The Clozapine Handbook

9781108447461

Real-world and clinical trial data support that clozapine is the only effective antipsychotic for treatment resistant schizophrenia and other severe mental illnesses. Clozapine also reduces rates of suicidality, psychiatric hospitalization and all-cause mortality. However, clozapine is underutilized for two reasons: misunderstandings of its efficacy benefits and misapprehension of, limited knowledge or misinformation about the management of treatment related risks and adverse effects.

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Foreword

It is 30 years since the Clozaril Collaborative Study Group published the pivotal trial results in September 1988 that established clozapine’s efficacy in treatment-resistant schizophrenia, with subsequent research noting clozapine’s unique benefit for suicidal and persistently aggressive schizophrenia patients [ 1–3 ]. Over the ensuing decades no other medication has proven effective for this multiplicity of uses, yet many candidate patients throughout the world are deprived of a clozapine trial. That clozapine is underutilized has been lamented in numerous publications, and remains a source of consternation for the psychiatric profession as treatment-resistant patients are repeatedly exposed to ineffective medications with little likelihood of response.

Yet, there is hope in reversing the long-standing problem of mental health clinicians refusing to prescribe a potentially effective and in some instances life-saving/life-changing medication. The past half decade has the seen the rise of initiatives to increase clozapine use in certain parts of Europe and the United States, efforts that are informed by a body of literature documenting the benefits accrued to the individual, as well as to a society at large that bears the economic and social burdens of managing treatment-resistant schizophrenia. In 2015 the United States Food and Drug Administration (FDA) modernized and streamlined its clozapine prescribing guidelines, and in doing so created an evidenced-based model that can be emulated throughout the world. There have also been advances in our understanding of effective strategies to manage common adverse effects such as sialorrhea and constipation, and data-driven approaches to more vexing problems such as fever occurring during the initial 6–8 weeks of clozapine treatment.

Despite overwhelming international support in favor of increased clozapine access, one stumbling block is the need to support and nurture relevant clinicians, many of whom cite lack of education regarding clozapine’s nuances as a primary reason to avoid prescribing this medication [ 4 , 5 ]. The present volume thus appears at an opportune time, and, in a comprehensive manner, covers the latest information and updated guidelines in a practical and easily accessible format. Nowhere is this breadth of information and clinical insights about clozapine use provided within a single volume; moreover, of great benefit to clinicians is the manner in which Dr. Meyer and Dr. Stahl walk the reader through common issues in clozapine management and present a rationale for the next steps.

The time has come to turn the tide on the regrettable practice patterns that lead to clozapine underutilization. It is hoped that clinicians and health-care systems will take advantage of this valuable handbook to increase patient access to clozapine.

John M. Kane MD

Professor and Chairman, Department of Psychiatry, The Donald and Barbara

Zucker School of Medicine at Hofstra/Northwell

Senior Vice President, Behavioral Health Services,

Northwell Health

References

1. Kane , J. , Honigfeld , G. , Singer , J. , et al. ( 1988 ). Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine . Archives of General Psychiatry , 45 , 789–796 .

2. Meltzer , H. Y. , Alphs , L. , Green , A. I. , et al. ( 2003 ). Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT) . Archives of General Psychiatry , 60 , 82–91 .

3. Krakowski , M. I. , Czobor , P. , Citrome , L. , et al. ( 2006 ). Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder . Archives of General Psychiatry , 63 , 622–629 .

4. Nielsen , J. , Dahm , M. , Lublin , H. , et al. ( 2010 ). Psychiatrists’attitude towards and knowledge of clozapine treatment . Journal of Psychopharmacology , 24 , 965–971 .

5. Cohen , D. ( 2014 ). Prescribers fear as a major side-effect of clozapine . Acta Psychiatrica Scandinavica , 130 , 154–155 .

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DOI: 10.1017/9781108553575

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First published 2020

Printed in the United States of America by Sheridan Books, Inc.

A catalogue record for this publication is available from the British Library.

Library of Congress Cataloging-in-Publication Data

Names: Meyer, Jonathan M., 1962–author. | Stahl, Stephen M., 1951–author. |

Title: The clozapine handbook / Jonathan M. Meyer, Stephen M. Stahl.

Other titles: Stahl's handbooks.

Description: Cambridge ; New York, NY : Cambridge University Press, 2019. | Series: Stahl's handbooks | Includes bibliographical references and index.

Identifiers: LCCN 2018054843 | ISBN 9781108447461 (paperback : alk. paper)

Classification: LCC RM333.5 | NLM QV 77.9 | DDC 615.7/882–dc23

LC record available at https://lccn.loc.gov/2018054843

ISBN 978-1-108-44746-1 Paperback

Cambridge University Press has no responsibility for the persistence or accuracy of URLs for external or third-party internet websites referred to in this publication and does not guarantee that any content on such websites is, or will remain, accurate or appropriate.

Every effort has been made in preparing this book to provide accurate and up-to-date information that is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors, and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors, and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

Chapter 1	Chapter 9
The Efficacy Story: Treatment-Resistant Schizophrenia, Psychogenic Polydipsia, Treatment-Intolerant Schizophrenia, Suicidality, Violence, Mania and Parkinson’s Disease Psychosis	Managing Sialorrhea
Chapter 2	Chapter 10
Addressing Clozapine Positive Symptom Nonresponse in Schizophrenia Spectrum Patients	Managing Seizure Risk and Stuttering
Chapter 3	Chapter 11
Initiating Clozapine	Managing Metabolic Adverse Effects
Chapter 4	Chapter 12
Discontinuing Clozapine and Management of Cholinergic Rebound	Fever, Myocarditis, Interstitial Nephritis, DRESS, Serositis and Cardiomyopathy
Chapter 5	Chapter 13
Binding Profile, Metabolism, Kinetics, Drug Interactions and Use of Plasma Levels	Managing Enuresis and Incontinence, Priapism, Venous Thromboembolism, Neuroleptic Malignant Syndrome, Tardive Dyskinesia and Obsessive Compulsive Disorder
Chapter 6	Chapter 14
Understanding Hematologic Monitoring and Benign Ethnic Neutropenia	Eosinophilia, Leukocytosis, Thrombocytopenia, Thrombocytosis, Anemia, Hepatic Function Abnormalities
Chapter 7	Chapter 15
Managing Constipation Chapter 8 Managing Sedation, Orthostasis and Tachycardia	Special Topics: Child and Adolescent Patients, Elderly Patients, Patients With Intellectual Disability, Pregnancy and Risk for Major Congenital Malformation, Lactation, Overdose, Postmortem Redistribution

Index

List of Contributors

Index

A1C values,

absolute neutrophil count (ANC),

,

baseline,

DARC genotype,

low baseline, addressing,

–

low, and treatment interruption,

–

monitoring guidelines, USA,

threshold,

,

UK hematologic monitoring,

ACHIEVE protocol,

adherence. See nonadherence

adolescents,

,

–

adverse effects of clozapine,

intellectually disabled,

plasma clozapine levels,

principles for clozapine use,

randomized double-blind studies,

African descent,

,

aggression,

–

,

agranulocytosis,

,

akathisia,

,

alanine aminotransferase (ALT),

,

alpha1 antagonism,

,

alpha-synuclein,

amisulpride,

,

amphetamines,

anemia,

,

–

general approach to,

incidence of,

anticholinergics,

approximate equivalents,

cholinergic rebound,

,

constipation and,

,

daily maximum limits,

equivalencies,

,

sialorrhea and,

,

anticonvulsants,

,

antidepressants, tricyclic,

,

antihypertensives,

antiparkinsonian medications,

antipsychotics. See also individual antipsychotics

augmenting clozapine,

–

consensus criteria for an adequate trial,

double-blind trials,

mortality studies,

plasma levels,

provision of appropriate,

–

real-world effectiveness studies,

tapering,

weight gain and,

,

antisocial personality disorders,

aripiprazole,

,

OCD and,

sedation and,

armodafinil,

aromatic hydrocarbon receptor (AhR),

aspartate aminotransferase (AST),

,

aspiration pneumonia,

atenolol,

atonic seizures,

atropine,

,

Australia, clozapine registration,

bacterial infections,

,

–

clozapine management during,

minimization of risk,

bariatric surgery,

baseline laboratory measures,

baseline vital signs,

baseline work-up,

,

baseline, low, ANC,

–

Bazett formula,

,

benign ethnic neutropenia (BEN),

,

–

ANC threshold,

definition of,

diagnosis,

hematologic monitoring,

hematologic monitoring, UK,

hematologic monitoring, USA,

benzodiazepines,

benztropine,

cholinergic rebound,

,

BID dosing,

binding profile,

–

bioavailability,

,

bipolar disorder, manic phase of,

bisacodyl,

body mass index (BMI),

,

botulinum toxin-A,

,

botulinum toxin-B,

,

–

breastfeeding,

,

–

Brief Psychiatric Rating Scale (BPRS),

,

Bristol Stool Form Scale,

,

bulk-forming laxatives,

,

bupropion,

caffeine,

Cal-DSH,

,

Canada, clozapine registration,

carbachol,

,

carbamazepine,

,

cardiac malformations,

cardiomyopathy,

,

–

cardiovascular disease,

,

caregivers

checklist of information,

dosages and,

initiating clozapine and,

monitoring role,

CATIE study,

,

CBC monitoring, point-of-care,

Child–Pugh criteria,

children,

,

–

adverse effects of clozapine,

plasma clozapine levels,

principles for clozapine use,

randomized, double-blind studies,

chlorpromazine,

,

cholinergic rebound,

,

ileus risk,

Kane study,

liver function and,

cholestasis,

cholinergic rebound

chlorpromazine,

,

clozapine,

definition,

diabetes patients,

ileus and,

management of,

–

neuroleptic malignant syndrome,

severe neutropenia,

symptoms,

ciprofloxacin,

Clinical Global Impression (CGI) severity scale,

,

clonazepam,

clonidine,

,

clozapine individual adverse effects

adverse effects,

,

. See also individual adverse effects

binding profile,

–

cholinergic rebound,

comparative double-blind trials,

discontinuing. See discontinuing clozapine

dose reduction. See dose reduction

ECT and,

FDA approval,

FDA prescribing guidelines,

first synthesis of,

hematologic monitoring. See hematologic monitoring

impact of delays in commencing,

initiating. See initiating clozapine

mania and,

metabolic adverse effects. See metabolic adverse effects

metabolism and kinetics,

–

mortality and,

,

pivotal trial,

plasma levels. See plasma clozapine levels

pregnancy outcome and,

–

prescriber fear,

primary metabolites,

product registration,

real-world effectiveness studies,

,

slow tapering of,

smoking and,

suicide and,

titration. See titration

underutilization,

,

underutilization, adolescents,

underutilization, treatment-resistant schizophrenia,

,

utilization, strategies for increasing,

clozapine efficacy,

,

background,

–

Parkinson’s disease psychosis,

–

plasma levels monitoring,

–

psychogenic polydipsia,

–

suicidality,

treatment-intolerant schizophrenia,

treatment-resistant mania,

–

treatment-resistant schizophrenia,

–

violence and aggression,

–

clozapine positive symptom nonresponse,

–

antipsychotic augmentation,

–

ECT and,

–

increasing plasma levels,

–

nonantipsychotic augmentation,

–

patient adherence and,

–

clozapine resource centers,

clozapine-N-oxide,

,

CLOZARIL,

,

Clozaril Collaborative Study Group,

colonic transit time (CTT),

,

complete blood count (CBC),

,

compression stockings,

congenital malformations,

,

congestive heart failure,

constipating medications,

constipation,

,

–

,

–

criteria,

–

first-line agents for,

,

opioid-induced,

,

prevalence and postulated mechanisms,

PRN medications,

treatment,

–

corpora cavernosa,

C-reactive protein (CRP),

,

creatinine,

CYP

inducers,

inhibitors,

,

CYP 1A2,

,

clozapine metabolism and,

inducers,

infections and,

inhibitors,

metabolic ratio and,

,

smoking, caffeine and genetic polymorphisms,

–

CYP 2D6,

,

inhibitors,

CYP 3A4,

CYP P450 inhibitors,

CYP/PGP inducer effects,

CYP polymorphisms,

,

daily maximum limits,

DARC genotype,

,

delays in commencing clozapine,

delusions, violence and,

deutetrabenazine,

diabetes mellitus,

,

–

criteria for,

diagnosis,

gestational,

,

initiating clozapine,

risk factors,

diabetic ketoacidosis (DKA),

,

dietary counseling,

,

diminishing tolerability,

,

diphenhydramine,

,

disability-adjusted life year,

discontinuing clozapine,

–

. See also cholinergic rebound

metabolic effects and,

myocarditis,

orthostasis and,

Parkinson’s disease psychosis,

–

priapism,

sedation and,

,

sialorrhea and,

divalproex,

,

. See also valproate

adverse effects,

,

seizures and,

,

thrombocytopenia and,

divided doses, plasma levels and,

dizziness,

docusate,

,

donepezil,

dopamine D2 antagonism,

,

occupancy with clozapine,

dopamine D2 antagonism intolerance,

,

antipsychotic options,

antipsychotic trials,

dose reduction,

constipation and,

sedation and,

dose titration trial,

,

DRESS,

,

mortality,

Drooling Severity and Frequency Scale,

,

drug abuse

methylphenidate and amphetamines,

modafinil and,

DSM-5, psychosis scoring,

Duffy antigens,

Dutch Clozapine Collaboration Group,

dyslipidemia,

,

ECG,

,

cardiomyopathy,

myocarditis,

,

necessity of,

ECT

clozapine and,

clozapine nonresponders,

–

EEG,

seizures and,

elimination half-life,

enemas,

enuresis,

,

–

,

approaches to treatment,

eosinophilia,

,

–

DRESS,

,

incidence of,

thresholds,

US language on,

eosinophils,

baseline,

reference ranges,

UK reference ranges,

ephedrine,

epilepsy,

erectile dysfunction,

ethnicity. See also African descent

diabetes risk factor,

metabolic adverse effects and,

platelet count and,

exercise,

,

–

extrapyramidal symptoms,

factor Xa inhibitors,

falls,

,

famotidine,

fatty liver index,

FDA

clozapine approval,

clozapine prescribing guidelines,

inhibitor/inducer definitions,

fever,

,

–

clozapine-related, case series,

definition,

general principles of approaching,

filgrastim,

,

–

,

first-dose effect,

floppy infant syndrome,

fludrocortisone,

,

fluvoxamine,

formulations,

,

Framingham Formula,

,

Fridericia Formula,

,

gabapentin,

G-CSF levels,

,

generalized seizures,

genetic polymorphisms,

,

gestational diabetes mellitus,

,

glucagon-like peptide-1 (GLP-1),

glutamate neurotransmission,

glycine,

glycine transporters,

glycopyrrolate,

sialorrhea,

,

goserelin,

granulocytosis,

guanfacine,

Hale classification,

hallucinations,

,

haloperidol,

aggression and,

Kane study,

response threshold,

heart transplantation,

hematologic guidelines, USA and UK,

hematologic monitoring. See also absolute neutrophil count (ANC)

UK,

,

USA,

,

HemoCue WBC DIFF,

hemoglobin,

hepatic function abnormalities,

,

–

general approach to tests,

HF-1854,

high-density lipoprotein (HDL),

histamine H1 antagonism,

HLA markers,

,

hyperosmolar hyperglycemic states (HHS),

hypersalivation. See sialorrhea

hypertension,

,

criteria for,

hypertriglyceridemia,

hyponatremia,

hypotension,

orthostasis

orthostatic. See orthostasis

ileus

diagnosing,

mortality,

,

rechallenging,

risk,

,

treatment, post-rechallenging,

when to suspect,

iloperidone,

impulsive violence,

,

incontinence,

,

–

,

approaches to treatment,

inducers,

CYP,

,

strength of,

,

inflammatory cytokines,

informed consent,

inhibitors,

CYP,

,

strength of,

,

initiating clozapine,

–

,

–

baseline laboratory measures,

baseline vital signs,

baseline work-up,

,

checklist of information,

fomulations,

managing orthostasis,

managing sedation,

monitoring during,

monitoring, inpatient,

monitoring, outpatient,

patient discussions prior to,

QT correction formula,

registration,

tapering concomitant medications,

–

titration,

–

instrumental violence,

insulin resistance,

,

intellectual disability (ID) patients,

,

–

adverse effects,

nonpsychotic,

–

psychotic,

interleukin-5 (IL-5),

InterSePT study,

,

interstitial nephritis,

,

routine laboratory monitoring,

summary of cases,

intramuscular (IM) formulation,

,

ipratropium,

,

irritable bowel syndrome (IBS),

Kane criteria,

Kane study,

Ki nM receptors,

kinetics, clozapine,

–

laboratory error,

,

lactulose,

lamotrigine,

,

left ventricular dysfunction,

left ventricular ejection fraction (LVEF),

,

leukocytosis,

general approach to,

incidence of,

leukopenia,

levetriacetam,

,

levodopa psychosis,

levodopa-induced dyskinesias (LID),

Lewy bodies,

lifestyle modification,

–

linaclotide,

,

lithium,

,

augmentation,

granulocytosis and,

lubiprostone,

,

magnesium,

,

magnesium citrate,

magnesium hydroxide,

mania,

,

treatment-resistant,

–

medication nonadherence. See nonadherence

memantine,

metabolic adverse effects,

–

. See also weight gain

discontinuing clozapine,

monitoring parameters,

principles of managing on clozapine,

metabolic ratio (MR),

,

adolescents and children,

guidelines for interpreting,

infections and,

–

older patients,

overdose and,

metabolic syndrome,

,

components of,

criteria for,

prevalence of,

metabolism, clozapine,

–

metformin,

,

–

children and adolescents,

methylphenidate,

mineral oil (liquid paraffin),

minocycline,

mirabegron,

,

mirtazapine,

modafinil,

monitoring,

inpatient,

outpatient,

mortality

clozapine and,

–

,

DRESS,

ileus,

,

postmortem redistribution,

,

–

severe neutropenia,

,

smoking,

suicide and,

muscarinic M1/M3 antagonism,

muscarinic M1/M5 agonism,

muscarinic M3 antagonism,

muscarinic antagonism,

,

muscarinic intrinsic activity,

,

myocarditis,

,

–

essential facts,

incidence of,

monitoring for,

routine laboratory monitoring,

time to onset,

myoclonic jerking,

neuroleptic malignant syndrome (NMS),

,

–

diagnostic criteria,

neutropenia,

,

benign ethnic neutropenia (BEN)

ANC levels, monitoring,

BEN. See benign ethnic neutropenia (BEN)

children and adolescents,

hypothesized mechanism,

other sources of,

severe. See severe neutropenia

terminology,

time course and risk factors,

valproate and,

,

neutrophilia,

,

causes of,

nicotine replacement therapy,

NMDA glutamate receptors,

,

Nocturnal Hypersalivation Rating Scale,

,

nonadherence,

–

,

plasma levels and,

rates,

nonalcoholic fatty liver disease (NAFLD),

,

nonantipsychotic augmentation

clozapine nonresponders,

–

norclozapine,

,

. See also metabolic ratio (MR)

binding profile,

–

infections and,

plasma levels,

sialorrhea and,

obesity, criteria for,

obsessive compulsive disorder,

,

approach to new onset,

olanzapine,

aggression and,

cholinergic rebound,

double-blind trials,

Parkinson’s disease psychosis,

,

response threshold,

suicide and,

tapering,

older patients,

,

–

adverse effects of clozapine,

,

omeprazole,

,

opioids, constipation and,

,

oral formulations,

,

oral suspension,

orally disintegrating tablet (ODT),

organized violence,

orthostasis,

,

–

,

clozapine initiation,

definition,

falls and,

seizures and,

tachycardia and,

vital signs,

overactive bladder,

overdose,

,

–

paralytic ileus,

Parkinson’s disease (PD),

medications,

Parkinson’s disease psychosis (PDP),

–

consensus definition,

discontinuing clozapine,

–

titration levels,

partial seizures,

patient discussions,

checklist,

patient nonadherence. See nonadherence

PEG-3350,

,

perphenazine,

Petrides’ study,

PGP,

CYP/PGP inducer effects,

phenytoin,

,

physical activity vital sign (PAVS),

,

pimavanserin,

,

5HT2A affinity,

D2 antagonism intolerance,

Parkinson’s disease psychosis,

,

pirenzepine,

pivotal clozapine trial,

plasma antipsychotic levels,

plasma clozapine levels,

,

–

adolescents and children,

clozapine nonresponders and,

–

conversion formulas,

decreasing, for constipation,

early in treatment,

infections and,

–

markedly below expected,

markedly higher than expected,

–

monitoring efficacy,

–

nonresponders,

older patients,

,

overdose and,

postmortem redistribution,

principles for obtaining,

threshold,

units used,

,

upper limits,

,

platelet count,

,

–

platelets, UK reference ranges,

,

plecanatide,

,

point of futility,

,

point-of-care CBC monitoring,

Porirua constipation protocol,

Positive and Negative Syndrome Scale (PANSS),

postmortem redistribution,

,

–

predatory violence,

pregnancy,

,

–

anticonvulsants and,

clozapine and,

–

thrombocytopenia and,

prescriber fear,

priapism,

,

–

,

primary metabolites, clozapine,

primary polydipsia,

,

propensity scores,

propranolol,

,

prucalopride,

,

psychogenic polydipsia,

–

psychotic violence,

psychotropics

constipation and,

tapering,

PSYCLOPS trial,

psyllium,

PubMed, clozapine publications in,

pulmonary embolism,

,

QHS dosing,

QT correction formula,

QT monitoring,

QT prolongation,

quetiapine,

adverse effects,

D2 antagonism intolerance,

mortality rates,

Parkinson’s disease psychosis,

,

tapering,

rechallenging

eosinophilia,

ileus,

interstitial nephritis,

myocarditis,

priapism,

severe neutropenia,

RegiSCAR,

registration,

repetitive transcranial magnetic stimulation (rTMS),

response threshold,

,

haloperidol,

olanzapine,

rhabdomyolysis,

ribavirin,

risperidone,

,

Rome IV diagnostic criteria,

salivary glands,

schizoaffective disorder, bipolar type,

schizophrenia treatment-resistant schizophrenia

antipsychotic mortality studies,

childhood onset,

costs in the US,

disease burden of,

enuresis and,

prevalence,

,

prevalence, age-standardized,

real-world effectiveness studies,

treatment-intolerant,

treatment-resistant. See treatment-resistant schizophrenia

violence risk estimates,

schizophrenia spectrum disorders

antipsychotic options,

,

clozapine initiation,

mortality and,

plasma levels,

suicidality and,

secondary polydipsia,

secretogogues,

,

–

,

sedation,

,

–

,

effects,

falls and,

seizures,

,

–

,

clozapine and,

,

dose-dependency and,

,

–

neonatal,

treatment of,

–

types and frequencies,

sennosides,

serositis,

,

serotonergic motility agents,

–

serotonin 5HT2a inverse agonism,

serotonin 5HT2a occupancy with clozapine,

serotonin 5HT2a receptors,

,

sertraline,

serum creatinine,

serum osmolality,

,

severe cutaneous adverse reactions (SCARs),

severe neutropenia,

,

breastfeeding and,

estimates for clozapine,

fever and,

mortality from,

,

other medications and,

rechallenging,

time course of,

–

sialorrhea,

,

–

clozapine-induced,

–

prevalence,

treatment principles,

–

single nucleotide polymorphisms (SNPs),

smoking,

–

anticholinergics and,

,

clozapine and,

CYP 1A2 activity and,

inhibitor/inducer effects and,

monitoring,

mortality rates,

titration and,

,

SNARE proteins,

,

sodium benzoate,

SSRIs,

,

Stevens–Johnson Syndrome,

,

stimulants,

stool form nomenclature,

–

,

STRIDE protocol,

stuttering,

,

substance use, violence and,

suicidality,

,

InterSePT study,

,

overdose and,

type 1 and type 2 events,

sulpiride,

systemic inflammation,

tachycardia,

,

–

,

decision algorithm,

definition,

tardive dyskinesia,

,

thrombin inhibitors,

thrombocytopenia,

,

–

general approach to,

incidence of,

,

thrombocytosis,

,

–

general approach to,

incidence of,

timing, plasma levels and,

titration,

–

children and adolescents,

,

clozapine,

dose titration trial,

,

older patients,

,

principles of,

,

rapid,

,

slower,

tonic–clonic seizures,

topiramate,

,

transabdominal ultrasound,

,

traveling, difficulties in,

treatment-intolerant schizophrenia,

treatment-resistant mania,

–

treatment-resistant schizophrenia

adolescents,

,

children,

clozapine efficacy,

–

clozapine underutilization,

,

consensus criteria for an adequate trial,

costs of,

ECT and,

Kane criteria,

olanzapine trials,

pivotal clozapine trial,

plasma level ranges,

prevalence,

suicidality and,

tricyclic antidepressants,

,

trihexyphenidyl,

troponin,

troponin I/T level,

,

UGT1A 4,

UK

clozapine prescriptions,

clozapine registration,

eosinophil/platelet reference ranges,

,

hematologic monitoring,

,

UK Diabetes Prevention Program trial,

urinalysis,

urine osmolality,

,

urodynamic testing,

,

USA. See also FDA

clozapine prescribing guidelines,

clozapine prescriptions,

clozapine registration,

costs of schizophrenia,

eosinophilia, language on,

guidelines on dose adjustment,

hematologic guidelines,

hematologic monitoring,

,

valbenazine,

valproate,

,

. See also divalproex

neutropenia risk,

,

valproic acid,

,

varenicline,

venous thromboembolism,

,

–

,

risk assessment tool,

violence,

–

,

risk estimates in schizophrenia,

viral infections,

,

–

clozapine management during,

minimization of risk,

visual hallucinations,

VMAT2 inhibitors,

,

waist circumference,

,

warfarin,

weight gain,

,

antipsychotic-related,

,

children and adolescents,

nonmodifiable risk factors,

white blood cells (WBCs),

,

leukocytosis,

low, and treatment interruption,

–

racial variations,

UK hematologic monitoring,

WHO Global Burden of Disease Study 2016,

withdrawal symptoms. See cholinergic rebound

Young Mania Rating Scale (YMRS) score,

,

Young Mania Rating Scale (YMRS) score,

,

Zollinger–Ellison syndrome,

List of Contributors

Stephen Stahl
California Department of State Hospitals, Sacramento, University of California San Diego, California, USA, and University of Cambridge, Cambridge, UK

Jonathan Meyer
Department of Psychiatry, University of California–San Diego, San Diego, California Department of State Hospitals, and Patton State Hospital, California, USA

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Discontinuing Clozapine and Management of Cholinergic Rebound

Introduction
Principles
A Management of Cholinergic Rebound
B Provision of Appropriate Antipsychotic Therapy
C Parkinson’s Disease Psychosis
Summary Points
References

Introduction

The need to discontinue clozapine is a lamentable but medically necessary event in certain circumstances, and at times must be accomplished abruptly. In instances when the patient can be tapered off gradually (e.g. dilated cardiomyopathy), the risk of cholinergic rebound symptoms is lessened and the clinician can focus on making an informed choice about antipsychotic treatment. Although no agent equals clozapine’s efficacy for treatment-resistant schizophrenia, 35% of a group of schizophrenia outpatients with poor antipsychotic response (n = 99) who were considered candidates for clozapine had subtherapeutic plasma levels of their current antipsychotic [ 1 ]. Thus, a certain fraction of patients who end up on clozapine were failures due to inadequate dosing of prior antipsychotics, poor adherence or kinetic issues. As will be discussed below, this is an important consideration for patients deemed treatment-resistant but who did not experience adverse effects of prior antipsychotic treatment, particularly those related to D ₂ antagonism. This understanding may open the door to revisiting prior antipsychotics, but with careful monitoring of adherence and drug exposure via use of plasma levels [ 2 ].

A withdrawal syndrome following abrupt discontinuation of chlorpromazine (including some on concurrent anticholinergic antiparkinsonian medications) was first described in a 1959 study (n = 28). The cluster of symptoms comprised “acute, uncomfortable reactions characterized by tension, fear, restlessness, insomnia, increased perspiration, and vomiting” [ 3 ]. For the 17 patients who developed clinically significant withdrawal reactions, three developed symptoms on the second day, nine on the third day, three on the fourth day, and two on the fifth day. The author also noted: “The symptoms had not entirely subsided until two weeks after the sudden withdrawal” [ 3 ]. This classic description of cholinergic rebound was not recognized for many years as the product of cholinergic supersensitivity due to the complex pharmacology of chlorpromazine, combined with the prevalent use of anticholinergic antiparkinsonian agents with higher-potency antipsychotics. Twenty years later it finally became clear that the central nervous system (CNS) and systemic symptoms described in 1959 were related to removal of potent muscarinic antagonism, and not the dopaminergic property of the antipsychotic [ 4 ]. Lieberman introduced the term “cholinergic rebound” in 1981 to reinforce the concept that this is a phenomenon related to tolerance of and abrupt withdrawal of a muscarinic antagonist, with the severity related to the prior anticholinergic load [ 5 ].

Principles

During abrupt discontinuation, management of cholinergic rebound is critical to prevent central nervous system and peripheral adverse effects.
The decision on which antipsychotic to start in lieu of clozapine is based on detailed knowledge of prior response and tolerability.
Previous antipsychotic trials previously deemed treatment failures must be reassessed for evidence of inadequate dosing or nonadherence, especially when there was no documentation of adverse effects related to D ₂ antagonism.
ECT is an underutilized but effective treatment for schizophrenia and must be considered when pharmacotherapy is inadequate.
Parkinson’s disease psychosis (PDP) patients have limited options. In areas where it is available, pimavanserin is a potent, selective 5HT _2A antagonist approved for PDP that lacks any activity at dopamine receptors. Despite weak efficacy data, lack of approved indication, and a twofold increase in mortality rates, the weak D ₂ antagonist quetiapine is commonly used.

Clozapine possesses over sevenfold higher affinity for the muscarinic M ₁ receptor than does chlorpromazine, and by 1974 early reports of a clozapine withdrawal syndrome were alluded to; however, not until wider commercial release in 1989 was the problem recognized, with five case reports emerging by 1994. In 1996 a dedicated study of clozapine withdrawal symptoms was performed in 28 clozapine-treated inpatients enrolled in a kinetic study, all of whom received 200 mg/day for 1 month. No adjunctive psychotropics were allowed aside from benzodiazepines or chloral hydrate for sleep. Over the week after abrupt discontinuation 12 patients experienced mild withdrawal symptoms (agitation, headache, nausea), four had moderate symptoms (nausea, vomiting, diarrhea) and one patient experienced a rapid-onset psychotic episode with manic features requiring hospitalization [ 6 ]. The use of anticholinergics was effective for the mild and moderate symptoms, which were ascribed to cholinergic rebound, although most were not symptom-free until 5–7 days after onset of the withdrawal syndrome. The manic episode was also deemed related to cholinergic rebound, although it did not respond to anticholinergic medications as did somatic symptoms. (NB: Case reports and one clinical trial of the acetylcholinesterase inhibitor donepezil support the cholinergic hypothesis for mania. In a double-blind, placebo-controlled study of adjunctive donepezil for treatment-resistant mania, the donepezil cohort had twofold higher Young Mania Rating Scale scores than the placebo group after 6 weeks: 20.17 ± 3.66 vs. 11.20 ± 4.60 (p = 0.01) [ 7 ]). As has been discussed throughout this handbook, effective management of common adverse effects such as tachycardia, sialorrhea and constipation, and a timely approach to fever presenting in the first 2 months of treatment, can minimize the need to discontinue clozapine treatment, the complex decisions that ensue regarding antipsychotic options, and need to address cholinergic rebound symptoms.

Box 4.1 Cholinergic Rebound Symptoms *

Mild: sleep disturbance, vivid dreams, nightmares
Moderate: anxiety, nausea, diarrhea, sweating, urinary urgency
Severe: confusion, delirium, catatonia

* Comment: By its actions at striatal cholinergic interneurons, cholinergic rebound may also induce parkinsonism, akathisia or dystonia if the patient is being exposed to another source of D ₂ antagonism. In this context the effect of cholinergic rebound can be thought of as “anti-benztropine” [ 15 ].

The Clozapine Handbook

9781108447461

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Foreword

References

Medical Disclaimer

Table of Contents

Foreword

Introduction

Index

List of Contributors

Index

List of Contributors

Introduction