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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
Managing Seizure Risk and Stuttering
Unlike the complexity of addressing metabolic adverse effects, seizure management is extremely successful to the extent that recent reviews comment that it should never be a reason to discontinue clozapine treatment . Evidence suggests that psychiatric providers may have adopted this position, as case data on 316 new clozapine starts from 2007 to 2011 at the South London and Maudsley National Health Service Foundation Trust did not list seizures among reasons for clozapine cessation, although 20 other forms of adverse drug reactions were cited . Seizures are not unique to clozapine, and antipsychotic package insert warnings in the United States consider this a class effect, although the mechanisms for this common property remain unknown. Recent reviews note rates ranging from 0.2% to 0.5% with other antipsychotics, and a 9% incidence with high-dose chlorpromazine (≥ 1000 mg/day) . Experience during clinical trials led Novartis to include the following package insert warning:
Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizures in 61 of 1743 patients exposed to clozapine during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%). The risk of seizure is dose related.
The first large data set covering 1481 clozapine-treated patients was published in 1991, and reported a seizure rate of 2.8% . The data also indicated a dose-dependent relationship, with a rate of 1.0% at doses < 300 mg/day, 2.7% for 300–599 mg/day, and 4.4% at doses ≥ 600 mg/day . Although the incidence in this group was 2.8%, the authors estimated the cumulative risk as high as 10% at 3.8 years. However, a subsequent 1994 analysis by these same authors of 5629 patients found only 71 cases of tonic–clonic seizures, or a rate of 1.3% . Of relevance to the debate about dose and seizure risk, the 1994 review noted that seizures tended to occur in two patterns: at low doses (< 300 mg/day) during the titration phase, and at high doses (≥ 600 mg/day) during the maintenance phase . The only other risk was a prior history of seizures or epilepsy, with seizures in those patients often occurring early in treatment at low doses. Of those who were rechallenged, 78.3% continued on clozapine.
Seizures are not uncommon but easily managed in most patients. It should never be a reason to discontinue clozapine treatment.
Routine EEG screening is not warranted due to the high prevalence of minor findings, and should not be used in asymptomatic patients. Seizure treatment is based on clinically evident seizure activity.
The relationship between dose (or plasma level) and seizure induction is not clear as some develop seizures during the early titration at low doses.
Seizures often occur shortly after a dose increase or a jump in plasma level due to addition of a cytochrome P450 inhibitor, or removal of an inducer (e.g. smoking cessation). Patients who have tolerated stable high levels for months without seizure activity do not require additional measures.
New-onset stuttering has been observed rarely during titration or after dose increases and is hypothesized to be related to subclinical epileptiform activity. Dose reduction and slower retitration resolve the problem.
Due to the low prevalence of seizures, prophylactic anticonvulsants should not be used as these will be unnecessary in > 90% of patients.
When an anticonvulsant is needed, divalproex is the medication of choice as it best covers the spectrum of tonic–clonic and myoclonic events and has modest kinetic interactions with clozapine.
Although the 1994 postmarketing incidence of 1.3% is closer to that seen with other antipsychotics, subsequent case series with variable periods of exposures reported incidence rates as high as 22% . Given the greater scrutiny with clozapine treatment, and the lack of systematic tracking for other antipsychotics, the true incidence and the magnitude of risk difference compared to other antipsychotics may never be known. As noted in Box 10.1, this is one of several unresolved issues with regards to the association between clozapine treatment and seizure induction.
1. What is the relative risk of seizures for clozapine-treated patients compared to those on other antipsychotics?
2. Does rapid titration increase seizure risk?
3. Is there a well-defined dose (and plasma level) threshold for increased seizure risk?
A 2015 paper neatly sums up the issues after an extensive review of the relevant literature:
Clinically, most practitioners have adopted a theoretical maximum of 600 mg/day, but the literature presents several cases of seizures occurring at lower doses. The same controversies and uncertainties exist for the ability to predict increased risk of seizure using clozapine serum concentrations. The utility of clozapine serum concentration for the purpose of seizure prevention is debated within the literature, mainly because of the lack of a well-established concentration threshold. It would be a safe assumption that seizure is more likely at higher concentrations (i.e. > 1000 ng/ml or > 3057 nmol/l), but similar to total oral dose, seizures still occur at lower concentrations (i.e. < 300 ng/ml or < 900 nmol/l). Based on conflicting evidence, clozapine-induced seizures are not solely based on total dose or serum concentration. 
While this lack of certainty may appear daunting, the unclear relationship between many of these variables and the appearance of clinically evident seizures implies that the titration of clozapine should be made primarily with regards to the usual tolerability concerns including orthostasis and sedation. Moreover, the absence of a well-defined plasma-level relationship supports the use of clozapine at levels up to 1000 ng/ml or 3057 nmol/l if lower levels are tolerated and there is a need for greater efficacy (see Table 5.8) .
1. Due to the absence of a clear relationship between seizure induction and the rapidity of titration or dose, early dose adjustments should be based on other tolerability concerns (e.g. orthostasis, sedation).
2. Electroencephalographic (EEG) abnormalities without clinical seizure activity are not uncommon in clozapine-treated patients. Routine EEG monitoring is not recommended and should be performed only when clinically evident actions raise the suspicion of a seizure.
3. Patients in need of greater efficacy should not be deprived of clozapine treatment with levels as high as 1000 ng/ml or 3057 nmol/l due to concerns about seizures.
4. Divalproex is the anticonvulsant of choice for clozapine-related tonic–clonic, myoclonic or atonic seizures. Due to the risks of divalproex treatment (e.g. neutropenia, thrombocytopenia, weight gain, hyperammonemia), and the low incidence of clozapine-related seizures even at higher plasma clozapine levels, patients should not be placed on routine prophylactic anticonvulsant therapy.
5. Seizures often occur after a recent dose increase (e.g. titration phase) or an increased plasma level due to kinetic factors (addition of a CYP P450 inhibitor, removal of a CYP 450 inducer, smoking cessation). Patients who tolerate high levels without seizure activity do not require additional measures.
6. If a seizure occurs:
a. Scenario 1: After a dose adjustment or due to mitigating kinetic factors. Obtain a plasma clozapine level (ideally as a 12-hour trough), hold clozapine for 24 hours, and reduce back to the prior tolerated clozapine dose (if after a dose increase), or adjust the dose based on the expected kinetic effect. (See Chapter 5 for discussion of kinetic effects of various CYP 450 inhibitors and smoking cessation.) Recheck the plasma clozapine level at steady state. Presumably the patient will remain seizure-free at a plasma level previously tolerated. If a second seizure occurs, or higher plasma levels are anticipated due to the need for further titration, add divalproex.
b. Scenario 2: No recent dose adjustment or known kinetic factors. Obtain a plasma clozapine level (ideally as a 12-hour trough), check renal and hepatic function, look at medication history, hold clozapine for 24 hours and reduce the dose by 25%. If no cause can be found (e.g. benzodiazepine or alcohol withdrawal), and the plasma level is consistent with prior stable levels, add divalproex. If levels are > 30% above prior stable levels, adjust the clozapine dose, and recheck the plasma clozapine level at steady state. Presumably the patient will remain seizure-free at a plasma level previously tolerated. If a second seizure occurs, add divalproex.