Review

Pharmacotherapy to control
behavioral symptoms in children
with autism
1. Introduction
Carolyn A Doyle & Christopher J McDougle†
2. Background †
Harvard Medical School; and Lurie Center for Autism, Department of Psychiatry, Lexington, MA,
3. Pharmacological treatments USA
4. Expert opinion
Introduction: Autistic disorder, Asperger’s disorder, and pervasive develop-
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Sussex Library on 09/07/13

mental disorder not otherwise specified (PDD-NOS) are pervasive develop-

mental disorders (PDDs) frequently associated with behavioral symptoms
that may require pharmacotherapy to manage.
Areas covered: Behavioral symptoms in children with autism include interfer-
ing repetitive behaviors, irritability, and hyperactivity and inattention, among
others. The psychotropic medications examined in this review include: seroto-
nin reuptake inhibitors, typical and atypical antipsychotics, medications used
to treat attention-deficit/hyperactivity disorder, naltrexone, buspirone, dival-
proex sodium, lamotrigine, levetiracetam, memantine, mirtazapine, riluzole,
pioglitazone, and topiramate.
Expert opinion: For the treatment of interfering repetitive behaviors, seroto-
nin reuptake inhibitors demonstrate less efficacy and are more poorly toler-
For personal use only.

ated in children with autism compared to adults. Antipsychotics are the

most efficacious drugs for the treatment of irritability in children with autism
and other PDDs. For the treatment of hyperactivity and inattention, psychos-
timulants demonstrate some benefit. However, they are overall less effica-
cious and cause more side effects in children with PDDs compared to
typically developing children with attention-deficit/hyperactivity disorder.
Results from double-blind, placebo-controlled trials of these agents and
others for the treatment of the behavioral symptom domains described above
will be discussed in this review.

Keywords: Asperger’s disorder, autism, autistic disorder, pervasive developmental disorder,

treatment

Expert Opin. Pharmacother. (2012) 13(11):1615-1629

1. Introduction

Autistic disorder (autism) is a pervasive developmental disorder (PDD) occurring at

a median rate of 5 per 10,000 individuals, with a range of 2 to 20 cases per
10,000 [1]. Most large-scale clinical trials have studied patients with autism alone
or any combination of autism, PDD-not otherwise specified (NOS), and Asperger’s
disorder. In this review, these three diagnostic subtypes will collectively be referred
to as ‘PDDs’.
For the purpose of this review, behavioral symptoms targeted by pharmacother-
apy in children with autism will be grouped into the following domains: interfering
repetitive behaviors, irritability, and hyperactivity and inattention. Although the
efficacy of many medications differs in children with PDDs compared with typically
developing children, numerous studies have found safe and effective treatments for
these symptom domains.
Studies of pharmacotherapy in PDDs use a variety of instruments to determine
treatment response and efficacy. The Clinical Global Impression Severity and

10.1517/14656566.2012.674110 © 2012 Informa UK, Ltd. ISSN 1465-6566 1615

All rights reserved: reproduction in whole or in part not permitted
 C. A. Doyle & C. J. McDougle
Article highlights.
. For the treatment of interfering repetitive behaviors,
serotonin reuptake inhibitors demonstrate less efficacy
and are more poorly tolerated in children with autism
compared to adults.
.
Antipsychotics are the most efficacious drugs for the
treatment of irritability in children with autism and other
PDDs, often with concurrent improvements observed in
stereotypy and hyperactivity.
. For the treatment of hyperactivity and inattention,
psychostimulants demonstrate some benefit but are
overall less efficacious and cause more side effects in
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Sussex Library on 09/07/13
children with PDDs compared to typically developing
children with ADHD.
. Other medications that may be useful for behavioral
symptoms include naltrexone, divalproex sodium,
levetiracetam, memantine, mirtazapine, and
pioglitazone, although further research is needed.
This box summarizes key points contained in the article.
Improvement scales (CGI-S and CGI-I, respectively) are
commonly used, with a score of ‘much improved’ or ‘very
much improved’ corresponding to treatment response. The
Aberrant Behavior Checklist (ABC) is a five-subscale,
For personal use only.
parent-completed checklist also frequently used, measuring
the domains of irritability and agitation, lethargy and social
withdrawal, stereotypic behavior, hyperactivity and non-
compliance, and inappropriate speech. The Children’s Yale--
Brown Obsessive Compulsive Scale for Pervasive Develop-
mental Disorders compulsion scale (CY-BOCS-PDD) is
another measure of repetitive behaviors in autism. The Con-
ners Parent Rating Scale (CPRS) or Teacher Rating Scale
(CTRS) are frequently used in studies of hyperactivity and
inattention. These were the most commonly encountered out-
come measurements from the studies reviewed, although this
list is not exhaustive.
Articles for this review were located using Medline, under
the keywords ‘autism’, ‘pervasive developmental disorders’,
‘treatment’, and using the names of specific medications.
Articles were limited to the English language and those
published in 1984 or later.
2. Background
2.1 Diagnostic criteria
Autism, as defined in the Diagnostic and Statistical Manual of
Mental Disorders, 4th edition (DSM-IV), is a PDD characte-
rized by impaired reciprocal social interaction, aberrant
language development or communication skills, and the pres-
ence of repetitive, stereotyped behavior, interests, or acti-
vities [1]. Delay or dysfunction in social interaction,
language, or symbolic or imaginative play must be present
before age 3 years.
Asperger’s disorder also requires impairment in social
interaction and a pattern of restricted or stereotyped behavior,
1616 Expert Opin. Pharmacother. (2012) 13(11)
but differs in that language development is preserved. The
prevalence of Asperger’s disorder is not known, but it is
diagnosed five times more frequently in males [1].
PDD-NOS is diagnosed when there is a severe and perva-
sive social impairment associated with impaired communica-
tion, or with the presence of stereotyped behaviors, but the
criteria for autistic disorder or Asperger’s disorder are not
met [1].
Rett’s disorder and childhood disintegrative disorder
are the two remaining PDDs. They are much more rare,
with different developmental courses and, at times, treat-
ment approaches. They are not included in the studies
reviewed here.
2.2 Behavioral symptoms
Interfering stereotyped behaviors in PDDs may include repe-
titive motor mannerisms like hand or finger-flapping, clap-
ping, whole-body rocking, or spinning. The individual may
have inflexible adherence to non-functional routines or rit-
uals. Compared to patients with obsessive-compulsive disor-
der (OCD), the repetitive thoughts and behaviors that occur
in PDDs include more repetitive ordering; hoarding; telling
or asking; touching, tapping, or rubbing; and self-damaging
or self-mutilating behaviors [2].
The symptom domain of irritability in PDDs refers to
impulsive aggression, severe temper tantrums, or self-injuri-
ous behavior (SIB) [3]. Moderate-to-severe irritability occurs
in up to 30% of children and adolescents with PDDs [4].
Hyperactivity and inattention, as observed in attention-def-
icit/hyperactivity disorder (ADHD), are common in individ-
uals with PDDs. Although a diagnosis of a PDD is excluded
with a concurrent diagnosis of ADHD, an estimated
40 -- 59% of children diagnosed with PDDs also meet criteria
for ADHD [5,6].
3. Pharmacological treatments
3.1 Serotonin reuptake inhibitors
Serotonin reuptake inhibitors (SRIs) are efficacious in the
treatment of interfering repetitive behaviors in OCD [7],
which has led researchers to examine their effects on the ste-
reotyped behaviors in autism. Serotonin abnormalities are
implicated in the pathophysiology of PDDs [8-10], but studies
examining the effectiveness of SRIs in the treatment of PDDs
have yielded mixed results. SRIs that are FDA approved for
the treatment of OCD and that have been studied in children
with PDDs include clomipramine, fluoxetine, fluvoxamine,
and sertraline. Other SRIs examined in children with PDDs
include citalopram and escitalopram. Venlafaxine, a
serotonin-norepinephrine reuptake inhibitor (SNRI), and
trazodone, a serotonin antagonist and reuptake inhibitor
(SARI), have also been studied in children with PDDs.
3.1.1Clomipramine
Clomipramine, a tricyclic antidepressant with potent
serotonin reuptake-blocking properties, is FDA approved for
 Pharmacotherapy to control behavioral symptoms in children with autism
the treatment of OCD in children, adolescents and adults. In
a meta-analysis of treatment for pediatric OCD, clomipra-
mine was found to be superior to paroxetine, fluoxetine, flu-
voxamine, and sertraline [11]. Clomipramine has since shown
some efficacy in the treatment of interfering repetitive behav-
iors in children with PDDs, although side effects and need for
close monitoring limit its utility.
In a double-blind study of children and adolescents with
autism, clomipramine was more effective than placebo and
desipramine at decreasing stereotypies, anger, and compulsive,
ritualized behavior [12]. Another double-blind study found
clomipramine to be statistically comparable to haloperidol, a
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Sussex Library on 09/07/13
typical antipsychotic, in improving irritability and stereotypy
in children and adults with autism [13]. Unfortunately, these
results only represented 37.5% of individuals able to complete
the trial of clomipramine, as the rest were limited by side
effects. Clomipramine was not beneficial in an open-
label study of children with autism aged 3.5 -- 8.7 years [14].
Again, many participants experienced significant side effects.
Adverse effects in the above-mentioned studies included
cardiac QTc prolongation, tachycardia, diaphoresis, urinary
retention, nausea, vomiting, decreased appetite, constipation,
diarrhea, insomnia, fatigue, drowsiness, enuresis, lip-licking,
increased irritability, aggression, temper tantrums, and
For personal use only.
seizure.
Mean doses of clomipramine were in the range of 100 --
150 mg/day.
3.1.2 Fluoxetine
Fluoxetine has shown some efficacy in managing interfering
repetitive behaviors in children with PDDs. In the only dou-
ble-blind, placebo-controlled crossover study of 45 children
with PDDs, aged 5 -- 17 years, fluoxetine was superior to pla-
cebo in decreasing repetitive behaviors as measured by the
CY-BOCS [15]. Adverse effects were not significantly different
between fluoxetine and placebo.
In an open-label study, children and adults with autism,
aged 7 -- 28 years, showed a 65% response rate as measured
by the CGI-I, with a similar response for perseverative and
compulsive behaviors [16]. Younger children treated with
open-label fluoxetine, aged 2 -- 7 years, demonstrated an 81%
response rate, with 40% showing an ‘excellent’ response [17].
Doses of fluoxetine in the range of 0.2 -- 1.4 mg/kg/day in
one study, and in another started at 2.5 mg/day for 1 week,
then increasing until therapeutic effect was achieved, with an
average final dose of 9.9 mg/day. In the study that included
adults, fluoxetine was dosed at 20 mg daily and increased
until therapeutic effect was achieved or side effects occurred.
3.1.3Fluvoxamine
Fluvoxamine has shown poor tolerability and a limited
response in managing interfering repetitive behaviors in two
double-blind, placebo-controlled studies of children with
PDDs. This contradicts data regarding use in adults with
autism, where fluvoxamine led to improvements in repetitive
Expert Opin. Pharmacother. (2012) 13(11)
behaviors, maladaptive behaviors, aggression, and language
use [18].
In the first study of fluvoxamine in children and adoles-
cents with PDDs, aged 5 -- years, there was only 1 responder
out of 18 (5%), with side effects experienced in 78% of par-
ticipants [19]. Adverse effects included insomnia, hyperactivity,
agitation, aggression, increased rituals, anxiety, anorexia,
increased appetite, irritability, decreased concentration, and
impulsivity. The dose of fluvoxamine was started at 25 mg
every other day and increased by 25 mg every 3 -- 4 days
as tolerated.
A second crossover study examined 18 younger children
with autism, aged 3 -- 8 years, taking fluvoxamine for repeti-
tive behaviors [20]. Only 5 of 18 (28%) participants were con-
sidered responders. Dose was titrated up to 1.5 mg/kg/day for
body weight.
3.1.4 Sertraline
Sertraline has demonstrated some efficacy in managing
aggression, SIB, and interfering repetitive behaviors in adults
with PDDs [21,22]. However, data in children is limited to
one existing case series of nine patients with autism, aged
6 -- 12 years [23]. There were improvements in ‘transition-
induced behavior’, defined as panic, anxiety, irritability, or
agitation, although 33% had a loss of initial response after
3 -- 7 months. Doses were in the range of 25 -- 50 mg/day,
with 22% worsening above 75 mg/day.
3.1.5 Citalopram
In children and adolescents with PDDs, citalopram demon-
strated poor control of repetitive behaviors and a greater like-
lihood of adverse effects in a multisite, double-blind, placebo-
controlled study [24]. Mean age of participants was 9.4 years
and outcome measurements included the CGI-I and CY-
BOCS. Adverse effects included hyperactivity, increased
energy level, impulsivity, and gastrointestinal symptoms.
The mean dose was 16.5 ± 6.5 mg/day.
Conversely, two retrospective reviews of citalopram in chil-
dren and adolescents with PDDs deemed citalopram effective
at decreasing a number of symptoms that included stereoty-
pies and preoccupations, but also aggression, anxiety, and
disturbed mood [25,26].
3.1.6 Escitalopram
Data on escitalopram in the treatment of children with PDDs
is limited to one open-label study, where children aged
6 -- 17 years showed improvements on the CGI-I and all sub-
scales of the ABC, including Stereotypy [27]. Those deemed
‘responders’ were defined in reference to the Irritability sub-
scale score (ABC-I), and not specific to medication effect on
repetitive behaviors.
Side effects experienced included irritability and hyperac-
tivity. Dosages were increased on a forced titration schedule
from 2.5 to 20 mgdaily with variability in effective dose.
1617
 C. A. Doyle & C. J. McDougle
3.1.7 Venlafaxine
Data on venlafaxine is limited, but promising. One retrospec-
tive study of 10 children, adolescents, young adults treated
with venlafaxine resulted in a 60% response rate using the
CGI-I [28]. There were improvements in repetitive behaviors,
restricted interests, social deficits, communication and lan-
guage function, inattention, and hyperactivity. Dosages were
in the range of 6.25 -- 50 mg/day and venlafaxine was effective
at low doses (mean dose 24.37 mg/day).
Three case reports highlight three individuals with autism,
aged 17 to 23 years, whose aggression, SIB, and ADHD
symptoms improved on venlafaxine dosed at 18.75 mg/
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day [29].
3.1.8 Trazodone
This heterocyclic antidepressant was shown to reduce aggres-
sion and SIB in one case report of a 17-year-old male with
autism and severe mental retardation (MR) [30]. The patient
either did not tolerate previous psychotropic medications or
symptoms had not been well managed. The effective dosage
was 100 mg in the morning, 100 mg in the afternoon, and
50 mg at night.
3.2 Antipsychotics
For personal use only.
The most efficacious medications for the treatment of irrita-
bility in individuals with PDDs are the antipsychotics, with
risperidone and aripiprazole being FDA approved for the
treatment of irritability in children and adolescents with autis-
tic disorder. Numerous other typical and atypical antipsy-
chotics have been studied with positive results, although side
effects may limit their utility.
3.2.1 Typical antipsychotics
Typical antipsychotics have overall higher potency for antago-
nizing dopamine-2 receptors compared to atypical antipsy-
chotics. They include chlorpromazine, trifluoperazine,
thiothixene, trifluperidol, fluphenazine, molindone, haloperi-
dol, and pimozide. Studies of haloperidol and pimozide have
provided the most data specific to the treatment of children
with PDDs.
3.2.1.1 Haloperidol
Haloperidol is the most critically studied antipsychotic medi-
cation for managing or reducing symptoms associated with
autism [31]. It has been beneficial for managing irritability,
hyperactivity, and stereotypy, but patients are at risk for devel-
oping dyskinesias, particularly with long-term use.
A summary of all double-blinded, placebo-controlled studies
is reviewed here.
The earliest studies of haloperidol examined cohorts of chil-
dren with autism in the age range of 2 -- 7.5 years [32-35]. Hal-
operidol was superior to placebo in reducing stereotypies and
social withdrawal in children aged > 4.5 years, while the com-
bination of haloperidol with behavioral therapy was the most
effective at facilitating imitative speech [32]. Haloperidol
1618 Expert Opin. Pharmacother. (2012) 13(11)
resulted in reduced rates of stereotypy and improved orienta-
tion to the study raters in a small study of nine patients [33].
Although haloperidol also resulted in decreased maladaptive
behaviors with a trend toward discriminatory learning [34], a
later crossover study found no difference between haloperidol
and placebo in discrimination learning [35]. The most common
adverse event was dose-related sedation, although side effects
were minimal. Dyskinesias were rare.
In three of the above studies [32,34,35], higher IQ was predic-
tive of a greater reduction in behavioral symptoms, older chil-
dren responded more favorably to haloperidol, and there was
a greater reduction in symptoms with greater severity of ill-
ness [36]. Symptom reduction during short-term haloperidol
treatment was not found to be related to development of
dyskinesias with long-term haloperidol treatment.
Two studies have looked at the safety and efficacy of long-
term haloperidol treatment (‡ 6 months) in children with
autism aged 2 -- 8 years. In the first, participants showed a
reduction in maladaptive symptoms, with the greatest
response in those with irritability, labile and angry affect,
and uncooperativeness [37]. A subset of children switched to
placebo after study discontinuation required additional halo-
peridol treatment for the recurrence of severe symptoms, sup-
porting the drug’s efficacy. The second longitudinal study
revealed that 34% (40 of 118) of children developed dyskine-
sias with long-term haloperidol treatment [38]. Those who
appeared most at risk for developing dyskinesias included
female children with autism and those treated longer or with
higher haloperidol doses.
In all of the above-mentioned studies, haloperidol was
dosed in the range of 0.5 -- 4.0 mg/day.
Haloperidol has been compared with two other typical
antipsychotics in the management of autism: fluphenazine
and pimozide [39,40]. All three demonstrated efficacy but, in
comparison, haloperidol was found to be more effective
than fluphenazine in reducing withdrawal, aggression, and
stereotypies. Acute dystonic reaction, akathisia, and sedation
were observed side effects.
In a crossover study with clomipramine, haloperidol was
favored in the treatment of children and adults with autism,
aged 10 -- 36 years, particularly for hyperactivity, irritability,
and global symptom severity [13]. However, a significant num-
ber were unable to complete the study due to side effects and
lack of efficacy with clomipramine. Clomipramine was not
better tolerated; nor was it superior to haloperidol in the
management of stereotypy, as was originally hypothesized.
Haloperidol and risperidone, an atypical antipsychotic,
were compared and both deemed safe and well tolerated in
the treatment of autism. However, risperidone was more
effective in treating impulsivity, behavioral symptoms, lan-
guage skills and impaired sociability [41]. This study included
30 children with autism, aged 8 -- 18 years. Risperidone led to
a greater increase in prolactin, whereas haloperidol resulted in
increased alanine amino transferase (ALT), a liver enzyme.
Dosages were in the range of 0.01 -- 0.08 mg/kg/day. In a
 Pharmacotherapy to control behavioral symptoms in children with autism
follow-up, open-label, continuation study, risperidone was
more efficacious and better tolerated than haloperidol in the
long-term maintenance treatment of symptoms associated
with autism [42].
3.2.1.2Pimozide
There is one double-blinded, placebo-controlled study of
pimozide and haloperidol in children with behavioral distur-
bance, 39% of whom were autistic [40]. Results showed
response to both antipsychotic treatments without significant
difference between haloperidol and placebo. Pimozide was
superior to placebo in the cluster group ‘abnormal
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Sussex Library on 09/07/13
symptoms’, particularly in sleep disturbance and excretion
disorders. Participants ranged in age from 3 to 16 years.
Adverse events with both antipsychotics included
sleepiness. Dosing for pimozide was 1 -- 9 mg/day and for
haloperidol was 0.75 -- 6.75 mg/day.
3.2.2Atypical antipsychotics
The atypical antipsychotics antagonize both serotonin and
dopamine receptors, with less dopamine receptor potency
compared with typical antipsychotics -- particularly at lower
dosages. Due to a higher risk of extrapyramidal symptoms
(EPS) observed with typical antipsychotics, atypical antipsy-
For personal use only.
chotics have largely replaced typical antipsychotics in the
treatment of symptoms associated with autism.
3.2.2.1Clozapine
Clozapine is rarely used to treat symptoms associated with
PDDs, as it carries the risk of agranulocytosis and requires fre-
quent blood draws to monitor for this life-
threatening condition [43]. The data include a case series and
two case reports of clozapine treatment in children with
autism, all of whom had severe behavioral symptoms that
were not well managed on previous psychotropic medications.
In the case series, three children (two 8-year-old boys and one
12-year-old girl) were treated with increasing doses of cloza-
pine (200 -- 450 mg/day) [44]. They responded with marked
improvement on the CPRS. A 17-year-old Hispanic male
with comorbid severe MR and worsening aggression towards
others was treated with clozapine, titrated up to 275 mg/
day over 15 days, which resulted in improved compliance
with staff [45]. Finally, a 15-year-old girl who was hospitalized
for recurrent and sudden outbursts of aggression showed dra-
matically improved behavior after treatment with clozapine
475 mg/day [46].
3.2.2.2Risperidone
After demonstrating efficacy in several double-blind, placebo-
controlled trials, risperidone was FDA approved for the treat-
ment of irritability associated with autism in children and
adolescents aged 5 -- 16 years.
One study of risperidone in children with autism, aged
5 -- 17 years, revealed a 57% decrease in irritability as
measured by the ABC-I subscale, compared with 14% in
Expert Opin. Pharmacother. (2012) 13(11)
the placebo group [47]. In the risperidone group, 69% were
responders versus 12% in the placebo group. Similarly,
another study in children with PDDs (aged 5 -- 12 years)
revealed a 64% decrease in irritability in the risperidone group
using the ABC-I subscale compared with 31% in the placebo
group [48]. Eighty-seven percent of the risperidone group
showed response, versus 40% in the placebo group.
Two trials have demonstrated increased relapse rates with
risperidone discontinuation in children with PDDs, aged
5 -- 17 years, compared with continuous treatment. In a dou-
ble-blind, placebo-controlled study, relapse occurred in 8 of
12 (67%) participants who received placebo after responding
to risperidone, compared with 3 of 12 (25%) who received
continuous risperidone treatment [49]. In an open-label study,
relapse occurred in 62.5% of 32 participants who received
placebo after responding to risperidone, versus 12.5% who
received continuous risperidone treatment [50].
In the studies mentioned above, doses of risperidone were
in the range of 0.5 -- 3.5 mg/day. Side effects included
increased appetite, weight gain, fatigue, somnolence, drowsi-
ness, dizziness, anxiety, drooling, upper respiratory tract infec-
tions, and rhinitis. One study noted a statistically significant
increase in heart rate and systolic blood pressure [48]. That
same study also observed that somnolence resolved in 86%
of participants, and there was no significant difference in
EPS between treatment and placebo groups.
Risperidone has been studied in two placebo-
controlled studies of children aged < 5 years, with mixed
results. The first was a study of 24 children with PDDs,
aged 2.5 -- 6 years [51]. Although safe and well tolerated, ris-
peridone dosed at 0.5 -- 1.5 mg/day for 6 months showed
only minimally greater improvement in target symptoms,
with insufficient findings to direct treatment. Another
double-blinded study from India examined children with
autism, aged 2 -- 9 years [52]. This revealed a 63% response
rate as measured by a ‡ 20% improvement from baseline in
the Childhood Autism Rating Scale (CARS), with no res-
ponders in the placebo group. There was also an 89%
response rate as measured by the Children’s Global
Assessment Scale (CGAS), compared with 10% in the
placebo group.
Adverse effects in the above studies included transient seda-
tion, weight gain, hypersalivation, and elevated prolactin lev-
els without galactorrhea. Transient dyskinesias occurred in
15% of the risperidone-treated group from the India study.
Risperidone treatment coupled with parent management
training (average of 10.9 sessions) was found to reduce some
symptom domains more effectively than risperidone treat-
ment alone [53]. Participants in this study included 124 chil-
dren with PDDs, aged 4 -- 13 years, who exhibited frequent
tantrums, SIB, and aggression. After 24 weeks, the combina-
tion treatment group had a greater reduction in irritability,
stereotypic behavior, and hyperactivity/noncompliance
compared with the monotherapy group. Doses were in the
range of 0.5 -- 3.5 mg/day. The combination group required
1619
 C. A. Doyle & C. J. McDougle

a lower mean risperidone dose than the monotherapy group, are limited and show mixed results, with adverse events
1.98 versus 2.26 mg/day, to achieve its results. frequently leading to drug discontinuation.
Two open-label studies of quetiapine examined patients
with autism, although only two patients completed the first
3.2.3 Olanzapine
study and six completed the second [60,61]. Two patients
Studies of olanzapine in children and adolescents with PDDs
from each study were deemed responders. The study examin-
have shown favorable results among a wide range of symp-
ing subjects aged 10 -- 17 years suggested that quetiapine
toms, including irritability, hyperactivity, affective relations,
may not be effective in adolescents with autism, although the
and language.
size of the study sample may limit its interpretation. Patients
In the only double-blind, placebo-controlled study of olan-
dropped out of one study due to lack of improvement and
zapine, in 11 children with PDDs, aged 6 -- 14 years, 50%
inability to tolerate dose increases. Side effects included
percent were considered responders compared with 20% in
sedation, behavioral activation, akathisia, and probable seizure.
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the placebo group [54].

The first retrospective chart review revealed a 40% response
The bulk of olanzapine studies have been open-label, looking
rate to quetiapine in 20 patients with PDDs, aged
at patients with autism and PDD-NOS. The first set out to
5 -- 28 years [62]. Treatment lasted anywhere between 4 and
study communication problems in children with PDDs, aged
180 weeks. Adverse events occurred in 50% of patients and
6 -- 16 years, but revealed significant improvements in irritabi-
led to drug discontinuation in three patients. In another retro-
lity, hyperactivity, and excessive speech [55]. Paradoxically, only
spective chart review, quetiapine led to improvement in con-
13% were considered responders. This discrepancy may have
duct, inattention, and hyperactivity in 60% of patients with
been a function of the participants’ initial low average ABC-I
PDDs, aged 5 -- 19 years [63]. These patients’ behavioral
score at study entry. Another open-label study of 40 males
symptoms had failed to respond to previous psychosocial
with autism, aged 7 -- 17 years, showed significant reductions
interventions and at least two psychoactive agents.
in irritability, lethargy, stereotyped behavior, hyperactivity, and
The most commonly reported adverse effects included
inappropriate speech [56]. In a group of seven individuals with
weight gain and sedation. Although one study included dos-
PDDs, aged 5 -- 42 years, olanzapine led to an 85% response
For personal use only.

ages as low as 25 mg daily, most dosages of quetiapine were

rate with significant improvements in overall symptoms of
in the range of 100 -- 800 mg/day.
autism, motor restlessness or hyperactivity, social relatedness,
affectual relations, sensory responses, language usage, SIB,
3.2.5 Ziprasidone
aggression, irritability or anger, anxiety, and depression [57].
Current data on ziprasidone in children with PDDs is limited
No significant changes in repetitive behavior were observed.
with no published double-blind, placebo-controlled studies.
In a study of 12 males with Asperger’s disorder, aged 10 -- 15
However, the existing data has been promising. Ziprasidone
years, 75% responded to olanzapine [58]. There were significant
leads to less overall weight gain compared with the other
differences between baseline and completion scores of internal-
atypical antipsychotics, which is attractive to many patients.
izing and externalizing behaviors on the Child Behavior Check-
However, it is associated with a prolonged cardiac QTc
list (Parent and Teacher). Notably, concurrent psychostimulant
interval, which may limit its use.
treatment was continued where applicable.
The first open-label study revealed a 50% response rate in
Long-term olanzapine treatment was examined in a case
12 individuals with PDDs aged 8 -- 20 years [64]. Two partici-
series including two children with PDDs, aged 8 and 11 years,
pants with comorbid bipolar disorder were rated ‘much
and five adults aged 20 -- 52 years [59]. After 52 weeks, 6 of
worse’. Another open-label study revealed a 75% response
7 patients were responders as measured by the CGI, although
rate in 12 adolescents with autism, aged 12 -- 18.5 years [65].
concurrent psychotropic medications were continued in the
Final dosages were in the range of 20 -- 160 mg/day.
two children.
The most common adverse events in these studies included
In the above studies, adverse effects included increased
transient sedation. One patient with a history of tardive dyski-
appetite, weight gain, sedation, and loss of strength. One
nesia experienced oral dyskinesia that ceased after ziprasidone
study revealed no treatment-emergent side effects [56]. EPS
discontinuation [64]. Dystonic reactions occurred in two other
was observed in three children but disappeared after reduction
patients but resolved, one independently and the other with
of olanzapine dose [55]. No weight gain was experienced in the
the addition of diphenhydramine [65]. Weight loss in one
case series patients, which was attributable to receiving con-
study was thought to be secondary to discontinuation of prior
current dietary management and/or behavioral intervention.
antipsychotic medications [64]. In another study, ziprasidone
Doses started at 2.5 or 5 mg/day and were titrated slowly
was weight neutral, total cholesterol was decreased (without
up to 10 or 20 mg/day.
changes in triglycerides or low-density lipoproteins), and
there was a clinically insignificant increase of the mean QTc
3.2.4Quetiapine interval (14.7 ms) [65].
There are no published double-blind, placebo-controlled Case reports of two children with autism, aged 7 and
studies of quetiapine in children with PDDs. Other studies 15 years, respectively, showed improvements in multiple

1620 Expert Opin. Pharmacother. (2012) 13(11)

 Pharmacotherapy to control behavioral symptoms in children with autism
symptoms on ziprasidone [66,67]. Both had shown a poor
response to past psychotropic medications. The 7-year-old
showed improved agitation, impulsivity, mood, cognitive per-
formance, and language. The 15-year-old, who was continued
on concurrent methylphenidate, showed improved maladap-
tive behaviors, attention to tasks, hyperactivity, impulsivity,
and listening.
No weight gain or adverse effects were noted in either
patient. Doses were 10 and 60 mg/day, respectively.
3.2.6 Aripiprazole
Following two large, double-blind, placebo-controlled stud-
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Sussex Library on 09/07/13
ies, aripiprazole became FDA approved for the treatment of
irritability in children and adolescents with autistic disorder,
aged 6 -- 17 years [68,69]. There were no statistically significant
differences between 5, 10, or 15 mg/day, and dosages as low
as 2 mg/day was deemed more efficacious than placebo.
Adverse events that led to discontinuation in these studies
included sedation, drooling, tremor, aggression, and weight
increase. EPS such as tremor, hyperactivity, akathisia, and
dyskinesia have been reported [68,70].
A long-term, open-label study considered aripiprazole safe,
well tolerated, and able to reduce irritability for up to 1 year in
patients with autism, aged 6 -- 17 years [70,71].
For personal use only.
Results from open-label trials examining children with
PDDs have generally been favorable. Five males with PDDs,
aged 5 -- 18 years, all demonstrated response to open-
label aripiprazole for significant irritability, as did 88% of
25 patients with Asperger’s disorder or PDD-NOS [72,73].
However, a retrospective chart review revealed that aripipra-
zole was only helpful in 37% of patients with PDDs and
38% of those with PDDs and MR in managing aggression,
hyperactivity, impulsivity, and SIB [74]. The ages of these
32 patients were in the range of 5 -- 19 years.
3.2.7 Paliperidone
Paliperidone is the major active metabolite of risperidone.
Given the beneficial effect of risperidone in individuals with
autism, paliperidone is an intriguing possibility for treatment.
The available published data, however, are limited to two
case reports.
These cases examined a 20-year-old male and 16-year-old
female with autism and comorbid MR [75]. They had previ-
ously demonstrated minimal response to psychotropic medi-
cations in the management of severe aggression and
irritability. They were continued on some concurrent psycho-
tropic medications while treated with paliperidone. Both
demonstrated significant reductions in irritability and aggres-
sion, with no adverse effects or EPS observed. ECGs were
normal, weight decreased, and fasting lipids improved in
both patients. Doses were in the range of 6 -- 12 mg/day.
3.3Medications for ADHD symptoms
Children with PDDs who have symptoms of ADHD respond
to ADHD medications at a reduced rate compared with
Expert Opin. Pharmacother. (2012) 13(11)
typically developing peers, and often with undesirable side
effects. Medications studied include methylphenidate
(MPH), atomoxetine, clonidine, and guanfacine. The subjects
chosen for these studies were selected as having both PDD
and symptoms of ADHD.
3.3.1 Methylphenidate
Psychostimulants are the pharmacologic treatments of choice
in typically developing children with ADHD, with a response
rate of 70 -- 80% [76,77]. Children with PDDs, however, are
less likely to respond to stimulants like MPH and more likely
to experience adverse effects compared to children with
ADHD. There is evidence to suggest that the subtype of
PDD may affect response to stimulants, with those with
autism and PDD-NOS responding less well to stimulants
than those with Asperger’s disorder. Preschool-aged children
may respond with comparable rates to older children but
with increased adverse effects.
In one double-blind, placebo-controlled trial, there were
statistically significant reductions in hyperactivity in children
with autism, aged 7 -- 11 years [78]. Similarly, another study
revealed that 62% of autistic children aged 5.6 -- 11.2 years
had a ‡ 50% reduction in hyperactivity, with additional
improvements in inappropriate speech and stereotypies [79].
The largest double-blind, placebo-controlled study of
MPH treatment resulted in a 49% response rate, with 18%
of patients discontinuing the study due to side effects [80]. Irri-
tability was the most common side effect. Hyperactivity was
decreased more than inattention, and worsening of repetitive
behavior was uncommon [81]. Notably, children with autism
showed lower response rates than those with Asperger’s disor-
der or PDD-NOS [80]. This was also concluded in a retrospec-
tive chart review of 195 patients with PDDs, aged
2 -- 19 years [82]. Patients with Asperger’s disorder were less
likely to exhibit the adverse effect of agitation.
MPH treatment in preschool-aged children (aged
3 -- 5 years) with developmental disorders (most with
PDDs) resulted in a 50% response rate [83]. However, over
half experienced adverse effects, including increased stereo-
typic behavior. Other adverse effects noted in all of these stud-
ies included irritability, headache, stomach ache, decreased
appetite, weight loss, drowsiness, insomnia, depression, and
emotional lability.
Dosages varied from 10 -- 20 mgtwice daily in one study [78]
to a weight-based model of 0.3 -- 0.6 mg/kg/day [79], to
titrating up to ‘optimal dose’ in preschool-aged children [83].
3.3.2 Atomoxetine
Atomoxetine is a norepinephrine-selective reuptake inhibitor
that is FDA approved for the treatment of ADHD. Studies
of atomoxetine in children with PDDs suggest a favorable
response in at least half of patients treated, with mild to
moderate side effects.
The first and only published double-blind study revealed
a response rate of 56 versus 25% with placebo, with
1621
 C. A. Doyle & C. J. McDougle
atomoxetine deemed superior to placebo in managing hyper-
activity [84]. In a retrospective chart review, a 60% response
rate was revealed in children with PDDs aged 6 -- 19 years,
although 80% took at least one concomitant psychotropic
medication [85]. Improvements were noted in conduct,
hyperactivity, inattention, and learning.
Significant improvements in ADHD symptoms were also
found in two additional open-label studies of children with
PDDs aged 6 -- 14 years, with a 75% response rate in one
cohort [86,87]. Irritability, social withdrawal, stereotypy, and
repetitive speech were also improved, although to a lesser
extent [86].
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Sussex Library on 09/07/13
Adverse effects varied in the above trials. In most of these
studies, adverse effects were described as ‘mild to moderate’
or tolerable, although the discontinuation rate due to side
effects in one open-label study was 42% [87]. Reported effects
included gastrointestinal symptoms, decreased appetite, irrita-
bility, ear ringing, mood swings, sleep problems, and
sedation. Rarer events included severe mood swings and
recurrent violence requiring hospitalization. Stereotypy was
not observed.
Doses were in the range of 1.2 -- 1.4 mg/kg/day.
3.3.3 Clonidine
For personal use only.
Clonidine is an alpha-2 adrenergic agonist that is approved
for the treatment of hypertension, although an extended-
release formulation is FDA approved for the treatment of
ADHD in children aged 6 -- 17 years. Clonidine has exhibited
modest efficacy in the short-term treatment of ADHD symp-
toms and irritability, as evidenced by two double-blind,
placebo-controlled studies of individuals with autism [88,89].
In one of the studies, transdermal clonidine resulted in signif-
icant improvement on the CGI scale and in sensory responses,
affectual reactions, and social relationships.
Adverse effects have included drowsiness, sedation, and
decreased activity. Dosages range from 0.15 -- 0.20 mgday
in one study to 0.005 mg/kg/day in the other.
There is one open-label study that found clonidine helpful
for sleep initiation and maintenance in children with PDDs,
specifically reducing sleep initiation latency and night awak-
ening [90]. Doses used included 0.05 -- 0.1 mg at bedtime,
with two participants using a transdermal patch.
3.3.4 Guanfacine
Guanfacine is another alpha-2 adrenergic agonist. Immediate
release (IR) guanfacine is FDA approved for the treatment of
hypertension in adolescents and adults but only the extended-
release formulation is approved for the treatment of ADHD
in children aged 6 -- 17 years. Guanfacine IR is sometimes
used clinically (‘off-label’) to treat ADHD symptoms in typi-
cally developing children and children with PDDs. The avail-
able data show modest efficacy in controlling ADHD
symptoms.
The only double-blind, placebo-controlled trial used a
cohort of 11 children with developmental disabilities, seven
1622 Expert Opin. Pharmacother. (2012) 13(11)
of whom had autism or PDD-NOS, treated with guanfacine
IR in addition to concomitant psychotropic medications [91].
There were statistically significant drug--placebo differences
in hyperactivity and 57% of the children with PDD were
deemed responders. There were no changes in irritability.
Response rate in a retrospective chart review of children
with PDDs receiving guanfacine IR was only 24% [92]. Most
specifically, about one-quarter of patients showed improve-
ments in hyperactivity, inattention, and insomnia. Respond-
ers were less likely to have been treated with stimulants in
the past, less likely to have been tried on other psychotropic
medications, and were less aggressive at baseline. Those with
PDD-NOS and Asperger’s disorder (39.3 and 33.3%,
respectively) were more likely to respond than those with
autism (13%).
An open-label trial had better results, demonstrating a 48%
response rate to guanfacine IR in children with PDD who had
previously shown poor response or intolerance to MPH [93].
Adverse effects in these studies included drowsiness, sleep
disturbance, irritability, constipation, headache, and noctur-
nal enuresis. In general, no significant changes in blood
pressure, heart rate, or ECG were noted.
Dosing were mostly in the range of 1 -- 3 mg/day. In the
chart review, dosing were 0.25 -- 9 mg/day with a mean
dose of 2.6 mg/day, divided two to three times daily.
Data on guanfacine XR (extended release) is limited to
two case reports of children with PDDs, a 4-year-old girl
and a 9-year-old boy with irritability and symptoms of
ADHD [94]. Both showed significant improvement after
8 weeks of treatment.
3.4 Other medications
3.4.1 Naltrexone
This opioid antagonist is FDA approved for the treatment of
alcohol and opioid dependence. Naltrexone has been studied
in the treatment of symptoms associated with autism with
mixed results. Most double-blinded, placebo-controlled tri-
als have demonstrated limited utility in the treatment of
SIB and stereotypy. Some improvement in hyperactivity
and restlessness in subjects with PDDs has been reported.
The effective treatment of core social impairment has not
been observed [95-99].
In these studies, naltrexone was typically dosed at 0.5, 1.0,
or 2.0 mg/kg/day.
3.4.2 Buspirone
This anxiolytic is FDA approved for the treatment of general-
ized anxiety disorder in adults. Studies in children with PDDs
are limited, with no known published double-blinded,
placebo-controlled trials. An open-label study of 22 children
with PDDs, however, resulted in significant improvement
on the CGI, as well as improvement in symptoms of anxiety
and irritability [100]. Buspirone was well tolerated except in
one child who developed an orofacial-lingual dyskinesia,
which remitted after discontinuation.
 Pharmacotherapy to control behavioral symptoms in children with autism
3.4.3 Divalproex sodium
This anticonvulsant and mood stabilizer has been demon-
strated to be efficacious in treating epilepsy, bipolar disorder,
mood lability, and impulsive aggression. Double-blinded,
placebo-controlled studies have shown mixed results in the
management of repetitive behaviors and irritability in subjects
with PDDs. In the treatment of 30 children and adolescents
with PDDs, aged 6 -- 20 years, there was no significant treat-
ment difference between divalproex sodium and placebo [101].
However, in the treatment of irritability in 55 children and
adolescents with PDDs, aged 5 -- 17 years, a response rate of
62.5% was found with the drug versus 9% with placebo [102].
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Sussex Library on 09/07/13
An early open-label trial also noted improvements in affective
instability, impulsivity, and aggression [103]. Divalproex
sodium has also led to improvement in repetitive behaviors
in a double-blind, placebo-controlled trial of 13 children
with PDDs, as measured by the CY-BOCS [104].
3.4.4Lamotrigine
The only double-blinded, placebo-controlled study of this
anticonvulsant in children with PDDs examined 28 boys
with autism, aged 3 -- 11 years [105]. No significant differences
between lamotrigine and placebo were found in the treatment
of symptoms associated with autism.
For personal use only.
3.4.5Levetiracetam
There are no published double-blinded, placebo-controlled
studies of this anticonvulsant in the treatment of children
with PDDs. However, an open-label trial of 10 autistic
boys, aged 4 -- 10 years, showed improvements in inattention,
hyperkinesis, and impulsivity [106]. Statistically significant
improvements occurred in mood instability, although aggres-
sive behavior was improved only in subjects who were not
weaned from other aggression-reducing medications.
3.4.6Memantine
Memantine is an NMDA-receptor antagonist that is FDA
approved for the treatment of Alzheimer’s dementia. There
are no published double-blind, placebo-controlled studies
of this drug in PDD, although open-label studies and case
reports have been promising. An 8-week, open-label study
examined 14 male patients with PDDs, aged 3 -- 12 years,
and showed significant improvements on the ABC subscales
of Hyperactivity, Lethargy, and Irritability, as well as on a
memory test [107]. There were no significant differences on
the CGI-S or CGI-I scales, and hyperactivity caused two
subjects to discontinue the drug. Another open-label study
examined 151 autistic subjects, aged 2.5 -- 26 years, treated
with memantine and concomitant psychotropic medications
for 1 -- 20 months [108]. Language function, social behavior,
and self-stimulatory stereotypic behaviors improved signifi-
cantly, with 124 of 151 (82%) continuing on memantine.
Worsened behavior occurred in 22 of 151 (14.5%).
A retrospective review of 18 patients with PDDs, aged
6 -- 19 years, treated with open-label memantine found
Expert Opin. Pharmacother. (2012) 13(11)
11 of 18 (61%) to be responders, with improvements in
social withdrawal and inattention [109]. Adverse effects
occurred in 7 of 18 (39%) patients and included irritability,
rash, emesis, increased seizure frequency, and excessive
sedation. In these studies, dosage were in the range of
2.5 -- 30 mg/day.
One case report demonstrated improvement in disruptive
behavior, as well as decreased social withdrawal and impulsi-
vity, in a 23-year-old autistic man treated with meman-
tine [110]. Another showed improvement in OCD symptoms
and social interaction in a 15-year-old boy with OCD and
Asperger’s disorder treated with adjunctive memantine [111].
Dosages were 5 and 10 mg/day, respectively.
3.4.7 Mirtazapine
Mirtazapine is a tetracyclic antidepressant that antagonizes
both alpha-2 adrenergic and serotonin receptors. It is FDA
approved for the treatment of major depressive disorder.
There are no published placebo-controlled studies of mirtaza-
pine in PDD. One 4-week, open-label study examined
26 autistic subjects, aged 3.8 -- 23.5 years [112]. Nine of 26 sub-
jects (34.6%) were judged responders, with modest improve-
ments noted in aggression, self-injury, irritability,
hyperactivity, anxiety, depression, and insomnia. Adverse
effects were minimal and included increased appetite, irrita-
bility, and transient sedation. Dosage ranged from 7.5 to
45 mgdaily.
Another open-label study found mirtazapine useful in man-
aging excessive masturbation or inappropriate sexual behav-
iors in 8 of 10 subjects (80%) with autism, aged
5.2 -- 16.4 years [113]. Mirtazapine was titrated up to
15 -- 30 mg/day and tolerated well with the most common
side effects of increased appetite, weight gain, and sedation.
Case reports examined two 13-year-old males and one
5-year-old male with autism successfully treated with mirtaza-
pine for the management of excessive masturbation and other
inappropriate sexual behaviors [114-116]. Dosages were in the
range of 5 -- 30 mg/day. In one subject, heightened activity
and agitation were experienced at higher doses.
3.4.8 Pioglitazone
Pioglitazone is an agonist of the peroxisome proliferator-
activated receptor gamma (PPAR-g), a nuclear hormone
receptor that modulates insulin insensitivity in
type 2 diabetes. It also induces apoptosis in activated T-lym-
phocytes and has anti-inflammatory effects in glial cells.
There is speculation that the pathophysiology of autism may
linked to immune and inflammatory responses, and that pio-
glitazone may be of benefit. One study examined open-
label treatment in 25 autistic children, aged 3 -- 17 years,
treated with pioglitazone for 3 -- 4 months [117]. The ABC
subscales of irritability, lethargy, stereotypy, and hyperactivity
showed significant decreases and improved behaviors were
inversely correlated with age. Dosage was in the range of
30 -- 60 mg/day and no adverse effects were noted.
1623
 C. A. Doyle & C. J. McDougle
3.4.9 Riluzole
Riluzole is a glutamate inhibitor that is FDA approved for
the treatment of amyotrophic lateral sclerosis (ALS). There
are no published double-blinded, placebo-controlled
studies of this drug in PDD, but a case series in three autis-
tic individuals demonstrated promising results for the treat-
ment of interfering repetitive behaviors [118]. The
individuals were aged 15 -- 20 years, had diagnoses of
autism and MR, and had tried previous psychotropic
medications for the management of their symptoms. In
all participants there were reductions in interfering repeti-
tive behaviors, and two exhibited decreased irritability,
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Sussex Library on 09/07/13
aggression, and SIB. Adverse effects included mild
anemia in one individual. Dosages were in the range of
100 -- 200 mg/day.
3.4.10 Topiramate
There are no published double-blinded, placebo-
controlled studies of this anticonvulsant alone in PDD,
although one randomized study highlights adjunctive treat-
ment with risperidone. This study randomized 40 children
with autism, aged 4 -- 12 years, to receive risperidone plus
topiramate or placebo for 8 weeks for control of disruptive
behavior symptoms [119]. The topiramate group had a
For personal use only.
greater reduction in ABC--Community subscale scores for
Irritability, Stereotypic Behavior, and Hyperactivity/Non-
compliance. Risperidone was titrated to 2 and 3 mg/
day and topiramate to 100 and 200 mg/day based
on weight.
Open-label studies targeting behavioral symptoms have
demonstrated limited success in PDD. One trial examined
topiramate treatment (mostly adjunctive) in 5 autistic
boys, aged 9 -- 13 years, for 10 -- 33 weeks [120]. Two of
5 (40%) were deemed responders, with improvements in
hyperactivity, interpersonal behavior, irritability or anger,
anxiety, and depression. Maximum dosage was 2.5 mg/
kg/day. A retrospective chart review of open-label topira-
mate in 15 subjects with PDDs, aged 8 -- 18 years, found
8 of 15 subjects (53%) to be treatment responders [121].
Differences from baseline in CPS subscale ratings were in
conduct, hyperactivity, and inattention. Dosage was in the
range of 100 -- 400 mg/day, given twice daily as tolerated.
Although topiramate was well tolerated in the first study
with minimal side effects, three subjects discontinued
in the latter study due to cognitive difficulties and one
skin rash.
Topiramate was examined in two males with PDD-NOS,
aged 15 and 16 years, for the treatment of skin picking [122].
Both subjects discontinued the drug due to a lack of efficacy
but tolerated it well with minimal side effects. Open-
label topiramate was also given to 10 autistic children, aged
8 -- 19 years, with the goal of reducing antipsychotic-
induced weight gain, although three subjects discontinued
the drug due to behavioral adverse effects, including agitation
and hyperactivity [123].
1624 Expert Opin. Pharmacother. (2012) 13(11)
4. Expert opinion
The behavioral symptoms targeted by pharmacologic treat-
ment in children with PDDs discussed in this review largely
include interfering repetitive behaviors, irritability, and hyper-
activity and inattention. Serotonin reuptake inhibitors dem-
onstrate less efficacy in the treatment of interfering repetitive
behaviors in children with PDDs compared to adults with
autism. Among the SRIs in double-blind, placebo-
controlled trials, fluoxetine is the only drug to show signifi-
cant improvement in children with PDDs. The beneficial
response observed with clomipramine treatment is offset by
its significant adverse effects, often limiting its use altogether.
The limited data with venlafaxine is promising, suggesting a
potential role in managing repetitive behaviors in some chil-
dren with PDDs. Fluvoxamine has shown poor tolerability
and a limited response in managing interfering repetitive
behaviors in children with PDDs; the response in adults
with autism has been more favorable. There is limited, gener-
ally unfavorable data supporting the use of sertraline, citalo-
pram, escitalopram, and trazodone for interfering repetitive
behaviors in children with PDDs. Recent preliminary data
with riluzole, a drug that is FDA approved for the treatment
of ALS, indicates that it may be worthy of additional study
for this symptom domain in PDD.
Antipsychotics are the most efficacious drugs for the treat-
ment of irritability in children with autism and other PDDs,
with risperidone and aripiprazole FDA approved for this pur-
pose. There are often concurrent improvements observed in
stereotypy and hyperactivity with the use of antipsychotics
in PDDs. Typical antipsychotics demonstrate efficacy, but
their use is limited by the risks of EPS and tardive dyskinesia.
Atypical antipsychotics show the best efficacy, but are associ-
ated with common side effects including increased appetite,
weight gain, sedation, metabolic changes, and EPS. Clozapine
has been useful in isolated cases of refractory maladaptive
behaviors, but is significantly limited by its risk of agranulocy-
tosis and the need for strict monitoring of blood count.
Promising directions include continued research into the use
of ziprasidone, given its decreased risk of weight gain, and
paliperidone, given its similarities to risperidone. Other
potential atypical antipsychotics to be studied in the future
include asenapine and iloperidone.
In the treatment of hyperactivity and inattention, most
ADHD medications are effective in about half of children
with PPDs. Methylphenidate is more likely to cause adverse
side effects, like irritability, which can lead to discontinuation.
Atomoxetine, a non-stimulant treatment for ADHD, has
shown significant benefit and minimal and tolerable side
effects in children with PDDs. Clonidine and guanfacine
may be limited by the side effect of drowsiness, although
this can be helpful if there is a disturbance in sleep initiation.
Naltrexone may have a role in treating hyperactivity and
restlessness in children with PDDs. The effects of naltrexone
on irritability, SIB, and social impairment have been less
 Pharmacotherapy to control behavioral symptoms in children with autism

consistent than had been anticipated. Buspirone may be help-
ful in managing symptoms of anxiety, although controlled tri-
als are needed. Divalproex sodium may be helpful for some
patients in managing irritability, affective instability, impul-
sivity, and aggression. The results of studies with this drug,
however, have been inconsistent. Lamotrigine has not shown
beneficial effects in children with PDDs. Levetiracetam has
shown some benefit in managing inattention, hyperkinesis,
impulsivity, and mood instability. Memantine may be useful
in the treatment of memory functioning, hyperactivity, leth-
argy, and irritability, with some evidence to suggest utility
in helping language function, social behavior, and self-
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Sussex Library on 09/07/13
Significant progress has been made in the development of
effective drug treatment for many symptoms associated with
PDDs. Additional research is necessary to identify drugs
with more benefit for interfering repetitive behaviors. Drugs
with an improved safety profile are needed for the treatment
of irritability. Preliminary results from studies of atomoxetine
and guanfacine are encouraging for ADHD symptoms. Mem-
antine, mirtazapine, and pioglitazone have offered novel
approaches to treating behavioral symptoms associated with
PDDs and may warrant further research. Beyond these target
symptom domains, the development of pharmacologic treat-
ments for the core social and communicative impairments

stimulatory stereotypic behaviors. Mirtazapine was well toler-
ated but showed only modest effectiveness for treating the
associated symptoms of PDDs. It may, however, be an effec-
tive treatment for inappropriate sexual behaviors in young
patients with autism. Pioglitazone shows promise in treating
irritability, lethargy, stereotypy, and hyperactivity, although
further studies are needed. Topiramate has shown some utility
in treating behavioral symptoms in children with PDDs as
both a monotherapy and adjunctive medication, but the
results have not been consistent.
of autism are needed.
Declaration of interest
The authors declare no conflict of interest. This work was
supported by the State of Indiana Division of Mental Health
and Addiction Services and Indiana University Health (to
C Doyle) and the Nancy Lurie Marks Family Foundation,
Autism Speaks, and the National Institute of Mental Health
(ROIRH776600, ROIMH083739) (to CJ McDougle).

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Affiliation
Carolyn A Doyle1 MD &
Christopher J McDougle†2 MD
†
Author for correspondence
1
Indiana University School of Medicine; and
Christian Sarkine Autism Treatment Center,
Riley Hospital for Children,
Department of Psychiatry, IN, USA
2
Harvard Medical School; and
Lurie Center for Autism,
Department of Psychiatry,
1 Maguire Road, Lexington,
MA 02421, USA
Tel: +1 781 860 1700;
Fax: +1 781 860 1766;
E-mail: cmcdougle@partners.org
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