15 - Chapter 10 Drug treatment of psychiatric symptoms

01 - Prescribing in human immunodeficiency virus (

Prescribing in human immunodeficiency virus (HIV)

The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd. Chapter 10 Prescribing in human immunodeficiency virus (HIV) People living with human immunodeficiency virus (PLWH) may experience symptoms of mental illness because of a variety of factors (Box 10.1). In practice, several of these factors may coexist within an individual.1 When prescribing psychotropics, the following principles should be adhered to: ■ ■Start with a low dose and titrate according to tolerability and response. ■ ■Select the simplest dosing regimen possible. (Remember that the patient’s drug ­regimen is likely to be complex already.) ■ ■Select an agent with the fewest adverse effects. Consider drug interactions, medical comorbidities and any ongoing substance misuse. ■ ■Ensure that management is conducted in close co-­operation with the HIV specialists and the rest of the multidisciplinary team. Drug treatment of psychiatric symptoms occurring in the context of other conditions Box 10.1  Factors contributing to the development of psychiatric symptoms in people living with HIV ■ ■Primary (or pre-­existing) psychiatric disorders ■ ■Neurobiological changes caused by HIV in the CNS ■ ■Other infections or CNS tumours ■ ■Antiretroviral drugs and other medical treatments ■ ■Alcohol or substance misuse (particularly crystal methamfetamine and GHB/GBL) ■ ■Adverse psychosocial factors (e.g. stigma, social isolation) ■ ■Awareness of a chronic disease requiring strict adherence to medication CNS, central nervous system; GHB/GBL, gamma hydroxybutyrate/gamma butyrolactone.

02 - HIV treatment advances and mental health

HIV treatment advances and mental health

03 - Psychotic illness

Psychotic illness

04 - Depression

Depression

804 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Although most psychotropic agents are thought to be safe in PLWH, definitive data are lacking in many cases. PLWH may be more sensitive to higher doses, adverse effects and to interactions.2 Patients with advanced HIV disease are particularly more likely to suffer exaggerated adverse reactions to psychotropic medication. HIV treatment advances and mental health Treatment of HIV infection has evolved in recent years to include long-­acting injectable antiretroviral therapy (ART) (e.g. cabotegravir/rilpivirine)3 aiming to improve adherence to and persistence with treatment.3 Ensuring continuous ART is crucial for a number of reasons including the fact that inflammation associated with untreated HIV can worsen pre-­existing cognitive decline in people with psychosis. Successful treatment with ART is associated with a lower risk of mental health disorders.4 In those at high risk of psychiatric relapse and poor compliance with medicines, long-­acting injections of both antipsychotics and antiretrovirals are available and could be used concurrently. Psychotic illness For most PLWH and comorbid psychosis, treatment is similar to that used in people without HIV5 but with some specific considerations. PLWH are more susceptible to extrapyramidal side effects (EPSEs) because HIV, a neurotropic virus, enters the brain and replicates in the basal ganglia leading to dopaminergic neuronal loss.6 In addition to this, both HIV and ART are implicated in metabolic abnormalities, hyperlipidaemia, weight gain and insulin resistance.7 Use of second-­generation antipsychotics (SGAs) in PLWH has been shown to increase the cardiovascular risk and metabolic complications compared with those not on SGAs.8 Likewise, QT interval prolongation can be a complication of HIV progression, HIV comorbidities and use of antiretrovirals as well as antipsychotics.9 Pharmacokinetic interactions should be considered and are discussed further in this section. SGAs are clearly first-­line options for the treatment of psychosis in PLWH although close physical health monitoring is essential, as is the use of preventative measures if required. Clozapine is a treatment option in PLWH10–12 and comorbid treatment-­resistant schizophrenia. Haematological abnormalities, including leukopenia, neutropenia, lymphopenia, thrombocytopenia and anaemias, are frequent complications of HIV13 as well as ART. Clozapine treatment may be erroneously interrupted if these are considered as clozapine-­induced, with detrimental consequences for the treatment of both HIV and psychosis. The safe and effective management of the additive haematological, metabolic and cardiovascular effects of clozapine and ART and complex pharmacokinetic interactions require the close collaboration of specialist medical teams and pharmacists. Clozapine may also be helpful in the treatment of individuals with HIV-­associated psychosis with drug-­induced parkinsonism.14 Depression Depression is the most common mental health disorder in PLWH, with prevalence estimated to be between 14% and 78%.1 Depressive symptoms can be a consequence of HIV infection or ART or of a pre-­existing disorder. Untreated depression in PLWH is associated with reduced viral suppression and faster HIV illness progression.15 Antidepressants

05 - Bipolar affective disorder

Bipolar affective disorder

06 - Secondary mania (HIV mania)

Secondary mania (‘HIV mania’)

07 - Anxiety disorders

Anxiety disorders

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 are more effective than placebo in the treatment of depression in PLWH16 and may improve adherence to ART.17 Selective serotonin reuptake inhibitors (SSRIs) are preferred as first-­line agents. Escitalopram/citalopram18,19 probably have lower risk of pharmacokinetic interactions, although one study found no difference between the efficacy of escitalopram and placebo, possibly because of a large placebo response.20 Electrocardiogram (ECG) monitoring is recommended when citalopram/escitalopram is co-­administered with ART that prolongs the QT interval.9,21 Mirtazapine is effective22,23 and may be ­beneficial in coexisting HIV wasting and depression24 or in reducing methamfetamine use  among active users.25 The serotonin–noradrenaline reuptake inhibitors (SNRIs) duloxetine and venlafaxine were found to be as effective as SSRIs for depressive symptoms in PLWH.26 Bupropion was effective with similar tolerability to SSRIs in a 6-­week ­open-­label study in a small number of HIV-­positive, depressed out-­patients.27 The adverse effect burden of tricyclic antidepressants (TCAs) may limit efficacy and compliance, although their use may be appropriate, particularly in patients troubled with insomnia, irritable bowel disease or painful neuropathy related to HIV or ART. Constipation and dry mouth are frequently reported in PLWH on TCAs.16 Monoamine oxidase inhibitors (MAOIs) are not recommended in PLWH. Bipolar affective disorder Mania in PLWH can be primary (pre-­existing bipolar affective disorder) or, rarely, ­secondary (‘HIV mania’ associated with late-­stage HIV infection). Treatment of bipolar disorder in HIV is similar to that in the general population.27 Lithium is renally excreted and so cytochrome P450 (CYP) interactions are unlikely. However, its use can be problematic in renal impairment, something which is often seen in PLWH. Lithium may be used cautiously in PLWH for primary bipolar disorder with close monitoring to avoid development of toxicity. Carbamazepine should be avoided because of significant drug interactions with ART and the risk of blood dyscrasias.28 Valproate is a known teratogen and should not be used in women of childbearing age.29 Its use is also best avoided with other hepatotoxic drugs (e.g. nevirapine, rifampicin)28 and where there is infection involving the liver (e.g. hepatitis C, mycobacterium avium complex30). Mood-­stabilising antipsychotics such as risperidone, quetiapine, aripiprazole and olanzapine may be preferred. Secondary mania (‘HIV mania’) Secondary mania may infrequently be seen in advanced illness in the context of HIV-­ associated neurocognitive disorders or central nervous system (CNS) opportunistic infections. The primary aim is to identify and treat the potential underlying cause (infections, substance misuse, alcohol withdrawal, metabolic abnormalities). Secondary mania may respond to quetiapine, olanzapine, aripiprazole or ziprasidone31 but their efficacy has not been demonstrated in clinical trials. Anxiety disorders Anxiety disorders, including generalised anxiety disorder, obsessive compulsive disorder, panic disorder and post-­traumatic stress disorder (PTSD), are highly prevalent in PLWH.32 Treatment follows standard guidelines for the management of anxiety disorders, with

08 - HIV associated neurocognitive disorders (HAND

HIV-associated neurocognitive disorders (HAND)

09 - Delirium

Delirium

10 - Substance use disorders

Substance use disorders

806 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 SSRIs being the first-­line options. Benzodiazepines may have some utility in the acute treatment of anxiety but require caution because of potential misuse, possible drug interactions and a higher risk of sedative and neurocognitive adverse effects in PLWH.33 Lorazepam is metabolised by non-­CYP pathways, and so has a lower risk of interactions. Clonazepam has no active metabolites and so it may be a preferred short-­term option for PLWH.34,35 Buspirone may also be helpful.34 HIV-­associated neurocognitive disorders (HAND) HAND encompasses three sub-­disorders, ranging from the more common asymptomatic neurocognitive impairment (ANI) to a mild neurocognitive disorder (MND) and the more severe but less common HIV-­associated dementia (HAD). Screening for cognitive impairment is recommended in PLWH using scales such as the MoCA or the three-­item Cognitive Concerns Questionnaire.36 In 2023, the International HIV-­Cognition Working Group published recommendations to better define the cognitive impairment in HIV.37 Treatment involves the use of ART with high CNS penetration effectiveness (e.g. raltegravir), aiming to achieve therapeutic levels in the CNS with minimal ­drug-­related neurotoxicity. Cognitive rehabilitation is an essential treatment component. Effective treatment of depression is essential as is management of substance use disorders and physical health comorbidities. Psychostimulants, modafinil, memantine, lithium and valproate have been studied but there is currently no licensed treatment for HAND.38 Delirium Delirium in HIV can be difficult to differentiate from HAND, although onset of delirium is more acute and its severity may fluctuate. Organic causes should be identified and treated. Antipsychotics are probably not effective in treating delirium and so should only be used as a last resort in severe cases and when non-­pharmacological measures fail.27 Early studies document the efficacy of haloperidol, but the lowest possible dose should be used given the high incidence of EPSEs, particularly in those with advanced HIV (e.g. doses used in delirium in palliative care may be considered).27 Benzodiazepines should be used cautiously as they may worsen delirium except when alcohol or ­benzodiazepine withdrawal is the precipitating factor.27 Substance use disorders Substance use disorders are highly prevalent in PLWH. Commonly used substances include alcohol, stimulants (including cocaine and methamfetamine), benzodiazepines, opioids and cannabinoids. The potential for interactions between drug use and prescribed medicines should be considered. Treatment should be offered to PLWH with comorbid substance use disorders. Naltrexone is safe and effective for alcohol relapse prevention in PLWH,39 while acamprosate has not been studied in this population and has a high tablet burden. Methadone and buprenorphine are possible evidence-­based options for opioid use disorder but care is required with ART drug interactions.27,40

11 - Interactions between antiretroviral drugs and

Interactions between antiretroviral drugs and psychotropics

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Interactions between antiretroviral drugs and psychotropics Pharmacokinetic interactions between antiretroviral drugs and psychotropics occur frequently and can be clinically significant. Potential interactions should be investigated for all patients receiving antiretrovirals and psychotropics concomitantly and include current prescribed medication, alternative/herbal treatments, recreational drugs and other non-­prescribed medicines. Interactions are numerous and complex. Readers are directed to regularly updated online resources for information about individual ­pharmacokinetic interactions such as www.hiv-­druginteractions.org (also available as an app). Pharmacodynamic interactions may also occur, usually through overlapping adverse effects. Potential pharmacodynamic interactions are shown in Table 10.1. Table 10.1  Potential pharmacodynamic interactions with antiretrovirals.40,41 Potential adverse effect Implicated antiretroviral drug(s)21,42,43 Implications for psychotropic prescribing Bone marrow suppression Zidovudine (anaemia, neutropenia) Concurrent use with certain psychotropics (e.g. clozapine) may increase the risk of myelosuppression/neutropenia Bone mineral density (BMD) reduction Tenofovir disoproxil fumarate (TDF) (tenofovir alafenamide has smaller decline of BMD) NNRTIs, PIs, INSTIs: decreases in BMD following any regimen May compound the reductions in BMD possible with prolactin elevating antipsychotics Creatine kinase (CK) elevations Dolutegravir, emtricitabine, raltegravir May be important to acknowledge associated link if diagnosis of NMS is being considered ECG changes Efavirenz, rilpivirine, saquinavir/ ritonavir: QT prolongation Atazanavir, lopinavir saquinavir: PR prolongation May increase risk of arrhythmias associated with certain psychotropic drugs Cardiovascular effects Abacavir, darunavir/ritonavir, lopinavir/ritonavir Cardiovascular events (e.g. myocardial infarction) occurred in some cohorts Renal effects TDF (risk increased if used with ritonavir) Tenofovir alafenamide: less impact on renal function versus TDF Atazanavir (kidney stones, tubo-­interstitial nephritis) Proteinuria, hypophosphataemia, glycosuria, hypokalaemia, renal tubular Gastrointestinal disturbances Atazanavir, darunavir, dolutegravir, didanosine, elvitegravir/cobicistat, fosamprenavir, indinavir, lopinavir, nelfinavir, raltegravir, saquinavir, tipranavir, zidovudine May compound gastrointestinal disturbances associated with certain psychotropics (e.g. SSRIs) (Continued )

12 - Adverse psychiatric effects of antiretroviral

Adverse psychiatric effects of antiretroviral drugs

808 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Table 10.2  Summary of psychiatric adverse drug reactions (ADRs) with antiretroviral drugs.21,40–45 Drug Adverse psychiatric effects/comments Nucleoside reverse transcriptase inhibitors Abacavir Depression, anxiety, nightmares, labile mood, mania, psychosis. Very few cases reported. In all reported cases, the patient rapidly returned to baseline after discontinuing drug. Didanosine Lethargy, nervousness, anxiety, confusion, sleep disturbance, mood disorders, psychosis, mania. Very rare. Emtricitabine Confusion, irritability, insomnia Tenofovir alafenamide Insomnia Zidovudine Sleep disturbance, vivid dreams, agitation, mania, depression, psychosis, delirium. Psychiatric ADRs are usually dose-­related. Onset varies widely, from <24 hours to 7 months. Non-­nucleoside reverse transcriptase inhibitors Efavirenz Somnolence, insomnia, abnormal dreams, impaired concentration, depression, psychosis, suicidal ideation. Symptoms usually subside or diminish after 2–4 weeks. However, subtler long-­term neuropsychiatric effects may occur. Can exacerbate psychiatric symptoms; avoid in patients with a history of psychiatric illness. Adverse psychiatric effects of antiretroviral drugs Psychiatric adverse events have been reported with most antiretroviral drugs, but a causal relationship remains uncertain for many. Efavirenz has been most commonly implicated, and HIV guidelines suggest avoiding its use in patients with psychiatric comorbidity. Table 10.2 summarises the most important psychiatric adverse effects of antiretroviral drugs. Note that this is not an exhaustive list and readers are directed to the summaries of product characteristics/product labelling for greater detail. Potential adverse effect Implicated antiretroviral drug(s)21,42,43 Implications for psychotropic prescribing Seizure(s) Darunavir, efavirenz, maraviroc, ritonavir, saquinavir, zidovudine May increase seizure risk associated with certain psychotropic drugs (e.g. clozapine) Metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia All combination antiretroviral therapy Raltegravir, elvitegravir, dolutegravir: greater risk of weight gain May compound risk of metabolic adverse effects associated with certain psychotropic drugs (particularly SGAs) INSTIs, integrase strand transfer inhibitors; NMS, neuroleptic malignant syndrome; NNRTIs, non-­nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors. Table 10.1  (Continued )

13 - References

References

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 A 2023 systematic review concluded that dolutegravir-­based regimens led to higher discontinuation rates due to neuropsychiatric adverse effects compared with those treated with bictegravir, emtricitabine and tenofovir alafenamide. Antiretroviral ­regimen choice should evidently take into account the individual’s risk factors for ­developing neuropsychiatric adverse effects.46 References

  1. Hoare J, et  al. Global systematic review of common mental health disorders in adults living with HIV. Curr HIV/AIDS Rep 2021; 18:569–580.
  2. Hill L, et al. Pharmacotherapy considerations in patients with HIV and psychiatric disorders: focus on antidepressants and antipsychotics. Ann Pharmacother 2013; 47:75–89.
  3. Wang W, et al. Safety and efficacy of long-­acting injectable agents for HIV-­1: systematic review and meta-­analysis. JMIR Public Health Surveill 2023; 9:e46767.
  4. Ba DM, et al. Human immunodeficiency virus (HIV) treatment with antiretroviral therapy mitigates the high risk of mental health disorders associated with HIV infection in the US population. Open Forum Infect Dis 2023; 10:ofad555.
  5. Cohen M, et al. Comprehensive Textbook of AIDS Psychiatry: A Paradigm for Integrated Care. Oxford: Oxford University Press; 2017.
  6. Amod F, et al. A review of movement disorders in persons living with HIV. Parkinsonism Relat Disord 2023; 114:105774.
  7. Ergin HE, et al. HIV, antiretroviral therapy and metabolic alterations: a review. Cureus 2020; 12:e8059.
  8. Ferrara M, et al. The concomitant use of second-­generation antipsychotics and long-­term antiretroviral therapy may be associated with increased cardiovascular risk. Psychiatry Res 2014; 218:201–208.
  9. Liu J, et al. QT prolongation in HIV-­positive patients: review article. Indian Heart J 2019; 71:434–439.
  10. Nejad SH, et  al. Clozapine use in HIV-­infected schizophrenia patients: a case-­based discussion and review. Psychosomatics 2009; 50:626–632.
  11. Sanz-­Cortés S, et al. A case report of schizophrenia and HIV: HAART in association with clozapine. J Psychiatric Intensive Care 2009; 5:47–49.
  12. Whiskey E, et al. Clozapine, HIV and neutropenia: a case report. Ther Adv Psychopharmacol 2018; 8:365–369.
  13. Duguma N, et al. Hematological parameters abnormalities and associated factors in HIV-­positive adults before and after highly active antiretroviral treatment in Goba Referral Hospital, southeast Ethiopia: a cross-­sectional study. SAGE Open Med 2021; 9:20503121211020175.
  14. Lera G, et al. Pilot study with clozapine in patients with HIV-­associated psychosis and drug-­induced parkinsonism. Mov Disord 1999; 14:128–131.
  15. Lesko CR, et al. Depression and HIV viral nonsuppression among people engaged in HIV care in an urban clinic, 2014–2019. AIDS 2021; 35:2017–2024. Table 10.2  (Continued ) Drug Adverse psychiatric effects/comments Etravirine Sleep disturbance Nevirapine Visual hallucinations, persecutory delusions, mood changes, nightmares and vivid dreams, depression. A handful of cases have been reported. Onset of symptoms was within the first couple of weeks. Symptoms all resolved on discontinuation of nevirapine. Rilpivirine Depression, suicidality, sleep disturbances. A similar adverse effect profile to efavirenz but a lower incidence of each event. May exacerbate psychiatric symptoms; consider avoiding in patients with a history of psychiatric illness. Integrase strand transfer inhibitors Dolutegravir, elvitegravir, raltegravir Insomnia, depression, suicidal ideation (particularly with dolutegravir and symptoms may appear within first months of treatment) Bictegravir Depression incidence similar to dolutegravir (though suicidality greater for dolutegravir) but further data required Cabotegravir Limited data but incidence appears low – also long acting and so effects may be prolonged

810 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 16. Eshun-­Wilson I, et al. Antidepressants for depression in adults with HIV infection. Cochrane Database Syst Rev 2018; 1:CD008525. 17. Gokhale RH, et al. Depression prevalence, antidepressant treatment status, and association with sustained HIV viral suppression among adults living with HIV in care in the United States, 2009–2014. AIDS Behav 2019; 23:3452–3459. 18. Currier MB, et al. Citalopram treatment of major depressive disorder in Hispanic HIV and AIDS patients: a prospective study. Psychosomatics 2004; 45:210–216. 19. Freudenreich O, et  al. Psychiatric treatment of persons with HIV/AIDS: an HIV-­psychiatry consensus survey of current practices. Psychosomatics 2010; 51:480–488. 20. Hoare J, et al. Escitalopram treatment of depression in human immunodeficiency virus/acquired immunodeficiency syndrome: a randomized, double-­blind, placebo-­controlled study. J Nerv Ment Dis 2014; 202:133–137. 21. European AIDS Clinical Society. Guidelines version 10.1 October 2020. 2020 (last accessed May 2024); https://www.eacsociety.org/media/ guidelines-­10.1_finaljan2021_1.pdf. 22. Patel S, et al. Escitalopram and mirtazapine for the treatment of depression in HIV patients: a randomized controlled open label trial. ASEAN J Psychiatry 2013; 14:3139. 23. Elliott AJ, et al. Mirtazapine for depression in patients with human immunodeficiency virus. J Clin Psychopharmacol 2000; 20:265–267. 24. Badowski M, et  al. Pharmacologic management of human immunodeficiency virus wasting syndrome. Pharmacotherapy 2014; 34:868–881. 25. Coffin PO, et al. Effects of mirtazapine for methamphetamine use disorder among cisgender men and transgender women who have sex with men: a placebo-­controlled randomized clinical trial. JAMA Psychiatry 2020; 77:246–255. 26. Mills JC, et al. Comparative effectiveness of dual-­action versus single-­action antidepressants for the treatment of depression in people living with HIV/AIDS. J Affect Disord 2017; 215:179–186. 27. Hirsch CH, et  al. HIV-­associated neurocognitive disorders and delirium. In: Bourgeois JA, Cohen MAA, Makurumidze G (eds.) HIV Psychiatry: A Practical Guide for Clinicians. Cham: Springer Nature; 2022:181–233. 28. Gallego L, et al. Psychopharmacological treatments in HIV patients under antiretroviral therapy. AIDS Rev 2012; 14:101–111. 29. Medicines and Healthcare Products Regulatory Agency. New valproate safety measures apply from 31 January 2024; https://www.gov.uk/ government/news/new-­valproate-­safety-­measures-­apply-­from-­31-­january. 30. Pieper AA, et al. Depression, mania, and schizophrenia in HIV-­infected patients. 2021 (last accessed May 2024); https://pro.uptodatefree.ir/ Show/4864. 31. Spiegel DR, et  al. The successful treatment of mania due to acquired immunodeficiency syndrome using ziprasidone: a case series. J Neuropsychiatry Clin Neurosci 2010; 22:111–114. 32. Armoon B, et al. HIV related stigma associated with social support, alcohol use disorders, depression, anxiety, and suicidal ideation among people living with HIV: a systematic review and meta-­analysis. Int J Ment Health Syst 2022; 16:17. 33. Saloner R, et al. Benzodiazepine use is associated with an increased risk of neurocognitive impairment in people living with HIV. J Acquir Immune Defic Syndr 2019; 82:475–482. 34. Brogan K, et al. Management of common psychiatric conditions in the HIV-­positive population. Curr HIV/AIDS Rep 2009; 6:108–115. 35. Bourgeois J, et al. HIV Psychiatry. Cham: Springer; 2022. 36. Wang Y, et al. Global prevalence and burden of HIV-­associated neurocognitive disorder. Neurology 2020; 95:e2610–e2621. 37. Nightingale S, et al. Cognitive impairment in people living with HIV: consensus recommendations for a new approach. Nat Rev Neurol 2023; 19:424–433. 38. Elendu C, et al. HIV-­related neurocognitive disorders: diagnosis, treatment, and mental health implications: a review. Medicine (Baltimore) 2023; 102:e35652. 39. Farhadian N, et al. Effectiveness of naltrexone treatment for alcohol use disorders in HIV: a systematic review. Subst Abuse Treat Prev Policy 2020; 15:24. 40. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. 2024 (last accessed May 2024); https://clinicalinfo.hiv.gov/sites/default/files/guidelines/ documents/adult-­adolescent-­arv/guidelines-­adult-­adolescent-­arv.pdf. 41. Waters L, et al. BHIVA guidelines on antiretroviral treatment for adults living with HIV-­1 2022. HIV Med 2022; 23 Suppl 5:3–115. 42. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Department of Health and Human Services. 2017 (last accessed August 2024); https://clinicalinfo.hiv.gov/en/guidelines/hivclinical-guidelines-adult-and-adolescent-arv/whats-new. 43. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: ­recommendations for a public health approach, 2nd edn. 2016; http://www.who.int/hiv/pub/arv/arv-­2016/en. 44. Parker C. Psychiatric effects of drugs for other disorders. Medicine 2016; 44:768–774. 45. Préta LH, et al. Association of depression and suicidal behaviour reporting with HIV integrase inhibitors: a global pharmacovigilance study. J Antimicrob Chemother 2023; 78:1944–1947. 46. Pérez-­Valero I, et al. Real-­world discontinuations due to neuropsychiatric symptoms in people living with HIV treated with second-­generation integrase inhibitors: a systematic review. Expert Rev Anti Infect Ther 2023; 21:655–665.

14 - Epilepsy

Epilepsy

15 - Psychiatric comorbidities in epilepsy

Psychiatric comorbidities in epilepsy

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Epilepsy Psychiatric comorbidities in epilepsy People with epilepsy (PWE) have an elevated prevalence of several psychiatric disorders including depression (13–37%), anxiety (20%) and psychosis (5%).1,2 Suicide is threefold higher in PWE compared with the general population3 and is an important cause of premature mortality.4 The link between epilepsy and mental illness is bidirectional as patients with depression, anxiety and psychosis have an increased risk of developing new-­onset epilepsy.5,6 Suicide attempts are also associated with the development of ­epilepsy.7 This bidirectional relationship might be explained by a common underlying pathology between mental illness and epilepsy. Disturbances in neurotransmission, ­neuroinflammation and the hypothalamic–pituitary–adrenal (HPA) axis have all been suggested8 to be the shared pathology. Interictal psychiatric disorders (with symptoms occurring independently of seizures) are likely to require treatment with psychotropics.9–11 When prescribing psychotropics to people with epilepsy, the following general principles12,13 should be adhered to: ■ ■First, rule out other possible causes of psychiatric symptoms (both peri-­ictal and iatrogenic – Table 10.3). ■ ■Optimise the treatment of epilepsy (ideally before prescribing psychotropics). ■ ■Consider using psychotropics with known antiseizure properties (e.g. antiseizure medications in bipolar disorder). ■ ■Check for interactions with antiseizure medications. ■ ■Start with a low dose and titrate according to tolerability and response (proconvulsive effects are dose-­related). ■ ■If seizures do occur, consider changing the psychotropic drug or optimising the antiseizure medication. Table 10.3  Possible causes of psychiatric symptoms in people with epilepsy (PWE) and their management.5 Cause of symptoms Description Management Interictal psychiatric disorders Symptoms occurring independently of seizures. Although common in PWE, other causes and relatedness to seizures should be ruled out first. Likely to require treatment with psychotropics. See Table 10.5 for more information about the use of specific psychotropics in PWE. Peri-­ictal symptoms PWE may experience psychiatric symptoms that are temporally related to seizures. All peri-­ictal psychiatric symptoms (pre-­ictal, postictal and ictal) are initially treated by optimising antiseizure medications.12 Peri-­ictal depressive symptoms do not appear to respond to treatment with antidepressants.14,15 Postictal psychosis can remit spontaneously or respond to treatment with low doses of antipsychotics.16 Short-­term symptomatic treatment with a benzodiazepine or antipsychotic is recommended for up to 3 months.17 Taper off carefully after symptom resolution.15 There is no evidence that psychotropics can prevent ictal symptoms.18 Pre-­ictal symptoms Typically presents as a dysphoric mood preceding a seizure by a period of 30 minutes to hours to 2 or 3 days. Postictal symptoms Typically presents between several hours to 7 days following a seizure (depression, anxiety, suicidal ideation and psychosis reported) PWE and interictal psychiatric disorders may experience worsening of symptoms previously in remission (breakthrough symptoms). Ictal symptoms May present as ictal fear/panic (most commonly), depressive symptoms or, rarely, psychosis. (Continued )

16 - Psychiatric side effects of antiseizure medic

Psychiatric side effects of antiseizure medications

812 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Psychiatric side effects of antiseizure medications Virtually all antiseizure medications are known to have psychotropic effects. These effects can be both helpful and unhelpful. The adverse and beneficial psychiatric side effects of antiseizure medications are summarised in Table 10.4. Cause of symptoms Description Management Para-­ictal episodes ‘forced normalisation’ (psychiatric symptoms emerging as a result of a reduction in seizure frequency) Psychotic or, less commonly, severe affective symptoms following seizure remission in PWE Rapid medication titration schedules, rapid seizure control, previously medication-­resistant epilepsy, and temporal lobe epilepsy may be risk factors.16 A decision should be made on how to proceed with antiseizure medications and psychotropics through a process of shared decision-­making with carers.15 Symptomatic treatment with antipsychotics or antidepressants may be indicated. Iatrogenic psychiatric symptoms Changes in treatments for seizures could result in psychiatric symptoms as a result of: Starting antiseizure medications with known negative psychotropic properties (particularly in those with a psychiatric history). Stopping antiseizure medications with beneficial psychotropic properties (e.g. mood stabilisation). Starting antiseizure medications with enzyme-­inducing properties in people stable on psychotropics. Surgery for epilepsy: de novo postsurgical episodes of depression, anxiety and, rarely, psychosis have been reported. Exacerbation of pre-­existing conditions more common. Symptoms are managed by resolving the underlying cause in the first instance. Consider switching antiseizure medications with known negative psychotropic properties to better tolerated antiseizure medications (see Table 10.4). Antiseizure medications can lower folate levels which may affect mood. Folate levels should be checked and low levels remedied if necessary. If changing antiseizure medications is not suitable, antidepressants can be considered for iatrogenic depressive symptoms.19 Postsurgical neuropsychiatric symptoms may be treated successfully with psychotropics.18 Table 10.3  (Continued ) Table 10.4  Adverse and beneficial psychiatric side effects of antiseizure medications.5,20,21 Antiseizure medication Adverse psychiatric symptoms Psychiatric benefits Barbiturates, primidone Behavioural disturbance/ADHD symptoms, depression, cognitive impairment Anxiolytic, hypnotic   Benzodiazepines Brivaracetam Depression, aggression, rage, suicidality None reported Carbamazepine, eslicarbazepine, oxcarbazepine Insomnia Mood stabilising, anti-­manic

17 - Interactions of antiseizure medications22

Interactions of antiseizure medications22

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Interactions of antiseizure medications22 Pharmacokinetic interactions Important pharmacokinetic interactions occur in both directions between antiseizure medications and psychotropics, primarily mediated through cytochrome enzymes.9,23 Psychotropics with enzyme-­inhibiting effects (e.g. fluoxetine, fluvoxamine, paroxetine and, at higher doses, sertraline) may increase antiseizure plasma levels. This is especially relevant to antiseizure medications with a narrow therapeutic index (e.g. carbamazepine and phenytoin). Plasma levels should be monitored, and dosage adjustment may be required. Citalopram and escitalopram are very weak inhibitors of CYP1A2 and CYP2D6, and so may be preferred in some cases. Some antiseizure medications are potent enzyme inducers (e.g. phenytoin, carbamazepine, phenobarbital, primidone) and others are weak inducers (e.g. oxcarbazepine at doses ≥900mg/day, topiramate at doses ≥400mg/day). These drugs can lower plasma levels of many psychotropics, leading to treatment failure. Antiseizure medication Adverse psychiatric symptoms Psychiatric benefits Ethosuximide Behavioural disturbance, depression, psychosis None reported Felbamate Anxiety, depression None reported Gabapentin, pregabalin Depression and anxiety on cessation Anxiolytic Lacosamide None reported None reported Lamotrigine Anxiogenic in some. Behavioural disturbance in cognitive impairment Antidepressant, mood stabilising Levetiracetam Anxiety, behavioural disturbance, depression, suicidality None confirmed Perampanel Behavioural disturbance, depression, psychosis None reported Phenytoin Behavioural disturbance, depression Anti-­manic Rufinamide Anxiety, insomnia None reported Tiagabine Behavioural disturbance, depression Anxiolytic Topiramate Anxiety, behavioural disturbance, depression, psychosis Unclear. Possible anti-­manic/antipsychotic Valproate Behavioural disturbance (at high doses in children) Mood stabilising, anti-­manic, anti-­panic Vigabatrin Behavioural disturbance/ADHD symptoms, depression, psychosis None reported Zonisamide Behavioural disturbance, depression None confirmed Table 10.4  (Continued)

18 - Psychotropics and the risk of seizures in peo

Psychotropics and the risk of seizures in people with epilepsy

814 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Pharmacodynamic interactions14 Adverse effects with antiseizure medications that may overlap with psychotropic adverse effects include: ■ ■Weight gain: caused by some antiseizure medications (e.g. carbamazepine, gabapentin, pregabalin, valproate). ■ ■Sexual adverse effects: with phenobarbital and primidone but possible with all enzyme-­inducing antiseizure medications. ■ ■Hyponatraemia: with carbamazepine and oxcarbazepine (note, if severe, can provoke seizures). ■ ■Osteoporosis and osteopenia: reported with long-­term use of enzyme-­inducing antiseizure medications. ■ ■Blood dyscrasias: reported with valproate, carbamazepine11 and especially with felbamate. Psychotropics and the risk of seizures in people with epilepsy In the general population, the annual incidence of unprovoked seizures is about 50 per 100,000 persons.24,25 It is notable that the incidence of unprovoked seizures in the placebo arms of randomised controlled trials of antidepressants and antipsychotics is approximately 15-­fold higher, suggesting that both depression and psychosis are risk factors for seizures.26 A bidirectional relationship between epilepsy and several psychiatric illnesses has been demonstrated, whereby not only do PWE have a higher risk of developing a psychiatric illness, but people with psychiatric illness have a higher risk of developing epilepsy.5,6 This bidirectional relationship exists for depression, anxiety, psychosis and suicidality.5–7 Thus, the occurrence of seizures may, in some cases, be the expression of the natural progression of a psychiatric illness and be unrelated to the use of psychotropics. Reports of seizures associated with psychotropics must factor in this bidirectional relationship between psychiatric illness and epilepsy. For example, although observational studies have reported an association between antidepressant treatment and seizures,27 a similar association is also found with non-­drug treatments for depression (counselling, for example).28 These findings are consistent with depression itself being the main risk factor for seizures. In fact, one analysis of controlled studies with psychotropics showed that the incidence of seizures was substantially lower among patients receiving most antidepressants (e.g. SSRIs) in comparison with those randomised to placebo.26 Nonetheless, definitive data are lacking in PWE29,30 and certain psychotropics have a dose-­related risk of seizures within usual dose ranges. Most can cause seizures in overdose. Note also that almost all antidepressants and antipsychotics have been associated with hyponatraemia (see sections on hyponatraemia in Chapters 1 and 3) and seizures may occur if this is severe.18,31 General guidance on the safety of psychotropics in PWE is summarised in Table 10.5. Electroconvulsive therapy (ECT) has anticonvulsive properties and is worth considering in the treatment of depression in patients with unstable epilepsy.9,18,23 ECT does not appear to cause or worsen epilepsy.18,32

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Table 10.5  Psychotropics in epilepsy. Safety in epilepsy Drug Comments Antidepressants Low risk – good choices33 SSRIs Recommended in PWE.15,19 SSRIs may be anticonvulsant at therapeutic doses14 but proconvulsant in overdose.34 SSRIs with the lowest risk of interactions with antiseizure medications are generally preferred (citalopram/escitalopram, followed by sertraline).15,19,35,36 Escitalopram is preferred over citalopram in PWE (lower risk of seizures in overdose).37 Others have low risk of seizures (e.g. fluoxetine37) but drug interactions with antiseizure medications should be considered.15,19 Fluoxetine may be less likely to provoke seizures in older people than escitalopram or citalopram.38 Some evidence that sertraline is safe and effective in PWE.39 Mirtazapine Recommended in PWE.19,40 Not known to be proconvulsive.26 Duloxetine Recommended for PWE.12,19 Risk of seizures is probably negligible.37,38 Probably low risk – use with caution (limited evidence) Agomelatine Not known to be proconvulsive.41 Anticonvulsant in animal models.37 MAOIs Not known to be proconvulsive at therapeutic doses.37 Low risk of seizures in overdose.18 Moclobemide Not known to be proconvulsive.37 Anticonvulsant in animal models.37 Reboxetine Small open-­label study suggests no problems in PWE.42 Vortioxetine Not known to be proconvulsive.37,43 One report of successful use of vortioxetine in three PWE.44 Moderate risk – care required Lithium Low risk of seizures.37 Anticonvulsant in animal models.37 However, limited data showing both increases and decreases in seizures frequency in PWE.37 At standard plasma levels lithium is probably not proconvulsive.45 For bipolar, consider anticonvulsant mood stabilisers.46 Trazodone Limited data suggest some risk of seizures.37,47 Venlafaxine Effective in PWE12 and has been recommended19 but mixed evidence on seizure risk.37 Vilazodone Limited data. Seizure exacerbation in a patient with epilepsy has been reported.37 Higher risk – avoid (proconvulsive at therapeutic doses14) Amoxapine Several reports of seizures at therapeutic doses47 Bupropion Dose-­related risk of seizures (particularly with immediate-­release formulations).37 Risk is less with slow-­release formulations at doses under 300mg/day.37 At least one study found no increased risk with bupropion.48 Maprotiline Several reports of seizures at therapeutic doses.47 TCAs Most TCAs are epileptogenic at higher doses (particularly clomipramine and amitriptyline11,26,47). Doxepin possibly lower risk (one small study in PWE).37 SNRIs are preferred over TCAs in PWE18 (Continued )

816 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Table 10.5  (Continued) Safety in epilepsy Drug Comments Antipsychotics Low risk – good choices Amisulpride/sulpiride Considered to be safe in PWE.49 Renally excreted, so low risk of pharmacokinetic interactions with antiseizure medications. Seizures uncommon in overdose.50 Aripiprazole Rarely lowers seizure threshold.5 Incidence of seizures similar to placebo in RCTs.26 Ziprasidone High-­potency FGAs e.g. fluphenazine, haloperidol, trifluoperazine, flupentixol. Low risk of lowering the seizure threshold.5 Risperidone Unlikely to lower the seizure threshold.5 Incidence of seizures similar to placebo in RCTs.26 Has been recommended for PWE.35,51 Evidence of safety in a case series of adolescents with epilepsy.52 Probably low risk – use with caution (limited evidence) Asenapine Seizure rate similar to placebo in RCTs.53 Data and clinical experience of use in PWE is extremely limited. Brexpiprazole Cariprazine Lurasidone Moderate risk – care required Olanzapine Olanzapine and quetiapine both associated with seizures in RCTs.26 Overall risk of reducing the seizure threshold is considered to be low5 and olanzapine has been recommended by some for PWE.35 Data relating to olanzapine are difficult to interpret. EEG changes are seen in some but not all studies54 and it has been reported to be both anticonvulsant55 and proconvulsant.56 Quetiapine has a high risk of drug interaction in PWE.51 Quetiapine Higher risk – care required Clozapine Most proconvulsive antipsychotic.35 However, has been used successfully in PWE stable on antiseizure medications without worsening seizures57 and even in treatment-­resistant epilepsy.58 Note, should not be used with carbamazepine (risk of blood dyscrasias and reduced clozapine levels). Lamotrigine is the antiseizure medication of choice. Higher risk – avoid Low-­potency FGAs (e.g. chlorpromazine) Best avoided in PWE.34 Doses of chlorpromazine above 1g/day have a 9% incidence of seizures. Loxapine Highest rate of seizures among the FGAs.59 Depot antipsychotics None of the depot preparations currently available is thought to be epileptogenic, however the kinetics of depots are complex (seizures may be delayed). If seizures do occur, the offending drug may not be easily withdrawn. Depots should be used with extreme care. Zotepine Has established dose-­related proconvulsive effect50 Drugs for ADHD Low risk Methylphenidate Three RCTs support safety and efficacy in children with epilepsy at therapeutic doses (0.3–1mg/kg/day).11 Two single-­dose RCTs and one open-­label extension study demonstrated no effect on seizures in adults.60,61 A large case–control study found an increased rate of seizures after the start of methylphenidate but not in the longer term.62 This is difficult to interpret but suggests caution would be appropriate. May be a higher risk of seizures at higher doses.63

19 - Epilepsy and driving

Epilepsy and driving

20 - References

References

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Epilepsy and driving In the UK, people with epilepsy may not drive a car if they have had a seizure while awake in the previous year. However, they may be eligible to drive if seizures occur only during sleep and this has been an established nocturnal pattern for at least 3 years. The consequences of inducing seizure with antidepressants or antipsychotics can therefore be significant. For further information see https://www.gov.uk/epilepsy-­and-­driving. Other countries have different rules, but most require a seizure-­free period of between 6 and 36 months.71 References

  1. Scott AJ, et al. Anxiety and depressive disorders in people with epilepsy: a meta-­analysis. Epilepsia 2017; 58:973–982.
  2. Clancy MJ, et al. The prevalence of psychosis in epilepsy; a systematic review and meta-­analysis. BMC Psychiatry 2014; 14:75.
  3. Wang H, et al. Suicidality and epilepsy: a systematic review and meta-­analysis. Front Psychiatry 2023; 14:1097516.
  4. Thurman DJ, et al. The burden of premature mortality of epilepsy in high-­income countries: a systematic review from the Mortality Task Force of the International League Against Epilepsy. Epilepsia 2017; 58:17–26.
  5. Kanner AM. Management of psychiatric and neurological comorbidities in epilepsy. Nat Rev Neurol 2016; 12:106–116.
  6. Hesdorffer DC. Comorbidity between neurological illness and psychiatric disorders. CNS Spectr 2016; 21:230–238.
  7. Hesdorffer DC, et al. Occurrence and recurrence of attempted suicide among people with epilepsy. JAMA Psychiatry 2016; 73:80–86.
  8. Kanner AM. Can neurochemical changes of mood disorders explain the increase risk of epilepsy or its worse seizure control? Neurochem Res 2017; 42:2071–2076.
  9. Curran S, et al. Selecting an antidepressant for use in a patient with epilepsy. Safety considerations. Drug Saf 1998; 18:125–133.
  10. Blumer D, et al. Treatment of the interictal psychoses. J Clin Psychiatry 2000; 61:110–122.
  11. Mula M. The pharmacological management of psychiatric comorbidities in patients with epilepsy. Pharmacol Res 2016; 107:147–153.
  12. Elger CE, et al. Diagnosing and treating depression in epilepsy. Seizure 2017; 44:184–193.
  13. Anbarasan D. Psychoactive medications and seizures—­challenges and pitfalls. Neurol Rep 2016; 9:24–27.
  14. Kanner AM. Most antidepressant drugs are safe for patients with epilepsy at therapeutic doses: a review of the evidence. Epilepsy Behav 2016; 61:282–286.
  15. Kerr MP, et al. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy. Epilepsia 2011; 52:2133–2138.
  16. Josephson CB, et al. Psychiatric comorbidities in epilepsy. Int Rev Psychiatry 2017; 29:409–424.
  17. Maguire M, et al. Epilepsy and psychosis: a practical approach. Pract Neurol 2018; 18:106–114.
  18. Mula M. Neuropsychiatric Symptoms of Epilepsy. Basel: Springer International Publishing; 2016.
  19. Villanueva V, et al. Proposed recommendations for the management of depression in adults with epilepsy: an expert consensus. Neurol Ther 2023; 12:479–503. Table 10.5  (Continued) Safety in epilepsy Drug Comments Probably low risk64,65 – use with caution (limited data) Amfetamines Data are limited to one small retrospective study in PWE.11 No patients who had well-­controlled epilepsy experienced an increase in seizure frequency.66 Dexamfetamine was historically used as an adjunctive antiseizure agent.67 Atomoxetine Data are limited to one small retrospective study in PWE.11 Discontinuation rates were high (though none due to seizure exacerbation68). Seizure rate similar to placebo for patients without epilepsy.69 Low risk Acetylcholinesterase inhibitors: donepezil/ rivastigmine/ galantamine No increased risk of seizures has been observed.70 This table contains information about the proconvulsive effects of antidepressants and antipsychotics when used in therapeutic doses. See Chapter 13 for information about supratherapeutic doses. EEG, electroencephalogram; MAOIs, monoamine oxidase inhibitors; PWE, people with epilepsy; TCAs, tricyclic antidepressants.

818 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 20. Schmidt D, et al. Drug treatment of epilepsy in adults. BMJ 2014; 348:g254. 21. Piedad J, et al. Beneficial and adverse psychotropic effects of antiepileptic drugs in patients with epilepsy: a summary of prevalence, ­underlying mechanisms and data limitations. CNS Drugs 2012; 26:319–335. 22. Spina E, et al. Clinically significant pharmacokinetic drug interactions of antiepileptic drugs with new antidepressants and new ­antipsychotics. Pharmacol Res 2016; 106:72–86. 23. Harden CL, et al. Mood disorders in patients with epilepsy: epidemiology and management. CNS Drugs 2002; 16:291–302. 24. Ngugi AK, et al. Incidence of epilepsy: a systematic review and meta-­analysis. Neurology 2011; 77:1005–1012. 25. Wigglesworth S, et al. The incidence and prevalence of epilepsy in the United Kingdom 2013–2018: a retrospective cohort study of UK ­primary care data. Seizure 2023; 105:37–42. 26. Alper K, et al. Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biol Psychiatry 2007; 62:345–354. 27. Wu CS, et al. Seizure risk associated with antidepressant treatment among patients with depressive disorders: a population-­based case-­ crossover study. J Clin Psychiatry 2017; 78:e1226–e1232. 28. Josephson CB, et al. Association of depression and treated depression with epilepsy and seizure outcomes: a multicohort analysis. JAMA Neurol 2017; 74:533–539. 29. Farooq S, et al. Interventions for psychotic symptoms concomitant with epilepsy. Cochrane Database Syst Rev 2015; 12:CD006118. 30. Maguire MJ, et al. Antidepressants for people with epilepsy and depression. Cochrane Database Syst Rev 2014; 4:CD010682. 31. Maramattom BV. Duloxetine-­induced syndrome of inappropriate antidiuretic hormone secretion and seizures. Neurology 2006; 66:773–774. 32. Ray AK. Does electroconvulsive therapy cause epilepsy? J ECT 2013; 29:201–205. 33. Tallarico M, et al. Antidepressant drugs for seizures and epilepsy: where do we stand? Curr Neuropharmacol 2023; 21:1691–1713. 34. Steinert T, et al. [Epileptic seizures during treatment with antidepressants and neuroleptics]. Fortschr Neurol Psychiatr 2011; 79:138–143. 35. Mula M. Epilepsy and psychiatric comorbidities: drug selection. Curr Treat Options Neurol 2017; 19:44. 36. National Institute for Health and Care Excellence. Depression in adults with a chronic physical health problem: recognition and management. Clinical Guidance [CG91] 2009 (last updated and checked May 2024); http://www.nice.org.uk/CG91. 37. Steinert T, et al. Epileptic seizures under antidepressive drug treatment: systematic review. Pharmacopsychiatry 2018; 51:121–135. 38. Finkelstein Y, et  al. Second-­generation anti-­depressants and risk of new-­onset seizures in the elderly. Clin Toxicol (Phila) 2018; 56:1179–1184. 39. Gilliam FG, et al. A trial of sertraline or cognitive behavior therapy for depression in epilepsy. Ann Neurol 2019; 86:552–560. 40. Craig DP, et al. Risk of seizures with antidepressants: what is the evidence? Drug Ther Bull 2020; 58:137–140. 41. Servier Laboratories Limited. Summary of product characteristics. Valdoxan (agomelatine). 2021 (last accessed May 2024); https://www. medicines.org.uk/emc/medicine/21830. 42. Kuhn KU, et al. Antidepressive treatment in patients with temporal lobe epilepsy and major depression: a prospective study with three ­different antidepressants. Epilepsy Behav 2003; 4:674–679. 43. Lundbeck Limited. Summary of product characteristics. Brintellix (vortioxetine) tablets 5, 10 and 20mg. 2024 (last checked May 2024); https://www.medicines.org.uk/emc/medicine/30904. 44. Siwek M, et al. Case report: vortioxetine in the treatment of depressive symptoms in patients with epilepsy – case series. Front Pharmacol 2022; 13:852042. 45. Bojja SL, et al. What is the role of lithium in epilepsy? Curr Neuropharmacol 2022; 20:1850–1864. 46. Knott S, et al. Epilepsy and bipolar disorder. Epilepsy Behav 2015; 52:267–274. 47. Johannessen Landmark C, et  al. Proconvulsant effects of antidepressants  – what is the current evidence? Epilepsy Behav 2016; 61:287–291. 48. Chu C-­S, et al. Antidepressant drugs use and epilepsy risk: a nationwide nested case-­control study. Epilepsy Behav 2023; 140:109102. 49. Elnazer H, et al. Managing aggression in epilepsy. BJPsych Advances 2017; 23:253. 50. Steinert T, et al. Seizures. In: Manu P, Flanagan RJ, Donaldson K, eds. Life-­threatening Effects of Antipscyhotic Drugs. San Diego, CA: Academic Press; 2016:207–222. 51. Agrawal N, et al. Treatment of psychoses in patients with epilepsy: an update. Ther Adv Psychopharmacol 2019; 9:2045125319862968. 52. Gonzalez-­Heydrich J, et al. No seizure exacerbation from risperidone in youth with comorbid epilepsy and psychiatric disorders: a case series. J Child Adolesc Psychopharmacol 2004; 14:295–310. 53. IBM Watson Health. IBM micromedex solutions. 2024; https://www.ibm.com/watson-­health/about/micromedex. 54. Jackson A, et al. EEG changes in patients on antipsychotic therapy: a systematic review. Epilepsy Behav 2019; 95:1–9. 55. Qiu X, et  al. Antiepileptic effect of olanzapine in epilepsy patients with atypical depressive comorbidity. Epileptic Disord 2018; 20:225–231. 56. Mansoor M, et al. Generalised tonic-­clonic seizures on the subtherapeutic dose of olanzapine. BMJ Case Rep 2019; 12:e230018. 57. Langosch JM, et al. Epilepsy, psychosis and clozapine. Hum Psychopharmacol 2002; 17:115–119. 58. Jette Pomerleau V, et al. Clozapine safety and efficacy for interictal psychotic disorder in pharmacoresistant epilepsy. Cogn Behav Neurol 2017; 30:73–76. 59. Habibi M, et al. The impact of psychoactive drugs on seizures and antiepileptic drugs. Curr Neurol Neurosci Rep 2016; 16:71. 60. Adams J, et al. Methylphenidate, cognition, and epilepsy: a 1-­month open-­label trial. Epilepsia 2017; 58:2124–2132. 61. Adams J, et  al. Methylphenidate, cognition, and epilepsy: a double-­blind, placebo-­controlled, single-­dose study. Neurology 2017; 88:470–476.

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 62. Man KKC, et al. Association between methylphenidate treatment and risk of seizure: a population-­based, self-­controlled case-­series study. Lancet Child Adolesc Health 2020; 4:435–443. 63. Eaton C, et al. Stimulant and non-­stimulant drug therapy for people with attention deficit hyperactivity disorder and epilepsy. Cochrane Database Syst Rev 2022; 7:CD013136. 64. Besag F, et al. Psychiatric and behavioural disorders in children with epilepsy (ILAE Task Force Report): epilepsy and ADHD. Epileptic Disord 2016; 18:S8–S15. 65. Besag F, et al. Psychiatric and behavioural disorders in children with epilepsy (ILAE Task Force Report): when should pharmacotherapy for psychiatric/behavioural disorders in children with epilepsy be prescribed? Epileptic Disord 2016; 18:S77–S86. 66. Gonzalez-­Heydrich J, et al. Comparing stimulant effects in youth with ADHD symptoms and epilepsy. Epilepsy Behav 2014; 36:102–107. 67. Schubert R. Attention deficit disorder and epilepsy. Pediatr Neurol 2005; 32:1–10. 68. Torres A, et al. Tolerability of atomoxetine for treatment of pediatric attention-­deficit/hyperactivity disorder in the context of epilepsy. Epilepsy Behav 2011; 20:95–102. 69. Williams AE, et  al. Epilepsy and attention-­deficit hyperactivity disorder: links, risks, and challenges. Neuropsychiatr Dis Treat 2016; 12:287–296. 70. Ha J, et al. Association of cognitive enhancers and incident seizure risk in dementia: a population-­based study. BMC Geriatr 2022; 22:480. 71. Ooi WW, et al. International regulations for automobile driving and epilepsy. J Travel Med 2006; 7:1–4.

21 - 22q11.2 deletion syndrome

22q11.2 deletion syndrome

22 - Clinical features

Clinical features

820 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 22q11.2 deletion syndrome Clinical features 22q11.2 deletion syndrome (22q11.2DS), the most common microdeletion syndrome in humans, is a multisystem disorder with a heterogenous presentation which varies greatly in severity between affected individuals.1 Prevalence is estimated at 1 in 2148 live births.1,2 The syndrome has been known by many names (including velocardiofacial syndrome and DiGeorge syndrome) in part because of its broad phenotypic range of clinical features (Table 10.6). Table 10.6  Selected clinical features and risks in people with 22q11.2 deletion syndrome.1,3 Clinical risks Cognitive and adaptive functioning Intellectual disabilities Deficits in adaptive functioning Endocrinological Hypocalcaemia and hypoparathyroidism Hypomagnesaemia Thyroid disease (usually hypothyroidism) Obesity and type 2 diabetes mellitus Gastroenterology General gastrointestinal symptoms (constipation, dysphagia) GERD Fatty liver Psychiatric disorders Anxiety Psychosis Autism spectrum disorder ADHD Cardiovascular Congenital cardiac defects Hypertension, arrhythmia, heart failure, aortic root dilation Genitourinary Congenital anomalies, renal cysts, renal failure Menstrual disorders (e.g. dysmenorrhoea) Neurology Seizures, often secondary (e.g. to hypocalcaemia) Early-­onset Parkinson’s disease Other motor disorders (e.g. dystonia, myoclonus) Sleep Sleep pattern disruptions Obstructive sleep apnoea Haematology Mild to moderate thrombocytopenia, mild cytopenias Immune thrombocytopenia Impaired haemostasis (e.g. epistaxis, menorrhagia) GERD, gastro-­esophageal reflux disease.

23 - Psychiatric disorders in people with 22q11.2D

Psychiatric disorders in people with 22q11.2DS

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Psychiatric disorders in people with 22q11.2DS Around 60% of people with 22q11.2DS meet diagnostic criteria for some type of ­psychiatric disorder during their lives.4 Children with 22q11.2DS have an elevated prevalence of anxiety, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders.2 Anxiety disorders are profoundly increased in adults, with about 2–3 times the expected population prevalence.1 Schizophrenia is diagnosed in ­approximately one in every four to five adults with 22q11.2DS.1 Box 10.2 summarises the general principles of prescribing in 22q11.2DS. Few studies have evaluated the safety and efficacy of psychotropics in people with 22q11.2DS. However, standard pharmacological (and non-­pharmacological) treatments for ADHD, anxiety, mood disorders and schizophrenia appear to be effective and treatment protocols used in the general population should be followed.1,5 Current evidence and opinion on the treatment of psychiatric disorders in people with 22q11.2DS are summarised in Table 10.7. Box 10.2  General principles of prescribing in 22q11.2 deletion syndrome6,7 ■ ■22q11.2DS confers an increased risk of treatable psychiatric disorders ■ ■Standard pharmacological treatment protocols should be followed ■ ■Consider the individual patient comorbidities and clinical features (Table 10.6) that may increase the propensity to adverse effects from psychotropics (e.g. arrhythmias, seizures, weight gain, EPSEs) ■ ■Endocrine abnormalities (e.g. hypoparathyroidism and hypothyroidism) should be corrected before starting psychotropics because they can mimic psychiatric symptoms and complicate ­treatment with psychotropics4,5 DS, deletion syndrome; EPSEs, extrapyramidal side effects. Table 10.7  Management of psychiatric disorders in people with 22q11.2 deletion syndrome.8 Psychiatric disorder Treatments ADHD There is a theoretical risk of psychosis with psychostimulants in people with 22q11.2DS but standard treatment protocols are advised.4 In those with congenital heart disease, cardiology advice should be sought before initiating stimulant medications.9 Three studies support the efficacy of methylphenidate in children with 22q11.2DS.4,10 Treatment was generally well tolerated. A comprehensive cardiovascular assessment before and during treatment is recommended. Depression and anxiety Both depression and anxiety appear to respond favourably to SSRIs.4 Further management after treatment failure follows standard protocols. Caution should be exercised with drugs that lower the seizure threshold (e.g. bupropion).7 Obsessive compulsive disorder One study of four people with OCD and 22q11.2DS found a mean rate of improvement of 35% in symptom score after treatment with fluoxetine (30–60mg/day). Treatment was well tolerated.11 (Continued )

24 - References

References

822 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 References

  1. Boot E, et al. Updated clinical practice recommendations for managing adults with 22q11.2 deletion syndrome. Genet Med 2023; 25:100344.
  2. McDonald-­McGinn DM, et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers 2015; 1:15071.
  3. Bayat M, et al. Neurological manifestation of 22q11.2 deletion syndrome. Neurol Sci 2022; 43:1695–1700.
  4. Mosheva M, et al. Effectiveness and side effects of psychopharmacotherapy in individuals with 22q11.2 deletion syndrome with comorbid psychiatric disorders: a systematic review. Eur Child Adolesc Psychiatry 2020; 29:1035–1048.
  5. Fung WL, et al. Practical guidelines for managing adults with 22q11.2 deletion syndrome. Genet Med 2015; 17:599–609.
  6. Tanham M, et al. The effectiveness and tolerability of pharmacotherapy for psychosis in 22q11.2 deletion syndrome: a systematic review. Aust NZ J Psychiatry 2024; 58:393–403.
  7. Van L, et al. Mental health in adults with 22q11. 2 deletion syndrome. In: McDonald-­McGinn DM, ed. The Chromosome 22q11. 2 Deletion Syndrome. London: Academic Press; 2022:322–337.
  8. Baker K, et al. Psychiatric illness. Consensus document on 22q11 deletion syndrome (22q11DS) MaxAppeal. 2017; https://www.maxappeal.org. uk/library-­consensus-­document.
  9. Chung LM, et al. Safety of stimulant medications for attention deficit hyperactivity disorder in paediatric congenital heart disease. J Paediatr Child Health 2023; 59:580–588. Psychiatric disorder Treatments Schizophrenia Standard treatment protocols are generally recommended.1,5 People with 22q11.2DS may be more susceptible to seizures and EPSEs with antipsychotics.7,8 EPSEs must be distinguished from motor problems that may be a direct effect of the 22q11.2DS (diagnosis of Parkinson’s disease may be delayed if misattributed to antipsychotics).7 Specialist neurological opinion and neuroimaging have been recommended to distinguish Parkinson’s disease from antipsychotic-­induced parkinsonism.6 There is a significantly elevated risk of obesity in 22q11.2DS so metabolic adverse effects should be closely monitored.12 Those with cardiac abnormalities have an increased risk of QTc prolongation.8 Close ECG monitoring is recommended.8 Antipsychotics with a low effect on the QT interval are preferred8 (note that hypocalcaemia can also prolong the QT interval7). Low starting doses and slow dose titrations are recommended.8 Case reports have described the successful use of various antipsychotics, with remission of psychosis in 41% of published reports.6 Treatment resistance has been described in 19% of case series and 8% of case reports (although treatment failure was due to adverse effects rather than inefficacy in some).6 Clozapine was found to be effective in one retrospective study of 20 patients with 22q11.2DS.4 Compared with matched controls, lower doses were needed (a median of 250mg/day vs 450mg/ day). However, half of the 22q11.2DS group experienced at least one serious adverse effect from clozapine, primarily seizures, but also myocarditis and neutropenia. Several case reports further support the efficacy of clozapine at low doses (median of 200mg/day) for people with 22q11.2DS, while highlighting the risk of both seizures (generalised or myoclonic) and thrombocytopenia.12 Overall, clozapine appears to have demonstrable efficacy at lower than usual doses, but the risk of rare serious adverse events appears to be relatively high.4 Adjunctive anticonvulsants should be considered12 to mitigate the increased seizure risk when prescribing clozapine.1 Several authors advocate the use of lower starting doses and slower titrations.6 Seizures with other antipsychotics: investigate low calcium and magnesium levels in all cases and ensure adequate treatment.13 Adjunctive anticonvulsants can be considered1 although they should not be prescribed routinely as many do not experience seizures.6 Other agents: drugs that act directly against catecholamine excess may also be effective. Metyrosine, used as a monotherapy or as an adjunctive agent, was found to be effective in 22 of 29 patients in one study.14 An additional positive case report has been published15 but there are no further recent studies. There is a single case study where methyldopa was used successfully.16 DS, deletion syndrome; EPSEs, extrapyramidal side effects; OCD, obsessive compulsive disorder. Table 10.7  (Continued)

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 10. Maeder J, et al. Selective effects of methylphenidate on attention and inhibition in 22q11.2 deletion syndrome: results from a clinical trial. Int J Neuropsychopharmacol 2022; 25:215–225. 11. Gothelf D, et  al. Obsessive-­compulsive disorder in patients with velocardiofacial (22q11 deletion) syndrome. Am J Med Genet B Neuropsychiatr Genet 2004; 126b:99–105. 12. De Boer J, et al. Adverse effects of antipsychotic medication in patients with 22q11.2 deletion syndrome: a systematic review. Am J Med Genet A 2019; 179:2292–2306. 13. Bassett AS, et al. Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr 2011; 159:332–339. 14. Faedda GL, et al. 4.19 Treatment of velo-­cardio-­facial syndrome-­related psychosis with metyrosine. J Am Acad Child Adolesc Psychiatry 2016; 55:S169. 15. Engebretsen MH, et  al. Metyrosine treatment in a woman with chromosome 22q11.2 deletion syndrome and psychosis: a case study. Int J Dev Disabil 2019; 65:116–121. 16. O’Hanlon JF, et al. Replacement of antipsychotic and antiepileptic medication by L-­alpha-­methyldopa in a woman with velocardiofacial syndrome. Int Clin Psychopharmacol 2003; 18:117–119.

25 - Learning disabilities

Learning disabilities

26 - General considerations1

General considerations1

27 - Key practice areas

Key practice areas

824 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Learning disabilities General considerations1 Prescribing psychotropic medications for people with learning disabilities (LD) is a ­challenging and controversial area of psychiatric practice.2,3 There are concerns that psychotropic drugs of all kinds (antipsychotics, antidepressants, benzodiazepines [both regular and as required] and antiepileptics as mood stabilisers) are overprescribed with poor review and assessment of their benefit. The LD field is notable in having only a small therapeutics research base of its own, with particular ethical and practical considerations regarding how emotional and behavioural disturbances are classified and treated. Although prescribing for individuals with mild or borderline intellectual impairment may be undertaken by mainstream mental health services, the assessment and treatment of behavioural and emotional disorders in people with more marked (or, as in the case of autism, atypical) patterns of significant cognitive impairment should be undertaken in the first instance by, or at least in consultation with, specialist clinicians. The term ‘dual diagnosis’ in this context refers to the co-­occurrence of an identifiable psychiatric disorder (mental illness, personality disorder) and LD. ‘Diagnostic overshadowing’ is the misattribution of emotional or behavioural problems to LD itself rather than a comorbid condition. LD is an important risk factor for all psychiatric disorders (including dementia, particularly for individuals with Down’s syndrome).4 Where it is possible to diagnose a mental illness using conventional or modified criteria then drug treatment in the first instance should, in general, be similar to that in the population at large. Most treatment guidelines are increasingly stating their intended applicability to people with LD. Mental illness may present in unusual ways in LD, for example depression as self-­ injurious behaviour, or persecutory ideation as complaints of being ‘picked on’. Conversely, behaviours such as self-­talk may be normal in some individuals but ­mistakenly identified as a disorder such as psychosis. In general, diagnosis becomes increasingly complex with increasing severity of disability and associated communication impairment. Comorbid autistic spectrum disorder has special assessment considerations and in its own right is an important risk factor for psychiatric disorder, in particular anxiety and depression, bipolar spectrum disorder, severe obsessional behaviour, anger disorders and psychosis-­like episodes that may not meet criteria for schizophrenia but nonetheless require treatment. Autistic traits are common among patients using LD services. Guidance on the treatment of mental health problems in autism can be found in Chapter 5. Key practice areas Capacity and consent It is uncommon for patients in LD services (who often represent a subpopulation of those identified with special educational needs in childhood) to have sufficient understanding of their treatment in order to be able to take truly informed decisions. There is inevitably an increased onus on the clinician to bear the weight of decision-­making. The patient’s decision-­making capacity, depending on the severity of intellectual

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 impairment, may be improved through appropriate verbal and written ­communication. The involvement of carers in this process is generally essential. Physical comorbidity, especially epilepsy Epilepsy is over-­represented in LD populations, becoming more prevalent as severity increases, with approximately one-­third of affected individuals developing a seizure disorder by early adulthood. Special consideration is needed when considering the use of medications that may lower seizure threshold or interact with drugs used for epilepsy. Assessment of care environments Behavioural and emotional disturbance may sometimes be a reflection of problems or failings in the care environment. Different staff in a care home may have different thresholds of tolerance (or make different attributions) for these difficulties which can lead to varied reports of their significance and impact. Allowing for a period of prospective assessment and using simple assessment tools (e.g. simple ABC or sleep charts) can be very helpful to the clinician in making judgements about recommending medication. If medication is used in a care home, staff may need special education in its use and anticipated adverse effects and, for ‘as required’ medications, clear guidelines for its use. This may make it difficult to initiate certain treatments in the community. Adverse effect sensitivity It is widely thought that people with LD are especially sensitive to adverse effects of psychotropics and more at risk of long-­term effects such as the metabolic syndrome. However, we only know of one study that has given support to this view. A cohort study extracting information from a large UK primary care database compared the incidence of EPSEs of antipsychotics in adults with LD with that in adults without LD. The incidence of EPSEs was 30% higher in people with LD than in those without LD.5 It is good practice to start at lower doses and increase more slowly than might be usual in general psychiatric practice. Notable adverse effects include worsening of seizures, sedation, extrapyramidal reactions (including with risperidone at normal doses, especially in individuals who already have mobility problems), problems with swallowing (with clozapine and other antipsychotics) and worsening of cognitive function with anticholinergic medications (see Chapter 6). Psychological interventions In the absence of an identifiable mental illness (including atypical presentations) with  clear treatment implications, psychological interventions such as functional ­behavioural analysis should be considered as first-­line intervention for all but the most serious or intractable presentations of behavioural disturbance (Table 10.8). In studies where it has been possible to infer the severity of challenging behaviour, treatment response is generally associated with more severe problems at baseline.

826 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Table 10.8  Some notes on currently and historically used medications for behaviour disorder. Drug class Clinical applications Notes Antipsychotics6 Use in psychosis with LD is justified Used across a broad range of behavioural disturbances7 May be useful for aggression and irritability The most widely used8,9 yet most controversial medication for behavioural problems.10,11 Although an RCT12 casts doubt on their efficacy for this indication the study was not without its problems and there is a significant body of other evidence supporting their use, including a number of small RCTs in children with LD. Discontinuation studies in long-­term treatment commonly (but not always) show re-­emergence of problem behaviours. NICE suggests considering slow withdrawal of antipsychotics in all those who do not have psychotic symptoms.13 The UK STOMP programme promotes deprescribing of antipsychotics.14 It has been successful, but antipsychotics are often replaced by other psychotropics.15 A 2022 analysis of UK NHS data suggests antidepressants now replace antipsychotics as the most widely prescribed psychotropic.16 Before the advent of SGAs the best evidence was for haloperidol17 in the context of autism and for zuclopenthixol for behavioural disturbance.18 Zuclopenthixol may reduce aggression and challenging behaviour.19 Among SGAs the best evidence is for risperidone20,21 at low dose (0.5–2mcg) for aggression and mood instability, particularly with associated autism though also in non-­autistic cases. Aripiprazole has a US FDA licence for behavioural disturbance in young people with autism.22,23 Some evidence to support olanzapine24 and case reports of clozapine25 for very severe cases of aggression, though not widely used and unlikely to be used outside highly specialist (in-­patient) settings. In 2015, Cochrane uncovered 38 case reports and chart reviews but found no RCT evidence for the use of clozapine in psychosis in LD.26 Results for quetiapine are modest at best.27 SSRIs Helpful for severe anxiety and obsessionality in autistic spectrum disorder. Use here is off-­licence unless an additional diagnosis of anxiety disorder or OCD is made Also used as a first-­line alternative to antipsychotics for aggression and impulsivity Commonly used in combination with antipsychotics though limited evidence base for combination treatment. Effectiveness in absence of mood or anxiety spectrum disorder is unclear, however, and a 2013 Cochrane review was pessimistic28 about the evidence for their effectiveness for behaviour disorder in autistic children (who may be at heightened risk of adverse effects) though a little more encouraging for use in adults. Some good evidence for fluoxetine in OCD in LD/autism although the drop-­out rate is high.29 Generally, quality of trials is poor and effects may be exaggerated by use in less severe cases.30 Caution needed because of the risk of precipitation of hypomania in this population.31 As with antipsychotics, there are major concerns about overprescribing.32 Venlafaxine is probably not effective.33

28 - References

References

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 References

  1. Deb S. The use of medications for the management of problem (challenging) behaviours in adults who have intellectual disabilities. University of Hertfordshire. 2012 (revised 2018, last accessed July 2024); https://www.intellectualdisability.info/mental-­health/articles/the-­use-­of- ­medications-­for-­the-­management-­of-­problem-­behaviours-­in-­adults-­who-­have-­intellectual-­disabilities.
  2. Sheehan R, et al. Psychotropic prescribing in people with intellectual disability and challenging behaviour. BMJ 2017; 358:j3896.
  3. Ji NY, et al. Pharmacotherapy for mental health problems in people with intellectual disability. Curr Opin Psychiatry 2016; 29:103–125.
  4. Cooper SA, et  al. Mental ill-­health in adults with intellectual disabilities: prevalence and associated factors. Br J Psychiatry 2007; 190:27–35.
  5. Sheehan R, et al. Movement side effects of antipsychotic drugs in adults with and without intellectual disability: UK population-­based cohort study. BMJ Open 2017; 7:e017406.
  6. Antochi R, et al. Psychopharmacological treatments in persons with dual diagnosis of psychiatric disorders and developmental disabilities. Postgrad Med J 2003; 79:139–146. Drug class Clinical applications Notes Anticonvulsants34 Aggression and self-­injury Some uncontrolled studies supporting sodium valproate35 in LD populations though evidence is not strong and research findings are contradictory. However, valproate remains best supported of the anticonvulsants for mood lability and aggression, partly because of positive studies in non-­LD groups.36 Limited studies of lamotrigine, mostly in children, suggest no effect, at least in autism and in the absence of affective instability.27 Data for carbamazepine also unconvincing, but it is still widely used.37 Lithium38 Licensed for the treatment of self-­injurious behaviour and aggression Some RCT evidence39 for LD but there have been no studies in this population for many years,3 although there has been one fairly recent positive RCT for its use in aggression in adolescents without developmental impairment.40 Experience suggests it can be very helpful in individual cases where other treatments have failed and is possibly underused, though adverse effects can be problematic. Perhaps best considered where there is a sub-­syndromal or non-­specific ‘affective component’. Some authorities suggest that, on close examination, challenging behaviour may occur in the context of very rapid cycling bipolar disorder in some individuals with severe and profound LD and that the diagnosis is easily missed. Some RCT evidence that short-­term use is reasonably well tolerated (at 6mg/kg).41 Methylphenidate Effective in ADHD associated with LD NICE13 conducted a meta-­analysis and found clear benefit for methylphenidate (and risperidone and clonidine) in ADHD in the context of LD. Insomnia is common. Naltrexone42 Has been used for severe self-­injurious behaviour43 Evidence not strong and results are inconsistent. Use may still be an option in severe and intractable cases. One case of successful treatment of kleptomania.44 Overall, clinical use has declined of late.45 FDA, Food and Drug Administration; LD, learning disability; OCD, obsessive compulsive disorder. Table 10.8  (Continued)

828 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 7. Lunsky Y, et al. Antipsychotic use with and without comorbid psychiatric diagnosis among adults with intellectual and developmental ­disabilities. Can J Psychiatry 2017; 63:361–369. 8. Deb S, et al. Characteristics and the trajectory of psychotropic medication use in general and antipsychotics in particular among adults with an intellectual disability who exhibit aggressive behaviour. J Intellect Disabil Res 2015; 59:11–25. 9. Sheehan R, et al. Mental illness, challenging behaviour, and psychotropic drug prescribing in people with intellectual disability: UK population based cohort study. BMJ 2015; 351:h4326. 10. Deb S, et al. The effectiveness of antipsychotic medication in the management of behaviour problems in adults with intellectual disabilities. J Intellect Disabil Res 2007; 51:766–777. 11. Roy D, et al. Pharmacologic management of aggression in adults with intellectual disability. J Intellect Disabil Res 2013; 1:28–43. 12. Tyrer P, et al. Risperidone, haloperidol, and placebo in the treatment of aggressive challenging behaviour in patients with intellectual disability: a randomised controlled trial. Lancet 2008; 371:57–63. 13. National Institute of Health and Care Excellence. Mental health problems in people with learning disabilities: prevention, assessment and management. NICE Guideline [NG54]. 2016 (last checked November 2020, last accessed March 2024); https://www.nice.org.uk/Guidance/ NG54. 14. Shankar R, et al. Stopping, rationalising or optimising antipsychotic drug treatment in people with intellectual disability and/or autism. Drug Ther Bull 2019; 57:10–13. 15. Deb S, et al. UK psychiatrists’ experience of withdrawal of antipsychotics prescribed for challenging behaviours in adults with intellectual disabilities and/or autism. Br J Psych Open 2020; 6:e112. 16. Branford D, et  al. Antidepressant prescribing for adult people with an intellectual disability living in England. Br J Psychiatry 2022; 221:488–493. 17. Malone RP, et al. The role of antipsychotics in the management of behavioural symptoms in children and adolescents with autism. Drugs 2009; 69:535–548. 18. Malt UF, et al. Effectiveness of zuclopenthixol compared with haloperidol in the treatment of behavioural disturbances in learning disabled patients. Br J Psychiatry 1995; 166:374–377. 19. Hassler F, et  al. Treatment of aggressive behavior problems in boys with intellectual disabilities using zuclopenthixol. J Child Adolesc Psychopharmacol 2014; 24:579–581. 20. Nagaraj R, et  al. Risperidone in children with autism: randomized, placebo-­controlled, double-­blind study. J Child Neurol 2006; 21:450–455. 21. Pandina GJ, et al. Risperidone improves behavioral symptoms in children with autism in a randomized, double-­blind, placebo-­controlled trial. J Autism Dev Disord 2007; 37:367–373. 22. Owen R, et  al. Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics 2009; 124:1533–1540. 23. Marcus RN, et al. A placebo-­controlled, fixed-­dose study of aripiprazole in children and adolescents with irritability associated with autistic disorder. J Am Acad Child Adolesc Psychiatry 2009; 48:1110–1119. 24. Fido A, et al. Olanzapine in the treatment of behavioral problems associated with autism: an open-­label trial in Kuwait. Med Princ Pract 2008; 17:415–418. 25. Zuddas A, et al. Clinical effects of clozapine on autistic disorder. Am J Psychiatry 1996; 153:738. 26. Ayub M, et al. Clozapine for psychotic disorders in adults with intellectual disabilities. Cochrane Database Syst Rev 2015; 9:CD010625. 27. Stigler KA, et  al. Pharmacotherapy of irritability in pervasive developmental disorders. Child Adolesc Psychiatr Clin N Am 2008; 17:739–752. 28. Williams K, et al. Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Syst Rev 2013; 8:CD004677. 29. Reddihough DS, et al. Effect of fluoxetine on obsessive-­compulsive behaviors in children and adolescents with autism spectrum disorders: a randomized clinical trial. JAMA 2019; 322:1561–1569. 30. Myers SM. Citalopram not effective for repetitive behaviour in autistic spectrum disorders. Evid Based Ment Health 2010; 13:22. 31. Cook Jr, EH, et al. Fluoxetine treatment of children and adults with autistic disorder and mental retardation. J Am Acad Child Adolesc Psychiatry 1992; 31:739–745. 32. Oswald DP, et al. Medication use among children with autism spectrum disorders. J Child Adolesc Psychopharmacol 2007; 17:348–355. 33. Carminati GG, et al. Using venlafaxine to treat behavioral disorders in patients with autism spectrum disorder. Prog Neuropsychopharmacol Biol Psychiatry 2016; 65:85–95. 34. Deb S, et al. The effectiveness of mood stabilizers and antiepileptic medication for the management of behaviour problems in adults with intellectual disability: a systematic review. J Intellect Disabil Res 2008; 52:107–113. 35. Ruedrich S, et al. Effect of divalproex sodium on aggression and self-­injurious behaviour in adults with intellectual disability: a retrospective review. J Intellect Disabil Res 1999; 43 Pt 2:105–111. 36. Donovan SJ, et al. Divalproex treatment for youth with explosive temper and mood lability: a double-­blind, placebo-­controlled crossover design. Am J Psychiatry 2000; 157:818–820. 37. Unwin GL, et al. Use of medication for the management of behavior problems among adults with intellectual disabilities: a clinicians’ ­consensus survey. Am J Ment Retard 2008; 113:19–31. 38. Pary RJ. Towards defining adequate lithium trials for individuals with mental retardation and mental illness. Am J Ment Retard 1991; 95:681–691. 39. Craft M, et  al. Lithium in the treatment of aggression in mentally handicapped patients. A double-­blind trial. Br J Psychiatry 1987; 150:685–689.

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 40. Malone RP, et  al. A double-­blind placebo-­controlled study of lithium in hospitalized aggressive children and adolescents with conduct ­disorder. Arch Gen Psychiatry 2000; 57:649–654. 41. Yuan J, et al. Lithium treatment is safe in children with intellectual disability. Front Mol Neurosci 2018; 11:425. 42. Campbell M, et al. Naltrexone in autistic children: an acute open dose range tolerance trial. J Am Acad Child Adolesc Psychiatry 1989; 28:200–206. 43. Barrett RP, et al. Effects of naloxone and naltrexone on self-­injury: a double-­blind, placebo-­controlled analysis. Am J Ment Retard 1989; 93:644–651. 44. Mouaffak F, et al. Kleptomania treated with naltrexone in a patient with intellectual disability. J Psychiatry Neurosci 2020; 45:71–72. 45. Sabus A, et  al. Management of self-­injurious behaviors in children with neurodevelopmental disorders: a pharmacotherapy overview. Pharmacotherapy 2019; 39:645–664.

29 - Huntingtons disease

Huntington’s disease

30 - Motor symptoms

Motor symptoms

830 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Huntington’s disease Huntington’s disease (HD) is a genetic neurodegenerative disease with an estimated prevalence of 4.88 individuals per 100,000 worldwide, and a higher incidence in Europe and North America.1 The mutant Huntington protein causes neuronal dysfunction and death through several mechanisms, resulting in a triad of motor, cognitive and neuropsychiatric symptoms.2 There are currently no disease-­modifying treatments3,4 so symptomatic therapies are used to improve quality of life (Box 10.3). There are few controlled studies to guide practice in this area,3 although some direction can be drawn from published expert opinion and clinical experience. A summary of the available literature is given in this section. Readers are directed to the reports cited for details of dosage regimens and further information about tolerability. Clinicians who treat patients with HD are encouraged to publish reports of both positive and negative outcomes to increase the primary literature base. Motor symptoms Motor disturbances follow a biphasic course  – an initial hyperkinetic phase with prominent chorea which tends to plateau over time, and a later hypokinetic phase characterised by bradykinesia, dystonia, balance and gait disturbance.7 With regard to chorea, the goal of treatment is not to obliterate movements but to reduce their severity to achieve better tolerability.5 Treatment pathways are available to guide management.8 First-­line treatments include tetrabenazine (licensed) or SGAs (unlicensed) (Table 10.9).8 Monotherapy is preferred to prevent an increased risk of adverse effects and complicating the management of non-­motor symptoms.8 Box 10.3  General principles of pharmacological symptom management in Huntington’s disease5,6 ■ ■Tailor management to the needs of the individual patient (treatment is typically initiated when symptoms become bothersome, interfering or socially stigmatising) ■ ■Check whether existing medications are causing or exacerbating symptoms before commencing new treatments ■ ■Prioritise treatment to target the most troublesome symptoms first, with consideration of comorbid features ■ ■Balance therapeutic benefit with the potential for adverse effects ■ ■Start with a low dose and titrate according to tolerability and response (patients are relatively more sensitive to cognitive and motor adverse effects which may also be difficult to distinguish from disease progression) ■ ■Regularly follow up with patients to address changes in treatment (because symptomology evolves with disease progression)

31 - Mental and behavioural symptoms

Mental and behavioural symptoms

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Mental and behavioural symptoms A wide variety of mental and behavioural symptoms occur in HD, including anxiety, depression, suicidality, preservation, disinhibition, irritability, apathy and, rarely, psychosis.13 Mental and behavioural symptoms can emerge before motor disturbances and reduce quality of life substantially.13 In comparison with other HD features, psychiatric symptoms are perhaps the most amenable to pharmacotherapy.6 In general, psychiatric treatment choices are selected as they would be in other conditions5 although patients are relatively more sensitive to adverse effects.5 The most commonly prescribed psychotropics are summarised in Tables  10.10 and  10.11 (mostly based on low-­quality evidence).13 Table 10.9  Evidence and experience regarding the pharmacological treatment of motor symptoms in Huntington’s disease (HD). Symptoms Treatment Chorea Tetrabenazine: unlike antipsychotics, tetrabenazine’s effectiveness is well established.2,3,8 However, adverse effects including sedation, depression and parkinsonism may limit its clinical benefit. In clinical practice, many prefer to use tetrabenazine first line in patients without depressive symptoms and suicidal behaviour.8 Compliance with a multiple daily dosing regimen (e.g. three times a day) is needed. Other VMAT2 inhibitors: deutetrabenazine and valbenazine are licensed in the USA for the treatment of chorea in HD.2,4,9 Where available, they may be preferred over tetrabenazine owing to an improved pharmacokinetic and adverse effect profile,2,9 although direct comparisons are lacking.4 Antipsychotics: considered first-­line treatment in clinical practice, particularly in the presence of depression, aggression, psychosis or when poor drug compliance is suspected5,8,10 despite a lack of data from RCTs.2 SGAs such as aripiprazole, risperidone or olanzapine are used most commonly.8,11 Potentially limiting adverse effects include dyskinesia, parkinsonism and metabolic syndrome.5 FGAs have been used successfully but are less popular in clinical practice because of the risk of EPSEs.10 LAI antipsychotics have been used in some published case reports, in cases of non-­ compliance or motor fluctuations with oral antipsychotics.12 For severe chorea, antipsychotics and VMAT2 inhibitors have been used in combination.8 Note that VMAT2 inhibitors have the potential for QT prolongation, as do most antipsychotics. Hypokinetic rigidity Levodopa may provide partial and temporary relief of symptoms.8 Note the potential for such drugs to exacerbate behavioural disturbances. Rigidity may be caused/worsened by antipsychotics or tetrabenazine; dose reduction or discontinuation should be considered in the first instance, after weighing any derived benefits against symptom severity.8 Positive case reports exist for amantadine and dopamine agonists (although guidelines do not make recommendations on their use).8 Myoclonus Valproate or clonazepam has been suggested, used alone or combination.8 Levetiracetam is a therapeutic alternative.8 Dystonia Low-­dose tetrabenazine has been suggested11 and a 2022 review concluded that deutetrabenazine is likely also to be effective.2 Botulinum toxin injections have been suggested for focal dystonia;8 clonazepam or baclofen has been suggested for non-­focal dystonia.5 EPSEs, extrapyramidal side effects; LAI, long-­acting injectable; VMAT2, vesicular monoamine transporter 2.

832 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Table 10.10  Pharmacological treatment of mental and behavioural symptoms in Huntington’s disease (HD). Symptoms Treatment Anxiety Reported 16.7–24% lifetime prevalence in HD.13 There are no RCTs to guide choice; however, olanzapine 5mg/day substantially improved anxiety symptoms in one small open-­label pilot study.13 SSRIs and SNRIs have been suggested as first-­line treatment.5,8 Some guidelines have recommended considering SGAs (quetiapine8, risperidone or olanzapine) for anxiety associated with personality or behavioural disturbances14 or when other treatments fail.8 Anxiolytics such as benzodiazepines or buspirone may also be useful.11,14 Depression Reported 30–70% prevalence in HD.15 Treatment is typically required because depression is linked to a lower quality of life in HD and increases the risk of suicide.13,15 There are almost no RCTs to guide choice.11,16 However, most experts agree that depression in HD responds well to antidepressants. SSRIs are the preferred first-­line treatment5,8 but this is based on a less than perfect literature base.17 SSRIs: two controlled trials examined the effects of fluoxetine and citalopram in non-­depressed patients with HD. Despite excluding depressed patients, both showed near significant improvements in depressive symptoms.16 Note that VMAT2 inhibitors are metabolised by CYP2D6; so inhibitors of this enzyme (e.g. fluoxetine, paroxetine) are predicted to increase exposure to active metabolites. SNRIs: venlafaxine was effective in an uncontrolled study;16 however, one in five developed adverse effects such as nausea and irritability.13 TCAs: beneficial effects reported in some cases18 but generally their use should be avoided or limited. Anticholinergic properties of TCAs may worsen hyperkinesias and cognition.11,18 Toxicity in overdose may also make them less suitable choices (suicidality is increased in HD13). Others: Mirtazapine was used successfully in one case report of severe depression.5 In a case registry study it was one of the most frequently prescribed treatments for depression in HD.13 Bupropion and SSRIs were found to be superior to SNRIs in one analysis of an observational study.19 Lithium produced improvements in suicidality in a small case series16 but experience is very limited, and tolerability may be poor. MAOIs have been used in earlier case studies;18 a lack of recent experience and important interactions with VMAT2 inhibitors make these less suitable. ECT can be used safely and effectively and may be considered in life-­threatening cases.8,20 Obsessive compulsive behaviours or perseveration There are no RCTs.21 International consensus supports the use of SSRIs first line;8 use of clomipramine is also supported13 but tolerability may be poor. Case studies document the successful use of fluoxetine, paroxetine and sertraline.5 One study of two patients with perseveration and aggression reported beneficial effects with buspirone.13 For ideational perseveration, consensus also supports the use of olanzapine or risperidone (particularly if associated with irritability).8 Irritability or agitation22 Reported prevalence of 38–73% in HD. Initial management is non-­pharmacological (e.g. by addressing possible triggers such as pain or akathisia and using behavioural/psychological approaches). No medications are approved specifically, but expert consensus supports the use of SSRIs as preferred first-­line agents, with antipsychotics being the next most favoured alternative monotherapy. Clinical features influence treatment choice. For example, SGAs (e.g. olanzapine, risperidone, quetiapine) may be preferred in the presence of chorea, acute irritability, aggression or impulsivity. Benzodiazepines are a widely used adjunctive therapy. Guidelines have also recommended mirtazapine or mianserin in patients not benefitting from maximum doses of SSRIs, especially in those with a comorbid sleep disorder. In cases non-­responsive to antidepressants and/or antipsychotics, adjunctive mood stabilisers have also been recommended.8 The effect of dextromethorphan/quinidine for irritability in HD is, at the time of writing, being studied in a phase III RCT.4 Aggressive behaviours: a wide variety of psychotropics have been used with reported beneficial effects (e.g. antipsychotics, lithium, valproate, propranolol, medroxyprogesterone, SSRIs, buspirone).18,23 Antipsychotics have been used most commonly. The evidence base is too limited to make specific treatment recommendations23 but low-­dose antipsychotics can be considered.5 ECT was helpful in a few case reports of agitation refractory to pharmacotherapy.20

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Symptoms Treatment Apathy Common in HD and appears to worsen with disease progression.13 Some sedative medications (e.g. antipsychotics, benzodiazepines, tetrabenazine) may contribute, so dose reduction or withdrawal should be considered.8 In one small open study of 16 participants, cariprazine was associated with improvements in apathy, depressive symptoms and cognitive test scores.11 Bupropion was studied in one multicentre RCT and found to be ineffective.11 Other agents, including methylphenidate, atomoxetine, modafinil, amantadine and bromocriptine, have been trialled with little success.13 Psychosis One of the least prevalent psychiatric manifestations of HD, perhaps because of the use of antidopaminergics for motor symptoms.13 There are no RCTs to guide choice11 – treatment is empirical. Note that antipsychotic drugs may exacerbate any underlying movement disorder. VMAT2 inhibitors may have antipsychotic activity24 but they are not drugs of choice for psychosis in HD. SGAs: olanzapine and risperidone are used most frequently.13 Low starting doses are recommended.5 Case reports support the efficacy of risperidone, quetiapine, aripiprazole and amisulpride.18 Clozapine may be considered in refractory cases6,18 or akinetic forms of HD with debilitating parkinsonian symptoms.8,11 FGAs: used less frequently due to the risk of dystonia and parkinsonism; however, haloperidol has been used when chorea is also problematic to the patient.18 MAOIs, monoamine oxidase inhibitors; TCAs, tricyclic antidepressants; VMAT2, vesicular monoamine transporter 2. Table 10.10  (Continued) Table 10.11  Summary of treatments for mental state and behavioural changes in Huntington’s disease.6,8,13 Symptoms Most commonly prescribed pharmacological treatments Alternatives Anxiety SSRIs, mirtazapine, pregabalin, venlafaxine Olanzapine, risperidone, quetiapine, benzodiazepines, propranolol, buspirone Depression or suicidality SSRIs, bupropion, mirtazapine, venlafaxine TCAs; ECT in refractory cases Obsessive compulsive behaviours SSRIs Clomipramine Irritability or agitation SSRIs, SGAs (olanzapine, risperidone, sulpiride), tiapride, benzodiazepines Anticonvulsants (lamotrigine, carbamazepine, valproate), TCAs, buspirone, propranolol; consider trial of an analgesic Apathy None None Psychosis Olanzapine, risperidone, haloperidol, sulpiride, tiapride, LAI antipsychotics Clozapine, quetiapine LAI, long-­acting injectable; TCAs, tricyclic antidepressants.

32 - Cognitive symptoms

Cognitive symptoms

33 - References

References

834 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Cognitive symptoms Cognitive disturbances may emerge many years before motor disturbances.7 The progression of cognitive decline is gradual25 and dementia is inevitable in late stages. Although a wide variety of agents have been studied,2,11 none has become established treatment and the benefit of most remains unclear.26 There is insufficient evidence to support the use of acetylcholinesterase inhibitors27 and no evidence to support any other medications to treat dementia in HD.11,28 References

  1. Medina A, et al. Prevalence and incidence of Huntington’s disease: an updated systematic review and meta-­analysis. Mov Disord 2022; 37:2327–2335.
  2. Ferreira JJ, et al. An MDS evidence-­based review on treatments for Huntington’s disease. Mov Disord 2022; 37:25–35.
  3. Mestre T, et al. Therapeutic interventions for disease progression in Huntington’s disease. Cochrane Database Syst Rev 2009; 2009:CD006455.
  4. Van de Roovaart HJ, et al. Huntington’s disease drug development: a phase 3 pipeline analysis. Pharmaceuticals (Basel) 2023; 16:1513.
  5. Killoran A, et al. Current therapeutic options for Huntington’s disease: good clinical practice versus evidence-­based approaches? Mov Disord 2014; 29:1404–1413.
  6. Anderson KE, et  al. Clinical management of neuropsychiatric symptoms of Huntington disease: expert-­based consensus guidelines on ­agitation, anxiety, apathy, psychosis and sleep disorders. J Huntingtons Dis 2018; 7:355–366.
  7. McColgan P, et al. Huntington’s disease: a clinical review. Eur J Neurol 2018; 25:24–34.
  8. Bachoud-­Lévi AC, et al. International guidelines for the treatment of Huntington’s disease. Front Neurol 2019; 10:710.
  9. Furr Stimming E, et al. Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington’s disease (KINECT-­HD): a phase 3, randomised, double-­blind, placebo-­controlled trial. Lancet Neurol 2023; 22:494–504.
  10. Unti E, et al. Antipsychotic drugs in Huntington’s disease. Expert Rev Neurother 2017; 17:227–237.
  11. Saft C, et al. Symptomatic treatment options for Huntington’s disease (guidelines of the German Neurological Society). Neurol Res Pract 2023; 5:61.
  12. Javelot H, et al. Benefit of long-­acting paliperidone in Huntington’s disease: a case report. Int Clin Psychopharmacol 2021; 36:101–103.
  13. Eddy CM, et al. Changes in mental state and behaviour in Huntington’s disease. Lancet Psychiatry 2016; 3:1079–1086.
  14. Desamericq G, et al. Guidelines for clinical pharmacological practices in Huntington’s disease. Rev Neurol (Paris) 2016; 172:423–432.
  15. Jellinger KA. The pathobiology of depression in Huntington’s disease: an unresolved puzzle. J Neural Transm 2024; doi: 10.1007/ s00702-­024-­02750-­w.
  16. Moulton CD, et al. Systematic review of pharmacological treatments for depressive symptoms in Huntington’s disease. Mov Disord 2014; 29:1556–1561.
  17. Zadegan SA, et al. Treatment of depression in Huntington’s disease: a systematic review. J Neuropsychiatry Clin Neurosci 2024; doi: 10.1176/ appi.neuropsych.20230120.
  18. van Duijn E. Medical treatment of behavioral manifestations of Huntington disease. Handb Clin Neurol 2017; 144:129–139.
  19. McLauchlan DJ, et al. Different depression: motivational anhedonia governs antidepressant efficacy in Huntington’s disease. Brain Commun 2022; 4:fcac278.
  20. Yahya A, et al. Electroconvulsive therapy in Huntington’s disease. Prog Neurol Psychiatry 2021; 25:33–38.
  21. Oosterloo M, et al. Obsessive-­compulsive and perseverative behaviors in Huntington’s disease. J Huntingtons Dis 2019; 8:1–7.
  22. Karagas NE, et al. Irritability in Huntington’s disease. J Huntingtons Dis 2020; 9:107–113.
  23. Fisher CA, et al. Aggression in Huntington’s disease: a systematic review of rates of aggression and treatment methods. J Huntingtons Dis 2014; 3:319–332.
  24. 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.
  25. Ross CA, et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol 2014; 10:204–216.
  26. Van der Vaart T, et al. Treatment of cognitive deficits in genetic disorders: a systematic review of clinical trials of diet and drug treatments. JAMA Neurol 2015; 72:1052–1060.
  27. Li Y, et  al. Cholinesterase inhibitors for rarer dementias associated with neurological conditions. Cochrane Database Syst Rev 2015; 3:CD009444.
  28. O’Brien JT, et  al. Clinical practice with anti-­dementia drugs: a revised (third) consensus statement from the British Association for Psychopharmacology. J Psychopharmacol 2017; 31:147–168.

34 - Multiple sclerosis

Multiple sclerosis

35 - Depression

Depression

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Multiple sclerosis Individuals with multiple sclerosis (MS) experience a variety of psychiatric and neurological disorders. These include depression, anxiety, pathological laughter and crying (pseudobulbar affect, PBA), mania, euphoria, psychosis, bipolar disorder, fatigue and cognitive impairment. Psychiatric disorders result from a variety of factors – the psychological impact of MS diagnosis and its prognosis, perceived lack of social support or unhelpful coping styles, increased stress, iatrogenic effects of treatments used with MS and MS-­related inflammation and damage to neuronal pathways.1 Depression In people with MS, depression is common with a point prevalence of 14–31%2,3 and lifetime prevalence of up to 50%.4,5 Suicide rates are 2–7.5 times higher than the general population6 and suicidality is seen in more than a fifth of people with MS.7 Depression in MS is often associated with fatigue and pain, although the relationship direction is unclear.8 Overlapping symptoms of depression, PBA and MS can complicate diagnosis and so co-­operation between neurologists and psychiatrists is essential to ensure optimal treatment. Depression in MS may result from structural changes in the brain related to MS pathology and, as such, it may differ fundamentally from non-­MS depression.9,10 Suggested treatments are described in Table 10.12. Table 10.12  Recommendations for treatment for depression in multiple sclerosis (MS). Step Intervention Screen for depression with PHQ-­9 HADS/BDI11/CES-­D.12 Exclude or treat any organic causes. Consider iatrogenic effects of medications as potential cause of depression. Ensure there is no past history of mania or bipolar disorder. People with mild depression should be considered for CBT13 or self-­help.14 Guidelines recommend SSRIs as first-­line treatment12,15,16 but have been criticised for the dearth of MS-­specific data.17 Sertraline was as effective as CBT in one trial18 but paroxetine was equivalent to placebo in another.19 Fluoxetine was effective in MS-­related depression in a small case series.20 For those with comorbid pain, consideration should be given to treating with an SNRI such as duloxetine21 or venlafaxine.22 One RCT of desipramine showed it was more effective than placebo but tricyclics in general are often poorly tolerated.23 In 2011, a Cochrane review was not convinced by many of the studies cited here,24 but there is little reason to suppose that antidepressants are any less effective in depression associated with physical illness.25 In 2023, bupropion was shown to be effective in a small RCT.26 Vortioxetine may also improve both depression and anxiety.27 CBT is the most appropriate psychological intervention with best efficacy in comparison with supportive therapy or usual care, and should be used in conjunction with medication for those who are moderately to severely depressed.18,28,29 Mindfulness training may also help.30 Omega-­3 fatty acids are ineffective.31 Because of reduced tolerability of adverse effects in this patient group, medications should be titrated from an initial half dose. Many MS patients are prescribed low-­dose TCAs for pain/bladder disturbance, so SSRIs should be used with caution and patients should be observed for serotonin syndrome. If SSRIs are not tolerated or there is no response, there are limited data that moclobemide is effective and well tolerated.32,33 There are no published trials on venlafaxine, duloxetine and mirtazapine but these are used widely. Mirtazapine may worsen fatigue, at least initially. Venlafaxine and duloxetine are used for pain management in MS.34 ECT could be considered for people who are actively suicidal or severely depressed and at high risk, but it may trigger an exacerbation of MS symptoms, although some studies suggest that no neurological disturbance occurs.35 CBT, cognitive behaviour therapy; TCAs, tricyclic antidepressants.

36 - Anxiety

Anxiety

37 - Pseudobulbar affect

Pseudobulbar affect

38 - Bipolar disorder

Bipolar disorder

39 - Psychosis

Psychosis

836 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Anxiety Anxiety affects many people with MS, with a point prevalence of up to 50%36 and lifetime incidence of 35–37%.37 Elevated rates in comparison with the general ­population are seen for generalised anxiety disorder, panic disorder, obsessive compulsive disorder37 and social anxiety. The uncertainty of prognosis is a major cause of anxiety in MS.38 There are no published trials for the drug treatment of anxiety in MS, but SSRIs can be used and, in non-­responsive cases, venlafaxine might be considered (based on practice in non-­MS patients). Bupropion may also be effective.26 Benzodiazepines may be used for acute and severe anxiety but only for a maximum of 4 weeks and should not be prescribed in the long term. Buspirone and beta-­blockers could also be considered although there is no demonstrated efficacy in MS. Pregabalin is also licensed for anxiety and may be useful in this population group especially where pain relief is required.39,40 People with MS may also respond to cognitive behaviour therapy (CBT). Generally, ­treatment is as for non-­MS anxiety disorders. Pseudobulbar affect Around 25% of individuals with MS experience pathological laughing or crying or other incongruence of affect.41 It is more common in the advanced stages of the disease and is associated with cognitive impairment.37 There have been a few open-­label trials recommending the use of small doses of TCAs such as amitriptyline or SSRIs such as fluoxetine42,43 in MS. Citalopram,44 nortriptyline45 and sertraline46 have been investigated in people with post-­stroke pathological laughing or crying and have shown reasonable efficacy and rapid response. Valproic acid may be effective.47 The combination of ­dextromethorphan and low-­dose quinidine (DMq) is effective.48 Dextromethorphan plus fluoxetine may show similar effects.49 In these combinations, dextromethorphan (an analgesic and cough suppressant) is the active ingredient and quinidine/fluoxetine the metabolic inhibitor. DMq is approved by the US Food and Drug Administration (FDA) as Nuedexta and once held approval in the EU but is not marketed there. Bipolar disorder The lifetime prevalence of bipolar disorder in MS is just less than 10%.50 Lithium can cause diuresis and thus lead to increased difficulties with tolerance in people with MS-­ related bladder disorder. Mania accompanied by psychosis could be treated with low-­ dose antipsychotics such as risperidone, olanzapine51 or ziprasidone.52 Patients requiring psychiatric treatment for steroid-­induced mania with psychosis have been shown to respond to olanzapine.53 Psychosis Psychosis is relatively uncommon compared with other psychiatric disorders.52 A 2015 meta-­analysis estimated the prevalence of psychosis to be 4.3%.1 In a very few cases, psychosis is the presenting complaint of MS.54 There have been few

40 - Cognitive impairment

Cognitive impairment

41 - Fatigue

Fatigue

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 ­published trials, but risperidone or clozapine has been recommended because of the low risk of extrapyramidal symptoms.55 On this basis, olanzapine, aripiprazole and ­quetiapine might also, in theory at least, be possible options. ECT has been used in refractory cases.56 Risperidone, quetiapine, olanzapine and, particularly, clozapine may have ­beneficial immunomodulatory properties.57 Psychosis may rarely be the presentation of an MS relapse in which case steroids may be beneficial but would need to be given under close supervision. Note also the small risk of psychotic reactions in patients receiving tetrahydrocannabinol (THC)-­containing formulations.58,59 Cognitive impairment Cognitive impairment occurs in at least 40–65% of people with MS. Some of the medications commonly prescribed can worsen cognition, such as tizanidine, diazepam and ­gabapentin.60 Although there are no published trials, evidence from clinical case studies suggests that the treatment of sleep difficulties, depression and fatigue can enhance cognitive function.60 There have been two small trials with donepezil for people with mild to moderate cognitive impairment showing moderate efficacy.61,62 A larger study found no effect.63 Similarly, data supporting the use of memantine are weak.64 Overall, no treatment has proven worthwhile efficacy65 and disease-­modifying agents offer greater promise.66 Fatigue Fatigue is a common symptom in MS, with up to 80% of people affected.67 The aetiology of fatigue is unclear but there have been suggestions that disruption of neuronal networks,68 depression or psychological reactions,55 sleep disturbances, inflammation69 or medication may play a role in its development. Pharmacological and non-­ pharmacological strategies67 should be used in a treatment strategy. Non-­pharmacological strategies include reviewing history for any possible contributing factors, assessment and treatment of underlying depression if present, medication, pacing activities and appropriate exercise. One trial suggests that CBT reduces fatigue scores.70 Pharmacological strategies include the use of amantadine71 or modafinil. In the UK, National Institute for Health and Care Excellence (NICE) guidelines suggest no medicine should be used routinely but that amantadine could have a small benefit and should be offered.72 A Cochrane review of amantadine in people with MS suggested that the quality and outcomes of the amantadine trials are inconsistent and that therefore efficacy remains unclear.71 A meta-­analysis of 11 RCTs found supporting data for amantadine73 and a later (2020) meta-­analysis confirmed its value.74 Modafinil has mixed results in clinical trials, but a meta-­analysis of five RCTs75 found clear benefit. Despite doubts over its efficacy, modafinil is widely used in MS.76 A 2023  meta-­analysis of five studies suggested benefit for vitamin D supplementation.77

42 - References

References

838 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 References

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Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 39. Solaro C, et al. Pregabalin for treating paroxysmal painful symptoms in multiple sclerosis: a pilot study. J Neurol 2009; 256:1773–1774. 40. Bittner S, et  al. [Pregabalin and gabapentin in multiple sclerosis: clinical experiences and therapeutic implications]. Nervenarzt 2011; 82:1273–1280. 41. Nabizadeh F, et  al. Pseudobulbar affect in neurodegenerative diseases: a systematic review and meta-­analysis. J Clin Neurosci 2022; 100:100–107. 42. Feinstein A, et al. The effects of anxiety on psychiatric morbidity in patients with multiple sclerosis. Mult Scler 1999; 5:323–326. 43. Feinstein A, et al. Prevalence and neurobehavioral correlates of pathological laughing and crying in multiple sclerosis. Arch Neurol 1997; 54:1116–1121. 44. Andersen G, et al. Citalopram for post-­stroke pathological crying. Lancet 1993; 342:837–839. 45. Robinson RG, et al. Pathological laughing and crying following stroke: validation of a measurement scale and a double-­blind treatment study. Am J Psychiatry 1993; 150:286–293. 46. Burns A, et al. Sertraline in stroke-­associated lability of mood. Int J Geriatr Psychiatry 1999; 14:681–685. 47. Johnson B, et al. Crying and suicidal, but not depressed. Pseudobulbar affect in multiple sclerosis successfully treated with valproic acid: case report and literature review. Palliat Support Care 2015; 13:1797–1801. 48. Pioro EP, et al. Dextromethorphan plus ultra low-­dose quinidine reduces pseudobulbar affect. Ann Neurol 2010; 68:693–702. 49. McGrane I, et  al. Treatment of pseudobulbar affect with fluoxetine and dextromethorphan in a woman with multiple sclerosis. Ann Pharmacother 2017; 51:1035–1036. 50. Joseph B, et al. Prevalence of bipolar disorder in multiple sclerosis: a systematic review and meta-­analysis. Evid Based Ment Health 2021; 24:88–94. 51. Patten SB, et al. Biopsychosocial correlates of lifetime major depression in a multiple sclerosis population. Mult Scler 2000; 6:115–120. 52. Davids E, et al. Antipsychotic treatment of psychosis associated with multiple sclerosis. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28:743–744. 53. Budur K, et al. Olanzapine for corticosteroid-­induced mood disorders. Psychosomatics 2003; 44:353. 54. Camara-­Lemarroy CR, et al. The varieties of psychosis in multiple sclerosis: a systematic review of cases. Mult Scler Relat Disord 2017; 12:9–14. 55. Jefferies K. The neuropsychiatry of multiple sclerosis. Adv Psychiatric Treat 2006; 12:214–220. 56. Narita Z, et al. Possible effects of electroconvulsive therapy on refractory psychosis in primary progressive multiple sclerosis: a case report. Neuropsychopharmacol Rep 2018; 38:92–94. 57. Stamoula Ε, et al. Atypical antipsychotics in multiple sclerosis: a review of their in vivo immunomodulatory effects. Mult Scler Relat Disord 2022; 58:103522. 58. Aragona M, et al. Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: a double-­blind, placebo controlled, crossover study. Clin Neuropharmacol 2009; 32:41–47. 59. Black N, et al. Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-­analysis. Lancet Psychiatry 2019; 6:995–1010. 60. Pierson SH, et al. Treatment of cognitive impairment in multiple sclerosis. Behav Neurol 2006; 17:53–67. 61. Krupp LB, et al. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology 2004; 63:1579–1585. 62. Greene YM, et al. A 12-­week, open trial of donepezil hydrochloride in patients with multiple sclerosis and associated cognitive impairments. J Clin Psychopharmacol 2000; 20:350–356. 63. Krupp LB, et  al. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis. Neurology 2011; 76:1500–1507. 64. Lovera JF, et  al. Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-­controlled trial. Mult Scler 2010; 16:715–723. 65. Chen MH, et al. Cognitive efficacy of pharmacologic treatments in multiple sclerosis: a systematic review. CNS Drugs 2020; 34:599–628. 66. Patti F. Treatment of cognitive impairment in patients with multiple sclerosis. Expert Opin Investig Drugs 2012; 21:1679–1699. 67. Bakshi R. Fatigue associated with multiple sclerosis: diagnosis, impact and management. Mult Scler 2003; 9:219–227. 68. Sepulcre J, et  al. Fatigue in multiple sclerosis is associated with the disruption of frontal and parietal pathways. Mult Scler 2009; 15:337–344. 69. Ormstad H, et al. Chronic fatigue and depression due to multiple sclerosis: immune-­inflammatory pathways, tryptophan catabolites and the gut-­brain axis as possible shared pathways. Mult Scler Relat Disord 2020; 46:102533. 70. Van KK, et al. A randomized controlled trial of cognitive behavior therapy for multiple sclerosis fatigue. Psychosom Med 2008; 70:205–213. 71. Pucci E, et al. Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst Rev 2007; 1:CD002818. 72. National Institute for Health and Care Excellence. Multiple sclerosis in adults: management. NICE guideline [NG220]. 2022 (last checked May 2024); https://www.nice.org.uk/guidance/ng220. 73. Yang TT, et al. Pharmacological treatments for fatigue in patients with multiple sclerosis: a systematic review and meta-­analysis. J Neurol Sci 2017; 380:256–261. 74. Perez DQ, et al. Efficacy and safety of amantadine for the treatment of fatigue in multiple sclerosis: a systematic review and meta-­analysis. Neurodegener Dis Manag 2020; 10:383–395. 75. Shangyan H, et al. Meta-­analysis of the efficacy of modafinil versus placebo in the treatment of multiple sclerosis fatigue. Mult Scler Relat Disord 2018; 19:85–89. 76. Davies M, et al. Safety profile of modafinil across a range of prescribing indications, including off-­label use, in a primary care setting in England: results of a modified prescription-­event monitoring study. Drug Saf 2013; 36:237–246. 77. López-­Muñoz P, et al. Effect of vitamin D supplementation on fatigue in multiple sclerosis: a systematic review and meta-­analysis. Nutrients 2023; 15:2861.

43 - Parkinsons disease

Parkinson’s disease

44 - Depression

Depression

840 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Parkinson’s disease Psychiatric comorbidity is common in Parkinson’s disease (PD). Approximately 25% of PD patients will suffer from major depression, a further 25% from milder forms of depression, 25% from anxiety spectrum disorders and 25% from psychosis.1–3 The risk of developing dementia is 3.5–6-­fold higher, depending on definition, than in age-­ and gender-­matched controls.4 Depression and anxiety often precede PD diagnosis. Anti-­parkinsonian treatment is likely to increase psychiatric comorbidity. Indeed treatment-­linked prolonged cognitive processing may be a harbinger of more disabling morbidity, like deficits in attention, multitasking and difficulties in sequencing and planning.5 While depression and anxiety can occur at any time in the course of PD, psychosis, dementia and delirium are more prevalent in the later stages of the illness. Close co-­operation between the psychiatrist and prescriber of anti-­parkinsonian ­medication is often required to optimise treatment for this group of patients. Depression Depression in PD predicts greater cognitive decline, deterioration in functioning and progression of motor symptoms,6 possibly reflecting more advanced and widespread neurodegeneration involving a variety of neurotransmitter pathways7 and/or inability/ disinclination to seek or comply with remedial therapies. Depression may also occur after the withdrawal of dopamine agonists.8 Similarly, cyclical mood changes follow the on/off fluctuations associated with the levodopa dosage cycle. Suggested treatments are described in Table 10.13. Table 10.13  Recommendations for treatment of depression in Parkinson’s disease (PD). Step Intervention Exclude/treat organic causes such as hypothyroidism (the prevalence of which is relatively high in PD6). SSRIs are considered to be first-­line treatment although the effect size is modest.9–11 Some patients may experience a worsening of motor symptoms,12,13 in particular tremor. Sertraline is the preferred SSRI in PD.14 Care must be taken when combining SSRIs with selegiline (or rasagiline), as the risk of serotonin syndrome is increased.6 The SNRIs venlafaxine15 and duloxetine16 also appear to have some effect although venlafaxine may modestly worsen motor symptoms.15 TCAs are generally poorly tolerated because of their anticholinergic (can worsen cognitive problems and constipation) and alpha-­blocking effects (can worsen symptoms of autonomic dysfunction). A 2022 network meta-­analysis17 showed that dopamine agonists and SSRIs have the highest efficacy and acceptability. Limited evidence supports the safe and effective use of agomelatine,18,19 bupropion20 and vortioxetine.21 Consider augmentation with dopamine agonists/releasers such as pramiprexole.22 Note though that these drugs increase the risk of impulse control disorders.23,24 They have also rarely been associated with the development of psychosis.25 Dopamine agonists are effective antidepressants when used as a single agent.26 Consider ECT. Depression and motor symptoms generally respond well6 but the risk of inducing delirium is high,27 particularly in patients with pre-­existing cognitive impairment. Follow the algorithm for treatment-­resistant depression (see ’Drug treatment of depression’ in Chapter 3) from this point. Be aware of the increased propensity for adverse effects and drug interactions in this patient group. TCAs, tricyclic antidepressants.

45 - Psychosis

Psychosis

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Psychosis Psychosis in PD is often characterised by visual hallucinations.28 Auditory hallucinations and delusions occur far less frequently,29 and usually in younger patients.30 Psychosis and dementia frequently coexist. Having one predicts the development of the other.31 Sleep disorders are also an established risk factor for the development of psychosis.32 The exact aetiology of PD psychosis is poorly understood. In the majority of patients, psychotic symptoms are thought to be secondary to dopaminergic medication rather than part of PD itself. Psychosis secondary to medication may be determined at least in part through polymorphisms of the ACE gene.33 From the limited data available, anticholinergics and dopamine agonists seem to be associated with a higher risk of inducing psychosis than levodopa or catechol-­O-­methyltransferase (COMT) inhibitors.29,34 Psychosis is a major contributor to caregiver distress and a risk factor for institutionalisation and early death.31 Suggested treatments are described in Table 10.14. Table 10.14  Recommendations for treatment of psychosis in Parkinson’s disease (PD). Step Intervention Exclude organic causes (delirium). Optimise the environment to maximise orientation and minimise problems due to poor caregiver–patient interactions. If the patient has insight and hallucinations are infrequent and not troubling, do not treat. Consider reducing or stopping anticholinergics and dopamine agonists. Monitor for signs of motor deterioration. Be prepared to restart/increase the dose of these drugs again to achieve the best balance between psychosis and mobility. Consider an atypical antipsychotic. The efficacy of clozapine (see step 7) is unequivocally supported by placebo-­controlled RCTs.28 In contrast, there are several negative placebo-­controlled trials for quetiapine and olanzapine.28 Low-­dose quetiapine (25–200mg a day) is the least badly tolerated and may have marginal efficacy.35 It is probably reasonable to try quetiapine36 before clozapine but the success rate is minimal. Olanzapine, ziprasidone and aripiprazole are likely to all have greater adverse effects on motor function than quetiapine and have no proven therapeutic effect. Risperidone and conventional antipsychotics should be avoided completely. All antipsychotics may be relatively less effective in managing psychotic symptoms in patients with dementia, and such patients may be more prone to developing motor and cognitive adverse effects.37 Antipsychotics have been associated with an increased risk of vascular events in the elderly. In PD all antipsychotics are linked to increased mortality38 although the effect of clozapine is not known. Consider a cholinesterase inhibitor, particularly if the patient has comorbid dementia.39 Cholinesterase inhibitors may also reduce the risk of falls.40 Early use of these drugs does not prevent or reduce episodes of psychosis although there is some benefit on cognition.41,42 Try clozapine. Clozapine is highly effective in PD psychosis but widely underused.43 It also has useful anti-­tremor properties equivalent to benztropine.44 A 2023 European study45 reported that only 1% of PD psychosis patients received clozapine (72% received quetiapine). Start at 6.25mg – usual dose 25–35mg/day.28,46 Usually safe but neuroleptic malignant syndrome has been reported.47 Monitor as for clozapine in schizophrenia. Older people are more prone to develop serious blood dyscrasia. A case of aplastic anaemia has been reported.48 Overall, clozapine is safer than other antipsychotics in PD psychosis.49 Consider ECT.50 Psychotic and motor symptoms usually respond well51 but the risk of inducing delirium is high,27 particularly in patients with pre-­existing cognitive impairment.

46 - Pimavanserin

Pimavanserin

47 - Cholinesterase inhibitors

Cholinesterase inhibitors

48 - Other treatments

Other treatments

842 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Pimavanserin Pimavanserin is a 5-­HT2A receptor inverse agonist available in the USA and some other countries. It is effective in PD psychosis but has no dopamine receptor activity and does not worsen PD movement disorder or seem to increase mortality.52,53 It is more effective and better tolerated than quetiapine54 and olanzapine.35 Its therapeutic effects seem to increase with the age of the patient.55 Pimavanserin and clozapine are the only drugs unreservedly recommended for PD psychosis.56 A network meta-­analysis suggested only these two drugs had efficacy in PD, while having minimal effect on motor function.49 Clozapine may be effective in pimavanserin non-­responders.57 Cholinesterase inhibitors Cholinesterase inhibitors have been shown to improve cognition, delusions and hallucinations in patients with Lewy body dementia (which has many similarities to PD). Motor function may deteriorate.58,59 Improvements in cognitive functioning are modest.60–62 A Cochrane review and some large RCTs61,63,64 concluded that there is evidence that cholinesterase inhibitors lead to improvements in global functioning, cognition, behavioural disturbance and activities of daily living in PD. Again, motor function may deteriorate64,65 with particular increase in tremor.62 Evidence for memantine is mixed.66,67 Discontinuation of anticholinergic drugs should improve cognition and psychosis – PD patients often have a very high anticholinergic burden, some of this unrelated to the treatment of PD itself.68 Where confounding by indication is removed (where dementia risk could be better explained by indication than a medicine), the classes of medicine with anti-cholinergic properties indicated in dementia are reduced somewhat.69 RCTs are needed to compare deprescribing of maintenance medicines with their continuation in diseases with dementia.5 Other treatments Many patients with PD use complementary therapies, some of which may be modestly beneficial; see Zesiewicz et al.70 Caffeine (and perhaps nicotine)71 may offer a protective effect against the development of PD and also modestly improve motor function in established disease.72 Box 10.4 summarises the treatment of PD. Box 10.4  Simplified summary of treatment in Parkinson’s disease Depression in PD Sertraline is first choice. Venlafaxine and duloxetine are next option. Consider agomelatine or bupropion. Pramipexole is an option in those not already on a dopamine agonist. Psychosis in PD Try low-­dose quetiapine but withdraw if ineffective. Clozapine is the drug of choice for PD psychosis. Pimavanserin may be used where available. Electroconvulsive therapy is a last resort.

49 - References

References

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 References

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  22. Barone P, et al. Pramipexole versus sertraline in the treatment of depression in Parkinson’s disease: a national multicenter parallel-­group randomized study. J Neurol 2006; 253:601–607.
  23. Antonini A, et al. A reassessment of risks and benefits of dopamine agonists in Parkinson’s disease. Lancet Neurol 2009; 8:929–937.
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  26. Ziaei E, et al. Comparison of pramipexole and citalopram in the treatment of depression in Parkinson’s disease: a randomized parallel-­group trial. J Res Med Sci 2022; 27:55.
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  28. Friedman JH. Parkinson’s disease psychosis 2010: a review article. Parkinsonism Relat Disord 2010; 16:553–560.
  29. Ismail MS, et  al. A reality test: How well do we understand psychosis in Parkinson’s disease? J Neuropsychiatry Clin Neurosci 2004; 16:8–18.
  30. Kiziltan G, et al. Relationship between age and subtypes of psychotic symptoms in Parkinson’s disease. J Neurol 2007; 254:448–452.
  31. Factor SA, et al. Longitudinal outcome of Parkinson’s disease patients with psychosis. Neurology 2003; 60:1756–1761.
  32. Reich SG, et al. Ten most commonly asked questions about the psychiatric aspects of Parkinson’s disease. Neurologist 2003; 9:50–56.
  33. Lin JJ, et al. Genetic polymorphism of the angiotensin converting enzyme and L-­dopa-­induced adverse effects in Parkinson’s disease. J Neurol Sci 2007; 252:130–134.
  34. Stowe RL, et al. Dopamine agonist therapy in early Parkinson’s disease. Cochrane Database Syst Rev 2008; 2:CD006564.
  35. Yunusa I, et al. Comparative efficacy, safety, and acceptability of pimavanserin and other atypical antipsychotics for Parkinson’s disease psychosis: systematic review and network meta-­analysis. J Geriatr Psychiatry Neurol 2023; 36:417–432.
  36. Divac N, et al. The efficacy and safety of antipsychotic medications in the treatment of psychosis in patients with Parkinson’s disease. Behav Neurol 2016; 2016:4938154.

844 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 37. Prohorov T, et al. The effect of quetiapine in psychotic Parkinsonian patients with and without dementia. An open-­labeled study utilizing a structured interview. J Neurol 2006; 253:171–175. 38. Weintraub D, et  al. Association of antipsychotic use with mortality risk in patients with Parkinson disease. JAMA Neurol 2016; 73:535–541. 39. D’Angremont E, et al. Cholinesterase inhibitors for treatment of psychotic symptoms in Alzheimer disease and Parkinson disease: a meta-­ analysis. JAMA Neurol 2023; 180:813–823. 40. Chung KA, et al. Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease. Neurology 2010; 75:1263–1269. 41. Sawada H, et al. Early use of donepezil against psychosis and cognitive decline in Parkinson’s disease: a randomised controlled trial for 2 years. J Neurol Neurosurg Psychiatry 2018; 89:1332–1340. 42. Van Mierlo TJM, et al. Rivastigmine for minor visual hallucinations in Parkinson’s disease: a randomized controlled trial with 24 months follow-­up. Brain Behav 2021; 11:e2257. 43. Friedman JH. Clozapine is severely underused in Parkinson’s disease patients. Mov Disord Clin Pract 2022; 9:1021–1024. 44. Friedman JH, et al. Benztropine versus clozapine for the treatment of tremor in Parkinson’s disease. Neurology 1997; 48:1077–1081. 45. Pirttilä A, et al. Hospitalization and the risk of initiation of antipsychotics in persons with Parkinson’s disease. J Am Med Dir Assoc 2023; 24:1290–1296.e4. 46. Pintor L, et al. Ziprasidone versus clozapine in the treatment of psychotic symptoms in Parkinson disease: a randomized open clinical trial. Clin Neuropharmacol 2012; 35:61–66. 47. Mesquita J, et al. Fatal neuroleptic malignant syndrome induced by clozapine in Parkinson’s psychosis. J Neuropsychiatry Clin Neurosci 2014; 26:E34. 48. Ziegenbein M, et al. Clozapine-­induced aplastic anemia in a patient with Parkinson’s disease. Can J Psychiatry 2003; 48:352. 49. Iketani R, et al. Efficacy and safety of atypical antipsychotics for psychosis in Parkinson’s disease: a systematic review and Bayesian network meta-­analysis. Parkinsonism Relat Disord 2020; 78:82–90. 50. Factor SA, et al. Combined clozapine and electroconvulsive therapy for the treatment of drug-­induced psychosis in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 1995; 7:304–307. 51. Martin BA. ECT for Parkinson’s? CMAJ 2003; 168:1391–1392. 52. Sarva H, et al. Evidence for the use of pimavanserin in the treatment of Parkinson’s disease psychosis. Ther Adv Neurol Disord 2016; 9:462–473. 53. Rissardo JP, et al. Pimavanserin and Parkinson’s disease psychosis: a narrative review. Brain Sci 2022; 12:1286. 54. Alipour-­Haris G, et al. Comparison of pimavanserin versus quetiapine for hospitalization and mortality risk among medicare beneficiaries with Parkinson’s disease psychosis. Mov Disord Clin Pract 2023; 10:406–414. 55. Mansuri Z, et al. Pimavanserin in the treatment of Parkinson’s disease psychosis: meta-­analysis and meta-­regression of randomized clinical trials. Innov Clin Neurosci 2022; 19:46–51. 56. Wilby KJ, et al. Evidence-­based review of pharmacotherapy used for Parkinson’s disease psychosis. Ann Pharmacother 2017; 51:682–695. 57. Thames BH, et al. Clozapine: efficacy for Parkinson disease psychosis in patients refractory to pimavanserin. Parkinsonism Relat Disord 2023; 109:105356. 58. Richard IH, et al. Rivastigmine-­induced worsening of motor function and mood in a patient with Parkinson’s disease. Mov Disord 2001; 16 Suppl 1:33–34. 59. McKeith I, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-­blind, placebo-­controlled international study. 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Caffeine for treatment of Parkinson disease: a randomized controlled trial. Neurology 2012; 79:651–658.

50 - Atrial fibrillation

Atrial fibrillation

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Atrial fibrillation Atrial fibrillation (AF) is the most common cardiac arrhythmia. It particularly affects older people but may occur in an important proportion of people aged less than 40 years. Risk factors include anxiety, obesity, diabetes, hypertension, long-­standing aerobic exercise and high alcohol consumption.1–3 AF itself is not usually life-­threatening but stasis of blood in the atria during fibrillation predisposes to clot formation and substantially increases the risk of stroke.4 The use of warfarin or direct-­acting oral anticoagulants is therefore essential.3 AF can be defined as ‘lone’ or paroxysmal (occurring infrequently, and spontaneously reverting to sinus rhythm), persistent (repeated and prolonged [>1 week] episodes usually, if temporarily, responsive to treatment) or permanent (unresponsive). Risk of stroke is increased in all three conditions.3 Treatment may involve DC conversion, rhythm control (usually flecainide, propafenone or amiodarone) or rate control (with diltiazem, verapamil or sotalol). With rhythm control the aim is to maintain sinus rhythm, although this is not always achieved. With rate control, AF is allowed to continue but ventricular response is controlled and the ventricles are filled passively. Many people with paroxysmal or persistent AF can be effectively cured of the condition by catheter or cryoablation of aberrant electrical pathways,5,6 now a routine and effective procedure.7 AF is commonly encountered in psychiatry not least because of the high rates of obesity, diabetes and alcohol misuse seen in mental health patients. The onset of AF also provokes prescription of antidepressants, anxiolytics and hypnotics.8 When considering the use of psychotropics several factors need to be taken into account: ■ ■Interactions between psychotropics and anticoagulant therapy. ■ ■Arrhythmogenicity of psychotropics prescribed. AF usually results from cardiovascular disease, and drugs affecting cardiac ion channels may increase mortality in these patients, especially those with ischaemic disease.9,10 Drugs that prolong the QT interval may also increase the risk of incident AF11 although their effect on established AF is not known. ■ ■Effect on ventricular rate: some drugs induce reflex tachycardia via postural hypotension, others (clozapine, quetiapine) directly increase heart rate. ■ ■Reported association between individual psychotropics and AF (Table 10.15). ■ ■Risk of interaction with co-­prescribed antiarrhythmics or rate-­controlling drugs. ■ ■Whether AF is paroxysmal (aim to avoid precipitating AF), persistent (aim to avoid prolonging AF) or permanent (aim to avoid increasing ventricular rate).

846 The Maudsley® Prescribing Guidelines in Psychiatry Table 10.15  Recommendations for using psychotropics in atrial fibrillation (AF). CHAPTER 10 Condition Suggested drugs Drugs to avoid Schizophrenia/ schizoaffective disorder The condition itself may be associated with an increased risk of AF12 In paroxysmal or persistent AF, cariprazine, brexpiprazole or lurasidone may be appropriate choices. In permanent AF with rate control, drug choice is less crucial but probably best to avoid drugs with potent effects on the ECG (ziprasidone, pimozide, etc.) and those that increase heart rate. One case–control study suggested antipsychotics increase risk of AF by 17%13 All antipsychotics appear to increase the risk of bleeding when combined with DOACs in AF.14 Bipolar disorder Valproate Lithium Carbamazepine Depression Untreated depression predicts recurrence of AF27 SSRIs but beware interaction with warfarin and other anticoagulants29 as severe bleeding risk is increased.30 Presence of AF increases risk of depression and anxiety28 Animal studies suggest an antiarrhythmic effect for SSRIs.31,32 Paroxetine improved paroxysmal AF in a series of non-­depressed patients.33 Venlafaxine does not directly affect atrial conduction34 and may cardiovert paroxysmal AF.35 One study suggested no increased risk of bleeding when combined with DOACs,36 another suggested a particular risk of bleeding when SNRIs are combined with apixaban.37 Mirtazapine and trazodone may increase bleeding risk when combined with DOACs in AF.37 AF incidence falls after starting antidepressant treatment.38,39 No evidence that agomelatine affects cardiac conduction or clotting. AF reported with clozapine,15,16 olanzapine,17,18 aripiprazole19,20 and paliperidone.21 Causation not clearly established but avoid use in lone, paroxysmal or persistent AF. Avoid QT-­prolonging drugs in ischaemic heart disease (see section on QT prolongation in Chapter 1). Association of antipsychotics with AF13 may be linked to metabolic disturbance22 although some studies suggest no link between antipsychotics and AF.23 Mood stabilisers appear not to affect risk of AF. Valproate may cause AV conduction block.24 One case of AF following lithium overdose25 and one in chronic toxicity.26 Avoid tricyclics in coronary disease.40 Tricyclics may provoke AF41,42 but do not increase risk of haemorrhage when combined with warfarin29 or DOACs.37 One database study suggested antidepressants in general do not increase risk of AF43 although another suggested both depression and antidepressant use are linked to incident AF.44

51 - References

References

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 References

  1. Chen LY, et al. Epidemiology of atrial fibrillation: a current perspective. Heart Rhythm 2007; 4:S1–S6.
  2. Tully PJ, et al. Anxiety, depression, and stress as risk factors for atrial fibrillation after cardiac surgery. Heart Lung 2011; 40:4–11.
  3. National Institute for Health and Care Excellence. Atrial fibrillation: diagnosis and management. NICE guideline [NG196]. 2021 (last accessed August 2024); https://www.nice.org.uk/guidance/ng196.
  4. Lakshminarayan K, et al. Clinical epidemiology of atrial fibrillation and related cerebrovascular events in the United States. Neurologist 2008; 14:143–150.
  5. Rodgers M, et al. Curative catheter ablation in atrial fibrillation and typical atrial flutter: systematic review and economic evaluation. Health Technol Assess 2008; 12:iii–iv, xi–xiii, 1–198.
  6. Latchamsetty R, et al. Catheter ablation of atrial fibrillation. Cardiol Clin 2014; 32:551–561.
  7. Saglietto A, et al. Impact of atrial fibrillation catheter ablation on mortality, stroke, and heart failure hospitalizations: a meta-­analysis. J Cardiovasc Electrophysiol 2020; 31:1040–1047.
  8. Hagengaard L, et  al. Incident atrial fibrillation and risk of psychoactive drug redemptions and psychiatric hospital contacts: a Danish Nationwide Register-­based Follow-­up Study. Eur Heart J Qual Care Clin Outcomes 2021; 7:76–82.
  9. Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med 1992; 327:227–233.
  10. Epstein AE, et al. Mortality following ventricular arrhythmia suppression by encainide, flecainide, and moricizine after myocardial infarction. The original design concept of the Cardiac Arrhythmia Suppression Trial (CAST). JAMA 1993; 270:2451–2455.
  11. Zhang N, et  al. Prolonged corrected QT interval in predicting atrial fibrillation: a systematic review and meta-­analysis. Pacing Clin Electrophysiol 2018; 41:321–327.
  12. Emul M, et al. P wave and QT changes among inpatients with schizophrenia after parenteral ziprasidone administration. Pharmacol Res 2009; 60:369–372.
  13. Chou RH, et al. Antipsychotic treatment is associated with risk of atrial fibrillation: a nationwide nested case-­control study. Int J Cardiol 2017; 227:134–140.
  14. Chen CM, et al. Major bleeding risk in atrial fibrillation patients co-­medicated with non-­vitamin K oral anticoagulants and antipsychotics. Front Pharmacol 2022; 13:819878.
  15. Cam B, et al. [Clozapine and olanzapine associated atrial fibrillation: a case report]. Turk Psikiyatri Dergisi 2015; 26:221–226.
  16. Low Jr, RA, et al. Clozapine induced atrial fibrillation. J Clin Psychopharmacol 1998; 18:170.
  17. Waters BM, et al. Olanzapine-­associated new-­onset atrial fibrillation. J Clin Psychopharmacol 2008; 28:354–355.
  18. Yaylaci S, et al. Atrial fibrillation due to olanzapine overdose. Clin Toxicol (Phila) 2011; 49:440. Condition Suggested drugs Drugs to avoid Anxiety disorders (anxiety symptoms increase risk of AF)45 Benzodiazepines (although a 2022 cohort study found a hugely increased risk of incident AF in benzodiazepine users46) SSRIs (see above) Tricyclics (see above) Several reported cases of pregabalin-­ and gabapentin-­associated AF47,48 and one cohort study suggested increased risk of AF49 with both drugs Promethazine may increase the risk of being hospitalised with AF50 Alzheimer’s disease Acetylcholinesterase inhibitors (but beware bradycardic effects in patients with paroxysmal ’vagal’ AF [paroxysmal AF provoked by low heart rate]) Rivastigmine has least interaction potential Memantine may be able to prevent and terminate AF51 Avoid cholinesterase inhibitors in paroxysmal ‘vagal’ AF AV, atrioventricular; DOACs, direct-­acting oral anticoagulants. Table 10.15  (Continued)

848 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 19. D’Urso G, et  al. Aripiprazole-­induced atrial fibrillation in a patient with concomitant risk factors. Exp Clin Psychopharmacol 2018; 26:509–513. 20. Stefatos A, et al. Atrial fibrillation and injected aripiprazole: a case report. Innov Clin Neurosci 2018; 15:43–45. 21. Schneider RA, et al. Apparent seizure and atrial fibrillation associated with paliperidone. Am J Health Syst Pharm 2008; 65:2122–2125. 22. Zeng J, et al. Metabolic disorder caused by antipsychotic treatment may facilitate the development of atrial fibrillation. Int J Cardiol 2017; 239:14. 23. Polcwiartek C, et al. Electrocardiogram characteristics and their association with psychotropic drugs among patients with schizophrenia. Schizophr Bull 2020; 46:354–362. 24. Davutoglu V, et al. Valproic acid as a cause of transient atrio-­ventricular conduction block episodes. J Atr Fibrillation 2017; 9:1520. 25. Kalcik MDM, et al. Acute atrial fibrillation as an unusual form of cardiotoxicity in chronic lithium overdose. J Atr Fibrillation 2014; 6:1009. 26. Acharya S, et al. Lithium-­induced cardiotoxicity: a rare clinical entity. Cureus 2020; 12:e7286. 27. Lange HW, et al. Depressive symptoms predict recurrence of atrial fibrillation after cardioversion. J Psychosom Res 2007; 63:509–513. 28. Patel D, et al. A systematic review of depression and anxiety in patients with atrial fibrillation: the mind-­heart link. Cardiovasc Psychiatry Neurol 2013; 2013:159850. 29. Quinn GR, et al. Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin. Am J Cardiol 2014; 114:583–586. 30. Komen JJ, et al. Concomitant anticoagulant and antidepressant therapy in atrial fibrillation patients and risk of stroke and bleeding. Clin Pharmacol Ther 2020; 107:287–294. 31. Pousti A, et al. Effect of sertraline on ouabain-­induced arrhythmia in isolated guinea-­pig atria. Depress Anxiety 2009; 26:E106–E110. 32. Pousti A, et al. Effect of citalopram on ouabain-­induced arrhythmia in isolated guinea-­pig atria. Hum Psychopharmacol 2003; 18:121–124. 33. Shirayama T, et al. Usefulness of paroxetine in depressed men with paroxysmal atrial fibrillation. Am J Cardiol 2006; 97:1749–1751. 34. Emul M, et  al. The influences of depression and venlafaxine use at therapeutic doses on atrial conduction. J Psychopharmacol 2009; 23:163–167. 35. Finch SJ, et al. Cardioversion of persistent atrial arrhythmia after treatment with venlafaxine in successful management of major depression and posttraumatic stress disorder. Psychosomatics 2006; 47:533–536. 36. Shao IY, et al. Association of type of antidepressant initiation with bleeding risk in atrial fibrillation patients taking oral anticoagulants. Drugs Real World Outcomes 2021; 8:383–391. 37. Chang KH, et al. Major bleeding risk in patients with non-­valvular atrial fibrillation concurrently taking direct oral anticoagulants and antidepressants. Front Aging Neurosci 2022; 14:791285. 38. Andrade C. Antidepressants and atrial fibrillation: the importance of resourceful statistical approaches to address confounding by indication. J Clin Psychiatry 2019; 80:19f12729. 39. Fenger-­Grøn M, et al. Depression, antidepressants, and the risk of non-­valvular atrial fibrillation: a nationwide Danish matched cohort study. Eur J Prevent Cardiol 2019; 26:187–195. 40. Taylor D. Antidepressant drugs and cardiovascular pathology: a clinical overview of effectiveness and safety. Acta Psychiatr Scand 2008; 118:434–442. 41. Moorehead CN, et al. Imipramine-­induced auricular fibrillation. Am J Psychiatry 1965; 122:216–217. 42. Rosen BH. Case report of auricular fibrillation following the use of imipramine (Tofranil). J Mt Sinai Hosp NY 1960; 27:609–611. 43. Lapi F, et al. The use of antidepressants and the risk of chronic atrial fibrillation. J Clin Pharmacol 2015; 55:423–430. 44. Fu Y, et al. Association of depression, antidepressants with atrial fibrillation risk: a systemic review and meta-­analysis. Front Cardiovasc Med 2022; 9:897622. 45. Eaker ED, et al. Tension and anxiety and the prediction of the 10-­year incidence of coronary heart disease, atrial fibrillation, and total mortality: the Framingham Offspring Study. Psychosom Med 2005; 67:692–696. 46. Hu X, et al. Hypnotics use is associated with elevated incident atrial fibrillation: a propensity-­score matched analysis of cohort study. J Pers Med 2022; 12:1645. 47. Chilkoti G, et al. Could pregabalin premedication predispose to perioperative atrial fibrillation in patients with sepsis? Saudi J Anaesth 2014; 8 Suppl 1:S115–S116. 48. Park SH, et al. Atrial fibrillation induced by gabapentin: a case report. J Med Case Rep 2023; 17:236. 49. Ortiz de Landaluce L, et al. Gabapentin and pregabalin and risk of atrial fibrillation in the elderly: a population-­based cohort study in an electronic prescription database. Drug Saf 2018; 41:1325–1331. 50. Sessa M, et al. The risk of fractures, acute myocardial infarction, atrial fibrillation and ventricular arrhythmia in geriatric patients exposed to promethazine. Expert Opin Drug Saf 2020; 19:349–357. 51. Xie D, et al. Memantine targets glutamate receptors in atrial cardiomyocytes to prevent and treat atrial fibrillation. Cell Discov 2022; 8:76.

52 - Bariatric surgery

Bariatric surgery

53 - Pharmacokinetic changes following bariatric s

Pharmacokinetic changes following bariatric surgery

54 - Medication formulations5,6

Medication formulations5,6

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Bariatric surgery Psychiatric illness is relatively common in patients who have undergone bariatric surgery.1 Over a third of those seeking bariatric surgery are prescribed psychotropics.2 Bariatric surgery can be associated with clinically important changes in drug pharmacokinetics, although it is difficult to predict exactly how psychotropics will be affected because of interindividual differences and rather limited data. There is clearly a need for close treatment monitoring and the ongoing monitoring of symptoms after bariatric surgery.3 Surgical procedures can be classified as: ■ ■Predominantly restrictive: sleeve gastrectomy and gastric banding. ■ ■Predominantly malabsorptive: biliopancreatic diversion and jejunoileal bypass. ■ ■Mixed restrictive/malabsorptive: Roux-­en-­Y gastric bypass (RYGB) and gastric reduction duodenal switch (GRDS). Absorption following bariatric surgery is drug-­specific and shows high variability among individuals. It can be affected by many factors including route of administration, dosage form, patient-­specific factors, pharmacokinetic/pharmacodynamic considerations and type of surgery; it can be temporary or permanent.4,5 Malabsorptive procedures (including RYGB and GRDS) have a relatively greater potential to alter drug absorption. Most data are derived from studies of patients undergoing RYGB. It is not clear how these data relate to the consequences of other procedures. Pharmacokinetic changes following bariatric surgery All procedures may alter the following: ■ ■Tablet disintegration and dissolution times via changes in gastric pH and mixing. ■ ■Area for drug absorption (reduced gastric and/or functional intestinal surface area). ■ ■Rate of absorption via changes in the gastric emptying rate. ■ ■Drug distribution via loss of adipose tissue (especially lipid-­soluble drugs) and altered protein binding. ■ ■Drug metabolism owing to improvements in hepatic function after weight loss. ■ ■Drug excretion via changes in renal function after weight loss. Malabsorptive surgical procedures may further lead to: ■ ■Changes in the availability of certain enzymes and transporters. ■ ■Altered lipophilic drug solubilisation (bypassing proximal small intestine bile salts). ■ ■Reduced intestinal wall drug metabolism via decreased intestinal length. Medication formulations5,6 Any formulation that prolongs drug disintegration or dissolution can potentially impair drug absorption following bariatric surgery. Switching to immediate-­release formulations before surgery is generally recommended. Orodispersible and liquid preparations do not go through a disintegration phase, and may be preferred if reduced absorption from solid tablets is suspected.7 Very large tablets (e.g. over 10mm in diameter) should be avoided as passage may be impeded by restrictive procedures.

55 - Antidepressants

Antidepressants

850 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Antidepressants Table 10.16 summarises the use of antidepressants in bariatric surgery. Table 10.16  Antidepressants in bariatric surgery. Medication Specific evidence and considerations SSRIs4,8,9 Evidence demonstrates that plasma levels may be significantly reduced following RYGB or sleeve gastrectomy. The concentration of SSRIs may drop initially and then rebound within a few months; dose adjustments occurring in the immediate postoperative period might be temporary. Malabsorption has been implicated in cases of discontinuation symptoms and loss of efficacy. Sertraline and vortioxetine absorption appear to be the most affected and fluoxetine the least. SNRIs9–11 Suggest avoid duloxetine owing to significant reduction in levels and risk of discontinuation syndrome. The absorption of venlafaxine MR capsules seems not to be altered by RYGB Mirtazapine9,12–14 Plasma levels may be significantly reduced following RYGB or sleeve gastrectomy. Dose increase is often needed. Increased appetite and weight gain are possible. TCAs15,16 Single case report suggests therapeutic plasma levels can be achieved within usual dose range after RYGB. Plasma levels may be increased after significant weight loss. Consider monitoring levels and reducing dose. Agomelatine No data available on absorption after bariatric surgery. Follow general recommendations. Dextromethorphan and bupropion There are no studies of the combined formulation after bariatric surgery No pharmacokinetic changes after bariatric surgery were reported for dextromethorphan liquid in the short or long term.5,17 In an in vitro model bupropion was found to have a significantly higher dissolution after RYGB which may lead to increased bioavailability.18 Esketamine nasal spray19 Primarily absorbed via nasal mucosa. Problems after bariatric surgery are not expected. General summary ■ ■Antidepressants are the best-studied psychotropics in the bariatric population. Current evidence suggests that antidepressant absorption is reduced after surgery (though studies are mostly limited to SSRIs after RYGB). ■ ■Signs of reduced absorption may include the rapid development of discontinuation symptoms and later loss of efficacy. Patients should be made aware of discontinuation symptoms and signs of relapse and seek medical advice if they occur. ■ ■Patients require close monitoring as those at risk of reduced absorption cannot be reliably predicted. ■ ■The risk of gastric bleeds with bariatric surgery will probably be increased by serotonergic antidepressants. MR, modified release; RYGB, Roux-­en-­Y gastric bypass; TCAs, tricyclic antidepressants.

56 - Antipsychotics

Antipsychotics

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Antipsychotics Table 10.17 summarises the use of antipsychotics in bariatric surgery. Table 10.17  Antipsychotics in bariatric surgery. Medication Specific evidence and considerations Aripiprazole20 One case report of subtherapeutic levels post RYGB using aripiprazole tablets that became therapeutic on switching to suspension. Available as an LAI. Asenapine21 Primarily absorbed via oral mucosa. Problems after bariatric surgery are not expected One case report of successful use after RYGB. Brexpiprazole No data available on absorption after bariatric surgery Cariprazine No data available on absorption after bariatric surgery The absorption of oral contraceptives may be reduced after bariatric surgery.22 Therefore, to ensure highly effective contraception for women prescribed cariprazine, non-­oral methods are recommended. Clozapine23–­25 Two case reports of relapse after RYGB26 Take drug plasma levels before surgery and regularly monitor after. Constipation is common after surgery; the manufacturer recommends close monitoring and active treatment. Check smoking status (quitting before surgery is encouraged); adjust dose accordingly. Haloperidol27 Single case report suggests levels after RYGB are similar to those generally reported in the literature. Iloperidone No data available on absorption after bariatric surgery Lumateperone No data available on absorption after bariatric surgery Lurasidone Risk of reduced absorption with reduced or inconsistent calorific intake perioperatively. Must be taken with food for absorption (350kcal). One case report of relapse following GRDS. Significant reduction in bioavailability and peak serum concentration.28 One case report post-­RYGB showed significant reduction in plasma concentration with no worsening of psychotic symptoms.29 Consider switching to alternatives before surgery. Olanzapine One report of reduction in dose-­adjusted drug concentration following bariatric surgery30 One case report following RYGB of continued efficacy with no dose adjustment required31 In an in vitro model olanzapine was found to have a significantly lower dissolution after RYGB which may lead to decreased bioavailability.32 Follow general recommendations. Quetiapine7,30,33 Dose-­adjusted concentrations decreased following bariatric surgery. Switching to immediate-­release preparation and dividing doses above 300mg has been recommended. Risperidone34 Consider switching stable patients to an equivalent dose of paliperidone LAI. Risperidone LAI has been used successfully when oral treatment was not tolerated after bariatric surgery. Ziprasidone35 Must be taken with food for absorption (500kcal); risk of reduced absorption with reduced/inconsistent calorific intake perioperatively. Consider switching to alternatives before surgery. (Continued )

57 - Mood stabilisers

Mood stabilisers

852 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Mood stabilisers Table 10.18 summarises the use of mood stabilisers in bariatric surgery. General summary ■ ■Antipsychotics are not well studied in bariatric surgery. Data are limited to case reports or theoretical concerns. ■ ■Monitor for decreased efficacy. Adjust dose accordingly or consider switching to another antipsychotic. ■ ■Depot antipsychotics avoid the risk of reduced absorption after surgery. Given the limited data on pharmacokinetic changes after surgery and interindividual variability, routinely switching to depot antipsychotics before surgery may not be justified.7 However, depot preparations remain an option for those stabilised on treatment available as a depot or in patients demonstrating signs of reduced bioavailability after surgery. ■ ■Bariatric surgery may contribute additional cardiac stressors to patients with QT prolongation.36 ECG monitoring before and after surgery is recommended. GRDS, gastric reduction duodenal switch; LAI, long-­acting injection; RYGB, Roux-­en-­Y gastric bypass. Table 10.17  (Continued) Table 10.18  Mood stabilisers in bariatric surgery. Medication Summary of evidence and considerations Carbamazepine Carbamazepine CR levels have been observed to both increase and decrease following bariatric surgery.37 In a case series of eight following sleeve gastrectomy, levels were found to be reduced in half the cases, with two resulting in deterioration of previously well-­controlled illness. One case had increased levels.38 Single case report of agranulocytosis possibly related to increased plasma levels after sleeve gastrectomy.38 Baseline plasma carbamazepine levels, FBC, renal function and LFTs with ongoing monitoring recommended.38 Lamotrigine38 Increased, decreased or unchanged lamotrigine levels after bariatric surgery are all possible; monitor for adverse effects and loss of efficacy. Lithium39,40 (see below) Cases of lithium toxicity following RYGB and sleeve gastrectomy have been reported. Switch to an equivalent dose of lithium citrate solution in divided doses. In the preoperative period, plasma levels may be affected by prescribed dietary changes. In the postoperative period, plasma levels may be affected by malabsorption (mainly absorbed via small intestine), fluid shifts and weight loss (lithium clearance increased in obesity). Valproate7,41,42 Single case report suggests that absorption may be significantly reduced after malabsorptive procedures; no data on restrictive procedures. Dose reductions may be necessary after weight loss (plasma levels related to body weight). Switch to liquid preparation before surgery or if malabsorption suspected on enteric-­coated tablets. Avoid CR preparations. Baseline plasma valproate levels, FBC and LFTs with ongoing monitoring recommended. Monitor for clinical signs of poor tolerability, possibly occurring at normal plasma levels. General summary ■ ■The literature on mood stabilisers after bariatric surgery is limited to a few case reports; the use of lithium requires particular care owing to its narrow therapeutic index. ■ ■The absorption of oral contraceptives may be reduced after bariatric surgery.22 In patients prescribed teratogenic mood stabilisers, non-­oral methods of contraception are recommended. CR, controlled release; FBC, full blood count; LFTs, liver function tests; RYGB, Roux-­en-­Y gastric bypass.

58 - Lithium around the time of bariatric surgery

Lithium around the time of bariatric surgery

59 - Other medicines

Other medicines

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Lithium around the time of bariatric surgery The continued use of lithium throughout the perioperative phases of bariatric surgery requires particularly close monitoring. The following guidance is based on available case reports and expert opinion.40 ■ ■Monitor lithium plasma levels preoperatively and perform a scale-­based clinical assessment of mood. ■ ■Educate the patient preoperatively on the importance of drinking 2.5–3 litres of fluid per day (including liquid meal replacement). ■ ■Postoperatively assess for toxicity by monitoring lithium plasma levels and renal function weekly for 6  weeks (as fluid intake gradually increases), 2-­weekly for 6  months and monthly thereafter. Resume usual lithium monitoring 1 ­year post-­ bariatric surgery. ■ ■If plasma levels increase by >25% or approach 1.2mmol/L consider decreasing the lithium dose. ■ ■Withhold lithium if signs of toxicity are present and review the dose. ■ ■To prevent dehydration, counsel the patient to alert their physician or psychiatrist in case of any changes in food or fluid intake or severe vomiting. ■ ■Monitor mental state periodically, using formal rating scales if possible. Other medicines Table 10.19 summarises the use of other medicines in bariatric surgery. Table 10.19  Miscellaneous agents in bariatric surgery. Medication Summary of evidence and considerations Antimuscarinics No data available on absorption after bariatric surgery Benzodiazepines43–46 Bioavailability probably unaffected, shorter time to peak concentration Lisdexamfetamine47 A single-­dose case–control study found no significant differences in lisdexamfetamine and active metabolite d-­amfetamine following RYGB compared to non-­surgical controls. Due to potential for inter­individual differences, monitor for adverse effects and loss of efficacy. Methadone48 Substantial increase in bioavailability after sleeve gastrectomy in one case report, possibly related increased rate of gastric emptying; consider plasma level and QT monitoring Methylphenidate49,50 Conflicting limited data; one case report of reduced treatment efficacy after RYGB that resolved after switching to transdermal patch suggesting reduced oral bioavailability; another reported signs of toxicity Modafinil No data available on absorption after bariatric surgery Orexin antagonists No data available on absorption after bariatric surgery Pregabalin17 Increased levels shortly after surgery and decreased values in the long term post-­surgery; monitor for adverse effects and loss of efficacy Solriamfetol No data available on absorption after bariatric surgery Zolpidem In an in vitro model found to have non-­significant lower dissolution after RYGB.32 Food delays the onset of effect; take on an empty stomach.51 RYGB, Roux-­en-­Y gastric bypass.

60 - General recommendations

General recommendations

61 - Psychotropics with a risk of weight gain afte

Psychotropics with a risk of weight gain after bariatric surgery

854 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 General recommendations Box 10.5 outlines the general recommendations for prescribing in bariatric surgery, while Box 10.6 summarises the strategies used in patients who show signs of reduced bioavailability. Psychotropics with a risk of weight gain after bariatric surgery Around 70% of patients regain a significant amount of weight (more than 10% of lowest postoperative weight) within 5 years of bariatric surgery.52 There has been conflicting information on how psychotropics affect weight loss outcomes after surgery. One study reported no significant differences in total weight loss 1 year post-­surgery between those on psychotropics and those not.2 Another reported that treatment with antidepressants, particularly SNRIs and TCAs, was associated with reduced weight loss after gastric bypass surgery53 and another found that those on obesogenic medications lost statistically significantly less excess weight than controls.54 Medicines with a high risk of weight gain should be avoided where possible. Binge eating disorder, problematic alcohol use and depressive symptoms are associated with postoperative weight gain.52 Box 10.6  General management strategies for patients demonstrating signs of reduced bioavailability ■ ■Consider non-­oral routes of administration where available (e.g. depots for patients stable on antipsychotics) ■ ■Dividing doses may improve malabsorption related to a reduced stomach capacity after surgery ■ ■Switching modified/prolonged/delayed-­release to immediate-­release formulations ■ ■Switching solid tablets to liquid or orodispersible preparations to bypass disintegration phase ■ ■Switching large tablets to smaller ones ■ ■In cases where doses have been increased to account for reduced bioavailability, monitor for emergent adverse effects as bioavailability may normalise over time Box 10.5  General recommendations for prescribing in bariatric surgery7,14 Before surgery ■ ■Do not routinely increase doses; clinically relevant malabsorption cannot be reliably predicted ■ ■Assess mental state before surgery using validated scales and consider measuring baseline drug plasma levels ■ ■Switch modified-­release/ enteric-­coated preparations to immediate-­release tablets or to liquid preparations After surgery (0–­6 weeks) ■ ■Assess mental state using validated scales ■ ■Closely monitor for signs of adverse effects and drug malabsorption (symptom re-­emergence, discontinuation symptoms) ■ ■Regularly monitor drug plasma levels if clinically indicated ■ ■If malabsorption suspected consider the recommended strategies ■ ■If medication toxicity suspected withhold and reassess dose After surgery (>6 weeks after) ■ ■Continue regular monitoring for the first year postoperatively using validated scales, although frequency can be reduced if stable ■ ■Monitor for an increase in adverse effects, especially if doses were increased in the acute postoperative period ■ ■Consider returning to pre-­surgical treatment regimen after 1 year (depending on clinical history)

62 - Alcohol55,56

Alcohol55,56

63 - Wider considerations14,57

Wider considerations14,57

64 - References

References

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Alcohol55,56 Gastric bypass surgery is associated with accelerated alcohol absorption, higher maximum alcohol concentrations and a longer time to elimination. There is also an increased risk of alcohol misuse disorders after gastric bypass. Data are less clear for sleeve gastrectomy and there is no evidence that gastric banding leads to any changes. Wider considerations14,57 Despite severe mental illness often being considered a contraindication for bariatric surgery it has been shown to be effective in those with schizophrenia and bipolar affective disorder. Because of the variability of pharmacokinetic changes of psychiatric medicines, it is important to monitor patients closely for adverse effects and loss of efficacy, and medicines should be adjusted accordingly if required. Significant improvements in mental health are well documented following surgery, however deterioration can also occur. Depression and/or eating disorders may persist, re-­emerge or newly develop and there is an increased risk of self-­harm, suicide, alcohol disorder and opioid misuse following bariatric surgery. References

  1. Dawes AJ, et  al. Mental health conditions among patients seeking and undergoing bariatric surgery: a meta-­analysis. JAMA 2016; 315:150–163.
  2. Hawkins M, et al. Psychiatric medication use and weight outcomes one year after bariatric surgery. Psychosomatics 2020; 61:56–63.
  3. Gondek W. Psychiatric suitability assessment for bariatric surgery. In: Sockalingam S, Hawa R, eds. Psychiatric Care in Severe Obesity: An Interdisciplinary Guide to Integrated Care. Cham: Springer International Publishing; 2017:173–186.
  4. Lorico S, et al. Medication management and pharmacokinetic changes after bariatric surgery. Can Fam Physician 2020; 66:409–416.
  5. Alalwan AA, et al. Drug absorption in bariatric surgery patients: a narrative review. Health Sci Rep 2022; 5:e605.
  6. Girolamo T, et al. Bariatric surgery and medicines: from first principles to practice. Aust Prescr 2022; 45:162–166.
  7. Bingham KS, et al. Psychopharmacology in bariatric surgery patients. In: Sockalingam S, Hawa R, eds. Psychiatric Care in Severe Obesity: An Interdisciplinary Guide to Integrated Care. Cham: Springer International Publishing; 2017:313–333.
  8. Pasi P, et al. Plasma concentrations of SSRI/SNRI after bariatric surgery and the effects on depressive symptoms. Front Psychiatry 2023; 14:1132112.
  9. Maass D, et al. Changes in serum concentration of antidepressants after bariatric surgery and recommendations for postbariatric surgery antidepressant therapy. J Acad Consult Liaison Psychiatry 2024; 65:261–270.
  10. Roerig JL, et al. A comparison of duloxetine plasma levels in postbariatric surgery patients versus matched nonsurgical control subjects. J Clin Psychopharmacol 2013; 33:479–484.
  11. Hamad GG, et  al. The effect of gastric bypass on the pharmacokinetics of serotonin reuptake inhibitors. Am J Psychiatry 2012; 169:256–263.
  12. Teixeira FV, et al. Mirtazapine (Remeron) as treatment for non-­mechanical vomiting after gastric bypass. Obes Surg 2005; 15:707–709.
  13. Huerta S, et al. Intractable nausea and vomiting following Roux-­en-­Y gastric bypass: role of mirtazapine. Obes Surg 2006; 16:1399.
  14. Coughlin JW, et al. Psychotropic medications in metabolic and bariatric surgery: research updates and clinical considerations. Curr Psychiatry Rep 2022; 24:89–98.
  15. Broyles JE, et al. Nortriptyline absorption in short bowel syndrome. J Parenter Enteral Nutr 1990; 14:326–327.
  16. Jobson K, et al. Weight loss and a concomitant change in plasma tricyclic levels. Am J Psychiatry 1978; 135:237–238.
  17. Lau C, et  al. Impact of bariatric surgery in the short and long term: a need for time-­dependent dosing of drugs. Obes Surg 2023; 33:3266–3302.
  18. Konstantinidou SK, et al. The effects of bariatric surgery on pharmacokinetics of drugs: a review of current evidence. Curr Nutr Rep 2023; 12:695–708.
  19. Jannsen-­Cilag Ltd. Summary of product characteristics. Spravato 28mg nasal spray, solution. 2024 (last accessed August 2024); https://www. medicines.org.uk/emc/product/10977/smpc.
  20. Kuzin M, et al. Switching from aripiprazole tablets to oral suspension in a patient with Roux-­en-­Y gastric bypass: a case report. J Clin Psychopharmacol 2023; 43:300–302.
  21. Tabaac BJ, et al. Pica patient, status post gastric bypass, improves with change in medication regimen. Ther Adv Psychopharmacol 2015; 5:38–42.
  22. Merhi ZO. Challenging oral contraception after weight loss by bariatric surgery. Gynecol Obstet Investig 2007; 64:100–102.

856 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 23. Kaltsounis J, et al. Intravenous valproate treatment of severe manic symptoms after gastric bypass surgery: a case report. Psychosomatics 2000; 41:454–456. 24. Afshar S, et al. The effects of bariatric procedures on bowel habit. Obes Surg 2016; 26:2348–2354. 25. Leyden Delta BV. Summary of product characteristics. Zaponex 100mg tablets. 2020 (last accessed August 2024); https://www.medicines.org. uk/emc/product/7715/smpc. 26. Mahgoub Y, et al. Schizoaffective exacerbation in a Roux-­en-­Y gastric bypass patient maintained on clozapine. Prim Care Companion CNS Disord 2019; 21:19l02462. 27. Fuller AK, et al. Haloperidol pharmacokinetics following gastric bypass surgery. J Clin Psychopharmacol 1986; 6:376–378. 28. Ward HB, et al. Lurasidone malabsorption following bariatric surgery: a case report. J Psychiatr Pract 2019; 25:313–317. 29. McGrane IR, et al. Roux-­en-­Y gastric bypass and antipsychotic therapeutic drug monitoring: two cases. J Pharm Pract 2021; 34:503–506. 30. Wallerstedt SM, et al. Serum concentrations of antidepressants, antipsychotics, and antiepileptics over the bariatric surgery procedure. Eur J Clin Pharmacol 2021; 77:1875–1885. 31. Brito ME, et al. Patients with schizophrenia undergoing gastric bypass surgery: a case series study. Obes Surg 2020; 30:3813–3821. 32. Seaman JS, et al. Dissolution of common psychiatric medications in a Roux-­en-­Y gastric bypass model. Psychosomatics 2005; 46:250–253. 33. Miller AD, et  al. Medication and nutrient administration considerations after bariatric surgery. Am J Health Syst Pharm 2006; 63:1852–1857. 34. Brietzke E, et al. Long-­acting injectable risperidone in a bipolar patient submitted to bariatric surgery and intolerant to conventional mood stabilizers. Psychiatry Clin Neurosci 2011; 65:205. 35. Gandelman K, et al. The impact of calories and fat content of meals on oral ziprasidone absorption: a randomized, open-­label, crossover trial. J Clin Psychiatry 2009; 70:58–62. 36. Woodard G, et al. Cardiac arrest during laparoscopic Roux-­en-­Y gastric bypass in a bariatric patient with drug-­associated long QT ­syndrome. Obes Surg 2011; 21:134–137. 37. Triplett JD, et al. The effect of weight reduction surgery on the efficacy and tolerability of epilepsy pharmacotherapy. Epilepsy Behav 2021; 124:108307. 38. Porat D, et  al. Carbamazepine therapy after bariatric surgery: eight sleeve gastrectomy cases and review of the literature. 2022; 32:3481–3486. 39. Bingham KS, et al. Perioperative lithium use in bariatric surgery: a case series and literature review. Psychosomatics 2016; 57:638–644. 40. Ayub S, et al. Lithium toxicity following Roux-­en-­Y gastric bypass: mini review and illustrative case. Ment Health Clin 2022; 12:214–218. 41. Dahan A, et al. Lithium toxicity with severe bradycardia post sleeve gastrectomy: a case report and review of the literature. Obes Surg 2019; 29:735–738. 42. Brown CS, et al. Antiseizure medication use in gastric bypass patients and other post-­surgical malabsorptive states. Epilepsy Behav Rep 2021; 16:100439. 43. Tandra S, et  al. Pharmacokinetic and pharmacodynamic alterations in the Roux-­en-­Y gastric bypass recipients. Ann Surg 2013; 258:262–269. 44. Chan LN, et al. Proximal Roux-­en-­Y gastric bypass alters drug absorption pattern but not systemic exposure of CYP3A4 and P-­glycoprotein substrates. Pharmacotherapy 2015; 35:361–369. 45. Brill MJ, et al. The pharmacokinetics of the CYP3A substrate midazolam in morbidly obese patients before and one year after bariatric surgery. Pharm Res 2015; 32:3927–3936. 46. Ochs HR, et al. Diazepam absorption: effects of age, sex, and Billroth gastrectomy. Dig Dis Sci 1982; 27:225–230. 47. Steffen KJ, et al. Lisdexamfetamine pharmacokinetic comparison between patients who underwent Roux-­en-­Y gastric bypass and nonsurgical controls. Obes Surg 2021; 31:4289–4294. 48. Strømmen M, et al. Bioavailability of methadone after sleeve gastrectomy: a planned case observation. Clin Ther 2016; 38:1532–1536. 49. Azran C, et al. Impaired oral absorption of methylphenidate after Roux-­en-­Y gastric bypass. Surg Obes Relat Dis 2017; 13:1245–1247. 50. Ludvigsson M, et al. Methylphenidate toxicity after Roux-­en-­Y gastric bypass. Surg Obes Relat Dis 2016; 12:e55–e57. 51. Greenblatt DJ, et al. Influence of food on pharmacokinetics of zolpidem from fast dissolving sublingual zolpidem tartrate tablets. J Clin Pharmacol 2013; 53:1194–1198. 52. Noria SF, et  al. Weight regain after bariatric surgery: scope of the problem, causes, prevention, and treatment. Curr Diab Rep 2023; 23:31–42. 53. Plaeke P, et al. Postoperative continuation of antidepressant therapy is associated with reduced short-­term weight loss following Roux-­en-­Y gastric bypass surgery. Langenbecks Arch Surg 2019; 404:621–631. 54. Leggett CB, et al. The effects of provider-­prescribed obesogenic drugs on post-­laparoscopic sleeve gastrectomy outcomes: a retrospective cohort study. Int J Obes 2019; 43:1154–1163. 55. Ivezaj V, et al. Changes in alcohol use after metabolic and bariatric surgery: predictors and mechanisms. Curr Psychiatry Rep 2019; 21:85. 56. Parikh M, et al. ASMBS position statement on alcohol use before and after bariatric surgery. Surg Obes Relat Dis 2016; 12:225–230. 57. Stogios N, et al. Antipsychotic-­induced weight gain in severe mental illness: risk factors and special considerations. Curr Psychiatry Rep 2023; 25:707–721.

65 - Menopause

Menopause

66 - Diagnosis

Diagnosis

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Menopause The menopause transition is a phase in a woman’s reproductive life where ovarian function declines, menstruation stops and production of the female reproductive hormones oestrogen, progesterone and testosterone significantly declines. The menopause signifies a date in time 12 months after a women’s last menstrual period (LMP). The normal age range for the menopause is 45–55 years. The perimenopause is the phase leading up to a women’s LMP characterised by erratic ovarian function and fluctuations in hormones. Perimenopausal symptoms typically arise 2–7 years prior to the LMP. About 75% of women experience menopausal symptoms (Table 10.20), 25% of women experience severe menopausal symptoms and 20% of women experience life-­ long symptoms.1,2 Symptoms associated with the menopause should be considered in women older than 40. However, women may experience an early menopause before 45 years of age, or premature ovarian insufficiency (POI) below 40 years of age, so symptoms may present earlier. Diagnosis Clinical diagnosis using the Greene Climacteric questionnaire is sufficient in most women older than 40 years presenting with typical symptoms. In women younger than 45 years, two raised follicle-­stimulating hormone (FSH) levels >30mIU/mL, taken 6 weeks apart, tested on days 2–5 of the menstrual cycle may help confirm a diagnosis if clinical symptoms are not conclusive.1,3 Table 10.20  Menopause symptoms. Vasomotor Physical Genitourinary Psychological Hot flushes/flashes Sleep disturbance Urinary frequency Anxiety Night sweats Muscular aches and pains Nocturia Low mood Excessive sweating Period changes – flow, duration, frequency Vaginal dryness/irritation Loss of motivation Cold chills Headaches/migraines Weight gain Tinnitus Breast tenderness Heart palpitations Acne Fatigue and low energy Vulval itching and irritation Frequent UTIs Low libido Loss of sexual pleasure Vaginal discomfort Mood swings Tearfulness Increased PMS Poor concentration and focus Brain fog Poor word-­finding and short-­term memory Irritability PMS, premenstrual syndrome; UTIs, urinary tract infections.

67 - Psychological symptoms of the menopause

Psychological symptoms of the menopause

858 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Psychological symptoms of the menopause Depression and anxiety The impact of the menopause on mental well-­being is significant. Suicidal ideation is present in around 6% of women experiencing menopause-­related psychological symptoms. There is a 2–5-­fold increase in the risk of depression during the perimenopause.4 Hormone replacement therapy (HRT) is first-­line treatment for menopausal insomnia, anxiety and depression.1 Psychosis The decline in production of protective oestrogens is thought to be the reason that women show an increased risk of psychosis later in life (particularly at menopause) that is not observed in men, with one study suggesting that first hospital admission rates for psychosis are twice as high in women (21%) than in men (10%) after the age of 40. Pharmacodynamics Oestrogen is thought to have complex effects on dopamine transmission and receptor sensitivity, as well as antipsychotic binding. Human positron emission tomography (PET) studies have revealed that women have more D2 receptors in the brain compared with men. As oestrogen is thought to enhance antipsychotic binding affinity to these receptors, declining oestrogen levels in menopause serve to reduce antipsychotic activity.5–7 Consequently, many women require higher doses of antipsychotic medication after menopause to maintain previous effect.8 Pharmacokinetics Gender variations in the pharmacokinetics of psychotropic drugs are often not considered but may play an important role in drug efficacy and adverse effects. Factors such as gastrointestinal transit time, drug distribution of lipophilic drugs (e.g. antipsychotics) and drug elimination can vary with age and with hormonal changes seen during and after menopause.9 Oestrogen and progesterone can decrease levels of glycoproteins responsible for binding to antipsychotic drugs. Declining levels of these hormones may therefore result in less free drug entering the brain.9 Oestrogens are also thought to influence the activity and expression of some of the enzymes responsible for the hepatic metabolism of antipsychotics, i.e. oestrogens can induce and inhibit CYP isoenzymes (Table 10.21).9 Alternative treatments and drug interactions Polypharmacy in menopausal women is common, with many women using alternative treatments (such as herbal remedies) to address menopausal symptoms. It is important that drug interactions are ruled out when prescribing antipsychotic medication.10 The use of several medications, for example for sleep, pain and depression, may also affect protein binding of concurrent antipsychotics leading to changes in the ability for ­certain drugs to enter the brain.5

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Long-­acting injections (LAIs) Switching to an antipsychotic depot may improve levels of drugs that are mainly ­hepatically metabolised by CYP enzymes, as first-­pass metabolism is avoided.6 The use of antipsychotic depot injections should be considered if oral medications appear to lose efficacy in menopause.10 Longer dosage intervals for LAIs may be beneficial in menopause as older women tend to eliminate drugs more slowly than their male counterparts.12 Risk of adverse effects Increasing age coupled with oestrogen loss in menopause can make women more vulnerable to antipsychotic-­related adverse effects. Older women are more vulnerable to QTc prolongation and motor symptoms (parkinsonism, akathisia and tardive dyskinesia) and therefore it is best to avoid antipsychotic drugs that may worsen these adverse effects.8 Increased adiposity in menopause may be associated with a heightened risk for Table 10.21  Summary of antipsychotic/oestrogen interactions.5,8,11 Isoenzyme Substrates Effect of oestrogen on enzyme activity Recommendations CYP1A2 Clozapine, olanzapine Inhibits Oestrogen is thought to inhibit/reduce CYP1A2 activity and thus doses of antipsychotics that are mainly metabolised by this isoenzyme may need to be increased at menopause. Extra care should be given to antipsychotic dosing in menopausal women who smoke. CYP3A4 Aripiprazole, quetiapine, lurasidone Induces Women generally have a higher expression of CYP3A4 enzyme than men, and menopause may cause reduced expression of this enzyme. High levels of oestrogen in pregnancy are thought to increase the metabolism via CYP3A4, further suggesting that oestrogen (and progesterone) play a role in rate of hepatic drug metabolism. Lower doses of CYP3A4-­metabolised antipsychotics may be required in menopause, particularly if onset of menopause causes an increase in adverse effects. CYP2D6 Aripiprazole, haloperidol, risperidone, zuclopenthixol Possibly induces CYP2D6 activity is generally higher in women than men. The clinical relevance of increased activity may be small, particularly as there may be genetic variations in the CYP2D6 gene. Some evidence suggests that doses of aripiprazole may require lowering at menopause (this may also be because it is metabolised by CYP3A4). CYP2C19 Clozapine (minor route) Possibly inhibits Females reportedly have a 40% lower enzyme activity than men. This difference is thought to be most pronounced from 18 to 40 years (generally prior to onset of menopause). As stated previously, clozapine doses may need to be higher in menopausal women, however this needs to be balanced against risk of adverse effects. More regular therapeutic drug monitoring may be required.

860 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 adverse effects such as insulin resistance, diabetes, sleep apnoea, cardiovascular disease and hypertriglyceridaemia.13 Prolactin levels Persistently high prolactin levels may cause hypo-­oestrogenic states and subsequently induce iatrogenic menopause.12 This may worsen psychotic symptoms and cognition5 as well as further increase the risk of osteoporosis in an already vulnerable group.8,13 There is some evidence to suggest that high prolactin levels can also increase the risk of breast cancer.13 Genitourinary problems and sexual dysfunction (including diminished libido) are issues that can be troublesome due to menopause and can be further worsened by hyperprolactinaemia.12 It is important to note that hormones other than prolactin and oestrogen (e.g. progesterone) may play a potentially key role when considering antipsychotic use in menopause, although further research is required in this area.5 Oestrogen augmentation for psychosis Treatment with adjunct oestrogenic medications may be beneficial in helping to relieve menopausal symptoms as well as improving psychotic symptoms and increasing the efficacy of antipsychotic drugs.8 Recent meta-­analyses have shown that selective oestrogen receptor modulators (SERMs) such as raloxifene (60–120mg/day) are a safe and effective adjunct for treating schizophrenia in menopausal women.14 Raloxifene may be more suitable for long-­term use than HRT as it has oestrogenic effects on the brain and bone tissue but anti-­oestrogenic effects on other tissues such as the breast and uterus (therefore reducing the risk of breast and uterine cancer).8,15 Both HRT and SERMs may increase the risk of venous thromboembolism (VTE)16 and so potential risks and benefits of using these drugs as oestrogen-­augmenting agents should be balanced individually, for example oestrogen replacement therapy may not be appropriate for those with a history of thromboembolic conditions.8 The preferred options for treating menopausal women with antipsychotic medications are summarised in Box 10.7. Box 10.7  Summary of preferred antipsychotic options for menopausal women8,12 First option(s): aripiprazole, lurasidone Second option(s): olanzapine, quetiapine, clozapine Avoid where possible: amisulpride, risperidone, paliperidone and FGAs Monitor: weight, bone mineral density, blood pressure, blood glucose, cholesterol and prolactin levels (especially if using prolactin-­raising antipsychotics); therapeutic drug monitoring – due to hormonal fluctuations17 ■ ■Consider augmentation with raloxifene or HRT at an early stage, i.e. at the beginning of ­menopause/perimenopausal stage, where appropriate15,18 ■ ■If the efficacy of previously effective antipsychotic doses wanes at menopause, review the drug dose ■ ■Be mindful of the risk of dose-­related adverse effects such as weight gain and cardiovascular and cerebrovascular events6 ■ ■Switching to prolactin-­sparing medications can benefit both mental and physical health13 ■ ■Consider adding anti-­diabetic drugs (where appropriate) such as metformin which may help to prevent excess weight gain19 ■ ■Consider using LAIs as an option if oral medication becomes ineffective6 HRT, hormone replacement therapy; LAIs, long-­acting injections.

68 - Elderly care

Elderly care

69 - Use of HRT

Use of HRT

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Elderly care Genitourinary symptoms of menopause (GSM) may be a factor in agitation and aggression in elderly care. Consider vaginal atrophy and localised vaginal oestrogen or ospemifene use in women presenting with GSM symptoms, recurrent urinary tract infections, recurrent candida, urinary leakage and vaginal discomfort.20,21 Use of HRT For most women, HRT is a very safe and effective first-­line option for treatment of menopausal symptoms, reducing osteoporosis and cardiovascular disease risk,21–23 although there are some contraindications and precautions to its use (Table 10.22). Treatment options 1 Perimenopause: sequential combined HRT (oestrogen + progesterone cover in luteal phase for 12–14  days of cycle) ± localised vaginal oestrogen, and testosterone (Table 10.23). 2 Post menopause: continuous combined HRT (oestrogen + progesterone) ± local vaginal oestrogen, and testosterone (Table 10.23). Combined HRT – oestrogen and progesterone – is required in all women except those who have had a total hysterectomy who may have oestrogen-­only treatment. Oral oestrogen imposes a small increase in thrombus risk and therefore transdermal oestrogen is preferred when there is an increased risk of VTE or stroke.1,23 Table 10.22  Summary of the risks of using hormone replacement therapy (HRT). Contraindications to HRT use Precautions for HRT use Risks Oestrogen-­dependent malignant tumours Undiagnosed vaginal bleeding Pregnancy Active liver disease with abnormal LFTs Active or recent thromboembolic disorder (angina/MI) Active or idiopathic VTE untreated Untreated endometrial hyperplasia Symptomatic fibroids Untreated hypertension Migraine with aura – clot risk Epilepsy – lamotrigine interaction Endometriosis – choice of HRT important VTE/stroke – choice of HRT important Heart disease – choice of HRT important Endometrial hyperplasia and cancer Clot risk – dependent on type of HRT Breast cancer risk – small increased risk for women over 50 years. Use patient counselling aided by WHC Irregular bleeding – see Table 10.25 Adverse effects – see Table 10.25 MI, myocardial infarction; VTE, venous thromboembolism; WHC, Women’s Health Concern.

862 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 Local treatment options with GSM Additional topical treatment options when GSM symptoms are prominent are given in Table 10.24. Table 10.23  Hormone replacement therapy (HRT) products and regimens. Estradiol Progesterone Sequential combined HRT – perimenopause (prescribe by brand name) Patch: 25–100mcg twice weekly Micronised progesterone 200mg on, days 15–28 of cycle Estradiol gel 0.6mg/g: 1–4 pumps daily Progesterone 200mg on, days 15–28 of cycle Estradiol gel sachets: 0.5–1.5mg daily Medroxyprogesterone acetate 10mg od, days 16–27 of cycle Estradiol 1.53mg/spray: 1–3 sprays daily Levonorgestrel 52mg IUD Estradiol hemihydrate/valerate tablets: 1–2mg daily Combined products: ■ ■Estradiol hemihydrate 50mcg/24h and norethisterone acetate 11.2mg combined patch, used for 14/28 days, and estradiol 50mcg patch used for 14/28 days. Applied twice weekly ■ ■Estradiol 1mg/2mg with dydrogesterone 10mg tablets – calendar pack one daily ■ ■Estradiol 1mg/2mg with norethisterone 1mg tablets – calendar pack one daily Continuous combined HRT – post menopause (prescribe by brand name) Estradiol patch: 25–100mcg twice weekly Micronised progesterone 100mg on Estradiol gel 0.6mg/g: 1–4 pumps daily Progesterone 100mg on Estradiol gel sachets: 0.5–1.5mg daily Medroxyprogesterone acetate 2.5–5mg od Estradiol 1.53mg/spray: 1–3 sprays daily Levonorgestrel 52mg IUD Estradiol hemihydrate/valerate tablets: 1–2mg daily Combined products: ■ ■Estradiol hemihydrate 50mcg/24h and norethisterone acetate 11.2mg combined patch, applied twice weekly ■ ■Estradiol 0.5/1mg with 2.5/5mg dydrogesterone tablets: 1 od ■ ■Estradiol 2mg with 1mg norethisterone tablets: 1 od IUD, intrauterine device; od, once a day; on, every night. Table 10.24  Topical vaginal oestrogen or GSM treatment. Drug Dose Estradiol 10mcg vaginal tablets One pv daily for 14 days and then twice weekly Estriol 0.03mg pessary One pv daily for 21 days and then twice weekly Estriol 1mg cream 1 applicator daily for 4 weeks and then twice weekly Prasterone 6.5mg pessary One daily Ospemifene 60mg oral One daily with food GSM, genitorurinary symptoms of menopause; pv, per vagina.

70 - References

References

Drug treatment of psychiatric symptoms in the context of other conditions CHAPTER 10 Starting treatment Start HRT at 25–50mcg estradiol patch dose equivalents (1mg estradiol tablet/1–2 pumps estradiol 0.6mg/g gel). Increase after 6–8 weeks if symptomatic. Higher doses of estradiol may require additional progesterone for endometrial protection.24 HRT is not a contraceptive. Management of adverse effects Table 10.25 outlines the management of the possible adverse effects of HRT. References

  1. National Institute for Health and Care Excellence. Menopause: diagnosis and management. NICE guideline [NG23]. 2015 (last updated December 2019, last checked December 2023); https://www.nice.org.uk/guidance/ng23.
  2. Avis NE, et al. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med 2015; 175:531–539.
  3. Greene JG. Constructing a standard climacteric scale. Maturitas 1998; 29:25–31.
  4. El Khoudary SR, et al. The menopause transition and women’s health at midlife: a progress report from the Study of Women’s Health Across the Nation (SWAN). Menopause 2019; 26:1213–1227.
  5. González-­Rodríguez A, et al. The association between hormones and antipsychotic use: a focus on postpartum and menopausal women. Ther Adv Psychopharmacol 2019; 9:2045125319859973.
  6. González-­Rodríguez A, et al. The effect of menopause on antipsychotic response. Brain Sci 2022; 12:1342.
  7. Brand BA, et al. Estrogens in schizophrenia: progress, current challenges and opportunities. Curr Opin Psychiatry 2021; 34:228–237.
  8. Brand BA, et al. Antipsychotic medication for women with schizophrenia spectrum disorders. Psychol Med 2022; 52:649–663.
  9. Seeman MV. Men and women respond differently to antipsychotic drugs. Neuropharmacology 2020; 163:107631.
  10. Seeman MV. Treating schizophrenia at the time of menopause. Maturitas 2012; 72:117–120.
  11. Choi SY, et  al. Isoform-­specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos 2013; 41:263–269.
  12. Lange B, et al. How gender affects the pharmacotherapeutic approach to treating psychosis – a systematic review. Expert Opin Pharmacother 2017; 18:351–362.
  13. Brand BA, et al. Towards better care for women with schizophrenia-­spectrum disorders. Lancet Psychiatry 2022; 9:330–336.
  14. 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.
  15. Sommer IE, et al. Women with schizophrenia-­spectrum disorders after menopause: a vulnerable group for relapse. Schizophr Bull 2022; 49:136–143. Table 10.25  Management of adverse effects of hormone replacement therapy (HRT). Adverse effect Comments Breast tenderness Bloating Spotting Common within first 3–6 months, or on dose adjustment, normally transient. Headaches Nausea Common in first 3 months of starting or dose increase. May need slower titration. Mood swings Increase in PMS symptoms Increased anxiety/agitation Often common when starting for first month, then transient. Consider progesterone intolerance if beyond 1 month or severe. Irregular bleeding Common for the first 3 months. Refer for investigation if after 4–6 months it has not settled or patient has been on HRT for a while and it is a new presentation. PMS, premenstrual syndrome.

864 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 10 16. González-­Rodríguez A, et al. Women with schizophrenia over the life span: health promotion, treatment and outcomes. Int J Environ Res Public Health 2020; 17:5594. 17. Brand BA, et al. Evidence-­based recommendations for the pharmacological treatment of women with schizophrenia spectrum disorders. Curr Psychiatry Rep 2023; 25:723–733. 18. Culbert KM, et al. Risk for midlife psychosis in women: critical gaps and opportunities in exploring perimenopause and ovarian hormones as mechanisms of risk. Psychol Med 2022; 52:1612–1620. 19. Seeman MV. Selecting the right treatment plan for schizophrenia in postmenopausal women: an update of the literature. Expert Rev Neurother 2023; 23:515–523. 20. Hamoda H, et al. The British Menopause Society and Women’s Health Concern 2020 recommendations on hormone replacement therapy in menopausal women. Post Reprod Health 2020; 26:181–209. 21. Chakrabarti R, et  al. Prescribing hormone replacement therapy: key considerations for primary care physicians. Br J Gen Pract 2023; 73:330–332. 22. Weiss SR, et al. A randomized controlled trial of four doses of transdermal estradiol for preventing postmenopausal bone loss. Transdermal Estradiol Investigator Group. Obstet Gynecol 1999; 94:330–336. 23. Boardman HM, et al. Hormone therapy for preventing cardiovascular disease in post-­menopausal women. Cochrane Database Syst Rev 2015; 2015:CD002229. 24. British Menopause Society (BMS). Progestogens and endometrial protection. BMS consensus statement. 2021; https://thebms.org.uk/wp-­ content/uploads/2021/10/14-­BMS-­TfC-­Progestogens-­and-­endometrial-­protection-­01H.pdf.