06 - Chapter 1 Schizophrenia and related psychoses 01 - ANTIPSYCHOTIC DRUGS ANTIPSYCHOTIC DRUGS 02 - General introduction General introduction 03 - Classification of antipsychotics Classification of antipsychotics 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 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 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. 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. 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. 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. 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. 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. 100 - Clinical effectiveness Clinical effectiveness 101 - Adverse effects Adverse effects 102 - Summary 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. 103 - References 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. 104 - Electroconvulsive therapy and psychosis Electroconvulsive therapy and psychosis 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 106 - Adverse effects Adverse effects 107 - Summary 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. 108 - References 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. 109 - Omega 3 fatty acid (fish oils) in schizophren Omega-3 fatty acid (fish oils) in schizophrenia 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. 110 - Treatment Treatment 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 112 - Overall Overall 113 - Summary recommendations fish oils (PUFAs) Summary recommendations – fish oils (PUFAs) 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. 115 - Alternative routes of administration 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) 116 - Inhaled Inhaled 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 118 - Intravenous Intravenous 119 - Sublingual Sublingual 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. 120 - Buccal Buccal 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.19,20 122 - Rectal Rectal 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. 124 - Stopping antipsychotics Stopping antipsychotics 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.20 126 - 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).12 127 - 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. 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. 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. 13 - References 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. 130 - References References 124 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References 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. National Institute for Health and Care Excellence. Dementia: assessment, management and support for people living with dementia and their carers [NG97]. 2018 (last checked September 2023, last accessed December 2023); https://www.nice.org.uk/guidance/ng97. 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. Morant N, et  al. Experiences of reduction and discontinuation of antipsychotics: a qualitative investigation within the RADAR trial. EClinicalMedicine 2023; 64:102135. 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. Viguera AC, et  al. Clinical risk following abrupt and gradual withdrawal of maintenance neuroleptic treatment. Archives of General Psychiatry 1997; 54:49–55. 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. Chouinard G, et al. Atypical antipsychotics: CATIE study, drug-­induced movement disorder and resulting iatrogenic psychiatric-­like symptoms, supersensitivity rebound psychosis and withdrawal discontinuation syndromes. Psychother Psychosom 2008; 77:69–77. Howes OD, et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry 2012; 69:776–786. Joyce JN. D2 but not D3 receptors are elevated after 9 or 11 months chronic haloperidol treatment: influence of withdrawal period. Synapse 2001; 40:137–144. Quinn R. Comparing rat’s to human’s age: how old is my rat in people years? Nutrition 2005; 21:775–777. Marsden CD. Is tardive dyskinesia a unique disorder? Psychopharmacology Suppl 1985; 2:64–71. Schoretsanitis G, et al. Predictors of lack of relapse after random discontinuation of oral and long-­acting injectable antipsychotics in clinically stabilized patients with schizophrenia: a re-­analysis of individual participant data. Schizophr Bull 2022; 48:296–306. 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. Lako IM, et al. Estimating dopamine D₂ receptor occupancy for doses of 8 antipsychotics: a meta-­analysis. J Clin Psychopharmacol 2013; 33:675–681. Holford N. Pharmacodynamic principles and the time course of delayed and cumulative drug effects. Transl Clin Pharmacol 2018; 26:56–59. Leucht S, et al. Dose–response meta-­analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry 2020; 177:342–353. 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. 131 - ANTIPSYCHOTIC ADVERSE EFFECTS ANTIPSYCHOTIC ADVERSE EFFECTS 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. 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Revisiting antipsychotic-­induced akathisia: current issues and prospective challenges. Curr Neuropharmacol 2017; 15:789–798. 51. Stryjer R, et  al. Treatment of neuroleptic-­induced akathisia with the 5-­HT2A antagonist trazodone. Clin Neuropharmacol 2003; 26:137–141. 52. 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. 53. Stryjer R, et al. Mianserin for the rapid improvement of chronic akathisia in a schizophrenia patient. Eur Psychiatry 2004; 19:237–238. 54. Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med 2004; 26:265–270. 55. Rathbone J, et al. Anticholinergics for neuroleptic-­induced acute akathisia. Cochrane Database Syst Rev 2006; (3):CD003727. 56. Vanegas-­Arroyave N, et  al. An evidence-­based update on anticholinergic use for drug-­induced movement disorders. CNS Drugs 2024; 38:239–254. 57. Glazer WM. Expected incidence of tardive dyskinesia associated with atypical antipsychotics. J Clin Psychiatry 2000; 61 Suppl 4:21–26. 58. 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. 59. Bai YM, et al. Risperidone for severe tardive dyskinesia: a 12-­week randomized, double-­blind, placebo-­controlled study. J Clin Psychiatry 2003; 64:1342–1348. 60. Tenback DE, et al. Effects of antipsychotic treatment on tardive dyskinesia: a 6-­month evaluation of patients from the European Schizophrenia Outpatient Health Outcomes (SOHO) Study. J Clin Psychiatry 2005; 66:1130–1133. 61. Woods SW, et al. Incidence of tardive dyskinesia with atypical versus conventional antipsychotic medications: a prospective cohort study. J Clin Psychiatry 2010; 71:463–474. 62. Pena MS, et al. Tardive dyskinesia and other movement disorders secondary to aripiprazole. Mov Disord 2011; 26:147–152. 63. Stegmayer K, et al. Tardive dyskinesia associated with atypical antipsychotics: prevalence, mechanisms and management strategies. CNS Drugs 2018; 32:135–147. 64. Simpson GM. The treatment of tardive dyskinesia and tardive dystonia. J Clin Psychiatry 2000; 61 Suppl 4:39–44. 65. Peritogiannis V, et al. Can atypical antipsychotics improve tardive dyskinesia associated with other atypical antipsychotics? Case report and brief review of the literature. J Psychopharmacol 2010; 24:1121–1125. 66. Kishi T, et  al. Valbenazine for tardive dyskinesia: a systematic review and network meta-­analysis. Int Clin Psychopharmacol 2023; 38:369–374. 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. 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. 69. 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. 70. 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. 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 2010; 72:615–621. 72. Bergman H, et al. 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. 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) 135 - References 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. 136 - Treatment of tardive dyskinesia Treatment of tardive dyskinesia 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. 138 - Treatment additional agents Treatment – additional agents 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. 14 - High dose antipsychotic medication prescribin High-dose antipsychotic medication: prescribing and monitoring 140 - References 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 Merrill RM, et al. Tardive and spontaneous dyskinesia incidence in the general population. BMC Psychiatry 2013; 13:152. Kane JM, et al. Tardive dyskinesia: prevalence, incidence, and risk factors. J Clin Psychopharmacol 1988; 8 4 Suppl:52s–56s. de Leon J. The effect of atypical versus typical antipsychotics on tardive dyskinesia: a naturalistic study. Eur Arch Psychiatry Clin Neurosci 2007; 257:169–172. Halliday J, et al. Nithsdale Schizophrenia Surveys 23: movement disorders: 20-­year review. Br J Psychiatry 2002; 181:422–427. Kane JM. Tardive dyskinesia circa 2006. Am J Psychiatry 2006; 163:1316–1318. Eberhard J, et  al. Tardive dyskinesia and antipsychotics: a 5-­year longitudinal study of frequency, correlates and course. Int Clin Psychopharmacol 2006; 21:35–42. 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. Aripiprazole-­related tardive dyskinesia. CNS Spectr 2006; 11:435–439. 27. Fountoulakis KN, et al. Amisulpride-­induced tardive dyskinesia. Schizophr Res 2006; 88:232–­234. 28. Sachdev P. Early extrapyramidal side-­effects as risk factors for later tardive dyskinesia: a prospective study. Aust N Z J Psychiatry 2004; 38:445–449. 29. Yoshida K, et al. Tardive dyskinesia in relation to estimated dopamine D2 receptor occupancy in patients with schizophrenia: analysis of the CATIE data. Schizophr Res 2014; 153:184–188. 30. Saucedo Uribe E, et al. Preliminary efficacy and tolerability profiles of first versus second-­generation Long-­Acting Injectable antipsychotics in schizophrenia: a systematic review and meta-­analysis. J Psychiatr Res 2020; 129:222–233. 31. 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. 32. 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. 33. Kenney C, et al. Metoclopramide, an increasingly recognized cause of tardive dyskinesia. J Clin Pharmacol 2008; 48:379–384. 34. Pappa S, et al. Spontaneous movement disorders in antipsychotic-­naive patients with first-­episode psychoses: a systematic review. Psychol Med 2009; 39:1065–1076. 35. Puri BK, et al. Spontaneous dyskinesia in first episode schizophrenia. J Neurol Neurosurg Psychiatry 1999; 66:76–78. 36. McCreadie RG, et al. Spontaneous dyskinesia and parkinsonism in never-­medicated, chronically ill patients with schizophrenia: 18-­month follow-­up. Br J Psychiatry 2002; 181:135–137. 37. Duncan D, et al. Tardive dyskinesia: how is it prevented and treated? Psychiatric Bulletin 1997; 21:422–425. 38. Simpson GM. The treatment of tardive dyskinesia and tardive dystonia. J Clin Psychiatry 2000; 61 Suppl 4:39–­44. 39. Bergman H, et  al. Antipsychotic reduction and/or cessation and antipsychotics as specific treatments for tardive dyskinesia. Cochrane Database Syst Rev 2018; 2:CD000459. 40. Bergman H, et al. Anticholinergic medication for antipsychotic-­induced tardive dyskinesia. Cochrane Database Syst Rev 2018; 1:CD000204. 41. Owens DC. Tardive dyskinesia update: treatment and management. BJPsych Advances 2019; 25:78–89. 42. 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. 43. Pardis P, et  al. Clozapine and tardive dyskinesia in patients with schizophrenia: a systematic review. J Psychopharmacol 2019; 33:1187–1198. 44. Mentzel TQ, et al. Clozapine monotherapy as a treatment for antipsychotic-­induced tardive dyskinesia: a meta-­analysis. J Clin Psychiatry 2018; 79:17r11852. 45. Wong J, et al. 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. 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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. 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Mov Disord 2013; 28:1748–1749. 141 - Antipsychotic induced weight gain 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) 142 - Time course Time course 143 - Doseresponse 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) 144 - References References Schizophrenia and related psychoses CHAPTER 1 References 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. 145 - Treatment of antipsychotic induced weight gai Treatment of antipsychotic-induced weight gain 146 - Monitoring Monitoring 147 - Treatment and prevention 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) 148 - References References Schizophrenia and related psychoses CHAPTER 1 References 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. 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. 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. American Diabetes Association, et al. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004; 27:596–601. Vandenberghe F, et al. Importance of early weight changes to predict long-­term weight gain during psychotropic drug treatment. J Clin Psychiatry 2015; 76:e1417–1423. Lipkovich I, et al. Early evaluation of patient risk for substantial weight gain during olanzapine treatment for schizophrenia, schizophreniform, or schizoaffective disorder. BMC Psychiatry 2008; 8:78. Fitzgerald I, et al. Predicting antipsychotic-­induced weight gain in first episode psychosis: a field-­wide systematic review and meta-­analysis of non-­genetic prognostic factors. Eur Psychiatry 2023; 66:e42. National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults. Quality standard [QS80]. 2015 (last accessed February 2024); https://www.nice.org.uk/guidance/qs80. 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. 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. 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.22 150 - 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 Caroff SN, et al. Neuroleptic malignant syndrome. Med Clin North Am 1993; 77:185–202. Tse L, et al. Neuroleptic malignant syndrome: a review from a clinically oriented perspective. Curr Neuropharmacol 2015; 13:395–406. Belvederi Murri M, et al. Second-­generation antipsychotics and neuroleptic malignant syndrome: systematic review and case report analysis. Drugs R D 2015; 15:45–62. Ware MR, et al. Neuroleptic malignant syndrome: diagnosis and management. Prim Care Companion CNS Disord 2018; 20:17r02185. Tan CM, et al. Neuroleptic malignant syndrome. CMAJ 2023; 195:E1481. Rodriguez OP, et al. A case report of neuroleptic malignant syndrome without fever in a patient given aripiprazole. J Okla State Med Assoc 2006; 99:435–438. Singhai K, et al. Atypical neuroleptic malignant syndrome: a systematic review of case reports. Gen Hosp Psychiatry 2019; 60:12–19. Szota AM, et al. Atypical neuroleptic malignant syndrome: case reports and diagnostic challenges. J Psychoactive Drugs 2022; 54:284–293. Meltzer HY, et al. Marked elevations of serum creatine kinase activity associated with antipsychotic drug treatment. Neuropsychopharmacology 1996; 15:395–405. Schneider M, et al. Neuroleptic malignant syndrome: evaluation of drug safety data from the AMSP program during 1993–2015. Eur Arch Psychiatry Clin Neurosci 2020; 270:23–33. Gurrera RJ. Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome. Am J Psychiatry 1999; 156:169–180. Levenson JL. Neuroleptic malignant syndrome. Am J Psychiatry 1985; 142:1137–1145. 152 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 13. Hermesh H, et al. High serum creatinine kinase level: possible risk factor for neuroleptic malignant syndrome. J Clin Psychopharmacol 2002; 22:252–256. 14. Picard LS, et  al. Atypical neuroleptic malignant syndrome: diagnostic controversies and considerations. Pharmacotherapy 2008; 28:530–535. 15. Gurrera RJ, et al. An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. J Clin Psychiatry 2011; 72:1222–1228. 16. Gurrera RJ. A systematic review of sex and age factors in neuroleptic malignant syndrome diagnosis frequency. Acta Psychiatr Scand 2017; 135:398–408. 17. Su YP, et al. Retrospective chart review on exposure to psychotropic medications associated with neuroleptic malignant syndrome. Acta Psychiatr Scand 2014; 130:52–60. 18. Nielsen RE, et al. Neuroleptic malignant syndrome—an 11-­year longitudinal case-­control study. Can J Psychiatry 2012; 57:512–518. 19. Viejo LF, et al. Risk factors in neuroleptic malignant syndrome: a case–control study. Acta Psychiatr Scand 2003; 107:45–49. 20. Spivak B, et  al. Neuroleptic malignant syndrome during abrupt reduction of neuroleptic treatment. Acta Psychiatr Scand 1990; 81:168–169. 21. Spivak B, et al. Neuroleptic malignant syndrome associated with abrupt withdrawal of anticholinergic agents. Int Clin Psychopharmacol 1996; 11:207–209. 22. Olmsted TR. Neuroleptic malignant syndrome: guidelines for treatment and reinstitution of neuroleptics. South Med J 1988; 81:888–891. 23. Lattanzi L, et al. Subcutaneous apomorphine for neuroleptic malignant syndrome. Am J Psychiatry 2006; 163:1450–1451. 24. Kuhlwilm L, et al. The neuroleptic malignant syndrome—a systematic case series analysis focusing on therapy regimes and outcome. Acta Psychiatr Scand 2020; 142:233–241. 25. Pileggi DJ, et al. Neuroleptic malignant syndrome. Ann Pharmacother 2016; 50:973–981. 26. Schönfeldt-­Lecuona C, et al. Treatment of the neuroleptic malignant syndrome in international therapy guidelines: a comparative analysis. Pharmacopsychiatry 2020; 53:51–59. 27. Francis A, et al. Is lorazepam a treatment for neuroleptic malignant syndrome? CNS Spectr 2000; 5:54–57. 28. Morcos N, et al. Electroconvulsive therapy for neuroleptic malignant syndrome: a case series. J ECT 2019; 35:225–230. 29. Aki Ö E, et al. A severe neuroleptic malignant syndrome treated with daily electroconvulsive therapy: a case report. Turk Psikiyatri Derg 2022; 33:139–142. 30. Katzell L, et al. Rapid symptom control in neuroleptic malignant syndrome with electroconvulsive therapy: a case report. Front Psychiatry 2023; 14:1143407. 31. Shin HW, et al. Neuroleptic malignant syndrome induced by phenytoin in a patient with drug-­induced Parkinsonism. Neurol Sci 2014; 35:1641–1643. 32. Wells AJ, et al. Neuroleptic rechallenge after neuroleptic malignant syndrome: case report and literature review. 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. 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.91 152 - References References 158 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References Rogers JP, et al. Evidence-­based consensus guidelines for the management of catatonia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2023; 37:327–369. Solmi M, et al. Prevalence of catatonia and its moderators in clinical samples: results from a meta-­analysis and meta-­regression analysis. Schizophr Bull 2018; 44:1133–1150. Morrison JR. Catatonia. Retarded and excited types. Arch Gen Psychiatry 1973; 28:39–41. Walther S, et al. Structure and neural mechanisms of catatonia. Lancet Psychiatry 2019; 6:610–619. Mann SC, et al. Catatonia, malignant catatonia, and neuroleptic malignant syndrome. Current Psychiatry Reviews 2013; 9:111–119. Takacs R, et al. Catatonia in affective disorders. Current Psychiatry Reviews 2013; 9:101–105. Mangas MCC, et al. P-­167: catatonia in bipolar disorder. Eur Psychiatry 2012; 27 Suppl 1:1. Huang YC, et al. Rapid relief of catatonia in mood disorder by lorazepam and diazepam. Biomed J 2013; 36:35–39. Vasudev K, et al. What works for delirious catatonic mania? BMJ Case Rep 2010; 2010:bcr0220102713. Neuhut R, et al. Resolution of catatonia after treatment with stimulant medication in a patient with bipolar disorder. Psychosomatics 2012; 53:482–484. Ghaffarinejad AR, et al. Periodic catatonia: challenging diagnosis for psychiatrists. Neurosciences (Riyadh) 2012; 17:156–158. Oldham MA, et al. Alcohol and sedative-­hypnotic withdrawal catatonia: two case reports, systematic literature review, and suggestion of a potential relationship with alcohol withdrawal delirium. Psychosomatics 2016; 57:246–255. Banerjee D. Etizolam withdrawal catatonia: the first case report. Asian J Psychiatr 2018; 37:32–33. Fink M. Rediscovering catatonia: the biography of a treatable syndrome. Acta Psychiatr Scand Suppl 2013; (441):1–47. Bartolommei N, et al. Catatonia: a critical review and therapeutic recommendation. J Psychopathol 2012; 18:234–246. Lee J. Dissociative catatonia: dissociative-­catatonic reactions, clinical presentations and responses to benzodiazepines. Aust N Z J Psychiatry 2011; 45:A42. Suzuki K, et al. Hysteria presenting as a prodrome to catatonic stupor in a depressive patient resolved with electroconvulsive therapy. J ECT 2006; 22:276. Alwaki A, et al. Catatonia: an elusive diagnosis. Neurology 2013; 80 Suppl 1:P05.127. Dhadphale M. Eye gaze diagnostic sign in hysterical stupor. Lancet 1980; 2:374–375. Gomez J. Hysterical stupor and death. Br J Psychiatry 1980; 136:105–106. Petrides G, et al. Synergism of lorazepam and electroconvulsive therapy in the treatment of catatonia. Biol Psychiatry 1997; 42:375–381. Nahar A, et al. Catatonia among women with postpartum psychosis in a mother–baby inpatient psychiatry unit. Gen Hosp Psychiatry 2017; 45:40–43. Csihi L, et al. Catatonia during pregnancy and the postpartum period. Schizophr Res 2024; 263:257–264. 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. Schizophrenia and related psychoses CHAPTER 1 25. Biles TR, et al. Should catatonia be conceptualized as a pathological response to trauma? J Nerv Ment Dis 2021; 209:320–323. 26. Bonomo N, et al. Rapid resolution of catatonia secondary to post traumatic stress disorder with secondary psychotic features through scheduled zolpidem tartrate. BMC Psychiatry 2023; 23:258. 27. Mazzone L, et al. Catatonia in patients with autism: prevalence and management. CNS Drugs 2014; 28:205–215. 28. Dhossche DM, et al. Catatonia in psychiatric illnesses. In: Fatemi SH, Clayton PJ, eds. The Medical Basis of Psychiatry. Totowa, NJ: Humana Press; 2008:471–486. 29. Shetageri VN, et al. Case report: catatonia as a presenting symptom of Wilsons disease. Indian J Psychiatry 2011; 53 Suppl 5:S93–S94. 30. Cardinal RN, et al. Psychosis and catatonia as a first presentation of antiphospholipid syndrome. Br J Psychiatry 2009; 195:272. 31. Rogers JP, et al. Catatonia and the immune system: a review. Lancet Psychiatry 2019; 6:620–630. 32. Edinoff AN, et al. Catatonia: clinical overview of the diagnosis, treatment, and clinical challenges. Neurol Int 2021; 13:570–586. 33. Wadi L, et  al. Electroconvulsive therapy for catatonia in anti-­NMDA receptor encephalitis: a case series. J Neuroimmunol 2024; 386:578271. 34. Pustilnik S, et al. Catatonia as the presenting symptom in systemic lupus erythematosus. J Psychiatr Pract 2011; 17:217–221. 35. Sundaram TG, et al. Catatonia in systemic lupus erythematosus: case based review. Rheumatol Int 2022; 42:1461–1476. 36. Lander M, et al. Review of withdrawal catatonia: what does this reveal about clozapine? Transl Psychiatry 2018; 8:139. 37. Sienaert P, et al. Adult catatonia: etiopathogenesis, diagnosis and treatment. Neuropsychiatry 2013; 3:391–399. 38. Huang TL, et  al. Lorazepam reduces the serum brain-­derived neurotrophic factor level in schizophrenia patients with catatonia. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33:158–159. 39. Sienaert P, et al. A clinical review of the treatment of catatonia. Front Psychiatry 2014; 5:181. 40. Fink M, et  al. Neuroleptic malignant syndrome is malignant catatonia, warranting treatments efficacious for catatonia. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:1182–1183. 41. Lin CC, et al. The lorazepam and diazepam protocol for catatonia due to general medical condition and substance in liaison psychiatry. PLoS One 2017; 12:e0170452. 42. Javelot H, et al. Zolpidem test and catatonia. J Clin Pharm Ther 2015; 40:699–701. 43. Bastiampillai T, et al. Treatment refractory chronic catatonia responsive to zolpidem challenge. Aust N Z J Psychiatry 2016; 50:98. 44. Peglow S, et al. Treatment of catatonia with zolpidem. J Neuropsychiatry Clin Neurosci 2013; 25:E13. 45. Bush G, et al. Catatonia. II. Treatment with lorazepam and electroconvulsive therapy. Acta Psychiatr Scand 1996; 93:137–143. 46. Rosebush PI, et al. Catatonia: re-­awakening to a forgotten disorder. Mov Disord 1999; 14:395–397. 47. Ungvari GS, et al. Lorazepam for chronic catatonia: a randomized, double-­blind, placebo-­controlled cross-­over study. Psychopharmacology (Berl) 1999; 142:393–398. 48. Dutt A, et al. Phenomenology and treatment of catatonia: a descriptive study from north India. Indian J Psychiatry 2011; 53:36–40. 49. Zaman H, et al. Benzodiazepines for catatonia in people with schizophrenia or other serious mental illnesses. Cochrane Database Syst Rev 2019; 8:CD006570. 50. Luchini F, et al. Catatonia and neuroleptic malignant syndrome: two disorders on a same spectrum? Four case reports. J Nerv Ment Dis 2013; 201:36–42. 51. Mishima T, et al. [Diazepam-­responsive malignant catatonia in a patient with an initial clinical diagnosis of neuroleptic malignant syndrome: a case report]. Brain Nerve 2011; 63:503–507. 52. Rodriguez S, et al. Neuroleptic malignant syndrome or catatonia? A case report. J Crit Care Med (Targu Mures) 2020; 6:190–193. 53. Fink M. Expanding the catatonia tent: recognizing electroconvulsive therapy responsive syndromes. J ECT 2021; 37:77–79. 54. Taylor MA, et al. Catatonia in psychiatric classification: a home of its own. Am J Psychiatry 2003; 160:1233–1241. 55. Cristancho P, et al. Successful use of right unilateral ECT for catatonia: a case series. J ECT 2014; 30:69–72. 56. Philbin D, et al. Catatonic schizophrenia: therapeutic challenges and potentially a new role for electroconvulsive therapy? BMJ Case Rep 2013; 2013:bcr2013009153. 57. Takebayashi M. [Electroconvulsive therapy in schizophrenia]. Nihon Rinsho 2013; 71:694–700. 58. Oviedo G, et al. Trends in the administration of electroconvulsive therapy for schizophrenia in Colombia: descriptive study and literature review. Eur Arch Psychiatry Clin Neurosci 2013; 263 Suppl 1:S98. 59. Pompili M, et al. Indications for electroconvulsive treatment in schizophrenia: a systematic review. Schizophr Res 2013; 146:1–9. 60. Ogando Portilla N, et al. 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. 153 - ECG changes QT prolongation ECG changes – QT prolongation 154 - Introduction Introduction 155 - QT prolongation 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.12 156 - Other ECG changes Other ECG changes 157 - Quantifying risk 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.63 158 - Other risk factors 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.83,84 159 - ECG monitoring ECG monitoring 16 - Adverse effects 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.42 160 - Metabolic inhibition 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. 161 - Other cardiovascular risk factors Other cardiovascular risk factors 162 - Summary Summary 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 Sicouri S, et al. 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Prediction of torsade de pointes from the QT interval: analysis of a case series of amisulpride overdoses. Clin Pharmacol Ther 2011; 90:243–245. 27. O’Neal WT, et  al. Association between QT-­interval components and sudden cardiac death: the ARIC study (Atherosclerosis Risk in Communities). Circ Arrhythm Electrophysiol 2017; 10:e005485. 28. Witchel HJ, et al. Psychotropic drugs, cardiac arrhythmia, and sudden death. J Clin Psychopharmacol 2003; 23:58–77. 29. Melo L, et al. An updated safety review of the relationship between atypical antipsychotic drugs, the QTc interval and torsades de pointe As: implications for clinical use. Expert Opin Drug Saf 2024; 23:1127–1134. 30. Strom BL, et al. Comparative mortality associated with ziprasidone and olanzapine in real-­world use among 18,154 patients with schizophrenia: the ziprasidone observational study of cardiac outcomes (ZODIAC). Am J Psychiatry 2011; 168:193–201. 31. Chung AK, et al. Effects on prolongation of Bazett’s corrected QT interval of seven second-­generation antipsychotics in the treatment of schizophrenia: a meta-­analysis. J Psychopharmacol 2011; 25:646–666. 32. Vandael E, et al. Development of a risk score for QTc-­prolongation: the RISQ-­PATH study. Int J Clin Pharm 2017; 39:424–432. 33. CredibleMeds®. Tucson, AZ: CredibleMeds; 2024; https://www.crediblemeds.org. 34. Hui WK, et al. Melperone: electrophysiologic and antiarrhythmic activity in humans. J Cardiovasc Pharmacol 1990; 15:144–149. 35. Glassman AH, et  al. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001; 158:1774–1782. 36. Harrigan EP, et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol 2004; 24:62–69. 37. 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. 38. Dineen S, et al. QTc prolongation and high-­dose olanzapine [Letter]. Psychosomatics 2003; 44:174–175. 39. Gupta S, et al. Quetiapine and QTc issues: a case report [Letter]. J Clin Psychiatry 2003; 64:612–613. 40. Su KP, et al. A pilot cross-­over design study on QTc interval prolongation associated with sulpiride and haloperidol. Schizophr Res 2003; 59:93–94. 41. Stollberger C, et al. Antipsychotic drugs and QT prolongation. Int Clin Psychopharmacol 2005; 20:243–251. 42. Ward DI. Two cases of amisulpride overdose: a cause for prolonged QT syndrome. Emerg Med Australas 2005; 17:274–276. 43. Vieweg WV, et al. 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. 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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. 164 - Effects of antipsychotic medications on plasm Effects of antipsychotic medications on plasma lipids 165 - Effect of antipsychotic medications on lipids Effect of antipsychotic medications on lipids 166 - Olanzapine 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 167 - Clozapine Clozapine 168 - Screening and monitoring Screening and monitoring 169 - Clinical management of dyslipidaemia 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 17 - Recommendations Recommendations 170 - Summary of monitoring Summary of monitoring 171 - References 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). 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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. 172 - Diabetes and impaired glucose tolerance Diabetes and impaired glucose tolerance 173 - Schizophrenia Schizophrenia 174 - Antipsychotic medications Antipsychotic medications 175 - First generation antipsychotic medications First-generation antipsychotic medications 176 - Second generation antipsychotic medications 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 177 - Predicting antipsychotic related diabetes Predicting antipsychotic-related diabetes 178 - Monitoring 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). 179 - Treatment of antipsychotic related diabetes Treatment of antipsychotic-related diabetes 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. 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. 181 - References References 178 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References Schimmelbusch WH, et al. The positive correlation between insulin resistance and duration of hospitalization in untreated schizophrenia. Br J Psychiatry 1971; 118:429–436. Waitzkin L. A survey for unknown diabetics in a mental hospital. I. Men under age fifty. 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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. 182 - Blood pressure changes with antipsychotics Blood pressure changes with antipsychotics 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) 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) 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. 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) 187 - References 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. 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 189 - Contraindications Contraindications 19 - References References 20 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References Royal College of Psychiatrists. The Risks and Benefits of High-­Dose Antipsychotic Medication. College Report CR190. London: Royal College of Psychiatrists; 2014. 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. Roh D, et al. Antipsychotic polypharmacy and high-­dose prescription in schizophrenia: a 5-­year comparison. Aust N Z J Psychiatry 2014; 48:52–60. Campos Mendes J, et al. Patterns of antipsychotics’ prescription in Portuguese acute psychiatric wards: a cross-­sectional study. Psychiatry Res 2016; 246:142–148. Martinho S, et al. Antipsychotic polypharmacy and high-­dose antipsychotics in involuntary patients: a seven-­year audit of discharge prescriptions in an acute care unit. Psychiatr Q 2021; 92:1–14. Kaikoushi K, et al. Prescription patterns in psychiatric compulsory care: polypharmacy and high-­dose antipsychotics. BJPsych Open 2021; 7:e149. 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. Davis JM, et al. Dose response and dose equivalence of antipsychotics. J Clin Psychopharmacol 2004; 24:192–208. Gardner DM, et al. International consensus study of antipsychotic dosing. Am J Psychiatry 2010; 167:686–693. 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. 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. 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. 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. 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. 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. 190 - Management Management 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.38 192 - 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. 193 - Sexual dysfunction and antipsychotics Sexual dysfunction and antipsychotics 194 - The human sexual response The human sexual response 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. 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. 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. 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 Korchia T, et al. 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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. 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Women’s sexual dysfunction associated with psychiatric disorders and their treatment. Womens Health 2018; 14:1745506518762664. 199 - Pneumonia Pneumonia 20 - Combined antipsychotics (antipsychotic polyph Combined antipsychotics (antipsychotic polypharmacy) 200 - Background 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. 201 - Mechanisms Mechanisms 202 - Summary 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.20 203 - References References 206 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References Dzahini O, et al. Antipsychotic drug use and pneumonia: systematic review and meta-­analysis. J Psychopharmacol 2018; 32:1167–1181. Cepaityte D, et al. Exploring a safety signal of antipsychotic-­associated pneumonia: a pharmacovigilance–pharmacodynamic study. Schizophr Bull 2020; 47:672–681. Luykx JJ, et al. Pneumonia risk, antipsychotic dosing, and anticholinergic burden in schizophrenia. JAMA Psychiatry 2024; 81:967–975. Rohde C, et al. Antipsychotic medication exposure, clozapine, and pneumonia: results from a self-­controlled study. Acta Psychiatr Scand 2020; 142:78–86. Chan HY, et al. Is antipsychotic treatment associated with risk of pneumonia in people with serious mental illness? The roles of severity of psychiatric symptoms and global functioning. J Clin Psychopharmacol 2019; 39:434–440. Chen YH, et al. Poor clinical outcomes among pneumonia patients with schizophrenia. Schizophr Bull 2011; 37:1088–1094. Nose M, et  al. Antipsychotic drug exposure and risk of pneumonia: a systematic review and meta-­analysis of observational studies. Pharmacoepidemiol Drug Saf 2015; 24:812–820. Tolppanen AM, et al. Antipsychotic use and risk of hospitalization or death due to pneumonia in persons with and those without Alzheimer disease. Chest 2016; 150:1233–1241. Cepaityte D, et al. Exploring a safety signal of antipsychotic-­associated pneumonia: a pharmacovigilance-­pharmacodynamic study. Schizophr Bull 2021; 47:672–681. Chen YH, et al. Analysis of risk factors for hospital-­acquired pneumonia in schizophrenia. Front Psychiatry 2024; 15:1414332. Kuo CJ, et al. Second-­generation antipsychotic medications and risk of pneumonia in schizophrenia. Schizophr Bull 2013; 39:648–657. Yang SY, et al. Antipsychotic drugs, mood stabilizers, and risk of pneumonia in bipolar disorder: a nationwide case-­control study. J Clin Psychiatry 2013; 74:e79–e86. Trifiro G, et al. Association of community-­acquired pneumonia with antipsychotic drug use in elderly patients: a nested case-­control study. Ann Intern Med 2010; 152:418–440. Kang N, et al. Association between initial clozapine titration and pneumonia risk among patients with schizophrenia in a Korean tertiary hospital. Schizophr Res 2024; 268:107–113. Cheng SY, et al. Benzodiazepines and risk of pneumonia in schizophrenia: a nationwide case-­control study. Psychopharmacology (Berl) 2018; 235:3329–3338. 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. Schoretsanitis G, et  al. An update on the complex relationship between clozapine and pneumonia. Expert Rev Clin Pharmacol 2021; 14:145–149. Villasante-­Tezanos AG, et al. Pneumonia risk: approximately one-­third is due to clozapine and two-­thirds is due to treatment-­resistant schizophrenia. Acta Psychiatr Scand 2020; 142:66–67. Hung GC, et al. Antipsychotic reexposure and recurrent pneumonia in schizophrenia: a nested case-­control study. J Clin Psychiatry 2016; 77:60–66. Mace S, et al. Incident infection during the first year of treatment: a comparison of clozapine and paliperidone palmitate long-­acting injection. J Psychopharmacol 2022; 36:232–237. 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. 204 - Switching antipsychotics 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) 205 - References 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 Stanniland C, et al. Tolerability of atypical antipsychotics. Drug Saf 2000; 22:195–214. Tarsy D, et al. Effects of newer antipsychotics on extrapyramidal function. CNS Drugs 2002; 16:23–45. Caroff SN, et al. Movement disorders associated with atypical antipsychotic drugs. J Clin Psychiatry 2002; 63 Suppl 4:12–19. Lemmens P, et al. A combined analysis of double-­blind studies with risperidone vs. placebo and other antipsychotic agents: factors associated with extrapyramidal symptoms. Acta Psychiatr Scand 1999; 99:160–170. Taylor DM. Aripiprazole: a review of its pharmacology and clinical use. Int J Clin Pract 2003; 57:49–54. 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. Garnock-­Jones KP. Cariprazine: a review in schizophrenia. CNS Drugs 2017; 31:513–525. Garnock-­Jones KP. Brexpiprazole: a review in schizophrenia. CNS Drugs 2016; 30:335–342. Buckley PF. Efficacy of quetiapine for the treatment of schizophrenia: a combined analysis of three placebo-­controlled trials. Curr Med Res Opin 2004; 20:1357–1363. Pringsheim T, et al. The assessment and treatment of antipsychotic-­induced akathisia. Can J Psychiatry 2018; 63:719–729. Rettenbacher MA, et al. Early changes of plasma lipids during treatment with atypical antipsychotics. Int Clin Psychopharmacol 2006; 21:369–372. Ball MP, et al. Clozapine-­induced hyperlipidemia resolved after switch to aripiprazole therapy. Ann Pharmacother 2005; 39:1570–1572. Chrzanowski WK, et al. Effectiveness of long-­term aripiprazole therapy in patients with acutely relapsing or chronic, stable schizophrenia: a 52-­week, open-­label comparison with olanzapine. Psychopharmacology (Berl) 2006; 189:259–266. De Hert M, et al. A case series: evaluation of the metabolic safety of aripiprazole. Schizophr Bull 2007; 33:823–830. 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. Kemp DE, et al. Weight change and metabolic effects of asenapine in patients with schizophrenia and bipolar disorder. J Clin Psychiatry 2014; 75:238–245. Haddad PM. Antipsychotics and diabetes: review of non-­prospective data. Br J Psychiatry Suppl 2004; 47:S80–S86. Berry S, et al. Improvement of insulin indices after switch from olanzapine to risperidone. Eur Neuropsychopharmacol 2002; 12:316. Gianfrancesco FD, et al. Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. J Clin Psychiatry 2002; 63:920–930. 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. 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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. 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Lancet Psychiatry 2023; 10:860–876. 206 - Venous thromboembolism Venous thromboembolism 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. 208 - Mechanisms Mechanisms 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. 21 - Poor response to antipsychotic monotherapy Poor response to antipsychotic monotherapy 210 - Summary Summary 211 - Practice points Practice points 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. 213 - REFRACTORY SCHIZOPHRENIA AND CLOZaPINE REFRACTORY SCHIZOPHRENIA AND CLOZaPINE 214 - Clozapine initiation schedules Clozapine initiation schedules 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. 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 20 125 217 - 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. 218 - Intramuscular clozapine Intramuscular clozapine 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. 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 220 - Optimising clozapine treatment Optimising clozapine treatment 221 - Using clozapine alone Using clozapine alone 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. 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 Taylor D, et al. A prescription survey of the use of atypical antipsychotics for hospital inpatients in the United Kingdom. Int J Psychiatry Clin Pract 2000; 4:41–46. Murphy B, et al. Maintenance doses for clozapine. Psychiatr Bull 1998; 22:12–14. Taylor D. Pharmacokinetic interactions involving clozapine. Br J Psychiatry 1997; 171:109–112. Lane HY, et al. Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics. J Clin Psychiatry 1999; 60:36–40. 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. Taylor D, et al. The use of clozapine plasma levels in optimising therapy. Psychiatr Bull 1995; 19:753–755. 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. Perry PJ. Therapeutic drug monitoring of antipsychotics. Psychopharmacol Bull 2001; 35:19–29. Kronig MH, et al. Plasma clozapine levels and clinical response for treatment-­refractory schizophrenic patients. Am J Psychiatry 1995; 152:179–182. Polcwiartek C, et al. The clinical potentials of adjunctive fluvoxamine to clozapine treatment: a systematic review. Psychopharmacology (Berl) 2016; 233:741–750. Leising J, et  al. High-­dose fluvoxamine augmentation to clozapine in treatment-­resistant psychosis. J Clin Psychopharmacol 2021; 41:186–190. Watras M, et al. A therapeutic interaction between cimetidine and clozapine: case study and review of the literature. Ther Adv Psychopharmacol 2013; 3:294–297. Gee S, et al. Optimising treatment of schizophrenia: the role of adjunctive fluvoxamine. Psychopharmacology (Berl) 2016; 233:739–740. 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. Chakrabarti S. Clozapine resistant schizophrenia: newer avenues of management. World J Psychiatry 2021; 11:429–448. Etchecopar-­Etchart D, et  al. Comprehensive evaluation of 45 augmentation drugs for schizophrenia: a network meta-­analysis. EClinicalMedicine 2024; 69:102473. 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. Taylor D, et al. Augmentation of clozapine with a second antipsychotic: a meta analysis. Acta Psychiatr Scand 2012; 125:15–24. 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. Demjaha A, et al. Dopamine synthesis capacity in patients with treatment-­resistant schizophrenia. Am J Psychiatry 2012; 169:1203–1210. 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. 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) 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) 226 - References References 230 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References Millgate E, et  al. Neuropsychological differences between treatment-­resistant and treatment-­responsive schizophrenia: a meta-­analysis. Psychol Med 2022; 52:1–13. Yoshimura B, et al. The critical treatment window of clozapine in treatment-­resistant schizophrenia: secondary analysis of an observational study. Psychiatry Res 2017; 250:65–70. Shah P, et al. 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Phase 2 results indicate evenamide, a selective modulator of glutamate release, is associated with clinically important long-­ term efficacy when added to an antipsychotic in patients with treatment-­resistant schizophrenia. Int J Neuropsychopharmacol 2023; 26:523–528. Bugarski-­Kirola D, et al. Efficacy and safety of adjunctive bitopertin versus placebo in patients with suboptimally controlled symptoms of schizophrenia treated with antipsychotics: results from three phase 3, randomised, double-­blind, parallel-­group, placebo-­controlled, multicentre studies in the SearchLyte clinical trial programme. Lancet Psychiatry 2016; 3:1115–1128. Garay RP, et al. Potential serotonergic agents for the treatment of schizophrenia. Expert Opin Investig Drugs 2016; 25:159–170. de Bartolomeis A, et al. Update on novel antipsychotics and pharmacological strategies for treatment-­resistant schizophrenia. Expert Opin Pharmacother 2022; 23:2035–2052. Akhondzadeh S, et al. Beneficial antipsychotic effects of allopurinol as add-­on therapy for schizophrenia: a double blind, randomized and placebo controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29:253–259. Brunstein MG, et  al. A clinical trial of adjuvant allopurinol therapy for moderately refractory schizophrenia. J Clin Psychiatry 2005; 66:213–219. Buie LW, et  al. Allopurinol as adjuvant therapy in poorly responsive or treatment refractory schizophrenia. Ann Pharmacother 2006; 40:2200–2204. Dickerson FB, et al. A double-­blind trial of adjunctive allopurinol for schizophrenia. Schizophr Res 2009; 109:66–69. Kontaxakis VP, et al. Switching to amisulpride monotherapy for treatment-­resistant schizophrenia. Eur Psychiatry 2006; 21:214–217. Lochmann van Bennekom MWH, et al. Efficacy and tolerability of antipsychotic polypharmacy for schizophrenia spectrum disorders: a systematic review and meta-­analysis of individual patient data. Schizophr Res 2024; 272:1–11. Kane JM, et al. Aripiprazole for treatment-­resistant schizophrenia: results of a multicenter, randomized, double-­blind, comparison study versus perphenazine. J Clin Psychiatry 2007; 68:213–223. 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) Schizophrenia and related psychoses CHAPTER 1 20. Crossman AM, et  al. Tolerability of high-­dose aripiprazole in treatment-­refractory schizophrenic patients. J Clin Psychiatry 2006; 67:1158–1159. 21. Kishi T, et al. Asenapine add-­on treatment for schizophrenia adults who received antipsychotics: a 52-­week, open-­label study. Psychiatry Clin Neurosci 2023; 77:365–366. 22. Tachibana M, et al. Effectiveness of blonanserin for patients with drug treatment-­resistant schizophrenia and dopamine supersensitivity: a retrospective analysis. Asian J Psychiatr 2016; 24:28–32. 23. Tang S, et al. Efficacy of add-­on blonanserin in treatment-­resistant schizophrenia therapy: a retrospective cohort study. Asian J Psychiatr 2024; 91:103867. 24. Aubel T. Cariprazine: patients with treatment-­resistant schizophrenia. Neuropsychiatr Dis Treat 2021; 17:2327–2332. 25. Montgomery A, et al. Cariprazine: an alternative treatment for clozapine-­resistant schizophrenia? Clin Psychopharmacol Neurosci 2023; 21:202–206. 26. Boydstun C, et al. Cariprazine: an augmentation strategy for treatment-­resistant schizophrenia with pro-­cognitive and anti-­hostility effects. Int Clin Psychopharmacol 2023; 38:361–366. 27. Valmaggia LR, et al. Cognitive-­behavioural therapy for refractory psychotic symptoms of schizophrenia resistant to atypical antipsychotic medication: randomised controlled trial. Br J Psychiatry 2005; 186:324–330. 28. Polese D, et al. Treatment-­resistant to antipsychotics: a resistance to everything? Psychotherapy in treatment-­resistant schizophrenia and nonaffective psychosis: a 25-­year systematic review and exploratory meta-­analysis. Front Psychiatry 2019; 10:210. 29. Corripio I, et al. Deep brain stimulation in treatment resistant schizophrenia: a pilot randomized cross-­over clinical trial. EBioMedicine 2020; 51:102568. 30. Tsai GE, et al. D-­alanine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 2006; 59:230–234. 31. Heresco-­Levy U, et al. D-­serine efficacy as add-­on pharmacotherapy to risperidone and olanzapine for treatment-­refractory schizophrenia. Biol Psychiatry 2005; 57:577–585. 32. Ermilov M, et al. A pilot double-­blind comparison of d-­serine and high-­dose olanzapine in treatment-­resistant patients with schizophrenia. Schizophr Res 2013; 150:604–605. 33. 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. 34. Grover S, et al. Effectiveness of electroconvulsive therapy in patients with treatment resistant schizophrenia: a retrospective study. Psychiatry Res 2017; 249:349–353. 35. Chanpattana W, et al. Electroconvulsive therapy in treatment-­resistant schizophrenia: prediction of response and the nature of symptomatic improvement. J ECT 2010; 26:289–298. 36. Ravanic DB, et al. Long-­term efficacy of electroconvulsive therapy combined with different antipsychotic drugs in previously resistant schizophrenia. Psychiatr Danub 2009; 21:179–186. 37. 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 2024; 268:252–260. 38. Kulkarni J, et al. Estradiol for treatment-­resistant schizophrenia: a large-­scale randomized-­controlled trial in women of child-­bearing age. Mol Psychiatry 2015; 20:695–702. 39. 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. 40. Meskanen K, et al. A randomized clinical trial of histamine 2 receptor antagonism in treatment-­resistant schizophrenia. J Clin Psychopharmacol 2013; 33:472–478. 41. Chen X, et al. Efficacy and safety of extract of Ginkgo biloba as an adjunct therapy in chronic schizophrenia: a systematic review of randomized, double-­blind, placebo-­controlled studies with meta-­analysis. Psychiatry Res 2015; 228:121–127. 42. Meltzer H, et al. W162 lurasidone is an effective treatment for treatment resistant schizophrenia. Neuropsychopharmacology 2015; 40 Suppl 1:S546. 43. Meltzer HY, et al. Lurasidone improves psychopathology and cognition in treatment-­resistant schizophrenia. J Clin Psychopharmacol 2020; 40:240–249. 44. Lowe P, et al. When the drugs don’t work: treatment-­resistant schizophrenia, serotonin and serendipity. Ther Adv Psychopharmacol 2018; 8:63–70. 45. Lieberman JA, et  al. A randomized, placebo-­controlled study of memantine as adjunctive treatment in patients with schizophrenia. Neuropsychopharmacology 2009; 34:1322–1329. 46. 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. 47. Rezaei F, et al. Memantine add-­on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized, double-­blind, placebo-­controlled study. J Clin Psychopharmacol 2013; 33:336–342. 48. Levkovitz Y, et al. A double-­blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-­phase schizophrenia. J Clin Psychiatry 2010; 71:138–149. 49. Miyaoka T, et al. Minocycline as adjunctive therapy for schizophrenia: an open-­label study. Clin Neuropharmacol 2008; 31:287–292. 50. Kelly DL, et al. Adjunctive minocycline in clozapine-­treated schizophrenia patients with persistent symptoms. J Clin Psychopharmacol 2015; 35:374–381. 51. Chaudhry IB, et al. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-­blind placebo-­controlled clinical trial in patients on standard treatment. J Psychopharmacol 2012; 26:1185–1193. 52. Joffe G, et al. Add-­on mirtazapine enhances antipsychotic effect of first generation antipsychotics in schizophrenia: a double-­blind, randomized, placebo-­controlled trial. Schizophr Res 2009; 108:245–251. 232 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 53. Berk M, et al. Mirtazapine add-­on therapy in the treatment of schizophrenia with atypical antipsychotics: a double-­blind, randomised, placebo-­controlled clinical trial. Hum Psychopharmacol 2009; 24:233–238. 54. Delle CR, et al. Add-­on mirtazapine enhances effects on cognition in schizophrenic patients under stabilized treatment with clozapine. Exp Clin Psychopharmacol 2007; 15:563–568. 55. Sepehrmanesh Z, et al. Therapeutic effect of adjunctive N-­acetyl cysteine (NAC) on symptoms of chronic schizophrenia: a double-­blind, randomized clinical trial. Prog Neuropsychopharmacol Biol Psychiatry 2017; 82:289–296. 56. Bulut M, et al. Beneficial effects of N-­acetylcysteine in treatment resistant schizophrenia. World J Biol Psychiatry 2009; 10:626–628. 57. 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. 58. Breier A, et al. Comparative efficacy of olanzapine and haloperidol for patients with treatment-­resistant schizophrenia. Biol Psychiatry 1999; 45:403–411. 59. Conley RR, et al. Olanzapine compared with chlorpromazine in treatment-­resistant schizophrenia. Am J Psychiatry 1998; 155:914–920. 60. Sanders RD, et al. An open trial of olanzapine in patients with treatment-­refractory psychoses. J Clin Psychopharmacol 1999; 19:62–66. 61. Taylor D, et al. Olanzapine in practice: a prospective naturalistic study. Psychiatr Bull 1999; 23:178–180. 62. Bitter I, et al. Olanzapine versus clozapine in treatment-­resistant or treatment-­intolerant schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28:173–180. 63. Tollefson GD, et al. Double-­blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine. Biol Psychiatry 2001; 49:52–63. 64. Gannon L, et  al. High-­dose olanzapine in treatment-­resistant schizophrenia: a systematic review. Ther Adv Psychopharmacol 2023; 13:20451253231168788. 65. Bronson BD, et  al. Adverse effects of high-­dose olanzapine in treatment-­refractory schizophrenia. J Clin Psychopharmacol 2000; 20:382–384. 66. Kelly DL, et al. Adverse effects and laboratory parameters of high-­dose olanzapine vs. clozapine in treatment-­resistant schizophrenia. Ann Clin Psychiatry 2003; 15:181–186. 67. 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. 68. Heresco-­Levy U, et al. High-­dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry 2004; 55:165–171. 69. 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. 70. Zheng W, et al. Adjunctive ondansetron for schizophrenia: a systematic review and meta-­analysis of randomized controlled trials. J Psychiatr Res 2019; 113:27–33. 71. Martínez-­Andrés JA, et al. Switching from clozapine to paliperidone palmitate-­3-­monthly improved obesity, hyperglycemia and dyslipidemia lowering antipsychotic dose equivalents in a treatment-­resistant schizophrenia cohort. Int Clin Psychopharmacol 2020; 35:163–169. 72. 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. 73. Salimi S, et al. A placebo controlled study of the propentofylline added to risperidone in chronic schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:726–732. 74. Reznik I, et al. Long-­term efficacy and safety of quetiapine in treatment-­refractory schizophrenia: a case report. Int J Psychiatry Clin Pract 2000; 4:77–80. 75. De Nayer A, et al. Efficacy and tolerability of quetiapine in patients with schizophrenia switched from other antipsychotics. Int J Psychiatry Clin Pract 2003; 7:59–66. 76. Larmo I, et al. Efficacy and tolerability of quetiapine in patients with schizophrenia who switched from haloperidol, olanzapine or risperidone. Hum Psychopharmacol 2005; 20:573–581. 77. Boggs DL, et al. Quetiapine at high doses for the treatment of refractory schizophrenia. Schizophr Res 2008; 101:347–348. 78. Lindenmayer JP, et al. A randomized, double-­blind, parallel-­group, fixed-­dose, clinical trial of quetiapine at 600 versus 1200 mg/d for patients with treatment-­resistant schizophrenia or schizoaffective disorder. J Clin Psychopharmacol 2011; 31:160–168. 79. Usall J, et al. Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a 24-­week double-­blind, randomized, parallel, placebo-­controlled trial. Schizophr Bull 2016; 42:309–317. 80. Usall J, et al. Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a double-­blind, randomized, placebo-­ controlled trial. J Clin Psychiatry 2011; 72:1552–1557. 81. Weiser M, et al. Raloxifene plus antipsychotics versus placebo plus antipsychotics in severely ill decompensated postmenopausal women with schizophrenia or schizoaffective disorder: a randomized controlled trial. J Clin Psychiatry 2017; 78:e758–e765. 82. Kulkarni J, et al. Effect of adjunctive raloxifene therapy on severity of refractory schizophrenia in women: a randomized clinical trial. JAMA Psychiatry 2016; 73:947–954. 83. Farokhnia M, et al. A double-­blind, placebo controlled, randomized trial of riluzole as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia. Psychopharmacology (Berl) 2014; 231:533–542. 84. Breier AF, et al. 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. 227 - Restarting clozapine after a break in treatme 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. 228 - References 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. 229 - Initiation of clozapine in the community Initiation of clozapine in the community 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. 230 - Relative contraindications to community initi Relative contraindications to community initiation 231 - Essential criteria for suitability for commun Essential criteria for suitability for community initiation 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. 233 - Mandatory blood monitoring and registration Mandatory blood monitoring and registration 234 - Dosing 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. 235 - Adverse effects Adverse effects 236 - Recommended additional monitoring Recommended additional monitoring 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.) 238 - Serious cardiac adverse effects Serious cardiac adverse effects 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. 24 - The use of combined antipsychotic medications The use of combined antipsychotic medications in clinical practice 240 - CLOZAPINE ADVERSE EFFECTS CLOZAPINE ADVERSE EFFECTS 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) 242 - References References Schizophrenia and related psychoses CHAPTER 1 References 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. Warner JP, et al. Clozapine and urinary incontinence. Int Clin Psychopharmacol 1994; 9:207–209. Jeong SH, et  al. A 2-­year prospective follow-­up study of lower urinary tract symptoms in patients treated with clozapine. J Clin Psychopharmacol 2008; 28:618–624. 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. Tanzer T, et al. Treatment strategies for clozapine-­induced nocturnal enuresis and urinary incontinence: a systematic review. CNS Spectr 2023; 28:133–144. Schoretsanitis G, et  al. An update on the complex relationship between clozapine and pneumonia. Expert Rev Clin Pharmacol 2021; 14:145–149. Luykx JJ, et al. Pneumonia risk, antipsychotic dosing, and anticholinergic burden in schizophrenia. JAMA Psychiatry 2024; 81:967–975. 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. 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Epilepsy Behav 2019; 95:1–9. 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) 244 - References References Schizophrenia and related psychoses CHAPTER 1 References Thompson A, et al. Late onset neutropenia with clozapine. Can J Psychiatry 2004; 49:647–648. Bhanji NH, et al. Late-­onset agranulocytosis in a patient with schizophrenia after 17 months of clozapine treatment. J Clin Psychopharmacol 2003; 23:522–523. Sedky K, et al. Clozapine-­induced agranulocytosis after 11 years of treatment [Letter]. Am J Psychiatry 2005; 162:814. de Araujo CF, et  al. Delayed-­onset severe neutropenia associated with clozapine with successful rechallenge at lower dose. J Clin Psychopharmacol 2021; 41:77–79. Kang BJ, et al. Long-­term patient monitoring for clozapine-­induced agranulocytosis and neutropenia in Korea: when is it safe to discontinue CPMS? Hum Psychopharmacol 2006; 21:387–391. Panesar N, et al. Late onset neutropenia with clozapine. Aust N Z J Psychiatry 2011; 45:684. Tourian L, et  al. Late-­onset agranulocytosis in a patient treated with clozapine and lamotrigine. J Clin Psychopharmacol 2011; 31:665–667. Hawe R, et al. Response to clozapine-­induced microscopic colitis: a case report and review of the literature. J Clin Psychopharmacol 2008; 28:454–455. Shah V, et al. Clozapine-­induced ischaemic colitis. BMJ CaseRep 2013; 2013:bcr2012007933. Linsley KR, et al. Clozapine-­associated colitis: case report and review of the literature. J Clin Psychopharmacol 2012; 32:564–566. Baptista T. A fatal case of ischemic colitis during clozapine administration. Rev Bras Psiquiatr 2014; 36:358. Rodriguez-­Sosa JT, et al. 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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. 245 - Clozapine serious haematological adverse effe Clozapine: serious haematological adverse effects 246 - Agranulocytosis Agranulocytosis 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. 248 - References References 252 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References 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. 249 - Clozapine serious cardiovascular adverse effe Clozapine: serious cardiovascular adverse effects 25 - Conclusion Conclusion 250 - Thromboembolism Thromboembolism 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 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. 253 - References References 256 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References Paciullo CA. Evaluating the association between clozapine and venous thromboembolism. Am J Health Syst Pharm 2008; 65:1825–1829. Walker AM, et al. Mortality in current and former users of clozapine. Epidemiology 1997; 8:671–677. Hagg S, et al. Association of venous thromboembolism and clozapine. Lancet 2000; 355:1155–1156. Davis S, et al. Antiphospholipid antibodies associated with clozapine treatment. Am J Hematol 1994; 46:166–167. Axelsson S, et al. In vitro effects of antipsychotics on human platelet adhesion and aggregation and plasma coagulation. Clin Exp Pharmacol Physiol 2007; 34:775–780. 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. Allenet B, et al. Antipsychotic drugs and risk of pulmonary embolism. Pharmacoepidemiol Drug Saf 2012; 21:42–48. Huang J, et al. Association between antipsychotics and pulmonary embolism: a pharmacovigilance analysis. Expert Opin Drug Saf 2024; doi: 10.1080/14740338.2024.2396390. Dai L, et al. The association and influencing factors between antipsychotics exposure and the risk of VTE and PE: a systematic review and meta-­analysis. Curr Drug Targets 2020; 21:930–942. Lacut K. Association between antipsychotic drugs, antidepressant drugs, and venous thromboembolism. Clin Adv Hematol Oncol 2008; 6:887–890. Masopust J, et  al. Risk of venous thromboembolism during treatment with antipsychotic agents. Psychiatry Clin Neurosci 2012; 66:541–552. Jonsson AK, et al. Venous thromboembolism in recipients of antipsychotics: incidence, mechanisms and management. CNS Drugs 2012; 26:649–662. Maly R, et al. Assessment of risk of venous thromboembolism and its possible prevention in psychiatric patients. Psychiatry Clin Neurosci 2008; 62:3–8. Ronaldson KJ. Cardiovascular disease in clozapine-­treated patients: evidence, mechanisms and management. CNS Drugs 2017; 31:777–795. Khan AA, et  al. Clozapine and incidence of myocarditis and sudden death: long term Australian experience. Int J Cardiol 2017; 238:136–139. Youssef DL, et al. Incidence and risk factors for clozapine-­induced myocarditis and cardiomyopathy at a regional mental health service in Australia. Australas Psychiatry 2016; 24:176–180. Tirupati S, et al. High rates of myocarditis with clozapine in the Hunter region of Australia. Schizophr Res 2024; 264:543–548. Cohen D, et  al. Beyond white blood cell monitoring: screening in the initial phase of clozapine therapy. J Clin Psychiatry 2012; 73:1307–1312. Kilian JG, et al. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999; 354:1841–1845. Freudenreich O. Clozapine-­induced myocarditis: prescribe safely but do prescribe. Acta Psychiatr Scand 2015; 132:240–241. Ronaldson KJ, et al. Clozapine-­induced myocarditis, a widely overlooked adverse reaction. Acta Psychiatr Scand 2015; 132:231–240. Qubad M, et al. When, why and how to re-­challenge clozapine in schizophrenia following myocarditis. CNS Drugs 2024; 38:671–696. Siskind D, et al. Systematic review and meta-­analysis of rates of clozapine-­associated myocarditis and cardiomyopathy. Aust N Z J Psychiatry 2020; 54:467–481. La Grenade L, et al. Myocarditis and cardiomyopathy associated with clozapine use in the United States [Letter]. N Engl J Med 2001; 345:224–225. Marder SR, et al. Physical health monitoring of patients with schizophrenia. Am J Psychiatry 2004; 161:1334–1349. Annamraju S, et al. Early recognition of clozapine-­induced myocarditis. J Clin Psychopharmacol 2007; 27:479–483. Wehmeier PM, et al. Chart review for potential features of myocarditis, pericarditis, and cardiomyopathy in children and adolescents treated with clozapine. J Child Adolesc Psychopharmacol 2004; 14:267–271. McNeil JJ, et al. Clozapine-­induced myocarditis: characterisation using case-­control design. Eur Heart J 2013; 34 Suppl 1:688. Richardson N, et al. Clozapine-­induced myocarditis and patient outcomes after drug rechallenge following myocarditis: a systematic case review. Psychiatry Res 2021; 305:114247. Reinders J, et al. Clozapine-­related myocarditis and cardiomyopathy in an Australian metropolitan psychiatric service. Aust N Z J Psychiatry 2004; 38:915–922. Manu P, et al. Clozapine rechallenge after major adverse effects: clinical guidelines based on 259 cases. Am J Ther 2018; 25:e218–e223. Bellissima BL, et al. A systematic review of clozapine-­induced myocarditis. Int J Cardiol 2018; 259:122–129. Nguyen B, et al. Successful clozapine re-­challenge following myocarditis. Australas Psychiatry 2017; 25:385–386. Otsuka Y, et al. Clozapine-­induced myocarditis: follow-­up for 3.5 years after successful retrial. J Gen Fam Med 2019; 20:114–117. Noël MC, et  al. Clozapine-­related myocarditis and rechallenge: a case series and clinical review. J Clin Psychopharmacol 2019; 39:380–385. Hosseini SA, et al. Successful clozapine re-­challenge after suspected clozapine-­induced myocarditis. Am J Case Rep 2020; 21:e926507. Rostagno C, et al. Beta-­blocker and angiotensin-­converting enzyme inhibitor may limit certain cardiac adverse effects of clozapine. Gen Hosp Psychiatry 2008; 30:280–283. 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. 254 - Clozapine induced hypersalivation 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) 255 - References 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. 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 257 - Prevention and simple management of CIGH Prevention and simple management of CIGH 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.8,40 259 - Clozapine rechallenge following severe consti Clozapine rechallenge following severe constipation 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. 260 - Key message Key message 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. 262 - Clozapine, neutropenia and lithium Clozapine, neutropenia and lithium 263 - Mild neutropenia Mild neutropenia 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). 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.22,23 266 - Concurrent medications Concurrent medications 267 - Management options Management options 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).36 269 - 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. 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 Harrington M, et al. 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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. 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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. 270 - References 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. 271 - Clozapine and chemotherapy Clozapine and chemotherapy 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. 273 - References 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. 274 - Genetic testing for clozapine treatment Genetic testing for clozapine treatment 275 - Response Response 276 - Agranulocytosis 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. 277 - Benign ethnic neutropenia Benign ethnic neutropenia 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. 279 - Other adverse effects Other adverse effects 28 - Antipsychotic prophylaxis Antipsychotic prophylaxis 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. 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 30 - Multi episode schizophrenia Multi-episode schizophrenia 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. 32 - Adherence to antipsychotic treatment Adherence to antipsychotic treatment 33 - Dose for prophylaxis Dose for prophylaxis 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 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. 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. 37 - Negative symptoms Negative symptoms 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 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. 40 - References References Schizophrenia and related psychoses CHAPTER 1 References Messinger JW, et al. Avolition and expressive deficits capture negative symptom phenomenology: implications for DSM-­5 and schizophrenia research. Clin Psychol Rev 2011; 31:161–168. Foussias G, et al. Dissecting negative symptoms in schizophrenia: opportunities for translation into new treatments. J Psychopharmacol 2015; 29:116–126. Strauss GP, et al. Reconsidering the latent structure of negative symptoms in schizophrenia: a review of evidence supporting the 5 consensus domains. Schizophr Bull 2019; 45:725–729. Rucci P, et al. 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Schizophr Bull 2015; 41:892–899. Németh G, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-­blind, controlled trial. Lancet 2017; 389:1103–1113. Ivanov SV, et al. Early clinical effects of novel partial D3/D2 agonist cariprazine in schizophrenia patients with predominantly negative symptoms (open-­label, non-­controlled study). Front Psychiatry 2021; 12:770592. Németh G, et al. Addressing negative symptoms of schizophrenia pharmacologically with cariprazine: evidence from clinical trials, a real-­ world study, and clinical cases. Expert Opin Pharmacother 2022; 23:1467–1468. Speller JC, et al. One-­year, low-­dose neuroleptic study of in-­patients with chronic schizophrenia characterised by persistent negative symptoms: amisulpride v. haloperidol. Br J Psychiatry 1997; 171:564–568. Krause M, et al. Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-­analysis. Eur Arch Psychiatry Clin Neurosci 2018; 268:625–639. Danion JM, et al. Improvement of schizophrenic patients with primary negative symptoms treated with amisulpride. Amisulpride Study Group. Am J Psychiatry 1999; 156:610–616. Leucht S, et al. Amisulpride, an unusual ‘atypical’ antipsychotic: a meta-­analysis of randomized controlled trials. Am J Psychiatry 2002; 159:180–190. Liang Y, et al. Effectiveness of amisulpride in Chinese patients with predominantly negative symptoms of schizophrenia: a subanalysis of the ESCAPE study. Neuropsychiatr Dis Treat 2017; 13:1703–1712. 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. 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. 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. 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. 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) 44 - Treatment algorithms for schizophrenia Treatment algorithms for schizophrenia 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 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)* 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 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. 49 - First generation antipsychotics place in the First-generation antipsychotics – place in therapy 50 - Nomenclature Nomenclature 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 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. 53 - NICE guidelines for the treatment of schizoph NICE guidelines for the treatment of schizophrenia1 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 55 - References 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. 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? 57 - Optimal dosage Optimal dosage 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 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), 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 61 - Summary 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 62 - References 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. 63 - Acutely disturbed or violent behaviour Acutely disturbed or violent behaviour 64 - Oralinhaled treatment Oral/inhaled treatment 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 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. 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 68 - References References Schizophrenia and related psychoses CHAPTER 1 References 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. Bak M, et al. The pharmacological management of agitated and aggressive behaviour: a systematic review and meta-­analysis. Eur Psychiatry 2019; 57:78–100. deSouza IS, et al. Rapid tranquilization of the agitated patient in the emergency department: a systematic review and network meta-­analysis. Am J Emerg Med 2022; 51:363–373. Currier GW, et al. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. J Clin Psychiatry 2004; 65:386–394. Ganesan S, et al. Effectiveness of quetiapine for the management of aggressive psychosis in the emergency psychiatric setting: a naturalistic uncontrolled trial. Int J Psychiatry Clin Pract 2005; 9:199–203. Simpson JR, Jr., et al. Impact of orally disintegrating olanzapine on use of intramuscular antipsychotics, seclusion, and restraint in an acute inpatient psychiatric setting. J Clin Psychopharmacol 2006; 26:333–335. Hsu WY, et al. Comparison of intramuscular olanzapine, orally disintegrating olanzapine tablets, oral risperidone solution, and intramuscular haloperidol in the management of acute agitation in an acute care psychiatric ward in Taiwan. J Clin Psychopharmacol 2010; 30:230–234. Pratts M, et al. A single-­dose, randomized, double-­blind, placebo-­controlled trial of sublingual asenapine for acute agitation. Acta Psychiatr Scand 2014; 130:61–68. 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. Kwentus J, et al. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-­controlled clinical trial with inhaled loxapine. Bipolar Disord 2012; 14:31–40. Allen MH, et al. Efficacy and safety of loxapine for inhalation in the treatment of agitation in patients with schizophrenia: a randomized, double-­blind, placebo-­controlled trial. J Clin Psychiatry 2011; 72:1313–1321. 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. Comparison of intramuscular ziprasidone, olanzapine, or aripiprazole for agitation: a quantitative review of efficacy and safety. J Clin Psychiatry 2007; 68:1876–1885. Paris G, et al. Short-­acting intramuscular second-­generation antipsychotic drugs for acutely agitated patients with schizophrenia spectrum disorders: a systematic review and network meta-­analysis. Schizophr Res 2021; 229:3–11. Perrin E, et al. A prospective, observational study of the safety and effectiveness of intramuscular psychotropic treatment in acutely agitated patients with schizophrenia and bipolar mania. Eur Psychiatry 2012; 27:234–239. Ferraz Goncalves JA, et al. Comparison of haloperidol alone and in combination with midazolam for the treatment of acute agitation in an inpatient palliative care service. J Pain Palliat Care Pharmacother 2016; 30:284–288. Chan EW, et al. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-­blind, placebo-­controlled clinical trial. Ann Emerg Med 2013; 61:72–81. 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. Raveendran NS, et al. Rapid tranquillisation in psychiatric emergency settings in India: pragmatic randomised controlled trial of intramuscular olanzapine versus intramuscular haloperidol plus promethazine. BMJ 2007; 335:865. Huf G, et al. Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomised controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promethazine. BMJ 2007; 335:869. Alexander J, et al. Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting. Pragmatic randomised trial of intramuscular lorazepam v. haloperidol plus promethazine. Br J Psychiatry 2004; 185:63–69. Dib JE, et al. Rapid tranquillisation in a psychiatric emergency hospital in Lebanon: TREC-­Lebanon: a pragmatic randomised controlled trial of intramuscular haloperidol and promethazine v. intramuscular haloperidol, promethazine and chlorpromazine. Psychol Med 2022; 52:2751–2759. Taylor DM, et al. Midazolam–droperidol, droperidol, or olanzapine for acute agitation: a randomized clinical trial. Ann Emerg Med 2017; 69:318-­326.e1. Kittipeerachon M, et al. Intramuscular olanzapine versus intramuscular aripiprazole for the treatment of agitation in patients with schizophrenia: a pragmatic double-­blind randomized trial. Schizophr Res 2016; 176:231–238. Klein LR, et al. Intramuscular midazolam, olanzapine, ziprasidone, or haloperidol for treating acute agitation in the emergency department. Ann Emerg Med 2018; 72:374–385. Huang CL, et al. Intramuscular olanzapine versus intramuscular haloperidol plus lorazepam for the treatment of acute schizophrenia with agitation: an open-­label, randomized controlled trial. J Formos Med Assoc 2015; 114:438–445. Calver L, et al. The safety and effectiveness of droperidol for sedation of acute behavioral disturbance in the emergency department. Ann Emerg Med 2015; 66:230-­238.e1. Thiemann P, et al. Prospective study of haloperidol plus lorazepam versus droperidol plus midazolam for the treatment of acute agitation in the emergency department. Am J Emerg Med 2022; 55:76–81. Powney MJ, et al. Haloperidol for psychosis-­induced aggression or agitation (rapid tranquillisation). Cochrane Database Syst Rev 2012; 11:CD009377. Ostinelli EG, et al. Haloperidol for psychosis-­induced aggression or agitation (rapid tranquillisation). Cochrane Database Syst Rev 2017; 7:CD009377. 72 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 31. National Institute for Health and Care Excellence. Violence and aggression: short-­term management in mental health, health and community settings. NICE guideline [NG10]. 2015 (reviewed May 2023, last checked December 2024); https://www.nice.org.uk/guidance/NG10. 32. Huf G, et al. Haloperidol plus promethazine for psychosis-­induced aggression. Cochrane Database Syst Rev 2016; 11:CD005146. 33. Kishi T, et  al. Intramuscular olanzapine for agitated patients: a systematic review and meta-­analysis of randomized controlled trials. J Psychiatr Res 2015; 68:198–209. 34. Khokhar MA, et al. Droperidol for psychosis-­induced aggression or agitation. Cochrane Database Syst Rev 2016; 12:CD002830. 35. Satterthwaite TD, et al. A meta-­analysis of the risk of acute extrapyramidal symptoms with intramuscular antipsychotics for the treatment of agitation. J Clin Psychiatry 2008; 69:1869–1879. 36. van Harten PN, et al. Acute dystonia induced by drug treatment. BMJ 1999; 319:623–626. 37. Pharmacovigilance Working Party. Public Assessment Report on Neuroleptics and Cardiac safety, in particular QT prolongation, cardiac arrhythmias, ventricular tachycardia and torsades de pointes. 2006. 38. Essential Pharma Ltd (Malta). Summary of Product Characteristics. HALDOL Decanoate (haloperidol decanoate) 100 mg/ml solution for injection. 2023 (last checked December 2024); https://www.medicines.org.uk/emc/product/15246/smpc. 39. Miceli JJ, et al. Effects of high-­dose ziprasidone and haloperidol on the QTc interval after intramuscular administration: a randomized, single-­ blind, parallel-­group study in patients with schizophrenia or schizoaffective disorder. Clin Ther 2010; 32:472–491. 40. Suzuki A, et al. Histamine H1-­receptor antagonists, promethazine and homochlorcyclizine, increase the steady-­state plasma concentrations of haloperidol and reduced haloperidol. Ther Drug Monit 2003; 25:192–196. 41. Lerner Y, et al. Acute high-­dose parenteral haloperidol treatment of psychosis. Am J Psychiatry 1979; 136:1061–­1064. 42. Martel ML, et al. A large retrospective cohort of patients receiving intravenous olanzapine in the emergency department. Acad Emerg Med 2016; 23:29–35. 43. Cole JB, et al. A prospective observational study of patients receiving intravenous and intramuscular olanzapine in the emergency department. Ann Emerg Med 2017; 69:327–­336.e2. 44. Calver L, et al. A prospective study of high dose sedation for rapid tranquilisation of acute behavioural disturbance in an acute mental health unit. BMC Psychiatry 2013; 13:225. 45. Mantovani C, et al. Are low doses of antipsychotics effective in the management of psychomotor agitation? A randomized, rated-­blind trial of 4 intramuscular interventions. J Clin Psychopharmacol 2013; 33:306–312. 46. Taylor D, et al. Buccal midazolam for rapid tranquillisation. Int J Psychiatry Clin Pract 2008; 12:309–311. 47. Spain D, et al. Safety and effectiveness of high-­dose midazolam for severe behavioural disturbance in an emergency department with suspected psychostimulant-­affected patients. Emerg Med Australas 2008; 20:112–120. 48. Chan EW, et al. Intramuscular midazolam, olanzapine, or haloperidol for the management of acute agitation: a multi-­centre, double-­blind, randomised clinical trial. EClinicalMedicine 2021; 32:100751. 49. Zaman H, et al. Benzodiazepines for psychosis-­induced aggression or agitation. Cochrane Database Syst Rev 2017; 12:CD003079. 50. Li SF, et al. Safety and efficacy of intravenous combination sedatives in the ED. Am J Emerg Med 2013; 31:1402–1404. 51. MacNeal JJ, et al. Use of haloperidol in PCP-­intoxicated individuals. Clin Toxicol (Phila) 2012; 50:851–853. 52. Mankowitz SL, et al. Ketamine for rapid sedation of agitated patients in the prehospital and emergency department settings: a systematic review and proportional meta-­analysis. J Emerg Med 2018; 55:670–681. 53. Kim HK, et al. Safety and efficacy of pharmacologic agents used for rapid tranquilization of emergency department patients with acute agitation or excited delirium. Expert Opin Drug Saf 2021; 20:123–138. 54. Pierre JM. Time to retire haloperidol? For emergency agitation, evidence suggests newer alternatives may be a better choice. Current Psychiatry 2020; 19:18–28. 55. Huf G, et al. Physical restraints versus seclusion room for management of people with acute aggression or agitation due to psychotic illness (TREC-­SAVE): a randomized trial. Psychol Med 2012; 42:2265–2273. 56. Amdisen A, et al. Serum concentrations and clinical effect of zuclopenthixol in acutely disturbed, psychotic patients treated with zuclopenthixol acetate in Viscoleo. Psychopharmacology (Berl) 1986; 90:412–416. 57. Amdisen A, et al. Zuclopenthixol acetate in viscoleo: a new drug formulation. An open Nordic multicentre study of zuclopenthixol acetate in Viscoleo in patients with acute psychoses including mania and exacerbation of chronic psychoses. Acta Psychiatr Scand 1987; 75:99–107. 58. Lowert AC, et al. Acute psychotic disorders treated with 5% zuclopenthixol acetate in ‘Viscoleo’ (‘Cisordinol-­Acutard’), a global assessment of the clinical effect: an open multi-­centre study. Pharmatherapeutica 1989; 5:380–386. 59. Balant LP, et al. Clinical and pharmacokinetic evaluation of zuclopenthixol acetate in Viscoleo. Pharmacopsychiatry 1989; 22:250–254. 60. Chakravarti SK, et al. Zuclopenthixol acetate (5% in ‘Viscoleo’): single-­dose treatment for acutely disturbed psychotic patients. Curr Med Res Opin 1990; 12:58–65. 61. Baastrup PC, et al. A controlled Nordic multicentre study of zuclopenthixol acetate in oil solution, haloperidol and zuclopenthixol in the treatment of acute psychosis. Acta Psychiatr Scand 1993; 87:48–58. 62. Chin CN, et al. A double blind comparison of zuclopenthixol acetate with haloperidol in the management of acutely disturbed schizophrenics. Med J Malaysia 1998; 53:365–371. 63. Taymeeyapradit U, et al. Comparative study of the effectiveness of zuclopenthixol acetate and haloperidol in acutely disturbed psychotic patients. J Med Assoc Thai 2002; 85:1301–1308. 64. Brook S, et al. A randomized controlled double blind study of zuclopenthixol acetate compared to haloperidol in acute psychosis. Hum Psychopharmacol 1998; 13:17–20. 65. Chouinard G, et al. A double-­blind controlled study of intramuscular zuclopenthixol acetate and liquid oral haloperidol in the treatment of schizophrenic patients with acute exacerbation. J Clin Psychopharmacol 1994; 14:377–384. 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. 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 70 - Advice on prescribing LAIs 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 71 - Differences between LAIs 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. 72 - References References Schizophrenia and related psychoses CHAPTER 1 References 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. Kirson NY, et al. Efficacy and effectiveness of depot versus oral antipsychotics in schizophrenia: synthesizing results across different research designs. J Clin Psychiatry 2013; 74:568–575. Marcus SC, et al. Antipsychotic adherence and rehospitalization in schizophrenia patients receiving oral versus long-­acting injectable anti­ psychotics following hospital discharge. J Manag Care Spec Pharm 2015; 21:754–768. Nielsen RE, et al. Second-­generation LAI are associated to favorable outcome in a cohort of incident patients diagnosed with schizophrenia. Schizophr Res 2018; 202:234–240. Kishimoto T, et al. Effectiveness of long-­acting injectable vs oral antipsychotics in patients with schizophrenia: a meta-­analysis of prospective and retrospective cohort studies. Schizophr Bull 2018; 44:603–619. Ceraso A, et al. Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev 2020; 8:CD008016. 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. Wang D, et al. Long-­acting injectable second-­generation antipsychotics vs placebo and their oral formulations in acute schizophrenia: a systematic review and meta-­analysis of randomized-­controlled-­trials. Schizophr Bull 2024; 50:132–144. 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. 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. Kane JM, et  al. Optimizing treatment choices to improve adherence and outcomes in schizophrenia. J Clin Psychiatry 2019; 80:IN18031AH18031C. Kishimoto T, et al. Long-­acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-­analysis of randomised, cohort, and pre-­post studies. Lancet Psychiatry 2021; 8:387–404. 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. 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. 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. 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. 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. 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. 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. Kane JM, et al. Treatment journey from diagnosis to the successful implementation of a long-­acting injectable antipsychotic agent in young adults with schizophrenia. J Clin Psychiatry 2023; 84:22m14544. Correll CU, et al. Pharmacokinetic characteristics of long-­acting injectable antipsychotics for schizophrenia: an overview. CNS Drugs 2021; 35:39–59. 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. 73 - Depot antipsychotics summary of pharmacokine 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. 74 - References 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. Balant-­Gorgia AE, et al. Antipsychotic drugs: clinical pharmacokinetics of potential candidates for plasma concentration monitoring. Clin Pharmacokinet 1987; 13:65–90. Gitlin MJ, et al. Persistence of fluphenazine in plasma after decanoate withdrawal. J Clin Psychopharmacol 1988; 8:53–56. Heres S, et al. Pharmacokinetics of olanzapine long-­acting injection: the clinical perspective. Int Clin Psychopharmacol 2014; 29:299–312. 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. Janssen Pharmaceuticals Inc. Highlights of Prescribing Information. INVEGA TRINZA® (paliperidone palmitate) extended-­release injectable suspension for intramuscular use. 2024 (last checked November 2024); https://www.janssenlabels.com/package-­insert/product-­monograph/ prescribing-­information/INVEGA+TRINZA-­pi.pdf. Janssen Pharmaceuticals Ltd. Highlights of Prescribing Information: INVEGA HAFYERA™ (paliperidone palmitate) extended-­release injectable suspension, for gluteal intramuscular use. 2021 (last checked November 2024); https://www.accessdata.fda.gov/drugsatfda_docs/ label/2021/207946s010lbl.pdf. Barnes TR, et al. Long-­term depot antipsychotics. A risk-­benefit assessment. Drug Saf 1994; 10:464–479. Ogden DA, et al. Determination of pipothiazine in human plasma by reversed-­phase high-­performance liquid chromatography. J Pharm Biomed Anal 1989; 7:1273–1280. US Center for Drug Evaluation and Research. Clinical Pharmacology and Biopharmaceutics Review(s). PERSERIS (Risperidone, RBP-­7000, Risperidone ATRIGEL). 2018 (last checked February 2025); https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210655Orig1s000Cl inPharmR.pdf. Shandong Luye Pharmaceutical Co Ltd. Highlights of Prescribing Information. RYKINDO® (risperidone) for extended-­release injectable suspension for intramuscular use. 2023 (last checked November 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/ 212849s000lbl.pdf. 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. Laboratorios Farmacéuticos Rovi S A Madrid Spain. Highlights of Prescribing Information. RISVAN® (risperidone) for extended-­release injectable suspension for intramuscular use. 2024 (last checked November 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2024/214835s000lbl.pdf. Laveille C, et al. Development of a population pharmacokinetic model for the novel long-­acting injectable antipsychotic risperidone ISM®. Br J Clin Pharmacol 2024; 90:2256–2270. Teva Neuroscience Inc. Highlights of Prescribing Information. UZEDY (risperidone) extended-­release injectable suspension for subcutaneous use. 2023 (last checked November 2024); https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/213586s000lbl.pdf. Viala A, et al. Comparative study of the pharmacokinetics of zuclopenthixol decanoate and fluphenazine decanoate. Psychopharmacology (Berl) 1988; 94:293–297. Soni SD, et al. Plasma levels of fluphenazine decanoate. Effects of site of injection, massage and muscle activity. Br J Psychiatry 1988; 153:382–384. 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. 76 - References 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. 77 - Aripiprazole long acting injection Aripiprazole long-acting injection 78 - Aripiprazole 1 monthly Aripiprazole 1-monthly 79 - One injection start One-injection start 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. 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 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. 83 - References 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. 84 - Olanzapine long acting injection Olanzapine long-acting injection 85 - Switching Switching 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 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 88 - References 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. 89 - Paliperidone palmitate long acting injection Paliperidone palmitate long-acting injection 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) 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) 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 93 - References 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. 94 - Risperidone long acting injection Risperidone long-acting injection 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. 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. 97 - References 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. 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