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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 Enuresis and Incontinence, Priapism, Venous Thromboembolism, Neuroleptic Malignant Syndrome, Tardive Dyskinesia and Obsessive Compulsive Disorder
Along with metabolic problems, there are a number of other adverse effects not unique to clozapine, but which present unique treatment considerations given the absence of alternatives to clozapine for many patients. An important part of prescribing clozapine is developing patient rapport, and conveying the message that embarrassing adverse effects such as nocturnal enuresis and incontinence can occur in up to 40% of patients, and will be addressed, especially if persistent. Normalizing the experience through education and elucidation of a prior history of such problems is a helpful means of initiating the discussion, and imparting to patients that this is not an unusual issue, and that there are standard approaches to these problems . Nonetheless, direct inquiry is the best method for elucidating complaints about enuresis or incontinence. Large studies of clozapine treatment discontinuation often cite “patient preference” when no specific reason is provided. Given the high prevalence of enuresis early in treatment, and the fact that it may persist in 20% of patients, the absence of this complaint from the literature on clozapine discontinuation suggests a lack of communication with providers [1–3].
Once elicited through patient questioning, nocturnal enuresis and incontinence are generally treatable and should not be causes for treatment discontinuation. Priapism and venous thromboembolism (VTE) represent a more significant challenge, especially as there can be risk of recurrence with significant medical consequences [4,5] The decision to rechallenge patients who have experienced priapism or VTE requires a knowledge of the management options, and a nuanced approach involving assessment of patient decision-making capacity, treatment alternatives for the medical and psychiatric conditions, and the input of caregivers. NMS and TD are much rarer with clozapine than priapism or VTE, and also present less of a management dilemma due to the success with rechallenge in clozapine-related NMS cases , and the availability of multiple evidence-based TD treatments in the form of vesicular monoamine transporter type 2 inhibitors . New-onset obsessive compulsive symptoms can occur rarely with other atypical antipsychotics, but is reported more often with clozapine. This also should not be a reason for treatment discontinuation, although the management can require some mental flexibility on the clinician’s part when the use of selective serotonin reuptake inhibitor (SSRI) antidepressants is precluded by a prior mania history . As with many of the adverse effects discussed in this volume, the ultimate goal is to maintain patients on clozapine when possible, particularly when there are no acceptable therapeutic options to manage resistant psychosis.
Incontinence and enuresis are more common with clozapine than with other antipsychotics in schizophrenia patients, and can occur in up to 40% of patients early in treatment. Approximately 20% report persistent problems with nocturnal enuresis. This adverse effect must be assessed by direct inquiry – patient embarrassment leads to underreporting and underdiagnosis. Different approaches are needed for patients who only experience nocturnal enuresis vs. those who have daytime incontinence.
Priapism is related to inherent patient sensitivity and is reported among many medications with potent alpha1-adrenergic antagonism. This is a medical emergency that requires urgent treatment to prevent tissue necrosis and permanent erectile dysfunction.
Increased risk for venous thromboembolism is not unique to clozapine, and the risk associated with clozapine may not be significantly greater than for other antipsychotics, possibly due to patient factors (e.g. smoking, obesity, inactivity).
The development of neuroleptic malignant syndrome (NMS) is very rare, and generally related to the concurrent use of another potent dopamine D2 antagonist. Clozapine rechallenge has been successful in seven of seven reported cases.
Tardive dyskinesia (TD) is also rare with clozapine and not a reason for treatment discontinuation. Use of newer approved agents for TD is the most evidence-based approach.
New-onset obsessive compulsive symptoms can occur with clozapine. Treatment approach will depend on whether dose reduction is possible, and whether the patient has a prior mania history that precludes use of selective serotonin reuptake inhibitors.