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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
Fever, Myocarditis, Interstitial Nephritis, DRESS, Serositis and Cardiomyopathy
Managing clozapine-treated patients requires clinicians to become familiar with specific medical concerns not typically seen with other antipsychotics. Among the many unique adverse events associated with clozapine treatment is a constellation of fever and immune-mediated pathologies including myocarditis, interstitial nephritis, serositis and drug reaction with eosinophilia and systemic symptoms (DRESS) . While the onset of fever during the first weeks of clozapine treatment is a common and often benign occurrence, swift action is necessary with the goal of recognizing and addressing more serious issues or minimizing a treatment interruption when evidence for systemic problems is lacking. The latter concept is important, as fever during the first weeks of therapy may appear in approximately 20% of patients, and therefore is not a reason to permanently discontinue clozapine treatment when there is no evidence for myocarditis, interstitial nephritis, or other systemic drug reactions. Cardiomyopathy is another unusual clozapine-related syndrome that is typically a later development, but presents a distinct group of clinical and ethical challenges when clozapine withdrawal fails to induce meaningful improvements in left ventricular ejection fraction (LVEF). Through a greater understanding of the time course and phenomenology of fever, myocarditis, interstitial nephritis, serositis, DRESS and cardiomyopathy clinicians can make evidence-based decisions about withholding clozapine treatment, and when resumption or rechallenge appears feasible.
Onset of fever occurs in 20% of patients during the first 8 weeks of treatment, and commonly occurs without evidence of drug reaction, interstitial nephritis or myocarditis. In addition to routine fever work-up, troponin I/T levels, C-reactive protein (CRP), BUN/creatinine and urinalysis will help rule out myocarditis and interstitial nephritis. Benign fever is not a reason to permanently discontinue clozapine treatment, although it may be held temporarily during the fever work-up.
Myocarditis occurs in up to 3.0% of patients, but is fatal if not recognized and clozapine discontinued. Onset is during the first 6 weeks (with rare exceptions), and should be considered in a patient experiencing fever without cause, or when a patient complains of malaise or flu-like symptoms, (particularly chest pain) without fever. Twenty per cent of cases may not experience fever.
The troponin I/T level will be more than two times the upper limit of normal in over 90% of myocarditis cases. However, 7% of cases with left ventricular impairment by echocardiography will not have abnormal troponin levels, but will have CRP > 100 mg/l. Both troponin and CRP should be ordered when myocarditis is suspected. Other laboratory tests (e.g. eosinophil count) and ECG are less sensitive and less specific.
Interstitial nephritis, serositis and drug reaction with eosinophilia and systemic symptoms (DRESS) are less common than myocarditis, but should also be suspected during the first 60 days of clozapine treatment when fever occurs without cause, or in patients reporting malaise or flu-like symptoms.
Cardiomyopathy is an adverse effect occurring after many months or years of clozapine treatment. It should be suspected when patients complain of feeling tired (without recent medication changes), leg swelling, palpitations or shortness of breath.