Comparative Effectiveness Review
Number 189

Effective Health Care Program
Medical Therapies for Children With Autism
Spectrum Disorder—An Update
Executive Summary
Introduction
Autism spectrum disorder (ASD) is aneurodevelopmental disorder broadly
defined by impaired social communication
as well as restricted or repetitive patternsof behavior and interest. As defined by
the Diagnostic and Statistical Manual of
Mental Disorders, Fifth edition (DSM-5),
specific features of ASD include deficits
in social and emotional reciprocity (e.g.,
atypical social approaches, conversational
impairment, atypical sharing of interests,
attention, and affect); deficits in nonverbal
communication (e.g., poorly integrated
verbal and nonverbal communication,
atypical body-language and gesture use,
deficits in use and understanding of
nonverbal communication), and deficits
in maintaining appropriate relationships(e.g., challenges with peer interest,
vulnerabilities forming friendships,
difficulties adjusting behavior to suit social
contexts) as well as restricted and repetitive
patterns of behavior such as stereotyped
speech, motor movements, or use ofobjects; excessive adherence to routine orinsistence on sameness; intense interest
patterns; and atypical sensory interests
or responses. Symptoms of the disorder
impair and limit everyday functioning
and are thought to be evident in earlychildhood; although they may not be fully
evident until later ages. Although notcore symptoms, many children with ASD
may also have significant cognitive andlanguage impairments.

e

1

Purpose of Review
To assess effectiveness and safety of
medical interventions for children with
autism spectrum disorder.
Key Messages• Despite many randomized
trials, confidence in reported
improvements (strength ofevidence, SOE) remains low formost interventions.
– Risperidone and aripiprazole
improved challenging behaviors
in the short term (<6 months,
high SOE), but side effects
include weight gain andextrapyramidal symptoms.
– Methylphenidate andatomoxetine improved
hyperactivity; SOE is low, withfew studies addressing eachagent. Side effects include
behavior and appetite changes.
– Omega-3 fatty acids,
N-acetylcysteine, andtetrahydrobiopterin did not
improve outcomes in small
short-term studies (low SOE).
– Data are inadequate to draw
conclusions about other agents
due to variation in interventions
and outcomes.

Treatment of ASD

KQs were as follows:

The manifestation and severity of symptoms of ASD differ
widely, and treatments include a range of behavioral,
psychosocial, educational, medical, and complementary
approaches1-4 that vary by a child’s age and developmental
status. The goals of treatment for ASD typically focus
on improving core deficits in communication, social
interactions, or restricted behaviors, as changing thesefundamental deficits may help children develop greater
functional skills and independence.5 Treatment frequently
is complicated by symptoms or comorbidities that
may warrant targeted intervention. Individual goals fortreatment vary for different children and may include
combinations of approaches such as behavioral andmedical therapies; parents may also pursue complementary
and alternative medicine therapies.

KQ1: Among children ages 2-12 with ASD, what isthe comparative effectiveness (benefits and harms) of
medical treatments?
a. What are the effects on core symptoms (e.g., deficits
in social communication and interaction; restricted,
repetitive patterns of behavior, interests, or activities
including hyper- or hypo- reactivity to sensory
input or unusual interest in sensory aspects of theenvironment) in the short term (<6 months)?
b. What are the effects on commonly associatedsymptoms (e.g., motor, medical, mood/anxiety,irritability, and hyperactivity) in the short term (<6months)?
c. What are the longer term effects (≥6 months) oncore symptoms (e.g., social deficits, communication
deficits, and repetitive behaviors)?

The antipsychotics risperidone (Risperdal) and aripiprazole(Abilify) have been specifically approved by the U.S.
Food and Drug Administration (FDA) for treatment of
irritability and challenging behaviors in ASD. Many othermedications are used off –label to manage behavioral
symptoms such as anxiety and hyperactivity. In addition,
devices such as hyperbaric oxygen chambers may be used
to treat symptoms of ASD.

d. What are the longer term effects (≥6 months)
on commonly associated symptoms (e.g.,
motor, medical, mood/anxiety, irritability, andhyperactivity)?
KQ2: Among children ages 2-12 with ASD, what are themodifiers of outcome for different medical treatments?

Scope and Key Questions (KQs)

a. Is the effectiveness of the therapies reviewed affectedby the frequency, duration, intensity, or dose of theintervention?

Scope of the Review
This review updates findings reported in the 2011
AHRQ review Therapies for Children with ASD6 witha focus on studies of medical interventions. We defined
medical interventions broadly as interventions involving
the administration of external substances to the bodyor use of external, nonbehavioral procedures to treat
symptoms of ASD, which includes pharmacologic agents,
diet therapies, vitamins and supplements, chelating
agents, electroconvulsive therapy, transcranial magnetic
stimulation and hyperbaric oxygen, among othermodalities. We used this broad definition, developed with
input from our clinical experts, in order to capture thelandscape of medically-related interventions used to treat
children with ASD. A companion review updating findings
related to interventions targeting sensory challenges isavailable on the AHRQ Effective Health Care Web site.

b. Is the effectiveness of the therapies reviewed
affected by co-interventions or prior treatment, orthe training and/or experience of the individual
providing the therapy?
c. What characteristics (e.g., age, symptom severity),
if any, of the child modify the effectiveness of thetherapies reviewed?
d. What characteristics, if any, of the family modify theeffectiveness of the therapies reviewed?
KQ3: What is the time to effect of medical
interventions?
KQ4: What is the evidence that effects measured at theend of the treatment phase predict long-term functional
outcomes of medical interventions?

Key Questions

KQ5: Is the effectiveness of medical interventions
maintained across environments or contexts (e.g.,
people, places, materials)?

We developed KQs in consultation with Key Informants
and Task Order Officers. KQs were posted for review to
the AHRQ Effective Health Care Web site.

2

Analytic Framework

KQ6: What evidence supports specific componentsof treatment with medical interventions as driving
outcomes, either within a single treatment or acrosstreatments?

The analytic framework (Figure A) illustrates the
population, interventions, and outcomes that guided theliterature search and synthesis.

Figure A. Analytic framework
Time to Effect
KQ3

Final Health OutcomesIntermediate OutcomesChildren ages
2-12 years
diagnosedwith ASD

MedicalIntervention
KQ1

KQ2

ASD symptom severity
Expressive or receptive
language/communication
Academic skill development
Maladaptive behaviors
Distress
Adaptive skills development
Social skills/interaction
Harms of interventions

KQ6

Symptom severity or
diagnostic outcome
Functional communication
Cognitive skills
Motor skills
Adaptive independence
Academic engagement/
attainment
Social participation
Psychosocial well-being
Psychosocial adaptation
Harms of interventions

Long-termfunctional
outcomes
KQ4

Child, family, andintervention characteristics

KQ5

Intervention
context

ASD=autism spectrum disorder; KQ=Key Question

Methods

literature and surveillance findings, we focused the review
update on medical approaches and approaches to address
sensory challenges (reported in a separate update). These
areas reflect both areas of clinical relevance and sufficient
newly published literature for a review update.

Topic Surveillance
The topic for a 2011 report on therapies for children withASD6 was nominated by Autism Speaks in a public processusing the Effective Health Care Web site. AHRQ published
an update addressing behavioral interventions in 2014.7
We conducted a surveillance process to assess the need
to update the earlier report by contacting topic experts
about the relevance of the KQs and new evidence that may
address them. In consultation with clinical experts andstakeholders, and based on our preliminary scan of the

Literature Search Strategy
To ensure comprehensive retrieval of relevant studies of
medical therapies for children with ASD, we used four
key databases: the MEDLINE® medical literature database
via the PubMed® interface; EMBASE (Excerpta Medica
Database); the Cumulative Index of Nursing and Allied3Inclusion Criteria

Health Literature (CINAHL); and PsycINFO®. Searchstrategies applied a combination of controlled terms andkey words. We last conducted searches for the review in
September 2016.

Table A lists our inclusion criteria. We focused the review
on children between 2 and 12 years of age. We chose
to limit the age range to this span because a) diagnosis
of ASD earlier than age 2 is less established and b)adolescents likely have substantially different challenges
and would warrant different interventions than children in
the preschool, elementary, and middle school age groups.

We hand searched the reference lists of recent systematic
reviews or meta-analyses of studies addressing therapies
for ASD. The investigative team also scanned the reference
lists of studies included after the full-text review phase for
additional potentially relevant studies.
Table A. Inclusion criteria
Category

Criteria

Study population

Children ages 2-12 with ASD (mean age plus standard deviation is ≤ 12 years and 11 months)

Publication languages

English only

Admissible evidence(study design and othercriteria)

Admissible designs
Randomized controlled trials, prospective and retrospective cohort studies with comparison groups, andnonrandomized controlled trials
Other criteria
Original research studies published from 2010—present and not addressed in prior reviews
Studies must have relevant population and ≥20 participants with ASD (non-RCTs) or at least 10 total
participants (RCTs)
Studies must address one or more of the following for ASD:
• Outcomes of interest• Treatment modality of interest• Predictors or drivers of treatment outcomes (e.g., biomarkers, clinical changes)• Maintenance of outcomes across environments or contexts• Sufficiently detailed methods and results to enable data extraction• Reporting of outcome data by target population or intervention

ASD = autism spectrum disorder; RCT = randomized controlled trial

Study Selection

Risk-of-Bias Assessment of Individual Studies

Two reviewers independently assessed each abstract andthe full text of studies proceeding to full text review. A
senior reviewer adjudicated disagreements in full text
review .

We evaluated the overall methodologic risk of bias ofindividual studies using the ASD-specific assessment
approach developed and used in our prior reviews ofinterventions for ASD and informed by the Methods
Guide for Effectiveness and Comparative Effectiveness
Reviews.8 Two senior investigators assessed each included
study independently with disagreements resolved throughdiscussion. Appendix D of the main report includes ratingsfor each study.

Data Extraction and Synthesis
Data were initially extracted by one team member andreviewed for accuracy by a second. We summarized data
for KQs qualitatively using summary tables as studies were
too heterogeneous to allow for meta-analyses.

4Strength of the Body of Evidencecompletion of that report; thus we describe a total of 76
studies in the review.

Two senior investigators graded the strength of theevidence (SOE) for key intervention/outcome pairs using
methods based on the Methods Guide for Effectivenessand Comparative Effectiveness Reviews.8 We assessed
the domains of study limitations (low, medium, high levelof limitation), consistency (inconsistency not present,
inconsistency present, unknown), directness (direct,
indirect), precision (precise, imprecise), and reporting bias
(detected, unsuspected). The full team reviewed the final
SOE designations. The possible grades were:

The 76 studies included in the review comprised 72
randomized controlled trials (RCTs), 2 nonrandomized
trials, and 2 retrospective cohort studies. Studies addressed
the following categories:• Antipsychotics: 11 RCTs and one retrospective cohort
study (n=1055 children) with low (n=7) and moderate(n=5) risk of bias.
• Medications to treat attention deficit hyperactivity
disorder (ADHD): Five RCTs (n=265 children) withlow (n=4) and moderate (n=1) risk of bias.

• High: High confidence that the evidence reflects thetrue effect. Further research is unlikely to change
estimates.

• Combination medical and behavioral treatments:
Three RCTs and two nonrandomized trials (n=419
children) with low (n=2), moderate (n=1) and high(n=2) risk of bias.

• Moderate: Moderate confidence that the evidence
reflects the true effect. Further research may change ourconfidence in the estimate of effect and may change theestimate.

• Nutritional supplements and dietary interventions:
19 RCTs (n=732 children) with low (n=4), moderate(n=10), and high (n=5) risk of bias.

• Low: Low confidence that the evidence reflects the true
effect. Further research is likely to change confidence
in the estimate of effect and is also likely to change theestimate.

• Risperidone adjuncts: 14 RCTs (n =561 children)with low (n=12) and moderate (n=2) risk of bias.
• Hyperbaric oxygen therapy: Three RCTs (n=150
children) with low (n=2) and moderate (n=1) risk ofbias.

• Insufficient: Evidence is either unavailable or does not
permit a conclusion.9
Applicability• N-acetylcysteine: Two RCTs (n=123 children) with low
and moderate risk of bias.

We assessed the applicability of findings reported in the
included literature addressing our KQs to the general
population of children with ASD by determining the
population, intervention, comparator, and setting in eachstudy and developing an overview of these elements foreach intervention category. We anticipated that areas inwhich applicability would be especially important todescribe would include ASD severity, comorbidities, age attreatment, and intervention characteristics such provider,dosing/intensity, and setting. Applicability tables are in
Appendix E of the full report.

• Tetrahydrobiopterin: Two RCTs (n=56 children) withlow and moderate risk of bias.
• Other interventions: 13 RCTs and 1 retrospective
cohort study (n=829 children) with low (n=6), moderate(n=7), and high (n=1) risk of bias. We categorizedstudies as “other” if we could not assess strength ofevidence for interventions and outcomes reported (i.e.,
insufficient strength of evidence) and the studies did not
fall under a broader category of intervention such as
diet or nutritional supplements.
Overall, 39 studies had low, 29 had moderate, and 8
had high risk of bias. Despite the high number of low
and moderate risk of bias studies, few studies addressed
the same interventions or outcomes, and most studies
included few participants, evaluated only in the short term(<6 months). Thus, evidence for many agents remains
insufficient. Because few studies addressed subquestions
under Key Questions (KQ) 1 and 2, we present results inthe aggregate under each of these KQ.

Results
We identified 6583 nonduplicative titles or abstracts withpotential relevance, with 554 proceeding to full text review.
We excluded 469 studies at full text review. We included
68 unique studies (85 publications) in the review. In
addition to these 68 studies published since the completionof our original review of therapies for children with ASD
in 2011, we include 12 comparative studies addressed in
the 2011 review that also addressed an agent reported onin the current review. Four studies included in the 2011
review now include followup analyses published since the5KQ1. Benefits and Harms of Medical
Treatments(ABC) in the adjunct groups compared with placebo plus
risperidone.

Antipsychotics. Studies of antipsychotics addressed
either risperidone or aripiprazole and reported significant
improvements in measures of challenging behavior in
the short term (<6 months) in children receiving the
medications compared with those receiving placebo.
Harms of these agents, including extrapyramidal
symptoms and weight gain, were also clinically significant.
Studies reporting longer term followup (up to 21 months
for risperidone) reported continued effectiveness in mostchildren but did not include control groups.

Hyperbaric oxygen therapy. Three RCTs of hyperbaric
oxygen used different doses and reported inconsistentoutcomes and harms.

Medications to treat ADHD. RCTs of methylphenidate,
atomoxetine, and guanfacine reported improvements
in hyperactivity and other challenging behaviors withtreatment compared with placebo. Clinically significant
side effects were associated with methylphenidate
including aggressive behavior and appetite changes.
Harms reported with atomoxetine and guanfacine included
irritability, gastrointestinal symptoms, drowsiness, anddecreased appetite.

Other medical interventions. Few studies addressed thesame agent or outcomes. Studies of donepezil, melatonin,
bumetanide, citalopram, amantadine, divalproex,
prednisolone, and transcranial stimulation reported
some positive effects on outcomes including symptom
severity, language, and sleep. Studies of oxytocin andmecamylamine reported no statistically significant effects.
Harms reported in studies comparing these interventions
were diverse, and their clinical significance is difficult todetermine.

N-acetylcysteine. N-acetylcysteine had no effect on social
skills outcomes in two small RCTs. Harms of this agent
were not clinically significant.
Tetrahydrobiopterin. Tetrahydrobiopterin had no effecton symptom severity and was not associated with clinicallysignificant harms.

Studies of combined medical and behavioral
treatments. In three of the five studies of combined
medical and behavioral treatments, the addition of abehavioral therapy (e.g., cognitive behavioral therapy,
parent training) did not increase effectiveness overmedical therapy alone. In two small trials, bumetanide
plus applied behavior analysis improved symptom severity
more than applied behavioral analysis alone and stem
cell transplantation plus rehabilitation therapy improved
symptom severity, lethargy, and stereotypy more thanumbilical cord blood cell transplant plus rehabilitation
therapy or rehabilitation therapy alone.

KQ2. Modifiers of Treatment Outcomes
Few studies reported modifiers, and few were likely
adequately powered to detect effects. In one subanalysis,
higher baseline irritability was associated with greater
improvement in irritability than was low severity inimprovement with risperidone. Greater weight gain
was associated with less irritability improvement in therisperidone group. In another study of risperidone, younger
age and better communication skills were associated withgreater gains in communication but not with gains in dailyliving skills or socialization.

Diet and nutritional supplements. Omega-3 fatty acidsupplementation did not affect challenging behaviors
and was not associated with clinically significant harms.
Seven studies addressed variations of the gluten-free diet,but studies addressed different outcomes and different
approaches to restricted and control diets. Similarly, anumber of RCTs with low or moderate risk of bias
addressed other agents, but studies were small and few
addressed the same agent or outcomes.

Studies of stimulants identified no significant phenotypic
predictors of effects (e.g., baseline cognitive skills, age,IQ), but one genetic analysis identified seven genetic
variations that predicted response to methylphenidate.
Modifiers reported in studies of other agents were varied
and included cognitive skills, age, and symptom severity.
No characteristics had consistent effects.

Risperidone adjuncts. Study medications added torisperidone included celecoxib, minocycline, Ginkgo
biloba, memantine, topiramate, riluzole, buspirone,
N-acetylcysteine (addressed in 2 studies), amantadine ,pioglitazone, pentoxifylline, galantamine, and piracetam.
Most studies (12 of 14) reported improvements in
irritability measured on the Aberrant Behavior Checklist

While several studies reported changes in the number ofchildren responding to a given agent over time, studies
typically did not provide data to determine the initiation ofeffects.

KQ3. Time to Effect of Interventions

6KQ4. Evidence that Effects Measured at
the End of Treatment Predict Long-Term
Functional Outcomes

KQ6. Drivers of Treatment Outcomes
We did not identify any studies that provided data toaddress this KQ.

Few studies had longer term followup and those withmore than 6 months of treatment or followup typically did
not report functional outcomes. In one study, risperidone
use was not associated with changes in IQ: changes frombaseline to the end of study in class assignment (e.g.,
special education, regular classroom) were not significant.

Discussion
State of the Literature
We identified a total of 76 unique comparative studies,
primarily (n=72) RCTs, addressing medical interventions.
Most studies were small (median 40 total participants/
study) and addressed variable agents. Most studies
had placebo comparators, while five compared apharmaceutical agent to behavioral treatment or combined
pharmaceutical and behavioral treatment. Studies weretypically of short duration (<6 months, range 4 days to 24
months), with few studies reporting longer term followup
after the immediate intervention period.

KQ5. Effectiveness Across Environments orContexts
Seven studies reported teacher ratings of outcome
measures that provide some information to address thisKQ, but the limited results preclude conclusions. One
RCT of omega-3 fatty acids reported no significant
group differences in teacher ratings of challenging
behaviors (parents also rated few measures as improved),
while another RCT of docosahexaenoic acid (DHA)
supplementation versus placebo reported improvement inparent-rated social skills in children receiving placebo vs.
those receiving DHA, while teachers rated communication
as more improved in the treatment group comparedwith placebo. An RCT of challenge foods introduced
to a gluten-free diet reported no statistically significant
changes in behavior as rated by parents or teachers on
the Connors scale. An RCT of levetiracetam vs. placebo
reported no significant group differences on any parent- orteacher- rated measures but also noted that teachers, but
not parents, rated children in the placebo arm as more
improved on irritability compared with the levetiracetamgroup.

The methodologic rigor of studies has increased
substantially compared with those studies reported in our
2011 review of therapies for children with autism spectrum
disorder (ASD).6 However, while studies were generally
well conducted, evidence remains insufficient for mostinterventions due to small sample sizes, lack of long term
followup, and heterogeneous agents and populations.
Despite the number of new studies, we can make few
conclusions beyond those reached in our 2011 review.
Evidence supports the effectiveness of antipsychotics in
improving challenging behaviors, but with significant
harms. Methylphenidate also improves hyperactivity
but with significant harms. Evidence is promising for
the ADHD medication atomoxetine. More studies haveaddressed combination approaches, but data are inadequate
to draw conclusions. Data were limited and inconsistent forother interventions.

RCTs of methylphenidate reported general agreement
between parent and teacher ratings of hyperactivity. In one
RCT, both parents and teachers considered hyperactivity
and impulsive behavior to be significantly improved in
the treatment group compared with placebo, but teachers(vs. parents) reported no significant group differences
in inattention or oppositional behavior. Finally, one
RCT of atomoxetine reported significant teacher-rated
improvements in hyperactivity in the atomoxetine groupcompared with placebo but teacher ratings of cognitive
problems/inattention, oppositional behavior, or overall
ADHD symptoms did not differ between groups. In
another RCT comparing atomoxetine alone, atomoxetine+ parent training , placebo alone, and placebo + parent
training, parents, but not teachers, rated children in active
treatment groups as significantly improved on measuresof ADHD, inattention, hyperactivity, and oppositional
behavior.

Strength of Evidence
KQ1. Benefits and Harms of Medical Treatments
Antipsychotics. Our confidence in the conclusionthat risperidone and aripiprazole improve challenging
behaviors in the short term (<6 months), with clinicallysignificant harms, is high (high strength of evidence).
Behaviors improved in the longer term (≥6 months) withthese agents compared with placebo, but our confidence inthis conclusion is low (low strength of evidence) as only
five studies had ≥6 months followup. In studies comparing
risperidone and aripiprazole, BMI increased with bothdrugs over treatment durations of 6 months to more than 2
years, but group differences were not significant. We have
low confidence that effects on BMI do not differ between

7

agents given the few studies addressing this outcome (lowstrength of evidence). Other outcomes (e.g., challenging
behaviors, attention) were not consistently addressed; thus
we considered strength of evidence insufficient for allother intervention/outcome pairs. Table B outlines findings
for all comparisons with greater than insufficient strengthof evidence.

evidence). Data in two small studies of methyl-B12 were
inadequate to draw conclusions (insufficient strength ofevidence). While seven studies addressed variations of
the gluten-free diet, studies addressed different outcomes
and different approaches to restricted and control diets;
thus, data were inadequate to make conclusions about the
body of evidence (insufficient strength of evidence). Data
were inadequate to allow conclusions about the relative
effectiveness of other dietary interventions (e.g., camels’
milk, challenge foods containing gluten) compared withplacebo (insufficient strength of evidence).

Medications to treat ADHD. Methylphenidate versus
placebo improved hyperactivity and was associated withclinically significant harms (Table B). Our confidence inthese conclusions is low as studies were small and shortterm (low strength of evidence). Data were inadequate toassess effects on social communication and oppositional
behavior (insufficient strength of evidence). Findings for
oppositional behavior were inconsistent in two studies;thus, we could not assess the strength of evidence(insufficient). We considered the evidence inadequate tocomment on potential effects on social communication or
oppositional behavior (insufficient strength of evidence).

Risperidone adjuncts. Data were inadequate to assess
effects of risperidone plus adjunctive agents including
amantadine, buspirone, celecoxib, memantine, riluzole,
Gingko biloba, pioglitazone, or topiramate on any outcome
assessed as no study addressed the same adjunctive agent(insufficient strength of evidence). While two RCTs
addressed risperidone plus N-acetylcysteine, data areinadequate to comment on effects given the small numberof participants and high attrition (insufficient SOE).

We found positive effects of atomoxetine compared withplacebo on hyperactivity in children with ASD and ADHD
in the short term (<6 months), with effects maintained overthe longer term (≥6 months) (Table B). Our confidence
in this conclusion is low (low strength of evidence).
Atomoxetine was associated with harms considered to beclinically moderate, and our confidence in this conclusion
is low (low strength of evidence). Data were inadequate
to assess effects on inattention as studies reported
inconsistent findings (insufficient strength of evidence).

Hyperbaric oxygen therapy. Three RCTs of hyperbaric
oxygen used different doses and reported inconsistent
results. We considered SOE to be insufficient to assess
effects.
N-acetylcysteine. N-acetylcysteine had no effect onsocial skills outcomes in two small RCTs; harms of thisagent were not clinically significant. Our confidence
in these conclusions is low (low strength of evidence)(Table B). Data were inadequate to assess effects on otheroutcomes given inconsistent findings in these two studies(insufficient strength of evidence).

Data were inadequate in a small study of guanfacine
to draw conclusions about effects on any outcomes(insufficient strength of evidence).
Studies of combination medical and behavioral
treatments. Given that combination therapies were
investigated in single studies, we could not makeconclusions about their effects on any outcomes(insufficient strength of evidence).

Tetrahydrobiopterin. Tetrahydrobiopterin had no effecton symptom severity and was not associated with clinicallysignificant harms. Our confidence in these conclusions
is low (low strength of evidence) (Table B). Data were
inadequate to assess effects on other outcomes (insufficientstrength of evidence).

Nutritional supplements and dietary interventions.
Omega-3 fatty acid supplementation and placebo did
not affect challenging behaviors. Our confidence in thisconclusion is low (low strength of evidence for no effect)(Table B). We also have low confidence in the conclusionthat omega-3 supplementation was associated withminimal harms (low strength of evidence).

Studies of other medical interventions. Data were
inadequate to make conclusions about the effectsof amantadine, bumetanide, divalproex, oxytocin,
mecamylamine, prednisolone, citalopram, melatonin, andneurostimulation vs. placebo as few studies addressed
the same agents or outcomes (insufficient strength ofevidence).

Despite the number of RCTs with low or moderate riskof bias addressing other agents, evidence was inadequate
to make conclusions about all clinical efficacy and harms
outcomes because few, small, underpowered studies
addressed each diet or supplement (insufficient strength of8

Table B. Summary of evidence in studies addressing medical interventions for children with
ASD

Intervention
andcomparator

Number/Typeof Studies(Total N
Participants)

Key
Outcome(s)Strength of
Evidence(SOE) Grade

Findings

Antipsychotics
Risperidone vs.
placebo

Aripiprazole vs.
placebo

Risperidone vs.
aripirazole

3 RCT (274)

Challenging
behavior(<6 months)

High SOE

Significant improvement in treatment group vs.
placebo in 3 RCTs with 6-8 week treatment phases;
improvement maintained in 2 RCTs with 6 monthsof treatment

3 RCT (118)

Challenging
behavior(≥6 months)

Low SOE

Improvement maintained in 1 RCT with 6 monthsof treatment and in one open label extension with nocomparison group with mean 21 months treatment
duration; in another open label extension, morechildren relapsed with placebo vs. risperidone

9 RCT (262)
1 Retrospective
cohort (72)

Harms

High SOE
for clinicallysignificant harms
associated withrisperidone

Harms including weight gain, appetite changes,
drowsiness, fatigue, extrapyramidal symptoms,
drooling/hypersalivation, and gastrointestinal
symptoms consistently reported

2 RCT (316)

Challenging
behavior(<6 months)

High SOE

Significant improvements in 2 short-term RCTs intreatment groups

2 RCT (415)

Challenging
behavior(≥6 months)

Low SOE

In longer term followup, no differences in time
to relapse of symptoms between aripiprazole andplacebo groups in one 16 week RCT and continued
improvements in ABC in one 52-week open label
continuation with no control arm

4 RCT (422) 1
Retropective chort
(70)

Harms

High SOE
for clinicallysignificant harms
associated witharipiprazole

Harms including weight gain, appetite changes,
somnolence, extrapyramidal symptoms, drooling/
hypersalivation, infection, and gastrointestinal
symptoms consistently reported

1 RCT (37) 1
Retropective
cohort (142)

BMI change

Low SOE for
no difference in
effects

BMI increased with both drugs over treatment
durations of 6 months to more than 2 years, butgroup differences were not significant

9Table B. Summary of evidence in studies addressing medical interventions for children withASD (continued)
Intervention
andcomparator

Number/Typeof Studies(Total N
Participants)

Key
Outcome(s)Strength of
Evidence(SOE) GradeMPH vs. placebo 2 RCT (90)Hyperactivity

Low SOE

Significant improvement with MPH compared withplacebo on parent and teacher-rated measures;
differential effect of dose not clear (little effect on 1
study and linear effect in another); SOE is low given
small sample size and lack of long-term followup

2 RCT (90)

Oppositional
behavior

Low SOE for noeffectSignificant improvement with MPH on parentrated measure at medium dose level only in 1
RCT; no differences on teacher-rated measures. No
differences in teacher-, parent-, or clinician-rated
measures in another RCT

2 RCT (90)Harms

Low SOE forassociationof MPH withclinicallysignificant harms

Rates of children experiencing harms ranged from
0-75%; higher rates reported for repetitive behaviors
or speech, loss of appetite, and irritability. Irritability
responsible for withdrawals (n=6) in one RCT; SOE
is low given small sample size

2 RCT (113)Hyperactivity(≤ 3 months)

Low SOE for
improvements inthe short-term

Significant improvements in rating of hyperactivity
in treatment group compared with placebo in bothstudies

3 RCT (241)

Harms

Low SOE
for clinicallymoderate harms
associated withatomoxetine

No serious adverse events reported; most harms
attenuated over open label extension phase

Omega-3
supplementation
vs. placebo

3 RCT (119)

Challenging
behaviors

Low SOE for noeffectNo significant differences between groups in threesmall, short-term RCTs

Harms

Low SOE for
minimal harms

No clinically significant harms reported in any study

N-acetylcysteinevs. placebo

2 RCT (127)Social skills

Low SOE forlack of effectNo significant effects in either small, short-term
RCT

Harms

Low SOE for
minimal harms

No study reported harms considered clinicallyimportant

Symptomseverity

Low SOE forlack of effectNo significant effects in either small, short-term
RCT

Harms

Low SOE for
minimal harms

No study reported harms considered clinicallyimportantFindings

Medications to treat ADHD

Atomoxetine vs.
placebo

Other agents

Tetrahydrobiopterin
vs. placebo

2 RCT (54)

ADHD = attention deficit hyperactivity disorder; ASD = autism spectrum disorder; BMI = body mass index; MPH = methylphenidate;
RCT = randomized controlled trial; SOE = strength of evidence10but likely reflects the heterogeneity of the broader
population of children with ASD.

Other Key Questions
Few studies reported modifying characteristics, and no
characteristics were consistent modifiers. Few studies
reported data to assess time to effect of interventions.
Few studies had longer-term followup and those few with
6 months or more of treatment or followup typically did
not report functional outcomes; thus our understanding ofwhether effects at the end of treatment predict functional
outcomes is limited. Four studies reported teacher ratingsof outcome measures that provide some information toaddress effectiveness of treatments across environments
or contexts, but the limited results preclude conclusions.
Finally, we did not identify studies that provided data toaddress drivers of treatment outcomes.

Studies addressed a variety of agents and typically reported
use of concurrent medications or other therapies. Most
agents studied are accessible in the United States albeit
with few receiving FDA approval for use. Comparators
among nonplacebo controlled studies varied, and few
studies assessed the effect of concomitant behavioral
or other therapies, though many children with ASD
receive multiple interventions. The treatments studied
may not adequately reflect the broad range of treatment
combinations used in the general population of children
with ASD.
As noted, few studies evaluated longer term treatment(≥6 months); short treatment and followup periods limit
our ability to understand potential longer term outcomessuch as academic achievement or longer term harms.

Applicability
Study participants were generally recruited from specialty
clinical service programs and represent non–primarycare populations. As such, families of these children
may be seeking a higher level of care than those of thebroader population of children with ASD based upon
more severe or acute symptoms, including aggression
or other challenging behaviors. Most studies of medical
interventions targeted elementary school aged and older
children with autism, with little data on the treatment ofyounger children. Most studies included majority malepopulations (consistent with the male prevalence of ASD).

Overall, the heterogeneity of these studies parallels theheterogeneity of children with ASD, and some findings
may be more applicable to children with specific levelsof baseline severity or comorbidities. These limitations
to generalizability likely reflect both the significant
heterogeneity of ASD itself as well as its associatedfeatures, such as irritability. Thus, while there is a growing
evidence base for treating certain symptoms in certain
populations, these findings underscore the continued needfor individualized treatment approaches that are informedby the emerging evidence base for benefits as well as
harms of medical intervention, with careful considerationof symptom presentation and functioning level relative to
study populations and applicability of the known literature.

Studies also included children with highly variable
severity of challenging behaviors, ASD symptom severity,and cognitive impairment. Studies of pharmacologicalagents often sampled children with high levels of specificsymptom patterns (e.g., children with severe challenging
behavior at baseline where parents may be willing topursue pharmacologic intervention and trial participation)
who may not reflect the wider population of children with
ASD in whom these challenges may not be present. Mostof the studies reported including children with at least
moderate level of severity of ASD. Studies of stimulants
included children with cognitive impairment and withcomorbidities including attention deficit hyperactivity
disorder, oppositional defiant disorder, and obsessive
compulsive disorder. Studies of other approaches had
similarly heterogeneous populations. Dietary andnutritional studies included some younger children, withseverity of autism not well described or the degree ofintellectual functioning not well characterized in moststudies. This heterogeneity in population characteristics
may limit the generalizability of findings to children withdiffering levels of symptom expression or comorbidities

Limitations of the Comparative Effectiveness
Review Process
We included studies published in English only and did notinclude unpublished data. In our scan of a random sample
of 150 non-English abstracts retrieved by our MEDLINE
search, only two studies appeared to meet inclusion
criteria; thus, given the high percentage of ineligible itemsin this scan (99%), we concluded that excluding nonEnglish studies would not introduce significant bias into
the review. We recognize that this preliminary scan did
not address the entire corpus of ASD literature in otherlanguages.
We also included only comparative studies of medical
interventions with at least 10 children with ASD. To ensurecomprehensive coverage of the literature, we included
comparative studies with a smaller sample size that would

11

have been excluded in our 2011 review (which requireda sample size of 30) in the present report. We did notconduct a de novo search for such studies but re-examinedthe excluded studies from the prior review. This approach
may have overlooked relevant studies.
Given heterogeneity in treatment regimens, outcomes
addressed in each study, and patient populations, we werelimited in our ability to meta-analyze findings or identify
potential subgroups that may respond more favorably to
specific treatments. Finally, we used a nonvalidated tool toassess risk of bias, though we note that the tool evaluates
similar constructs to those assessed in tools such as thatused by the Cochrane Collaboration, with the addition of
ASD-specific domains.
Limitations of the Evidence BaseAs noted, studies in the review had small sample sizes andtypically limited duration of intervention and followup
after intervention, despite significant improvements instudy design and execution over time. Populations acrossstudies were heterogeneous in terms of challenging
behaviors, ASD symptom severity, age, and comorbidities.
Few studies addressed the same agent and outcomes,
and few assessed potential factors that may modify
effectiveness or drive effects of interventions. Many (n=63)
studies also explicitly noted that concomitant interventions
were held steady during the study treatment period;
however, few studies reported specific analyses to control
for or assess the effects of additional treatments.
Despite these limitations, investigators have madesignificant improvements in incorporating commonlyused measures of symptom severity and behavior tofacilitate comparisons across studies. Studies also typicallydescribed interventions fully, used standardized diagnostic
processes and blinded assessors, and reported on the use or
restriction of concomitant interventions.
Implications for Clinical and Policy
Decisionmaking
This review provides some evidence for decisionmaking
about medical interventions for children with ASD. The
clearest evidence favors the use of the antipsychotics
risperidone and aripiprazole to address challenging
behaviors in the short-term (<6 months); however,clinicians and caregivers must balance the significant
harms of these agents. The significant side effect profiles
make it clear that although these drugs are efficacious,
caution is warranted regarding their use in patients without
severe impairments or risk of injury. Few studies addressed

longer term effects of these agents; thus, our confidence
in longer term (≥6 months) effectiveness is low. Studies ofadjuncts to risperidone typically reported positive effects
on challenging behaviors, but few studies addressed thesame agents, precluding our ability to draw conclusions
about their effectiveness.
Some evidence supports the use of methylphenidate andatomoxetine for hyperactivity, but few comparative studies
addressed each agent, so our confidence in effects islimited. Given that many children with ASD are currently
treated with medical interventions, strikingly little
evidence exists to support clear benefit for most medical
interventions, especially in the realm of interventions
such as restrictive diets and supplements. Studies ofnutritional supplements or specialized diets were typicallyunderpowered and provided little evidence of effects ofthese approaches. Several agents were addressed in single
studies, which limits conclusions about their effects.
Decisional dilemmas remain regarding characteristicsof the child, family, or intervention that may modify
effectiveness or predict which children may be most
likely to benefit from a given approach. Similarly, theliterature base is currently insufficient to inform ourunderstanding of the time to effect of interventions, longer
term effectiveness of interventions, generalizability ofeffects outside the treatment context, effectiveness andapplicability to broader ASD populations, and componentsthat may drive effectiveness.
Research Gaps and Areas for Future
Research
Improving research in this area should include
methodologic considerations of power and sample sizeand durability of effects. Sample size and participant
followup were frequently insufficient to allow firm
conclusions. Duration of treatment and followup weregenerally short (<6 months); those studies with longer
duration of treatment were typically open label extensionsof RCTs and lacked control arms. While duration was
typically short, retaining participants in studies, especiallyin placebo arms, is difficult when parents or children
perceive little improvement in symptoms. Longer durationof treatment, however, is also important to rule out
meaningful improvements in placebo groups and help
inform our understanding of the placebo effect.
Few studies provided data on long-term outcomes after
cessation of treatment. Future studies should extend thefollowup period and assess the degree to which outcomesare durable in “real world” situations. The literature

of atomoxetine generally reported fewer harms than
did studies of methylphenidate in children with ADHD
symptoms, exploring differences in safety profiles is an
important area for additional research.

includes many single studies of various agents. Studies ofadjuncts to risperidone, for example, examined different
adjunct agents, with some positive effects on challenging
behaviors reported with most. Understanding which agentsshould be examined further is lacking. Another critical areafor further research is identifying which children are likely
to benefit from particular interventions. To date, studies
have provided limited characterization of the subpopulationof children who experience positive response to medical
interventions and limited characterization of the extent
or type of behavioral challenges children experience atbaseline.

Conclusions
Risperidone and aripiprazole ameliorated challenging
behaviors in the short term (<6 months), but had clinicallysignificant side effects. Methylphenidate and atomoxetine
were also associated with improvements in hyperactivity
in small, short-term RCTs (with uncontrolled open
label extensions). Atomoxetine plus parent training was
not more effective for hyperactivity than atomoxetine
alone. Omega-3 fatty acid supplementation was not
associated with improvements in challenging behaviors,
and N-acetylcysteine and tetrahydrobiopterin were
not associated with improvements in social skills andsymptom severity, respectively. Some positive effects werereported with other agents studied (risperidone adjuncts,
melatonin), but few studies addressed the same agent
or outcomes. Data on longer term (≥6 months) results
and harms of interventions are lacking. Similarly, more
research is needed to understand characteristics of thechild or treatment that modify outcomes and whether
effectiveness of interventions generalizes across different
settings such as the home or school. Current evidence
also does not inform our understanding of components ofinterventions that may drive effects. Some therapies holdpromise and warrant further study, and the conduct ofstudies has improved considerably over time (i.e., growing
number of RCTs and use of standardized measures).
However, additional studies with larger, well-characterized
populations over longer time frames, and that utilize
transparent and rigorous methods that permit comparison
across studies, would further inform decisionmaking.

Children with ASD also typically receive multiple typesof therapies, but few studies addressed combinations of
medical and behavioral or other categories of interventions
or a medical treatment compared with a nonmedical
treatment. Few attempted to account for potential effects
on ongoing interventions. This not only limited our ability
to interpret the effects of medical treatments in isolation
but represents a significant gap for families and providers
in choosing additional treatments that may bolster (orimpair) the effects of behavioral, medication, or othertherapies. Few studies (n=10) compared active treatments,and future research to assess comparative effectiveness ofantipsychotics, ADHD medications, and other medications
is necessary.
In addition, much of the medical intervention literature
relies on baseline and outcome measures that have specificlimits in understanding individualized response. Future
research attempting to elucidate potential biobehavioral
markers of response may prove useful. Research inunderstanding outcomes of importance to patients andcaregivers, such as quality of life, is also lacking.
Harms reporting varied across studies; some studies
amply described how harms were tracked, while others
listed harms with no indication of how they were assessed(e.g., parent recall, checklist, clinician assessment duringfollowup). This lack of reporting makes comparing
harms across studies difficult. For instance, while studies
of atomoxetine generally reported fewer harms than
did studies of methylphenidate in children with ADHD
symptoms, exploring differences in safety profiles is an
important area for additional research.

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Harms reporting varied across studies; some studies
amply described how harms were tracked, while others
listed harms with no indication of how they were assessed(e.g., parent recall, checklist, clinician assessment duringfollowup). This lack of reporting makes comparing
harms across studies difficult. For instance, while studies

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Full Report
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A, Warren Z. Medical Therapies for Children With
Autism Spectrum Disorder—An Update. Comparative
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Evidence-based Practice Center under Contract No. 2902015-00003-I.) AHRQ Publication No. 17-EHC009-EF.
Rockville, MD: Agency for Healthcare Research andQuality; May 2017. www.effectivehealthcare.ahrq.gov/
reports/final.cfm. doi: 10.23970/AHRQEPCCER189.

AHRQ Pub. No.17-EHC009-1-EF
May 2017
www.ahrq.gov