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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
Discontinuing Clozapine and Management of Cholinergic Rebound
The need to discontinue clozapine is a lamentable but medically necessary event in certain circumstances, and at times must be accomplished abruptly. In instances when the patient can be tapered off gradually (e.g. dilated cardiomyopathy), the risk of cholinergic rebound symptoms is lessened and the clinician can focus on making an informed choice about antipsychotic treatment. Although no agent equals clozapine’s efficacy for treatment-resistant schizophrenia, 35% of a group of schizophrenia outpatients with poor antipsychotic response (n = 99) who were considered candidates for clozapine had subtherapeutic plasma levels of their current antipsychotic . Thus, a certain fraction of patients who end up on clozapine were failures due to inadequate dosing of prior antipsychotics, poor adherence or kinetic issues. As will be discussed below, this is an important consideration for patients deemed treatment-resistant but who did not experience adverse effects of prior antipsychotic treatment, particularly those related to D2 antagonism. This understanding may open the door to revisiting prior antipsychotics, but with careful monitoring of adherence and drug exposure via use of plasma levels .
A withdrawal syndrome following abrupt discontinuation of chlorpromazine (including some on concurrent anticholinergic antiparkinsonian medications) was first described in a 1959 study (n = 28). The cluster of symptoms comprised “acute, uncomfortable reactions characterized by tension, fear, restlessness, insomnia, increased perspiration, and vomiting” . For the 17 patients who developed clinically significant withdrawal reactions, three developed symptoms on the second day, nine on the third day, three on the fourth day, and two on the fifth day. The author also noted: “The symptoms had not entirely subsided until two weeks after the sudden withdrawal” . This classic description of cholinergic rebound was not recognized for many years as the product of cholinergic supersensitivity due to the complex pharmacology of chlorpromazine, combined with the prevalent use of anticholinergic antiparkinsonian agents with higher-potency antipsychotics. Twenty years later it finally became clear that the central nervous system (CNS) and systemic symptoms described in 1959 were related to removal of potent muscarinic antagonism, and not the dopaminergic property of the antipsychotic . Lieberman introduced the term “cholinergic rebound” in 1981 to reinforce the concept that this is a phenomenon related to tolerance of and abrupt withdrawal of a muscarinic antagonist, with the severity related to the prior anticholinergic load .
During abrupt discontinuation, management of cholinergic rebound is critical to prevent central nervous system and peripheral adverse effects.
The decision on which antipsychotic to start in lieu of clozapine is based on detailed knowledge of prior response and tolerability.
Previous antipsychotic trials previously deemed treatment failures must be reassessed for evidence of inadequate dosing or nonadherence, especially when there was no documentation of adverse effects related to D2 antagonism.
ECT is an underutilized but effective treatment for schizophrenia and must be considered when pharmacotherapy is inadequate.
Parkinson’s disease psychosis (PDP) patients have limited options. In areas where it is available, pimavanserin is a potent, selective 5HT2A antagonist approved for PDP that lacks any activity at dopamine receptors. Despite weak efficacy data, lack of approved indication, and a twofold increase in mortality rates, the weak D2 antagonist quetiapine is commonly used.
Clozapine possesses over sevenfold higher affinity for the muscarinic M1 receptor than does chlorpromazine, and by 1974 early reports of a clozapine withdrawal syndrome were alluded to; however, not until wider commercial release in 1989 was the problem recognized, with five case reports emerging by 1994. In 1996 a dedicated study of clozapine withdrawal symptoms was performed in 28 clozapine-treated inpatients enrolled in a kinetic study, all of whom received 200 mg/day for 1 month. No adjunctive psychotropics were allowed aside from benzodiazepines or chloral hydrate for sleep. Over the week after abrupt discontinuation 12 patients experienced mild withdrawal symptoms (agitation, headache, nausea), four had moderate symptoms (nausea, vomiting, diarrhea) and one patient experienced a rapid-onset psychotic episode with manic features requiring hospitalization . The use of anticholinergics was effective for the mild and moderate symptoms, which were ascribed to cholinergic rebound, although most were not symptom-free until 5–7 days after onset of the withdrawal syndrome. The manic episode was also deemed related to cholinergic rebound, although it did not respond to anticholinergic medications as did somatic symptoms. (NB: Case reports and one clinical trial of the acetylcholinesterase inhibitor donepezil support the cholinergic hypothesis for mania. In a double-blind, placebo-controlled study of adjunctive donepezil for treatment-resistant mania, the donepezil cohort had twofold higher Young Mania Rating Scale scores than the placebo group after 6 weeks: 20.17 ± 3.66 vs. 11.20 ± 4.60 (p = 0.01) ). As has been discussed throughout this handbook, effective management of common adverse effects such as tachycardia, sialorrhea and constipation, and a timely approach to fever presenting in the first 2 months of treatment, can minimize the need to discontinue clozapine treatment, the complex decisions that ensue regarding antipsychotic options, and need to address cholinergic rebound symptoms.
Mild: sleep disturbance, vivid dreams, nightmares
Moderate: anxiety, nausea, diarrhea, sweating, urinary urgency
Severe: confusion, delirium, catatonia
* Comment: By its actions at striatal cholinergic interneurons, cholinergic rebound may also induce parkinsonism, akathisia or dystonia if the patient is being exposed to another source of D2 antagonism. In this context the effect of cholinergic rebound can be thought of as “anti-benztropine” .