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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
Sialorrhea may be the most common adverse effect of clozapine treatment, with prevalence estimates ranging from 30% to 90%, yet it is often underreported, underrecognized, and undertreated, leading to treatment dissatisfaction and discontinuation, social consequences, and possible medical morbidity in the form of aspiration events. Recent data indicate that the prevalence is likely closer to the 90% figure based on a detailed 2016 study of 98 clozapine-treated patients who were assessed for hypersalivation using two rating scales: the Nocturnal Hypersalivation Rating Scale and the Drooling Severity and Frequency Scale . Sialorrhea was experienced by 92% of subjects overall, more commonly at night (85% of subjects) than in the daytime (48%). Daytime symptoms were severe in 18%, and sialorrhea was considered frequent or occurring on a constant basis in 20%. Importantly, sialorrhea had at least a moderate impact on the quality of life in 15% of study subjects. While many studies of clozapine discontinuation focus on physician determined medical concerns, sialorrhea emerges as the third most common adverse drug reaction cited by patients as a reason for discontinuing treatment, behind sedation and nausea . Importantly, sialorrhea during clozapine therapy has been associated with reports of aspiration pneumonia . The extent of pneumonia risk from clozapine treatment has been quantified in three studies, with rates 1.99–3.18 times higher in clozapine-treated patients compared with other antipsychotics . Supporting this concept is the finding that pulmonary illness was the most common cause (32%) of medically related hospital admissions for clozapine-treated patients at one major US medical center, of which 58% were for pneumonia . Lastly, parotitis has also been reported and associated with hypersalivation .
A highly prevalent problem that causes social embarrassment, increases risk for treatment discontinuation, and may result in medical complications (e.g. aspiration pneumonia).
Locally applied therapies must be tried first, as use of systemic anticholinergic medications will double the risk for ileus. Atropine 1% drops sublingually or ipratropium 0.06% spray intraorally are first-line agents.
When patients fail first-line therapy, botulinum toxin-B injections into salivary glands is the preferred second-line therapy due to extensive double-blind, placebo-controlled trial data for sialorrhea due to medications or neurological causes.
If botulinum toxin-B injections are not effective, other nonanticholinergic options to consider include alpha-adrenergic modulators (e.g. clonidine) and possibly amisulpride.
A systemic anticholinergic medication should be considered the treatment of last resort due to the increased risk for ileus, and for fatal ileus. If a systemic anticholinergic must be used, glycopyrrolate is the preferred medication due to limited CNS penetration. The addition of glycopyrrolate must be accompanied by vigilant tracking of constipation, and aggressive management of gastrointestinal hypomotility should it occur.
Unfortunately, clinicians are forced to confront this problem with a virtual absence of well-designed clinical trials that focus specifically on clozapine and sialorrhea. The 2008 Cochrane review on clozapine-induced hypersalivation lamented: “The quality of reporting was poor with no studies clearly describing allocation concealment and much data were missing or unusable.” They concluded: “There are currently insufficient data to confidently inform clinical practice. The limitations of these studies are plentiful and the risk of bias is high” . Nonetheless, there are some insights and treatment principles that can be gleaned from these studies. Importantly, sialorrhea is not unique to clozapine treatment, and is seen in an array of neurological disorders (i.e. cerebral palsy, Parkinson’s disease), or secondary to medications such as acetylcholinesterase inhibitors [7,8]. Fortunately, there are a large number of randomized, double-blind, placebo-controlled trials in this literature, including six studies alone utilizing botulinum toxin-B . As the pathophysiology of hypersalivation during clozapine treatment is not distinct from other common etiologies, one can use this larger body of data from sialorrhea treatment studies to devise rational strategies for managing this vexing issue during clozapine therapy.