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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
Eosinophilia, Leukocytosis, Thrombocytopenia, Thrombocytosis, Anemia, Hepatic Function Abnormalities
One need not specialize in hematology to prescribe clozapine, but the concern about neutropenia compels all clinicians to develop expertise with concepts such as benign ethnic neutropenia (BEN), and the dose-dependent impact of divalproex/valproate on neutrophil counts and neutropenia risk. The mandatory monitoring has also revealed a propensity for clozapine to induce other hematological abnormalities including eosinophilia, neutrophilia, abnormal platelet counts, and anemia. This spectrum of hematologic abnormalities is not unique to clozapine, but an analysis of 285 antipsychotic-treated patients found that persistent anemia, neutrophilia and eosinophilia occurred at significantly higher rates compared to other antipsychotics during the first 18 weeks of therapy . A retrospective Canadian study of 1-year hematologic outcomes among 101 new clozapine starts found a cumulative incidence of 48.9% for neutrophilia (> 7500/mm3), 5.9% for eosinophilia (> 1500/mm3), and 3% each for thrombocytosis (> 500,000/mm3) and thrombocytopenia (< 100,000/mm3) . An Italian study of 2404 patients reported a leukocytosis rate of 7.7% using the total WBC threshold of 15,000/mm3 . Most of the aberrations were self-limited and did not necessitate treatment interruption. Anemia may have multiple causes, and one study of 96 new clozapine starts found that 24.5% developed anemia during the first 2 years of treatment, but it was not a cause of treatment discontinuation .
Eosinophilia without evidence of organ involvement is not a reason to permanently discontinue clozapine. When there is no evidence of organ involvement or other systemic reaction to clozapine eosinophilia is self-limited and resolves without need for treatment interruption, unless dictated by local prescribing guidelines.
Exposure to divalproex/valproate is associated with neutropenia (see Chapters 6 and 10), but also thrombocytopenia and rarely anemia. Use of alternate agents is necessary to determine whether clozapine (or another etiology) is the offending medication.
Thrombocytopenia (not due to other causes) and thrombocytosis each occur at rates no higher than 3%. These are usually self-limited processes that resolve without need for treatment interruption unless dictated by local prescribing guidelines. Extremely low (< 50,000/mm3) or high (> 750,000/mm3) platelet counts pose risk for bleeding or thrombosis and will necessitate treatment interruption.
Anemia can be associated with clozapine treatment (once other causes have been ruled out), but is not a reason for treatment discontinuation.
Moderate elevations of transaminases (ALT, AST) > 2 times the upper limit of normal (ULN) not part of a systemic reaction do occur early in clozapine treatment in over 30%. When presenting after longer periods (e.g. months or years), nonalcoholic steatohepatitis due to insulin resistance is the likely etiology.
Patients have been successfully rechallenged after manifesting ALT or AST levels exceeding 3 times ULN but who had no prior evidence of fever or other systemic reaction.
While clozapine is prone to a host of unusual adverse effects, in certain instances the problem relates not to clozapine but to other medical conditions, or to the concurrent use of medications, especially divalproex/valproate. Thrombocytopenia rates during the first 24 weeks of divalproex are 18% when defined as a platelet count < 100,000/mm3, with a significant negative correlation found between valproate levels and platelet counts . Divalproex has direct effects on hematopoiesis and is not uncommonly associated with macrocytosis, but anemia and pure red cell aplasia have also been reported [6,7]. The overarching principle is that for each cell line abnormality there are a small number of considerations to evaluate before hematology or other expertise is required. Moreover, these problems typically develop insidiously and do not require urgent action, permitting time for any necessary work-up or concurrent medication changes. Having a comfort level with the expected rates and course of these hematological abnormalities will allow clinicians to focus their energies on more daunting and persistent problems such as weight gain, sialorrhea, and constipation. Eosinophilia and leukocytosis should not be reasons for discontinuing clozapine treatment. Thrombocytosis and thrombocytopenia may necessitate temporary cessation, but are only rarely grounds for permanently stopping clozapine therapy .
Abnormalities of hepatic function tests present another source of worry for many clinicians, and may be a more prevalent problem for clozapine compared to other antipsychotics. An early prospective trial found that 37.3% of clozapine-treated patients had alanine aminotransferase (ALT) levels more than 2 times the upper limit of normal (ULN) during the first 18 weeks of treatment compared to 16.6% for a haloperidol-treated cohort . As with certain hematological issues this is typically a transient phenomenon: 61% of patients who exhibited an ALT > 2 times ULN at any point in weeks 1–6 of the 18 week study had ALT levels ≤ 2 times ULN during weeks 13–18 . In a manner analogous to the anemia work-up, the time course and severity will help guide appropriate diagnostic testing to evaluate nonmedication-related reasons for changes in liver function tests. Early increases in ALT or aspartate aminotransferase (AST) beyond 3 times ULN may require a pause in clozapine treatment, but in the absence of systemic illness (e.g. drug reaction with eosinophilia and systemic symptoms syndrome [DRESS]), rechallenge with adjusted titration and careful monitoring often allows patients to be successfully resumed on clozapine .