JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY

Volume 00, Number 00, 2016 Brief Report

ª Mary Ann Liebert, Inc.
Pp. 1–4
DOI: 10.1089/cap.2015.0216

Clozapine for Drug-Refractory Irritability

in Individuals with Developmental Disability

Logan K. Wink, MD, Ismail Badran, MD, Ernest V. Pedapati, MD, Rena Sorensen, PhD,
Stacy C. Benton, RN, Mark C. Johnson, MD, Gregory Wissel, BS, and Craig A. Erickson, MD

Abstract
Objectives: In this case series, we describe the acute clinical impact and tolerability of rapid titration of clozapine for
treatment of refractory irritability in five hospitalized youth with developmental disability. We offer this descriptive report in
an effort to expand the evidence base guiding treatment of refractory aggression in this population.
Methods: Five youth with developmental disability and severe irritability were admitted to a 10-bed psychiatric crisis
stabilization unit where they received thorough psychiatric and medical evaluation. Informed consent was obtained in
each case, and each patient underwent rapid titration onto clozapine. Clozapine monitoring guidelines were followed for
all patients throughout treatment, and clinical severity at baseline and improvement with treatment was measured by use
of the Clinical Global Impressions-Severity scale (CGI-S) and the Clinical Global Impressions-Improvement scale
(CGI-I).
Results: One female and four males diagnosed with developmental disability and at least one other psychiatric diagnosis,
mean age of 13.1 – 2.1 years, and mean CGI-S at baseline of 5.8, each received clozapine treatment by rapid titration. The
mean therapeutic total daily dose of clozapine was 380 – 200 mg. All patients demonstrated acute clinical improvement with
the mean final CGI-I of 2.0, or ‘‘much improved.’’
Conclusion: These initial results support the potential utility of clozapine rapid titration for treatment of severe refractory
irritability in youth with developmental disability. These patients tolerated clozapine treatment in the short term. Future
studies are needed to thoroughly evaluate the long-term safety of clozapine treatment in this population.

Introduction viduals with developmental disability (Politte and McDougle 2014;

Ayub et al. 2015).

A ggression, self-injurious behavior (SIB), and severe

tantrums are common targets of pharmacotherapy in indi-
viduals with developmental disability. The pharmacological
mainstays of treatment for this symptom cluster (referred to in this
article as ‘‘irritability’’) are second-generation antipsychotics
(SGAs), although alpha agonists, mood stabilizers, and anticon-
vulsants are also frequently employed (Ayub et al. 2015). To date,
no medications are FDA approved for the management of irrita-
bility symptoms associated with idiopathic developmental dis-
ability, although aripiprazole and risperidone are both approved to
treat irritability in youth with autism spectrum disorders (ASD)
(Research Units on Pediatric Psychopharmacology Autism 2002;
US Food and Drug Administration 2006; Marcus et al. 2009; Owen
et al. 2009). Furthermore, despite the prevalence of behavioral
symptoms refractory to first-line treatments in these individuals
(Adler et al. 2014), evidence for the use of SGAs beyond risper-
idone and aripiprazole is even more limited. In particular, cloza-
pine, which is an SGA used regularly in treatment-refractory
mental illness, has been studied only in a limited capacity in indi-
Clozapine is a mild dopamine D2 receptor antagonist with dis-
tinct selectivity for mesolimbic neurons and action at serotonin,
histamine, and noradrenergic receptors. The first approved SGA,
clozapine, is a proven therapy for individuals with treatment-
resistant bipolar disorder and schizophrenia (Lally and MacCabe
2015; Li et al. 2015). Clozapine also has demonstrated effective-
ness in reducing aggression in psychiatrically ill adults and ado-
lescents (Chalasani et al. 2001; Chengappa et al. 2002). In the ASD
literature, which is often referenced as a prescribing guide in idi-
opathic developmental disability, clozapine has been shown to be
well tolerated and effective in reducing irritability in several case
reports (Chen et al. 2001; Gobbi and Pulvirenti 2001; Lambrey
et al. 2010). More recently, rapid titration of clozapine for treatment
of severe psychiatric symptoms and agitation in individuals with
psychotic and affective disorders has been demonstrated safe and
effective (Ifteni et al. 2014a, 2014b; Poyraz et al. 2015). Despite
compelling evidence that clozapine may be rapidly effective for
controlling aggression symptoms, it has yet to be studied in a
controlled way for any treatment indication in individuals with

Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.

1
2 WINK ET AL.
developmental disability (Ayub et al. 2015). Furthermore, cloza-
pine is typically used only as a ‘‘last resort’’ in individuals with
developmental disability due to the potential of severe adverse
effects, including lowered seizure threshold, cardiomyopathy,
weight gain, metabolic adverse effects, and agranulocytosis
(Maayan and Correll 2011).
In the following case series, we describe the clinical impact and
tolerability of rapid titration of clozapine targeting irritability in
five youth with developmental disability hospitalized for severe
irritability that was refractory to first-line antipsychotic medication
treatment. We offer this descriptive report in an effort to expand the
evidence base guiding treatment of irritability symptoms refractory
to first-line treatments in this population.
Methods
The five individuals described in this case series were each ad-
mitted to a 10-bed psychiatric crisis stabilization unit designed for
children and adolescents with moderate to severe developmental
disability. All patients received a thorough psychiatric and medical
evaluation at the time of admission, including review of psychiatric
symptoms, detailed review of past and current pharmacotherapy,
and evaluation of comorbid medical illness. Psychiatric diagnoses
were made by a clinician with expertise in developmental disability
(C.A.E.), based on the Diagnostic and Statistical Manual of Mental
Disorders, 5th edition (DSM-5) (American Psychiatric Association
2013). Medical illnesses believed to potentially contribute to be-
havioral symptoms (i.e., constipation, viral illness, neurologic
concerns) were evaluated and treated in all cases. Patients were
selected for potential clozapine treatment due to highly dangerous
levels of irritability that previously had been nonresponsive to first-
line medication trials. In these cases, the irritability symptoms were
deemed to be the most pressing symptoms to be addressed during
hospitalization. Other psychiatric illnesses that may have impacted
behaviors (i.e., attention-deficit/hyperactivity disorder [ADHD])
were not directly addressed beyond continuation of previously
initiated treatment.
Following discussion of the risks and potential benefits of
clozapine treatment with the patients’ legal guardians, informed
consent was obtained in each case. Each patient then underwent
rapid titration onto clozapine targeting refractory irritability
symptoms (method described in each case below). Vital signs, in-
cluding temperature, heart rate, and blood pressure, were recorded
daily. Complete blood counts (CBCs) with differentials, including
absolute neutrophil count (ANC), were obtained before initiating
treatment and repeated twice a week during titration. Daily as-
sessment for adverse effects was completed by discussion with the
patient (when possible), daily nursing evaluation, direct care staff
report, physician examination, and guardian report throughout the
inpatient stay. For patients followed posthospitalization, adverse
effects were monitored at all office visits and phone calls, and vital
signs were assessed at all office visits. Clozapine monitoring
guidelines were followed for all patients throughout treatment
(HLS Therapeutics 2015).
Each patient’s severity of illness at baseline was measured using
the Clinical Global Impressions-Severity scale (CGI-S) by the
treating physician (C.A.E.) (Guy 1976). The CGI-S is a clinician-
rated global assessment of symptom severity scale ranging from 1
to 7 (1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill;
4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among
the most extremely ill patients). As a qualitative measure of treat-
ment response, Clinical Global Impressions-Improvement scale
(CGI-I) scores were determined following clozapine treatment
(also by C.A.E.) (Guy 1976). The CGI-I is a clinician-rated global
assessment of symptom change rated on a scale from 1 to 7
(1 = very much improved; 2 = much improved; 3 = minimally im-
proved; 4 = no change; 5 = minimally worse; 6 = much worse; and
7 = very much worse).
Results
One female and four males were included in this series. All five
were diagnosed with developmental disability (ASD and/or cog-
nitive impairment) and at least one other psychiatric diagnosis. All
five patients suffered from severe irritability, which negatively
impacted their quality of life, and had not responded to first-line
pharmacotherapy (all participants had previous failed trials of
risperidone and aripiprazole). All were medically stable at baseline.
Ages ranged from 11 to 17 years, with mean age of 13.1 – 2.1 years.
The patients were taking an average of 4.0 – 0.7 psychotropic med-
ications at admission, including SGAs, mood-stabilizers, stimulants,
a-agonists, and benzodiazepines. Mean CGI-S at baseline was
5.8. Mean therapeutic total daily dose (TDD) of clozapine was
380 – 200 mg. Mean final CGI-I anchored to symptoms targeted with
clozapine treatment was 2.0 (‘‘much improved’’). All patients tol-
erated rapid titration onto clozapine without an acute adverse effect,
vital signs remained stable in all patients, and no cases of agranu-
locytosis occurred. Each case is described in detail below.
Patient 1
Patient 1 was an 11-year-old female with a history of ASD,
intermittent explosive disorder (IED), ADHD, and mixed
receptive-expressive language disorder. She also suffered from a
stable spinal cord syrinx resulting in chronic urinary retention. She
was admitted to the inpatient psychiatric unit for worsening im-
pulsivity and aggressive behaviors. CGI-S at admission was 5.
Medication changes before admission included increasing doses of
methylphenidate and oxcarbazepine without benefit. At the time of
admission, psychiatric medications included clonidine, guanfacine,
amitriptyline, methylphenidate, oxcarbazepine, and olanzapine.
Previous antipsychotic medication trials included risperidone, ar-
ipiprazole, quetiapine, and haloperidol. The patient was titrated off
olanzapine. Clozapine treatment was initiated at 25 mg and in-
creased by 25 mg per day until a minimum effective dose of 100 mg
twice daily was reached. Following discharge from the hospital, the
patient had a reemergence of aggressive behaviors and was read-
mitted 3 weeks later to continue upward titration of clozapine. She
was subsequently discharged a second time on 250 mg twice daily
with the dose ultimately increased to 300 mg twice daily (600 mg
TDD) in outpatient follow-up. Her aggressive behaviors remitted
with clozapine therapy, and she experienced no reported adverse
effects beyond mildly increased appetite. This patient had a notable
2.7-kg weight loss over the first 12 weeks of treatment with clo-
zapine. Weekly CBCs remained stable throughout treatment. CGI-I
anchored to symptoms targeted with clozapine treatment was 2.
Patient 2
Patient 2 was a 12-year-old male with a history of IED, ADHD,
chronic motor tic disorder, mild cognitive impairment, and mixed
receptive-expressive language disorder. He was admitted to the
inpatient psychiatric unit for worsening physical aggression at
home and school. CGI-S at admission was 6. He had been admitted
to inpatient psychiatry 1 month previously for similar aggressive
CLOZAPINE IN DEVELOPMENTAL DISABILITY
behaviors, and discharged on both haloperidol and ziprasidone,
which proved to be ineffective in managing his impulsivity and
violence. At the time of admission, his medications included hal-
operidol, ziprasidone, lisdexamfetamine, and olanzapine. Previous
antipsychotic medication trials included risperidone, aripiprazole,
and chlorpromazine. During hospitalization, ziprasidone and hal-
operidol were tapered and discontinued. Clozapine treatment was
subsequently initiated at 25 mg daily. Clozapine was increased by
25–50 mg daily until a minimum effective dose of 250 mg twice
daily was reached 2 weeks later. After discharge, the patient con-
tinued to be aggressive, requiring readmission 4 weeks after starting
treatment. Clozapine was further increased to 300 mg twice daily
(600 mg TDD). Following the second discharge, the patient experi-
enced more frequent violence-free days and was more responsive to
verbal de-escalation when agitated. He suffered no significant ad-
verse effects related to clozapine, with only minor reported sedation.
Weight increased 4.1 kg over the first 12 weeks of treatment. The
patient’s CBC remained stable with the exception of an ANC <2.0 on
two occasions, both resolved with repeat CBC. CGI-I anchored to
symptoms targeted with clozapine treatment was 2.
Patient 3
Patient 3 was a 13-year-old male with a history of ASD, IED,
moderate cognitive impairment, and complex partial epilepsy. He
was admitted to the inpatient psychiatric unit for increasing ag-
gressive behavior at home and school. CGI-S at admission was 6.
He had previous admissions on the unit with brief periods of suc-
cessful control of his problematic behavior, but was noted to be
more aggressive since last discharge with significant psychomotor
agitation. Previous antipsychotic medication trials included ris-
peridone and aripiprazole. At the time of this admission, his sei-
zures were well controlled on topiramate and oxcarbazepine. His
psychotropic medications included risperidone, trazodone, zolpi-
dem, and melatonin. Risperidone was weaned and discontinued,
and trials of olanzapine and then haloperidol were initiated. Both
trials proved largely ineffective and were discontinued. Subse-
quently rapid titration of clozapine was initiated. The patient re-
ceived an initial dose of clozapine 25 mg, with dosage increased by
25–50 mg daily until minimum effective dose of 100 mg twice daily
was reached. Due to increased aggression at home following dis-
charge, clozapine was further increased to 125 mg twice daily
(250 mg TDD) without adverse effects. Guardian reported great
reduction in aggressive behaviors at home. The patient’s CBC was
stable, and no adverse effects were reported. This patient’s weight
initially increased by 2.8 kg over the first 6 weeks of treatment, but
subsequently decreased to 0.4 kg below baseline weight after 6
months of treatment. CGI-I anchored to symptoms targeted with
clozapine treatment was 1.
Patient 4
Patient 4 was a 16-year-old male with a history of ASD, IED, and
mild cognitive impairment. He was admitted to the inpatient psy-
chiatric unit with increased physical aggression, including episodes
of hitting, kicking, and raising fists in a threatening manner. Family
members were most concerned with his inability to remain safe
during car drives, and the father reportedly had to restrain the pa-
tient for safety several times in the days before admission. The
patient suffered intermittent cycles of aggression, which were in-
terspersed with periods of low energy and dulled senses, as he
seemed to be ‘‘doped up’’ on risperidone per parent report. CGI-S at
admission was 6. Previous antipsychotic medication trials included
3
risperidone, aripiprazole, ziprasidone, and quetiapine. At admis-
sion, risperidone was weaned and discontinued. Clozapine was
initiated at 25 mg, with a 25 mg increase each day until a minimum
effective dose of 100 mg twice daily was reached (200 mg TDD).
After discharge, the patient had occasional, but less frequent peri-
ods of mild aggression toward his mother. The reduction in his
overall irritability allowed therapeutic interventions to be more
impactful. This patient did not follow up in our clinic post-
discharge, due to lack of proximity to our medical center. However,
adequate outpatient follow-up with weekly CBC at a community
clinic was ensured. He tolerated clozapine without complaints of
serious adverse effects. Weight remained stable through the first 8
weeks of treatment. CBC was stable throughout treatment. CGI-I
anchored to symptoms targeted with clozapine treatment was 3.
Patient 5
Patient 5 was a 12-year-old male with a history of ASD, IED,
ADHD, and moderate cognitive impairment. He had a history of
repeated hospitalizations for SIB, physical aggression, and property
destruction. Previous trials of antipsychotic and mood-stabilizing
medications included risperidone, aripiprazole, olanzapine, que-
tiapine, chlorpromazine, divalproex, and lithium. Due to increas-
ingly aggressive behaviors, he was admitted to the inpatient
psychiatric unit to begin treatment with clozapine. CGI-S at ad-
mission was 6. Psychotropic medications at admission included
chlorpromazine, divalproex, and methylphenidate extended re-
lease. Chlorpromazine was weaned and discontinued and clozapine
was started at 25 mg, with a 25 mg daily increase until a minimum
effective dose of 125 mg twice daily (250 mg TDD) was reached on
day 10 of treatment. The patient was subsequently discharged from
the hospital with improved behavior. He experienced a drop in
white blood cell count (WBC) and ANC during week 9 of treat-
ment, however repeat CBC demonstrated normalization of the
WBC and ANC. Depakote was believed to have played a role in the
low WBC count and was discontinued without an ill effect. The
patient continued to demonstrate improvement in aggressive be-
havior both at home and school. Weight climbed by 3.3 kg over the
first 16 weeks of treatment. CGI-I anchored to symptoms targeted
with clozapine treatment was 2.
Discussion
In this case series, we present the successful rapid titration of
clozapine in five youth with developmental disability admitted to
our inpatient psychiatric unit with severe refractory irritability
symptoms. In all five consecutively treated patients, rapid titration
of clozapine was well tolerated and free of significant treatment
limiting significant adverse effects. There were no notable changes
in vital signs (heart rate and blood pressure), no increase in seizure
frequency, no cardiac-related events, and no cases of agranulocy-
tosis. Weight gain was reported in only two out of five patients in
the time period reviewed (range 8 weeks to 6 months). These re-
fractory patients were quickly stabilized on clozapine and tolerated
the burden of weekly blood draws. All patients demonstrated sig-
nificant clinical improvement with mean CGI-I score anchored to
symptoms targeted with clozapine treatment of 2.0, or ‘‘much
improved.’’
These initial results support the potential utility of clozapine for
treatment of severe refractory irritability in youth with develop-
mental disability. However, this report is limited by the small
sample size, lack of a blinded independent CGI-I rater, short time
course, and lack of a control group for comparison. Furthermore, all
4 WINK ET AL.
five patients in this report received intensive behavior, speech, and
occupational therapy while hospitalize, and the impact of these
treatments in stabilizing the patients’ behavior was not quantified in
this report. In addition, we do not have available data on potential
metabolic adverse effects of clozapine treatment in these patients,
although overall weight gain was limited. Future controlled studies
using parallel-groups design, which compare clozapine to standard
approaches, including polypharmacy and behavioral interventions,
may provide further evidence for the effectiveness of this often
overlooked medication. In addition, detailed review of potential
adverse effects, including impact on weight, metabolic profile,
seizure activity, cardiac functioning, and CBC, must be included in
future study. Such studies may shed light on questions of long-term
safety and tolerability, as well as overall effectiveness in this
difficult-to-treat population.
Disclosures
All contributing authors have read and approved the submission
of this article to the journal. In addition, all authors report no direct
conflicts with the content of this report. Dr. Wink’s current research
is supported by the Simons Research Foundation, Autism Speaks,
Riovant Sciences Ltd, and Cures Within Reach. Dr. Wink has served
as a past consultant for Otsuka. Dr. Pedapati receives research sup-
port from the Cincinnati Children’s Hospital Research Foundation.
Dr. Erickson is a consultant to and holds equity in Confluence
Pharmaceuticals and is a consultant to Neurotrope. Dr. Erickson is a
past consultant to Alcobra Pharmaceuticals, the Roche Group, and
Novartis. Dr. Erickson holds nonrelated IP held by CCHMC and
Indiana University. Dr. Erickson receives research grant support
from the John Merck Fund, CCHMC, Autism Speaks, the National
Fragile X Foundation, The Roche Group, Neuren Pharmaceuticals,
and Riovant Sciences Ltd. Dr. Badran, Dr. Sorensen, Ms. Benton, Dr.
Johnson, and Mr. Wissel have no disclosures to report.
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Address correspondence to:
Logan K. Wink, MD
Cincinnati Children’s Hospital Medical Center
University of Cincinnati College of Medicine
3333 Burnet Avenue MLC 4002
Cincinnati, OH 45229
E-mail: logan.wink@cchmc.org