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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
Special Topics: Child and Adolescent Patients, Elderly Patients, Patients With Intellectual Disability, Pregnancy and Risk for Major Congenital Malformation, Lactation, Overdose, Postmortem Redistribution
Clozapine’s effectiveness for treatment-resistant schizophrenia and mania, and its anti-aggressive properties, has led to trials for younger and older patients with severe mental disorders, and for those with intellectual disability (ID) who have treatment-resistant psychosis or nonpsychotic behavioral disorders. There is a paucity of double-blind data supporting some of these uses, but a compelling picture of efficacy based on case series and a small number of clinical trials. The common theme for these patient groups is managing tolerability concerns through adjustment of initial titration, use of plasma clozapine levels, and careful tracking of adverse effects. Pregnant women represent a patient population with a different set of issues; however, recent developments in the literature on major congenital malformations and first-trimester antipsychotic exposure support the conclusion that atypical antipsychotics as a class are not associated with increased risk . This finding is consistent with the available clozapine case data, and thereby allows clinicians to focus their energies on monitoring for maternal gestational diabetes, and minimization of postnatal exposure to avoid excessive sedation in the newborn . Clinicians should be familiar with the risk nomenclature and data on psychotropics during breastfeeding as a matter of routine clinical competence; however, due to risk of neutropenia, clozapine is the only antipsychotic that is absolutely contraindicated in breastfeeding women .
Clozapine is effective for treatment-resistant adolescent and childhood onset schizophrenia. Schizophrenia patients under age 18 may respond to plasma levels below the response thresholds defined for adults (i.e. < 350 ng/ml or < 1070 nmol/l). Lack of efficacy at these lower plasma levels should prompt further titration, assuming no dose-limiting adverse effects.
Initial titration for children and young adolescents is based on body weight and tolerability. Patients under age 18 are more sensitive to weight gain, so prophylactic metformin should be started along with clozapine. Very young patients (age 8–13) started on clozapine may also develop akathisia in a manner not seen with older adolescents or adults.
Clozapine has been used successfully in older schizophrenia patients from ages 65 to 100 years. Slower titrations must be used to minimize the risk of sedation and orthostasis, both of which can result in falls. Older age is not a reason to withdraw clozapine or refuse to commence clozapine in a treatment-resistant schizophrenia patient. With advancing age (i.e. ≥ 70 years of age), patients may require lower doses and maintain psychiatric stability even with plasma clozapine levels below the response threshold of 350 ng/ml or 1070 nmol/l.
For intellectually disabled (ID) adults with treatment-resistant psychosis, clozapine remains the antipsychotic of choice. There are limited data to support use of clozapine to manage aggression and self-injurious behavior in nonpsychotic adult ID patients, mostly derived from case reports. Careful monitoring for adverse effects, especially constipation, is crucial in ID patients, many of whom may lack communication abilities to adequately describe somatic complaints.
According to the latest research, atypical antipsychotics as a class do not increase risk for major congenital malformations. For treatment-resistant patients requiring clozapine, it should be continued throughout pregnancy, but breastfeeding is precluded due to the risk of neutropenia in the infant.
Clozapine shows a biphasic elimination process after overdose. Supportive measures in a monitored hospital setting are needed to manage sedation, orthostasis, tachycardia, myoclonus or seizure issues until plasma levels return to the patient’s therapeutic baseline. Clozapine remains the antipsychotic of choice for schizophrenia patients with a history of suicidality. Overdose is not a reason to discontinue clozapine treatment, but to institute measures (e.g. restricted medication supply) to minimize its recurrence.
Clozapine is highly lipophilic and undergoes extensive postmortem redistribution. Interpretation of postmortem drug levels requires knowledge of the sample source (i.e. central or peripheral), and whether appropriate measures were taken to isolate the peripheral blood vessel from central sources.
Lastly, clozapine is associated with lower rates of self-harm in schizophrenia spectrum patients compared to other antipsychotics, but intentional and unintentional overdose do occur, and at times can lead to fatal outcomes . Kinetic data provide useful guidelines for monitoring patients shortly after the overdose. When clozapine-treated patients expire due to natural or unnatural causes, the accuracy of postmortem drug levels depends on a number of factors including time to postmortem examination and implementation of procedures that minimize “contamination” from central blood sources . An appreciation of the literature on postmortem redistribution of lipophilic molecules such as clozapine, and the preferred methods for obtaining postmortem drug levels, is crucial to anyone involved in such cases as the treating clinician, or as an expert witness.