Maudsley 14th.pdf

The Maudsley® Prescribing Guidelines in Psychiatry The Maudsley Guidelines Other books in the Maudsley Prescribing Guidelines series include: The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry David Taylor, Fiona Gaughran, Toby Pillinger The Maudsley Guidelines on Advanced Prescribing in Psychosis Paul Morrison, David Taylor, Phillip McGuire The Maudsley® Prescribing Guidelines in Psychiatry 14th Edition David M. Taylor, BSc, MSc, PhD, FFRPS, FRPharmS, FRCP , Edin FRCPsychHon Director of Pharmacy and Pathology, Maudsley Hospital and Professor of Psychopharmacology, King’s College, London, UK Thomas R. E. Barnes, MBBS, MD, FRCPsych, DSc Emeritus Professor of Clinical Psychiatry at Imperial College London and joint head of the Prescribing Observatory for Mental Health at the Royal College of Psychiatrists’ Centre for Quality Improvement, London, UK Allan H. Young, MB, ChB, MPhil, PhD, FRCP, FRCPsych Chair of Mood Disorders and Director of the Centre for Affective Disorders in the Department of Psychological Medicine in the Institute of Psychiatry, Psychology and Neuroscience at King’s College, London, UK This edition first published 2021 © 2021 David M. Taylor All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of David M. Taylor, Thomas R. E. Barnes, and Allan H. Young to be identified as the author(s) of this work has been asserted in accordance with law. 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A catalogue record for this book is available from the Library of Congress Paperback ISBN: 9781119772224; ePDF ISBN: 9781119772248; epub ISBN: 9781119772231 Cover design by Wiley Set in 10/12pt Sabon by Integra Software Services, Pondicherry, India 10 9 8 7 6 5 4 3 2 1 Contents Prefacexi Acknowledgmentsxii Notes on using The Maudsley® Prescribing Guidelines in Psychiatryxiii xv List of abbreviations Part 1 Drug treatment of major psychiatric conditions 1 Chapter 1 Schizophrenia and related psychoses 3 ANTIPSYCHOTIC DRUGS 3 General introduction 3 8 Antipsychotics – general principles of prescribing Antipsychotics – minimum effective doses 9 Antipsychotics – quick reference for licensed maximum doses 12 Antipsychotics – equivalent doses 14 High-dose antipsychotics: prescribing and monitoring 16 20 Combined antipsychotics (antipsychotic polypharmacy) Antipsychotic prophylaxis 25 Negative symptoms 32 Monitoring38 Relative adverse effects – a rough guide 41 Treatment algorithms for schizophrenia 42 First-generation antipsychotics – place in therapy 46 NICE guidelines for the treatment of schizophrenia 48 Antipsychotic response – to increase the dose, to switch, to add or just wait – what is the right move? 51 Acutely disturbed or violent behaviour 56 Antipsychotic depots/long-acting injections (LAIs) 67 Depot/LAI antipsychotics – pharmacokinetics 72 Management of patients on long-term depots/LAIs 74 77 Aripiprazole long-acting injection Olanzapine long-acting injection 80 Paliperidone palmitate long-acting injection 83 Risperidone long-acting injection 87 Risperidone subcutaneous long-acting injection 91 vi Contents Newer long-acting injectable antipsychotic preparations 92 Penfluridol weekly 95 Electroconvulsive therapy and psychosis 96 Omega-3 fatty acid (fish oils) in schizophrenia 99 Stopping antipsychotics 102 ANTIPSYCHOTIC ADVERSE EFFECTS 109 Extrapyramidal symptoms 109 Akathisia114 Treatment of tardive dyskinesia 117 Antipsychotic-induced weight gain 123 Treatment of antipsychotic-induced weight gain 125 Neuroleptic malignant syndrome 131 Catatonia135 ECG changes – QT prolongation 141 149 Effect of antipsychotic medications on plasma lipids Diabetes and impaired glucose tolerance 153 Blood pressure changes with antipsychotics 160 Hyponatraemia in psychosis 164 Hyperprolactinaemia168 Sexual dysfunction 172 Pneumonia181 Switching antipsychotics 183 Venous thromboembolism 187 REFRACTORY SCHIZOPHRENIA AND CLOZAPINE 190 190 Clozapine initiation schedule 192 Intramuscular clozapine Optimising clozapine treatment 193 Alternatives to clozapine 198 Re-starting clozapine after a break in treatment 207 Guidelines for the initiation of clozapine for patients based in the community 208 CLOZAPINE ADVERSE EFFECTS 212 212 Clozapine: common adverse effects Clozapine: uncommon or unusual adverse effects 217 Clozapine: serious haematological and cardiovascular adverse effects 222 Clozapine-induced hypersalivation 227 Clozapine-induced gastrointestinal hypomotility (CIGH) 232 Clozapine, neutropenia and lithium 236 Clozapine and chemotherapy 242 Clozapine-genetic testing for clozapine treatment 244 Chapter2 Bipolar disorder 247 Lithium247 Valproate257 Carbamazepine264 Antipsychotics in bipolar disorder 269 Antipsychotic long-acting injections in bipolar disorder 274 Physical monitoring for people with bipolar disorder 277 Treatment of acute mania or hypomania 279 Rapid cycling bipolar affective disorder 285 Contents vii Bipolar depression Prophylaxis in bipolar disorder Stopping lithium and mood stabilisers Chapter 3 288 296 301 Depression and anxiety disorders 305 Introduction to Depression 305 Official guidance on the treatment of depression 305 Antidepressants – general overview 307 Recognised minimum effective doses of antidepressants 312 Drug treatment of depression 314 Management of treatment-resistant depression – first choice 317 Management of treatment-resistant depression – second choice 321 323 Treatment-resistant depression – other reported treatments Ketamine328 Psychotic depression 332 Switching antidepressants 336 Antidepressant withdrawal symptoms 343 348 Stopping antidepressants Electroconvulsive therapy (ECT) and psychotropic drugs 353 Psychostimulants in depression 357 Post-stroke depression 362 Antidepressants – alternative routes of administration 366 374 Antidepressant prophylaxis Drug interactions with antidepressants 378 Cardiac effects of antidepressants – summary 383 Antidepressant-induced arrhythmia 389 Antidepressant-induced hyponatraemia 393 398 Antidepressants and hyperprolactinaemia 401 Antidepressants and diabetes mellitus Antidepressants and sexual dysfunction 404 SSRIs and bleeding 409 417 St. John’s Wort Antidepressants: relative adverse effects – a rough guide 421 Anxiety spectrum disorders 423 436 Benzodiazepines in the treatment of psychiatric disorders Benzodiazepines, z-drugs and gabapentinoids: dependence, detoxification and discontinuation 440 Benzodiazepines and disinhibition 448 Chapter 4 Addictions and substance misuse 451 Introduction451 Alcohol dependence 453 Alcohol withdrawal delirium – delirium tremens 472 Opioid dependence 474 Nicotine and smoking cessation 503 Pharmacological treatment of dependence on stimulants 511 GHB and GBL dependence 514 Benzodiazepine misuse 517 Synthetic cannabinoid receptor agonists (SCRAs) 520 viii Contents Part 2 Drug-induced acute behavioural disturbance (ABD) in acute admissions Interactions between ‘street drugs’ and prescribed psychotropic drugs Drugs of misuse – a summary Substance misuse in pregnancy 524 526 530 535 Drug treatment of special patient groups 537 Chapter 5 Children and adolescents Principles of prescribing practice in childhood and adolescence Depression in children and adolescents Bipolar illness in children and adolescents Psychosis in children and adolescents Anxiety disorders in children and adolescents Obsessive compulsive disorder (OCD) and body dysmorphic disorder (BDD) in children and adolescents Post-traumatic stress disorder in children and adolescents Attention deficit hyperactivity disorder Autism Spectrum Disorder Tics and Tourette syndrome Melatonin in the treatment of insomnia in children and adolescents Rapid tranquillisation (RT) in children and adolescents Doses of commonly used psychotropic drugs in children and adolescents 539 539 541 547 554 556 561 567 569 578 587 593 596 599 Chapter 6 Prescribing in older people 601 General principles 601 Dementia604 Safer prescribing for physical conditions in dementia 631 Management of behavioural and psychological symptoms of dementia (BPSD) 644 A guide to medication doses of commonly used psychotropics in older adults 657 Covert administration of medicines within food and drink 667 673 Treatment of depression in older people Chapter 7 Pregnancy and breastfeeding 679 679 Drug choice in pregnancy What to include in discussions with pregnant women 681 Breastfeeding702 Chapter 8 Hepatic and renal impairment Hepatic impairment Renal impairment Part 3 Prescribing in specialist conditions 723 723 735 755 Chapter 9 Drug treatment of other psychiatric conditions 757 Borderline personality disorder (BPD) 757 Eating disorders 761 Delirium767 Contents ix Chapter 10 Drug treatment of psychiatric symptoms occurring in the context of other disorders 777 General principles of prescribing in HIV 777 Epilepsy785 22q11.2 deletion syndrome 794 Learning disabilities 797 803 Huntington’s disease – pharmacological treatment Multiple sclerosis 808 Parkinson’s disease 814 Atrial fibrillation – using psychotropics 819 Recommendations – psychotropics in AF 820 Psychotropics in bariatric surgery 822 Prescribing in patients with psychiatric illness at the end of life 829 Part 4 Other aspects of psychotropic drug use 831 Chapter 11 Pharmacokinetics Plasma level monitoring of psychotropic drugs Interpreting postmortem blood concentrations Acting on clozapine plasma concentration results Psychotropics and cytochrome (CYP) function Smoking and psychotropic drugs Drug interactions with alcohol 833 833 847 849 851 856 860 Chapter 12 Other substances 865 Caffeine865 Nicotine871 Chapter 13 Psychotropic drugs in special conditions Psychotropics in overdose Driving and psychotropic medicines Psychotropics and surgery 875 875 883 889 Chapter 14 897 897 905 907 917 Miscellany Enhancing medication adherence Re-starting psychotropic medications after a period of non-compliance Biochemical and haematological effects of psychotropics Summary of psychiatric side effects of non-psychotropics Prescribing drugs outside their licensed indications (‘off-label’ prescribing or unapproved use of approved drugs) Examples of acceptable use of drugs outside their product licences/labels The Mental Health Act in England and Wales Site of administration of intramuscular injections Intravenous formulations in psychiatry 923 925 927 932 937 Index943 Preface This 14th edition of The Guidelines has been written under extraordinary circumstances: the coronavirus pandemic. This global phenomenon has radically altered the lives and working practices of billions of people, and most of us are now familiar, either personally or vicariously, with the experience of the serious physical illness that is associated with COVID-19. Those working in healthcare have been particularly grievously affected, caring for those made ill by the disease while risking infection themselves. In this environment, the writing of a book has an extremely low priority, if any at all. It is in this context that I give boundless and sincere thanks to all those who have contributed to this edition of The Guidelines under such challenging conditions. Of course, mental health problems have not gone away during the pandemic, and the optimal treatment of mental illness remains a vital imperative. This objective will be all the more critical as we come to deal with the mental health consequences of the pandemic. This edition of The Guidelines has been thoroughly updated to include influential research published since 2017 and all major psychotropic drugs introduced since that time. This edition is also somewhat expanded by the inclusion of new sections on such subjects as the management of agitated delirium, psychotropics at the end of life, intravenous psychotropic formulations, intramuscular clozapine and weekly oral penfluridol. As with previous editions, the 14th edition is written with the intention of having worldwide utility, but it retains its mild emphasis on UK practice. I would like to pay special tribute to Siobhan Gee for her numerous meticulously prepared contributions on the use of clozapine, Mark Horowitz for his evidence-based and patient-centred guidance on discontinuation of psychotropics, Delia Bishara for her near single-handed production of the chapter on older adults, and Ian Osborne for his contributions on an exceptionally varied range of subjects. Emily Finch deserves particular recognition for organising the writing of the chapter on addictions for the last ten editions of The Guidelines. Lastly, I would like to thank my assistant Ivana Clark for managing the production of this edition with patience and an unparalleled attention to detail. David M.Taylor London March 2021 Acknowledgments The following have contributed to the 14th edition of The Maudsley® Prescribing Guidelines in Psychiatry. Alice Debelle Andrea Danese Andrew Wilcock Annabel Price Anne Connolly Bruce Clark Claire Wilson Colin Drummond Daniel Harwood David Mirfin Deborah Robson Delia Bishara Derek Tracy Ebenezer Oloyede Elizabeth Naomi Smith Emily Finch Emmert Roberts Eromona Whiskey Francis Keaney Frank Besag Gabriel Ruane Georgina Boon Hubertus Himmerich Ian Osborne Irene Guerrini Iris Rathwell Ivana Clark James Stone Jane Marshall Janet Treasure Jemma Theivendran Jonathan Rogers Justin Sauer Kalliopi Vallianatou Kwame Peprah Louise Howard Luke Baker Luke Jelen Marinos Kyriakopoulos Mark Horowitz Max Henderson Mike Kelleher Nicola Funnell Nicola Kalk Nilou Nourishad Oluwakemi Oduniyi Paramala Santosh Paul Gringras Paul Moran Petrina Douglas-Hall Sameer Jauhar Shubhra Mace Siobhan Gee Sotiris Posporelis Stephanie J Lewis Stephen Barclay Notes on using The Maudsley® Prescribing Guidelines in Psychiatry The main aim of The Guidelines is to provide clinicians with practically useful advice on the prescribing of psychotropic agents in both commonly and less commonly encountered clinical situations. The advice contained in this handbook is based on a combination of literature review, clinical experience and expert contribution. We do not claim that this advice is necessarily ‘correct’ or that it deserves greater prominence than the guidance provided by other professional bodies or special interest groups. We hope, however, to have provided guidance that helps to assure the safe, effective and economic use of medicines in psychiatry. We hope also to have made clear precisely the sources of information used to inform the guidance given. Please note that many of the recommendations provided here go beyond the licensed or labelled indications of many drugs, both in the UK and elsewhere. Note also that, while we have endeavoured to make sure all quoted doses are correct, clinicians should always consult statutory texts before prescribing. Users of The Guidelines should also bear in mind that the contents of this handbook are based on information available to us in March 2021. Much of the advice contained here will become out‐dated as more research is conducted and published. No liability is accepted for any injury, loss or damage, however caused. Notes on inclusion of drugs The Guidelines are used in many other countries outside the UK. With this in mind, we have included in this edition those drugs in widespread use throughout the Western world in March 2021. These include drugs not marketed in the UK, such as brexpiprazole, desvenlafaxine, pimavanserin and vilazodone, amongst several others. Many older drugs or those not widely available (e.g. levomepromazine, pericyazine, maprotiline, zotepine, oral loxapine, etc.) are either only briefly mentioned or not included on the basis that these drugs are not in widespread use at the time of writing. Notes on using The Maudsley® Prescribing Guidelines in Psychiatry xv Contributors’ Conflict of Interest Most of the contributors to The Guidelines have received funding from pharmaceutical manufacturers for research, consultancy or lectures. Readers should be aware that these relationships inevitably colour opinions on such matters as drug selection or preference. We cannot, therefore, guarantee that the guidance provided here is free of indirect influence of the pharmaceutical industry but hope to have mitigated this risk by providing copious literature support for statements made. As regards direct influence, no pharmaceutical company has been allowed to view or comment on any drafts or proofs of The Guidelines, and none has made any request for the inclusion or omission of any topic, advice or guidance. To this extent, The Guidelines have been written independent of the pharmaceutical industry. List of abbreviations AACAP American Academy of Child and Adolescent Psychiatry angiotensin‐converting enzyme ACE ACh acetylcholine AChE acetylcholinesterase AChE‐I acetylcholinesterase inhibitor ACR albumin: creatinine ratio AD Alzheimer’s disease ADAS‐cog Alzheimer’s Disease Assessment Scale – cognitive subscale alcohol dehydrogenase ADH ADHD attention deficit hyperactivity disorder ADIS Anxiety Disorders Interview Schedule ADL activities of daily living adverse drug reaction ADR AF atrial fibrillation AIDS acquired immune deficiency syndrome AIMS Abnormal Involuntary Movement Scale ALP alkaline phosphatase ALT alanine transaminase/ aminotransferase ANC absolute neutrophil count ANNSERS Antipsychotic Non‐Neurological Side‐Effects Rating Scale APA American Psychological Association angiotensin II receptor blocker ARB ASD autism spectrum disorders ASEX Arizona Sexual Experience Scale aspartate aminotransferase AST AUDIT Alcohol Use Disorders Identification Test blood alcohol concentration BAC BAP British Association for Psychopharmacology blood–brain barrier BBB bd bis die (twice a day) body dysmorphic disorder BDD BDI Beck Depression Inventory BDNF brain‐derived neurotrophic factor BED binge eating disorder BEN benign ethnic neutropenia BMI body mass index BN bulimia nervosa BP blood pressure borderline personality disorder BPD BPSD behavioural and psychological symptoms of dementia butyrylcholinesterase BuChE CAM Confusion Assessment Method CAMS Childhood Anxiety Multimodal Study CATIE Clinical Antipsychotic Trials of Intervention Effectiveness cognitive behavioural therapy CBT List of abbreviations xvii CBZ carbamazepine CDRS Children’s Depression Rating Scale CDT carbohydrate‐deficient transferrin CES‐D Centre for Epidemiological Studies Depression scale CGAS Children’s Global Assessment Scale CGI Clinical Global Impression scales CI confidence interval CIBIC‐Plus Clinician’s Interview‐Based Impression of Change CIGH clozapine‐induced gastrointestinal hypomotility CIWA‐Ar Clinical Institute Withdrawal Assessment of Alcohol scale revised CK creatine kinase CKD chronic kidney disease CKD‐EPI Chronic Kidney Disease Epidemiology Collaboration CNS central nervous system COMT catechol‐O‐methyltransferase COPD chronic obstructive pulmonary disease COX cyclo‐oxygenase creatinine phosphokinase CPK CPP child–parent psychotherapy CPSS Child PTSD Symptom Scale CrCl creatinine clearance CREB cAMP response element‐binding protein CRP C‐reactive protein CUtLASS Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study CVA cerebrovascular accident CY‐BOCS Children’s Yale‐Brown Obsessive Compulsive Scale CYP cytochrome P drug attitude inventory DAI DESS Discontinuation–Emergent Signs and Symptoms scale DEXA dual‐energy X‐ray absorptiometry DHEA dehydroepiandrosterone DIVA Diagnostic Interview for DSM‐IV ADHD DLB dementia with Lewy bodies DMDD disruptive mood dysregulation disorder DOAC direct‐acting oral anticoagulant DoLS Deprivation of Liberty Safeguards Diagnostic and Statistical Manual of Mental Disorders DSM DVLA Driver and Vehicle Licensing Agency early after depolarisation EAD ECG electrocardiogram ECT electroconvulsive therapy EDTA ethylenediaminetetraacetic acid EEG electroencephalogram eGFR estimated glomerular filtration rate EMDR eye movement desensitisation and reprocessing EOSS early‐onset schizophrenia‐spectrum EPA eicosapentanoic acid EPS extrapyramidal symptoms ER extended release xviii List of abbreviations ERK extracellular signal‐regulated kinase ERP exposure and response prevention ES effect size ESR erythrocyte sedimentation rate FAST functional assessment staging full blood count FBC FDA Food and Drug Administration (USA) FGA first‐generation antipsychotic FPG fasting plasma glucose FTI Fatal Toxicity Index GABA γ‐aminobutyric acid GAD generalised anxiety disorder GASS Glasgow Antipsychotic Side‐effect Scale GBL gamma-butyrolactone G‐CSF granulocyte colony‐stimulating factor GFR glomerular filtration rate GGT γ‐glutamyl transferase GHB γ‐hydroxybutyrate GI gastrointestinal GM‐CSF granulocyte‐macrophage colony-stimulating factor GSK3 glycogen synthase kinase 3 HADS Hospital Anxiety and Depression Scale HAMA Hamilton Anxiety Rating Scale HAND HIV‐associated neurocognitive disorders HD Huntington’s disease HDL high‐density lipoprotein HDRS Hamilton Depression Rating Scale HIV human immunodeficiency virus 5‐hydroxy‐methyl‐tolterodine 5‐HMT HPA hypothalamic‐pituitary‐adrenal HR hazard ratio IADL instrumental activities of daily living ICD International Classification of Diseases ICH intracerebral haemorrhage IFG impaired fasting glucose intra‐gastric IG IJ intra‐jejunal IM intramuscular IMCA independent mental capacity advocate IMHP intramuscular high potency INR international normalised ratio immediate release IR IV intravenous intravenous high potency IVHP Kiddie‐SADS Kiddie‐Schedule for Affective Disorders and Schizophrenia long‐acting injection LAI LD learning disability LDL low‐density lipoprotein LFTs liver function tests LGIB lower gastrointestinal bleeding LSD lysergic acid diethylamide MADRS Montgomery‐Asberg Depression Rating Scale mane morning monoamine oxidase inhibitor MAOI MARS Medication Adherence Rating Scale MASC Multidimensional Anxiety Scale for Children Mental Capacity Act MCA mild cognitive impairment MCI MDA 3,4‐methylenedioxyamphetamine MDMA 3,4‐methylenedioxymethamphetamine MDRD Modification of Diet in Renal Disease MHRA Medicines and Healthcare Products Regulatory Agency myocardial infarction MI MMSE Mini Mental State Examination MR modified release MS mood stabilisers/multiple sclerosis neonatal abstinence syndrome NAS NICE National Institute for Health and Care Excellence NMDA N‐methyl‐D‐aspartate neuroleptic malignant syndrome NMS NNH number needed to harm NNT number needed to treat nocte at night List of abbreviations xix NPI neuropsychiatric inventory NRT nicotine replacement therapy NSAID non‐steroidal anti‐inflammatory drug neurovascular coupling NVC OCD obsessive compulsive disorder od omni die (once a day) OD overdose OGTT oral glucose tolerance test OOWS Objective Opiate Withdrawal Scale opioid substitution treatment OST PANDAS Paediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus PANS Paediatric Acute‐onset Neuropsychiatric Syndrome PANSS Positive and Negative Syndrome Scale PBA pseudobulbar affect PCP phencyclidine Parkinson’s disease PD PDD pervasive developmental disorders PDD‐NOS pervasive developmental disorders not otherwise specified P‐gp P‐glycoprotein Patient Health Questionnaire‐9 PHQ‐9 PICU psychiatric intensive care unit pathological laughter and crying PLC PLWH people living with HIV post‐mortem redistribution PMR po per os (by mouth) POMH‐UK Prescribing Observatory for Mental Health PPH post‐partum haemorrhage proton pump inhibitor PPI prn pro re nata (as required) prothrombin time PT PTSD post‐traumatic stress disorder PWE people with epilepsy qds quarter die sumendum (four times a day) QTc QT interval adjusted for heart rate RC responsible clinician RCADS Revised Children’s Anxiety and Depression Scale RCT randomised controlled trial relative infant dose RID RIMA reversible inhibitor of monoamine oxidase A RLAI risperidone long‐acting injection ROMI Rating of Medication Influences scale RPG random plasma glucose RR relative risk RRBI restricted repetitive behaviours and interests RT rapid tranquillisation RTA road traffic accident rTMS repetitive transcranial magnetic stimulation RUPP Research Units on Paediatric Psychopharmacology RYGB Roux‐en‐Y gastric bypass SADQ Severity of Alcohol Dependence Questionnaire Short Alcohol Withdrawal Scale SAWS SCARED Screen for Child Anxiety and Related Emotional Disorders SCIRS Severe Cognitive Impairment Rating Scale SCRA synthetic cannabinoid receptor agonist SGA second‐generation antipsychotics SIADH syndrome of inappropriate antidiuretic hormone SIB severe impairment battery SJW St. John’s wort systemic lupus erythematosus SLE SNRI serotonin–noradrenaline reuptake inhibitor SOAD second opinion appointed doctor SPC summary of product characteristics SPECT single photon emission computed tomography SROM slow release oral morphine SS steady state xx List of abbreviations SSRI selective serotonin reuptake inhibitor STAR*D Sequenced Treatment Alternatives to Relieve Depression programme STS selegiline transdermal system TADS Treatment of Adolescents with Depression Study TCA tricyclic antidepressant tardive dyskinesia TD tDCS transcranial direct current stimulation TDP torsades de pointes tds ter die sumendum (three times a day) TEAM Treatment of Early Age Mania TF‐CBT trauma‐focused cognitive behavioural therapy TFT thyroid function test THC/CBD tetrahydrocannabinol/ cannabidiol TIA transient ischaemic attack TMS transcranial magnetic stimulation TORDIA Treatment of Resistant Depression in Adolescence TPR temperature, pulse, respiration TRS treatment‐resistant schizophrenia TS Tourette syndrome U&Es urea and electrolytes UGIB upper gastrointestinal bleeding UDP‐glucuronosyl transferase UGT VaD vascular dementia vagal nerve stimulation VNS VTE venous thromboembolism white blood cell WBC WCC white cell count WHO World Health Organization XL extended release YMRS Young Mania Rating Scale ZA zuclopenthixol acetate Part 1 Drug treatment of major psychiatric conditions Chapter 1 Schizophrenia and related psychoses ANTIPSYCHOTIC DRUGS General introduction Classification of antipsychotics Before the 1990s, antipsychotics (or major tranquillisers as they were then known) were classified according to their chemistry. The first antipsychotic, chlorpromazine, was a phenothiazine compound – a tricyclic structure incorporating a nitrogen and a sulphur atom. Further phenothiazines were generated and marketed, as were chemically similar thioxanthenes, such as flupentixol. Later entirely different chemical structures were developed according to pharmacological paradigms. These included butyrophenones (haloperidol), diphenylbutylpiperidines (pimozide) and substituted benzamides (sulpiride and amisulpride). Chemical classification remains useful but is rendered somewhat redundant by the broad range of chemical entities now available and by the absence of any clear structure-activity relationships for newer drugs. The chemistry of some older drugs does relate to their propensity to cause movement disorders. Piperazine phenothiazines (e.g. fluphenazine, trifluoperazine), butyrophenones and thioxanthenes are most likely to cause extrapyramidal effects, while piperidine phenothiazines (e.g. pipotiazine) and benzamides are the least likely. Aliphatic phenothiazines (e.g. chlorpromazine) and diphenylbutylpiperidines (pimozide) are perhaps somewhere in-between. Relative liability for inducing extrapyramidal symptoms (EPS) was originally the primary factor behind the typical/atypical classification. Clozapine had long been known as an atypical antipsychotic on the basis of its low liability to cause EPS and its failure in animal-based antipsychotic screening tests. Its re-marketing in 1990 signalled the beginning of a series of new medications, all of which were introduced with claims (of varying degrees of accuracy) of ‘atypicality’. Of these medications, perhaps only clozapine and, possibly, quetiapine are completely atypical, seemingly having a very low The Maudsley® Prescribing Guidelines in Psychiatry, Fourteenth Edition. David M. Taylor, Thomas R. E. Barnes and Allan H. Young. © 2021 David M. Taylor. Published 2021 by John Wiley & Sons Ltd. CHAPTER 1 4 The Maudsley® Prescribing Guidelines in Psychiatry liability for EPS. Others show dose-related effects, although, unlike with typical drugs, therapeutic activity can usually be achieved without EPS. This is possibly the real distinction between typical and atypical drugs: the ease with which a dose can be chosen (within the licensed dosage range), which is effective but does not cause EPS (e.g. compare haloperidol with olanzapine). The typical/atypical dichotomy does not lend itself well to classification of antipsychotics in the middle ground of EPS liability. Thioridazine was widely described as atypical in the 1980s but is a ‘conventional’ phenothiazine. Sulpiride was marketed as atypical but is often classified as typical. Risperidone, at its maximum dose of 16mg/ day (10mg in the USA), is just about as ‘typical’ as a drug can be. Alongside these difficulties is the fact that there is nothing either pharmacologically or chemically which clearly binds these so-called atypicals together as a group, save perhaps a general but not universal finding of preference for D2 receptors outside the striatum. Nor are atypicals characterised by improved efficacy over older drugs (clozapine and one or two others excepted) or the absence of hyperprolactinaemia (which is usually worse with risperidone, paliperidone and amisulpride than with typical drugs). Lastly, some more recently introduced agents (e.g. pimavanserin) have antipsychotic activity and do not cause EPS but have almost nothing in common with other atypicals in respect to chemistry, pharmacology or adverse effect profile. In an attempt to get around some of these problems, typicals and atypicals were reclassified as first- or second-generation antipsychotics (FGA/SGA). All drugs introduced since 1990 are classified as SGAs (i.e. all atypicals), but the new nomenclature dispenses with any connotations regarding atypically, whatever atypicality may mean. However, the FGA/SGA classification remains problematic because neither group is defined by anything other than time of introduction – hardly the most sophisticated pharmacological classification system. Perhaps more importantly, date of introduction is often wildly distant from date of first synthesis. Clozapine is one of the oldest antipsychotics (synthesised in 1959), while olanzapine is hardly in its first flush of youth, having first been patented in 1971. These two drugs are of course SGAs – apparently the most modern of antipsychotics. In this edition of The Guidelines, we conserve the FGA/SGA distinction more because of convention than some scientific basis. Also, we feel that most people know which drugs belong to each group – it thus serves as a useful shorthand. However, it is clearly more sensible to consider the properties of individual antipsychotics when choosing drugs to prescribe or in discussions with patients and carers. With this in mind, the use of Neuroscience-based Nomenclature (NbN)1 – a naming system that reflects pharmacological activity – is strongly recommended. Choosing an antipsychotic The NICE guideline for medicines adherence2 recommends that patients should be as involved as possible in decisions about the choice of medicines that are prescribed for them, and that clinicians should be aware that illness beliefs and beliefs about medicines influence adherence. Consistent with this general advice that covers all of healthcare, the NICE guideline for schizophrenia emphasises the importance of patient choice rather than specifically recommending a class or individual antipsychotic as first-line treatment.3 Antipsychotics are effective in both the acute and maintenance treatment of schizophrenia and other psychotic disorders. They differ in their pharmacology, pharmacokinetics, overall efficacy/effectiveness and tolerability, but perhaps more importantly, response and tolerability differ between patients. This variability of individual response means that there is no clear first-line antipsychotic medication that is preferable for all. Relative efficacy Following the publication of the independent CATIE4 and CUtLASS5 studies, the World Psychiatric Association reviewed the evidence relating to the relative efficacy of 51 FGAs and 11 SGAs and concluded that, if differences in EPS could be minimised (by careful dosing) and anticholinergic use avoided, there was no convincing evidence to support any advantage for SGAs over FGAs.6 As a class, SGAs may have a lower propensity for EPS and tardive dyskinesia (TD),7 but this is somewhat offset by a higher propensity to cause metabolic side effects. A meta-analysis of antipsychotic medications for first-episode psychosis8 found few differences between FGAs and SGAs as groups of drugs but minor advantages for olanzapine and amisulpride individually. A later network meta-analysis of first-episode studies found small efficacy advantages for olanzapine and amisulpride and overall poor performance for haloperidol.9 When individual non-clozapine SGAs are compared, initial summary data suggested that olanzapine is marginally more effective than aripiprazole, risperidone, quetiapine and ziprasidone, and that risperidone has a minor advantage over quetiapine and ziprasidone.10 FGA-controlled trials also suggest an advantage for olanzapine, risperidone and amisulpride over older drugs.11,12 A network meta-analysis13 broadly confirmed these findings, ranking amisulpride second behind clozapine and olanzapine third. These three drugs were the only ones to show clear efficacy advantages over haloperidol. The magnitude of differences was again small (but potentially substantial enough to be clinically important)13 and must be weighed against the very different side effect profiles associated with individual antipsychotics. A 2019 network meta-analysis of 32 antipsychotics14 ranked amisulpride as the most effective drug for positive symptoms and clozapine as the best for both negative symptoms and overall symptom improvement. Olanzapine and risperidone were also highly ranked for positive symptom response. The greatest (beneficial) effect on depressive symptoms was seen with sulpiride, clozapine, amisulpride, olanzapine and the dopamine partial agonists, perhaps reflecting the relative absence of neuroleptic-induced dysphoria common to most FGAs.15 There was a tendency for more recently introduced drugs to have a lower estimated efficacy – a phenomenon that derives from the substantial increase in placebo response since 1970.16 Clozapine is clearly the drug of choice in refractory schizophrenia17 although, bizarrely, this is not a universal finding,18 probably because of the nature and quality of many active-comparator trials.19,20 Both FGAs and SGAs are associated with a number of adverse effects. These include weight gain, dyslipidaemia, increases in plasma glucose/diabetes,21,22 hyperprolactinaemia, hip fracture,23 sexual dysfunction, EPS including neuroleptic malignant syndrome,24 anticholinergic effects, venous thromboembolism (VTE),25 sedation and postural hypotension. The exact profile is drug-specific (see individual sections on CHAPTER 1 Schizophrenia and related psychoses 5 CHAPTER 1 6 The Maudsley® Prescribing Guidelines in Psychiatry specific adverse effects), although comparative data are not robust26 (see largescale meta-analyses13,27 for rankings of some adverse effect risks). Adverse effects are a common reason for treatment discontinuation,28 particularly when efficacy is poor.13 Patients do not always spontaneously report side effects however,29 and psychiatrists’ views of the prevalence and importance of adverse effects differ markedly from patient experience.30 Systematic enquiry, along with a physical examination and appropriate biochemical tests, is the only way accurately to assess their presence and severity or perceived severity. Patient-completed checklists such as the Glasgow Antipsychotic Side-effect Scale (GASS)31 can be a useful first step in this process. The clinician-completed Antipsychotic Non-Neurological Side-Effects Rating Scale (ANNSERS) facilitates a more detailed and comprehensive assessment.32 Non-adherence to antipsychotic treatment is common, and here the guaranteed medication delivery associated with depot/long-acting injectable antipsychotic preparations is unequivocally advantageous. In comparison with oral antipsychotics, there is strong evidence that depots are associated with a reduced risk of relapse and rehospitalisation.33–35 The introduction of SGA long-acting injections has to some extent changed the image of depots, which were sometimes perceived as punishments for miscreant patients. Their tolerability advantage probably relates partly to the better definition of their therapeutic dose range, meaning that the optimal dose is more likely to be prescribed (compare aripiprazole, with a licensed dose 300mg or 400mg a month, with flupentixol, which has a licensed dose in the UK of 50mg every four weeks to 400mg a week). The optimal dose of flupentixol is around 40mg every 2 weeks:27 just 5% of the maximum allowed. As already mentioned, for patients whose symptoms have not responded sufficiently to adequate, sequential trials of two or more antipsychotic drugs, clozapine is the most effective treatment,36–38 and its use in these circumstances is recommended by NICE.3 The biological basis for the superior efficacy of clozapine is uncertain.39 Olanzapine should probably be one of the two drugs used before clozapine.10,40 A case might also be made for a trial of amisulpride: it has a uniformly high ranking in meta-analyses, and one trial found continuation with amisulpride to be as effective as switching to olanzapine.41 This trial also suggested clozapine might be best placed as the second drug used, given that switching provided no benefit over continuing with the first prescribed drug. This chapter covers the treatment of schizophrenia with antipsychotic drugs, the relative adverse effect profile of these drugs and how adverse effects can be managed. References 1. Zohar J, et al. A review of the current nomenclature for psychotropic agents and an introduction to the Neuroscience-based Nomenclature. Eur Neuropsychopharmacol 2015; 25:2318–2325. 2. National Institute for Clinical Excellence. Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence. Clinical Guidance [CG76]. 2009 (last checked March 2019); https://www.nice.org.uk/Guidance/CG76. 3. National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management. Clinical Guidance [CG178]. 2014 (last checked March 2019); https://www.nice.org.uk/guidance/cg178. 4. Lieberman JA, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209–1223. 5. Jones PB, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63:1079–1087. 6. Tandon R, et al. World Psychiatric Association Pharmacopsychiatry Section statement on comparative effectiveness of antipsychotics in the treatment of schizophrenia. Schizophr Res 2008; 100:20–38. 7. Tarsy D, et al. Epidemiology of tardive dyskinesia before and during the era of modern antipsychotic drugs. Handb Clin Neurol 2011; 100:601–616. 8. Zhang JP, et al. Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis. Int J Neuro Psychopharmacol 2013; 16:1205–1218. 9. Zhu Y, et al. Antipsychotic drugs for the acute treatment of patients with a first episode of schizophrenia: a systematic review with pairwise and network meta-analyses. Lancet Psychiatry 2017; 4:694–705. 10. Leucht S, et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry 2009; 166:152–163. 11. Davis JM, et al. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003; 60:553–564. 12. Leucht S, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373:31–41. 13. Leucht S, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382:951–962. 14. Huhn M, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet 2019; 394:939–951. 15. Voruganti L, et al. Neuroleptic dysphoria: towards a new synthesis. Psychopharmacology 2004; 171:121–132. 16. Leucht S, et al. Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, Bayesian meta-analysis, and meta-regression of efficacy predictors. Am J Psychiatry 2017; 174:927–942. 17. Siskind D, et al. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and metaanalysis. Br J Psychiatry 2016; 209:385–392. 18. Samara MT, et al. Efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia: a network meta-analysis. JAMA Psychiatry 2016; 73:199–210. 19. Taylor DM. Clozapine for treatment-resistant schizophrenia: still the gold standard? CNS Drugs 2017; 31:177–180. 20. Kane JM, et al. The role of clozapine in treatment-resistant schizophrenia. JAMA Psychiatry 2016; 73:187–188. 21. Manu P, et al. Prediabetes in patients treated with antipsychotic drugs. J Clin Psychiatry 2012; 73:460–466. 22. Rummel-Kluge C, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res 2010; 123:225–233. 23. Sorensen HJ, et al. Schizophrenia, antipsychotics and risk of hip fracture: a population-based analysis. Eur Neuro Psychopharmacol 2013; 23:872–878. 24. Trollor JN, et al. Comparison of neuroleptic malignant syndrome induced by first- and second-generation antipsychotics. Br J Psychiatry 2012; 201:52–56. 25. Masopust J, et al. Risk of venous thromboembolism during treatment with antipsychotic agents. Psychiatry Clin Neurosci 2012; 66:541–552. 26. Pope A, et al. Assessment of adverse effects in clinical studies of antipsychotic medication: survey of methods used. Br J Psychiatry 2010; 197:67–72. 27. Bailey L, et al. Estimating the optimal dose of flupentixol decanoate in the maintenance treatment of schizophrenia-a systematic review of the literature. Psychopharmacology 2019; 236:3081–3092. 28. Falkai P. Limitations of current therapies: why do patients switch therapies? Eur Neuropsychopharmacol 2008; 18 Suppl 3:S135–S139. 29. Yusufi B, et al. Prevalence and nature of side effects during clozapine maintenance treatment and the relationship with clozapine dose and plasma concentration. Int Clin Psychopharmacol 2007; 22:238–243. 30. Day JC, et al. A comparison of patients’ and prescribers’ beliefs about neuroleptic side-effects: prevalence, distress and causation. Acta Psychiatr Scand 1998; 97:93–97. 31. Waddell L, et al. A new self-rating scale for detecting atypical or second-generation antipsychotic side effects. J Psychopharmacology 2008; 22:238–243. 32. Ohlsen RI, et al. Interrater reliability of the Antipsychotic Non-Neurological Side-Effects Rating Scale measured in patients treated with clozapine. J Psychopharmacol 2008; 22:323–329. 33. Tiihonen J, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ 2006; 333:224. 34. Leucht C, et al. Oral versus depot antipsychotic drugs for schizophrenia–a critical systematic review and meta-analysis of randomised longterm trials. Schizophr Res 2011; 127:83–92. 35. Leucht S, et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012; 379:2063–2071. 36. Kane J, et al. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45:789–796. 37. McEvoy JP, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006; 163:600–610. 38. Lewis SW, et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull 2006; 32:715–723. 39. Stone JM, et al. Review: the biological basis of antipsychotic response in schizophrenia. J Psychopharmacology 2010; 24:953–964. 40. Agid O, et al. An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry 2011; 72:1439–1444. 41. Kahn RS, et al. Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching study. Lancet Psychiatry 2018; 5:797–807. CHAPTER 1 Schizophrenia and related psychoses 7 CHAPTER 1 8 The Maudsley® Prescribing Guidelines in Psychiatry General principles of prescribing The lowest possible dose should be used. For each patient, the dose should be titrated to the lowest known to be effective (see the section on minimum effective doses); dose increases should then take place only after one or two weeks of assessment during which the patient is clearly showing poor or no response. (There is gathering evidence that lack of response at 2 weeks is a potent predictor of later poor outcome, unless dose or drug is changed.) With regular dosing of long-acting injections, plasma levels rise for at least 6–12 weeks after initiation, even without a change in dose (see the section on depot pharmacokinetics in this chapter). Dose increases during this time are therefore difficult to evaluate. The preferred method is to establish efficacy and tolerability of oral medication at a particular dose and then give the equivalent dose of that drug in LAI form. Where this is not possible, the target dose of LAI for an individual should be that established to be optimal in clinical trials (although such data are not always available for older LAIs). For the large majority of patients, the use of a single antipsychotic (with or without additional mood stabiliser or sedatives) is recommended. Apart from exceptional circumstances (e.g. clozapine augmentation), antipsychotic polypharmacy should generally be avoided because of the increased adverse effect burden and risks associated with QT prolongation and sudden cardiac death (see the section on combined antipsychotics in this chapter). Combinations of antipsychotics should only be used where response to a single antipsychotic (including clozapine) has been clearly demonstrated to be inadequate. In such cases, the effect of the combination against target symptoms and adverse effects should be carefully evaluated and documented. Where there is no clear benefit, treatment should revert to single antipsychotic therapy. In general, antipsychotics should not be used as ‘when necessary’ sedatives. Timelimited prescriptions of benzodiazepines or general sedatives (e.g. promethazine) are recommended (see the section on rapid tranquillisation in this chapter). Responses to antipsychotic drug treatment should be assessed using recognised rating scales and outcomes documented in patients’ records. Those receiving antipsychotics should undergo close monitoring of physical health (including blood pressure, pulse, ECG, plasma glucose and plasma lipids) (see appropriate sections in this chapter). When withdrawing antipsychotics, reduce the dose slowly in a hyperbolic regimen which minimises the risks of withdrawal symptoms and rebound psychosis. [Note: This section is not referenced. Please see relevant individual sections in this chapter for detailed and referenced guidance.] Minimum effective doses Table 1.1 suggests the minimum dose of antipsychotic likely to be effective in first- or multiepisode schizophrenia. Most patients will respond to the dose suggested, although others may require higher doses. Given the variation in individual response, all doses should be considered approximate. Primary references are provided where available, but consensus opinion has also been used. Only oral treatment with commonly used drugs is covered. Table 1.1 Minimum effective dose/day – antipsychotics Drug First episode Multi-episode Chlorpromazine1 200mg* 300mg Haloperidol 2mg 4mg Sulpiride8 400mg* 800mg 10mg* 15mg Amisulpride11–16 300mg* 400mg* Aripiprazole7,17–22 10mg 10mg Asenapine 10mg* 10mg Blonanserin24 Not known 8mg Brexpiprazole25–27 2mg* 4mg Cariprazine 1.5mg* 1.5mg Iloperidone7,21,22,30 4mg* 8mg Lumateperone Not known 42mg* Lurasidone 40mg HCl/37mg base* 40mg HCl/37mg base Olanzapine4,7,33–35 5mg 7.5mg Paliperidone 3mg* 3mg Pimavanserin Not known 34mg** Quetiapine39–44 150mg* (but higher doses often used45) 300mg 3,7,46–49 Risperidone 2mg 4mg 7,21,50–52 Ziprasidone 40mg* 80mg FGAs 2–7 Trifluoperazine 9,10 SGAs 7,22,23 28,29 31 7,32 22 36–38 *Estimate – too few data available **FDA-approved for Parkinson’s disease psychosis; dose in schizophrenia not known CHAPTER 1 Schizophrenia and related psychoses 9 10 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 References 1. Dudley K, et al. Chlorpromazine dose for people with schizophrenia. Cochrane Database Syst Rev 2017; 4:Cd007778. 2. McGorry PD. Recommended haloperidol and risperidone doses in first-episode psychosis. J Clin Psychiatry 1999; 60:794–795. 3. Schooler N, et al. Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial. Am J Psychiatry 2005; 162:947–953. 4. Keefe RS, et al. Long-term neurocognitive effects of olanzapine or low-dose haloperidol in first-episode psychosis. Biol Psychiatry 2006; 59:97–105. 5. Donnelly L, et al. Haloperidol dose for the acute phase of schizophrenia. Cochrane Database Syst Rev 2013; Cd001951. 6. Oosthuizen P, et al. A randomized, controlled comparison of the efficacy and tolerability of low and high doses of haloperidol in the treatment of first-episode psychosis. Int J Neuropsychopharmacol 2004; 7:125–131. 7. Leucht S, et al. Dose equivalents for second-generation antipsychotics: the minimum effective dose method. SchizophrBull 2014; 40:314–326. 8. Soares BG, et al. Sulpiride for schizophrenia. Cochrane Database Syst Rev 2000; CD001162. 9. Armenteros JL, et al. Antipsychotics in early onset schizophrenia: systematic review and meta-analysis. Eur Child Adolesc Psychiatry 2006; 15:141–148. 10. Koch K, et al. Trifluoperazine versus placebo for schizophrenia. Cochrane Database Syst Rev 2014; Cd010226. 11. Mota NE, et al. Amisulpride for schizophrenia. Cochrane Database Syst Rev 2002; CD001357. 12. Puech A, et al. Amisulpride, and atypical antipsychotic, in the treatment of acute episodes of schizophrenia: a dose-ranging study vs. haloperidol. The Amisulpride Study Group. Acta Psychiatr Scand 1998; 98:65–72. 13. Moller HJ, et al. Improvement of acute exacerbations of schizophrenia with amisulpride: a comparison with haloperidol. PROD-ASLP Study Group. Psychopharmacology 1997; 132:396–401. 14. Sparshatt A, et al. Amisulpride – dose, plasma concentration, occupancy and response: implications for therapeutic drug monitoring. Acta Psychiatr Scand 2009; 120:416–428. 15. Buchanan RW, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. SchizophrBull 2010; 36:71–93. 16. Galletly C, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders. Aust N Z J Psychiatry 2016; 50:410–472. 17. Taylor D. Aripiprazole: a review of its pharmacology and clinical utility. Int J Clin Pract 2003; 57:49–54. 18. Cutler AJ, et al. The efficacy and safety of lower doses of aripiprazole for the treatment of patients with acute exacerbation of schizophrenia. CNS Spectr 2006; 11:691–702. 19. Mace S, et al. Aripiprazole: dose-response relationship in schizophrenia and schizoaffective disorder. CNS Drugs 2008; 23:773–780. 20. Sparshatt A, et al. A systematic review of aripiprazole – dose, plasma concentration, receptor occupancy and response: implications for therapeutic drug monitoring. J Clin Psychiatry 2010; 71:1447–1456. 21. Liu CC, et al. Aripiprazole for drug-naive or antipsychotic-short-exposure subjects with ultra-high risk state and first-episode psychosis: an open-label study. J Clin Psychopharmacol 2013; 33:18–23. 22. Leucht S, et al. Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry 2020; 177:342–353. 23. Citrome L. Role of sublingual asenapine in treatment of schizophrenia. Neuropsychiatr Dis Treat 2011; 7:325–339. 24. Tenjin T, et al. Profile of blonanserin for the treatment of schizophrenia. Neuropsychiatr Dis Treat 2013; 9:587–594. 25. Correll CU, et al. Efficacy of brexpiprazole in patients with acute schizophrenia: review of three randomized, double-blind, placebo-controlled studies. Schizophr Res 2016; 174:82–92. 26. Malla A, et al. The effect of brexpiprazole in adult outpatients with early-episode schizophrenia: an exploratory study. Int Clin Psychopharmacol 2016; 31:307–314. 27. Kane JM, et al. A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophr Res 2015; 164:127–135. 28. Garnock-Jones KP. Cariprazine: a review in schizophrenia. CNS Drugs 2017; 31:513–525. 29. Citrome L. Cariprazine for acute and maintenance treatment of adults with schizophrenia: an evidence-based review and place in therapy. Neuropsychiatr Dis Treat 2018; 14:2563–2577. 30. Crabtree BL, et al. Iloperidone for the management of adults with schizophrenia. Clin Ther 2011; 33:330–345. 31. Correll CU, et al. Efficacy and safety of lumateperone for treatment of schizophrenia: a randomized clinical trial. JAMA Psychiatry 2020; 77:349–358. 32. Meltzer HY, et al. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study. Am J Psychiatry 2011; 168:957–967. 33. Sanger TM, et al. Olanzapine versus haloperidol treatment in first-episode psychosis. Am J Psychiatry 1999; 156:79–87. 34. Kasper S. Risperidone and olanzapine: optimal dosing for efficacy and tolerability in patients with schizophrenia. Int Clin Psychopharmacol 1998; 13:253–262. 35. Bishara D, et al. Olanzapine: a systematic review and meta-regression of the relationships between dose, plasma concentration, receptor occupancy, and response. JClinPsychopharmacol 2013; 33:329–335. 36. Mathis MV, et al. The US Food and Drug Administration’s Perspective on the New Antipsychotic Pimavanserin. J Clin Psychiatry 2017; 78:e668–e673. 37. Ballard C, et al. Pimavanserin in Alzheimer’s Disease Psychosis: efficacy in patients with more pronounced psychotic symptoms. J Prev Alzheimers Dis 2019; 6:27–33. 38. Nasrallah HA, et al. Successful treatment of clozapine-nonresponsive refractory hallucinations and delusions with pimavanserin, a serotonin 5HT-2A receptor inverse agonist. Schizophr Res 2019; 208:217–220. 39. Small S, et al. Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group. Arch Gen Psychiatry 1997; 54:549–557. 40. Peuskens J, et al. A comparison of quetiapine and chlorpromazine in the treatment of schizophrenia. Acta Psychiatr Scand 1997; 96:265–273. 41. Arvanitis LA, et al. Multiple fixed doses of ‘Seroquel’ (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. Biol Psychiatry 1997; 42:233–246. 42. Kopala LC, et al. Treatment of a first episode of psychotic illness with quetiapine: an analysis of 2 year outcomes. Schizophr Res 2006; 81:29–39. 43. Sparshatt A, et al. Quetiapine: dose-response relationship in schizophrenia. CNS Drugs 2008; 22:49–68. 44. Sparshatt A, et al. Relationship between daily dose, plasma concentrations, dopamine receptor occupancy, and clinical response to quetiapine: a review. J Clin Psychiatry 2011; 72:1108–1123. 45. Pagsberg AK, et al. Quetiapine extended release versus aripiprazole in children and adolescents with first-episode psychosis: the multicentre, double-blind, randomised tolerability and efficacy of antipsychotics (TEA) trial. Lancet Psychiatry 2017; 4:605–618. 46. Lane HY, et al. Risperidone in acutely exacerbated schizophrenia: dosing strategies and plasma levels. J Clin Psychiatry 2000; 61:209–214. 47. Williams R. Optimal dosing with risperidone: updated recommendations. J Clin Psychiatry 2001; 62:282–289. 48. Ezewuzie N, et al. Establishing a dose-response relationship for oral risperidone in relapsed schizophrenia. J Psychopharm 2006; 20:86–90. 49. Li C, et al. Risperidone dose for schizophrenia. Cochrane Database Syst Rev 2009; Cd007474. 50. Bagnall A, et al. Ziprasidone for schizophrenia and severe mental illness. Cochrane Database Syst Rev 2000; CD001945. 51. Taylor D. Ziprasidone – an atypical antipsychotic. Pharm J 2001; 266:396–401. 52. Joyce AT, et al. Effect of initial ziprasidone dose on length of therapy in schizophrenia. Schizophr Res 2006; 83:285–292. CHAPTER 1 Schizophrenia and related psychoses 11 CHAPTER 1 12 The Maudsley® Prescribing Guidelines in Psychiatry Licensed maximum doses The following table lists the licensed maximum doses of antipsychotics according to the EMA labelling as of February 2021. Drug Maximum dose FGAs – oral Chlorpromazine 1000mg/day Flupentixol 18mg/day Haloperidol 20mg/day Levomepromazine 1200mg/day Pericyazine 300mg/day Perphenazine 24mg/day (64mg/day hospitalised patients) Pimozide 20mg/day Sulpiride 2400mg/day Trifluoperazine 20mg/day Zuclopenthixol 150mg/day SGAs – oral Amisulpride 1200mg/day Aripiprazole 30mg/day Asenapine 20mg/day (sublingual) Cariprazine 6mg/day Clozapine 900mg/day Lurasidone 160mg (HCl)/148mg (base)/day Olanzapine 20mg/day Paliperidone 12mg/day Quetiapine 750mg/day schizophrenia (800mg/day for MR preparation) 800mg/day bipolar disorder Risperidone 16mg/day Sertindole 24mg/day Long-acting injections Aripiprazole depot 400mg/month Flupentixol depot 400mg/week Fluphenazine depot 100mg every 14–35 days Haloperidol depot 300mg every 4 weeks Paliperidone depot 1-monthly 150mg/month Drug Maximum dose Paliperidone depot 3-monthly 525mg every 3 months Pipotiazine depot 200mg every 4 weeks Risperidone (Janssen) 50mg every 2 weeks Zuclopenthixol depot 600mg/week The following table lists the licensed maximum doses of antipsychotics available outside the EU, according to FDA labelling (as of February 2021) Drug Maximum dose SGAs – oral Blonanserin* 24mg/day oral1 (80mg/day patch2) Brexpiprazole 4mg/day Iloperidone 24mg/day Lumateperone 42mg/day Molindone 225mg/day Pimavanserin 34mg/day RBP-7000 (risperidone 1-monthly) 120mg/month Ziprasidone 160mg/day *Available only in China, Japan and South Korea at the time of writing. References 1. Inoue Y, et al. Safety and effectiveness of oral blonanserin for schizophrenia: a review of Japanese post-marketing surveillances. J Pharmacol Sci 2021; 145:42–51. 2. Nishibe H, et al. Striatal dopamine D2 receptor occupancy induced by daily application of blonanserin transdermal patches: phase 2 study in Japanese patients with schizophrenia. Int J Neuropsychopharmacol 2020; 24:108–117. CHAPTER 1 Schizophrenia and related psychoses 13 CHAPTER 1 14 The Maudsley® Prescribing Guidelines in Psychiatry Equivalent doses Knowledge of equivalent dosages is useful when switching between FGAs. Estimates of ‘neuroleptic’ or ‘chlorpromazine’ equivalence, in milligrams a day, between these medications are based on clinical experience, expert panel opinion (using various methods) and any dopamine binding studies available. Table 1.2 provides approximate equivalent doses for FGAs.1–4 The values given should be seen as a rough guide when switching from one FGA to another and are no substitute for clinical titration of the new medication dose against adverse effects and response. Equivalent doses of SGAs may be less clinically relevant as these medications tend to have better defined, evidence-based licensed dose ranges. There are several different ways of calculating equivalence based on, for example, defined daily dose,5 minimum effective dose6,7 and average dose.8 These methods give different estimates of equivalence. A very rough guide to equivalent SGA daily dosages is given in the Table 1.3.3,4,7–9 There is considerable disagreement about exact equivalencies, even amongst the references cited here. Clozapine is not included because this has a distinct initial titration schedule and a high dose-plasma level variability and because it probably has a different mechanism of action. Comparing potencies of FGAs with SGAs introduces yet more uncertainty with respect to dose equivalence. Very approximately, 100mg chlorpromazine is equivalent to 1.5mg risperidone.3 Table 1.2 Equivalent doses of first generation antipsychotics Drug Equivalent dose (consensus) Range of values in literature Chlorpromazine 100mg/day Reference Flupentixol 3mg/day 2–3mg/day Flupentixol depot 10mg/week 10–20mg/week Fluphenazine 2mg/day 1–5mg/day Fluphenazine depot 5mg/week 1–12.5mg/week Haloperidol 2mg/day 1.5–5mg/day Haloperidol depot 15mg/week 5–25mg/week Pericyazine 10mg/day 10mg/day Perphenazine 10mg/day 5–10mg/day Pimozide 2mg/day 1.33–2mg/day Pipotiazine depot 10mg/week 10–12.5mg/week Sulpiride 200mg/day 133–300mg/day Trifluoperazine 5mg/day 2.5–5mg/day Zuclopenthixol 25mg/day 25–60mg/day Zuclopenthixol depot 100mg/week 40–100mg/week Table 1.3 Second-generation antipsychotics – approximate equivalent doses3–10 Drug Approximate equivalent dose Amisulpride 400mg Aripiprazole 15mg Asenapine 10mg Blonanserin ~ Brexpiprazole 2mg Cariprazine 1.5mg Clotiapine 100mg Iloperidone 12mg Lumateperone ~ Lurasidone 80mg (74mg base) Melperone 300mg Molindone 50mg Olanzapine 10mg Paliperidone LAI 100mg/month Pimavanserin ~ Quetiapine 400mg Risperidone oral 4mg Risperidone LAI 50mg/2 weeks Risperidone RBP-7000 120mg/month Ziprasidone 80mg ~Unknown equivalence at time of writing. References 1. Foster P. Neuroleptic equivalence. Pharm J 1989; 243:431–432. 2. Atkins M, et al. Chlorpromazine equivalents: a consensus of opinion for both clinical and research implications. Psychiatric Bull 1997; 21:224–226. 3. Patel MX, et al. How to compare doses of different antipsychotics: a systematic review of methods. Schizophr Res 2013; 149:141–148. 4. Gardner DM, et al. International consensus study of antipsychotic dosing. Am J Psychiatry 2010; 167:686–693. 5. Leucht S, et al. Dose equivalents for antipsychotic drugs: the ddd method. Schizophr Bull 2016; 42 Suppl 1:S90–S94. 6. Rothe PH, et al. Dose equivalents for second generation long-acting injectable antipsychotics: the minimum effective dose method. Schizophr Res 2018; 193:23–28. 7. Leucht S, et al. Dose equivalents for second-generation antipsychotics: the minimum effective dose method. Schizophr Bull 2014; 40:314–326. 8. Leucht S, et al. Dose equivalents for second-generation antipsychotic drugs: the classical mean dose method. Schizophr Bull 2015; 41:1397–1402. 9. Woods SW. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry 2003; 64:663–667. 10. Leucht S, et al. Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry 2020; 177:342–353. CHAPTER 1 Schizophrenia and related psychoses 15 CHAPTER 1 16 The Maudsley® Prescribing Guidelines in Psychiatry High-dose antipsychotics: prescribing and monitoring ‘High dose’ antipsychotic medication can result from the prescription of either a single antipsychotic medication at a dose above the recommended maximum or two or more antipsychotic medications concurrently that, when expressed as a percentage of their respective maximum recommended doses and added together, result in a cumulative dose of more than 100%.1 In clinical practice, antipsychotic polypharmacy and PRN antipsychotic medication are strongly associated with high-dose prescribing.2,3 Efficacy There is no firm evidence that high doses of antipsychotic medication are any more effective than standard doses for schizophrenia. This holds true for the use of antipsychotic medication for rapid tranquillisation, relapse prevention, persistent aggression and the management of acute psychotic episodes.1 Despite this, in the UK, approximately a quarter to a third of hospitalised patients on antipsychotic medication have been observed to be on a high dose,2 while the national audit of schizophrenia in 2013, reporting on prescribing practice for over 5,000 predominantly community-based patients, found that, overall, 10% were prescribed a high dose of antipsychotic medication.4 Examination of the dose–response effects of a variety of antipsychotic medications has not found any evidence of greater efficacy for doses above accepted licensed ranges.5,6 Efficacy appears to be optimal at relatively low doses: 4mg/day risperidone;7 300mg/day quetiapine,8 olanzapine 10mg,9,10 etc. Similarly, treatment with LAI risperidone at a dose of 100mg 2-weekly offers no benefits over 50mg 2-weekly,11 and 320mg/ day ziprasidone12 is no better than 160mg/day. All currently available antipsychotic medications (with the possible exception of clozapine) exert their antipsychotic effect primarily through antagonism (or partial agonism) at post-synaptic dopamine receptors. There is increasing evidence that in some patients with schizophrenia, refractory symptoms do not seem to be driven through dysfunction of dopamine pathways,13–16 and so increasing dopamine blockade in such patients is of uncertain value. Just as importantly, the law of mass action dictates that dose increases bring about successively smaller increases in dopamine occupancy once the threshold for efficacy has been reached.17 Dold et al.18 conducted a meta-analysis of RCTs that compared continuation of standard-dose antipsychotic medication with dose escalation in patients whose schizophrenia had proved to be unresponsive to a prospective trial of standard-dose pharmacotherapy with the same antipsychotic medication. In this context, there was no evidence of any benefit associated with the increased dosage. There are a small number of RCTs that have examined the efficacy of high versus standard dosage in patients with a diagnosis of treatment-resistant schizophrenia (TRS).1 Some demonstrated benefit,19 but the majority of these studies are old, the number of patients randomised is small and study design is poor by current standards. Some studies used daily doses equivalent to more than 10g chlorpromazine. In a study of patients with first-episode schizophrenia, increasing the dose of olanzapine up to 30mg/day and the dose of risperidone up to 10mg/day in non-responders to standard doses yielded only a 4% absolute increase in overall response rate; switching to an alternative antipsychotic, including clozapine, was considerably more successful.20 One small (n = 12) open study of high-dose quetiapine (up to 1400mg/day) found modest benefits in a third of subjects,21 but other, larger studies of quetiapine have shown no benefit for higher doses.8,22,23 A further RCT of high-dose olanzapine (up to 45mg/day) versus clozapine for treatment-resistant schizophrenia found similar efficacy for the two treatments, but concluded that, given the small sample size, it would be premature to conclude that they were equivalent.24 A systematic review of relevant studies comparing olanzapine at above standard dosage with clozapine for TRS concluded that while olanzapine, particularly in higher dosage, might be considered as an alternative to clozapine in TRS, clozapine still had the most robust evidence for efficacy.25 The most recent systematic analysis of dose response26 largely confirmed the observation of a flat or horizontal dose–response curve above a certain dose for all antipsychotics, with the possible exceptions of olanzapine and lurasidone (with these two drugs, there is evidence that doses at the upper end of the licensed range are somewhat more effective than lower doses10,27). This systematic review also suggested that doses above which no additional benefit was likely were somewhat higher than those stated above, e.g. risperidone 6.3mg/day; quetiapine 482mg/day. Importantly, however, there was no evidence to support the use of doses of any drug above its licensed does range. Adverse effects The majority of side effects associated with antipsychotic treatment are dose-related. These include EPS, sedation, postural hypotension, anticholinergic effects, QTc prolongation and coronary heart disease mortality.28–31 High-dose antipsychotic treatment is clearly associated with a greater side-effect burden.12,23,28,32,33 There is some evidence that antipsychotic dose reduction from very high (mean 2253mg chlorpromazine equivalents per day) to high (mean 1315mg chlorpromazine equivalents per day) dose leads to improvements in cognition and negative symptoms.34 Recommendations The use of high-dose antipsychotic medication should be an exceptional clinical practice and only ever employed when adequate trials of standard treatments, including clozapine, have failed. If high-dose antipsychotic medication is prescribed, it should be standard practice to review and document the target symptoms, therapeutic response and side effects, ideally using validated rating scales, so that there is ongoing consideration of the risk-benefit ratio for the patient. Close physical monitoring (including ECG) is essential. CHAPTER 1 Schizophrenia and related psychoses 17 18 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Prescribing high-dose antipsychotic medication Before using high doses, ensure that: Sufficient time has been allowed for response (see section on time to response). At least two different antipsychotic medications have been tried sequentially (including, if possible, olanzapine). Clozapine has failed or not been tolerated due to agranulocytosis or other serious adverse effect. Most other side-effects can be managed. A small proportion of patients may also decline to take a clozapine regimen. Medication adherence is not in doubt (use of blood tests, liquids/dispersible tablets, depot/LAI antipsychotic preparations, etc). Adjunctive medications such as antidepressants or mood stabilisers are not indicated. Psychological approaches have failed or are not appropriate. The decision to use high doses should: Be made by a senior psychiatrist Involve the multidisciplinary team Be done, if possible, with a patient’s informed consent Process Rule out contraindications (ECG abnormalities, hepatic impairment) Consider and minimise any risks posed by concomitant medication (e.g. potential to cause QTc prolongation, electrolyte disturbance or pharmacokinetic interactions via CYP inhibition) Document the decision to prescribe high dosage in the clinical notes along with a description of target symptoms. The use of an appropriate rating scale is advised Adequate time for response should be allowed after each dosage increment before a further increase is made Monitoring Physical monitoring should be carried out as outlined in the section on monitoring All patients on high doses should have regular ECGs (base-line, when steady-state serum levels have been reached after each dosage increment, and then every 6 to 12 months) Additional biochemical/ECG monitoring is advised if drugs that are known to cause electrolyte disturbances or QTc prolongation are subsequently co-prescribed Target symptoms should be assessed after 6 weeks and 3 months. If insufficient improvement in these symptoms has occurred, the dose should be decreased to the normal range Schizophrenia and related psychoses 19 1. Royal College of Psychiatrists. Consensus statement on high-dose antipsychotic medication. College Report CR190 2014. 2. Paton C, et al. High-dose and combination antipsychotic prescribing in acute adult wards in the UK: the challenges posed by p.r.n. prescribing. Br J Psychiatry 2008; 192:435–439. 3. Roh D, et al. Antipsychotic polypharmacy and high-dose prescription in schizophrenia: a 5-year comparison. Aust N Z J Psychiatry 2014; 48:52–60. 4. Patel MX, et al. Quality of prescribing for schizophrenia: evidence from a national audit in England and Wales. Eur Neuropsychopharmacol 2014; 24:499–509. 5. Davis JM, et al. Dose response and dose equivalence of antipsychotics. J Clin Psychopharmacol 2004; 24:192–208. 6. Gardner DM, et al. International consensus study of antipsychotic dosing. Am J Psychiatry 2010; 167:686–693. 7. Ezewuzie N, et al. Establishing a dose-response relationship for oral risperidone in relapsed schizophrenia. J Psychopharm 2006; 20:86–90. 8. Sparshatt A, et al. Quetiapine: dose-response relationship in schizophrenia. CNS Drugs 2008; 22:49–68. 9. Kinon BJ, et al. Standard and higher dose of olanzapine in patients with schizophrenia or schizoaffective disorder: a randomized, doubleblind, fixed-dose study. J Clin Psychopharmacol 2008; 28:392–400. 10. Bishara D, et al. Olanzapine: a systematic review and meta-regression of the relationships between dose, plasma concentration, receptor occupancy, and response. J Clin Psychopharmacol 2013; 33:329–335. 11. Meltzer HY, et al. A six month randomized controlled trial of long acting injectable risperidone 50 and 100 mg in treatment resistant schizophrenia. Schizophr Res 2014; 154:14–22. 12. Goff DC, et al. High-dose oral ziprasidone versus conventional dosing in schizophrenia patients with residual symptoms: the ZEBRAS study. J Clin Psychopharmacol 2013; 33:485–490. 13. Egerton A, et al. Dopamine and glutamate in antipsychotic-responsive compared with antipsychotic-nonresponsive psychosis: a multicenter positron emission tomography and magnetic resonance spectroscopy study (STRATA). Schizophr Bull 2020; 47:505–516. 14. Kapur S, et al. Relationship between dopamine D2 occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 2000; 157:514–520. 15. Demjaha A, et al. Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. Am J Psychiatry 2012; 169:1203–1210. 16. Gillespie AL, et al. Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? A systematic review. BMC Psychiatry 2017; 17:12. 17. Horowitz MA, et al. Tapering Antipsychotic Treatment. JAMA Psychiatry 2020; 78:125–126. 18. Dold M, et al. Dose escalation of antipsychotic drugs in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Res 2015; 166:187–193. 19. Aubree JC, et al. High and very high dosage antipsychotics: a critical review. J Clin Psychiatry 1980; 41:341–350. 20. Agid O, et al. An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry 2011; 72:1439–1444. 21. Boggs DL, et al. Quetiapine at high doses for the treatment of refractory schizophrenia. Schizophr Res 2008; 101:347–348. 22. Lindenmayer JP, et al. A randomized, double-blind, parallel-group, fixed-dose, clinical trial of quetiapine at 600 versus 1200 mg/d for patients with treatment-resistant schizophrenia or schizoaffective disorder. J Clin Psychopharmacol 2011; 31:160–168. 23. Honer WG, et al. A randomized, double-blind, placebo-controlled study of the safety and tolerability of high-dose quetiapine in patients with persistent symptoms of schizophrenia or schizoaffective disorder. J Clin Psychiatry 2012; 73:13–20. 24. Meltzer HY, et al. A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia. J Clin Psychiatry 2008; 69:274–285. 25. Souza JS, et al. Efficacy of olanzapine in comparison with clozapine for treatment-resistant schizophrenia: evidence from a systematic review and meta-analyses. CNS Spectr 2013; 18:82–89. 26. Leucht S, et al. Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry 2020; 177:342–353. 27. Loebel A, et al. Lurasidone dose escalation in early nonresponding patients with schizophrenia: a randomized, placebo-controlled study. J Clin Psychiatry 2016; 77:1672–1680. 28. Osborn DP, et al. Relative risk of cardiovascular and cancer mortality in people with severe mental illness from the United Kingdom’s General Practice Rsearch Database. Arch Gen Psychiatry 2007; 64:242–249. 29. Ray WA, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009; 360:225–235. 30. Barbui C, et al. Antipsychotic dose mediates the association between polypharmacy and corrected QT interval. PLoS One 2016; 11:e0148212. 31. Weinmann S, et al. Influence of antipsychotics on mortality in schizophrenia: systematic review. Schizophr Res 2009; 113:1–11. 32. Bollini P, et al. Antipsychotic drugs: is more worse? A meta-analysis of the published randomized control trials. Psychol Med 1994; 24:307–316. 33. Baldessarini RJ, et al. Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses. Arch Gen Psychiatry 1988; 45:79–90. 34. Kawai N, et al. High-dose of multiple antipsychotics and cognitive function in schizophrenia: the effect of dose-reduction. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:1009–1014. CHAPTER 1 References CHAPTER 1 20 The Maudsley® Prescribing Guidelines in Psychiatry Combined antipsychotics (antipsychotic polypharmacy) In psychiatric practice, prescriptions for combined antipsychotic medications are common1–3 and often long term.4 The medications combined are likely to include LAI antipsychotic preparations,5,6 quetiapine7 and FGAs,8 the last of these perhaps reflecting the frequent use of haloperidol and chlorpromazine as PRN medications. Poor response to antipsychotic monotherapy National clinical audits conducted in the UK as part of a Prescribing Observatory for Mental Health (POMH-UK) quality improvement programme9 found that the most common reasons recorded for prescribing regular, combined antipsychotic medications were a poor response to antipsychotic monotherapy and a period of crossover while switching from one antipsychotic to another. The use of combined antipsychotic medications has been found to be associated with younger patient age, male gender, and increased illness severity, complexity and chronicity, as well as poorer functioning, inpatient status and a diagnosis of schizophrenia.2,7,10–12 These associations largely reinforce the notion that antipsychotic polypharmacy is used where schizophrenia has proved to be refractory to trials of antipsychotic monotherapy.10,13–15 Nonetheless, there is a lack of robust evidence that the efficacy of combined antipsychotic medications is superior to treatment with a single antipsychotic.16 A meta-analysis of 16 RCTs in schizophrenia, comparing augmentation with a second antipsychotic with continued antipsychotic monotherapy, found that combining antipsychotic medications lacked double‐blind/high‐quality evidence for overall efficacy.17 Furthermore, in patients with schizophrenia, the effects of a change back from antipsychotic polypharmacy to monotherapy, even when carefully conducted, are uncertain. While the findings of two randomised studies suggested that the majority of patients may be successfully switched from antipsychotic polypharmacy to monotherapy without loss of symptom control,18,19 another reported greater increases in symptoms after six months in those participants who had switched to antipsychotic monotherapy,20 although the expectation is that such exacerbations can be successfully managed.18 Long-term antipsychotic treatment A non-interventional, population-based study in Hungary, sought to compare the effectiveness of antipsychotic monotherapy with the use of combined antipsychotic medications over a one-year observation period. The investigators concluded that while the results provided evidence for the superiority of monotherapy over polypharmacy for SGAs in terms of all-cause treatment discontinuation in schizophrenia, polypharmacy was associated with a lower likelihood of mortality and psychiatric hospitalisations.21 Similarly, a 20-year, observational study in Finland reported on the risk of rehospitalisation in a cohort of 62,250 hospital-treated patients with schizophrenia. To minimise selection bias, the investigators used within-individual analyses, with each patient used as their own control. The main finding was that antipsychotic combinations, particularly those including clozapine and LAI antipsychotic medications, were associated with a slightly lower risk of psychiatric rehospitalisation than monotherapy.22 Although the interpretation of such real-world findings is hindered by the issue of confounding by indication,23 there are perhaps several plausible explanations. It may be that combining antipsychotic medications with different receptor profiles can be more effective and lead to better therapeutic efficacy and/or a lower side-effect burden and therefore better outcomes. It may also be that co-prescribing two antipsychotic medications improves medication adherence in that it increases the likelihood that a patient may use at least one of them.22 A more complicated and speculative explanation relates to the finding that, in clinical practice, clozapine and LAI antipsychotic preparations appear to be the most effective monotherapies for relapse prevention in schizophrenia.24 Thus, adding a second antipsychotic medication to clozapine or an LAI antipsychotic medication in an attempt to mitigate metabolic side effects (e.g. by adding aripiprazole) or manage symptoms of agitation, anxiety or sleep disturbance (e.g. by adding olanzapine or quetiapine) might enhance a patient’s engagement in their treatment and improve adherence to the effective antipsychotic treatment that has been augmented. Adverse effects Evidence for possible harm with combined antipsychotic medications is perhaps more convincing. Clinically significant side effects have been associated with combined antipsychotic medications, which may partly reflect that such a regimen is commonly a highdose prescription.8,25 There are reports of an increased prevalence and severity of EPS,26,27 increased metabolic side effects and diabetes,20,28,29 sexual dysfunction,30 an increased risk of hip fracture,31 paralytic ileus,32 grand mal seizures,33 prolonged QTc34 and arrhythmias.13 Switching from antipsychotic polypharmacy to monotherapy has been shown to lead to worthwhile improvements in cognitive functioning.19 The evidence relating to an increased mortality with a continuing antipsychotic polypharmacy regimen is inconsistent. Two large case–control studies and a database study35–37 found no increased mortality in patients with schizophrenia receiving antipsychotic polypharmacy, compared with antipsychotic monotherapy. However, a 10-year prospective study of a cohort of 88 patients with schizophrenia reported that receiving more than one antipsychotic medication concurrently was associated with substantially increased mortality.17,38 These investigators explored the possibility that the use of combined antipsychotic medications might be a proxy for greater severity/increased refractoriness of psychiatric illness but found no association between mortality and any measured index of illness severity, although these measures focussed on negative symptoms and cognitive deficits. Furthermore, analysis of data from a large anonymised mental healthcare database (2007–2014) of 10,945 adult patients with serious mental illness who had been prescribed a single antipsychotic or polypharmacy for six months or more, revealed a weak association between regular, long-term antipsychotic polypharmacy and all-cause mortality and natural causes of death.39 However, the authors concluded that the evidence for the association was limited, even after controlling for the effect of dose. Another study, involving the follow-up of 99 patients with schizophrenia over a 25-year period, found that those prescribed three antipsychotics simultaneously were twice as likely to die as those who had been prescribed only one.40 These authors also considered the possibility of indication bias influencing the findings, speculating that combined antipsychotic medication might be more likely to be prescribed for the most severe schizophrenia. CHAPTER 1 Schizophrenia and related psychoses 21 CHAPTER 1 22 The Maudsley® Prescribing Guidelines in Psychiatry Given the association between combined antipsychotic medication and a greater side-effect burden,15,41 it follows that it should be standard practice to document in the clinical records the rationale for prescribing combined antipsychotics in individual cases, along with a clear account of the benefits and side effects of an individual trial of the strategy. Medico-legally, this would seem to be prudent although in practice it is rarely done.42 The use of combined antipsychotic medications in clinical practice There are myriad possible antipsychotic medication combinations but very limited data on their relative risk–benefit profiles in relation to overall therapeutic response or target symptom clusters. The clinical disadvantages of antipsychotic polypharmacy include an increased side-effect burden, higher total dosage, increased risk of drug–drug interactions, poorer medication adherence related to the complexity of the treatment, and difficulties in the attribution of any response to one or more of the individual antipsychotic medications prescribed, leading to difficulty in determining the implications for an optimal longer-term regimen.6 Despite the limited supportive evidence base, the use of antipsychotic polypharmacy is an established custom and practice in many countries.43–45 Furthermore, the general consensus across treatment guidelines that the use of combined antipsychotic medication for the treatment of refractory psychotic illness should be considered only after other, evidence-based, pharmacological treatments such as clozapine have been exhausted, is not consistently followed in clinical practice.6,12,13,46–48 However, it should be noted that a trial of clozapine augmentation with a second antipsychotic medication to enhance efficacy is a potentially supportable practice49–53 (see the section on clozapine augmentation in this chapter). Other antipsychotic polypharmacy strategies with potentially valid rationales are the addition of aripiprazole to reduce body weight in patients receiving clozapine54,55 and to normalise prolactin levels in those on haloperidol56 and risperidone LAI57 (although not amisulpride58). Polypharmacy with aripiprazole in such circumstances may thus represent worthwhile, evidence-based practice, albeit in the absence of regulatory trials demonstrating safety. In many cases, however, using aripiprazole alone might be a more logical choice. Conclusion Some of the findings reported above might be considered to challenge the prevailing consensus that prescribing more than one antipsychotic medication is unlikely to improve efficacy and may increase medical morbidity.59,60 Nevertheless, on the evidence currently available relating to efficacy and the potential for serious adverse effects, the routine use of combined, non-clozapine, antipsychotic medications may be best avoided. Schizophrenia and related psychoses 23 There is a lack of robust evidence supporting the efficacy of combined, non-clozapine, antipsychotic medications There is substantial evidence supporting the potential for harm and so the use of combined antipsychotic medications, which is commonly a high-dose prescription, should generally be avoided. Combined antipsychotic medications are commonly prescribed and this practice seems to be relatively resistant to change As a minimum requirement, all patients who are prescribed combined antipsychotic medications should be systematically monitored for side effects (including an ECG) and any beneficial effect on the symptoms of psychotic illness carefully documented. Some antipsychotic polypharmacy strategies (e.g. combinations with aripiprazole) show benefits for tolerability but not efficacy. References 1. Harrington M, et al. The results of a multi-centre audit of the prescribing of antipsychotic drugs for in-patients in the UK. Psychiatric Bull 2002; 26:414–418. 2. Gallego JA, et al. Prevalence and correlates of antipsychotic polypharmacy: a systematic review and meta-regression of global and regional trends from the 1970s to 2009. Schizophr Res 2012; 138:18–28. 3. Sneider B, et al. Frequency and correlates of antipsychotic polypharmacy among patients with schizophrenia in Denmark: a nation-wide pharmacoepidemiological study. Eur Neuropsychopharmacol 2015; 25:1669–1676. 4. Procyshyn RM, et al. Persistent antipsychotic polypharmacy and excessive dosing in the community psychiatric treatment setting: a review of medication profiles in 435 Canadian outpatients. J Clin Psychiatry 2010; 71:566–573. 5. Aggarwal NK, et al. Prevalence of concomitant oral antipsychotic drug use among patients treated with long-acting, intramuscular, antipsychotic medications. J Clin Psychopharmacol 2012; 32:323–328. 6. Barnes T, et al. Antipsychotic long acting injections: prescribing practice in the UK. Br J Psychiatry Suppl 2009; 52:S37–S42. 7. Novick D, et al. Antipsychotic monotherapy and polypharmacy in the treatment of outpatients with schizophrenia in the European Schizophrenia Outpatient Health Outcomes Study. J Nerv Ment Dis 2012; 200:637–643. 8. Paton C, et al. High-dose and combination antipsychotic prescribing in acute adult wards in the UK: the challenges posed by p.r.n. prescribing. Br J Psychiatry 2008; 192:435–439. 9. Prescribing Observatory for Mental Health. Topic 1g & 3d. Prescribing high dose and combined antipsychotics on adult psychiatric wards. 2017; Prescribing Observatory for Mental Health CCQI1272. 10. Correll CU, et al. Antipsychotic polypharmacy: a comprehensive evaluation of relevant correlates of a long-standing clinical practice. Psychiatr Clin North Am 2012; 35:661–681. 11. Baandrup L, et al. Association of antipsychotic polypharmacy with health service cost: a register-based cost analysis. Eur J Health Econ 2012; 13:355–363. 12. Kadra G, et al. Predictors of long-term (≥6 months) antipsychotic polypharmacy prescribing in secondary mental healthcare. Schizophr Res 2016; 174:106–112. 13. Grech P, et al. Long-term antipsychotic polypharmacy: how does it start, why does it continue? Ther Adv Psychopharmacol 2012; 2:5–11. 14. Malandain L, et al. Correlates and predictors of antipsychotic drug polypharmacy in real-life settings: results from a nationwide cohort study. Schizophr Res 2018; 192:213–218. 15. Fleischhacker WW, et al. Critical review of antipsychotic polypharmacy in the treatment of schizophrenia. Int J Neuropsychopharmacol 2014; 17:1083–1093. 16. Ortiz-Orendain J, et al. Antipsychotic combinations for schizophrenia. Schizophr Bull 2018; 44:15–17. 17. Galling B, et al. Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis. World Psychiatry 2017; 16:77–89. 18. Essock SM, et al. Effectiveness of switching from antipsychotic polypharmacy to monotherapy. Am J Psychiatry 2011; 168:702–708. 19. Hori H, et al. Switching to antipsychotic monotherapy can improve attention and processing speed, and social activity in chronic schizophrenia patients. J Psychiatr Res 2013; 47:1843–1848. 20. Constantine RJ, et al. The risks and benefits of switching patients with schizophrenia or schizoaffective disorder from two to one antipsychotic medication: a randomized controlled trial. Schizophr Res 2015; 166:194–200. 21. Katona L, et al. Real-world effectiveness of antipsychotic monotherapy vs. polypharmacy in schizophrenia: to switch or to combine? A nationwide study in Hungary. Schizophr Res 2014; 152:246–254. 22. Tiihonen J, et al. Association of antipsychotic polypharmacy vs monotherapy with psychiatric rehospitalization among adults with schizophrenia. JAMA Psychiatry 2019; 76:499–507. 23. Goff DC. Can adjunctive pharmacotherapy reduce hospitalization in schizophrenia?: insights from administrative databases. JAMA Psychiatry 2019; 76:468–470. CHAPTER 1 Summary CHAPTER 1 24 The Maudsley® Prescribing Guidelines in Psychiatry 24. Tiihonen J, et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29823 patients with schizophrenia. JAMA Psychiatry 2017; 74:686–693. 25. López de Torre A, et al. Antipsychotic polypharmacy: a needle in a haystack? Gen Hosp Psychiatry 2012; 34:423–432. 26. Carnahan RM, et al. Increased risk of extrapyramidal side-effect treatment associated with atypical antipsychotic polytherapy. Acta Psychiatr Scand 2006; 113:135–141. 27. Gomberg RF. Interaction between olanzapine and haloperidol. J Clin Psychopharmacol 1999; 19:272–273. 28. Suzuki T, et al. Effectiveness of antipsychotic polypharmacy for patients with treatment refractory schizophrenia: an open-label trial of olanzapine plus risperidone for those who failed to respond to a sequential treatment with olanzapine, quetiapine and risperidone. Human Psychopharmacology 2008; 23:455–463. 29. Gallego JA, et al. Safety and tolerability of antipsychotic polypharmacy. Exp Opin Drug Saf 2012; 11:527–542. 30. Hashimoto Y, et al. Effects of antipsychotic polypharmacy on side-effects and concurrent use of medications in schizophrenic outpatients. Psychiatry Clin Neurosci 2012; 66:405–410. 31. Sorensen HJ, et al. Schizophrenia, antipsychotics and risk of hip fracture: a population-based analysis. Eur Neuro Psychopharmacol 2013; 23:872–878. 32. Dome P, et al. Paralytic ileus associated with combined atypical antipsychotic therapy. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:557–560. 33. Hedges DW, et al. New-onset seizure associated with quetiapine and olanzapine. Ann Pharmacother 2002; 36:437–439. 34. Beelen AP, et al. Asymptomatic QTc prolongation associated with quetiapine fumarate overdose in a patient being treated with risperidone. Hum Exp Toxicol 2001; 20:215–219. 35. Baandrup L, et al. Antipsychotic polypharmacy and risk of death from natural causes in patients with schizophrenia: a population-based nested case-control study. J Clin Psychiatry 2010; 71:103–108. 36. Chen Y, et al. Antipsychotics and risk of natural death in patients with schizophrenia. Neuropsychiatr Dis Treat 2019; 15:1863–1871. 37. Tiihonen J, et al. Polypharmacy with antipsychotics, antidepressants, or benzodiazepines and mortality in schizophrenia. ArchGenPsychiatry 2012; 69:476–483. 38. Waddington JL, et al. Mortality in schizophrenia. Antipsychotic polypharmacy and absence of ad

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