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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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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,
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Cambridge University Press is part of the University of Cambridge.
It furthers the University’s mission by disseminating knowledge in the pursuit of education, learning, and research at the highest international levels of excellence.
Information on this title: www.cambridge.org/9781108447461
© Jonathan M. Meyer and Stephen M. Stahl 2020
This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press.
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)
Subjects: | MESH: Clozapine – administration & dosage | Clozapine – therapeutic use | Clozapine – adverse effects | Antipsychotic Agents | Schizophrenia – drug therapy
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.
|The Efficacy Story: Treatment-Resistant Schizophrenia, Psychogenic Polydipsia, Treatment-Intolerant Schizophrenia, Suicidality, Violence, Mania and Parkinson’s Disease Psychosis||Managing Sialorrhea|
|Addressing Clozapine Positive Symptom Nonresponse in Schizophrenia Spectrum Patients||Managing Seizure Risk and Stuttering|
|Initiating Clozapine||Managing Metabolic Adverse Effects|
|Discontinuing Clozapine and Management of Cholinergic Rebound||Fever, Myocarditis, Interstitial Nephritis, DRESS, Serositis and Cardiomyopathy|
|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|
|Understanding Hematologic Monitoring and Benign Ethnic Neutropenia||Eosinophilia, Leukocytosis, Thrombocytopenia, Thrombocytosis, Anemia, Hepatic Function Abnormalities|
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|
California Department of State Hospitals, Sacramento, University of California San Diego, California, USA, and University of Cambridge, Cambridge, UK
Department of Psychiatry, University of California–San Diego, San Diego, California Department of State Hospitals, and Patton State Hospital, California, USA
Managing Metabolic Adverse Effects
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 . 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 . 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) . 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 .
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 . 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 resistanceduring 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 . 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 . 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) .
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 .
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.
|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|