Acta Psychiatr Scand 2018: 138: 379–400 © 2018 John Wiley & Sons A/S.

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
All rights reserved ACTA PSYCHIATRICA SCANDINAVICA
DOI: 10.1111/acps.12918

Review
Systematic review and guide to management
of core and psychiatric symptoms in youth
with autism
Ameis SH, Kassee C, Corbett-Dick P, Cole L, Dadhwal S, Lai M-C, S. H. Ameis1,2,3 , C. Kassee1,
Veenstra-VanderWeele J, Correll CU. Systematic review and guide to P. Corbett-Dick4, L. Cole4,
management of core and psychiatric symptoms in youth with autism S. Dadhwal1, M.-C. Lai1,2,3,
J. Veenstra-VanderWeele5,
Objective: Evidence-based guidance of clinical decision-making for the C. U. Correll6,7,8
management of Autism Spectrum Disorder (ASD) is lacking, particularly for
co-occurring psychiatric symptoms. This review evaluates treatment evidence
for six common symptom targets in children/adolescents with ASD and
provides a resource to facilitate application of the evidence to clinical practice.
Method: A systematic search identified randomized controlled trials (RCTs)
and high-quality systematic reviews published between 2007 and 2016, focused
on: social interaction/communication impairment, stereotypic/repetitive
behaviours, irritability/agitation, attention-deficit/hyperactivity disorder
symptoms, mood or anxiety symptoms, and sleep difficulties. We then
completed qualitative evaluation of high-quality systematic reviews/meta-
analyses and quantitative evaluation of recently published RCTs not covered by
prior comprehensive systematic reviews.
Results: Recently published RCTs focused on social interaction and
communication impairment (trials = 32) using psychosocial interventions.
Interventions for irritability/agitation (trials = 16) were mainly
pharmacological. Few RCTs focused on other symptom targets (trials = 2–5/
target). Integration of these results with our qualitative review indicated that
few established treatment modalities exist, and available evidence is limited by
small studies with high risk of bias.
Conclusion: Given the current evidence-base, treatment targets must be clearly
defined, and a systematic approach to intervention trials in children/adolescents
with ASD must be undertaken with careful consideration of the limitations of
safety/efficacy data.

Summations
• Evaluation of the evidence-base across treatments for core and commonly co-occurring behavioural symp-
toms in children with ASD demonstrates that few established treatment modalities exist, and treatment evi-
dence is largely based on small studies with high risk of bias.
• SSRIs are commonly prescribed in children with ASD; however, studies evaluating treatment of anxiety and
mood symptoms with this class of medications are completely lacking, and studies of SSRIs for treatment of
stereotypic/repetitive behaviours in ASD have been negative.
• Clinicians should work with families to assess treatment targets, evaluate the evidence-base, employ a sys-
tematic approach to intervention trials and help families navigate safety/efficacy of available interventions.
Considerations
• The current review did not evaluate the treatment literature in its entirety. The aim of this review was to summa-
rize findings from prior high-quality systematic review and extend these findings through objective evaluation of
recently published RCTs to provide a concise guide to the current treatment literature.
• Our quantitative review includes the examination of recently published RCTs that evaluated efficacy of treat-
ment interventions focused on any of six symptom targets as primary outcome measures. Studies that exam-
ined effects of interventions on any of our six target symptoms as a secondary outcome were not included
nor were studies of interventions aimed at treating ASD symptoms broadly.

379
Ameis et al.

1
Child, Youth and Emerging Adult Program, Centre for Addiction and Mental Health (CAMH), Campbell Family Mental Health Research Institute, Toronto, ON, 2Department of
Psychiatry, Hospital for Sick Children, Toronto, ON, 3Department of Psychiatry, University of Toronto, Toronto, ON, Canada, 4Division of Developmental and Behavioural
Pediatrics, University of Rochester School of Nursing, University of Rochester Medical Centre, Rochester, NY, 5New York Presbyterian Hospital Center for Autism and the
Developing Brain, New York State Psychiatric Institute, Columbia University, New York, NY, 6The Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, NY,
7
Hofstra Northwell School of Medicine, Hempstead, NY, USA and 8Department of Child and Adolescent Psychiatry, Charit
e Universitätsmedizin, Berlin, Germany
Key words: autism; child and adolescent psychiatry; clinical aspects; review of the literature; treatment
Stephanie H. Ameis, Child, Youth and Emerging Adult Program, The Centre for Addiction and Mental Health, 80
Workman Way, #5224, Toronto, ON, Canada, M6J 1H4.
E-mail: stephanie.ameis@camh.ca

Accepted for publication May 21, 2018

Introduction The clinical management of children and adoles-

cents with ASD begins with the development of an
Autism spectrum disorder (ASD) is a lifelong neu-
evidence-based treatment plan for core symptoms
rodevelopmental condition that is prevalent in the
centring around educational and behavioural
general population (1, 2). In 2008, one in 65 eight-
interventions (7). Only two psychotropic medica-
year-old children across 14 U.S. communities had an
tions, risperidone and aripiprazole, are approved
ASD (3), with boys being affected three times more
by the U.S. Food and Drug Administration
frequently than girls (4). Care planning challenges in
(FDA) for use in children and adolescents with
ASD include determining: (i) the presence of co-
ASD, with indications specifically for irritability,
occurring language disorders, intellectual disability
rather than core ASD symptoms. Despite limited
(present in 40%) (5) and level of functioning; (ii)
evidence, other psychotropic medications are com-
indication for laboratory investigation for genetic or
monly used to treat co-occurring psychiatric symp-
metabolic causes of ASD (present in >10%) (6); and
toms. Among 2843 youth in the Autism Speaks
(iii) the presence of co-occurring medical or psychi-
Autism Treatment Network (AS-ATN), 46% of 6–
atric disorders requiring intervention (7).
11-year-olds and 66% of 12–17-year-olds with
Common co-occurring medical problems in
ASD were prescribed psychotropic medications
ASD include epilepsy (>10%), feeding disorders
(15). A review of studies reporting use of different
and gastrointestinal problems (primarily chronic
drug classes in individuals with ASD indicated that
constipation) (7). Clinically significant psychiatric
antipsychotics are the most commonly used fol-
symptoms are present in >50% of children and
lowed by ADHD medications (stimulants) and
adolescents with ASD and include irritability/agi-
antidepressants (16). Rates of use of psychosocial
tation, attention-deficit/hyperactivity disorder
interventions are not well documented.
(ADHD, ~40–60%), anxiety (~30–80%), depres-
In recent years, large consensus groups have
sion and sleep disruption (8–11). Accurate diag-
conducted systematic reviews and meta-analyses
nosis of co-occurring psychiatric symptoms
providing high-quality comprehensive evaluation
remains challenging due to lack of standardized
of studies and guidelines focused on treatment of
psychiatric assessment tools validated for use in
core symptoms of ASD and associated clinical
children with ASD (necessitating use of tools
challenges (17–19). The National Institute for
developed for the assessment of children without
Health and Care Excellence (NICE) guideline
ASD), communication impairments, symptom
number 170 (18), focused on the management and
overlap between ASD and co-occurring disorders,
support of children and adolescents with ASD, is
and symptom presentation that may differ across
the most recently published, comprehensive and
the ASD population (11, 12). Assessment strate-
rigorous, submitting a breadth of treatment studies
gies include integrating family report, child obser-
to evaluation using the Grading of Recommenda-
vation and collateral history from teachers/
tions Assessment, Development and Evaluation
therapists with the use of available objective rat-
(GRADE) approach (20). However, the accessibil-
ing scales to carefully delineate psychiatric symp-
ity and ease of reference of such comprehensive
toms that extend beyond ASD core features (11,
guidelines may be limited by their length (~800–
12). Treatment principles for psychiatric symp-
900 pages) and further interpretation may help
tom targets in non-ASD children/adolescents
facilitate application to everyday clinical decision-
may not be generalizable to those with ASD, as
making. Comprehensive review and provision of
exemplified by data indicating that treatment
guidance around treatment of psychiatric symp-
response may be lower in ASD and side-effect
tom targets have yet to be undertaken.
burden higher with some treatments (13, 14).

380

Aims of the study
Here, we review the scientific evidence for effi-
cacy of available treatments on core and com-
monly co-occurring psychiatric symptom targets
in children and adolescents (≤18 years old) with
ASD. Evidence for six treatment targets is evalu-
ated: (i) social interaction or communication
impairment, (ii) stereotypic or repetitive beha-
viours, (iii) irritability/agitation (including beha-
viours that challenge such as tantrums,
aggression and self-injury), (iv) ADHD symp-
toms, (v) mood or anxiety symptoms, (vi) sleep
difficulties. The current systematic review aims
to provide a concise, yet comprehensive, evalua-
tion of the treatment literature. Evaluation of
recently published treatment evidence is inte-
grated with summaries of results from prior
high-quality systematic reviews and meta-ana-
lyses to provide one clinically oriented resource
to facilitate evidence-based treatment decision-
making in children and adolescents with ASD.
Methods
Research questions
The key question addressed in this review was:
what is the evidence supporting the effectiveness of
psychosocial, pharmacological or biomedical inter-
ventions directed at any of our six symptom targets
as primary outcomes in children and adolescents
with ASD?
We conducted a systematic search to identify
both high-quality systematic reviews published
between 2007 and 2016, as well as recently pub-
lished randomized controlled trials (RCTs). Our
evaluation of the literature relevant to our review
was divided into: (i) qualitative evaluation of
recent and distant literature through summary and
interpretation of results from high-quality system-
atic reviews and meta-analyses identified by our
search; (ii) quantitative evaluation of recently pub-
lished RCTs that were not covered by prior high-
quality comprehensive systematic review.
Eligibility criteria
Eligibility criteria for qualitative review inclusion
were as follows: (i) a systematic review with or with-
out meta-analysis, (ii) involving human participant
ages ≤18 years, (iii) with ASD, (iv) focused on treat-
ments directed at any one or more of the six targets,
(v) appraised to be of ‘high’ quality, based on the
utilization of principles outlined in the PRISMA
checklist (21) for reporting systematic review and
Symptom target management for youth with ASD
meta-analyses of studies that evaluate healthcare
interventions, and (vi) written in English.
Eligibility criteria for quantitative review inclusion
were as follows: (i) an RCT; (ii) involving human
participants age ≤18 years; (iii) with ASD; (iv) use of
a psychosocial, pharmacological, biomedical or
mixed/combined intervention; (v) clearly stated pri-
mary outcome(s) focused on any of our six symptom
targets (stated above); (vi) ≥12 participants per treat-
ment arm; (vii) written in English; and (viii) pub-
lished after 2013, to ensure evaluation of the recent
literature without duplicating evaluation of studies
included in the NICE guideline (with search period:
1995 up to January 2013) (18).
All abstracts for systematic reviews/meta-ana-
lyses published between 2007 and 2016 were
screened for inclusion into our qualitative evalua-
tion and all abstracts for RCTs, published between
2013 and 2016, were screened for inclusion into
our quantitative review (see Figure 1).
Search procedure
Studies were selected through a systematic multi-
stage process. We searched Medline, Embase, Psy-
cInfo and Cochrane (published between January
2007 and March 2016) combining three categories
(ASD, treatments, systematic review or meta-ana-
lysis) of relevant Keywords and Medical Subject
Headings (see Appendix S1 including search strat-
egy for details).
Data extraction for systematic review
After duplicates were removed, a total of 261 full-
text articles (110 RCTs and 151 systematic
reviews/meta-analyses) were appraised for inclu-
sion. Appraisal of all articles was conducted
between September 2016 and February 2017 by
two investigators (CK, SA). Each investigator
independently assessed titles and associated
abstracts to select articles for full-text review. All
full-text articles were subjected to study eligibility
criteria and studies that still met criteria after
investigators read the complete article were
selected for inclusion.
Forty-four papers included in the final synthesis
were systematic reviews/meta-analyses.
Forty studies included in the final synthesis were
RCTs. Examples of excluded systematic reviews/
meta-analyses were those with out-of-scope popu-
lations (i.e. adults, general disability population),
those with out-of-scope targets (i.e. cognition,
adaptive functioning) and those that were of low
methodological quality (e.g. insufficient description
of methods, no description of included/excluded
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Ameis et al.

Fig. 1. PRISMA Flow chart showing selection of included studies. [Colour figure can be viewed at wileyonlinelibrary.com]

studies for evaluation). Examples of excluded Evaluation and synthesis of treatment data
experimental studies were non-RCTs, RCTs with
To provide a comprehensive evaluation and concise
out-of-scope populations (e.g. adults, developmen-
summary of the available treatment evidence across
tal/intellectual disabilities in general, or specific
our targets, results from our qualitative evaluation
genetic disorders such as Fragile X or Rett syn-
of the treatment literature for each target include:
drome), RCTs aimed at improving non-medical or
(i) a focused summary of findings from the NICE
non-psychiatric domains (e.g. employment rates,
guideline (18), which includes high-quality evaluation
general academic performance, daily living skills),
of the evidence-base relevant to each of our targets,
or RCTs with primary outcomes focused on gener-
and (ii) integration with findings from additional
alized symptoms (i.e. improvement of ASD symp-
high-quality systematic reviews/meta-analyses identi-
toms broadly), and RCTs without clearly stated
fied through systematic search. Summary of findings
primary outcomes.

382

from psychosocial, pharmacological and biomedical
interventions is presented. The Cochrane Collabora-
tion Risk of Bias Tool (22) was used to evaluate the
quality of each RCT included in our final quantita-
tive synthesis of the recent treatment literature. The
Cochrane Risk of Bias Tool assesses a study based
on the presence of a narrative description of evi-
dence-based methodological features, which are as
follows: sequence generation, allocation conceal-
ment, blinding of participants and personnel, blind-
ing of outcome assessors, complete outcome data
available, no selective outcome reporting or other
sources of bias not covered by the preceding cate-
gories. An assessment of ‘yes’, ‘no’ or ‘unclear’, was
made for a particular study based on whether there
was sufficient description for each category. This
assessment provided an overall ranking of ‘Low Risk
of Bias’ (yes in all categories), ‘High Risk of Bias’
(one or more categories with a ‘no’ rating) or
‘Unclear Risk of Bias’ (‘unclear’ in one or more cate-
gories, without any category receiving a ‘no’ rating).
The standardized mean difference (SMD) was
calculated to measure effect size for the primary
outcome measure of the RCT using the final
post-test means and standard deviations (SD) for
each treatment group. For those studies with mul-
tiple primary outcomes, one outcome was selected
for SMD calculation and used in the final synthe-
sis, based on: (i) the reliability of the measure (i.e.
a standardized measure and/or a blinded measure
was preferentially selected, if available), (ii) the
directness of the measure for a given intervention
(e.g. in a study with multiple primary outcomes, a
theory of mind (ToM) measure was selected as the
primary endpoint for an intervention focused on
improving ToM skills) and (iii) if the measure was
used by other studies evaluated for the same target
to optimize comparison between studies.
The following formulas were used for SMD cal-
culation:
X1  X2
Cohen0 s d ¼ rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
2 2
ðn1 1ÞSD1 þðn2 1ÞSD2
n1 þn2 2
and Hedges’s g (SMD)
 
3
= Cohen’s d 9 1 
4ðn1 þ n2 Þ  9
Of the 40 evaluated RCTs, it was not possible to
calculate SMD for seven studies (see Tables S1-
S6), due to insufficient information, and/or results
reported in a non-standardized way (e.g. change
scores, for which the SMD would be intrinsically
different than an SMD calculated with post-test
means). Final clinical practice implications were
Symptom target management for youth with ASD
made by the team of authors and positive results
for each treatment target were ranked according to
the criteria in Table 1. Studies were considered to
be small (n = 20–39/arm), medium (n = 40–74/
arm) or large (n ≥ 75/arm), based on consensus
among authors and informed by the size of studies
across the ASD treatment literature.
Results and clinical practice recommendations
Impaired social interaction and communication
Summary of qualitative review. In addition to the
NICE guideline, nine systematic reviews (23–31),
and 10 Cochrane reviews (32–41) were relevant to
impaired social communication as a treatment tar-
get in ASD.
The NICE guideline (18) evaluated 32 psychoso-
cial trials examining interventions directed at
impaired social communication in ASD (26 exam-
ining this target as primary outcome, six as sec-
ondary outcome) (42–73). Due to differences in
comparators and outcome measures, few meta-
analyses were possible. Of the meta-analyses that
were conducted, the highest quality results received
low to moderate quality ratings (summarized
below). Caregiver or preschool–teacher-mediated
social communication interventions vs. treatment
as usual in young children with ASD showed small
significant effects in favour of the intervention on:
social interaction (two studies, low quality) (58,
62), number of communication acts (three studies,
low quality) (58, 59, 62) and increased joint shared
attention (five studies, moderate quality (58, 62,
63, 65, 73). Meta-analysis of three studies of chil-
dren/adolescents (mean age 8.5–15 years) with
ASD without intellectual disability favoured social
skills group interventions over treatment-as-usual
on social skills (61, 69, 70), and on self- and
researcher-rated social skill knowledge following
intervention (moderate and large effects, respec-
tively, with low-quality evidence). Study quality
was mostly downgraded due to sample size and
lack of blinding among participants and outcome
assessors. The NICE guideline (18) evaluated one
small psychopharmacological trial of N-acetylcys-
teine vs. placebo treatment on social communica-
tion as a secondary outcome (74), without positive
effects. Twelve biomedical trials directed at
Table 1. Evidence categories for clinical practice implications
Established Evidence from ≥2 well-designed double-blind, parallel RCTs showing
evidence superiority to placebo on primary outcome measure
Emerging Limited positive evidence from >1 RCT or a meta-analysis showing
evidence superiority to placebo on primary or secondary outcome measures
383
Ameis et al.
impaired social communication in ASD (four
examining this target as primary outcome, eight as
secondary outcome) were also evaluated (75–86).
Separate low to very low-quality studies provide
limited evidence of effects of using a gluten/casein-
free diet (80, 81) or neurofeedback (86) vs. treat-
ment-as-usual on social communication outcomes.
Study quality ratings were downgraded due to lack
of blinding, selective reporting and small samples.
Based on their review, the NICE guideline recom-
mended parent- or teacher-mediated psychosocial
social communication interventions that use play-
based strategies to improve joint attention and
reciprocal attention for young children. Peer-
mediated social communication interventions were
recommended for school-age children. No biomed-
ical or pharmacological interventions were recom-
mended for targeting social communication
symptoms.
Building on the NICE guideline’s recommenda-
tion for parent- or teacher-mediated social
communication interventions in young children,
meta-analyses of parent-mediated interventions,
including a recent Cochrane review (34) of six
studies (316 participants) found small positive
effects on parent–child interaction and increased
parent-reported child communication. However,
interpretation is limited by high levels of bias due
to lack of blinding and problems related to alloca-
tion, concealment and reporting of outcome data.
A Cochrane review that largely covers the same
material evaluated by the NICE guideline (18)
showed small to moderate effects of social skills
group interventions on social competence and
friendship quality following intervention in studies
focused mainly on school-age children with ASD
without intellectual disability; however, data were
limited due to high risk of bias among available
studies (33). Another Cochrane review evaluated
efficacy of ToM interventions, including 22 RCTs
(695 participants, preschool age to adults, n = 10–
61 participants per study) (35). This review of
ToM interventions included studies of ToM train-
ing approaches (five trials), and interventions
focused on precursors to ToM skills (emotion
recognition strategies, seven trials; joint attention
and social communication, nine trials; imitation
teaching, one trial). Meta-analysis indicated large
effects of emotion recognition training on facial
emotion recognition (four studies), but little evi-
dence for the generalization of these skills to the
real world (35). Moderate effects for joint attention
interventions on joint engagement (two studies)
and small positive effects for studies focused on
ToM precursor skill interventions on general
384
measures of social communication were also
found. Available studies show little evidence of
generalization of skills to everyday life, and evi-
dence was limited overall by the lack of a priori
identification of primary outcome measures.
A number of additional systematic reviews were
relevant to impaired social communication as a
treatment target. Reviews of early intensive beha-
vioural interventions (EIBI) that provide intensive
intervention (10–40 h/week) to young children with
ASD (~2–5 year-olds) using applied behavioural
analysis (ABA) principles mainly showed effects on
IQ and adaptive behaviour in ASD (24, 25, 30, 32,
87). However, some reviews of EIBI interventions
highlight potential effects on communication (87)
and socialization including a Cochrane review of
the literature (32). Overall quality of the evidence is
rated as low due to lack of randomized trials. A
recent systematic review and meta-analysis of the
Treatment and Education of Autistic and Related
Communication Handicapped Children
(TEACCH) approach, wherein structured teaching
is applied in a predictable and comfortable environ-
ment conducive to promoting independence,
showed moderate effects of treatment on social
functioning in studies including school-age children
with ASD (27). No effect on communication was
found. The TEACCH intervention also brought
about large effects on outcomes related to problem
and maladaptive behaviours. However, confidence
in these results is limited due to concerns regarding
allocation concealment and use of intent-to-treat
analysis. In addition, lower effect sizes were found
in TEACCH studies employing more rigorous
design (27). A Cochrane review of music therapy
(provided over 1 week to 7 months) vs. placebo,
standard treatment or no treatment, evaluated 10
small RCTs or controlled trials (6/10 studies with
n < 10; 9/10 studies used cross-over design) and
found large effects for the intervention on social
interaction outside of therapy (n = 57 participants,
moderate quality), small to moderate effects on ver-
bal/non-verbal communication within therapy
(n = 30–139 participants) and moderate effects on
initiating interaction (n = 22 participants) (36).
Overall evidence for music therapy in children (2–
9 years of age) with ASD was rated as moderate to
low due to study design and small sample sizes (36).
A systematic review of computer-based interven-
tions used to teach communication skills to children
with ASD found just one controlled study that has
been published and concluded that there is cur-
rently very limited evidence that training with com-
puter software may improve specific
communication skills (e.g. production of spoken

words, sentence imitation, phonological awareness)
and there is no evidence of generalizability to every-
day life (29).
Reviews of interventions focused on improving
communication as a target using the Pic-
ture Exchange Communication System (PECS)
provide limited evidence for immediate but unsus-
tained effects on communication but not speech,
based on three small group studies, including two
RCTs. Meta-analysis was not possible due to dif-
ferences in outcome measures used (28, 31).
Finally, with respect to biomedical interventions,
Cochrane reviews on gluten/casein-free diets (37),
secretin (38), chelation (39), hyperbaric oxygen
therapy (40), omega-3 fatty acids (41) reinforce the
NICE guideline’s conclusions of not recommend-
ing any of these interventions for the treatment of
core ASD deficits, including impaired social inter-
action and communication. In addition to lack of
evidence of any benefit with treatment, Cochrane
reviews highlight concerns regarding serious
adverse events with chelation (e.g. kidney impair-
ment and reported death) (39), and risk of ear
barotrauma with hyperbaric oxygen therapy (40),
concerns that warrant emphasis in clinical discus-
sions with parents considering these treatment
options.
Summary of quantitative review. Fifteen studies
(Table S1a–c) met inclusion criteria for targeting
impaired social communication in ASD [12 psy-
chosocial (88–99), two biomedical (100, 101) and
one mixed biomedical/psychosocial intervention
(102)]. Most recently published psychosocial inter-
ventions provided single study data evaluating
unique intervention approaches with the exception
of parent-mediated (three trials) (91, 93, 95) and
computer-based (three trials) (94, 96, 99)
approaches. Two medium-sized parent-mediated
interventions in young children with ASD, con-
ducted by the same research group, found positive
effects favouring weekly training sessions with
parent–child dyads (encouraging joint attention,
symbolic play, engagement and regulation) vs.
parent-only education over 10–12 weeks on joint
parent-child interaction (small to large effects) (91,
93). Risk of bias was evaluated as high for these
studies due to lack of participant blinding. A third
small study of a parent-mediated intervention,
including a broader age range of children, failed to
find significant effects on dyadic communication
(95). Two small computer-based interventions
focused on ToM training failed to bring about
treatment effects on social communication out-
comes (94, 99), while a third small study found
Symptom target management for youth with ASD
positive effects on social symptoms following a
computer-based social skills intervention; however,
bias across studies was rated as unclear to high
(96). Single study data also showed positive results
following a number of other interventions on out-
comes related to impaired social interaction,
including: ToM intervention vs. waitlist (88), piv-
otal response therapy vs. parent education (89),
CBT vs. facilitated play (98), behavioural therapy
with speech-generating support vs. behavioural
therapy alone (92) and a monthly play intervention
vs. education (97).
For biomedical interventions, one small study
with unclear risk of bias found positive results
favouring an exercise intervention over control on
communication; however, the 95% CI of the SMD
crossed the line of no effect (100). A second small
study did not find any effect of intranasal oxytocin
vs. placebo on social communication scores in
ASD (101). Finally, one trial failed to find a signifi-
cant effect of combined social skills and d-cycloser-
ine vs. placebo on social responsiveness (with
unclear risk of bias) (102).
Clinical practice implications
• Based on evidence from prior meta-ana-
lyses, the strength of the evidence for
improvement in impaired social communi-
cation for the following interventions can
be considered emerging: social skills groups
for school-age children with ASD without
intellectual disability, parent-mediated inter-
ventions for young children with ASD,
EIBI for young children, educational
approaches for school-age children and
music therapy for children based on studies
including 2–9 year olds.
• Although further studies are needed to estab-
lish the efficacy of parent-mediated interven-
tions focused on joint attention and social
communication, a number of studies and
meta-analyses evaluating parent- and tea-
cher-mediated interventions in young chil-
dren with ASD consistently point to small
effects of treatment on joint attention.
Stereotypic/Repetitive behaviours
Summary of qualitative review. In addition to the
NICE guideline (18), five systematic reviews (103–
107) and six Cochrane reviews on interventions for
core ASD symptoms including repetitive beha-
385
Ameis et al.
viours (37–41, 108) were identified as relevant to
stereotypic/repetitive behaviours as a treatment
target.
The NICE guideline evaluated five studies
examining the effects of psychosocial interven-
tions on stereotypic/repetitive behaviours as a
secondary outcome measure (no psychosocial
studies were evaluated examining effects on this
target as primary outcome). Among these stud-
ies, no effect was found for behavioural, social
communication or cognitive interventions on
stereotypic/repetitive behaviours. The quality of
evidence for each study was rated as low to very
low. A small effect of combined treatment with
risperidone and a 9-week parent-training pro-
gramme on compulsions was found, although
quality of evidence was rated as low due to risk
of bias (e.g. lack of blinding, small sample size)
(109). Other systematic reviews of psychosocial
interventions found limited evidence from low-
quality single case studies for behavioural inter-
ventions aimed at reducing stereotypic/repetitive
behaviours in ASD (103) and an overall lack of
available studies in the literature examining this
target as a primary outcome (104).
For pharmacological interventions evaluated by
the NICE guideline (18), meta-analysis of two
studies (110, 111) that examined the selective sero-
tonin reuptake inhibitors (SSRIs) fluoxetine (111)
and citalopram (110), respectively, compared to
placebo, found no effect of SSRI treatment on
scales measuring compulsions or repetitive beha-
viours (nor on the Clinical Global Impressions-
Improvement Scale, CGI-I) in ASD. Risk of bias
was moderate due to the size of the overall sample
(<400). Significant side-effects including beha-
vioural activation were found with citalopram
treatment. Three moderate to large antipsychotic
trials showed a small but significant effect of treat-
ment with risperidone or aripiprazole on compul-
sions as a secondary outcome measure (112–114).
Risk of bias was rated as moderate based on the
sample size (<400). Statistically significant harms
were associated with antipsychotic treatment (e.g.
weight gain, increased appetite). Finally, one small
study with a low-quality rating found no sec-
ondary effect of N-acetylcysteine treatment vs. pla-
cebo on stereotypic/repetitive behaviours (74).
Other identified systematic reviews provide sup-
plemental information on the state of the evidence
for pharmacological interventions targeting stereo-
typic/repetitive behaviours in ASD. Carrasco et al.
(105) reviewed all trials of SSRIs targeting stereo-
typic/repetitive behaviours in ASD and found five
published and five unpublished but completed tri-
als (7/10 conducted in children or adolescents).
386
Across six studies providing data (four in children/
adolescents), meta-analysis revealed a small signifi-
cant effect of SSRIs on stereotypic/repetitive beha-
viours (SMD = 0.22, 95% CI 0.07–0.37) that did
not persist following adjustment for publication
bias in the literature (105). In addition, a 2013
Cochrane review evaluating nine studies including
children/adolescents concluded that there is no evi-
dence to support the use of SSRIs to treat core
symptoms of ASD in children (108). Finally, a sys-
tematic review of naltrexone (an opioid antagonist)
found no evidence for treatment benefit on core
ASD deficits, including stereotypic/repetitive beha-
viours (106).
For biomedical interventions reviewed in the
NICE guideline (18), a single small trial found
moderate to large primary effects of Kata exercise
intervention on stereotyped behaviours (115). The
quality of evidence was rated as low due to sample
size and lack of blinding. Another small study
found a large statistically significant secondary
effect of neurofeedback vs. treatment-as-usual for
parent-rated stereotypic/repetitive behaviours (86).
Study quality was rated as very low. Additional
small biomedical studies examining stereotypic
and repetitive behaviours as a secondary effect of
treatment found no effect of secretin (76), chelation
therapy (79), hyperbaric oxygen therapy (78) or L-
carnosine treatment (85) when compared to pla-
cebo. The quality of evidence across studies was
rated as low to very low. Although a large signifi-
cant secondary effect was found for a gluten/ca-
sein-free diet vs. treatment as usual on ‘bizarre
behaviour’ in a very small trial (81), another small
trial of this dietary intervention showed no effect
on stereotypic/repetitive behaviours in ASD (80)
(quality of evidence low to very low). One
Cochrane review of gluten/casein-free diets (two
trials, with n = 35 children) (37), one systematic
review of ketogenic diets (107), one Cochrane
review of secretin (16 trials, with n > 900 children
with ASD) (38), one Cochrane review of chelation
(one trial, n = 77) (39), one Cochrane review of
hyperbaric oxygen therapy (40) and omega-3 fatty
acids (41), all found no evidence of efficacy for core
ASD symptoms, including stereotypic/repetitive
behaviours. See previous section regarding serious
concerns regarding harm with chelation therapy
and hyperbaric oxygen therapy.
Summary of quantitative review. One study
(Table S2) met inclusion criteria for targeting
stereotypic/repetitive behaviours in ASD (116).
This single small trial with high risk of bias found
no effect of an 8-week parent group intervention
compared to delayed intervention on stereotypic/

repetitive behaviours (95% CI for outcomes
crossed the line of no effect).
Clinical practice implications
• There is emerging evidence for positive effects
of atypical antipsychotics, as a medication
class, on stereotypic/repetitive behaviours in
ASD based on studies evaluating this target
as a secondary outcome. Due to lack of stud-
ies examining this target as a primary out-
come and concerns that side-effects outweigh
the benefit of treatment effects, these medica-
tions are not recommended as primary treat-
ment for stereotypic/repetitive behaviours in
ASD.
Irritability/agitation
Summary of qualitative review. In addition to the
NICE guideline (18), five systematic reviews (117–
121) and one Cochrane review (122) were relevant
to targeting irritability/agitation in ASD. Of note,
this target domain was termed: ‘behaviour that
challenges’ in the NICE guideline (18).
The NICE guideline (18) evaluated 13 psychoso-
cial trials examining interventions directed at beha-
viour that challenges in ASD (four examining this
target as primary outcome, nine as secondary out-
come) (43, 57, 61, 69–71, 109, 123–128). Significant
effect sizes varying from small to large for separate
studies evaluating animal-based, behavioural, cog-
nitive behaviour therapy (CBT) and parent-train-
ing interventions were found. However, the quality
of evidence across these studies was rated as low to
very low due to small sample sizes, lack of blinding
and selective reporting. Meta-analysis of studies of
social skills group interventions indicated moder-
ate effects of intervention on a parent-rated mea-
sure of conflict, although quality rating of this
evidence was also low.
The NICE guideline (18) evaluated 18 pharma-
cological trials examining interventions directed
at behaviour that challenges (15 examining this
target as primary outcome, three as secondary
outcome) (74, 110, 112–114, 129–141). Meta-ana-
lysis of four moderate to large antipsychotic tri-
als (6–8 weeks duration) (113, 114, 129, 130) that
examined aripiprazole or risperidone vs. placebo
indicated: (i) clinical response (>25% improve-
ment on autism behaviour checklist-irritability
subscale, ABC-I, and/or rating of improved/very
much improved on CGI-I) was over twice as
likely in children on either medication vs.
Symptom target management for youth with ASD
placebo; (ii) large significant effect of treatment
on continuous symptoms of irritability/agitation
(ABC-I) (quality rating low to moderate); and
(iii) small to large secondary effects on ABC-
measured symptoms of lethargy (small effect,
moderate quality), stereotyped behaviour (med-
ium effect, moderate quality), hyperactivity (large
effect, moderate quality) and inappropriate
speech (medium effect, low quality). Meta-analy-
sis from two studies (112, 129) also indicated
that low dose risperidone or aripiprazole treat-
ment was 1.5 times more likely to bring about
treatment response vs. placebo (low-quality evi-
dence). Statistically significant and concerning
side-effects were associated with all antipsychotic
doses (e.g. increased risk of any adverse event,
weight gain, increased appetite, leptin change
score). Moderate quality evidence from two dis-
continuation RCTs indicated that relapse of irri-
tability/agitation was 72% less likely when
antipsychotic treatment was continued (113, 131).
Meta-analysis of two small anticonvulsant (dival-
proex) trials failed to find a significant effect of
treatment on the ABC-I (quality rating low) in
ASD (133, 134). In addition, single study data
found no evidence of effect for citalopram (110),
amantadine (140), naltrexone (138) or atomox-
etine (141) on irritability/agitation; however, evi-
dence quality was largely low. A small study of
N-acetylcysteine (74) showed a large effect of
treatment on irritability/agitation but the 95%
CI crossed the line of no effect. Large significant
effects on irritability/agitation were found for
combination treatment of risperidone with pirac-
etam (a cognitive enhancer) (136), pentoxifylline
(methylxanthine) (137) or antihistamines (cypro-
heptadine) (139), over monotherapy with risperi-
done in separate small single studies conducted
by the same research group, although these stud-
ies did not provide clinical information of when
adjunctive treatment might be indicated.
The NICE guideline (18) evaluated 15 biomedi-
cal trials focused on treatment of behaviour that
challenges in ASD (75–79, 82–84, 142–148). A
medium positive effect of a comprehensive multivi-
tamin/mineral supplement on parental global
impression of hyperactivity and tantrum was
found in a moderately sized study with moderate
quality rating (84). A medium positive effect was
also found for Thai massage in a small study with
low-quality rating and on the Connor’s ADHD
subscale of hyperactivity, although no significant
effects were found for other subscales, including
conduct problems (142). Other evaluated biomedi-
cal trials did not find effects for acupuncture (low
quality) (75, 149), secretin (moderate quality) (76,
387
Ameis et al.
77), hyperbaric oxygen therapy (low to very low
quality) (78, 143), chelation therapy (low quality)
(79), omega-3 fatty acids (low quality) (82, 83),
ginkgo biloba (low quality) (144), dimethylglycine
(low quality) (145), auditory integration therapy
(low quality) (146) or immunoglobulin therapy
(low quality) (147).
A recent high-quality, comprehensive system-
atic review and meta-analysis (120) evaluated evi-
dence for monotherapy treatment of irritability/
agitation in ASD including 11 RCTs (811 youth)
and identified risperidone (effect size, ES = 0.9),
aripiprazole (ES = 0.8) and N-acetylcysteine
(ES = 0.7) as agents that have demonstrated large
effect sizes favouring treatment over placebo (pri-
mary endpoint, ABC-I). Although N-acetylcys-
teine showed a large effect size, this result is
based on single study evidence from a small
(n = 33) sample and the 95% CI for ES, as calcu-
lated in the NICE guideline (18) crossed the line
of no effect (74). The review discussed concerning
adverse effects with atypical antipsychotics and
highlighted a lower side-effect burden for
extrapyramidal symptoms and sedation in arip-
iprazole vs. risperidone, but similar profiles for
increased weight gain. In contrast, no statistically
significant adverse events were found with N-acet-
ylcysteine (120).
Additional systematic reviews focused on phar-
macological treatment of irritability/agitation in
ASD conclude that while short-term treatment
with risperidone or aripiprazole has demonstrated
efficacy for treatment of irritability/agitation in
ASD; however, risks of adverse effects may out-
weigh potential treatment benefits. In addition, lit-
tle evidence provides guidance around risks
associated with long-term treatment (117–119,
122).
A practice pathway (121) provides detailed clini-
cal guidance around the assessment and manage-
ment of irritability/agitation and aggression in
children and adolescents with ASD, consistent
with NICE recommendations, indicating the need
for: (i) careful assessment of symptoms and safety
risk, (ii) evaluation and management of contribut-
ing factors (i.e. medical, psychosocial stress, com-
munication factors, maladaptive reinforcement,
psychiatric comorbidity) and (iii) consideration of
psychopharmacological treatment for symptoms
that are severe or unresponsive to non-pharmaco-
logical approaches (121).
Summary of quantitative review. Thirteen studies
met inclusion criteria for targeting irritability/agi-
tation in ASD (Table S3a-b), including two
388
psychosocial (150, 151) and 11 pharmacological
interventions (152–162).
Bearss et al., (151) found statistically significant
results favouring a parent-training programme
over a parent-education group in a large psychoso-
cial study, while Gabriels et al., (150) found signifi-
cant results for therapeutic horseback riding
compared to a barn activity control in a moder-
ately sized sample. Although small to moderate
effects were found on irritability/agitation (on
ABC-I), both studies were evaluated to have a high
risk of bias due to lack of blinding.
Of the 11 pharmacological trials evaluated, nine
small single trials with low risk of bias (152, 154–
160, 162) investigated combined treatment with
risperidone plus a second agent over risperidone
alone, using the ABC-I as primary endpoint (see
Table S3a-b). Single study data for a wide range of
drug classes were investigated with significant
small to large effects favouring combined treat-
ment over risperidone alone. Of note, the same
research group conducted all evaluated studies and
no clear information is available as to which
patients should be trialled on combined treatments
compared to monotherapy to guide clinical deci-
sion-making. The two remaining pharmacological
trials investigated lurasidone (20 mg/day or
60 mg/day) (161) and aripiprazole vs. placebo
respectively (153). Loebel et al., 2016 (161) did not
find statistically significant between-group differ-
ences in ABC-I scores favouring lurasidone,
although CGI-I scores (secondary outcome) were
significantly higher at week 6 of lurasidone
(20 mg) treatment vs. placebo. Adverse events
were higher with lurasidone (e.g. irritability, nau-
sea/vomiting) vs. placebo. In a relapse prevention
trial recruiting children/adolescents who
responded to aripiprazole over 13–26 weeks of
treatment (Phase 1) (153) investigators found that
while there was no statistically significant differ-
ence between treatment vs. placebo in time to
relapse (over subsequent 16 weeks, Phase 2), haz-
ard ratio and number-needed-to-treat analysis sug-
gested that some patients benefit from
maintenance aripiprazole treatment (163; 121).
Clinical practice implications
• Efficacy of short-term risperidone and arip-
iprazole for treatment of irritability in ASD is
established. Due to risk of concerning side-
effects, these medications should be used only
in children with high irritability/aggression
when lower-risk, evidence-based treatments
have been exhausted and for symptoms that

interfere significantly with safety or function-
ing (121) Routine side-effect monitoring is
indicated; see Ameis et al., (163). Based on
one positive RCT, evidence for N-acetylcys-
teine can be considered emerging. Two recent
resources provide detailed step-by-step clini-
cal guidance on addressing irritability/aggres-
sion in ASD (18, 121).
• Based on limited positive RCTs, evidence for
psychosocial interventions including parent
training, horseback riding, CBT and beha-
vioural therapy on irritability/agitation as a
primary outcome measure can be considered
emerging.
ADHD
Summary of qualitative review. In addition to the
NICE guideline (18), three systematic reviews (13,
164, 165) and two Cochrane reviews (37, 41) were
relevant to targeting ADHD symptoms in ASD.
The NICE guideline (18) evaluated one pharma-
cological trial examining the effects of atomoxetine
vs. placebo on ADHD symptoms as a primary out-
come (141) and two studies examining effects of
biomedical treatments on ADHD symptoms as a
secondary outcome (80, 166). No psychosocial
studies were identified or evaluated. Two psy-
chopharmacological studies reporting on primary
and secondary effects from the same clinical trial
that examined the effect of methylphenidate on
ADHD symptoms were excluded from evaluation
based on concerns regarding high risk of carry-
over effects due to cross-over design without a
wash-out phase and no available first-period data
(167, 168).
The pharmacological trial (141) evaluated in the
NICE guideline (18) found a small significant effect
favouring atomoxetine over placebo on parent-
rated ADHD symptoms (ADHD-Rating Scale) in
a medium-sized study that was given a moderate
quality rating due to sample size. However, effects
were not significant on other parent-rated mea-
sures, on teacher-rated measures or clinician-rated
CGI-I for ADHD symptoms. Side-effects were
reported in 81% of atomoxetine and 65% of pla-
cebo-treated participants (decreased appetite, nau-
sea and early morning awakening were the most
commonly reported side-effects).
Biomedical interventions evaluated by the NICE
guideline (18) showed a moderate significant sec-
ondary effect favouring gluten/casein-free diet over
treatment-as-usual on ADHD symptoms, although
evidence quality was rated as low to very low (80).
Symptom target management for youth with ASD
No effect of omega-3 fatty acids on ADHD symp-
toms was found in a small trial with very low-qual-
ity rating (83). Consistent with the NICE
guideline, Cochrane reviews concluded that: (i)
there is no evidence that treatment with omega-3
improves symptoms of hyperactivity in ASD,
although larger and more rigorous studies are
needed to make definitive conclusions (41), and (ii)
there is no evidence for gluten/casein-free diets for
treatment of ADHD symptoms (37).
Other high-quality systematic reviews provide
additional information regarding treatment of
ADHD symptoms in ASD. A meta-analysis
(164) found moderate effects favouring methyl-
phenidate over placebo on hyperactivity based
on three very small cross-over studies (n = 10–13
total) (169–171) and a 4th small cross-over study
(n = 66) by the Research Units on Pediatric Psy-
chopharmacology (RUPP) Autism Network
group, excluded from evaluation by the NICE
guideline due to concerns regarding carry-over
effects (172). The RUPP cross-over study found
small to moderate effect sizes favouring low- to
high-dose methylphenidate over placebo on
symptoms of hyperactivity in school-age children
but only a trend-level difference in overall rates
of response between treatment and placebo and
noted that effect sizes were lower and side-effect
burden was higher in ASD (i.e. impaired sleep,
irritability, appetite decrease, gastrointestinal dis-
comfort) compared to prior literature on chil-
dren/adolescents with a primary ADHD
diagnosis without ASD (172). A systematic
review evaluating the same studies reviewed by
Reichow et al. (164) came to similar conclusions
regarding potential utility of methylphenidate
treatment for ADHD symptoms in ASD. Maha-
jan et al.(13) conducted a systematic review and
outlined clinical pathways for symptom evalua-
tion and medication choice for the treatment of
ADHD symptoms based on the limited available
evidence for treatment of ADHD symptoms in
ASD at the time the review was completed. The
recommended clinical pathway begins with the
choice of methylphenidate or amphetamine salts
as first-line treatment, and atomoxetine or guan-
facine as second-line treatment (13). Of note,
this pathway was defined prior to the publica-
tion of recent guanfacine and atomoxetine stud-
ies in ASD(173, 174). Antipsychotics were also
included as a third-line treatment option based
on findings of significant secondary effects on
hyperactivity (measured by the ABC-Hyperactiv-
ity Subscale) across small to large studies of
either risperidone or aripiprazole vs. placebo
(13).
389
Ameis et al.
Summary of quantitative review. Four studies
(Table S4a-c) met inclusion criteria for targeting
ADHD symptoms in ASD. Two trials tested phar-
macological (174, 175), one tested a biomedical
(176), and one tested a combined intervention
approach (173). In Scahill et al. (174) a statisti-
cally significant between-group difference favour-
ing guanfacine over placebo on hyperactivity
(ABC-H; primary outcome) was found (large
effect, total n = 62: guanfacine n = 30/placebo
n = 32). Fifty per cent of participants on guan-
facine were rated as much improved or very much
improved on the CGI-I (vs. 9.4% on placebo).
The trial was small overall, although with an
otherwise low risk of bias. Subject drop-out was
similar between guanfacine and placebo-treated
groups (n = 4/group). Drowsiness, fatigue, emo-
tional fragility, tearfulness and irritability were
common side-effects leading to dose reduction in
the guanfacine-treated group. Blood pressure and
pulse were lower at 4 weeks on guanfacine treat-
ment and returned to normal by week 8 (174). A
small, cross-over trial (175), with high risk of bias,
that did not report the first period of treatment
prior to cross-over, found statistically significant
improvement in symptoms with low, medium and
high-dose methylphenidate treatment vs. placebo
on the ADHD index of the Connor’s Teacher
Rating Scale. Significant loss of appetite and
impaired sleep was noted for children on high
methylphenidate doses (175).
A recent small study of omega-3 fatty acid
treatment vs. placebo, with low risk of bias, found
no statistically significant difference in hyperactiv-
ity as measured by ABC-H (parent and teacher),
although treatment was well tolerated (176).
Finally, a 4-arm study (n = 128 total) (173) com-
pared atomoxetine alone, atomoxetine plus par-
ent-training, placebo plus parent-training and
placebo treatments. Parent training (10 weekly
sessions) for this study was adapted from the
RUPP parent training manual focusing on pre-
venting behaviour problems, time-outs, planned
ignoring and reinforcement (151). Statistically sig-
nificant effects on the SNAP-IV parent-rated
ADHD subscale were found for all treatment
arms compared to placebo (ES = 0.4–0.7). Larger
effect sizes were found for atomoxetine vs. pla-
cebo and atomoxetine plus parent-training vs. pla-
cebo. The 95% CI for the parent training plus
placebo vs. placebo comparison crossed the line
of no effect. Significant differences in CGI-I scores
were found in both treatment arms including ato-
moxetine (CGI-I much improved/very much
improved was ~49% in atomoxetine alone, ~47%
in atomoxetine plus parent-training, ~29% in
390
placebo plus parent-training and ~19% in placebo
arms). Drop-out rates were 17% vs. 28% in ato-
moxetine vs. placebo arms. Decreased appetite,
impaired sleep and abdominal pain occurred more
commonly with atomoxetine treatment (173).
Clinical practice implications
• Based on prior systematic reviews and
recently published RCTs, there is now emerg-
ing evidence of positive treatment effects with
methylphenidate, atomoxetine and guan-
facine for targeting ADHD symptoms in
ASD.
• Atypical antipsychotics may also be helpful
in treating hyperactivity symptoms in ASD
(emerging evidence); however, no study has
examined the effects of these medications on
ADHD symptoms as a primary outcome and
use of antipsychotics should be limited to sev-
ere behavioural disruption due to significant
side-effect concerns with this medication
class.
• Helpful clinical pathways to guide the evalua-
tion and management of ADHD symptoms
in children with ASD can be found in (13).
Mood and anxiety
Summary of qualitative review. In addition to the
NICE guideline (18), six systematic reviews (177–
182) and two Cochrane reviews were relevant to
targeting mood or anxiety symptoms in ASD (108,
183).
The NICE guideline (18) reviewed four small
CBT trials directly targeting anxiety in children/
adolescents with ASD with an IQ above 70 (126,
184–186). Meta-analyses of CBT studies in the
NICE guideline found moderate confidence in find-
ings indicating that children/adolescents with ASD
were 12 times more likely to lose their anxiety diag-
nosis and seven times more likely to show improve-
ment of anxiety symptoms (on CGI-I) following
CBT vs. treatment-as-usual. Confidence in large
effect sizes found for reductions in continuous mea-
sures of anxiety symptoms with CBT was low to
very low due to risk of bias (e.g. lack of blinding,
small samples) (18). In addition, NICE reviewed
two trials on omega-3 fatty acids (82, 83) and one
trial on chelation (187) for anxiety symptoms as a
secondary outcome, with no effects found, and low
to very low-quality evidence (see results section on
impaired social interaction and communication for
serious safety concerns with chelation therapy).

Recent systematic reviews that have largely eval-
uated the same literature as reviewed between the
NICE guideline and our quantitative review below
suggest that CBT has evidence of efficacy for treat-
ment of anxiety in children/adolescents with ASD
(177–179). In one review (177), this conclusion was
based on an effect size of >0.8 found across most
of the eight small RCTs examined (126, 185, 186,
188–192). Additional findings of interest suggest
that parent and clinician-reported measures are
more sensitive to measuring change in anxiety after
CBT than child self-reports (180, 181) and that
individualized CBT may be more effective than
group CBT (180).
There are currently no RCTs in the published
literature that specifically evaluate pharmacologi-
cal interventions to target anxiety in ASD. Sys-
tematic reviews (177, 193) mention preliminary
evidence for the efficacy of dextromethorphan
(194) and buspirone (195) based on small studies
without a control group. Two Cochrane reviews
summarize the evidence for SSRIs and tricyclic
antidepressants (TCAs) for treatment of chil-
dren/adolescents with autism; however, the stud-
ies reviewed focused on repetitive behaviours as
a treatment target (108, 183). Clinical trials
examining the efficacy of these treatments for
anxiety and mood symptoms have yet to be
undertaken. Of note, we know of no RCT that
has examined efficacy of psychosocial, pharma-
cological or biomedical interventions on mood
symptoms as a specific target in children/adoles-
cents with ASD.
Summary of quantitative review. Five studies
(Table S5) met inclusion criteria targeting anxi-
ety in ASD (189, 191, 196–198). All were psy-
chosocial interventions focused on the use of
CBT for treatment of a variety of anxiety disor-
ders in older children/adolescents with ASD with
IQ above 70. All RCTs were found to have high
risk of bias due to un-blinded participants and/
or outcome assessors. Three of the four small
CBT studies evaluated (189, 197, 198) demon-
strated statistical significance on anxiety out-
comes of interest (all SMD > 0.8). An additional
small CBT trial utilizing a multimodal anxiety
and social skills intervention (191) did not find
statistically significant outcomes for anxiety.
Although the addition of three more trials with
positive results continues to support prior stud-
ies indicating that CBT is a useful intervention
for anxiety in ASD (189, 197, 198), methodolog-
ical limitations (i.e. sample sizes, lack of blind-
ing) limit the strength of the evidence for this
intervention.
Symptom target management for youth with ASD
Clinical practice implications
• A number of studies have found positive evi-
dence that CBT undertaken in children/ado-
lescents with ASD, without intellectual
disability, and with a variety of anxiety disor-
ders leads to clinical improvement in anxiety
symptoms and should be pursued when clini-
cally significant symptoms of anxiety arise in
children and adolescents with ASD. How-
ever, as all single studies examining CBT for
anxiety in ASD have been small and with
methodological limitations, the strength of
evidence for this treatment is considered
emerging.
• Clinicians should exercise caution when pre-
scribing SSRIs, TCAs or other agents for the
treatment of mood or anxiety symptoms as a
target in individuals with ASD, using objec-
tive tools to screen for treatment targets and
monitor benefits and side-effects as trials
focused on treatment of this target in ASD
are lacking.
Sleep difficulties
Summary of qualitative review. In addition to the
NICE guideline (18), three systematic reviews
(199–201) were identified as being relevant to sleep
disturbance.
The NICE guideline (18) reviewed five trials rele-
vant to sleep as a target in ASD (83, 84, 141, 202,
203). Cortesi et al., (202) compared CBT, mela-
tonin, and combined CBT and melatonin to pla-
cebo on sleep problems as a primary outcome
measure, in a medium-sized study. Overall, med-
ium to large effects were found for efficacy of CBT
on multiple sleep outcomes (e.g. sleep onset, total
sleep time, sleep efficiency and sleep problems) and
the confidence in results was rated as moderate
(202). Cortesi et al., (202) and an additional small
trial (203) also found moderate confidence in large
effect sizes favouring melatonin over placebo on
similar primary outcomes as listed above for CBT
(202). Moderate confidence in medium to large
effects favouring melatonin over CBT and for
combined CBT and melatonin over either CBT
alone or melatonin alone was also found in this
same trial (202). The NICE guideline (18) also
identified one low-quality negative study that
examined the effects of atomoxetine on sleep as a
secondary outcome (141). In addition, the use of
omega-3 fatty acids for sleep problems were not
391
Ameis et al.
recommended, based on two studies that examined
effects on sleep as a secondary outcome measure
(83, 84).
Additional systematic reviews (199, 200) also
found some evidence for the efficacy of mela-
tonin in ASD, with little to no adverse events
reported (199, 200). Clinical practice recommen-
dations provided by the NICE guideline (18)
recommended that clinicians follow a treatment
pathway when targeting sleep in ASD that
begins with: (i) a comprehensive assessment of
sleep problems and (ii) development and imple-
mentation of a specified plan to address prob-
lems. Based on the NICE recommendation,
pharmacological interventions should only be
implemented in conjunction with non-pharmaco-
logical interventions and in consultation with a
physician specialist, and when sleep problems
persist despite implementation of a sleep plan or
when disturbance has a significant negative
impact on function. Consistent with findings
from the NICE guideline, a recent systematic
review and practice pathway for insomnia in
children/adolescents with ASD (201) recom-
mends screening of all children/adolescents with
ASD for insomnia, assessment/management of
contributing medical problems, and primary use
of educational/behavioural interventions and
consideration of pharmacological intervention
only if non-pharmacological approaches are not
feasible or in situations where insomnia has
reached a crisis.
Summary of quantitative review. Two studies
(Table S6a–b) met inclusion criteria targeting sleep
difficulties in ASD (204, 205). Both were small tri-
als with high risk of bias due to un-blinded partici-
pants and/or outcome assessors. Johnson et al.
(204) compared a psychosocial parent-training
programme to parent education, for the reduction
in sleep disturbances in children. A statistically sig-
nificant difference between groups was found, but
the 95% CI crossed the line of no effect. Gringras
et al. (205) found no significant effect for the use
of weighted blankets to improve sleep.
Clinical practice implications
• Based on prior systematic reviews, there is
emerging evidence in support of the use of
melatonin treatment for sleep problems in
ASD.
• Non-pharmacological approaches that aim to
address sleep problems should be
392
implemented prior to considering the addi-
tion of a pharmacological intervention to tar-
get sleep.
• Detailed clinical guidance on management of
sleep difficulties in ASD can be found in (18)
and (202).
Discussion
Here, we present a systematic review, evaluation
and synthesis of the treatment literature focused
on targeting core (i.e. social communication diffi-
culties and stereotypic/repetitive behaviours) and
commonly co-occurring psychiatric symptoms (i.e.
irritability/agitation, ADHD, mood and anxiety
symptoms, sleep difficulties) in children and ado-
lescents with ASD, providing a concise resource to
guide evidence-based clinical decision-making and
treatment planning.
Overall, this review indicated that for core
impairment in social communication in ASD,
treatment options are mainly psychosocial with
emerging evidence from a number of studies that
parent-mediated interventions for young children
may improve joint attention. Social skills groups
for school-age children without intellectual disabil-
ity, education, EIBI, music therapy and ToM
interventions may also improve outcome measures
related to social communication. However, it
remains unclear whether treatment effects may
generalize to functioning in everyday life for any
social communication treatment with emerging
evidence. For stereotypic/repetitive behaviours,
treatment research has largely focused on SSRIs,
without evidence of efficacy for this treatment tar-
get. Very little additional research is available to
guide treatment decisions targeting stereotypic/
repetitive behaviours.
Our review of common psychiatric targets indi-
cated that there is established evidence for the use
of risperidone and aripiprazole for the treatment
of significant irritability/agitation. However, due
to risk of side-effects, these medications should be
reserved for cases where all other therapeutic
options have been exhausted, and perhaps utilized
only after other pharmacological treatments with
less evidence for efficacy but minor side-effect pro-
files have been considered (e.g. N-Acetylcysteine)
(120, 121). When atypical antipsychotics are used
and significant weight gain ensues, a recent small
RCT provides preliminary evidence that met-
formin treatment may result in reduction in body
mass index (BMI) (206). This preliminary RCT of

metformin treatment, compared treatment to pla-
cebo in children with ASD (age 6–17) who were
previously treated with either risperidone or arip-
iprazole and who had significant weight gain since
starting on antipsychotic treatment (206). The
study found a significant change (reduction) in
BMI z-score following 16 weeks of metformin
treatment (difference in BMI z-score: 0.10, 95%
CI 0.16 to 0.04) (206). For the treatment of
ADHD symptoms in ASD, a small number of
recently published RCTs suggest that treatment
with methylphenidate, atomoxetine or guanfacine
have efficacy for this treatment target, although
larger, more rigorous studies are needed before
these treatments can be considered established.
For treatment of comorbid anxiety disorders, sev-
eral studies have now shown positive efficacy of
CBT in children and adolescents with ASD with-
out intellectual disability. Although larger and
more rigorous studies are still needed, CBT can be
considered as first-line treatment for anxiety in
children and adolescents with ASD without intel-
lectual disability. In considering sleep as a treat-
ment target, treatments with emerging evidence,
such as melatonin, should be considered only after
factors contributing to sleep problems are thor-
oughly assessed and addressed. Finally, our review
yielded no available research to guide treatment of
mood symptoms in children and adolescents with
ASD, highlighting a very significant gap in the
treatment literature.
A number of important themes emerge from our
review. First, as in other neurodevelopmental dis-
orders, treatments targeting mechanisms of illness
are as yet unavailable in ASD. While studies
focused on pharmacological treatments tend to
provide the most rigorously evaluated evidence of
efficacy, information regarding the confidence and
strength of the effect of treatment (based on effect
size information and potentially secondary out-
come data, such as the CGI) needs to be consid-
ered in order to weigh potential benefits against
the known and unknown risks of long-term use,
especially in a vulnerable paediatric population
still undergoing growth and development. In the
light of the available evidence, treatment decision-
making is complicated by the task of weighing dif-
ferent aspects of the evidence-base. An example is
the choice between guanfacine and methylpheni-
date for the treatment of ADHD symptoms, con-
sidering data from a single, small, well-designed
study of guanfacine showing a large, clinically sig-
nificant treatment effect and good side-effect pro-
file, compared with several positive findings from
small and medium-sized methylphenidate trials
with methodological limitations indicating higher
Symptom target management for youth with ASD
side-effect burden in children with ASD and
ADHD compared to the non-ASD population. In
these cases, clinicians must use additional informa-
tion to guide decision-making, including: (i) careful
assessment of the precise problem in need of
targeting, (ii) what strategies may be used to
address the problem prior to undertaking a phar-
macological trial with risk for side-effects, (iii)
weigh potential benefits of treatment against
potential side-effects and (iv) the length of the
treatment trial necessary to determine response
before moving on to another agent.
Another important theme emerging from the
review is the difficulty of evaluating and comparing
evidence between psychosocial and pharmacologi-
cal trials. Often the nature of psychosocial (and
often biomedical) interventions makes it impossi-
ble to blind participants/parents to group/interven-
tion assignment, raising concerns regarding
reporting bias around outcomes, and downgrading
the quality of trials on this basis when using stan-
dard evaluation tools. However, based on our
review many other addressable factors continue to
contribute to the difficulty of evaluating the psy-
chosocial evidence in ASD, such as the large num-
ber of small-sized single studies of unique
interventions, lack of blinded outcome assessors,
use of waitlist controls that generally inflate effect
sizes, poor definition around primary outcome
measures and lack of consistency among outcome
measures reported, which limits cross-study com-
parison. Similar issues are inherent in the biomedi-
cal intervention literature. Consensus for
implementing a standard design across studies that
includes recommended use of a consistent outcome
measure would clearly strengthen evaluation
across this literature. Finally, based on the overall
low quality of biomedical interventions reviewed
here and concerns regarding safety of particular
interventions (e.g. chelation, hyperbaric oxygen
therapy), it is imperative that clinicians ask
patients and caregivers about biomedical interven-
tion use, and provide clear feedback and assistance
for navigating issues of safety, efficacy and cost-
benefit regarding these interventions.
An important limitation of the current review
includes the choice not to undertake a comprehen-
sive systematic review and evaluation of the treat-
ment literature in its entirety. Instead, we chose to
focus on evaluating recently published RCTs not
yet submitted to rigorous evaluation by prior com-
prehensive reviews. Further, in our quantitative
review, we evaluated studies focused on specific
targets of interest as primary outcome measures
rather than extending to secondary outcome mea-
sures and inclusion of studies evaluating efficacy of
393
Ameis et al.
comprehensive treatments on ASD symptoms
broadly. These decisions were made to maintain
the ability to present a concise and clinically rele-
vant review that builds on prior resources and can
be consulted quickly and efficiently. However, in
integrating results of our quantitative and qualita-
tive reviews, each treatment target section provides
reasonable coverage across the recent, distant and
broader ASD literature to provide clinically appli-
cable conclusions for the treating clinician and
provides clear reference to high-quality resources
for additional consultation. Finally, when multiple
primary outcome measures were examined in a sin-
gle study, our approach was to select a specific
measure for SMD calculation. Although some bias
may have been introduced by this selection, con-
cerns are mitigated by specific criteria used for out-
come measure selection.
In the light of the available evidence-base for
interventions targeting core and co-occurring psy-
chiatric symptoms in children with ASD, treating
clinicians must undertake careful diagnostic evalua-
tion to characterize functionally impairing symp-
tom targets (including consideration of triggers,
exacerbating and alleviating factors) as an essential
first step in the clinical care of their patients. The
second step for management of difficulties encoun-
tered by individuals with ASD may then be the
development of a patient-centred treatment plan
based on the best available evidence. Discussion of
psychosocial, pharmacological and biomedical ther-
apeutic options with patients and families must be
undertaken to refine the plan and prioritize which
treatment options to pursue first. This process needs
to include: (i) careful evaluation of the current evi-
dence, (ii) discussion of risks and benefits of inter-
ventions, (iii) discussion of treatment expectations
and (iv) agreement on the use of objective outcome
measures to track therapeutic and adverse effects.
Advanced, individualized treatment planning is
imperative for effectively addressing target symp-
toms that cause impairment in children and adoles-
cents with ASD and promoting optimal
development and function across settings.
Declaration of interests
SA, CK, PC-D, LC, M-CL report no biomedical financial
interests or potential conflict of interests. JV has been a consul-
tant/received research funding from Roche, Novartis,
SynapDx, Seaside Therapeutics and Forest. He has received
honoraria for editorial activities with Springer and Wiley.
CUC has been a consultant and/or advisor to or has received
honoraria from: Alkermes, Allergan, Bristol-Myers Squibb,
Gerson Lehrman Group, IntraCellular Therapies, Janssen/
J&J, LB Pharma, Lundbeck, Medavante, Medscape, Neuro-
crine, Otsuka, Pfizer, Sunovion, Takeda and Teva. He has
394
provided expert testimony for Bristol-Myers Squibb, Janssen
and Otsuka. He served on a Data Safety Monitoring Board for
Lundbeck and Pfizer. He received grant support from Takeda.
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Supporting Information
Additional Supporting Information may be found in the online
version of this article:
Table S1. Social interaction and communication impairment.
Table S2. Stereotypic/Repetitive behavior.
Table S3. Irritability/Agitation.
Table S4. Attention Deficit/Hyperactivity Disorder (ADHD).
Table S5. Mood and anxiety.
Table S6. Sleep.
Appendix S1. Details on systematic search procedure.