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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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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 Efficacy Story: Treatment-Resistant Schizophrenia, Psychogenic Polydipsia, Treatment-Intolerant Schizophrenia, Suicidality, Violence, Mania and Parkinson’s Disease Psychosis
The 60th anniversary of clozapine’s synthesis by Schmutz and Eichenberger at Wander Pharmaceuticals was celebrated in 2018, although the chemists involved hoped that their tricyclic compound HF-1854 would possess antidepressant effects [ 1 ]. In January 1961, the first pharmacological report on HF-1854 described an agent with sedative and antiadrenergic properties that resembled chlorpromazine, but which did not induce catalepsy [ 1 ]. Further animal testing reported in December 1961 established a range of activities comparable to chlorpromazine but without the catalepsy induction seen with haloperidol. In 1962 the first open clinical trial of HF-1854 found limited efficacy at the dose of 160 mg TID (n = 19), but later that year Gross and Langer in Vienna found good results in 21 of 28 patients at similar dosing, again without neurological adverse effects [ 2 ]. Further trial reports to Wander Pharmaceuticals in 1966 by Hippius in Berlin and Engelmeier in Vienna indicated that this was an effective but sedating antipsychotic that appeared free of neurological side effects. Wander completed further toxicological assays in 1967 and embarked on multiple clinical trials resulting in product registration in 1971, and marketing the following year under the trade name Leponex [ 1 ]. A spate of severe neutropenia cases from Finland in 1975 led to clozapine’s withdrawal from the market in most countries, although it was available under humanitarian programs with hematological monitoring [ 3 ].
Clozapine is the only effective antipsychotic for treatment-resistant schizophrenia. When treatment resistance is rigorously defined using all three Kane criteria, the response rate to most antipsychotics is < 5%, and for olanzapine 7%.
Delaying clozapine initiation beyond 3 years after illness onset significantly reduces the likelihood of response.
Compared to other antipsychotics, real-world data indicate that clozapine-treated patients have lower rehospitalization rates, and decreased mortality from all causes (natural and unnatural).
Clozapine is uniquely effective in schizophrenia patients with psychogenic polydipsia.
Clozapine is effective for schizophrenia patients with suicidality on the basis of a large clinical trial vs. olanzapine. Clozapine has an approved indication for this purpose in the US.
Clozapine’s impact on suicidality and aggression is independent of the antipsychotic effect.
Clozapine has proven efficacy in treatment-resistant mania when used adjunctively with mood-stabilizing medications, and is effective in nonpsychotic bipolar patients.
Prior to the development of pimavanserin, clozapine was the antipsychotic with the strongest evidence for efficacy and tolerability in Parkinson’s disease psychosis.
Three double-blind studies comparing clozapine to other antipsychotics were published in the 1970s and 1980s based on perceived benefit in those who did not respond to other agents, or improved tolerability in patients with a history of severe intolerance to D 2 antagonism (i.e. akathisia, parkinsonism, tardive dyskinesia (TD) or neuroleptic malignant syndrome (NMS)). While clozapine was clearly better tolerated and more effective than chlorpromazine among those with a history of D 2 sensitivity [ 4 ], the two large efficacy trials used modest dosages of the comparator antipsychotics (chlorpromazine 360 mg/day, haloperidol 7.6 mg/day), raising doubts about clozapine’s greater effectiveness [ 5 ]. The latter question was definitively settled with publication of the pivotal clozapine trial for treatment-resistant schizophrenia in 1988, using criteria elaborated by Dr. John Kane for this purpose [ 6 ]. A crucial element of the trial design was the third criterion for treatment resistance: demonstrating in a prospective manner failure to respond to high levels of D 2 antagonism. Fewer than 2% of patients met response criteria in the prospective haloperidol arm of the Kane study (mean dose 61 mg/day), while 80% were nonresponders and 18% intolerant of high-dose haloperidol. Using only those schizophrenia patients who met all three of the treatment-resistance criteria (n = 268), response rates in the short (6-week) double-blind, randomized trial were 4% for the chlorpromazine arm vs. 30% for the clozapine group [ 6 ]. Additional experience over the next decade combined with insights regarding therapeutic plasma levels has increased the expected clozapine response rate to at least 40% in longer-term studies, with values up to 60% reported [ 7 ]. Clozapine has also demonstrated efficacy in schizophrenia patients with psychogenic polydipsia, an effect seen with doses as low as 300 mg/day [ 8 ].
1. At least three periods of treatment in the preceding 5 years with antipsychotics (from at least two different chemical classes) at dosages equivalent to or greater than 1000 mg/day of chlorpromazine for a period of 6 weeks, each without significant symptomatic relief.
2. No period of good functioning within the preceding 5 years.
3. Failure to respond to a prospective high-dose trial of a typical antipsychotic (haloperidol at doses up to 60 mg/day or higher administered with benztropine 6 mg/day). Response was defined as a 20% decrease in the Brief Psychiatric Rating Scale (BPRS) total score plus either a post-treatment Clinical Global Impression (CGI) severity rating of mildly ill (≤ 3) or a post-treatment BPRS score≤ 35.
The unique benefits of clozapine extend beyond treatment-resistant schizophrenia and include a number of other uses, many of which are supported by rigorous double-blind, placebo or active comparator trials. In some instances, the value of clozapine lies in its low affinity for D 2 receptors, thus permitting treatment of schizophrenia patients intolerant of D 2 antagonism, or Parkinson’s disease psychosis (PDP) patients. For other applications, the underlying mechanism for clozapine’s effectiveness is unknown, but it appears independent of the antipsychotic effect when employed for treatment-resistant mania, in schizophrenia patients with persistent aggression, and in schizophrenia patients with a history of suicidality. By mastering the details of hematologic monitoring and management of adverse effects, clinicians have a range of evidence-based uses for clozapine in difficult-to-treat patient groups.