The Maudsley Prescribing Guidelines in Psychiatry (2021) 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 Adva...

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. Registered Office(s) John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial Office The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print-on-demand. Some content that appears in standard print versions of this book may not be available in other formats. Limit of Liability/Disclaimer of Warranty The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. 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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 List of abbreviations xv Part 1    Drug treatment of major psychiatric conditions 1 Chapter 1   Schizophrenia and related psychoses 3 ANTIPSYCHOTIC DRUGS 3 General introduction 3 Antipsychotics – general principles of prescribing 8 Antipsychotics – minimum effective doses 9 Antipsychotics – quick reference for licensed maximum doses 12 Antipsychotics – equivalent doses 14 High-dose antipsychotics: prescribing and monitoring 16 Combined antipsychotics (antipsychotic polypharmacy) 20 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 Aripiprazole long-acting injection 77 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 Effect of antipsychotic medications on plasma lipids 149 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 Clozapine initiation schedule 190 Intramuscular clozapine 192 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 Clozapine: common adverse effects  212 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 288 Prophylaxis in bipolar disorder 296 Stopping lithium and mood stabilisers 301 Chapter 3 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 Treatment-resistant depression – other reported treatments 323 Ketamine328 Psychotic depression 332 Switching antidepressants 336 Antidepressant withdrawal symptoms 343 Stopping antidepressants 348 Electroconvulsive therapy (ECT) and psychotropic drugs 353 Psychostimulants in depression 357 Post-stroke depression 362 Antidepressants – alternative routes of administration 366 Antidepressant prophylaxis 374 Drug interactions with antidepressants 378 Cardiac effects of antidepressants – summary 383 Antidepressant-induced arrhythmia 389 Antidepressant-induced hyponatraemia 393 Antidepressants and hyperprolactinaemia 398 Antidepressants and diabetes mellitus 401 Antidepressants and sexual dysfunction 404 SSRIs and bleeding 409 St. John’s Wort 417 Antidepressants: relative adverse effects – a rough guide 421 Anxiety spectrum disorders 423 Benzodiazepines in the treatment of psychiatric disorders 436 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 Drug-induced acute behavioural disturbance (ABD) in acute admissions 524 Interactions between ‘street drugs’ and prescribed psychotropic drugs 526 Drugs of misuse – a summary 530 Substance misuse in pregnancy 535 Part 2    Drug treatment of special patient groups 537 Chapter 5   Children and adolescents 539 Principles of prescribing practice in childhood and adolescence 539 Depression in children and adolescents 541 Bipolar illness in children and adolescents 547 Psychosis in children and adolescents 554 Anxiety disorders in children and adolescents 556 Obsessive compulsive disorder (OCD) and body dysmorphic disorder (BDD) in children and adolescents 561 Post-traumatic stress disorder in children and adolescents 567 Attention deficit hyperactivity disorder  569 Autism Spectrum Disorder 578 Tics and Tourette syndrome 587 Melatonin in the treatment of insomnia in children and adolescents 593 Rapid tranquillisation (RT) in children and adolescents 596 Doses of commonly used psychotropic drugs in children and adolescents 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 Treatment of depression in older people 673 Chapter 7 Pregnancy and breastfeeding 679 Drug choice in pregnancy  679 What to include in discussions with pregnant women 681 Breastfeeding702 Chapter 8 Hepatic and renal impairment 723 Hepatic impairment 723 Renal impairment 735 Part 3    Prescribing in specialist conditions 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 Huntington’s disease – pharmacological treatment 803 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 833 Plasma level monitoring of psychotropic drugs 833 Interpreting postmortem blood concentrations 847 Acting on clozapine plasma concentration results 849 Psychotropics and cytochrome (CYP) function 851 Smoking and psychotropic drugs 856 Drug interactions with alcohol 860 Chapter 12 Other substances 865 Caffeine865 Nicotine871 Chapter 13 Psychotropic drugs in special conditions 875 Psychotropics in overdose 875 Driving and psychotropic medicines 883 Psychotropics and surgery 889 Chapter 14 Miscellany 897 Enhancing medication adherence 897 Re-starting psychotropic medications after a period of non-compliance 905 Biochemical and haematological effects of psychotropics 907 Summary of psychiatric side effects of non-psychotropics 917 Prescribing drugs outside their licensed indications (‘off-label’ prescribing or unapproved use of approved drugs) 923 Examples of acceptable use of drugs outside their product licences/labels 925 The Mental Health Act in England and Wales 927 Site of administration of intramuscular injections 932 Intravenous formulations in psychiatry 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 person- ally 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, intra- venous psychotropic formulations, intramuscular clozapine and weekly oral penfluri- dol. 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 Jane Marshall Andrea Danese Janet Treasure Andrew Wilcock Jemma Theivendran Annabel Price Jonathan Rogers Anne Connolly Justin Sauer Bruce Clark Kalliopi Vallianatou Claire Wilson Kwame Peprah Colin Drummond Louise Howard Daniel Harwood Luke Baker David Mirfin Luke Jelen Deborah Robson Marinos Kyriakopoulos Delia Bishara Mark Horowitz Derek Tracy Max Henderson Ebenezer Oloyede Mike Kelleher Elizabeth Naomi Smith Nicola Funnell Emily Finch Nicola Kalk Emmert Roberts Nilou Nourishad Eromona Whiskey Oluwakemi Oduniyi Francis Keaney Paramala Santosh Frank Besag Paul Gringras Gabriel Ruane Paul Moran Georgina Boon Petrina Douglas-Hall Hubertus Himmerich Sameer Jauhar Ian Osborne Shubhra Mace Irene Guerrini Siobhan Gee Iris Rathwell Sotiris Posporelis Ivana Clark Stephanie J Lewis James Stone 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 eco- nomic 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 brexpipra- zole, 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 influ- ence of the pharmaceutical industry but hope to have mitigated this risk by providing copious literature support for statements made. As regards direct influence, no pharma- ceutical 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 ARB angiotensin II receptor blocker Adolescent Psychiatry ASD autism spectrum disorders ACE angiotensin‐converting enzyme ASEX Arizona Sexual Experience Scale ACh acetylcholine AST aspartate aminotransferase AChE acetylcholinesterase AUDIT Alcohol Use Disorders AChE‐I acetylcholinesterase inhibitor Identification Test ACR albumin: creatinine ratio BAC blood alcohol concentration AD Alzheimer’s disease BAP British Association for ADAS‐cog Alzheimer’s Disease Assessment Psychopharmacology Scale – cognitive subscale BBB blood–brain barrier ADH alcohol dehydrogenase bd bis die (twice a day) ADHD attention deficit hyperactivity BDD body dysmorphic disorder disorder BDI Beck Depression Inventory ADIS Anxiety Disorders Interview BDNF brain‐derived neurotrophic Schedule factor ADL activities of daily living BED binge eating disorder ADR adverse drug reaction BEN benign ethnic neutropenia AF atrial fibrillation BMI body mass index AIDS acquired immune deficiency BN bulimia nervosa syndrome BP blood pressure AIMS Abnormal Involuntary BPD borderline personality disorder Movement Scale BPSD behavioural and psychological ALP alkaline phosphatase symptoms of dementia ALT alanine transaminase/ BuChE butyrylcholinesterase aminotransferase CAM Confusion Assessment Method ANC absolute neutrophil count CAMS Childhood Anxiety Multimodal ANNSERS Antipsychotic Non‐Neurological Study Side‐Effects Rating Scale CATIE Clinical Antipsychotic Trials of APA American Psychological Intervention Effectiveness Association CBT cognitive behavioural therapy  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 CPK creatinine phosphokinase 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 DAI drug attitude inventory 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 DSM  Diagnostic and Statistical Manual of Mental Disorders DVLA Driver and Vehicle Licensing Agency EAD early after depolarisation 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 IM intramuscular kinase IMCA independent mental capacity ERP exposure and response advocate prevention IMHP intramuscular high potency ES effect size INR international normalised ratio ESR erythrocyte sedimentation rate IR immediate release FAST functional assessment staging IV intravenous FBC full blood count IVHP intravenous high potency FDA Food and Drug Administration Kiddie‐SADS Kiddie‐Schedule for Affective (USA) Disorders and Schizophrenia FGA first‐generation antipsychotic LAI long‐acting injection FPG fasting plasma glucose LD learning disability FTI Fatal Toxicity Index LDL low‐density lipoprotein GABA γ‐aminobutyric acid LFTs liver function tests GAD generalised anxiety disorder LGIB lower gastrointestinal bleeding GASS Glasgow Antipsychotic LSD lysergic acid diethylamide Side‐effect Scale MADRS Montgomery‐Asberg Depression GBL gamma-butyrolactone Rating Scale G‐CSF granulocyte colony‐stimulating mane morning factor MAOI monoamine oxidase inhibitor GFR glomerular filtration rate MARS Medication Adherence Rating GGT γ‐glutamyl transferase Scale GHB γ‐hydroxybutyrate MASC Multidimensional Anxiety Scale GI gastrointestinal for Children GM‐CSF granulocyte‐macrophage MCA Mental Capacity Act colony-stimulating factor MCI mild cognitive impairment GSK3 glycogen synthase kinase 3 MDA 3,4‐methylenedioxyam- HADS Hospital Anxiety and phetamine Depression Scale MDMA 3,4‐methylenedioxymetham- HAMA Hamilton Anxiety Rating Scale phetamine HAND HIV‐associated neurocognitive MDRD Modification of Diet in Renal disorders Disease HD Huntington’s disease MHRA Medicines and Healthcare HDL high‐density lipoprotein Products Regulatory Agency HDRS Hamilton Depression Rating Scale MI myocardial infarction HIV human immunodeficiency virus MMSE Mini Mental State Examination 5‐HMT 5‐hydroxy‐methyl‐tolterodine MR modified release HPA hypothalamic‐pituitary‐adrenal MS mood stabilisers/multiple HR hazard ratio sclerosis IADL instrumental activities of daily NAS neonatal abstinence syndrome living NICE National Institute for Health ICD International Classification of and Care Excellence Diseases NMDA N‐methyl‐D‐aspartate ICH intracerebral haemorrhage NMS neuroleptic malignant syndrome IFG impaired fasting glucose NNH number needed to harm IG intra‐gastric NNT number needed to treat IJ intra‐jejunal nocte at night  List of abbreviations  xix NPI neuropsychiatric inventory RCADS Revised Children’s Anxiety and NRT nicotine replacement therapy Depression Scale NSAID non‐steroidal anti‐inflammatory RCT randomised controlled trial drug RID relative infant dose NVC neurovascular coupling RIMA reversible inhibitor of monoam- OCD obsessive compulsive disorder ine oxidase A od omni die (once a day) RLAI risperidone long‐acting injection OD overdose ROMI Rating of Medication Influences OGTT oral glucose tolerance test scale OOWS Objective Opiate Withdrawal RPG random plasma glucose Scale RR relative risk OST opioid substitution treatment RRBI restricted repetitive behaviours PANDAS Paediatric Autoimmune and interests Neuropsychiatric Disorder RT rapid tranquillisation Associated with Streptococcus RTA road traffic accident PANS Paediatric Acute‐onset rTMS repetitive transcranial magnetic Neuropsychiatric Syndrome stimulation PANSS Positive and Negative Syndrome RUPP Research Units on Paediatric Scale Psychopharmacology PBA pseudobulbar affect RYGB Roux‐en‐Y gastric bypass PCP phencyclidine SADQ Severity of Alcohol Dependence PD Parkinson’s disease Questionnaire PDD pervasive developmental SAWS Short Alcohol Withdrawal Scale disorders SCARED Screen for Child Anxiety and PDD‐NOS pervasive developmental Related Emotional Disorders disorders not otherwise specified SCIRS Severe Cognitive Impairment P‐gp P‐glycoprotein Rating Scale PHQ‐9 Patient Health Questionnaire‐9 SCRA synthetic cannabinoid receptor PICU psychiatric intensive care unit agonist PLC pathological laughter and crying SGA second‐generation PLWH people living with HIV antipsychotics PMR post‐mortem redistribution SIADH syndrome of inappropriate po per os (by mouth) antidiuretic hormone POMH‐UK Prescribing Observatory for SIB severe impairment battery Mental Health SJW St. John’s wort PPH post‐partum haemorrhage SLE systemic lupus erythematosus PPI proton pump inhibitor SNRI serotonin–noradrenaline prn pro re nata (as required) reuptake inhibitor PT prothrombin time SOAD second opinion appointed PTSD post‐traumatic stress disorder doctor PWE people with epilepsy SPC summary of product qds  quarter die sumendum (four characteristics times a day) SPECT single photon emission QTc QT interval adjusted for heart computed tomography rate SROM slow release oral morphine RC responsible clinician SS steady state xx  List of abbreviations SSRI selective serotonin reuptake TIA transient ischaemic attack inhibitor TMS transcranial magnetic STAR*D Sequenced Treatment stimulation Alternatives to Relieve TORDIA Treatment of Resistant Depression programme Depression in Adolescence STS selegiline transdermal system TPR temperature, pulse, respiration TADS Treatment of Adolescents with TRS treatment‐resistant Depression Study schizophrenia TCA tricyclic antidepressant TS Tourette syndrome TD tardive dyskinesia U&Es urea and electrolytes tDCS transcranial direct current UGIB upper gastrointestinal bleeding stimulation UGT UDP‐glucuronosyl transferase TDP torsades de pointes VaD vascular dementia tds  ter die sumendum (three times VNS vagal nerve stimulation a day) VTE venous thromboembolism TEAM Treatment of Early Age Mania WBC white blood cell TF‐CBT trauma‐focused cognitive WCC white cell count behavioural therapy WHO World Health Organization TFT thyroid function test XL extended release THC/CBD tetrahydrocannabinol/ YMRS Young Mania Rating Scale cannabidiol 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 chemi- cally similar thioxanthenes, such as flupentixol. Later entirely different chemical struc- tures 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 struc- ture-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 pri- mary 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 clozap- ine 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.  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 dis- CHAPTER 1 tinction 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. com- pare haloperidol with olanzapine). The typical/atypical dichotomy does not lend itself well to classification of antipsy- chotics 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 dif- ficulties 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 atypi- cals 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 chem- istry, pharmacology or adverse effect profile. In an attempt to get around some of these problems, typicals and atypicals were re- classified 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 pharmaco- logical 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 pharma- cological 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 medi- cines influence adherence. Consistent with this general advice that covers all of health- care, 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  Schizophrenia and related psychoses  5 Antipsychotics are effective in both the acute and maintenance treatment of schizo- phrenia and other psychotic disorders. They differ in their pharmacology, pharmacoki- CHAPTER 1 netics, 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 pro- pensity 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 net- work meta-analysis of first-episode studies found small efficacy advantages for olan- zapine 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, risperi- done and amisulpride over older drugs.11,12 A network meta-analysis13 broadly con- firmed 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 symp- toms and clozapine as the best for both negative symptoms and overall symptom improvement. Olanzapine and risperidone were also highly ranked for positive symp- tom response. The greatest (beneficial) effect on depressive symptoms was seen with sulpiride, clozapine, amisulpride, olanzapine and the dopamine partial agonists, per- haps 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 hyperprolactinae- mia, hip fracture,23 sexual dysfunction, EPS including neuroleptic malignant syn- drome,24 anticholinergic effects, venous thromboembolism (VTE),25 sedation and postural hypotension. The exact profile is drug-specific (see individual sections on  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). CHAPTER 1 Adverse effects are a common reason for treatment discontinuation,28 particularly when efficacy is poor.13 Patients do not always spontaneously report side effects how- ever,29 and psychiatrists’ views of the prevalence and importance of adverse effects dif- fer 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 medi- cation delivery associated with depot/long-acting injectable antipsychotic preparations is unequivocally advantageous. In comparison with oral antipsychotics, there is strong evi- dence 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 ari- piprazole, 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 olanzap- ine.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 rela- tive 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.  Schizophrenia and related psychoses  7 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. CHAPTER 1 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 schizo- phrenia: 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 meta- analysis. 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 schizo- phrenia: 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 long- term 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 ret- rospective 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 schizophreni- form disorder (OPTiMiSE): a three-phase switching study. Lancet Psychiatry 2018; 5:797–807.  8  The Maudsley® Prescribing Guidelines in Psychiatry General principles of prescribing CHAPTER 1 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 phar- macokinetics 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 cir- cumstances (e.g. clozapine augmentation), antipsychotic polypharmacy should gener- ally be avoided because of the increased adverse effect burden and risks associated with QT prolongation and sudden cardiac death (see the section on combined antip- sychotics in this chapter). Combinations of antipsychotics should only be used where response to a single antip- sychotic (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, treat- ment should revert to single antipsychotic therapy. In general, antipsychotics should not be used as ‘when necessary’ sedatives. Time- limited prescriptions of benzodiazepines or general sedatives (e.g. promethazine) are 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 appro- priate 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 chap- ter for detailed and referenced guidance.]  Schizophrenia and related psychoses  9 Minimum effective doses CHAPTER 1 Table 1.1 suggests the minimum dose of antipsychotic likely to be effective in first- or multi- episode schizophrenia. Most patients will respond to the dose suggested, although others may require higher doses. Given the variation in individual response, all doses should be considered approximate. Primary references are provided where available, but 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 FGAs Chlorpromazine1 200mg* 300mg Haloperidol 2–7 2mg 4mg Sulpiride8 400mg* 800mg Trifluoperazine 9,10 10mg* 15mg SGAs Amisulpride11–16 300mg* 400mg* Aripiprazole7,17–22 10mg 10mg Asenapine 7,22,23 10mg* 10mg Blonanserin24 Not known 8mg Brexpiprazole25–27 2mg* 4mg Cariprazine 28,29 1.5mg* 1.5mg Iloperidone7,21,22,30 4mg* 8mg Lumateperone 31 Not known 42mg* Lurasidone 7,32 40mg HCl/37mg base* 40mg HCl/37mg base Olanzapine4,7,33–35 5mg 7.5mg Paliperidone 22 3mg* 3mg Pimavanserin 36–38 Not known 34mg** Quetiapine39–44 150mg* (but higher doses often used45) 300mg Risperidone 3,7,46–49 2mg 4mg Ziprasidone 7,21,50–52 40mg* 80mg *Estimate – too few data available **FDA-approved for Parkinson’s disease psychosis; dose in schizophrenia not known  10  The Maudsley® Prescribing Guidelines in Psychiatry References CHAPTER 1 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. haloperi- dol. 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 thera- peutic 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-con- trolled 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.  Schizophrenia and related psychoses  11 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. CHAPTER 1 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.  12  The Maudsley® Prescribing Guidelines in Psychiatry Licensed maximum doses CHAPTER 1 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 150mg/month 1-monthly  Schizophrenia and related psychoses  13 Drug Maximum dose CHAPTER 1 Paliperidone depot 525mg every 3 months 3-monthly 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 out- side 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.  14  The Maudsley® Prescribing Guidelines in Psychiatry Equivalent doses CHAPTER 1 Knowledge of equivalent dosages is useful when switching between FGAs. Estimates of ‘neuroleptic’ or ‘chlorpromazine’ equivalence, in milligrams a day, between these medi- cations 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 equiva- lence. 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 refer- ences 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 differ- ent 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  Schizophrenia and related psychoses  15 Table 1.3 Second-generation antipsychotics – approximate equivalent doses3–10 CHAPTER 1 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.  16  The Maudsley® Prescribing Guidelines in Psychiatry High-dose antipsychotics: prescribing and monitoring CHAPTER 1 ‘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 antipsy- chotic medication for rapid tranquillisation, relapse prevention, persistent aggression and the management of acute psychotic episodes.1 Despite this, in the UK, approxi- mately 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 risperi- done 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 recep- tors. 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 succes- sively 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 stand- ard-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 ben- efit 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 treat- ment-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.  Schizophrenia and related psychoses  17 In a study of patients with first-episode schizophrenia, increasing the dose of olanzap- ine up to 30mg/day and the dose of risperidone up to 10mg/day in non-responders to CHAPTER 1 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 mod- est 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 olan- zapine, 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 observa- tion of a flat or horizontal dose–response curve above a certain dose for all antipsychot- ics, 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 prolon- gation 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 equiv- alents 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.  18  The Maudsley® Prescribing Guidelines in Psychiatry Prescribing high-dose antipsychotic medication CHAPTER 1 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.