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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
The decision to start clozapine therapy derives from the accepted, evidence-based uses for this medication including treatment-resistant schizophrenia spectrum disorders, schizophrenia patients with a history of suicidality, schizophrenia spectrum patients with persistent aggression, treatment-resistant mania, and psychosis associated with Parkinson’s disease (see Chapter 1). As was discussed in Chapter 1, the greatest conundrum in determining whether a schizophrenia patient is truly resistant to other treatment is high rates of nonadherence, with subtherapeutic plasma antipsychotic levels seen in 35–44% of outpatients deemed to have treatment-resistant illness . Once a patient is a candidate based on clinical criteria, patients and caregivers must be educated about the unique benefits of clozapine, its common adverse effects, and the demands of monitoring. With many outpatients this is a conversation that is often performed over an extended period as patients try and fail other options and come to trust the clinician’s suggestion that the benefits of clozapine outweigh the burdens of treatment. An important principle to guide these discussions is that significant delays in starting clozapine may reduce the likelihood of response in treatment-resistant schizophrenia. A review of response rates among 90 patients who remained on clozapine for at least 3 months found that the response rate was 82% for those who started clozapine within 2.8 years of meeting clinical criteria for treatment resistance, but fell to 31% when clozapine was started > 2.8 years after reaching this benchmark .
The work-up is limited to common labs, EKG, and usually a physical examination
Evaluation of QT intervals requires the appropriate heart rate correction formula
Registration of clozapine with the appropriate system for each country is required
Titration of clozapine is geared towards the indication (e.g. schizophrenia, Parkinson’s disease psychosis, etc.), acuity, age, the treatment setting (inpatient vs. outpatient), concurrent medications, and the presence of variables that influence clozapine disposition (e.g. smoking, use of cytochrome P450 inhibitors or inducers, functional cytochrome P450 polymorphisms)
At times clozapine is started in an inpatient setting; if so, enlisting the support of outpatient caregivers is crucial to treatment success, as they too will share the burdens of monitoring and treatment. The alacrity with which a caregiver can alert clinicians about adverse effects, and the caregiver’s ability to convincingly reassure a patient that clozapine’s benefits outweigh its burdens, may forestall unnecessary treatment termination. For certain outpatients, difficulties encountered in traveling may be the biggest barrier to treatment, but highly motivated caregivers may work with clinic personnel to troubleshoot these obstacles and devise strategies to facilitate transporting a patient to necessary laboratory and clinic appointments. Even with compulsory inpatient treatment, a discussion is critical to inform the patient about the reason clozapine is being utilized (e.g. persistent aggression despite high plasma levels of standard antipsychotics), the goals of treatment, and the frequency of monitoring. As with outpatient caregivers, educated hospital personnel will also be more motivated to work with resistant patients in obtaining laboratory measures with the understanding that clozapine is the best option to bring symptomatic relief or reduce violent behavior .