, product ‘labelling’ has a similar legal status to EU licensing. The decision of a manufacturer to seek a Product Licence for a given indication is essentially a commercial one. Potential sales are balanced against the cost of conducting the necessary clinical trials. Drugs may be effective outside their licensed indications for different disease states, age ranges, doses and durations. The absence of a formal Product Licence or labelling may reflect the absence of controlled trials supporting the drug’s efficacy in these areas. In some cases (e.g. sertraline or quetiapine in generalised anxiety disorder [GAD]) there is sufficient evidence but a licence has not been sought by the manufacturer. Importantly, however, it is also possible that trials have been conducted but have given negative or equivocal results. Clinicians often assume that drugs with a similar mode of action will be similarly effective for a given indication. This may encourage the assumption that the official labelling for one drug indicates efficacy and safety of another, similar drug. However, apparently similar drugs may differ in respect to active metabolites and in regard to receptor affinity. Prescribing a drug within its licence or labelling does not guarantee that the patient will come to no harm. Likewise, prescribing outside a licence does not mean that the risk–benefit ratio is automatically adverse. For example, sertraline and fluoxetine are no less effective for GAD than alternative, licensed drugs.2 Prescribing outside a licence, usually called ‘off-label’, does confer extra responsibilities on prescribers, who will be expected to be able to show that they acted in accordance with a respected body of medical opinion (the Bolam test)3 and that their action was capable of withstanding logical analysis (the Bolitho test).4 In the UK, both have effectively been superseded, or at least clarified, by the Montgomery vs Lanarkshire Health Board appeal case decision5 which stated: An adult person of sound mind is entitled to decide which, if any, of the available forms of treatment to undergo, and her consent must be obtained before treatment interfering with her bodily integrity is undertaken. The doctor is therefore under a duty to take reasonable care to ensure that the patient is aware of any material risks involved in any recommended treatment, and of any reasonable alternative or variant treatments. The test of materiality is whether, in the circumstances of the particular case, a reasonable person in the patient’s position would be likely to attach significance to the risk, or the doctor is or should reasonably be aware that the particular patient would be likely to attach significance to it. Thus, in the UK at least, the prescriber has a duty to make a patient aware of any material risks associated with the prescribing of any medicines and to outline alternatives.

946 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 The General Medical Council allows doctors to prescribe off-label but only where the prescriber is satisfied that there is enough evidence or experience to support efficacy and safety.6 In the USA, it is lawful to prescribe off-label ‘within a legitimate health care practitioner–patient relationship’.7 Marketing of off-label use is forbidden but information may be provided following an unsolicited request.8 Off-label prescribing represents a significant proportion of prescribing in mental health conditions in the USA.9,10 A similar degree of off-label prescriptions is seen in other countries.11–13 Off-label prescribing in psychiatry is less likely to be supported by a strong evidence base than off-label prescribing in other areas of medicine.14 In psychiatry, small (underpowered) studies (with wide confidence intervals) often influence practice, particularly with respect to treatment-resistant illness (a great many examples can be found in this book). When these small studies are combined in the form of a meta-analysis, considerable heterogeneity is often found, suggesting publication bias (i.e. that some negative studies are not published). Treatments may therefore become incorporated into ‘routine custom and practice’ in the absence of robust evidence supporting efficacy and/or tolerability, and these treatments may sometimes continue to be used despite the findings of later, larger and more definitive negative studies and meta-analyses. An example of widespread off-label prescribing of a psychotropic in non-mental health conditions is amitriptyline – 93% of UK primary care prescriptions are off-label.15 The psychopharmacology special interest group at the Royal College of Psychiatrists published a consensus statement on the use of licensed medicines for unlicensed uses.16 They noted that unlicensed use is common in general adult psychiatry, with cross- sectional studies showing that up to 50% of patients are prescribed at least one drug outside the terms of its licence. They also note that the prevalence of this type of prescribing is likely to be higher in patients under the age of 18 or over 65, in those with a learning disability, in women who are pregnant or lactating and in those patients who are cared for in forensic psychiatry settings. The main recommendations in the consensus statement are summarised in Box 14.1. Box 14.1 Recommendations before prescribing ‘off-label’ ■ ■Exclude licensed alternatives (e.g. they have proved ineffective or poorly tolerated). ■ ■Ensure familiarity with the evidence base for the intended unlicensed use. If unsure, seek advice from another clinician (and possibly a specialist pharmacist). ■ ■Consider and document the potential risks and benefits of the proposed treatment. Share this risk assessment with the patient, and carers if applicable. Document the discussion and the patient’s consent or lack of capacity to consent. ■ ■If prescribing responsibility is to be shared with primary care, ensure that the risk assessment and consent issues are shared with the GP. ■ ■Monitor for efficacy and adverse effects; start a low dose and increase slowly. ■ ■Consider publishing the case to add to the body of knowledge. ■ ■Withdraw any treatment that is ineffective or where emergent risks outweigh the benefits. The more experimental the unlicensed use is, the more important it is to adhere to the above guidance.

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21 - Examples of acceptable use of drugs outside t

Examples of acceptable use of drugs outside their licences/labels

Prescribing psychotropics CHAPTER 14 The advice is largely echoed by more recent publications from the American Psychiatric Association17 (who note that off-label prescribing should be reimbursed) and the Royal Australian and New Zealand College of Psychiatrists18 who emphasise shared decision-making and the presumption of capacity. Examples of acceptable use of drugs outside their licences/labels Table 14.5 gives examples of common unlicensed uses of drugs in psychiatric practice. These examples would all fulfil the Bolam and Bolitho criteria in principle. An exhaustive list of unlicensed uses is impossible to prepare as the evidence base is constantly changing and because the expertise and experience of prescribers vary. A particular strategy may be justified in the hands of a specialist in psychopharmacology based in a tertiary referral centre but be much more difficult to justify if initiated by someone with a special interest in psychotherapy who rarely prescribes. Note that some drugs do not have a UK licence for any indication. Two commonly prescribed examples in psychiatric practice are immediate-release formulations of melatonin (used to treat insomnia in children and adolescents) and pirenzepine (used to treat clozapine-induced hypersalivation). Awareness of the evidence base and documentation of potential benefits, adverse effects and patient consent are especially important here. Table 14.5 Examples of common unlicensed uses of drugs in psychiatric practice. Drug/drug group Unlicensed use(s) Further information Second-generation antipsychotics Psychotic illness other than schizophrenia Licensed indications vary markedly, and in most cases are unlikely to reflect real differences in efficacy between drugs. Clozapine Bipolar disorder Substantial evidence to support efficacy when standard treatments have failed to control symptoms Cyproheptadine Akathisia Some evidence to support efficacy in this distressing and difficult to treat adverse effect of antipsychotics Fluoxetine/sertraline Generalised anxiety disorder Substantial supporting evidence Ketamine (racemate) Refractory depression Substantial evidence with both racemate and S-isomer Melatonin (circadin) Insomnia in children Licence covers adults >55 years only. Probably preferable to unlicensed formulations of melatonin. Naltrexone Self-injurious behaviour in people with learning disabilities Limited evidence base Acceptable in specialist hands Sodium valproate Treatment and prophylaxis of bipolar disorder Established clinical practice Evidence from other valproate preparations

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References

948 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 References

EMC. Summary of Product Characteristics. 2024; http://www.medicines.org.uk/emc/.
Baldwin D, et al. Efficacy of drug treatments for generalised anxiety disorder: systematic review and meta-analysis. BMJ 2011; 342:d1199.
Bolam v Friern Barnet Hospital Management Committee [1957] 1 WLR582.
Bolitho v City and Hackney Health Authority [1997] 3 WLR1151.
British and Irish Legal Information Institute. Montgomery (Appellant) v Lanarkshire Health Board (Respondent) (Scotland). 2015; http://www.bailii.org/uk/cases/UKSC/2015/11.html.
General Medical Council. Good practice in prescribing and managing medicines and devices. 2021 (last checked September 2024); https://www.gmc-uk.org/guidance/ethical_guidance/14316.asp.
Buckman Co. v. Plaintiffs’ Legal Comm. 531 U.S. 341. 2001; https://www.law.cornell.edu/supct/html/98-1768.ZO.html.
FindLaw. Off-label use promotion is protected free speech. 2019 (last accessed September 2024); https://www.findlaw.com/legalblogs/second- circuit/off-label-use-promotion-is-protected-free-speech/.
Vijay A, et al. Patterns and predictors of off-label prescription of psychiatric drugs. PLoS One 2018; 13:e0198363.
Leslie DL, et al. Off-label use of antipsychotic medications in Medicaid. Am J Manag Care 2012; 18:e109–117.
Ishtiak-Ahmed K, et al. Treatment indications and potential off-label use of antidepressants among older adults: a population-based descriptive study in Denmark. Int J Geriatr Psychiatry 2022; 37:10.1002/gps.5841.
Martínez CE, et al. Antidepressant use and off-label prescribing in primary care in Spain (2013-2018). An Pediatr (Engl Ed) 2022; 97:237–246.
Hefner G, et al. Off-label use of antidepressants, antipsychotics, and mood-stabilizers in psychiatry. J Neural Transm (Vienna) 2022; 129:1353–1365.
Epstein RS, et al. The many sides of off-label prescribing. Clin Pharmacol Ther 2012; 91:755–758.
Wong J, et al. Off-label indications for antidepressants in primary care: descriptive study of prescriptions from an indication based electronic prescribing system. BMJ 2017; 356:j603.
Royal College of Psychiatrists. Use of licensed medicines for unlicensed applications in psychiatric practice (2nd edition) (CR210 Dec 2017). 2017 (last accessed September 2024); https://www.rcpsych.ac.uk/improving-care/campaigning-for-better-mental-health-policy/college- reports/2017-college-reports/use-of-licensed-medicines-for-unlicensed-applications-in-psychiatric-practice-2nd-edition-cr210-dec-2017.
American Psychiatric Association. APA official actions: position statement on off-label treatments. 2021 (last accessed September 2024); https://www.psychiatry.org/getattachment/053eae03-9e23-422f-ab75-2ea052eb6c81/Position-Off-Label-Treatments.pdf.
Royal Australian New Zealand College of Psychiatrists (RANZCP). ‘Off-label’ prescribing in psychiatry. Professional Practice Guideline 4. 2023 (last accessed September 2024); https://www.ranzcp.org/getmedia/edc66b1d-005b-411d-b277-5c7fddc71ba2/ppg-4-off-label-prescribing- december-2023.pdf.

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23 - The Mental Health Act in England and Wales

The Mental Health Act in England and Wales

Prescribing psychotropics CHAPTER 14 The Mental Health Act in England and Wales The 1983 Mental Health Act (MHA) as amended by the 2007 MHA is the legislation within England and Wales that provides the framework for detaining and treating people with mental disorder in hospital. It also allows for the supervision of people in the community. Mental health law as it pertains to other countries is not covered in this book. The guidance here provides a quick summary of the sections that prescribers are likely to come across in their day-to-day work (Box 14.2). It is not an exhaustive list. The Act has a statutory Code of Practice for practitioners and Chapter 25 of the Code provides detailed guidance on the treatment rules of the Act.1 The MHA can be accessed at www.legislation.gov.uk. The power to treat under S58 is only for treatment of mental disorder. Physical treatment (generally) is governed by the normal rules of consent or, if the person lacks capacity, the authority of the Mental Capacity Act. The Responsible Clinician (RC) is usually the patient’s consultant. For the first 3 months of detention, the RC may give medication with or without consent to a person under one of the detention sections named for the treatment of their mental disorder. Thereafter, the patient’s consent or a second opinion must be sought. The 3 months’ countdown starts when medication for mental disorder is first administered while the patient is detained. This includes a patient detained under S2 who is then, without a break, detained under S3. For practical purposes the 3-month rule is usually calculated from the date of first detention. Box 14.2 Civil and forensic detention sections Section 2 Admission for assessment which lasts for up to 28 days Section 3 Admission for treatment which may last up to 6 months and is renewable Section 36 Remand to hospital for treatment Section 37 Hospital Order made by the courts (runs like an S3) Notional 37 Treat as if subject to S37. This term is used informally under a number of different circumstances. One example is where a patient was previously detained under S47/49 and their restriction order expires. Section 38 Interim Hospital Order Section 41 Restriction order: an order made by the Crown Court restricting discharge. Accompanies S37 and is written as S37/41. Section 47 Transfer to hospital of prisoners Section 49 A restriction order which usually accompanies S47 (written as S47/49) Section 48 Applies to unsentenced prisoners in need of urgent treatment and is accompanied by S49 (written as S48/49) Section 58 Treatment requiring consent or a second opinion Please note in law it is the Responsible Clinician (RC) who is accountable for the operation of S58

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24 - Completion of forms T2 and T3

Completion ofÂ forms T2 andÂ T3

19 - Chapter 14 Prescribing psychotropics

25 - Arranging and preparing for SOAD visits

Arranging and preparing for SOAD visits

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26 - Statutory consultees

Statutory consultees

950 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 If a patient consents to treatment, the RC completes a form T2. If a patient has not given consent or has not got the capacity to consent, a Second Opinion Appointed Doctor (SOAD) is called. The SOAD then completes a form T3. A copy of the forms T2 and T3 should be kept with the patient’s medication chart as recommended in paragraph 25.75 of the Code of Practice.1 Completion of forms T2 and T3 The following should be stated on the forms: ■ ■The name of the drug or the class of drug. ■ ■If the class of drug is stated, the number of drugs allowed at any one time. ■ ■The route of administration. ■ ■The maximum dosage with reference to BNF guidance. For example: Antipsychotic,second generation 1 oral within B ( ) × NF maximum dose limits. For a patient who has capacity and is consenting to treatment and is only willing to take a particular drug, it is appropriate for the RC to write the name of the drug instead of the name of the class of drug on the T2. For example: Olanzapine tablets only(oral)within BNF maximum dose limits. Psychotropics not found in the BNF may be written on a T2 or T3 with their indication. For example: Melperone tablets oral up to a maximum of 25mg dai ( )

ly for the treatment of schizophrenia.

Non-psychotropics used for the treatment of mental disorder should be included on the T2 and T3, for example omega-3 fatty acids (fish oils) in schizophrenia. Antimuscarinics used to treat hypersalivation and the extrapyramidal side effects of antipsychotics should be included too. Arranging and preparing for SOAD visits The Code of Practice 25.51 states: ‘Clinicians should consider seeking a review by a specialist mental health pharmacist before seeking a SOAD certificate, particularly if the patient’s medication regime is complex or unusual.’ Statutory consultees The SOAD should consult with two people before issuing a T3. One must be a nurse. The other must not be a nurse or a doctor. Both must have been involved with the patient’s treatment. These two people are known as statutory consultees. Mental health pharmacists can perform this role where they have been involved in any recent review of a patient’s medication.

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27 - What is consent

19 - Chapter 14 Prescribing psychotropics

28 - What is capacity

What is capacity?

Prescribing psychotropics CHAPTER 14 The Code of Practice 25.56 states: Statutory consultees may expect to have a private discussion with the SOAD and to be listened to with consideration. Issues that the consultees may be asked about include, but are not limited to: ■ ■the proposed treatment and the patient’s ability to consent to it; ■ ■their understanding of the past and present views and wishes of the patient; ■ ■other treatment options and the way in which the decision on the treatment proposal was arrived at; ■ ■the patient’s progress and the views of the patient’s carers; and ■ ■where relevant, the implications of imposing treatment on a patient who does not want it and the reasons why the patient is refusing treatment. What is consent? The Code of Practice 24.34 defines consent as: … the voluntary and continuing permission of a patient to be given a particular treatment, based on a sufficient knowledge of the purpose, nature, likely effects and risks of that treatment, including the likelihood of its success and any alternatives to it. Permission given under any unfair or undue pressure is not consent. For a patient to consent formally they must have the ‘capacity’ to make a decision. What is capacity? The Mental Capacity Act 2005 states that: ■ ■People must be assumed to have capacity unless it is established that they lack capacity. ■ ■People are not to be treated as unable to make a decision unless all practicable steps to help them do so have been taken without success. ■ ■People are not to be treated as unable to make a decision merely because they make an unwise decision. A patient is deemed to lack capacity if they cannot: ■ ■Understand relevant information about the decision to be made; or ■ ■Retain that information in their mind; or ■ ■Use or weigh that information as part of the decision-making process; or ■ ■Communicate their decision (by talking, using sign language or any other means). The patient needs to fail on only one of the four points above to be deemed not to have capacity. Capacity may change over time so reassessment is important. A person may lack capacity about one decision but not about another.

19 - Chapter 14 Prescribing psychotropics

29 - Section 62 urgent treatment

SectionÂ 62 urgent treatment

19 - Chapter 14 Prescribing psychotropics

30 - Section 132 duty of managers of hospitals to

Section 132 duty of managers of hospitals to give information to detained patients

19 - Chapter 14 Prescribing psychotropics

31 - Electroconvulsive therapy (ECT)

Electroconvulsive therapy (ECT)

952 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 Section 62 urgent treatment If after 3 months medication is needed urgently to treat a patient’s mental disorder and it is not covered by a T2 or T3, S62 may be applied. The Code of Practice 25.38 states: This applies only if the treatment in question is immediately necessary to: ■ ■save the patient’s life; ■ ■prevent a serious deterioration of the patient’s condition, and the treatment does not have unfavourable physical or psychological consequences which cannot be reversed; ■ ■alleviate serious suffering by the patient, and the treatment does not have unfavourable physical or psychological consequences which cannot be reversed and does not entail significant physical hazard; or ■ ■prevent patients behaving violently or being a danger to themselves or others, and the treatment represents the minimum interference necessary for that purpose, does not have unfavourable physical or psychological consequences which cannot be reversed and does not entail significant physical hazard. Each Trust should design a form for the clinician in charge of treatment (usually the consultant) to state what the treatment is, why it is immediately necessary and the length of treatment. Section 132 duty of managers of hospitals to give information to detained patients With regard to S132 and consent to treatment the Code of Practice 4.20 states: Patients must be told what the Act says about treatment for their mental disorder. In particular they must be told: ■ ■the circumstances (if any) in which they can be treated without their consent – and the circumstances in which they have the right to refuse treatment; ■ ■the role of second opinion appointed doctors (SOADs) and the circumstances in which they may be involved; and ■ ■(where relevant) the rules on electroconvulsive therapy (ECT) and medication administered as part of ECT. Electroconvulsive therapy (ECT) Section 58a deals with ECT. Treatment for ECT is authorised on forms: T4 For consenting adults 18 and over, may be written by the RC or SOAD T5 For consenting patients under 18, to be written by SOAD only T6 For patients who lack capacity, to be written by SOAD only

19 - Chapter 14 Prescribing psychotropics

32 - Community patients

Community patients

19 - Chapter 14 Prescribing psychotropics

33 - Reference

Reference

Prescribing psychotropics CHAPTER 14 All patients under the age of 18 who are to receive ECT, whether or not they are detained under the MHA, must have treatment authorised on a T5 or T6. Patients who have the capacity to consent must not receive ECT unless they do consent (in emergencies this can, however, be over-ridden under S62 of the Act). There is no 3-month rule with regard to ECT and this also applies to medication given as part of ECT. Hence a form for ECT must always be in place regardless of the first date of detention. The forms should indicate the maximum number of treatments the patient is to receive (Code of Practice paragraph 25.23). Community patients Patients on a Community Treatment Order (CTO) should have treatment authorised on one of the following forms: CTO11 Written by SOAD, after 1 month on a CTO, when the patient lacks capacity CTO12 Written by the RC when the patient has capacity and is consenting to treatment, after 1 month on a CTO There is no legal authority to give patients medication in the community if they refuse it. Reference

Gov.UK. Code of practice: Mental Health Act 1983. 2017 (last accessed August 2024); https://www.gov.uk/government/publications/ code-of-practice-mental-health-act-1983#history.

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34 - Site of administration of intramuscular injec

Site of administration of intramuscular injections

954 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 Site of administration of intramuscular injections Table 14.6 gives the sites of administration formally permitted in the individual product’s EU licence. Other routes and sites may be possible but pharmacokinetic analysis of administration via these sites is generally not available. Table 14.6 Sites of administration of intramuscular injections. Antipsychotic generic name and formulation Licensed site(s) of administration Typical antipsychotic (FGA) depots Bromperidol decanoate in sesame oil (available in Belgium, Germany, Italy, Luxembourg and the Netherlands1,2) Deep intramuscular injection into the gluteal muscle. SPCs in some countries recommend to alternate injections into the left and right sides to prevent pain at the injection site.3 Flupentixol decanoate in thin vegetable oil derived from coconuts Deep intramuscular injection into the upper outer buttock (dorsogluteal) or lateral thigh (vastus lateralis).4 As with all oil-based injections it is important to ensure, by aspiration before injection, that inadvertent intravascular entry does not occur.5 This probably applies to dorsogluteal injections only; for all other sites where there are no major blood vessels close to the injection site, this is unnecessary.4 Fluphenazine decanoate in sesame oil Deep intramuscular injection into the gluteal region.4 Has also been administered into the lateral surface of the thigh muscle but this is unlicensed. Administration into the deltoid is not recommended by manufacturer.6 In the USA, licensed to be used ‘intramuscularly or subcutaneously’. The site of administration is not specified. Drug leakage appears to be lower after SC injection than after intramuscular administration.7 Fluspirilene in vegetable oil8 (available in some EU countries, Canada, Argentina and Israel9) Deep intramuscular injection into the gluteal muscle (intragluteal). Because of its microcrystalline form, irritation and inflammation symptoms may occur at the injection site. Manufacturer recommends to alternate between left and right gluteal muscles.3,10 Haloperidol decanoate in sesame oil Deep intramuscular injection into the gluteal region.4 It is recommended to alternate between the two gluteal muscles.11 As the administration of volumes greater than 3mL is uncomfortable for the patient, such large volumes are not recommended.11,12 Can also be administered into the deltoid muscle according to the manufacturer.13 Although this is an unlicensed use, one trial suggests it is safe and effective.14 Perphenazine decanoate in sesame oil (used in the Nordic countries, Belgium, Portugal and the Netherlands15) Deep intramuscular injection.15,16 No other information available.

Table 14.6 (Continued ) Antipsychotic generic name and formulation Licensed site(s) of administration Perphenazine enanthate in sesame oil (in clinical use in the Nordic countries, Belgium, Portugal and the Netherlands15) Pipotiazine palmitate in sesame oil4 (variable availability) Zuclopenthixol decanoate in thin vegetable oil derived from coconuts Atypical antipsychotic (SGA) depots Gluteal muscle administration4 Aripiprazole Prefilled syringe for prolonged-release suspension Aripiprazole lauroxil Prefilled syringe for extended-release suspension Aripiprazole lauroxil nanocrystal dispersion Prefilled syringe for extended-release suspension Olanzapine pamoate monohydrate Powder and vehicle for prolonged-release suspension Paliperidone palmitate 1-monthly Prolonged-release suspension for injection every month Prescribing psychotropics Deep intramuscular injection into the gluteal region.15,17 Administration should be by deep intramuscular injection into the gluteal region.18 Deep intramuscular injection into the upper outer buttock (dorsogluteal) or lateral thigh (vastus lateralis).4 As with all oil-based injections it is important to ensure, by aspiration before injection, that inadvertent intravascular entry does not occur.19 Gluteal injections should be alternated between the two gluteal muscles. Deltoid muscle administration4,20 Deltoid injections should be alternated between the two deltoid muscles.20 The powder and vehicle vials and the prefilled syringe are for single use only.4 Intramuscular administration into the deltoid or gluteal (441mg dose only) muscle.4,21 CHAPTER 14 Intramuscular injection into the deltoid or gluteal muscle.22 Not intended for repeat dosing. Given as a single dose to initiate treatment with aripiprazole lauroxil.22 Olanzapine pamoate monohydrate should only be administered by deep intramuscular gluteal injection by a healthcare professional trained in the appropriate injection technique and in locations where post-injection observation and access to appropriate medical care in the case of overdose can be assured.23 Injected slowly, deep into the deltoid or dorsogluteal muscle (the two initial loading doses should be administered in the deltoid muscle so as to attain therapeutic concentrations rapidly).4,24 Following the second initiation dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle. Administration should be in a single injection. The dose should not be given in divided injections.24 (Continued )

956 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 Table 14.6 (Continued ) Antipsychotic generic name and formulation Licensed site(s) of administration Paliperidone palmitate 3-monthly Prolonged-release suspension for injection every 3 months Deltoid muscle administration25 The specified needle for administration of Trevicta into the deltoid muscle is determined by the patient’s weight (see manufacturer’s advice). It should be administered into the centre of the deltoid muscle. Deltoid injections should be alternated between the two deltoid muscles. Gluteal muscle administration25 To be administered into the upper outer quadrant of the gluteal muscle. Gluteal injections should be alternated between the two gluteal muscles. Paliperidone palmitate 6-monthly Prolonged-release suspension for injection every 6 months Byannli is for gluteal intramuscular use only. It must not be administered by any other route. Each injection must be administered only by a healthcare professional giving the full dose in a single injection. It should be injected slowly, deep into the upper outer quadrant of the gluteal muscle. A switch between the two gluteal muscles should be considered for future injections in the event of injection site discomfort. Needles from the 3-monthly or 1-monthly paliperidone palmitate injectable pack or other commercially available needles must not be used when administering Byannli.26 Risperidone microspheres (Consta) Powder and vehicle for prolonged-release suspension Following reconstitution, administer via deep intramuscular deltoid or gluteal injection.27 Risperidone ISM (Okedi) Powder and solvent for extended-release suspension After reconstitution, administer by deep intramuscular deltoid or gluteal injection.28 Risperidone 2-weekly injection (Rykindo) Prefilled syringe and powder vial for prolonged-release suspension After reconstitution, administer via intramuscular injection into the gluteal muscle.29 Risperidone subcutaneous long-acting injections (Perseris [RBP-7000], Uzedy [TV-46000]) Extended-release suspension Subcutaneous administration in the abdomen or upper arm.30,31 Prior to administration of Perseris (RBP-7000), the liquid and powder syringes need to be mixed by passing the contents back and forth between the syringes. Intramuscular injections for rapid tranquilisation Aripiprazole Solution for injection To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended.32 Haloperidol Solution for injection Intramuscular administration.33 Preferably, the gluteal muscle is selected when the dosage volume is high. The deltoid muscle is preferred for low doses of the injection. However, there is no information on the dosage limit for these specific muscle groups. Choice of site is at the discretion of the prescriber according to the manufacturer.34

19 - Chapter 14 Prescribing psychotropics

35 - References

References

Prescribing psychotropics CHAPTER 14 Table 14.6 (Continued ) Antipsychotic generic name and formulation Licensed site(s) of administration Lorazepam Solution for injection Intramuscular administration. Can be administered into the gluteal, deltoid or frontal thigh area according to the manufacturer.35 A 1:1 dilution of Ativan injection with normal saline or Sterile Water for Injection BP is recommended in order to facilitate intramuscular administration and absorption.18 Olanzapine Powder for solution for injection Inject slowly, deep into the muscle mass. The exact site of administration is not specified and choice of muscle site should be a clinical decision according to the manufacturer.36 Not to be used intravenously* or subcutaneously. Use the solution immediately within 1 hour of reconstitution.37 *Intravenous use has been reported38,39 but is off-licence/label. Promethazine hydrochloride Solution for injection By deep intramuscular injection into a large muscle.40 Can be administered into the thigh, upper arm or gluteal region. Ensure muscle mass is sufficient for the volume being injected.6 Other intramuscular injections Clotiapine 40mg/4mL injection (available in Argentina, Belgium, Israel, Italy, Luxembourg, South Africa, Spain, Switzerland and Taiwan41) By intramuscular injection.41 No other information available. Clozapine intramuscular injection 25mg/mL (unlicensed)42,43 Only for deep intramuscular administration into the gluteal muscle. 25mg IM clozapine = 50mg oral. The maximum volume that can be injected into each site is 4mL (100mg). For doses greater than 100mg daily, the dose may be divided and administered into two sites. (Injection sites should be rotated as per usual IM practice.) Administration into the lateral thigh and deltoid muscles has been used in one case series.42 FGA, first-generation antipsychotic; ISM, in situ microparticles; SC, subcutaneous; SGA, second-generation antipsychotic; SPC, summary of product characteristics. References

Purgato M, et al. Bromperidol decanoate (depot) for schizophrenia. Cochrane Database Syst Rev 2012; 11:CD001719.
Riboldi I, et al. Practical guidance for the use of long-acting injectable antipsychotics in the treatment of schizophrenia. Psychol Res Behav Manag 2022; 15:3915–3929.
Eumedica. Medical Information Department – written communication, 2020.
Janssen UK. Guidance on the Administration to Adults of Oil-Based Depot and Other Long-Acting Intramuscular Antipsychotic Injections, 7th edn. 2022 (last accessed August 2024); https://www.hpft.nhs.uk/media/6180/guidance-on-im-administration-of-oil-based-depots-and- other-long-acting-antipsychotic-injections-7th-edition.pdf.
Lundbeck Ltd. Summary of product characteristics. Depixol 20mg/ml solution for injection (flupentixol decanoate). 2021 (last accessed August 2024); https://www.medicines.org.uk/emc/product/995/smpc.
Sanofi. Medical Information Department – verbal and written communication, 2017.
Glazer WM, et al. Injection site leakage of depot neuroleptics: intramuscular versus subcutaneous injection. J Clin Psychiatry 1987; 48:237–239.
Spanarello S, et al. The pharmacokinetics of long-acting antipsychotic medications. Curr Clin Pharmacol 2014; 9:310–317.
Abhijnhan A, et al. Depot fluspirilene for schizophrenia. Cochrane Database Syst Rev 2007; 2007:CD001718.
iMedikament.de. IMAP. 2024 (last accessed August 2024); https://imedikament.de/imap.

958 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 14 11. Essential Pharma Ltd. Medical Information Department – written communication, 2024. 12. Essential Pharma Ltd (Malta). Summary of product characteristics. HALDOL Decanoate (haloperidol decanoate) 100mg/ml solution for injection. 2023 (last checked August 2024); https://www.medicines.org.uk/emc/product/15246/smpc#gref. 13. Janssen. Medical Information Department – verbal and written communication, 2024. 14. McEvoy JP, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA 2014; 311:1978–1987. 15. Quraishi S, et al. Depot perphenazine decanoate and enanthate for schizophrenia. Cochrane Database Syst Rev 2000; 2:CD001717. 16. Laakeinfo.fi. PERATSIN DECANOATE solution for injection 108mg/ml (perphenazine decanoate). 2023 (last accessed August 2024); https://laakeinfo.fi/Medicine.aspx?m=2333. 17. Starmark JE, et al. Abscesses following prolonged intramuscular administration of perphenazine enantate. Acta Psychiatr Scand 1980; 62:154–157. 18. myHealthbox 2012-2024. Summary of Product Characteristics. 2024 (last accessed August 2024); https://myhealthbox.eu/en/. 19. Lundbeck Ltd. Summary of product characteristics. Clopixol 200mg/ml solution for injection (zuclopenthixol decanoate). 2022 (last accessed August 2024); https://www.medicines.org.uk/emc/product/6414/smpc. 20. Otsuka Pharmaceuticals (UK) Ltd. Summary of product characteristics. Abilify Maintena 300mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe (aripiprazole). 2024 (last accessed August 2024); https://www.medicines.org.uk/emc/ product/12955/smpc%202022. 21. Alkermes Inc. Highlights of prescribing information. ARISTADA® (aripiprazole lauroxil) extended-release injectable suspension for intramuscular use. 2018 (last accessed August 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/207533s013lbl.pdf. 22. Alkermes Inc. Highlights of prescribing information. ARISTADA INITIO® (aripiprazole lauroxil) extended-release injectable suspension, for intramuscular use. 2023; https://www.aristada.com/downloadables/ARISTADA-INITIO-PI.pdf. 23. Eli Lily and Company Ltd. Summary of product characteristics. Zypadhera (olanzapine pamoate monohydrate) 210mg powder and solvent for prolonged release suspension for injection. 2023 (last assessed August 2024); https://www.medicines.org.uk/emc/product/6429/smpc. 24. Janssen-Cilag Ltd. Summary of product characteristics. Xeplion (paliperidone) 25mg, 50mg, 75mg, 100mg, and 150mg prolonged-release suspension for injection. 2023 (last accessed May 2024); https://www.medicines.org.uk/emc/product/7652/smpc. 25. Janssen-Cilag Ltd. Summary of product characteristics. TREVICTA 175mg, 263mg, 350mg, 525mg prolonged release suspension for injection. 2023 (last accessed August 2024); https://www.medicines.org.uk/emc/medicine/32050. 26. Janssen-Cilag Ltd. Summary of product characteristics. Byannli 700mg prolonged-release suspension for injection in pre-filled syringe (paliperidone). 2023 (last accessed August 2024); https://www.medicines.org.uk/emc/product/13307/smpc. 27. Janssen-Cilag Ltd. Summary of product characteristics. RISPERDAL CONSTA 25mg powder and solvent for prolonged-release suspension for intramuscular injection (risperidone). 2022 (last assessed August 2024); https://www.medicines.org.uk/emc/medicine/9939. 28. ROVI Biotech Ltd. Summary of product characteristics. Okedi (risperidone) 100mg powder and solvent for prolonged-release suspension for injection pre-filled syringes. 2023 (last accessed August 2024); https://www.medicines.org.uk/emc/product/13778/smpc. 29. Shandong Luye Pharmaceutical Co Ltd. Highlights of prescribing information. RYKINDO® (risperidone) for extended-release injectable suspension for intramuscular use. 2023 (last checked June 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/212849s000lbl.pdf. 30. Indivior UK Ltd. Highlights of prescribing information. PERSERIS (risperidone) for extended-release injectable suspension, for subcutaneous use. 2018 (last accessed September 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210655s000lbl.pdf. 31. Teva Neuroscience Inc. Highlights of prescribing information. UZEDY (risperidone) extended-release injectable suspension for subcutaneous use. 2024 (last checked June 2024); https://www.uzedy.com/globalassets/uzedy/prescribing-information.pdf. 32. Otsuka Pharmaceutical (UK) Ltd. Summary of product characteristics. Abilify 7.5mg/ml solution for injection (intramuscular) (aripiprazole). 2023 (last accessed August 2024); https://www.medicines.org.uk/emc/product/6239/smpc. 33. ADVANZ Pharma. Summary of product characteristics. Haloperidol injection BP 5mg/ml. 2024 (last accessed August 2024); https://www. medicines.org.uk/emc/product/514. 34. Concordia International. Medical Information Department – verbal and written communication, 2017. 35. Macure Pharma UK Ltd. Medical Information Department – written communication, 2024. 36. Lilly UK. Medical Information Department – verbal and written communication, 2017. 37. Eramol (UK) Ltd. Summary of product characteristics. Xyquila 10mg powder for solution for injection (olanzapine). 2023 (last accessed August 2024); https://www.medicines.org.uk/emc/product/15138/smpc. 38. Wang M, et al. A retrospective comparison of the effectiveness and safety of intravenous olanzapine versus intravenous haloperidol for agitation in adult intensive care unit patients. J Intensive Care Med 2022; 37:222–230. 39. Khorassani F, et al. Intravenous olanzapine for the management of agitation: review of the literature. Ann Pharmacother 2019; 53:853–859. 40. Sanofi. Medical Information Department – written communication, 2024. 41. Carpenter S, et al. Clotiapine for acute psychotic illnesses. Cochrane Database Syst Rev 2004; 4:CD002304. 42. Henry R, et al. Evaluation of the effectiveness and acceptability of intramuscular clozapine injection: illustrative case series. BJPsych Bull 2020; 44:239–243. 43. Casetta C, et al. A retrospective study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis. Br J Psychiatry 2020; 217:506–513.

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Note: Page numbers in bold indicate tables and in italics indicate figures, where they fall outside the text range. 5a-reductase inhibitors, psychiatric adverse effects 971 5HT see 5-hydroxytryptamine 22q11.2 deletion syndrome (22q11.2DS) 820–823 clinical features and risks 820 general prescribing principles 821 managing psychiatric disorders 821–822 Abilify MyCite, adherence monitoring aid 933 Abnormal Involuntary Movement Scale 127 acamprosate, preventing relapse after alcohol detoxification 489–490 ACE see angiotensin-converting enzyme acetaldehyde, metabolism of alcohol 895 acetaminophen see paracetamol acetylcholinesterase inhibitors (AChE-Is) Alzheimer’s disease 630, 632–636, 642, 649 dementia with Lewy bodies 648 management of behavioural and psychological symptoms of dementia 671 mechanism of action 630, 631 mild cognitive impairment 648 older patients and dementia 654–658, 659, 689 other dementias 647, 648, 649 rare dementias associated with neurological conditions 649 use in Parkinson’s disease 842 vascular dementia 647 activated partial thromboplastin time, psychotropic agent effects 965 activation adverse effects, depression in children and adolescents 571 Acuphase see zuclopenthixol acetate acute behavioural disturbance use of term 543 see also drug-induced excited states acutely disturbed/violent behaviour 62–73 oral/inhaled treatment 62 parenteral treatment 62–65 practical measures 65 zuclopenthixol acetate 66–67 acute mania, treatments 310–315 AD see Alzheimer’s disease adapted Naranjo adverse drug reaction scale 972, 973 addiction 477–560 see also alcohol dependence; dependence syndrome; drugs of misuse; illicit drugs; new psychoactive substances; nicotine dependence; opioid dependence; smoking; substance misuse and dependence ADH see alcohol dehydrogenase ADHD see attention deficit hyperactivity disorder adherence 927–936 antipsychotics 30, 928–929, 933–934 assessing 929, 930 clinician-patient relationship 939 definitions and terminology 927 enhancing medication adherence 931–934 factors affecting 929 impacts of non-adherence 928–929 intervention 932 intervention research of poor quality 931 lithium 284 monitoring and assessing attitudes 931 object relations 939 rates and degrees 927–928 relational aspects 939–944 relational factors influencing clinicians 939 relational factors influencing patients 940 restarting medications after period of non-compliance 937–938 strategies 931 administration of medicines alternative routes 115–118 covertly in food and drink, older people 629, 694–699 covertly in food and drink for older people 629, 694–699 site of intramuscular injections 954–957 adolescents bulimia nervosa/binge eating disorder 794 see also children and adolescents adrenergic a2 agonists, tics and Tourette’s syndrome 615 ADRs see adverse drug reactions aducanumab, Alzheimer’s disease treatment 646 adverse drug reactions adapted Naranjo adverse drug reaction scale 972, 973 Naranjo scale 972, 973 adverse drug reactions (ADRs) anticholinergic effects of antipsychotics 43–44 antipsychotics in menopausal women 859–860 Index

976 Index adverse drug reactions (ADRs) (cont’d) biochemical effects of psychotropics 959, 960–965 discussion with patients 941 haematological effects of psychotropics 959, 965–966 increased incidence and severity in older people 627–628 non-psychotropics with psychiatric effects 969–974 psychiatric adverse effects of non-psychotropic drugs 969–974 psychiatric effects of antiseizure medications 812–813 psychotropic sensitivity in people with learning difficulties 825 see also extrapyramidal side effects AF see atrial fibrillation age effects changes in pharmacodynamics 627–628 depression in children and adolescents 570 see also children and adolescents; older people aggressive behaviours Huntington’s disease 832 paradoxical/disinhibitory drug reactions, benzodiazepines 471–473 valproate treatment 290 agitation and irritability, Huntington’s disease 832, 833 agomelatine in overdose 913 smokers 892 agonist replacement therapy, limited evidence for stimulant use disorder 532 agranulocytosis 245, 251, 267–268, 275–276, 959, 966 akathisia 43, 44, 127, 128, 131–134 alanine aminotransferase (ALT) 960 albumin hepatic impairment 753, 754 psychotropic agent effects 960 alcohol dehydrogenase (ADH) 895, 896 alcohol dependence 479–497 in children and adolescents 493 clinical assessment 479–480 mild 480, 485 moderate 480, 485 in older people 493 pharmacologically assisted withdrawal 482–487 in pregnancy 492–493 preventing relapse after detoxification 489–492 severe 480, 486 Wernicke’s encephalopathy/thiamine deficiency 487–488 withdrawal 480–489 alcohol detoxification benzodiazepines 484–486 carbamazepine 487 community or in-patient 482 fixed dose treatment regimen 485–486 pharmacologically assisted withdrawal 482–487 preventing relapse 489–492 symptom-triggered treatment regimen 486 alcohol use amnesia 898 ataxia 898 bariatric surgery effects 855 disulfiram reaction 490 driving impairment 922 electrolyte disturbances 898 health guidance 479 metabolism of 895 pharmacodynamic interactions 897–899 pharmacokinetic interactions 895–897 psychotropic drug combination 895–899 sedation 897 alcohol use disorder (AUD) comorbid mental health disorders 494–496 see also alcohol dependence Alcohol Use Disorders Identification Test (AUDIT) 480, 482 alcohol withdrawal 480–489 benzodiazepines 484–487 common interventions 484 community detoxification 482 delirium tremens 480, 481, 482, 486 mild 480, 484 pharmacologically assisted/ detoxification 482–487 seizures 480, 481 severe 481, 484 severity assessment 480, 483 treating somatic symptoms 488–489 treatment interventions 484 aldehyde dehydrogenase 895, 896 alkaline phosphatase in blood, psychotropic agent effects 960 allopurinol 226 α2A-adrenoceptor agonists, see also guanfacine alpha blockers, older patients with urinary retention, drug safety 658 alpha-lipoic acid, for antipsychotic-induced weight gain 145 ALT see alanine aminotransferase alternative therapies Alzheimer’s disease management 641, 643–645 inclusion on MHA forms T2 and T3 950 see also complementary therapies; natural remedies Alzheimer’s disease (AD) atrial fibrillation patients 847 cognitive enhancers 630–641 adverse effects 635–637 combination treatment 634 dosing and formulations 633–634 drug interactions 637–640 drug tolerability 634–635 efficacy 632 mechanism of action 630 switching drugs 632–633 differentiating from vascular dementia 647 management with alternative substances 641, 643–645 NICE guidelines 642 novel antibody treatments 646–647 amantadine for antipsychotic-induced weight gain 145 for fatigue in multiple sclerosis 837 for tardive dyskinesia 136 ambivalence about medication, clinicians understanding patients 940–941 amfebutamone see bupropion amfetamines attention deficit hyperactivity disorder in adults 798–800 breastfeeding mothers 747 depression 388 in pregnancy 727 stimulant use disorder 533–534 see also methamphetamine use disorder amino acids, for tardive dyskinesia 137 amisulpride 3, 4 clozapine augmentation 221 efficacy 3 in overdose 915 plasma level monitoring 869–870 target range 868 use in patients with hepatic impairment 754, 756, 761 amitriptyline antidepressant 337 for clozapine-induced hypersalivation 258, 259 post-stroke pain treatment 393 in pregnancy 720 serotonin reuptake inhibition 404 ammonia in blood, psychotropic agent effects 960 amnesia, alcohol effects 898 amylase in blood, psychotropic agent effects 961 AN see anorexia nervosa Anafranil see clomipramine analgesics headache after ECT 384 managing behavioural and psychological symptoms of dementia 668 opioid avoidance for patients on naltrexone 490, 518 opioid substitution treatment combination 518–519

safety in older patients/dementia 660–661 see also non-steroidal anti-inflammatory drugs; opioids; paracetamol angiotensin-converting enzyme (ACE) inhibitors, lithium interaction 284–285 angiotensin II receptor antagonists, lithium interaction 285 anhedonia, stimulant use detoxification 535 ANI see asymptomatic neurocognitive impairment anorexia nervosa (AN) 792–794 antidepressants 793 co-morbid conditions 792, 794 monitoring when on oral electrolyte supplementation 794 NICE guidelines 795 psychological symptom treatment 793 relapse prevention 794 treating physical aspects 793–794 weight restoration 792 Antabuse see disulfiram antiamyloid therapy, Alzheimer’s disease treatment 646–647 antibiotics psychiatric adverse effects 969 safety in older patients/dementia 662 anticholinergic adverse effects of antipsychotics 43–44 anticholinergic burden, cognitive impairment 642 anticoagulants, safety/use in older patients/ dementia 662 anticonvulsants benzodiazepine properties 484 borderline personality disorder 789 people with learning difficulties 827 use in alcohol withdrawal management 480, 481 see also antiseizure medications anti-dementia drugs 630–649 use in renal impairment 778 see also cognitive enhancers antidepressants adverse effects, relative and absolute risks 444–445 with alcohol 899 anorexia nervosa 793 antipsychotic augmentation 35 with antipsychotics for psychotic depression 362 anxiety spectrum disorders 340 arrhythmia induction 411–415 atrial fibrillation patients 846 bariatric surgery patients 850 bipolar depression 321 bleeding risks 432–439 borderline personality disorder 789 breastfeeding mothers 735, 736, 737–740 bulimia nervosa/binge eating disorder 794–795 cardiac effects 406–408, 409–415 choice 338–339 co-prescribed with warfarin leading to non-GI bleeding risk 433 diabetes mellitus 423–425 dosing 626 increasing if insufficient response 345, 346 driving impairment 922 drug interactions 401–405 pharmacodynamic effects 402, 404–405 pharmacokinetic effects 401–402, 403 duration of treatment 340 effectiveness 337 electroconvulsive therapy combination 384 Fatal Toxicity Index 412 glucose homeostasis effects 423–425 hyperbolic tapering 366, 376, 379, 382 hyperprolactinaemia 420–422 hyponatraemia induction 416–419 ketamine 357 managing behavioural and psychological symptoms of dementia 672–673 managing treatment-resistant depression 348–356, 357 minimum effective doses 342, 366 natural 440–443 next-steps if no response 340 onset of action 338 in overdose 913–915 overview 337–341 perioperative bleeding risks with non-SSRI antidepressants 437 pharmacodynamic drug interactions 402, 404–405 pharmacokinetic drug interactions 401–402, 403 post-stroke prophylaxis 393 practical application of tapering 380–381 in pregnancy 719–722 prolactin effects 420 prophylaxis 393, 397–400 relapse risk of discontinuation after medium/long term use 398–399 relative adverse effects 338–339, 412 risks to people with epilepsy 815 St John’s wort 440–443 sexual dysfunction 426–431 smokers 893 stopping 378 sudden cardiac death 411, 412 suicidality 339 suicide risks in children and adolescents 570–571 swapping and stopping guide 368–371 switching 345, 366–372 tapering 366, 376, 378–382 Index target ranges 874 use in older people with depression 688–693 use in patients with hepatic impairment 753, 757–758, 761 use in patients with renal impairment 772–775 use in stimulant use disorder 535 antidepressant withdrawal at risk patients 375 avoidance 375–376 clinical relevance 375 incidence and severity of symptoms 373–374 signs and symptoms 373–376 stopping 378 switching 366–367 time course 374 treatment 376 troubleshooting during tapering 381 antiemetics, safety in older patients/ dementia 658–659 antihistamines driving impairment 923 safety in older patients/dementia 661, 674 antihypertensives, safety/use in older patients/dementia 661 anti-inflammatory drugs, Alzheimer’s disease management 644–645 antimalarials psychiatric adverse effects 969 QT prolongation 165 antiparkinsonian treatments, psychiatric adverse effects 970 antipsychotic depot, see also long-acting injectable antipsychotics Antipsychotic Non-Neurological Side-Effects Rating Scale 4 antipsychotics adherence to treatment 30, 928–929, 933–934 administration of 115–118 buccal 117 inhalation 115, 116 intranasal 115, 116–117 intravenous 117 rectal 116, 118 sublingual 115, 117 transdermal 116 adverse effects 1, 2, 3–4, 23–24, 30, 43–44, 126–213 acute kidney injury risk 769 agranulocytosis 245, 251, 267–268 akathisia 43, 44, 127, 128, 131–134, 207 atrial fibrillation risk 846 blood pressure changes 182–185 cardiomyopathy 254 cardiovascular adverse effects 253–257 colitis 245

978 Index antipsychotics (cont’d) constipation 241, 263–266 delirium 245 diabetes and impaired glucose tolerance 174–181, 207 dyslipidaemia 207 dystonia 127, 128 ECG changes (QTc prolongation) 161–168, 207 eosinophilia 245 extrapyramidal symptoms 126–130, 207 gastrointestinal hypomotility 241, 263–266 gastrointestinal necrosis 245 haematological adverse effects 251–252 heat stroke 245 hepatic failure/enzyme abnormalities 245 hyperglycaemia 186 hyperlipidaemia 186 hyperprolactinaemia 190–194, 196, 207 hypersalivation 241, 258–262 hypertension 183–184 hyponatraemia 186–189 hypothermia 245 interstitial lung disease 245 interstitial nephritis 245 knee-buckling 245 myocarditis 253–254, 255 neuroleptic malignant syndrome 150–153 neutropenia 267–272 ocular effects 245 orthostatic hypotension 182–183, 207 in overdose 913–915 pancreatitis 246 parotid gland swelling 246 pericardial effusion 246 pericarditis 246 plasma lipids 169–173 pneumonia 204–206 polyserositis 246 pseudoparkinsonism 127–128 QTc prolongation 161–168, 207 renal injury risk 769 sedation 207 sexual dysfunction 195–203, 207 skin reactions 246 stuttering 246 tardive dyskinesia 120, 127, 128, 135–140, 208 thrombocytopenia 246 thromboembolism 211–213, 246, 253 venous thromboembolism 211–213, 253 weight gain 141–149, 208 with alcohol 895–899 antidepressant augmentation 35 with antidepressants for psychotic depression 362 augmentation of 58–59 bariatric surgery patients 851–852 bipolar disorder 300–304, 305–307, 310, 311 depression 301, 319 first generation 300 mania 300, 301, 302 second generation 300–302 specific drugs 301–302 borderline personality disorder 788 breastfeeding mothers 736, 741–743 with caffeine 903 children and adolescents 590, 598, 606, 615–616, 623, 626 choosing 2–3 classification of 1–2 clozapine augmentation 221 combinations of 7, 22–25, 58–59 discontinuation of 7, 28, 29, 30–31, 119–125 pattern of tapering 121–122 reduction of olanzapine 121, 122 tapering in practice 122 when to attempt discontinuation 123 driving impairment 922 equivalent doses 14–15 first-generation adverse effects 3–4, 49 classification 2 diabetes, antipsychotic-related 174 equivalent doses 14 long-acting injectable antipsychotics 75, 76 maximum doses 11, 12 minimum effective doses 8 nomenclature 49 penfluridol 106–107 relative efficacy 3 role of older antipsychotics 49–50 treatment algorithm 46 treatment of negative symptoms 35 hepatic impairment 754–756, 761 high-dose 55–56 adverse effects 18, 76 efficacy 17–18 prescribing and monitoring 17–19 recommendations 19 Huntington’s chorea 831 increased free plasma levels in hepatic impairment 753–754 long-term treatment 8–84 managing behavioural and psychological symptoms of dementia 668 maximum doses 11–12 menopausal women 858, 859, 860 minimum effective doses 8 monitoring 40–41 monotherapy poor response to 22 switching to 59 mortality risks in dementia patients 669 neurobiology of withdrawal 120 oestrogen interactions 858, 859, 860 optimal dosage 55 options for menopausal women 860 in overdose 915–916 people with 22q11.2 deletion syndrome 822 people with epilepsy, risks 816 people with learning difficulties 826 plasma level variations 56–57 polypharmacy 22–25, 59, 95, 226 adverse effects 23–24 long-term treatment 22–23 poor response to antipsychotic monotherapy 22 poor tolerability 207–210 in pregnancy 715–718 first-generation 715–716 neurodevelopment effects 717–718 second-generation 716–717 preventing sudden cessation by non-compliance 933 principles of prescribing 7 prophylaxis 28–33 alternative views 31 discontinuation of 30–31 dose for 30 reducing 28 relative adverse effects 43–44 relative efficacy 3–4 renal impairment 769–771 response assessment 7 second-generation 49, 50 adverse effects 3–4 classification 2 diabetes, antipsychotic-related 174–176 equivalent doses 14, 15 long-acting injectable antipsychotics 4, 75 maximum doses 11, 12 minimum effective doses 8 neuroleptic malignant syndrome association 151 optimal dosage 55 relative efficacy 3 treatment algorithm 46 treatment of negative symptoms 35 smokers 892–893 stopping 7, 28, 30–31, 90, 119–125 hyperbolic reduction schedule 121, 122 pattern of tapering 121–122 reduction of olanzapine 121, 122 tapering in practice 122 when to attempt discontinuation 123 withdrawal effects 119–120, 123 suppositories 118 switching medication 57–58, 207–210 target ranges 868–873, 873–874 teratogenic potential 715–717

topiramate 221, 228 use in patients with hepatic impairment 754–756, 761 use patients with in renal impairment 769–771 withdrawal effects 119–120, 123 see also individual drug names antiretroviral therapy (ART) adverse psychiatric effects 808–809 human immunodeficiency virus treatment 804 interactions with psychotropic drugs 804, 807–808 pharmacokinetic interactions with other drugs 545 antiseizure medications 882 driving impairment 922 interactions with psychotropic drugs 813–814 managing behavioural and psychological symptoms of dementia 673 psychiatric side-effects (adverse and beneficial) 812–813 use in alcohol dependence treatment 492 see also anticonvulsants; valproate antispasmodics, safety in older patients/ dementia 659 anxiety children and adolescents with autism spectrum disorder 610 comorbid alcohol use disorder 495 drug treatment in anorexia nervosa 793 Huntington’s disease 832, 833 menopausal women 858 in pregnancy 726–727 anxiety spectrum disorders 446–475 atrial fibrillation patients 847 benzodiazepines 446, 460 caffeine effects 905 children and adolescents 582–586 after prescribing 584–585 before prescribing 582–583 clinical guidance 582 diagnostic issues 582 dosages 585 what to prescribe 583–584 cognitive behavioural therapy 447, 448, 449 multiple sclerosis 836 NICE guidelines 448–449 and nicotine 909 people living with human immunodeficiency virus 805–806 pre-school children 586 psychological approaches 448 specific drugs used 449–455 SSRIs/SNRIs 446–447 see also generalised anxiety disorder; obsessive-compulsive disorder; panic disorder; post-traumatic stress disorder; social phobia anxiolytic effect, benzodiazepines 460 anxiolytics driving impairment 922 use in renal impairment 776–777 see also benzodiazepines apathy, Huntington’s disease 832, 833 apgar scores, medications in pregnancy 720, 723, 724 aripiprazole 8, 11, 15, 24, 43 for antipsychotic-induced weight gain 145 Aristada 12, 88 bipolar disorders 301, 305, 306, 316 borderline personality disorder 788 cardiac safety of 164 clozapine augmentation 221 effects on impulse control disorders 560 hyperprolactinaemia 191 long-acting injections 85–89 bipolar disorder 305, 306 brands 88 delayed doses 86, 87 doses and frequencies 77, 85, 86, 87 switching to 86 in overdose 915 pharmacokinetics 81 plasma level monitoring 870 pneumonia association 204–205 in pregnancy 717, 718 QTc prolongation 164 rapid-cycling bipolar affective disorder 316 target range 868 weight restoration in anorexia nervosa 792 Aristada (aripiprazole lauroxil) 12, 88 arrhythmia cardiovascular risk factors 166 clozapine 240 flumazenil 70 induction by antidepressants 411–415 physiological risk factors 164 psychotropic drug risks 845 ART see antiretroviral therapy ascites, risk in hepatic impairment 753, 754 ASD see autism spectrum disorder asenapine bipolar disorder 301 psychosis 8, 11, 12, 15, 43 sublingual 62, 117 aspartate aminotransferase (AST), psychotropic agent effects 961 aspirin, valproate interactions 292 assessing adherence 929, 930 AST see aspartate aminotransferase asymptomatic neurocognitive impairment (ANI), HIV related 806 ataxia, alcohol effects 898 atomoxetine, attention deficit hyperactivity disorder in adults 799, 801 atrial fibrillation (AF) 845–848 Index psychiatric conditions increasing risk 846, 847 psychotropic drug prescription 845–847 treatment 845 types 845 atropine 258, 259, 489, 660 attachment style of patients affecting relationship with clinician 941 attention deficit hyperactivity disorder (ADHD) in adults 798–802 diagnosis 798 NICE guidelines 800 non-stimulant medication 798, 799, psychostimulants 798, 799, 800 amfetamines 533 borderline personality disorder relationship 789 caffeine effects 905 children with 22q11.2 deletion syndrome 821 children and adolescents 562, 563, 574, 597–604 bipolar disorder/bipolar affective disorder relationship 574 diagnostic issues 597 inattention, overactivity and impulsiveness symptoms in autism spectrum disorder 607–608 melatonin use for insomnia 620–621 prescribing guidelines 597–598, 599–602 drug use in renal impairment 778 medication risks in people with epilepsy 816–817 and nicotine 909 in pregnancy 727 stimulant use disorder 533 atypical eating disorders 795 atypical/typical antipsychotic classification 1–2 AUD see alcohol use disorder AUDIT see Alcohol Use Disorders Identification Test autism spectrum disorder (ASD) children and adolescents 605–613, 620–621 inattention, overactivity and impulsiveness symptoms 607–608 melatonin use for insomnia 620–621 pharmacological treatment of co- occurring disorders and problem behaviours 607–610 pharmacological treatment of core symptoms 605–606 restricted repetitive behaviours and interests 606 social and communication impairment 606 psychotropic drugs used 826–827

980 Index baclofen, preventing relapse after alcohol detoxification 492 BALANCE study, bipolar disorder 290, 326 bariatric surgery 849–856 drug pharmacokinetic alterations 849 general recommendations for psychotropic prescribing 854 lithium in perioperative phases 853 medication formulation considerations 849 mental health after surgery 855 psychiatric illness risk 849 Barnes Akathisia Rating Scale 127 basophils, psychotropic agent effects 965 Bazett’s correction formula 162 BDD see body dysmorphic disorder BED see binge eating disorder behavioural changes, benzodiazepine induced disinhibition 471–473 behavioural disturbance see acutely disturbed/violent behaviour; aggressive behaviours; drug-induced excited states behavioural and psychological symptoms of dementia (BPSD) 667–679 non-drug management measures 667–668 pharmacological measures 668–679 beneficial psychiatric effects, antiseizure medications 812–813 benign ethnic neutropenia (BEN) 268, 269, benperidol 43 benzhexol (trihexyphenidyl), clozapine- induced hypersalivation 259 benzodiazepinea, breastfeeding 746 benzodiazepine dependence 464, 540–542 dose reduction recommendations 540 novel illicit drugs 540 overuse of prescribed medication 540 polysubstance use 541, 542 withdrawal management 466–469, 540–542 benzodiazepines 64–65 adverse effects 461–462 adverse effects of long-term use 464, 465 alcohol withdrawal treatment 484–487 anxiolytic effect 460 breastfeeding mothers 746 with caffeine 903 for catatonia 154–155 concentration in normal dosing and UK legal limit 923 dependence/withdrawal/ discontinuation 464–465, 540–542 diazepam equivalent doses 466, 467 direct taper or switch to diazepam 466 disinhibition 471–473 driving impairment 922 drug interactions 462 fixed dose regimen for alcohol withdrawal 485–486 hypnotic effect 460 long-term use effects 464–465 mania treatment in bipolar disorder 310, 311–312 for neuroleptic malignant syndrome 151 not recommended for managing behavioural and psychological symptoms of dementia 671–672 in overdose 917 pregnancy 541 process before tapering 468 psychiatric disorder treatment 460–463 reduction schedules 469 sedatives in hepatic impairment 761 smokers 892 stopping 466 symptom-triggered regimen for alcohol withdrawal 485, 486–487 tapering 466 tapering patterns 467 tapering process 468 for tardive dyskinesia 136 troubleshooting during tapering process 468–469 use in anxiety spectrum disorders 446 use in children and adolescents with autism spectrum disorder 609 use in depression 461 use in pregnancy 726 use in psychosis 461 withdrawal management 466–469, 540–542 symptoms 465 benztropine, clozapine-induced hypersalivation 259 beta agonists, safety in older patients/ dementia/Parkinsons 659 betahistine, for antipsychotic-induced weight gain 145 bethanechol, for constipation treatment 265 bicarbonate in blood, psychotropic agent effects 961 bilirubin in blood, psychotropic agent effects 961 binge eating disorder (BED) 794–795 comorbid depression 795 NICE guidelines 795 biochemical effects of psychotropics 959, 960–965 bipolar disorder/bipolar affective disorder 279–334 antipsychotic drugs 300–304, 311 long-acting injections 305–307 atrial fibrillation patients 846 carbamazepine 295–299 children and adolescents 573–579 after prescribing 574 attention deficit hyperactivity disorder relationship 574 before prescribing 573 clinical guidance 573–574 depression treatments 577 first-line treatments 577 mania treatments 575–576, 577 specific issues 574–575 what to prescribe 573, 575–577 comorbid alcohol use disorder 495 depression 319–325 antipsychotics 301, 302 lithium 280 meta-analysis of drug studies 319 valproate 290 disruptive mood dysregulation disorder relationship 574 lithium 279–288 maintenance treatment 280 prophylaxis 326, 327, 328 stopping/withdrawal effects 331–332 tapering 332–333 mania acute/hypomania 310–315 antipsychotic treatments 300, 301, 302, 311 benzodiazepines 310, 311–312 lithium treatment 279–280 treatment strategies 310 valproate treatment 289–290 multiple sclerosis 836 other treatments 574–575 people living with human immunodeficiency virus 805 physical monitoring 283, 291, 297, 308–309 postpartum psychosis risk 715 in pregnancy 722, 725–726 prophylaxis 326–330 antipsychotics 301, 302 carbamazepine 295–296 lithium 326, 327, 328 valproate 290 rapid cycling type 290, 316–318 relapse after stopping medication 332 stopping lithium and other mood stabilisers 331–334 tapering lithium 332–333 valproate 289–294 bleeding gastrointestinal irritant drugs 753 SSRI effects 393–394, 404, 409, 432–439 warfarin interactions with SSRIs 846 see also platelets blonanserin 8, 12, 15, 43, 227 blood-brain barrier, increased permeability with old age 628 blood clotting antipsychotics risk of pathological clotting 212 see also bleeding; platelets blood count, antipsychotic medication monitoring 40

blood lipids, antipsychotic medication monitoring 40 blood pressure changes 182–185 antipsychotic medication monitoring 41 hypertension 41, 183–184, 241 orthostatic hypotension 182–183, 207 blood tests biochemical effects of psychotropics 959, 960–965 haematological effects of psychotropics 959, 965–966 blood transfusion in surgery, SSRI risks 436–437 BN see bulimia nervosa body dysmorphic disorder (BDD) 587–592 children and adolescents 587–594 NICE guidelines 588–589 psychological therapies 447, 587 SSRIs/SNRIs 447, 588 treatment duration and follow-up 591 treatment initiation 589 treatment-refractory cases 590 bone loss, anorexia nervosa risk 794 bone marrow suppression, antiretrovirals 807 bone mineral density (BMD), reduction by antiretrovirals 807 borderline personality disorder (BPD) 787–791 antidepressants 789 antipsychotics 788 botulinum toxin 790 co-morbid mental health conditions 787, 788 crisis management 790 drug treatment evidence 788–790 ketamine 790 lack of evidence for drug treatments 787–788 mood stabilisers and anticonvulsants 789 omega-3 fatty acids 790 opioid antagonists 789 sedatives, short term use recommended 788 botulinum toxin borderline personality disorder 790 clozapine-related hypersalivation 259 tardive dyskinesia 137 BPD see borderline personality disorder BPSD see behavioural and psychological symptoms of dementia bradykinesia 35 see also pseudoparkinsonism breast enlargement 196 breastfeeding antidepressants 735, 737–740 antipsychotics 736, 741–743 general prescribing principles 734–735, 736 measuring infant exposure to drugs 734 mood stabilisers 736, 744–745 not permitted with lithium use 736 stimulants 747 use of psychotropic medications 734–747 bremelanotide use in patients with hepatic impairment 761 use in patients with renal impairment 778 brexanolone, in overdose 913 brexpiprazole 8, 12, 15, 43, 915 British Association for Psychopharmacology catatonia 156 dementia recommendations 649 bronchodilators, safety in older patients/ dementia 659–660 buccal administration, antipsychotics 117 bulimia nervosa (BN) 794–795 comorbid depression 795 NICE guidelines 795 buprenorphine analgesia for patients on opioid substitution treatment 519 blocking other opioids 506, 507, 519 cautions 513 conventional induction 508–509 intoxication 513 liver function effects 513 low-dose induction 509 methadone comparison 503 opioid substitution treatment 501, 503, 506–514 overdose 513 prolonged-release injection/ Buvidal 509–510 timecourse of withdrawal symptoms 501 transferring back to methadone 512–513 transition from methadone 510–512 treatment methods and doses 508, 509 withdrawal 501, 516–517 buprenorphine with naloxone (Suboxone) 513 bupropion (amfebutamone) 145, 259 adverse effects 527 attention deficit hyperactivity disorder in adults 799, 801 borderline personality disorder 789 clinical effectiveness 527 contraindicated in anorexia nervosa 794 nicotine addiction 527, 529 not recommended in bulimia nervosa/ binge eating disorder 795 in overdose 914 in pregnancy 721, 722 preparations and doses 527, 529 buspirone, in overdose 917 butyrophenones, in overdose 915 caffeine 901–907 anxiety disorders 905 attention deficit hyperactivity disorder 905 Index dose and psychotropic effects of 902–903, 902 drink types 901 energy drinks 901, 904 general effects of 902 interactions 903 intoxication 903–904 mood disorders 905 pharmacokinetics 902–903 schizophrenia 904 withdrawal effects 902 calcium antagonists, for tardive dyskinesia 137 calcium in blood, psychotropic agent effects 961 calcium levels, long-term lithium use 282 cannabis/cannabinoids 36, 546, 550, 558, capacity and consent assessment in older people 694 covert administration of medicines in food and drink 629, 694–699 learning difficulties 824–825 Mental Health Act 629, 694–698, 950, 951 right not to take medication 931 carbamazepine 295–299 adverse effects 296–297 bipolar disorder 295–299, 310, 311 depression 295 discontinuation 297, 298 drug interactions 297–298 formulations 295 indications 295–296, 298 lithium interactions 286 mania 295 mechanism of action 295 in overdose 916 plasma levels 296 prescribing 298 pre-treatment tests and monitoring 297, 298 prophylaxis 295–296 smokers 892 target range 868 teratogenicity 297, 714, 723–724 carbohydrate-deficient transferrin (CDT), psychotropic agent effects 961 cardiac arrhythmia, atrial fibrillation 845–848 cardiac death 161, 166 cardiac drugs, safety/use in older patients 662 cardiac effects antidepressants 406–408, 409, 411–412 drug-induced excited states 543, 544 torsades de pointes/QT interval prolongation risk with methadone 506 cardiac malformation in infants, maternal mental health problems and lithium 723

982 Index cardiomyopathy 254 cardiovascular agents, psychiatric adverse effects 970 cardiovascular disease 169 cardiovascular effects, antiretrovirals 807 cardiovascular mortality 176 cardiovascular risks, acetylcholinesterase inhibitors in Alzheimer’s disease 637 care homes and environments, learning difficulties 825 cariprazine 8, 11, 15, 43 bipolar disorder 301, 321 in overdose 915 catatonia 154–160 algorithm for treatment of catatonic stupor 157 associated psychiatric and medical conditions 154 ECT treatment 155 in schizophrenia 155 sub-types 154 treatment 154–156, 158 CATIE study 58 CBT see cognitive behavioural therapy CDT see carbohydrate-deficient transferrin cerebrolysin, Alzheimer’s disease management 643–644 cerebrovascular disease see vascular dementia cerebrovascular events anticoagulants reducing risks 662 antipsychotic risks 212, 669 see also stroke checklist for prescribing clinician factor 942–943 patient/clinician relationship 943 patient factor 942 checklists, adherence assessment 931 chemotherapeutic agents, psychiatric adverse effects 971 chemotherapy, clozapine contraindicated 273–274 child neurodevelopment, antipsychotic exposure during pregnancy 717–718 children, 22q11.2 deletion syndrome 821 children and adolescents 561–626 alcohol misuse 493 antipsychotics use 568, 573, 580, 590, 606, 615–616 augmentation of other drug treatments 590 first-generation antipsychotics 580, 615 rapid tranquillisation 623 second-generation antipsychotics 568, 573, 580, 590, 608, 615–616, 623 anxiety, with autism spectrum disorder 610 anxiety disorders 582–586 chlorpromazine 1, 8, 11, 14, 28, 43, 118 chlorprothixene, possible teratogen 716 chocolate, Alzheimer’s disease management 644 cholesterol 169, 170, 962 cholinesterase inhibitors see acetylcholinesterase inhibitors chorea, Huntington’s disease 830, 831 chronic kidney disease (CKD), psychiatric disorders 769 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, glomerular filtration rate estimation 766 cigarette smoking see smoking CIGH see clozapine-induced GI hypomotility cimetidine, psychiatric adverse effects 971 citalopram as antidepressant 337, 338 binge eating disorder 794 switching antidepressants 366 use in patients with hepatic impairment 761 CK see plasma creatine kinase CKD see chronic kidney disease CKD-EPI see Chronic Kidney Disease Epidemiology Collaboration Clinical Institute Withdrawal Assessment of Alcohol Scale - Revised (CIWA-Ar) 482, 483, 484, 485, 486, 537 Clinical Opiate Withdrawal Scale (COWS) 501, 502 clinician-patient relationship attachment style of patients 941 collaboration enhancing medication adherence 931 importance to outcomes 939 prescribing influences 943 clinicians responsibilities with ‘off-label’ prescribing 945 seeking support 943 training in compliance therapy and adherence 933–934 clomipramine (Anafranil) in pregnancy 719 serotonin reuptake inhibition 404 clonazepam, concentration in normal dosing and UK legal limit 923 clonidine, clozapine-induced hypersalivation 259 clotiapine 8, 15, 957 clotting factor synthesis reduction, hepatic impairment 753 clozapine 214–277 adverse effects 239, 241–277 agranulocytosis 245, 251, 267–268 cardiomyopathy 254 cardiovascular adverse effects 240, 253–257 approved psychotropic medications 563–564 attention deficit hyperactivity disorder 597–604 medication continuing into adulthood 799 symptoms 562, 563, 574, 607–608 autism spectrum disorder 605–613, 620–621 bipolar disorder 573–579 body dysmorphic disorder 587–594 bulimia nervosa/binge eating disorder 794 cognitive behavioural therapy 566–567, 574, 587, 590, 595 depression 566–572 with autism spectrum disorder 610 irritability (aggression, self-injurious behaviour, and severe disruptive behaviours) in autism spectrum disorder 608 lack of engagement with psychological therapies 587 lithium plasma levels 281 melatonin use for sleep disturbance/ insomnia 575, 609–610, 620–622 obsessive compulsive disorder 587–594 with autism spectrum disorder 610 optimising lithium treatment for prophylaxis in bipolar disorder 327 post-traumatic stress disorder 595–596 pre-school children, anxiety disorders 586 prescribing principles 561–565 psychosis 580–581 psychotropic drug starting doses 626 rapid tranquillisation 623–625 relative infant dose 734 restricted repetitive behaviours and interests, autism spectrum disorder 606 selective serotonin reuptake inhibitors 566–567, 583–584, 585, 588 sleep disturbance in autism spectrum disorder 609–610 social and communication impairment, autism spectrum disorder 606 SSRI use 566–567, 583–584, 585, 588 suicidal ideation risk with SSRIs 588 symptom rating scales 573 tics and Tourette’s syndrome 614–619 adrenergic a2 agonists 615 antipsychotics 615–616 use of adult treatments 562 depression 568–569 mania 574 obsessive compulsive disorder 592 chlordiazepoxide, alcohol withdrawal treatment 485–486 chloride in blood, psychotropic agent effects 962

colitis 245 common adverse effects 241–242 constipation 241, 263–266, 882 delirium 245 eosinophilia 245 gastrointestinal hypomotility 263–266 gastrointestinal necrosis 245 haematological adverse effects 251–252 heat stroke 245 hepatic failure/enzyme abnormalities 245 hypersalivation 241, 258–262 hypertension association 184, 241 hypothermia 245 interstitial nephritis 245 knee-buckling 245 myocarditis 253–254, 255 neutropenia 267–272 nocturnal enuresis 242 ocular effects 245 pancreatitis 246 parotid gland swelling 246 pericardial effusion 246 pericarditis 246 pneumonia 242 pneumonia association 204, 205 polyserositis 246 sedation 242 seizures 242 skin reactions 246 stuttering 246 tachycardia 184, 234, 242, 253, 255 thrombocytopenia 246 thromboembolism 246, 253 uncommon adverse effects 245–246 venous thromboembolism 253 weight gain 242 augmentation of treatment 220–222 bipolar disorder 301–302 borderline personality disorder 788 with caffeine 903 chemotherapy contraindication 273–274 clozapine/norclozapine ratio 871 combined medications 24 community initiation 236–240 adverse effects 239 dosing 237, 238 essential criteria for 236 initial work-up 236–237 mandatory blood monitoring and registration 237 recommended additional monitoring 239 relative contraindications 236 serious cardiac adverse effects 240 switching from other antipsychotics 239 titration schedules 238 delay/underuse of 57 dosing 214–218, 237, 238 ECT augmentation 108–109 EEG test 41 efficacy 3–4 efficacy for negative symptoms 35 genetic testing for treatment 275–277 agranulocytosis 275–276 benign ethnic neutropenia 276 glucose tolerance impairment association 174–175 hyponatraemia treatment 187 initiation schedules 214–218 interruptions in treatment 234–235 intramuscular clozapine 219 lithium use with 269–270, 271 maximum dose 11 ‘off-label’ prescribing 947 in overdose 915 people with 22q11.2 deletion syndrome 822 people living with human immunodeficiency virus and treatment-resistant schizophrenia 804 plasma level monitoring 870–871, 881–882 plasma lipids, effect on 170 possible risks in pregnancy 717 prescribing of 7 relative efficacy 3 restarting after a break in treatment 234–235 site of administration of intramuscular injections 957 smokers 892 smokers/non-smokers, dosing regimens 216–218 switching from other antipsychotics 239 target range 868 titration schedules 214–215, 216–218, 238 treatment optimisation 220–225 treatment-resistant schizophrenia 214–233 alternatives to clozapine 226–233 dosing regimen 214–218 faster titrations 215 intramuscular clozapine 219 treatment optimisation 220–225 clozapine-induced GI hypomotility (CIGH) 263–266, 882 clozapine rechallenge following severe constipation 265 management of suspected acute CIGH 264 prevention and simple management 264 risk factors 263 clozapine-related life-threatening agranulocytosis (CRLTA) 251 cocaine, stimulant use disorder 533 Cochrane review acute behavioural disturbance 63 benzodiazepines 64–65 Index catatonia treatment 155 long-acting injectable antipsychotics 74 smoking cessation 909 Cockroft and Gault equation, creatinine clearance calculation 766, 767 COCP see combined oral contraceptive pill cognitive behavioural therapy (CBT) anxiety spectrum disorders 447, 448, 449 benzodiazepine withdrawal 541, 542 children and adolescents 566–567, 574, 587, 590, 595 psychosis 929 cognitive decline, anticholinergic drugs 654, 658 cognitive disturbances and decline, Huntington’s disease 834 cognitive enhancers adverse effects 631, 635–637 Alzheimer’s disease 630–641 combination treatment 634 discontinuation 640–641 dose tolerability 634–635 dosing and formulations 633–634 drug interactions 637–640 efficacy 632 managing behavioural and psychological symptoms of dementia 671 mechanism of action 630, 631 switching drugs 632–633 see also acetylcholinesterase inhibitors; memantine cognitive impairment anticholinergic burden 642 multiple sclerosis 837 people living with human immunodeficiency virus 806 see also Alzheimer’s disease; dementia; mild cognitive impairment; vascular dementia collaboration between the patient and the prescriber, enhancing medication adherence 931 combination nicotine replacement therapy 524, 529–530 combination therapies bipolar depression 319, 322 prophylaxis in bipolar disorder 327, 328 psychotic depression 362, 364 combined oral contraceptive pill (COCP), premenstrual syndrome 474–475 communication, patient factor in prescribing 942 communication with patients, adherence relationship 933–934 community detoxification, alcohol withdrawal 482 Community Treatment Order (CTO), Mental Health Act 953 complementary therapies, Parkinson’s disease 842

984 Index compliance use of term 927 see also adherence ‘compliance therapy’ 933 compulsion, dependence syndrome 477–478 concurrent illnesses, drug interactions in older people 627 consent see capacity and consent constipation causing drugs, avoid in hepatic impairment 754 constipation, clozapine-induced 263–266, clozapine rechallenge following severe constipation 265 prevention and management 241, 264 risk factors 263 controlled drugs psychostimulants used for attention deficit hyperactivity disorder in adults 798, 799 see also illicit drugs corticosteroids agents, psychiatric adverse effects 971 countertherapeutic use of medication 942 countertransference, clinicians 939, 942 covert administration of medicines in food and drink, older people 629, 694–699 COVID-19 pandemic 268 valproate preventative effects 290 COWS see Clinical Opiate Withdrawal Scale COX-2 inhibitors, lithium interactions 285–286 CrCl see creatinine clearance C-reactive protein in blood, psychotropic agent effects 961 creatine kinase, psychotropic agent effects 962 creatine kinase (CK) elevations, antiretrovirals 807 creatinine in blood, psychotropic agent effects 962 creatinine clearance (CrCl), renal function assessment 766, 767 creatinine phosphokinase, antipsychotic medication monitoring 41 CRLTA see clozapine-related life-threatening agranulocytosis Crocus sativus (saffron), Alzheimer’s disease management 643 cross-tapering, switching antidepressants 366 CTO see Community Treatment Order cultural beliefs, influencing adherence 940 CYP see cytochrome function cyproheptadine, ‘off-label’ prescribing 947 cytisine adverse effects 526 clinical effectiveness for smoking cessation 526 nicotine addiction 526, 529 preparations and doses 526, 529 cytochrome (CYP) function 883–891 alcohol and substrates for enzymes 896, 897, 898 antidepressant interactions with enzymes 339, 401, 401–402, 403 caffeine metabolism/clearance 903 enzyme phenotype frequency by ancestry 889–890 genetics 888–891 nicotine/smoking effects 903, 910 environmental lithium effects 279 Huntington’s disease 834 inappropriate sexual behaviour 680–687 Lewy bodies 630, 642, 648, 649, 842 management of behavioural and psychological symptoms of dementia 667–679 mild cognitive impairment/pre-clinical dementia 648 other kinds 648–649 Parkinson’s disease 842 people living with human immunodeficiency virus 806 safer prescribing 654–666 vascular 647 dementia with Lewy bodies (DLB) 630, 642, 648, 649, 842 dependence definition/diagnosis 477–478 see also addiction; substance misuse and dependence dependence syndrome, definition 477–478 depot antipsychotic medications 4, 29, 74–80, 95 comparison of types 76 doses and frequencies 77–78 improving adherence and outcomes 4, 29, 928–929, 932–933 pharmacokinetics 81 prescribing advice 75–76 reduction of 123 restarting after period of non-compliance 937 schizophrenia 29, 53 site of administration of intramuscular injections 954–957 depression 335–445 atrial fibrillation patients 846 basic prescribing principles 335–336 children and adolescents 566–572 acute phase 569–570 after prescribing 569–570 with autism spectrum disorder 610 before prescribing 567 clinical guidance 566–571 diagnostic issues 566 discontinuation phase 570 maintenance phase 570 specific issues 570 what to prescribe 567–569 chronic kidney disease 769 comorbid alcohol use disorder 494 comorbid with eating disorders 794, 795 diabetes mellitus association 423 drug treatment summary chart 344, 345–347 Huntington’s disease 832, 833 ketamine as treatment 351, 357–361 lithium DAI see Drug Attitude Inventory DAOAs see direct-acting oral anticoagulants daridorexant in overdose 917 use in patients with hepatic impairment 761 use in patients with renal impairment 777 database studies, antidepressant associated hyponatraemia 416, 417 DBM see dibenzoylmethane DBS see deep brain stimulation DBT see dialectical behaviour therapy decision making, relational aspects 939–943 deep brain stimulation (DBS) 137, 227, 230, 592 delirium 245 analgesics causing 660 antibiotics association 662, 663 anticholinergic drug effects 654, 658 antipsychotics used to manage 117, 118 benzodiazepine reactions similar to 471 caffeine at high doses 902 clozapine adverse effects 245 constipation effects in dementia patients 658 ECT/lithium effects 384, 385 excited delirium see drug-induced excited states gamma-butyrolactone withdrawal 534, 537 GHB/GBL withdrawal 534, 537 haloperidol treating in older people 706 hyperthermia and drug-induced excited states 543 opioid effects 660 people living with human immunodeficiency virus 806 post-injection delirium sedation syndrome 76, 77, 91 delirium tremens, severe alcohol withdrawal 480, 481, 482, 486 demeclocycline 187, 188 dementia 630–653 Alzheimer’s disease 630–647 antipsychotic prescriptions 119 drug recommendations and drugs to avoid 663–664

augmentation of antidepressants in unipolar depression 280 prophylaxis of unipolar depression 281 managing behavioural and psychological symptoms of dementia 672–673 menopausal women 858 multiple sclerosis 835 natural remedies St John’s wort 440–443 taken without doctor’s knowledge 442 NICE guidelines 336 nicotine effects 909 older people 688–693 Parkinson’s disease 840 people living with human immunodeficiency virus 804–805 post stroke 393–396 in pregnancy 719–726 psychostimulants 388–392 psychotic symptoms 362–365 St John’s wort 440–443 sexual dysfunction 426 stimulant use association 535 treatment resistant 348–356 use of benzodiazepines 461 see also antidepressants; bipolar disorder designer drugs see new psychoactive substances; synthetic cannabinoids detoxification opioid substitution treatment 500 see also alcohol detoxification deutetrabenazine hepatic impairment 761 renal impairment 778 for tardive dyskinesia 136 dexamfetamine, attention deficit hyperactivity disorder in adults 798, 800 dextromethorphan, in overdose 914 DHA see docosahexanoic acid diabetes mellitus antidepressants 423–425 antipsychotic-related 174–181 comorbid depression 423 see also glucose homeostasis dialectical behaviour therapy (DBT), borderline personality disorder 787 diazepam 68 with alcohol 898 benzodiazepine withdrawal 540, 541 concentration in normal dosing and UK legal limit 923 switching from benzodiazepines 466 diazepam equivalent doses, benzodiazepines 466, 467 dibenzoylmethane (DBM), Alzheimer’s disease management 645 DiGeorge syndrome (22q11.2 deletion syndrome) 820–823 diphenhdyramine, clozapine-induced hypersalivation 259 direct-acting oral anticoagulants (DOACs) atrial fibrillation patients 845, 846 citalopram/escitalopram not affecting 394 possible SSRI interactions 394 renal function assessment 766 discontinuation symptoms when switching antidepressants 366–367 see also withdrawal discontinuation syndrome, donepezil 632 disinhibition benzodiazepines 471–473 clinical implications 472 incident rates 471 mechanism 472 risk factors 471–472 subjective reports 472 see also paradoxical/disinhibitory/ aggressive drug reactions disruptive mood dysregulation disorder (DMDD), bipolar disorder relationship 574 distribution of drugs, changes with old age 628 disulfiram (Antabuse), preventing relapse after alcohol detoxification 491–492 diuretics, lithium interaction 285 diversion and misuse of prescribed drugs opioids 503, 512, 513, 514 stimulants for ADHD in adults 798, 799 DLB see dementia with Lewy bodies DOACs see direct-acting oral anticoagulants docosahexanoic acid (DHA) see omega-3 fatty acids doctor see clinician donanemab, Alzheimer’s disease treatment 646 donepezil Alzheimer’s disease treatment 630–637, 638, 640, 642 for tardive dyskinesia 137 dopamine and norepinephrine-reuptake inhibitors see bupropion dopaminergic agents and dopamine partial agonists, possible effects on impulse control disorders 560 dosage reduction see tapering dose-related adverse drug effects, increased in hepatic impairment 753 Driver and Vehicle Licensing Agency (DVLA), UK 923–924 driving and psychotropic medicines 921–926 duty of driver 923 duty of prescriber 924 effects of mental illness 921 medication-induced sedation 923 Index psychotropic drug groups causing impairments 922 UK General Medical Council guidelines for prescribers 924 UK law 921–923 driving restrictions, people with epilepsy 817 dronabinol, weight restoration in anorexia nervosa 792 droperidol 64, 65 drug administration see administration of medicines Drug Attitude Inventory (DAI) 931 drug half-life 866 see also pharmacokinetics drug-induced excited states 543–544 hyperthermia risk 543, 544 identification 543 illicit drugs 543–544 illicit and misused drugs 543–544 management 543–544 outcomes 544 pathophysiology 543 restraint risks 543 drug-induced parkinsonism see pseudoparkinsonism drug interactions acetylcholinesterase inhibitors 637–638, 638–639 alternative treatments used by menopausal women 858 antidepressants 339, 401–405 pharmacodynamic interactions 402, 404–405 pharmacokinetic interactions 401–402 atrial fibrillation patients 847 carbamazepine 297–298 changes with old age 627, 628–629 illicit drugs with prescribed psychotropic drugs 545, 546–548 lithium 284–286, 286 ACE inhibitors 284–285 sodium levels 284–285 memantine 637–638, 640 post stroke depression 393 valproate 292 drugs of misuse summary 549–553 see also diversion and misuse of prescribed drugs; illicit drugs; substance misuse and dependence dual diagnosis, substance misuse with mental illness 477 dual reuptake inhibitors adverse effects relative to other antidepressants 338 see also duloxetine; venlafaxine duloxetine borderline personality disorder 789 in overdose 914 in pregnancy 721 smokers 892

986 Index duty of managers of hospitals to give information to detained patients, S132 of the Mental Health Act dyslipidaemia 169 clinical management 170–171 switching antipsychotics 207 dystonia extrapyramidal effects 127, 128 Huntington’s disease 830, 831 see also pseudoparkinsonism early-onset schizophrenia spectrum (EOSS) disorder 580 eating disorders 792–797 anorexia nervosa 792–794 atypical/eating disorders not otherwise specified 795 bulimia nervosa/binge eating disorder 794–795 comorbid depression 794, 795 NICE guidelines 795 Ebstein’s anomaly (cardiac malformation), lithium in pregnancy 723, 725 ECG changes, antiretrovirals 807 ECT see electroconvulsive therapy efavirenz, psychiatric adverse reactions 808 eGFR see estimated glomerular filtration rate eicosapentaenoic acid (EPA) see omega-3 fatty acids elderly people atrial fibrillation 845–848 genitourinary symptoms of menopause 861 optimising lithium treatment for prophylaxis in bipolar disorder 327 electrocardiogram (ECG) monitoring antipsychotic medication users 41, 165 methadone users with QT prolongation risk factors 506 see also QTc prolongation electroconvulsive therapy (ECT) 108–110, 227 adverse effects 109 for catatonia 155 children and adolescents 568, 569 drug resistant depression treatment 351 managing behavioural and psychological symptoms of dementia 675 in pregnancy 722 psychotic depression treatment 363 psychotropic drug combination 384–386 S58a of the Mental Health Act 952–953 for treatment-resistant schizophrenia 108–109 electrolytes alcohol effects 898 anorexia nervosa 793–794 antipsychotic medication monitoring 40 see also sodium levels electronic nicotine vaping devices see nicotine vaping devices embolic events, SSRIs decreasing risk 433 emergency situations, rapid tranquilisation 68–69 energy drinks, caffeine content 901, 904 environmental lithium, high levels inversely related to suicide and dementia at a population level 279 eosinophilia 245 eosinophils, psychotropic agent effects 965 EOSS see early-onset schizophrenia spectrum disorder EPA see eicosapentaenoic acid epilepsy 811–819 learning difficulties comorbidity 825 psychiatric comorbidities 811–812 see also people with epilepsy EPSEs see extrapyramidal side effects EPS (extrapyramidal symptoms) see extrapyramidal side effects erectile dysfunction 199, 200 erythrocyte sedimentation rate, psychotropic agent effects 966 escitalopram smokers 893 use in patients with hepatic impairment 761 esketamine, enantiomer of ketamine 357 esketamine (intranasal) treatment resistant depression 336, 351, 357, 359 see also ketamine Espranor orodispersible buprenorphine brand 507, 508 estimated glomerular filtration rate (eGFR), renal impairment assessment 766 ethanol see alcohol excited delirium use of term 543 see also drug-induced excited states excretion of drugs, changes with old age 628 excretory capacity of the kidney, estimation in renal impairment assessment 766 expectations of treatment, placebo and nocebo effects 941 extended release (ER) preparations intramuscular injections 955, 956 memantine for older adults 633 extended release preparations, see also long-acting injectable antipsychotics; modified-release preparations; prolonged release injections; slow-release oral morphine extrapyramidal side effects (EPSEs) 1–2, 3, 126–130 amisulpride 869 children 623 features of most common symptoms 127–128 first generation antipsychotics 580 high-dose antipsychotics 56 methamphetamine use plus antipsychotics 534 patient sensitivity 75 people with learning difficulties 825 people living with human immunodeficiency virus 804, 806 smoking alleviating symptoms 909 switching antipsychotics 207 treatment 128 see also pseudoparkinsonism family, improving medication adherence 932, 933 fasting plasma glucose (FPG) test 176, 177 Fatal Toxicity Index (FTI), antidepressants 412 fatigue multiple sclerosis 837 psychostimulants to reduce in depression 388, 389 fentanyl dependence, buprenorphine low-dose induction 509 ferritin in blood, psychotropic agent effects 962 FGAs see first-generation antipsychotics financial incentives, improving adherence 933 first-generation antipsychotics (FGAs) adverse effects 3–4, 49 bipolar disorder 300 children and adolescents 580 classification of 2 equivalent doses 14 impaired glucose tolerance and diabetes 174 long-acting injectable antipsychotics 75, 76 maximum doses 11, 12 minimum effective doses 8 nomenclature 49 penfluridol 106–107 people with learning difficulties 826 in pregnancy 715–716 relative efficacy 3 role of older antipsychotics 49–50 site of administration of intramuscular injections 954–955 treatment algorithm 46 treatment of negative symptoms 35 fish oils dyslipidaemia treatment 171 mild/moderate depressions in older adults 689 schizophrenia treatment/ prevention 111–114 for tardive dyskinesia 137 see also omega-3 fatty acids fixed-dose regimens, benzodiazepines for alcohol withdrawal management 485

fluid restriction, hyponatraemia treatment 187, 188 flumazenil, guidelines for use of 70 flunitrazepam, concentration in normal dosing and UK legal limit 923 fluoxetine bipolar depression 322 borderline personality disorder 789 bulimia nervosa 794 children and adolescents autism spectrum disorder 610 depression/bipolar disorder 566–568, 569, 570–571, 574 ‘off-label’ prescribing 947 in pregnancy 720 suicidality in children and adolescents 566, 570–571, 588, 610 flupentixol bipolar disorder 305, 306 borderline personality disorder 789 long-acting injection doses and frequencies 77 pharmacokinetics 81 fluphenazine, smokers 893 fluvoxamine for antipsychotic-induced weight gain 145 smokers 893 for tardive dyskinesia 137 folic acid, Alzheimer’s disease management 643 forms T2 and T3, Mental Health Act 950 forms T4/T5/T6, Mental Health Act 952–953 formulations of drugs impaired absorption following bariatric surgery 849 problems with tablets when tapering 382 FPG see fasting plasma glucose test FRAMES principles (feedback, responsibility, advice, menu, empathy, self-efficacy), NICE public health guidance on harmful drinking 479 frontotemporal dementias 648–649 FTI see Fatal Toxicity Index full blood count, antipsychotic medication monitoring 40 galantamine Alzheimer’s disease 630–636, 639, 642 mild cognitive impairment 636 gambling disorder 560 gamma-aminobutyric acid A (GABA-A) 897 gamma-butyrolactone (GBL; pro-drug of GHB) 537–539 see also gamma-hydroxybutyrate and gamma-butyrolactone gamma-glutamyl transferase (GGT), psychotropic agent effects 963 gamma-hydroxybutyrate (GHB) and gamma-butyrolactone dependence 537–539 planned elective withdrawal 538–539 unplanned withdrawal 538 withdrawal management 537–539 withdrawal syndrome 534, 537 GASS see Glasgow Antipsychotic Side-effect Scale gastro-esophageal reflux disease (GERD) 22q11.2 deletion syndrome 820 clozapine 241 gastrointestinal bleeding, SSRI risks 433–434 gastrointestinal disorders, drug safety in older patients/dementia 658–659 gastrointestinal disturbances, antiretrovirals 807 gastrointestinal hypomotility, clozapine-induced 263–266 gastrointestinal irritant drugs, increased risk of bleeding in hepatic impairment 753 gastrointestinal necrosis 245 GBL see gamma-butyrolactone G-CSF see granulocyte-colony stimulating factor generalised anxiety disorder (GAD) NICE guidelines 448 pregabalin 447–448 specific drugs used 449–450 SSRIs/SNRIs 446 valproate treatment 290 generalised seizures, severe alcohol withdrawal 480, 481 General Medical Council, UK, guidelines for prescribers, medical conditions and safe driving 924 genetics of cytochrome function 888–891 genetic testing, for clozapine treatment 275–277 genitourinary symptoms of menopause (GSM) 857, 861, 862 gestational diabetes, antipsychotics risk 716–717 GFR see glomerular filtration rate GGT see gamma-glutamyl transferase GHB see gamma-hydroxybutyrate Ginkgo biloba 136, 222, 227, 641, 643 G see gamma-hydroxybutyrate and gamma-butyrolactone GABA-A see gamma-aminobutyric acid A gabapentin borderline personality disorder 789 tardive dyskinesia 137 use in patients with hepatic impairment 761 gabapentinoids (GABA analogues), addiction/physical dependence and withdrawal 464, 465, 469 GAD see generalised anxiety disorder galactorrhoea 196 Index ginseng, Alzheimer’s disease management 643 Glasgow Antipsychotic Side-effect Scale (GASS) 4 glomerular filtration rate (GFR), estimation for renal impairment assessment 766 glucocorticoid receptor blocking, psychotic depression treatment 364 glucose in blood, psychotropic agent effects 963 glucose homeostasis antidepressant effects 423–425 SSRIs improving control 423 see also diabetes mellitus glucose tolerance impairment, antipsychotic- related 174–181, 207 glutamate, role in cognitive function/ dementia 630, 631, 672 glycated haemoglobin (HbA1c) 53, 175, 176, 177, 424, 432, 963 glycopyrrolate, clozapine-induced hypersalivation 259 gonadotrophin-releasing hormone agonists, medical menopause induction test 475 granulocyte-colony stimulating factor (G-CSF) 270–271 GSM see genitourinary symptoms of menopause guanfacine attention deficit hyperactivity disorder in adults 799, 801 clozapine-induced hypersalivation 259 gynaecological and obstetric haemorrhage, SSRI risks 435–436 H2 see histamine-2 HAD see HIV-associated dementia haematological effects of psychotropics 959, 965–966 haemodialysis, depression treatment 769 haemoglobin, psychotropic agent effects 966 half-life of drugs 866 see also pharmacokinetics haloperidol 8, 11, 14, 43, 49, 50 acute behavioural disturbance 62, 63, 65 clozapine augmentation 221 intravenous administration 117 long-acting injections, doses and frequencies 77 pharmacokinetics 81 possible teratogen 716 smokers 893 haloperidol decanoate 11, 14 Hamilton Depression Rating Scale (HAM-D), drug effect assessment 337, 345 HAND see HIV-associated neurocognitive disorders HbA1c see glycated haemoglobin

988 Index HD see Huntington’s disease HDL see high-density lipoprotein cholesterol heat stroke 245 hepatic CYP enzymes antidepressant interactions 401–402, 403 see also cytochrome function hepatic damage clozapine induced 245 hepatitis B and C infection effects 545 toxicity assessment in new drugs 762 valproate induced 291 hepatic encephalopathy, from reduced drug metabolism in hepatic impairment 753, 754 hepatic impairment in patients 753–767 antidepressants 753, 757–758, 761 antipsychotics 754–756, 761 lower starting doses recommended 753–754 mood stabilisers 759, 761 sedatives 754, 760, 761 stimulants 760 hepatitis B and C infections, drug metabolism effects 545 hepatotoxicity assessment in new drugs 762 avoiding known drugs in hepatically impaired patients 754 herbal medicine see natural remedies high-density lipoprotein (HDL) cholesterol 169 high-dose antipsychotics 17 adverse effects 18 efficacy 17–18 recommendations 19 highly protein-bound drugs, increased toxicity in hepatic impairment 753–754 hirudin, Alzheimer’s disease management 643 histamine-2 (H2) antagonists, safety in older patients/dementia 662 HIV, see also human immunodeficiency virus; people living with human immunodeficiency virus HIV-associated dementia (HAD) 806 HIV-associated neurocognitive disorders (HAND) 806 HIV mania, secondary mania in people living with human immunodeficiency virus 805 hormonal treatments, premenstrual syndrome 474–475 hormone replacement therapy (HRT) 861–863 adverse effect management 863 depression/anxiety treatment for menopausal women 858 local treatments for GSM 861, 862 products and regimens 861, 862, 863 risks 861 starting treatment 863 versus raloxifene for psychosis treatment in menopausal women 860 hospital managers, duty to give information to detained patients under S132 of the Mental Health Act 952 HRT see hormone replacement therapy 5HT6 receptor antagonist, Alzheimer’s disease management 644 human immunodeficiency virus (HIV) 803–810 treatment advances 804 see also people living with human immunodeficiency virus Huntington’s disease (HD) 830–834 cognitive symptoms 834 general principles of pharmacological symptom management 830–831 mental and behavioural symptoms 831–833 motor symptoms 830–831 huperzine A, Alzheimer’s disease management 643 hyperbolic tapering antidepressants 366, 376, 379, 382 benzodiazepine 467 lithium for bipolar disorder 333 hypercalcaemia, lithium 282 hypercholesterolaemia 170 hyperglycaemia 174, 186 hyperlipidaemia 170, 171, 186 hyperparathyroidism, lithium 282 hyperprolactinaemia 2, 24, 41, 50, 190–194, 196 antidepressants 420–422 contraindications 191 effects of antipsychotic medication on prolactin concentration 190 management 191, 192 switching antipsychotics 207 hypersalivation 258–262 clozapine 241 oral anticholinergic agents, safety in older patients/dementia 660 treatment 258, 259–260 hypersensitivity reactions, drug-induced hepatic damage 762 hypertension 41, 183–184, 241 hyperthermia, drug-induced excited states 543, 544 hypertriglyceridemia 169, 171 hypnotic effect, benzodiazepines 460 hypnotics breastfeeding mothers 736, 746 driving impairment 922 in pregnancy 727 use in renal impairment 776–777 hypoalbuminaemia, hepatic impairment 753, 754 hypoglycaemia 898 hypokalaemia, anorexia nervosa 793–794 hypokinetic phase/rigidity, Huntington’s disease 830, 831 hypomania, treatments 310–315 hyponatraemia 186–189 antidepressants 416–419 lithium retention and toxicity 286 other psychoactive prescribed drugs 418 and syndrome of inappropriate antidiuretic hormone 186, 188 treatment 187–188 and water intoxication 186 hypo-oestrogenic states, high prolactin levels in menopausal women 860 hypophosphataemia, anorexia nervosa 794 hypotension 41, 43, 44 clozapine 241 orthostatic 182–183, 207 hypothermia 245 hypothyroidism, lithium risk 282 Hy’s rule, assessment of hepatotoxicity of new drugs 762 iatrogenic dependence, benzodiazepines/ z-drugs/gabapentinoids 464, 540 idalopirdine (5HT6 receptor antagonist), Alzheimer’s disease management 644 ideational perseveration, Huntington’s disease 832 illicit drugs drug-induced excited state 543–544 drugs of misuse summary 549–553 interactions with prescribed psychotropic drugs 545–548, 546–548 see also new psychoactive substances; substance misuse and dependence iloperidone 8, 12, 15, 43, 915 IM see intramuscular... immediate-release (IR) preparations attention deficit hyperactivity disorder treatments 600, 620, 799, 800 medication doses for older adults 633, 700 modified release stimulant preparations preferred in adults 799 impulsive behaviour, disinhibitory drug reactions, benzodiazepines 471–473 inappropriate sexual behaviour in older people 680–687 incongruence of affect, multiple sclerosis 836 infant exposure relative infant dose 734 see also breastfeeding inhaled administration acutely disturbed/violent patients 62 antipsychotics 62, 115, 116 injectable diamorphine, prescribing guidelines for opioid dependency 514

injections site of administration of intramuscular injections 954–958 see also long-acting injectable antipsychotics in-patient detoxification, alcohol withdrawal 482 INR see international normalised ratio in situ microparticle technology see risperidone ISM insomnia melatonin use in children and adolescents 575, 609–610, 620–622 menopausal women 858 people living with human immunodeficiency virus 805, 808, in pregnancy 726–727 see also sleep disturbance integrase strand transfer inhibitors, psychiatric adverse reactions 809 intentional non-adherence 932 interferons-α and -β, psychiatric adverse effects 971 international normalised ratio (INR), psychotropic agent effects 967 interstitial lung disease 245 interstitial nephritis 245 intracranial/intracerebral haemorrhage, SSRI risks 434–435 intramuscular (IM) injections, acute behavioural disturbance 62–66 intranasal antipsychotics 115, 116–117 intranasal esketamine, treatment resistant depression 336, 351, 357, 359 intranasal ipratropium, clozapine-induced hypersalivation 259 intranasal naloxone 499 involuntary movements, abnormal see tardive dyskinesia ipratropium nasal spray, clozapine-induced hypersalivation 259 IR see immediate-release preparations irritability (aggression, self-injurious behaviour, and severe disruptive behaviours), children and adolescents with autism spectrum disorder 608 irritability and agitation, Huntington’s disease 832, 833 isotretinoin, psychiatric adverse effects 971 racemic mixture 357 route of administration 357–358 treatment resistant depression 351, 357–361 see also esketamine ketoacidosis, diabetic 174, 175 kidneys see chronic kidney disease; renal... knee-buckling 245 lactate in blood, psychotropic agent effects 963 LAI see long-acting injectable antipsychotics lamotrigine borderline personality disorder 789 clozapine augmentation 221 life-threatening cutaneous reactions 937 in overdose 916 restarting after period of non- compliance 937, 938 target range 868 laxative misuse/abuse 792, 961, 962 laxatives 239, 241, 264–265, 658, 882 LDL see low-density lipoprotein cholesterol learning difficulties 824–829 capacity and consent 824–825 epilepsy comorbidity 825 general considerations 824 prescribing practice 824–825 lecanemab, Alzheimer’s disease treatment 646 legal issues Mental Health Act England and Wales (1983) 949–953 ‘off label’ prescribing 945–946 UK drug-driving law 921–923 see also capacity and consent lemborexant managing sleep disturbance in dementia 674 in overdose 917 use in patients with hepatic impairment 761 leukopenia, psychotropic agent effects 966 levetiracetam, for tardive dyskinesia 137 Levodopa, hypokinetic rigidity in Huntington’s disease 831 levomepromazine 11, 43 Lewy body dementia 630, 642, 648, 649, LFTs see liver function tests libido 196, 199 linaclotide, for constipation treatment 265 lipids see plasma lipids lipoproteins in blood, psychotropic agent effects 963 liraglutide, for antipsychotic-induced weight gain 145 lisdexamfetamine attention deficit hyperactivity disorder in adults 798–800 borderline personality disorder 789 bulimia nervosa/binge eating disorder 795 KarXT (xanomeline-trospium), Alzheimer’s disease management 645 ketamine 65, 68, 357–361 anti-suicidal effects 339 bipolar depression 321 borderline personality disorder 790 dosing recommendations 358 mechanism of antidepressant action 357 ‘off-label’ prescribing 947 in overdose 914 psychotic depression treatment 363 Index lithium 279–288 adherence/non-compliance limiting effectiveness 284 adverse effects 282–283 with alcohol 899 augmentation of antidepressants in unipolar depression 280 bariatric surgery patients 852, 853 bipolar disorder 279–288 depression 280 mania 279–280, 310, 311 stopping treatment 331–334 suicide risk 281 borderline personality disorder 789 with caffeine 903 clinical indications 279–281, 284 clozapine use with 269–270, 271 depression treatment 280–281 discontinuation 283–284 driving impairment 922 drug interactions 283, 284–286 environmental concentration inversely related to suicide and dementia at a population level 279 formulations 282 mania, acute treatment 279–280, 310, 311 mechanism of action 279 on-treatment monitoring 283, 284 optimising treatment for different ages 327 in overdose 916 patients on long-term lithium 280 people with learning difficulties people living with human immunodeficiency virus 805 plasma levels 281 postpartum 736 in pregnancy 723, 725 pre-treatment tests 283 prophylaxis for unipolar depression 281, 399 renal effects 282, 285 renal function assessment 766 target range 868 teratogenicity 283 thyroid effects 282 toxicity 282–283 use in patients with hepatic impairment 754, 759, 761 withdrawal effects 331–332 liver function tests (LFTs) interpretation 753, 762 monitoring to access drug effects 41, 754, 762 see also hepatic damage lofepramine, in overdose 914 lofexidine, clozapine-induced hypersalivation 259 lone atrial fibrillation 845

990 Index long-acting injectable (LAI) antipsychotics 4, 7, 23, 29, 74–80 advice on prescribing 75–76 aripiprazole 85–89 for bipolar disorder 83–84, 300, 301, 302, 305–306, 326–327 clozapine augmentation 221 differences between 76 doses and frequencies 77–78 equivalent doses 14, 15 management of patients 83–84 maximum doses 11, 12 for menopausal women 859 olanzapine 90–92 paliperidone palmitate 93–98 risperidone 94, 99–105 test doses 75 long-acting oral antipsychotics improving adherence 933 preventing sudden cessation 932–933 restarting after period of non-compliance 937 loop diuretics, lithium interaction 285 loperamides, safety in older patients/ dementia 658 lorazepam 68, 155 catatonia treatment 155 concentration in normal dosing and UK legal limit 923 rapid tranquillisation of children and adolescents 623 use in patients with hepatic impairment 761 low-density lipoprotein (LDL) cholesterol 169 low-dose aspirin co-prescribed with SSRIs, GI bleeding risk 433, 434 loxapine 43, 893 lumateperone 8, 12, 15, 43, 208, 915 lung disease, interstitial 245 lurasidone 8, 11, 15, 43 bipolar depression 302 cardiac safety of 164 clozapine augmentation 221 in overdose 916 QTc prolongation 164 lymphocytes, psychotropic agent effects 966 MADRS see Montgomery-Asberg Depression Rating Scale maintenance for drug dependence, opioid substitution treatment 500, 501–504 maintenance phase, children and adolescents with depression 570 maintenance treatment bipolar disorder 326–330 psychotic depression 363–364 schizophrenia 29, 53 major depressive disorder (MDD) 335–361 bipolar depression comparison 319 older people 688 see also depression malabsorptive surgical procedures, bariatric surgery 849 mania people living with human immunodeficiency virus 805 treatment in children and adolescents 575–576 mania (bipolar disorder) antipsychotics 300, 301, 302, 311 benzodiazepines 310, 311–312 carbamazepine 295 lithium treatment 279–280 treatment options 310–315 valproate treatment 289–290 manic switch, depression in children and adolescents 571 MAOIs see monoamine oxidase inhibitors MARS see Medication Adherence Rating Scale MCI see mild cognitive impairment MDD see major depressive disorder MDRD see Modification of Diet in Renal Disease mean cell haemoglobin concentration, psychotropic agent effects 966 medical foods, Alzheimer’s disease management 644 medical menopause, assessing premenstrual syndrome/premenstrual dysphoric disorder 475 Medication Adherence Rating Scale (MARS) 931 medication-taking aids 932 melatonin adverse effects, children and adolescents 621 for antipsychotic-induced weight gain 146 children and adolescents 620, 621, 626 description 620 efficacy 620 managing behavioural and psychological symptoms of dementia 674 ‘off-label’ prescribing 947 sleep disturbance/insomnia treatment, children and adolescents 575, 609–610, 620–622, 626 for tardive dyskinesia 137 melperone 15 memantine 222, 227 Alzheimer’s disease 630–634, 636–637, 640, 641 borderline personality disorder 789 immediate release versus extended release 633 managing behavioural and psychological symptoms of dementia 671 methods of action in AD treatment 630, 631 vascular dementia 647 memory, clinicians’ procedural memory and unconscious influences 939 menopause 857–864 depression/anxiety 858 diagnosis 857 elderly care 861 genitourinary symptoms and treatments 857, 861, 862 hormone replacement therapy 861–863 increased adiposity effects 859–860 psychological symptoms 857, 858–860 psychosis 858–860 mental capacity see capacity and consent Mental Health Act (MHA), England and Wales (1983) 629, 682, 694–698, 949–953 mephedrone, misuse and dependence 533, 537, 543 metabolic abnormalities, antiretrovirals 808 metformin for antipsychotic-induced weight gain 146 possible mood improvement in type II diabetes 424 methadone buprenorphine comparison 503 cautions 505–506 general hospital settings 504, 505 hepatic/renal dysfunction 505 initiation of treatment 504 intoxication 505 opioid substitution treatment 501, 503–506 in overdose 506, 917 psychiatric hospital settings 504–505 titration schedules 504, 505 transferring back from buprenorphine 512–513 transition to buprenorphine 510–512 withdrawal 516 methamphetamine use disorder 533–534 detoxification 534 psychotic symptoms 534–535 methylphenidate attention deficit hyperactivity disorder in adults 798–800 borderline personality disorder 789 driving impairment 922 people with learning difficulties 827 in pregnancy 727 psychotic depression treatment 364 metreleptin, weight restoration in anorexia nervosa 792 MHA see Mental Health Act (MHA) MI see myocardial infarction mianserin, in overdose 914 microdeletion syndrome, 22q11.2 deletion syndrome 820–823

midazolam 64, 65 mild alcohol withdrawal 480 mild cognitive impairment (MCI), treatments 636, 643, 646, 648 mild neurocognitive disorder (MND), HIV related 806 mineral supplements anorexia nervosa 793 see also nutritional supplements minimum effective doses antidepressants 342, 366 antipsychotics 8 determining for patient 84 minocycline 226, 227 mirtazapine in overdose 914 in pregnancy 721–722 smokers 893 weight restoration in anorexia nervosa 792 missed doses of psychotropic medication 937 MND see mild neurocognitive disorder moclobemide 914 modafinil for antipsychotic-induced weight gain 146 depression 388 fatigue in multiple sclerosis 837 not recommended in pregnancy 727 in overdose 917 Modification of Diet in Renal Disease (MDRD) formula, glomerular filtration rate estimation 766 modified-release (MR) preparations methylphenidate 600 stimulants for attention deficit hyperactivity disorder in adults 798, 799, 800 see also extended release preparations; slow-release oral morphine molindone 12, 15 monoamine oxidase inhibitors (MAOIs) adverse effects, relative to other antidepressants 338 with alcohol 899 with caffeine 903 electroconvulsive therapy combination 385 glucose homeostasis 423, 424 hyponatraemia 416, 417, 418 interaction with tyramine-containing foods 338–339 not recommended for people living with human immunodeficiency virus 805 not recommended in pregnancy 722 in overdose 914 pharmacodynamic drug interactions 404–405 serotonin syndrome 367 swapping and stopping antidepressants 368 monoclonal antibodies, Alzheimer’s disease treatment 646 monocytes, psychotropic agent effects 966 montelukast, psychiatric adverse effects 971 Montgomery-Asberg Depression Rating Scale (MADRS), drug effect assessment 345 Montgomery vs Lanarkshire Health Board appeal case decision, ‘off-label’ prescribing 945 mood disorders caffeine effects 905 see also bipolar disorder; depression mood elevation, psychostimulants use in depression 388 mood stabilisers adverse effects, rationale for reducing/ stopping 331 with alcohol 899 bariatric surgery patients 852 bipolar depression 319 bipolar disorder 279–299, 310–311 stopping treatment 331–334 borderline personality disorder 789 breastfeeding mothers 736, 744–745 combinations for rapid-cycling bipolar affective disorder 316 managing behavioural and psychological symptoms of dementia 673 non-antipsychotic agents for bipolar illness in pregnancy 723–725 in overdose 916–917 use in patients with hepatic impairment 759, 761 use in renal impairment 775–776 withdrawal effects 331–332 see also carbamazepine; lithium; valproate mood-stabilising anticonvulsants, chronic kidney disease risk 769 mortality antipsychotic polypharmacy versus monotherapy 22, 23 antipsychotics versus other risk factors 166 cardiovascular with antipsychotics 18, 166, 176 diabetes-related with antipsychotics 174 drug-induced hyperthermia 544 neuroleptic malignant syndrome 151 motivation of patients adherence 929, 932, 933 readiness to change 940 movement disorders, and nicotine 910 MR see modified-release MS see multiple sclerosis multiple sclerosis (MS) 835–839 anxiety 836 bipolar disorder 836 cognitive impairment 837 depression 835 fatigue 837 Index pseudobulbar affect 836 psychosis 836–837 multisubstance misuse see polysubstance abuse muscle rigidity see pseudoparkinsonism muscular spasm, uncontrolled see dystonia mutual aid and peer support, stimulant abstinence 532 myasthenia gravis, acetylcholinesterase inhibitors use in older patients/ dementia 660 myocardial function effects, drug-induced excited states 543 myocardial infarction (MI), SSRI protective effects 433 myocarditis 253–254, 255 myoclonus clozapine 241, 871 Huntington’s disease 831 lithium 269 nalmefene, alcohol dependence 490–491 naloxone buprenorphine combination (Suboxone) 513 injection or internasal treatment 499 opioid overdose treatment 499 naltrexone for antipsychotic-induced weight gain 146 borderline personality disorder 789 gambling disorder 560 ‘off-label’ prescribing 947 people with learning difficulties 827 preventing relapse after alcohol detoxification 490 preventing relapse after opioid detoxification 517–518 for tardive dyskinesia 137 NAPLS see North American Prodromal Longitudinal Studies Naranjo adverse drug reaction scale (adapted) 972, 973 National Confidential Inquiry into Suicide and Homicide by People with Mental Illness 928 National Institute for Health and Care Excellence (NICE) guidelines anxiety spectrum disorders 448–449 attention deficit hyperactivity disorder in adults 800 attention deficit hyperactivity disorder in children and adolescents 599 borderline personality disorder 788 dementia 642 depression 336 eating disorders 795 generalised anxiety disorder 448 hypercholesterolaemia 170 obsessive compulsive disorder 449 panic disorder 448 prophylaxis in bipolar disorder 327

992 Index National Institute for Health and Care Excellence (NICE) guidelines (cont’d) psychotic disorder monitoring 176 relapse prevention after alcohol detoxification 489, 490, 492 schizophrenia 2, 52–54 National Poisons Information Service (NPIS) 538 natural remedies Alzheimer’s disease management 641, 643 drug interactions in menopausal women 858 Ginkgo biloba 136, 222, 227, 641, 643 non-standardised preparations 440, 441 potential risks 442 St John’s wort 440–443 taken without doctor’s knowledge 442 nausea, clozapine 241 NbN see Neuroscience-based Nomenclature NE see norepinephrine negative predictive value (NPV) 275 neonatal problems first-generation antipsychotics risk 716 tricyclic antidepressant withdrawal 720 nephritis, interstitial 245 nephrotoxic drugs, renal function assessment 766 Netherlands Clozapine Collaboration Group 267 NEURAPRO trial 111–112 neurocognitive disorders HIV related 806 inappropriate sexual behaviour in older people 680–687 see also dementia neurodevelopment, antipsychotic exposure during pregnancy 717–718 neuroleptic malignant syndrome (NMS) 150–153 catatonic stupor in 155, 156 renal impairment 769 restarting antipsychotics 150 risk factors 150, 151 signs and symptoms 150 treatment 150, 151 neurological conditions, rare dementias 649 neuromodulation stimulant use disorder 533 see also transcranial magnetic stimulation Neuroscience-based Nomenclature (NbN) 2, 49 neurotoxicity, lithium 283 neutropenia agranulocytosis 267–268 benign ethnic neutropenia 268, 269 clozapine-related 251, 267–272 granulocyte-colony stimulating factor 270–271 lithium 269–270 neutrophils, psychotropic agent effects 966 new psychoactive substances (NPSs/designer drugs) 477, 540, 543, 544 NICE see National Institute for Health and Care Excellence nicotine 908–911 attention deficit hyperactivity disorder 909 depression and anxiety 909 drug interactions 910 movement disorders 910 Parkinson’s disease 910 psychotropic effects 908 schizophrenia 908–909 smoking cessation and withdrawal symptoms 910 see also smoking nicotine dependence 523–531, 910 bupropion 527, 529 cytisine 526, 529 electronic vaping devices 527–528, 530 nicotine replacement therapy 523–524, treatment algorithms 528–530 varenicline 524–526 withdrawal symptoms 910 nicotine replacement therapy (NRT) 523–524 adverse effects 524 clinical effectiveness 524 combination of formulations 524, 529–530 preparations and doses 525, 529–530 nicotine vaping devices (vaping) 527–528, 530 adverse effects 528 clinical effectiveness 528 preparations and doses 528, 530 N-methyl-D-aspartate (NMDA) receptor antagonists Alzheimer’s disease 630 see also ketamine NMS see neuroleptic malignant syndrome nocebo effects, patient expectations of treatment 941 nocturnal enuresis, management 242 non-adherence impacts 928–929 lithium 284 rates and degrees of adherence 927–928 restarting psychotropic medications after period of non-compliance 937–938 non-competitive N-methyl-D-aspartate receptor antagonists 630 non-compliance see non-adherence non-iatrogenic benzodiazepine dependence 540 non-nucleoside reverse transcriptase inhibitors 808–809 non-steroidal anti-inflammatory drugs (NSAIDs) Alzheimer’s disease management 644–645 co-prescribed with SSRIs, GI bleeding risk 433, 434 lithium interactions 285–286 safety in older patients/dementia 660 norclozapine 871 norepinephrine (NE)-modulating agents see viloxazine norepinephrine (NE)-reuptake inhibitors see atomoxetine; bupropion North American Prodromal Longitudinal Studies (NAPLS) 112 NPIS see National Poisons Information Service NPSs see new psychoactive substances NPV see negative predictive value NRT see nicotine replacement therapy NSAIDs see non-steroidal anti-inflammatory drugs nucleoside reverse transcriptase inhibitors, psychiatric adverse reactions 808 nutritional supplements Alzheimer’s disease management 643, 644 anorexia nervosa 793–794 fatigue in multiple sclerosis 837 obesity 145, 145–146, 166, 169, 176, 580, see also weight gain Objective Opiate Withdrawal Scale (OOWS) 501 object relations 939 obsessive compulsive behaviours, Huntington’s disease 832, 833 obsessive compulsive disorder (OCD) alternative and experimental treatments 591 children and adolescents 587–594 with autism spectrum disorder 610 clinical guidance 587, 588–589 need for drug treatment 587 psychological therapies 587 SSRI use 588 NICE guidelines 449, 588–589 specific drugs used 453–454 SSRIs/SNRIs 447 treatment duration and follow-up 591 treatment initiation 589 treatment-refractory cases 590 use of adult treatments 592 obstetric and gynaecological haemorrhage, SSRI risks 435–436 OCD see obsessive compulsive disorder ocular effects, and antipsychotics 245 oesophageal varices, consequences of reduced hepatic blood flow 753 oestrogen antipsychotics effects 858 decline in menopausal women 857, 858, 860 selective oestrogen receptor modulators 860

oestrogen augmentation psychosis treatment adjunct for menopausal women 860 see also hormone replacement therapy ‘off-label’ prescribing (outside a drug’s licensed indications) 945–948 legal issues 945–946 recommendations 946–947 OGTT see oral glucose tolerance tests Okedi see risperidone ISM olanzapine acute behavioural disturbance 62, 63 acute kidney injury risk 769 bipolar depression 322 bipolar disorder 302, 310 borderline personality disorder 788 children and adolescents, adverse effects 573, 574 dose reductions 121, 122 doses and frequencies 77, 90 efficacy 3 glucose tolerance impairment association 175 linear dose reductions 121 long-acting injections 90–92 in overdose 916 pharmacokinetics 81 plasma level monitoring 871–872 plasma lipids, effect on 169–170 post-injection delirium sedation syndrome 91 rapid-cycling bipolar affective disorder 316 risks in pregnancy 716, 717 smokers 893 stopping 90 suppositories 118 target range 869 weight restoration in anorexia nervosa 792 olanzapine/fluoxetine combination, children and adolescents with bipolar depression 574, 577 olanzapine pamoate 11, 15 olanzapine/samidorphan combination, bipolar disorder 302 older people 627–712 Alzheimer’s disease 630–647 behavioural and psychological symptoms of dementia management 667–679 covert administration of medicines in food and drink 629, 694–699 dementia 630–687 depression 688–693 dose recommendations for common psychotropics 700–712 general prescribing principles 627–629 inappropriate sexual behaviour 680–687 safer prescribing/cognitive risks 654–666 omega-3 (polyunsaturated) fatty acids (fish oils or supplements) Alzheimer’s disease management 643 borderline personality disorder 790 dyslipidaemia treatment 171 mild/moderate depressions in older adults 689 schizophrenia treatment and prevention 111–114, 221 tardive dyskinesia 137 ondansetron 137, 226, 228 OOWS see Objective Opiate Withdrawal Scale opioid antagonists, borderline personality disorder 789 opioid dependence 498–522 changes in prescribing practice 498 overdoes 498–499 prescribing psychotropic medications 515 timecourse of withdrawal symptoms 501 opioid receptor agonists, buprenorphine blocking other opioids 506, 507 opioids detoxification and reduction regimens 516–518 diversion potential of prescribed substances 503, 512, 513, 514 driving impairment 922 misuse 498–522 overdose risk after detoxification 518 overdose symptoms and treatment 498–499 psychiatric adverse effects 969 relapse prevention with naltrexone 517–518 safe storage importance 505 safety in older patients/ dementia 660–661 transferring from prescription drugs to buprenorphine 512 opioid substitution treatment (OST) 500–519 alternative oral preparations 514 induction and stabilisation of maintenance treatment 501 injectable diamorphine 514 pain control in patients 518–519 relapse prevention with naltrexone 517–518 safe prescribing 501 slow-release oral morphine 514 see also buprenorphine; methadone opioid withdrawal buprenorphine 516–517 community settings 516–517 methadone 516 specialist addiction in-patient settings 517 timecourse of symptoms 501 treatment of symptoms 515 validated scales 501 Index oral glucose tolerance tests (OGTT) 176, 177 oral nicotine products see nicotine replacement therapy orexin antagonists see lemborexant; suvorexant orlistat for antipsychotic-induced weight gain 146 for constipation treatment 265 orodispersible drug administration, Espranor/buprenorphine 507–508 orthostatic hypotension 182–183, 207 OST see opioid substitution treatment osteoporosis, anorexia nervosa risk 794 overdose, psychotropics in 913–920 oxazepam catatonia treatment 155 concentration in normal dosing and UK legal limit 923 use in patients with hepatic impairment 761 oxcarbazepine, risks in pregnancy 724 P450 (CYP) pathways inhibition by different SSRIs 339 see also cytochrome function packed cell volume, psychotropic agent effects 966 paediatric autoimmune neuropsychiatric disorder associated with Streptococcus (PANDAS) 617 pain control for patients on opioid substitution treatment 518–519 see also analgesics paliperidone pharmacokinetics 81 target range 869 use in patients with hepatic impairment 761 paliperidone palmitate long-acting injections 29, 31, 93–98 dose and administration 11, 77, 93 pancreatitis 246 panic disorder NICE guidelines 448 specific drugs used 450–451 SSRIs/SNRIs 446–447 use of benzodiazepines 446 paracetamol (acetaminophen) for behavioural and psychological symptoms of dementia 668 hepatotoxicity 762 pain in alcohol withdrawal 489 safety in older patients/dementia 660 paradoxical disinhibitory/aggressive drug reactions, benzodiazepines 471–473 parenteral thiamine, prophylaxis against Wernike’s encephalopathy in alcohol dependency 484–485

994 Index parenteral treatment, for acutely disturbed/ violent patients 62–65 parkinsonian symptoms dementia with Lewy bodies 648 see also pseudoparkinsonism Parkinson’s disease (PD) 840–844 cholinesterase inhibitors 842 complementary therapies 842 depression 840 and nicotine 910 pimavanserin use 842 psychiatric adverse effects of treatments 970 psychosis 841–842 parotid gland swelling 246 paroxetine in pregnancy 720 use in patients with hepatic impairment 761 paroxysmal atrial fibrillation 845 pathological laughing or crying (pseudobulbar affect), multiple sclerosis 836 patient factors, affecting adherence 940–942 patient monitoring bipolar disorder 283, 291, 297, 308–309 mitigating serious consequences of non-adherence 928 plasma level monitoring of psychotropic drugs 865–878 PD see Parkinson’s disease PDSS see post-injection delirium sedation syndrome penfluridol 43, 106–107 people with epilepsy (PWE) 811–819 driving restrictions 817 drug interactions between antiseizure medications and psychotropics 813–814 possible causes of psychiatric symptoms 811–812 prescribing principles 811 psychiatric comorbidities 811–812 psychiatric side effects of antiseizure medications 812–813 seizure risk from psychotropic drugs 814–817 people living with human immunodeficiency virus (PLWH) 803–810 bipolar affective disorder 805 depression 804–805 factors contributing to psychiatric symptoms 803 prescribing principles 803–804 psychosis 804 secondary mania 805 see also human immunodeficiency virus pericardial effusion 246 pericarditis 246 pericyazine 11, 14 perimenopause 857, 861 perioperative blood loss, SSRI risks 436–437 permanent atrial fibrillation 845 perospirone 12 perphenazine 11, 14, 43 Perseris (RBP-7000) 101–102 persistent atrial fibrillation 845 personal and cultural beliefs, influencing adherence 940 personality disorders antipsychotic prescriptions 119, 331 benzodiazepines causing disinhibition 472 substance misuse 477 see also borderline personality disorder P-glycoprotein (P-gp) 883 pharmacodynamic drug interactions with alcohol 897–898 antidepressants 339, 402, 404–405 antiretroviral drugs and psychotropics 807–808 antiseizure medications and psychotropics 814 pharmacodynamics changes in older people 627–628 menopause effects 858 pharmacokinetic drug interactions antidepressants 401–402, 403 antiretroviral drugs and psychotropics 807 antiseizure medications and psychotropics 813 pharmacokinetics 865–899 caffeine 902–903 changes in older people 627, 628 cytochrome function 883–891 depot antipsychotics 81 drug interactions with alcohol 895–899 half-life increased in hepatic impairment 754 impaired drug absorption following bariatric surgery 849 menopause effects 858 plasma level monitoring of psychotropic drugs 865–878 postmortem blood concentrations 879–880 smoking and psychotropic drugs 892–894 phenothiazines, in overdose 916 phenytoin, target range 869 phosphate in blood, psychotropic agent effects 964 pimavanserin 8, 12, 15, 208 managing behavioural and psychological symptoms of dementia 675 use in Parkinson’s disease 842 pitolisant 761, 778, 917 placebo and nocebo effects, patient expectations of treatment 941 plasma creatine kinase (CK) 150 plasma drug levels, elevated due to reduced hepatic blood flow 753 plasma glucose levels, antipsychotic medication monitoring 40 plasma level monitoring of psychotropic drugs 865–878 amisulpride 869–870 aripiprazole 870 clozapine 870–871, 881–882 first-order pharmacokinetics 865 interpretation of results 867 olanzapine 871–872 quetiapine 872–873 risperidone 873 sampling time 866, 868–869 steady state 865–866, 868–869 target ranges 867–869 plasma levels risperidone long-acting injections 99 variations in 56–57 plasma lipids 169–173 screening and monitoring 170, 171 see also dyslipidaemia plasma protein synthesis reduction, hepatic impairment 753 platelets agents associated with aggregation 967 psychotropic agent effects 967 SSRI effects bleeding 393–394, 404, 409, 432–437 decreasing embolic events/MI risk 433 plecanatide, for constipation treatment 265 PMDD see premenstrual dysphoric disorder PMR see postmortem redistribution PMS see premenstrual syndrome pneumonia, antipsychotic-induced 204–206, 242 polypharmacy, menopausal women 858 polyserositis 246 polysubstance abuse benzodiazepine dependence 541, 542 opioids and cocaine, substitution therapy reducing both 534 polyunsaturated fatty acids (PUFAs) see omega-3 fatty acids PORT see Program of Rehabilitation and Therapy study positive predictive value (PPV) 275 post-injection delirium sedation syndrome (PDSS) 76, 77, 91 post menopause, continuous combined HRT 861 postmortem blood concentrations 879–880 postmortem redistribution (PMR) 879 postpartum depression 719 postpartum haemorrhage, antidepressant use in pregnancy 435–436, 720, 721, 722 postpartum medication, breastfeeding mothers 734–737

postpartum psychosis 715 post-SSRI sexual dysfunction (PSSD) 428–429 post stroke depression 393–396 prophylaxis 393 SSRI risks 393–394 post-traumatic stress disorder (PTSD) benzodiazepine use 446 children and adolescents 595–596 specific drugs used 452 SSRIs/SNRIs 447 postural hypotension see orthostatic hypotension potassium levels, psychotropic agent effects 964 power to treat, under S58 of the Mental Health Act 949–950 PPH see postpartum haemorrhage PPIs see proton pump inhibitors PPV see positive predictive value pramipexole, bipolar depression 321 pregabalin generalised anxiety disorder 447–448 in overdose 917 in pregnancy 724–725 use in opiate misusers 519 use in patients with hepatic impairment 761 pregnancy 713–733 alcohol use 492–493 benzodiazepines 541 depression/antidepressants 719–726 evidence of psychotropic drug effects 713 gynaecological and obstetric haemorrhage risk 435–436 newly diagnosed mental illness 714 planning when taking psychotropic drugs 714 psychiatric illness as risk factor 713 psychosis 715–718 selective serotonin reuptake inhibitors 435–436, 720–721 substance misuse 492–493, 554–559 tricyclic antidepressants 719–720 in women taking psychotropic drugs 714 premature ejaculation, antidepressants as treatment 426, 428 premenstrual dysphoric disorder (PMDD) 474 medical menopause using gonadotrophin- prescribers, duty of, medical conditions and safe driving 924 prescribing checklists, relational aspects 942–943 prescribing drugs outside their licensed indications (off-label) 945–948 legal issues 945–946 recommendations 946–948 preterm delivery risk antidepressants 720 antipsychotics 716, 717 lithium 723 tricyclic antidepressants 720 primavanserin 43, 916 procedural memory, clinicians’ unconscious influences 939 prochlorperazine 117, 118 pro-drugs, not recommended in hepatic impairment 754 Product Licences 945 Program of Rehabilitation and Therapy (PORT) study 112 prolactin levels antidepressant effects 420–422 antipsychotic medication monitoring 41 elevation 43, 44 menopausal women 860 psychotropic agent effects 190, 964 prolonged QT interval see QTc prolongation prolonged-release injection, buprenorphine/ Buvidal 509–510 prolonged release preparations, see also extended release preparations; long-acting injectable antipsychotics; modified-release preparations; slow-release oral morphine promazine 43 promethazine acutely disturbed or violent behaviour in schizophrenia 63, 64, 68 breastfeeding 746 not recommended for managing behavioural and psychological symptoms of dementia 674 in pregnancy 726 prophylaxis antidepressants 397–400 after first episode of depression 397 dosing 399 post stroke 393 for recurrent depression 397–398 bipolar disorder 281, 290, 326–330 lithium for depression/mood disorders 281 post stroke depression 393 thiamine for Wernicke’s encephalopathy in alcohol dependency 487–488 propranolol, for tardive dyskinesia 137 protein in blood, psychotropic agent effects 964 proteinuria, renal impairment assessment 766 releasing hormone agonists 475 premenstrual syndrome (PMS) 474–475 hormonal treatment 474–475 medical menopause using gonadotrophin- releasing hormone agonists 475 non-hormonal treatment 474 pharmacological management chart 474 prenatal exposure to medications see pregnancy pre-school children, anxiety disorders 586 Index prothrombin time (PT), psychotropic agent effects 967 proton pump inhibitors (PPIs), safety in older patients/dementia 662 prucalopride, for constipation treatment 265 pseudobulbar affect, multiple sclerosis 836 pseudoparkinsonism (drug-induced parkinsonism) 34, 35, 43, 44, 50, 126, 127, 128, 291, 804 PSSD see post-SSRI sexual dysfunction psychiatric adverse effects of non- psychotropic drugs 969–974 antiretroviral therapy 808–809 differential diagnosis 972–973 drugs and effects 969–972 Naranjo scale 972, 973 psychiatric symptoms in the context of other disorders 803–864 psychodynamic interventions adherence 929 depression 336 psychoeducation 932 psychological/psychosocial interventions anorexia nervosa 795 anxiety spectrum disorders 448 behavioural disturbance in people with learning difficulties 825 benzodiazepine withdrawal 466, 468, 541, 542 borderline personality disorder 787 children and adolescents 566, 568, 587, 597 depression 336, 337, 566, 568 improving medication adherence 932, 933–934 learning disabilities 825 schizophrenia 29, 52, 53, 54, 230 see also cognitive behavioural therapy; dialectical behaviour therapy psychosis acute behavioural disturbance 62–73 atrial fibrillation patients 846 cannabis 36 catatonic stupor in 155 children and adolescents 580–581 during pregnancy 715–718 electroconvulsive therapy 108–110 first episode 28–29, 31 duration of treatment 54 negative symptoms 34 NICE guidelines 52–53 treatment algorithm 45 gamma-butyrolactone withdrawal 534, 537 Huntington’s disease 832, 833 menopausal women 858–860 methamphetamine use disorder 534–535 multi-episode 29–30 multiple sclerosis 836–837 and nicotine 908–909

996 Index psychosis (cont’d) oestrogen augmentation in menopausal women 860 oestrogen decline reducing antipsychotic activity in menopausal women 858 people living with human immunodeficiency virus 804 postpartum 715, 736 prevention with polyunsaturated fatty acids 111–114 relapse, withdrawal-associated 119 and sexual dysfunction 195–196 ‘super-sensitivity psychosis’ 31 use of benzodiazepines 461 see also schizophrenia and related psychoses psychosocial interventions see psychological/ psychosocial interventions psychostimulants attention deficit hyperactivity disorder in adults 798, 799, 800 depression 388–392 psychotherapies, post-traumatic stress disorder 595 psychotic depression 362–365 acute treatment 362 combination therapies 362, 364 ECT treatment 363 ketamine 363 maintenance treatment 363–364 psychotropic drugs with alcohol 895–899 driving impairment 921–926 interactions with illicit drugs 545, 546–548 in overdose 913–920 plasma level monitoring 865–878 steady state 865–866, 868–869 target ranges 867–869 smokers 892–894 target ranges 867–869 use in renal impairment 769–778, 779 PT see prothrombin time PTSD see post-traumatic stress disorder PUFAs see polyunsaturated fatty acids PUFAs (polyunsaturated fatty acids) see omega-3 fatty acids pure red cell aplasia, psychotropic agent effects 967 PWE see people with epilepsy pyridoxine, for tardive dyskinesia 136 QTc prolongation antipsychotic-related 43, 44, 161–168 cardiovascular risk factors 166 ECG monitoring 165 management 166 metabolic inhibition 165 non-psychotropic association 165 physiological risk factors 164 QT interval 161–162 risk factors 164–165 risk quantification 162–164 switching antipsychotics 207 methadone risk 506 prescribing in atrial fibrillation patients 845 quercetin Alzheimer’s disease management 645 for tardive dyskinesia 137 questionnaires adherence assessment 930, 931 severity of alcohol dependence 480, 482, 485 quetiapine acute kidney injury risk 769 bipolar disorder 302 borderline personality disorder 788 glucose tolerance impairment association 175 in overdose 916 plasma level monitoring 872–873 rapid-cycling bipolar affective disorder 316 risks in pregnancy 717 target range 869 thyroid function tests 41 weight restoration in anorexia nervosa 792 patient factors 940–942 prescribing checklist 942–943 relational aspects of prescribing practice 939–944 relative infant dose (RID), medication in breastfeeding mothers 734 renal adverse effects antiretrovirals 807 lithium 282 renal function, NSAIDs affecting sodium/ lithium reabsorption 285 renal impairment in patients 766–785 anti-dementia drugs 778 antidepressants 772–775 antipsychotics 769–771 anxiolytics and hypnotics 776–777 classification of stages 767 clinical guidance 768 lithium 282 methadone 505 monitoring 768 mood-stabilisers 775–776 other psychotropic drugs 768 recommended psychotropic drugs 779 repetitive transcranial magnetic stimulation (rTMS) for catatonia 155–156 for negative symptoms in schizophrenia 36 for tardive dyskinesia 137 restarting psychotropic medications after a break in treatment 234–235 after neuroleptic malignant syndrome 150 after period of non-compliance 937–938 restlessness (akathisia) 43, 44, 127, 128, 131–134 restraint, exacerbating risks in drug-induced excited states 543 restricted repetitive behaviours and interests (RRBIs), core symptom of autism spectrum disorder 606 reticulocyte count, psychotropic agent effects 967 re-titration, after period of non-adherence to medication regime 937, 938 RID see relative infant dose rilpivirine, psychiatric adverse reactions 809 risk awareness, clinician responsibilities to patients 945 Risperdal Consta 99–101, 103 risperidone 2, 3, 8, 29, 58, 228 bipolar disorder 302, 305–306 clozapine augmentation 221 efficacy 3, 17 equivalent dose 15 glucose tolerance impairment association 175 maximum dose 11 maximum doses 12 in overdose 916 raloxifene 228, 860 see also selective oestrogen receptor modulators rapid-cycling bipolar affective disorder 290, 316–318 rapid tranquilisation (RT) 62, 68–70 children and adolescents 623–625 physical monitoring 69 remedial measures 70 site of administration of intramuscular injections 956–957 Rating of Medication Influences (ROMI) scale 931 RBP-7000 (Perseris) 101–102 readiness to change, influencing adherence 940 recommendations to patients, adherence 927 rectal administration, antipsychotics 116, 118 recurrent depression, prophylaxis 397–398 red blood count/red cell distribution width, psychotropic agent effects 967 reduced hepatic blood flow, consequences of hepatic impairment 753 reduced metabolism of drugs changes with old age 628 hepatic impairment 753 refractory schizophrenia see treatment-resistant schizophrenia refusal of treatment, older people’s mental health and capacity 629, 694–699 relational aspects of adherence clinician factors 939

pharmacokinetics 81 plasma level monitoring 873 possible teratogen 716 relative adverse effects 43 target range 869 use in children and adolescents with autism spectrum disorder 609, 610 weight restoration in anorexia nervosa 792 risperidone intramuscular injection (Rykindo) 100, 103 risperidone ISM (in situ microparticles) 81, 100, 101, 103, 873, 956 risperidone long-acting injections (RLAIs) 12, 15, 81, 99–105, 103 approximate dose equivalence 94 bipolar disorder 305–306 blood levels following discontinuation 99 doses and frequencies 78 equivalent doses 103 intramuscular injections 99–101 plasma concentrations timescale 99 Rykindo 100, 103 subcutaneous injections 101–102 switching from 100 RISQ-PATH study 163 Risvan see risperidone ISM rivastigmine, Alzheimer’s disease 630–636, 639, 642 RLAIs see risperidone long-acting injections road traffic accidents (RTAs), psychotropic drugs and driving impairment 922 ROMI see Rating of Medication Influences scale routine monitoring, mitigating serious consequences of non-adherence 928 Roux-en-Y gastric bypass (RYGB) 849 RRBI see restricted repetitive behaviours and interests RT see rapid tranquilisation RTAs see road traffic accidents rTMS see repetitive transcranial magnetic stimulation RYGB see Roux-en-Y gastric bypass Rykindo see risperidone intramuscular injection antipsychotic response 55–61 atrial fibrillation patients 846 caffeine effects 904 cardiometabolic risk factors 169 catatonia 155 comorbid alcohol use disorder 495–496 diabetes association 174 electroconvulsive therapy 108–109 first episode 28–29, 31 duration of treatment 54 negative symptoms 34 treatment algorithm 45 maintenance treatment 29, 53 multi-episode 29–30 negative symptoms 34–39 NICE guidelines 2, 53–54 and nicotine 908–909 people with 22q11.2 deletion syndrome 822 people living with human immunodeficiency virus 804 poorly responsive to standard antipsychotic treatment 57–59 prescribing practice for 17 QTc prolongation 161 relapse 28, 29, 30, 31 withdrawal-associated 120 relapse/acute exacerbation, treatment algorithms 46–47 suicide risk 29 ‘super-sensitivity psychosis’ 31 treatment adherence 30, 928–929, 933–934 algorithms 45–48 NICE guidelines 2, 52–54 polyunsaturated fatty acids 111–114 for poorly responsive schizophrenia 57–59 treatment-resistant 18, 53–54, 108–109, 214–233 see also antipsychotics second-generation antidepressants anorexia nervosa 794 see also bupropion; monoamine oxidase inhibitors; tricyclic antidepressants second-generation antipsychotics (SGAs) 49, 50 adverse effects 3–4 bipolar disorder 300–302 borderline personality disorder 788 children and adolescents 568, 573, 580, 590, 608, 615, 623 classification 2 diabetes, antipsychotic-related 174–176 equivalent doses 14, 15 long-acting injectable antipsychotics 4, 75 maximum doses 11, 12 minimum effective doses 8 neuroleptic malignant syndrome association 151 ‘off-label’ prescribing 947 SADQ see Severity of Alcohol Dependence Questionnaire safer prescribing, older people/ dementia 654–666 saffron see Crocus sativus St John’s wort (SJW) (Hypericum perforatum), treating depression 440–443 SAWS see Short Alcohol Withdrawal Scale schizoaffective disorder, atrial fibrillation patients 846 schizophrenia and related psychoses 1–277 acute behavioural disturbance 62–73 adherence to treatment 30 Index optimal dosage 55 people with learning difficulties 826 people living with human immunodeficiency virus 804 in pregnancy 716–717 relative efficacy 3 site of administration of intramuscular injections 955–956 treatment algorithm 46 treatment of negative symptoms 35 Second Opinion Appointed Doctor (SOAD), the Mental Health Act 950–951, 953 sedation 43, 44 alcohol effects 897 management 242 medication-induced 923 over-sedation 64 switching antipsychotics 207 sedatives antihistamines not recommended for behavioural and psychological symptoms of dementia 674 ‘high-dose sedation’ 64 in pregnancy 726–727 respiratory depression role in death from opioid agonists overdose 545 use in patients with hepatic impairment 754, 760, 761 see also benzodiazepines; promethazine seizures antiretrovirals 808 drug risks for people with 22q11.2 deletion syndrome 820, 821–822 management 242, 882 psychotropic drug risks in people with epilepsy 814–817 severe alcohol withdrawal 480, 481 selective oestrogen receptor modulators (SERMs) psychosis treatment adjunct for menopausal women 860 see also raloxifene selective serotonin reuptake inhibitors (SSRIs) adverse effects relative to other antidepressants 338 anxiety spectrum disorders 446–447 arrhythmia risk 411 atrial fibrillation patients 845, 846 bipolar depression 322 bleeding risks 432–439 gastrointestinal 433–434 gynaecological and obstetric haemorrhage 435–436 intracranial/intracerebral haemorrhage 434–435 mechanisms 432 post stroke depression 393–394 risk factors 432–433 surgical and postoperative 436–437

998 Index selective serotonin reuptake inhibitors (SSRIs) (cont’d) body dysmorphic disorder 447 with caffeine 903 cardiac effects 406–408, 409, 411–412 co-prescribed with low-dose aspirin/ NSAIDs, GI bleeding risk 433, 434 co-prescribed with warfarin, non-GI bleeding risk 433, 434 driving impairment 922 gastric acid secretion effects 432 gastrointestinal effects 432, 433–434 generalised anxiety disorder 446 hyperprolactinaemia induction 420 hyponatraemia induction 416, 417, 418 increased free plasma levels in hepatic impairment 753–754 increased risk of bleeding in hepatic impairment 753 interactions with anticoagulants 846 lithium interactions 286 obsessive compulsive disorder 447 in overdose 914 panic disorder 446–447 people with learning difficulties 826 people living with human immunodeficiency virus 805, 806 pharmacodynamic drug interactions 404 pharmacokinetic drug interactions 401 platelet effects 393–394, 404, 409, 432, 433 bleeding 432–439 decreasing embolic events/MI risk 433 post stroke depression 393–394 post-traumatic stress disorder 447 in pregnancy 720–721 premenstrual syndrome treatment 474 sexual dysfunction 199, 427, 428–429 social phobia 447 type II diabetes improvement 423 use in children and adolescents 566–567, 583–584, 585, 588 withdrawal symptoms 373 semaglutide, for antipsychotic-induced weight gain 146 SERMs see selective oestrogen receptor modulators serotonergic antidepressants, treatment of sexual dysfunction 426, 428 serotonin-noradrenaline reuptake inhibitors (SNRIs) anxiety spectrum disorders 446–447 hyperprolactinaemia induction 420 hyponatraemia induction 416, 417 pharmacokinetic drug interactions 401, 404 in pregnancy 720 use in children and adolescents 583, 584, 585, 592, 598 serotonin reuptake inhibition see selective serotonin reuptake inhibitors serotonin syndrome renal impairment 769 switching antidepressants 367 sertindole 11, 15, 43, 228 sertraline bulimia nervosa/binge eating disorder 794 ‘off-label’ prescribing 947 in pregnancy 720 use in patients with hepatic impairment 761 severe alcohol dependence 480, 486 severe alcohol withdrawal 481, 484 Severity of Alcohol Dependence Questionnaire (SADQ) 480, 482, 485 sexual behaviour (inappropriate) in older people 680–687 sexual drive reduction by hormone implants 682 sexual dysfunction antidepressants 426–431 effects of antipsychotics 195–203, 196–197, 207 effects of psychosis 195–196 management of antidepressant effects 428–429 selective serotonin reuptake inhibitors 199, 427, 428–429 treatment 198, 199 SGAs see second-generation antipsychotics Short Alcohol Withdrawal Scale (SAWS) 482, 484, 485, 486 SIADH see syndrome of inappropriate antidiuretic hormone sialorrhoea see hypersalivation site of administration of intramuscular injections 954–958 SJW see St John’s wort skin diseases, and antipsychotics 246 sleep disturbance children and adolescents autism spectrum disorder 609–610 use of melatonin 575, 609–610, 620–622 managing behavioural and psychological symptoms of dementia 674 see also insomnia slow-release oral morphine (SROM) 514 smokers/non-smokers, clozapine dosing regimens 216–218 smoking with caffeine 903 cessation 523–531, 909 pregnant women with mental illness 714 and psychotropic drugs 892–894 see also nicotine SNRIs see serotonin-noradrenaline reuptake inhibitors SOAD see Second Opinion Appointed Doctor social and communication impairment, core symptom of autism spectrum disorder in children and adolescents 606 social phobia (social anxiety disorder) 447, 454–455 sodium levels lithium toxicity 283, 284–286 psychotropic agent effects 964 sodium oxybate, for tardive dyskinesia 137 sodium valproate clozapine augmentation 221 ‘off-label’ prescribing 947 solriamfetol in overdose 917 use in patients with hepatic impairment 761 use in renal impairment 778 Souvenaid (dietary supplement), Alzheimer’s disease management 644 special educational needs see learning difficulties SROM see slow-release oral morphine SSRIs see selective serotonin reuptake inhibitors statins no evidence for benefit in vascular dementia 647 preventing cardiovascular events 170, 171 safety/use in older patients 661 vascular dementia 647 stimulants attention deficit hyperactivity disorder in adults 798, 799, 800 breastfeeding mothers 747 definition 532 depression 388–392 use in patients with hepatic impairment 760 see also psychostimulants stimulant use disorder (SUD) 532–536 amfetamines/ methamphetamine 533–534 cocaine 533 depression/anhedonia from abstinence 535 polysubstance abuse, opioids plus cocaine 534 psychotic symptoms 534–535 stopping medication abrupt cessation by non-compliant patients 928 antidepressants 339, 378 antipsychotics 119–125 benzodiazepines 466 lithium 331–334 long-acting antipsychotics reducing impacts of non-adherence 932–933 see also withdrawal

sulpiride 8, 11, 14, 43 clozapine augmentation 221 clozapine-induced hypersalivation treatment 260 typical or atypical classification 2 use in patients with hepatic impairment 754, 756, 761 see also amisulpride suppositories, antipsychotics 116, 118 surgical and postoperative bleeding, SSRI risks 436–437 surgical procedures, bariatric surgery 849–856 suvorexant managing sleep disturbance in dementia 674 in overdose 917 use in patients with hepatic impairment 761 switching between drugs antidepressants 366–372 general guidelines 366–367 swapping and stopping guide 368–370 timing 345–346 within and between drug classes 345 symptom-triggered regimen, benzodiazepines for alcohol withdrawal management 485 syndrome of inappropriate antidiuretic hormone (SIADH) 186, 188 synthetic cannabinoids 543 stroke antipsychotic risks 212–213, 669 dyslipidaemia 171 post stroke depression 393–396 stupor see catatonia stuttering, and antipsychotics 246 sublingual administration antipsychotics 115, 117 buprenorphine 503, 507–508 Suboxone (buprenorphine with naloxone) 513 substance misuse and dependence alcohol 479–497 benzodiazepine misuse 540–542 concurrent alcohol and other substance use disorders 493–494 drugs of misuse summary 549–553 dual diagnosis with mental illness 477 illicit drug interactions with prescribed psychotropic drugs 545–548 mixed substance use 532 mutual aid and peer support for stimulant abstinence 532 nicotine dependence 523–531 opioid dependence 498–522 people living with human immunodeficiency virus 806 personality disorders 477 pregnancy 554–559 stimulant use disorder 532–536 SUD see stimulant use disorder sudden cardiac death, antidepressants 411, 412 suicidality antidepressant cessation 339 antidepressant use in adolescents and young adults 339 antidepressant use balance 339 body dysmorphic disorder in children and adolescents 587, 588 cognitive behavioural therapy decreasing effects of fluoxetine 566 depression in children and adolescents 570–571 environmental lithium effects 279 fluoxetine use in children and adolescents 566, 570–571, 588, 610 Huntington’s disease 832, 833 lithium reducing risk in bipolar and unipolar depression 281, 284 non-adherence impacts 928 obsessive compulsive disorder in children and adolescents 587, 588 overdose of psychotropics 913 peri-natal risks from psychotropic medication withdrawal 713 psychotic depression 362 PTSD in children and adolescents 595 schizophrenia 29 SSRI use in children and adolescents 566, 570–571, 584, 588, 610 valproate risk 291 tachycardia, clozapine effects 184, 234, 242, 253, 255 tapering antidepressants 366, 376, 378–382 benzodiazepines 466–469 drug formulation problems 382 z-drugs/gabapentinoids 469 tardive dyskinesia (TD) 3, 29, 50, 120, 127, 128 switching antipsychotics 208 treatment 135–140 tDCS see transcranial direct current stimulation temazepam concentration in normal dosing and UK legal limit 923 use in patients with hepatic impairment 761 use in patients with renal impairment 777 teratogenic potential antidepressants 721, 722 carbamazepine 297, 714, 723–724 first generation antipsychotics 715–716 mood stabilisers (eg valproate) 714, 723–724 second generation antipsychotics 716–717 valproate 292 Index test doses, long-acting injectable antipsychotics 75 testosterone in blood, psychotropic agent effects 964 tetrabenazine Huntington’s chorea 831 tardive dyskinesia 136 theophylline, safety in older patients/ dementia 659 therapeutic threshold 867 thiamine deficiency (Wernicke’s encephalopathy), alcohol dependency 487–488 thiamine (vitamin B1) injections, alcohol withdrawal adjunctive treatment 484–485 thiazide diuretics, lithium interaction 285 thrombocytopenia 246, 291, 745, 820 thromboembolism 211–213, 246, 253, 860 thyroid adverse effects, lithium 282 thyroid function tests, antipsychotic medication monitoring 41 thyroid-stimulating hormone, psychotropic agent effects 964 thyroxine in blood, psychotropic agent effects 964 tics and Tourette’s syndrome children and adolescents 614–619 adrenergic a2 agonists 615 antipsychotics 615–616 comorbid conditions 614 education and behavioural treatments 614 pharmacological treatments 614–615 recommended treatments 617 TMS see transcranial magnetic stimulation tobacco see nicotine; smoking tolerance, dependence syndrome 477–478 topical vaginal oestrogen 862 topiramate 35, 228 for antipsychotic-induced weight gain 146 borderline personality disorder 789 clozapine augmentation 221 teratogenic risk 714, 724 torsades de pointes, methadone risk 506 Tourette’s syndrome (TS) children and adolescents 614–619 see also tics training of practitioners, compliance therapy and adherence 933–934 tranquilisation see rapid tranquilisation transaminases, drug induced increase in hepatic impairment 754 transcranial direct current stimulation (tDCS) 36, 156 transcranial magnetic stimulation (TMS) stimulant use disorder 533 see also repetitive transcranial magnetic stimulation

1000 Index transdermal patches antipsychotics 116 equivalent doses 15 maximum doses 12 nicotine 494, 524, 616 trazodone Alzheimer’s disease management 645 driving impairment 922 increased free plasma levels in hepatic impairment 753–754 in overdose 915 in pregnancy 721 smokers 893 TRBD see treatment-resistant bipolar disorder TRD see treatment resistant depression treatment framework, clinicians using knowledge of their normal practices to avoid psychological factors influencing decision-making 939 treatment preferences of patients, affecting outcomes 941–942 treatment-resistant bipolar disorder (TRBD), clozapine 301–302 treatment resistant depression (TRD) 348–356 addition of extra drugs 348–349, 351 commonly used treatments 348–350 ketamine 351, 357–361 less commonly used treatments 351–352 potential therapies 353–356 treatment-resistant schizophrenia (TRS) 18 and clozapine 214–233 alternatives to clozapine 226–233 dosing regime 214–218 intramuscular clozapine 219 treatment optimisation 220–225 NICE guidelines 53–54 tremor see pseudoparkinsonism tricyclic antidepressants (TCAs) adverse effects relative to other antidepressants 338 with alcohol 899 arrhythmogenic activity 411 driving impairment 922 hyperprolactinaemia 420, 420 increased free plasma levels in hepatic impairment 753–754 not recommended for managing behavioural and psychological symptoms of dementia 673 in overdose 915 people living with human immunodeficiency virus 805 pharmacodynamic drug interactions 404 pharmacokinetic drug interactions 402 in pregnancy 719–720 psychotic depression 362 smokers 893 target range 869 trifluoperazine 8, 11, 14, 44 triglycerides in blood, psychotropic agent effects 965 triiodothyronine in blood, psychotropic agent effects 965 TRS see treatment-resistant schizophrenia TS see Tourette’s syndrome TV-46000 see Uzedy typical/atypical antipsychotic classification 1–2 tyramine-containing foods, monoamine oxidase inhibitor interactions 338–339 adverse effects 526 clinical effectiveness 525 nicotine addiction 524–526 preparations and doses 526, 529 vascular dementia (VaD) 647 velocardiofacial syndrome (22q11.2 deletion syndrome) 820–823 venlafaxine in overdose 915 possible teratogen 721 venous thromboembolism (VTE) antipsychotic risks 211–213 clozapine adverse effects 253 oestrogen augmentation risk in menopausal women 860 risk of pathological blood clotting 212 Vienna High Risk (VHR) study 111 viloxazine, attention deficit hyperactivity disorder in adults 799, 801 violent behaviour see acutely disturbed/ violent behaviour vitamin B1 (thiamine), alcohol withdrawal adjunctive treatment 484–485 vitamin B6 akathisia adjunctive treatment 131 hyperprolactinaemia 191 vitamin D3 intake, hyperprolactinaemia 191 vitamin D supplementation anorexia nervosa 793 fatigue in multiple sclerosis 837 vitamin E for tardive dyskinesia 136 vitamin K, prophylactic if caprbamazepine given in pregnancy 724, 726 vitamin K-dependent clotting factor synthesis reduction, hepatic impairment 753 vitamin and mineral supplements, anorexia nervosa 793 vitamin replacement, alcohol withdrawal adjunctive treatment 484–485 vitamin supplements Alzheimer’s disease management 643 hyperprolactinaemia 191, 192 VMAT2 inhibitors, Huntington’s chorea 831 vortioxetine in overdose 915 use in patients with hepatic impairment 761 VTE see venous thromboembolism UGIB see upper gastro-intestinal bleeding UGT see uridine diphosphate glucuronosyltransferase unintentional non-adherence 932 upper gastro-intestinal bleeding (UGIB), antidepressants 433 urate (uric acid) in blood, psychotropic agent effects 965 urea in blood, psychotropic agent effects 40, 965 urgent treatment, S62 of the Mental Health Act 952, 953 uridine diphosphate glucuronosyltransferase (UGT) 883 urinary incontinence, anticholinergic drugs 658 urine testing for illicit drugs, in psychiatric care settings 549 Uzedy (TV-46000) risperidone injections 12, 15, 81, 101–102, 103 VaD see vascular dementia vaginal bleeding abnormalities, SSRI risks 435 valbenazine for tardive dyskinesia 136 use in patients with hepatic impairment 761 use in renal impairment 778 valproate 229, 883 adverse effects 291 bipolar disorder 289–294, 310, 311 borderline personality disorder 789 discontinuation 291, 292 drug interactions 292 formulations 289, 292 indications 289–290, 292 mechanism of action 289 not recommended for dementia patients 673 in overdose 916 pharmacokinetics 290 plasma levels 290 prescribing 292 pre-treatment tests and monitoring 291, 292 restricted use 311 target range 869 teratogenic risk 292, 714, 723–726 use in pregnancy 714, 723–726 vaping see nicotine vaping devices varenicline warfarin atrial fibrillation patients 845, 846 co-prescribed with SSRIs, non-GI bleeding risk 433, 434 water intoxication 186 WCC see white cell count weight changes after bariatric surgery 854 antipsychotic medication monitoring 40

weight gain 43, 44, 141–149 after bariatric surgery 854 dose-response 142 drugs to aid weight restoration in anorexia nervosa 792 management 242 risk/extent of 141–142 switching antipsychotics 208 time course 142 treatment 144–149 Wernicke-Korsakoff syndrome 485 Wernicke’s encephalopathy (thiamine deficiency), alcohol dependence 487–488 white cell count (WCC) 267, 268, 269, 271 withdrawal antipsychotics 119–120, 123 benzodiazepines 464–465, 540–542 buprenorphine 501, 516–517 caffeine 902 gabapentinoids 464, 469 gamma-hydroxybutyrate or gamma- butyrolactone 534, 537–539 lithium and other mood stabilisers, bipolar disorder 331 methadone 516 non-adherence impacts 937 role of hyperbolic tapering 379 z-drugs 464, 469 see also alcohol withdrawal; antidepressant withdrawal; opioid withdrawal women of child-bearing potential avoid contra-indicated drugs even if not planning pregnancy 714 see also teratogenic potential xanomeline 8, 12, 15, 44 xanomeline-trospium (KarXT), Alzheimer’s disease management 645 Index ZA see zuclopenthixol acetate z-drugs (zolpidem/zopiclone/zaleplon) breastfeeding 746 dependence and withdrawal 464, 469 insomnia in dementia patients 674 in overdose 917 in pregnancy 727 for tardive dyskinesia 137 use in patients with hepatic impairment 761 ziprasidone 8, 12, 15, 17, 44, 229 clozapine augmentation 221 in overdose 916 zonisamide, for antipsychotic-induced weight gain 146 zotepine 229 zuclopenthixol 11, 14, 44, 893 zuclopenthixol acetate (ZA) 66–67 zuclopenthixol decanoate 12, 14, 81

20 - Chapter 15 Miscellany

01 - Biochemical and haematological effects of psy

Biochemical and haematological effects of psychotropics

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 15 Biochemical and haematological effects of psychotropics Almost all psychotropics have haematology- or biochemistry-related adverse effects that may be detected using routine blood tests. While many of these changes are idiosyncratic and not clinically significant, others, such as the agranulocytosis associated with agents such as clozapine, will require regular monitoring of the full blood count. In general, where an agent has a high incidence of biochemical/haematological adverse effects or a rare but potentially fatal effect, regular monitoring is required as discussed in other sections. For other agents, laboratory-related adverse effects are comparatively rare (prevalence usually less than 1%), are often reversible upon cessation of the putative offending agent and are not always clinically significant. It should further be noted that medical comorbidity, polypharmacy and the effects of non-prescribed agents including substances of abuse and alcohol may also influence biochemical and haematological parameters. In some cases, where a clear temporal association between starting the agent and the onset of laboratory changes is unclear, then withdrawal and rechallenge with the agent in question may be considered. Where there is doubt as to the aetiology and significance of the effect, the appropriate source of expert advice should always be consulted. Tables 15.1 and 15.2 summarise those agents with identified biochemical and haematological effects from information compiled from various sources.1–9 In many cases the evidence for these various effects is limited, with information obtained mostly from case reports, case series and information supplied by manufacturers. For further details about each individual agent, the reader is encouraged to consult the appropriate section of this book as well as other specialist sources, particularly product literature relating to individual drugs. Miscellany

960 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 15 Table 15.1 Summary of biochemical changes associated with psychotropics. Parameter Reference range10 Agents reported to raise levels Agents reported to lower levels Alanine aminotransferase (ALT) F: ≤34U/L M: ≤45U/L (may be higher in obesity) Antipsychotics: asenapine, benperidol, cariprazine, clozapine, haloperidol, loxapine, lumateperone tosylate, olanzapine, phenothiazines, quetiapine, risperidone/paliperidone Antidepressants: agomelatine, bupropion, MAOIs, mianserin, mirtazapine, SNRIs, SSRIs (especially paroxetine and sertraline), TCAs, trazodone, vortioxetine Anxiolytics/hypnotics: barbiturates, benzodiazepines, buspirone, clomethiazole, promethazine, suvorexant, tasimelteon, zolpidem Mood stabilisers: carbamazepine, lamotrigine, valproate Other: alcohol, atomoxetine, beta-blockers, caffeine, cocaine, disulfiram, naltrexone, opioids, stimulants (abused) Vigabatrin Albumin 35–50g/L (gradually decreases after age 40) Microalbuminuria may be a feature of metabolic syndrome secondary to psychotropic use (especially phenothiazines, clozapine, olanzapine and possibly quetiapine) Chronic use of amfetamine or cocaine Alkaline phosphatase 50–120U/L Baclofen, beta-blockers, benzodiazepines, caffeine (excess/chronic use), carbamazepine, citalopram, clozapine, disulfiram, duloxetine, galantamine, haloperidol, loxapine, memantine, modafinil, nortriptyline, olanzapine, phenytoin, sertraline, topiramate, trazodone, valbenazine, valproate; also associated with agents causing NMS Buprenorphine, fluoxetine (in children), zolpidem (rarely) Ammonia 11–32μmol/L (increased following meals and exercise) Barbiturates, carbamazepine, tobacco smoking, topiramate, valproate (may present with signs of encephalopathy) None known

Miscellany CHAPTER 15 Table 15.1 (Continued ) Parameter Reference range10 Agents reported to raise levels Agents reported to lower levels Amylase 28–100U/L Alcohol (acute), donepezil, opioids, pregabalin, rivastigmine, SSRIs (rarely) Agents associated with pancreatitis: alcohol, carbamazepine, clozapine, olanzapine, valproate None known Aspartate aminotransferase (AST) F: ≤34U/L M: ≤45U/L As for ALT; baclofen. Note: ALT is preferred as an indicator of liver damage Trifluoperazine, vigabatrin Bicarbonate 22–29mmol/L Laxative abuse Agents associated with SIADH: all antidepressants, antipsychotics (clozapine, haloperidol, olanzapine, phenothiazines, pimozide, risperidone/paliperidone, quetiapine); carbamazepine; also associated with agents causing metabolic acidosis (alcohol, cocaine, topiramate, zonisamide) Bilirubin ≤21μmol/L (total) Amitriptyline, atomoxetine, benzodiazepines, carbamazepine, chlordiazepoxide, chlorpromazine, citalopram, clomethiazole, clozapine, disulfiram, fluphenazine, imipramine, lamotrigine, meprobamate, milnacipran, olanzapine, phenothiazines, phenytoin, promethazine, sertraline, valbenazine, valproate; also associated with agents causing cholestasis/ hepatic damage Barbiturates C-reactive protein <10mg/L Buprenorphine (rare); also associated with agents causing myocarditis (clozapine) None known Calcium 2.20–2.60mmol/L (total, adjusted) 1.15–1.34mmol/L (ionised) Lithium (rare) Barbiturates, carbamazepine, haloperidol, valproate Carbohydrate- deficient transferrin (CDT) ≤1.5% Alcohol (CDT levels of 1.6–1.9% suggest high intake; levels ≥2% suggest excessive intake) None known (Continued )

962 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 15 Table 15.1 (Continued ) Parameter Reference range10 Agents reported to raise levels Agents reported to lower levels Chloride 95–108mmol/L Agents causing hyperchloraemic metabolic acidosis: topiramate, zonisamide Medications associated with SIADH: all antidepressants, antipsychotics (clozapine, haloperidol, olanzapine, phenothiazines, pimozide, risperidone/paliperidone, quetiapine); carbamazepine, laxative abuse Cholesterol (total) ≤5.2mmol/L (usually compared with recommended action limits rather than reference ranges) Antipsychotics, especially those implicated in the metabolic syndrome (clozapine, olanzapine, phenothiazines, quetiapine). Rarely: aripiprazole, beta-blockers (additive effects with clozapine), carbamazepine, disulfiram, duloxetine, memantine, mirtazapine, modafinil, phenytoin, rivastigmine, sertraline, venlafaxine Prazosin, thyroid agents Creatine kinase F: 25–200U/L M: 40–320U/L (range for people of European descent; may be higher in other ethnic groups) Bremelanotide, brexpiprazole, cariprazine, clonidine, clozapine (when associated with seizures), cocaine, dexamfetamine, donepezil, lumateperone, olanzapine, pregabalin; also associated with agents causing NMS and SIADH; agents administered intramuscularly None known Creatinine F: 55–100μmol/L M: 60–120μmol/L Clozapine, lithium, lurasidone, thioridazine, valproate; medications associated with rhabdomyolysis (benzodiazepines, dexamfetamine, pregabalin, thioridazine); also associated with agents causing renal impairment, NMS and SIADH None known Ferritin F: 15–150mcg/L M: 30–400mcg/L (increases with age) Alcohol (acutely and in alcoholic liver disease) None known

Miscellany CHAPTER 15 Table 15.1 (Continued ) Parameter Reference range10 Agents reported to raise levels Agents reported to lower levels Gamma-glutamyl transferase (GGT) F: ≤38U/L M: ≤55U/L (limits twofold higher in persons of African ancestry) Antidepressants: mirtazapine, SSRIs (paroxetine and sertraline implicated), TCAs, trazodone, venlafaxine Anticonvulsants/mood stabilisers: carbamazepine, lamotrigine, phenobarbitone, phenytoin, valproate Antipsychotics: benperidol, chlorpromazine, clozapine, fluphenazine, haloperidol, olanzapine, quetiapine Other: alcohol, barbiturates, clomethiazole, dexamfetamine, modafinil, tobacco smoking None known Glucose Fasting: 2.8–6.1mmol/L Random: <11.1mmol/L Antidepressants: MAOIs, SSRIs/SNRIs,* TCAs* Antipsychotics: chlorpromazine, clozapine, haloperidol,* olanzapine,* quetiapine and others Substances of abuse: amfetamine, methadone, opioids Other: baclofen, beta- blockers,* bupropion,* caffeine* (in diabetics), clonidine, dexmedetomidine,* donepezil, gabapentin, galantamine, lithium,* nicotine, sympathomimetics, thyroid agents, valbenazine Alcohol; rarely with duloxetine, haloperidol, pregabalin, TCAs Medications associated with metabolic syndrome may result in raised or decreased glucose levels HbA1c 20–39mmol/mol Lithium, MAOIs, SSRIs Lactate dehydrogenase 90–200U/L (levels rise gradually with age) Benzodiazepines, clozapine, methadone, TCAs (especially imipramine), valproate; also associated with agents causing NMS None known Lipoproteins: HDL

1.2mmol/L Carbamazepine, nicotine, phenobarbital, phenytoin Beta-blockers, olanzapine, phenothiazines, valproate Lipoproteins: LDL <3.5mmol/L Beta-blockers, caffeine (controversial), carbamazepine, chlorpromazine, clozapine, iloperidone, memantine, mirtazapine, modafinil, olanzapine, phenothiazines, quetiapine, risperidone/ paliperidone, rivastigmine, venlafaxine Prazosin (Continued )

964 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 15 Table 15.1 (Continued ) Parameter Reference range10 Agents reported to raise levels Agents reported to lower levels Phosphate 0.8–1.5mmol/L Dexamfetamine; also associated with agents causing NMS Carbamazepine, lithium, mianserin, topiramate Potassium 3.5–5.3mmol/L Beta-blockers, lithium Alcohol, disulfiram, caffeine, cocaine, haloperidol, lithium, mianserin, pregabalin, reboxetine, rivastigmine, sodium oxybate, sympathomimetics, topiramate, zonisamide; may also be a feature of delirium tremens Prolactin Normal: <350mU/L Abnormal:

600mU/L Antidepressants: especially amoxapine, MAOIs and TCAs; SSRIs and venlafaxine also implicated Antipsychotics: amisulpride, haloperidol, pimozide, risperidone/paliperidone, sulpiride and others (aripiprazole,† asenapine, brexpiprazole, cariprazine, clozapine, lurasidone, olanzapine, quetiapine and ziprasidone have minimal effects on prolactin levels) Other: benzodiazepines, buspirone, deutetrabenazine, opioids, ramelteon, tetrabenazine, valbenazine Aripiprazole, dopamine agonists, pirenzepine Protein (total) 60–80g/L None known Olanzapine (rarely) Sodium 133–146mmol/L Lithium (in overdose) Antidepressants: especially SSRIs/ SNRIs; others also implicated – see section on hyponatraemia in Chapter 3 Antipsychotics: all (via SIADH) Mood stabilisers: carbamazepine, lithium, valproate Other: benzodiazepines, clonidine, donepezil, memantine, rivastigmine Testosterone F: 0.22–2.9nmol/L M: 9.9–27.8nmol/L Diazepam Opioids, ramelteon Thyroid- stimulating hormone 0.3–4.0mU/L Aripiprazole, carbamazepine, lithium, quetiapine, rivastigmine, sertraline, valproate (slightly) Moclobemide, thyroid agents Thyroxine Free: 9–26pmol/L Total: 60–150nmol/L Rarely; amfetamine (heavy abuse), moclobemide, propranolol Barbiturates, carbamazepine, liothyronine, lithium (causes decreased T4 secretion), opioids, phenytoin, valproate. Rarely implicated: aripiprazole, clozapine, quetiapine, rivastigmine, sertraline

Miscellany CHAPTER 15 Table 15.2 Summary of haematological changes associated with psychotropics. Parameter Reference range Agents reported to raise counts/levels Agents reported to lower counts/levels Activated partial thromboplastin time 23–33 seconds Phenothiazines (especially chlorpromazine) Modafinil (rare) Basophils 0.0–0.1×109/L Clozapine, TCAs (especially desipramine) None known Eosinophils 0.04–0.40×109/L Amoxapine, beta-blockers, bupropion, buspirone, carbamazepine, chloral hydrate, chlorpromazine, clonazepam, clozapine, donepezil, fluphenazine, haloperidol, loxapine, meprobamate, maprotiline, methylphenidate (IV abuse only), modafinil, naltrexone (parenterally administered), olanzapine, promethazine, quetiapine, risperidone/ paliperidone, SSRIs, TCAs, tetrazepam, tryptophan,* valproate, venlafaxine; may also be a feature of agents causing a hypersensitivity syndrome None known Table 15.1 (Continued ) Parameter Reference range10 Agents reported to raise levels Agents reported to lower levels Triglycerides None known Triiodothyronine Free: 3.0–6.8pmol/L Total: 1.2–2.9nmol/L Heroin, methadone Free T3: valproate Total T3: carbamazepine, lithium, propranolol Urate (uric acid) F: 0.16–0.36mmol/L M: 0.21–0.43mmol/L (increases with age) Alcohol (acute), caffeine (false positive), clozapine, levodopa, olanzapine, pindolol, prazosin, topiramate, zonisamide Sertraline (slightly) Urea 2.5–7.8 mmol/L (increases with age) Carbamazepine, levodopa; rarely with agents associated with anticonvulsant hypersensitivity syndrome and rhabdomyolysis None known *May also be associated with hypoglycaemia. †May also be associated with subnormal prolactin levels. F, female; HbA1c, haemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; M, male; MAOIs, monoamine oxidase inhibitors; NMS, neuroleptic malignant syndrome; SIADH, syndrome of inappropriate antidiuretic hormone; TCAs, tricyclic antidepressants. (Continued )

966 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 15 Table 15.2 (Continued ) Parameter Reference range Agents reported to raise counts/levels Agents reported to lower counts/levels Erythrocyte sedimentation rate F: 1–12mm/h M: 1–10mm/h (increases with age) Clozapine, dexamfetamine, levomepromazine, maprotiline, SSRIs Buprenorphine Haemoglobin F: 115–165g/L M: 130–180g/L Clozapine, testosterone, tobacco smoking Aripiprazole, barbiturates, buprenorphine, bupropion, carbamazepine, chlordiazepoxide, chlorpromazine, donepezil, duloxetine, galantamine, MAOIs, memantine, meprobamate, mianserin, phenytoin, promethazine, rivastigmine, tramadol, trifluoperazine, vigabatrin Lymphocytes 1.5–4.5×109/L Naltrexone, opioids, tobacco smoking, valproate; may also be a feature of drugs causing hypersensitivity syndrome Alcohol (chronic), chloral hydrate, clozapine, lithium, mirtazapine (rarely) Mean cell haemoglobin 27–32pg Medications associated with megaloblastic anaemia, e.g. all anticonvulsants, nitrous oxide None known Mean cell haemoglobin concentration 320–360g/L Mean cell volume 80–100fL Alcohol Monocytes 0.2–0.8×109/L Haloperidol None known Neutrophils 2.0–7.5×109/L (may be lower in people of African descent owing to benign ethnic neutropenia) Bupropion, carbamazepine,† citalopram, chlorpromazine, clozapine,† duloxetine, fluoxetine, fluphenazine, haloperidol, lamotrigine, lithium, maprotiline, olanzapine, quetiapine, risperidone/paliperidone, rivastigmine, tiotixene, trazodone, venlafaxine Agents associated with agranulocytosis: amoxapine, aripiprazole, barbiturates, carbamazepine, chlordiazepoxide, chlorpromazine, clozapine,‡ cocaine (adulterated), diazepam, fluphenazine, haloperidol, meprobamate, mianserin, mirtazapine, olanzapine, pirenzepine, promethazine, risperidone/paliperidone, TCAs (especially imipramine), tranylcypromine, valproate Agents associated with leucopenia: amitriptyline, amoxapine, asenapine, bupropion, carbamazepine, cariprazine, chlorpromazine, citalopram, clomipramine, clonazepam, clozapine, duloxetine, fluoxetine, fluphenazine, galantamine, haloperidol, lamotrigine, lorazepam, lumateperone, lurasidone, memantine, meprobamate, mianserin, mirtazapine, modafinil, nitrous oxide, olanzapine, oxazepam, phenelzine, pregabalin, promethazine, quetiapine, tranylcypromine, valproate, venlafaxine, ziprasidone Agents associated with neutropenia: clozapine, sertraline, trazodone, valproate Packed cell volume F: 0.37–0.47L/L M: 0.40–0.52L/L Clozapine (rare), testosterone Benzodiazepines (rare), buprenorphine, naltrexone, vigabatrin

Miscellany CHAPTER 15 Table 15.2 (Continued ) Parameter Reference range Agents reported to raise counts/levels Agents reported to lower counts/levels Platelets 150–450×109/L Lamotrigine, lithium† Alcohol, barbiturates, beta-blockers, benzodiazepines, bupropion, buspirone, carbamazepine, chlordiazepoxide, chlorpromazine, clonazepam, clonidine, clozapine,† cocaine, diazepam, donepezil, duloxetine, fluoxetine, fluphenazine, lamotrigine, meprobamate, methadone, methylphenidate, mirtazapine, naltrexone, nitrous oxide, olanzapine, pirenzepine, promethazine, quetiapine, risperidone/ paliperidone, rivastigmine, sertraline, TCAs, tranylcypromine, trazodone, trifluoperazine, valproate, venlafaxine, ziprasidone; may also be a feature of drugs causing hypersensitivity syndrome Agents associated with impaired platelet aggregation: chlordiazepoxide, citalopram, diazepam, fluoxetine, fluvoxamine, paroxetine, piracetam, sertraline, valproate Prothrombin time (PT)/international normalised ratio (INR) PT: 10–13 seconds INR: 0.8–1.2 Chloral hydrate, disulfiram, fluoxetine, fluvoxamine, mirtazapine, valproate; also agents interacting with warfarin Barbiturates, carbamazepine, phenytoin, tiotixene Red blood count F: 3.8–5.8×1012/L M: 4.5–6.5×1012/L Lithium, testosterone Buprenorphine, carbamazepine, chlordiazepoxide, chlorpromazine, donepezil, haloperidol, meprobamate, phenytoin, quetiapine, trifluoperazine Red cell distribution width 11.5–14.5% Agents associated with anaemia, e.g. carbamazepine, chlordiazepoxide, citalopram, clonazepam, diazepam, lamotrigine, memantine, mirtazapine, sertraline, tranylcypromine, trazodone, valproate, venlafaxine None known Reticulocyte count 0.5–2.5% (or 50–100×109/L) None known Carbamazepine, chlordiazepoxide, chlorpromazine, meprobamate, phenytoin, trifluoperazine Agents associated with pure red cell aplasia: carbamazepine, clozapine, valproate *Previous reports of eosinophilia-myalgia syndrome may have been due to a contaminant from a single manufacturer. †May raise or lower levels. ‡Note that in rare cases clozapine has been associated with a ‘morning pseudo-neutropenia’ with lower levels of circulating neutrophil levels. As neutrophil counts may follow circadian rhythms, repeating the FBC at a later time of day may be instructive. F, female; M, male; MAOIs, monoamine oxidase inhibitors; TCAs, tricyclic antidepressants.

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02 - References

References

968 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 15 References

Joint Formulary Committee. British National Formulary (online). London: BMJ and Pharmaceutical Press; https://www.medicinescomplete.com/.
Aronson J. Meyler’s Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions. Amsterdam: Elsevier Science; 2015.
Foster R. Clinical Laboratory Investigation and Psychiatry. A Practical Handbook. New York: Informa; 2008.
Oyesanmi O, et al. Hematologic side effects of psychotropics. Psychosomatics 1999; 40:414–421.
Stubner S, et al. Blood dyscrasias induced by psychotropic drugs. Pharmacopsychiatry 2004; 37 Suppl 1:S70–S78.
Pharmaceutical Press. Martindale: The Complete Drug Reference. 2024; https://www.medicinescomplete.com/.
National Institute of Diabetes and Digestive and Kidney Diseases. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012; https://www.ncbi.nlm.nih.gov/books/NBK547852/.
Medicines Complete. AHFS Drug Information. 2024; https://www.medicinescomplete.com/mc/ahfs/current/.
US Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs. 2024; https://www.accessdata.fda.gov/scripts/cder/daf/.
Association for Laboratory Medicine. Analyte Monographs Alongside the National Library of Medicine Catalogue. 2024; https://labmed.org. uk/our-resources/science-knowledge-hub/analyte-monographs.html.

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03 - Summary of psychiatric adverse effects of non

Summary of psychiatric adverse effects of non-psychotropics

Miscellany CHAPTER 15 Summary of psychiatric adverse effects of non-psychotropics It is increasingly recognised that non-psychotropic medications can induce a wide range of psychiatric symptoms.1 Up to two-thirds of all drugs have potential psychiatric adverse effects listed in their product labelling,2 although in most cases the evidence supporting a causal link is limited. Psychiatric adverse effects are poorly characterised in drug clinical trials, often only becoming apparent during post-marketing surveillance.3 Given this level of uncertainty, suspected psychiatric adverse effects should be diagnosed and managed on a case-by-case basis. As a general guide, the psychiatric adverse effects of non-psychotropics are shown in Table 15.3. For individual drugs and agents not listed in this table, additional sources of information and the product literature should be consulted. Note that psychiatric adverse effects of drugs used in psychiatry and drugs for human immunodeficiency virus (HIV) and epilepsy are summarised elsewhere in this book. Table 15.3 Summary of psychiatric adverse drug reactions (ADRs) with non-psychotropics.4–7 Drug Psychiatric adverse effect Comment Analgesics Opioids Sedation, dysphoria, confusion, mood changes including euphoria, sleep disturbances, hallucinations, psychosis, delirium, dependence Psychiatric ADRs are relatively common with opioids. Psychosis during opioid withdrawal has also been reported rarely.8 5HT1 agonists (e.g. sumatriptan) Fatigue, anxiety, panic attacks Antibiotics Cephalosporins, penicillins, quinolones (including fluoroquinolones), tetracyclines Sleep disturbances (insomnia and somnolence, abnormal dreams, nightmares), anxiety, delirium and confusional states, depression and agitation, psychotic symptoms (e.g. hallucinations, suicidal ideation) All antibiotics can cause delirium. Patients with underlying medical conditions can be at higher risk of developing psychiatric ADRs. Of the quinolones, ciprofloxacin causes the most psychiatric ADRs, including mood disturbances, agitation and confusion. Onset of psychiatric ADRs can be fast, e.g. after one dose. Isoniazid9 Mania, psychosis Mood-elevating properties have long been noted. In rare cases has been associated with the emergence of manic/psychotic symptoms. Antimalarials Chloroquine, mefloquine Psychosis including hallucinations, panic attacks, suicidal ideation and attempts, anxiety, depression, restlessness, confusion. Abnormal dreams/nightmares are common with mefloquine. Symptoms begin early in treatment. Patients should be advised to stop treatment if these develop and seek medical advice. Psychiatric ADRs are more common with mefloquine than chloroquine. Reactions can even occur after discontinuation of the drug. Mefloquine should not be prescribed for patients with an active or a history of a psychiatric diagnosis. (Continued )

970 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 15 Table 15.3 (Continued ) Drug Psychiatric adverse effect Comment Antiparkinsonian treatments Levodopa Visual hallucinations, depression, hypomania, sleep disturbances, abnormal dreams, cognitive impairment, agitation, psychosis, delirium Dopamine agonists Sedation, psychomotor agitation, anxiety, akathisia, sleep disturbances, psychosis, cognitive impairment, delirium, visual hallucinations These are associated with more psychiatric adverse effects than levodopa Amantadine Decreased concentration, sleep disturbances, visual hallucinations, irritability, anxiety, depression, euphoria, fatigue, psychosis, delirium Selegiline (MAO-B inhibitor) Sleep disturbances, agitation, psychosis Primary metabolites include levamfetamines Entacapone (COMT inhibitor) Sleep disturbances, hallucinations, delirium Cardiovascular agents ACE inhibitors (e.g. captopril, lisinopril) Fatigue, hallucinations, delirium, mood disturbances Captopril most strongly associated with mood effects. Overall limited psychiatric ADRs. Beta-blockers Fatigue, sedation, sleep disturbances and nightmares, cognitive impairment, depression, hallucinations, psychosis, delirium Disturbances more common with lipophilic beta-blockers (e.g. propranolol, metoprolol) than with hydrophilic beta-blockers (e.g. atenolol, sotalol, nadolol). Propranolol most commonly associated with depressive symptoms, but even with this drug causality has not clearly been established. Reports of psychiatric ADRs from numerous clinical trials are equivocal. Calcium channel blockers (e.g. diltiazem, amlodipine) Mood changes, lethargy, dysphoria, mania, psychosis, delirium, akathisia Causal association not clearly demonstrated Statins10–12 (e.g. simvastatin, atorvastatin) Cognitive impairment, memory impairment, depression, emotional lability, irritability, sleep disturbance Causal associations between statins and changes in mood, sleep and cognition have not been established in systematic reviews of RCTs. Statins penetrate the blood–brain barrier; simvastatin has the highest permeability. Switching to hydrophilic statins (e.g. pravastatin, rosuvastatin) has been suggested in suspected cases of moderate to severe psychiatric ADRs.

Miscellany CHAPTER 15 Table 15.3 (Continued ) Drug Psychiatric adverse effect Comment Corticosteroids Glucocorticoids (e.g. betamethasone, prednisolone, prednisone) Mood disorders, mania/ hypomania (particularly with higher doses),13 suicidal ideation, euphoria, agitation, sleep disturbances, psychosis and delirium, dementia, cognitive impairment Clear causal association. Most substantial associations are with depression and mania.14 Onset of psychiatric ADRs is often very sudden, and within the first 1–2 weeks of starting treatment. Symptoms generally respond to dose decreases and have been reported in association with several routes of administration (including oral, parenteral and inhaled), although are probably less common with inhalation. Symptoms usually resolve on gradual discontinuation, although duration of symptoms varies considerably. Other agents 5α-reductase inhibitors (e.g. finasteride)15 Depression, anxiety, suicidality A pharmacovigilance database study of finasteride found associations with suicidality and other psychological adverse events in younger patients receiving treatment for alopecia but not older patients receiving treatment for BPH.16 Chemotherapeutic agents (e.g. 5-fluorouracil, asparaginase, bortezomib, ifosfamide, vincristine) More commonly: cognitive impairment, delirium, psychosis Less commonly: depression, anxiety, suicidal ideation Almost all chemotherapeutic agents are associated with significant psychiatric ADRs, which may be multifactorial in origin (i.e. secondary to the disease process, ADRs and psychological distress). Cancer therapy- associated cognitive changes include difficulty in executive functions, multitasking, short-term memory recall and attention. Cognitive changes seem to be dose- dependent, and certain drugs (methotrexate, fludarabine, cytarabine, 5-fluorouracil, cisplatin) are associated with worse cognitive effects. Cimetidine Cognitive impairment, delirium Interferons-α and -β Depression, loss of efficacy of previously effective antidepressants, suicidal ideation, delirium, non-specific psychiatric symptoms. Rare case reports of psychosis and mania with interferon-α. Psychiatric ADRs are relatively unlikely with interferon-β but much more widely reported with interferon-α. Interferon-α-associated depression responds to antidepressants, use of which can be preventative. Novel diagnostic biomarkers have been investigated to predict which patients are likely to develop interferon-α-associated psychiatric ADRs. (Continued )

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04 - Differential diagnosis of psychiatric adverse

Differential diagnosis of psychiatric adverse effects

972 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 15 Differential diagnosis of psychiatric adverse effects A wide range of confounding factors complicate the diagnosis (and perhaps also the recognition) of psychiatric adverse effects. For example, physical illness, co-prescribed medication, non-prescribed agents and pre-existing mental illness may all influence the clinical presentation and outcome. Factors determining the probability of a causal relationship between drugs and psychiatric adverse effects are shown in Box 15.1. To further support clinical decision-making, the Naranjo scale can be used to assess the likelihood of any adverse reaction being drug-related (Table 15.4). Although cessation of the implicated non-psychotropic might be indicated in some cases, such decisions require individual considerations beyond the scope of this book. Table 15.3 (Continued ) Drug Psychiatric adverse effect Comment Isotretinoin17 Depression, suicidal ideation, psychosis Sporadic reports of psychiatric ADRs but a causal link between isotretinoin therapy and depression, anxiety, mood changes or suicidal ideation/suicide has not been established. A recent meta-analysis found no epidemiological evidence to suggest an increased risk of suicide and psychiatric conditions with isotretinoin.18 Moreover, isotretinoin may be associated with a lower risk of suicide attempt following treatment.18 Rare, idiosyncratic reactions cannot be ruled out; if they occur the drug should be discontinued. Risk is no higher in those with prior suicide attempts and is not dose- or treatment-duration-related. Montelukast19 Sleep disorders, hallucinations, anxiety, depression, obsessive compulsive symptoms The UK MHRA has issued warnings about neuropsychiatric reactions associated with montelukast. Reactions have been reported in adults, adolescents and children. Evidence is conflicting, with one systematic review identifying associations with anxiety and sleeping disorders but not suicide and depression-related events.20 ACE, angiotensin-converting enzyme; BPH, benign prostatic hyperplasia; COMT, catechol-O-methyltransferase; 5HT, 5-hydroxytryptamine; MAO-B, monoamine oxidase B; MHRA, Medicines and Healthcare products Regulatory Agency; RCTs, randomised controlled trials.

Miscellany CHAPTER 15 Box 15.1 Factors determining the probability of a causal relationship between drugs and psychiatric adverse effects4,21 ■ ■Temporal relationship between the drug exposure and the psychiatric adverse effect ■ ■Evidence of the specific psychiatric adverse effect occurring with the suspected drug ■ ■Plausible pharmacological mechanism for the psychiatric adverse effect (e.g. dopamine agonists and psychosis) ■ ■Presence of alternative explanations for symptoms (e.g. pre-existing mental illness, de novo psychiatric illness, other drugs) ■ ■Response of symptoms to the withdrawal of the drug ■ ■Effect of rechallenge with the same drug Table 15.4 Adapted Naranjo adverse drug reaction (ADR) probability scale criteria.22 Questions Yes No NA/unknown

Are there previous conclusive reports on this reaction? +1 0
Did the ADR appear after the suspected drug was administered? +2 –1
Did the ADR improve when the drug was discontinued? +1 0
Did the ADR appear with rechallenge? +2 –1
Are there alternative causes for the ADR? –1 +2
Did the reaction appear when placebo was given? –1 +1
Was the drug detected in the blood at toxic levels? +1 0
Was the ADR more severe when the dose was increased, or less severe when the dose was decreased? +1 0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1 0
Was the ADR confirmed by any objective evidence? +1 0 Probability score: ≥9 = definite; 5–8 = probable; 1–4 = possible; ≤0 = doubtful.

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