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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Managing Metabolic Adverse Effects

Introduction
Principles
A Monitoring Metabolic Parameters
B Weight Gain
Metformin
Aripiprazole, Bariatric Surgery
C Insulin Resistance and Type 2 Diabetes Mellitus
D Dyslipidemia
E Exercise and Lifestyle Modification
F Smoking
Summary Points
References

Introduction

The primary use of clozapine is for schizophrenia spectrum patients with a history of suicidality or treatment-resistant psychosis. Although clozapine itself imposes significant metabolic burden, this is overlaid on the twofold higher rates of metabolic disorders (type 2 diabetes mellitus, metabolic syndrome) and twofold greater standardized mortality rates for cardiovascular disease in this patient population. Multiple factors contribute to this risk profile including lifestyle (e.g. smoking, dietary habits, sedentary behavior), metabolic effects of medications, and biological aspects of schizophrenia itself detectable in treatment-naive patients [ 1 ]. Given clozapine’s metabolic impact, combined with the reality that patients may remain on clozapine throughout their lives, ongoing management of cardiometabolic risk is integral to the care of clozapine-treated individuals [ 2 ]. Despite this confluence of medication and disease-related risk, the use of clozapine is associated with lower mortality rates from unnatural and natural causes. Investigators compared mortality trends in 14,754 individuals with schizophrenia, schizoaffective disorder or bipolar disorder followed in London from 2007 to 2011. There was a significant association between clozapine use (n = 748) and lower mortality even after controlling for confounders including clinical monitoring and disease severity (adjusted hazard ratio 0.4; 95% CI 0.2–0.7; p = 0.001) [ 3 ]. This adds to prior data from an 11-year Finnish study which showed that clozapine markedly reduces suicide-related mortality, while no pronounced differences for ischemic heart disease mortality were found between antipsychotics [ 4 ].

Principles

Nearly all clozapine-treated patients will manifest one or more metabolic adverse effects, with weight gain occurring very early in treatment.
Given the high prevalence and early onset of weight gain, all patients are candidates for the two evidence-based treatments which must be started when clozapine is commenced: metformin and exercise (including dietary counseling).
Laboratory monitoring of metabolic parameters can be adjusted based on known risks for diabetes. Physical activity must be tracked as a vital sign, along with smoking behavior.
When they occur, diabetes and dyslipidemia are managed with usual medications.
Metabolic adverse effects are generally never a reason to discontinue clozapine.

Nonetheless, substantial changes in cardiovascular risk are seen in long-term studies, and clozapine is considered in the highest risk group among all antipsychotics for weight gain, dyslipidemia and adverse impact on insulin resistance. Naturalistic data for 96 clozapine-treated patients spanning 21 years of follow-up (mean duration of clozapine use 13 years) noted elevated cardiovascular risk during the first 10 years of treatment, although there was a slight decline in risk after the first decade [ 2 ]. This sobering reality drives home the point that management of cardiometabolic issues is inherent to clozapine treatment, and that management strategies must be implemented at the time clozapine is commenced. In addition to the combined impact of the medication and the diagnosis of schizophrenia, many patients will possess one or more nonmodifiable factors that add to risk for weight gain or insulin resistance during clozapine treatment. The principles outlined in Box 11.1 are thus based on the proposition that clozapine itself is a medication with significant metabolic burden, and that nearly 100% of clozapine-exposed patients will manifest one of the common triad of metabolic adverse effects (weight gain, insulin resistance, dyslipidemia). While numerous medications have been tried for clozapine-related obesity and metabolic disturbances (topiramate, sibutramine, phenylpropanolamine, modafinil, atomoxetine, rosiglitazone) these have not demonstrated benefit for patients on clozapine, although there might be positive data for use with other antipsychotics [ 5 ]. Metformin has repeatedly been proven effective for weight gain in numerous double-blind, placebo-controlled trials, and also significantly improves three of the five components of metabolic syndrome: waist circumference, fasting glucose and triglycerides [ 6 ]. As will be discussed below, all patients starting clozapine should be considered candidates for metformin at the outset of clozapine treatment, to which exercise and dietary counseling must be added. The longitudinal management of cardiometabolic risk represents an opportunity to integrate best practices from psychiatry, primary care and psychology into a concerted team effort to promote lifelong healthy behaviors and treat manageable medical conditions with the goal of keeping patients on clozapine and forestalling major cardiovascular events. With the exception of emergencies such as diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic states (HHS), or out of control diabetes during which a temporary cessation of clozapine may be helpful, metabolic adverse effects should not be a reason for discontinuing clozapine treatment, as noted in recent reviews ( Table 11.1 ) [ 7 ].

Box 11.1 Principles in Managing Metabolic Adverse Effects of Clozapine

1. Clozapine is among the highest-risk antipsychotics for metabolic dysfunction. Nearly 100% of clozapine-exposed patients will manifest one of the common triad of metabolic adverse effects (weight gain, insulin resistance, dyslipidemia).
2. Nonmodifiable risk factors also contribute to increased risk for metabolic adverse effects:
- a. Weight gain: younger age, female gender, nonwhite race/ethnicity, family history.
- b. Insulin resistance: schizophrenia diagnosis, nonwhite race/ethnicity, family history.
3. Within the range of doses commonly used for schizophrenia spectrum disorders, there is no evidence of a dose relationship for metabolic disorders. Dose reduction is therefore not a strategy to mitigate or treat these issues.
4. Metformin has the greatest evidence base supporting benefit for weight gain, and should be started concurrently with clozapine.
- a. Metformin is safe for patients with eGFR ≥ 30 ml/min, but use should be reviewed when eGFR falls below 45 ml/min [ 18 ].
- b. Metformin should be started at 500 mg PO qam. Higher initial doses cause gastrointestinal adverse effects (e.g. diarrhea, nausea). Use of extended release forms may improve tolerability.
- c. To reduce side effects metformin should titrated over a 3-week period with 500 mg qam the first week, 500 mg BID or 1000 mg XR qam the second week, and 1000 mg BID or 2000 mg XR qam starting week 3 if tolerated. If 2000 mg/day is not tolerated, try 1500 mg/day (metformin 750 mg BID or 1500 mg metformin XR qam).
- d. For patients with normal eGFR (e.g.≥ 60 ml/min), yearly eGFR is sufficient. When eGFR falls below 60 ml/min, monitor every 3–6 months. When eGFR falls below 45 ml/min the metformin dose should be reduced by 50% and eGFR checked every 3 months. Metformin must be stopped when eGFR is < 30 ml/min.
5. All patients must be enrolled in a structured exercise program that should be maintained indefinitely unless the patient has shown ability to exercise independently.
6. Dietary counseling must be offered to all patients and caregivers starting with the beginning of clozapine therapy.
7. Routine periodic screening as noted in Table 11.3 .
8. Physical activity should be tracked in the same manner as other vital signs ( Table 11.3 )
9. In stable patients, smoking status must be documented routinely and cessation medications and programs offered regularly.

Table 11.1 Metabolic issues and discontinuing clozapine [ 7 ].

Complication	Grounds for discontinuation	Comments
Weight gain	Almost never	Try behavioral approaches, metformin
Hypertension	Almost never	Usual management
Dyslipidemia	Almost never	Usual management, especially agents that lower triglycerides
Metabolic syndrome	Almost never	Treat individual components
Diabetes mellitus	Out of control diabetes	Try usual management first and correct other diabetogenic causes. Generally manageable
Diabetic ketoacidosis or hyperosmolar hyperglycemic state	Acute episode	Hold clozapine during acute episode. Rechallenge after stabilization with tight monitoring

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