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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,
Northwell Health
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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.
Chapter 1 |
Chapter 9 |
---|---|
The Efficacy Story: Treatment-Resistant Schizophrenia, Psychogenic Polydipsia, Treatment-Intolerant Schizophrenia, Suicidality, Violence, Mania and Parkinson’s Disease Psychosis | Managing Sialorrhea |
Chapter 2 |
Chapter 10 |
Addressing Clozapine Positive Symptom Nonresponse in Schizophrenia Spectrum Patients | Managing Seizure Risk and Stuttering |
Chapter 3 |
Chapter 11 |
Initiating Clozapine | Managing Metabolic Adverse Effects |
Chapter 4 |
Chapter 12 |
Discontinuing Clozapine and Management of Cholinergic Rebound | Fever, Myocarditis, Interstitial Nephritis, DRESS, Serositis and Cardiomyopathy |
Chapter 5 |
Chapter 13 |
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 |
Chapter 6 |
Chapter 14 |
Understanding Hematologic Monitoring and Benign Ethnic Neutropenia | Eosinophilia, Leukocytosis, Thrombocytopenia, Thrombocytosis, Anemia, Hepatic Function Abnormalities |
Chapter 7 |
Chapter 15 |
Managing Constipation Chapter 8 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 |
Stephen Stahl
California Department of State Hospitals, Sacramento, University of California San Diego, California, USA, and University of Cambridge, Cambridge, UK
Jonathan Meyer
Department of Psychiatry, University of California–San Diego, San Diego, California Department of State Hospitals, and Patton State Hospital, California, USA
Managing Sedation, Orthostasis and Tachycardia
In 2016 the United States Food and Drug Administration (FDA) added the category of falls as subsection 5.9 of the Warnings and Precautions listings for all antipsychotic package inserts. This mandated language reflected the concept that changes in blood pressure or alertness may not meet criteria for orthostatic hypotension or sedation as an adverse event during clinical trials, yet together they increase the risk of falling. Increased fall risk, especially among older patients, is one concern related to sedation and orthostasis when starting clozapine, but the other concern is that a patient will find tiredness or dizziness unacceptable when commencing treatment and refuse to continue with clozapine. Using case register data from the South London and Maudsley National Health Service Foundation Trust, it was found that 45% of 316 new clozapine starts from 2007 to 2011 discontinued clozapine within 2 years of initiation [1]. Moreover, 52% of the discontinuations were due to patient decision, and adverse drug reactions were 2.6 times more likely to be the cause than dislike of laboratory visits [1].
While there is a study of rapid clozapine titration for severely ill forensic inpatients [2], and a similar study for treatment-resistant schizophrenia inpatients [3], clinicians must be mindful that many patients may not be under compulsory treatment orders and will opt to terminate a clozapine trial when experiencing adverse effects. Sedation and orthostasis are two commonly encountered issues when starting clozapine that may be exacerbated by rapid dose escalation, so prescribers must be adept at modifying titration schedules and swiftly responding to the occurrence of these side effects in order to maximize patient retention. Tachycardia may at times be due to untreated orthostasis, but is also frequently encountered in those without such problems. Although not a primary focus of patient complaints and easily treated in most instances, it is unfortunately still cited as a cause of treatment discontinuation by clinicians [1], despite expert recommendations that tachycardia should not be a reason to stop clozapine [4]. A recurring theme in this volume is that treatment-resistant schizophrenia spectrum patients have no viable options should clozapine therapy be terminated. Recognizing and managing burdensome adverse effects such as sedation and orthostasis, and appreciating that tachycardia is not a reason to stop clozapine, are all useful concepts in the successful implementation of clozapine therapy.
Sedation must be addressed, as it is the most common adverse drug reaction cited by newly started patients as a reason for treatment discontinuation. Management strategies include administering all or most of the dose at bedtime, slowing the titration, and minimizing other sedating medications.
For minimally symptomatic patients on stable clozapine doses who are still bothered by sedation, consider modest dose reductions if plasma clozapine levels are at the higher end of the therapeutic range (700–1000 ng/ml or 2140–3057 mmol/l).
Adjunctive aripiprazole or modafinil can be considered for sedation when other methods have failed, but the supporting data are weak.
Orthostasis occurs early in treatment and is initially managed by maintaining adequate fluid and salt intake, slowing the titration, minimizing other alpha1-adrenergic antagonists and adjusting doses of antihypertensives. If those steps are not effective, the volume expanding mineralocorticoid fludrocortisone should be used.
Tachycardia is first addressed by ruling out orthostasis. Tachycardia without orthostatic hypotension is never a reason to stop clozapine. When other causes have been eliminated, persistent tachycardia is managed using the selective beta1-adrenergic antagonist atenolol.