The Clozapine Handbook Stahl's Handbooks - 1st Edition

The Clozapine Handbook
The Clozapine Handbook

Stahl’s Handbooks
Jonathan M. Meyer
University of California, San Diego
Stephen M. Stahl
University of California, San Diego
With illustrations by
Nancy Muntner
Neuroscience Education Institute
University Printing House, Cambridge CB2 8BS, United Kingdom
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Information on this title: www.cambridge.org/9781108447461
DOI: 10.1017/9781108553575
© Jonathan M. Meyer and Stephen M. Stahl 2020
This publication is in copyright. Subject to statutory exception and to the provisions of relevant
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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.
Jonathan M. Meyer, M.D. is a Clinical Professor of Psychiatry at
the University of California San Diego, and a Psychopharmacology
Consultant to the California Department of State Hospitals. Over the
past 36 months Dr. Meyer reports having served as a consultant to
Acadia Pharmaceuticals, Alkermes, Allergan, Intra-Cellular Therapies,
Merck, Neurocrine and Teva Pharmaceutical Industries; he has served
on the speakers bureaus for Acadia Pharmaceuticals, Alkermes,
Allergan, Intra-Cellular Therapies, Merck, Neurocrine, Otsuka America,
Inc., Sunovion Pharmaceuticals and Teva Pharmaceutical Industries.
Stephen M. Stahl, M.D., PhD, Dsc (Hon.) is an Adjunct Professor of
Psychiatry at the University of California San Diego, Honorary Visiting
Senior Fellow at the University of Cambridge, UK and Director of
Psychopharmacology for California Department of State Hospitals.
Over the past 36 months (January 2016 – December 2018) Dr. Stahl
has served as a consultant to Acadia, Adamas, Alkermes, Allergan,
Arbor Pharmaceutcials, AstraZeneca, Avanir, Axovant, Axsome, Biogen,
Biomarin, Biopharma, Celgene, Concert, ClearView, DepoMed, Dey,
EnVivo, EMD Serono, Ferring, Forest, Forum, Genomind, Innovative
Science Solutions, Intra-Cellular Therapies, Janssen, Jazz, Lilly,
Lundbeck, Merck, Neos, Novartis, Noveida, Orexigen, Otsuka,
PamLabs, Perrigo, Pfizer, Pierre Fabre, Reviva, Servier, Shire, Sprout,
Sunovion, Taisho, Takeda, Taliaz, Teva, Tonix, Trius, Vanda, Vertex
and Viforpharma; he has been a board member of RCT Logic and
Genomind; he has served on speakers bureaus for Acadia, Astra
Zeneca, Dey Pharma, EnVivo, Eli Lilly, Forum, Genentech, Janssen,
Lundbeck, Merck, Otsuka, PamLabs, Pfizer Israel, Servier, Sunovion
and Takeda and he has received research and/or grant support
from Acadia, Alkermes, AssureX, Astra Zeneca, Arbor Pharmaceuticals,
Avanir, Axovant, Biogen, Braeburn Pharmaceuticals, BristolMyer
Squibb, Celgene, CeNeRx, Cephalon, Dey, Eli Lilly, EnVivo, Forest,
Forum, GenOmind, Glaxo Smith Kline, Intra-Cellular Therapies,
ISSWSH, Janssen, JayMac, Jazz, Lundbeck, Merck, Mylan, Neurocrine,
Neuronetics, Novartis, Otsuka, PamLabs, Pfizer, Reviva, Roche,
Sepracor, Servier, Shire, Sprout, Sunovion, TMS NeuroHealth Centers,
Takeda, Teva, Tonix, Vanda, Valeant and Wyeth
All illustrations by Nancy Muntner provided by permission of

Neuroscience Education Institute.
Co nt en t s
Foreword ix
Introduction 1
1. The Efficacy Story: Treatment-Resistant
Schizophrenia, Psychogenic Polydipsia, Treatment-
Intolerant Schizophrenia, Suicidality, Violence,
Mania and Parkinson’s Disease Psychosis 10
2. Addressing Clozapine Positive Symptom
Nonresponse in Schizophrenia Spectrum Patients 44
3. Initiating Clozapine 60
4. Discontinuing Clozapine and Management of
Cholinergic Rebound 78
5. Binding Profile, Metabolism, Kinetics, Drug
Interactions and Use of Plasma Levels 90
6. Understanding Hematologic Monitoring and Benign
Ethnic Neutropenia 114
7. Managing Constipation 140
8. Managing Sedation, Orthostasis and Tachycardia 158
9. Managing Sialorrhea 172
10. Managing Seizure Risk and Stuttering 190
11. Managing Metabolic Adverse Effects 204
vii
Contents
12. Fever, Myocarditis, Interstitial Nephritis, DRESS,

Serositis and Cardiomyopathy 224
13. Managing Enuresis and Incontinence, Priapism,
Venous Thromboembolism, Neuroleptic Malignant
Syndrome, Tardive Dyskinesia and Obsessive
Compulsive Disorder 242
14. Eosinophilia, Leukocytosis, Thrombocytopenia,
Thrombocytosis, Anemia, Hepatic Function
Abnormalities 258
15. Special Topics: Child and Adolescent Patients,
Elderly Patients, Patients with Intellectual Disability,
Pregnancy and Risk for Major Congenital
Malformation, Lactation, Overdose, Postmortem
Redistribution 276
Index 307
viii
Fo re w ord
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
ix
F o r e w or d
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
x
F o re w ord
References
1. Kane, J., Honigfeld, G., Singer, J., et al. (1988). Clozapine for the treatment-resistant
schizophrenic. A double-blind comparison with chlorpromazine. Archives of General Psychiatry, 45,
789–796.
2. Meltzer, H. Y., Alphs, L., Green, A. I., et al. (2003). Clozapine treatment for suicidality in
schizophrenia: International Suicide Prevention Trial (InterSePT). Archives of General Psychiatry, 60,
82–91.
3. Krakowski, M. I., Czobor, P., Citrome, L., et al. (2006). Atypical antipsychotic agents in the
treatment of violent patients with schizophrenia and schizoaffective disorder. Archives of General
Psychiatry, 63, 622–629.
4. Nielsen, J., Dahm, M., Lublin, H., et al. (2010). Psychiatrists’ attitude towards and knowledge of
clozapine treatment. Journal of Psychopharmacology, 24, 965–971.
5. Cohen, D. (2014). Prescribers fear as a major side-effect of clozapine. Acta Psychiatrica
Scandinavica, 130, 154–155.
xxii
Introduction
The year 2018 marked the 60th anniversary of clozapine’s synthesis, and the 30th
anniversary of the September 1988 Archives of General Psychiatry paper by Kane
and colleagues documenting clozapine’s superior efficacy in treatment-resistant
schizophrenia [1]. The peer view literature since 1988 demonstrates ongoing interest
in clozapine, with 350–450 papers per year listed in PubMed (see Figure 1). The
ensuing decades have also seen other evidence-based uses for clozapine (e.g.
schizophrenia patients with suicidality or aggression, Parkinson’s disease psychosis,
treatment-resistant mania), but treatment-resistant schizophrenia spectrum disorders
remain the most common indication. Lamentably, clozapine remains significantly
underutilized for treatment-resistant schizophrenia despite compelling evidence of
efficacy in this population, and the enormous individual and societal benefits that can
accrue from effective management of treatment-resistant patients [2].
To fully appreciate the economic impact of treatment-resistant schizophrenia,
one must understand the enormity of the disease burden exacted by schizophrenia.
Schizophrenia prevalence remains low, with the global estimate of 0.28% remaining
unchanged from 1990 to 2016. The 2016 age distribution of disease also mirrored
that in 1990, but the total number of cases rose nearly 60% due to population
increases (see Figure 2 and Table 1). There are now close to 21 million persons
worldwide with schizophrenia, most of whom require extensive supportive resources.
A 2012 meta-analysis indicated that only 13.5% of schizophrenia patients meet
criteria for functional recovery; moreover, in addition to lengthy periods of disability,
schizophrenia patients suffer premature mortality due to natural and unnatural causes
[3]. The World Health Organization (WHO) quantifies the dual impact of disorders using
the outcome of disability-adjusted life year, a measure that sums the years lived with
disability and those lost due to early mortality. Schizophrenia ranked twelfth overall
among 310 conditions (i.e. diseases or injuries) studied in the WHO Global Burden of
Disease Study 2016, and acute schizophrenia carried the highest disability weight
1
INTRODUCTION
Figure 1. Clozapine-related publications in PubMed (1970–2017).

500
450
400
350
300
250
200
150
100
50
0
1970 1975 1980 1985 1990 1995 2000 2005 2010 2015
among all disorders [3,4]. Despite its low global prevalence of 0.28%, schizophrenia
contributed 13.4 million years of life lost due to disability in 2016. This represented
1.7% of the total in the 2016 WHO study, a value sixfold greater than the prevalence of
schizophrenia. For the United States (US) alone, the combination of direct health care
costs, direct nonhealth-care costs (law enforcement, homeless shelters, health-care
training and research) and indirect costs (productivity loss from disability, premature
mortality, caregiving) was estimated at $155.7 billion for 2013 [5]. The largest
components were excess costs associated with unemployment (38%), productivity
loss due to caregiving (34%) and direct health-care costs (24%).
Treatment-resistant schizophrenia patients are but a fraction of the schizophrenia
population, yet they exert an outsized influence on the costs associated with this
disorder. While there is active debate about the definition of treatment resistance for
clinical and research purposes, an estimated 20–30% of schizophrenia patients fail
to adequately respond to two or more documented antipsychotic trials of sufficient
dosage and duration [6,7]. A 2014 review on the social and economic burden of
treatment-resistant schizophrenia found 65 papers published from 1996 to 2012 to
provide data for relative cost estimates [6]. Based on this extensive literature review,
annual costs for patients with schizophrenia in the US were three- to 11-fold higher
2
IN T R O D U C T IO N
for those who were treatment-resistant, with hospitalization costs and total health-
resource utilization 10-fold higher among this cohort than for schizophrenia patients in
general (see Figure 3). The authors concluded that treatment-resistant schizophrenia
Figure 2. Mean schizophrenia prevalence by age in 2016.

0.70%
0.60%
0.50%
Prevalence
0.40%
0.30%
0.20%
0.10%
0.00%
<1
1–4
5–9
10–14
15–19
20–24
25–29
30–34
35–39
40–44
45–49
50–54
55–59
60–64
65–69
70–74
75–79
80–84
85–89
90–94
95+
Age
(Adapted from: Charlson, F. J., Ferrari, A. J., Santomauro, D. F., et al. (2018). Global
epidemiology and burden of schizophrenia: findings from the Global Burden of Disease
Study 2016. Schizophrenia Bulletin 44, 1195–1203.)
Table 1 Age-standardized schizophrenia prevalence in 1990 and 2016 [3].

Total number of
Prevalence (%)
cases (in 1000s)
Region 1990 2016 1990 2016
Southeast Asia, East Asia, and Oceania 5869.3 9109.4 0.38 0.38
Central Europe, Eastern Europe, and Central
865.9 987.0 0.20 0.21
Asia
South Asia 2112.1 3986.1 0.25 0.25
Australasia 71.5 105.9 0.33 0.33
Western Europe 1029.4 1242.9 0.24 0.25
High-income North America 884.6 1214.7 0.30 0.30
Latin America and Caribbean 635.0 1186.5 0.20 0.20
North Africa and Middle East 443.9 1014.7 0.18 0.19
Sub-Saharan Africa 619.0 1314.1 0.19 0.19
Global 13,122.1 20,883.0 0.28 0.28
3
INTRODUCTION
Figure 3. Health-care costs per patient-year for US patients with treatment-resistant
schizophrenia, all schizophrenia patients, and the US average (2012 USD).
180,000 Treatment-Resistant Schizophrenia
Schizophrenia
150,000 US Average
120,000
US Dollars
90,000
60,000
30,000
0
Antipsychotic Drug Hospitalization Total Health Resource
Costs Costs Use
(Adapted from: Kennedy, J. L., Altar, C. A., Taylor, D. L., et al. (2014). The social and
economic burden of treatment-resistant schizophrenia: a systematic literature review.
International Clinical Psychopharmacology, 29, 63–76 [6].)
conservatively adds more than $34 billion in annual direct medical costs in the US [6].
On a personal level, quality of life for schizophrenia patients who are unresponsive or
intolerant to treatment is 20% lower than that of patients who achieve more robust
symptomatic improvement [6].
Clinicians are often more focused on alleviating individual suffering than the
societal impact of disease burden, but despite widespread availability and compelling
efficacy data clozapine remains underutilized for treatment-resistant schizophrenia
[2]. Although 20–30% of schizophrenia patients are treatment-resistant, only six of 50
states in the US report that more than 10% of schizophrenia patients have received
a prescription for clozapine; moreover, many clozapine candidates are subjected to
years of multiple, ineffective antipsychotic trials. Systemic issues are one disincentive
to clozapine use for outpatients, with one workgroup noting that most mental health-
care systems lack “a centralized infrastructure for coordinating the array of services
required by persons receiving clozapine” [2]. While one might assume that more
densely populated urban areas would have the resources to support new clozapine
4
treatment, a 2014 analysis of US clozapine prescribing in 2002–2005 noted that, on

a county level, there was no significant effect of population density or measures of
poverty or income on clozapine initiation, though a higher density of psychiatrists (≥ 15
per 100,000 population) was associated with a greater likelihood of commencing
clozapine [8]. Certain factors, such as age, gender, race, substance use and medical
comorbidity all played roles in clozapine usage, but geographic location emerged as a
significant overriding predictor, suggesting that local culture in certain areas reinforces
evidence-based practice, while that in other areas tolerates the notion that “We don’t
prescribe clozapine in this area” as an acceptable response to managing treatment-
resistant schizophrenia (see Figure 4). Bolstering this argument are data from that
2014 analysis which indicate that patients residing in US counties that had historically
Figure 4. Clozapine prescribing rates among publicly insured adults with
schizophrenia in the United States (2006–2009).
Missing data 0.8–2.4% 2.5–4.9%
5.0–7.4% 7.5–9.9% 10.0–15.6%
(Adapted from: Olfson, M., Gerhard, T., Crystal, S., et al. (2016). Clozapine for
schizophrenia: state variation in evidence-based practice. Psychiatric Services, 67,
152 [16].)
5
INTRODUCTION
high clozapine usage were nearly twice as likely to start clozapine as patients residing
in historically low-use counties [8]. This problem is not unique to the US, as 2002
prescribing data from the United Kingdom (UK) found a 34-fold variation in clozapine
use across National Health Service (NHS) trusts [9]. One practical obstacle to clozapine
treatment among patients of African descent has been benign ethnic neutropenia
(BEN), but revisions of absolute neutrophil count (ANC) thresholds for BEN individuals
in many countries has markedly reduced the impact of this benign variant [10].
PRESCRIBER FEAR
While recent US changes to ANC thresholds for all patients (including new BEN
thresholds) have enlarged the pool of individuals who can start clozapine, there is
one barrier that no regulatory authority can overcome, and that is clinician fear of
prescribing clozapine [10,11]. Despite the overwhelming evidence that patients
on clozapine have lower mortality from natural and unnatural causes, enhanced
quality of life due to reduced symptom burden, and that no other antipsychotic is
robustly effective for treatment-resistant schizophrenia, numerous papers document
overestimation of safety concerns combined at times with a misunderstanding of
the tremendous efficacy difference between clozapine and other antipsychotics for
treatment-resistant schizophrenia. In an article entitled “Prescribers Fear as a Major
Side-Effect of Clozapine”, Professor Dan Cohen (Mental Health Organization North-
Holland North, Heerhugowaard, The Netherlands) comments:
This unscientific and irrational fear is a clinically relevant phenomenon as it
causes psychiatrists to withhold their patients an effective, evidence-based
treatment, thereby unnecessarily prolonging their patients’ suffering. [11]
The net result is that many psychiatrists either refuse to prescribe clozapine, or do
so in a limited manner, a finding seen in studies across the globe including the US,
Denmark, India and the UK [12–15]. Given the enormous social and economic impact
of clozapine use, large health-care systems have taken note of this gap between
evidence-based practice and the routine underuse of clozapine for treatment-resistant
schizophrenia, and have commenced initiatives to promote clozapine prescribing. In
the UK, variation in clozapine use across NHS trusts was reduced from 34-fold in 2002
to 5-fold by 2006 in part due to the publication of national guidelines recommending
clozapine after inadequate response to two antipsychotics [9]. In other places,
more intensive, coordinated efforts have been devised employing some or all of the
principles outlined in Box 1.
6
Box 1 Strategies for Increasing Clozapine Utilization [11,15]

1. Establishment of national or regional (e.g. state-wide) clozapine expertise
centers tasked with performing three essential functions:
a. Real-time consultation without a fee on treatment indications,
clozapine initiation, drug–drug interactions, prevention or
management of adverse effects.
b. Provide educational outreach to mental health professionals through
lectures, publications, and written summaries of important clinical
points (e.g. constipation management).
c. Modernizing local clozapine prescribing guidelines (as recently
performed in the US) to reduce initiation and treatment burdens,
remove unnecessary monitoring requirements (e.g. total white blood
cell count), lower absolute neutrophil count (ANC) thresholds for all
patients, establish appropriate lower ANC thresholds for those with
benign ethnic neutropenia, and other evidence-based changes as
indicated by developments in the literature.
2. Development of a national or regional (e.g. state-wide) pharmacy
surveillance system to identify all schizophrenia patients that are
prescribed a third antipsychotic other than clozapine. When this occurs,
the prescriber must provide documentation justifying this choice in lieu
of clozapine. Such documentation must include the fact that the patient
has been informed of the specific benefits of clozapine (e.g. symptom
reduction, mortality reduction, lower suicide rate), and include the
patient’s signature (and that of a caregiver or guardian if the patient lacks
capacity) noting the date of the discussion.
3. Incentivizing clinic systems to promote clozapine prescribing through
financial methods (e.g. money for training or technical assistance).
4. Publication of regional clozapine usage rates for clinic systems (per
100 schizophrenia spectrum patients) on an annual basis to clearly
identify persistent areas of underutilization. Detailed action plans will be
demanded from centers with low levels of clozapine use.
5. Creation of internet-based education programs geared towards
consumers and family members. One model is the New York State
Office of Mental Health web-based module “Considering Clozapine” that
provides information about clozapine (including benefits and risks), and
includes a series of testimonials from consumers who describe personal
benefits from clozapine along with its challenges.
Elements of these programs include support and education of clinicians to

enhance their ability to manage clozapine-treated patients, and ongoing system-wide
surveillance of clozapine usage rates to reinforce the new cultural norm that underuse
of clozapine is a mark of substandard psychiatric practice. The engendered fear of
7
INTRODUCTION
using clozapine is often simply a byproduct of inadequate education and not clinician
indifference to the patient’s condition, but providing information to clinicians, patients
and families about clozapine’s benefits is not enough. The creation of a clozapine
resource center was an important aspect of programs established in the Netherlands
and in New York State. These centers were typically staffed by knowledgeable senior
psychiatrists and thereby allowed clinicians immediate answers to pressing questions
during working hours. The value of the personal connection and the immediacy of
the response cannot be underestimated. In the Netherlands prescriptions for all
antipsychotics rose 8.2% from 2008 and 2012, but through the efforts of the Dutch
Clozapine Collaboration Group (www.clozapinepluswerkgroep.nl) clozapine use in this
same interval rose by 20% [11]. Across the state of New York the proportion of new
clozapine starts increased by 40% from 2009 to 2013 following commencement of
their “Best Practices Initiative – Clozapine” in 2010 [15]. Importantly, the quarterly
percentage change in rate of clozapine initiation among state run facilities was
threefold higher than in other settings, illustrating the concept that local changes in
culture with respect to clozapine prescribing are self-reinforcing. As more clinicians in
a practice setting develop comfort with and expertise in clozapine prescribing, those
who fail to meet the new expectations of competence will increasingly be viewed in a
negative light by their colleagues.
CONCLUSIONS
There is a worldwide effort to increase clozapine use, but many clinicians lack
access to expert consultation services or other centralized resources of information
about clozapine. It is hoped that this volume will serve as a unified guide for those
clinicians who strive to provide optimal, evidence-based care for their patients in
need of clozapine. The focus of this handbook is on the practical management of
clozapine initiation and adverse effects, with the idea that each chapter will present
a self-contained discussion of a particular topic for the busy clinician. As the reader
will discover, there is a paucity of double-blind, placebo-controlled trials governing
most aspects of clozapine side-effect management, but patients must be treated
with the best tools available, and this handbook uses the extant literature to guide
clinicians through various options. The net goal is to demystify the use of clozapine,
and empower mental health providers everywhere to provide their patients with this
effective, and at times life-saving, medication.
8
References
789–796.
2. Kelly, D. L., Freudenreich, O., Sayer, M. A., et al. (2018). Addressing barriers to clozapine
underutilization: a national effort. Psychiatric Services, 69, 224–227.
3. Charlson, F. J., Ferrari, A. J., Santomauro, D. F., et al. (2018). Global epidemiology and burden
of schizophrenia: findings from the Global Burden of Disease Study 2016. Schizophrenia Bulletin, 44,
1195–1203.
4. Vos, T., Abajobir, A. A., Abbafati, C., et al. (2017). Global, regional, and national incidence,
prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–
2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet, 390, 1211–1259.
5. Cloutier, M., Aigbogun, M. S., Guerin, A., et al. (2016). The economic burden of schizophrenia in
the United States in 2013. Journal of Clinical Psychiatry, 77, 764–771.
6. Kennedy, J. L., Altar, C. A., Taylor, D. L., et al. (2014). The social and economic burden
of treatment-resistant schizophrenia: A systematic literature review. International Clinical
Psychopharmacology, 29, 63–76.
7. Howes, O. D., McCutcheon, R., Agid, O., et al. (2017). Treatment-resistant schizophrenia:
Treatment Response and Resistance in Psychosis (TRRIP) Working Group consensus guidelines on
diagnosis and terminology. American Journal of Psychiatry, 174, 216–229.
8. Stroup, T. S., Gerhard, T., Crystal, S., et al. (2014). Geographic and clinical variation in clozapine
use in the United States. Psychiatric Services, 65, 186–192.
9. Downs, J. and Zinkler, M. (2007). Clozapine: National review of postcode prescribing. Psychiatric
Bulletin, 31, 384–387.
10. Sultan, R. S., Olfson, M., Correll, C. U., et al. (2017). Evaluating the effect of the changes in FDA
guidelines for clozapine monitoring. Journal of Clinical Psychiatry, 78, e933–e939.
11. Cohen, D. (2014). Prescribers fear as a major side-effect of clozapine. Acta Psychiatrica
12. Nielsen, J., Dahm, M., Lublin, H., et al. (2010). Psychiatrists’ attitude towards and knowledge of
clozapine treatment. Journal of Psychopharmacology, 24, 965–971.
13. Grover, S., Balachander, S., Chakarabarti, S., et al. (2015). Prescription practices and attitude of
psychiatrists towards clozapine: A survey of psychiatrists from India. Asian Journal of Psychiatry, 18,
57–65.
14. Tungaraza, T. E. and Farooq, S. (2015). Clozapine prescribing in the UK: Views and experience of
consultant psychiatrists. Therapeutic Advances in Psychopharmacology, 5, 88–96.
15. Carruthers, J., Radigan, M., Erlich, M. D., et al. (2016). An initiative to improve clozapine
prescribing in New York State. Psychiatric Services, 67(4), 369–371.
16. Olfson, M., Gerhard, T., Crystal, S., et al. (2016). Clozapine for schizophrenia: state variation in
evidence-based practice. Psychiatric Services, 67, 152.
9
1
QUICK CHECK
The Efficacy Story: Treatment-Resistant
Schizophrenia, Psychogenic Polydipsia,
Treatment-Intolerant Schizophrenia,
Suicidality, Violence, Mania and
Parkinson’s Disease Psychosis
Introduction 10
Principles 11
A Treatment-Resistant Schizophrenia 13
• Impact of Delays in Commencing Clozapine 16
• Clozapine and Mortality 18
• Psychogenic Polydipsia 21
B Treatment-Intolerant Schizophrenia 24
C Suicidality 25
D Violence and Aggression 27
E Treatment-Resistant Mania 31
F Parkinson’s Disease Psychosis (PDP) 33
Summary Points 37
References 38
INTRODUCTION
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
10
1: THE EFFICACY STORY 1
PRINCIPLES
• 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 treatment resistance is
identified 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.
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].
11
1: THE EFFICACY STORY
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 D2 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 D2
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 D2 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].
Box 1.1 Essential Components of the Kane Definition of Treatment-Resistant

Schizophrenia for Patients Enrolled in the Pivotal Clozapine Trial
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.
12
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 D2 receptors, thus permitting treatment of schizophrenia
patients intolerant of D2 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.
A Treatment-Resistant Schizophrenia
While inconvenient, criterion 3 of the Kane 1988 criteria is central to a research

definition of treatment resistance. Studies using “modified Kane criteria” that lack this
crucial element report unrealistically high response rates for atypical antipsychotics
other than clozapine. The enormous impact of criterion 3 can be seen in the three
double-blind studies of olanzapine for treatment-resistant schizophrenia (Table 1.1).
Response rates to olanzapine at doses up to 50 mg/day were 0% and 7% in the two
studies that included criterion 3 [9,10], but response to olanzapine was 50% when this
step was omitted [11].
Unfortunately the literature is littered with numerous papers in which patients with
varying degrees of treatment resistance and intolerance are grouped together, leading
the unwary reader to question clozapine’s benefit in treatment-resistant patients.
Adding to the confusion was a 2016 meta-analysis that included literally any definition
of treatment resistance in its examination of the literature, and reviewed studies
that also enrolled treatment-intolerant patients [12]. Although that meta-analysis
did not change perceptions regarding clozapine’s efficacy for treatment-resistant
schizophrenia, it reinforced the concept that one must take a jaundiced view of studies
for treatment-resistant schizophrenia that do not subject patients to a prospective
antipsychotic trial and rely solely on historical records of prior antipsychotic treatment.
Aside from treatment resistance, there are many reasons that patients may fail to
respond adequately to an antipsychotic, with nonadherence, underdosing and kinetic
issues playing significant roles. To further emphasize this point, in a recent outpatient
13
Table 1.1 Double-blind olanzapine trials using strict criteria for treatment-resistant
schizophrenia.
Reference Population included % Responders
Treatment-resistant schizophrenia, defined by Kane
criteria:
• Inpatients with poor function for ≥ 5 years
• Historical failure with two typical antipsychotics
for at least 6 weeks on daily doses > 1000 mg/day
Conley et chlorpromazine equivalents Olanzapine 7%1
al., 1998 • Failure of a prospective 6-week haloperidol trial at
[9] Chlorpromazine 0%
daily doses of 10–40 mg
Study method: 8-week fixed-dose trial of olanzapine
25 mg/day vs. chlorpromazine 1200 mg/day (n = 84).
Response defined as ≥ 20% improvement in the total
BPRS score, endpoint BPRS score ≤ 35, and a CGI
severity score ≤ 3.
Treatment-resistant schizophrenia, defined by Kane
criteria:
• Inpatients with poor function for ≥ 5 years
• Historical failure with two typical antipsychotics
for at least 6 weeks on daily doses > 1000 mg/d
chlorpromazine equivalents
• Failure of a prospective 6-week haloperidol trial at
daily doses of 10–40 mg
Conley et Olanzapine 0%
al., 2003 Study method: Double-blind, randomized crossover
[10] study of olanzapine 50 mg/day vs. clozapine Clozapine 20%
450 mg/day (with option for reduction to 30 mg/day
olanzapine or 300 mg/day clozapine for tolerability)
(n = 23). Patients received 8 weeks on olanzapine or
clozapine including a 2-week titration to the target
dose. At the end of 8 weeks subjects were switched
to the other medication. Response was defined as
≥ 20% improvement in total BPRS score, and a final
BPRS score ≤ 35 or a 1 point improvement on the CGI
severity score.
Treatment-resistant schizophrenia, defined as
historical failure of two or more trials of typical or
atypical antipsychotics “with usually adequate doses”
for at least 6 weeks.
Meltzer et Olanzapine 50%2
al., 2008 Study method: 1-year double-blind study of
[11] olanzapine up to 45 mg/day and clozapine up to Clozapine 60%
900 mg/day (n = 40). Response was defined as ≥ 20%
improvement in total PANSS score at 6 months, or
at 6 weeks if drop out was due to reasons other than
lack of efficacy.
Comments
1. Twenty-seven olanzapine-treated subjects who failed to respond in this study were titrated on
open-label clozapine and followed for 8 weeks. Using the same response definition as the prior
trial, 41% met response criteria on clozapine [71].
2. No prospective trial of high-dose typical antipsychotic (Kane criterion 3).
14
study of 99 schizophrenia patients deemed treatment-resistant, 35% had plasma

antipsychotic levels that were subtherapeutic [13].
One positive outcome of the confusing 2016 meta-analysis was a sharpening
of the debate regarding the need to define treatment resistance in research and
clinical settings [14]. There is little question that, when rigorously defined using
all three Kane criteria, the anticipated response rate to antipsychotics other than
clozapine is < 5%, compared to rates ≥ 40% for clozapine. Because implementing
criterion 3 is often impractical for routine clinical care, a consensus panel published
guidelines in 2017 to help clinicians ascertain when patients are treatment-
resistant. Included in this recommendation is that the term “refractory” no longer be
used (Table 1.2).
Table 1.2 Consensus criteria for defining an adequate antipsychotic trial in

resistant schizophrenia patients [14].
Minimum requirement Optimum requirement
• ≥ 6 weeks at a therapeutic • ≥ 6 weeks at a therapeutic dosage

dosage • Record minimum and mean (SD)
Duration • Record minimum and mean duration for each treatment episode
(SD) duration for each
treatment episode
• Equivalent to ≥ 600 mg of • Equivalent to ≥ 600 mg of
chlorpromazine per day chlorpromazine per day
Dosage
• Record minimum and mean • Record minimum and mean (SD)
(SD) dosage for each drug dosage for each drug
• ≥ Two past adequate • ≥ Two past adequate treatment
treatment episodes with episodes with different antipsychotic
different antipsychotic drugs drugs, and at least one utilizing a
Number of long-acting injectable antipsychotic
antipsychotics • Specify median number of (for at least 4 months)
failed antipsychotic trials
• Specify median number of failed
antipsychotic trials
• ≥ 80% of prescribed doses • Same as the minimum criteria, with
taken the addition of trough antipsychotic
• Adherence should be serum levels measured on at least
assessed using at least two occasions separated by at least
two sources (pill counts, 2 weeks (without prior notification
dispensing chart reviews, of patient)
Current
adherence and patient/caregiver report)
• Antipsychotic plasma levels
monitored on at least one
occasion
• Specify methods used to
establish adherence
15
These criteria emphasize that clinicians must be mindful of high nonadherence

rates in schizophrenia patients before concluding that prior antipsychotic trials were
failures. When prior trials lacked plasma levels, or had features associated with
antipsychotic nonadherence (e.g. missed refills, homelessness, substance use, no
documented adverse effects), it is not unreasonable to conduct a trial with a long-acting
injectable and plasma level monitoring to confirm adequate antipsychotic exposure. If
prior trials employed relatively weaker D2 antagonists (e.g. quetiapine) or a D2 partial
agonist (e.g. aripiprazole, brexpiprazole, cariprazine), and there is no history of unusual
D2 sensitivity at routine doses, one should consider use of a stronger D2 antagonist
for the depot formulation. Clinicians can be guided by the literature in cases where
exploring higher antipsychotic plasma levels appears feasible in a nonresponding and
adherent patient (by plasma levels) who is not exhibiting dose-limiting adverse effects
[15]. Nonetheless, despite a clinician’s best efforts, at least 20–30% of schizophrenia
patients will be inadequate responders to nonclozapine antipsychotics.
Outside of the academic sphere, there are large data sets that substantiate
clozapine’s effectiveness in ‘real-world’ circumstances. Table 1.3 summarizes the
latest and best-designed of these studies. Two of these studies examined enormous
samples of schizophrenia patients (18,869 and 29,823) for up to 8 years [16,17],
while another looked at two matched cohorts of 3123 schizophrenia patients who met
clinically defined criteria for treatment resistance [18].
By selecting those patients who would be deemed treatment-resistant by routine
clinical standards, the latter study emphasizes the benefits of clozapine compared
to other antipsychotics for that population [18]. As opposed to the outcomes
found in an inpatient research unit or highly supervised research clinic, these
naturalistic data sets provide a compelling picture of clozapine’s effectiveness in
the hands of clinicians working with a challenging population with varying degrees
of motivation, adherence and illness severity. Regardless of the treatment setting,
clozapine remains the option with best chance of success for the treatment-resistant
schizophrenia patient.
• One important variable in maximizing the chance of clozapine response involves

Impact of Delays in Commencing Clozapine
minimizing the time to initiation once the patient meets clinical criteria for treatment
resistance. Given the reluctance of many clinicians to prescribe clozapine, it is
not surprising that the literature documents unnecessary delays in commencing
16
Table 1.3 Summary of large real-world effectiveness studies in schizophrenia

2016–2017.
Reference Comments
Sample: Retrospective analysis of outcomes for 18,869 adult schizophrenia
patients living in Quebec, Canada and starting an antipsychotic between
January 1998 and December 2005.
Outcomes of interest: Any mental health event (suicide, hospitalization
or emergency visit for mental disorders), and any physical health event
(death other than suicide, hospitalization or emergency visit for physical
disorders).
Vanasse
et al., Results: Compared to FGAs, patients on quetiapine at the time of the event
2016 [16] was associated with increased risk of mental health events (HR = 1.38, 95%
CI 1.24–1.54, p < 0.0001) and also of physical health events (HR = 1.24, 95%
CI 1.12–1.37, p < 0.0001). Patients not using any antipsychotic were also
at an increased risk of mental health events (HR = 1.54, 95% CI 1.44–1.65,
p < 0.0001), and physical health events (HR = 1.24, 95% CI 1.17–1.32,
p < 0.0001). Clozapine was associated with slightly lower risk of mental or
physical health events than FGAs, and was associated with markedly lower
rates of discontinuation or antipsychotic switching compared to FGA and
other SGAs.
Sample: Retrospective examination of outcomes for 3123 adult
schizophrenia patients extracted from US national Medicaid data 2001–
2009 with clinical evidence of treatment resistance that required clozapine.
This cohort was matched with a similar cohort of 3123 patients with clinical
evidence of treatment resistance that initiated a standard antipsychotic.
Stroup et Outcomes of interest: Hospital admission for a mental disorder. Secondary
al., 2016 efficacy outcomes included discontinuation of the antipsychotic, and use of
[18] an additional antipsychotic.
Results: Initiation of clozapine was associated with a significantly lower
rate of psychiatric hospital admission (HR = 0.78, 95% CI 0.69–0.88).
Clozapine was also associated with lower rates of antipsychotic
discontinuation (HR = 0.60, 95% CI 0.55–0.65), and the need for an
additional antipsychotic (HR = 0.76, 95% CI 0.70–0.82).
Sample: Retrospective examination of outcomes for 29,823 patients in
Sweden with a schizophrenia diagnosis who were 16–64 years of age in 2006.
Psychiatric outcomes were analyzed for July 1, 2006, to December 31, 2013.
Outcomes of interest: Risk of rehospitalization and treatment failure
(defined as psychiatric rehospitalization, suicide attempt, discontinuation or
switch to other medication, or death).
Tiihonen Results: Risk of psychiatric rehospitalization was the lowest during
et al., monotherapy with once-monthly long-acting injectable paliperidone
2017 [17] (HR = 0.51; 95% CI 0.41–0.64), long-acting injectable zuclopenthixol
(HR = 0.53, 95% CI 0.48–0.57), clozapine (HR = 0.53, 95% CI 0.48–0.58),
long-acting injectable perphenazine (HR = 0.58, 95% CI 0.52–0.65), and
long-acting injectable olanzapine (HR = 0.58, 95% CI 0.44–0.77) compared
with no use of antipsychotic medication. Oral flupentixol (HR = 0.92, 95% CI
0.74–1.14), quetiapine (HR = 0.91; 95% CI 0.83–1.00), and oral perphenazine
(HR = 0.86, 95% CI 0.77–0.97) were associated with the highest risk of
rehospitalization.
FGA, first-generation antipsychotic; SGA, second-generation antipsychotic; HR, hazard ratio.
17
clozapine treatment. A clinical review of all 149 patients started on clozapine at the
South London and Maudsley NHS Foundation Trust from 2006 to 2010 found that the
mean delay in initiating clozapine was 47.7 months, with 36% of patients receiving
antipsychotic polypharmacy and 34% receiving high-dose antipsychotic therapy
during the delay [19]. A subsequent paper covering 162 clozapine starts at the Istanbul
Faculty of Medicine, Department of Psychiatry noted a mean delay of 29 months after
fulfilling treatment-resistance criteria [20]. While those who responded to clozapine
tended to be younger, have shorter illness duration and fewer numbers of adequate
antipsychotic trials before clozapine, the extent of delay in starting clozapine was
an independent contributor to the odds of clozapine response [20]. The mean delay
in initiating clozapine in the good response group was 21 months, compared to
47 months in those with minimal or no improvement (p = 0.04). Utilizing the concept
that the biological onset of treatment resistance was not when the patient was
finally deemed to have failed their second antipsychotic but when that period of
exacerbation commenced, a group from a tertiary care inpatient hospital in Okayama,
Japan analyzed data in 90 new clozapine starts who remained on treatment for at
least 3 months (see Figure 1.1) [21]. Using this definition, they found that a delay in
clozapine initiation of 2.8 years best predicted those who would benefit from clozapine
treatment. In patients with a delay ≤ 2.8 years the response rate was 81.6%, while it
fell to 30.8% in those with a delay > 2.8 years. Consistent with the Turkish data, older
age and longer duration of illness were associated with lower response rates.
• Symptomatic exacerbation and rehospitalization are inherent to schizophrenia, but

Clozapine and Mortality
so is increased risk of mortality from all causes, natural and unnatural (i.e. accidents,
suicide) [22]. Increasingly sophisticated database studies indicate that clozapine is
associated with lower mortality rates than other antipsychotics, that clozapine reduces
mortality from both natural and unnatural causes, and that the mortality reduction is
not solely due to increased clinical monitoring or other treatment factors (Table 1.4).
The impact of clozapine on mortality is only present if the patient continues on
clozapine. A 2018 meta-analysis of 24 long-term mortality studies found mortality rate
ratios were 44% lower in patients continuously treated with clozapine (compared to
other antipsychotics), but were not significant lower in those who ever used clozapine
[23]. The loss of clozapine’s protective effect on mortality emerges soon after
18
Figure 1.1. Delaying the time to starting clozapine reduces likelihood of response
in resistant schizophrenia.
First episode Initiation of
of schizophrenia clozapine
Inadequate Inadequate
Inadequate response Response to Period of nonresponse to response to
to first antipsychotic first antipsychotic adherence second antipsychotic third antipsychotic
Onset of treatment- Diagnosis of treatment-

resistant schizophrenia resistant schizophrenia
Duration of Illness
Delay in initiation
of clozapine
(Adapted from: Yoshimura, B., Yada, Y., So, R., et al. (2017). The critical treatment
window of clozapine in treatment-resistant schizophrenia: Secondary analysis of an
observational study. Psychiatry Research, 250, 65–70 [21].)
treatment stoppage, with Danish data showing that mortality was highest in periods
after clozapine discontinuation (HR: 2.65, 95% CI 1.47–4.78) [22].
What is interesting about this literature is that the Quebec study (Table 1.3)
showed that clozapine lowered the odds of all physical health events despite
subanalayses showing that current clozapine use was associated with higher risk
for serious physical health events (i.e. hospitalization or death from nonpsychiatric
medical causes) [16]. As noted in Chapters 7 and 9, use of clozapine is associated
with constipation and sialorrhea that in some cases can result in ileus or aspiration
pneumonia. As clinicians become more adept at managing those two adverse effects
of clozapine, it will be interesting to note whether the mortality gap between clozapine
and other antipsychotics further widens in favor of clozapine for treatment-resistant
schizophrenia patients. Antipsychotic treatment is the foundation upon which patients
can build skills to achieve functional goals, but such goals can only be attained if the
patient remains alive. Even with clozapine’s burden of somatic adverse effects, the
19
Table 1.4 Summary of recent large antipsychotic mortality studies in schizophrenia.

Reference Comments
Sample: Nationwide registers in Finland were used to examine mortality
in 66,881 outpatients with schizophrenia between 1996 and 2006, and to
link these data with the use of antipsychotic drugs. Perphenazine was
used as the comparison medication.
Outcomes of interest: All-cause mortality using Cox regression models
Tiihonen et
for the period. Secondary outcomes included mortality due to suicide
al., 2009 [32]
and ischemic heart disease.
Results: Compared with current use of perphenazine, the highest risk
for overall mortality was recorded for quetiapine (adjusted HR = 1.41,
95% CI 1.09–1.82), and the lowest risk for clozapine (HR = 0.74, 95%
CI 0.60–0.91). Use of clozapine significantly decreased risk of death by
suicide (HR = 0.34, 95% CI 0.20–0.57), and did not increase risk of death
due to ischemic heart disease.
Sample: The South London and Maudsley National Health Service
Foundation Trust case register linked to a national (UK) mortality
database was used to identify 14,754 individuals with serious mental
illnesses including schizophrenia, schizoaffective and bipolar disorders
aged ≥ 15 years.
Hayes et al., Outcomes of interest: The effect of clozapine on mortality over a 5-year
2015 [72] period (2007–2011) using Cox regression models for the period.
Results: There was a significant association between being prescribed
clozapine and lower mortality after controlling for numerous potential
confounders including clinical monitoring associated with clozapine
use and markers of disease severity (adjusted HR = 0.4, 95% CI 0.2–0.7;
p = 0.001). For natural causes of death the adjusted HR = 0.5 (95% CI
0.2–0.9). For unnatural causes of death the adjusted HR = 0.2 (95% CI
0.05–0.9).
Sample: The Danish National Prescription Registry and clinical databases
were used to identify a cohort of 2370 individuals with treatment-resistant
schizophrenia after January 1, 1996. The cohort was followed until death,
first episode of self-harm, emigration, or June 1, 2013.
Wimberley et Outcomes of interest: Time to all-cause death and time to first episode
al., 2017 [22] of self-harm were analyzed in Cox regression models for the period.
Results: The absence of clozapine treatment was associated with an
elevated all-cause mortality (HR = 1.88, 95% CI 1.16–3.05) in adjusted
models. Estimates were substantially higher for no antipsychotic
treatment (HR = 2.50, 95% CI 1.50–4.17) and nonclozapine antipsychotic
treatment (HR = 1.45, 95% CI 0.86–2.45*). Mortality was highest in periods
after clozapine discontinuation (HR = 2.65, 95% CI 1.47–4.78). When
compared with clozapine, nonclozapine antipsychotics were associated
with an elevated rate of self-harm (HR = 1.36, 95% CI 1.04–1.78).
Sample: Meta-analysis of 24 mortality studies in adults diagnosed with
schizophrenia spectrum disorders who had received clozapine treatment
Vermeulen et with > 52 weeks of follow-up.
al., 2019 [23]
Outcome of interest: Comparative mortality rates between clozapine
and other antipsychotics.
continued overleaf
20
Table 1.4 continued
Reference Comments
Results: For clozapine-treated patients, 1327 deaths were recorded
during 217,691 patient-years of follow-up. Mortality rate ratios (mRR)
Vermeulen et were significantly lower in patients continuously treated with clozapine
al., 2019 [23] compared to other antipsychotics (mRR = 0.56, 95% CI 0.36–0.85).
cont’d The mRR of studies including patients who ever used clozapine
during follow-up compared to other antipsychotics was not significant
(mRR = 0.74, 95% CI 0.38–1.45).
HR, hazard ratio.
* Not statistically significant.
published literature indicates that clozapine lowers the risk of premature mortality
compared to other options for resistant schizophrenia.
• Primary polydipsia is a scenario of increased water intake occurring in the absence

Psychogenic Polydipsia
of impairment in water excretion. This can be distinguished from the secondary

polydipsia seen with lithium-treated patients who increase water intake due to
obligatory losses from nephrogenic diabetes insipidus. Both groups may have low urine
osmolality, but the latter group maintains normal serum osmolality and serum sodium
levels, while the primary polydipsia patient will suffer from severe hyponatremia and
low serum osmolality during water binges [24]. The association of water intoxication
and schizophrenia was reported in the pre-antipsychotic era, with a 1923 paper
correlating increased water excretion with greater psychosis severity. By 1936 it was
noted that excessive water intake occurred in approximately 25% of patients and
was the most common metabolic abnormality in the severely mentally ill; moreover, it
could be associated with life-threatening hyponatremia [24]. Modern prevalence data
obtained over 5 years in a state hospital (1996–200) confirm that polydipsia continues
to be present in at least 20% of chronic psychiatric inpatients [25]. The excessive
drinking in primary polydipsia is not due to excessive thirst, but is motivated instead by
delusions or psychic discomfort that is relieved by water binges [24].
Shortly after clozapine’s approval in 1989, cases emerged in which water
intoxication associated with schizophrenia was not addressed by typical
antipsychotics, but which responded to clozapine. A 1996 case series of five state
hospital patients with polydipsia who met Kane criteria reported that all were
successfully discharged on clozapine and had no recurrence of polydipsia over
17 months of outpatient follow-up [26]. A subsequent 24-week open-label study
21
was performed in eight male schizophrenia patients with polydipsia to document

longitudinal changes in urine and serum osmolality after starting clozapine [8].
The protocol involved 6 weeks with a typical antipsychotic (per Kane criterion 3),
followed by sequential 6-week periods of clozapine at 300, 600 and then 900 mg/
day (if tolerated). During treatment with typical antipsychotics both serum and urine
osmolality remained grossly abnormal; however, on clozapine the mean plasma
osmolality normalized, and rose on average by 15.2 mosm/kg (95% CI 5.5–25.0);
moreover, this effect was evident at the dose of 300 mg/day of clozapine (see Figures
1.2 and 1.3) [8]. With ongoing clozapine titration, urine osmolality also normalized.
No other prospective clozapine studies have emerged for polydipsia, but the
Figure 1.2. Mean plasma osmolality during 6 weeks of typical antipsychotic

treatment followed by 6 weeks each of clozapine at 300, 600 and then 900 mg/day
in schizophrenia patients with polydipsia.
Typical antipsychotic Clozapine dose (mg/day)
290 300 600 900

Plasma Osmolality (mosm/kg)
280
270
0
6 12 18 24
Weeks
(Adapted from: Canuso, C. M. and Goldman, M. B. (1999). Clozapine restores water

balance in schizophrenic patients with polydipsia–hyponatremia syndrome. Journal of
Neuropsychiatry and Clinical Neuroscience, 11, 86–90 [8].)
22
Figure 1.3. Mean urine osmolality during 6 weeks of typical antipsychotic

treatment followed by 6 weeks each of clozapine at 300, 600 and then 900 mg/day
in schizophrenia patients with polydipsia.
Typical antipsychotic Clozapine dose (mg/d)
300 600 900
300
Urine Osmolality (mosm/kg)
250
200
150
100
0
6 12 18 24
Weeks
(Adapted from: Canuso, C. M. and Goldman, M. B. (1999). Clozapine restores water

balance in schizophrenic patients with polydipsia–hyponatremia syndrome. Journal of
Neuropsychiatry and Clinical Neuroscience, 11, 86–90 [8].)
accumulated literature is substantial enough that a 2010 comprehensive review

of water imbalance issues in psychosis patients concluded that primary polydipsia
generally appears resistant to antipsychotics except clozapine. Evidence-based
treatment options for preventing water intoxication includes targeted fluid restriction,
clozapine therapy, and removal of agents that may be causing hyponatremia (e.g.
carbamazepine, valproate, sodium-wasting diuretics). The titration and therapeutic
plasma levels for schizophrenia spectrum polydipsia patients are consistent with the
use of clozapine for treatment-resistant schizophrenia.
23
B Treatment-Intolerant Schizophrenia
Early in its clinical development, clozapine’s extremely low rate of neurological

adverse became apparent, leading to small trials in patients with tardive dyskinesia
(TD), and for patients intolerant of D2 antagonism due to akathisia, parkinsonism,
acute dystonia or neuroleptic malignant syndrome (NMS) [27]. While use in TD patients
was a focus of several studies, evidence for benefit in D2 antagonist-intolerant patients
is based on experience reported in case series where these patients were often
included along with treatment-resistant individuals [28]. The conclusions from this
case-based literature is that clozapine is unlikely to induce acute movement disorders,
although there are a handful of NMS cases reported [29]. With respect to TD, both the
efficacy outcomes and quality of prior studies led the American Academy of Neurology
to state that the data were insufficient to support or refute use of clozapine for
tardive syndromes [30]. Despite the abundance of case data, only three prospective
studies involving a switch to clozapine for TD management were of sufficient quality
to be reviewed: two were positive, one was not. A subsequent 2018 review found no
further data to indicate that antipsychotic switching is an evidence-based practice for
management of TD [31].
Since clozapine’s reintroduction in 1989 the psychopharmacology landscape
has changed in two ways: there are numerous options to high-potency typical
antipsychotics, and there are three vesicular monoamine transporter type 2 (VMAT2)
inhibitors available for TD treatment. The expanded group of atypical antipsychotics
(including the D2 partial agonists) provides a range of options for those with significant
sensitivity to D2 antagonism. Quetiapine has very low D2 affinity and consequentially
low rates of acute movement disorders, but enthusiasm for its use as a schizophrenia
treatment has waned based on real-world effectiveness data associating quetiapine
with higher rates of overall mortality [32], rehospitalization[17], any mental health event
(suicide, hospitalization or emergency visit) or physical health event (death other than
suicide, hospitalization or emergency visit for physical disorders) [16]. Although the pool
of treatment-intolerant patients is smaller than when first-generation antipsychotics
were the only available choices, these individuals do exist and should be offered
clozapine. For stable TD patients who require ongoing antipsychotic therapy, the
addition of a VMAT2 inhibitor is preferable to antipsychotic switching as the combination
is well tolerated in severely mentally ill individuals on antipsychotic therapy (see Chapter
13). Clozapine should be considered if there are other ongoing sources of treatment
intolerance (e.g. akathisia), or the patient meets clinical criteria for treatment resistance.
24
C Suicidality
Conceptually, suicide and violence are separate domains of schizophrenia

spectrum disorders that are not necessarily driven by psychotic thought processes,
and thus respond incompletely to traditional antipsychotic therapy [33]. A review
of suicidal acts among 10,118 schizophrenia patients participating in placebo-
controlled clinical trials found that rates of suicide and attempted suicide did not differ
significantly between the placebo-treated and drug-treated groups despite greater
symptom reduction for the latter [34]. Patients with schizophrenia spectrum disorders
have ninefold higher rates of unnatural causes of death (suicide, violent accidents)
compared to the general population, with suicide risk especially prominent in the
first 5 years after diagnosis [35,36]. Death from suicide comprises 30% of all causes
of mortality in studies of new-onset schizophrenia patients, but wanes over ensuing
decades. The estimated lifetime risk of death from suicide is 4.9% in patients with
schizophrenia [36].
The impact of clozapine on suicidality was first noticed in treatment-resistant
schizophrenia patients, but the antisuicide effects were later seen in those
without treatment resistance, and in bipolar disorder patients [37–39]. From these
observations the foundation was laid for a large international trial to examine
clozapine’s comparative efficacy vs. olanzapine in a nonresistant schizophrenia
population. The International Suicide Prevention Trial (InterSePT) enrolled 980
patients at high risk for suicide due to prior attempts or current symptoms, with 24
months of follow-up (see Figure 1.4) [40]. In this cohort of schizophrenia patients
who were not treatment-resistant, clozapine’s superior impact on suicidality was
clearly independent of the reduction in psychotic symptoms, as both clozapine and
olanzapine had comparable improvements in total Positive and Negative Syndrome
Scale (PANSS) scores. This principle will be echoed in data supporting clozapine’s
effect on aggression: the reduction in suicidality and violence is independent of
clozapine’s antipsychotic effect. The InterSePT study resulted in an indication
for reducing risk of recurrent suicidal behavior in patients with schizophrenia or
schizoaffective disorder “who are judged to be at chronic risk for re-experiencing
suicidal behavior, based on history and recent clinical state” [41]. Naturalistic
data summarized in Table 1.4 substantiate the findings from InterSePT: clozapine
treatment is associated with a reduction of 66–80% in deaths by suicide or other
unnatural causes, and a 36% lower rate of self-harm compared with nonclozapine
antipsychotics.
25
Figure 1.4. Time to suicidal events in the InterSePT study.

Type 1 Event Type 2 Event
0.5 0.5
0.4
Cumulative Probability
37%
32%
0.3
28%
24%
0.2
0.1
Clozapine Olanzapine Clozapine Olanzapine
0.0
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Months Months
HR, hazard ratio. Type 1 Event: Significant suicide attempt or hospitalization due to imminent
suicide risk. Type 2 Event: Worsening suicidality.
(Adapted from: Meltzer, H. Y., Alphs, L., Green, A. I., et al. (2003). Clozapine treatment
for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT).
Archives of General Psychiatry, 60, 82–91 [40].)
Box 1.2 Important Conclusions from the 24-Month Prospective, Randomized

International Suicide Prevention Trial (InterSePT) [40]
1. In this group of 980 schizophrenia patients who were not treatment-
resistant but at high risk for suicide, clozapine and olanzapine had
comparable reductions in symptom ratings (PANSS total score).
2. Despite equivalent reduction in psychosis symptoms, clozapine was
superior to olanzapine for overall suicidal behavior (HR = 0.76; 95% CI
0.58–0.97). Specifically, fewer clozapine-treated patients:
– attempted suicide
– required hospitalizations or needed rescue interventions to prevent suicide
– required concomitant treatment with antidepressants or anxiolytics/
hypnotics
3. Clozapine delayed the time to occurrence of suicidal events compared
to olanzapine treatment, and this effect was increasingly more significant
over time for both Type 1 and Type 2 events as defined below:
Type 1 Event: Significant suicide attempt or hospitalization due to imminent
suicide risk
Type 2 Event: Worsening suicidality (as indicated by a rating of “much
worse” or “very much worse” from baseline on the Clinical Global
Impression Severity of Suicidality scale)
26
D Violence and Aggression
The association between psychosis and violence has been noted for over
a century, but only in recent decades have there been systematic attempts to
understand the intrinsic neurobiological factors and extrinsic factors (e.g. substance
use) that moderate this risk. Quantifying this risk has been challenging because
violence or aggression can include a spectrum of behaviors from verbal threats to
physical violence or murder. The lack of consensus definitions for the term “violence”
in research papers leads to a range of reported rates [42]. Despite these limitations,
a comprehensive 2009 review noted that violence risk is increased for both male
and female schizophrenia patients, and that substance use further increases risk of
violence 3.7- to 4.2-fold in this population compared to psychosis patients without
substance use (see Figure 1.5) [43,44].
Aggression in undermedicated or untreated schizophrenia patients is approached
with standard pharmacological interventions including antipsychotics alone or
with mood stabilizers (if there is a bipolar diathesis) [33]. The more problematic
clinical scenario revolves around the type of schizophrenia patient encountered
Figure 1.5. Risk estimates for violence in schizophrenia and other psychoses for
male samples, female samples and mixed gender samples.
OR (95%CI)
Males 3.98 (2.98, 5.31)
Mixed Genders 5.02 (3.41, 7.39)
Females 7.85 (4.00, 15.40)
.5 1 2 4 8 16 32
Odds Ratio
OR, Odds Ratio; CI, Confidence Interval.

(Adapted from: Fazel, S., Gulati, G., Linsell, L., et al. (2009). Schizophrenia and
violence: Systematic review and meta-analysis. PLoS Medicine, 6, e1000120 [43].)
27
in psychiatric inpatient and forensic settings who remains persistently aggressive

despite antipsychotic treatment. In addressing the persistently violent schizophrenia
spectrum patient, one must first categorize the nature of the aggression. The
most robust and empirically validated classification method was developed within
the New York State Hospital system based on reviewed videotaped assaults
supplemented with assailant and victim interviews to determine the motivation
for each violent act. These detailed assessments led the authors to conclude that
three categories could be used to define aggressive acts: psychotic, impulsive, and
predatory (also called organized or instrumental) [33]. The latter group comprises
intentional acts for secondary gain (e.g. theft, intimidation), and requires a custodial
solution, not pharmacotherapy. Psychotic violence is due to persistent delusions
or hallucinations that drive behaviors, while impulsive acts involve inappropriate
responses to real-world stimuli. A classic example of impulsive violence is a patient
who assaults a peer after being gently bumped in a line despite the innocuous
nature of the contact and the fact that the assault will have repercussions for
Figure 1.6. Violence is a separate symptom dimension of schizophrenia.
POSITIVE
Delusions
Hallucinations
AGGRESSIVE
Verbal
Physical
Property
COGNITIVE NEGATIVE AFFECTIVE

Attention Diminished expression Depression
Working memory Apathy Suicidality
Processing speed Avolition Anxiety
28
the assailant (e.g. legal, loss of privileges, etc.). Utilizing this classification, there
are two core concepts that underlie treatment of ongoing violence in medicated
schizophrenia patients:
a. Among persistently aggressive forensic schizophrenia inpatients the most
common type of assault is impulsive (54%), followed by organized (29%) and
psychotic (17%) [45].
b. Impulsive violence/aggression is a separate symptom dimension of
schizophrenia that may not respond to nonclozapine antipsychotics (see
Figure 1.6) [33].
The initial approach to any violent patient requires the clinician to classify
the nature of the violence. That motivated by delusions or hallucinations involves
optimization of antipsychotic treatment, and use of clozapine in those who are
treatment-resistant. For those who are impulsive, further antipsychotic titration
is appropriate if there are no dose-limiting adverse effects (e.g. akathisia,
parkinsonism). In schizophrenia patients who continue to be impulsively violent
despite maximal use of nonclozapine antipsychotics, clozapine is the preferred
agent, and its anti-aggressive property in these individuals is independent of its
impact on psychotic symptoms. Evidence for this assertion comes from studies
summarized in Table 1.5 [46]. The most rigorous study design was a randomized,
double-blind, parallel-group, 12-week trial specifically for physically assaultive New
York State Hospital patients with schizophrenia or schizoaffective disorder [47].
At study end there were nonsignificant numerical changes in PANSS total scores
across all three drug groups, but clozapine significantly reduced verbal, physical and
total aggression scores compared to haloperidol or olanzapine. Clozapine’s effect
was more pronounced in those with cognitive dysfunction, despite the fact that
poor executive function at study baseline predicted higher levels of aggression (see
Figure 1.7) [48].
Further evidence that clozapine’s anti-aggression effect is independent of
its antipsychotic properties includes a small case series of clozapine therapy for
impulsive aggression among nonpsychotic patients with antisocial personality
disorders. Not only did clozapine significantly decrease rates of impulsive aggression
and violence in this cohort, it did so at a mean plasma level of 171 ng/ml, well below
the 350 ng/ml threshold used to manage treatment-resistant schizophrenia [49].
A 2018 review outlines the challenges to prescribing clozapine in forensic settings,
29
Table 1.5 Summary of randomized studies of clozapine for aggression in

schizophrenia.
Reference Comments
Sample: Randomized, double-blind, 40-day trial of clozapine vs.
chlorpromazine in 48 patients with chronic schizophrenia, 75% of whom
were experiencing acute symptoms or exacerbation of chronic symptoms.
Niskanen et
Outcomes of interest: Change in BPRS score.
al., 1974 [73]
Results: Improvements in tension, hostility and excitement were seen
in the clozapine group compared to baseline, with no between-group
differences in BPRS scores.
Sample: Open-label, 14-week randomized trial in aggressive inpatients
with schizophrenia (n = 12), schizoaffective disorder (n = 2) or dementia
with psychotic features (n = 1). Subjects were randomized to clozapine
or remaining on their current antipsychotic.
Chow et al.,
Outcomes of interest: Change in total score on the MOAS. Secondary
1996 [74]
outcome was change in PANSS total score.
Results: Aggression scores improved in the clozapine group at week
10 and at week 14 compared to baseline. PANSS total scores did not
improve for either group.
Sample: Randomized, double-blind, 14-week trial of clozapine,
olanzapine, risperidone or haloperidol in 157 adult inpatients (ages
18–60) with total PANSS ≥ 60, suboptimal response to treatment and
Citrome et al.,
poor functioning over the prior 2 years.
2001 [75]
Outcome of interest: Change in PANSS total score, and total
Volavka et al.,
aggression severity score.
2002 [76]
Results: Atypical antipsychotics were superior to haloperidol for
Volavka et al.,
symptom reduction, and clozapine was superior to haloperidol in
2004 [77]
reducing the number and severity of aggressive incidents. Risperidone
and olanzapine had less antipsychotic efficacy in aggressive patients;
the opposite was true for clozapine.
Sample: Randomized, double-blind, parallel-group, 12-week trial.
Subjects were physically assaultive inpatients with schizophrenia or
schizoaffective disorder in New York State psychiatric facilities randomly
assigned to clozapine (n = 37), olanzapine (n = 37) or haloperidol (n = 36).
Outcome of interest: Changes in total score on the MOAS-30, and the
three MOAS-30 subscales (physical aggression against other people,
verbal aggression, and physical aggression against objects). Nursing
Krakowski et staff reported all behaviors on a monitoring form with 30- to 60-minute
al., 2006 [47] intervals. Research personnel interviewed the nursing staff after each
event.
Results: There were no significant between-group differences for mean
change in PANSS total score. Clozapine was superior to olanzapine for
change in MOAS-30, for physical aggression against other people, and
for verbal aggression. Clozapine was superior to haloperidol for MOAS-
30 total score, and for physical aggression against other people, verbal
aggression, and physical aggression against objects.
BPRS,Brief Psychiatric Rating Scale; MOAS, Modified Overt Aggression Scale; PANSS, Positive and
Negative Syndrome Scale
30
Figure 1.7. Clozapine’s superiority for aggression compared to olanzapine and

haloperidol among schizophrenia patients with cognitive dysfunction.
120
100 Olanzapine
80
Total MOAS Score
60
Haloperidol
40
Clozapine
20
0
–1.5 –1.0 –0.5 0.0 0.5 1.0 1.5
Baseline Executive Function (z-score units)
MOAS, Modified Overt Aggression Scale.

(Adapted from: Krakowski, M. I. and Czobor, P. (2012). Executive function predicts
response to antiaggression treatment in schizophrenia: A randomized controlled trial.
Journal of Clinical Psychiatry, 73, 74–80 [48].)
including the lack of an intramuscular formulation in most countries, and the greater
attention required for management of adverse effects. Nonetheless, the authors note
the cost-effectiveness of clozapine treatment as an important part of any strategy to
manage aggressive, severely mentally ill patients in health-care and criminal justice
systems [50].
E Treatment-Resistant Mania
The value of clozapine for treatment-resistant mania was noted in case reports
as early as 1977 [51], but not until 1994 was a trial conducted in patients who met
a standardized definition of treatment resistance: documented response failure or
31
intolerance to lithium, an anticonvulsant, and at least two typical antipsychotics.

All subjects (n = 25) in that 13-week open-label trial met DSM-IIIR criteria for the
manic phase of bipolar disorder or schizoaffective disorder, bipolar type [52]. At study
endpoint, 72% of patients demonstrated at least 50% decrease in the Young Mania
Rating Scale (YMRS) score. A subsequent 1-year trial with 38 treatment-resistant
patients meeting DSM-IV criteria for the manic phase of schizoaffective or bipolar
disorder randomly assigned subjects to adjunctive open-label clozapine (n = 19)
or treatment as usual (TAU) (n = 19), with monthly ratings of mood and psychosis
symptoms [53]. Significant between-group differences were found in scores on all
rating scales except the Hamilton Depression scale, and medication use decreased
significantly in the clozapine group. Importantly, patients with nonpsychotic bipolar I
disorder randomized to clozapine exhibited similar improvement in mania symptoms
as did the entire clozapine-treated group, providing evidence that clozapine’s antimanic
effect is independent of the antipsychotic effect [53]. There were differences in mean
clozapine doses between those with schizophrenia spectrum disorders (623 mg/
day) and nonpsychotic bipolar I patients (234 mg/day). A subsequent 12-week trial
of 22 bipolar I patients with mania and psychotic features noted a mean dose among
completers of 334 mg/day [54]. Double-blind, placebo controlled adjunctive studies do
not exist, but there are case series for use in rapid cycling bipolar disorder [55].
Real-world data support the conclusions of open-label studies that clozapine
is effective for treatment-resistant mania in bipolar I patients. Using the Denmark
national database for the years 1996–2007, investigators examined outcomes
in bipolar disorder patients started on clozapine (n = 326) specifically excluding
those with a schizophrenia spectrum disorder. The study used a mirror image
design to look at comparative hospital days, number of psychiatric admissions,
and medication usage for the 2 years before and 2 years after starting clozapine
[56]. After a mean follow-up of 544 ± 280 days, the number of hospital bed
days decreased by 80% from 178 to 35 (p < 0.001), and the mean number of
admissions decreased by 37.5% from 3.2 to 2.0 (p < 0.001). Overall, 74% had
reduced bed days and 40% were not admitted at all while on clozapine. Using
defined daily doses (DDD), the number of psychotropic medications decreased by
13% from 4.5 to 3.9 DDD (p = 0.045). Nonpsychiatric hospital visits for intentional
self-harm or medication overdose also decreased significantly from 8.3% to 3.1%
(p = 0.004). The mean clozapine dose at the end of follow-up was 307.4 mg/day.
After 1 year of clozapine exposure, use of medications to manage nonpsychiatric
32
medical conditions did not increase. As noted in schizophrenia, clozapine is only

effective for mania when patients adhere to treatment. Bipolar patients deemed
“irregular” clozapine users in a Taiwan analysis by virtue of low medication
possession ratios had twofold higher adjusted risk for emergency room visits, and
2.5 times greater risk for hospitalizations compared to more adherent clozapine
patients [57].
Box 1.3 Essential Facts about Use of Clozapine For Treatment-Resistant Mania
1. Adjunctive clozapine is equally effective in treatment-resistant
nonpsychotic bipolar patients and those with a diagnosis of
schizoaffective disorder, bipolar type.
2. Use of clozapine is associated with reduced hospital admissions, number
of hospital days, hospital visits for self-harm or intentional overdose, and
total psychotropic medication use.
3. Mean endpoint doses for bipolar I patients in long-term studies of 1 year
or more range from 234 to 305 mg/day [53,56]. Higher doses (and plasma
levels) typical of schizophrenia spectrum disorders are usually needed for
schizoaffective disorder, bipolar type patients. There is one study of rapid
clozapine titration among treatment-resistant bipolar disorder inpatients,
but this reduced time to discharge readiness by less than 4 days. In a
forced titration study that advanced clozapine by 25 mg/day to a target
dose of 550 mg/day (if tolerated), only 14 of 22 manic bipolar I patients
managed to complete the 12-week trial [54].
F Parkinson’s Disease Psychosis (PDP)
Parkinson’s disease (PD) is a neurodegenerative disorder related to the neuronal

accumulation of alpha-synuclein in histologically distinct complexes called Lewy
bodies. The worldwide prevalence of PD is estimated at > 7 million, of which
more than 50% will develop symptoms of Parkinson’s disease psychosis (PDP).
The prevalence of PDP increases to 75% of patients in those with PD and related
dementia. In 2007 a consensus definition for PDP was elaborated that included the
existence of hallucinations, delusions, illusions or false sense of presence for at least
1 month in a patient previously diagnosed with PD and in whom other etiologies
have been ruled out (e.g. delirium) [58]. The development of PDP is associated with
increased caregiver burden, increased likelihood of nursing home placement, and is
associated with increased mortality [59].
33
For most of the twentieth century, PD was viewed primarily as a motor disease
related to loss of dopamine neurons in the nigrostriatal pathway, but PD is now
recognized as a multisystem disease associated with cognitive impairment related
to loss of cholinergic neurons, depression due to loss of noradrenergic neurons,
autonomic and other nonmotor symptoms [60]. In prior decades PDP was often
referred to as levodopa psychosis under the belief that excessive dopaminergic
stimulation from dopamine agonist treatment was the principal underlying cause.
It is now understood that the pathophysiology of PDP is due to loss of serotonergic
midbrain dorsal raphe neurons from to the accumulated Lewy body burden in these
cells. The loss of this serotonin signal results in upregulation and supersensitivity of
postsynaptic 5HT2A receptors, a finding confirmed by neuroimaging of PD patients
with and without psychosis [61]. That increased stimulation of 5HT2A receptors can
induce psychotic symptoms has been known for decades based on elucidation of
common mechanisms among hallucinogens such as psilocybin and lysergic acid
diethylamide.
The therapeutic dilemma in treating PDP relates to the profound loss of dopamine
neurons in the dorsal striatum, and the inability to tolerate antipsychotics that
possess moderate D2 affinity without significant worsening of motor symptoms.
Recognition that clozapine was associated with extremely low risk for drug-induced
parkinsonism led to a 1990 study exploring its tolerability in six PDP patients at
doses ranging from 75 to 250 mg/day (mean 170.8 mg/day) [62]. This early study
noted a 50% response rate, but 50% also experienced worsening motor symptoms
at those doses. These findings informed the design of the two seminal PDP studies
published in 1999, one from a French group and the second from a US consortium.
Each study was a double-blind, placebo-controlled 4-week trial, and both enrolled a
total of 60 subjects. Based on high rates of motoric worsening in the 1990 study, the
starting clozapine dose in each trial was 6.25 mg/day, with titration every 3–4 days
based on response and tolerability. In the French study mean endpoint clozapine
dose was 36 mg/day, while it was 24.7 mg/day in the US-based Psychosis and
Clozapine in the treatment of Parkinsonism (PSYCLOPS) trial [63,64]. At these
low doses, clozapine was significantly more effective than placebo in both trials,
and with large effect sizes; moreover, there was no exacerbation of parkinsonism
in the PSYCLOPS study, while 22% of patients in the French trial noted mild or
transient worsening of parkinsonism, although no patient discontinued the study
for this reason. Results from the 12-week PSYCLOPS extension study (n = 53)
34
confirmed the efficacy of low-dose clozapine for PDP (mean 28.8 mg/day), again
without worsening of underlying Parkinson’s disease symptoms as noted by ratings
of motor function or need for higher doses of dopamine agonist medications [65].
Recent naturalistic data are consistent with the clinical trials findings. A retrospective
review of 36 PDP patients treated at one center (mean age 68 years) noted that 33%
had complete response, and 33% a partial response to clozapine [66]. Highlighting
the practical issues involved with clozapine administration, the overall retention
rate on clozapine was only 41%, and the most common reasons for discontinuation
were frequent blood testing (28%), refusal of medical staff to continue clozapine
after nursing home placement (11%) and neutropenia (8%). Only 2.8% stopped
clozapine due to worsening motor symptoms, and a similar proportion discontinued
treatment due to orthostasis or delirium (2.8% for each). The possible benefit of
clozapine for levodopa-induced dyskinesias (LID) was later studied in 50 PD patients
without psychosis in a 10-week, double-blind, placebo-controlled, multicenter trial.
The principal outcome was change in the LID “on” time (hours per day). At a mean
clozapine dose of 39.4 mg/day, clozapine treatment was associated with reduction in
the duration of “on” periods from 5.68 h/day to 3.98 h/day, while the placebo group
slightly worsened from 4.54 h/day to 5.28 h/day [67].
Over the ensuing decade other atypical antipsychotics have been used in PDP
patients with results primarily reported in case series. Most have proved ineffective
and were associated with significant motoric worsening (olanzapine, risperidone,
ziprasidone, aripiprazole) [68]. Only olanzapine and quetiapine were examined
in double-blind studies as summarized in Table 1.6. In all trials olanzapine was
ineffective, and in the largest studies olanzapine exacerbated parkinsonian symptoms.
Quetiapine was generally ineffective, but did not induce motoric adverse effects.
Despite widespread use for PDP, a recent meta-analysis concluded that: “Given
the randomized controlled trial-derived evidence, quetiapine should not be used in
this indication, unless further studies have clarified this issue” [69]. Concerns over
quetiapine were further heightened by results of a large retrospective study exploring
180-day mortality rates in 7877 PD patients starting antipsychotic treatment and
7877 PD patients who did not take an antipsychotic matched for age, sex, race, year
of treatment, presence and duration of dementia, duration of PD, delirium, medical
comorbidity, and hospitalization. In this study, mortality was increased by a factor of
2.16 for quetiapine [70]. Unfortunately, the number of clozapine cases was too small to
analyze separately.
35
Table 1.6 Summary of double-blind studies for Parkinson’s disease psychosis [68].
Reference Effect on Effect on
Medication(N ) psychosis motor
symptoms symptoms
The French Clozapine Parkinson
Clozapine (n = 60) +++ 0
Study Group 1999 [64]
Parkinson Study Group 1999 [63] Clozapine (n = 60) +++ 0
Goetz et al., 2000 [78] Olanzapine (n = 15) 0 –
Breier et al., 2002 [79] Olanzapine (n = 160) 0 –
Ondo et al., 2002 [80] Olanzapine (n = 30) 0 0
Ondo et al., 2005 [81] Quetiapine (n = 31) 0 0
Rabey et al., 2007 [82] Quetiapine (n = 58) 0 0
Shotbolt et al., 2009 [83] Quetiapine (n = 24) 0 0
Fernandez et al., 2009 [84] Quetiapine (n = 16) + 0
Friedman et al., 2010 [85] Pimavanserin (n = 298) + 0
Cummings et al., 2014 [59] Pimavanserin (n = 199) ++ 0
Despite its efficacy data, a limiting factor in clozapine use for PDP relates to the
mandatory hematological monitoring, as a weekly laboratory trip can prove daunting
for a patient group comprised of older individuals with limited mobility. To obviate this
issue, researchers have sought to harness clozapine’s effectiveness in a molecule that
does not require laboratory monitoring. At the low doses used for PDP one of clozapine’s
most prominent receptor actions is at 5HT2A, and this is likely the primary site of action
based on the known pathophysiology of this disorder. This insight led to development of
the potent selective 5HT2A antagonist pimavanserin for PDP (Ki 0.087 nM), with US FDA
approval granted in 2016 [59]. Pimavanserin lacks affinity for dopaminergic, cholinergic,
alpha-adrenergic and histaminergic receptors, and in clinical trials had no impact
on ratings of motor function. While pimavanserin is a promising development in PDP
treatment, it is currently only available in the US, so clozapine remains the mainstay of
PDP management worldwide, and for those who fail to respond to pimavanserin.
Box 1.4 Essential Facts about Use of Clozapine for Parkinson’s Disease Psychosis
1. The initial starting dose is 6.25 mg PO QHS (quaque hora somni – every
night at bedtime). The clozapine dose can be advanced in 6.25 mg
increments as needed every 3–4 days, with most patients responding at
doses < 50 mg/day. The mean doses reported in clinical studies range
from 25 to 36 mg/day.
2. Routine hematological monitoring must be performed.
3. While generally well tolerated, sedation, orthostasis, worsening motor
symptoms and constipation have been reported.
36
Summary Points
a. Clozapine is the only antipsychotic with compelling efficacy data in treatment-

resistant schizophrenia, and in schizophrenia spectrum patients with
psychogenic polydipsia, suicidality or aggression that does not respond to other
antipsychotics.
b. Clozapine’s effectiveness for suicidality and aggression is independent of the
antipsychotic effect.
c. In real-world use clozapine reduces hospitalization rates, and is associated
with lower mortality rates from unnatural causes (suicide, accidents) and from
natural causes.
d. Clozapine’s efficacy as an adjunctive agent for treatment-resistant mania is also
independent of the antipsychotic effect.
e. Clozapine is a mainstay for the treatment of PDP, although pimavanserin is
approved in the US for this indication. Quetiapine appears ineffective in most
PDP trials and is associated with a 2.16-fold increased mortality risk over
180 days compared to PD patients on no antipsychotic.
37
References
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Domino (Ed.), History of Psychopharmacology, vol. 2 (pp. 95–106). Arlington, MA: Domemtech/NPP
Books.
2. Gross, H. and Langner, E. (1966). Das wirkungsprofil eines chemisch neuartigen
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814–816.
3. Amsler, H. A., Teerenhovi, L., Barth, E., et al. (1977). Agranulocytosis in patients treated with
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42
2
QUICK CHECK
Addressing Clozapine Positive Symptom
Nonresponse in Schizophrenia Spectrum
Patients
Introduction 44
Principles 45
A Is My Patient Adherent? 45
B Should the Plasma Level Be Increased? 47
C Antipsychotic Augmentation 48
D Electroconvulsive Therapy 50
E Nonantipsychotic Augmentation Strategies 53
Summary Points 56
References 57
INTRODUCTION
Clozapine provides the best option for treatment-resistant schizophrenia patients,

but at least 40% will have suboptimal response. Although numerous adjunctive
pharmacological strategies have been explored in clozapine nonresponders, none
present a compelling picture of superior outcomes. Echoing this sentiment, a 2015
review on biological approaches notes that improvement is modest with medication
strategies, although electroconvulsive therapy (ECT) is more promising despite the
paucity of controlled studies [1]. These conclusions may engender a certain amount
of therapeutic nihilism; however, before deciding that clozapine is ineffective and
embarking on a litany of adjunctive options, there is a short list of strategies that
may convert nonresponders into responders. Given the tepid response to adjunctive
options, the best hope for most patients is optimizing clozapine exposure through
assessment of plasma levels and addressing tolerability issues that impose barriers to
titration.
44
2: CLOZAPINE POSITIVE SYMPTOM NONRESPONSE
2
PRINCIPLES
• Medication nonadherence can occur with clozapine-treated patients and must 2

be ruled out as a cause of inadequate response.
• Although a plasma clozapine level of 350 ng/ml (1070 nmol/l) is used as a
threshold for response, many patients require levels substantially higher. If
tolerated, levels as high as 1000 ng/ml (3057 nmol/l) should be pursued in
search of efficacy.
• All tolerability issues that limit titration to higher doses (and plasma levels)
must be addressed. The best hope for response will come from optimizing
clozapine.
• Adjunctive antipsychotics with greater D2 affinity can be tried in clozapine
nonresponders, but effect sizes are small.
• Electroconvulsive therapy (ECT) is an effective adjunctive strategy for
treatment-resistant schizophrenia, with greater effect sizes seen when
combined with clozapine than with other antipsychotics.
• Nonantipsychotic adjunctive medications have limited efficacy data (e.g.
minocycline, memantine, topiramate, high-dose famotidine), but can be tried if
tolerated and there is insufficient efficacy from use of a D2 antagonist and ECT.
A Is My Patient Adherent?
Medication nonadherence is common in schizophrenia, and a primary cause

for antipsychotic failure (Figure 2.1). In an outpatient sample of 99 schizophrenia
patients deemed treatment-resistant, 35% had plasma antipsychotic levels that were
subtherapeutic [2]. Although the use of clozapine may be associated with better
adherence than other antipsychotic treatments, the only method to unequivocally
assess adherence is through measurement of plasma antipsychotic levels [3]. As
noted in Chapter 3, up to 30% variation in trough plasma clozapine levels is not
unusual even with adherent patients. When fluctuations exceed 50% nonadherence
must be suspected, assuming no change in clozapine dose, or exposure to inhibitors
or inducers. Oral dissolving tablet and liquid preparations should be considered in
these circumstances, along with observed medication administration and routine
measurement of plasma levels. (See Chapter 5 for more extensive discussion about
45
use of clozapine plasma levels.) Like many antipsychotics, clozapine has a response
threshold defined by plasma level, with the cut-off of 350 ng/ml (1070 nmol/l) chosen
on the basis of numerous studies [4]. Although levels above this value do not guarantee
response, patients with levels consistently below have lower response rates. The first
goal for the poorly adherent patient is minimizing excessive fluctuations in plasma
levels that suggest nonadherence, and achieving a trough plasma clozapine level
consistently > 350 ng/ml (> 1070 nmol/l). Patients can be persistently nonadherent, so
clinicians must be equally persistent in using all tools to maximize and verify adherence
on an ongoing basis. Once nonadherence has been excluded as a cause for inadequate
clozapine response, a systematic approach to further dose titration can be explored.
Figure 2.1. Rates of adherence in stable schizophrenia patients over 4 weeks.

60
Adherent
Proportion of Sample (%)
40
20
0
0–20 21–40 41–60 61–80 81–100
Adherence Rates (%)
(Adapted from: Remington, G., Teo, C., Mann, S., et al. (2013b). Examining levels
of antipsychotic adherence to better understand nonadherence. Journal of Clinical
Psychopharmacology, 33, 261–263 [31].)
46
2
B Should the Plasma Level Be Increased?
As discussed in Chapter 5, having a plasma clozapine level above the response 2

threshold of 350 ng/ml or 1070 nmol/l increases the chance of response; however,
some misinterpret this fact and incorrectly conclude that a patient who fails to
respond at a level above threshold is a clozapine failure. For many patients the
optimum plasma level for response is significantly higher than the threshold value
[5]. The threshold level of 350 ng/ml or 1070 nmol/l was elaborated as a concept
so that clinicians have an initial target in those not responding at a given dose for
a reasonable period of time, typically 3 weeks based on recent clinical trials. In
nonresponders without dose-limiting adverse effects, the literature clearly justifies
exploring levels up to 1000 ng/ml or 3057 nmol/l if tolerated. Very few patients will
respond at levels > 1000 ng/ml or > 3057 nmol/l (the so-called “point of futility”),
although clinicians may encounter rare patients who tolerate and respond to such
levels.
Box 2.1 Principles for Titrating Clozapine

1. The likelihood of response < 350 ng/ml or 1070 nmol/l is low (but not
zero). If tolerated, this is a reasonable initial target.
2. Many laboratories report an “upper limit” for clozapine levels of 600 ng/
ml (1834 nmol/l) or 700 ng/ml (2140 nmol/l), but there are clearly patients
who benefit from and tolerate these high plasma levels [5]. Given
the limited alternatives for resistant schizophrenia, patients must not
be deprived of a clozapine trial with higher plasma levels, assuming
tolerability.
3. Once the dose is increased, patients should be given 2–3 weeks to
respond before further titration if adverse effects are not limiting. In a
dose titration trial, time to response once the patient reached a dose
where they responded was 17 days on average (range of 2–56 days). No
late response was found among nonresponders despite a mean follow-
up period of 75 weeks [32].
4. Nonresponders without dose-limiting adverse effects must not be left on
the same dose and at the same plasma level for months on end hoping
for “late response.”
5. As levels reach the point of diminishing tolerability (> 700 ng/ml or
> 2140 nmol/l), they should be rechecked after each dose increase
of 50 mg/day. Very few patients will respond at levels > 1000 ng/ml
or > 3057 nmol/l (the so called “point of futility”), but clinicians may
encounter rare patients who seemingly tolerate and respond to such
levels.
47
As discussed throughout this volume, effective treatment of dose-limiting

adverse effects is critical to providing each patient an adequate clozapine trial. Due
to concerns about QT issues and seizures, some may be reluctant to push plasma
levels beyond what a local laboratory designates as the therapeutic range. As noted
in Chapter 3, the older literature on QT prolongation with clozapine relied on data
using the Bazett QT correction formula [6]. It is now clear that for patients with heart
rates ≥ 80 BPM (a common occurrence with clozapine), the Bazett formula grossly
overcorrects and provides a distorted picture of clozapine’s impact on the QT interval
[7]. Although the Fridericia and Framingham formulas are preferable to Bazett, most
machine-generated QTc values still use the obsolete Bazett formula. For this reason,
QTc values that look concerning (i.e. ≥ 400 ms) should be recalculated using a
non-Bazett formula via web-based or smartphone app QT calculators [8]. The use of
a modern QT correction method will help point out those cases of QT prolongation
that are simply artifacts of outdated technology, thereby facilitating further clozapine
dose increases. Chapter 10 provides an extensive discussion of seizure risk, and
notes three important facts: slower titration may help mitigate risk; seizures occur
uncommonly, even at high plasma levels; prophylactic anticonvulsants should not
be used as these will be unnecessary in over 90% of patients. The development
of intolerable adverse effects despite heroic countermeasures is a reason to limit
clozapine titration; clinician fear of manageable problems such as seizures based on a
misunderstanding of the risk is not [9].
C Antipsychotic Augmentation
Despite titration to maximum tolerable levels, a significant proportion of clozapine-

treated schizophrenia patients may not respond adequately, prompting a search
for any adjunctive strategy to manage persistent positive symptoms. Numerous
antipsychotic and other biological strategies have been examined over the years using
a variety of outcome measures to define response. In well-designed clinical trials,
response is typically defined as symptom reduction exceeding a certain threshold
(e.g. ≥ 30%) using a standard rating instrument such as the Positive and Negative
Syndrome Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS). Anecdotes and
small case series often lack an anchored measure of symptom reduction and are
difficult to interpret for that reason.
48
2
Clozapine has low affinity for D2, so the adjunctive use of a stronger D2
antagonist makes pharmacological sense. Unfortunately, the road to clozapine
for most patients is littered with failed trials of such agents, so the addition of
2
risperidone to a prior haloperidol nonresponder lacks intuitive appeal. Nonetheless,
this approach has been studied extensively and a 2012 meta-analysis of 14
studies (n = 734) by noted clozapine expert David Taylor, PharmD (Maudsley,
London, UK) found a small effect size of 0.24 [10]. The antipsychotics used in
these augmentation studies included amisulpride, aripiprazole, chlorpromazine,
haloperidol, pimozide, risperidone, sertindole, and sulpiride. Since that review
another double-blind, placebo-controlled adjunctive amisulpride trial (400 mg/day)
was published (n = 68), but augmentation did not increase chance of response at
the 12-week endpoint, and greater adverse effects were seen in the adjunctive
amisulpride cohort [11].
There are few comparative studies with two antipsychotic augmentation arms, but
one of the largest and longest studies examined outcomes between a D2 antagonist
(haloperidol) and a partial agonist antipsychotic (aripiprazole). In this 12-month,
randomized, controlled, open-label trial, 106 Italian patients who were inadequate
responders to clozapine at doses ≥ 400 mg/day for at least 6 months were enrolled.
Starting from a median baseline BPRS score of 60, mean decrease in BPRS over the
12 months of treatment was under 13%, and was similar between the aripiprazole
and haloperidol groups (7.0 vs. 7.9 point reduction, respectively; p = 0.389). All-cause
withdrawal rates were also not significantly different between the two adjunctive
arms: 37% vs. 28% in the aripiprazole and haloperidol groups, respectively (p = 0.43)
(see Figure 2.2) [12].
A 2017 Cochrane review specifically examined trials with two different
antipsychotic augmentation arms, incorporating the results of the Italian study
with other smaller studies [13]. Using these inclusion criteria, five comparative
studies with 309 participants were reviewable. The quality of the evidence was
low, and no one antipsychotic appeared superior to any other for augmenting
clozapine among a list that included amisulpride, aripiprazole, haloperidol,
quetiapine, sulpiride, and ziprasidone. Based on these results and those from
the Taylor 2012 review, the following conclusions should guide antipsychotic
augmentation attempts.
49
Figure 2.2. Comparative trial of adjunctive aripiprazole vs. haloperidol.

Month
0 3 6 9 12
0
–2
–4
Change in BPRS
–6
–8
–10
–12
–14
Clozapine + Haloperidol Clozapine + Aripiprazole
(Adapted from: Cipriani, A., Accordini, S., Nose, M., et al. (2013). Aripiprazole versus
haloperidol in combination with clozapine for treatment-resistant schizophrenia:
A 12-month, randomized, naturalistic trial. Journal of Clinical Psychopharmacology, 33,
533–537 [12].)
Box 2.2 Principles for Use of a Second Antipsychotic to Augment Clozapine

1. There is no compelling evidence that any one antipsychotic is superior
for augmenting clozapine.
2. The effect size for antipsychotic augmentation is small (0.24), but the
strategy is still worth pursuing.
3. Choice of antipsychotic should be based on avoidance of additive
adverse effects with clozapine (e.g. orthostasis, sedation, constipation,
metabolic), and a patient history of sensitivity to D2 antagonism.
D Electroconvulsive Therapy
Electroconvulsive therapy (ECT) has proven efficacy for schizophrenia, but is not
as commonly used for this purpose in Western countries as for treatment-resistant
major depressive episodes. A 2005 Cochrane review commented that ECT was more
50
2
effective than sham treatment for schizophrenia, but less so than antipsychotics;
moreover, there was limited evidence at that time to suggest that ECT combined
with antipsychotics resulted in greater improvement than antipsychotics alone [14].
2
Nonetheless, shortly after clozapine’s approval a pioneer in ECT research, Max
Fink, MD suggested adjunctive ECT for clozapine nonresponders, and case reports
gradually emerged over the next decade [15]. While the addition of ECT to clozapine
appeared safe and not associated with high rates of prolonged seizure as was feared,
no controlled trials were published until the 2015 study by Petrides reignited interest
in combining ECT with clozapine [16]. In this single-blind, 8-week trial, clozapine
nonresponders were assigned to clozapine treatment as usual (TAU) (n = 19) or
clozapine combined with bilateral ECT (n = 20) administered thrice-weekly for weeks
1–4, then twice-weekly for weeks 5–8. Response was rigorously defined: ≥ 40%
decrease in the psychotic symptom subscale of the BPRS, plus a Clinical Global
Impression (CGI) severity rating < 3 (see Box 2.4), and a global impression of being
much improved. None of the TAU group met response criteria, but 50% of the ECT +
clozapine group were classified as responders (Figure 2.3). In the crossover phase, all
19 patients from the TAU group received 8 weeks of the ECT protocol and 47% met
response criteria [16].
Box 2.3 Electroconvulsive Therapy (ECT) in Clozapine Nonresponders

1. ECT is effective as adjunctive treatment in schizophrenia, with
retrospective data suggesting it is more effective when combined with
clozapine that with other antipsychotics.
2. Prolonged seizure (< 5%) and delirium (< 5%) are uncommon when
combined with clozapine. Post-treatment hypertension was noted
in one study from India (17%). Mild cognitive impairment occurs in
approximately 10% of patients and is not persistent. Severe impairment
is not reported. Pre-ECT tachycardia must be managed.
3. The majority of papers reported use of bilateral electrode placement for
schizophrenia (all antipsychotics). There is no consensus on whether
bitemporal or bifrontal is more effective or induces less cognitive
dysfunction.
4. In the one controlled trial of ECT + clozapine, the mean number of
treatments over 8 weeks was 15. Retrospective case series report
a mean of 14 treatments, with some responding in as few as five
treatments.
5. Sustained response without additional ECT treatment is often noted, but
some may need maintenance ECT.
51
Figure 2.3. Changes in psychosis symptoms over 8 weeks of adjunctive ECT.

20
BPRS Total Psychosis Score
15
10
Clozapine
Clozapine + ECT
0 2 4 6 8
Weeks
(Adapted from: Petrides, G., Malur, C., Braga, R. J., et al. (2015). Electroconvulsive
therapy augmentation in clozapine-resistant schizophrenia: A prospective, randomized
study. American Journal of Psychiatry, 172, 52–58 [16].)
Since 2015 there has been an explosion of interest regarding the addition of ECT
to antipsychotic therapy for treatment-resistant schizophrenia patients, with nine
papers published in 2017 alone [17]. The bulk of these are retrospective reviews,
although one study randomized patients to one of three ECT electrode placements,
but with no control group. The Petrides study provides the best efficacy data for
ECT added to clozapine, but several conclusions can be gleaned from the newer
papers as summarized in Box 2.3 [17]. The superiority of ECT + clozapine compared
to ECT + other antipsychotics was found in one large retrospective inpatient study
examining post-treatment hospital days over the following year, and a related review
of all available studies [18,19]. Two case series comprised exclusively of clozapine-
treated patients (n = 66) also noted no persistent cognitive adverse effects, or unusual
patterns of prolonged seizure activity or delirium [20,21]. These conclusions are
consistent with larger reviews summarizing all of the case literature for combined
52
2
ECT + clozapine treatment [22]. More controlled randomized trials will be helpful to
resolve important questions about the choice of ECT electrode placement, unilateral
vs. bilateral treatment, treatment parameters and schedules, the duration of sustained
2
response, and any long-term cognitive impact compared to a control group [23].
Nonetheless, there is a compelling picture of efficacy and tolerability for adjunctive
ECT in clozapine nonresponders, and this treatment modality should be pursued before
the more questionable nonantipsychotic medication strategies mentioned below.
There are case reports and series for the use of repetitive transcranial magnetic
stimulation (rTMS) for schizophrenia. While high-frequency rTMS over the dorsolateral
prefrontal cortex and low-frequency rTMS over the temporoparietal cortex do appear
safe in clozapine-treated patients, efficacy in clozapine-refractory patients remains
uncertain [24].
E Nonantipsychotic Augmentation Strategies
Nonantipsychotic pharmacological augmentation strategies have been studied

including anticonvulsants, glutamate signal modulators, and anti-inflammatory agents.
For some molecules (e.g. lamotrigine, topiramate), the reduction in positive symptoms
seen when added to other antipsychotics was not seen when combined with clozapine.
As discussed in Chapter 5, clozapine is hypothesized to exert its unique benefit partly
via interaction with the glycine co-agonist site on N-methyl-d-aspartate (NMDA)
glutamate receptors [25]. Increasing glycinergic activity through agonists or glycine
reuptake inhibitors improves efficacy of nonclozapine antipsychotics, but not clozapine.
In three studies where glycine was administered in daily doses of 30–60 g to clozapine-
treated patients, positive symptoms significantly worsened [26]. A comprehensive
2017 review of all randomized clinical trials for augmentation strategies used with
antipsychotics found that no combinations with clozapine outperformed controls [27].
Aside from case reports, one is left with a group of trials that have methodological
limitations, but may provide some glimpses of hope for those who fail antipsychotic
augmentation or ECT. Table 2.1 lists options that pose no significant safety hazard,
and can be considered. It must be noted that the meta-analyses endorsing divalproex/
valproate, topiramate and minocycline included a significant number of studies that
were excluded from the 2017 review due to high risk of bias or other concerns. These
are suggested mostly due to the accrued clinical experience that their use poses
no immediate safety hazard. However, because of tolerability issues with divalproex
(weight gain, neutropenia risk) and topiramate (sedation, cognitive dysfunction) these
53
Table 2.1 Nonantipsychotic pharmacological augmenting strategies to consider.

Medication Comments
Nine randomized, controlled studies with small effect on total
psychopathology (n = 658). Generally well tolerated, but long-term
Divalproex/
neutropenia risk presents an issue at higher serum valproate levels.
valproate
Modest kinetic interaction with clozapine – clozapine levels should be
rechecked [33].
Some improvement in total psychopathology and positive symptoms
Topiramate across five randomized, controlled studies (n = 270) with mean dose
165 mg/day. Not well tolerated [33].
Eight double-blind, adjunctive, placebo-controlled studies, most 100 mg
BID, (mean dose 172 mg/day). Mean duration 18.5 weeks. Improvements
Minocycline
in total symptoms, negative symptoms and cognition seen, but marked
differences between studies. Well-tolerated [34,35].
Two randomized, double-blind, placebo-controlled 12-week studies of
20 mg/day (total n = 73). Improvement in positive symptoms, negative
Memantine symptoms and cognition noted. One-year open-label extension found
benefits in all symptom domains. Well tolerated in studies up to 12
months [36–38].
One double-blind, high-dose study at 100 mg BID, started without
titration. Well tolerated over 4 weeks. 11/30 subjects in the trial were on
Famotidine
clozapine. At endpoint, significant improvements in PANSS total score
and general psychopathology subscores noted [39].
One double-blind, 6-week, three-arm study of 1g/day, 2g/day or placebo
Sodium added to clozapine (n = 60). Well tolerated. Both doses of sodium
benzoate benzoate were superior to placebo for negative symptoms, and 2 g/day
was better than placebo for PANSS total score, and positive subscore [40].
agents should not be continued longer than 8 weeks as augmenting medications

if clinically significant impact on positive symptoms is not seen. Minocycline is an
antibiotic hypothesized to work via an anti-inflammatory mechanism and is well
tolerated as an adjunctive agent, although perhaps not very effective. Memantine,
a low-affinity uncompetitive NMDA antagonist, and sodium benzoate, a d-amino
acid oxidase inhibitor, are thought to exert their effects via glutamate modulation,
somewhat contrary to the theory proposed above. At NMDA receptors, the amino acid
d-serine acts as a co-agonist at the glycine site. By blocking the enzyme responsible
for its metabolism (d-amino acid oxidase), sodium benzoate will increase the d-serine
signal at the glycinergic site on the NMDA receptor. Because there is only one study
of adjunctive sodium benzoate with clozapine, more data will help clarify whether this
is effective. Famotidine’s efficacy is based on hypotheses regarding brain histamine
signaling. Although well tolerated, the local pharmacy may be perplexed by the dose,
although patients with Zollinger–Ellison syndrome (ulcers due to gastrinoma) take
doses up to 800 mg/day with no ill effects [28].
54
2
Before embarking on any of these nonantipsychotic strategies, an effort should be
made to rate baseline symptoms, especially as the trial might extend over many months
and new providers may not have a sense of the pretreatment baseline. The one-item
2
Clinical Global Impression (CGI) severity scale is very easy to use, and correlates extremely
well with gold-standard schizophrenia rating scales during antipsychotic trials of acutely ill
schizophrenia patients [29]. On pages 743–744 of the Diagnostic & Statistical Manual of
Mental Disorders, 5th Edition (DSM-5) there is a proposed dimensional scoring instrument
for psychosis that captures positive symptoms, negative symptoms and cognition [30].
The DSM-5 assessment should not be used for research purposes as the psychometric
properties are not known, but the anchored definitions may be helpful in a clinical setting.
Box 2.4 The Clinical Global Impression (CGI) Severity Scale

1. Normal
2. Borderline mentally ill, not at all ill
3. Mildly ill
4. Moderately ill
5. Markedly ill
6. Severely ill
7. Among the most extremely ill patients
Except for the two anticonvulsants divalproex and topiramate, it is not

unreasonable to consider a trial of up to 26 weeks for these nonantipsychotic
medications, assuming no tolerability concerns emerge. It is important that no other
substantial medication changes be made during that time to better assess whether
the new molecule has any value. Although many of these medications are inexpensive,
there is no point in subjecting a patient to years of an ineffective agent, especially
given the number of medications that might be needed to manage the mental illness
and clozapine-related adverse effects.
55
Summary Points
a. Before concluding that a patient is a clozapine failure, one must rule out
adherence issues, and push plasma levels to the point of significant response,
intolerability or futility.
b. Tolerability issues that limit titration to higher doses must be addressed. Fear
of adverse effects (e.g. seizures) is not a valid reason to avoid pursuing higher
plasma clozapine levels.
c. Adjunctive antipsychotics with greater D2 affinity can be tried in clozapine
nonresponders, albeit with small effect sizes.
d. Adjunctive electroconvulsive therapy (ECT) is an effective strategy for treatment-
resistant schizophrenia patients on clozapine, and is well tolerated.
e. Nonantipsychotic adjunctive medications that have limited efficacy data can be
tried if adjunctive antipsychotics or ECT do not yield sufficient benefit.
56
2
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290–291.
16. Petrides, G., Malur, C., Braga, R. J., et al. (2015). Electroconvulsive therapy augmentation in
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35. Xiang, Y. Q., Zheng, W., Wang, S. B., et al. (2017). Adjunctive minocycline for schizophrenia: A
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59
3
QUICK CHECK
Initiating Clozapine
Introduction 60
Principles 61
A Baseline Work-Up 62
B Registration 66
C Titration 67
• Minimizing Cytochrome P450 Inhibitors or Inducers
Prior to Starting Clozapine 69
• Patient Discussions Prior To Initiation 70
• Monitoring During Initiation 71
• Choice of Formulation 71
• Tapering Concomitant Medications 73
Summary Points 75
References 76
INTRODUCTION
The decision to start clozapine therapy derives from the accepted, evidence-
based uses for this medication including treatment-resistant schizophrenia spectrum
disorders, schizophrenia patients with a history of suicidality, schizophrenia
spectrum patients with persistent aggression, treatment-resistant mania, and
psychosis associated with Parkinson’s disease (see Chapter 1). As was discussed
in Chapter 1, the greatest conundrum in determining whether a schizophrenia
patient is truly resistant to other treatment is high rates of nonadherence, with
subtherapeutic plasma antipsychotic levels seen in 35–44% of outpatients deemed
to have treatment-resistant illness [1]. Once a patient is a candidate based on
clinical criteria, patients and caregivers must be educated about the unique benefits
of clozapine, its common adverse effects, and the demands of monitoring. With many
60
3: INITIATING CLOZAPINE
3
PRINCIPLES
• The work-up is limited to common labs, EKG, and usually a physical

examination
• Evaluation of QT intervals requires the appropriate heart rate correction 3
formula
• Registration of clozapine with the appropriate system for each country is
required
• Titration of clozapine is geared towards the indication (e.g. schizophrenia,
Parkinson’s disease psychosis, etc.), acuity, age, the treatment setting
(inpatient vs. outpatient), concurrent medications, and the presence of
variables that influence clozapine disposition (e.g. smoking, use of cytochrome
P450 inhibitors or inducers, functional cytochrome P450 polymorphisms)
outpatients this is a conversation that is often performed over an extended period as

patients try and fail other options and come to trust the clinician’s suggestion that
the benefits of clozapine outweigh the burdens of treatment. An important principle
to guide these discussions is that significant delays in starting clozapine may reduce
the likelihood of response in treatment-resistant schizophrenia. A review of response
rates among 90 patients who remained on clozapine for at least 3 months found
that the response rate was 82% for those who started clozapine within 2.8 years of
meeting clinical criteria for treatment resistance, but fell to 31% when clozapine was
started > 2.8 years after reaching this benchmark [2].
At times clozapine is started in an inpatient setting; if so, enlisting the support
of outpatient caregivers is crucial to treatment success, as they too will share the
burdens of monitoring and treatment. The alacrity with which a caregiver can alert
clinicians about adverse effects, and the caregiver’s ability to convincingly reassure
a patient that clozapine’s benefits outweigh its burdens, may forestall unnecessary
treatment termination. For certain outpatients, difficulties encountered in traveling
may be the biggest barrier to treatment, but highly motivated caregivers may work
with clinic personnel to troubleshoot these obstacles and devise strategies to facilitate
transporting a patient to necessary laboratory and clinic appointments. Even with
compulsory inpatient treatment, a discussion is critical to inform the patient about
the reason clozapine is being utilized (e.g. persistent aggression despite high plasma
levels of standard antipsychotics), the goals of treatment, and the frequency of
61
monitoring. As with outpatient caregivers, educated hospital personnel will also be

more motivated to work with resistant patients in obtaining laboratory measures with
the understanding that clozapine is the best option to bring symptomatic relief or
reduce violent behavior [3].
A Baseline Work-Up
The approved indications for clozapine treatment and definitions of treatment

resistance vary between countries, so clinicians must be alert to local regulations
regarding “off-label” use of clozapine and any additional paperwork required [4]. A
baseline work-up must be performed for all patients starting clozapine even if the
patient has prior experience with clozapine. The purpose of this evaluation is to establish
that hematological thresholds are met and to document baseline physical health status.
For patients who have recently been discontinued from clozapine (e.g. < 90 days) and
are candidates to resume treatment, hematological measures are sufficient, but as
the time from last treatment lengthens (e.g. ≥ 12 months) prudence dictates a more
thorough evaluation. In some parts of the world, elements of this baseline work-up
are mandated by the local health trust, regulatory authority, clinic or hospital policy,
but in many instances clinicians are left to choose what seems best from a myriad of
conflicting recommendations. The sections below outline the minimum necessary items
to be obtained prior to commencing clozapine therapy (see Tables 3.1–3.3).
Table 3.1 Baseline vital signs.

Measure Rationale Response to abnormal results
Appropriate work-up for fever
Up to 20% incidence of benign
etiology if temperature is ≥ 38°C.
Temperature fever during early weeks of
Hold clozapine initiation until
clozapine therapy.
resolved.
Work-up to determine whether
etiology is due to hypovolemia,
Resting heart Tachycardia is a common
or orthostasis due to effects of
rate adverse effect from clozapine.
current medications. Hold clozapine
initiation until resolved.
Orthostasis is a common
If orthostatic changes are present
adverse effect from clozapine.
upon standing, work-up to
Consider adding orthostatic
determine whether etiology is due to
Blood pressure BP measurements to routine
hypovolemia or medication related
seated BP in those with
orthostasis. Hold clozapine initiation
complaints of dizziness on
until resolved.
standing.
continued overleaf
62
3
Table 3.1 continued

Obesity by itself is not a
contraindication to clozapine
Weight and
Weight gain is a common use, but may prompt use of more
body mass
index (BMI)
adverse effect from clozapine. aggressive measures (e.g. lifestyle, 3
metformin) to mitigate weight gain at
the start of clozapine treatment.
Both the physical examination
The nature of the response depends
and the history obtained prior
on the abnormalities found during
to the exam provide important
the history or exam. Of particular
data. For example, questions
concern is a history of, or physical
regarding symptoms of heart
Physical findings consistent with, persistent
failure or constipation elicit
examination constipation, poorly controlled
information that could possibly
seizure disorder or congestive
be missed from vital signs,
heart failure, all of which must
ECG or laboratory measures.
be addressed prior to clozapine
Smoking status and history of
initiation.
seizures must be noted.
Table 3.2 Baseline laboratory measures.

Baseline absolute neutrophil
count (ANC) is required to
Those with baseline ANC below
commence clozapine. Some
Complete treatment thresholds must be
countries still require a total
blood count investigated for potential causes,
white blood cell count (WBC),
(CBC) with including medications (e.g.
but only ANC is tracked in the
differential antipsychotics, divalproex) and benign
US. Baseline eosinophil is useful
ethnic neutropenia (BEN).
as eosinophilia may occur during
treatment with clozapine.
Appropriate work-up depending on the
Rule out previously undiagnosed
abnormality found. Baseline creatinine
Chemistry physical ailments such as
is necessary should the patient later
panel renal or hepatic dysfunction, or
be suspected of developing clozapine-
electrolyte disturbances.
induced interstitial nephritis.
A1C values ≥ 6.5% are diagnostic
Rule out untreated diabetes
of diabetes. In those with known
mellitus (DM) and to establish
A1C DM, values > 7.0% represent less
a baseline, especially for those
than ideal control and need to be
with known DM.
addressed.
Significant abnormalities must be
Rule out untreated dyslipidemia
addressed, particularly markedly
and establish baseline,
Lipid panel elevated fasting triglycerides, given
especially for those with known
clozapine’s known effects on insulin
dyslipidemia.
resistance.
63
Table 3.3 Additional baseline measures for consideration.

Cardiology consultation for abnormal
findings. As noted below the
Rule out untreated conduction appropriate QT correction formula
ECG or other cardiac issues. Often should be applied if the resting
required. heart rate (HR) is > 72 beats per
minute (BPM). (See discussion
on QT.)
Rule out undocumented
constipation among patients Address current issues impacting
Abdominal with a history of constipation, gastrointestinal motility prior to
X-ray or who are poor historians. treatment if X-ray suggests significant
May be required in some constipation.
locales.
Box 3.1 Which QT Correction Formula to Use for QT Monitoring?

Tachycardia is often associated with QT prolongation due to the persistent use
of the Bazett rate correction formula on most ECG machines. This formula was
derived in 1920 from 39 healthy male controls and significantly overcorrects
the QTc for faster heart rates [21]. For this reason, American Heart Association
guidelines for ECG interpretation recommend against using Bazett’s formula
with high heart rates, as the “adjusted QT values may be substantially in
error” [22]. A recent analysis of 6600 adults mean age 60 years old also
found that Bazett performed worst of all formulas even among patients with
HR < 90 BPM [23].
Bazett Formula: QTcB = QT/√RR (Note: RR is expressed in seconds.)
Fridericia Formula: QTcFri = QT/ 3√RR (Note: RR is expressed in seconds.)
Framingham Formula: QTcFra = QT + 0.154(1– RR) (Note: RR is expressed in
seconds.)
Examples on how to use each formula (HR 80 BPM, RR = 0.75 sec, QT
uncorrected = 400 ms or 0.4 sec):
a. Bazett: 0.400 sec/(0.75)1/2 = 0.462 sec = 462 ms
b. Fridericia: 0.400 sec/(0.75)1/3 = 0.440 sec = 440 ms
c. Framingham: 0.400 sec + 0.154(1 – 0.75) = 0.439 sec = 439 ms
64
3
Table 3.4 Results of various QT rate correction formulas (example: uncorrected
QT = 400 ms).
Heart rate RR interval QTcB QTcF QTcFra
(BPM) (sec) (Bazett) (ms) (Fridericia) (ms) (Framingham) (ms)
60 1.00 400 400 400
72 0.83 438 425 426 3
80 0.75 462 440 439
90 0.67 490 458 451
100 0.60 516 474 462
110 0.56 542 490 470
120 0.50 566 504 477
Box 3.2 Comments on the Baseline Work-Up

a. Why no waist circumference? Although waist circumference is a criterion for
the metabolic syndrome, in clinical practice there is significant variability in
measurements between examiners to an extent that does not exist with BMI.
Changes in BMI thus serve as a more accurate measure of changes in weight.
In many analyses BMI values that are in the specific obesity range for that
ethnic group (e.g. ≥ 30 kg/m2 for Europid individuals) are excellent surrogate
markers for the waist circumference criterion of metabolic syndrome. One
can adequately monitor for the presence of the metabolic syndrome using the
standard laboratory values and blood pressure combined with BMI.
b. Is an ECG necessary? The high prevalence of tachycardia combined with
the common use of the Bazett QT correction formula present a skewed
picture of clozapine’s risk for cardiac adverse effects. A recent analysis of
cardiovascular outcomes among 3262 Danish outpatients commencing
clozapine found that cardiovascular adverse effects were rare and no
greater than for other antipsychotic agents [24]. Despite these recent
data, an ECG is typically required in most health-care settings as part of
the baseline work-up. For older patients there may be considerable value
in the baseline ECG to document existing abnormalities that might later
be inaccurately ascribed to clozapine.
c. Are a baseline troponin I/T, C-reactive protein and an echocardiogram necessary? As
will be discussed in Chapter 12, myocarditis is an uncommon (reported
rates 0.1–3.0%) but potentially fatal complication of clozapine treatment
seen during the first 6 weeks of treatment. While troponin I/T, C-reactive
protein (CRP) and echocardiogram are considered standard care in
those suspected of myocarditis, one group of Australian researchers has
suggested obtaining these labs and an echocardiogram at baseline [18].
Without further research into the value of the baseline echocardiogram,
given cost and feasibility issues this recommendation has not seen
widespread adoption. Troponin and CRP levels may be useful during the
first 6 weeks of treatment to screen for myocarditis (see Chapter 12).
65
B Registration
Most countries have a coordinated system for registering patients prior to

receiving clozapine treatment. There are several purposes: (a) to track neutrophil
counts so that ongoing patients have clozapine withheld when counts are below
dispensing thresholds; (b) to ensure that patients are not rechallenged without the
clinician’s explicit knowledge of prior episodes of severe neutropenia; (c) to help
clinicians find periods of prior clozapine exposure, particularly when clozapine may
have been terminated for unclear reasons; and (d) to limit clozapine prescribing
to those with presumed expertise. Clinicians must also be registered to prescribe
clozapine in nearly every country, and in some countries (e.g. US) may be required to
pass a brief online examination to ensure they understand the hematologic monitoring
scheme and are aware of the existence of benign ethnic neutropenia (BEN).
In some countries a separate registry may be overseen by each manufacturer, a
process that causes two types of problems: (a) all registries must be checked prior to
commencing clozapine; and (b) patients must be reregistered if they move to an area
that uses a different supplier, or require a formulation from a different manufacturer.
In the US, this problem was resolved in 2013 by creation of a central site that
consolidated data from each of six manufacturers within the US (see Table 3.5) [4].
Table 3.5 Clozapine registry resources for Canada, the US, UK, and Australia.
Country Clozapine registration
a. Auro-Pharma: AA-Clozapine Risk Management Program
www.aaclozapine.ca
Canada1 b. Mylan Pharmaceuticals GenCAN www.gencan.ca
c. Novartis: Clozaril Support and Assistance Network (CSAN)
https://psp-force-com.pspgw.ca
United Clozapine Risk Evaluation & Mitigation Strategy (Clozapine REMS)
States2 www.clozapinerems.com
a. Britannia Pharmaceuticals Denzapine Monitoring System
www.denzapine.co.uk
United
Kingdom1
b. Mylan Pharmaceuticals Clozaril Patient Monitoring Service
CPMS) www.clozaril.co.uk
c. Zaponex Treatment Access System (ZTAS) www.ztas.co.uk
a. Novartis Clozaril Patient Monitoring System www.ecpms
.com.au
Australia 1,3
b. Pfizer Australia Clopine Central www.clopine.com.au/

ClopineCentral/
1. Manufacturer specific registry; 2. Central registry for all manufacturers; 3. Prior to acquisition by
Pfizer, Hospira created a joint database with Novartis, the Clozapine Exclusion Database (www
.clozapine.com.au). Pfizer now has its own site.
66
3
C Titration
Given the enormous number of patient and clinical variables, the concept of a
standard clozapine titration is a myth. For example, a relatively rapid titration might
be both tolerable and safe for a highly symptomatic or aggressive younger patient 3
residing on an inpatient unit where vital signs can be monitored routinely, and adverse
effects noted immediately [5]. For an older outpatient with a history of orthostasis a
more gradual titration may be more appropriate. The patient’s smoking status must
also be factored into any titration schedule, as nonsmokers will achieve plasma
clozapine levels 50% greater than will smokers for any given dose [6]. Even with
excellent clinician rapport and caregiver support many patients may refuse to continue
with clozapine for treatable issues such as sialorrhea, sedation and orthostasis,
issues that are often the products of overly ambitious titration schedules [7]. As
clozapine remains the treatment of choice for resistant schizophrenia, and for suicidal
or aggressive schizophrenia spectrum patients, clozapine refusal for these adverse
effects is a clinical outcome to be avoided. With these considerations in mind, Box 3.3
lists some principles that govern any clozapine initiation.
Box 3.3 Basic Principles for Initiating Clozapine

1. “Standard” clozapine titration schedules recommended by the institution,
clinic or presented in the literature must be individualized. Prolonged
titration over many months should be avoided, but schedules may need
to be adjusted based on tolerability and the clinical scenario.
2. Aggressive management of early adverse effects such as constipation
(see Chapter 7), sialorrhea (see Chapter 9), sedation and orthostasis (see
Chapter 8) is important to maximize the likelihood of a successful trial.
3. Timely tapering of concurrent medications whose adverse effects overlap
with that of clozapine is a necessary component of strategies to minimize
adverse effects.
Given these caveats, below are some suggested titration options broken down into
more or less aggressive schedules as might be suitable for inpatients or outpatients
(see Tables 3.6 and 3.7). While smoking is generally precluded on inpatient units, this
is not universally true, so each table has a dosing modifier for those who continue to
smoke, bearing in mind that consumption of as few as seven cigarettes per day may
be sufficient to fully induce cytochrome P450 1A2 [8]. Clozapine’s peripheral half-life
ranges from 9 to 17 hours [9], leading many clinicians to advocate for BID dosing;
67
Table 3.6 Faster titration (suitable for inpatient settings).

Day Adult dose (smoker) (mg QHS) Adult dose (nonsmoker) (mg QHS)
1 25* 12.5
2 50 25
3 100 50
5 150 75
7 200 100
10 250 125
12 300 150
14 350 175
16 400 200
Continued titration based on steady-state plasma level obtained approximately 5–7 days after the
increase on Day 16 and the clinical response (see Target Plasma Levels).
* QHS (Latin quaque hora somni) = every night at bedtime.
Table 3.7 Slower titration (suitable for outpatient settings).

Day Adult dose (smoker) (mg QHS) Adult dose (nonsmoker) (mg QHS)
1 25 12.5
3 50 25
6 100 50
9 150 75
12 200 100
15 250 125
18 300 150
21 350 175
24 400 200
Continued titration based on steady-state plasma level obtained approximately 5–7 days after
the increase on Day 18 and the clinical response (see Target Plasma Levels).
however, several facts need to be considered: (a) the half-life of the active metabolite
norclozapine is closer to 20 hours [10]; (b) in North America clozapine is prescribed
once daily in 75% of chronic schizophrenia patients without demonstrable loss of
efficacy [11]; (c) clozapine and norclozapine are high-affinity antagonists at histamine
H1 (Ki values: 2.0 and 3.4 nM, respectively), and clozapine is also an antagonist at
multiple muscarinic receptors, resulting in significant sedation. For these reasons, the
suggested schedules above recommend bedtime dosing. (For a detailed discussion of
clozapine initiation in children or adolescents, see Chapter 15).
68
3
• Minimizing Cytochrome P450 Inhibitors or Inducers Prior to Starting
Clozapine
As discussed in Chapter 5, clozapine’s metabolism is primarily through cytochrome
P450 (CYP) 1A2, especially at lower plasma levels, with contributions from CYP 2C19,
3A4, 2C9, and 2D6 that are 24%, 22%, 12% and 6%, respectively [12]. In particular, 3
the combination of clozapine with the strong 1A2 inhibitors fluvoxamine or ciprofloxacin
has been associated with reported fatalities, and these agents should not be routinely
combined with clozapine. Strong inhibitors of the other isoenzymes listed may double
clozapine plasma levels, so a 50% downward adjustment to the titration doses must be
made if these agents cannot be discontinued prior to starting clozapine. Carbamazepine
and omeprazole decrease clozapine exposure as much as 50% through induction of
CYP 3A4 and P-glycoprotein (carbamazepine) or CYP 1A2 (omeprazole). Alternatives
to these agents must be sought and commenced prior to starting clozapine, with a
preference for using divalproex given its superiority to other anticonvulsants for those
rare patients who develop clozapine-related myoclonic or generalized seizures.
Rapid Titration: Two studies of extremely rapid titration exist in the literature,
with patients achieving mean daily doses of 100 mg in the first 4 hours, 260 mg by
day 5, and 400 mg by day 7 [5,13]. It is worth noting that 90% of the patients in one
study were smokers, as were 54% in the second study. While one study (n = 38) had
no patients with seizures, severe hypotension or other significant adverse effects, in
the second study, 36% of the rapid titration group (n = 25) developed hypotension
compared to 19% of a standard titration group (n = 26) (number needed to harm
(NNH) = 6), although only 12% of the rapid titration group developed excessive
sedation compared to 19% of the standard titration group [13].
Comments: Faster titrations may be acceptable for younger patients, those who
reside close to a clinic, and those who have reliable caregiver support.
Plasma Levels: Obtaining plasma levels early in treatment allows for an
assessment of progress towards minimum response thresholds, as well as problems
with adherence or unusually rapid metabolism. Particularly when levels are markedly
below what might be expected for the given dose, bearing in mind smoking status
and interacting medications, repeating levels can help determine whether adherence
or genetic factors are the cause, or there are laboratory issues with the assay [6]. (See
Chapter 5 for an extensive discussion of factors influencing clozapine metabolism and
the use of plasma levels.) For schizophrenia spectrum disorders, there is an extensive
literature on the minimum response threshold. The 12-hour trough plasma level
69
(obtained prior to administration of morning clozapine if on divided doses) is used

to assess clozapine exposure. The response threshold of 350 ng/ml or 1070 nmol/l
is cited most commonly in the literature [14], although some may respond at lower
levels, and many may require levels more than twofold higher.
Parkinson’s Disease Psychosis (see Chapter 1 for more discussion): Pimavanserin, a
potent and selective 5HT2A inverse agonist, has been approved for the treatment of
Parkinson’s disease psychosis (PDP) [15], but it may not be available in all countries,
and may prove inadequate for some patients. Clozapine has proven effective for PDP,
with mean daily doses in the range of 25–36 mg/day in the two pivotal double-blind,
placebo-controlled trials [16,17]. Daily doses as low as 6.25 mg may be effective
for PDP, and this is the recommended starting dose given at bedtime. Doses can
be advanced by 6.25 mg increments every 3–4 days based on tolerability and
symptomatic response. Rarely are doses ≥ 50 mg/day required.
• Many hospitals or clinics have mandated informed consent or information forms

Patient Discussions Prior To Initiation
to document discussions with the patient about aspects of clozapine treatment.
Table 3.8 Suggested checklist of patient and caregiver information prior to

starting treatment.
Item Date
1. The indication for clozapine has been explained.
2. The reasons for clozapine monitoring have been explained.
3. Clozapine’s common side effects have been explained and actions to take
should they occur.
4. Signs and symptoms of infection have been explained and what to do
should they occur.
5. The importance of regular blood tests has been discussed and what may
happen if they miss their blood test.
6. Discuss the importance of continuing clozapine.
7. Document that dietary and lifestyle advice has been given to the patient.
8. What to do if they miss a dose, especially if more than 48 hours has elapsed.
9. Explain how smoking can affect clozapine levels and the importance of
letting the prescriber know if they intend to stop or cut down smoking, or
start smoking.
10. Whom to contact in an emergency both during and after office hours.
70
3
Whether a checklist or special consent form is required or not, it is important to
demonstrate that the patient has been informed about the important considerations
in their treatment. A review of various practices worldwide notes common elements
that ought to be documented by the prescribing clinician, typically via checklist
(see Table 3.8). Items 1–8 are appropriate for inpatients and outpatients, while 3
items 9 and 10 will apply to outpatients.
• The only mandatory laboratory monitoring during the first few months of clozapine
Monitoring During Initiation
treatment is the routine CBC used to determine the absolute neutrophil count. However,
a number of clinical outcomes ought to be tracked during the first 3 months of
clozapine therapy, both to manage signs of intolerability that might cause a patient to
refuse clozapine, and to monitor for myocarditis, which presents predominantly during
weeks 1–7 of treatment, with most cases occurring within 28 days of initiation [18].
• Clozapine is available in tablet and orally disintegrating tablet (ODT) forms,

Choice of Formulation
and in some countries also exists as an oral suspension (50 mg/ml), and as an

intramuscular (IM) formulation. All orally administered forms, including the suspension,
are bioequivalent on a milligram basis, as are different tablets made by various
manufacturers [19]. The oral bioavailability is 60–70%. A significant decrease in plasma
clozapine level when switching between oral formulations, especially when transitioning
from suspension or ODT forms to tablets, ought to raise suspicion of nonadherence,
unless obvious supervening issues are noted (e.g. resumption of smoking, addition of a
CYP inducer such as omeprazole). ODT and suspension forms are typically reserved for
those with adherence issues, but there may be other reasons that these formulations
are utilized. The IM formulation is primarily for inpatient use, and employed almost
exclusively to initiate treatment because administering higher daily maintenance doses
would require multiple injections. The strength of the IM formulation is 25 mg/ml and
ampoules usually contain 5 ml (125 mg). The IM preparation is painful and must be
administered by deep intramuscular injection in the gluteus, with a maximum injection
volume of 4 ml. As the bioavailability of the IM form is 100%, doses used are 50% of the
comparable oral dose.
71
Box 3.4 Monitoring During Inpatient or Outpatient Clozapine Initiation

Clinical inpatient monitoring following initiation: Most hospitals have
established protocols for clozapine initiation that include daily observation
for sedation, sialorrhea, and constipation, and routine monitoring of
orthostatic vital signs and temperature. Orthostatic blood pressures are
obtained first after having the patient lay flat for 5 minutes, then 1 minute
and 3 minutes after standing. Orthostatic hypotension is defined as a fall
in systolic blood pressure of ≥ 20 mmHg or in diastolic blood pressure of
≥ 10 mmHg upon standing, often with compensatory tachycardia. The
frequency at which orthostatic vital signs are checked is higher during
the first 3–4 weeks of titration, and may be obtained as often as multiple
times per day depending on institutional mandates, patient age, history
of orthostasis, or presence of medications that increase likelihood for
orthostasis. The frequency tapers off after the first few weeks to a monthly
assessment, especially as the patient achieves stable plasma levels and
establishes tolerability. The frequency of temperature assessments parallels
that of blood pressure, with once- to thrice-daily readings in the early weeks
of treatment. Unlike blood pressure, routine temperature readings are often
stopped after 8 weeks of treatment because the patient has passed the
highest risk period for myocarditis and interstitial nephritis.
Clinical outpatient monitoring following initiation: There is enormous
variation in the degree of recommended monitoring. Many clinics having
established protocols that mandate frequent daily contacts with a nurse
or other clinically trained personnel during the first week of initiation, with
vital signs and other assessments performed. These are tapered to twice-
daily assessments in week 2, and then weekly for the first 4 months of
treatment. However, in many countries patients are started on treatment
by private providers, in clinics that do not have staff or nursing personnel
to perform daily contacts, or in parts of the world where the distance
to a clinic is 15–25 km, precluding the type of frequent attention that is
possible in a highly staffed urban setting. In these instances, the caregiver
must have a firm grasp on the signs or symptoms of interest, and must be
provided with a contact number that can reach a clinician 24 hours per day.
Dizziness, sedation, fever or malaise, constipation > 48 hours, other bodily
complaints (e.g. chest pain), and sialorrhea all represent instances where
close contact with the clinician can immediately address the situation.
Automated blood pressure cuffs can be considered for caregivers to track
orthostatic vital signs during the early weeks of treatment (with proper
instruction and demonstration of competence); daily temperature readings
can also be performed by caregivers. The goal is to not deprive patients
in need of clozapine of this important medication due to logistical or other
circumstances that might not be considered ideal in well-funded urban
clinics. There are no data to indicate that commencing clozapine treatment
in patients who reside with motivated and competent caregivers increases
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3
the risk for adverse outcomes in instances where daily clinical contact is
not possible. When clinical contact is made during the first 2 months of
treatment, a complete set of vital signs ought to be obtained that includes
one assessment of orthostatic blood pressure, especially if tachycardia is
present or if there is any complaint of dizziness.
3
• Minimizing the pharmacodynamic interactions that can contribute to constipation,

Tapering Concomitant Medications
sedation or orthostasis risk is crucial to improving the success of a clozapine trial.

Box 3.5 lists some strategies focusing on pharmacodynamic interactions by
benzodiazepines and anticholinergic agents.
Box 3.5 Handling Benzodiazepines and Anticholinergic Medications When

Commencing Clozapine
Benzodiazepines: These agents should not be commenced just prior to or
concurrent with clozapine initiation, as the combined sedating effects may
result in delirium, with reported cases of respiratory arrest. In patients who have
been on stable benzodiazepine doses without evidence of sedation, every effort
must be made to taper down the benzodiazepine (and ideally off) prior to com-
mencing clozapine, especially if the patient is on high daily doses. If the patient
on long-standing benzodiazepine therapy cannot be completely weaned off
benzodiazepines prior to starting clozapine, titration schedules may need to be
modified to minimize oversedation, the patient observed carefully for evidence
of sedation, and the benzodiazepine taper continued at a rate that the patient
can tolerate.
Anticholinergics: Clozapine is strongly antimuscarinic, with 50–100 mg of
oral clozapine equaling the anticholinergic potency of 1 mg of benztropine [25].
Clozapine therapy is associated with constipation and a risk for ileus, and the
ileus risk is doubled with the concurrent use of strongly anticholinergic agents
(see Table 3.9) [26].
Table 3.9 List of common strongly anticholinergic medications.

Chlorpromazine, olanzapine, quetiapine (> 600 mg/
Psychotropics day), amitriptyline, nortriptyline, clomipramine,
imipramine, desipramine
Antiparkinsonian medications Benztropine, diphenhydramine, trihexyphenidyl
Oxybutynin, tolterodine, darifenacin, solifenacin,
Nonpsychiatric medications
trospium, glycopyrrolate
73
Among all antipsychotics, chlorpromazine presents the greatest risk for ileus
when combined with clozapine, as it is strongly antimuscarinic. If possible, convert
chlorpromazine to an equivalent dose of a medium- or high-potency antipsychotic
prior to starting clozapine. If not possible, use aggressive measures to minimize
risks of severe constipation (see Chapter 7), and cross-taper with clozapine in a
chlorpromazine:clozapine ratio of approximately 100 mg:100 mg for nonsmokers, and
a chlorpromazine:clozapine ratio of 100 mg:200 mg for smokers. For quetiapine, the
taper can proceed with a quetiapine:clozapine ratio of approximately 200 mg:100 mg
for nonsmokers, and 100 mg:100 mg for smokers. For olanzapine, an approximate
taper is a olanzapine:clozapine ratio of approximately 10 mg:100 mg for nonsmokers,
and 10 mg:200 mg for smokers. It is worth recalling that some treatment-resistant
patients derive modest benefit from D2 antagonism despite therapeutic clozapine levels.
If the removal of chlorpromazine or olanzapine results in decompensation despite
optimization of clozapine levels [20], add a source of D2 antagonism in a form that does
not increase risk for constipation, orthostasis or sedation. For patients on antipsychotics
lacking receptor affinities that increase risk for constipation, orthostasis or sedation
(e.g. aripiprazole), the current antipsychotic dose can be maintained until clozapine is at
a minimum therapeutic plasma level. At that juncture, the antipsychotic can be tapered
off, again bearing in mind that the patient my have realized some benefit from the prior
agent, albeit limited in nature. If the patient becomes symptomatically worse as the
prior antipsychotic is tapered, resume the prior dose that maintained stability, titrate
clozapine further, and then try again to taper the prior antipsychotic.
Any tricyclic antidepressants should be tapered off in lieu of other agents,
preferably those that will not have pharmacokinetic interactions with clozapine (see
Chapter 5). Antiparkinsonian medications can be cross-tapered with clozapine in the
manner shown in Box 3.6.
Box 3.6 Approximate Anticholinergic Equivalents

Nonsmokers: 50 mg clozapine = 1 mg benztropine = 2.5 mg
trihexyphenidyl = 25 mg diphenhydramine
Smokers: 100 mg clozapine = 1 mg benztropine = 2.5 mg
It is important to recall that a number of medications used for overactive bladder

are potent antimuscarinic agents. If possible, taper these medications off prior to
or during the early initiation period of clozapine treatment to minimize the risk of
74
3
constipation and ileus. The presence of other constipating agents such as oral iron
supplements and opioids (see below) must be minimized or eliminated completely
prior to starting clozapine.
Other Constipating Medications: iron (ferrous sulfate or gluconate), hydrocodone,
oxycodone, codeine, hydromorphone, morphine, fentanyl, methadone, oxymorphone, 3
tramadol.
Orthostasis Inducing Medications: certain psychotropics (low-potency
antipsychotics, iloperidone), medications for benign prostatic hypertrophy
(prazosin, terazosin), and antihypertensives may all contribute to increased risk of
orthostasis during clozapine initiation through a variety of mechanisms. In particular,
antipsychotics that are strong alpha1-adrenergic antagonists need to be tapered as
clozapine is started, with consideration given to tapering other alpha1-adrenergic
antagonists (prazosin, terazosin) or substituting an agent such as tamsulosin with
lower hypotension risk (if being used for urinary symptoms). For antihypertensive
medications, close consultation with the primary care provider is important to reach a
joint decision on which medications to taper if orthostasis becomes a clinical problem.
Summary Points
a. Clozapine titration must be individualized based on patient variables and the

presence of kinetic interactions with medications or smoking behavior.
b. ECG machines using a linear QT rate correction formula such as Framingham
are preferable.
c. Tapering off medications that cause pharmacodynamic interactions (e.g.
anticholinergics, benzodiazepines, alpha1-adrenergic antagonists, constipating
medications) or unsafe kinetic interactions (fluvoxamine, ciprofloxacin) prior to
commencing clozapine decreases risk of adverse outcomes that might result in
clozapine discontinuation.
75
References
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and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients.
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17. The French Clozapine Parkinson Study Group. (1999). Clozapine in drug-induced psychosis in
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4
QUICK CHECK
Discontinuing Clozapine
and Management of
Cholinergic Rebound
Introduction 78
Principles 79
A Management of Cholinergic Rebound 81
B Provision of Appropriate Antipsychotic Therapy 83
C Parkinson’s Disease Psychosis 86
Summary Points 87
References 88
INTRODUCTION
The need to discontinue clozapine is a lamentable but medically necessary

event in certain circumstances, and at times must be accomplished abruptly. In
instances when the patient can be tapered off gradually (e.g. dilated cardiomyopathy),
the risk of cholinergic rebound symptoms is lessened and the clinician can focus
on making an informed choice about antipsychotic treatment. Although no agent
equals clozapine’s efficacy for treatment-resistant schizophrenia, 35% of a group
of schizophrenia outpatients with poor antipsychotic response (n = 99) who were
considered candidates for clozapine had subtherapeutic plasma levels of their
current antipsychotic [1]. Thus, a certain fraction of patients who end up on clozapine
were failures due to inadequate dosing of prior antipsychotics, poor adherence or
kinetic issues. As will be discussed below, this is an important consideration for
patients deemed treatment-resistant but who did not experience adverse effects
of prior antipsychotic treatment, particularly those related to D2 antagonism. This
understanding may open the door to revisiting prior antipsychotics, but with careful
monitoring of adherence and drug exposure via use of plasma levels [2].
A withdrawal syndrome following abrupt discontinuation of chlorpromazine
(including some on concurrent anticholinergic antiparkinsonian medications) was
78
4: STOPPING CLOZAPINE AND CHOLINERGIC REBOUND
4
PRINCIPLES
• During abrupt discontinuation, management of cholinergic rebound is critical

to prevent central nervous system and peripheral adverse effects.
• The decision on which antipsychotic to start in lieu of clozapine is based on
detailed knowledge of prior response and tolerability.
• Previous antipsychotic trials previously deemed treatment failures must be
4
reassessed for evidence of inadequate dosing or nonadherence, especially
when there was no documentation of adverse effects related to D2
antagonism.
• ECT is an underutilized but effective treatment for schizophrenia and must be
considered when pharmacotherapy is inadequate.
• Parkinson’s disease psychosis (PDP) patients have limited options. In areas
where it is available, pimavanserin is a potent, selective 5HT2A antagonist
approved for PDP that lacks any activity at dopamine receptors. Despite weak
efficacy data, lack of approved indication, and a twofold increase in mortality
rates, the weak D2 antagonist quetiapine is commonly used.
first described in a 1959 study (n = 28). The cluster of symptoms comprised “acute,
uncomfortable reactions characterized by tension, fear, restlessness, insomnia,
increased perspiration, and vomiting” [3]. For the 17 patients who developed clinically
significant withdrawal reactions, three developed symptoms on the second day, nine
on the third day, three on the fourth day, and two on the fifth day. The author also
noted: “The symptoms had not entirely subsided until two weeks after the sudden
withdrawal” [3]. This classic description of cholinergic rebound was not recognized
for many years as the product of cholinergic supersensitivity due to the complex
pharmacology of chlorpromazine, combined with the prevalent use of anticholinergic
antiparkinsonian agents with higher-potency antipsychotics. Twenty years later it
finally became clear that the central nervous system (CNS) and systemic symptoms
described in 1959 were related to removal of potent muscarinic antagonism, and not
the dopaminergic property of the antipsychotic [4]. Lieberman introduced the term
“cholinergic rebound” in 1981 to reinforce the concept that this is a phenomenon
related to tolerance of and abrupt withdrawal of a muscarinic antagonist, with the
severity related to the prior anticholinergic load [5].
79
Clozapine possesses over sevenfold higher affinity for the muscarinic M1 receptor
than does chlorpromazine, and by 1974 early reports of a clozapine withdrawal
syndrome were alluded to; however, not until wider commercial release in 1989
was the problem recognized, with five case reports emerging by 1994. In 1996 a
dedicated study of clozapine withdrawal symptoms was performed in 28 clozapine-
treated inpatients enrolled in a kinetic study, all of whom received 200 mg/day for
1 month. No adjunctive psychotropics were allowed aside from benzodiazepines
or chloral hydrate for sleep. Over the week after abrupt discontinuation 12 patients
experienced mild withdrawal symptoms (agitation, headache, nausea), four had
moderate symptoms (nausea, vomiting, diarrhea) and one patient experienced a
rapid-onset psychotic episode with manic features requiring hospitalization [6]. The
use of anticholinergics was effective for the mild and moderate symptoms, which
were ascribed to cholinergic rebound, although most were not symptom-free until
5–7 days after onset of the withdrawal syndrome. The manic episode was also
deemed related to cholinergic rebound, although it did not respond to anticholinergic
medications as did somatic symptoms. (NB: Case reports and one clinical trial of
the acetylcholinesterase inhibitor donepezil support the cholinergic hypothesis
for mania. In a double-blind, placebo-controlled study of adjunctive donepezil for
treatment-resistant mania, the donepezil cohort had twofold higher Young Mania
Rating Scale scores than the placebo group after 6 weeks: 20.17 ± 3.66 vs.
11.20 ± 4.60 (p = 0.01) [7]). As has been discussed throughout this handbook,
effective management of common adverse effects such as tachycardia, sialorrhea
and constipation, and a timely approach to fever presenting in the first 2 months
of treatment, can minimize the need to discontinue clozapine treatment, the
complex decisions that ensue regarding antipsychotic options, and need to address
cholinergic rebound symptoms.
Box 4.1 Cholinergic Rebound Symptoms*

Mild: sleep disturbance, vivid dreams, nightmares
Moderate: anxiety, nausea, diarrhea, sweating, urinary urgency
Severe: confusion, delirium, catatonia
* Comment: By its actions at striatal cholinergic interneurons, cholinergic
rebound may also induce parkinsonism, akathisia or dystonia if the patient is
being exposed to another source of D2 antagonism. In this context the effect
of cholinergic rebound can be thought of as “anti-benztropine” [15].
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4
A Management of Cholinergic Rebound
When a clinician has the luxury of time, the best method for managing cholinergic
rebound is to prevent its occurrence by slowly tapering clozapine. For patients on full
therapeutic doses (typically ≥ 300 mg/day) the taper can proceed up to 100 mg each
week until a dose of 100 mg/day is reached. At that point, the clozapine dose can be
consolidated to bedtime (if not already), and the taper proceed by 25 mg increments every
4–7 days until discontinued. Mild cholinergic rebound symptoms in the form of sleep 4
disturbance can be managed with modest diphenhydramine doses (25–50 mg) at bedtime.
In cases where clozapine must be stopped abruptly and will not be resumed at full
dose within 48 hours, anticholinergic medication must be used to prevent cholinergic
rebound. The literature over the past two decades is replete with cases of severe
rebound with delirium when appropriate anticholinergic therapy was not administered
[8]. Not only is clozapine a potent antimuscarinic medication, it is used in high
milligram doses, thus exposing patients to a systemic anticholinergic burden not
seen with other antipsychotics or even high doses of antiparkinsonian medications
[9]. Based on studies of serum anticholinergicity, a clozapine dose in the range of
50–100 mg/day is approximately equivalent to benztropine 1 mg/day [10]. The use of
an anticholinergic atypical antipsychotic to cover cholinergic rebound and underlying
psychotic disorder seems appealing, and olanzapine is touted as the leading candidate
based in part on slightly greater efficacy in a small fraction (7–9%) of treatment-
resistant schizophrenia patients [11,12]. While olanzapine has high in vitro muscarinic
M1 affinity (Ki 2.5 nM), it provides nowhere near the anticholinergic activity of clozapine
(M1 Ki 6.2 nM) due to the larger clozapine doses used in nearly every application
except Parkinson’s disease psychosis (PDP). Assays of patients taking olanzapine
(mean dose 15 mg/day) show serum anticholinergic activity less than 20% of that
seen with patients on clozapine (mean dose 444 mg/day) [13]. Thus, an abrupt switch
from clozapine to olanzapine can result in rebound symptoms including delirium, and
this has been reported in the literature [14]. Chlorpromazine is a weaker M1 antagonist
than clozapine, may not adequately manage rebound symptoms, and may be an
unappealing choice for patients with a history of sensitivity to D2 antagonism. The
use of a separate anticholinergic medication to manage rebound symptoms allows
this agent to be tapered off over time, and also allows the clinician flexibility in the
antipsychotic chosen to manage the psychiatric disorder. Benztropine or other strongly
anticholinergic medications used for cholinergic rebound must be started in the first 24
hours after clozapine is discontinued, using the dosing equivalence in Box 4.2.
81
Box 4.2 Approximate Anticholinergic Equivalents

Comments:
1. Benztropine is the preferred agent for managing cholinergic rebound,
but diphenhydramine can also be used. Trihexyphenidyl has greater
abuse potential and may not be available in certain forensic settings.
Other atypical antipsychotics (e.g. olanzapine) do not provide sufficient
anticholinergic activity to mitigate rebound for patients on therapeutic doses
of clozapine [14]. Chlorpromazine is one option for those without marked
sensitivity to D2 antagonism; however, use of a separate anticholinergic
medication provides maximum flexibility in antipsychotic choice.
2. Local guidelines may limit the maximum daily benztropine dose to 6 or
8 mg/day. Although these doses may not equal the anticholinergic load
from clozapine, they should be sufficient to forestall moderate and severe
cholinergic rebound symptoms. Due to the short half-life, benztropine
(and other anticholinergics) must be administered at least twice per day.
3. Benztropine (or other anticholinergic medication) should not be tapered
for at least 2 weeks after clozapine discontinuation unless the clozapine
dose was ≤ 50 mg/day, and the taper should not start until all withdrawal
symptoms have abated for at least 1 week. A slow taper of no more
than 1 mg/day (benztropine equivalent) per week will minimize the risk
of rebound symptoms. Once a benztropine equivalent dose of 1 mg/day
is reached, the taper should proceed by 0.5 mg/day each week. If mild
withdrawal symptoms occur (e.g. sleep disturbance, vivid dreams), the
prior anticholinergic dose must be resumed, and the taper commenced
the subsequent week at a slower rate (e.g. 0.5 mg/day each week).
Exact equivalent doses to that provided by clozapine may not be possible due to the
daily maximum limits for anticholinergic medications. (In the US these are: benztropine
6 mg/day, trihexyphenidyl 15 mg/day, diphenhydramine 300 mg/day.) Nonetheless, the
use of an anticholinergic agent will greatly decrease the severity of, or completely abate
the development of cholinergic rebound. Cholinergic rebound symptoms from higher
clozapine doses may not resolve for 2–3 weeks. For this reason, the anticholinergic
medication must not be discontinued abruptly, but instead tapered very slowly over
several weeks starting no sooner than 2 weeks after clozapine was abruptly discontinued
unless the clozapine dose was very low (e.g. ≤ 50 mg/day). In patients who are receiving
another source of D2 antagonism (e.g. haloperidol, risperidone), abruptly stopping the
82
4
anticholinergic agent may itself induce rebound effects including the tendency to promote
parkinsonism, acute dystonia and akathisia [15]. If a patient develops sleep disturbance
(i.e. vivid dreams, nightmares) or systemic symptoms (e.g. gastrointestinal disturbance)
during the taper, the most recent higher dose should be resumed, and the taper slowed.
B Provision of Appropriate Antipsychotic Therapy

4
Patients often require clozapine treatment due to treatment-resistant schizophrenia,
schizophrenia with suicidality or schizophrenia with aggression, and by definition were
considered failures on other antipsychotics. However, prior treatment failure may have
been due to a number of factors including inadequate doses prescribed by the clinician,
substance use, treatment nonadherence, or kinetic reasons (e.g. unrecognized exposure
to cytochrome P450 inducers, or presence of cytochrome P450 ultrarapid metabolizer
status). When patients were deemed treatment-resistant despite never manifesting
common D2 antagonism adverse effects, significant questions must be raised about the
adequacy of prior antipsychotic trials. The approach to those patients will be very different
than for individuals with a history of extreme sensitivity to dopamine D2 antagonism in
the form of neuroleptic malignant syndrome, parkinsonism, akathisia or dystonia from
other antipsychotics. For the latter group, there is no debate about the adequacy of prior
antipsychotic exposure, and the treatment options are considerably narrower.
Although clozapine was initially approved in 1989 based on efficacy in treatment-
resistant schizophrenia, one of its common uses was for patients intolerant of D2
antagonism from first-generation antipsychotics. Patients with exquisite sensitivity to D2
blockade still exist, but represent a smaller pool of clozapine-treated patients since the
advent of atypical antipsychotics. If a patient with history of marked intolerance of D2
antagonism must be discontinued from clozapine, one can consider weak antagonists
such as quetiapine, agents with low rates of acute movement disorders such as
iloperidone, and electroconvulsive therapy (ECT). In some cases, novel strategies must
be considered, including off-label adjunctive use of newer medications without D2
activity such as pimavanserin, a selective and potent 5HT2A antagonist (Ki 0.087 nM).
Pimavanserin is indicated for PDP, but in a double-blind schizophrenia study enhanced the
efficacy of risperidone 2 mg/day to the extent that symptom reduction for this combination
strategy was equivalent to that for risperidone monotherapy at the dose of 6 mg/day
[16]. The presence of potent 5HT2A antagonism also helps mitigate the development
of akathisia or parkinsonism, and this property is the basis for trials of mirtazapine, a
moderate 5HT2A antagonist, added to antipsychotics for akathisia management [17].
83
Box 4.3 Antipsychotic Options for Schizophrenia Spectrum Patients with Marked
Sensitivity to D2 Antagonism
1. Included in this group are patients with a documented history of acute
parkinsonism, dystonia or akathisia after modest exposure to D2
antagonists.
2. Quetiapine is a weak D2 antagonist (Ki 380 nM) and the most likely
agent to be tolerated. Moreover, there are two large studies of doses up
to 1200 mg/day if such dosing is permitted by local guidelines [26,27].
Iloperidone had low rates of acute parkinsonism, dystonia or akathisia
in clinical trials up to the maximum dose of 12 mg BID, and can also
be considered [28]. Titration should proceed more cautiously than with
quetiapine as iloperidone is a more potent D2 antagonist (Ki 6.3 nM),
although other properties of the molecule may help mitigate risk for
D2-related adverse effects. Rates of orthostasis with iloperidone noted
in the package insert may be somewhat lessened in this context as
patients have developed tolerance to alpha1-adrenergic antagonism from
exposure to clozapine. Nonetheless, rapid titration should be avoided.
3. Given the paucity of therapeutic options, one could consider the off-
label use of pimavanserin in combination with quetiapine or iloperidone.
Pimavanserin is a potent serotonin 5HT2A inverse agonist (Ki 0.087 nM)
approved for treatment of Parkinson’s disease psychosis, and is devoid
of affinity for any dopamine receptors [20]. Moreover, pimavanserin has
been shown to enhance the efficacy of risperidone but not haloperidol,
implying that its most plausible use as an augmenting agent might be in
the context of a relatively weaker D2 antagonist [16].
4. ECT remains an evidence-based but often underutilized option for
schizophrenia, and at times is employed successfully in clozapine
nonresponders [29].
In patients where D2 sensitivity is not an issue, one must rely on the prior pattern
of response and tolerability to guide treatment. Bearing in mind that 35–44% of
schizophrenia outpatients deemed treatment-resistant had subtherapeutic plasma
antipsychotic levels when measured, strong consideration should be given to using
plasma levels to guide future antipsychotic therapy, and to exploring higher plasma
levels if tolerability is not an issue [1]. While decidedly inferior to clozapine for resistant
schizophrenia, olanzapine may have slightly greater efficacy than other antipsychotics,
and clinical trials have demonstrated adequate tolerability up to plasma levels of
200 ng/ml (640 mmol/l), with the major adverse effect being constipation [18]. In
general, antipsychotic doses should be advanced when tolerability is not limiting
until one of two hard endpoints is reached: significant symptomatic improvement or
84
4
intolerability. There is a small subset of patients who will never develop D2-related
adverse effects, so plasma levels must be tracked to avoid proceeding past the point
of futility where the likelihood of response is remote [19].
Box 4.4 Antipsychotic Options for Schizophrenia Spectrum Patients Without a

History of Marked Sensitivity to D2 Antagonism
1. Included in this group are patients without a documented history of acute
parkinsonism, dystonia or akathisia, or who only experienced these 4
events with higher doses of D2 antagonists.
2. At least 35% of outpatients deemed treatment-resistant have
subtherapeutic plasma antipsychotic levels. For patients who have never
experienced parkinsonism, dystonia or akathisia, scour the clinical record
for evidence of treatment nonadherence (or occasionally cytochrome
P450 ultrarapid metabolizer status). Plasma antipsychotic levels on oral
antipsychotic therapy prior to the clozapine trial will be very helpful.
3. Whether the prior failure was due to inadequate dosing, kinetic reasons
or nonadherence, tracking the subsequent antipsychotic trial with plasma
levels will help resolve these issues. The following two options are
appealing due to the extensive body of data on concentration/oral dose
relationships and response thresholds.
a. The response threshold for haloperidol is 3–5 ng/ml (8.0–13.3 nmol/l),
with few patients tolerating levels > 20 ng/ml (80 nmol/l), although
levels up to 30 ng/ml (80 nmol/l) can be pursued if tolerated [19].
Haloperidol Concentration/Oral Dose Relationships in CYP 2D6
Extensive Metabolizers [30]
2 mg/day –> 1.57 ± 1.42 ng/ml (4.18 ± 3.78 nmol/l)
10 mg/day –> 7.79 ± 4.79 ng/ml (20.72 ± 12.74 nmol/l)
b. Olanzapine may capture 7–9% more responders among treatment-

resistant schizophrenia patients compared to nonclozapine
antipsychotics [11,12]. The response threshold for olanzapine is
23 ng/ml (74 nmol/l), and tolerability threshold is close to 200 ng/ml
(640 nmol/l), with constipation being the primary adverse effect at
high plasma levels [18,19].
Olanzapine Concentration/Oral Dose Relationships in CYP 1A2
Extensive Metabolizers [30]
10 mg –> 20 ng/ml (64 nmol/l) (nonsmokers)
14 mg –> 20 ng/ml (64 nmol/l) (smokers)
4. ECT remains an evidence-based but often underutilized option for

schizophrenia, and at times is employed successfully in clozapine
nonresponders [29].
85
C Parkinson’s Disease Psychosis
More than 50% of patients with Parkinson’s disease develop psychosis as a

consequence of pathologic processes related to the disease itself, and not primarily
due to D2 agonist therapy as previously hypothesized. Psychosis is the most common
cause of nursing home placement in nondemented PD patients, and has enormous
impact on patients and caregivers [20]. The pathophysiology of psychosis in PDP
is due to the accumulation of subcortical Lewy body burden that causes death of
serotonin-producing dorsal raphe neurons. This loss of the serotonin signal results
in upregulation of postsynaptic 5HT2A receptors and receptor supersensitivity.
The concept that excessive 5HT2A receptor stimulation may cause psychosis with
prominent visual hallucinations had been known from studies of lysergic acid
diethylamide (LSD) and other hallucinogenic compounds whose activity is blocked
by 5HT2A antagonists. PD patients are notoriously intolerant of D2 antagonism, and
respond in a robust manner to only one antipsychotic, low-dose clozapine. In the two
widely cited 4-week, double-blind, placebo-controlled trials, the mean doses were
25–36 mg/day with a large effect size [21,22]. No significant motoric effects were
seen during low-dose clozapine treatment. There are numerous failed trials for other
atypical antipsychotics, including quetiapine, and recent data indicate that quetiapine
and atypical antipsychotics (except clozapine) are associated with twofold increased
mortality rates when used in PD patients [23].
Based on the finding that clozapine in low doses acts primarily at 5HT2A receptors,
a novel compound pimavanserin was designed as a potent 5HT2A antagonist (Ki
0.087 nM) (technically an inverse agonist), with no appreciable affinity for adrenergic,
dopaminergic, muscarinic, histaminergic, adrenergic or GABA-ergic receptors.
Because it is devoid of affinity for dopamine receptors, pimavanserin avoids the
motoric worsening seen with most antipsychotics, and was approved by the US
FDA in 2016 for treatment of PDP [20]. For PDP patients who must be removed
from clozapine, consultation with a neurologist specializing in movement disorders
should be considered, as these specialists have the greatest experience with this
clinical scenario. Based on the history, one can consider modest adjustments to
dopamine agonist exposure to see if this improves psychosis symptoms; however,
the PDP patient who needs clozapine has usually exhausted this option early in
the course of their psychosis, often due to intolerable motoric exacerbation when
dopamine agonist therapy was lessened. When clozapine needs to be discontinued,
86
4
pimavanserin represents the best of the remaining choices, although it may not be
available outside of the US. The approved dose is 34 mg once daily, and separation
from placebo appeared at week 2 of the pivotal 6-week trial, so patients should be
advised that efficacy may not be seen for several weeks [20]. As pimavanserin lacks
histaminic or muscarinic antagonism, clozapine should ideally be tapered off by
12.5 mg/day each week, or diphenhydramine used to mitigate rebound insomnia,
because this symptom may worsen PDP symptoms. When pimavanserin is not
accessible, many clinicians have resorted to quetiapine, mostly due to the paucity 4
of other viable options. Quetiapine’s advantage over other antipsychotics is that it is
a very weak D2 antagonist, and should not worsen motor symptoms; however, it did
not prove effective in three of four clinical trials, although some patients do report
benefit [24]. Moreover, naturalistic data from over 15,000 PD patients found that
quetiapine increased mortality twofold compared to matched PD patients not receiving
antipsychotic treatment (OR 2.16, 95% CI 1.88–2.48) [23]. As with schizophrenia, ECT
remains an option for PD patients, and may produce improvements in psychosis, mood
and motor symptoms [25].
Summary Points
a. Management of cholinergic rebound must start within 24 hours after clozapine

discontinuation, using appropriate equivalent doses of benztropine. Olanzapine
is not sufficiently anticholinergic to prevent cholinergic rebound.
b. After abrupt clozapine discontinuation, the anticholinergic agent should not be
tapered for 2–3 weeks unless the clozapine dose was ≤ 50 mg/day, and then at
no more than the equivalent of 1 mg/day of benztropine each week.
c. For schizophrenia spectrum patients the antipsychotic choice to replace
clozapine depends on whether there is a documented history of significant
sensitivity to D2 antagonism. Patients who are exquisitely sensitive to D2
blockade have many fewer options.
d. ECT is an effective treatment for schizophrenia, including some treatment-
resistant cases.
e. The viable options for Parkinson’s disease psychosis patients who must stop
clozapine include pimavanserin, possibly quetiapine and ECT.
87
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89
5
QUICK CHECK
Binding Profile, Metabolism,
Kinetics, Drug Interactions
and Use of Plasma Levels
Introduction 90
Principles 91
A Clozapine Metabolism and Kinetics 91
• CYP 1A2: Impact of Smoking, Caffeine and Genetic
Polymorphisms 94
• BID vs. QD Dosing and Relationship to Hypotheses About
Clozapine’s Efficacy 97
B Binding Profile of Clozapine and Its Primary Active Metabolite
Norclozapine 98
C Plasma Levels 102
• Response to Levels Markedly Above or Below Expected
Values, and Suspected Nonadherence 103
• Serious Bacterial or Viral Infections: Impact on Clozapine
Levels and Metabolic Ratio 106
• Use of Levels to Monitor Efficacy 108
Summary Points 111
References 112
INTRODUCTION
Clinicians must be knowledgeable about the mechanisms, metabolic pathways,

and kinetics of all prescribed medications, but this is especially true for agents with
narrower therapeutic indices such as clozapine. Armed with this information, one can
maximize the potential for a successful clozapine trial in a patient who may lack other
viable therapeutic options. While the properties underlying clozapine’s unique efficacy
profile are not fully elucidated, there are extensive data on peripheral and central
nervous system (CNS) kinetics, drug–drug and environmental interactions, and plasma
levels to inform routine clinical care. (Throughout this volume clozapine plasma levels
90
5: KINETICS, INTERACTIONS, PLASMA LEVELS
5
PRINCIPLES
• Clozapine’s high affinity for muscarinic, histaminic and alpha1-adrenergic

receptors is associated with risk for constipation, sedation and orthostasis.
Norclozapine’s muscarinic agonism is responsible for sialorrhea.
• Clinicians must be aware of environmental (e.g. smoking), drug interaction
and genetic influences on clozapine metabolism. The mean plasma
clozapine:norclozapine ratio of 1.32 will be altered when subjected to
significant kinetic effects.
• Plasma clozapine levels must be tracked to determine adherence and 5
adequacy of the treatment trial. Response correlates best with the 12-hour
trough clozapine level and not the combined concentration of clozapine +
norclozapine. Likelihood of response in schizophrenia spectrum patients is low
with trough clozapine levels below 350 ng/ml or 1070 nmol/l.
• Serious bacterial or viral infections can be associated with downregulation
of cytochrome P450 1A2 activity. The net result is a marked jump in plasma
clozapine levels, metabolic ratio and clozapine-related adverse effects.
will be presented in ng/ml and nmol/l units. Some laboratories may report levels in
μg/l, which is exactly equivalent to ng/ml.)
A Clozapine Metabolism and Kinetics
Clozapine is predominantly administered in the form of tablets, suspension or

orally dissolving tablets (ODT), all of which are considered bioequivalent when studied
by comparative assays [1,2]. Nonetheless, clinicians are advised to routinely check
plasma clozapine levels 1 week after changing preparations to make sure levels have
remained stable, and to account for the possibility of improved patient adherence
when going from tablets to ODT or oral suspension. The bioavailability for all oral
forms is 60%, without apparent impact from food. An intramuscular (IM) formulation
(25 mg/ml) is available in a limited number of countries and it is 100% bioavailable, so
IM doses are approximately half of the intended oral doses.
As seen in Figure 5.1, clozapine is converted to an active metabolite, norclozapine
(also called N-desmethylclozapine), and the inactive clozapine-N-oxide, along with
other minor metabolites without known clinical significance.
91
Figure 5.1. Structure of clozapine and its primary metabolites.
N
N
Cl
N
H O
H Clozapine
N N
N N
N N
Cl Cl
N N
H H
Norclozapine Clozapine-N-oxide
(N-desmethylclozapine)
Clozapine exhibits linear pharmacokinetics within the usual therapeutic range and
is a substrate for multiple cytochrome P450 (CYP) isoenzymes, and also for the efflux
transporter P-glycoprotein (PGP). Among the CYP isoenzymes that contribute to its
metabolism, CYP 1A2 is the most important, especially at lower plasma concentrations
(Table 5.1). In addition to being susceptible to inhibition by other medications, CYP 1A2 is
also inducible, and has a number of functional polymorphisms. Among the most useful
facts to remember, the ratio of clozapine to norclozapine plasma levels (also called the
metabolic ratio or MR) is 1.32 in patients who are extensive metabolizers at all relevant
CYP isoenzymes, and who are not being exposed to inhibitors or inducers. This MR
reference value is derived from an analysis of nearly 5000 samples obtained from over
2000 patients [3]. Values significantly greater than 1.32 (e.g. > 2.00) reflect a nontrough
value, slow metabolism or the presence of inhibitors [4]. Similarly, metabolic ratios ≤ 1.00
reflect the presence of inducers (e.g. smoking, omeprazole, carbamazepine) (see section
C, Plasma Levels). As will be discussed in section C, Plasma Levels, it may be difficult
to predict the net effect of multiple concurrent medications or environmental agents
(e.g. smoking) that influence CYP activity, making plasma level monitoring critical to
documenting clozapine exposure. Importantly, assuming there is no change in the use of
concomitant medications or smoking behavior (e.g. cessation or resumption), the MR will
remain unchanged during periods of poor adherence unless the patient takes the clozapine
92
5
Table 5.1 Fast facts about clozapine metabolism and kinetics [29].
• Tablets
• Oral dissolving tablet (ODT)
Formulations
• Oral suspension (50 mg/ml)
• Intramuscular (25 mg/ml) (in some countries)
• Bioavailability: 60%
Bioavailability (oral)
• No impact of food on bioavailability
• Half-life: 12 (4–66) hours
• TMax 2.5 hours
Kinetics • Dose adjustments may be necessary in patients with
significant renal impairment (CrCl < 30 ml/min) or severe
hepatic impairment (Child–Pugh Class C)*
5
• The mean contributions of CYPs 1A2, 2C19, 3A4, 2C9, and
2D6 are 30%, 24%, 22%, 12%, and 6%, respectively. In some
studies CYP 1A2 is responsible for 40–55% of clozapine
biotransformation
Metabolism • CYP 1A2 is the most important form at low concentrations,
which is in agreement with clinical findings
• The ratio of clozapine to norclozapine trough plasma
concentrations in nonsmokers who are CYP 1A2 extensive
metabolizers is 1.32 [3]
• Fluvoxamine increases serum levels 5–10-fold**
CYP inhibitor effects • Strong 2D6 or 3A4 inhibitors may increase clozapine levels as
much as 100%**
• Loss of smoking-related 1A2 induction results in ≥ 50%
CYP/PGP inducer increase in serum levels
effects • Carbamazepine, phenytoin, and omeprazole decrease levels on
average by 50%**
* Child–Pugh criteria: low serum albumin, high total bilirubin, elevated INR (derived from plasma
prothrombin time), and the presence of ascites or hepatic encephalopathy. Class C patients
have severe advanced liver disease with 1-year survival under 50% and are rarely encountered
in routine psychiatric practice. Alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) are not part of the criteria and are not a basis for adjustment of medication dosages [30].
** See Table 5.2 for guidance on dosing adjustments with inhibitors and inducers.
just prior to obtaining a plasma level. Nonadherence with oral clozapine will result in low
and erratic trough levels, as will be mentioned in section C, but does not alter the MR.
Given the narrow therapeutic index for clozapine, including case reports of fatality
with concomitant use of clozapine and strong CYP 1A2 inhibitors, most package
inserts provide detailed information about adjustment of clozapine in the context of the
addition or removal of drugs with known kinetic interactions [5]. Often lacking from
these advisories are standard definitions for what distinguishes a strong, moderate or
weak inhibitor or inducer, and these are included in Box 5.1.
93
Box 5.1 US FDA Definitions of Inhibitors/Inducers

Strong inhibitors: increase the area under the curve (AUC) of a victim drug via
a given metabolic pathway ≥ 5-fold
Moderate inhibitors: increase the AUC of a victim drug via a given metabolic
pathway ≥ 2-fold to < 5-fold
Weak inhibitors: increase the AUC of a victim drug via a given metabolic
pathway ≥ 1.25-fold to < 2-fold
Strong inducers: decrease the AUC of a victim drug via a given metabolic
pathway ≥ 80%
Moderate inducers: decrease the AUC of a victim drug via a given metabolic
pathway ≥ 50% to < 80%
Weak inducers: decrease the AUC of a victim drug via a given metabolic
pathway < 50%
The updated US clozapine prescribing guidelines contain a useful table addressing

the clinical scenario, and the nature and magnitude of the kinetic interaction ( Table 5.2).
Based on the standard definitions, Table 5.3 provides a list of CYP inhibitors and inducers
among commonly encountered medications. Although divalproex is a known inhibitor of
the phase II enzyme UGT1A4, its presence may modestly increase or decrease clozapine
levels depending on smoking status, and possibly serum valproate levels [6,7]. In large
kinetic modeling studies, valproic acid was estimated to increase levels in nonsmokers
(effect size +16%), but reduce levels in smokers (effect size –22%) [6]. When starting
clozapine, clinicians must consult the latest information about interactions with
concomitant medications, and check plasma clozapine levels early in treatment (e.g. at a
dose of 100 mg/day). Similarly, when medications with potential kinetic interactions are
added to or removed from the regimen of a patient on clozapine, a repeat clozapine level
needs to be obtained once the new medication is at steady state.
• CYP 1A2: Impact of Smoking, Caffeine and Genetic Polymorphisms

CYP 1A2 accounts for about 13% of the total CYP content in human liver, but is
the primary isoenzyme regulating clozapine metabolism, accounting for 30–55% of
CYP-mediated metabolism. Throughout the population there are more than 15-fold
differences in CYP 1A2 messenger RNA levels and more than 40-fold differences in its
expression [8]. Polymorphisms not only impact baseline activity, but also the response
to inducers such as those present in cigarette smoke. When unexpectedly high plasma
clozapine levels and metabolic ratios (i.e. > 2.00) are encountered without exposure to
known inhibitors, and these are replicated with a repeat plasma level, it is likely due to
94
5
Table 5.2 US guidelines on dose adjustment in patients taking concomitant
medications.
Comedications Scenarios
Initiating clozapine while taking a
comedication
Discontinuing a comedication while
OR
continuing clozapine
Adding a comedication while taking
clozapine
Strong CYP 1A2 Use one-third of the clozapine Increase clozapine dose
inhibitors dose. based on clinical response.
Monitor for lack of
Monitor for adverse reactions.
Moderate or weak effectiveness. Consider
Consider reducing the clozapine
CYP 1A2 inhibitors
dose if necessary.
increasing clozapine dose if 5
necessary.
Monitor for lack of
Monitor for adverse reactions.
Strong CYP 2D6 or effectiveness. Consider
Consider reducing the clozapine
3A4 inhibitors* increasing clozapine dose if
dose if necessary.
necessary.
Concomitant use is not
recommended. However, if the
Strong CYP 3A4 inducer is necessary, it may Reduce clozapine dose
inducers be necessary to increase the based on clinical response.
clozapine dose. Monitor for
decreased effectiveness.
Monitor for adverse
Moderate or weak Monitor for decreased
reactions. Consider reducing
CYP 1A2 or 3A4 effectiveness. Consider increasing
the clozapine dose if
inducers the clozapine dose if necessary.
necessary.
* Dose adjustments may be necessary in patients who are CYP2D6 poor metabolizers.
Table 5.3 Selected list of common CYP inhibitors and inducers.

Strong Moderate/weak
Fluvoxamine, ciprofloxacin,
CYP 1A2 inhibitors Oral contraceptives, caffeine
enoxacin
Paroxetine, bupropion,
CYP 2D6 inhibitors Duloxetine
fluoxetine, quinidine
Ketoconazole, itraconazole,
Amprenavir, aprepitant,
posaconazole, clarithromycin,
atazanavir, diltiazem,
nefazodone, ritonavir, saquinavir,
CYP 3A4 inhibitors erythromycin, fluconazole,
nelfinavir, indinavir, boceprevir,
fosamprenavir, grapefruit juice,
telaprevir, telithromycin,
imatinib, verapamil
conivaptan
CYP 1A2 inducers Smoking, omeprazole
Phenytoin, carbamazepine,
CYP 3A4 inducers Oxcarbazepine, St. John’s wort
phenobarbital, rifampin
95
the presence of one or more nonfunctional CYP 1A2 alleles [4]. Genetic testing for CYP
1A2 polymorphisms can be helpful to alert future providers to the patient’s particular
variant (see Table 5.4).
Table 5.4 List of functional CYP 1A2 single nucleotide polymorphisms (SNP).
(Source: www.snpedia.com/index.php/SNPedia; accessed September 30, 2018.)
Allele rs SNP designation Nucleotide change Functional effect
(older nomenclature)
*1 Wild type Extensive metabolizer (normal)
*1C rs2069514 –3860G>A Decreased activity
*1F rs762551 –163C>A Increased inducibility
Decreased activity and
*1 K rs12720461 –729C>T
inducibility
*1 K rs2069526 –739T>G Decreased activity
*3 rs56276455 2385G>A Decreased activity
*4 rs72547516 2499A>T Decreased activity
*6 rs28399424 5090C>T No activity
*7 no identifier 3533G>A No activity
*11 rs72547513 558C>A Decreased activity
Smoking induces CYP 1A2 activity by the action of aryl hydrocarbons at the
aromatic hydrocarbon receptor (AhR). Nicotine itself plays no role in this process. The
AhR is a cytosolic transcription factor that remains inactive and bound to a protein
complex in the absence of a ligand. Upon binding of an appropriate ligand (e.g. aryl
hydrocarbons from smoke), an interacting protein is released from the complex
and translocated to the nucleus where it binds to the CYP 1A2 promoter region and
increases expression of messenger RNA [8]. CYP 1A2 appears to be fully induced after
regular use of only 7–12 cigarettes per day [9], and this induction results in a mean
1.66-fold increase in CYP 1A2 activity [8]. The higher clozapine dose required for
smokers to achieve comparable plasma levels as nonsmokers is fully explained by this
phenomenon. Upon complete cessation of smoking, the induction effects are lost and
CYP 1A2 levels return gradually to baseline. When studied in a sample of 12 individuals
who smoked at least 20 cigarettes per day, the half-life of the CYP 1A2 activity
decrease following smoking cessation was 38.6 hours (range 27.4–54.4 hours) [10].
Caffeine is a substrate for CYP 1A2 and historically has been used as a probe to
measure CYP 1A2 activity. While not an inhibitor, caffeine in large doses may compete
with clozapine for CYP 1A2, thereby increasing plasma clozapine levels. In a sample
96
5
Box 5.2 Smoking and Clozapine
1. Smoking as few as 7–12 cigarettes/day is sufficient to fully induce
CYP 1A2, with a net increase of 1.66-fold in enzyme activity. Aryl
hydrocarbons induce CYP 1A2 expression. Nicotine plays no role.
2. Upon smoking cessation the CYP 1A2 activity declines with a half-life of
38.6 hours (range 27.4–54.4 h). CYP 1A2 activity will therefore return to
baseline after 5 half-lives, or 8 days on average.
3. Plasma clozapine levels must be rechecked after any change in smoking
status, ideally after 7 days and 14 days, and doses adjusted.
4. When outpatient smokers treated with clozapine are placed in
situations without access to cigarettes for more than 48 hours, doses 5
ought to be lowered by 10% every 48 hours to a maximum reduction
of 50%. Plasma levels on days 7 and 14 can be used to guide further
dose adjustments.
5. The loss of induction from smoking will increase plasma clozapine levels
at least 50%. In patients whose clozapine level as a smoker was in the
high therapeutic range (600–1000 ng/ml or 1800–3000 nmol/l) this can
result in severe toxicity as clozapine levels rise and CYP 1A2 becomes
saturated, resulting in nonlinear kinetics.
of nonsmoking volunteers who ingested 400–1000 mg/day of caffeine, there was a

19% increase in mean total clozapine exposure (p = 0.05) and a 14% decrease in
mean oral clozapine clearance (p = 0.05) compared to values without caffeine [11].
While the effect of caffeine may not be clinically significant in most individuals, there
are case reports of patients increasing their clozapine levels twofold or more during
periods of excessive caffeine intake. As will be discussed in section C, Plasma Levels,
if there is doubt about the kinetic effect of an increase in caffeine intake, a repeat
trough plasma clozapine level is useful.
• BID vs. QD Dosing and Relationship to Hypotheses About

Clozapine’s Efficacy
Due to the short peripheral half-life, low levels of D2 occupancy even at peak
plasma levels, and concerns about the tolerability of large single doses, clozapine
was brought to market with recommendations for multiple daily dosing, typically
BID. As practice has evolved over the ensuing decades, the standard in many
parts of the world is to commence clozapine with a single daily QHS dose. A 2016
review of nearly 1000 clozapine-treated individuals managed at academic centers
97
in Toronto and New York noted that once daily dosing was employed in 75% of
patients without an apparent loss of efficacy, even though doses exceeding 200 mg/
day were administered in over 84% of the samples from each site [12]. Moreover,
among nonsmokers in state hospital settings within California, single QHS doses up to
500 mg are well tolerated. Putative advantages of QHS dosing including possibly lower
rates of daytime sedation, and improved adherence among outpatients. Nonetheless,
there is an absence of controlled comparative data, so clinicians can tailor dosing
schedules to patient needs, bearing in mind that many patients do well with QHS
dosing, but that others may respond better with BID dosing.
B Binding Profile of Clozapine and Its Primary Active Metabolite

Norclozapine
The clinical effects of clozapine are related to the activities of clozapine and its
primary metabolite norclozapine. The activity of norclozapine is distinct enough from
clozapine that it was studied by itself as a potential antipsychotic [13]. That the trials
of norclozapine were not successful may relate to methodological issues, but it may
also relate to the concept that the combined actions of clozapine and norclozapine
may be necessary to achieve the antipsychotic benefit. Although in vitro assays
indicate that clozapine-N-oxide has high affinity for both M1 and 5HT2A receptors,
it represents < 10% of the active moiety (clozapine + metabolites) [14]. Moreover,
data from primate studies indicate clozapine-N-oxide has high affinity for the PGP
efflux transporter, which limits CNS penetration [15]. Unfortunately, the mechanisms
that underlie clozapine’s unique efficacy are not explained by the affinity of clozapine
or norclozapine for monoamine receptors. Nonetheless, the monoamine receptor
affinities (Table 5.5) and intrinsic activity at muscarinic receptors (Table 5.6) correlate
with several features of clozapine treatment.
Table 5.5 Binding profile at cloned human receptors (Ki nM) [13] and PDSP Ki
database.
Brain/
plasma
D2 5HT2A 5HT2C 5HT1A M1 M3 α1A α1B H1 ratio in
PGP KO
vs. WT
Clozapine 20 5.0 39.8 123.7 6.17 6.31 7.9 7.0 0.32 1.6 [31]
Norclozapine 63 5.0 15.9 13.9 67.6 158 5.0 85.2 6.3 ?
(Source: pdsp.med.unc.edu/pdsp.php; accessed September 30, 2018.)
KO, knockout; WT, wild-type.
98
5
Table 5.6 Muscarinic intrinsic activity relative to the full agonist carbachol [13].
M1 M2 M3 M4 M5
Clozapine 24 ± 3% 65 ± 8% NR 57 ± 5% NR
Norclozapine 72 ± 5% 106 ± 9% 27 ± 4% 87 ± 8% 48 ± 6%
Carbachol 101 ± 2% 101 ± 5% 102 ± 3% 96 ± 3% 105 ± 3%
Box 5.3 Properties Related to Known Receptor Affinities

D2 antagonism: both clozapine and norclozapine have low affinity for this
receptor, and this is associated with extremely low risk for parkinsonism and
akathisia. 5
M1 and M3 antagonism: clozapine has high affinity for both of these muscarinic
receptors, and weak intrinsic activity at M1, and therefore acts as an
antagonist. This significant antagonist activity is associated with high rates of
constipation and other peripheral anticholinergic adverse effects.
M1–M5 agonism: norclozapine has significant intrinsic agonist activity at multiple
muscarinic receptors except for M3. While these agonist properties are not
sufficient to mitigate most peripheral anticholinergic effects of clozapine, they
are hypothesized to be responsible for inducing sialorrhea.
H1 antagonism: clozapine and to a lesser extent norclozapine have significant
affinity, contributing to sedation and impaired satiety.
α1 antagonism: clozapine and norclozapine have significant affinity resulting in
risk for orthostasis.
5HT2A inverse agonism: clozapine and norclozapine have significant affinity, and
are inverse agonists. G-protein-coupled receptors have low levels of basal
activity even in the absence of a ligand. While a potent antagonist will block
ligand actions, it does not alter the level of basal activity. An inverse agonist
will reduce the level of basal activity below baseline. The clinical implications
of potent 5HT2A inverse agonism include: (a) increased presynaptic dopamine
release in nigrostriatal neurons, thereby decreasing risk for parkinsonism,
akathisia, acute dystonia; and (b) decreased dopamine neurotransmission in
the limbic portions of the striatum, possibly contributing to the antipsychotic
effect.
The discovery that clozapine possesses potent 5HT2A binding led to the
development of other atypical antipsychotics, although none have approached
clozapine’s efficacy in resistant schizophrenia. Inverse agonists at 5HT2A receptors
mitigate the development of antipsychotic-induced parkinsonism and akathisia
through binding to presynaptic dopaminergic neurons in the nigrostriatal pathway.
99
Blocking the inhibitor signal from serotonin facilitates increased synaptic release
of dopamine. This action is the basis for the use of mirtazapine to treat akathisia:
mirtazapine has moderate affinity for 5HT2A receptors (Ki 69 nM), but this is
sufficient at doses of 30–60 mg/day to relieve the akathisia associated with D2
antagonism.
That potent 5HT2A inverse agonism has antipsychotic effects was proven
in successful trials of pimavanserin for Parkinson’s disease psychosis (PDP).
Pimavanserin has subnanomolar 5HT2A affinity (Ki 0.87 nM) with no appreciable
binding at dopaminergic, adrenergic, muscarinic, histaminergic, GABAergic or
glutamatergic receptors [16]. Although potent 5HT2A inverse agonism by itself
is effective for PDP, it may not be sufficient to treat the more complex illness of
schizophrenia. Nonetheless, there is one clinical trial showing that the combination of
pimavanserin plus risperidone 2 mg/day achieved efficacy comparable to risperidone
6 mg/day without pimavanserin [17]. Both clozapine and norclozapine are weaker D2
antagonists than risperidone, with D2 occupancy only transiently exceeding 50%, so it
is biologically plausible that the significant 5HT2A inverse agonism of these molecules
contributes appreciably to the antipsychotic effect. Moreover, the time course of 5HT2A
receptor occupancy demonstrates a longer half-life than that seen for D2 binding
(Figures 5.2 and 5.3). This property that may help explain the efficacy seen with once-
daily dosing [18].
While not crucial to routine practice, clinicians ought to be aware of another
theory for clozapine’s efficacy – its putative impact on glutamate neurotransmission.
The glutamate hypofunction hypothesis of schizophrenia derives from the known
psychotomimetic and cognitive disrupting effects of N-methyl-d-aspartate (NMDA)
glutamate receptor antagonists such as phencyclidine (PCP). Based on this
finding, it is hypothesized that NMDA receptor hypofunction might be inherent to
schizophrenia pathophysiology [19]. The NMDA receptor has binding sites for both
glutamate and a co-agonist glycine, and clinical trials have been conducted with
agents that act as NMDA agonists through various mechanisms, including inhibition
of CNS glycine transporters (GlyT1). While the addition of the GlyT1 inhibitor
sarcosine to nonclozapine antipsychotics improves schizophrenia symptoms, it
was not beneficial when added to clozapine, implying that clozapine possessed an
optimal level of glycinergic activity [20]. Supporting this concept are in vitro data
demonstrating that clozapine has selective activity at GlyT1 in a manner not seen
with other antipsychotics or norclozapine, and in vivo animal data supporting a
glycinergic mechanism [21,22]. In the few trials when glycine itself was given to
100
5
Figures 5.2 and 5.3. Predicted D2 and 5HT2A occupancy with clozapine 200 mg/
day (solid line), 300 mg/day (dotted line) and 400 mg/day (dashed line) [18].
100 400 mg
300 mg
Clozapine D2 Median % Occupancy
200 mg
80
60
40 5
20
400 600 800 1000 1200 1400

Time (Min)
Clozapine 5HT2A Median % Occupancy
100 400 mg
300 mg
200 mg
80
60
40
20
400 600 800 1000 1200 1400

Time (Min)
(Adapted from: Li, C. H., Stratford, R. E., Jr., Velez de Mendizabal, N., et al. (2014).
Prediction of brain clozapine and norclozapine concentrations in humans from a scaled
pharmacokinetic model for rat brain and plasma pharmacokinetics. Journal of Translational
Medicine, 12, 203 [18].)
101
clozapine patients in doses of 30–60 g/day, it worsened the positive symptoms of

schizophrenia [23].
C Plasma Levels
Given the varied binding properties and actions of clozapine and norclozapine there
was a healthy debate in the literature whether clinicians should track the summed
levels of both molecules or each one individually. The accumulated data over the past
30 years points to the following conclusions.
1. Plasma clozapine levels, and not the concentration of clozapine + norclozapine,
best correlate with efficacy.
2. With proper sample storage both serum and plasma clozapine levels are
acceptable and highly correlated, with serum levels on average only 3% higher
than hematocrit corrected plasma levels [24]. [NB: Throughout this volume
“plasma level” will be used as the default term for the sake of simplicity.]
3. The primary use of norclozapine levels is to track CYP 1A2 activity. Assuming
that trough plasma levels are obtained consistently at approximately the same
time since the evening dose (± 2 hours), the ratio of clozapine to norclozapine
levels (the metabolic ratio or MR ) ought not to change significantly between
determinations. Significant changes in MR therefore reflect the addition or
removal of an inhibitor or inducer. The one exception to this rule (discussed
below) is a marked increase in clozapine plasma levels and MR accompanying
severe bacterial or viral infections [25]. When the timing of trough levels is
consistent, dose adjustments or nonadherence should also not alter MR, with
the exception of overdose situations where CYP 1A2 may become saturated,
and clozapine levels increase disproportionately compared to norclozapine
levels. Box 5.4 details some rough guidelines for interpreting changes in MR.
There is increasing enthusiasm over the use of plasma level monitoring to track
patient exposure to antipsychotic agents, explore problems of nonadherence or kinetic
interactions, and determine a future course of treatment when inadequate response
or significant adverse effects arise. The principles that govern obtaining useful plasma
levels are very similar to those employed for monitoring of lithium and many other oral
medications, and are given in Box 5.5.
102
5
Box 5.4 Guidelines for Interpreting the Metabolic Ratio (MR)
1. MR = 1.32: The expected mean value for nonsmokers who are CYP 1A2
extensive metabolizers.
2. MR << 1.32: Trough values of 1.00 or less reflect exposure to an inducer
(e.g. smoking, carbamazepine, omeprazole), or CYP 1A2 ultrarapid
metabolizer status.
3. MR >> 1.32: Trough values greater than 2.00 reflect exposure to inhibitors
of the main CYP enzymes involved in clozapine metabolism: 1A2, 2C19,
2D6 or 3A4, or poor metabolizer status, especially at CYP 1A2 or CYP
2D6. As clozapine is principally metabolized via CYP 1A2, strong CYP
2D6 or 3A4 inhibitors will typically increase clozapine levels by 40–100%,
generating MR values in the range of 1.80–2.60. Conversely, strong 1A2
5
inhibitors (e.g. fluvoxamine, ciprofloxacin) may increase clozapine levels
up to 10-fold, with resulting MR values of 3.00 or greater. CYP poor
metabolizers will typically have MR values comparable to those seen with
use of strong 2D6 or 3A4 inhibitors.
4. MR ≥ 3.0 during medical illness. A marked increase in MR from baseline
in the context of serious bacterial or viral infections may occur, with MR
values on average around 3.0 (range 1.4–8.6). This change in clozapine
metabolism reflects an inhibitory effect of inflammatory cytokines on CYP
1A2 activity [25]. (See Box 5.6.)
• Response to Levels Markedly Above or Below Expected Values,

and Suspected Nonadherence
For patients starting on clozapine, an initial level is best obtained early in therapy
to gain a sense of drug metabolism and possible nonadherence. Many clinicians
choose a round number such as 100 mg QHS or 200 mg QHS as the point at which
they obtain plasma levels during titration, waiting at least 5–7 days on that dose so
clozapine will be at steady state. Issues with drug metabolism will be reflected in
MR values that differ markedly from that expected based on the patient’s current
exposure to inhibitors or inducers (especially smoking). A good rule of thumb when
the results do not jive with the clinical scenario is to repeat the level, preferably on the
same dose. If it is not possible to recheck on the same dose due to slow laboratory
turnaround (in some instances 7–14 days or more), try choosing another multiple
of 100 mg to make the math easier, as clozapine exhibits linear pharmacokinetics
within the usual therapeutic range. The presence of two data points will greatly clarify
the appropriate course of action. In particular, poor adherence will be reflected by
103
Box 5.5 Principles for Obtaining Clozapine levels

1. Timing: The gold standard is a 12-hour (± 2 h) trough value obtained
at steady state (i.e. after 5–7 days), but consistency is also important.
If a patient who receives their daily clozapine at 8 pm cannot make
it to a laboratory until 10 am, this should be the agreed upon time
for future levels to be drawn. Samples obtained within a time span
of approximately 4 hours (10–14 h postdose) do not show significant
median differences [32]. However, as the timing of blood draws deviates
significantly (e.g. > 4 h) the levels will be more difficult to interpret, as
will the MR, as more (or less) time has elapsed for the formation of
norclozapine. While a 16-hour trough is less than ideal, it is preferable to
having no documentation of plasma levels.
2. Divided doses: For patients who receive their clozapine in two (or
occasionally three) daily doses, the morning dose must be held until the
level is drawn. Communication of this with outpatients and caregivers is
crucial. If the patient and caregiver are unsure whether the morning dose
was administered prior to the laboratory visit, then simply repeat the
level. When clozapine is administered shortly before a level is obtained
the MR will be much higher than baseline values because little time has
passed for clozapine’s metabolism. The morning dose ought to be taken
as soon as possible after the level is drawn.
3. Interpreting the result: Using a nomogram or online calculator, the
clinician can generate a rough estimate of what the expected plasma
level will be for the administered dose, bearing in mind important patient
variables (age, gender, smoking status, weight), and the presence of
known inhibitors or inducers [3].
4. Variability of results: Using 723 samples from 61 patients, the mean
coefficient of variation for sequential plasma concentrations of clozapine
and of norclozapine were both approximately 30% [33]. Given this
level of variability of ± 30% between determinations, clinicians are
advised that more than one plasma level may be necessary to make an
appropriate clinical decision. Importantly, clinicians must be alert to the
possibility of laboratory error, as some laboratories may be more expert
than others in performing clozapine and norclozapine assays [34].
marked fluctuations (> 50%) in plasma clozapine levels for a given dose between
determinations.
a. Plasma levels significantly below what is expected: When there
are no prior plasma levels for the patient and the value is more than 50%
below that predicted using a nomogram or calculator that adjusts for dose
104
5
and demographic variables (especially smoking), nonadherence is the likely
culprit. As noted above, a repeat level will be instructive. Marked plasma level
fluctuations (> 50%) on the same dose will indicate nonadherence, while
consistent levels (especially with multiple data points) with limited fluctuation
may indicate absorption issues. For patients with an established baseline,
fluctuations up to 30% are to be expected. When fluctuations exceed 50%
nonadherence must be suspected, again assuming no change in dose, or
exposure to inhibitors or inducers.
b. Plasma levels significantly higher than expected: The first rule
of thumb is patient safety as determined by clinical evaluation. When no prior 5
levels are available, many clinicians become alarmed when very high levels
are returned from the laboratory (e.g. > 1000 ng/ml or > 3000 nmol/l) and
reflexively reduce doses without first determining whether the level fits the
clinical picture. Most patients with very high plasma concentrations typically
exhibit adverse effects consistent with the level including sedation, orthostasis,
tachycardia or sialorrhea. As will be discussed below, very high clozapine
levels are also seen in in the context of severe bacterial or viral infections
due to the impact of cytokines on CYP 1A2 activity. Before any actions are
taken, a few steps need to be performed. (a) The patient must be evaluated
in person, including consideration of an ECG if deemed appropriate (using the
appropriate rate correction formula if tachycardic) (see Chapter 3), assessment
of the possibility of serious infection, and the presence or absence of adverse
effects noted. (b) For those on divided daily doses, an attempt ought to be
made to determine if the level was a true trough, or if a morning dose was
inadvertently given prior to the blood draw. (c) An estimated plasma level
needs to be calculated based on dose, presence of inhibitors/inducers, and
demographics to assess how far the obtained value is from the expected
result. When there are adverse effects, the dose ought to be reduced to bring
levels below 1000 ng/ml or 3000 nmol/l, and perhaps lower depending on
the severity of the adverse effect. Abrupt discontinuation should be avoided,
as it will cause marked cholinergic rebound and possible delirium. Dose
reduction is preferable. When there is a complete absence of adverse effects,
evidence of a serious infection or ECG findings, a suspicion of laboratory error
needs to be raised and this hypothesis noted in the record as the reason for
not changing the dose and for ordering a repeat level for the next morning.
Occasional patients will also be encountered who both tolerate and respond
105
to very high plasma levels (1000–1200 ng/ml or 3057–3669 nmol/l), and who

decompensate at lower plasma levels.
When baseline plasma levels are available, and no significant change has occurred
with respect to kinetically interfering medications or habits (e.g. smoking cessation),
a level markedly higher than expected raises three possibilities. (a) The morning
dose was inadvertently given prior to the blood draw. This will result in an increase
in the MR compared to prior baseline values because limited time has elapsed for
clozapine to be converted to norclozapine. (b) There is a serious infection that has
markedly increased plasma clozapine levels (see below). (c) The high plasma level is
due to laboratory error. As noted above, the patient must be evaluated and systemic
complaints or adverse effects noted, particularly if they have changed in severity.
When there is a complete absence of systemic symptoms of infection, adverse effects
or ECG findings, or the patient appears to be at baseline, the suspicion of laboratory
error ought to be raised and noted as the reason for not changing the dose and for
ordering a repeat level the next morning.
• Serious Bacterial or Viral Infections: Impact on Clozapine Levels

and Metabolic Ratio
Over the past 25 years, there has been a steady accumulation of case reports
documenting unexpected increases in plasma clozapine levels associated with serious
bacterial, and occasionally viral, infections. The changes in clozapine metabolism
are substantial, and not related to the use of antibiotics or other medications with
kinetic effects. A 2018 review of the 40 existing cases noted that the median baseline
level (in the 25 cases where reported) was 550 ng/ml (1681 nmol/l), but jumped to
a mean level of 1811 ng/ml (5536 nmol/l) during the period of infection [25]. Not all
patients exhibited signs of excessive clozapine exposure, but adverse effects were
common with sedation occurring in 48%, delirium 20%, speech disturbance 15%,
and gait disturbance 12.5%. Myoclonus (n = 7) or generalized seizures (n = 1) were
also reported. Nearly every patient was hospitalized due to the seriousness of the
underlying medical problem, with 57.5% having a respiratory infection, 32.5% urinary,
7.5% gastrointestinal and 5% orthopedic, with three cases (0.75%) having concurrent
respiratory and urinary tract infections [25]. Of note, 30% of cases did not have fever
at the time of presentation.
Norclozapine levels obtained during the infection were available for half of
the cases, and the mean MR was markedly elevated at 3.0 (range 1.4–8.6). This
106
5
Box 5.6 Principles for Managing Clozapine during Periods of Infection
1. While quickly resolving and less serious infections may not impact
clozapine metabolism, any inflammatory process of sufficient severity
and duration (including subacute conditions such as osteomyelitis) may
cause downregulation of CYP 1A2 activity, and a sudden increase in
plasma clozapine levels and MR.
2. Educate patients, caregivers and nonpsychiatric clinicians involved with
the patient’s care to be vigilant for the development of signs consistent
with high clozapine levels during periods of acute or chronic serious
infections. All parties should be particularly sensitive to new-onset
sedation, and not to assume that complaints of tiredness are solely due
to the medical condition. 5
3. Obtain a trough clozapine level immediately upon any medical
hospitalization, especially when the admission is for infection. Although
the plasma level result may not be available for a week or more, it can be
useful in adjusting clozapine doses.
4. Only 50% of published cases involving plasma level increases during
infection had clinical symptoms [25], so the clozapine dose need not be
reflexively decreased in all hospitalized patients. However, those who
exhibit any new or worsening adverse effects should have the clozapine
dose reduced by approximately 50%, bearing in mind that further dose
reduction may be needed if adverse effects persist several days after
the dose reduction. Abrupt discontinuation should be avoided due to
the risks associated with cholinergic rebound and rebound psychosis. A
repeat trough plasma level should be drawn at steady state 5 days after
any dosage change to help guide future decision-making.
5. Although acute signs of sepsis or infection may resolve quickly during
treatment for the underlying condition, the levels of inflammatory
cytokines can remain elevated for longer periods, thereby prolonging
the time course of subnormal CYP 1A2 capacity. Patients can remain
on lower than normal clozapine doses for an extended time (e.g. weeks)
while CYP 1A2 activity slowly returns to normal, with the caveat that
plasma levels are equivalent to pre-infection values.
6. Weekly monitoring of plasma clozapine levels can document the
resolution of infection-mediated impact on clozapine metabolism. During
this time, the MR will gradually return to its baseline value. Clozapine
doses should be increased if breakthrough psychiatric symptoms
develop, or levels have dropped below pre-infection values.
combination of elevated MR coincident with a tripling of the plasma clozapine

level points to a process impacting CYP 1A2-mediated clozapine metabolism. The
leading hypothesis is that inflammatory cytokines mobilized due to the infection and
107
related stress can downregulate CYP 1A2 expression as much as 90%, resulting
in a marked decrease in CYP 1A2 capacity in the same manner as would be seen
with administration of a strong CYP 1A2 inhibitor [25]. The true prevalence of this
problem in clozapine-treated patients with serious infections is unknown, but likely
is underreported as plasma clozapine levels are often not drawn during periods of
infection. Thus, in the absence of documented changes in plasma clozapine levels
and MR, the most common complaint (sedation) may be ascribed to tiredness from
the medical illness itself. Given the potential seriousness of clozapine toxicity in the
context of a severe medical illness, clinicians should keep in mind the following
principles outlined in Box 5.6. The goal is to adjust clozapine doses in patients who
require such intervention, but avoid complete discontinuation of clozapine, especially
abrupt cessation that can result in cholinergic rebound and rebound psychosis.
• Depending on the country in which one resides, clozapine levels may be reported
Use of Levels to Monitor Efficacy
in ng/ml or nmol/l. Units as μg/l are occasionally used and are identical to values in
ng/ml. For the mathematically inclined, conversion formulas between these two units
are provided below which rely on the molecular weight of clozapine (326.83 g/mol).
Table 5.7 provides comparable values for a range of commonly encountered plasma
levels.
a. Converting to nmol/l to ng/ml: level (nmol/l) × 0.32683
b. Converting ng/ml to nmol/l: level (ng/ml) × 3.057
Table 5.7 Clozapine plasma levels in ng/ml and nmol/l.

Level in ng/ml Level in nmol/l
200 611
300 917
400 1223
500 1528
600 1834
700 2140
800 2446
900 2571
1000 3057
108
5
Table 5.8 Clozapine plasma level ranges for resistant schizophrenia.
Response threshold Diminishing tolerability Point of futility
Level in ng/ml 350 700–1000 > 1000

Level in nmol/l 1070 2140–3057 > 3057
Table 5.8 is informed by numerous reviews that document a mean threshold

for response in resistant schizophrenia around 350 ng/ml or 1070 nmol/l, and a
therapeutic range up to 1000 ng/ml or roughly 3000 nmol/l [26]. Patients treated for
Parkinson’s disease psychosis typically require such minute doses (6.25–50 mg/day)
5
that plasma levels are not useful.
While many laboratories report an “upper limit” of 600 ng/ml (1834 nmol/l) or
700 ng/ml (2140 nmol/l), there are clearly patients who benefit from and tolerate
these high plasma levels [27]. Given the lack of viable alternatives for resistant
schizophrenia and other common uses, patients must not be deprived of a trial of
clozapine with higher plasma levels, assuming tolerability up to that point.
Once the trough plasma level has crossed the therapeutic threshold, patients
need to be given 2–3 weeks to look for any signals of response before deciding on
further titration, assuming adverse effects are not limiting. In a dose titration trial, the
mean time to response (± SD) once a patient reached the dose (and level) at which
they finally responded was 17 (± 14) days, with a range of 2–56 days. Importantly, no
late response was found among nonresponders despite a mean follow-up period of
75 weeks [28]. While some clinicians cite old literature touting very late response (6
months or longer), these nonsystematic data do not stand up to the rigorous methods
used in later trials. Nonresponders without dose-limiting adverse effects must not be
left at the same plasma level for months on end hoping for “late response.” Titration
ought to proceed even when levels exceed what a particular laboratory has arbitrarily
decided is the upper threshold, as the literature clearly justifies exploring levels up
to 1000 ng/ml or 3057 nmol/l if tolerated. As levels reach the point of diminishing
tolerability, they need to be rechecked after each dose increase of 50 mg/day. Very
few patients will respond at levels > 1000 ng/ml or > 3057 nmol/l (the so called
“point of futility”), but clinicians may encounter rare patients who seemingly tolerate
and respond to such levels. Documentation of response after careful titration, and the
absence of significant adverse effects, is important so that other clinicians understand
the context for maintaining a patient with seemingly heroic plasma concentrations.
109
Box 5.7 Principles for Titrating Clozapine

1. The likelihood of response < 350 ng/ml or 1070 nmol/l is low (but not
zero). If tolerated, this is a reasonable initial target.
2. Many laboratories report an “upper limit” for clozapine levels of 600 ng/
ml (1834 nmol/l) or 700 ng/ml (2140 nmol/l), but there are clearly patients
who benefit from and tolerate these high plasma levels [27]. Given
the limited alternatives for resistant schizophrenia, patients must not
be deprived of a clozapine trial with higher plasma levels, assuming
tolerability.
3. Once the dose is increased, patients should be given 2–3 weeks to
respond before further titration if adverse effects are not limiting. In a
dose titration trial, time to response once the patient reached a dose
where they responded was 17 days on average (range of 2–56 days). No
late response was found among nonresponders despite a mean follow-
up period of 75 weeks [28].
4. Nonresponders without dose-limiting adverse effects must not be left on
the same dose and at the same plasma level for months on end hoping
for “late response.”
5. As levels reach the point of diminishing tolerability (> 700 ng/ml or
> 2140 nmol/l), they should be rechecked after each dose increase
of 50 mg/day. Very few patients will respond at levels > 1000 ng/ml
or > 3057 nmol/l (the so-called “point of futility”), but clinicians may
encounter rare patients who seemingly tolerate and respond to such
levels.
6. Concentration oral dose relationships (assuming MR = 1.32) [3]:
40 year old male, weight 80 kg:
Concentration (ng/ml) = 1.08 x oral dose (mg/d) (nonsmoker)
Concentration (ng/ml) = 0.67 x oral dose (mg/d) (smoker)
40 year old female, weight 70 kg:
Concentration (ng/ml) = 1.32 x oral dose (mg/d) (nonsmoker)
Concentration (ng/ml) = 0.80 x oral dose (mg/d) (smoker)
110
5
Summary Points
a. The mechanisms underlying clozapine’s unique efficacy are not clear, but many
of the adverse effects can be predicted by receptor binding and activity at
certain sites: α1 antagonism (orthostasis), H1 antagonism (sedation and weight
gain), M1 and M3 antagonism (constipation), and M1–M5 agonism (sialorrhea).
b. Single daily bedtime dosing is the norm in many parts of the world without
apparent loss of efficacy. Single QHS doses up to 500 mg are routinely
employed.
c. Familiarity with interpreting the metabolic ratio (ratio of clozapine:norclozapine 5
plasma levels) is very helpful in making clinical decisions.
d. Serious bacterial or viral infections can result in downregulation of cytochrome
P450 1A2 activity by inflammatory cytokines, with a resultant increase in
clozapine levels up to threefold, and an increase in the MR to 3.0. Plasma levels
and clinical symptoms of clozapine toxicity should be monitored for during any
hospitalization for infection. Patients, caregivers and other clinicians involved
with the patient must be alerted to the potential jump in plasma clozapine levels
during serious infections, and the most common symptoms.
e. Plasma clozapine levels correlate better with efficacy than the sum of
clozapine + norclozapine levels. Tracking plasma (or serum) levels is crucial to a
successful clozapine trial.
f. Nicotine itself plays no role in CYP 1A2 induction, it is the aryl hydrocarbons
generated from burning the tobacco leaf. After smoking cessation or switching
from cigarettes to an e-cigarette, a patient will lose their CYP 1A2 induction over
the next week, and clozapine levels may rise 50% or more.
111
References
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tablets compared with clozapine solid oral 100-mg tablets after multiple doses in patients with
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2. Couchman, L., Morgan, P. E., Spencer, E. P., et al. (2010). Plasma clozapine and norclozapine
in patients prescribed different brands of clozapine (Clozaril, Denzapine, and Zaponex). Therapeutic
Drug Monitoring, 32, 624–627.
4. Couchman, L., Morgan, P. E., Spencer, E. P., et al. (2010). Plasma clozapine, norclozapine,
and the clozapine:norclozapine ratio in relation to prescribed dose and other factors: Data from a
therapeutic drug monitoring service, 1993–2007. Therapeutic Drug Monitoring, 32, 438–447.
5. Meyer, J. M., Proctor, G., Cummings, M., et al. (2016). Ciprofloxacin and clozapine – A
potentially fatal but underappreciated interaction. Case Reports in Psychiatry, 2016, 5606098.
6. Diaz, F. J., Santoro, V., Spina, E., et al. (2008). Estimating the size of the effects of co-
medications on plasma clozapine concentrations using a model that controls for clozapine doses and
confounding variables. Pharmacopsychiatry, 41, 81–91.
7. Diaz, F. J., Eap, C. B., Ansermot, N., et al. (2014). Can valproic acid be an inducer of clozapine
metabolism? Pharmacopsychiatry, 47, 89–96.
8. Zhou, S. F., Wang, B., Yang, L. P., et al. (2010). Structure, function, regulation and polymorphism
and the clinical significance of human cytochrome P450 1A2. Drug Metabolism Reviews, 42, 268–354.
9. Haslemo, T., Eikeseth, P. H., Tanum, L., et al. (2006). The effect of variable cigarette
consumption on the interaction with clozapine and olanzapine. European Journal of Clinical
10. Faber, M. S. and Fuhr, U. (2004). Time response of cytochrome P450 1A2 activity on cessation of
heavy smoking. Clinical Pharmacology & Therapeutics, 76, 178–184.
11. Hagg, S., Spigset, O., Mjorndal, T., et al. (2000). Effect of caffeine on clozapine pharmacokinetics
in healthy volunteers. British Journal of Clinical Pharmacology, 49, 59–63.
13. Weiner, D. M., Meltzer, H. Y., Veinbergs, I., et al. (2004). The role of M1 muscarinic receptor
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14. Frazier, J. A., Cohen, L. G., Jacobsen, L., et al. (2003). Clozapine pharmacokinetics in children and
adolescents with childhood-onset schizophrenia. Journal of Clinical Psychopharmacology, 23, 87–91.
15. Raper, J., Morrison, R. D., Daniels, J. S., et al. (2017). Metabolism and distribution of clozapine-
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17. Meltzer, H. Y., Elkis, H., Vanover, K., et al. (2012). Pimavanserin, a selective serotonin
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18. Li, C. H., Stratford, R. E., Jr., Velez de Mendizabal, N., et al. (2014). Prediction of brain
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brain and plasma pharmacokinetics. Journal of Translational Medicine, 12, 203.
19. Coyle, J. T., Tsai, G. and Goff, D. C. (2002). Ionotropic glutamate receptors as therapeutic targets
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20. Lane, H. Y., Huang, C. L., Wu, P. L., et al. (2006). Glycine transporter I inhibitor, N-methylglycine
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and plasma samples from schizophrenic patients. Therapeutic Drug Monitoring, 30, 41–45.
25. Clark, S. R., Warren, N. S., Kim, G., et al. (2018). Elevated clozapine levels associated with
infection: A systematic review. Schizophrenia Research, 192, 50–56.
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determine cause of death. Australiann & New Zealand Journal of Psychiatry, 46, 816–825.
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standardized trial. American Journal of Psychiatry, 154, 1243–1247.
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The need for consensus. Therapeutic Drug Monitoring, 28, 696–699.
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6
QUICK CHECK
Understanding Hematologic
Monitoring and Benign Ethnic
Neutropenia
Introduction 114
Principles 115
A Neutropenia Time Course and Risk Factors 117
• Benign Ethnic Neutropenia 118
• Addressing Low Baseline ANC 120
• Time Course of Severe Neutropenia 123
• Hypothesized Mechanism for Neutropenia 125
B Basic Hematologic Monitoring Guidelines and Response 126
• US Monitoring 126
• UK Monitoring 128
• Eosinophilia and Thrombocytopenia 131
C anaging Frequent Treatment Interruption
M
Due to Low WBC/ANC 131
D Response to Severe Neutropenia 134
• Rechallenging Severe Neutropenia Patients With
Filgrastim Support 134
E Point-of-Care CBC Monitoring 136
Summary Points 137
References 138
INTRODUCTION
Many nonchemotherapy medications are associated with neutropenia risk [1],

but it was the cluster of 16 severe clozapine-related neutropenia cases reported
from Finland in mid-summer 1975 with a 50% fatality rate that prompted clozapine’s
withdrawal [2]. Clozapine was subsequently reintroduced to the world market in the
late 1980s based on demonstrable efficacy in treatment-resistant schizophrenia, albeit
with mandatory hematologic monitoring and patient tracking.
114
6: UNDERSTANDING HEMATOLOGIC MONITORING AND BENIGN ETHNIC NEUTROPENIA
6
PRINCIPLES
• Absolute neutrophil count (ANC) monitoring requirements have changed in the

past half-decade, and now differ between the US and other countries.
• The possibility of benign ethnic neutropenia (BEN) must be ruled out in
individuals with low baseline ANC. Individuals with BEN have lower ANC
thresholds for starting and remaining on clozapine. Patients with BEN are at
lower risk for the development of severe neutropenia.
• Other causes of neutropenia, especially medications such as valproate, must
be explored in those who do not have BEN but who have subnormal ANC
values.
• Lithium and filgrastim must be considered for individuals with or without 6
BEN who have ANC below the threshold for commencing clozapine, or who
experience treatment interruptions due to low ANC values.
• The period of greatest risk for neutropenia occurs during the first 6 months,
but most countries mandate monthly ANC monitoring starting at week 52 for
as long as the patient remains on clozapine.
• The median time to resolution of severe neutropenia from clozapine is 12
days.
Despite common elements around the world, clinicians must be mindful of

variations in country-specific monitoring details including frequency of blood draws,
whether a complete blood count (CBC) with differential or only the absolute neutrophil
count (ANC) is tracked, how benign ethnic neutropenia (BEN) is managed, and the
response to laboratory abnormalities [3]. Table 6.1 illustrates some basic differences
in US and UK programs, including the change in US terminology from agranulocytosis
for ANC values < 500/mm3 to severe neutropenia.
The purpose of this chapter is to provide clinicians with the core principles that
underlie all clozapine monitoring schemes, including the period of highest neutropenia
risk, hypothesized mechanisms and risk factors for neutropenia, the diagnosis of
BEN, time course and management of severe neutropenia, and the use of lithium and
filgrastim to stimulate neutrophil production. Throughout this chapter and others in
this handbook severe neutropenia will replace the older terminology of agranulocytosis
to denote ANC counts < 500/mm3.
115
Table 6.1 Some differences in US and UK clozapine hematologic monitoring.

UK US
WBC parameters Total WBC and ANC ANC
1. WBC ≥ 3500/mm3 and ANC 1. ANC ≥ 1500/mm3
Threshold ≥ 2000/mm3
for starting 2. BEN ANC ≥ 1000/mm3
clozapine 2. B
EN WBC ≥ 3000/mm3 and
ANC ≥ 1500/mm3
1. Weekly through week 18 1. Weekly through week 26
2. Biweekly through week 52 2. Biweekly through week 52
Basic monitoring
frequency 3. Monthly after week 52 3. Monthly after week 52
4. U
p to 4 weeks after 4. Up to 4 weeks after
discontinuation discontinuation
Based on WBC and ANC, counts Neutropenia is classified as
are classified using Green, Amber mild, moderate, or severe
and Red indicators based on ANC. “Severe
Terminology for
neutropenia” replaces the
neutropenia
previous terms severe leukopenia,
severe granulocytopenia, or
agranulocytosis
Rechallenge
possible
after severe No Yes
neutropenia
(agranulocytosis)
1. Written confirmation of the BEN 1. Consider hematology
diagnosis is required from a consultation before initiating or
consultant hematologist and during treatment as necessary
completion of “Confirmation 2. BEN-specific ANC thresholds
Benign ethnic of Benign Ethnic Neutropenia for commencing, holding and
neutropenia Monitoring Criteria Approval stopping clozapine
Form”
3. Package insert notes that BEN
2. B
EN-specific WBC and ANC patients are not at increased
thresholds for commencing, risk for developing neutropenia
holding and stopping clozapine
1. Eosinophilia defined as > 1000/ 1. Eosinophilia defined as > 700/
mm3 pretreatment and > 3000/ mm3. Clinicians alerted to
mm3 while on treatment. evaluate promptly for signs/
Initiation or continuation of symptoms of systemic
treatment not recommended if reactions, rash or other allergic
detected symptoms, myocarditis, or
2. Biweekly monitoring for high other organ specific disease
Eosinophil and eosinophil (> 3000/mm3) or low associated with eosinophilia
platelet counts platelet counts (< 50 K) 2. Mention of drug reaction with
eosinophilia and systemic
symptoms syndrome (DRESS),
also known as drug-induced
hypersensitivity syndrome (DIHS)
3. No specified reference ranges
for platelet counts or response
to aberrant values
116
6
A Neutropenia Time Course and Risk Factors
Within the US all antipsychotics carry package insert warnings about risk for
leukopenia and neutropenia, but these occurrences are considered too infrequent
to necessitate routine laboratory surveillance. For clozapine the estimates of severe
neutropenia rates range from 0.38% to 2.0%, with a 2018 meta-analysis of 108
publications placing the incidence at 0.9% (95% CI 0.7–1.1%) [4]. These values
are sufficiently high to demand routine blood count monitoring to decrease the risk
of sepsis and fatality. The success of this approach was documented in early US
data obtained shortly after the US Food and Drug Administration (FDA) approval on
September 26, 1989. During the years 1990–1994, 99,502 individuals were started
on clozapine and placed in the Novartis-maintained US registry. Based on rates
derived from pre-registry data worldwide, the use of monitoring decreased the rate of 6
severe neutropenia by over 60%, and of related deaths by nearly 92% [5]. The 2018
meta-analysis covering clozapine-related neutropenia concludes that the risk of death
related to neutropenia from clozapine use is only 0.013% [4]. It is worth noting that the
0.38% incidence of severe neutropenia from the early US sample of 99,502 patients
resulted in a change in CBC monitoring for weeks 26–52 from weekly to every 14 days.
In 2015 the FDA approved new clozapine hematologic monitoring guidelines based
on findings from a quarter century of clozapine experience [6]. Embedded in these
changes are several important insights (Box 6.1).
Box 6.1 Concepts Underlying New US Clozapine Guidelines

1. Clozapine therapy is associated with neutropenia but not leukopenia. No
additional safety benefit is conferred by having separate thresholds for
total WBC. Only ANC monitoring is necessary.
2. The minimum starting ANC threshold of 2000/mm3 and the thresholds for
increased monitoring and treatment interruption were unnecessarily high.
3. Those of African descent had markedly lower rates of clozapine utilization
and continuation, in part due to the presence of BEN. Moreover, patients
with BEN are at lower risk for severe neutropenia than other individuals,
and can safely be started on clozapine with an ANC threshold of 1000/
mm3.
Utilizing these revised US guidelines, a retrospective analysis of hematologic

outcomes from a cohort of 246 US veterans with schizophrenia treated from
1999 to 2012 was performed to explore the implications of this policy change on
117
clozapine interruptions. No episodes of severe neutropenia were observed during the

study period, but under the revised recommendations the proportion of treatment
interruptions among those starting clozapine would have decreased by 80% [6].
• That individuals of African descent might have lower WBC values than norms
Benign Ethnic Neutropenia
derived from Caucasians was first noted in a 1941 US paper, but it was not until 1966
that an extensive analysis of samples from healthy African Americans referred to a St.
Louis hematology department led the authors to develop a concept of racial variations
in WBC [7]. Importantly, the authors noted that, despite subnormal leukocyte counts,
these individuals did not appear to be at risk for infection. Over the next decade
the term benign ethnic neutropenia (BEN) was elaborated, and its association with
variations in Duffy blood group antigens described [8].
The Duffy group was recognized in 1950 as another set of red blood cell
antigens that pose a risk for transfusion reactions, with proteins also expressed
in various tissues (endothelium, brain, heart, kidney and pancreas). The two forms
of the Duffy antigen were designated A and B, and the respective surface markers
Fya, Fyb. In 1968, the gene that controls expression of what was now known as
the Duffy antigen receptor for chemokines (DARC) was located to chromosome 1
(1q21–q22), and the two allele groups FY*A and FY*B were found to differ by only a
single nucleotide polymorphism (SNP) 125G>A [8]. Although it was known in 1954
that a significant proportion of those with African descent did not present either
DARC surface Fy antigens [designated as Fy (a–/b–) or null/null], not until 2008
was the SNP most strongly associated with null/null status identified. This SNP,
rs2814778, is a functional T46C polymorphism located in the DARC gene promoter
region, with the CC genotype present among 70–75% of black people. It is only in
these individuals who are [Fy (a–/b–)] that DARC proteins are not expressed, and it
is only these individuals who manifest lower ANC values than norms derived from
predominantly Caucasian populations. Interestingly, the absence of RBC DARC
surface antigens prevents invasion by the malarial organisms Plasmodium vivax and
Plasmodium knowlesi [9].
African heritage has the strongest association with BEN, but it has been reported
from groups in nearby Middle Eastern areas, particularly Yemenite Jews and certain
Arab populations [10]. Despite these associations, 24% of children evaluated for BEN
in an academic New York hematology clinic reported ethnicities other than African or
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6
Middle Eastern [11]. As has been shown in a number of studies, it is DARC genetics
and not self-identified race that determines whether an individual has BEN [12,13]. As
seen in Table 6.2, only those who have the null/null variant [Fy (a–/b–)] will manifest
low ANC.
Table 6.2 ANC values by DARC genotype in a cohort of 6005 self-identified African
Americans [12].
DARC (a/b) genotype N Mean ANC (/mm3)
–/– 4111 2459
+/– 1647 3982
+/+ 247 4013
The current definition of BEN in adults is recurrent ANC less than 1500/mm3 in
6
the absence of other secondary causes of neutropenia, such as infections, drugs,
cancer, autoimmune diseases, metabolic disturbances, and hematologic disorders.
Those with BEN often have an ANC that at times exceeds 1500/mm3, but 2% may
have values in the range of 500–1000/mm3 [14]. Consistent with the terminology,
this is a benign variant and is not associated with increased risk of infection or
infection-related complications. Moreover, those with BEN have normal bone marrow
morphology, and other leukocyte counts are normal [10]. Individuals of African
descent also appear to be at lower risk for the development of severe neutropenia
during clozapine treatment [15].
Once the BEN diagnosis is established, the individual must be registered as
such so that appropriate standards for initiation and management of ANC values
are applied. Prior to the creation of BEN-specific ANC criteria, many of these
patients were either deemed ineligible for clozapine, or had clozapine trials
terminated due to ANC values that dipped below the threshold for continuation [15].
Whether due to poor record keeping or inaccurate understanding of nomenclature,
some of these patients were deemed “not rechallengeable” or were recorded as
having experienced “agranulocytosis” despite ANC values ≥ 500/mm3. When the
records fail to reveal ANC counts < 500/mm3 these patients must be considered
as candidates for clozapine treatment. As will be discussed below, the US has
modified language in clozapine package inserts that permits individuals with severe
neutropenia to be rechallenged under certain circumstance (see section B, US
Monitoring).
119
Box 6.2 Considerations in Making the BEN Diagnosis

1. Suspect BEN in individuals with a pattern of ANC values < 1500/mm3,
particularly when one of the following have been present:
a. Low ANC during periods when not exposed to medications
associated with neutropenia (especially valproate and
antipsychotics).
b. Low ANC values despite varying classes of antipsychotics.
c. Absence of other conditions associated with persistent neutropenia.
d. African or Middle Eastern heritage is suggestive, but it can occur in
those of mixed heritage.
2. Confirming the BEN diagnosis:
a. In many countries a hematology consultant must see the patient and
attest to the BEN diagnosis. This typically will involve genetic testing,
but the consultant is responsible for establishing the diagnosis.
b. Where a hematology consultation is not required, the gold standard
is genetic testing for DARC polymorphisms. Only those who are null/
null [Fy (a–/b–)] have BEN. Presence of either antigen [(Fy a+/b–) or
[Fy (a–/b+)] is not associated with low ANC values and BEN.
c. In some countries (e.g. US) a clinician who is not a hematologist
(i.e. psychiatrist) may designate the individual as having BEN due
to overwhelming clinical evidence (e.g. meeting all criteria 1a–1d)
without genetic testing. In those circumstances it is incumbent
on the clinician to eliminate all other possible causes, particularly
ongoing exposure to valproate.
• In those without genetic evidence of BEN yet who do not meet the ANC threshold
Addressing Low Baseline ANC
for starting clozapine, or for those with BEN but whose ANC at times is < 1000/mm3,
other sources of neutropenia must be sought. Certain syndromes such as cyclic
neutropenia are exceedingly rare (1 in 1 million persons), but autoimmune neutropenia
and viral illnesses are included in the differential, along with exposure to xenobiotics
in the form of medications. For many patients, medication-related neutropenia will
be the primary cause of persistently low ANC. Medications other than clozapine have
been associated with severe neutropenia, and a few have Level 1 evidence based on
findings of a definite causal relationship (Table 6.3).
Unfortunately, the list of medications that induce milder forms of neutropenia is
quite extensive, so a review of CBC records during periods of exposure to various
120
6
Table 6.3 Nonchemotherapy medications with either Level 1 (definite) or Level 2
(probable) evidence for severe neutropenia [29].
Class Level 1 Medications (# of Level 2 Medications (# of probable
definite cases as of 2007) cases as of 2007)
Aminopyrine (2), diclofenac Acetaminophen (1), bucillamine
Analgesic/ (1), diflunisal (1), dipyrone (1), fenoprofen (1), mefenamic acid
nonsteroidal anti- (6), ibuprofen (1) (1), naproxen (2), pentazocine (2),
inflammatory phenylbutazone (1), piroxicam (1),
sulindac (1)
Disopyramide (1),
Ajmaline (4), amiodarone (1),
Antiarrhythmics procainamide (3), quinidine
aprindine (1)
(3)
Abacavir (2), amodiaquine (10),
amoxicillin-clavulanic acid (1),
cefamandole (1), cefepime (2),
ceftriaxone (6), cephalexin (1),
Ampicillin (1), carbenicillin
cephalothin (3), cephapirin (4), 6
(1), cefotaxime (1),
cephradine (1), chloroguanide (1),
cefuroxime (1), flucytosine
clarithromycin (1), cloxacillin (1),
(1), fusidic acid (1),
Antibiotics/HIV dapsone (17), hydroxychloroquine
imipenem-cilastatin (1),
(2), indinavir (1), isoniazid (1),
nafcillin (1), oxacillin (2),
mebendazole (1), nifuroxazide (1),
penicillin G (4), quinine (2),
nitrofurantoin (1), norfloxacin (1),
ticarcillin (1)
penicillin-G procaine (1), piperacillin
(1), terbinafine (5), trimethoprim-
sulfamethoxazole (3), vancomycin (5),
zidovudine (2)
Anticonvulsants Phenytoin (1) Carbamazepine (3), lamotrigine (4)
Antihelminthic Levamisole (2)
Antithyroid Propylthiouracil (1) Carbimazole (21), methimazole (55)
Clopidogrel (1), Bepridil (1), bezafibrate (1), captopril
Cardiovascular methyldopa (1), ramipril (1), (9), metolazone (1), ticlopidine (15),
spironolactone (1) vesnarinone (2)
Famotidine (3), mesalazine (1),
Cimetidine (1),
Gastrointestinal metiamide (4), omeprazole (2),
metoclopramide (1)
pirenzepine (2), ranitidine (4)
Immune
Gold (5), penicillamine (2),
modulator/ Infliximab (1)
sulfasalazine (12)
rheumatologic
Amoxapine (1), clomipramine (1),
cyanamide (1), desipramine (1),
dothiepin (1), doxepin (1), imipramine
Chlorpromazine (2),
Psychotropics (1), indalpine (1), maprotiline (1),
fluoxetine (1)
meprobamate (1), methotrimeprazine
(1), mianserin (9), olanzapine (1),
thioridazine (1), ziprasidone (1)
121
medications, and during periods of no treatment, can shed light on whether low ANC
is a persistent issue or developed subsequent to a specific agent. Among patients
with severe mental illness, the more likely offenders are other antipsychotics or
anticonvulsants, especially valproic acid or divalproex. While valproate is known to
induce concentration-dependent thrombocytopenia in 5–40% of patients, the reported
neutropenia rate ranges from 5% to 26% [16]. Table 6.4 provides a comparison with
phenytoin from a group managed in an epilepsy clinic in Utrecht.
Table 6.4 WBC and ANC counts in patients on valproate or phenytoin [16].
Valproate Phenytoin
WBC (/mm3) 7.94 7.85

ANC (/mm3) 4.36 5.23
Linear regression analyses of these data revealed a significant correlation between

valproic acid serum concentration and the ANC (rp = –0.26; p < 0.001) [16]. This finding
has been replicated in studies examining neutropenia during clozapine treatment: use
of valproate was associated with twofold increased neutropenia risk (OR 2.28, 95% CI
1.27–4.11, p = 0.006), with greater associations for higher valproate doses [17].
Box 6.3 Suggested Approach to those with Low Baseline ANC (< 1500/mm3 For
the General Population, Or < 1000/mm3 For Those With BEN)
1. DARC genetic testing ought to be performed in any individual when there
is suspicion of BEN.
2. Scour all available laboratory records for ANC values obtained during
periods without exposure to medications associated with neutropenia
(especially valproate and antipsychotics, but nonpsychiatric medications
must also be considered).
3. If there are periods with ANC values above the clozapine initiation
threshold and a pattern suggestive of drug-induced neutropenia,
systematically transition the patient away from possible offending agents
one at a time, allowing 4 weeks to establish new ANC values after each
agent is discontinued and before another change is made.
4. If steps 1–3 do not resolve the issue, consider hematology consultation
to look for other conditions associated with persistent neutropenia.
When the above fail to satisfactorily achieve ANC values consistently above
the appropriate initiation threshold (BEN or non-BEN), then adjunctive
strategies using lithium or filgrastim to support ANC counts must be
considered. These are discussed below in the subsection Managing
Frequent Treatment Interruption Due to Low WBC/ANC.
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6
• Data amassed from 11,555 US patients treated from February 1990 to April 1991
Time Course of Severe Neutropenia
documented that the highest period of severe neutropenia risk occurred during the
first 6 months of treatment, with a marked decline in cases reported after 12 months
(Figure 6.1).
Figure 6.1. Hazard rates of severe neutropenia by month of follow-up.
0.012
0.010
Rate of Agranulocytosis (%)
0.008
6
0.006
0.004
0.002
0.000
0 2 4 6 8 10 12 14 16 18 20
Follow-Up (Months)
(Adapted from: Alvir, J. M., Lieberman, J. A., Safferman, A. Z., et al. (1993). Clozapine-
induced agranulocytosis. Incidence and risk factors in the United States. New England
Journal of Medicine, 329, 162–167 [30].)
The cumulative 12-month rate was 0.80% (95% CI 0.61–0.99%) and the
18-month rate was 0.91% (95% CI 0.62–1.20%). These early data are nearly
identical to those found in a 2018 meta-analysis of 108 studies covering clozapine-
related neutropenia which calculated a severe neutropenia incidence of 0.9% (95%
CI 0.7–1.1%) [4]. The peak incidence of severe neutropenia occurs at 1 month of
exposure and declines to negligible levels after 1 year of treatment. Consistent with
these data, routine monitoring schemes mandate higher frequency during the first
123
4–6 months of treatment (weekly), decreasing to every 2 weeks for the remainder of
the first year of treatment, and monthly after week 52. Due to case reports of severe
neutropenia occurring after years of clozapine exposure, monthly monitoring continues
indefinitely. When patients have extended treatment interruptions, or interruption due
to CBC abnormalities, the clock may be “reset” to a higher monitoring frequency as
mandated by local guidelines (see discussion below).
The unpredictable timing of severe neutropenia episodes has not precluded
manufacturers from including warnings about “downward trends,” “single drops” or
“substantial drops” in total WBC and/or ANC for the past two decades. The recently
updated US prescribing guidelines have removed all mention of trend data or drops as
these changes did not prove predictive of severe neutropenia events and resulted in
unnecessary concern and additional monitoring. Nonetheless, these are still commonly
found worldwide, and clinicians must be mindful of the necessary response to these
events. For example, the 2015 UK Zaponex® Treatment Access System manual states:
If a Single Drop or Downward Trend is detected in a patient’s blood result
history and the WBC count value falls below 7.0 × 109/l, a Single Drop/
Downward Trend Warning will be faxed to the patient’s healthcare providers.
The consultant is then advised by ZTAS to assess the patient’s general health
and determine whether or not an increase of the monitoring frequency to twice
weekly is necessary until the blood results have stabilized.
Associations between older age and female gender appeared during the early
analysis of severe neutropenia cases, but none of these are significant enough to
alter routine monitoring schemes, and recent data have cast doubt on the gender
association [18]. Certain genetic polymorphisms have been associated with clozapine-
induced severe neutropenia, especially the human leukocyte antigen (HLA) markers
HLA-DQB1 and HLA-B [19]. The largest genetic study to date examined 66 severe
neutropenia cases and 5583 clozapine-treated controls, and then combined their
results with findings from the Clozapine-Induced Agranulocytosis Consortium (163
cases and 7970 controls) [20]. In addition to replicating the previously identified
variant in HLA-DQB1 (OR = 15.6, p = 0.015, positive predictive value = 35.1%), this
analysis found an association with a SNP (rs149104283) located on the intron of
hepatic transporter genes (OR = 4.32, p = 1.79 × 10–8), loci previously implicated in
simvastatin-induced myopathy and docetaxel-induced neutropenia. Two other markers
of interest were also identified. At the present time, the presence of these genetic
markers is not robust enough to alter monitoring frequency or preclude initiating
clozapine treatment.
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6
While demographic and genetic risk factors are neither modifiable nor actionable,
the ongoing use of valproate preparations has been confirmed as a risk factor for
forms of neutropenia that lead to discontinuation of clozapine treatment. Clinical
records of 136 patients who discontinued clozapine due to a neutropenic event
were matched 1:1 with clozapine-treated controls by duration of treatment. In
the multivariable analysis, the concurrent use of valproate doubled the risk of
discontinuation due to neutropenia (OR 2.28, 95% CI 1.27–4.11, p = 0.006), and this
risk was positively correlated with higher valproate dose [17]. Although the purpose
of this analysis was not to specifically examine severe neutropenia cases, it highlights
concerns about valproate-induced neutropenia, especially for those exposed to higher
doses and serum levels [16]. While valproate or divalproex are the medications of
choice for clozapine-associated seizure phenomena (see Chapter 10), alternative
mood stabilizers, particularly lithium, need to be considered when starting clozapine, 6
especially for patients whose ANC values might hover slightly above the threshold for
treatment interruption or increased monitoring frequency.
• Despite multiple in vivo and in vitro studies, the exact mechanism of clozapine-
Hypothesized Mechanism for Neutropenia
associated severe neutropenia has not been definitively identified, although immune
hypotheses carry greater weight than those centering on direct bone marrow toxicity
[21]. Different mechanisms might underlie milder forms of neutropenia seen during
clozapine therapy [22], but the significant association with certain HLA haplotypes
combined with in vitro assay results from patients who have experienced severe
neutropenia point strongly to an immune basis for severe neutropenia. It is for this
reason that patients who developed severe neutropenia during clozapine treatment
were not to be rechallenged, and this precept is generally applied in most countries.
Two recent developments have modified this position: (a) Revised US prescribing
guidelines now state that, in patients who have had severe neutropenia: “For some
patients who experience severe CLOZARIL related neutropenia, the risk of serious
psychiatric illness from discontinuing CLOZARIL treatment may be greater than the
risk of rechallenge (e.g., patients with severe schizophrenic illness who have no
treatment options other than CLOZARIL). A hematology consultation may be useful
in deciding to rechallenge a patient. In general, however, do not rechallenge patients
who develop severe neutropenia with CLOZARIL or a clozapine product.” (b) There
is now a literature comprising 30 cases (as of 2017) in which patients with a history
of neutropenia were rechallenged with clozapine while simultaneously receiving
125
filgrastim to stimulate neutrophil production. After a median follow-up of 12 months,

76% of cases were able to continue clozapine (see section below, Rechallenging
Severe Neutropenia Patients and Filgrastim Support).
B Basic Hematologic Monitoring Guidelines and Response
• As noted previously, the recently revised US monitoring guidelines differ from

US Monitoring
others worldwide in several major areas: the use of ANC only without total WBC; lower
thresholds for starting clozapine for general population and BEN patients; removal of
language about responding to sudden drops or other changes in ANC values aside
from changes in ANC levels that coincide with degrees of neutropenia; removal of
guidelines for platelet or eosinophil counts. Tables 6.5 and 6.6 present treatment
recommendations based on ANC levels for the general patient population and BEN
patients, respectively.
Table 6.5 US treatment recommendations based on ANC monitoring for the

general patient population.
ANC level Treatment recommendations ANC monitoring
• Initiate treatment • Weekly from initiation to 6
• If treatment interrupted for months
Normal
< 30 days, continue monitoring as • Every 2 weeks from 6 to 12
range (≥
before months
1500/mm3)
• If treatment interrupted for • Monthly after 12 months
≥ 30 days, monitor as if new patient
• Three times weekly until ANC
Mild ≥ 1500/mm3
neutropenia*
• Continue treatment • Once ANC ≥ 1500/mm3, return
(1000–1499/
mm3) to patient’s last “normal range”
ANC monitoring interval**
• Daily ANC until ≥ 1000/mm3
THEN
Moderate • Interrupt treatment for suspected • Three times weekly until ANC
neutropenia* clozapine-induced neutropenia ≥ 1500/mm3
(500–999/ • Recommend hematology • Once ANC ≥ 1500/mm3, check
mm3) consultation ANC weekly for 4 weeks, then
return to patient’s last “normal
range” ANC monitoring interval**
continued overleaf
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6
Table 6.5 continued

• Interrupt treatment for suspected
clozapine-induced neutropenia THEN
Severe • Recommend hematology • Three times weekly until ANC
neutropenia* consultation ≥ 1500/mm3
(< 500/mm3) • Do not rechallenge unless • If patient is rechallenged, resume
prescriber determines benefits treatment as a new patient under
outweigh risks “normal range” monitoring once
ANC ≥ 1500/mm3
* Confirm all initial reports of ANC < 1500/mm3 with a repeat ANC measurement within 24 hours.
** If clinically appropriate.
Table 6.6 US treatment recommendations based on ANC monitoring for patients

with benign ethnic neutropenia. 6
• Obtain at least two baseline
ANC levels before initiating
treatment • Weekly from initiation to 6
Normal BEN range months
• If treatment interrupted
(established ANC
for < 30 days, continue • Every 2 weeks from 6 to 12
baseline ≥ 1000/
monitoring as before months
mm3)
• If treatment interrupted for • Monthly after 12 months
≥ 30 days, monitor as if
new patient
• Three times weekly until
ANC ≥ 1000/mm3 or ≥ patient’s
known baseline
• Continue treatment • Once ANC ≥ 1000/mm3, or is
BEN neutropenia* above the patient’s known
(500–999/mm3) • Recommend hematology
baseline, check the ANC
consultation
weekly for 4 weeks, then
return to patient’s last “normal
BEN range” ANC monitoring
interval**
• Interrupt treatment for THEN
suspected clozapine-
• Three times weekly until ANC ≥
induced neutropenia
BEN severe patient’s baseline
• Recommend hematology
neutropenia* (< 500/ • If patient is rechallenged,
consultation
mm3) resume treatment as a new
• Do not rechallenge unless patient under “normal BEN
prescriber determines range” monitoring once
benefits outweigh risks ANC ≥ 1000/mm3 or at patient’s
baseline
* The package insert recommends confirming all initial reports of ANC < 1500/mm3 with a repeat
ANC measurement within 24 hours for the general patient population. For BEN patients,
values < 1000/mm3 should be confirmed with a repeat ANC measurement within 24 hours.
** If clinically appropriate.
127
The US guidelines do not contain specific information about responding to

late results, but failure to obtain ANC values at the designated interval prevents
pharmacies from dispensing the next scheduled quantity of clozapine. If treatment is
interrupted for 2–29 days or more, the patient must be titrated to the prior tolerated
dose starting at no more than 12.5 mg BID the first day. No guidance is provided on
the rapidity of titration, but shorter interruptions might allow very rapid resumption of
the prior dose, while those of 2–4 weeks might require more gradual increases as the
patient may have lost tolerance to the sedating and orthostatic properties of clozapine.
Interruptions of 30 days or more necessitate treating the patient as a new start, with
weekly ANC monitoring for the first 6 months.
• The UK monitoring scheme uses both total WBC and ANC values, and this is typical
UK Monitoring
of most countries worldwide. Tables are provided for initiation (Table 6.7), and routine
monitoring once on treatment (Table 6.8). The UK also has separate thresholds for
those identified as having BEN (Table 6.9). To simplify clinical decisions, results are
Table 6.7 UK reference values for new patients or those who experience an
interruption in treatment.
Blood counts × 109/l Classification Action
WBC ≥ 4.0 • Treatment may be initiated at the

discretion of the treating consultant
AND Green
• Clozapine may be prescribed and
neutrophils ≥ 2.5 dispensed for 7 days
• Treatment with clozapine may be
WBC ≥ 3.5 and < 4.0 initiated when the treating consultant
AND/OR Amber considers the patient eligible
neutrophils ≥ 2.0 and < 2.5 • Additional blood sampling is advised to
ensure blood counts are not dropping
• The blood result is not valid to initiate
clozapine treatment
WBC ≥ 3.0 and < 3.5
• Additional blood sampling is required
AND/OR Amber
• Treatment may only be initiated on a
neutrophils ≥ 1.5 and < 2.0
Green result or intermediate Amber as
described above
WBC < 3.0 • The blood result is not valid to initiate

clozapine treatment
AND/OR Red
• Investigate the cause of the abnormal
neutrophils < 1.5 blood result
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6
Table 6.8 UK reference values for routine results.
WBC ≥ 3.5
AND Green • Continue clozapine treatment
neutrophils ≥ 2.0
WBC ≥ 3.0 and < 3.5 • Increase monitoring frequency (twice-
AND/OR weekly) until results have stabilized in
Amber the Green range
neutrophils ≥ 1.5 and
< 2.0 • Assess the clinical status of the patient
• Stop clozapine treatment immediately
• Daily blood tests until results are in the
Green range
• Additional Red alert procedures
WBC < 3.0
(immediate clinical evaluation for
AND/OR Red infection, retrieving patient’s clozapine 6
neutrophils < 1.5 supply, consultation with hematologist)
• Patient is not rechallengeable and
their details are placed into the Central
Non-Rechallengeable Database
(CNRD)
Table 6.9 UK reference values for patients with benign ethnic neutropenia.
WBC ≥ 3.0
AND Green • Continue clozapine treatment
neutrophils ≥ 1.5
WBC ≥ 2.5 and < 3.0 • Increase monitoring frequency (twice-
AND/OR weekly) until results have stabilized in the
Amber Green range
neutrophils ≥ 1.0 and
< 1.5 • Assess the clinical status of the patient
• Stop clozapine treatment immediately
• Daily blood tests until results are in the
Green range
• Additional Red alert procedures
WBC < 2.5 (immediate clinical evaluation for
AND/OR Red infection, retrieving patient’s
clozapine supply, consultation with
neutrophils < 1.0 hematologist)
• Patient is not rechallengeable and
their details are placed into the
Central Non-Rechallengeable Database
(CNRD)
129
Table 6.10 UK follow-up actions for missing results.

A blood test result
Action
is not in the system
At the “expected • The late flag L is displayed with the patient’s record until a new
next test date” blood result has been entered.
• Courtesy reminder – Late Results is sent to health-care
providers.
• For weekly and fortnightly monitored patients the previous result
7 days after the
is no longer valid for dispensing clozapine to the patient.
expected test date
• The registry may contact health-care providers by telephone to
discuss missing follow-up information and/or change the patient
status to Interrupted.
• Additional weekly Reminders – Late Results are sent to health-
care providers.
14–28 days after • The previous result is no longer valid for dispensing clozapine
the expected test to the patient.
date • The registry contacts health-care providers by telephone to
discuss missing follow-up information.
• Change of patient status to Interrupted.
Table 6.11 UK monitoring frequency after treatment break.

Monitoring Monitoring frequency after treatment
Duration of treatment break
frequency break
Weekly ≤ 3 days Weekly, continue 18 weeks period
Weekly, continuing the 18 weeks
period; patient must have at least 6
Weekly > 3 days but ≤ 1 week weeks of weekly monitoring prior to a
decrease of the monitoring frequency
to fortnightly
Weekly > 1 week Weekly, restart 18 weeks period
Fortnightly ≤ 3 days Fortnightly, continue
Weekly monitoring for 6 weeks, then
Fortnightly > 3 days but ≤ 4 weeks
continue fortnightly
Fortnightly > 4 weeks Weekly, restart 18 weeks period
Monthly ≤ 3 days 4-Weekly, continue
Weekly monitoring for 6 weeks, then
Monthly > 3 days but ≤ 4 weeks
continue 4-weekly
Weekly, restart 18 weeks period, after
Monthly > 4 weeks
18 weeks, switch to 4-weekly
130
6
classified in a color-coded manner as Green, Amber or Red as noted in Tables 6.7–6.9.
UK guidelines specify certain responses for late or missing CBC results (Table 6.10)
and provide detailed instructions on the CBC monitoring frequency after treatment
interruptions (Table 6.11).
• As will be discussed in Chapter 12 there is concern about eosinophilia due to the

Eosinophilia and Thrombocytopenia
association with myocarditis; moreover, eosinophilia may also occur as part of other
drug hypersensitivity syndromes. As noted in Table 6.12, the UK has specific guidance
about increasing the monitoring frequency to twice-weekly for high eosinophil counts
(> 3000/mm3) or for low platelet counts (< 50 K). (The occurrence of eosinophilia,
thrombocytopenia, thrombocytosis and leukocytosis will be discussed in Chapter 14.)
6
Table 6.12 UK reference ranges for eosinophils and platelets.
Value Action
Initiation/continuation of clozapine treatment is
> 1000/mm – 3
not recommended
pretreatment
High eosinophils Increase monitoring frequency
> 3000/mm3 –
on-treatment Clozapine therapy should be started only after
blood results have stabilized under 1000/mm3
not recommended
Low platelets < 50 K Increase monitoring frequency
Clozapine therapy should be started only after
blood results have stabilized at or above 50 K
C Managing Frequent Treatment Interruption Due

to Low WBC/ANC
The need to increase monitoring frequency or interrupt clozapine treatment

imposes an enormous burden on clinicians and patients, and increases the risk
that the patient may refuse to continue with treatment. Even with the lower US BEN
thresholds, there are subsets of patients with BEN whose routine ANC naturally dips
below 1000/mm3 and thus must be subjected to ANC checks three times per week
until their values return to 1000/mm3 or above. In patients where removal of offending
medications, especially valproate, and even hematology consultation has failed to
131
find a reversible cause for ANC/WBC values that trigger increased monitoring or
interruption, there are two off-label strategies documented in the literature to increase
ANC values: lithium and filgrastim.
Box 6.4 Considerations in Using Lithium Augmentation for Low ANC/WBC

1. Goal: The goal of lithium therapy is to completely prevent low ANC/WBC
values that trigger increased monitoring frequency or interruption.
2. Eligible patients: Indefinite use of lithium at full therapeutic serum levels
might be needed to achieve the desired goal, so only patients who do
not possess medical contraindications to long-term lithium use are
candidates. This analysis involves consideration of estimated glomerular
filtration rate (eGFR) and other medical issues. Certain medications that
present unique hazards during lithium treatment (hydrochlorothiazide,
lisinopril) will also have to be changed to alternative agents. The typical
lithium monitoring requirements must be performed at a minimum every
6 months including (but not limited to): lithium levels, thyroid stimulating
hormone, eGFR and serum calcium. (For further details on lithium
prescribing see [31].)
3. Dosing and adjustment: Regardless of indication, lithium has a 24-hour brain
half-life and should only be prescribed once per day, typically at bedtime.
Importantly, use of lithium more than once per day significantly increases
the risk of renal insufficiency [32]. Because the hematopoietic effect may
take 2–3 weeks, there is no need for aggressive early dosing, especially
where the tolerability of lithium is unknown. In some instances 300 mg
QHS may achieve satisfactory results, but higher doses are commonly
employed. Trough serum levels are obtained 1 week after each dosage
change and a repeat CBC approximately 3 weeks after each dosage
change. There is no nomogram to calculate lithium requirements based
on nadir ANC values, but the failure to achieve the goal as stated above
must prompt further dose increases up to a maximum serum level
1.0 meq/l (1.0 mmol/l). No greater hematopoietic effect is seen for higher
serum levels.
While the association between lithium and granulocytosis has been recognized
for decades, it was not proven until 1978 that lithium-induced granulocytosis
is not merely a redistribution of neutrophils that are marginated or are in bone
marrow reserves [23]. Lithium enhances the production of granulocyte colony-
stimulating factor (G-CSF), and directly stimulates the proliferation of pluripotential
stem cells [23]. During lithium exposure there are significant increases in bone
132
6
Box 6.5 Considerations in Using Filgrastim Augmentation for Low ANC/WBC
1. Goal: The goal of filgrastim therapy is to completely prevent low ANC/
WBC values that trigger increased monitoring frequency or interruption.
2. Eligible patients: The only contraindication to the use of filgrastim is
a history of serious allergic reactions to human granulocyte colony-
stimulating factors such as filgrastim or pegfilgrastim. Consultation with
a hematologist might be necessary to prescribe filgrastim, and local
regulations might vary on who can prescribe filgrastim depending on
inpatient vs. outpatient status.
3. Dosing and adjustment: The hematopoietic effect of filgrastim is seen
within 24–48 hours, but the duration of effect is quite variable between
patients. Filgrastim is available in vials or prefilled syringes containing
300 or 480 μg. A test dose of 300 μg subcutaneously is typically
given and the ANC values tracked 2 times per week for the next 2 6
weeks and then weekly through week 4 to determine whether the ANC
remains above the necessary thresholds, and that ANC values do not
stay above 10,000/mm3 for excessive periods. There is no nomogram
to calculate filgrastim requirements based on nadir ANC values, but
the failure to achieve the goal as stated above must prompt further
dose increases. In some instances the literature reports thrice weekly
doses of 300 μg might be necessary to achieve ANC/WBC values that
do not fall below triggering thresholds, but dosing for some patients
might be weekly [25]. Filgrastim must not be given when ANC values
exceed 10,000/mm3.
marrow colony-forming units and bone marrow organ cellularity. This effect occurs
reproducibly in animal and human studies, and exhibits a dose dependency within the
serum range of 0.30–1.0 meq/l (0.30–1.0 mmol/l) [23]. Higher serum levels in animal
models did not generate greater effects, and very high levels that would be toxic in
humans (5.0 meq/l or 5.0 mmol/l) cause bone marrow toxicity. At therapeutic doses of
900–1200 mg/day, the mean increase in ANC averaged 88% in one small trial, and the
effect was seen in the first week after lithium was initiated, although peak ANC values
may not occur until week 2 or 3 [24].
In patients who cannot take lithium or for whom lithium’s effect is insufficient
to prevent low ANC/WBC values that trigger increased monitoring frequency or
treatment interruption, the recombinant granulocyte colony-stimulating factor
filgrastim must be used. While the use of filgrastim has long been considered a
standard part of severe neutropenia management, only since 1998 have there been
133
cases of extended use to support patients with varying levels of clozapine-associated

neutropenia [25]. Weekly exposures of up to 4 years have been documented without
complications. Nonetheless, the package insert contains warnings about a number
of potentially serious and fatal adverse effects that clinicians must be aware, of
including: allergic reactions, splenic rupture, acute respiratory distress syndrome,
exacerbation of sickle cell disorders, glomerulonephritis, alveolar hemorrhage and
hemoptysis, capillary leak syndrome, thrombocytopenia, cutaneous vasculitis and
leukocytosis.
D Response to Severe Neutropenia
Severe neutropenia (referred to in older literature as agranulocytosis) occurs when

ANC values are < 500/mm3. This represents a medical emergency due to the risk of
sepsis, and must be managed appropriately from both the hematologic and psychiatric
perspectives. Nonetheless, with modern monitoring schemes and treatment, the
incidence of death related to neutropenia during clozapine use is estimated to be
0.013% (95% CI 0.01–0.017%) [4]. Importantly, the case fatality rate for severe
neutropenia once diagnosed is only 2.1% (95% CI 1.6–2.8%) [4].
There are three primary considerations when severe neutropenia occurs:
minimization of infection risk, management of cholinergic rebound from abrupt
discontinuation of clozapine, and provision of appropriate antipsychotic therapy
based on the patient’s history of response (even if limited) and tolerability. (Chapter 4
provides an extensive discussion of strategies for managing cholinergic rebound, and
considerations for antipsychotic therapy after clozapine discontinuation.)
• For patients who have demonstrably failed other antipsychotics, the removal of
Rechallenging Severe Neutropenia Patients With Filgrastim Support
clozapine treatment implies a lifetime of unremitting psychosis, suicidality, aggression,

or intolerable adverse effects. In this context, the revised US prescribing guidelines
acknowledge this reality, and contain a statement quoted previously, but which is
worth reiterating:
For some patients who experience severe CLOZARIL related neutropenia, the
risk of serious psychiatric illness from discontinuing CLOZARIL treatment may
be greater than the risk of rechallenge (e.g., patients with severe schizophrenic
illness who have no treatment options other than CLOZARIL).
134
6
Box 6.6 Response to Severe Neutropenia
Minimization of infection risk: The median duration of severe neutropenia from
clozapine is 12 days, and at times may extend to 21 days, so patients may
be at extended risk for infection and related complications [29]. For all
patients, the following steps are important.
1. Patient notification: If outpatient, immediately contact the individual
and have them transported to the clinic (or emergency department
if after hours) for physical examination and repeat CBC. All supplies
of clozapine must be removed from their control and they must be
informed that their use of clozapine must be abruptly stopped. Until
the ANC is safely above 500/mm3 all severe neutropenia patients
require close clinical surveillance to monitor for signs of infection and
daily blood monitoring. For most outpatients this is best accomplished
through hospital admission, with possible use of isolation precautions,
and oversight by a hematologist. Inpatients on a psychiatric unit 6
may best be served by transfer to a medical unit to minimize contact
with large numbers of other people that can present a source of
transmissible infection, and also to remove a source of risk due to
acts of aggression by other patients (e.g. scratching, biting). The
hematologist will also help manage any fever work-up and infectious
complications should they occur.
2. Use of filgrastim: An extensive review of the literature on neutropenia
not related to chemotherapy noted that the use of filgrastim at a mean
dose of 300 μg is useful in shortening the duration of ANC recovery time
without inducing any major adverse effects [33]. For more prolonged
episodes of severe neutropenia repeated doses may be used at the
discretion of the treating hematologist.
In addition to hematology consultation, extensive discussions with the patient,

caregivers, family and possibly ethicists ought to be considered as part of the decision
to rechallenge an individual who has previously experienced severe neutropenia. In
some instances, another cause of neutropenia was identified (e.g. use of ribavirin as
part of a hepatitis C treatment regimen in a patient on clozapine for 5 years), and the
causal link to clozapine lessened. Nonetheless, all parties involved must understand
the risks and what is at stake, including the fact that very frequent CBC monitoring
(2–3 times per week) may continue for an extended period of time before a more
routine schedule can be considered.
When the benefits of rechallenge are deemed to outweigh the risks, the
literature now supports the use of filgrastim when clozapine is commenced. This
135
will generally be performed in conjunction with a hematologist, and a prespecified

CBC monitoring plan created to ensure that ANC counts remain above thresholds
for treatment interruption or discontinuation, or do not persistently exceed 10,000/
mm3 due to the effects of filgrastim. A 2017 review documented 30 cases of
extended filgrastim treatment in patients with varying levels of clozapine-associated
neutropenia at doses ranging from 300 μg once weekly up to 300 μg three times
per week [25]. Given the immune hypothesis for severe neutropenia, one must
anticipate that the use of filgrastim may need to continue indefinitely, yet there is at
least one published case in which filgrastim was able to be tapered off after many
months [26].
E Use of Point-of-Care CBC Monitoring
Another option is the use of point-of-care (POC) blood monitoring devices in the
psychiatric clinic or deployed to the patient’s residence, obviating the need for a
laboratory visit [28]. As of 2019 there is one POC CBC device in the US (www.athelas.
com). This device was approved only after rigorous testing at multiple sites and in
multiple patient types (i.e. normal, medical conditions) had demonstrated coefficients
of variation for ANC and WBC values equivalent to that from an automated hematology
analyzer. The device can be operated by personnel in point of care settings, thereby
providing maximum flexibility in the time and place of ANC testing. This device also
uses a small 28 gauge lancet to obtain results from a finger-prick, a feature rated as
being less painful than venipuncture. The results are available in 6 minutes, and the
manufacturer has created an integrated network so that results are simultaneously
transmitted to the clozapine monitoring registry, the prescriber and the pharmacy. If
ANC results are within range, the pharmacy delivers medication directly to the patient
within 24 hours. The Athelas device will likely be followed by approval of other POC
devices, and the increasing adoption of this new technology, and its integrated system,
will become commonplace due to the convenience of testing, rapidity of results, and
decreased patient discomfort.
136
6
Summary Points
a. Monitoring and patient registry details vary considerably between countries, and
are occasionally updated, so clinicians must be attentive to local regulations and
developments.
b. Valproate is associated with neutropenia in a dose-dependent manner, and may
interfere with treatment initiation or continuation.
c. Benign ethnic neutropenia is now recognized in many countries, and must be
identified. Genetic testing for DARC null/null status (Fy (a–/b–)) is confirmatory.
d. Clinicians need to be expert at the use of lithium to forestall repeated increased
monitoring or treatment interruption, and understand the literature on use of
filgrastim.
6
e. Management of severe neutropenia requires minimization of infection risk,
prevention of cholinergic rebound, and provision of antipsychotic therapy.
f. While patients with clozapine-induced severe neutropenia have been deemed
not rechallengeable, updated US regulations now acknowledge that for select
patients the benefits might outweigh the risks. Hematology consultation and use
of filgrastim are important parts of this process.
137
References
1. Curtis, B. R. (2017). Non-chemotherapy drug-induced neutropenia: Key points to manage the
challenges. ASH Hematology, The Education Program, 2017, 187–193.
2. Amsler, H. A., Teerenhovi, L., Barth, E., et al. (1977). Agranulocytosis in patients treated with
clozapine. A study of the Finnish epidemic. Acta Psychiatrica Scandinavica, 56, 241–248.
3. Nielsen, J., Young, C., Ifteni, P., et al. (2016). Worldwide differences in regulations of clozapine
use. CNS Drugs, 30, 149–161.
4. Myles, N., Myles, H., Xia, S., et al. (2018). Meta-analysis examining the epidemiology of
clozapine-associated neutropenia. Acta Psychiatrica Scandinavica, 138, 101–109.
5. Honigfeld, G., Arellano, F., Sethi, J., et al. (1998). Reducing clozapine-related morbidity and
mortality: 5 years of experience with the Clozaril National Registry. Journal of Clinical Psychiatry,
59(Suppl 3), 3–7.
6. Sultan, R. S., Olfson, M., Correll, C. U., et al. (2017). Evaluating the effect of the changes in FDA
guidelines for clozapine monitoring. Journal of Clinical Psychiatry, 78, e933–e939.
7. Broun, G. O., Herbig, F. K. and Hamilton, J. R. (1966). Leukopenia in Negroes. New England
Journal of Medicine, 275, 1410–1413.
8. Paz, E., Bouzas, L., Hermida, J., et al. (2008). Evaluation of three dosing models for the
prediction of steady-state trough clozapine concentrations. Clinical Biochemistry, 41, 603–606.
9. Schmid, P., Ravenell, K. R., Sheldon, S. L., et al. (2012). DARC alleles and Duffy phenotypes in
African Americans. Transfusion, 52, 1260–1267.
10. Paz, Z., Nails, M. and Ziv, E. (2011). The genetics of benign neutropenia. Israel Medical
Association Journal, 13, 625–629.
11. Ortiz, M. V., Meier, E. R. and Hsieh, M. M. (2016). Identification and clinical characterization
of children with benign ethnic neutropenia. Journal of Pediatric Hematology and Oncology, 38,
e140–143.
12. Reich, D., Nalls, M. A., Kao, W. H., et al. (2009). Reduced neutrophil count in people of African
descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. PLoS
Genetics, 5, e1000360.
13. Dinardo, C. L., Kerbauy, M. N., Santos, T. C., et al. (2017). Duffy null genotype or Fy(a–b–)
phenotype are more accurate than self-declared race for diagnosing benign ethnic neutropenia in
Brazilian population. International Journal of Laboratory Hematology, 39, e144–e146.
14. Denic, S., Showqi, S., Klein, C., et al. (2009). Prevalence, phenotype and inheritance of benign
neutropenia in Arabs. BMC Blood Disorders, 9, 3.
15. Kelly, D. L., Kreyenbuhl, J., Dixon, L., et al. (2007). Clozapine underutilization and discontinuation
in African Americans due to leucopenia. Schizophrenia Bulletin, 33, 1221–1224.
16. Bartels, M., van Solinge, W. W., den Breeijen, H. J., et al. (2012). Valproic acid treatment is
associated with altered leukocyte subset development. Journal of Clinical Psychopharmacology, 32,
832–834.
17. Malik, S., Lally, J., Ajnakina, O., et al. (2018). Sodium valproate and clozapine induced
neutropenia: A case control study using register data. Schizophrenia Research, 195, 267–273.
18. Demler, T. L., Morabito, N. E., Meyer, C. E., et al. (2016). Maximizing clozapine utilization
while minimizing blood dyscrasias: Evaluation of patient demographics and severity of events.
International Clinical Psychopharmacology, 31, 76–83.
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19. Goldstein, J. I., Jarskog, L. F., Hilliard, C., et al. (2014). Clozapine-induced agranulocytosis is
associated with rare HLA-DQB1 and HLA-B alleles. Nature Communications, 5, 4757.
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1502–1508.
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method for total and differential white blood cell count in clozapine users. International Journal of
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Incidence and risk factors in the United States. New England Journal of Medicine, 329, 162–167.
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139
7QUICK CHECK
Managing Constipation
Introduction 140
Principles 141
A Prevalence and Postulated Mechanisms 142
• Constipation Criteria and Stool Form Nomenclature 143
B Treatment 144
• Efficacy of First-Line Agents 148
• Use of Secretogogues and Serotonergic Motility Agents 149
• PRN Medications 152
• Decreasing Plasma Clozapine Levels for
Difficult to Manage Constipation 152
C Diagnosing Possible Ileus 153
• Rechallenging the Ileus Patient 154
Summary Points 155
References 156
INTRODUCTION
Constipation is a common problem in western societies, but gastrointestinal

hypomotility (GIH) assumes greater significance during clozapine therapy for several
reasons: GIH is highly prevalent; GIH accounts for 36% of all medically related causes
of treatment discontinuation [1]; and in its most severe form, paralytic ileus, there
is a fatality rate of 15.0–27.5% [2]. Gastrointestinal illness accounted for 20% of all
medically related hospital admissions for clozapine-treated patients at one major US
medical center, of which 61% were for hypomotility-related problems [3]. The magnitude
of clozapine’s effect on motility is dramatic: the median colonic transit time (CTT) in one
study was 23 hours among inpatients on nonclozapine antipsychotics, compared to 104
hours for those on clozapine [4]. Moreover, 80% of the clozapine-treated patients had
140
7: CONSTIPATION
7
PRINCIPLES
• Due to high rates of gastrointestinal hypomotility, including constipation and

ileus, other strongly anticholinergic medications, or medications that induce
constipation by other mechanisms (e.g. opioids, iron supplements) should be
avoided if at all possible in clozapine-treated patients.
• The reported fatality rates from ileus of 15.0–27.5% are far greater than those
seen with severe neutropenia (2.2–4.2%).
• Medications for constipation must commence with the first prescription for
clozapine, initially starting with docusate, then polyethylene glycol (PEG)-3350
and a stimulant added in succession.
• Bulk laxatives (e.g. psyllium preparations) are not to be used in clozapine-
treated patients as very slow colonic transit times present a risk of
inspissation and exacerbation of constipation.
• For individuals who fail to respond to a combination of the three first-line
7
agents (docusate + PEG-3350 + stimulant), including those who have
experienced ileus, there is extensive experience in certain hospital systems
with secretogogues such as lubiprostone, and two cases of successful use of
the motility agent prucalopride (available in the US since 2018).
evidence of GIH, and transit times in all colonic segments were abnormal. Importantly,
clozapine-associated GIH occurred irrespective of gender, age, ethnicity, or length of
clozapine treatment [4]. Only plasma clozapine level correlated with GIH severity as
measured by transit time.
While neutropenia has extensive warnings and mandated monitoring protocols,
mitigation of GIH must garner significant clinical attention, and treatment must
start at the onset of clozapine titration. Clozapine discontinuation due to GIH or
the development of ileus need to be viewed as preventable outcomes. With careful
monitoring, aggressive use of inexpensive first-line agents, removal of other
offending medications, and use of newer intestinal secretogogues (e.g. lubiprostone,
linaclotide, plecanatide), or the motility medication prucalopride, clinicians have a
number of management strategies available to address this prevalent problem.
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7: CONSTIPATION
A Prevalence and Postulated Mechanisms
Based on a variety of clinical criteria the reported incidence of constipation for

clozapine-treated patients ranges from 32% to 60%. The use of colonic transit time
(CTT) provides a quantitative framework for understanding clozapine’s impact on
gastrointestinal motility. International data reveal a mean adult CTT of 28.79 (± 18.07)
hours [4]. By defining GIH as CTT more than 2 SD above the population mean, or
≥ 65 hours, 80% of clozapine-treated patients in a CTT study met criteria for GIH. In a
Danish study of 26,597 schizophrenia patients treated from 1996 to 2007, the use of
clozapine for schizophrenia was associated with a twofold increased risk for ileus (OR
1.99, 95% CI 1.21–3.29), and a sevenfold increased risk for fatal ileus (OR 6.73, 95%
CI 1.55–29.17) [5]. While constipation begins early in clozapine treatment, the Danish
data highlighted the fact that ileus tends to occur after more prolonged exposure
and in a dose-dependent manner. Among the 123 clozapine-related ileus cases, the
median time to developing ileus was 1528 days (interquartile range 1145–2039 days),
and the odds ratio increased by a factor of 1.33 (95% CI 1.15–1.54) for each 100 mg
of clozapine prescribed (p < 0.0001) [5].
Multiple mechanisms contribute to clozapine’s high incidence of constipation.
Despite norclozapine’s muscarinic agonism, clozapine is a potent muscarinic
antagonist across several receptor subtypes, and this appears to override the effect of
norclozapine on GI motility. Clozapine also possesses weak antagonism at serotonin
5HT3 receptors (Ki = 241 nM at cloned human receptors), which is also associated
with slower gastrointestinal motility. Not surprisingly, CTTs are positively correlated
with plasma clozapine levels (r = 0.451, p = 0.045) [4]. Clozapine’s high affinity for
histamine H1 receptors may also contribute to constipation risk due to decreased
activity. A 2018 paper using data from 176 clozapine-treated Finnish patients found
an association between the burden of genetic polymorphisms at receptors and other
sites associated with constipation and clozapine-related gastrointestinal symptoms
[6]. The other issue is the patient population who receives clozapine. These individuals
are often severely mentally ill, and may have behavioral risk factors for constipation
related to poor dietary habits, inactivity, and inadequate hydration. Moreover, some
may be very poor reporters of somatic complaints, and thus will escape detection
of significant GIH problems until a catastrophic event occurs. Given this confluence
of medication-related and patient-related variables, and the known fatality rates
from ileus, as much or greater attention must be paid to managing constipation as is
devoted to assessment of neutrophil counts.
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7: CONSTIPATION
7
• The Rome process is an international effort spanning the past 30 years to assist in
Constipation Criteria and Stool Form Nomenclature
the evidence-based diagnosis and treatment of functional gastrointestinal disorders

such as irritable bowel syndrome and chronic constipation [7]. Because clozapine-
associated GIH and constipation has a known cause, it would not be classified as
a functional disorder, but does resemble the type of treatment-related constipation
seen with chronic opioid use. The fourth edition of the Rome criteria (Rome IV) was
published in May 2016, and, for the first time, criteria for Opioid-Induced Constipation
(OIC) were elaborated. These criteria are essentially identical to those for functional
constipation with rewording of the first criterion to emphasize the connection with
medication use (Box 7.1).
Box 7.1 Rome IV Diagnostic Criteria for Opioid-Induced Constipation (C6) [7]
1. New, or worsening, symptoms of constipation when initiating, changing, or
increasing opioid therapy that must include two or more of the following: 7
a. Straining during more than one-fourth (25%) of defecations
b. Lumpy or hard stools (Bristol Stool Form Scale 1–2) more than one-
fourth (25%) of defecations
c. Sensation of incomplete evacuation more than one-fourth (25%) of
defecations
d. Sensation of anorectal obstruction/blockage more than one-fourth
(25%) of defecations
e. Manual maneuvers to facilitate more than one-fourth (25%) of
defecations (e.g. digital evacuation, support of the pelvic floor)
f. Fewer than three spontaneous bowel movements per week
2. Loose stools are rarely present without the use of laxatives
As criteria 1a–1f are not medication-specific, and the parameters are exactly the
same as for functional constipation, it is strongly suggested that hospital and clinical
systems, as well as future research efforts, all use Rome IV criteria when making
a diagnosis of clozapine-induced constipation. This standardization of diagnostic
criteria based on elements arrived at by international experts in gastrointestinal
motility disorders facilitates consistency in clinical and data-gathering activities.
The term GIH is best applied in settings when CTT is directly measured, and where
measured CTT values are ≥ 65 hours, or more than 2 SD greater than the population
mean. To standardize the descriptive terminology of stool appearance in clinical and
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7: CONSTIPATION
Figure 7.1. Bristol Stool Form Scale.
Type 1 Separate hard lumps, like nuts
Type 2 Sausage shaped but lumpy
Type 3 Like a sausage but with cracks on its surface
Type 4 Like a sausage or snake, smooth and soft
Type 5 Soft blobs with clear-cut edges
Type 6 Fluffy pieces with ragged edges, a mushy stool
Type 7 Watery, no solid pieces
(Adapted from: Lewis, S. J. and Heaton, K. W. (1997). Stool form scale as a useful guide
to intestinal transit time. Scandinavian Journal of Gastroenterology, 32, 920–924 [8].)
research settings, the Bristol Stool Form Scale is also strongly recommended [8]. The
Bristol Stool Form Scale (Figure 7.1) was developed over 25 years ago to provide an
evidence-based method for assisting clinicians in estimating CTT. The simplicity of
use even with children (using modified wording) has led to widespread application
throughout the world and translation into numerous languages. Rome IV OIC criterion
1b references the Bristol Stool Form Scale in describing the types of stools that would
qualify (category 1–2). Through the combined use of Rome IV medication-induced
constipation criteria developed for opioids, and the Bristol Stool Form Scale, all
members of the clinical team and outpatient caregivers can easily document that a
patient meets constipation criteria, as well as the response to treatment.
B Treatment
Aside from clozapine, other medication classes are also independently associated
with increased constipation risk in schizophrenia patients including tricyclic
antidepressants (OR 2.29, 9% CI 1.29–4.09), anticholinergics (OR 1.48, 95% CI 1.00–
2.19), and opioids (OR 2.14, 95% CI 1.36–3.36). The use of anticholinergics was also
144
7: CONSTIPATION
7
Table 7.1 List of common strongly anticholinergic and constipating medications.
Chlorpromazine, olanzapine, quetiapine (> 600 mg/
Psychotropics day), amitriptyline, nortriptyline, clomipramine,
imipramine, desipramine
Antiparkinsonian medications Benztropine, diphenhydramine, trihexyphenidyl
Oxybutynin, tolterodine, darifenacin, solifenacin,
Nonpsychiatric medications
trospium, glycopyrrolate
Iron (ferrous sulfate or gluconate), hydrocodone,
Other constipating medications oxycodone, codeine, hydromorphone, morphine,
fentanyl, methadone, oxymorphone, tramadol
significantly associated with a nearly sixfold increase in ileus risk (OR 5.88, 95% CI
1.47–23.58) [5]. Given the additive pharmacodynamic effects on motility, management
of clozapine-related constipation commences prior to the initiation of clozapine with
the attempt to minimize exposure to constipating medications as noted in Table 7.1. It
is important that clinicians are aware that a number of medications used for overactive
bladder are potent antimuscarinic agents. If possible these too ought to be tapered off 7
prior to or during the early initiation period of clozapine treatment to minimize the risk
of constipation and ileus. The presence of other constipating agents such as oral iron
supplements and opioids also should be diminished or eliminated completely prior to
starting clozapine.
Chapter 3 provides an extensive discussion about transitioning patients from
anticholinergic psychotropic medications or anticholinergic antiparkinsonian agents
as clozapine is started. For the latter, there are well-defined relationships that can be
employed to taper antiparkinsonian medications as clozapine is added (Box 7.2).
Box 7.2 Anticholinergic Equivalencies

As noted in Chapter 3, an important part of the pretreatment evaluation is an

assessment of current bowel function, seeking evidence for ongoing issues with
constipation. During this process, one must gather appropriate history, including
frequency and consistency of bowel movements (using the Bristol Stool Form
Scale), supplemented with a relevant physical examination. In some hospital and
clinic settings an abdominal X-ray is mandated, but even when not required may
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prove very useful when working with severely ill patients who are poor historians. If
sufficient evidence exists for constipation, the patient can be managed with the usual
strategies: minimization or discontinuation of offending agents when possible, and
use of the three first-line medication classes to treat constipation as delineated below.
Effective management of a pre-existing constipation problem may help forestall worse
problems with clozapine that lead to treatment discontinuation or ileus.
Despite the prevalence and seriousness of the problem, the 2017 Cochrane
systematic review of clozapine-induced constipation lamented: “There were no
data comparing the common pharmacological interventions for constipation, such
as lactulose, polyethylene glycol, stool softeners, lubricant laxatives, or of novel
treatments such as linaclotide. Data available were very poor quality and the trials had
a high risk of bias” [9]. Nonetheless, clinicians must treat patients using the limited
evidence that exists, and most recommendations suggest using inexpensive first-line
agents added sequentially before proceeding to the highly effective but more costly
intestinal secretogogues, or the motility medication prucalopride. Table 7.2 summarizes
the three classes of first-line agents used in managing constipation. With the exception
of lactulose, all are extremely inexpensive and available without a prescription. Despite
widespread use, the efficacy data for chronic constipation in the general population
Table 7.2 First-line agents for constipation.

Mechanism Starting Maximum Comments
dose effective
dose
Commonly used
Dioctyl sodium Anionic detergent
250 mg 250 mg despite a paucity of
sulfosuccinate that causes stool
QHS BID evidence supporting
(docusate or DSS) softening
efficacy [18].
Strong ACG
Polyethylene
recommendation.
glycol 3350 (PEG- Osmotic agent 17 g qD 17 g BID
High quality of
3350)
evidence.
Strong ACG
recommendation.
Lactulose Osmotic agent 30 ml qD 30 ml BID
Low quality of
evidence.
Strong ACG
5 mg recommendation.
Bisacodyl Stimulant 15 mg BID
QHS Moderate quality of
evidence.
8.6 mg 17.2 mg Absence of
Sennosides Stimulant
QHS BID controlled data.
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7
varies greatly. The comments in Table 7.2 reflect American College of Gastroenterology
(ACG) recommendations and their assessment of the evidence quality based on
standardized criteria for evaluation of clinical trial outcomes [10].
As indicated in Table 7.2, docusate theoretically acts to soften the stool but may
be less effective than believed, so strong consideration must be given to starting
docusate concurrently with a more effective medication. Osmotic agents draw water
into the luminal cavity with the ACG evaluators finding polyethylene glycol (PEG-3350
or MiraLax) both effective and having high-quality evidence. Lactulose is costlier
than PEG-3350, requires a prescription, and the quality of supporting data is low. In
the past clinicians had been reluctant to prescribe stimulant laxatives due to (now
disproved) concerns that these agents can damage the colon with long-term use,
and a weak evidence base. As noted above, there is still limited data for sennosides,
but convincing evidence for the efficacy of bisacodyl from well-designed randomized
clinical trials published since 2010 [10].
7
Box 7.3 Principles for Managing Clozapine-Induced Constipation
1. Pretreatment assessment of the patient must occur for evidence of
constipation prior to starting clozapine. Consider abdominal X-ray in
unreliable patients (if not mandatory).
2. Remove other anticholinergic or other constipating medications as much
as possible prior to starting clozapine, or taper off as clozapine is added.
3. Medications for constipation must commence with the first clozapine
prescription for every patient even when constipation is not a
current issue. Due to the limited efficacy data for docusate, consider
simultaneously starting a second agent with docusate.
4. Many patients require one medication from each class of first-line agents
simultaneously for adequate relief. No more than one agent from each
class ought to be used.
5. Bulk-forming laxatives must not be used due to slow transit times
presenting a risk of inspissation and worsening of the constipation
problem.
6. Failure to relieve constipation for 48 hours must prompt a change in
treatment (e.g. dose increase, additional agent of another class, use of
enemas or manual disimpaction).
7. Magnesium can be used sparingly as a PRN medication (1 time per week
or less), but not more often due to the risk of hypermagnesemia.
8. Signs of symptoms of ileus (see Box 7.4) must prompt immediate referral
to a general hospital setting for further evaluation.
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Unlike other patients with constipation, one important difference for managing
clozapine-induced constipation is the avoidance of psyllium and other bulk-forming
laxatives. Due to the markedly longer transit times in this patient population, these
agents may undergo inspissation (dehydration), thereby exacerbating the problem.
Multiple sources recommend against use of bulk-forming laxatives when managing
clozapine-treated patients or other patients with prolonged CTT including the 2015
edition of the Maudsley Prescribing Guidelines in Psychiatry [11], and experts in colonic
hypomotility [7] and GIH specific to clozapine therapy [12]. Neither mineral oil (liquid
paraffin) nor magnesium is considered appropriate for routine use. Mineral oil (liquid
paraffin) has limited efficacy data in adults and may be associated with unacceptable
adverse effects such as soiling. In the pediatric population it has been largely replaced
with PEG-3350. Excessive routine use of magnesium may result in hypermagnesemia,
especially among those with reduced renal function, so these agents are best reserved
for PRN use.
• Investigators in Porirua, New Zealand have performed the only prospective study of
Efficacy of First-Line Agents
CTT changes utilizing a standardized treatment protocol. With a sample of 14 patients

(10 male/4 female), median age 35 years, median plasma clozapine level 506 ng/
ml (1547 mmol/l) and median treatment duration 2.5 years, changes in CTT and
the proportion of patients with GIH (defined as ≥ 65 hours [> 2 SD from population
norms]) or severe GIH (defined as > 101 hours [> 4 SD from population norms]) were
tracked with radio-opaque markers while being treated with a regimen employing only
the classes of first-line medications (see Table 7.3).
Table 7.3 The Porirua protocol for clozapine-induced gastrointestinal hypomotility

and constipation [12].
Step 1 1. Start docusate 100 mg + senna 16 mg/night.
2. If still constipated after 48 hours, increase docusate and senna every
Step 2 2 days until no longer constipated or the maximum dose of docusate
(100 mg BID) and senna (16 mg BID) have been reached.
3. If still constipated after another 48 hours, perform digital rectal
examination and consult with an expert about the need for enemas or
Step 3
disimpaction. If impacted stop docusate + senna. If not, then add PEG-
3350 13.125 g BID.
4. If still constipated after another 48 hours, consult with an expert about
Step 4
formulation of an individualized regimen.
If diarrhea develops after any step, gradually reduce and discontinue
General rules
treatments in the reverse order that they were added.
The Bristol Stool Form Chart is recommended as a monitoring tool.
Medical evaluation for ileus if appropriate (see Box 7.4)
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7
Using this protocol, the median CTT decreased from 110 hours at baseline to 62
hours (p = 0.009). Moreover, the prevalence of GIH decreased from 86% to 50%,
and severe GIH from 64% to 21% [12]. These data echo naturalistic outcomes from
the 6500 patient California Department of State Hospitals (Cal-DSH). Cal-DSH is the
world’s largest state hospital system, and at any time has over 700 clozapine-treated
patients. Approximately 80% of patients on clozapine at Cal-DSH have constipation
issues managed using only the three first-line classes routinely, with availability of
PRN strategies (e.g. enemas).
Most aspects of the Porirua protocol are worth emulating, including: the
avoidance of bulk-forming laxatives; use of a tracking form; the insistence on adding
interventions every 48 hours if results are not seen. Many inpatients and outpatients
may refuse digital rectal examination, and expert consultation may not be immediately
available, so clinical judgement will need to be exercised when deciding on a course
of action at Step 3. As noted below (PRN Medications), if there is sufficient concern
about fecal impaction and the patient refuses digital examination, enemas are 7
preferable to agents that stimulate motility (e.g. magnesium).
• As data from the Porirua study and Cal-DSH indicate, even with assiduous
Use of Secretogogues and Serotonergic Motility Agents
application of medications from each class of first-line agents, 20–50% of patients

may continue to have GIH or symptomatic constipation. A new class of agents,
intestinal secretogogues, offer significant promise and are now extensively used in
Cal-DSH for treatment-resistant constipation or in those patients with a history of ileus
related to clozapine treatment.
The first of these agents, lubiprostone was approved by the United States Food and
Drug Administration (FDA) in January 2006 for the treatment of chronic constipation in
adults and for irritable bowel syndrome associated with constipation in women. In 2014,
lubiprostone was subsequently recommended for use in the UK by the National Institute
for Health and Care Excellence. Unlike stimulant or osmotic laxatives, lubiprostone is a
prostaglandin E1 analogue that stimulates voltage-sensitive chloride channels on the
luminal surface of gastrointestinal epithelial cells [13]. The net effect is an increase in
chloride-rich luminal secretions that soften the stool and promote motility. There are no
significant contraindications to its use aside from avoidance in those with mechanical
intestinal obstruction. The first successful use of lubiprostone was reported in a Cal-DSH
patient who developed ileus that required surgery without resection, but decompensated
markedly when the treating clinicians attempted to find alternatives to clozapine.
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The use of lubiprostone allowed this patient to resume clozapine therapy and he had
continued on clozapine for several years at the time the case was published [14].
Based on Cal-DSH formulary criteria, patients are eligible to try lubiprostone after
having failed the combination of maximum effective doses of docusate + an osmotic
agent + a stimulant. Within the Cal-DSH system, lubiprostone has been recommended
over the past 10 years for clozapine patients with treatment-resistant constipation,
and in many instances achieved sufficient efficacy to the extent that other medications
could be tapered off. As of March 1, 2018 there were 112 patients within Cal-DSH on
lubiprostone. A detailed review of patients at one Cal-DSH site noted that 38 of the
182 clozapine-treated patients were on lubiprostone (21%) with mean daily dose of
36.2 μg, and modal dose of 24 μg BID. Lubiprostone was so effective that 17 of the 38
patients were able to have all osmotic and stimulant medications withdrawn.
Recently, two newer medications have become available: linaclotide and
plecanatide. Linaclotide was approved by the FDA in August 2012 for constipation-
predominant irritable bowel syndrome and chronic idiopathic constipation, and
subsequently was also approved by the European Medicines Agency. It is an agonist
at guanylate cyclase-C receptors on the luminal membrane resulting in two effects:
increased luminal chloride and bicarbonate secretions, and inhibition of sodium ion
absorption, thereby increasing the secretion of water into the lumen [15]. Linaclotide
has minimal systemic absorption. Plecanatide is also a guanylate cyclase-C agonist
and was approved in the US in January 2017 for chronic idiopathic constipation.
Both linaclotide and plecanatide are contraindicated in patients who are suspected
of having a mechanical gastrointestinal obstruction. As of May 1, 2019 there were 16
Cal-DSH patients on linaclotide, but none yet on plecanatide.
Clinicians should not be deterred from using secretogogues despite the absence
of controlled data for clozapine-induced GIH. When managing serious and potentially
fatal treatment outcomes, clinicians often must act without the gold standard of
randomized, controlled studies. For example, there may never be controlled studies
of filgrastim use to support ANC values in those with a history of clozapine-related
neutropenia, but the accumulated case reports present a compelling picture of possible
benefit and limited adverse effects. Similarly, the only source of data on secretogogues
for clozapine-related GIH for the near future will likely be case-based. In addition to the
extensive Cal-DSH experience, lubiprostone has demonstrated efficacy in randomized
controlled studies of a related disorder, opioid-induced constipation, thus providing
more rationale to support the use of secretogogues for clozapine-treated patients [16].
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7
Recently available in the US, prucalopride is a selective serotonin 5HT4 agonist
that stimulates colonic mass movements and lacks QTc concerns seen with the
earlier compound cisapride. Prucalopride was initially approved in Europe in 2009 for
treatment of chronic constipation in women who fail standard laxative therapy, was
subsequently approved for men, and also approved in the UK, Canada and Australia. In
addition to being highly selective for 5HT4 receptors, prucalopride was well tolerated
in clinical trials, can be administered orally once daily (2 mg qD), and has low potential
for drug–drug interactions. The only contraindications are intestinal perforation or
obstruction, severe inflammatory conditions (e.g. Crohn’s disease, ulcerative colitis
or toxic megacolon), and severe renal impairment (eGFR < 30 ml/min). There is one
publication that summarizes use of prucalopride in two patients with clozapine-
induced GIH [17]. One patient went from a bowel movement every 5 days with a PRN
enema every 6 days, to a bowel movement every 2.7 days with PRN enemas every 27
days. The second patient had a limited increase in bowel movement frequency from
every 6 days to every 5.4 days, but no longer required PRN use of enemas (previously
7
every 15 days).
Table 7.4 Intestinal secretogogues.

Name Mechanism Starting Max. dose Comments
dose
Prostaglandin E1 Give with food and water
Lubiprostone 8 μg BID 24 μg BID
analogue No drug interactions
Give > 30 min before
Guanylate
Linaclotide 145 μg qD 290 μg qD first meal
cyclase-C agonist
No drug interactions
Guanylate
Plecanatide 3 mg qD 3 mg qD No drug interactions
cyclase-C agonist
At the time of their last review, the ACG gave the two available secretogogues
(lubiprostone and linaclotide) strong recommendations based on high quality
of evidence [10]. Prucalopride and plecanatide were not included in the review.
The biggest barrier to treatment with any of these newer medications is the cost.
However, given the system costs related to clozapine discontinuation (e.g. psychiatric
hospitalization, legal consequences, etc.), and the lack of therapeutic alternatives to
clozapine, the expense is justifiable in those who have failed less-costly regimens.
Moreover, none of these newer medications have significant drug–drug interactions,
so all are options in patients on complex medication regimens.
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• Many patients will have adequate control most weeks using various combinations
PRN Medications
of first-line agents, secretogogues, or prucalopride, but may have periods of

exacerbation. The two most commonly used options are enemas and magnesium-
containing preparations. Table 7.5 presents basic dosing facts and considerations in
use of PRN laxatives.
Frequent need for PRN medications indicates that routine treatment is suboptimal.
If the patient is on maximal doses of each class of first-line agents, a secretogogue
must be started. In the uncommon event that constipation remains problematic
despite routine agents + secretogogues or prucalopride, expert consultation is
necessary.
• Decreasing Plasma Clozapine Levels for Difficult to Manage

Constipation
As discussed in Chapter 5, tracking plasma clozapine levels is central to effective
management. As CTTs are linearly correlated with plasma clozapine levels, clinicians
should obtain a trough plasma level and review the course of treatment to determine
Table 7.5 Recommended PRN medications.

Dose Frequency Comments
Magnesium hydroxide
Low magnesium exposure
(5 ml contains 166.7 mg 5 ml PO Daily Avoid if impaction
Mg = 400 mg magnesium suspected
hydroxide)
Limit use due to high
magnesium load,
Magnesium citrate especially in older
(300 ml contains 2800 mg 300 ml PO individuals or patients
Weekly with decreased renal
Mg = 17.45 g magnesium
citrate) function
Avoid if impaction
suspected
Preferred agent if
impaction suspected
Enemas – mineral oil One per rectum Daily
and patient refuses
disimpaction
Phosphate enemas may
Enemas – water-based One per rectum Daily contribute to decline in
eGFR
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7: CONSTIPATION
7
whether the patient requires the current plasma level for optimal psychiatric response.
Often the patient has been carefully titrated to the present dose and level, so dose
reduction invites risk of psychotic exacerbation. In some instances the current plasma
level is not only in the upper end of the range (700–1000 ng/ml or 2140–3057 mmol/l)
but prior titration was rapid, with insufficient time allowed to determine response
before further dose escalation. Assuming that the patient is psychiatrically stable
and minimally symptomatic, one might consider a modest dose reduction of no more
than 5% every 4 weeks to determine whether psychiatric stability can be maintained
at lower plasma levels, but with improved tolerability. Plasma levels are rechecked
1–2 weeks after each dose decrease. Any increase in symptoms requires an
immediate end to the taper and resumption of the prior stable dose, with plasma level
confirmation 1 week later.
C Diagnosing Possible Ileus

7
Fatality rates from ileus vastly exceed those from severe neutropenia, so any
signs or symptoms suggestive of severe ileus must be responded to urgently. Box 7.4
contains a list of clinical features that demand urgent evaluation irrespective of the
time of day or day of the week. Outpatients must be urgently transported to a clinic
or emergency department for examination. When ileus suspicion is high, inpatients
and outpatients must be transferred to a general hospital (if not there already) for
evaluation and admission. Delays in this process increase the risk of bowel ischemia,
perforation and peritonitis.
When patients are admitted, they may be on NPO status for an extended time
due to the use of nasogastric suction precluding oral administration of medications.
Moreover, clozapine may be held to lower exposure and promote motility, especially if
surgery is performed. Analogous to the severe neutropenia patient who has clozapine
abruptly discontinued, there is a risk of cholinergic rebound and delirium. As the
oral route will not be available, consider using parenteral benztropine to mitigate
cholinergic rebound, administering small doses (e.g. 1 mg) intramuscularly as needed
based on clinical evidence of cholinergic rebound symptoms such as confusion
or frank delirium. The use of small doses and the parenteral route will hopefully
minimize benztropine’s impact on motility. Benztropine doses that provide equivalent
anticholinergic activity to the prior clozapine dose and level need not be used. The
goal is to prevent cholinergic rebound with the smallest possible exposure. (Chapter
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7: CONSTIPATION
4 provides an extensive discussion of strategies for managing cholinergic rebound,

and considerations for antipsychotic therapy after clozapine discontinuation.)
Box 7.4 When to Suspect Ileus

1. Moderate to severe abdominal pain or discomfort lasting more than 1
hour
OR
2. Abdominal pain/discomfort lasting more than 1 hour and at least one of
the following:
a. Vomiting (especially feculent vomitus)
b. Distension
c. Absent or high-pitched bowel sounds
d. Diarrhea (especially bloody)
e. Hemodynamic instability or other signs of sepsis
• Despite a clinician’s best efforts, some patients may develop ileus and require not
Rechallenging the Ileus Patient
only hospitalization for decompression, but surgical intervention with bowel resection.
As ileus can prove life-threatening, clinicians are understandably reluctant to restart
clozapine, especially when the patient has been gravely ill or required surgery.
Nonetheless, most of these patients have no therapeutic alternatives and need to
be approached with the same considerations as those who wish to rechallenge
patients with prior severe neutropenia. The case for rechallenging a patient with a
history of ileus, even with bowel resection, is strengthened when the patient was
deprived of a trial of an intestinal secretogogue or perhaps prucalopride. The first
case report of lubiprostone use was in a patient who developed poorly controlled
psychosis when managed with nonclozapine antipsychotics after hospitalization
and surgical exploration for clozapine-related ileus [14]. As most ileus patients have
failed combinations of first-line agents, the treatment algorithm during rechallenge
is inverted: secretogogues or prucalopride are started at the commencement of
clozapine therapy, and other classes added sequentially as needed (see Box 7.5).
Medication expense is often cited as a reason to prevent access to newer agents, but
the cost of medical hospitalization for ileus can exceed the annual medication cost of
a secretogogue or prucalopride by a factor of 100-fold or more.
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7: CONSTIPATION
7
Box 7.5 Constipation Medications During Clozapine Rechallenge After Ileus
1. Commence a secretogogue at the lowest available dose during the first
week of clozapine treatment. If diarrhea occurs, hold the secretogogue
and retry in 7–10 days.
2. As the clozapine titration proceeds, adjust the secretogogue dose so
that the patient has no constipation complaints, and has very rare need
for PRN medications (< 1 per fortnight). Consider switching to another
secretogogue with a different mechanism of action (if available in the
country) when maximum doses of the current agent are not sufficiently
effective. Do not combine secretogogues.
3. If constipation management remains inadequate despite maximal
secretogogue doses, sequentially add first-line agents starting with
docusate, then a stimulant or osmotic, and then combining maximum
doses of all three classes.
Summary Points 7
a. Treatment for constipation begins with the initiation of clozapine therapy,
and includes minimizing exposure to other anticholinergic and constipating
medications.
b. Even with combined use of first-line agents from each class, 20–50% of
clozapine-treated patients will have persistent hypomotility and constipation.
c. Intestinal secretogogues and possibly prucalopride offer significant benefit
for patients who fail maximal combined doses of docusate + an osmotic + a
stimulant. Lubiprostone has been used for 10 years in the California Department
of State Hospitals for treatment-resistant constipation. Experience is slowly
accruing with the newest secretogogues linaclotide and plecanatide, and with the
selective 5HT4 agonist prucalopride.
d. Secretogogues or prucalopride must be used when rechallenging patients who
have previously experienced ileus on first-line agents.
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7: CONSTIPATION
References
1. Pai, N. B. and Vella, S. C. (2012). Reason for clozapine cessation. Acta Psychiatrica Scandinavica,
125, 39–44.
2. Cohen, D. (2017). Clozapine and gastrointestinal hypomotility. CNS Drugs, 31, 1083–1091.
3. Leung, J. G., Hasassri, M. E., Barreto, J. N., et al. (2017). Characterization of admission types in
medically hospitalized patients prescribed clozapine. Psychosomatics, 58, 164–172.
4. Every-Palmer, S., Nowitz, M., Stanley, J., et al. (2016). Clozapine-treated patients have marked
gastrointestinal hypomotility, the probable basis of life-threatening gastrointestinal complications: A
cross sectional study. EBioMedicine, 5, 125–134.
5. Nielsen, J. and Meyer, J. M. (2012). Risk factors for ileus in patients with schizophrenia.
6. Solismaa, A., Kampman, O., Lyytikainen, L. P., et al. (2018). Genetic polymorphisms associated
with constipation and anticholinergic symptoms in patients receiving clozapine. Journal of Clinical
7. Lacy, B. E., Mearin, F., Chang, L., et al. (2016). Bowel disorders. Gastroenterology, 150,
1393–1407.
8. Lewis, S. J. and Heaton, K. W. (1997). Stool form scale as a useful guide to intestinal transit time.
Scandinavian Journal of Gastroenterology, 32, 920–924.
9. Every-Palmer, S., Newton-Howes, G. and Clarke, M. J. (2017). Pharmacological treatment for
antipsychotic-related constipation. Cochrane Database of Systematic Reviews, 1, Cd011128.
10. Wald, A. (2016). Constipation: Advances in diagnosis and treatment. JAMA, 315, 185–191.
11. Taylor, D., Paton, C. and Kapur, S. (2015). The Maudsley Prescribing Guidelines in Psychiatry,
12th Edition. Chichester: Wiley-Blackwell.
12. Every-Palmer, S., Ellis, P. M., Nowitz, M., et al. (2017). The Porirua Protocol in the treatment of
clozapine-induced gastrointestinal hypomotility and constipation: A pre- and post-treatment study.
CNS Drugs, 31, 75–85.
13. Lacy, B. E. and Levy, L. C. (2008). Lubiprostone: A novel treatment for chronic constipation.
Clinical Interventions in Aging, 3, 357–364.
14. Meyer, J. M. and Cummings, M. A. (2014). Lubiprostone for treatment-resistant constipation
associated with clozapine use. Acta Psychiatrica Scandinavica, 130, 71–72.
15. Love, B. L., Johnson, A. and Smith, L. S. (2014). Linaclotide: A novel agent for chronic
constipation and irritable bowel syndrome. American Journal of Health-System Pharmacy, 71,
1081–1091.
16. Nee, J., Zakari, M., Sugarman, M. A., et al. (2018). Efficacy of treatments for opioid-induced
constipation: A systematic review and meta-analysis. Clinical Gastroenterology and Hepatology, 16,
1569–1584.
17. Thomas, N., Jain, N., Connally, F., et al. (2018). Prucalopride in clozapine-induced constipation.
Australian & New Zealand Journal of Psychiatry, 52, 804.
18. Canadian Agency for Drugs and Technologies in Health. (2014). Dioctyl Sulfosuccinate or
Docusate (Calcium or Sodium) for the Prevention or Management of Constipation: A Review of the
Clinical Effectiveness. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health.
156
8QUICK CHECK
Managing Sedation,
Orthostasis and Tachycardia
Introduction 158
Principles 159
A Sedation 160
B Orthostasis 164
C Tachycardia 166
Summary Points 169
References 170
INTRODUCTION
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
158
8: SEDATION, ORTHOSTASIS AND TACHYCARDIA
8
PRINCIPLES
• 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.
8
• 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.
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.
159
A Sedation
Although sialorrhea and gastrointestinal hypomotility may be more prevalent,

sedation is frequently cited as a reason for early treatment discontinuation. In the
South London and Maudsley National Health Service Foundation Trust study of
316 patients commencing clozapine, sedation was the number one adverse drug
reaction (ADR) cited as a reason for discontinuation by both clinicians and by patients;
moreover, the risk of discontinuation was highest in the first few months of clozapine
treatment [1]. A prevalence estimate of 44% was cited in a 2016 review of clozapine
ADRs [5], and this is consistent with data from the Clinical Antipsychotic Trials of
Intervention Effectiveness (CATIE) study, in which the prevalence of “hypersomnia/
sleepiness” in phases 2 and 3 were 45% and 32%, respectively [6,7]. Sedation is
related to the combined effects of muscarinic and histamine H1 antagonism, and thus
might be expected to have a dose (or more accurately plasma level) relationship, but
this is not easily proven from the clinical trials data. The 2017 Cochrane review on
clozapine dosing noted that patients randomized to low-dose clozapine (150–300 mg/
day) had a lower risk of lethargy (RR 0.77, 95% CI 0.60 to 0.97) compared to standard
doses (301–600 mg/day), but this conclusion is based on results from one trial [8].
Analysis of naturalistic data from 30 patients on clozapine monotherapy at the Institut
de Neuropsiquiatria i Adiccions in Barcelona found that norclozapine levels correlated
with hours slept (r = 0.367, p = 0.03) [9].
In clinical practice patients are titrated to the dose necessary to achieve the desired
outcome (e.g. violence reduction, decrease in positive symptoms of schizophrenia)
using clinical response, plasma-level data and tolerability as guides. While tolerance
to sedation may develop over time, patients must agree to remain on clozapine for a
sufficient time for this process to occur. As noted above, the greatest risk for stopping
clozapine treatment due to an ADR is during the first few months of therapy. Below are
some principles to help manage sedation risk in patients starting clozapine therapy.
While there is a range of individual sensitivity to sedation, plasma levels can be very
helpful to guide future treatment in those who appear exquisitely sensitive despite
removing other offending medications and adjustment of the clozapine titration.
Frequent communication with patients and caregivers is important to emphasize that
excessive sedation is not acceptable and that every effort will be made to address
this complaint. If a patient has significant complaints of daytime sedation and poor
sleep quality prior to the clozapine trial, evaluation for obstructive sleep apnea may be
needed prior to commencing clozapine, as these will likely be worse.
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Box 8.1 Managing Sedation When Commencing Clozapine
1. Prior to starting treatment, minimize exposure to benzodiazepines and
anticholinergics. The strategies for tapering these agents are outlined in
Box 3.5.
2. Ask the patient to report problems with sedation as soon as they occur
so that adjustments can be made to the doses of existing medications,
or to the clozapine titration.
3. Clozapine is commonly prescribed as a single nightly QHS dose in
North American without apparent loss of efficacy [27]. This should be
considered for all patients during the early weeks of clozapine initiation.
Single doses up to 500 mg QHS in nonsmokers appear to be well
tolerated in clinical practice and should be considered for all patients
unless dose-limiting adverse effects occur that can be alleviated through
divided doses.
4. As noted in Chapter 3, titrations must be individualized based on the clinical
scenario, demographic variables (e.g. age), the presence of CYP inducers
(e.g. smoking, omeprazole, carbamazepine) or inhibitors and patient
response to clozapine itself. The concept of a standard titration is a myth.
5. When sedating medications cannot be withdrawn (e.g. a patient
transitioning from high-dose quetiapine or chlorpromazine to clozapine),
these agents should be cross-tapered with clozapine, with careful 8
attention paid to patient complaints of sedation.
6. If the patient complains of significant sedation, revert back to the last
prior clozapine dose, and taper off any existing sedating medications
to the extent possible, especially benzodiazepines, antiparkinsonian
medications, antihistamines. Once the complaints abate after 3–7 days,
the clozapine titration can proceed, but the rapidity of dose escalation
may need to be moderated. If the complaints persist despite these
measures, plasma clozapine levels may be very useful to determine
whether the patient is a poor metabolizer with higher than expected
levels for the dose (see Chapter 5), or just more sensitive to sedation.
At times, patients may not complain of sedation during the titration phase, but
notice the problem once they are psychiatrically improved and working on functional
goals. There are two options for these individuals once all other sedating medications
have been discontinued (including anticholinergic agents with CNS effects used
for overactive bladder): dose reduction (using plasma levels) or use of adjunctive
medications to promote daytime alertness. When considering dose reduction the
approach is very similar to that outlined in Chapter 7 (Decreasing Plasma Clozapine
Levels for Difficult to Manage Constipation). Dose reduction may be a viable strategy
161
when individuals are psychiatrically stable and minimally symptomatic, the plasma
level is at the high end of the therapeutic range, and there is evidence that the patient
may have been titrated rapidly to this plasma level without allowing sufficient time
to respond before each dose increase. There are limited data to provide guidance on
the extent to which decreasing the plasma clozapine level will improve complaints
of sedation. Among 133 clozapine-treated patients at the Institut de Neuropsiquiatria
i Adiccions in Barcelona who complained of excessive sedation, clozapine dose
reduction decreased the time spent asleep in < 20% of patients [9]. Nonetheless, it
may benefit selected patients, so the following approach is suggested.
1. Consider a dose reduction of no more than 5% every 4 weeks to determine
whether psychiatric stability can be maintained at lower plasma levels, but with
decreased sedation. Plasma levels are rechecked 1–2 weeks after each dose
decrease.
2. Any increase in symptoms requires an immediate end to the clozapine taper
and resumption of the prior stable dose, with plasma level confirmation 1 week
later.
When dose reduction is not an option or is not effective, adjunctive medications
can be considered. Among the available options, aripiprazole is somewhat compelling
as it is unlikely to cause symptomatic exacerbation and there is no abuse liability.
In the Barcelona cohort (n = 133) noted above, aripiprazole augmentation reduced
hours slept in 26.1% [9]. There are also data on the use of aripiprazole to address
residual schizophrenia symptoms, with four double-blind placebo-controlled trials
as of 2014 [10]. In those studies the degree of psychiatric improvement did not
reach statistical significance, although there was a trend towards benefit. At mean
aripiprazole doses ranging from 11.1 to 15.5 mg/day in each study, aripiprazole
was significantly more likely than placebo to induce akathisia or anxiety, so initial
doses should be modest (e.g. 2.5 mg/day) and patients observed for these adverse
effects. Aripiprazole should only be tried in patients on clozapine as antipsychotic
monotherapy, and dose adjustments are needed for cytochrome P450 (CYP) 2D6 poor
metabolizers, or those on 2D6 or 3A4 inhibitors, or 3A4 inducers. There are reports of
symptomatic worsening when aripiprazole is added to nonclozapine antipsychotics,
likely due to displacement of strong D2 antagonists by the partial agonist aripiprazole
[11]. Aripiprazole and its active metabolite reach steady state in 21 days, so if there is
no benefit for sedation after 3 weeks at a given dose, higher doses ought to be tried.
The adjunctive aripiprazole trial should be terminated for adverse effects (akathisia,
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8
anxiety, parkinsonism) or the maximum dose of 30 mg/day is reached (for those not
on CYP inhibitors or inducers or 2D6 poor metabolizers).
In the stimulant class, modafinil was approved in the US on December 24,
1998 to promote wakefulness in those with excessive daytime sedation, and the
active R enantiomer armodafinil was subsequently approved on June 15, 2007 for
a similar indication. Although the mechanism was not completely understood at
launch, modafinil has subsequently been characterized as a very weak but very
selective inhibitor of dopamine reuptake. In addition to compelling in vitro and in
vivo animal data, a human imaging study found that 200 mg of modafinil resulted in
51.4% dopamine transporter occupancy, and the 300 mg dose in 56.9% occupancy
[12]. By way of comparison, clinically relevant doses of methylphenidate occupy
60–70% of dopamine transporters [13]. Although modafinil appears to have lower
abuse risk than traditional stimulants, the abuse liability is not absent. There are
also rare reports of drug reaction with eosinophilia and systemic symptoms or
Stevens–Johnson syndrome. Nonetheless, modafinil is generally well tolerated and
has been studied extensively for negative symptoms and cognitive dysfunction in
schizophrenia and also for its impact on metabolic parameters [14–16]. It has not
proven successful for those purposes, and unfortunately only one of four randomized, 8
double-blind, placebo-controlled trials for sedation proved positive. It is worth noting
that the dose range of 200–300 mg/day was well tolerated in those studies without
apparent risk of symptomatic worsening [14], although there are rare case reports
of symptom exacerbation [17]. The starting dose is 100 mg qam (each morning),
and it can be advanced if needed by 100 mg/day each week to a maximum dose of
300 mg qam.
The use of methylphenidate and amphetamines is limited by their significant abuse
potential and the risk for exacerbation of positive psychotic symptoms. Nonetheless,
there are two early case reports from 1993 in which methylphenidate at doses of
5–30 mg/day was helpful when dose reduction was no longer possible [18]. In 2016,
three cases were reported in which extended-release methylphenidate (Concerta®)
was used to improve cognitive function with the specific goal of reducing persistent
impulsive violence in clozapine-treated forensic inpatients [19]. At doses of 18 or
36 mg once daily there was a significant reduction in violence and no worsening of
the underlying psychotic disorder. Although the medication was administered in a
highly controlled setting, even in controlled inpatient units concerns about abuse need
to be examined whenever a stimulant is prescribed. There are no data about use of
163
amphetamine preparations for sedation in clozapine-treated patients, and none for

other purposes (e.g. cognitive enhancement).
B Orthostasis
Orthostatic hypotension is defined as sustained reduction in systolic blood

pressure (SBP) of at least 20 mmHg or in diastolic blood pressure (DBP) of at least
10 mmHg within 3 min of standing. Although there are studies of rapid clozapine
titration as noted previously [2,3], minimizing orthostasis is one reason clozapine
is often titrated slowly. The US package insert contains multiple warnings about
orthostasis in bold type to alert clinicians to the potential seriousness of this
problem, and urges gradual titration as one mitigating strategy. Recent reviews cite a
prevalence of 9%, but patients may report complaints of dizziness or faintness without
meeting strict criteria for orthostatic hypotension [5]. In the CATIE trial, the prevalence
of “orthostatic faintness” in phases 2 and 3 were 12% and 24%, respectively [6,7].
As with sedation, there is a relationship with dose to the extent that those exposed
to low doses in clinical trials (150–300 mg/day) experienced less dizziness (RR 0.56,
95% CI 0.39 to 0.81) compared to standard doses (301–600 mg/day) [8]. While
several strategies are available to manage clozapine-related orthostasis, and expert
reviews recommend termination only for “continuous malignant syncope” despite
countermeasures [4], dizziness was the fourth most common reason for clinicians to
stop clozapine in the South London and Maudsley National Health Service Foundation
sample of 316 new starts [1].
The underlying mechanism relates to the high affinity of clozapine and
norclozapine for alpha1-adrenergic receptors and subsequent reduction in
peripheral vascular tone. Clozapine in particular is a nonselective antagonist at the
alpha1A-adrenergic and alpha1B-adrenergic receptors, and thus differs from newer
medications used for lower urinary tract symptoms in males that are selective
alpha1A-adrenergic antagonists (e.g. tamsulosin), and have lower rates of orthostasis.
There is marked individual variation in sensitivity to alpha1-adrenergic antagonism
with older age, baseline blood pressure, concurrent use of other alpha1-adrenergic
antagonists or antihypertensives, and the clozapine dose all influencing the ability
to tolerate a particular titration schedule. For patients not on medications that act
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8
Box 8.2 Managing Orthostasis When Commencing Clozapine
1. Prior to starting treatment, minimize exposure to nonselective alpha1-
adrenergic antagonists associated with orthostasis. (The strategies for
tapering these agents are outlined in Box 3.5.)
2. For older patients, those with a history of orthostasis, and patients
on agents that lower blood pressure (antihypertensives, nonselective
alpha1-adrenergic antagonists), consider slower titration schedules
until tolerability is established. As noted in Chapter 3, titrations must
be individualized based on the clinical scenario, demographic variables
(e.g. age), the presence of CYP inducers (e.g. smoking, omeprazole,
carbamazepine) or inhibitors and patient response to clozapine itself.
3. Frequent measurement of orthostatic blood pressures during the
first weeks of treatment as outlined in Chapter 3. Ask the patient to
report problems with dizziness as soon as they occur so that it can
be established that this is related to blood pressure changes (and not
other causes, e.g. Meniere’s disease), and so adjustments can be made
to doses of existing medications, or to the clozapine titration. Advise
patients to rise slowly when standing during the titration phase.
4. When nonselective alpha1-adrenergic antagonist antipsychotics cannot be
withdrawn (e.g. a patient transitioning from chlorpromazine to clozapine),
these should be cross-tapered with clozapine, with frequent orthostatic 8
vital sign measurements and attention to complaints of dizziness.
6. If the patient manifests orthostatic drops in blood pressure, revert back
to the last prior clozapine dose, encourage adequate oral fluid intake and
evaluate the role of existing medications.
a. If there are psychotropics with nonselective alpha1-adrenergic
antagonism, attempt to taper these further. If antihypertensives need
to be adjusted, consult with the primary care provider. For patients on
terazosin or prazosin for benign prostatic hypertrophy, switching to
selective alpha1A-adrenergic antagonists such as tamsulosin is associated
with markedly reduced blood pressure effects. Reassess blood pressure
frequently over the ensuing 3–7 days after changes are made.
b. If there are no offending medications besides clozapine, reassess
blood pressure frequently over the ensuing 3–7 days to see if tolerance
has developed.
7. If orthostasis persists despite these measures, the mineralocorticoid
fludrocortisone is the medication of choice, starting at 0.1 mg PO qD.
The main contraindication is presence of congestive heart failure. Doses
can be increased every 7–10 days based on blood pressure results to
a maximum of 0.3 mg qD. Patients on long-term therapy must have
potassium levels monitored every 2–3 months.
8. Use of compression stockings can be considered, but may be of limited
value and poorly tolerated in warmer climates.
165
as nonselective alpha1 antagonists there is a phenomenon known as the first dose

effect: marked sensitivity to the hypotensive effect is much greater with the first
dose of an antagonist and is lower when the same medication is dosed 72 hours
later [20]. This ongoing process of receptor desensitization and tolerance to the
hypotensive effect develops over days to weeks, but in some patients orthostatic
hypotension or dizziness complaints become dose-limiting and demand immediate
action to prevent falls and injuries, and to prevent the patient from refusing to persist
with clozapine.
The management of orthostasis very much parallels that of sedation with one
major exception: when the removal of offending medications other than clozapine,
adjustment of clozapine doses and increased fluid intake fail to yield meaningful
results there is a specific treatment for orthostasis: the potent mineralocorticoid
agonist fludrocortisone. Fludrocortisone has been available for over 60 years for
the management of orthostatic hypotension and is the drug of choice for conditions
such as postural orthostatic tachycardia syndrome [21]. Fludrocortisone acts on
renal distal tubule cells to promote reabsorption of sodium and water, thereby
expanding vascular volume. As some potassium wasting occurs, potassium
levels must be monitored every 2–3 months to prevent hypokalemia. The primary
contraindication is congestive heart failure. In addition to fludrocortisone one can
try compression stockings, but the benefit is often limited, and the stockings poorly
tolerated in warmer climates. Rare patients can be encountered who continue to
have problematic orthostasis despite maximum efforts including fludrocortisone
and extremely slow titrations, but for most patients orthostasis is not a reason to
terminate clozapine treatment.
C Tachycardia
Sustained tachycardia is defined as heart rate > 100 beats per minute (BPM) in
the resting state. For most medications with prominent alpha1-adrenergic antagonist
properties, reflex tachycardia would be the consequence of poor vasomotor tone,
and this is the first consideration when tachycardia is detected for clozapine-treated
patients; however, persistent tachycardia is reported at rates varying from 25% to
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8
54%, suggesting that other autonomic mechanisms are contributing [5,22]. Akin to
orthostasis, there is a dose relationship with rates on low-dose regimens (150–
300 mg/day) 57% of that seen with standard doses (301–600 mg/day) [8]. Despite
the fact that tachycardia management is straightforward, and expert reviews suggest
that tachycardia should never be grounds for discontinuing clozapine [4], it was the
third most common reason for clinicians to stop clozapine in the South London and
Maudsley National Health Service Foundation sample of 316 new starts [1].
Before concluding that persistent tachycardia is due to clozapine itself, the
clinician has a small number of considerations as outlined in Box 8.3. In addition
to short-term concerns that tachycardia may be due to orthostasis, additive
pharmacodynamic effects, infection, pain, drug reaction, systemic illness or
myocarditis, there is a long-term consideration: persistent tachycardia is associated
with increased mortality from cardiac and noncardiac causes [22]. Many clinicians
are aware that sustained tachycardia increases risk for cardiomyopathy [23];
however, a meta-analysis of 45 prospective cohort studies found that for each
increment of 10 BPM in resting heart rate there was an increased relative risk for
the following (after adjusting for risk related variables): 1.12 (95% CI 1.09–1.14) for
coronary artery disease, 1.05 (95% CI 1.01–1.08) for stroke, 1.12 (95% CI 1.02– 8
1.24) for sudden death, 1.16 (95% CI 1.12–1.21) for noncardiovascular diseases,
1.09 (95% CI 1.06–1.12) for all types of cancer and 1.25 (95% CI 1.17–1.34) for
noncardiovascular diseases excluding cancer [24]. As noted in Chapter 3 (see Box
3.1 and Table 3.4), another issue that arises from tachycardia is erroneous concerns
about QT prolongation. Many ECG machines continue to use the older Bazett QT
correction formula that was derived in 1920 from 39 healthy male controls and
significantly overcorrects the QTc for faster heart rates [25]. For this reason, American
Heart Association guidelines for ECG interpretation recommend against using Bazett’s
formula with high heart rates, as the “adjusted QT values may be substantially in
error” [26]. Unfortunately, many clinicians are not aware of these guidelines or even
what correction formula is used in their ECG machines, leading to unnecessary
alarm and concern. For all of these reasons, the goal of treatment is a resting heart
rate always under 100 BPM, and ideally closer to 80 BPM because each 10 BPM
increment increases mortality risk.
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Box 8.3 Decision Algorithm When Persistent Tachycardia is Detected

Step 1. Is it due to orthostasis? Strongly suspect when occurring shortly
after a dose increase, or after changes to the regimen that would
increase plasma clozapine levels.
a. Yes: For patients initiating clozapine, hold the titration and treat
the orthostasis.
b. Yes: For patients on established therapy: if there is a suspected
increase in the plasma level due to the addition of an inhibitor or
removal of an inducer (e.g. smoking cessation), obtain a plasma
clozapine level and reduce the dose based on the expected
kinetic impact of the change (see Chapter 5). If this is not
tolerated for psychiatric reasons, then treat the orthostasis.
c. No: See if items 2, 3 or 4 are considerations. If not, go to step 5.
Step 2. Have anticholinergic or adrenergic agonist medications been
added that promote tachycardia?
a. Yes: Taper these off in lieu of other agents, with the sole
exception of a patient with treatment-resistant sialorrhea who
requires glycopyrrolate. For the latter, go to step 5.
b. No: See if items 3 or 4 are considerations. If not, go to step 5.
Step 3. Is there infection, pain or systemic illness (including drug reactions
and interstitial nephritis)?
a. Yes: Treat the underlying condition. In some instances this may
require stopping clozapine (drug reactions, interstitial nephritis).
Once treated, go to step 5 if tachycardia persists.
b. No: See if item 4 is a consideration. If not, go to step 5.
Step 4. If occurring during the first 6 weeks of clozapine treatment, are
there signs or laboratory parameters suggestive of myocarditis (see
Chapter 12)?
a. Yes: Stop clozapine and provide supportive treatment.
b. No: Go to step 5.
Step 5. When none of items 1–4 are present, the treatment of choice is
atenolol, a selective beta1-adrenergic antagonist that does not
readily enter the CNS and is not hepatically metabolized.
a. Starting dose: 12.5 mg PO qam. Monitor for orthostasis.
b. Titration: If tachycardic with no signs of orthostasis, may increase
in 12.5 mg increments every 7 days. Most patients respond to
doses ≤ 50 mg/day, but doses up to 100 mg qam can be tried.
c. Conversion from propranolol: If a patient was started on propranolol for
tachycardia management, this can be converted to atenolol in the
ratio of 40 mg/day propranolol = 25 mg qam atenolol. If the patient
is on propranolol for akathisia or tremor, then employ propranolol
for tachycardia management using this dose equivalence.
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Summary Points
a. Sedation is a highly prevalent condition and affects 45% of clozapine-treated

patients. It is the most common adverse drug reaction cited by patients as a
reason for discontinuing treatment. Prompt recognition during the early phase of
treatment, adjustment of clozapine titration and minimizing concurrent sedating
agents are the core strategies for managing sedation. Careful dose reduction
can be considered in select cases with plasma-level guidance. Adjunctive
medications to promote wakefulness can be tried but may be disappointing.
b. Orthostasis should almost never be a reason to stop clozapine treatment.
Encouragement of adequate fluid intake, prompt recognition during the early
phase of treatment, adjustment of clozapine titration and minimizing concurrent
offending agents are the initial strategies. When these are insufficient, the potent
mineralocorticoid fludrocortisone is the treatment of choice.
c. Tachycardia should never be a reason to stop clozapine treatment. Persistent
clozapine-related tachycardia is diagnosed after eliminating other possible
causes including orthostasis, effects of other medications on heart rate,
infection, pain, drug reactions and systemic conditions. When these are ruled 8
out, the beta1-adrenergic antagonist atenolol is the treatment of choice.
169
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cohort study of patients commencing treatment. Schizophrenia Research, 174, 113–119.
3. Poyraz, C. A., Ozdemir, A., Saglam, N. G., et al. (2016). Rapid clozapine titration in patients with
treatment refractory schizophrenia. Psychiatry Quarterly, 87, 315–322.
603–613.
5. Citrome, L., McEvoy, J. P. and Saklad, S. R. (2016). Guide to the management of clozapine-
related tolerability and safety concerns. Clinical Schizophrenia & Related Psychoses, 10, 163–177.
6. McEvoy, J. P., Lieberman, J. A., Stroup, T. S., et al. (2006). Effectiveness of clozapine versus
olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond
to prior atypical antipsychotic treatment. American Journal of Psychiatry, 163, 600–610.
7. Stroup, T. S., Lieberman, J. A., McEvoy, J. P., et al. (2009). Results of phase 3 of the CATIE
schizophrenia trial. Schizophrenia Research, 107, 1–12.
8. Subramanian, S., Vollm, B. A. and Huband, N. (2017). Clozapine dose for schizophrenia.
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9. Perdigues, S. R., Quecuti, R. S., Mane, A., et al. (2016). An observational study of clozapine
induced sedation and its pharmacological management. European Neuropsychopharmacology, 26,
156–161.
10. Srisurapanont, M., Suttajit, S., Maneeton, N., et al. (2015). Efficacy and safety of aripiprazole
augmentation of clozapine in schizophrenia: A systematic review and meta-analysis of randomized-
controlled trials. Journal of Psychiatric Research, 62, 38–47.
11. Takeuchi, H. and Remington, G. (2013). A systematic review of reported cases involving
psychotic symptoms worsened by aripiprazole in schizophrenia or schizoaffective disorder.
Psychopharmacology (Berlin), 228, 175–185.
12. Kim, W., Tateno, A., Arakawa, R., et al. (2014). In vivo activity of modafinil on dopamine
transporter measured with positron emission tomography and [(1)(8)F]FE-PE2I. International Journal
of Neuropsychopharmacology, 17, 697–703.
13. Hannestad, J., Gallezot, J. D., Planeta-Wilson, B., et al. (2010). Clinically relevant doses of
methylphenidate significantly occupy norepinephrine transporters in humans in vivo. Biological
14. Saavedra-Velez, C., Yusim, A., Anbarasan, D., et al. (2009). Modafinil as an adjunctive treatment
of sedation, negative symptoms, and cognition in schizophrenia: A critical review. Journal of Clinical
15. Henderson, D. C., Freudenreich, O., Borba, C. P., et al. (2011). Effects of modafinil on weight,
glucose and lipid metabolism in clozapine-treated patients with schizophrenia. Schizophrenia
Research, 130, 53–56.
16. Andrade, C., Kisely, S., Monteiro, I., et al. (2015). Antipsychotic augmentation with modafinil
or armodafinil for negative symptoms of schizophrenia: Systematic review and meta-analysis of
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17. Neto, D., Spinola, C. and Gago, J. (2017). Modafinil in schizophrenia: Is the risk worth taking?
BMJ Case Reports, 2017,
18. Burke, M. and Sebastian, C. S. (1993). Treatment of clozapine sedation. American Journal of
Psychiatry, 150, 1900–1901.
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disordered women: A case series and brief review. CNS Spectrums, 21, 445–449.
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first dose of prazosin. Clinical Pharmacology and Therapeutics, 32, 41–47.
21. Testani, M., Jr. (1994). Clozapine-induced orthostatic hypotension treated with fludrocortisone.
Journal of Clinical Psychiatry, 55, 497–498.
22. Ronaldson, K. J. (2017). Cardiovascular disease in clozapine-treated patients: Evidence,
mechanisms and management. CNS Drugs, 31, 777–795.
23. Gupta, S. and Figueredo, V. M. (2014). Tachycardia mediated cardiomyopathy: Pathophysiology,
mechanisms, clinical features and management. International Journal of Cardiology, 172, 40–46.
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prolongation. Journal of Psychiatry and Neuroscience, 43, 71–72. 8
171
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QUICK CHECK
Managing Sialorrhea
Introduction 172
Principles 173
A Salivary Gland Innervation and Physiology 174
B Mechanism for Clozapine-Induced Sialorrhea and Risk Factors 175
C Treatment Principles 177
• Rating Scales 177
• Atropine Drops and Ipratropium Spray 179
• Botulinum Toxin-B 180
• Adrenergic Modulators (Clonidine) 183
• Amisulpride and Sulpiride 184
• Glycopyrrolate 185
Summary Points 186
References 187
INTRODUCTION
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 [1].
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%.
172
9: SIALORRHEA
9
PRINCIPLES
• 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 9
of gastrointestinal hypomotility should it occur.
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 [2]. Importantly, sialorrhea during clozapine therapy has been
associated with reports of aspiration pneumonia [3]. 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 [3].
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 [4]. Lastly, parotitis
has also been reported and associated with hypersalivation [5].
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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” [6]. 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 [9]. 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.
A Salivary Gland Innervation and Physiology
Humans have three main pairs of salivary glands: parotid, submandibular, and
sublingual glands, along with hundreds of minor submucosal glands. In the resting
state the majority of salivary fluid (68%) is provided by the submandibular and
sublingual glands, and 28% comes from the parotid. However, when stimulated,
53% of salivary fluid comes from the parotid gland and 46% from the submandibular
and sublingual glands [10]. The sublingual and minor salivary glands secrete mucus
and are responsible for most of the protein content in saliva. Salivary secretion
is controlled by brainstem salivary nuclei located in the medulla oblongata that
receive diffuse inputs from the central nervous system (e.g. hypothalamus, frontal
cortex, amygdala) and signals created by tactile, olfactory, temperature and taste
stimuli (Figure 9.1). Both inhibitory GABA-ergic and excitatory glycinergic neurons
form synapses with the salivary nuclei, but these cells also express muscarinic
M3 receptors, with central M3 antagonists decreasing salivary flow. Reflex salivary
secretion is centrally mediated via alpha2-adrenergic receptors, with agonists (e.g.
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9
Figure 9.1. Connections between central nervous system structures and salivary
gland.
Descending input from forebrain

and hypothalamus
(–) GABAergic; glycinergic

(+) glutamate; cholinergic
α2 adrenergic agonists
Ascending pathways
Salivary
nuclei
Taste signals from: Brainstem

cranial nerve VII (anterior 2/3 tongue)
cranial nerve IX (posterior 1/3 tongue)
NST
SCG
Thoracic
spinal cord 9
(Adapted from: Proctor, G. B. and Carpenter, G. H. (2014). Salivary secretion:

Mechanism and neural regulation. Monographs in Oral Science, 24, 14–29 [10].)
clonidine) exerting an inhibitory effect of salivary flow. Salivary glands receive both
parasympathetic and sympathetic innervation, with cholinergic response highly based
on activity at muscarinic M3 receptors, with evidence for involvement of M1, M4 and M5
[10,11].
B Mechanism for Clozapine-Induced Sialorrhea and Risk Factors
As discussed in Chapter 7, muscarinic antagonism from clozapine is the primary

cause of intestinal hypomotility, but it is the agonist effects of norclozapine that are
hypothesized to induce sialorrhea. Although norclozapine has lower muscarinic affinity
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than clozapine across multiple receptor subtypes, norclozapine has higher intrinsic
agonist activity, especially at M1 (see Tables 9.1 and 9.2) [12]. That M1 agonism may be
the predominant mechanism for clozapine-induced sialorrhea is based on the efficacy
of pirenzepine, a relatively selective M1 antagonist, for clozapine-induced sialorrhea
[13].
Table 9.1 Binding profile at cloned human receptors (Ki nM) [34] and PDSP Ki
database (pdsp.med.unc.edu/pdsp.php).
D2 5HT2A 5HT2C 5HT1A M1 M3 α1A α1B H1 Brain/
plasma
ratio in
PGP KO
VS. WT
Clozapine 20 5.0 39.8 123.7 6.17 6.31 7.9 7.0 0.32 1.6 [35]
Norclozapine 63 5.0 15.9 13.9 67.6 158 5.0 85.2 6.3 ?
Table 9.2 Muscarinic intrinsic activity relative to the full agonist carbachol [34].
M1 M2 M3 M4 M5
Clozapine 24 ± 3% 65 ± 8% NR 57 ± 5% NR
Norclozapine 72 ± 5% 106 ± 9% 27 ± 4% 87 ± 8% 48 ± 6%
Carbachol 101 ± 2% 101 ± 5% 102 ± 3% 96 ± 3% 105 ± 3%
Among patient variables, there is no obvious relationship with demographic

characteristics, and no studies examining the association with plasma levels and
sialorrhea. A 2017 Cochrane review on clozapine dosing did note a lower risk for
hypersalivation among those prescribed doses of 300 mg/day or less (RR 0.70, 95%
CI 0.57 to 0.84) [14], but there are no studies to suggest that decreasing clozapine
doses results in a meaningful reduction in sialorrhea. Chapter 7 contains a section
entitled “Decreasing Plasma Clozapine Levels for Difficult to Manage Constipation”
that presents a discussion of important considerations when deciding to lower
clozapine plasma levels to manage an adverse effect. In select patients this may be a
viable strategy when they are psychiatrically stable and minimally symptomatic, the
plasma level is at the high end of the therapeutic range, and there is evidence that
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9
the patient may have been titrated very rapidly to this plasma level without allowing
sufficient time to respond before each dose increase. Unlike constipation, there are no
data to provide guidance on the extent to which decreasing the plasma clozapine level
will improve sialorrhea severity. There is one potential genetic marker of interest that
was found during a study of M1, M3 and alpha2A-adrenergic receptor polymorphisms
in 237 clozapine-treated Finnish patients. While no association was found between
muscarinic subtype variants and sialorrhea, there was an association with an
alpha2A-adrenergic receptor single nucleotide polymorphism [15]. Although this finding
requires replication, it supports the use of clonidine, an alpha2A-adrenergic agonist, as
a third-line treatment option due to the role that alpha2A-adrenergic signaling plays in
reflex salivary secretion.
C Treatment Principles
There are two overarching principles in managing sialorrhea: (a) recognize that
this is a problem with potentially life-threatening medical consequences due to
aspiration events; and (b) reserve systemic anticholinergic medications as treatments
of last resort due to the doubling of ileus risk, which itself can be fatal. The choice of
treatments proceeds from less-costly, locally applied anticholinergic preparations with
limited systemic exposure, to more effective but costlier botulinum toxin-B injections. 9
For patients who fail these strategies, one should always consider nonanticholinergic
options before proceeding to glycopyrrolate, the systemic anticholinergic of choice due
to its limited CNS penetrance.
• Rating scales must be used to track treatment response, with the goal of having
Rating Scales
no or minimal symptoms throughout the day, including while sleeping. While nocturnal
sialorrhea presents a risk of aspiration, it is daytime sialorrhea that is the most
socially disabling aspect of the problem, and may further contribute to the isolation
of a severely mentally ill individual. Unfortunately, there are no comprehensive
rating scales for sialorrhea that incorporate severity, frequency and social impact,
although attempts have been made to create such a scale for Parkinson’s disease
patients [16]. Among the instruments commonly used in clinical trials, the two-
item Drooling Severity and Frequency Scale (DSFS) was initially created in 1988 to
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Box 9.1 Principles of Sialorrhea Treatment

1. Track hypersalivation with rating scales. The two-item Drooling Severity
and Frequency Scale is among the most commonly used instruments in
sialorrhea trials. This can be supplemented with the subject-rated single-
item Nocturnal Hypersalivation Rating Scale (see Table 9.3).
2. Use locally acting anticholinergic medications first: (a) atropine 1%
drops sublingually starting at bedtime (1–3 drops) and increasing to a
maximum dose of 3 drops TID; or (b) ipratropium 0.06% spray intraorally
starting at bedtime (1–3 sprays) and increasing to a maximum dose of 3
sprays TID.
3. Given the extensive clinical trials for sialorrhea of various causes
(medication induced, secondary to neurological disorders), botulinum
toxin-B salivary gland injections should be pursued as a second-line
agent due to the efficacy, tolerability and extended duration of benefit (up
to 20 weeks).
4. If botulinum toxin-B injections are not effective, other nonanticholinergic
options to consider include alpha-adrenergic modulators (e.g. clonidine)
and amisulpride.
5. Systemic anticholinergic medication should be considered the
treatment of last resort due to the twofold increased risk for ileus. If a
systemic anticholinergic must be used, glycopyrrolate is the preferred
medication due to limited CNS penetration. Antiparkinsonian medications
and tricyclic antidepressants should not be used. The addition of
glycopyrrolate must be accompanied by vigilant tracking of constipation,
and aggressive management of gastrointestinal hypomotility should it
occur.
quantify sialorrhea in cerebral palsy patients, and has been used extensively since
[17]. Moreover, the DSFS was suggested by an expert panel exploring rating scale
options for dysautonomia symptoms in Parkinson’s disease patients [16]. The DSFS
has good face validity and is comprised of two items: severity, rated on a 1–5-point
scale, and frequency on a 1–4-point scale (Table 9.3), The Nocturnal Hypersalivation
Rating Scale (NHS) is a validated single-item self-report instrument created in 1997
that rates severity on a 5-point scale (scored as 0–4) [18]. The combined use of
both instruments requires very little clinician time and provides both objective and
subjective measures that all members of the clinical team, patients and caregivers
can readily understand. Given the simplicity of use, outpatient caregivers can easily
provide ratings to the treating clinician between appointments so that dosage
adjustments of locally applied medications can be made when symptoms are not
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9
Table 9.3 Sialorrhea rating scales.
Scale Clinician or Measures Items
self-rated
Severity Drooling Severity Scale
1 = Never drools, dry
2 = Mild – drooling, only lips
wet
3 = Moderate – drool reaches
the lips and chin
4 = Severe – drool drips off chin
Drooling Severity and onto clothing
and Frequency Scale Clinician
5 = Profuse – drooling off
(DSFS) [17]
the body and onto objects
(furniture, books)
Frequency Drooling Frequency Scale
1 = No drooling
2 = Occasionally drools
3 = Frequently drools
4 = Constant drooling
0 = Absent
1 = Minimal (signs of saliva on
the pillow in the morning)
2 = Mild (hypersalivation wakes
the patient up once during
Nocturnal
night) 9
Hypersalivation Rating Self Severity
Scale NHS [18] 3 = Moderate (hypersalivation
wakes the patient up twice
during night)
4 = Severe (hypersalivation
wakes the patient up at least
3 times during night)
adequately controlled. The goal of treatment is to have DSFS frequency and severity
scores of 2 or lower, and an NHS score of 0 or 1.
• Avoidance of systemic anticholinergics led clinicians to try orally applied existing

Atropine Drops and Ipratropium Spray
products. Atropine is a potent nonselective muscarinic antagonist with a variety of

uses and modes of delivery, while ipratropium is a quaternary amine derivative of
atropine designed not to cross the blood–brain barrier when administered in larger
doses as an inhaled medication for asthma or nasal congestion. The first reports
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of atropine 1% ophthalmic drops placed sublingually and ipratropium bromide

0.03% nasal spray appeared in 2001, and by 2005 these had come to be viewed as
accepted and effective alternatives to systemic anticholinergics [19]. In subsequent
case reports the higher strength of ipratropium bromide (0.06%) was recommended
more commonly. As with many medications used to manage clozapine-related
sialorrhea, there are virtually no adequately designed and reported clinical trials,
although the accumulated case-based data provide compelling evidence for efficacy
and tolerability to the extent that these agents are considered first-line therapies
for this purpose. They are also readily available, inexpensive, and for the doses
employed, lacking in systemic adverse effects. The biggest barriers to effective use
are twofold: (a) need for multiple applications throughout the day; (b) decreased
efficacy if the patient can’t swish around the medication with a very small amount
of water (< 5 ml). The latter is often problematic, as the patient themselves, staff
or caregivers may use too much water for this step, diluting the medication and
resulting in large amounts being rinsed out. If a patient fails one agent, try the other
before proceeding to botulinum toxin. Despite the issues with atropine drops and
ipratropium spray, these can be very effective options for some patients (see Table
9.4). The goals of treatment are minimal symptom ratings on the DSFS and NHS as
noted previously. A DSFS score of 2 or more on frequency or severity, or NHS rating
> 1 despite maximal doses of each agent should prompt consultation for botulinum
toxin salivary gland injections.
• Botulinum toxin exerts its activity by binding to the presynaptic terminal of

Botulinum Toxin-B
cholinergic neurons and subsequently entering the cytoplasm where it interferes

with SNARE proteins that mediate vesicle fusion. The activated form of the toxin
protein consists of two polypeptides: a 100-kDa heavy polypeptide joined via disulfide
bonds to a 50-kDa lighter chain. The heavy chain contains binding regions for the
presynaptic nerve terminals, and binding results in uptake of the toxin protein into a
presynaptic vacuole [20]. The heavy chain then facilitates translocation of the separate
light chain from the vacuole into the cytoplasm of the presynaptic neuron. The light
chain is a protease that cleaves one of two SNARE proteins (SNAP-25, synaptobrevin)
needed for vesicle fusion and release of synaptic acetylcholine. The net effect is loss
of cholinergic neurotransmission and the classical symptoms of botulism: muscle
weakness. As will be discussed below, when administered into nonmuscular areas
(e.g. sweat or salivary glands), cholinergic activity is also diminished [21]. The
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9
Table 9.4 Using atropine 1% solution and ipratropium bromide 0.06% spray for
sialorrhea.
Initial dose Maximum Comments on use
dose
• Swish with a very small amount of
water (< 5 ml) and then spit
Atropine 1% 1–2 drops 3 drops • Using even a slightly larger volume
ophthalmic sublingually sublingually of water will dilute the effect greatly
drops QHS TID • If a patient cannot swish and spit
reliably, then simply have the drops
placed under the tongue
• Swish with a very small amount of
water (< 5 ml) and then spit
Ipratropium • Using even a slightly larger volume
1–3 sprays 3 sprays of water will dilute the effect greatly
bromide
intraorally intraorally
0.06% nasal • If a patient cannot swish and spit
QHS TID
spray reliably, then omit this step
• If preferred, can spray under the
tongue
physiologic effect slowly reverses over weeks and months as new SNARE proteins are
slowly regenerated. As depicted in Figure 9.2, there are multiple botulinum toxin types
that vary slightly in sequence and structure, and consequently act at different sites
among the SNARE proteins. Only two forms are commercially used: botulinum toxin-A
(BTX-A), which exists in several formulations with different potency, and botulinum 9
toxin-B (BTX-B).
BTX-A was approved in 1989 to treat blepharospasm and strabismus, but has been
widely used since for dystonia, spasticity, chronic pain, and cosmetic applications.
Although the neuromuscular effects of BTX-A were the primary focus of drug
development, it was known from animal studies that natural or pharmacologically
delivered botulinum toxin induces parasympathetic abnormalities, especially when
directly injected into postganglionic locations. Recognition that BTX-A might be useful
for autonomic purposes was first reported in 1994 when clinicians treating three
hemifacial spasm patients documented decreased localized sweating in a specific facial
area that persisted over several months [21]. This led to expanded uses for patients
with hyperhidrosis, and for sialorrhea via injections into the parotid and submandibular
glands [22]. Botulinum toxin B (BTX-B), also known as rimabotulinumtoxinB, was first
approved in December 2000 for cervical dystonia, but clinical experience revealed that
for autonomic purposes it possessed earlier onset than BTX-A, perhaps related to the
fact that BTX-B cleaves a site on the SNARE protein synaptobrevin, while BTX-A acts on
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Figure 9.2. Specific locations where forms of botulinum toxin act on SNARE
proteins.
Syntaxin 1A
C
D
BG
ACh
Synaptic cleft
F E
A
Synaptobrevin
SNAP-25
C
A-G: cleavage sites for various types of botulinum toxin

Neuronal
membrane
(Adapted from: Barr, J. R., Moura, H., Boyer, A. E., et al. (2005). Botulinum neurotoxin
detection and differentiation by mass spectrometry. Emerging Infectious Diseases, 11,
1578–1583 [20].)
SNAP-25. In crossover trials for sialorrhea associated with amyotrophic lateral sclerosis
or Parkinson’s disease, the mean duration of benefit was comparable between the two
agents (75 days BTX-A vs. 90 days for BTX-B), but the onset was 3 days sooner for
BTX-B (mean 3.2 days) than for BTX-A (mean 6.6 days) [23].
As of 2017 there were six randomized, double-blind, placebo-controlled trials of
BTX-B for sialorrhea of varying etiologies, with a mean duration of effect in larger
studies of 19.2 weeks [9]. BTX-B treatment was well tolerated with no serious adverse
events. The rates of presumed treatment-related adverse effects (dry mouth, change
in saliva thickness, mild transient dysphagia, mild weakness of chewing) occurred in
less than 10% of subjects. The studies varied in doses used and whether parotid and
submandibular glands were both injected. The lowest dose was 1000 U into each parotid
and 250 U into each submandibular gland, and the highest dose 4000 U into the parotid.
Only one study used ultrasound guidance, as later studies found this unnecessary.
The first case report of BTX-A use for clozapine-related sialorrhea was in 2004
[24], and subsequent case reports documenting efficacy and tolerability for this use
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9
led to botulinum toxin being endorsed for clozapine-related sialorrhea in reviews
published in 2007 and 2011 [19,25]. Despite the abundant efficacy data spanning 20
years across a range of disorders associated with sialorrhea, as recently as 2018 an
article touted the potential use of botulinum toxin as a “novel treatment” for clozapine-
induced sialorrhea [26]. The advantages of BTX-B in patients who have failed locally
applied atropine or ipratropium include the long duration of action, potentially up
to 4–6 months, and the absence of CNS or peripheral anticholinergic effects that
would be experienced from systemic medications. In experienced hands the injection
procedure is relatively quick once landmarks are mapped out. Ultrasound is not
commonly used or deemed necessary. The injections are administered with a very fine
30-gauge needle that minimizes patient discomfort.
In major metropolitan areas a variety of physicians are available to administer these
injections, particularly neurologists, otorhinolaryngologists, and also some physical
medicine specialists who may work with cerebral palsy patients. Given the severity of
clozapine-induced sialorrhea, injection of both parotid and submandibular glands is likely
necessary using higher dosages of BTX-B, but doses can always be adjusted depending
on the extent and duration of treatment response or complaints of adverse effects
(primarily dry mouth). As with locally applied anticholinergics, the goal of treatment is
to have DSFS frequency and severity scores of 2 or lower, and an NHS score of 0 or 1.
Although the initial cost is greater than inexpensive prescribed medications, much of the 9
system-wide expense will be recouped by avoiding hospital fees from treating aspiration
pneumonia in patients with poorly controlled sialorrhea, hospital fees from treating ileus
in patients who received systemic anticholinergics to manage sialorrhea, or psychiatric
hospitalization costs when patients refuse to continue with clozapine treatment.
• Reflex salivary secretion is centrally mediated via alpha -adrenergic receptors,

Adrenergic Modulators (Clonidine)
2
and agonists (e.g. clonidine and guanfacine) exert an inhibitory effect on salivary flow.
While norclozapine itself acts through cholinergic agonism, a polymorphism in the
alpha2A-adrenergic receptor was associated with risk for clozapine-induced sialorrhea
[15]. If replicated, this may increase enthusiasm for alpha2A-adrenergic agonists in
individuals with the particular variant if they exhibit unexpected benefit from these
agents in clinical studies.
The sum total of the world’s literature for guanfacine management of c lozapine-
induced sialorrhea is a single case report in 2004 in which 1 mg/day was effective
and tolerated, although there are data in intellectually disabled children [19]. There
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is a much larger body of case reports for clonidine dating back to 1992, although no
randomized trials. Some studies used the weekly transdermal patch delivering doses
of 0.1–0.2 mg/day, while others have used oral doses up to 0.1 mg/day [19]. At these
doses there was reduction in subjective complaints and severity of nocturnal salivation
as measured by the wet area on the pillow. While these doses were tolerated, there
is a risk of orthostasis and complaints of tiredness with use of alpha2-adrenergic
agonists, so they must be used cautiously and only in those who do not have
current evidence of orthostasis, tachycardia or sedation. The oral form of clonidine is
preferable to insure tolerability, and this can later be converted to transdermal patch
if sufficiently effective. If effective, the primary advantage is avoidance of systemic
anticholinergic effects and increased ileus risk. There is one retrospective chart review
of the alpha1-adrenergic receptor antagonist terazosin 2 mg QHS that appeared to
show effectiveness comparable to benztropine for clozapine-related hypersalivation,
but this has never been replicated and no cases reported in the subsequent literature
[27]. As terazosin and clonidine both carry orthostasis risks, the former offers no
advantage.
• Starting approximately 10 years ago, cases started to appear for use of the
Amisulpride and Sulpiride
substituted benzamides to manage clozapine-related hypersalivation [28]. Although

unavailable in North America, sulpiride and amisulpride are antipsychotics with
high affinity for both dopamine D2 and D3 receptors, and no appreciable binding to
muscarinic or alpha-adrenergic pathways [29]. While they have marked effects on
prolactin secretion, there is a relatively lower risk for parkinsonism and akathisia than
with typical antipsychotics, along with greater efficacy in some studies. Interestingly,
and by unknown mechanisms, the addition of these agents at low doses has been
reported to reduce the severity of hypersalivation, a fortuitous finding from an early
trial of amisulpride augmentation for inadequate responders to clozapine [19].
In addition to case reports, the utility of this option is supported by a prospective
randomized study of amisulpride 400 mg/day added to clozapine specifically for
symptomatic sialorrhea (n = 53). During the 2 weeks of treatment with amisulpride,
the mean NHS score dropped from 3.45 to 2.55 (p < 0.0001) [28]. While this is
encouraging, the final NHS rating of 2.55 implies that patients are awakened on
average of 1.5 times per night due to sialorrhea. Nonetheless, amisulpride was well
tolerated, and thus provides another inexpensive nonanticholinergic strategy that
could be sufficiently effective in some patients. Although 400 mg/day was used
in the prospective amisulpride trial, there are case reports of efficacy at doses of
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9
50–100 mg/day, and this is the recommended starting dose for this purpose [30]. The
amisulpride dose can be advanced every 2 weeks based on response using the DSFS
and NHS scores. In clozapine augmentation studies for schizophrenia symptoms doses
up to 800 mg/day have been used, but these higher amisulpride doses may incur risks
of QT prolongation and might offer no greater benefit for sialorrhea [31].
• While the use of systemic anticholinergics will increase the risk of ileus, at times
Glycopyrrolate
they must be used when patients have failed other treatment modalities. For these
patients the medication of choice is glycopyrrolate, a potent antagonist across all
muscarinic receptor subtypes that does not cross the blood–brain barrier. For this
reason it is preferable to any medication that has CNS effects, such as anticholinergic
antiparkinsonian agents or tricyclic antidepressants [32]. Clozapine itself presents a
significant CNS anticholinergic burden, so there is no compelling reason to add to this
effect, particularly when glycopyrrolate has demonstrable efficacy for sialorrhea of
varying etiologies in numerous randomized clinical trials [33]. Moreover, when directly
compared to biperiden in a randomized, double-blind, crossover study, glycopyrrolate
did not adversely impact cognition in a manner seen with biperiden [32].
Glycopyrrolate has erratic oral absorption with a reported TMax of 5 hours. The
duration of clinical effect is not well quantified in the literature, but most studies 9
use BID dosing unless the target is only nocturnal sialorrhea. Box 9.2 presents the
principles involved when adding a potent anticholinergic medication to existing
clozapine therapy, and the need for vigilance in managing the expected worsening of
constipation.
Box 9.2 Considerations During Use of Glycopyrrolate for Sialorrhea

1. Glycopyrrolate should be considered the treatment of last resort
after patients have failed botulinum toxin-B. As a potent nonselective
muscarinic antagonist, it will increase risk of ileus twofold.
2. Constipation must be tracked aggressively when added to clozapine-
treated patients. Consider increasing the doses of laxative agents when
starting glycopyrrolate, or adding another class of medication if at
maximal daily doses of current agents.
3. The starting dose is 1 mg BID, and this can be advanced every 1–2
weeks based on DSFS and NHS ratings, assuming that constipation is
adequately managed.
4. The maximum daily dose is 8 mg/day.
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Summary Points
a. Sialorrhea is a highly prevalent condition that may affect nearly 90% of

clozapine-treated patients, and has medical and social consequences.
b. Orally applied anticholinergics (atropine 1% solution, ipratropium bromide
0.06% spray) are the first-line treatments due to low cost and limited systemic
absorption.
c. Botulinum toxin-B (BTX-B) injection into the parotid and submandibular glands
has proven effective for sialorrhea from numerous etiologies (e.g. medications,
neurological disorders) with six double-blind, placebo-controlled trials through
2017. It is the second-line agent of choice. BTX-B has onset within 4 days of the
injection, duration of action that lasts 3–6 months, and no systemic effects.
d. Clonidine or amisulpride can be considered if the clinician wants to avoid using
a systemic anticholinergic due to the increased ileus risk.
e. Systemic anticholinergic medications are the treatments of last resort after
patients have failed orally applied medications (atropine, ipratropium) and
botulinum toxin-B injections, due to increased ileus risk. Agents with CNS
penetration (e.g. antiparkinsonian medications, tricyclic antidepressants) should
not be used due to the adverse impact on cognition. Glycopyrrolate is the
systemic anticholinergic of choice.
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9
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188
10
QUICK CHECK
Managing Seizure
Risk and Stuttering
Introduction 190
Principles 191
A Types of Clozapine-Associated Seizure Activity 194
B Routine EEG Monitoring or Anticonvulsant Prophylaxis 194
C The Relationship of Seizures to Dose or Plasma Level 196
D New-Onset Stuttering 197
E Treatment of Seizures 197
F Clozapine and ECT 200
Summary Points 201
References 202
INTRODUCTION
While weight gain and other adverse effects can be challenging to treat, seizure
management is extremely successful to the extent that recent reviews comment that
it should never be a reason to discontinue clozapine treatment [1]. 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 types of adverse drug reactions were cited [2]. 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)
[3]. Experience during clinical trials led Novartis to include the following package
insert warning:
190
10: SEIZURE RISK AND STUTTERING
PRINCIPLES
• 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 after 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.
10
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% [4]. 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 [3]. 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% [5]. Of relevance to the debate about dose
and seizure risk, the 1994 review noted that seizures tended to occur in two patterns: at
191
low doses (< 300 mg/day) during the titration phase, and at high doses (≥ 600 mg/day)
during the maintenance phase [5]. 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.
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% [3]. 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.
Box 10.1 Ongoing Debates Regarding Clozapine and Seizure Risk [3]
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. [3]
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) [6].
192
Box 10.2 General Principles Governing Clozapine Treatment and Seizure Risk
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
inhibitor, removal of a CYP inducer, smoking cessation). Patients who
tolerate high levels without seizure activity do not require additional
measures.
6. If a seizure occurs:
a. S
cenario 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 10
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.
193
Table 10.1 Seizure types and frequency reported in literature reviews [3,7].
Wong and Delva Williams and Park
(2007) (mean rates) (2015) (range)
Generalized
• Tonic–clonic 54% 17.5–70.0%
• Myoclonic and/or atonic 28% 25–42.8%
• Tonic–clonic with other seizure types 12%
Partial 6%
• Simple 3%
• Complex 3%
A Types of Clozapine-Associated Seizure Activity
Two extensive reviews of clozapine-associated seizures are summarized in

Table 10.1 [3,7]. The most common seizure is a generalized or tonic–clonic event.
Although individual papers report a wide range of values, generalized seizures
comprise more than half of reported events. Less obvious but equally important
are myoclonic or atonic seizures. Myoclonic events without loss of consciousness
may present as jerks or tic-like movements anywhere in the body, but more
commonly in the limbs or facial region. The latter at times can be confused with
tardive dyskinesia, but clinical context will usually help clarify the situation (e.g.
occurrence during clozapine titration). Atonic attacks result in loss of muscle tone,
with individuals falling when occurring in the lower limbs. These “drop attacks”
may be mistaken for orthostasis or the consequence of sedation, but the patient will
often provide a compelling history of an event occurring without dizziness, and due
to abrupt loss of muscle tone. Absence of orthostasis can be confirmed with blood
pressure measurements. Recognition of myoclonic and atonic events is important
not only to prevent injury, but due to the possible risk of a secondary generalized
seizure. Partial seizures (simple or complex) are very uncommon, and there is only
one case report in the literature of absence seizures that occurred in a 15-year-old
patient [3].
B Routine EEG Monitoring or Anticonvulsant Prophylaxis
Although the seizure incidence is under 5%, clinical interest spurred a number of
electroencephalographic (EEG) studies in clinically asymptomatic clozapine-treated
patients, some dating back to 1978. Two important conclusions emerged from this
literature:
194
a. High rates of asymptomatic EEG abnormalities can be found in clozapine-

treated patients, and the prevalence is linearly related to the plasma clozapine
level [8–10].
b. While there is a relationship between clozapine dose/plasma level and
clozapine-related EEG abnormalities, a relationship between dose/plasma level
and occurrence of seizures is not evident [10].
The latter point is critical, as close to 70% of patients whose plasma clozapine
level is 350 ng/ml or 1070 nmol/l, the typical threshold for clinical response, will
manifest some form of EEG abnormality [10]. However, less than 5% of these patients
might have clinical evidence of seizure activity. It is for this reason that routine EEG
monitoring is not recommended: more than 95% of the asymptomatic patients
administered prophylactic anticonvulsants based solely on EEG findings will not
benefit, but may sustain adverse effects. As will be discussed below, divalproex is
the anticonvulsant of choice for clozapine-related seizures, but its use increases
the risk for neutropenia twofold [11]. Moreover, divalproex combined with clozapine
will result in additional weight gain. For patients without a seizure history an EEG
is best reserved for confirmation of an unwitnessed generalized seizure, or when a
patient presents with myoclonic or atonic events without secondary generalization.
For patients without a seizure history, anticonvulsant treatment should only be
implemented when there is clinically evident seizure activity.
Patients with a known seizure disorder can be treated with clozapine, with multiple
case reports of successful therapy [3]. The underlying seizure disorder should be
10
managed with an anticonvulsant prior to commencing clozapine, and the patient
ideally should be seizure-free. Nonetheless, there is one case report of a psychotic
patient with treatment-resistant epilepsy (including episodes of status epilepticus)
whose psychosis markedly improved on clozapine 300 mg/day without an increase
in the seizure frequency [12]. The preferred anticonvulsant is divalproex as it best
covers the spectrum of clozapine-associated seizures and has modest kinetic effects.
In large kinetic modeling studies, valproic acid was estimated to increase clozapine
levels in nonsmokers with effect size 16%, and reduce level in smokers with effect
size 22% [13]. The issues with weight gain and neutropenia have been noted, but
use of divalproex also doubles myocarditis risk, although this is only of relevance
during the first 6 weeks of clozapine treatment [14]. Nonetheless, divalproex presents
the best option for long-term treatment. As noted in Chapter 5, the anticonvulsants
phenytoin and carbamazepine lower clozapine levels by 50% and are to be avoided;
achieving therapeutic plasma clozapine levels with this kinetic effect might not be
195
possible with the dosing limit of 900 mg/day in most countries. If the patient has been
stabilized on other anticonvulsants that have limited kinetic interactions with clozapine
(e.g. lamotrigine, topiramate, gabapentin, levetiracetam) no action need be taken.
For asymptomatic patients, there is no value in routine EEG surveillance; however, a
treating neurologist might opt for periodic monitoring in select patients who have had
prior difficulty achieving seizure control.
C The Relationship of Seizures to Dose or Plasma Level
The data from the 1991 paper continue to be widely quoted as evidence that seizure
risk increases in a dose-dependent fashion, yet many fail to refer to the much lower
rates cited in the 1994 paper with a sample size four times greater. As the data in Box
10.3 illustrate, not only is the overall rate lower in the 1994 sample, but the absolute
risk in patients with no prior seizure history is 1.5% on doses ≥ 600 mg/day, compared
to 0.9% for patients on the lowest doses [5]. Based on this risk difference, the number
needed to harm for higher doses is 166, meaning that one would have to treat 166
patients with doses ≥ 600 mg/day to have one additional patient experience a seizure
compared to doses < 300 mg/day. Another finding that often escapes mention is that
the greatest risk occurs in the lower and higher dosage ranges for those with no prior
seizure history. This would imply that some degree of tolerance to the impact on seizure
threshold may develop during titration, but that higher doses may eventually exceed
this capacity in some patients. With the exception of overdose situations with levels
>> 1000 ng/ml or >> 3057 nmol/l, data from the past 25 years fail to substantiate a
robust relationship between dose or plasma level and clinically evident seizure activity
[3]. That the rates for patients at higher doses are under 2% also argues against routine
anticonvulsant prophylaxis for any patient without a prior seizure history. Moreover,
once patients have achieved steady state after a dose increase and shown no seizure
activity after weeks or months, one can be reassured that, for this patient, that plasma
level appears insufficient to induce a seizure. When a seizure occurs in a patient on a
stable dose, one must look for kinetic interactions that may have abruptly increased the
Box 10.3 Rates of Seizures by Dosing Groups During Early Clozapine Studies [4,5]
< 300 mg/day 300–599 mg/day ≥ 600 mg/day

1991 (N = 1481) 1.0% 2.7% 4.4%
1994 (N = 5629) 1.6% 0.9% 1.9%
1994 (N = 5629)* 0.9% 0.8% 1.5%
* Excluding patients with prior seizure history.
196
plasma clozapine level (e.g. addition of a cytochrome P450 [CYP] inhibitor, withdrawal of
a CYP inducer, smoking cessation, renal or hepatic failure) or other factors that lowered
the seizure threshold (e.g. alcohol or benzodiazepine withdrawal).
Although the data indicate seizures can occur during the early titration phase, the
overall rate is low in those without a seizure history (0.9%), and may not relate to
the rapidity of titration, despite manufacturer warnings to the contrary. Recent data
from two studies of rapid clozapine titration for treatment-resistant schizophrenia or
bipolar patients found no seizures among 155 inpatients [3]. In the schizophrenia trial
(n = 111), the mean dose of 409 mg/day was reached after an average of 7.1 days
[15]. Given the idiosyncratic and unpredictable nature of seizure occurrence, dosage
titrations should proceed based on other clinical considerations of tolerability and
efficacy, as it is unclear to what extent any titration schedule may impact seizure risk.
D New-Onset Stuttering
There are 18 cases of new-onset stuttering in clozapine-treated patients, with

a survey study of 654 clozapine patients in west of Ireland noting six cases, or a
prevalence slightly under 1.0% [16]. Although there is no evidence of generalized
seizure activity, and several cases specifically report normal EEGs, myoclonic jerking
has been noted in some instances, and all cases have emerged during titration or after
dose increase, a pattern commonly seen with clozapine-induced seizures. For this
reason, the authors have hypothesized about the relationship with abnormal electrical
activity, although this remains speculative, particularly where the EEG was normal 10
[16]. Dose reduction usually resolves the problem; however, when this is ineffective
or results in psychotic exacerbation, there are multiple case reports supporting the
efficacy of an anticonvulsant. Orobuccolingual dyskinesia has been present in some
cases, although typically this causes problems with articulation and not language
fluency. The approach to dyskinesia would be the same as for other patients with
tardive dyskinesia (see Chapter 13).
E Treatment of Seizures
As with many aspects of clozapine-related care, there is an absence of systematic

trials examining various initial approaches (i.e. dose reduction, dose division) or the
comparative merits of anticonvulsants. The general principles outlined in Box 10.2
represent a synthesis of recommendations that generally agree on three points:
197
a. Reduce exposure to clozapine shortly after a seizure.

b. If not occurring during titration or after a dose increase, investigate possible
causes.
c. If the patient is anticipated to require dose (and plasma levels) above that
which induced the seizure, or if a second seizure occurs, divalproex is the
preferred anticonvulsant.
As clozapine’s greatest effect on seizure threshold occurs when brain concentrations
are at their peak, some publications (and manufacturer recommendations) suggest
Table 10.2 Anticonvulsants for clozapine-related seizures.*

Supporting data Concerns
Preferred options
• Effective for generalized seizures,
is the medication of choice for
myoclonic/atonic seizures • Weight gain
• Very modest kinetic interactions • Increased neutropenia
Divalproex/ with clozapine risk, especially with higher
valproate • Can be orally loaded at 30 mg/kg serum valproate levels
over 24 hours • Thrombocytopenia
• Greatest number of published case • Hyperammonemia
reports with clozapine
• Good tolerability
• Risk of Stevens–Johnson
• Effective for generalized seizures Syndrome/toxic epidermal
and recommended for myoclonic necrolysis with rapid
epilepsy when divalproex/valproate titration
cannot be used
• Modified titration required
Lamotrigine • Good tolerability when titrated when added to divalproex/
appropriately, limited weight gain valproate due to kinetic
• No kinetic interactions with interaction
clozapine • Cannot be loaded. May
• One case report with clozapine require many weeks before
therapeutic
• No kinetic interactions with
clozapine • Not effective for myoclonic
Gabapentin
seizures
• Two case reports with clozapine
• Not effective for myoclonic
seizures
clozapine
Topiramate • May cause cognitive
• May induce weight loss
dysfunction
• Two case reports with clozapine
• Metabolic acidosis
continued overleaf
198
Table 10.2 continued
Supporting data Concerns

Medications to avoid
• Lowers plasma clozapine
levels ≥ 50%
• Lowers plasma levels of
• Report of combined use with other antipsychotics
Phenytoin clozapine (from nationwide • Not effective for myoclonic
surveillance data) seizures
• Risk of Stevens–Johnson
syndrome/toxic epidermal
necrolysis
• Lowers plasma clozapine
levels ≥ 50%
• Lowers plasma levels of
other antipsychotics
• Hyponatremia
• Report of combined use with • Risk of Stevens–Johnson
clozapine (from nationwide syndrome/toxic epidermal
Carbamazepine surveillance data) necrolysis in certain Asian
• One case report of use for groups – mandatory
clozapine-related myoclonus genotyping for HLA-B*1502
in at-risk individuals
• Rare aplastic anemia and
agranulocytosis
• Can exacerbate myoclonus
in some patients
• Higher rates of
neuropsychiatric adverse 10
effects than other
Levetiracetam clozapine
anticonvulsants
• Effective for myoclonic seizures
• No data on use with
clozapine
• Cognitive dysfunction,
• Adjunctive benefit for nonclozapine- sedation and fall risk
related myoclonic epilepsy • Potential for misuse and
Clonazepam • Multiple case reports of combined dependence
use with clozapine in patients with • No data on use with
tardive dystonia clozapine as an
anticonvulsant
* For patients who have become pregnant or are planning a pregnancy, immediate consultation
with a neurologist is necessary due to the increased risk of physical anomalies and
neurodevelopmental impairment posed by anticonvulsants [20].
199
converting QHS doses into divided dosing with the goal of reducing the CMax. This may
temporarily obviate the need for an anticonvulsant, but for patients who seize during
the titration phase at subtherapeutic plasma levels, there is a significant likelihood
that another seizure will occur as the dose is increased further. Moreover, dividing the
dose incurs greater daytime sedation, and also may decrease outpatient medication
adherence compared to QHS dosing. For these reasons, adding divalproex when patients
have a seizure during dose titration may be prudent in most circumstances.
There are no controlled anticonvulsant trials for clozapine-related seizures, yet
divalproex has emerged as the medication of choice based on several criteria noted in
Table 10.2, including its spectrum of activity that covers myoclonic seizures [3]. Due to
the association between higher serum valproate levels and neutropenia (see Chapter
6), the lowest effective dose should be used to achieve effective seizure control. If
neutropenia does occur, it can be managed with the strategies outlined in Chapter
6. The additive weight gain risk must be acknowledged and addressed as quickly as
possible using all the options mentioned in Chapter 11. There is a paucity of cases on
other agents, but lamotrigine can be considered a second-line option for this purpose
if the patient cannot tolerate divalproex. Lamotrigine must be titrated slowly to avoid
risk of Stevens–Johnson Syndrome/toxic epidermal necrolysis, and if lamotrigine is
added to existing divalproex therapy the modified titration dosing schedule must be
followed due to the inhibition of lamotrigine metabolism by divalproex.
The older agents phenytoin and carbamazepine are avoided primarily for their
significant kinetic interactions with clozapine (and numerous other medications),
and carbamazepine’s small risk of neutropenia, yet there are early case reports of
carbamazepine–clozapine combination therapy [17,18]. Levetiracetam is a frequently
used anticonvulsant in the general population due to its spectrum of activity and
absence of kinetic interactions, but this medication should be avoided in those with
severe mental illness due to the high prevalence of neuropsychiatric side effects,
combined with the absence of any case data for use with clozapine [19]. If a patient
is planning to become pregnant or a pregnancy occurs, immediate neurologist
consultation must be sought due to the risk for developmental anomalies and long-
term cognitive effects associated with anticonvulsant use [20].
F Clozapine and ECT
An estimated 40–50% of treatment-resistant schizophrenia patients may fail to

adequately respond to clozapine. As discussed in Chapter 2, one evidence-based
200
strategy is the use of adjunctive electroconvulsive therapy (ECT). The practical concern
with combined clozapine and ECT is the induction of prolonged seizures, but this was
recently addressed in a comprehensive review published in 2015 [21]. Utilizing data
from case reports and a small number of open-label trials (40 total publications),
data on 208 patients who underwent combined treatment with clozapine and ECT
was amassed. Most were adults with treatment-resistant schizophrenia spectrum
disorders to whom ECT was added to clozapine for inadequate response. Short-term
response rates varying from 37.5% to 100% were reported, with a small number of
cases documenting sustained improvement over periods ranging from 3 weeks to 24
months. Side effects were as follows: delirium n = 5, tachycardia n = 5, and prolonged
seizures n = 4 [21]. Given the large number of cases and low rates of adverse effects
the authors concluded that the combination was effective and safe, and should be
used in patients with treatment-resistant schizophrenia and inadequate clozapine
response.
Summary Points
a. The seizure incidence is much lower than most clinicians anticipate, and there
are no compelling data to support a strong association with rapidity of titration
or dose/plasma level.
b. Seizures are never a reason to discontinue clozapine treatment. 10
c. Generalized (tonic–clonic) seizures are the most common form in clozapine-
treated patients, but clinicians should be alert for myoclonic or atonic events
occurring without secondary generalization and address these in the same
manner as generalized seizures.
d. The management strategy is straightforward and depends on whether the
seizure was associated with a titration, dose increase or jump in plasma
clozapine levels, or due to other factors (e.g. alcohol or benzodiazepine
withdrawal).
e. Divalproex is the anticonvulsant of choice due to its spectrum of activity
(generalized and myoclonic seizures), preponderance of case data for clozapine-
related seizures, and modest kinetic interactions.
201
References
603–613.
3. Williams, A. M. and Park, S. H. (2015). Seizure associated with clozapine: Incidence, etiology, and
management. CNS Drugs, 29, 101–111.
4. Devinsky, O., Honigfeld, G. and Patin, J. (1991). Clozapine-related seizures. Neurology, 41,
369–371.
5. Pacia, S. V. and Devinsky, O. (1994). Clozapine-related seizures: Experience with 5,629 patients.
Neurology, 44, 2247–2249.
7. Wong, J. and Delva, N. (2007). Clozapine-induced seizures: Recognition and treatment. Canadian
Journal of Psychiatry – Revue Canadienne de Psychiatrie, 52, 457–463.
8. Spatz, R., Lorenzi, E., Kugler, J., et al. (1978). [The incidence of abnormal EEG patterns with
clozapine therapy (Author’s transl)]. Arzneimittel-Forschung, 28, 1499–1500.
9. Gunther, W., Baghai, T., Naber, D., et al. (1993). EEG alterations and seizures during treatment
with clozapine. A retrospective study of 283 patients. Pharmacopsychiatry, 26, 69–74.
10. Varma, S., Bishara, D., Besag, F. M., et al. (2011). Clozapine-related EEG changes and seizures:
Dose and plasma-level relationships. Therapeutic Advances in Psychopharmacology, 1, 47–66.
11. Malik, S., Lally, J., Ajnakina, O., et al. (2018). Sodium valproate and clozapine induced
neutropenia: A case control study using register data. Schizophrenia Research, 195, 267–273.
12. Jette Pomerleau, V., Dubeau, F. and Ducharme, S. (2017). Clozapine safety and efficacy for
interictal psychotic disorder in pharmacoresistant epilepsy. Cognitive and Behaviorla Neurology, 30,
73–76.
13. Diaz, F. J., Santoro, V., Spina, E., et al. (2008). Estimating the size of the effects of co-
medications on plasma clozapine concentrations using a model that controls for clozapine doses and
confounding variables. Pharmacopsychiatry, 41, 81–91.
14. Ronaldson, K. J., Fitzgerald, P. B., Taylor, A. J., et al. (2012). Rapid clozapine dose titration and
concomitant sodium valproate increase the risk of myocarditis with clozapine: A case-control study.
16. Murphy, R., Gallagher, A., Sharma, K., et al. (2015). Clozapine-induced stuttering: An estimate of
prevalence in the west of Ireland. Therapeutic Advances in Psychopharmacology, 5, 232–236.
17. Peacock, L. and Gerlach, J. (1994). Clozapine treatment in Denmark: Concomitant psychotropic
medication and hematologic monitoring in a system with liberal usage practices. Journal of Clinical
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10
18. Bak, T. H., Bauer, M., Schaub, R. T., et al. (1995). Myoclonus in patients treated with clozapine: A
case series. Journal of Clinical Psychiatry, 56, 418–422.
19. Chen, B., Choi, H., Hirsch, L. J., et al. (2017). Psychiatric and behavioral side effects of
antiepileptic drugs in adults with epilepsy. Epilepsy & Behavior, 76, 24–31.
20. Bromley, R., Weston, J., Adab, N., et al. (2014). Treatment for epilepsy in pregnancy:
Neurodevelopmental outcomes in the child. Cochrane Database of Systematic Reviews, 10,
Cd010236.
21. Grover, S., Hazari, N. and Kate, N. (2015). Combined use of clozapine and ECT: A review. Acta
Neuropsychiatrica, 27, 131–142.
10
203
11
QUICK CHECK
Managing Metabolic
Adverse Effects
Introduction 204
Principles 205
A Monitoring Metabolic Parameters 208
B Weight Gain 210
• Metformin 211
• Aripiprazole, Bariatric Surgery 212
C Insulin Resistance and Type 2 Diabetes Mellitus 213
D Dyslipidemia 215
E Exercise and Lifestyle Modification 216
F Smoking 218
Summary Points 219
References 220
INTRODUCTION
The primary use of clozapine is for schizophrenia spectrum patients with a

history of suicidality or treatment-resistant psychosis. Although clozapine itself
imposes significant metabolic burden, this is overlaid on the twofold higher rates
of metabolic disorders (type 2 diabetes mellitus, metabolic syndrome) and twofold
greater standardized mortality rates for cardiovascular disease in this patient
population. Multiple factors contribute to this risk profile including lifestyle (e.g.
smoking, dietary habits, sedentary behavior), metabolic effects of medications, and
biological aspects of schizophrenia itself detectable in treatment-naive patients [1].
Given clozapine’s metabolic impact, combined with the reality that patients may
remain on clozapine throughout their lives, ongoing management of cardiometabolic
risk is integral to the care of clozapine-treated individuals [2]. Despite this
confluence of medication and disease-related risk, the use of clozapine is associated
with lower mortality rates from unnatural and natural causes. Investigators
204
11: METABOLIC ADVERSE EFFECTS
11
PRINCIPLES
• Nearly all clozapine-treated patients will manifest one or more metabolic

adverse effects, with weight gain occurring very early in treatment.
• Given the high prevalence and early onset of weight gain, all patients are
candidates for the two evidence-based treatments which must be started when
clozapine is commenced: metformin and exercise (including dietary counseling).
• Laboratory monitoring of metabolic parameters can be adjusted based on
known risks for diabetes. Physical activity must be tracked as a vital sign,
along with smoking behavior.
• When they occur, diabetes and dyslipidemia are managed with usual
medications.
• Metabolic adverse effects are generally never a reason to discontinue clozapine.
compared mortality trends in 14,754 individuals with schizophrenia, schizoaffective

disorder or bipolar disorder followed in London from 2007 to 2011. There was a
significant association between clozapine use (n = 748) and lower mortality even
after controlling for confounders including clinical monitoring and disease severity
(adjusted hazard ratio 0.4; 95% CI 0.2–0.7; p = 0.001) [3]. This adds to prior data
from an 11-year Finnish study which showed that clozapine markedly reduces
suicide-related mortality, while no pronounced differences for ischemic heart disease
mortality were found between antipsychotics [4].
Nonetheless, substantial changes in cardiovascular risk are seen in long-term 11
studies, and clozapine is considered in the highest risk group among all antipsychotics
for weight gain, dyslipidemia and adverse impact on insulin resistance. Naturalistic
data for 96 clozapine-treated patients spanning 21 years of follow-up (mean duration
of clozapine use 13 years) noted elevated cardiovascular risk during the first 10
years of treatment, although there was a slight decline in risk after the first decade
[2]. This sobering reality drives home the point that management of cardiometabolic
issues is inherent to clozapine treatment, and that management strategies must be
implemented at the time clozapine is commenced. In addition to the combined impact
of the medication and the diagnosis of schizophrenia, many patients will possess one
or more nonmodifiable factors that add to risk for weight gain or insulin resistance
205
Box 11.1 Principles in Managing Metabolic Adverse Effects of Clozapine

1. Clozapine is among the highest-risk antipsychotics for metabolic
dysfunction. Nearly 100% of clozapine-exposed patients will manifest
one of the common triad of metabolic adverse effects (weight gain,
insulin resistance, dyslipidemia).
2. Nonmodifiable risk factors also contribute to increased risk for metabolic
adverse effects:
a. Weight gain: younger age, female gender, nonwhite race/ethnicity,
family history.
b. Insulin resistance: schizophrenia diagnosis, nonwhite race/ethnicity,
family history.
3. Within the range of doses commonly used for schizophrenia spectrum
disorders, there is no evidence of a dose relationship for metabolic
disorders. Dose reduction is therefore not a strategy to mitigate or treat
these issues.
4. Metformin has the greatest evidence base supporting benefit for weight
gain, and should be started concurrently with clozapine.
a. Metformin is safe with eGFR ≥ 30 ml/min, but use should be
reviewed when eGFR falls below 45 ml/min [18]. Check B12 yearly.
b. Metformin should be started at 500 mg PO qam. Higher initial doses
cause gastrointestinal adverse effects (e.g. diarrhea, nausea). Use of
extended release forms may improve tolerability.
c. To reduce side effects metformin should titrated over a 3-week period
with 500 mg qam the first week, 500 mg BID or 1000 mg XR qam
the second week, and 1000 mg BID or 2000 mg XR qam starting
week 3 if tolerated. If 2000 mg/day is not tolerated, try 1500 mg/day
(metformin 750 mg BID or 1500 mg metformin XR qam).
d. For patients with normal eGFR (e.g. ≥ 60 ml/min), yearly eGFR is
sufficient. When eGFR falls below 60 ml/min, monitor every 3–6
months. When eGFR falls below 45 ml/min the metformin dose
should be reduced by 50% and eGFR checked every 3 months.
Metformin must be stopped when eGFR is < 30 ml/min.
5. All patients must be enrolled in a structured exercise program that should
be maintained indefinitely unless the patient has shown ability to exercise
independently.
6. Dietary counseling must be offered to all patients and caregivers starting
with the beginning of clozapine therapy.
7. Routine periodic screening as noted in Table 11.3.
8. Physical activity should be tracked in the same manner as other vital
signs (Table 11.3)
9. In stable patients, smoking status must be documented routinely and
cessation medications and programs offered regularly.
206
11
during clozapine treatment. The principles outlined in Box 11.1 are thus based on the
proposition that clozapine itself is a medication with significant metabolic burden,
and that nearly 100% of clozapine-exposed patients will manifest one of the common
triad of metabolic adverse effects (weight gain, insulin resistance, dyslipidemia). While
numerous medications have been tried for clozapine-related obesity and metabolic
disturbances (topiramate, sibutramine, phenylpropanolamine, modafinil, atomoxetine,
rosiglitazone) these have not demonstrated benefit for patients on clozapine, although
there might be positive data for use with other antipsychotics [5]. Metformin has
repeatedly been proven effective for weight gain in numerous double-blind, placebo-
controlled trials, and also significantly improves three of the five components of
metabolic syndrome: waist circumference, fasting glucose and triglycerides [6]. As will
be discussed below, all patients starting clozapine should be considered candidates
for metformin at the outset of clozapine treatment, to which exercise and dietary
counseling must be added. The longitudinal management of cardiometabolic risk
represents an opportunity to integrate best practices from psychiatry, primary care
and psychology into a concerted team effort to promote lifelong healthy behaviors and
treat manageable medical conditions with the goal of keeping patients on clozapine
and forestalling major cardiovascular events. With the exception of emergencies
such as diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic states (HHS), or
out of control diabetes during which a temporary cessation of clozapine may be
helpful, metabolic adverse effects should not be a reason for discontinuing clozapine
treatment, as noted in recent reviews (Table 11.1) [7].
Table 11.1 Metabolic issues and discontinuing clozapine [7].

Complication Grounds for Comments
11
discontinuation
Try behavioral approaches,
Weight gain Almost never
metformin
Hypertension Almost never Usual management
Usual management, especially
Dyslipidemia Almost never
agents that lower triglycerides
Metabolic syndrome Almost never Treat individual components
Try usual management first and
Diabetes mellitus Out of control diabetes correct other diabetogenic causes.
Generally manageable
Diabetic ketoacidosis Hold clozapine during acute
or hyperosmolar Acute episode episode. Rechallenge after
hyperglycemic state stabilization with tight monitoring
207
A Monitoring Metabolic Parameters
The key to managing metabolic risk is routine surveillance and early diagnosis
based on the latest guidelines. The hypertension criteria in the US were significantly
modified in late 2017, and thereby identified a new cohort of individuals as
candidates for antihypertensive treatment [8]. Worldwide there are variations in the
criteria listed in Table 11.2, so clinicians should be familiar with those employed
locally, as well as recent updates. In ethnically diverse populations, appropriate BMI
cutpoints should be used as indicators for increased efforts to manage weight gain.
Although waist circumference is a criterion for the metabolic syndrome, abdominal
obesity measurements are very inaccurate in the hands of most clinicians, so many
institutions eschew this in lieu of tracking BMI, especially as BMI values in the obese
category satisfy the waist circumference criterion [9]. Similarly, fasting laboratory
values may be difficult to obtain from some outpatients, so hemoglobin A1C can also
be used to track glycemic changes and diagnose diabetes mellitus. Table 11.3 outlines
a basic approach to monitoring synthesized from published recommendations. While
most concur on obtaining weight and blood pressure measures during monthly or
bimonthly clinical visits, the frequency of fasting glucose and lipids must be tailored
to inherent risk factors for cardiometabolic disease. In an individual with multiple
diabetes risks (Box 11.2), monthly monitoring for the first 6 months of treatment is not
unreasonable. As a general rule, metabolic laboratory measures are obtained more
frequently in the first year, and adjusted based on the patient’s needs. In the small
cohort of patients on long-term clozapine treatment who manifest no cardiometabolic
issues, fasting glucose and lipids must be obtained at least yearly.
Table 11.2 Criteria for hypertension, obesity, metabolic syndrome and diabetes
mellitus.
Measures
Europid individuals Asian individuals1
Overweight 25.0–29.99 kg/m2 23.0–27.49 kg/m2
Body mass index Class I obesity 30.0–34.49 kg/m2 27.5–32.49 kg/m2
Class II obesity 35.0–39.99 kg/m2 32.5–37.49 kg/m2
Class III obesity ≥ 40.0 kg/m2 ≥ 37.5 kg/m2
Systolic Diastolic
Normal < 120 mmHg and < 80 mmHg
Adult blood pressure2 Elevated 120–129 mmHg
and < 80 mmHg
Stage I hypertension 130–139 mmHg or 80–89 mmHg
Stage II hypertension ≥ 140 mmHg or ≥ 90 mmHg
continued overleaf
208
11
Table 11.2 continued
Measures
Blood Pressure Systolic BP > 130 mmHg or diastolic BP
> 85 mmHg, or treatment of previously
diagnosed hypertension
Waist Circumference4
Europid5 Male ≥ 94 cm (37.0 in.)
Female ≥ 80 cm (31.5 in.)
Asian5 Male ≥ 90 cm (35.4 in.)
Metabolic syndrome Female ≥ 80 cm (31.5 in.)
(at least three criteria
needed for diagnosis)3 HDL < 40 mg/dl (< 1.03 mmol/l) in males,
< 50 mg/dl (< 1.29 mmol/l) in females,
or specific treatment for this lipid abnormality
Triglycerides Fasting values > 150 mg/dl (> 1.7 mmol/l),
or specific treatment for this lipid
abnormality
Glucose Fasting plasma glucose > 100 mg/dl
(> 5.6 mmol/l), or previously diagnosed type 2
diabetes
Glucose Fasting values ≥ 126 mg/dl (≥ 7.0 mmol/l).
Fasting is defined as no caloric intake for at
least 8 hours7
OR
2-hour glucose ≥ 200 mg/dl (≥ 11.1 mmol/l)
during 75 gram oral glucose tolerance test
Diabetes mellitus6 OR
In a patient with classic symptoms of
hyperglycemia or hyperglycemic crisis,
a random plasma glucose ≥ 200 mg/dl
(≥ 11.1 mmol/l)
OR
Hemoglobin A1C ≥ 6.5% (≥ 48 mmol/mol) 11
Notes:
1. The BMI values for Asian individuals are suggested cutpoints for action, and may not directly
correspond to obesity classifications for Europid individuals [47].
2. Based on the 2017 updated guideline from the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines [8].
3. Based on 2006 International Diabetes Federation criteria [1].
4. If BMI is > 30 kg/m² central obesity can be assumed and waist circumference does not need to
be measured.
5. Europid values also apply to Subsaharan Africans, Mediterranean and Middle Eastern groups.
Asian values apply to Chinese, Japanese, Korean, Malay, Filipino, Asian-Indian groups, and to
Ethnic South and Central Americans.
6. Based on the 2018 American Diabetes Association criteria (American Diabetes Association 2018
[48]).
7. In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing.
209
Table 11.3 Routine monitoring.

Measures
Monthly or every clinical visit (if less than monthly).
Body mass (Given the significant variation between examiners in waist
index circumference measurements, this can be foregone in lieu of the
more accurate weight.)
Blood pressure Monthly or every clinical visit (if less than monthly).
a. Quarterly during first year, if normal then every 6–12 months.
Consider monthly or bimonthly fasting glucose in the first 6 months
Fasting glucose if multiple DM risk factors are present.
b. If fasting values are difficult to obtain, add hemoglobin A1C
Fasting lipids Quarterly during first year, if normal then every 6–12 months.
a. Inquired at every visit and quantified.
Smoking status b. When psychiatrically stable, smoking cessation programs and
medications should be offered quarterly.
Physical activity
Inquired at every monthly visit and recorded.
vital sign (PAVS)
B Weight Gain
The most robust hypothesis for antipsychotic-associated weight gain involves

histamine H1 antagonism of hypothalamic sites that regulate food intake [10]. Weight
gain is due to impaired satiety and not any direct impact on metabolic rate – patients
simply eat more [1]. There may be an additional contribution from 5HT2C antagonism
as shown in animal models and some early studies of 5HT2C polymorphisms with
antipsychotic-related weight gain, although this association is not consistently
found [11]. There are additional hypotheses focusing on how antipsychotics impact
regulation of hormones related to appetite, adiposity and glycemic control (leptin,
adiponectin, glucagon-like peptide-1) and changes in inflammatory markers, but
this information has no direct clinical application at the present time aside from the
compelling evidence that increased exercise reduces levels of systemic inflammation
and improves the physical and psychological quality of life among the severely
mentally ill (see section below on Exercise) [12].
Weight gain estimates vary widely depending on the time frame and population,
but 60–75% of patients will gain ≥ 4.5 kg during the first year of treatment [13].
Naturalistic long-term data from an American sample noted a mean increase of
13.5 kg after 10 years, of which 4.5 kg occurred in the first 10 weeks of clozapine
210
11
treatment [14]. Demographic factors that place patients at even higher weight gain
risk include: younger age, low baseline BMI, nonwhite race, and concurrent use of
divalproex [15]. As noted previously, genetic markers that predict weight gain are
of great interest but lack robustness to be employed in routine clinical care [11]. As
weight gain is an early complication of clozapine and carries long-term health risks,
all patients starting clozapine must receive maximum combined efforts to mitigate this
problem: dietary counseling and structured exercise (see below), and the antidiabetic
agent metformin.
• Metformin is a biguanide molecule synthesized in 1922 whose glucose-lowering

Metformin
properties in animals were noted in 1929 and promptly forgotten until human studies
in 1957 [16]. Metformin’s mechanisms are not completely understood, but it results
in improved insulin sensitivity and reduced hepatic gluconeogenesis. Metformin
increases the production of glucagon-like peptide-1 (GLP-1), a hormone whose levels
may be adversely affected by clozapine, and thereby stimulates insulin release,
inhibits glucagon secretion and possibly moderates appetite [17]. Unlike sulfonylureas,
metformin has a low rate of hypoglycemia and has been used extensively in
nondiabetic patients for management of prediabetic conditions and nonalcoholic fatty
liver. Importantly, use of metformin in nondiabetics is associated with mild weight loss,
possibly related to its GLP-1 effect, and decreased triglyceride levels due to greater
insulin actions at lipoprotein lipase, the enzyme primarily responsible for hydrolyzing
triglycerides [1,17]. Metformin also reduces risk of myocardial infarction and all-cause
mortality in newly diagnosed diabetics in a manner not seen with sulfonylureas or
insulin [18]. While older biguanide antidiabetics such as phenformin had unacceptable
rates of lactic acidosis, recent guidelines indicate that metformin is safe for those with
11
eGFR levels down to 30 ml/min, although ongoing use should be reviewed when the
eGFR falls below 45 ml/min [18]. Also, check vitamin B12 levels yearly.
Metformin has been studied extensively for antipsychotic-related weight gain
and metabolic adverse effects in adults and adolescents, primarily with agents of
highest risk: olanzapine and clozapine. A 2016 review of the eight placebo-controlled
trials specifically for clozapine-treated patients found that metformin was superior
to placebo with a mean difference of –3.12 kg in weight and –1.18 kg/m2 in BMI;
metformin also significantly improved fasting glucose and triglycerides [6]. Metformin
is generally well tolerated, but gastrointestinal (GI) adverse effects (diarrhea, nausea)
211
can occur at high rates with aggressive titration. Box 11.1 provides a titration used in
clinical trials that is designed to slowly advance the dose over several weeks, thereby
lessening the risk of GI side effects. Unless eGFR is a limiting factor, all patients
starting clozapine should commence metformin concurrently for the following reasons:
(a) weight gain is a pervasive problem and occurs early in treatment; (b) metformin
confers additional benefits beyond weight gain including triglyceride reduction and a
delay in the rates of type 2 diabetes among prediabetic patients [1].
• As noted previously, numerous other medications have been studied for clozapine-
Aripiprazole, Bariatric Surgery
related obesity and weight gain (topiramate, sibutramine, phenylpropanolamine,

modafinil, atomoxetine) without significant results (although there might be data for
use with other antipsychotics); however, there are two positive trials for adjunctive
aripiprazole at doses of 5–15 mg/day [5]. Due to its mechanism of action, aripiprazole
should only be tried in patients on clozapine as antipsychotic monotherapy as there
are reports of symptomatic worsening when aripiprazole is added to nonclozapine
antipsychotics, likely due to displacement of strong D2 antagonists by the partial
agonist aripiprazole [19]. Dose adjustments are needed for cytochrome P450 (CYP)
2D6 poor metabolizers, or those on 2D6 or 3A4 inhibitors, or 3A4 inducers. The
adjunctive aripiprazole trial should be terminated for adverse effects (akathisia,
anxiety, parkinsonism) or if no benefit is seen after 12–16 weeks.
Despite the best clinical efforts many patients will struggle with weight gain,
obesity and related complications. In recent years there has been increased
enthusiasm about considering the severely mentally ill as candidates for bariatric
surgery, assuming clinical stability. Two 2017 reviews found that weight loss outcomes
among schizophrenia patients were comparable to those with bipolar disorder or no
mental illness, without significant deterioration of psychiatric symptoms [20,21]. It
should be noted that those with schizophrenia spectrum disorders did have more
postoperative emergency department visits and hospital days compared to patients
with no mental illness [20]. If a clozapine-treated patient is deemed a bariatric surgery
candidate, close monitoring of clozapine plasma levels, and the serum levels of other
medications with narrow therapeutic indices (e.g. lithium valproate), is important so
that dosage adjustments can be made to maintain preoperative drug levels.
212
11
C Insulin Resistance and Type 2 Diabetes Mellitus
There are many hypotheses surrounding antipsychotic effects on glycemic

control, with both weight and weight-independent mechanisms invoked [22].
Regardless of the etiology, clozapine is placed in the highest antipsychotic risk group
for induction of metabolic syndrome and type 2 DM. Cross-sectional US data from
3123 clozapine-treated schizophrenia patients and matched schizophrenia patients
on other antipsychotics noted that rates of DM were twofold higher on clozapine:
2.8% vs. 1.4% for standard antipsychotics (HR 1.63, 95% CI 0.98–2.70) [23]. In a
US data set covering over 20 years of clozapine exposure, 42.7% of patients were
diagnosed with DM [2]. Moreover, the prevalence of the metabolic syndrome is
estimated to be as high as 61.6% [13]. Although there was early concern about
abrupt onset of diabetic ketoacidosis (DKA) shortly after commencing clozapine,
later studies demonstrated that these patients had untreated DM, with mean A1C
of 13.3% at time of admission for DKA [24]. Pretreatment screening is thus critical
so that undiagnosed DM can be addressed prior to starting clozapine. Table 11.1
presents criteria for DM and the related metabolic syndrome. The frequency of
laboratory monitoring should be titrated to the number of traditional DM risk factors
(Box 11.2). The same interventions used to manage weight gain (metformin, dietary
advice, exercise) are also helpful in mitigating risk for DM and metabolic syndrome.
It is important to emphasize that in prediabetic individuals enrolled in the long-term
UK Diabetes Prevention Program trial, treatment with metformin resulted in modest
weight loss and favorable changes in insulin sensitivity compared to placebo, all of
which contributed to a reduction in the risk of diabetes independent from associated
reductions in fasting glucose [25].
As with weight management, a number of medications other than metformin 11
have been studied in prediabetic schizophrenia patients including pioglitazone and
the injectable GLP-1 agonist exenatide. Short-term impact on metabolic parameters
can be seen, but these agents lack the robustness of metformin’s extensive benefits
on weight and numerous metabolic and clinical parameters including mortality [26].
A 2017 meta-analysis of pharmacological and behavioral interventions for glycemic
control in severely mentally ill adults found that behavioral interventions and metformin
led to clinically important improvements in glycemic measurements [26]. (The only
213
Box 11.2 Risk Factors for Type 2 Diabetes Mellitus [48]

1. First-degree relative with diabetes
2. High-risk race/ethnicity (e.g. African descent, Latino, Native American,
Asian descent, Pacific Islander)
3. History of cardiovascular disease
4. Hypertension (≥ 140/90 mmHg or on therapy for hypertension)
5. Low HDL cholesterol (< 35 mg/dl (< 0.90 mmol/l) and/or elevated
triglyceride level > 250 mg/dl (> 2.82 mmol/l)
6. Women with polycystic ovary syndrome
7. Physical inactivity
8. Other clinical conditions associated with insulin resistance (e.g. severe
obesity, acanthosis nigricans)
other strategy that also showed benefit was antipsychotic switching, an option not
typically available to patients on clozapine.) This preference for metformin is echoed
by conclusions from a 2017 Cochrane review of newer DM medications that noted an
absence of firm evidence that GLP-1 agonists (or dipeptidyl peptidase-4 inhibitors)
substantially influence the risk of developing type 2 DM and its complications in those
at increased risk for DM [27].
Clozapine-treated individuals who develop DM should be managed with the same
protocols as other DM patients. Interestingly, a meta-analysis of 10 studies comprising
33,910 schizophrenia patients with DM showed that people with schizophrenia
adhered to their DM medications on 4.6% more days per year than those without
schizophrenia (p < 0.01, 95% CI 2.4–6.7%) [28]. The development of DM is not a
reason to stop clozapine therapy, and there is no evidence to support dose reduction
for managing glycemic control; however, during emergency situations when a patient
has acute out of control DM, or is hospitalized for DKA or HHS, it is not unreasonable
to consider temporarily holding clozapine for 24–48 hours if absolutely necessary
while the patient is acutely ill, especially if there are issues with hypotension or
mental status changes. The cholinergic rebound that can result from any abrupt
cessation in clozapine treatment must also be adequately managed. (Chapter 4
provides an extensive discussion of strategies for managing cholinergic rebound, and
considerations for antipsychotic therapy after clozapine discontinuation.) Once glycemic
control has been reestablished, the patient can be rechallenged with clozapine, albeit
214
11
with tight glucose monitoring [29]. Switching from clozapine is to be avoided given the
absence of viable treatment options for most patients requiring clozapine.
Individuals who gain weight and become insulin-resistant are also at risk of
developing nonalcoholic fatty liver disease (NAFLD). This can occur in the early years
of antipsychotic therapy, and is associated with weight gain ≥ 7% and deleterious
changes in all of the five metabolic syndrome components [30]. Of clinical relevance,
abnormalities in transaminases (AST, ALT) will insidiously develop in NAFLD patients
who otherwise appear to lack risk factors for liver disease (e.g. nondrinkers,
noncarriers of hepatitis B or C, nonusers of valproate), at times leading to misguided
speculation that clozapine itself is causing hepatotoxicity. The diagnosis of NAFLD
should be rapidly confirmed with hepatic ultrasound due to the low cost, accessibility
and high sensitivity (80%) in patients with > 30% steatosis [31]. Treatment involves
adjustment or addition of medications to manage insulin resistance, and exercise.
D Dyslipidemia
As with glycemic control, there are many hypotheses about weight and weight-
independent mechanisms by which antipsychotics induce lipid abnormalities. The
proportion of clozapine-treated patients with dyslipidemia varies greatly depending
on the duration of treatment, with a 35% prevalence quoted in the literature [13].
Not surprisingly, those lipid abnormalities most closely tied with insulin resistance
and the metabolic syndrome are seen in clozapine-treated patients, particularly
hypertriglyceridemia and low high-density lipoprotein (HDL) cholesterol levels
[1]. HDL levels are also further depressed by inactivity and smoking, stressing
the importance of modifying these behaviors to raise HDL. The initial approach to
11
managing modest levels of hypertriglyceridemia (< 500 mg/dl) involves lifestyle
modification and improving insulin sensitivity, because the enzyme primarily
responsible for hydrolyzing triglycerides (lipoprotein lipase) is responsive to the
effects of insulin. Many clinicians use drugs to reduce triglyceride levels only when
they exceed 500 mg/dl (5.65 mmol/l) and especially when values approach 1000 mg/
dl (11.30 mmol/l), as these patients are at risk for pancreatitis. The initial choice
of agents (statin, fibrate) is dictated by a variety of clinical concerns including the
type of dyslipidemia and severity. Dyslipidemia is never a reason to discontinue
clozapine, and even severe hypertriglyceridemia can be managed without the need to
temporarily hold clozapine.
215
E Exercise and Lifestyle Modification
One of the contributors to high rates of cardiovascular mortality in schizophrenia

patients is sedentary behavior [32]. Exercise is one of the few evidence-based
therapies proven to benefit patients with severe mental illness, and should be
prescribed in the same manner as metformin at the outset of clozapine treatment.
While most clinicians are familiar with the impact on cardiometabolic measures,
a 2016 meta-analysis of 29 studies (n = 1109) found that exercise programs for
schizophrenia patients were superior to control conditions for psychiatric and global
outcomes including [33]:
• Total symptom severity (n = 719: Hedges’ g = 0.39, p < 0.001)
• Positive symptoms (n = 715: Hedges’ g = 0.32, p < 0.01)
• Negative symptoms (n = 854: Hedges’ g = 0.49, p < 0.001)
• General psychopathology (n = 475: Hedges’ g = 0.27, p < 0.05)
• Quality of life (n = 770: Hedges’ g = 0.55, p < 0.001)
• Global functioning (n = 342: Hedges’ g = 0.32, p < 0.01)
• Depressive symptoms (n = 337: Hedges’ g = 0.71, p < 0.001).
The putative impact of exercise on psychiatric symptoms may relate to reductions
in systemic inflammatory markers. Systemic inflammation occurs in concert with
metabolic dysfunction and contributes to risk of cardiovascular events, but may also
have adverse CNS consequences as noted in studies of patients with major depression
or schizophrenia [34].
The first step in assessing the impact of any exercise intervention is to quantify
the extent of a patient’s activity, and recording this on a regular basis in a manner akin
to other vital signs such as weight and blood pressure. The physical activity vital sign
(PAVS) has been specifically developed for the purpose of tracking physical activity in
primary care settings, and consists of a brief two-question assessment:
1. How many days during the past week have you performed physical activity
where your heart beats faster and your breathing is harder than normal for 30
minutes or more?
2. How many days in a typical week do you perform activity such as this?
Responses are reported as a score for each item: x/y. The goal of PAVS tracking is
to ascertain if patients meet the recommended 150 minutes per week of moderate
physical activity. Investigators using the PAVS found that BMI decreased 0.91 kg/m2
216
11
for every day of moderate intensity activity during a typical week in a general adult
sample (p < 0.001) [35]. With its ease of use, the PAVS has also been studied in
schizophrenia patients [36]. To assess fitness and metabolic status, a sample of 100
schizophrenia patients (mean age 38.1 years, 64% male, 64% smokers) completed
the PAVS and other metabolic screening. Only 39% met the recommended activity
levels (mean 187 ± 36 min/week). Moreover, less-active patients had 1.67 times
greater risk for being overweight or obese, 4.65 times the risk for hypertension, and
nearly threefold higher risk for metabolic syndrome [36].
A number of exercise and lifestyle intervention programs have been tailored
for patients with severe mental illness, including the ACHIEVE [37] and STRIDE
[38] protocols. The 18-month outcome data from ACHIEVE (n = 279) noted a mean
between-group difference in weight of –3.2 kg favoring the intervention participant
(–7.0 lb, p = 0.002) (see Figure 11.1). In addition, 37.8% of the participants in the
intervention group lost 5% or more of their initial weight, as compared with 22.7%
of those in the control group (p = 0.009) [37]. The 6-month data from STRIDE noted
a –4.4 kg difference with the control group, with sustained differences 6 months
after the program ended (–2.6 kg) [38]. These interventions are designed to be
delivered by staff without specialized expertise and involve dietary advice and
exercise starting at a level appropriate for sedentary persons, with gradual increases
in duration and intensity [37]. Incentives and tracking tools for participants help
reward progress, and recent data suggest that the use of telephone or internet-
based reminders may be preferred by younger patients [39]. Although attendance at
a weekly program may be challenging for patients, the results in the STRIDE study
were achieved with participants attending on average 14.5 of 24 sessions over 6
months [38].
11
Providing dietary advice is a core component of these programs, given the
data that schizophrenia patients have poor dietary habits in addition to sedentary
lifestyle [40]. With individual support and group sessions in a Danish cohort of 54
schizophrenia patients, consumption of fast food was reduced from 1.2 to 0.8 times
per week (p = 0.016), and consumption of soft drinks was reduced from 0.7 to
0.1 liters/day (p = 0.006) [41]. Dietary guidance should begin as early as possible
in treatment as much of the weight gain occurs in the first months of clozapine
treatment. Just as no patient should be deprived of metformin, exercise and related
dietary counseling also confer pleiotropic benefits and must be considered standard of
care for patients commencing clozapine therapy.
217
Figure 11.1. Weight loss during randomized behavioral intervention.
0
Weight Change (kg)
Control
–1
–2
–3
Intervention
–4
0 6 12 18
Months Since Randomization
(Adapted from: Daumit, G. L., Dickerson, F. B., Wang, N. Y., et al. (2013). A behavioral
weight-loss intervention in persons with serious mental illness. New England Journal of
Medicine, 368, 1594–1602 [37].)
F Smoking
Genetic and neuroimaging studies indicate that high rates of smoking and other
substance use disorders likely relate to the neurobiology of schizophrenia itself, and
are not a consequence of treatment [42]. Unfortunately, prospective data (up to 16.9
years of follow-up) show that smoking increases mortality rates more than sixfold
in patients with schizophrenia or bipolar disorder [43]. While smoking cessation is
more difficult for patients with severe mental illnesses, smoking can and should be
addressed, with compelling data for the safety and efficacy of bupropion [44] and also
the nicotine partial agonist varenicline [45]. The leading experts suggest that smokers
with schizophrenia spectrum disorders should not only be encouraged to quit smoking
218
11
but should also receive varenicline, bupropion with or without nicotine replacement
therapy (NRT), or NRT, all in combination with behavioral treatment for at least 12
weeks for the optimal chance at successful smoking cessation [46]. Discussions
about smoking cessation are best commenced when patients are clinically stable and
ready to tackle this issue, and are also on stable clozapine doses because changes in
plasma clozapine levels must be monitored once the cytochrome P450 1A2-inducing
properties of aryl hydrocarbons in smoke are removed. Like the PAVS, smoking should
be quantified and tracked along with other vital signs, and cessation discussed during
clinical encounters. While a patient may decline smoking cessation for years, he or she
may suddenly change their mind due to rising costs or health reasons, hence the need
for regular communication about this issue. It must be emphasized that switching
to an electronic cigarette (i.e. vaping) might be considered to decrease exposure to
harmful chemicals in cigarette smoke. While the health benefits of e-cigarettes are
not yet proven, by not burning the tobacco leaf patients will lose exposure to the aryl
hydrocarbons that induce cytochrome P450 (CYP) 1A2. Nicotine itself plays no role in
CYP 1A2 induction. After switching to the e-cigarette, a patient will lose their CYP 1A2
induction over the next week, and clozapine levels may rise 50% or more [49]. For
those who switch completely to an e-cigarette, close monitoring of plasma clozapine
levels is important.
Summary Points
a. Weight gain is a highly prevalent condition and starts early in treatment. All
patients are candidates for metformin and exercise/dietary counseling when
clozapine therapy is commenced.
b. Aside from metformin, there are limited data supporting other adjunctive
11
medications to mitigate weight gain and metabolic adverse effects, with the
possible exception of aripiprazole for weight parameters. Metformin has robust
data for reducing weight gain, improving indices of insulin resistance, delaying
onset of type 2 diabetes mellitus, and reducing rates of cardiovascular events
and mortality. Patients on metformin should have vitamin B12 levels checked
yearly.
c. The physical activity vital sign (PAVS) and smoking behavior must be tracked
along with weight, BMI and metabolic laboratory measures.
219
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12
Fever, Myocarditis,
Interstitial Nephritis,
DRESS, Serositis
and Cardiomyopathy
QUICK CHECK
Introduction 224
Principles 225
A Fever 226
B Myocarditis 228
C Interstitial Nephritis 232
D Drug Reaction with Eosinophilia and Systemic
Symptoms (DRESS) 234
E Serositis 235
F Cardiomyopathy 236
Summary Points 239
References 240
INTRODUCTION
Managing clozapine-treated patients requires clinicians to become familiar with

specific medical concerns not typically seen with other antipsychotics. Among the
many unique adverse events associated with clozapine treatment is a constellation of
fever and immune-mediated pathologies including myocarditis, interstitial nephritis,
serositis and drug reaction with eosinophilia and systemic symptoms (DRESS) [1].
While the onset of fever during the first weeks of clozapine treatment is a common
and often benign occurrence, swift action is necessary with the goal of recognizing
and addressing more serious issues or minimizing a treatment interruption when
evidence for systemic problems is lacking. The latter concept is important, as fever
during the first weeks of therapy may appear in approximately 20% of patients, and
therefore is not a reason to permanently discontinue clozapine treatment when there
is no evidence for myocarditis, interstitial nephritis, or other systemic drug reactions.
Cardiomyopathy is another unusual clozapine-related syndrome that is typically a
224
12: FEVER, MYOCARDITIS, NEPHRITIS, DRESS
12
PRINCIPLES
• Onset of fever occurs in 20% of patients during the first 8 weeks of treatment,
and commonly occurs without evidence of drug reaction, interstitial
nephritis or myocarditis. In addition to routine fever work-up, troponin I/T
levels, C-reactive protein (CRP), BUN/creatinine and urinalysis will help
rule out myocarditis and interstitial nephritis. Benign fever is not a reason
to permanently discontinue clozapine treatment, although it may be held
temporarily during the fever work-up.
• Myocarditis occurs in up to 3.0% of patients, but is fatal if not recognized
and clozapine discontinued. Onset is during the first 6 weeks (with rare
exceptions), and should be considered in a patient experiencing fever
without cause, or when a patient complains of malaise or flu-like symptoms,
(particularly chest pain) without fever. Twenty per cent of cases may not
experience fever.
• The troponin I/T level will be more than two times the upper limit of normal
in over 90% of myocarditis cases. However, 7% of cases with left ventricular
impairment by echocardiography will not have abnormal troponin levels, but
will have CRP > 100 mg/l. Both troponin and CRP should be ordered when
myocarditis is suspected. Other laboratory tests (e.g. eosinophil count) and
ECG are less sensitive and less specific.
• Interstitial nephritis, serositis and drug reaction with eosinophilia and
systemic symptoms (DRESS) are less common than myocarditis, but should
also be suspected during the first 60 days of clozapine treatment when fever
occurs without cause, or in patients reporting malaise or flu-like symptoms.
• Cardiomyopathy is an adverse effect occurring after many months or years
of clozapine treatment. It should be suspected when patients complain of
feeling tired (without recent medication changes), leg swelling, palpitations or 12
shortness of breath.
later development, but presents a distinct group of clinical and ethical challenges
when clozapine withdrawal fails to induce meaningful improvements in left ventricular
ejection fraction (LVEF). Through a greater understanding of the time course and
phenomenology of fever, myocarditis, interstitial nephritis, serositis, DRESS and
cardiomyopathy clinicians can make evidence-based decisions about withholding
clozapine treatment, and when resumption or rechallenge appears feasible.
225
A Fever
Fever can occur as a consequence of numerous medication- and

nonmedication-related disorders, but the incidence of drug-related fever is
substantially higher with clozapine than with other antipsychotics [2]. Rates as high
as 55% are reported for clozapine, but the incidence of fever depends heavily on
the temperature threshold of the particular study. When a temperature ≥ 37.5°C
was used to define fever in one study the rate was 44%, but was only 19% with a
threshold ≥ 38°C (Figure 12.1). As noted in Table 12.1, when fever is defined as a
temperature ≥ 38°C, the incidence in multiple retrospective studies ranges from
14% to 20%, consistent with an early figure of 15.2% from 1983 [2]. As with many
of clozapine’s unusual properties, the mechanism is unknown, but the leading
hypothesis, based on animal models, rests on altered cytokine levels [3]. The mean
time to onset is approximately 2 weeks after starting clozapine and nearly all
Figure 12.1. Incidence of clozapine-associated fever by temperature threshold.

50
40
Male
30 Female
Incidence (%)
Total
20
10
37.0 37.5 38.0 38.5 39.0 39.5 40.0 40.5

Temperature Threshold (°C)
(Adapted from: Jeong, S. H., Ahn, Y. M., Koo, Y. J., et al. (2002). The characteristics of
clozapine-induced fever. Schizophrenia Research, 56, 191–193 [4].)
226
12
Table 12.1 Summary of detailed case series of clozapine-related fever.
Study N Mean age Fever % Mean time Mean Mean max.
(SD) definition with to onset of fever temp (SD)
fever fever (SD) duration
(SD)
3.8 ± 2.6
Tham 13.8 ± 5.1
days
and 33.9 ± 9.0 ≥ 38°C days
93 20.4 (range 39.1 ± 0.74°C
Dickson years (tympanic) (range
1–12
2002 [5] 3–26 days)
days)
67% had
Jeong et median
33.4 ± 11.2 ≥ 37.5°C 3.1 ± 3.1
al., 2002 98 43.8 1
time to ??
years (axillary) days
[4] onset of 11
days
4.7 ± 3.0
Pui-yin 13.7 ± 7.1
days
Chung et 39.0 ± 12.2 ≥ 38°C days
227 13.72 (range 38.8 ± 0.5°C
al., 2008 years (tympanic) (range
1–12
[3] 5–47 days)
days)
Comments
1.
When the temperature threshold of 38°C was used, the rate was 19.4%.
2.
The incidence of all cases of fever was 18.1%, but 20% had identifiable nonclozapine-related
causes of fever (pneumonia, influenza, postoperative fever, neuroleptic malignant syndrome
from concurrent typical antipsychotic)
cases present in the first 6 weeks of treatment, with mean duration of the febrile
episode 4.5 days (range of 1–12 days) [3–5]. Due to concerns about neutropenia-
related infection, myocarditis, interstitial nephritis, and other drug reactions, an
etiology must be sought in all cases of fever presenting during the first 2 months
of clozapine treatment, but in 80% of instances no identifiable cause will be found
[3]. Importantly, a 1-year retrospective study of patients experiencing benign fever
during early clozapine treatment showed no evidence for unusual patterns of
intolerability (e.g. neutropenia), with all patients able to continue clozapine during
the first year of treatment [5].
12
Nonetheless, before concluding that any fever presenting during the first 2
months of clozapine exposure is benign, clinicians must exclude serious and
potentially life-threatening conditions, and this evaluation is best performed in an
emergency room setting where STAT test results and multiple test modalities are
available. This sense of urgency will impact the care of < 20% of new clozapine
starts, but the breadth of the approach outlined in Box 12.1 can often be performed
in < 12 hours, and will help identify less-common syndromes (interstitial nephritis,
DRESS and serositis) that might otherwise go overlooked when bacterial infection or
myocarditis are not found.
227
Box 12.1 General Principles for the Approach to Fever

1. Any fever (temperature ≥ 38°C) emerging in the first 8 weeks of clozapine
treatment should be evaluated immediately, as this is the period of
greatest risk period for myocarditis (first 6 weeks), and for interstitial
nephritis (first 8 weeks).
a. The patient must be evaluated in an emergency department setting where
a physical examination can be performed, and a complete blood count,
chemistry panel (including liver function tests, amylase, BUN/creatinine,
urinalysis, troponin I or T, and C-reactive protein) can be obtained in a
timely manner. Additional tests (e.g. chest X-ray, blood and urine cultures,
etc.) will often be performed as part of a routine fever work-up.
b. Confirmatory studies such as echocardiography (myocarditis,
pericarditis) or renal biopsy (interstitial nephritis) will be performed
based on evidence from the symptoms, physical examination, and
relevant abnormal laboratory findings.
c. DRESS and serositis are diagnosed based primarily on history of new
medication exposure, symptoms, physical examination, complete
blood count and chemistry panel results.
d. Clozapine should be held during the fever work-up. If more than
24 hours might elapse before resumption, coverage for cholinergic
rebound will be necessary for patients on doses > 50 mg/day (see
Chapter 4). If clozapine is held > 48 hours, retitration will be necessary.
2. The work-up when a fever occurs after more extended clozapine
treatment (i.e. ≥ 90 days) should focus on common sources of infection
(bacterial and viral) and evidence for severe neutropenia.
a. The need for a physical examination and any testing beyond a
complete blood count to rule out neutropenia will be determined
based on usual clinical criteria (i.e. history, symptoms).
b. Clozapine need not be held unless results confirm severe
neutropenia.
B Myocarditis
The association between clozapine exposure and severe neutropenia was

recognized in the mid-1970s and resulted in mandatory hematologic monitoring, but
myocarditis is equally prevalent, and also presents a risk for fatal outcomes if not
recognized. As with fever, the hypothesized mechanism is a hypersensitivity reaction
involving increased cytokine levels, with eosinophilic infiltrates found in myocardial
specimens during autopsy [6]. Although early case reports date back to 1980 [7], little
attention was given to sporadic cases of sudden death after commencing clozapine
until a 1999 review of 15 Australian cases appeared in Lancet [8]. This resulted in a
228
12
warning added to the Novartis Australia Clozaril® package insert in December 1999,
and created further interest in characterizing the phenomenon. There is little debate
regarding the association between clozapine initiation and myocarditis, with the
only question being the incidence of this condition. A range of values from 0.1% to
3.0% are quoted in the literature, with the higher figure provided by investigators in
Australia who have led the way in analyzing local cases, and argue that the increased
scrutiny within the country likely captures cases overlooked in other areas [6]. Another
hypothesis, although untested, is that the Australian population might possess an
enriched pool of certain genetic risks that increase myocarditis risk in a manner
seen with neutropenia [9]. Until comparable analyses emerge from other localities,
clinicians must proceed under the assumption that myocarditis is at least as common
as severe neutropenia, so vigilance is required during the risk period.
Figure 12.2 presents the clinical features and laboratory tests that can help
distinguish myocarditis cases from clozapine-treated controls without myocarditis.
Detailed case-control analyses have pointed to an elevation in the level of the muscle
Figure 12.2. Features of 75 myocarditis cases compared to matched clozapine-

treated controls.
100
Cases Controls
80
60
Percent
40
20
12
0
°C
in
PM
LN
l
g/
i
H
Pa
/m
38
m
m
U
B
20
m
2x
0
st
0
r≥
10
12
he
00
>
≥
ve
>
R
C
≥
<1
in
Fe
P
R
on
R
P
C
SB
op
Tr
(Adapted from: Ronaldson, K. J., Fitzgerald, P. B., Taylor, A. J., et al. (2011). A new
monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases
and 94 controls. Australian & New Zealand Journal of Psychiatry, 45, 458–465 [30].)
229
proteins troponin I or troponin T more than 2 times the upper limit of normal (ULN) or
marked elevations of C-reactive protein (an acute-phase protein) as the initial tests of
choice. Eosinophil counts are not predictive as these counts may peak up to 8 days after
maximal troponin levels are recorded [6]. There are rare cases in which neither fever nor
threshold elevations in troponin or CRP levels are present, yet the patient manifests other
criteria of ventricular injury such as chest pain or a drop in cardiac output with systolic
pressure falling below 100 mmHg. As with many of the hypersensitivity syndromes (e.g.
interstitial nephritis, serositis), there may be respiratory, gastrointestinal or urinary tract
complaints without evidence for infection. Although the presence of fever or systemic
symptoms in the first 8 weeks of a clozapine trial should prompt the addition of troponin
I or T and CRP to the battery of tests, echocardiography is recommended when other
clinical data suggest myocarditis as a possibility, and certainly to confirm the degree
of ventricular dysfunction once diagnosed. As is noted in Box 12.3, given the ease of
laboratory monitoring using troponin and CRP, the addition of these tests to routine
weekly blood counts for the first 6 weeks of treatment is both feasible and cost-effective.
Figure 12.3. Time to onset of myocarditis in 75 Australian cases.

35
30
25
Number of Patients
20
15
10
0
10–13 14–17 18–21 22–25 26–29 30–33
Duration of Clozapine Treatment (Days)
(Adapted from: Ronaldson, K. J., Fitzgerald, P. B., Taylor, A. J., et al. (2011). A new
monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases
and 94 controls. Australian & New Zealand Journal of Psychiatry, 45, 458–465 [30].)
230
12
The onset in nearly all recently reported cases is in the first 5 weeks of clozapine
treatment (Figure 12.3), but there is one reported case occurring on day 42, so the
risk period is best thought of as the first 6 weeks of clozapine treatment. An analysis
of 105 Australian cases found that a group of three factors accounted for up to 50% of
the risk variance in that population. One of these, older age (especially ≥ 50 years old)
is not modifiable, but rapid clozapine titration and the use of divalproex/valproate both
increased risk (Box 12.2) [10]. As noted in other sections, there are other tolerability
reasons to avoid rapid titration and the adverse effects of divalproex when possible.
Box 12.2 Essential Myocarditis Facts

1. The largest case-control series from Australia (n = 105) noted that all
cases occurred by day 33, and 83% presented in the window of days
14–21. At least one case exists of onset on day 42, so the period of
risk for myocarditis should be considered the first 6 weeks of treatment.
2. Eosinophil counts and EKG changes are neither sensitive nor specific
enough to be diagnostic.
3. Among laboratory measures, an elevation of troponin I or T ≥ 2 times the
upper limit of normal (ULN) is seen in nearly 90% of cases. In verified
myocarditis cases where troponin levels were < 2× ULN, a C-reactive
protein (CRP) level > 100 mg/l was found.
4. There are rare cases where troponin and CRP may fall short of these
thresholds. Echocardiography must be obtained when there is suspicion
of myocarditis based on clinical complaints occurring in the first 6
weeks of clozapine treatment (e.g. chest pain, drop in systolic blood
pressure below 100 mmHg), and to confirm the extent of left ventricular
dysfunction in those who meet criteria based on troponin or CRP levels.
5. Clozapine must be held during the work-up and discontinued
immediately when the diagnosis is confirmed. Supportive treatment and
continuous monitoring in an intensive care unit will be necessary. When
promptly recognized, the prognosis is excellent with expectation of
complete recovery of left ventricular function.
12
6. Among the modifiable factors, myocarditis risk increases by 26% for
each 250 mg of cumulative clozapine exposure in the first 9 days of
treatment, and concomitant divalproex/valproate use more than doubles
risk (OR = 2.59; 95% CI 1.51–4.42). Age ≥ 50 years also doubles risk
after controlling for other variables.
Once an individual has recovered from myocarditis, one is faced with the same
dilemmas as the severe neutropenia patient: whether there is a need to rechallenge
the patient if nonclozapine therapies prove woefully inadequate. Given the presumed
immune-mediated mechanism, the concern is that myocarditis will recur, but perhaps
231
with greater severity and decreased time to onset. A 2012 paper summarized the
existing data and noted that in eight of 13 cases the rechallenge was successful.
Among the unsuccessful challenges one patient had clozapine treatment terminated
due to fever and EKG changes but without troponin elevation, and several cases had
no troponin levels obtained, but had fever, systemic signs, tachycardia ≥ 130 BPM,
hypotension (n = 2) and CRP levels > 100 mg/l occurring after only 1–7 doses [11]. As
of 2018, there are 17 cases, of which 11 had successful rechallenges [12]. No obvious
factor predicted successful rechallenge, but consultation with a cardiologist, diligent
daily monitoring of temperature and blood pressure, and slow titration seem prudent
as the time to recurrence tends to be quite swift when myocarditis occurs.
C Interstitial Nephritis
Although clozapine-related myocarditis was increasingly recognized in the 1980s,

culminating with the 1999 review paper, the first case of acute interstitial nephritis
with a strong causal relationship to clozapine initiation did not emerge until 1999
[13]. This underrecognition of interstitial nephritis is not surprising, as the sum total
of the world’s published literature amounts to 18 cases (Table 12.2), compared to
250 myocarditis cases covered in a comprehensive 2017 review [6]. The overlap in
presenting features with myocarditis is quite significant: the majority of cases occur
within weeks of starting clozapine, fever occurs in 80% of cases, and there may be
Table 12.2 Summary of interstitial nephritis cases.

Study Age and Time to Fever Proteinuria Rash
gender onset
Elias et al., 1999 [13] 38 F 11 days No Unknown No
Fraser and Jibani 2000 [16]* 49 M 10 days Yes ?? No
Southall 2000 [31] 24 F 8 days Yes Yes No
Estebanez et al., 2002 [14] 69 M ≤ 90 days No Yes No
Au et al., 2004 [32] 33 M 14 days Yes Yes No
Hunter et al., 2009 [17] 57 F 2 days Yes Yes No
Kanofsky et al., 2011 [33] 28 M 6 days Yes Yes No
An et al., 2013 [34] 38 M 14 days Yes Yes No
Mohan et al., 2013 [15] 53 F 60 days Yes Yes No
Parekh et al., 2014 [35] 54 M 60 days Yes Yes No
Chan et al., 2015 [36] 29 F 26 days Yes Yes No
*
These authors noted that seven cases of acute renal failure related to clozapine
were reported to the UK Committee on the Safety of Medicines between
December 1989 and February 2009. Fever was documented in three. One patient
died, one remained dialysis-dependent, three recovered renal function, and
232 outcomes in two were unknown.
12
systemic complaints. There is one case report in which a patient was not diagnosed
until 90 days after commencing clozapine, but there is strong suspicion that symptoms
were overlooked prior to the obvious presentation of acute renal failure [14]. The
presence of two cases diagnosed 60 days from clozapine initiation establishes the
period of risk at 8 weeks, slightly longer than that for myocarditis. The initial laboratory
abnormalities can be detected with a urinalysis demonstrating proteinuria (and
possibly red blood cells), often accompanied by significant decreases in estimated
glomerular filtration rate (eGFR) as calculated from the serum creatinine [15]. As is
noted in Box 12.3, given the ease of laboratory monitoring using serum creatinine the
addition of this test to routine weekly blood counts for the first 8 weeks of treatment
is both feasible and cost-effective. Importantly, both creatinine and urinalysis must
be included in the work-up of any febrile episode presenting in the first 8 weeks of
clozapine treatment. The definitive confirmation will come from renal biopsy, but the
time course after starting clozapine, combined with the clinical features, abnormal
urinalysis and declining renal function should identify all cases of interstitial nephritis.
Box 12.3 Routine Laboratory Monitoring for Myocarditis and Interstitial

Nephritis
1. The greatest period of risk for myocarditis is the first 6 weeks of
treatment. A baseline troponin I/T and CRP prior to starting clozapine
is feasible and cost-effective. Recommendations for baseline
echocardiography in all clozapine-treated patients in the absence of
clinical manifestations of cardiac dysfunction have not seen widespread
adoption. The addition of routine troponin I/T and CRP to weekly CBC for
the first 6 weeks of treatment is feasible and cost-effective.
2. The greatest period of risk for interstitial nephritis is the first 2 months of
treatment. The addition of serum creatinine weekly for the first 8 weeks of
treatment is feasible and cost-effective.
Rechallenging patients with a prior episode of interstitial nephritis involves the 12

same concerns as for a prior episode of myocarditis: that this immune-mediated
problem will reoccur and more quickly than with the first episode. There are only two
papers that report outcomes in patients with a prior episode of interstitial nephritis.
In one case, the patient developed nephritis within 2 days of resuming clozapine, and
in the second case within 4 days despite the fact that the prior clozapine trial was 4
years earlier [16,17]. Unlike myocarditis, the absence of any successful rechallenges
in the literature poses concerns for any attempts [12].
233
D Drug Reaction with Eosinophilia and Systemic

Symptoms (DRESS)
This is but one of a group of severe cutaneous adverse reactions (SCARs) that
includes Stevens–Johnson syndrome/toxic epidermal necrolysis and acute generalized
exanthematous pustulosis [18]. Although these disorders possess overlapping features,
there are significant differences in prognosis and approach to the extent that a European
consensus group created criteria for each SCAR and a registry (RegiSCAR). DRESS is an
immune-mediated drug reaction resulting from T-cell stimulation that causes eosinophil
activation and end-organ cytotoxicity (e.g. pancreatitis, hepatitis, nephritis, myocarditis).
Although the general population incidence is 0.4 cases per 100,0000, the mortality rate
can be as high as 10%, hence the need for early recognition [19]. While the incidence
of eosinophilia (defined as an eosinophil count > 700/mm3) was 1% in early clozapine
clinical trials, this is but one component of DRESS criteria (Table 12.3) [18]. The onset
is typically 2–6 weeks after drug initiation, and the variable manifestations may
delay diagnosis when rash is absent. The pleiotropic presentation and high mortality
rate appear daunting, yet this is an exceedingly rare adverse effect of clozapine
treatment, with only five known cases [19–21]. The anticonvulsants divalproex (n = 7),
carbamazepine (n = 33) and lamotrigine (n = 17) are reported more frequently as
causes of DRESS in psychiatric patients [22]. Moreover, DRESS patients appear clinically
ill, often with fever, rash, and a variety of somatic symptoms that demand attention.
A 2016 review of all published psychotropic-related DRESS cases (n = 55) noted that
fever was the most common symptom (n = 38), followed by maculopapular rash (n =
32), elevated liver enzymes (n = 32), lymphadenopathy (n = 22), facial edema (n = 16),
and eosinophilia (n = 16) [22]. Using the RegiSCAR scoring system a “definite case”
is defined by a total score ≥ 5 [18]. Immediate cessation of clozapine and supportive
treatment in an intensive care unit are necessary, including use of corticosteroids and
other immune modulators [23]. Measures to mitigate cholinergic rebound, and provision
of appropriate antipsychotic therapy must also be instituted. (Chapter 4 provides an
extensive discussion of strategies for managing cholinergic rebound, and considerations
for antipsychotic therapy after clozapine discontinuation.) No specific surveillance
measures need be taken, but the existence of these cases reinforces the need to obtain
a physical examination and a set of basic laboratory measures when fever presents
during the early 6–8 weeks of clozapine treatment. These patients are not candidates
for rechallenge.
234
12
E Serositis
As part of a generalized immune-mediated reaction to clozapine, there are

reports of serosal involvement (22 cases), including pericarditis, pleuritis, colitis, or
polyserositis [24]. Many of the reported cases were also diagnosed with myocarditis,
while others would likely meet the RegiSCAR criteria for probable or definite DRESS
based on descriptions. The onset is typically during the early titration (range 8–70
days), although there are some late reports (e.g. 1–9 years) that might relate to other
factors [24]. While cases have been described without organ involvement (e.g. isolated
pericarditis without myocarditis), rather than considering this as a separate disorder,
serositis should be evaluated as a possible manifestation of a DRESS-like syndrome.
Table 12.3 RegisCAR DRESS criteria [18].

Score −1 0 1 2
1. Fever ≥ 38.5°C No/Unk Yes
2. Enlarged lymph nodes No/Unk Yes
3. Eosinophilia
700–1499/ ≥ 1500/mm3
– Eosinophil count
mm3
– Eosinophil proportion if 10–19.9% ≥ 20%
leukocytes < 4000/mm3
4. Atypical lymphocytes No/Unk Yes
5. Skin involvement
– Skin rash extent (% body
surface area) No/Unk > 50%
– Skin rash suggesting DRESS No Unk Yes
– Biopsy suggesting DRESS No Yes/Unk
6. Organ involvement (after
excluding other etiologies)1
– Liver No/Unk Yes
– Renal No/Unk Yes 12
– Skeletal muscle/heart No/Unk Yes
– Pancreas No/Unk Yes
– Other No/Unk Yes
Final score2 _____ points
Unk, unknown or not recorded.
1. Organ involvement scoring: 1 point = one organ; 2 points = two or more organs.
2. Final score interpretation: < 2: no case; 2–3: possible case; 4–5: probable case; ≥ 5:
definite case.
235
The clinical point to appreciate is that most of these patients report flu-like symptoms,
accompanied by fever and complaints related to the organ involved. In general, fever
occurring in the first 2 months of clozapine treatment demands evaluation, but the
presence of systemic complaints, including vague comments about malaise or flu-
like symptoms, should raise red flags concerning more serious immune-mediated
reactions. The serosal inflammation resolved in all reported cases after clozapine was
discontinued, with two patients experiencing recurrence upon rechallenge [24]. There
is one case report of a patient with pericarditis but no other organ involvement that was
successfully rechallenged, perhaps suggesting that the other rechallenge failures may
have been in patients who met one or more DRESS criteria [12].
F Cardiomyopathy
Cardiomyopathy is dissimilar to the other adverse effects described in this chapter,

as it is neither an early phenomenon during clozapine treatment, nor does it have
an obvious immune-mediated etiology. Although hypotheses previously focused
on cardiomyopathy as a consequence of undetected myocarditis, this has been
documented in only a few instances. More likely explanations include untreated
tachycardia, clozapine-mediated depletion of intracellular selenium, unknown direct
myocardial effects of clozapine and contributions from cardiometabolic disorders
that predispose to heart disease (e.g. disease, hypertension), and smoking [6]. That
clozapine might have a myocardial effect in some is supported by a study of 100
schizophrenia patients with no known prior heart disease history who had been
on clozapine > 1 year. While 27% of the clozapine cohort had LVEF values in the
impaired range (< 55%) by echocardiography, none of the schizophrenia patients
on nonclozapine antipsychotics > 1 year (n = 21) and healthy controls (n = 20) had
impaired LVEF [25]. Supporting the multihit hypothesis, impaired LV function in the
clozapine cohort was associated with metabolic syndrome criteria, elevated heart rate,
smoking and elevated neutrophil count.
The most common presentation is dilated cardiomyopathy, diagnosed when
LVEF is < 50% by echocardiography, or when the patient becomes symptomatic
with symptoms of congestive heart failure such as new-onset tiredness, peripheral
edema, orthopnea or exertional dyspnea. In the latter instances, LVEF values might
be significantly under 40% at the time of clinical presentation [6]. Some cases are
only diagnosed at autopsy after the patient has experienced sudden cardiac death
236
12
[26]. Less common is hypertrophic cardiomyopathy, in which LVEF is preserved but
the thickened ventricle becomes increasingly stiff and noncompliant [6]. The onset is
insidious, and the duration of clozapine treatment is typically 1 or more years in most
studies, with a range in larger samples from 8 months to 5.5 years. The prevalence
ranges from 0% to 12% depending on the sample size and whether patients were
identified due to symptomatic disease or through dedicated echocardiographic
screening. No study with a sample size ≥ 40 has reported a rate above 5%. The
prevalence is low enough that routine echocardiographic screening is not cost-
effective based on results of an Australian surveillance program [27]. There is no
basis for the use of routine troponin or CRP levels to predict cardiomyopathy, and it is
unknown whether certain genetic polymorphisms increase risk.
As routine echocardiograms are not cost-effective, clinicians must be alert to
any signs or symptoms suggestive of heart failure so that appropriate diagnostic
measures are ordered and treatment can begin. New complaints of tiredness without
obvious medication changes, leg swelling, palpitations or shortness of breath
should prompt further investigation, particularly when other cardiomyopathy risks
are present. Echocardiography is definitive and provides an estimate of LVEF. Given
the possible direct effect of clozapine itself in susceptible individuals, tapering off
clozapine is recommended along with introduction of standard therapy involving salt
restriction, angiotensin-converting enzyme inhibitors or angiotensin II receptor type-1
antagonists, diuretics, beta-adrenergic blockers and neprilysin inhibitors. The degree
of improvement after clozapine cessation is widely variable and must be documented
by ongoing measurements of LVEF.
Unlike myocarditis, nephritis or DRESS, cardiomyopathy is not an acute emergency
requiring abrupt discontinuation of clozapine treatment. This allows time to start
standard medical therapy while engaging in discussions with the patient, family and
caregivers about the diagnosis and the need to ascertain to what extent LVEF can
improve off clozapine and with medical therapy. Psychiatrically stable patients with 12
a history of treatment-resistant schizophrenia might value remaining on clozapine
with a degree of mental clarity (despite the foreshortened lifespan) over the prospect
of unremitting psychosis irrespective of the improved LVEF. Helpful to this discussion
is evidence from three cases in which standard cardiomyopathy treatment was
implemented and the patients rechallenged successfully with clozapine. Not only did
clozapine not induce further deterioration in cardiac function, there was evidence of
gradual improvement in LVEF [6]. A treatment plan can therefore be devised in which
237
clozapine is gradually withdrawn, standard cardiomyopathy treatment provided, and

heroic attempts made with nonclozapine antipsychotics to manage the mental illness
(e.g. high-dose olanzapine). Should the latter prove fruitless, the patient would be
rechallenged with clozapine under close cardiology supervision [12]. An assessment
of decision-making capacity and involvement of ethicists can be useful in permitting
a patient to remain on clozapine after rechallenge, irrespective of their cardiac status,
due to the failure of nonclozapine treatments. Higher functioning schizophrenia
patients with excellent psychosocial support might be considered candidates for
heart transplantation, the only treatment option with Stage D heart failure (defined as
advanced disease requiring hospital-based support, heart transplantation or palliative
care). Such decisions require close evaluation, but there are two published cases of
successful cardiac transplantation in patients with schizophrenia [28,29].
Box 12.4 Considerations in Cases of Clozapine-Related Cardiomyopathy

1. Suspect when patients complain of feeling tired (without obvious
medication changes), leg swelling, palpitations or shortness of breath.
2. All patients should receive standard therapy involving salt restriction,
angiotensin-converting enzyme inhibitors or angiotensin II receptor type-
1 antagonists, diuretics, beta-adrenergic blockers or neprilysin inhibitors.
3. Clozapine discontinuation is recommended to determine the maximum
degree of improvement. Abrupt discontinuation is not necessary, allowing
some time for tapering to avoid cholinergic rebound.
4. The possibility of clozapine rechallenge should be part of the treatment
plan when psychosis fails to respond to nonclozapine agents. Published
cases document lack of deterioration in cardiac parameters and
evidence of improved ventricular function (when combined with standard
medications for heart failure).
5. Heart transplantation is a viable consideration for stable, high-functioning
schizophrenia patients with good psychosocial support who have stage
D heart failure.
238
12
Summary Points
a. Most cases of fever are benign, but fever occurring in the first 8 weeks of
treatment demands work-up for myocarditis, interstitial nephritis, and DRESS,
including physical examination and some basic laboratory measures.
b. The addition of routine troponin I or T levels and CRP for the first 6 weeks
of treatment is a cost-effective method of screening for myocarditis. Serum
creatinine for the first 8 weeks of treatment is a cost-effective method of
screening for interstitial nephritis.
c. Routine periodic echocardiography is not a cost-effective method of screening
for cardiomyopathy. Clinicians should suspect this adverse effect when patients
on stable medication doses complain of feeling tired, or new complaints emerge
about leg swelling, palpitations or shortness of breath.
12
239
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13
Managing Enuresis and
Incontinence, Priapism, Venous
Thromboembolism, Neuroleptic
Malignant Syndrome, Tardive
Dyskinesia and Obsessive
Compulsive Disorder
QUICK CHECK
Introduction 242
Principles 243
A Nocturnal Enuresis and Incontinence 244
B Priapism 247
C Venous Thromboembolism 248
D Neuroleptic Malignant Syndrome 250
E Tardive Dyskinesia 252
F Obsessive Compulsive Disorder (OCD) 252
Summary Points 254
References 255
INTRODUCTION
Along with metabolic problems, there are a number of other adverse effects
not unique to clozapine, but which present unique treatment considerations given
the absence of alternatives to clozapine for many patients. An important part of
prescribing clozapine is developing patient rapport, and conveying the message that
embarrassing adverse effects such as nocturnal enuresis and incontinence can occur
in up to 40% of patients, and will be addressed, especially if persistent. Normalizing
the experience through education and elucidation of a prior history of such problems
is a helpful means of initiating the discussion, and imparting to patients that this
is not an unusual issue, and that there are standard approaches to these problems
[1]. Nonetheless, direct inquiry is the best method for elucidating complaints about
enuresis or incontinence. Large studies of clozapine treatment discontinuation
often cite “patient preference” when no specific reason is provided. Given the high
prevalence of enuresis early in treatment, and the fact that it may persist in 20% of
patients, the absence of this complaint from the literature on clozapine discontinuation
suggests a lack of communication with providers [1–3].
242
13: ENURESIS, PRIAPISM, VTE, TD, AND OCD
13
PRINCIPLES
• Incontinence and enuresis are more common with clozapine than with other
antipsychotics in schizophrenia patients, and can occur in up to 40% of
patients early in treatment. Approximately 20% report persistent problems
with nocturnal enuresis. This adverse effect must be assessed by direct
inquiry – patient embarrassment leads to underreporting and underdiagnosis.
Different approaches are needed for patients who only experience nocturnal
enuresis vs. those who have daytime incontinence.
• Priapism is related to inherent patient sensitivity and is reported among many
medications with potent alpha1-adrenergic antagonism. This is a medical
emergency that requires urgent treatment to prevent tissue necrosis and
permanent erectile dysfunction.
• Increased risk for venous thromboembolism is not unique to clozapine, and
the risk associated with clozapine may not be significantly greater than for
other antipsychotics, possibly due to patient factors (e.g. smoking, obesity,
inactivity).
• The development of neuroleptic malignant syndrome (NMS) is very rare,
and generally related to the concurrent use of another potent dopamine D2
antagonist. Clozapine rechallenge has been successful in seven of seven
reported cases.
• Tardive dyskinesia (TD) is also rare with clozapine and not a reason for
treatment discontinuation. Use of newer approved agents for TD is the most
evidence-based approach.
• New-onset obsessive compulsive symptoms can occur with clozapine.
Treatment approach will depend on whether dose reduction is possible, and
whether the patient has a prior mania history that precludes use of selective
serotonin reuptake inhibitors.
13
Once elicited through patient questioning, nocturnal enuresis and incontinence are
generally treatable and should not be causes for treatment discontinuation. Priapism
and venous thromboembolism (VTE) represent a more significant challenge, especially
as there can be risk of recurrence with significant medical consequences [4,5] The
decision to rechallenge patients who have experienced priapism or VTE requires a
knowledge of the management options, and a nuanced approach involving assessment
243
of patient decision-making capacity, treatment alternatives for the medical and

psychiatric conditions, and the input of caregivers. NMS and TD are much rarer with
clozapine than priapism or VTE, and also present less of a management dilemma due
to the success with rechallenge in clozapine-related NMS cases [6], and the availability
of multiple evidence-based TD treatments in the form of vesicular monoamine
transporter type 2 inhibitors [7]. New-onset obsessive compulsive symptoms can occur
rarely with other atypical antipsychotics, but is reported more often with clozapine. This
also should not be a reason for treatment discontinuation, although the management
can require some mental flexibility on the clinician’s part when the use of selective
serotonin reuptake inhibitor (SSRI) antidepressants is precluded by a prior mania
history [8]. As with many of the adverse effects discussed in this volume, the ultimate
goal is to maintain patients on clozapine when possible, particularly when there are no
acceptable therapeutic options to manage resistant psychosis.
A Nocturnal Enuresis and Incontinence
Nocturnal enuresis is not unique to clozapine, occurs with numerous medications

that have central nervous system (CNS) effects, and may be related to schizophrenia
itself as noted by Kraepelin [9]. There is a paucity of information on bladder
dysfunction among schizophrenia patients, with most studies relying on patient
self-report. Nonetheless, one study is available that used detailed questionnaires of
inpatients with schizophrenia (n = 63) or mood disorders (n = 45) to compare rates
of enuresis. The prevalence of nocturnal enuresis was twice as high in the psychosis
patients: 46% for the schizophrenia cohort vs. 20% for the mood diagnoses [9]. Only
one study has reported outcomes from urodynamic testing of incontinence complaints
in psychosis patients. Investigators in India found that six of eight antipsychotic-
treated patients had abnormal studies, with significant postvoid residual urine
volumes in two patients [10]. Numerous hypotheses have been advanced regarding
antipsychotic mechanisms that induce nocturnal enuresis, but the authors of the India
urodynamic study note: “These hypotheses have been derived indirectly from the
various treatments used to treat [urinary incontinence] in this situation; treatments
which had limited success only” [10].
What is apparent from the literature is that nocturnal enuresis is more common
with clozapine treatment, although it may improve over time. A 2016 review of
clozapine adverse effects noted a broad range of published prevalence rates (0.23–
42%), and commented on the limitations of the literature, especially for an adverse
244
13
effect that may be underreported due to patient embarrassment [5]. A retrospective
study of 61 Chinese inpatients on clozapine for at least 3 months noted that 41%
reported nocturnal incontinence, and 18% had incontinence at night and during
the day [11]. Over time, the prevalence of all incontinence symptoms diminished,
but persisted in 25% of patients. With systematic inquiry, 39% of a British cohort
of 103 clozapine-treated patients reported nocturnal enuresis [12]. A New Zealand
study compared nocturnal enuresis rates across multiple antipsychotics by asking
providers to directly query patients about “bed-wetting.” Among a sample of 606
antipsychotic-treated patients with mean age 40 years, of whom 60% were male,
nocturnal enuresis was found in 20.7% of patients on clozapine, compared to 9.6%
on olanzapine, 6.7% on quetiapine and 6.2% on risperidone [1]. Significant enuresis
risk factors included use of a second antipsychotic (24% vs. 4% for those without
enuresis) and a history of childhood bedwetting (43% vs. 20% for those without
enuresis).
Clozapine is sedating and has significant affinity for multiple receptors, especially
muscarinic cholinergic, so both central and peripheral mechanisms may contribute to
the problem. Cholinergic stimulation of muscarinic receptors (M3 in particular) on the
detrusor is necessary for contraction and bladder emptying, hence the use of selective
M3 antagonists for overactive bladder [13]. For those without overactive bladder
symptoms, exposure to an M3 antagonist impairs the contractile action of acetylcholine
at the detrusor to the extent that it may induce urinary retention, particularly in males.
Urinary retention may be the presenting complaint, but overflow incontinence may
also result due to incomplete voiding.
The general approach to incontinence and nocturnal enuresis outlined in Box
13.1 will depend on whether the complaint is solely a nighttime issue, whether
the problem persists, and the patient’s gender. If a patient sees a provider
who is unfamiliar with clozapine’s pharmacology, they must be reminded that
clozapine is strongly anticholinergic, and that the addition of other anticholinergic
medications may double the risk for ileus. Assessment can be aided by the use of
noninvasive transabdominal ultrasound. This relatively simple and painless test 13
provides information on postvoid residual urine volume, bladder wall thickness
and other parameters [14]. In instances where urodynamic testing is obtained that
documents overactive bladder symptoms not due to incomplete voiding, there is a
nonanticholinergic option: mirabegron. This agent is an agonist at beta3-adrenergic
receptors present in the detrusor, with the net effect being muscle relaxation and
increased bladder capacity. Urological consultation may be necessary in persistent
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Box 13.1 Approach to Incontinence Complaints

1. Prior to starting clozapine: Ask about current symptoms and nocturnal
enuresis (past and present).
2. Nocturnal enuresis developing during titration or after a dose increase:
a. Remind the patient that clozapine is sedating and not to be
embarrassed. Direct routine inquiry is best.
b. As tolerance may develop, consider slowing the titration and dividing
the dose if administered solely at bedtime. Ask the patient to minimize
fluids after 3 pm, avoid the use of diuretics at bedtime, and to empty
their bladder before sleep.
c. If persistent, attempt to taper off other antipsychotics, as their
presence increases the risk for nocturnal enuresis sixfold.
d. One study noted benefit from ephedrine titrated to 150 mg/day in
15/16 patients without adverse effects, but this is often not available
due to abuse liability [36]. There is one case report employing
pseudoephedrine titrated to 30 mg QID with complete resolution
of nocturnal incontinence [37]. There are three case reports for the
use of desmopressin, but in one instance severe hyponatremia
developed [38].
3. Daytime incontinence:
a. Inquire: Ask about symptoms of urgency, incomplete voiding,
changes in force of the urinary stream, and the frequency of urination.
b. In males: Assessment can be aided by a simple, noninvasive,
transabdominal ultrasound scan that provides information on postvoid
residual urine volume, bladder wall thickness and other parameters.
Overactive bladder (OAB) can be due to incomplete voiding and
overflow incontinence, so consider medications that relax the bladder
neck (e.g. tamsulosin) via selective α1A-adrenergic receptor antagonism
but have lower orthostasis rates than nonselective α1-adrenergic
receptor antagonists (e.g. prazosin). Anticholinergics for OAB should be
avoided for two reasons: they increase risk for ileus; and clozapine is
strongly anticholinergic, so additional muscarinic antagonism is unlikely
to remedy the problem. If a urodynamic study documents OAB, the
β3-adrenergic receptor agonist mirabegron is the preferred agent.
c. In females: Urinary retention and overflow incontinence is less likely.
Consider urological consultation as testing for pelvic floor weakness
and other causes may be needed. Anticholinergics for OAB should
be avoided for the same reasons as in males. If a urodynamic study
is performed that documents OAB, the β3-adrenergic receptor agonist
mirabegron is the preferred agent.
d. Urodynamic testing: This is very helpful when incontinence persists,
but is invasive, may be difficult to obtain, and the patient may not be
willing or able to cooperate.
246
13
cases, particular where initial measures have failed, and when anatomic issues
might be suspected (e.g. benign prostatic hypertrophy in males, pelvic floor
weakness in females). Urodynamic testing is somewhat invasive as it involves
inserting a urinary catheter, but typical tests require only 30 minutes and provide
information on urine flow, postvoid volumes, and other parameters if tolerated by the
patient [15,16].
B Priapism
Priapism is a medical emergency in which the penis remains erect for 4 or more
hours in the absence of stimulation, resulting in ischemia and significant pain. If not
promptly treated, complete erectile dysfunction can result due to tissue loss in the
corpora cavernosa [17]. Numerous medications are associated with priapism, many
of which share the common property of alpha1-adrenergic antagonism, including
trazodone, and multiple first- and second-generation antipsychotics [18]. Individual
predisposition clearly plays a role as some patients develop priapism on medications
with no known adrenergic properties (e.g. SSRIs). For clozapine, the presumed
mechanism relates to potent alpha1-adrenergic antagonism, yet there are less than 20
cases reported in the literature [19]. The onset is typically during the titration phase
or after a dose increase, although there is one unusual case of onset after 11 years of
clozapine treatment [20].
Emergency treatment is performed in a hospital setting, and involves initial
aspiration of blood from the engorged corpora cavernosa (at times with saline
irrigation), intracavernosal injection of sympathomimetics in certain cases, and,
if needed, surgery. The goal of the surgical shunt procedure is to create a fistula
that facilitates drainage of deoxygenated blood from the corpora cavernosa [17].
Discontinuation of clozapine is recommended when this is presumed to be the
offending agent, and appropriate management of cholinergic rebound and psychosis
commenced. (Chapter 4 provides an extensive discussion of strategies for managing
cholinergic rebound, and considerations for antipsychotic therapy after clozapine
13
discontinuation.) After resolution, the dilemma facing clinicians is whether to
rechallenge the patient with clozapine, especially when there may be little chance
of treatment success with other antipsychotics. Even with slow titrations, some
patients experience recurrence of priapism upon rechallenge with clozapine [4,19].
These patients likely represent a subgroup of very sensitive individuals, as there
are cases of patients experiencing the same problem with multiple antipsychotics
[18]. There are, however, three cases in which patients managed to continue with
247
clozapine [4,20,21]. Of note, the patient who developed priapism after 11 years
continued clozapine treatment without interruption after surgical shunting [20].
Despite requiring surgical decompression for priapism during his first clozapine trial,
one patient with treatment-resistant schizophrenia agreed to be rechallenged due to
inadequate response to other antipsychotics. After recurrence of priapism requiring
surgical intervention, he agreed to long-term use of the antiandrogen agent goserelin
(a gonadotropin-releasing hormone agonist) to prevent future recurrences rather than
having clozapine withdrawn and descending again into psychosis [4]. This patient
had the decision-making capacity to weigh the risks and benefits of various options,
but in other cases involvement of caregivers, urology experts and an ethicist might
be needed.
C Venous Thromboembolism
Antipsychotics as a class have been associated with approximately a 1.5-fold

increased risk for venous thromboembolism (VTE), but this effect is not seen in all
studies [22]. Not only are the putative mechanisms not well understood, certain
demographic factors related to the population of interest (e.g. smoking, obesity,
sedentary behavior) and possibly biological factors unrelated to medications may
play important roles [23]. A comprehensive meta-analysis of 17 published studies
noted that the adjusted odds ratio (AOR) for VTE or pulmonary embolism (PE) ranged
from 0.9 to 2.0 in the four largest studies comprising millions of antipsychotic-
exposed patients [22]. This translates roughly to three cases for every 10,000
antipsychotic users. Due to the small number of events, even the largest studies
lack statistical power to differentiate between agents, and for PE specifically, only
three studies are of sufficient quality for analysis. Based on this smaller pool of
PE studies, exposure to antipsychotics as a class does not appear to significantly
increase PE risk, but more data are needed to exclude the possibility of substantial
harm [22].
Despite the limited data on individual drugs, compared to antipsychotic nonusers
the AOR for clozapine is reported as 1.5–2.7, with values of 1.1–1.9 for olanzapine,
and 1.1–2.0 for risperidone [23]. The overlap in these odds ratios and their respective
confidence intervals raises questions whether clozapine’s VTE risk is significantly
different than for other antipsychotics. Even haloperidol has an AOR of 1.2 for PE in
a cohort study of 450,951 antipsychotic-exposed patients [24]. This is an important
248
13
consideration in the risk–benefit decision to rechallenge a patient with clozapine,
as switching to other agents may not necessarily lower VTE or PE risk. Prior to the
development of VTE, some hospitalized psychiatric patients might merit prophylaxis on
the basis of risks scores using a point system (Table 13.1) [25].
Table 13.1 A venous thromboembolism risk assessment tool for hospitalized

psychiatric patients [25].
1 point risks 2 point risks Total score VTE risk
• Immobilization (including • History of DVT or PE Score 0–3:
lower extremity paralysis) • Malignancy (active/treated) low
• Physical restraint • Age ≥ 75 years Score 4–7:
≥ 8 hours, catatonia medium*
• Acute infection (including
• Oral contraceptives, severe infection/sepsis) or Score ≥ 8:
hormone replacement acute respiratory disease high*
therapy (including exacerbation
• Obesity (BMI ≥ 30 kg/m2) of chronic respiratory
• Age 60–74 years disease)
• Varicose veins or venous
insufficiency
• Dehydration
• Thrombophilia
• Treatment with
antipsychotics
BMI, body mass index; DVT, deep vein thrombosis; PE, pulmonary embolism.
* Risks, benefits and necessity of prophylaxis should be considered for hospitalized inpatients with
scores ≥ 4 points.
After an initial episode of VTE (with or without PE) each patient should receive
prophylaxis, the length of which depends on a number of clinical factors. Warfarin,
factor Xa inhibitors and direct thrombin inhibitors are all treatment options, with the
choice of agent relating to the need for dietary adherence and additional monitoring
for warfarin, higher cost of newer agents, and proximity of hospital care in the event
of bleeding [26]. Given the confluence of medication- and patient-related risks that
promote recurrence, including smoking, obesity and the need for antipsychotic
treatment, work-up for primary hypercoagulable states may reveal underlying
13
disorders that require extended anticoagulant therapy [27].
A single episode of VTE (even with PE) is not a reason to discontinue clozapine,
but is a reason to pursue a risk management strategy to minimize modifiable factors
that increase risk, especially smoking, obesity and the use of certain contraceptives
249
in women. If the patient develops a second instance of VTE, the work-up for a primary
hypercoagulable state must be pursued. In addition, extensive discussions need to be
held with the patient and caregivers about the potential options. Considerations include:
a. Switching from clozapine to an agent that theoretically may have lower VTE/PE
risk, but which may be less effective for control of psychotic symptoms, and
which may not be entirely free of VTE or PE risk.
b. Lifetime anticoagulant therapy, including the burdens of monitoring, and the
bleeding risk.
As with priapism, the wishes of a patient who is a competent decision-maker must be
respected. Some may choose the risk of death due to VTE/PE or bleeding rather than
be removed from clozapine, while others may wish to try other antipsychotics with the
understanding that even haloperidol may impose some risk. When a patient decides to
discontinue clozapine, it need not be stopped abruptly, allowing time for appropriate
decisions to be made about alternate antipsychotics based on the patient’s history
(see Chapter 4).
D Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS) is a serious medical disorder from exposure

to dopamine D2 antagonists associated with hyperthermia, mental status alteration,
sympathetic nervous system lability, muscular rigidity and resultant marked elevation
in creatine kinase. While these and associated features have been described for over
40 years, standardized criteria were not arrived at until 2011. Box 13.2 provides the
International Consensus Diagnostic Criteria for NMS; moreover, a 2017 validation study
found that a cut-off score of 74 had the best agreement with modified DSM-IV-TR
criteria for NMS (sensitivity, 69.6%; specificity, 90.7%) based on detailed analysis of
211 cases, and agreed with consultant diagnoses in 85.7% of cases [28,29].
As a weak D2 antagonist, clozapine is a low-risk agent for inducing NMS and the
literature bears this out, yet the risk is not zero. However, there are less than 15 well-
documented NMS cases involving clozapine, some of which involve concurrent use of
other more potent D2 antagonists such as haloperidol [30,31]. Whether NMS occurs
with clozapine monotherapy, or the more likely scenario of combination antipsychotic
treatment, all sources of D2 antagonism should be withdrawn. Provisions also have
to be made for mitigating the cholinergic rebound from abrupt discontinuation of
clozapine for two important reasons:
250
13
a. Untreated cholinergic rebound may cause delirium, further exacerbating the
mental status changes associated with NMS [31].
b. Cholinergic rebound will induce even more extrapyramidal symptoms [32].
The latter is critical in this instance, as NMS patients already have the most
extreme form of an extrapyramidal reaction: cholinergic rebound will exacerbate
the problem (Chapter 4 provides an extensive discussion of strategies for managing
cholinergic rebound, and considerations for antipsychotic therapy after clozapine
discontinuation).
That many of the clozapine NMS cases were also receiving other sources of D2
antagonism may explain why clozapine rechallenge has been successful in seven
of seven cases where NMS had occurred during clozapine treatment [6]. The 100%
success rate is a strong argument for rechallenge, particularly when there were
mitigating factors contributing to the prior episode of NMS.
Table 13.2 International Consensus Diagnostic Criteria for Neuroleptic Malignant

Syndrome [28]
Criterion Priority score
Exposure to dopamine antagonist or dopamine agonist withdrawal
20
within the past 72 hours
Hyperthermia (> 100.4°F or > 38.0°C on at least two occasions,
18
measured orally)
Rigidity 17
Mental status alteration (reduced or fluctuating level of consciousness) 13
Creatine kinase elevation (at least 4 times the upper limit of normal) 10
Sympathetic nervous system lability, defined by at least two of the
following:
-- lood pressure elevation (systolic or diastolic ≥ 25% above
B
baseline)
10
-- lood pressure fluctuation (≥ 20 mmHg diastolic change or
B
≥ 25 mmHg systolic change within 24 hours)
-- Diaphoresis
-- Urinary incontinence
ypermetabolism, defined as heart rate increase (≥ 25% above
H
5
13
baseline) AND respiratory rate increase (≥ 50% above baseline)
Negative work-up for infectious, toxic, metabolic, or neurologic
7
causes
Comment: NMS is a clinical diagnosis; however, using the scoring system above, scores of 74 and
above agreed with 85.7% of clinical consultant diagnoses during a validation study of 211 NMS
cases [29].
251
E Tardive Dyskinesia
Tardive dyskinesia (TD) is a hyperkinetic movement disorder resulting

from exposure to dopamine receptor antagonists, primarily antipsychotics and
metoclopramide. TD is often irreversible, even when the offending medication is
discontinued, with complete remission occurring in < 30% of patients [7]. Older age
and higher potency D2 antagonism are significant risk factors for TD, but cases have
been reported for every antipsychotic, including clozapine, although the development
of TD on clozapine is often ascribed to prior antipsychotic exposure [33]. Nonetheless,
clozapine’s low risk for acute movement disorders (parkinsonism, dystonia, akathisia)
led to multiple studies exploring its benefit in patients with TD in whom antipsychotic
therapy cannot be stopped. The results of these studies were decidedly mixed,
and with the availability of three vesicular monoamine transporter type 2 (VMAT2)
inhibitors for TD treatment (tetrabenazine, deutetrabenazine, valbenazine), switching
to clozapine (or any other antipsychotic with low D2 affinity) is no longer an evidence-
based recommendation for patients who need antipsychotic treatment [7]. For the rare
patient who develops TD on clozapine, switching to another antipsychotic is unlikely
to impact the movement disorder, but is likely to result in relapse. Thus, clozapine
discontinuation is not recommended for patients who develop TD.
A more salient approach is the use of a VMAT2 inhibitor to treat TD while
maintaining the patient on clozapine. The two newest VMAT2 inhibitors
(deutetrabenazine, valbenazine) have approved indications for TD treatment in the
US. The majority of patients in the clinical trials remained on antipsychotic treatment,
and with no signal for psychiatric symptom exacerbation. Importantly, the drop-outs
due to adverse effects ranged between 10% and 12% for drug and placebo groups
alike across studies with deutetrabenazine and valbenazine, speaking to acceptable
tolerability even with ongoing psychotropic use [7]. The litany of other medications
tried for TD in the past (e.g. vitamin E) had poor evidence for efficacy according to an
American Academy of Neurology 2013 review paper [34]. Anticholinergics are effective
for parkinsonism and dystonia, but will exacerbate tardive dyskinesia [7].
F Obsessive Compulsive Disorder (OCD)
A 2016 review of atypical antipsychotics and obsessive compulsive symptoms

notes an interesting paradox: while atypical antipsychotics are often employed
to augment selective serotonin reuptake inhibitors (SSRIs) in treatment-resistant
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13
Box 13.2 Approach to New-Onset Obsessive Compulsive Symptoms
1. Clozapine discontinuation will resolve the problem, but this may be an
unacceptable choice for patients with treatment-resistant schizophrenia.
2. There may be a dose or plasma-level relationship with the onset of
new obsessive compulsive symptoms (OCS). Check the trough plasma
clozapine level, and consider a slow dose reduction (e.g. 5% per month)
in stable patients if there is evidence that the current plasma level
was achieved after rapid titration. The hypothesis is that the patient’s
psychosis may respond adequately at lower clozapine levels, and that
the OCS will also improve.
3. For schizophrenia patients with no history of mania, the use of SSRI
antidepressants is evidence-based. Avoid medications with significant
cytochrome P450 interactions with clozapine, including fluvoxamine,
fluoxetine and paroxetine. Sertraline is a good choice as it lacks
cytochrome P450 interactions, and has no QTc warning as seen with
citalopram or escitalopram. There is a small literature about the adjunctive
use of aripiprazole, and this can be considered in patients on clozapine as
antipsychotic monotherapy. (See Chapter 11 for discussion about concerns
when combining aripiprazole with more potent D2 antipsychotics.)
4. For patients with a history of mania, SSRI antidepressants must be
avoided due to the possible exacerbation of the mood disorder, even if
treated with mood stabilizers. Adjunctive aripiprazole can be considered
in patients on clozapine as antipsychotic monotherapy. (See Chapter 11
for discussion about concerns when combining aripiprazole with more
potent D2 antipsychotics.)
5. Consider use of evidence-based OCD behavioral therapies (exposure
and response prevention, stress management training) in lieu of, or in
addition to any medication changes.
obsessive compulsive disorder (OCD), atypical antipsychotics have been reported

to induce obsessive compulsive symptoms in schizophrenia patients [8]. Clozapine
appears to be associated with this adverse effect more than other antipsychotics,
possibly related to its higher affinity for 5HT2A receptors, although the underlying
mechanism is not fully understood. Nonetheless, every year several cases are 13
published in which new-onset OCD symptoms appear after commencing clozapine,
and improve abruptly upon discontinuation [35]. The approach to these patients (Box
13.2) depends on whether clozapine can be stopped or the dose (and plasma level)
reduced, and whether the patient has a prior history of mania that precludes use of
high-dose SSRI treatment needed for OCD management. In general, this should not
253
be a cause of clozapine discontinuation, but management can be complex when the

patient requires clozapine for a treatment-resistant schizophrenia spectrum disorder,
but also has a history of mania. For more intractable cases, consultation with a local
OCD expert may be useful to determine the best combination of behavioral therapies
(e.g. exposure and response prevention, stress management training) and other
pharmacological approaches.
Summary Points
a. Daytime incontinence is rarely due to overactive bladder (OAB), as clozapine is

strongly anticholinergic. Anticholinergics for OAB should be avoided as a routine
treatment of daytime incontinence for two reasons: they increase risk for ileus;
and clozapine is strongly anticholinergic, so additional muscarinic antagonism is
unlikely to remedy the problem.
b. Nocturnal enuresis may wane with time, but persists in approximately 20%. Use
of multiple antipsychotics increases risk sixfold.
c. The decision to rechallenge a patient with priapism relates in part to their
ability to understand the risks and benefits of rechallenge, and the presence
of antipsychotic alternatives with lower priapism risk, as recurrence has been
reported in some (but not all) rechallenge cases.
d. As the risk for venous thromboembolism may not be significantly greater for
clozapine than for other antipsychotics, the risk–benefit equation may tilt
towards ongoing anticoagulant therapy for cases of recurrence instead of
clozapine discontinuation.
e. The development of neuroleptic malignant syndrome on clozapine is typically
related to the concurrent use of another D2 antagonist, and not a reason for
permanently stopping clozapine. Clozapine rechallenge has been successful in
seven of seven reported cases.
f. Tardive dyskinesia (TD) is also rare with clozapine and not a reason for treatment
discontinuation. Use of VMAT2 inhibitors for TD is the best approach.
g. New-onset obsessive compulsive symptoms can occur with clozapine. Dose
reduction (if possible) and use of selective serotonin reuptake inhibitors are
common strategies, although a mania history precludes the latter. Behavioral
strategies should always be considered.
254
13
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14
QUICK CHECK
Eosinophilia, Leukocytosis,
Thrombocytopenia,
Thrombocytosis, Anemia,
Hepatic Function Abnormalities
Introduction 258
Principles 259
A Eosinophilia 261
B Leukocytosis 264
B Thrombocytopenia and Thrombocytosis 265
D Anemia 267
E Hepatic Function Abnormalities 268
Summary Points 272
References 273
INTRODUCTION
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 [1]. 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)
[2]. An Italian study of 2404 patients reported a leukocytosis rate of 7.7% using the
258
14: OTHER BLOOD DYSCRASIAS, LFT CHANGES
14
PRINCIPLES
• 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.
total WBC threshold of 15,000/mm3 [3]. 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
14
years of treatment, but it was not a cause of treatment discontinuation [4].
259
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 [5]. 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 [8].
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 [9]. 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 [9]. 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 [10].
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A Eosinophilia
Eosinophils are granulocytes akin to neutrophils, but which reside primarily at

tissue sites where they mediate a number of allergic responses. The development
of eosinophils from myeloid precursors is governed by levels of interleukin-5 (IL-5),
and once released, IL-5 and granulocyte colony-stimulating factor (G-CSF) are
the most important cytokine signals that govern trafficking and promote survival
[11]. Eosinophilia can occur as a reaction to numerous medications including
antipsychotics, as well as parasitic diseases, autoimmune disorders and neoplastic
syndromes. Due to the association between eosinophilia and serious adverse events
occurring in the first 6–8 weeks of treatment (e.g. myocarditis), early clozapine
package inserts contained stark warnings about eosinophilia, often including
requirements for treatment interruption when counts exceeded 3000/mm3. As noted in
Table 14.1, this language persists in many countries, but the accumulated data from
the past 30 years of postmarketing experience have led to several insights:
(a) eosinophilia should not be used as a means of diagnosing myocarditis or
interstitial nephritis – other tests are more specific and sensitive (see Chapter 12);
(b) eosinophilia is but one of many criteria necessary for the DRESS diagnosis;
(c) eosinophilia in the absence of systemic symptoms is not a reason to
discontinue clozapine treatment.
This evolved understanding of eosinophilia led to modified language in the most recent
US package insert (Box 14.1) which emphasizes that clozapine can be continued when
there is no evidence of organ involvement, and that it may resolve without intervention.
Table 14.1 UK reference ranges for eosinophils and platelets.

Value Action
> 1000/mm3 - Initiation/continuation of clozapine treatment is
Pretreatment not recommended
Increase monitoring frequency
High eosinophils Clozapine therapy should be started only after
> 3000/mm3 -
blood results have stabilized under 1000/mm3
On-treatment
not recommended
Increase monitoring frequency 14
Low platelets < 50K Clozapine therapy should be started only after
blood results have stabilized at or above 50K.
261
Box 14.1 US Language on Eosinophilia (Clozaril® Package Insert 2017)

Eosinophilia, defined as a blood eosinophil count of greater than 700/μl,
has occurred with CLOZARIL treatment. In clinical trials, approximately 1%
of patients developed eosinophilia. Clozapine-related eosinophilia usually
occurs during the first month of treatment. In some patients, it has been
associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis.
Such organ involvement could be consistent with a drug reaction with
eosinophilia and systemic symptoms syndrome (DRESS), also known as
drug-induced hypersensitivity syndrome (DIHS). If eosinophilia develops
during CLOZARIL treatment, evaluate promptly for signs and symptoms of
systemic reactions, such as rash or other allergic symptoms, myocarditis,
or other organ-specific disease associated with eosinophilia. If CLOZARIL-
related systemic disease is suspected, discontinue CLOZARIL immediately.
If a cause of eosinophilia unrelated to CLOZARIL is identified (e.g.,
asthma, allergies, collagen vascular disease, parasitic infections, and
specific neoplasms), treat the underlying cause and continue CLOZARIL.
Clozapine-related eosinophilia has also occurred in the absence of
organ involvement and can resolve without intervention. There are
reports of successful rechallenge after discontinuation of clozapine,
without recurrence of eosinophilia. In the absence of organ involvement,
continue CLOZARIL under careful monitoring. If the total eosinophil count
continues to increase over several weeks in the absence of systemic
disease, the decision to interrupt CLOZARIL therapy and rechallenge after
the eosinophil count decreases should be based on the overall clinical
assessment, in consultation with an internist or hematologist.
There are varying thresholds used to define eosinophilia (400/mm3, 500/mm3,

700/mm3) so prevalence estimates in the literature display a range of values. The US
package insert states that 1% experienced counts > 700/mm3 in early clinical trials,
while the rate was 2.2% in a large Italian study (n = 2404) with a threshold of 400/
mm3 after excluding those with other pathologies [3]. The Italian paper comments that
none of the eosinophilia cases required the interruption of clozapine administration,
and all spontaneously resolved 3–4 weeks after onset. Lastly, using a threshold of
1500/mm3 a 1-year study of 101 new clozapine starts found a cumulative incidence of
5.9% for eosinophilia [2].
Mandatory treatment interruption is required in many countries when eosinophil
counts exceed a predefined threshold (typically 3000/mm3), so clinicians in those
regions will have no option but to follow local guidelines. If clozapine must be held,
there are multiple reports in the literature of successful rechallenge where organ
involvement did not occur [12,13]. A slower titration during the rechallenge and
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14
more frequent CBC assessments for the first month (e.g. biweekly) might help
alleviate anxiety from other providers, but the expectation is that eosinophilia will
spontaneously resolve if no prior evidence of a systemic reaction. When there is no
mandated threshold for pausing clozapine treatment, it is still reasonable to consult
with an internist or hematologist if eosinophil counts continue to climb despite lack
of evidence for a systemic reaction or organ involvement (as recommended in the US
package insert). This expertise can help a clinician decide whether another medication
might be the offending agent, or if further work-up for parasitic or other illness
is needed. Once the 6–8-week risk period has passed for myocarditis, interstitial
nephritis and DRESS, the absence of systemic symptoms in a seemingly healthy
individual narrows down the differential diagnosis of eosinophilia considerably, with
self-limited drug reaction of no clinical consequence being the leading candidate.
Figure 14.1 provides an illustration of longitudinal eosinophil counts depicting the
self-limited nature of the problem in an otherwise asymptomatic patient continued on
clozapine therapy [14]. The underlying mechanism is unknown, but almost certainly
Figure 14.1. Time course of eosinophilia in a case without organ involvement.

4500 Clozapine dose 450
Absolute eosinophil count
4000 400
Absolute Eosinophil Count (per mm )
3
3500 350
Daily Clozapine Dose (mg)
3000 300
2500 250
2000 200
1500 150
1000 100
500 50
0 0
0 7 14 18 21 25 28 32 35 39 42 46 49 53 56 63 70 77
Day 14
(Adapted from: Ho, Y. C. and Lin, H. L. (2017). Continuation with clozapine after
eosinophilia: a case report. Annals of General Psychiatry, 16, 46 [14].)
263
involves cytokine activation. In particular, clozapine treatment has been associated

with increases in G-CSF levels, and this cytokine promotes eosinophil survival [15].
B Leukocytosis
To prescribe clozapine is to be intimately familiar with neutropenia, but there

is a significant rate of the opposite problem, neutrophilia. As with eosinophilia, the
underlying mechanism may relate to increases in G-CSF levels seen in some patients,
but this remains speculative [15]. The literature in this area is sparse, and consists of
a number of case reports, and aggregate data from three surveillance papers. Some
papers only report increases in total WBC, although the presumed effect is solely
on neutrophils. In the Italian study of 2404 patients, the prevalence of leukocytosis
was 7.7% using the WBC threshold of 15,500/mm3 [3]. While much smaller, a 1-year
Canadian study of 101 clozapine starts found a cumulative incidence of 48.9% for
neutrophilia (absolute neutrophil count > 7500/mm3)[2]. As with eosinophilia, the
appearance of leukocytosis is both early and self-limited in the vast majority of cases,
with rare exceptions. A 1994 study of 68 new clozapine starts indicated that 40.9%
met criteria for leukocytosis (WBC > 10,000/mm3), but this lasted only 1–3 weeks in
all patients but one individual whose WBC counts varied from 11,100 to 15,600/mm3
over the ensuing 2 years [16]. A series of seven persistent leukocytosis cases with no
known cause (aside from clozapine) was subsequently reported in 2007 (peak WBC
19,800/mm3) and another in 2010 (peak WBC 27,700/mm3) [17,18].
Before concluding that clozapine is the underlying etiology, two important causes of
neutrophilia must be excluded: infection (or other acute insults such as trauma, burns),
and the use of lithium. Lithium possesses G-CSF agonist properties that stimulate
neutrophil production, and at therapeutic serum levels can increase neutrophil counts
as much as 88% [19]. In one case of long-term clozapine-induced leukocytosis, the
patient remained on lithium, so the association with clozapine is unclear [20]. While
clozapine-induced chronic leukocytosis is decidedly rare, it must be included in the
differential diagnosis to obviate an expensive work-up for occult sources of infection
in an apparently healthy individual. In one case report, a patient underwent HIV testing,
Lyme antibody IgG/IgM testing, a sinus CT scan, pulmonary and abdominal CT scans
and a dental examination before it was concluded that clozapine was the cause [18].
Consultation with a hematologist knowledgeable about drug-related leukocytosis may
help confine the evaluation to likely sources of infection. Once these have been ruled out,
leukocytosis should never be a reason to stop clozapine treatment, even temporarily [8].
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14
Box 14.2 General Approach to Leukocytosis, Thrombocytopenia, Thrombocytosis
and Anemia
1. Leukocytosis:
a. Eliminate lithium use and infections as possible contributors.
b. Leukocytosis is almost always time-limited. In rare circumstances it
may persist in the absence of other etiologies. Expensive work-ups
are not necessary in otherwise healthy-appearing patients.
c. Leukocytosis is not a reason to hold or discontinue clozapine.
2. Thrombocytopenia:
a. Eliminate divalproex/valproate use as a possible contributor.
b. When not due to divalproex, thrombocytopenia is almost always time-
limited. In rare circumstances it may persist in the absence of other
etiologies.
c. Thrombocytopenia is not a reason to hold or discontinue clozapine
unless mandated by local prescribing guidelines or counts approach
50,000/mm3 after ruling out other etiologies.
3. Thrombocytosis:
a. Thrombocytosis is time-limited in all reported cases.
b. Thrombocytosis is not a reason to hold or discontinue clozapine,
unless the platelet count is extremely high (> 750,000/mm3).
4. Anemia:
a. Eliminate other causes including blood loss (e.g. gastrointestinal), iron
deficiency and divalproex/valproate use as possible etiologies.
b. When not due to another etiology or divalproex, anemia is not a
reason to hold or discontinue clozapine.
c. Long-term data indicate that almost 25% of clozapine-treated
patients will meet anemia criteria over 2 years of follow-up. Attention
should be given to hemoglobin and red blood cell indices provided
with routine hematological monitoring.
C Thrombocytopenia and Thrombocytosis
Platelet adhesion and aggregation are the first steps in hemostasis, so platelet
dysfunction can lead to bleeding or abnormal thrombosis when counts are
significantly below or above normal physiologic ranges. The normal platelet count is 14
150,000–450,000/mm3, so technically any value below 150,000/mm3 is considered
thrombocytopenia; however, there are racial/ethnic variations in platelet counts,
with values from 100,000 to 150,00/mm3 not uncommon in certain non-Western
265
groups, and there is also a benign phenomenon known as pregnancy-related

thrombocytopenia [21,22]. As chronic platelet counts of 100,000–150,000/mm3 in
these groups appear to pose no risk (in a manner analogous to low neutrophil counts
in benign ethnic neutropenia), a working definition of thrombocytopenia as a platelet
count < 100,000/mm3 is commonly used [21]. Mild bleeding can occur when the
count is less than 50,000/mm3, but the risk for serious bleeding does not appear until
the count is less than 20,000/mm3, and especially when under 10,000/mm3.
The best estimate of thrombocytopenia prevalence in a large sample (n = 6316)
comes from clozapine registry data amassed in the UK and Ireland January 1990–
July 1994. Only six cases of thrombocytopenia were found (rate 0.095%) using the
definition of platelet count < 50,000/mm3 [23]. Using a threshold of 100,000/mm3 the
Italian cohort (n = 2404) reported a rate of 0.083% [3], and the Canadian 1-year data
on 101 new clozapine starts cited a value of 3.0% [2]. When not due to other causes
this appears as a self-limited phenomenon, and resolution in most cases requires no
intervention [24]. As further evidence for the limited impact of clozapine on long-term
platelet indices, the Canadian sample of new starts reported no change in mean
platelet volume (MPV) for the 65 patients who had MPV data at baseline and after one
year of treatment [25].
Comparable to the focus on lithium exposure in cases of clozapine-related
leukocytosis, the primary consideration in thrombocytopenia is the concurrent
use of divalproex/valproate. Divalproex is known to induce thrombocytopenia in a
serum level-dependent manner, with rates as high as 17.7% reported in a 24-week
epilepsy monotherapy study (n = 265) using the threshold of 100,000/mm3, although
psychiatric samples have documented somewhat lower incidences [5]. Cross-
sectional data on 264 valproate-treated psychiatric patients in Pittsburgh found that
9.5% had mild thrombocytopenia (101,000–150,000/mm3) and 2.3% moderate
thrombocytopenia (40,000–100,000/mm3) for a total rate of 11.8% [26]. British data
on 126 individuals found a 5% rate using the threshold of 150,000/mm3 [27]. Higher
serum valproate levels in both of these studies were associated with lower platelet
counts.
When not due to the effects of divalproex, all of the available literature suggests
that thrombocytopenia is transient, and not a reason to hold clozapine treatment
in the majority of patients unless treatment interruption is dictated by prescribing
guidelines (see Table 14.1). The latest US package insert contains no comments about
platelet counts, and lists thrombocytopenia among a group of adverse effects noted
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in postmarketing experience. Nonetheless, there are two case reports of persistent
thrombocytopenia without leukopenia or other concurrent medication-related
etiologies [23,28]. The first case involved a 43-year-old male with chronic hepatitis
and cirrhosis, both of which may have contributed, but the second case was a healthy
22-year-old woman with schizophrenia who developed platelet counts under 100,000/
mm3 after 17 weeks of clozapine treatment, and whose counts dropped to 60,000/
mm3 over the next 4 months without leukopenia or anemia, and no other possible
etiologies. It was assumed that clozapine was the cause and was tapered off. Within
a week of stopping clozapine the platelet count improved, and after 6 weeks it was
180,000/mm3 [23].
A small number of thrombocytosis cases not due to the use of colony-stimulating
factors have appeared in the literature, but only two studies provide incidence
rates. Seven of 43 patients (17.9%) had at least one platelet count > 400,000/mm3
in one study, and 3% of a sample (n = 101) followed for 1 year had at least one
count > 500,000/mm3 [2,24]. In the 1-year study the mean time to thrombocytosis
was 12 weeks (range 4–22 weeks), with all cases resolving. High platelet counts
(> 750,000/mm3) present a risk for thrombosis, but this has been reported with
clozapine in only one case, and was directly related to the use of the G-CSF agonist
filgrastim for severe neutropenia [23]. There are no reported cases of persistent
thrombocytosis, so clinicians should monitor platelet counts under the assumption that
it is a self-limited process and should resolve without intervention.
D Anemia
Anemia presenting insidiously has many causes, with iron deficiency and blood
loss being leading etiologies. Autoimmune processes are also a consideration when
a new medication has been introduced. Based on hemoglobin values, red cell indices
(e.g. mean corpuscular volume (MCV), mean corpuscular hemoglobin content), and
the presence of reticulocytes (immature red blood cells), hypotheses can be formed
regarding the leading candidates, and further diagnostic work-up pursued.
Despite the abundance of CBC data from decades of clozapine prescribing,
there was no systematic study documenting clozapine’s impact on red blood cell or
hemoglobin indices until recent years. In 2015 a retrospective analysis was published 14
from data gathered during the first 2 years of treatment in 94 Canadian patients.
Using a hemoglobin threshold for anemia of < 12.0 g/dl for women and < 13.0 g/dl for
267
men, 24.5% of the sample developed anemia over the 2 years of clozapine, although
no patient discontinued treatment for this reason [4]. Among those who developed
anemia, in 87% it was recurrent or persistent. The majority of all anemia cases
(78%) were normochromic (normal mean corpuscular hemoglobin) and normocytic
(normal MCV), and anemia tended to occur more often in those with lower baseline
hemoglobin values and in nonsmokers. Smoking was protective of clozapine’s effect
due to the chronic carbon monoxide exposure and resultant higher hemoglobin and
mean corpuscular hemoglobin concentrations in these individuals [29]. Of note, cases
continued to develop throughout the 2 years of monitoring.
The underlying mechanism for the insidious development of anemia is unclear. In
vitro studies have indicated that the metabolite norclozapine may impact erythrocyte
development, but neither clozapine dose, nor plasma clozapine or norclozapine levels
were associated with anemia risk in the Canadian study [4]. There are two case
reports of pure red cell aplasia resulting from clozapine use, suggesting that rare
individuals might be uniquely susceptible. Because the predominant form of anemia
for the Canadian cohort was normochromic and normocytic, iron deficiency is ruled
out, as these patients would be microcytic (low MCV) in addition to having abnormal
iron studies. Renal failure, hypothyroidism, and pituitary failure are other causes of
normochromic, normocytic anemia, but were not seen, and toxic effects of other
medications were deemed unlikely.
The implications of these 2-year data are summarized in Box 14.2. Fortunately,
every patient on clozapine is monitored for anemia due to the routine complete blood
count obtained. Consultation with an internist can be helpful when anemia appears,
iron studies are normal, and additional hypotheses need to be considered before
concluding that the anemia is clozapine-related. Anemia is an adverse effect of a
number of other medications including divalproex, and a hematologist can be helpful
in evaluating the likelihood of other offending agents being present. Aside from the
extremely rare cases of red cell aplasia, anemia should never be a reason to stop
clozapine treatment.
E Hepatic Function Abnormalities
A number of medications and medical conditions commonly seen in schizophrenia

patients can induce abnormal liver function tests. Alcohol abuse, other antipsychotics,
anticonvulsants, and chronic hepatitis C are leading etiologies for abnormal liver
268
14
function tests in schizophrenia patients, but increasingly nonalcoholic fatty liver disease
(NAFLD) is recognized as a source of persistent hepatic disease. In a sample of 180
treatment-naive German schizophrenia patients followed for 3 years, 25.1% manifested
high scores on the fatty liver index, indicative of steatosis (i.e. fatty liver) [30]. Given the
range of possibilities and the high NAFLD prevalence among schizophrenia patients, the
etiology of abnormal liver function tests must be determined before initiating clozapine,
and appropriate treatment started including discontinuing offending medications. This
is especially true for patients diagnosed with NAFLD, as clozapine-associated weight
gain and worsening insulin resistance will exacerbate this problem.
That antipsychotics can induce liver function abnormalities has been known since
early experience with chlorpromazine. Interestingly, chlorpromazine tended to induce
changes indicating inflammation or “toxicity” in only 20% of cases with abnormal liver
function, while in 80% the pattern was one of cholestasis, with increases in alkaline
phosphatase and total bilirubin [9]. This cholestatic picture is not typically seen with
newer antipsychotics, so evidence of hepatotoxicity (inflammation) is tracked using
changes in the level of two enzymes: ALT and AST. Treatment decisions for most
medications are often based on whether AST or ALT levels exceed certain thresholds
such as 2 or 3 times the upper limit of normal (ULN). A early German study of 215
patients found that ALT or AST exceeded 2 times ULN in 31% of patients on clozapine
monotherapy [31]. A retrospective analysis of naturalistic data from the initial 18
weeks of treatment in an affiliated group of Austrian hospitals found that 37.3% of
clozapine-treated patients (n = 167) experienced ALT levels > 2 times ULN compared
to 16.6% for the haloperidol group (n = 71) [9]. There was lesser impact on AST, with
11.7% of clozapine patients and 0% of haloperidol patients having values > 2 times
ULN. There were no significant differences in rates of abnormalities for bilirubin or
alkaline phosphatase. Importantly, 61% of clozapine patients whose ALT exceeded 2
times ULN during the first 6 weeks of treatment had lower levels by weeks 13–18.
Surveillance data on drug-induced liver injury amassed from Berlin hospitals 2002–
2011 did not find significantly different rates between clozapine (five cases) and
olanzapine (six cases), with the 95% confidence intervals for the odds of developing
liver injury (compared to a control group) overlapping for the two antipsychotics [32].
There are limited additional data on this topic aside from a number of case reports.
In many instances these cases are labeled as examples of hepatotoxicity, but the 14
patient manifested fever and other systemic symptoms strongly suggestive of DRESS
[33]. As with the hematological issues discussed earlier in this chapter, the time
269
course, severity and associated features are very instructive in determining a course
of action. Significant ALT/AST abnormalities presenting early in treatment with fever
and other somatic complaints will point towards systemic reactions such as DRESS
syndrome, while insidious and later onset indicates other possibilities (e.g. NAFLD,
chronic hepatitis C, other medications).
Box 14.3 General Approach to Abnormal Liver Function Tests

1. Monitoring:
a. After starting treatment: there is no consensus, but liver function tests
must be included as part of the chemistry panel obtained during any
work-up of fever or systemic symptoms occurring during the first 60 days
of treatment (the risk period for DRESS and other systemic reactions).
b. Routine: yearly as part of routine annual history and physical
examination.
2. Response to abnormal ALT/AST with early onset (days to 8 weeks):
a. Systemic signs or fever present: discontinue clozapine while the
work-up for DRESS or other systemic reactions is proceeding.
b. No systemic signs or fever present: may continue clozapine while
values remain ≤ 3 times ULN. Evaluate for other causes including
effects of other medications (e.g. divalproex), or possibility of NAFLD,
especially in those who have gained significant weight and show
signs of insulin resistance (e.g. elevated serum triglycerides, elevated
fasting glucose). Consider a trial of dose reduction before ALT or AST
exceed 3 times ULN if no other cause is found. Clozapine will need
to be paused when ALT or AST exceed 3 times ULN, but rechallenge
should be considered (see below).
2. Late insidious onset (> 90 days):
a. Evaluate for other causes including effects of other medications (e.g.
divalproex), or possibility of NAFLD, especially in those who have
gained significant weight and show signs of insulin resistance (e.g.
elevated serum triglycerides, elevated fasting glucose).
b. If ALT/AST ≤ 3 × ULN there is no reason to hold or discontinue
clozapine. Consider a trial of dose reduction before ALT or AST
exceed 3 times ULN if no other cause is found. Clozapine will need
to be paused when ALT or AST exceed 3 times ULN, but rechallenge
should be considered (see below).
3. Rechallenge: should be considered in patients where no systemic
symptoms or fever accompanied the increase in ALT or AST and work-up
revealed no evidence of DRESS. Use slower titration, and check liver
function tests 2–3 times weekly for the first 4 weeks. The monitoring
frequency can be adjusted over time if results return to normal.
270
14
As with many of clozapine’s adverse effects, the underlying cause of
hepatotoxicity when not associated with an obvious systemic allergic response
is unknown [10]. When other etiologies have been excluded, management of
elevated ALT or AST often involves watchful waiting, as many early cases will
spontaneously resolve over time. When AST or ALT exceed 3 times ULN, pausing
treatment is necessary. In cases where no other cause is found, the liver function
tests will normalize over 1–4 weeks [10,34]. There are two well-documented
cases in which a patient was successfully rechallenged after manifesting ALT
or AST levels exceeding 3 times ULN but who had no prior evidence of fever or
other systemic reaction. In the second case, the patient underwent numerous
tests to exclude other etiologies including: serology for hepatitis A, B, and C, and
for HIV; serology for acute infection with Cytomegalovirus, herpes simplex, and
Epstein–Barr viruses; antinuclear antibody, liver–kidney microsomal antibody;
antimitochondrial antibody; smooth muscle antibody; perinuclear antineutrophil
cytoplasmic antibody; abdominal ultrasound [10]. All of the testing was normal, the
patient was rechallenged with thrice-weekly liver function tests, and the course
is illustrated in Figure 14.2. Upon rechallenge the AST and ALT climbed again
over the next 3 weeks as the dose was advanced to 500 mg/day. When the ALT
exceeded 200 IU/l a liver biopsy was performed that showed mild inflammatory
changes. The dose was reduced slightly to 400 mg/day, and the ALT and AST
normalized over the next week. The patient was discharged on 400 mg/day and
his liver function tests remained normal over the ensuing 9 months of outpatient
treatment. In the first case sporadic elevations of AST and ALT were noted after
rechallenge, but no intervention was performed when the patient again showed no
fever or systemic symptoms, and clozapine treatment continued. The liver function
tests normalized, and remained normal 1 year later on 600 mg/day [34]. These
cases provide a compelling argument that, with careful monitoring, patients can be
safely rechallenged with clozapine who have isolated AST or ALT elevations without
systemic symptoms during the prior trial. Although peak transaminase levels
may be higher than those seen in other patients, the time course and complete
resolution suggests that these patients are no different than many others who
experience elevated transaminases during early clozapine treatment.
14
271
Figure 14.2. Time course of liver function test changes in a patient without fever
or systemic symptoms rechallenged with clozapine.
Liver Biopsy,
Discontinuation Rechallenge 20% Dose Reduction
250
200
Values (U/l)
150
100
50
0
week 1 week 2 week 3 week 4 week 5 week 6 week 7 week 8 week 9
AST
ALT
(Adapted from: Erdogan, A., Kocabasoglu, N., Yalug, I., et al. (2004). Management of
marked liver enzyme increase during clozapine treatment: A case report and review of
the literature. International Journal of Psychiatry in Medicine, 34, 83–89 [10].)
Summary Points
a. Eosinophilia without evidence of organ involvement is not a reason to

permanently discontinue clozapine. It is self-limited and resolves without need
for treatment interruption.
b. Thrombocytopenia (not due to valproate or other causes) and thrombocytosis are
usually self-limited processes that resolve without need for treatment interruption.
c. Anemia can be associated with clozapine treatment, but is not a reason for
treatment discontinuation.
d. Moderate elevations of ALT or AST > 2 times ULN occur in over 30% of clozapine
patients, usually early in the treatment course. When presenting after longer
periods (e.g. months or years), NAFLD due to insulin resistance is the likely etiology.
e. Patients who had no prior evidence of fever or other systemic reaction from
clozapine have been successfully rechallenged after manifesting ALT or AST
levels exceeding 3 times ULN during the prior clozapine trial.
272
References
1. Fabrazzo, M., Prisco, V., Sampogna, G., et al. (2017). Clozapine versus other antipsychotics
during the first 18 weeks of treatment: A retrospective study on risk factor increase of blood
dyscrasias. Psychiatry Research, 256, 275–282.
2. Lee, J., Takeuchi, H., Fervaha, G., et al. (2015). The effect of clozapine on hematological indices:
A 1-year follow-up study. Journal of Clinical Psychopharmacology, 35, 510–516.
3. Lambertenghi Deliliers, G. (2000). Blood dyscrasias in clozapine-treated patients in Italy.
Haematologica, 85, 233–237.
4. Lee, J., Bies, R., Bhaloo, A., et al. (2015). Clozapine and anemia: A 2-year follow-up study.
5. Nasreddine, W. and Beydoun, A. (2008). Valproate-induced thrombocytopenia: A prospective
monotherapy study. Epilepsia, 49, 438–445.
6. Acharya, S. and Bussel, J. B. (2000). Hematologic toxicity of sodium valproate. Journal of
Pediatric Hematology and Oncology, 22, 62–65.
7. Chateauvieux, S., Eifes, S., Morceau, F., et al. (2011). Valproic acid perturbs hematopoietic
homeostasis by inhibition of erythroid differentiation and activation of the myelo-monocytic pathway.
Biochemical Pharmacology, 81, 498–509.
603–613.
9. Hummer, M., Kurz, M., Kurzthaler, I., et al. (1997). Hepatotoxicity of clozapine. Journal of Clinical
10. Erdogan, A., Kocabasoglu, N., Yalug, I., et al. (2004). Management of marked liver enzyme
increase during clozapine treatment: A case report and review of the literature. International Journal
of Psychiatry in Medicine, 34, 83–89.
11. Akuthota, P. and Weller, P. F. (2012). Eosinophils and disease pathogenesis. Seminars in
Hematology, 49, 113–119.
12. McArdle, P. A., Siskind, D. J., Kolur, U., et al. (2016). Successful rechallenge with clozapine after
treatment associated eosinophilia. Australasian Psychiatry, 24, 365–367.
14. Ho, Y. C. and Lin, H. L. (2017). Continuation with clozapine after eosinophilia: A case report. Annals
of General Psychiatry, 16, 46.
15. Pollmacher, T., Fenzel, T., Mullington, J., et al. (1997). The influence of clozapine treatment on
plasma granulocyte colony-stimulating (G-CSF) levels. Pharmacopsychiatry, 30, 118–121.
16. Hummer, M., Kurz, M., Barnas, C., et al. (1994). Clozapine-induced transient white blood count
disorders. Journal of Clinical Psychiatry, 55, 429–432.
17. Madhusoodanan, S., Cuni, L., Brenner, R., et al. (2007). Chronic leukocytosis associated with
clozapine: A case series. Journal of Clinical Psychiatry, 68, 484–488. 14
18. Sopko, M. A. and Caley, C. F. (2010). Chronic leukocytosis associated with clozapine treatment.
Clinical Schizophrenia & Related Psychoses, 4, 141–144.
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19. Focosi, D., Azzara, A., Kast, R. E., et al. (2009). Lithium and hematology: Established and
proposed uses. Journal of Leukocyte Biology, 85, 20–28.
20. Trinidad, E. D., Potti, A. and Mehdi, S. A. (2000). Clozapine-induced blood dyscrasias.
Haematologica, 85, E02.
21. Rodeghiero, F., Stasi, R., Gernsheimer, T., et al. (2009). Standardization of terminology,
definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: Report
from an international working group. Blood, 113, 2386–2393.
22. Kadir, R. A. and McLintock, C. (2011). Thrombocytopenia and disorders of platelet function in
pregnancy. Seminars in Thrombosis and Hemostasis, 37, 640–652.
23. Kate, N., Grover, S., Aggarwal, M., et al. (2013). Clozapine associated thrombocytopenia. Journal
of Pharmacology and Pharmacotherapy, 4, 149–151.
24. Atmaca, M., Kilic, F., Temizkan, A., et al. (2013). What about platelet counts in clozapine users?
Reviews of Recent Clinical Trials, 8, 74–77.
25. Lee, J., Powell, V. and Remington, G. (2014). Mean platelet volume in schizophrenia unaltered
after 1 year of clozapine exposure. Schizophrenia Research, 157, 134–136.
26. Conley, E. L., Coley, K. C., Pollock, B. G., et al. (2001). Prevalence and risk of thrombocytopenia
with valproic acid: Experience at a psychiatric teaching hospital. Pharmacotherapy, 21, 1325–1330.
27. Vasudev, K., Keown, P., Gibb, I., et al. (2010). Hematological effects of valproate in psychiatric
patients: What are the risk factors? Journal of Clinical Psychopharmacology, 30, 282–285.
28. Gonzales, M. F., Elmore, J. and Luebbert, C. (2000). Evidence for immune etiology in clozapine-
induced thrombocytopenia of 40 months’ duration: A case report. CNS Spectrums, 5, 17–18.
29. Malenica, M., Prnjavorac, B., Bego, T., et al. (2017). Effect of cigarette smoking on
haematological parameters in a healthy population. Medical Archives, 71, 132–136.
30. Morlan-Coarasa, M. J., Arias-Loste, M. T., Ortiz-Garcia de la Foz, V., et al. (2016). Incidence of
non-alcoholic fatty liver disease and metabolic dysfunction in first episode schizophrenia and related
psychotic disorders: A 3-year prospective randomized interventional study. Psychopharmacology
(Berlin), 233, 3947–3952.
31. Gaertner, H. J., Fischer, E. and Hoss, J. (1989). Side effects of clozapine. Psychopharmacology
(Berlin), 99(Suppl), S97–100.
32. Douros, A., Bronder, E., Andersohn, F., et al. (2015). Drug-induced liver injury: Results from the
hospital-based Berlin Case-Control Surveillance Study. British Journal of Clinical Pharmacology, 79,
988–999.
33. Wu Chou, A. I., Lu, M. L. and Shen, W. W. (2014). Hepatotoxicity induced by clozapine: A case
report and review of literature. Neuropsychiatric Disease and Treatment, 10, 1585–1587.
34. Eggert, A. E., Crismon, M. L., Dorson, P. G., et al. (1994). Clozapine rechallenge after marked
liver enzyme elevation. Journal of Clinical Psychopharmacology, 14, 425–426.
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15
QUICK CHECK
Special Topics: Child and Adolescent
Patients, Elderly Patients, Patients
With Intellectual Disability, Pregnancy
and Risk for Major Congenital
Malformation, Lactation, Overdose,
Postmortem Redistribution
Introduction 276
Principles 277
A Children and Adolescents 279
• Levels 282
• Adverse Effects 284
• Use in Mania 284
B Elderly 285
C Intellectual Disability 289
• Use of Clozapine in Nonpsychotic Adult ID Patients 290
• Use of Clozapine in Psychotic Adult ID Patients 291
D Pregnancy and Lactation 293
• Review of Clozapine and Pregnancy Outcomes 294
• Lactation 295
E Overdose 297
F Postmortem Redistribution 299
Summary Points 302
References 303
INTRODUCTION
Clozapine’s effectiveness for treatment-resistant schizophrenia and mania,

and its anti-aggressive properties, has led to trials for younger and older
patients with severe mental disorders, and for those with intellectual disability
(ID) who have treatment-resistant psychosis or nonpsychotic behavioral
disorders. There is a paucity of double-blind data supporting some of these
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15
PRINCIPLES
• Clozapine is effective for treatment-resistant adolescent and childhood onset

schizophrenia. Schizophrenia patients under age 18 may respond to plasma
levels below the response thresholds defined for adults (i.e. < 350 ng/ml or
< 1070 nmol/l). Lack of efficacy at these lower plasma levels should prompt
further titration, assuming no dose-limiting adverse effects.
• Initial titration for children and young adolescents is based on body weight
and tolerability. Patients under age 18 are more sensitive to weight gain, so
prophylactic metformin should be started along with clozapine. Very young
patients (age 8–13) started on clozapine may also develop akathisia in a
manner not seen with older adolescents or adults.
• Clozapine has been used successfully in older schizophrenia patients from
ages 65 to 100 years. Slower titrations must be used to minimize the risk
of sedation and orthostasis, both of which can result in falls. Older age is
not a reason to withdraw clozapine or refuse to commence clozapine in a
treatment-resistant schizophrenia patient. With advancing age (i.e. ≥ 70 years
of age), patients may require lower doses and maintain psychiatric stability
even with plasma clozapine levels below the response threshold of 350 ng/ml
or 1070 nmol/l.
• For intellectually disabled (ID) adults with treatment-resistant psychosis,
clozapine remains the antipsychotic of choice. There are limited data to
support use of clozapine to manage aggression and self-injurious behavior
in nonpsychotic adult ID patients, mostly derived from case reports. Careful
monitoring for adverse effects, especially constipation, is crucial in ID patients,
many of whom may lack communication abilities to adequately describe
somatic complaints.
• According to the latest research, atypical antipsychotics as a class do not
increase risk for major congenital malformations. For treatment-resistant
patients requiring clozapine, it should be continued throughout pregnancy, but
breastfeeding is precluded due to the risk of neutropenia in the infant.
• Clozapine shows a biphasic elimination process after overdose. Supportive
measures in a monitored hospital setting are needed to manage sedation,
orthostasis, tachycardia, myoclonus or seizure issues until plasma
15
continued overleaf
277
15: SPECIAL TOPICS
Principles continued
levels return to the patient’s therapeutic baseline. Clozapine remains

the antipsychotic of choice for schizophrenia patients with a history of
suicidality. Overdose is not a reason to discontinue clozapine treatment,
but to institute measures (e.g. restricted medication supply) to minimize its
recurrence.
• Clozapine is highly lipophilic and undergoes extensive postmortem
redistribution. Interpretation of postmortem drug levels requires knowledge
of the sample source (i.e. central or peripheral), and whether appropriate
measures were taken to isolate the peripheral blood vessel from central
sources.
uses, but a compelling picture of efficacy based on case series and a small
number of clinical trials. The common theme for these patient groups is
managing tolerability concerns through adjustment of initial titration, use of
plasma clozapine levels, and careful tracking of adverse effects. Pregnant
women represent a patient population with a different set of issues; however,
recent developments in the literature on major congenital malformations and
first-trimester antipsychotic exposure support the conclusion that atypical
antipsychotics as a class are not associated with increased risk [1]. This
finding is consistent with the available clozapine case data, and thereby
allows clinicians to focus their energies on monitoring for maternal gestational
diabetes, and minimization of postnatal exposure to avoid excessive sedation
in the newborn [2]. Clinicians should be familiar with the risk nomenclature
and data on psychotropics during breastfeeding as a matter of routine clinical
competence; however, due to risk of neutropenia, clozapine is the only
antipsychotic that is absolutely contraindicated in breastfeeding women [3].
Lastly, clozapine is associated with lower rates of self-harm in schizophrenia
spectrum patients compared to other antipsychotics, but intentional and unintentional
overdose do occur, and at times can lead to fatal outcomes [4]. Kinetic data provide useful
guidelines for monitoring patients shortly after the overdose. When clozapine-treated
patients expire due to natural or unnatural causes, the accuracy of postmortem drug
levels depends on a number of factors including time to postmortem examination and
implementation of procedures that minimize “contamination” from central blood sources
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15
[4]. An appreciation of the literature on postmortem redistribution of lipophilic molecules
such as clozapine, and the preferred methods for obtaining postmortem drug levels, is
crucial to anyone involved in such cases as the treating clinician, or as an expert witness.
A Children and Adolescents
Childhood-onset schizophrenia (COS), defined as symptom presentation before

the age of 13, is exceedingly rare, but many patients with schizophrenia will
present as teenagers, and a significant proportion of both groups will be identified
as treatment-resistant (see Table 15.1). In particular, COS is a model for treatment
resistance because most COS patients respond inadequately to nonclozapine
antipsychotics [5]. Unfortunately COS is so rare that a dedicated group at the US
National Institute of Mental Health (NIMH) managed to amass only 131 cases from
1990 to 2015 of patients started on clozapine therapy. Nonetheless, there are three
double-blind studies of treatment-resistant COS patients that point to clinically
meaningful efficacy differences compared to haloperidol or olanzapine, with the
largest effect size seen for negative symptom improvement. Although clozapine
treatment carries the same hematological monitoring burdens for children as for
adults, 72.5% of COS patients started on clozapine at NIMH or shortly thereafter
adhered to long-term clozapine therapy (≥ 2 years of treatment) with median dosage
Table 15.1 Summary of randomized, double-blind studies for childhood-onset

schizophrenia.
Study N Duration Mean age Mean Mean dose of Effect
(weeks) (years) clozapine comparator size for
dose (mg) (mg) outcomes
BPRS 0.26
Kumra, Haloperidol
21 6 14.0 ± 2.3 176 ± 149 SANS 1.16
1996 [58] 16 ± 8
CGAS 1.37
BPRS 1.0
Shaw, Olanzapine
25 8 12.3 ± 2.3 327 ± 113 SANS 0.7
2006 [59] 18.1 ± 4.3
CGI-S 0.6
BPRS 0.29
Kumra, Olanzapine
39 12 15.6 ± 2.1 403 ± 202 SANS 0.92
2008 [60] 26.2 ± 6.5
CGI-S 0.4
BPRS, Brief Psychiatric Rating Scale; SANS, Scale for the Assessment of Negative Symptoms;
CGAS, Children’s Global Assessment Scale; CGI-S, Clinical Global Impression – Severity. 15
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15: SPECIAL TOPICS
at follow-up of 500 mg/day (interquartile range: 275–500 mg/day) [5]. Despite the

early age at which clozapine was initiated, this retention rate significantly exceeds
that in adult patients, and speaks both to the long-term tolerability and comparative
efficacy of clozapine in COS. Children starting clozapine are also more sensitive to
akathisia, an uncommon adverse effect among adult clozapine patients [6]. The NIMH
group found akathisia in approximately 20% of their COS patients and recommends
vigilance for this adverse effect, as children often cannot describe the experience
adequately, and it can result in symptomatic worsening (see Box 15.1) [7]. The NIMH
group also found higher-than-expected rates of neutropenia, although this result may
be distorted by the large proportion of African Americans in the treatment cohort,
many of whom developed neutropenia (47%) using older ANC thresholds [8]. It is
thus unclear whether children are at higher neutropenia risk using the lower ANC
thresholds and BEN adjustments now present in the US. Without question children
are more sensitive to weight gain and lipid abnormalities, although these were
comparable to olanzapine in the double-blind trials [7]. All of the other common
adverse effects experienced in adults (e.g. constipation, orthostasis, sialorrhea,
tachycardia, enuresis) are also experienced by children, but without any pattern of
unusual sensitivity [7].
Unless working in a tertiary referral center, many clinicians can spend their
entire lives treating schizophrenia patients without encountering COS. Conversely,
adolescent-onset schizophrenia is quite common, with many programs dedicated to
early identification of treatment resistance in order to prevent unnecessary delays in
starting clozapine. As discussed in Chapter 1, a delay in commencing clozapine after
treatment resistance is recognized diminishes chances of response [9]. Despite the
association with earlier onset and treatment resistance, records of 112 adolescents
(mean age 15.2 years) at a German tertiary referral center found that 34% received
three or more antipsychotics before their first clozapine prescription, and 40%
received antipsychotic polypharmacy [10]. Although this prescribing pattern is
concerning, the mean time from first psychiatric hospitalization to clozapine initiation
was 1.1 ± 1.0 years, which compares favorably to general population data on
clozapine initiation. Using the Danish healthcare registry data from 1995 to 2006, 662
schizophrenia patients with onset before age 18 were located of whom only 17.6%
had started clozapine by December 31, 2008 [11]. There were three antipsychotic
trials on average prior to clozapine, and the mean time between first antipsychotic
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15
Box 15.1 Principles for Clozapine Use in Children and Adolescents
1. Clozapine is effective for childhood-onset schizophrenia (onset under age
13) and for treatment-resistant adolescent schizophrenia.
2. As younger age is associated with greater weight gain, prophylactic
metformin must be started at the outset. Metformin should be started at
500 mg with a meal once daily for 1 week, increased to 500 mg BID with
meals at week 2, and then slowly advanced by no more than 500 mg/
week. A metformin dose of 850 mg BID was well tolerated in children of
mean age 13.1 years [61]. If gastrointestinal adverse effects develop, try
extended-release preparations.
3. Titration should proceed based on tolerability (see Table 15.2), but a
reasonable starting dose is approximately 0.3 mg/kg rounded to the
nearest multiple of 6.25 mg (one-fourth of a 25-mg tablet). Thus, a 36-kg
11-year-old girl would receive 12.5 mg QHS as the initial dose, while an
adult-sized 16-year-old boy weighing 70 kg would start at 25 mg QHS.
The starting dose should never exceed 25 mg QHS due to concerns
about orthostasis and sedation.
4. Therapeutic levels seen in adults also achieve efficacy in children and
adolescents. These levels typically correspond to doses between 3.0 and
6.0 mg/kg, but many children and adolescents require higher doses and
plasma levels for sufficient efficacy. Management of adverse effects will
permit pursuit of higher plasma levels. As with adults there is generally
limited benefit for clozapine levels > 1000 ng/ml or > 3057 nmol/l.
5. The clozapine:norclozapine metabolic ratio (MR) of 1.32 seen in adult
nonsmokers is slightly higher in adolescents (1.60) [19]. The ratio may be
< 1.00 in children under 10.
6. Adverse effects: aside from weight gain, the only adverse effect that
is unusually common in COS and younger adolescents is akathisia,
occurring in approximately 20% [7]. The distress of akathisia not
uncommonly exacerbates underlying psychotic symptoms. Children may
not be able to describe akathisia symptoms clearly, so akathisia may
be unrecognized in a patient with worsening psychosis, prompting an
unnecessary increase in the clozapine dose. A high index of suspicion
must be maintained when worsening occurs during early titration or
shortly after a clozapine dose increase in a COS patient. Dose reduction
may prove diagnostic for akathisia as the cause of increased psychotic
symptoms. Propranolol starting in small doses (e.g. 5 mg TID) and
titrated as blood pressure tolerates is also effective in 50% of patients
[7]. Other adverse effects (e.g. constipation, sialorrhea, tachycardia,
seizures, etc.) are managed in the same manner as in adults, but doses of
medications may need to be adjusted for younger patients.
15
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15: SPECIAL TOPICS
treatment and clozapine initiation was 3.2 ± 2.9 years [11]. Underuse of clozapine
in adolescents remains a worldwide problem, with only 58.8% of patients deemed
eligible for a clozapine trial in an Australian first-episode psychosis program actually
starting clozapine [12].
The ability to recognize treatment resistance earlier in adolescent schizophrenia
patients is highlighted by the fact that onset before age 20 is associated with 2.5
times greater likelihood of treatment resistance, and for males threefold higher risk
[13]. Although onset in adolescence carries a better prognosis than COS, 10-year
follow-up data from 323 first-episode schizophrenia patients followed at the South
London and Maudsley NHS Trust showed that 23% were treatment-resistant.
Importantly, among those who were identified as treatment-resistant, 84% were
treatment-resistant from the onset of their illness [14]. For adolescents who are not
treatment-resistant, Cochrane meta-analyses published in 2013 and 2017 concluded
that there are few demonstrable efficacy differences between agents but significant
tolerability differences, especially with respect to weight gain [15,16].
Once an adolescent is identified as having schizophrenia, the possible need for
clozapine should be gently introduced as part of the concept that earlier onset is
associated with greater odds of treatment resistance. If the patient has failed two
antipsychotic trials (ideally with plasma levels to verify adequate exposure), clozapine
should be commenced as soon as possible, particularly when there has been minimal
response to prior treatment. Whether due to parent/guardian cooperation, or patient
recognition that other agents have offered little benefit, retention on clozapine remains
high in naturalistic settings, at rates very similar to those seen with the COS patients
started at NIMH. The Danish registry study found that 88.8% of patients prescribed
clozapine continued on it as evidenced by prescription refills [11]. A 2018 report from
a Melbourne first-episode program (mean age 19.5 years) also noted that 75.6%
of treatment-resistant patients started on clozapine remained on treatment [12]. In
addition, 76.6% of those who were commenced on clozapine achieved symptomatic
remission of positive psychotic symptoms by the time of discharge from the program
or transfer to adult mental health services.
• The data in COS and adolescent schizophrenia patients indicate that these
Levels
younger patients tend to respond at plasma clozapine levels slightly below the
thresholds used for adults, with response seen at times with levels < 300 ng/ml or
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15
< 917 nmol/l [7,17]. Nonetheless, as with adults, failure to respond after several
weeks at a particular plasma level is a reason to pursue further titration. In addition to
nonadherence and cytochrome P450 polymorphisms, age, gender and smoking status
will influence plasma clozapine levels. Data analyzed from 1408 samples obtained in
484 UK and Irish patients 8–17 years of age found that clozapine levels did correlate
with prescribed dose, and were 34% higher in females than in males, and 41% higher
in nonsmokers than in smokers. The mean metabolic ratio (MR), defined as the ratio of
clozapine to the metabolite norclozapine, is typically 1.32 in adults [18], but was 1.6 in
this large sample [19]. In young children aged 8–9 the plasma norclozapine level was
higher than that for clozapine, a finding noted in another small sample (n = 6) with
mean age of 13.3 years [17], but over time the MR assumes ratios closer to that seen
with adults as shown in Figure 15.1 [19].
Figure 15.1. Median clozapine and norclozapine plasma levels and median
clozapine dose by age in 1408 samples from 454 patients under age 18.
Clozapine
1000 Norclozapine 400
Dose
800
300
Clozapine Dose (mg/day)

Plasma Level (ng/ml)
600
200
400
100
200
0 0
8–9 10 11 12 13 14 15 16 17
(9) (23) (14) (63) (44) (74) (171) (352) (647)
Age
(number of samples)
(Adapted from: Couchman, L., Bowskill, S. V., Handley, S., et al. (2013). Plasma
clozapine and norclozapine in relation to prescribed dose and other factors in patients
aged <18 years: Data from a therapeutic drug monitoring service, 1994–2010. Early
Interventions in Psychiatry, 7, 122–130 [19].)
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• No unusual patterns of tolerability have been observed in children or adolescents

Adverse Effects
starting on clozapine with the one exception noted previously: COS and young
adolescent patients appear prone to developing akathisia in a manner rarely seen with
adult patients commencing clozapine [6]. While uncommon adverse events such as
myocarditis have been reported, there is no evidence of increased rates in younger
patients [12,20]. Tachycardia and orthostasis must be managed aggressively as
these appeared to be disproportionate causes of treatment discontinuation in a large
case series from an early psychosis service in Melbourne [12]. Adverse effects are
managed in the same manner as for adults, although doses of adjunctive medications
need to be adjusted in much younger patients. Consultation with a pediatrician can be
helpful to decide on initial doses and titration schedule of beta-adrenergic antagonists
for tachycardia, medications for constipation, and other agents.
• Some bipolar patients present early in life, and may experience mania
Use in Mania
that is resistant to treatment with usual combinations of mood stabilizers and

antipsychotics. Although there are no controlled data for adolescent mania, there
is one large case series describing the benefit of clozapine in 10 adolescent
Table 15.2. Child/adolescent clozapine titration.

Day Slower titration Day Faster titration
(mg QHS) (mg QHS)
1 12.5 1 12.5
3 25 3 25
6 50 5 50
9 75 7 75
12 100 9 100
15 125 11 125
18 150 13 150
21 175 15 175
24 200 17 200
QHS, at bedtime.
Comments:
1. All titrations must be adjusted based on tolerability, with sedation, orthostasis and
tachycardia being important limiting adverse effects. In childhood-onset schizophrenia,
akathisia with clozapine is also reported in a manner not seen with adults (see Box 15.1). As
with adults, a faster titration may be possible in inpatient settings where vital signs can be
monitored daily.
2. Unlike adults, the use of divided doses early in treatment may be necessary; however, the
bulk of the clozapine dose should be administered at bedtime.
3. A plasma clozapine level should be obtained at 100 mg/day, ideally after 4–5 days on that dose.
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inpatients (age range 12–17) with severe treatment-resistant acute manic or
mixed episodes [21]. All patients were successfully discharged after 15–28 days of
clozapine treatment, and changes in mood rating scales and in the Clinical Global
Impression – Severity scale were significant (p < 0.001). The mean clozapine dose
at time of discharge was 142.5 ± 73.6 mg/day (range 75–300 mg/day). Although
adverse effects did occur (sedation, enuresis, sialorrhea, increased appetite),
these were not severe enough to warrant dosage reduction. Long-term follow-up
(12–24 months) revealed a mean 10.7% weight gain, but no episodes of seizures
or neutropenia [21].
B Elderly
Treatment of older patients (i.e. those ≥ 60 years of age) creates concerns
related to increased intolerance of certain adverse effects, combined
with reduced drug clearance [22]. Aside from the double-blind studies for
Parkinson’s disease psychosis (see Chapter 1), there are no prospective
studies specifically targeting the use of clozapine for older severely mentally
ill patients; however, there are a number of papers that have retrospectively
examined outcomes in nondemented patients with schizophrenia spectrum
disorders. While many of these papers include data on older patients who
had been started on clozapine when younger, one group provided outcomes
data on 43 Israeli schizophrenia patients of mean age 69.4 ± 8.7 years, all
of whom were new starts to clozapine [23]. These patients had been ill on
average 39 years and had all failed at least three first- and second-generation
antipsychotics. Clozapine was well tolerated with no patients having to stop
treatment due to adverse effects. Plasma levels were not provided, but the
mean clozapine dose was 264 ± 110 mg/day (range 25–700 mg/day). Over
the next 5 years, psychiatric hospitalization rates were significantly lower than
for the 5-year period prior to clozapine therapy (0.41 vs. 3.8; p < 0.001). The
authors also noted that the mortality rate in the clozapine-treated cohort was
equal to that for other older schizophrenia patients treated at the same clinic
with nonclozapine antipsychotics [23].
The titration used in older patients is limited by tolerability, especially those
adverse effects that can contribute to fall risk [24]. As with younger adults, failure
to respond after several weeks at a particular plasma level without dose-limiting
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adverse effects is a reason to pursue further titration. The mean dose at which
older schizophrenia patients respond may be lower than that used with younger
patients even after controlling for differences in smoking behavior. Consistent
with the Israeli data noted above, dosing records from 778 UK and Irish elderly
schizophrenia patients (363 males, median age 67, range 65–100 years; 415
females, median age 68, range 65–90 years) yielded a median dose of 300 mg/
day in those aged 65–70 years, and 200 mg/day in those aged 75 and older (see
Figure 15.2) [25]. An important contributor to tolerability issues is decreased drug
metabolism with advanced age, along with decreased body mass. More than 1900
plasma level samples were obtained from this UK/Irish cohort, and the metabolic
ratio (MR) was 1.8 in this older patient sample, higher than the value of 1.32 in
younger adults [25]. Importantly, the plasma clozapine level was estimated to
Figure 15.2 Median clozapine and norclozapine plasma levels and median
clozapine dose by age in 1930 samples from 778 patients age 65 and older.
Clozapine
1200 Norclozapine 350
Dose
300
1000
Clozapine Dose (mg/day)

250
800
200
600
150
400
100
200
50
0 0
65–69 70–74 75–79 80–84 85+
(1215) (480) (161) (49) (25)
Age
(number of samples)
(Adapted from: Bowskill, S., Couchman, L., MacCabe, J. H., et al. (2012). Plasma
clozapine and norclozapine in relation to prescribed dose and other factors in patients
aged 65 years and over: Data from a therapeutic drug monitoring service, 1996–2010.
Human Psychopharmacology, 27, 277–283 [25].)
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Table 15.3 Clozapine titration for nonsmoking schizophrenia patients age 65 and
above not receiving cytochrome P450 inhibitors.
Day Dose (mg QHS)
1 12.5
3 25
6 50
9 75
12 100
15 125
18 150
21 175
24 200
QHS, at bedtime.
Comments
1. All titrations must be adjusted based on tolerability, with sedation, orthostasis and
tachycardia being important limiting adverse effects as they contribute to fall risk. As with
younger adults, a slightly faster titration may be possible in inpatient settings where vital
signs can be monitored daily. Clozapine levels in nonsmokers are 32% higher than for
smokers, so the titration in smokers can be increased by 33% (i.e. advancing the dose
every 2 days instead of every 3 days).
2. A plasma clozapine level should be obtained at 150 mg/day. A greater proportion of older
schizophrenia patients may respond at plasma levels below the response threshold seen
with younger adults (< 350 ng/ml or < 1070 nmol/l). In large naturalistic samples, the
median dose was 300 mg/day in those aged 65–70 years, and 200 mg/day in those aged
75 and older.
increase by 3% for each 10 kg decrease in body weight from 74 kg (the cohort
mean weight). Thus, as people advance beyond the age of 65, tracking plasma
clozapine levels is key to minimizing level creep that can be associated with aging.
Not only might patients require lower daily doses to maintain equivalent plasma
levels, they may remain psychiatrically stable at plasma levels below those needed
in prior decades, at times even below the response threshold of 350 ng/ml or
1070 nmol/l [25].
• There are a small number of adverse effects to which older patients are
Adverse Effects
more prone including the central nervous system (CNS) impact of histamine H1
antagonism and cholinergic antagonism, orthostasis from peripheral alpha1-
adrenergic blockade, and anticholinergic impact on gastrointestinal motility and
urination (in males) [24]. Mitigation of early problems with orthostasis or sedation
is crucial because even mild problems with alertness or dizziness can result in
15
a fall that itself can have catastrophic consequences. Although early analyses
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Box 15.2 Principles for Clozapine Use in Schizophrenia Patients ≥ 60 Years Old
1. Plasma clozapine levels may be higher for a given dose due to age-
related decreases in cytochrome P450 activity, and possibly lower serum
albumin levels. The clozapine:norclozapine metabolic ratio (MR) of 1.32
seen in younger adults is higher in those age 65 and older (MR = 1.8)
[25].
2. Older patients will be more sensitive to orthostasis and sedation, with
the net effect being higher fall rates than in younger patients. The starting
dose should be no higher than 12.5 mg QHS, and a slower titration must
be used in this age group along with careful monitoring of orthostatic vital
signs, and prompt action for complaints of dizziness or gait instability
(see Table 15.3).
3. Patients aged 65 and older will often require plasma clozapine levels
above the response threshold of 350 ng/ml or 1070 nmol/l; however,
there will be a substantial proportion of these older patients who achieve
therapeutic benefit with plasma levels below this threshold.
4. In established patients on clozapine, doses may need to be reduced as
the patient reaches age 65 due to tolerability reasons, or due to higher
plasma levels from reduced rates of drug metabolism. Possibly due to
reduced absorptive capacity, plasma levels decline in patients starting at
age 80 despite remaining on the same dose.
5. Adverse effects: older patients are more sensitive to developing
orthostasis (as noted above). They are also more sensitive to the sedating
effects of histamine H1 antagonism, and to anticholinergic effects
including CNS issues (sedation, confusion or delirium) and peripheral
adverse effects (constipation, urinary retention [in males]) [24]. The
management of adverse effects is similar to that for younger patients but
with greater diligence during the titration phase, and the possible need
for expert consultation due to comorbid medical problems, or complex
nonpsychiatric medication regimens that pose risk for drug–drug
interactions.
indicated an association between older age and neutropenia risk [26], this is
not consistently seen in later literature. Older patients need not be subjected to
hematological monitoring that differs from that in younger individuals. Once on
established therapy, attentiveness to peripheral anticholinergic issues including
constipation and urinary retention (in males) is important due to the higher
age-related prevalence of these problems independent of clozapine treatment.
Treatment of adverse effects is the same as for younger patients, bearing in mind
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15
the complexity of nonpsychiatric medical conditions and medications. Consultation
with a geriatrician can prove useful in circumstances where there is uncertainty
about a course of action due to underlying medical disorders or possible
interactions with other medications. With these caveats in mind, the data sets from
Israel and UK/Ireland indicate that clozapine has been used in patients up to age
100. The conclusions from this research are twofold: (a) schizophrenia spectrum
patients can be maintained on clozapine throughout their lifetime; and (b) patients
65 years of age and older need not be deprived of a clozapine trial solely on the
basis of age.
C Intellectual Disability
Intellectual disability (ID) patients represent a heterogeneous cohort of

individuals, some of whom manifest identifiable psychosis symptoms, while others
present problematic behaviors (e.g. self-injury, aggression) that do not respond
to behavioral interventions. Certain atypical antipsychotics have been approved
in the US and elsewhere for treatment of irritability associated with autistic
disorder in children and adolescents aged 5–16 years [27], but there are very few
double-blind, placebo-controlled studies of antipsychotic use in ID adults, with
clozapine being no exception. Although psychosis afflicts no more than 3% of the ID
population, antipsychotics are widely prescribed for behavioral disturbances despite
limited controlled studies supporting efficacy, tolerability, or improved quality of
life [28,29]. One significant problem for pharmacological trials in ID adults relates
to recruitment of a vulnerable population for medication studies. A 2010 paper
summarizes these challenges in describing the hurdles to recruiting aggressive
adult ID patients in Queensland, Australia to participate in a double-blind trial
comparing risperidone, haloperidol and placebo. The authors note that clinician
concerns over the efficacy of antipsychotics in these patients, ethical concerns
over medication trials in the ID population, and practical issues with engaging
treatment teams were all impediments [30]. The investigators did manage to recruit
86 subjects out of the intended sample of 120, and found that aggression declined
dramatically in all groups by 4 weeks, with placebo showing a 79% reduction in
aggressive events, compared to 57% reduction for the combined antipsychotic
cohort (p = 0.06) [31].
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• With the paucity of controlled data supporting obvious efficacy advantages for
Use of Clozapine in Nonpsychotic Adult ID Patients
nonclozapine antipsychotics in adult ID patients without psychosis, widespread

use of antipsychotics to manage challenging behavior is not the standard of care.
Nonetheless, there are instances where antipsychotics may prove useful, and
clinicians must develop expertise in managing their safe use in this patient group.
A leading expert on psychotropic use in the adult ID population, Professor Jose
De Leon MD (University of Kentucky Mental Health Research Center, Lexington,
KY) published a comprehensive guideline on the use of nonclozapine atypical
antipsychotics in ID adults, including information on: initiation, dosing, drug–drug
interactions, adverse drug reactions, and discontinuation syndromes [32]. (Note: this
review also provides drug utilization review forms for nonclozapine antipsychotics
to facilitate implementation of the guidelines.) In a manner analogous to the use of
clozapine for treatment-resistant mania, the application of clozapine for behavioral
disturbances in nonpsychotic adult ID patients has largely been motivated by lack of
response to traditional treatment, in this instance to the combination of behavioral
interventions and other psychotropics. Supporting this logic is the literature noting
that clozapine has unique benefits for suicidality and aggression, benefits that are
independent of its antipsychotic effects [33]. (See Chapter 1 for additional discussion
of clozapine’s anti-aggressive properties.) The literature on use of clozapine for
behavioral disturbances in nonpsychotic ID patients extends back to a 1974
publication describing 40 adolescents (mean age 16.4 years) with mild to profound
ID treated with clozapine in 1971–1972 [34]. Of note, 80% of those in the higher
IQ range (36–59) had good or very good improvement compared to only 20% of
those with more profound ID. Since that publication there have been several dozen
case reports and series published covering clozapine use in adult ID cohorts, but no
controlled studies and few papers mention use of any rating scales beyond a general
global impression [35]. When global impressions are reported, 14/14 papers noted
improvement. The doses employed ranged from 25 to 900 mg/day, but the dose
ranges cited most often are 200–500 mg/day, somewhat lower than those used for
treatment-resistant schizophrenia. The reasons for this are twofold: (a) the majority
of these patients are nonsmokers; (b) the anti-aggression effect of clozapine is
seen at lower plasma levels than that required for resistant schizophrenia [36].
As the majority of reports cite doses ≥ 200 mg/day, this is a reasonable target for
the initial titration, assuming tolerability. As will be discussed below in the section
on Adverse Effects, vigilance has to be maintained for all adverse effects but
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15
particularly constipation and orthostasis, as patients may not be able to adequately
verbalize these complaints. Before proceeding to higher dosages and plasma
clozapine levels, it is reasonable to allow at least 2–3 weeks to observe changes in
behavior patterns, bearing in mind the results of the Queensland study that indicate
a natural fluctuation in the frequency of aggression in adult ID patients. Longer
observation periods might be required before deciding that a particular dose/plasma
level is ineffective, especially when the problematic behavior is infrequent. When
problematic behaviors go into remission for extended periods, it is not unreasonable
to gradually taper down clozapine to ascertain whether there is ongoing need for this
medication, especially when environmental or behavioral interventions have been
implemented that may address precipitating circumstances for the behaviors.
• For ID patients with treatment-resistant schizophrenia clozapine remains

Use of Clozapine in Psychotic Adult ID Patients
the medication of choice, but this conclusion is not based on controlled trials, of
which there are none. This statement is derived solely from the absence of viable
therapeutic options, and the 31 publications (case reports or series, retrospective
chart reviews) that document improved psychiatric outcomes in psychotic adults
with ID that inadequately respond to nonclozapine antipsychotics [37]. Among the
largest case series in the past 20 years is a sample of 33 treatment-resistant ID
patients (17 male, 16 female) managed at an academic hospital in North Carolina,
88% diagnosed with psychotic disorders, and 12% diagnosed as bipolar I [38]. The
patients were of mean age 40 years, and were titrated using standard adult dosing
starting at 25 mg/day. All 33 patients were successfully discharged on clozapine
after a mean hospital stay of 39.9 ± 16.6 days, and 26 remained on clozapine as
outpatients through a mean 25 months of follow-up at a median dose of 400 mg/
day. Among the seven who stopped clozapine as outpatients, two were due to poor
adherence, four due to perceived lack of efficacy, and one was lost to follow-up.
Side effects were described as “mild and transient,” with constipation being the
most prevalent (30%). There were no significant cardiovascular side effects, no
seizures, and no treatment discontinuation due to severe neutropenia [38]. A 2004
paper described outcomes in 24 treatment-resistant adult ID patients managed at
a London, UK treatment center [39]. The cohort was 83% schizophrenia spectrum
disorders, 8% bipolar disorder, and 8% with no diagnosis other than ID. The patients
were of mean age 38 years, and had four antipsychotic trials on average prior to
clozapine. The mean maximum dose of clozapine was 488 mg/day, and 71% were 15
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deemed much improved or very much improved. Importantly, 53% of those from the
medium secure unit were discharged to homes in the community. Only four patients
discontinued treatment, three of which were due to neutropenia and one due to
worsening diabetes mellitus [39].
Box 15.3 Principles for Clozapine Use in Adult Patients with Intellectual Disability
1. For adult ID patients with treatment-resistant schizophrenia spectrum or
bipolar I disorders, target doses are generally comparable to those for
non-ID patients.
2. For nonpsychotic adult ID patients with behavioral disturbances, effective
doses may be lower than those often required for treatment-resistant
schizophrenia.
3. The starting dose should be no higher than 25 mg QHS, and a slower
titration is recommended to minimize issues with orthostasis and sedation.
Daily monitoring of orthostatic blood pressure is important during the first
2 weeks of treatment and for several days after dose increases. A daily
temperature should be obtained during the first 8 weeks of treatment, as
this is the risk period for developing myocarditis, interstitial nephritis and
other systemic drug reactions. Moreover, this patient group may be unable
to verbalize complaints of malaise or systemic symptoms that suggest a
serious drug reaction during the first 8 weeks of treatment.
4. Adverse effects: there is no unusual pattern of sensitivity, but vigilance
must be observed for any sign of constipation, as patients may be unable
to report issues until they become catastrophic. It may be preferable to
be aggressive with laxative use to the point of causing loose stools than
risk a patient developing ileus. A similar logic applies to the management
of sialorrhea: patients may not complain of nocturnal sialorrhea and thus
remain at risk for aspiration pneumonia unless aggressively managed.
Prophylactic metformin should also be started at the onset of clozapine
therapy to minimize weight gain. The general management of other
adverse effects is similar to that for non-ID patients.
• There is no unusual pattern of sensitivity to adverse effects in the adult ID

Adverse Effects
population, but constipation looms as the most easily overlooked and potentially life-
threatening problem in a group that may have limited verbal abilities or underreport
somatic complaints. Aggressive management of weight gain with prophylactic
metformin, sialorrhea with orally applied agents and constipation with use of multiple
agents should start early in treatment, as outlined in Box 15.3. Protocols must be
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15
in place to act promptly when initiatives to address adverse effects, especially
constipation, do not meet with results in a timely manner. For constipation, this is set
at 48 hours (see Chapter 7). For outpatients, appropriate education of caregivers is
a crucial part of the management process, as they will be the ones to note adverse
effects, implement measures to manage adverse effects, and quickly report the
success (or lack thereof) of new treatments.
D Pregnancy and Lactation
Antipsychotics have been available for 60 years without compelling evidence

of increased risk for major congenital malformations following first-trimester
exposure [40]. Nonetheless, the earlier literature was comprised primarily of case
reports and other nonsystematic collections of case data. Moreover, attempts
to perform comparative analyses with control groups were complicated by the
problem of confounding bias: those who received antipsychotics prior to 2000
were primarily schizophrenia spectrum patients, and thus had all of the associated
risks (e.g. smoking, substance use) and care access issues not seen in a control
group. Thus, any differential pregnancy outcome might be more related to the
cohort of women who received antipsychotic therapy, and not to the medication
itself [1].
With the broader use of antipsychotics for mood and other disorders, an
opportunity arose to examine a more diverse population of exposed women. In 2016,
Krista Huybrechts, PhD and her group in the Division of Pharmacoepidemiology and
Pharmacoeconomics at Harvard Medical School published a study that overcame
many of the limitations of the prior literature [1]. Using US data from 1,341,715
pregnancies in women enrolled in a Medicaid program from 3 months before their last
menstrual period through at least 1 month after delivery, the investigators identified
9258 pregnancies with a prescription for an atypical antipsychotic and 733 with
prescriptions for a typical antipsychotic that were filled during the first trimester (total
n = 9991). In addition to matching this sample with a control group for covariates
associated with increased risk of adverse birth outcomes, the two cohorts were also
matched on the basis of propensity scores. One important source of bias in pregnancy
outcome studies may depend more on characteristics that influence whether a
woman received antipsychotic therapy (e.g. diagnosis age, geographic location, race,
etc.). This issue can be managed in randomized studies because the likelihood of
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treatment exposure is equal. For naturalistic data sets, the assignment of treatment
is not random. Propensity score matching addresses the unevenness in real-world
drug prescribing by matching the antipsychotic-exposed and unexposed women on
the basis of empirically derived factors that influenced the likelihood (or propensity)
of getting an antipsychotic among the 1,341,715 pregnancies in this data set. The
groups can then be balanced for important covariates that relate to the outcome,
major congenital malformations.
As a point of comparison, data from the US put the rate of major congenital
malformations at 2–4% of live births, or 20–40 per 1000. In the Huybrechts study,
the absolute risks for major congenital malformations per 1000 live-born infants was
38.2 (95% CI 26.6–54.7) for those treated with typical antipsychotics and 44.5 (95%
CI 40.5–48.9) for those treated with atypical antipsychotics compared to 32.7 (95%
CI 32.4–33.0) for untreated women [1]. However, in the fully adjusted analysis, there
was no increased relative risk (RR) in the atypical antipsychotic exposed infants for
malformations overall (RR 1.05; 95% CI 0.96–1.16) or for cardiac malformations
(RR 1.06; 95% CI 0.90–1.24). In contrast, the risk remained elevated for risperidone,
especially among those who filled ≥ 2 prescriptions or had ≥ 1-day supply in the
first trimester (RR for any malformation 1.46 [95% CI 1.01–2.10]; RR for cardiac
malformations, 1.87 [95% CI 1.09–3.19]) [1]. Unfortunately, there were no clozapine-
exposed women in this large sample. Nonetheless, the important conclusion from
this study is that atypical antipsychotics as a class do not appear to be associated
with increased risk for major congenital malformations, although statements about
individual agents cannot be made due to lack of large samples. Risperidone is possibly
an exception, but the finding in this study requires replication from another data
source.
• In 2017, the British Association for Psychopharmacology published a consensus

Review of Clozapine and Pregnancy Outcomes
guidance paper on the use of psychotropic medication during preconception,

pregnancy and the postpartum period [3]. Using data from the Huybrechts study and
numerous other sources, the British Association for Psychopharmacology concluded
that if a woman is established on clozapine prior to conception, she should continue
with clozapine if the benefits are likely to outweigh the risks. This conclusion is
bolstered by a comprehensive review of clozapine safety during pregnancy and
lactation also published in 2017 [2]. The authors found four case-control or cohort
studies (n = 61), one summary paper (n = 102), individual case reports or case series
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15
(n = 18), and information located in the Novartis database (n = 523) [2]. With respect
to maternal risk, the only adverse effects noted were weight gain and a higher rate
of gestational diabetes mellitus (DM). The latter is based on a case-control analysis
of 11 clozapine-treated women that found a 2.4-fold increased risk of gestational
DM compared to controls without mental illness and receiving no antipsychotic
treatment [2]. Disentangling the specific impact of clozapine on risk of major
congenital malformations in a group of women with serious mental illness, some of
whom are taking multiple psychotropic medications or have behaviors associated
with adverse fetal outcomes (e.g. smoking, substance use, etc.), is fraught with many
of the issues noted at the beginning of this section. Nonetheless, the large data set
from Novartis noted 22 major congenital malformations among 523 cases (42.1 per
1000 live births), a rate very similar to the crude rate of 44.5 per 1000 live births for
those treated with the class of atypical antipsychotics in the Huybrechts study. The
limited data on miscarriages also do not point to increased risk. Due to clozapine’s
sedating properties and impact on seizure threshold, there are multiple case reports
of floppy infant syndrome at delivery and neonatal seizures. As noted in Box 15.4,
decreasing clozapine exposure in the 48 hours prior to delivery may help minimize
risk of seizures or poor infant tone. The dose reduction should be modest (i.e. ≤ 50%),
as discontinuing clozapine abruptly will induce cholinergic rebound or psychiatric
decompensation.
• Breastfeeding provides enormous benefits for mother and baby by strengthening

Lactation
the maternal bond and providing the infant with secretory antibodies and nutrients
important to short-term and long-term health [41]. Given the modern efforts to
encourage breastfeeding, a leading expert in the field (Thomas W. Hale, PhD,
Department of Pediatrics, Texas Tech University School of Medicine) has created
a risk classification scheme to help clinicians advise women taking a variety of
medications about the benefits and risks of breastfeeding [41]. The Hale classification
uses empirical observations combined with relative infant dose estimates (a method
to calculate infant drug exposure) to rank medications on a scale from L1 to L5
based on the degree of compatibility with breastfeeding. L1 is defined as compatible,
meaning that this is a widely used medication with supporting controlled trials
showing no adverse effects. The other categories are: L2, probably compatible;
L3, possibly compatible; L4, possibly hazardous; and L5, hazardous. Although the
quality of studies and accuracy of relative infant dose calculations for antipsychotics 15
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Box 15.4 Use of Clozapine during Pregnancy

1. As a class, atypical antipsychotics do not increase risk for major
congenital malformations following first-trimester fetal exposure [1].
On the basis of the accumulated data, the British Association for
Psychopharmacology concluded that if a woman is established on
clozapine prior to conception, she should continue with clozapine if the
benefits are likely to outweigh the risks.
2. For treatment-resistant schizophrenia or mania patients, the lack of
viable treatment options tilts the risk–benefit equation towards remaining
on clozapine. Poorly managed or relapsed severe mental disorders are
associated with worse pregnancy outcomes.
3. Use of clozapine during pregnancy is associated with 2.4-fold increased
risk for gestational diabetes mellitus (DM) compared to mothers not
taking antipsychotics [2]. How much of this risk can be separately
attributed to factors associated with the mental illness or clozapine is
unclear, but increased monitoring for gestational DM is recommended.
4. If possible, consideration can be given to modestly reducing the
clozapine dose in the 48 hours prior to delivery to minimize the risk
of floppy infant syndrome at delivery and neonatal seizures. The dose
reduction should be modest (no greater than 50%) to lessen risk of
psychiatric destabilization and cholinergic rebound symptoms. The full
clozapine dose must be resumed immediately following delivery.
5. Clozapine is highly lipophilic and accumulates in breast milk. Due to the
risk of severe neutropenia in the infant, breastfeeding is contraindicated.
is weak, nonclozapine antipsychotics are L2 or L3 level risk, meaning probably or

possibly compatible [41,42]. Were the antipsychotic any agent other than clozapine,
one could parse through the data to understand the extent of infant exposure and
possible adverse effects. The relative infant dose exposure for clozapine is quite low
(1.4%), but unfortunately clozapine presents a unique source of infant risk that is
not dose-dependent – severe neutropenia. For this reason, the British Association
for Psychopharmacology 2017 guidance paper advises that breastfeeding while on
clozapine is not recommended due to the risk of neutropenia in the infant [3]. The
subsequent 2017 review on the safety of clozapine during pregnancy and lactation
also noted that in a case series of four breastfed infants, one developed severe
neutropenia [2]. The true incidence of severe neutropenia in breastfed infants may
never be known, but at the present time the risk of this potentially fatal complication
appears to outweigh the multiple benefits of breastfeeding.
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E Overdose
In colloquial usage overdose most commonly refers to intentional acts, but

clinicians must be mindful that iatrogenic causes of excessive drug exposure (e.g.
unrecognized drug–drug interactions) or other kinetic issues (e.g. smoking cessation)
are all possible etiologies [4,43,44]. In most instances the need for supportive care
will be obvious; however, the decision to refer a patient for hospital evaluation and
monitoring should be based on the clinical scenario and not just the plasma clozapine
level (see Chapter 5, Response to Levels Markedly Above or Below Expected Values,
and Suspected Nonadherence). Spurious plasma clozapine levels that appear
inconsistent with the clinical presentation are a reason to repeat the plasma level. For
example, the laboratory returns a plasma clozapine level of 1400 ng/ml or 4280 nmol/l
in a patient on a stable clozapine dose whose baseline plasma level is 700 ng/ml or
2140 nmol/l. If the patient shows no evidence of sedation, orthostasis, tachycardia or
other plasma level-related adverse effects, and there is no viable explanation for the
sudden jump (e.g. smoking cessation), suspicion of laboratory error should be high.
The presentation in intentional clozapine overdose cases relates in part to the
dosage consumed, the presence of other medications or substances, and whether
the patient has been adherent with clozapine treatment and thus tolerant to some
degree to its adverse effects [45]. The leading expert on clozapine overdose (Dr.
Robert Flanagan, Medical Toxicology Unit, Guy’s and St Thomas’ NHS Foundation
Trust, London) notes that a dose of 300 mg in a clozapine-naive adult can cause
unconsciousness, while 400 mg may be life-threatening [45]. Conversely, a 19-year-
old female on clozapine 400 mg/day who ingested 5000 mg intentionally was
reported to suffer only from somnolence, intermittent agitation, tachycardia and slight
hypotension despite a plasma clozapine level 2.5 hours after ingestion of 3800 ng/
ml or 11,600 nmol/l [46]. Adults have survived ingestions as high as 10,000 mg, but
the degree to which an overdose is survivable primarily depends on the rapidity of
supportive care, with case reports in clozapine-naive toddlers, children and teenagers
describing complete recovery after receipt of prompt hospital interventions [47–50].
In addition to profound CNS depression, hypotension, tachycardia, generalized seizure
activity and myoclonus are not uncommon, and QT prolongation may also occur [48,
51–53]. The presence of rhabdomyolysis has been reported and is hypothesized to
be an epiphenomenon of myoclonic jerking. Significant elevations of creatine kinase
(>> 5000 U/l) require appropriate intravenous hydration to minimize risk of acute
renal tubular necrosis from myoglobin deposition [48]. Thromboembolic events have 15
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15: SPECIAL TOPICS
also been reported, so patients with prolonged hospital stays may require prophylaxis
[53]. Other complications related to aspiration of gastric contents, gastrointestinal
hypomotility, and circulatory collapse can occur and require specific management.
The 12-hour trough metabolic ratio (MR) (defined as the ratio of
clozapine:norclozapine) is typically 1.32 in adult nonsmokers, but shortly after an
overdose this will be increased markedly, with median MR values of 7.6 (range
5.3–18) noted among samples obtained soon after hospital admission [45]. The high
MR values are related to two processes: (a) the time since drug consumption may be
relatively short (e.g. several hours) so insufficient time has elapsed for conversion of
clozapine to norclozapine; (b) the metabolism of clozapine is primarily dependent on
cytochrome P450 (CYP) 1A2, and this mechanism becomes saturated at high plasma
clozapine levels [43]. As a result of these kinetic processes and delayed absorption,
clozapine and norclozapine clearance demonstrate a biphasic elimination curve
(Figure 15.3). Although single overdose cases and small series report a clozapine half-
life estimate in these circumstances < 20 hours, pharmacokinetic modeling software
using a larger Chinese cohort (n = 21) with mean overdose of 3740 mg (range
1250–10,000 mg) calculated a clozapine elimination half-life of 26.9 hours [50]. This
extended half-life may explain cases of prolonged tachycardia that persist up to 10
days after the overdose event [48]. Based on serial monitoring of plasma clozapine
levels, a time can be chosen to resume clozapine treatment when plasma levels
are at or expected to be slightly below the patient’s baseline. Withholding clozapine
for prolonged periods risks symptoms of cholinergic rebound as well as psychiatric
destabilization, all of which may complicate ongoing medical treatment.
For treatment-resistant schizophrenia or schizophrenia patients with a history
of suicidality, intentional overdose is not a reason to discontinue clozapine therapy,
as there are no viable therapeutic alternatives. Moreover, circumstances leading
to the overdose must be investigated to determine whether the precipitant was
related to undertreatment (e.g. subtherapeutic plasma clozapine levels) or clozapine
nonadherence, because both will be associated with increased suicide risk [45].
When recent plasma levels and other clinical data (e.g. medication refill records,
observed medication adherence) point to consistent medication adherence, other
stressors, borderline personality disorder or substance use may underlie the
overdose. In all instances of an intentional overdose, measures should be taken
to limit medication access. For suboptimally treated or poorly adherent patients,
routine monitoring of plasma clozapine levels is crucial to insuring that clozapine
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15
Figure 15.3. The time course of plasma clozapine and norclozapine levels in an
overdose case.
5000
500
Clozapine
Norclozapine
50
0 10 20 30 40 50 60 70 80 90 100 110 120 130
Time (Hours)
(Adapted from: Renwick, A. C., Renwick, A. G., Flanagan, R. J., et al. (2000).
Monitoring of clozapine and norclozapine plasma concentration-time curves in acute
overdose. Journal of Toxicology and Clinical Toxicology, 38, 325–328 [43].)
levels remain at the therapeutic threshold for that patient. For adherent patients
with personality disorder or substance use diagnoses, appropriate evidence-based
therapies must be provided including dialectical behavior therapy for borderline
personality disorder patients [54].
F Postmortem Redistribution
Fatal overdoses on clozapine are relatively less common than deaths from other
causes in clozapine-treated patients, but the contribution of clozapine to the patient’s
demise can become an issue when postmortem drug levels appear markedly elevated
[45]. When extensive time may have elapsed after death and before blood samples
15
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are obtained, postmortem redistribution of lipophilic antipsychotics occurs resulting

in distorted levels and inappropriate conclusions about the cause of death. This is
especially true when samples are not obtained from femoral veins but central sources
such as heart, vena cava or liver where postmortem redistribution effects are most
pronounced [55]. The first report discussing postmortem redistribution of clozapine
did not appear until 2003, and was based on the doubtful validity of an intracardiac
clozapine blood level of 4500 ng/ml (13,750 nmol/l) obtained from a deceased
patient who had been on a stable clozapine dose of 350 mg/day and who had refused
clozapine for 24 hours before her death [56]. The expected trough plasma level in
a female nonsmoker on 350 mg/day would be less than 500 ng/ml or 1500 nmol/l,
and presumably even lower due to medication refusal prior to death [18]. To explore
the correlation between antemortem and postmortem drug levels and MR values in
patients whose death was not due to clozapine overdose, Flanagan examined cases
from the UK/Ireland Clozaril Registry 1992–2003 [45]. In 38 cases where postmortem
drug levels were obtained the median MR was 1.5, very similar to the value of 1.32
expected in the general population, and markedly lower than that seen in fatal and
nonfatal overdose cases (4.4 and 7.6, respectively) [45]. Of these 38 cases, 21
also had plasma levels obtained within 30 days of death (median 14 days), with
no clozapine dose changes in 19/21 since the last level was obtained. The median
increase in postmortem levels was substantial: clozapine +489% and norclozapine
+371%; however, the median MR increased only from 1.03 to 1.56 [45]. Subsequent
data from animal studies and human cases have defined a number of considerations
in interpreting postmortem levels in clozapine-related deaths [45,55] (see Box 15.5).
The two most important principles are: (a) central postmortem clozapine levels are
unreliable and differ by 10-fold or more from those obtained in a peripheral vein;
(b) under ideal circumstances samples obtained from femoral veins may rise as much
as 1.5-fold after death even when the vein is ligated proximally to minimize central
contamination prior to the blood draw [57].
The use of plasma clozapine levels is crucial to effective management of
patients, but these data are useful when the question is raised of overdose vs.
postmortem redistribution of clozapine, and where a clinician may be accused of
patient mismanagement on the basis of elevated postmortem levels. The availability
of antemortem levels establishes the baseline MR and the baseline clozapine and
norclozapine levels for the prescribed dose, all of which are needed to interpret
postmortem levels. For anyone testifying in proceedings involving such issues, the
extensive list of concerns elaborated by Flanagan in 2012 are listed in Box 15.5 [55].
While pathologists are increasingly aware of the problem of postmortem distribution,
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15: SPECIAL TOPICS
15
improper withdrawal of femoral vein samples without proximal ligation still occurs, as
does reliance on central drug levels in determining a cause of death. The knowledge
to challenge such procedural errors or errant conclusions may spare families,
caregivers and colleagues from unfounded accusations, guilt or blame in certain cases
of clozapine-associated death.
Box 15.5 List of Issues to Address When Investigating a Clozapine-Related Death [55]
1. Is there circumstantial or pathological evidence of self-poisoning?
2. Is there evidence of prior recent exposure to clozapine (i.e. is the patient
likely to have been tolerant of the hypotensive effects of the drug)?
3. Was blood collected postmortem by venipuncture from a peripheral
vein before opening the body?
4. Was the patient prescribed any other drugs and were other drugs
looked for on toxicological analysis?
5. What was the clozapine dose and dosage regimen?
6. Were tablets or suspension dispensed?
7. Did smoking habit or clozapine dosage change recently?
8. Was there a history of substance abuse?
9. Was the blood norclozapine level measured?
10. Are antemortem plasma or whole blood clozapine/norclozapine results
available?
11. Was histology performed, especially heart and liver?
12. Was there evidence of pneumonia?
13. Was there clinical or postmortem evidence of vomiting, aspiration of
vomit, or other GI tract problem?
15
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Summary Points
a. Clozapine is effective for treatment-resistant adolescent and childhood-onset

schizophrenia, and younger patients may respond to plasma levels below the
response thresholds defined for adults.
b. Clozapine has been used successfully in older schizophrenia patients from
ages 65 to 100 years of age. Older age is not a reason to withdraw clozapine or
refuse to commence clozapine in a treatment-resistant schizophrenia patient.
c. Clozapine is the antipsychotic of choice for intellectually disabled adults with
treatment-resistant psychosis. There are some limited data to support use of
clozapine to manage aggression and self-injurious behavior in adult ID patients,
and its use in those circumstances must be balanced by careful monitoring for
somatic adverse effects.
d. Treatment-resistant patients requiring clozapine should continue the medication
throughout pregnancy with increased monitoring for weight gain and gestational
diabetes. Breastfeeding is contraindicated due to the risk of neutropenia in the
infant.
e. Supportive measures in a monitored hospital setting are needed after an
overdose to manage sedation, orthostasis, tachycardia, and seizures until
plasma levels return to the patient’s therapeutic baseline. Overdose is not
a reason to discontinue clozapine treatment, but to institute measures (e.g.
restricted medication supply) to minimize its recurrence.
f. Clozapine is highly lipophilic and undergoes extensive postmortem redistribution.
Interpretation of postmortem drug levels requires knowledge of the sample
source (i.e. central or peripheral), and whether appropriate measures were taken
to isolate the peripheral blood vessel from central sources.
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15
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306
Index
A1C values, 63 anticholinergics, 73

absolute neutrophil count (ANC), 6, approximate equivalents, 82
7, 115 cholinergic rebound, 80, 81
baseline, 63 constipation and, 144, 145
DARC genotype, 119 daily maximum limits, 82
low baseline, addressing, 120– equivalencies, 74, 145
122 sialorrhea and, 173, 178
low, and treatment interruption, anticonvulsants, 193, 195, 198,
131–134 200
monitoring guidelines, USA, 126 antidepressants, tricyclic, 74, 144
threshold, 116, 117 antihypertensives, 75
UK hematologic monitoring, 128 antiparkinsonian medications, 145
ACHIEVE protocol, 217 antipsychotics. See also
adherence. See nonadherence individual antipsychotics
adolescents, 277, 279–285 augmenting clozapine, 48–49
adverse effects of clozapine, 284 consensus criteria for an
intellectually disabled, 290 adequate trial, 15
plasma clozapine levels, 282 double-blind trials, 12
principles for clozapine use, 281 mortality studies, 20
randomized double-blind studies, plasma levels, 45
279 provision of appropriate, 83–86
African descent, 6, 117, 118, 119, real-world effectiveness studies,
280 17
aggression, 27–31, 289 tapering, 75
agranulocytosis, 115, 116 weight gain and, 210, 211
akathisia, 280, 281, 284 antisocial personality disorders, 29
alanine aminotransferase (ALT), 259, aripiprazole, 49, 212
260, 269, 270, 271 OCD and, 253
alpha1 antagonism, 99, 166, 247 sedation and, 162
alpha-synuclein, 33 armodafinil, 163
amisulpride, 49, 184 aromatic hydrocarbon receptor
amphetamines, 163 (AhR), 96
anemia, 259, 267–268 aspartate aminotransferase (AST),
general approach to, 265 259, 260, 269, 270, 271
incidence of, 259 aspiration pneumonia, 173
307
IN D E X
atenolol, 168 caffeine, 96

atonic seizures, 194 Cal-DSH, 149, 150
atropine, 173, 178, 179, 181 Canada, clozapine registration, 66
Australia, clozapine registration, 66 carbachol, 99, 176
carbamazepine, 69, 199, 200
bacterial infections, 103, 105, cardiac malformations, 294
106–108 cardiomyopathy, 167, 224, 225,
clozapine management during, 236–238
107 cardiovascular disease, 204, 205, 216
minimization of risk, 135 caregivers
bariatric surgery, 212 checklist of information, 70
baseline laboratory measures, 63 dosages and, 104
baseline vital signs, 62 initiating clozapine and, 61
baseline work-up, 62, 65 monitoring role, 72
baseline, low, ANC, 120–122 CATIE study, 160, 164
Bazett formula, 48, 64, 65, 167 CBC monitoring, point-of-care, 136
benign ethnic neutropenia (BEN), 6, Child–Pugh criteria, 93
7, 66, 115, 118–119 children, 277, 279–285
ANC threshold, 117 adverse effects of clozapine, 284
definition of, 119 plasma clozapine levels, 282
diagnosis, 119 principles for clozapine use, 281
hematologic monitoring, 116 randomized, double-blind studies,
hematologic monitoring, UK, 279
129 chlorpromazine, 10, 81, 190
hematologic monitoring, USA, cholinergic rebound, 78, 82
127 ileus risk, 74
benzodiazepines, 73 Kane study, 12
benztropine, 153 liver function and, 269
cholinergic rebound, 81, 82 cholestasis, 269
BID dosing, 97 cholinergic rebound
binding profile, 98–102 chlorpromazine, 78, 82
bioavailability, 72, 91, 93 clozapine, 80
bipolar disorder, manic phase of, 32 definition, 79
bisacodyl, 146 diabetes patients, 214
body mass index (BMI), 63, 65, ileus and, 153
208 management of, 81–83
botulinum toxin-A, 181, 182 neuroleptic malignant syndrome,
botulinum toxin-B, 173, 178, 250
180–183 severe neutropenia, 134
breastfeeding, 277, 278, 295–296 symptoms, 80
Brief Psychiatric Rating Scale ciprofloxacin, 69
(BPRS), 48, 49, 51 Clinical Global Impression (CGI)
Bristol Stool Form Scale, 143, 144, severity scale, 51, 55, 285
145 clonazepam, 199
bulk-forming laxatives, 147, 148 clonidine, 177, 183
bupropion, 218 clozapine
308
IN D E X
adverse effects, 105, 106, background, 10–13

284, 287, 288, 292. See also Parkinson’s disease psychosis,
individual adverse effects 33–36
binding profile, 98–102 plasma levels monitoring, 108–
cholinergic rebound, 80 109
comparative double-blind trials, psychogenic polydipsia, 21–24
12 suicidality, 25
discontinuing. See discontinuing treatment-intolerant
clozapine schizophrenia, 24
dose reduction. See dose treatment-resistant mania, 31–33
reduction treatment-resistant schizophrenia,
ECT and, 200 13–21
FDA approval, 117 violence and aggression, 27–31
FDA prescribing guidelines, viii clozapine positive symptom
first synthesis of, 10 nonresponse, 45–56
hematologic monitoring. See antipsychotic augmentation,
hematologic monitoring 48–49
impact of delays in commencing, ECT and, 50–53
16 increasing plasma levels, 47–48
initiating. See initiating clozapine nonantipsychotic augmentation,
mania and, 284 53–55
metabolic adverse effects. See patient adherence and, 45–46
metabolic adverse effects clozapine resource centers, 8
metabolism and kinetics, 91–98 clozapine-N-oxide, 91, 98
mortality and, 18, 21, 204 CLOZARIL, 125, 134, 262
pivotal trial, 12 Clozaril Collaborative Study Group,
plasma levels. See plasma viii
clozapine levels colonic transit time (CTT), 140, 142,
pregnancy outcome and, 294–295 148
prescriber fear, 6 complete blood count (CBC), 63, 71
primary metabolites, 91 compression stockings, 166
product registration, 11 congenital malformations, 277, 293,
real-world effectiveness studies, 295
16, 17 congestive heart failure, 166
slow tapering of, 81 constipating medications, 75
smoking and, 97 constipation, 19, 74, 140, 141–148,
suicide and, 26 149–155
titration. See titration criteria, 143–144
underutilization, viii, 1 first-line agents for, 146, 148
underutilization, adolescents, 282 opioid-induced, 143, 144
underutilization, treatment- prevalence and postulated
resistant schizophrenia, 4, 6 mechanisms, 142
utilization, strategies for PRN medications, 152
increasing, 7 treatment, 144–153
clozapine efficacy, 11, 37 corpora cavernosa, 247
309
IN D E X
C-reactive protein (CRP), 65, 225, sedation and, 158, 160

230, 231, 233 sialorrhea and, 173
creatinine, 233 divalproex, 53, 54, 55, 94, 125.
CYP See also valproate
inducers, 94 adverse effects, 259, 260
inhibitors, 93, 94 seizures and, 193, 195, 198, 200
CYP 1A2, 67, 69, 85 thrombocytopenia and, 266
clozapine metabolism and, 92 divided doses, plasma levels and,
inducers, 95 104
infections and, 107 dizziness,165
inhibitors, 95 docusate, 141, 146, 147
metabolic ratio and, 102, 103 donepezil, 80
smoking, caffeine and genetic dopamine D2 antagonism, 99, 250
polymorphisms, 94–97 occupancy with clozapine, 101
CYP 2D6, 85, 95 dopamine D2 antagonism
inhibitors, 95 intolerance, 12, 13, 24, 83
CYP 3A4, 95 antipsychotic options, 84
CYP P450 inhibitors, 193 antipsychotic trials, 16
CYP/PGP inducer effects, 93 dose reduction, 107
CYP polymorphisms, 94, 96 constipation and, 152
sedation and, 161
daily maximum limits, 82 dose titration trial, 109, 110
DARC genotype, 118, 119, 120 DRESS, 225, 228, 234, 262
delays in commencing clozapine, 16 mortality, 234
delusions, violence and, 28 Drooling Severity and Frequency
deutetrabenazine, 252 Scale, 172, 177, 178, 179
diabetes mellitus, 204, 207, 213–215 drug abuse
criteria for, 208 methylphenidate and
diagnosis, 208 amphetamines, 163
gestational, 295, 296 modafinil and, 163
initiating clozapine, 63 DSM-5, psychosis scoring, 55
risk factors, 214 Duffy antigens, 118
diabetic ketoacidosis (DKA), 207, Dutch Clozapine Collaboration
213 Group, 8
dietary counseling, 205, 206, 217 dyslipidemia, 63, 205, 207, 215
diminishing tolerability, 47, 109
diphenhydramine, 81, 82 ECG, 64, 65, 105, 167
disability-adjusted life year, 1 cardiomyopathy, 237
discontinuing clozapine, 79–80. myocarditis, 230, 231, 233
See also cholinergic rebound necessity of, 65
metabolic effects and, 207 ECT
myocarditis, 231 clozapine and, 200
orthostasis and, 158 clozapine nonresponders, 50–53
Parkinson’s disease psychosis, EEG, 194
86–87 seizures and, 193
priapism, 247 elimination half-life, 298
310
IN D E X
enemas, 152 gabapentin, 198

enuresis, 242, 243, 244–247, 254 G-CSF levels, 261, 264
approaches to treatment, 246 generalized seizures, 194
eosinophilia, 116, 131, 259, genetic polymorphisms, 94, 96
261–264 gestational diabetes mellitus, 295,
DRESS, 225, 228, 234, 262 296
incidence of, 258 glucagon-like peptide-1 (GLP-1),
thresholds, 262 211
US language on, 262 glutamate neurotransmission, 100
eosinophils, 261 glycine, 53
baseline, 63 glycine transporters, 100
reference ranges, 131 glycopyrrolate, 185
UK reference ranges, 261 sialorrhea, 173, 178
ephedrine, 246 goserelin, 248
epilepsy, 195 granulocytosis, 132
erectile dysfunction, 247 guanfacine, 183
ethnicity. See also
African descent Hale classification, 295
diabetes risk factor, 214 hallucinations, 28, 86
metabolic adverse effects and, 209 haloperidol, 49
platelet count and, 265 aggression and, 31
exercise, 205, 206, 216–217 Kane study, 12
extrapyramidal symptoms, 251 response threshold, 85
heart transplantation, 238
factor Xa inhibitors, 249 hematologic guidelines, USA and
falls, 158, 287 UK, 117
famotidine, 54 hematologic monitoring. See also
fatty liver index, 269 absolute neutrophil count (ANC)
FDA UK, 116, 128
clozapine approval, 117 USA, 116, 126, 127
clozapine prescribing guidelines, HemoCue WBC DIFF, 136
viii hemoglobin, 267
inhibitor/inducer definitions, 94 hepatic function abnormalities, 260,
fever, 62, 224, 225, 226–227 268–271
clozapine-related, case series, 227 general approach to tests, 270
definition, 226 HF-1854, 10
general principles of approaching, high-density lipoprotein (HDL),
228 215
filgrastim, 133, 134–136, 267 histamine H1 antagonism, 99,
first-dose effect, 166 HLA markers, 124, 125
floppy infant syndrome, 295 hyperosmolar hyperglycemic states
fludrocortisone, 165, 166 (HHS), 207
fluvoxamine, 69 hypersalivation. See sialorrhea
formulations, 72, 91, 93 hypertension, 207, 214
Framingham Formula, 64, 65 criteria for, 208
Fridericia Formula, 64, 65 hypertriglyceridemia, 215
311
IN D E X
hyponatremia, 21 intellectual disability (ID) patients,

hypotension, 69 277, 289–293
orthostatic. See orthostasis adverse effects, 292
nonpsychotic, 290–291
ileus psychotic, 291
diagnosing, 153 interleukin-5 (IL-5), 261
mortality, 140, 142, 153 InterSePT study, 25, 26
rechallenging, 154 interstitial nephritis, 225, 228, 232
risk, 73, 142 routine laboratory monitoring, 233
treatment, post-rechallenging, summary of cases, 232
155 intramuscular (IM) formulation, 72,
when to suspect, 154 91
iloperidone, 84 ipratropium, 173, 178, 179, 181
impulsive violence, 28, 29 irritable bowel syndrome (IBS), 149
incontinence, 242, 243, 244–247,
254 Kane criteria, 13
approaches to treatment, 246 Kane study, 12
inducers, 93 Ki nM receptors, 98
CYP, 94, 95 kinetics, clozapine, 91–98
strength of, 94, 95
inflammatory cytokines, 107 laboratory error, 105, 297
informed consent, 70 lactulose, 146
inhibitors, 93 lamotrigine, 198, 200
CYP, 94, 95 left ventricular dysfunction, 231
strength of, 94, 95 left ventricular ejection fraction
initiating clozapine, 61–62, 65–75 (LVEF), 225, 236, 237
baseline laboratory measures, 63 leukocytosis, 264
baseline vital signs, 62 general approach to, 265
baseline work-up, 62, 65 incidence of, 258
checklist of information, 70 leukopenia, 117
fomulations, 72 levetriacetam, 199, 200
managing orthostasis, 166 levodopa psychosis, 34
managing sedation, 161 levodopa-induced dyskinesias (LID),
monitoring during, 72 35
monitoring, inpatient, 72 Lewy bodies, 33
monitoring, outpatient, 72 lifestyle modification, 216–217
patient discussions prior to, 70 linaclotide, 150, 151
QT correction formula, 65 lithium, 125, 264
registration, 66 augmentation, 132
tapering concomitant granulocytosis and, 132
medications, 73–75 lubiprostone, 149, 150, 151
titration, 67–70
instrumental violence, 28 magnesium, 147, 148
insulin resistance, 205, 206, magnesium citrate, 152
213 magnesium hydroxide, 152
312
IN D E X
mania, 80, 253, 284 muscarinic antagonism, 142, 175,

treatment-resistant, 31–33 176
medication nonadherence. See muscarinic intrinsic activity, 99, 176
nonadherence myocarditis, 65, 168, 195, 225,
memantine, 54 228–232
metabolic adverse effects, 205–219. essential facts, 231
See also weight gain incidence of, 229
discontinuing clozapine, 207 monitoring for, 71
monitoring parameters, 208 routine laboratory monitoring, 233
principles of managing on time to onset, 229
clozapine, 206 myoclonic jerking, 297
metabolic ratio (MR), 92, 102, 281
adolescents and children, 283 neuroleptic malignant syndrome
guidelines for interpreting, 103 (NMS), 24, 243, 244, 250–251
infections and, 106–108 diagnostic criteria, 251
older patients, 286 neutropenia, 11, 195, 200
overdose and, 298 ANC levels, monitoring, 126
metabolic syndrome, 65, 204, 207 BEN. See benign ethnic
components of, 207 neutropenia (BEN)
criteria for, 208 children and adolescents, 280
prevalence of, 213 hypothesized mechanism, 125
metabolism, clozapine, 91–98 other sources of, 120
metformin, 205, 206, 207, severe. See severe neutropenia
211–212 terminology, 116
children and adolescents, 281 time course and risk factors, 117
methylphenidate, 163 valproate and, 122, 125
mineral oil (liquid paraffin), 148 neutrophilia, 258, 264
minocycline, 54 causes of, 264
mirabegron, 245, 246 nicotine replacement therapy, 219
mirtazapine, 100 NMDA glutamate receptors, 53, 54,
modafinil, 163 100
monitoring, 71 Nocturnal Hypersalivation Rating
inpatient, 71 Scale, 172, 178, 179
outpatient, 71 nonadherence, 45–46, 60
mortality plasma levels and, 104
clozapine and, 18–21, 204 rates, 16
DRESS, 234 nonalcoholic fatty liver disease
ileus, 140, 142, 153 (NAFLD), 215, 269, 270
postmortem redistribution, 278, nonantipsychotic augmentation
299–301 clozapine nonresponders, 53–55
severe neutropenia, 114, 134 norclozapine, 68, 91. See also
smoking, 218 metabolic ratio (MR)
suicide and, 25 binding profile, 98–102
muscarinic M1/M3 antagonism, 99 infections and, 106
muscarinic M1/M5 agonism, 99 plasma levels, 102
muscarinic M3 antagonism, 245 sialorrhea and, 175
313
IN D E X
obesity, criteria for, 208 PEG-3350, 141, 146, 148

obsessive compulsive disorder, 243, perphenazine, 20
244, 252 Petrides’ study, 51
approach to new onset, 253 PGP, 92
olanzapine, 84 CYP/PGP inducer effects, 93
aggression and, 31 phenytoin, 69, 122, 199, 200
cholinergic rebound, 81 physical activity vital sign (PAVS),
double-blind trials, 13 210, 216
Parkinson’s disease psychosis, pimavanserin, 70, 83
35, 36 5HT2A affinity, 100
response threshold, 85 D2 antagonism intolerance, 84
suicide and, 26 Parkinson’s disease psychosis,
tapering, 74 36, 86
older patients, 277, 285–289 pirenzepine, 176
adverse effects of clozapine, 287, pivotal clozapine trial, 12
288 plasma antipsychotic levels, 45
omeprazole, 69, 72, 92, 93, 95, 102, plasma clozapine levels, 46, 91,
121, 161, 165 102–109
opioids, constipation and, 143, 144 adolescents and children, 282
oral formulations, 72, 91 clozapine nonresponders and,
oral suspension, 72 47–48
orally disintegrating tablet (ODT), 72 conversion formulas, 108
organized violence, 28 decreasing, for constipation, 152
orthostasis, 62, 145, 164–166, 169 early in treatment, 69
clozapine initiation, 75 infections and, 106–108
definition, 164 markedly below expected, 104
falls and, 158 markedly higher than expected,
seizures and, 194 106–108
tachycardia and, 168 monitoring efficacy, 108–109
vital signs, 72 nonresponders, 47
overactive bladder, 246 older patients, 286, 288
overdose, 277, 278, 297–299 overdose and, 297
postmortem redistribution, 300
paralytic ileus, 140 principles for obtaining, 104
Parkinson’s disease (PD), 33 threshold, 47
medications, 145 units used, 90, 108
Parkinson’s disease psychosis upper limits, 109, 110
(PDP), 33–36 platelet count, 116, 131, 265–267
consensus definition, 33 platelets, UK reference ranges, 131,
discontinuing clozapine, 86–87 261
titration levels, 70 plecanatide, 150, 151
partial seizures, 194 point of futility, 47, 109
patient discussions, 70 point-of-care CBC monitoring, 136
checklist, 70 Porirua constipation protocol, 148
patient nonadherence. See Positive and Negative Syndrome
nonadherence Scale (PANSS), 48
314
IN D E X
postmortem redistribution, 278, repetitive transcranial magnetic

299–301 stimulation (rTMS), 53
predatory violence, 28 response threshold, 46, 47, 69, 109
pregnancy, 277, 278, 293–295 haloperidol, 85
anticonvulsants and, 200 olanzapine, 85
clozapine and, 294–295 rhabdomyolysis, 297
thrombocytopenia and, 266 ribavirin, 135
prescriber fear, 6 risperidone, 83, 100, 294
priapism, 243, 247–248, 254 Rome IV diagnostic criteria, 143
primary metabolites, clozapine, 91
primary polydipsia, 21, 23 salivary glands, 174
propensity scores, 293 schizoaffective disorder, bipolar
propranolol, 168, 281 type, 32
prucalopride, 141, 151, 154 schizophrenia
psychogenic polydipsia, 21–24 antipsychotic mortality studies, 20
psychotic violence, 28 childhood onset, 279
psychotropics costs in the US, 2
constipation and, 145 disease burden of, 1
tapering, 74 enuresis and, 244
PSYCLOPS trial, 34 prevalence, 1, 3
psyllium, 148 prevalence, age-standardized, 3
PubMed, clozapine publications in, 1 real-world effectiveness studies, 17
pulmonary embolism, 248, 250 treatment-intolerant, 24
treatment-resistant. See
QHS dosing, 97 treatment-resistant
QT correction formula, 65 schizophrenia
QT monitoring, 65 violence risk estimates, 27
QT prolongation, 167 schizophrenia spectrum disorders
quetiapine, 17 antipsychotic options, 84, 85
adverse effects, 24 clozapine initiation, 60
D2 antagonism intolerance, 84 mortality and, 25
mortality rates, 20 plasma levels, 69
Parkinson’s disease psychosis, suicidality and, 25
35, 36, 87 secondary polydipsia, 21
tapering, 74 secretogogues, 141, 149–151, 154
sedation, 159, 160–164, 169
rechallenging effects, 73
eosinophilia, 262 falls and, 158
ileus, 154 seizures, 48, 191–200, 201
interstitial nephritis, 233 clozapine and, 192, 193, 194
myocarditis, 231 dose-dependency and, 191, 193,
priapism, 247 196–197
severe neutropenia, 134 neonatal, 295
RegiSCAR, 234 treatment of, 197–200
registration, 66 types and frequencies, 194
315
IN D E X
sennosides, 146 stuttering, 191, 197

serositis, 225, 228, 235 substance use, violence and, 27
serotonergic motility agents, suicidality, 25, 278
149–151 InterSePT study, 25, 26
serotonin 5HT2a inverse agonism, 99 overdose and, 298
serotonin 5HT2a occupancy with type 1 and type 2 events, 26
clozapine, 101 sulpiride, 184
serotonin 5HT2a receptors, 34, 86 systemic inflammation, 216
sertraline, 253
serum creatinine, 233 tachycardia, 62, 65, 159, 166–167,
serum osmolality, 21, 22 169, 298
severe cutaneous adverse reactions decision algorithm, 167
(SCARs), 234 definition, 166
severe neutropenia, 115, 116 tardive dyskinesia, 24, 194, 197,
breastfeeding and, 296 243, 244, 252
estimates for clozapine, 117 thrombin inhibitors, 249
fever and, 228 thrombocytopenia, 122, 131, 259,
mortality from, 114, 134 265–267
other medications and, 121 general approach to, 265
rechallenging, 134 incidence of, 258, 266
time course of, 123–125 thrombocytosis, 259, 265–267
sialorrhea, 19, 173–186 general approach to, 265
clozapine-induced, 175–177 incidence of, 258
prevalence, 172 timing, plasma levels and, 104
treatment principles, 177–185 titration, 67–70
single nucleotide polymorphisms children and adolescents, 277,
(SNPs), 96 281, 284
smoking, 218–219 clozapine, 47
anticholinergics and, 74, 82 dose titration trial, 109, 110
clozapine and, 97 older patients, 285, 287
CYP 1A2 activity and, 96 principles of, 67, 110
inhibitor/inducer effects and, 94 rapid, 68, 69
monitoring, 210 slower, 68
mortality rates, 218 tonic–clonic seizures, 194
titration and, 67, 68, 69 topiramate, 53, 54, 55
SNARE proteins, 180, 182 transabdominal ultrasound, 245, 246
sodium benzoate, 54 traveling, difficulties in, 61
SSRIs, 252, 253 treatment-intolerant schizophrenia,
Stevens–Johnson Syndrome, 200, 24
234 treatment-resistant mania, 31–33
stimulants, 141 treatment-resistant schizophrenia
stool form nomenclature, 143–144, adolescents, 279, 280, 282
145 children, 279
STRIDE protocol, 217 clozapine efficacy, 13–21
316
IN D E X
clozapine underutilization, 4, 6 valbenazine, 252

consensus criteria for an valproate, 54, 198, 200. See also
adequate trial, 15 divalproex
costs of, 2 neutropenia risk, 122, 125
ECT and, 200 valproic acid, 94, 195
Kane criteria, 13 varenicline, 218
olanzapine trials, 13 venous thromboembolism, 243,
pivotal clozapine trial, 12 248–250, 254
plasma level ranges, 109 risk assessment tool, 249
prevalence, 2 violence, 27–31, 163
suicidality and, 25 risk estimates in schizophrenia, 27
tricyclic antidepressants, 74, 144 viral infections, 103, 105, 106–108
trihexyphenidyl, 82 clozapine management during, 107
troponin, 65 minimization of risk, 135
troponin I/T level, 225, 230, 231, 233 visual hallucinations, 86
VMAT2 inhibitors, 24, 252
UGT1A 4, 94
UK waist circumference, 65, 208, 209
clozapine prescriptions, 6 warfarin, 249
clozapine registration, 66 weight gain, 63, 65, 205
eosinophil/platelet reference antipsychotic-related, 210, 211
ranges, 131, 261 children and adolescents, 281
hematologic monitoring, 116, 128 nonmodifiable risk factors, 206
UK Diabetes Prevention Program white blood cells (WBCs), 7, 116
trial, 213 leukocytosis, 264
urinalysis, 233 low, and treatment interruption,
urine osmolality, 21, 23 131–134
urodynamic testing, 246, 247 racial variations, 118
USA. See also FDA UK hematologic monitoring, 128
clozapine prescribing guidelines, WHO Global Burden of Disease
94 Study 2016, 1
clozapine prescriptions, 5 withdrawal symptoms. See
clozapine registration, 66 cholinergic rebound
costs of schizophrenia, 2
eosinophilia, language on, 262 Young Mania Rating Scale (YMRS)
guidelines on dose adjustment, score, 32, 80
95 Young Mania Rating Scale (YMRS)
hematologic guidelines, 117 score, 33, 79
hematologic monitoring, 116, 126,
127 Zollinger–Ellison syndrome, 54
317

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The Clozapine Handbook

The Clozapine Handbook

Cambridge University Press is part of the University of Cambridge.

All illustrations by Nancy Muntner provided by permission of

12. Fever, Myocarditis, Interstitial Nephritis, DRESS,

Figure 1. Clozapine-related publications in PubMed (1970–2017).

Figure 2. Mean schizophrenia prevalence by age in 2016.

Table 1 Age-standardized schizophrenia prevalence in 1990 and 2016 [3].

treatment, a 2014 analysis of US clozapine prescribing in 2002–2005 noted that, on

Missing data 0.8–2.4% 2.5–4.9%

5.0–7.4% 7.5–9.9% 10.0–15.6%

Box 1 Strategies for Increasing Clozapine Utilization [11,15]

Elements of these programs include support and education of clinicians to

The 60th anniversary of clozapine’s synthesis by Schmutz and Eichenberger at

• Clozapine is the only effective antipsychotic for treatment-resistant

Pharmaceuticals in 1966 by Hippius in Berlin and Engelmeier in Vienna indicated that

Three double-blind studies comparing clozapine to other antipsychotics were

Box 1.1 Essential Components of the Kane Definition of Treatment-Resistant

The unique benefits of clozapine extend beyond treatment-resistant schizophrenia

While inconvenient, criterion 3 of the Kane 1988 criteria is central to a research

study of 99 schizophrenia patients deemed treatment-resistant, 35% had plasma

Table 1.2 Consensus criteria for defining an adequate antipsychotic trial in

• ≥ 6 weeks at a therapeutic • ≥ 6 weeks at a therapeutic dosage

These criteria emphasize that clinicians must be mindful of high nonadherence

• One important variable in maximizing the chance of clozapine response involves

Table 1.3 Summary of large real-world effectiveness studies in schizophrenia

FGA, first-generation antipsychotic; SGA, second-generation antipsychotic; HR, hazard ratio.

• Symptomatic exacerbation and rehospitalization are inherent to schizophrenia, but

Onset of treatment- Diagnosis of treatment-

Table 1.4 Summary of recent large antipsychotic mortality studies in schizophrenia.

Table 1.4 continued

• Primary polydipsia is a scenario of increased water intake occurring in the absence

of impairment in water excretion. This can be distinguished from the secondary

was performed in eight male schizophrenia patients with polydipsia to document

Figure 1.2. Mean plasma osmolality during 6 weeks of typical antipsychotic

Typical antipsychotic Clozapine dose (mg/day)

290 300 600 900

(Adapted from: Canuso, C. M. and Goldman, M. B. (1999). Clozapine restores water

Figure 1.3. Mean urine osmolality during 6 weeks of typical antipsychotic

300 600 900

(Adapted from: Canuso, C. M. and Goldman, M. B. (1999). Clozapine restores water

accumulated literature is substantial enough that a 2010 comprehensive review

Early in its clinical development, clozapine’s extremely low rate of neurological

Conceptually, suicide and violence are separate domains of schizophrenia

Figure 1.4. Time to suicidal events in the InterSePT study.

Box 1.2 Important Conclusions from the 24-Month Prospective, Randomized

D Violence and Aggression

Males 3.98 (2.98, 5.31)

Mixed Genders 5.02 (3.41, 7.39)

Females 7.85 (4.00, 15.40)

OR, Odds Ratio; CI, Confidence Interval.

in psychiatric inpatient and forensic settings who remains persistently aggressive

Figure 1.6. Violence is a separate symptom dimension of schizophrenia.

COGNITIVE NEGATIVE AFFECTIVE

Table 1.5 Summary of randomized studies of clozapine for aggression in

Figure 1.7. Clozapine’s superiority for aggression compared to olanzapine and

MOAS, Modified Overt Aggression Scale.

intolerance to lithium, an anticonvulsant, and at least two typical antipsychotics.

medical conditions did not increase. As noted in schizophrenia, clozapine is only