REVIEW ARTICLE

Medications for Adolescents and Young Adults With
Autism Spectrum Disorders: A Systematic Review
AUTHORS: Dwayne Dove, MD, PhD,a Zachary Warren,
PhD,a,b,c Melissa L. McPheeters, PhD,d,e Julie Lounds
Taylor, PhD,a,f Nila A. Sathe, MA, MLIS,e and Jeremy
Veenstra-VanderWeele, MDa,b,c,g
Departments of aPediatrics, bPsychiatry, dObstetrics andGynecology, and gPharmacology; cVanderbilt Kennedy Center
Treatment and Research Institute for Autism Spectrum
Disorders; eVanderbilt Evidence-based Practice Center, Institutefor Medicine and Public Health, Vanderbilt University Medical
Center; fVanderbilt Kennedy Center, Vanderbilt University,
Nashville, Tennessee
KEY WORDS
autism spectrum disorders, antipsychotics, risperidone,
serotonin reuptake inhibitors
ABBREVIATIONSABC—Aberrant Behavior Checklist
ASD—autism spectrum disorder
CGI-I—Clinical Global Impression of Improvement
RCT—randomized controlled trial
SRI—serotonin reuptake inhibitor
This project was funded under contract HHSA 290 2007 10065 I
from the Agency for Healthcare Research and Quality, US
Department of Health and Human Services. The authors of thisreport are responsible for its content. Statements in the report
should not be construed as endorsement by the Agency for
Healthcare Research and Quality or the US Department of Healthand Human Services.
www.pediatrics.org/cgi/doi/10.1542/peds.2012-0683
doi:10.1542/peds.2012-0683
Accepted for publication May 17, 2012
Address correspondence to Jeremy Veenstra-VanderWeele, MD,
465 21st Ave S, 7158 MRB III, Vanderbilt University Medical Center,
Nashville, TN 37212. E-mail: j.vvw@vanderbilt.edu

abstract
BACKGROUND AND OBJECTIVE: Although many treatments have beenstudied in children with autism spectrum disorders (ASDs), less attention has focused on interventions that may be helpful in adolescentsand young adults with ASD. The goal of this study was to systematicallyreview evidence regarding medication treatments for individuals between the ages of 13 and 30 years with ASD.
METHODS: The Medline, PsycINFO, and ERIC databases were searched(1980–December 2011), as were reference lists of included articles.
Two investigators independently assessed studies against predetermined inclusion/exclusion criteria. Two investigators independently
extracted data regarding participant and intervention characteristics,
assessment techniques, and outcomes and assigned overall quality andstrength of evidence ratings on the basis of predetermined criteria.
RESULTS: Eight studies of medications were identiﬁed that focused on
13- to 30-year-olds with ASD; 4 of the studies were of fair quality. The
strength of evidence was insufﬁcient for all outcomes associated withmedications tested in this population; however, the 2 available studiesof the atypical antipsychotic medication risperidone in this age range
were consistent with the moderate evidence in children with ASD fortreating problem behavior, including aggression, and high strength ofevidence for adverse events, including sedation and weight gain.
CONCLUSIONS: There is a marked lack of data on use of medication
treatments for adolescents and young adults with ASD. The evidence on
the use of risperidone in this age range is insufﬁcient when consideredalone but is consistent with the data in the population of children with
ASD. Pediatrics 2012;130:717–726

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2012 by the American Academy of Pediatrics(Continued on last page)

PEDIATRICS Volume 130, Number 4, October 2012

Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017717

Core symptoms of autism spectrum
disorders (ASDs), including impairments related to social communication
and restricted/repetitive behaviors andinterests, typically affect individuals
throughout their life span, althoughdevelopmental expression may vary.1
Given the lifelong nature of ASD, mostindividuals are exposed to multiple
interventions addressing different
target symptoms. In contrast to behavioral treatments, which may target
core symptoms, medication treatments
are primarily directed toward associated symptoms in individuals with ASD.
As part of a systematic review of therapies for adolescents and young adults(ages 13–30 years) with ASD, we
reviewed the literature on medication
treatments used to target associatedsymptoms. Information on other therapies (eg, behavioral, educational, allied health) addressed in the full
review can be found at http://www.
effectivehealthcare.ahrq.gov.

METHODS
Search Strategy
We searched Medline via the PubMedinterface, PsycINFO (psychology andpsychiatry literature), and ERIC (educational literature) from 1980 to December
2011 by using relevant controlled vocabulary terms and key terms related
to ASD (eg, autistic disorder) and therapy (eg, therapeutics). We also handsearched the reference lists of all
included articles and of recent narrative and systematic reviews related totherapies for ASD to identify potentiallyrelevant articles.
Study Selection
Study inclusion and exclusion criteria
were developed in consultation with anexpert panel of clinicians and researchers involved in ASD. All study designs were
included, and we required that studies
include at least 20 participants with ASD
between 13 and 30 years of age. Two718

investigators independently reviewed
each study against the inclusion criteria (Table 1) with disagreements
resolved through adjudication by asenior investigator.
We also required that studies be published in the year 1980 or later (after the
publication of standardized diagnostic
criteria for ASD in the Diagnostic andStatistical Manual of Mental Disorders,Third Edition).
Data Extraction
Using standardized forms, 2 investigators independently extracted data
regarding study design; descriptions of
the study populations, intervention,and comparison groups; and baselineand outcome data, as well as data
about adverse events. Data on the
conduct and timing of assessments
were also captured to inform the assessment of quality. Principal outcomes of interest included effects
on core symptoms of ASD and comorbid symptoms and conditions, including sleep, anxiety, hyperactivity, andchallenging behavior(eg, irritability/
agitation), as well as effects on familyrelated outcomes.
Study Quality Assessment
Two investigators independently assessed each study by using a quality
assessment form developed by the review team with input from experts in theﬁeld and adapted from a previous
Agency for Healthcare Research andQuality review of therapies for children
with ASD.2 We evaluated the following
elements with a series of yes/noquestions in each domain (eg, “Wereoutcomes coded and assessed byindividuals blinded to the intervention status of the participants?”):study design, diagnostic approach,participant ascertainment and characterization, intervention description, outcomes measurement, and statisticalanalysis.

Disagreements between assessors
were resolved through discussion toreach consensus. Overall assessmentof quality was determined with a prespeciﬁed algorithm that is available in
the full report.
The strength of evidence of the current
research was assessed by using
methods established in the Agency for
Healthcare Research and Quality Effective Health Care Program’s Methods
Guide for Effectiveness and Comparative Effectiveness Reviews.3 Assessments are based on consideration of
4 domains: risk of bias, consistency
in direction of the effect, directness
in measuring intended outcomes, andprecision of effect (Table 2). We determined the strength of evidence
separately for major interventionoutcome pairs by using a prespeciﬁed
approach described in detail in thefull review.
Data Synthesis
Given considerable heterogeneity in theinterventions and outcome measuresused in studies meeting our inclusion
criteria, we did not conduct any metaanalyses. Characteristics of study
populations and interventions weresummarized, and descriptive statistics
were used to report study outcomes.

RESULTS
Figure 1 outlines the ﬂow of articles
retrieved for the review. The originalliterature search was conducted fora broad review of all interventions foradolescents and young adults with
ASD, although only studies of medications are included in this analysis. As
noted in Fig 1, studies were mostcommonly excluded based on sample
size, population, and lack of relevance tothe questions addressed in the review.
Eight unique studies addressed medications in adolescents and young adults
with ASD. Of these, 5 were randomized
controlled trials (RCTs) and 3 were case

DOVE et al

Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

REVIEW ARTICLETABLE 1 Inclusion and Exclusion Criteria
Category

Criteria

Study population

Interventions

Comparators
Outcomes

Time period
Setting
Publication languages
Admissible evidence(study design and other criteria)
Admissible design

Study size
Other criteria

Adolescents or young adults (ages 13–30 years) with ASD(autistic disorder, Asperger syndrome, PDD-NOS) or
families/caregivers of individuals with ASD between theages of 13 and 30 years
Interventions aimed at ameliorating core symptoms of ASD,
affecting independent functioning, adaptive behavior, or
the transition process, or targeting family outcomes
Placebo
Other intervention
Social skills/interaction, language and communication,
repetitive and other maladaptive behaviors, motor
outcomes, psychological distress, adaptive skills
development, academic skills development, and family
outcomes, including family distress and family satisfaction
Studies published from 1980–present with no limits on timingof outcomes
Any setting, including educational, residential, and clinic
English only

Controlled trials, observational studies including prospective
and retrospective cohort studies, prospective andretrospective case series
At least 20 total individuals between 13 and 30 years of age with
ASD or family members of such individuals
Original research studies that provide sufﬁcient detailregarding methods and results to enable use andadjustment of the data and results
Patient populations must include adolescents or young adults
Ć(13–30 years of age) with ASD or families/caregivers ofĆindividuals with ASD between the ages of 13 and 30 years
Studies must address 1 or more of the following: (1)Ćtreatment modality aimed at modifying ASD core symptoms,Ćcommon comorbidities, family-related outcomes, orĆassisting with transitional issues; and (2) outcomes(including harms) related to interventions for ASD
Studies must include extractable data on relevant outcomes,
including data presented in text or tables (versus solely
in ﬁgures)Studies must present aggregate data (versus only data foreachindividual participant)

PDD-NOS, pervasive developmental disorder–not otherwise speciﬁed.

series. We located 3 studies addressing
antipsychotic medications4–6; 5 studies
addressing serotonin reuptake inhibitor(SRI) medications5,7–10; and 1 study
addressing the opioid receptor antagonist naltrexone.11 Tables 3 and 4
summarize study characteristics andkey results.

Antipsychotic Medications
One fair-quality RCT of risperidone6 included adults with autistic disorder orpervasive developmental disorder–not
otherwise speciﬁed. The mean 6 SD ageof the 31 individuals who began the trial
was 28.1 6 7.3 years, and mean full-scale
IQ was 54.6 6 23.9. Only 24 participants
completed the trial. The experimental design was a 12-week, randomized, doubleblind, placebo-controlled phase followed
by a 12-week, open-label risperidone
treatment phase for individuals from theplacebo group. Participants discontinued
all psychiatric medications for .4 weeks
before the trial started. Risperidone dosing could have ranged from 1 mg to 10
mg/day over the course of the study;
the highest end dose was 6 mg/day.
The primary outcomes were global

improvement, repetitive behavior, aggression, and social relatedness. Participants with a Clinical Global Impressionof Improvement (CGI-I) score of “muchimproved” or “very much improved”
were considered responders.
Fifty-seven percent (8 of 14 participants) were considered responders in
the risperidone group, whereas none
(0 of 16) in the placebo group were
responders (P , .002).6 Aggressive
behavior improved over time (P , .001)
for the risperidone group comparedwith the placebo group. This result wasconsistent with improvements overtime in the open-label phase (P , .05).
Repetitive behavior improved overtime (P , .001) for the risperidone
group compared with the placebogroup at each time point. This result
was consistent with improvements
over time in the open-label phase (P ,.03). Symptomatic improvements forthe risperidone group compared withplacebo were signiﬁcant over time forsensory motor (P , .004), affectual
reactions (P , .001), and overall score(P , .05). Differences for social relationships, sensory responses, or language were not signiﬁcant.
These results were largely consistent
with the improvements over time in the
open-label phase.6 Scores on clinicianrated visual analog scales were signiﬁcantly decreased in the risperidone
group compared with the placebogroup for “anxious or nervous”(P , .02), “depressed” (P , .03), and“irritable” (P , .01). There were no
signiﬁcant differences for “calm,” “eyecontact,” “happy,” “restless,” “social
interaction,” “talkative,” or “tired.” Sedation was the most prominent adverse event. Seven participants did notcomplete the trial (3 in the risperidone
arm and 4 in the placebo arm), with 6
participants dropping out due to lackof improvement or agitation, and 1
participant in the risperidone arm withabnormal gait.

PEDIATRICS Volume 130, Number 4, October 2012

Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

719

TABLE 2 Domains Used to Assess Strength of Evidence
DomainDescription

Risk of bias

Reﬂects issues in study design and conduct that could result inbiased estimates of effectReﬂects similarity of effect sizes seen across studies.
Consistency cannot be assessed when only 1 study
is available
Reﬂects the relationship between the intervention and theultimate health outcome of interest
Reﬂects the level of certainty around the effect observed

Consistency

Directness
Precision

A poor-quality crossover study addressed the safety and efﬁcacy of risperidone in 40 children, adolescents,
and adults with intellectual disability,
90% of whom had ASD.4 Twenty-three(57.5%) of participants responded fully (deﬁned as a 50% reduction in the
Aberrant Behavior Checklist [ABC]Irritability/Agitation subscale score).
Symptoms on the Neuroleptic Side
Effects Checklist that were the mostsigniﬁcant (P , .001) with treatment
included drowsiness, weight gain, andincreased appetite. Mean weight gain

during the entire study was 8.3 kg foradolescents and 6.0 kg for adults.
A fair-quality crossover study5 investigated the efﬁcacy of haloperidol forthe treatment of autism. The study design
was a double-blind, placebo-controlled,
crossover with random assignment to7-week phases of haloperidol, clomipramine, and placebo (clomipramine
results are summarized in the following SRI discussion). Haloperidol dosing
started at 0.25 mg at bedtime and increased in 0.25-mg increments every 2days until the dose was 0.50 mg twice

daily; further 0.25-mg adjustments
were then made every 3 to 4 days on
the basis of clinical assessment. The
dose was reduced to the last dose tolerated if adverse events were experienced. There was a dosage taper during
week 7 of each phase, and 1-week placebo washout periods between eachphase. No other psychotropic drugs
were allowed except benztropine.
Of the 37 participants recruited, 36(mean age: 16.3 years) were included inﬁnal analyses.5 The mean daily dose of
haloperidol was 1.3 mg. The mean duration of haloperidol treatment was 5.8
weeks, with 23 (69.7%) of 33 participants completing the 7-week treatment phase. Seven of 10 participants
who discontinued had adverse events,
including fatigue (n = 5), dystonia(n = 1), and depression (n = 1). The
mean duration of placebo treatment
was 5.4 weeks, with 21 (65.6%) of 32
participants completing the 7-weekphase; 1 of 9 participants who discontinued had adverse events (nosebleeds). The other 8 participants
discontinued due to lack of improvement in symptoms. Haloperidol versus
placebo was signiﬁcant for reductionsin ABC Hyperactivity/Deﬁance scores(P , .05) but not for the other ABC
subscales. The investigators noted thatcarryover of effects between phases
may have affected results in thiscrossover design, especially with theshort 1-week washout. Other comparisons between haloperidol and placebo
were not discussed.
SRI Medications

FIGURE 1
Disposition of articles identiﬁed for review. aNumbers do not tally because studies could be excluded for
multiple reasons. bOne study4 addresses an antipsychotic and an SRI.

720

Five studies of SRIs met our criteria.5,7–10
One fair-quality RCT7 investigated the
efﬁcacy of ﬂuvoxamine in adults with
autistic disorder. Participants were notreceiving any psychotropic medications
for at least 6 weeks before starting thetrial. The study randomized participants
to receive placebo or ﬂuvoxamine initiated at 50 mg daily and increased 50 mg

DOVE et al

Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

REVIEW ARTICLETABLE 3 Overview of Studies
Characteristic
Intervention
Antipsychoticsa
SRIsa
Opioid receptor antagonist
Treatment duration, mo.1 to #3
.3 to #6
.6 to #12
Study population
United States
EuropeOther
Total participants

RCTs(n = 5)

Prospective
Case Series (n = 2)

Retrospective
Case Series (n = 1)

Total
Literature (N = 8a)

3
2
1

0
2
0

0
1
0

3
5
1

4
1
0

2
0
0

0
0
1

6
1
1

3
1
1
172

2
0
0
77

1
0
0
23

6
1
1
272

a One study assessed both an antipsychotic agent and an SRI.

every 3 to 4 days to maximum clinicalresponse or a maximum dose of 300 mg/
day. All 30 participants (15 ﬂuvoxamine,
15 placebo) completed the 12-week trial.
The mean age was 30.1 6 7.1 years forthe ﬂuvoxamine group and 30.1 6 8.4
years for the placebo group. The mean
daily dose was 276.7 6 41.7 mg/day forthe ﬂuvoxamine group and 283.3 6 36.2
mg/day for the placebo group (difference not signiﬁcant). Global improvement as measured by using CGI-I was
higher for ﬂuvoxamine compared withplacebo (P , .001). Individuals wereclassiﬁed as responders if the CGI-I
scores were very much improved ormuch improved. There were signiﬁcantly
more responders (P , .001) in the ﬂuvoxamine group (8 of 15 participants)
compared with the placebo group (0 of15). On most measures of challenging
behavior, the scores for the ﬂuvoxaminegroup improved more than the scoresfor the placebo group. Adverse events inthe ﬂuvoxamine group included mild
sedation (n = 2) and nausea (n = 3).
There were no signiﬁcant changes in
anticholinergic effects, vital signs, routine laboratory analyses, or electrocardiogram results.
Another fair-quality study5 used a doubleblind, placebo-controlled crossover design to investigate the efﬁcacy of clomipramine and haloperidol for thetreatment of autism. Investigators

randomized participants to 7-weekphases of haloperidol, clomipramine,and placebo. Clomipramine dosing
started at 25 mg at bedtime and increased in 25-mg increments every 2days until the dose was 50 mg twice
daily; further 25-mg adjustments werethen made every 3 to 4 days on thebasis of clinical assessment. The dose
was reduced to the last dose tolerated
if adverse events were experienced.
There was a dosage taper during week
7 of each phase and 1-week placebo
washout periods between each phase.
No other psychotropic drugs wereallowed except benztropine. Of the 37
participants recruited, 36 (mean age:
16.3 years) were included in ﬁnal
analyses. The mean daily dose of clomipramine was 128.4 mg. The mean
duration of clomipramine treatment
was 4.5 weeks, with 12 (37.5%) of 32
participants completing the 7-weektreatment phase; 12 of 20 participants
who discontinued did so at least partially because of adverse events that
included fatigue or lethargy (n = 4),
tremor (n = 2), tachycardia (n = 1),
insomnia (n = 1), diaphoresis (n = 1),
nausea or vomiting (n = 1), decreased
appetite (n = 1), and preexisting rightbundle branch block (n = 1). The mean
duration of placebo receipt was 5.4
weeks, with 21 (65.6%) of 32 participants completing the 7-week phase;

1 of 9 participants who discontinued
had adverse events (nosebleeds). The
investigators noted that carryover ofeffects between phases may have affected results in this crossover design,especially with the short 1-weekwashout period.
One poor-quality study9 assessed the
efﬁcacy and tolerability of clomipramine by using a prospective openlabel case series design over 12
weeks. Of the 35 participants, 33 completed the study and were taking
a mean dose of 139 6 50 mg. Of the 33
participants completing the trial, 18(55%) were responders as determined based on the CGI-I score of verymuch improved or much improved.
Clomipramine treatment signiﬁcantly
reduced (P , .001) repetitive thoughts
and behaviors and aggression. Adverse
events, including seizures, constipation,weight gain, and sedation, were reported in 13 individuals.
Another poor-quality, 12-week, openlabel prospective case series8 investigated the efﬁcacy and tolerabilityof sertraline. Of the 42 participants, 37
completed the trial. The mean sertraline dose was 122.0 6 60.5 mg. Of the
42 participants starting the trial, 24(57%) were considered responders
based on CGI-I score of very much improved or much improved. Five participants withdrew from the study: 3
due to anxiety/agitation, 1 due to syncope, and 1 because of noncompliance.
Finally, a poor-quality retrospective
case series10 studied the therapeutic
effects and tolerability of ﬂuoxetine
and included 23 individuals with ASD(mean age: 15.9 6 6.2 years). CGI-S
ratings of overall clinical severity improved in 15 participants, as did ratings of perseverative or compulsive
behavior. Six of 23 participants experienced adverse events that “signiﬁcantly” interfered with function or
outweighed therapeutic beneﬁts. Adverse events reported overall included

PEDIATRICS Volume 130, Number 4, October 2012

Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

721

722

DOVE et al

Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017
G1: 64.6 6 27.2

G1: 30.2 6 7.0

G1: 30.1 6 7.1; G2: 30.1 6 8.4

Brodkin et al,9 1997; United States; G1: clomipramine,
35/33; G1a: responders, n = 18; G1b:
nonresponders, n = 15; poor quality

McDougle et al,7 1996; United States; G1: ﬂuvoxamine,
15/15; G2: placebo, 15/15; fair quality

G1: 82.5 6 26.8;
G2: 77.3 6 33.1

60.5 6 22.7 (28with intellectual
disability)

26.1 6 5.8

G1 + G2: 54.6 6 23.9

G1 + G2: 28.1 6 7.3

NRNR

NR, 40/40 withintellectual
disability

IQ, Mean 6 SD

Overall: 16.3 (SD NR)

G1 + G2: 22 6 13.1

Age, y, Mean 6 SD

Overall: 16.3 (SD NR)

SRIs
Remington et al,5 2001; Canada; G1: clomipramine;
G2: haloperidol; G3: placebo; Overall N: 37/36;
fair quality
McDougle et al,8 1998; United States; G1: sertraline,n = 42/37; G1a: AD; G1b: AS; G1c: PDD-NOS; poor
quality

Antipsychotic agents
Hellings et al,4 2006; United States; G1 + G2: placebophase, then dose risperidone, followed bycrossover to the other risperidone dose, thenanother placebo phase; placebo I phase: 3–5 wk ofplacebo, n = 40; acute-dose phase: G1 low-dose(n = 39) or G2 high-dose risperidone (n = 36);
placebo II phase: 3–5 wk of placebo, n = 33;
maintenance phase: optimal dose risperidone,n = 32; poor quality
Remington et al,5 2001; Canada; G1: clomipramine;
G2: haloperidol; G3: placebo; Overall N: 37/36;
fair quality
McDougle et al,6 1998; United States; G1: risperidone,
15/12; G2: placebo,16/12; G2a: open-label
risperidone after placebo, n = 15; fair quality

Study (Author, Year, Country
Groups, N; Enrollment/N Final; Study, Quality)

Outcome Measure/ Baseline
Scores, Mean 6 SD

Y-BOCS, total score: G1:
21.4 6 7.3; G2: 21.5 6 6.8

Y-BOCS, total score: G1a: 16.5 6 6.7;
G1b: 25.7 6 4.1; G1c: 18.2 6 4.8;
Vineland Maladaptive Behavior:
G1a: 27.0 6 9.4; G1b: 19.8 6 8.6;
G1c: 28.3 6 10.8; SIB-Q: G1a:32.7 6 16.5; G1b: 17.5 6 7.7;
G1c: 36.2 6 16.4;
Y-BOCS, total score: G1a: 18.7 6
6.8; G1b: 17.9 6 6.2; Y-BOCS,
compulsion subscale: G1a:13.7 6 3.3; G1b: 13.9 6 2.5;
Y-BOCS, obsession subscale:
G1a: 10 6 6.8; G1b: 6.7 6 6.2;
Brown Aggression Scale: G1a:10.6 6 7.4; G1b: 6.5 6 4.1

CARS; Overall: 41.867.1

Y-BOCS, compulsion: G1: 16.5 6
3.58; G2: 14.29 6 3.50; G2a:14.27 6 2.92; SIB-Q: G1:
47.8 6 19.5; G2: 37.7 6 11.9;
G2a: 32.43 6 15.89

CARS: overall, 41.8 6 7.1

ABC Irritability: G1 + G2, placebo I phase:
19.16 6 9.96; G1 + G2, placebo
II phase: 18.23 6 12.36

TABLE 4 Key Outcomes of Studies Assessing Medication Treatments in Adolescents and Young Adults With ASD

Y-BOCS, total score: G1a: 9.1 6 3.0; G1b: 17.3 6 7.8; P ,.001, G1 versus baseline; P , .001, G1a versus G1b; YBOCS, compulsion subscale: G1a: 6.9 6 2.1; G1b: 12.5
6 3.3; P , .001, G1 versus baseline; P , .001, G1a
versus G1b; Y-BOCS, obsession subscale: G1a: 4.4 6
2.8; G1b: 8 6 6.6; P , .001, G1 versus baseline; P ,.001, G1a versus G1b; Brown Aggression Scale: G1a:3.7 6 3.6; G1b: 6.4 6 4.6; P , .001, G1 versus
baseline; P , .001, G1a versus G1b
Y-BOCS, total score: G1: 13.7 6 9.1; G2: 21.9 6 6.7; P ,.003, G1 versus G2; Data for Vineland Maladaptive
Behavior and Brown Aggression Scale were notreported, although statistically signiﬁcant
improvements were noted

CARS: G1: 37.8 6 8.7; G2: 36.7 6 6.1; G3: 39.4 6 7.0; P ,.05, G2 versus baseline; ABC reported only
graphically
Y-BOCS, total score: G1a: 11.5 6 5.8; G1b: 27.8 6 5.3; G1c:
14.8 6 5.7; P = .005, G1 versus baseline; Vineland
Maladaptive Behavior Scale: G1a: 13.8 6 6.0; G1b:20.2 6 8.2; G1c: 19.5 6 9.1; P = .0001, G1 versus
baseline SIB-Q: G1a: 15.5 6 9.5; G1b: 18.8 6 7.7; G1c:
20.2 6 12.8; P = .0001, G1 versus baseline

CARS: G1: 37.8 6 8.7; G2: 36.7 6 6.1; G3: 39.4 6 7.0; P ,.05, G2 versus baseline; ABC reported only
graphically
Y-BOCS, compulsion: G1: 12.77 6 3.63; G2: 14.35 6 3.02; P, .001, G1 versus G2; G2a: 11.47 6 3.64; P , .03, G2a
versus baseline; SIB-Q: G1: 24.2 6 9.5; G2: 32.8 6 15.0;
P , .001, G2 versus G1; G2a: 23.07 6 13.45; P , .05,
G2a versus baseline

ABC Irritability: G1, Low-dose acute phase: 11.15 6 9.28;
G2, High-dose acute phase: 13.31 6 8.92; P = .13 G1
versus G2, P = .0002 G1 + G2 acute phase versus G1 +G2 placebo II; maintenance phase scores only
reported graphicallyOutcome Measure/Posttreatment
Scores, Mean 6 SD

AD, autistic disorder; AS, Asperger syndrome; CARS, Childhood Autism Rating Scale; CGI-S, Clinical Global Impression of Severity; G, group; NR, not reported; PDD-NOS, pervasive developmental disorder–not otherwise speciﬁed; SIB-Q, Self-Injurious Behavior
Questionnaire; Y-BOCS, Yale-Brown Obsessive Compulsive Scale.

ABC Stereotypy: G1 + G2: 10.0 6 4.7; G3 + G4: 9.0 6 4.8;
P = .018, G1 + G2 versus G3 + G4
ABC Stereotypy: G1 + G2:
9.7 6 4.7; G3 + G4: 8.3 6 5.2
NR
Overall: 29 6 6.0
Opioid receptor antagonist
Willemsen-Swinkels et al,11 1995; the Netherlands;
G1 + G2: 4-week naltrexone phase for cohorts 1 (50mg daily) and 2 (150 mg daily) (ASD patients only);
G3 + G4: 4-week placebo phase for cohorts 1 and 2(ASD patients only); overall N: 33/31; fair quality

CGI-S, total: 4.9 6 1.1; P , .002, G1 versus baseline;
CGI-S, compulsion: 4.7 6 1.6; P , .005, G1 versus
baseline
CGI-S, total: 5.7 6 0.8;
CGI-S, compulsion: 5.5 6 1.5
NR, 19 withintellectual
disability
15.9 6 6.2
Cook et al,10 1992; United States; G1: ﬂuoxetine, 23/23;
poor quality

Study (Author, Year, Country
Groups, N; Enrollment/N Final; Study, Quality)

TABLE 4 Continued

Age, y, Mean 6 SD

IQ, Mean 6 SD

Outcome Measure/ Baseline
Scores, Mean 6 SD

Outcome Measure/Posttreatment
Scores, Mean 6 SD

REVIEW ARTICLE

agitation (n = 5), insomnia (n = 4),
elated affect (n = 4), decreased appetite (n = 4), and increased screaming(n = 2).
Opioid Receptor Antagonist
One study of an opioid receptor antagonist met our review criteria.11 This fairquality randomized, double-blind crossover study tested the efﬁcacy and safetyof naltrexone on self-injurious behavior
and other autistic symptoms in intellectually disabled adults. Doses ofconcurrent medications, including antipsychotic agents, were held stable. The
study randomized participants to receive naltrexone or placebo, with a2-week, single-blinded placebo period
followed by a single dose of naltrexone(100 mg) with placebo for the remainderof that week. This phase was followed by
a 4-week treatment period, a 4-weekwashout period, and ﬁnally a crossoverto the second 4-week treatment period.
The ﬁrst cohort received naltrexone 50
mg/day, but the dose for the second
cohort was changed to naltrexone 150
mg/day. The primary outcome was selfinjurious behavior.
Of the 33 participants, 24 had autistic
disorder.11 Participants’ mean age was
29 years, and IQ was not reported.
Eleven participants were taking antipsychotic agents, with the dose held
steady during the study. The single
dose had no effect on the clinicianrated questionnaire, direct observation, self-injurious behavior, or plasma
b-endorphins. Plasma cortisol was
signiﬁcantly increased (P = .006) withnaltrexone compared with placebo.
Longer-term treatment (4 weeks) withnaltrexone resulted in a signiﬁcant increase in stereotypy as measured byusing the ABC Stereotypy subscale.11 Nochanges in any of the other outcome
measures were signiﬁcant. The study
did not report comparative statistics,
but the CGI-I scale indicated that placebo was superior to 50 mg/day ofnaltrexone in 12 of 18 participants. The
CGI-I scale also found that 50 mg/dayof naltrexone was better than placebo
in only 4 of 18 participants, whereas
placebo was superior in 12 of 18 participants. The CGI-I scale also showedthat 150 mg/day of naltrexone wasbetter than placebo in 5 of 14 participants, whereas placebo was superior
in an equal number of participants (5of 14). There were no signiﬁcant correlations between behavioral changes
after the single dose of 100-mg naltrexone and the 4-week treatmentswith naltrexone (50 or 150 mg).
Further analyses with groups divided
into participants with concurrent antipsychotic use and participants without
such use did not yield any signiﬁcanteffect for naltrexone versus placebo.11
Adverse events included 1 subject withan acute increase in self-injurious behavior, 1 subject with nausea andtiredness, and 3 participants with sedation. Liver function test results
remained within normal ranges.

DISCUSSION
Assessment of the Literature
The use of medications in adolescentsand young adults with ASD is extremelycommon.12 However, few data address
the effectiveness and harms of medications speciﬁcally in this population. Of
the 8 studies identiﬁed for this review,
most focused on the use of medications
to address speciﬁc challenging behaviors (ie, aggression or irritability). Fourstudies were fair quality,5–7,11 and 4
were poor.4,8–10
The most consistent ﬁndings wereidentiﬁed for antipsychotic medications.
An RCT studying risperidone foundimprovements in aggression, repetitive
behavior, sensory motor behaviors, andoverall behavioral symptoms.6 A crossover study of risperidone also showeda signiﬁcant reduction of irritability/
agitation ratings with risperidone treatment.4 A placebo-controlled crossover

PEDIATRICS Volume 130, Number 4, October 2012

Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017723

study found that haloperidol signiﬁcantly improved hyperactivity/deﬁance
ratings, but no signiﬁcant difference
was found for irritability/agitation orother symptoms.5 Although there islimited literature available on theuse of risperidone in adolescents oryoung adults with ASD, the efﬁcacy
of risperidone in studies including
mostly children was reported in ourprevious report to have moderate
strength of evidence for the treatmentof irritability/agitation,13 which is consistent with the results of the 1 fairquality RCT and 1 poor-quality crossover study in adults with ASD. The
available evidence across age groups
therefore seems consistent in demonstrating positive effects of risperidone
for irritability/agitation symptoms in
ASD.
A number of studies of SRIs wereidentiﬁed but with limited consistency
across studies as a whole. An RCT ofﬂuvoxamine showed decreases in repetitive behavior, aggression, autistic
symptoms, and language usage.7 In
contrast, no signiﬁcant differenceswere observed in a crossover study ofclomipramine versus placebo.5 Threecase series of SRIs were also identiﬁed,
including sertraline, ﬂuoxetine, andclomipramine, with each study reporting some beneﬁt to treatment.8–10 A
recent study not meeting criteria forthis review also contributes to thelimited data on SRIs. Hollander et al14
reported a placebo-controlled RCT of
ﬂuoxetine that included 37 individuals
with ASD (mean age: 34.31 years). They
found improvements in repetitive behavior and ASD symptoms in thetreatment group and mild adverse
events. This study used a different
medication than the 1 fair-quality study
in our age range, so it would be unlikely
to inﬂuence the strength of evidence
for a speciﬁc medication. It is possible,
however, that a systematic review of
SRIs in the broader age range of adults
724with ASD could provide data that might
increase our conﬁdence in the effect. A
crossover study of the opioid receptor
antagonist naltrexone found no significant improvements in problem behavior and showed worsening ofstereotyped behavior with naltrexone
treatment compared with placebo.11
Based on the included studies in adolescents and adults with ASD, thestrength of evidence (conﬁdence in theestimate) is insufﬁcient regarding adverse events associated with medications tested in this population. As in
the case of efﬁcacy, the data on adverse
events associated with risperidone,
including sedation and weight gain, areconsistent with the strong strength ofevidence for the association of treatment with these adverse events inchildren with ASD.13 The available evidence therefore seems consistent insupporting our understanding of therisk of these adverse events in ASD
without being limited to a speciﬁc age
range. Of course, this does not meanthat other medications tested in ASD
are free of adverse events. It is reasonable to expect that, in contrast to
efﬁcacy, which is more likely to be
speciﬁc to disorder and symptom, adverse events are more likely to extend
across diverse groups of participantsstudied. Clinicians evaluating the evidence and sharing information withfamilies routinely take this perspective,
as does the US Food and Drug Administration, in mandating that all adverse
events be listed for a drug, rather thanjust those for a particular indication.
As 1 example, the limited studies ofadults with ASD treated with risperidone indicate weight gain as an adverse event but in too few studies todraw a clear conclusion about thestrength of evidence. There is, however,high strength of evidence for weightgain in children with ASD treated withrisperidone, as noted in a previous
comparative effectiveness review.13

Similarly, Cochrane reviews foundsubstantial evidence for weight gain in
adults with schizophrenia or bipolar
disorder treated with risperidone.15,16
When the broader evidence base isconsidered, the consistency of theseﬁndings supports an association ofweight gain with risperidone in adults
with ASD, just as is true in children with
ASD and adults with other disorders.
This approach to assessing the evidence
for adverse events is outside of thescope of this review, but similar conclusions could be drawn with respect tosedation and extrapyramidal symptoms
with risperidone or haloperidol.
Future Directions
Overall, there is a dearth of evidence inall areas of care for adolescents andyoung adults with ASD. Basic understanding of the effects of aging on
health, cognitive skills, and otherdomains of functioning is absent, andthe lack of RCTs of medications, in which
substantial adverse events may be associated with medication use in adolescence, is notable. Medication studies
conducted in adolescents and young
adults have focused largely on problem
behaviors, and additional data areneeded on medical comorbidities inadolescents with ASD. Clear evidence
from earlier studies of antipsychotic
agents in children supports the use of
risperidone and aripiprazole in children with ASD.13 The only fair-quality
study of risperidone in adults is consistent with the ﬁndings in children,
but the strength of evidence based on
the adult literature alone is insufﬁcient
to draw ﬁrm conclusions. Population
studies may be helpful to empiricallygroup ASD patients according to age ina way that fosters more effective studiesof treatments. Understanding the ageappropriateness of potential medication treatments as based on social,physiologic, pharmacologic, and functional characteristics of the population
would help to prioritize future research,

DOVE et al

Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

REVIEW ARTICLE

including the ways in which medicalcomorbidities arise or increase as children with ASD move into adolescenceand adulthood. Increased use of standardized age groupings would facilitate comparisons of effectiveness within
medication treatment categories as wellas with nonmedical therapies. One way tosupport accomplishing this goal is bydeveloping treatment networks with adequate numbers of patients of varying
ages to participate in research.

in which individuals with ASD show
improvementsin social, communication,or behavioral function. Without somelevel of educational or social challenge,
it may be difﬁcult to assess medication response. Furthermore, somemedications may show beneﬁt only
during critical points of development,
making pediatric studies critical toassessing efﬁcacy, even when it is necessary to ﬁrst establish safety in older
populations.

reporting, particularly as it relates
to reporting of randomization approaches, characterization of study
participants, description of the intervention, and measures of ﬁdelity
and adherence. These are all necessary to understand correctly the potential impact of the interventions
being reported.

Thus far, medication treatment research in adolescents and young adults
with ASD has been limited to compounds that are already approved forother indications. As targeted treatments for ASD emerge, initial studies
will need to focus on adult populations
to establish safety before moving into
studies of adolescents and ﬁnally children. Study of compounds not yet on themarket could be facilitated with partnerships between the academic andpharmaceutical communities. It will be
critical to consider the appropriate
outcome measures and settings inwhich to study medication response in
adults. The heterogeneity in settings for
adults with ASD (eg, living at homeversus a group home) is a signiﬁcant
impediment to assessing symptom response. Ideally, medications would be
combined with an educational or psychosocial intervention that would mirror the school and therapeutic settings

Research is also needed to determine
whichoutcomesshould beused infuturestudies. The ABC is a widely used, easily
repeatable, and highly sensitive outcome measure for behavioral symptoms
in ASD, but it does not directly index coresocial communication symptoms oranxiety or mood symptoms, nor does it
capture broader outcomes such as
quality of life. More outcome measures
are needed to allow assessment ofa broader range of symptoms, particularly in individuals who may be higher
functioning. No studies provide adequate information on longer-term outcomes and particularly on outcomes
related to achieving goals for independence and quality of life. Substantial, foundational research should
be conducted to identify and validate
outcome measures in the adolescentand young adult population with ASD.

Given the number of individuals affected by ASD, there is a dramatic lackof evidence on best approaches totherapies for adolescents and young
adults with these conditions. Little evidence supports the use of medication
treatments in the adolescent and young
adult population. Although the studies
that have been conducted focused on
the use of medications to address
speciﬁc challenging behaviors, the effectiveness in managing irritability andagitation in this age group remains
largely unknown and can at best be
inferred from studies including mostly
younger children.

CONCLUSIONS

Finally, for all research in this area, we
encourage greater transparency in

ACKNOWLEDGMENTS
We are grateful for the contributions of
our review team, technical expert
panel members, and key informants.
We also appreciate the input of theparents who participated as we formulated our approach.

www.effectivehealthcare.ahrq.gov/searchfor-guides-reviews-and-reports/?pageaction=
displayproduct&productID=656. Accessed
July 6, 2012
3. Agency for Healthcare Research and Quality. Methods Guide for Effectiveness andComparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research
and Quality; 2008
4. Hellings JA, Zarcone JR, Reese RM, et al. A
crossover study of risperidone in children,

adolescents and adults with mental retardation. J Autism Dev Disord. 2006;36(3):401–411
5. Remington G, Sloman L, Konstantareas M,
Parker K, Gow R. Clomipramine versus
haloperidol in the treatment of autistic
disorder: a double-blind, placebo-controlled,
crossover study. J Clin Psychopharmacol.
2001;21(4):440–444
6. McDougle CJ, Holmes JP, Carlson DC, Pelton
GH, Cohen DJ, Price LH. A double-blind,

REFERENCES
1. Seltzer MM, Shattuck P, Abbeduto L,
Greenberg JS. Trajectory of development inadolescents and adults with autism. Ment
Retard Dev Disabil Res Rev. 2004;10(4):234–
247
2. Warren Z, Veenstra-VanderWeele J, Stone
W, et al. Therapies for children with autism
spectrum disorders. Comparative Effectiveness Review No. 26. AHRQ Publication No. 11EHC029-EF. Rockville, MD: Agency for Healthcare Research and Quality. Available at:

PEDIATRICS Volume 130, Number 4, October 2012

Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017725

placebo-controlled study of risperidone inadults with autistic disorder and otherpervasive developmental disorders. ArchGen Psychiatry. 1998;55(7):633–641
7. McDougle CJ, Naylor ST, Cohen DJ, Volkmar
FR, Heninger GR, Price LH. A double-blind,placebo-controlled study of ﬂuvoxamine inadults with autistic disorder. Arch Gen
Psychiatry. 1996;53(11):1001–1008
8. McDougle CJ, Brodkin ES, Naylor ST, Carlson
DC, Cohen DJ, Price LH. Sertraline inadults with pervasive developmental
disorders: a prospective open-label investigation. J Clin Psychopharmacol. 1998;
18(1):62–66
9. Brodkin ES, McDougle CJ, Naylor ST, Cohen
DJ, Price LH. Clomipramine in adults with
pervasive developmental disorders: a prospective open-label investigation. J Child

Adolesc Psychopharmacol. 1997;7(2):109–
121
10. Cook EH Jr, Rowlett R, Jaselskis C, Leventhal
BL. Fluoxetine treatment of children andadults with autistic disorder and mental
retardation. J Am Acad Child Adolesc Psychiatry. 1992;31(4):739–745
11. Willemsen-Swinkels SH, Buitelaar JK, Nijhof
GJ, van England H. Failure of naltrexonehydrochloride to reduce self-injurious andautistic behavior in mentally retarded
adults. Double-blind placebo-controlled studies. Arch Gen Psychiatry. 1995;52(9):766–773
12. Mandell DS, Morales KH, Marcus SC,
Stahmer AC, Doshi J, Polsky DE. Psychotropic
medication use among Medicaid-enrolled
children with autism spectrum disorders.
Pediatrics. 2008;121(3). Available at: www.
pediatrics.org/cgi/content/full/121/3/ e441

13. McPheeters ML, Warren Z, Sathe N, et al. A
systematic review of medical treatments forchildren with autism spectrum disorders.
Pediatrics. 2011;127(5). Available at: www.
pediatrics.org/cgi/content/full/127/5/e1312
14. Hollander E, Soorya L, Chaplin W, et al. A
double-blind placebo-controlled trial of ﬂuoxetine for repetitive behaviors and global
severity in adult autism spectrum disorders.
Am J Psychiatry. 2012;169(3):292–299
15. Rendell JM, Gijsman HJ, Bauer MS, Goodwin
GM, Geddes GR. Risperidone alone or in
combination for acute mania. Cochrane
Database Syst Rev. 2006;(1):CD004043
16. Komossa K, Rummel-Kluge C, Schwarz S,
et al. Risperidone versus other atypical antipsychotics for schizophrenia.
Cochrane Database Syst Rev. 2011;(1):CD006626(Continued from ﬁrst page)
FINANCIAL DISCLOSURE: Dr Dove has received training support from the National Institute of General Medical Sciences, the National Heart, Lung, and Blood
Institute, the National Institute of Child Health and Human Development, the Maternal Child Health Bureau, the American Heart Association, and the Autism Speaks
Autism Treatment Network; Dr Taylor has received research support from the National Institute of Mental Health, the Eunice Kennedy Shriver National Institute ofChild Health and Human Development, Autism Speaks, and the Marino Autism Research Institute; Dr Warren has received research support from the National
Institute of Mental Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Science Foundation, the Agency for
Healthcare Research and Quality, Autism Speaks, the Marino Autism Research Institute, and the Simons Foundation; Dr Veenstra-VanderWeele has received
research support from the National Institute of Mental Health, the National Institute of Child Health and Human Development, the Agency for Healthcare Research
and Quality, Autism Speaks, the American Academy of Child and Adolescent Psychiatry, NARSAD, Seaside Therapeutics, Roche Pharmaceuticals, and Novartis. He
has consulted for Novartis; and Dr McPheeters and Ms Sathe have indicated they have no ﬁnancial relationships relevant to this article to disclose.
FUNDING: The full review project was supported by the Agency for Healthcare Research and Quality (contract HHSA 290 2007 10065 I). Dr. Lounds Taylor was also
supported by the National Institute of Mental Health through a K01 award (K01 MH092598) during participation on the project and preparation of the manuscript.

726

DOVE et al

Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

Medications for Adolescents and Young Adults With Autism Spectrum
Disorders: A Systematic Review
Dwayne Dove, Zachary Warren, Melissa L. McPheeters, Julie Lounds Taylor, Nila A.
Sathe and Jeremy Veenstra-VanderWeele
Pediatrics 2012;130;717
DOI: 10.1542/peds.2012-0683 originally published online September 24, 2012;

Updated Information &Services

including high resolution figures, can be found at:
http://pediatrics.aappublications.org/content/130/4/717

References

This article cites 13 articles, 2 of which you can access for free at:
http://pediatrics.aappublications.org/content/130/4/717.full#ref-list-1

Subspecialty Collections

This article, along with others on similar topics, appears in thefollowing collection(s):Pharmacology
http://classic.pediatrics.aappublications.org/cgi/collection/pharmacol
ogy_sub
Therapeutics
http://classic.pediatrics.aappublications.org/cgi/collection/therapeutics_subPermissions & Licensing

Information about reproducing this article in parts (figures, tables) orin its entirety can be found online at:https://shop.aap.org/licensing-permissions/Reprints

Information about ordering reprints can be found online:
http://classic.pediatrics.aappublications.org/content/reprints

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by theAmerican Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2012 by the American Academy of Pediatrics. All rights reserved. Print
ISSN: .

Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017

Medications for Adolescents and Young Adults With Autism Spectrum
Disorders: A Systematic Review
Dwayne Dove, Zachary Warren, Melissa L. McPheeters, Julie Lounds Taylor, Nila A.
Sathe and Jeremy Veenstra-VanderWeele
Pediatrics 2012;130;717
DOI: 10.1542/peds.2012-0683 originally published online September 24, 2012;

The online version of this article, along with updated information and services, islocated on the World Wide Web at:
http://pediatrics.aappublications.org/content/130/4/717

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by theAmerican Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2012 by the American Academy of Pediatrics. All rights reserved. Print
ISSN: .

Downloaded from http://pediatrics.aappublications.org/ by guest on November 4, 2017