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Journal of Child Psychology and Psychiatry **:* (2020), pp **–** doi:10.1111/jcpp.13305

PRACTITIONER REVIEW

Practitioner Review: Pharmacological treatment

of attention-deficit/hyperactivity disorder symptoms
in children and youth with autism spectrum disorder:
a systematic review and meta-analysis
Rebecca Rodrigues,1* Meng-Chuan Lai,2,3,4,5,6* Adam Beswick,1 Daniel A. Gorman,3,4
7 2,3,4
Evdokia Anagnostou, Peter Szatmari, Kelly K. Anderson,1,8* and
2,3,4
Stephanie H. Ameis *
1
Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University,
London, ON, Canada; 2The Margaret and Wallace McCain Centre for Child, Youth and Family Mental Health,
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada;
3
Centre for Brain and Mental Health, Department of Psychiatry, The Hospital for Sick Children, Toronto, ON,
Canada; 4Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 5Autism
Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, UK; 6Department of Psychiatry,
National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; 7Holland Bloorview Kids Rehabilitation
Hospital, Bloorview Research Institute, Department of Pediatrics, University of Toronto, Toronto, ON, Canada;
8
Department of Psychiatry, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada

Background: Clinically significant attention-deficit/hyperactivity disorder (ADHD) symptoms are common and
impairing in children and youth with autism spectrum disorder(ASD). The aim of this systematic review and meta-
analysis was to (a) evaluate the efficacy and safety of pharmacotherapy for the treatment of ADHD symptoms in ASD
and (b) distil findings for clinical translation. Methods: We searched electronic databases and clinical trial registries
(1992 onwards). We selected randomized controlled trials conducted in participants <25 years of age, diagnosed with
ASD that evaluated ADHD outcomes (hyperactivity/impulsivity and inattention) following treatment with stimulants
(methylphenidate or amphetamines), atomoxetine, alpha-2 adrenergic receptor agonists, antipsychotics, tricyclic
antidepressants, bupropion, modafinil, venlafaxine, or a combination, in comparison with placebo, any of the listed
medications, or behavioral therapies. Data were pooled using a random-effects model. Results: Twenty-five studies
(4 methylphenidate, 4 atomoxetine, 1 guanfacine, 14 antipsychotic, 1 venlafaxine, and 1 tianeptine) were included.
Methylphenidate reduced hyperactivity (parent-rated: standardized mean difference [SMD] = .63, 95%
CI = .95, .30; teacher-rated: SMD = .81, 95%CI = 1.43, .19) and inattention (parent-rated: SMD = .36,
95%CI = .64, .07; teacher-rated: SMD = .30, 95%CI = .49, .11). Atomoxetine reduced inattention (parent-
rated: SMD = .54, 95%CI = .98, .09; teacher/investigator-rated: SMD = 0.38, 95%CI = 0.75, 0.01) and
parent-rated hyperactivity (parent-rated: SMD = .49, 95%CI = .76, .23; teacher-rated: SMD = .43, 95%
CI = .92, .06). Indirect evidence for significant reductions in hyperactivity with second-generation antipsychotics
was also found. Quality of evidence for all interventions was low/very low. Methylphenidate was associated with a
nonsignificant elevated risk of dropout due to adverse events. Conclusions: Direct pooled evidence supports the
efficacy and tolerability of methylphenidate or atomoxetine for treatment of ADHD symptoms in children and youth
with ASD. The current review highlights the efficacy of standard ADHD pharmacotherapy for treatment of ADHD
symptoms in children and youth with ASD. Consideration of the benefits weighed against the limitations of safety/
efficacy data and lack of data evaluating long-term continuation is undertaken to help guide clinical decision-making
regarding treatment of co-occurring ADHD symptoms in children and youth with ASD. Keywords: Attention-deficit/
hyperactivity disorder; ADHD; hyperactivity; impulsivity; inattention; autism spectrum disorder; pervasive
developmental disorder; pharmacotherapy; stimulants; atomoxetine; alpha-2 agonists; antipsychotics; tricyclic
antidepressants; venlafaxine; bupropion; modafinil..

Szatmari, 2015; Gillberg, 2010; Lai, Lombardo, &

Introduction
Autism spectrum disorder (ASD) is an early-onset
neurodevelopmental disorder characterized by a
high co-occurrence (>70%) of other neurodevelop-
mental and psychiatric challenges (Ameis &
*Authors contributed equally to this work.
Conflict of interest statement: See Acknowledgements for full
disclosures.
Baron-Cohen, 2014; Soke, Maenner, Christensen,
Kurzius-Spencer, & Schieve, 2018). The latest sys-
tematic review and meta-analysis indicated that in
population-based cohorts, 22% (95% confidence
interval, 95%CI 17%–26%) of individuals with ASD
meet the clinical criteria for attention-deficit/hyper-
activity disorder (ADHD), and the rate is even higher
in samples recruited from clinical settings (34%,
95%CI 29%–39%; Lai et al., 2019). Correspondingly,

© 2020 Association for Child and Adolescent Mental Health

Published by John Wiley & Sons Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main St, Malden, MA 02148, USA
2 Rebecca Rodrigues et al.
in children and adolescents with ADHD, 21% (95%CI
18%–24%) reach the diagnostic threshold for ASD
(Hollingdale et al., 2019). Dimensional traits of ASD
and ADHD also co-occur in the general population
(Polderman et al., 2014; Stergiakouli et al., 2017).
The co-occurrence of ASD and ADHD is also associ-
ated with greater impairment in adaptive functioning
and poorer health-related quality of life (Sikora,
Vora, Coury, & Rosenberg, 2012).
There may be a number of mechanisms resulting
in these high rates of phenotypic co-occurrence of
ADHD in individuals with ASD. Both ASD and ADHD
are common (Christensen et al., 2018; Willcutt,
2012) and highly heritable neurodevelopmental con-
ditions (Palladino, McNeill, Reif, & Kittel-Schneider,
2019; Sandin et al., 2017). Large-scale population
and registry-based studies consistently show famil-
ial coaggregation of ASD and ADHD clinical diag-
noses and dimensional traits (Ghirardi et al., 2018;
Ghirardi et al., 2019; Miller et al., 2019), indicative of
shared underlying etiological (e.g., genetic) factors.
Overlapping biological pathways cutting across ASD
and ADHD may involve overlapping rare mutations
in the form of copy number variants (Martin et al.,
2014), with effects on specific genetic pathways that
regulate neural migration and synaptic development
(Lionel et al., 2014). Nondistinct social cognitive
(Bora and Pantelis 2016) and executive functioning
characteristics (Craig et al., 2016) across samples
with ASD or ADHD may also be linked to similar
large-scale neural network properties found across
children with either diagnosis (Ameis et al., 2016;
Aoki et al., 2017; Di Martino et al., 2013). Conver-
gent findings are thus suggestive of shared neurode-
velopmental pathways that may confer risk for either
(or both) disorder(s) (Miller et al., 2019).
To date, one national guideline (National Institute
for Health & Care Excellence, 2013), five systematic
reviews (Cortese, Castelnau, Morcillo, Roux, & Bon-
net-Brilhault, 2012; Ghanizadeh, 2013; Mahajan
et al., 2012; Patra, Nebhinani, Viswanathan, &
Kirubakaran, 2019; Reichow, Volkmar, & Bloch,
2013), and three Cochrane reviews (James, Mont-
gomery, & Williams, 2011; Millward, Ferriter, Calver,
& Connell-Jones, 2008; Sturman, Deckx, & van
Driel, 2017) have evaluated the available literature
on the efficacy of pharmacological or other biomed-
ical interventions for ADHD symptoms in children
with ASD. These reviews largely include empirical
studies published up to 2013 and highlight (a)
evidence that methylphenidate and atomoxetine
improve symptoms of hyperactivity and possibly
inattention in children with ASD (Patra et al., 2019;
Sturman et al., 2017) and (b) a lack of evidence for
improvement of ADHD symptoms in ASD with
omega-3 fatty-acid supplements or gluten/casein-
free diets.
In addition, the Autism Treatment Network (ATN)
Psychopharmacology Committee published two rec-
ommended clinical pathways, one guiding symptom
evaluation and the other medication choice, based on
their review of studies published between 2000 and
2010 (Mahajan et al., 2012). Their recommendations
include initial optimization of medical, mental health,
and educational/behavioral interventions, followed
by first-line medication treatment with methylpheni-
date or amphetamine salts, second-line treatment
with atomoxetine or alpha-2 agonists (guanfacine or
clonidine), and reserved use of atypical antipsychotics
for children with severe impulsivity and associated
safety concerns (Mahajan et al., 2012).
The current literature suggests that additional
resources to guide clinical care for co-occurring
ASD and ADHD are needed for the following reasons.
First, psychotropic prescription rates are increasing
in children diagnosed with ASD (Dalsgaard, Nielsen,
& Simonsen, 2013; Frazier et al., 2011; Kamimura-
Nishimura et al., 2017). ADHD is the most common
co-occurring mental health diagnosis driving
increased rates of psychotropic drug use (Jobski,
H€ofer, Hoffmann, & Bachmann, 2017; Kamimura-
Nishimura et al., 2017) as well as long-term psy-
chotropic use (Houghton, Liu, & Bolognani, 2018).
Rates of polypharmacy in children with ASD are high
(Jobski et al., 2017). Finally, a variety of medication
classes are being prescribed, without established
evidence to support their use (Frazier et al., 2011;
Houghton et al., 2018; Jobski et al., 2017).
Since the publication of the aforementioned
reviews on the efficacy of pharmacological interven-
tions for ADHD symptoms in children with ASD, new
empirical studies are available that examine efficacy
of additional medications (Loebel et al., 2016;
McDougle, 2017; Scahill et al., 2015) enabling
meta-analysis and presentation of clinical effects
across different medication classes to inform clinical
recommendations. As prior meta-analyses on this
topic provide quantitative analysis of the evidence for
a single medication class (Reichow et al., 2013, Patra
et al., 2019, Sturman et al., 2017) and prior clinical
guidance is based on a systematic review of roughly
half of currently available RCTs, an updated system-
atic review and meta-analysis across different med-
ication classes and clinical interpretation would
provide valuable practical guidance for front-line
clinicians.
The present systematic review and meta-analysis
aims to synthesize and re-evaluate randomized con-
trolled trials (RCTs) for this indication, including all
relevant studies. We aim to update and expand on
previously published reviews to provide one compre-
hensive resource (with clear clinical utility) evaluat-
ing the following: (a) all available RCTs testing
efficacy of pharmacological treatments for ADHD
symptoms in children and youth with ASD, (b)
efficacy of medication treatment on secondary out-
comes relevant to general functioning, and (c) rates
of adverse events with treatment. Evidence for effi-
cacy is distilled, and recommendations for best
clinical practice are provided.
© 2020 Association for Child and Adolescent Mental Health

Methods
Protocol and registration
Prior to conducting this review, we published our protocol on
the International Prospective Register of Systematic Reviews
(PROSPERO; http://www.crd.york.ac.uk/prospero; protocol
number CRD42016052610). We adhered to the Preferred
Reporting Items for Systematic Review and Meta-Analyses
(PRISMA) guidelines (Moher et al., 2009).
Search strategy
We searched MEDLINE, Embase, CINAHL, PsycINFO, ERIC,
Cochrane Library, Web of Science, ClinicalTrials.gov (www.c
linicaltrials.gov), and the World Health Organization Interna-
tional Clinical Trials Registry Platform (WHO IRCTP; http://
www.who.int/ictrp/en/) from 1992 onwards. The MEDLINE
search strategy is available in the online supplement
(Appendix S1). We conducted forward and backward citation
searching of included studies and related systematic reviews
(Barnard, Young, Pearson, Geddes, & O’Brien, 2002; Cohen
et al., 2013; Deb et al., 2014; Fung et al., 2016; Ghanizadeh,
2013; Ghanizadeh, Tordjman, & Jaafari, 2015; Hirsch &
Pringsheim, 2016; Hurwitz, Blackmore, Hazell, Williams, &
Woolfenden, 2012; Mahajan et al., 2012; Reichow et al., 2013;
Sharma & Shaw, 2012; Siegel & Beaulieu, 2012; Sochocky &
Milin, 2013). We manually searched tables of contents of
relevant journals from 1992 onwards. We contacted authors of
abstracts or unpublished studies to determine whether studies
had subsequently been published in a peer-reviewed journal.
Our search was completed in April 2018.
Eligibility criteria and outcome measures
We considered RCTs including participants up to age 25 years
of age, diagnosed with a pervasive developmental disorder or
ASD according to the Diagnostic and Statistical Manual of
Mental Disorders, Fourth (DSM-IV) or Fifth editions (DSM-5),
or International Classification of Diseases, Tenth Revision
(ICD-10) criteria. Eligible interventions included amphetamine
salts and methylphenidate-based stimulants, atomoxetine,
alpha-2 adrenergic receptor agonists (guanfacine and cloni-
dine), antipsychotics (all first- and second-generation antipsy-
chotics listed in MEDLINE/Embase), tricyclic antidepressants
(all drugs under this category listed in MEDLINE/Embase),
bupropion, modafinil, or venlafaxine. We included studies that
used placebo, behavioral therapies (e.g., parent training), or
any of the aforementioned medications as comparators. We
excluded studies where one of the listed interventions was
used as an adjunctive treatment. We included studies evalu-
ating our primary outcome of ADHD symptoms (hyperactivity/
impulsivity and inattention) at any follow-up time point and
with any effect measure. Secondary outcomes included Clin-
ical Global Impression (CGI) rating scales (CGI-Improvement
[CGI-I] and CGI-Severity [CGI-S]), oppositional defiant disorder
(ODD) symptoms, parent–child interaction, parent/caregiver
stress, quality of life (QoL), cognitive functioning, and adaptive
functioning. Additional secondary outcomes were rates of
adverse events (AEs), serious AEs, and dropouts due to AEs.
Selection of studies
Retrieved citations were imported into Covidence for screening
(https://www.covidence.org/). One reviewer conducted title
and abstract screening (RR), and two reviewers (RR and AB)
each independently conducted full-text screening on every
article retrieved. Articles were selected for inclusion at the full-
text stage if they met our eligibility criteria. Disagreements
between reviewers (n = 64) were largely due to ambiguities in
© 2020 Association for Child and Adolescent Mental Health
Treating ADHD symptoms in autism 3
the inclusion criteria (e.g., whether studies including a placebo
versus an active comparator group should be included) and
were resolved through discussion among the research team
and further clarification of the criteria. Studies were included
in meta-analyses where data were available and where study
design and populations were comparable for pooling.
Data extraction
One author (RR) conducted a double data extraction using a
piloted data extraction sheet. Information on the study design,
participants, interventions (i.e., doses and form of administra-
tion), methods, baseline characteristics, and results was
extracted. Data on primary and secondary outcome measures,
including scales used, rater(s), follow-up, statistical analyses,
and results, were also extracted. Corresponding authors of
included studies were contacted when missing data were
encountered or for studies where point estimates were not
provided for our primary outcome measures.
Risk-of-bias assessment
Risk of bias was assessed using the Cochrane Risk of Bias
Assessment tool (Higgins & Green, 2011). Two authors (RR and
AB) independently rated each study as having low, high, or
unclear risk of bias for each domain: random sequence
generation, allocation concealment, blinding of participants
and personnel, blinding of outcome assessment, incomplete
outcome data, selective reporting, and other sources of bias,
such as industry funding. For risk-of-bias domains where
assessment of risk of bias may vary by outcome (e.g., blinding
of outcome assessment), we assessed risk of bias in terms of
our primary outcomes of ADHD symptoms. Disagreements
were discussed (among RR, AB, KKA) until a consensus was
reached.
Data synthesis and analysis
For ADHD outcome synthesis, where more than one measure
for the same symptom domain was included, the stated
primary outcome measure from each study was used for
meta-analyses. As in a previous review (Sturman et al., 2017),
clinician or other investigator ratings were combined with
teacher ratings in meta-analyses of ADHD symptoms, and
parent ratings were considered separately. For AEs, we pooled
findings wherever possible, regardless of rater.
For crossover studies, we calculated standardized mean
differences (SMD) for continuous outcomes, including ADHD
symptoms, using methods outlined in the Cochrane Handbook
for Systematic Reviews of Interventions (Higgins & Green,
2011). For parallel studies, SMDs for continuous outcomes
were calculated using Cohen’s d (Cohen, 1988). Effect sizes of
SMD = .2, .5, and .8 were considered to represent small,
medium, and large effects, respectively (Cohen, 1988). For
both crossover and parallel studies, we calculated mean
differences (MD) where the same scale was used, indicating
the absolute difference between groups on the scale used. For
crossover studies, we estimated or imputed correlation coef-
ficients in order to calculate standard errors that account for
the paired within-individual treatment comparisons (Elbourne
et al., 2002; Higgins & Green, 2011). Methods for estimating
and imputing correlation coefficients are detailed in the online
supplement (Appendix S2). We conducted sensitivity analyses
examining the impact of different correlation coefficient values
on our findings. For dichotomous outcomes, such as AEs, risk
differences (RD) were estimated by calculating the proportion
of patients in each treatment and comparison group who
experienced the event/outcome and calculating the difference
in proportions between groups. In studies where multiple
fixed doses were administered, treatment effects across dose
4 Rebecca Rodrigues et al.
groups were combined into one average using established
methods for parallel (Higgins & Green, 2011) and crossover
studies (Borenstein, Hedges, Higgins, & Rothstein, 2009).
Continuous outcomes were pooled using the generic inverse
variance (for analyses with crossover studies) or inverse
variance methods (for parallel studies), and dichotomous
outcomes were pooled using the Mantel-Haenszel method in
Review Manager, version 5.3. A random-effects model was
applied to all pooled data. Effects with two-sided 95% confi-
dence intervals (CI) excluding unity were considered statisti-
cally significant.
Heterogeneity was assessed using the I2 value with the
following cut-offs: 0%-25%=heterogeneity may not be impor-
tant; 25%–50% = moderate heterogeneity; 50%–75% =sub-
stantial heterogeneity, and 75%-100%=considerable
heterogeneity (Higgins & Green, 2011). Post hoc analyses to
explore potential sources of heterogeneity were conducted,
including a subgroup analysis of methylphenidate studies by
dose, and pooling ADHD outcomes assessed using the same
methods (i.e., same rater and scale). Given the small number of
studies in each intervention group (<10), neither publication
bias assessment nor risk-of-bias sensitivity analyses were
conducted.
Quality of evidence
Quality of evidence of included studies was assessed for
primary outcomes using the Grading of Recommendations
Assessment, Development and Evaluation (GRADE) Working
Group domains: study limitations, consistency of effect,
imprecision, indirectness, and publication bias. We rated the
quality of evidence as being high, moderate, low, or very low
(Higgins & Green, 2011). Two authors (RR and AB) discussed
the quality of evidence for ADHD outcomes within each domain
and reached a consensus. GRADEpro software was used to
create summary of findings tables (https://gradepro.org/).
Clinical interpretation of the evidence
Clinical recommendations and a figure depicting stepwise
suggestions for medication choice were drafted (by SHA)
following synthesis of the research evidence. This draft under-
went further review by M-CL. Drafts were then circulated to all
coauthors for discussion and revision. Where evidence gaps
were present, decisions were made regarding in text guidance
and each step of the stepwise medication choice pathway
based on collective clinical experience across coauthors (DAG,
PS, M-CL, EA, SHA) as well as consulting prior guidance in the
general ADHD treatment literature (i.e., without ASD). Pre-
sented recommendations are based on consensus agreement
across coauthors.
Results
Selection of studies and study characteristics
Our search retrieved 1,739 unique citations, of
which 126 were reviewed as full-text (Figure 1).
Twenty-five studies, published across 38 articles,
met our inclusion criteria. Attempts to obtain miss-
ing data and unpublished reports are summarized in
Table S1. Characteristics of studies and participants
are summarized in Table 1; detailed summaries of
individual study characteristics are available in the
online supplement. Interventions from placebo-con-
trolled studies included methylphenidate (4 studies;
Table S2; Ghuman et al., 2009; Handen, Johnson, &
Lubetsky, 2000; Jahromi et al., 2009; Pearson et al.,
2013; Posey et al., 2007; Research Units on Pediatric
Psychopharmacology (RUPP) Autism Network,
2005), atomoxetine (4 studies; Table S3; Arnold
et al., 2006; Handen et al., 2015; Harfterkamp
et al., 2012, 2014; Lecavalier et al., 2018; McDougle
et al., 2017; Smith et al., 2016; Tumuluru et al.,
2017; van der Meer et al., 2013), guanfacine (1
study; Table S4; Scahill et al., 2015), aripiprazole (4
studies; Table S5; Findling et al., 2014; Ichikawa
et al., 2017; Marcus et al., 2009; Owen et al., 2009;
Varni et al., 2012), risperidone (6 studies; Table S5;
Aman et al., 2008; Janssen Pharmaceutical K.K.,
2015; Kent et al., 2013; McDougle et al., 2005;
Nagaraj, Singhi, & Malhi, 2006; Research Units on
Pediatric Psychopharmacology (RUPP) Autism Net-
work, 2002; Shea et al., 2004; Troost et al., 2005,
2006), and lurasidone (1 study; Table S5; Loebel
et al., 2016). Two studies were head-to-head trials of
aripiprazole versus risperidone (Table S5; Gha-
nizadeh, Sahraeizadeh, & Berk, 2014; Lamberti
et al., 2016). An individual study investigating olan-
zapine versus haloperidol (Malone, Cater, Sheikh,
Choudhury, & Delaney, 2001) and individual pla-
cebo-controlled crossover trials of tianeptine (Nieder-
hofer, Staffen, & Mair, 2003) and venlafaxine
(Niederhofer, 2004) were also included. Given their
small sample sizes (n ≤ 14), findings from these
three studies are presented in Tables S6–S12. No
studies examining amphetamines, clonidine, mod-
afinil, or bupropion met our inclusion criteria. Par-
ticipants across studies were primarily male (~80%).
The mean age across studies ranged from 8 to
10 years. Intelligence quotient (IQ) of participants
was not consistently reported across studies. Mean
IQ of participants was 67 for methylphenidate stud-
ies (2 studies). Mean IQ of participants was 85 in
atomoxetine studies (3 studies). Studies of methyl-
phenidate, guanfacine, atomoxetine, aripiprazole,
and risperidone reported inclusion of participants
with wide ranging intellectual ability (see Table S5
for reported data, including percentage of partici-
pants reported to be in average IQ range, as well as
borderline, mild/moderate, or severe range for intel-
lectual disability).
Risk of bias of included studies is summarized in
Figures S1 and S2. Risk of bias was unclear in
approximately half of studies for random sequence
generation, allocation concealment, and blinding
domains. High risk of bias was most evident in
‘other bias’ due to pharmaceutical funding (Heres
et al., 2006; Lundh, Lexchin, Mintzes, Schroll, &
Bero, 2017; Spielmans & Parry, 2010) for 2/4
atomoxetine studies (Arnold et al., 2006; Harfter-
kamp et al., 2012), all aripiprazole studies (Findling
et al., 2014; Ichikawa et al., 2017; Marcus et al.,
2009; Owen et al., 2009), 3/6 risperidone studies
(Janssen Pharmaceutical K.K., 2015; Kent et al.,
2013; Shea et al., 2004), and the lurasidone study
(Loebel et al., 2016).
© 2020 Association for Child and Adolescent Mental Health
 Treating ADHD symptoms in autism 5

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for study selection. ARI,
aripiprazole; ATX, atomoxetine; MPH, methylphenidate; RIS, risperidone. aTwenty-five studies were included that were published across
38 articles; b4 MPH studies were included that were published across 5 articles; c4 ATX studies were included that were published across
five articles

Evidence synthesis Methylphenidate

Findings for ADHD outcomes are summarized in
Figure 2. Forest plots for meta-analyses (Fig-
ures S3–S5), GRADE summary of findings tables
(Tables S13–S19), secondary outcome findings from
individual studies (Table S20), and sensitivity anal-
yses (Tables S22–S25) are presented in the online
supplement.
Four studies provided data for ADHD outcomes
(Ghuman et al., 2009; Handen et al., 2000; Pearson
et al., 2013; RUPP, 2005). All four studies used a
crossover design, and study duration was short
(limited to 1–2 weeks). Three of four studies admin-
istered fixed doses (two to three dose levels). Treat-
ment effects were therefore averaged across each

© 2020 Association for Child and Adolescent Mental Health

 6
Table 1 Characteristics of included RCTs and pooled samples

Methylphenidate Atomoxetine vs. Aripiprazole vs. Risperidone vs. Aripiprazole vs. Lurasidone vs. Guanfacine vs.
vs. placebo placebo placebo placebo risperidone placebo placebo

RCT features
No. RCTs
RCT design (no. RCTs)
Country (no. RCTs)
4 4 3 2 2 1 1
Crossover (4) Crossover (1), Parallel (3) Parallel (2) Parallel (2) Parallel (1) Parallel (1)
parallel (3)
United States (4) United States (3), United States (2), United States (1), Iran (1), Italy (1) United States (1) United States (1)
Netherlands (1) Japan (1) Canada (1)
Rebecca Rodrigues et al.

No. of sites 8 14 107 12 2 40 5

Industry funding 0/4 RCTs 2/4 RCTs 3/3 RCTs 1/2 RCTs 0/2 RCTs 1/1 RCT 0 /1 RCT
Setting Outpatient (3), Not reported Inpatient/ Outpatient (1), Outpatient (1), not Outpatient Outpatient
inpatient/ outpatient (1), inpatient/ reported (1)
outpatient (1) not reported (2) outpatient (1)
Treatment duration 1–2 weeks 6–10 weeks 8 weeks 8 weeks 8–24 weeks 6 weeks 8 weeks
Dose Range: Mean (SD): Mean (SD): Mean (SD): Mean (SD): 20 mg/day Mode:
0.125 to 0.50 mg/ 1.3 (0.3) mg/kg/ 8.8 (5.0) mg/day 1.7 (0.7) mg/day 6.0 (3.3) mg/day 3 mg/day
kg/dose daya aripiprazole, 1.4
(0.8) mg/day
risperidone
No. RCTs with ADHD 4 4 0 0 1 0 1
symptoms as primary
outcome
Participant features
N 117 237 408 180 103 150 62
Age, mean (SD), range 7.4 (2.2), 3–14 9.2 (2.7), 5–17 9.7 (3.1), 6–17 8.2 (2.6), 5–17 8.9 (3.5), 4–18 10.7 (3.0), 6–17 8.5 (2.3), 5–14
Male, n (%) 101 (86) 200 (84) 356 (87) 143 (79) 83 (81) 122 (81) 53 (85)
Diagnosis, n (%)
Autistic disorder 80 (68) 119 (50) 408 (100) 156 (87) 38 (65)b 150 (100) 51 (82)
Asperger’s 8 (7) 31 (13) 0 (0) 12 (7) 8 (13)b 0 (0) 2 (3)
PDD-NOS 27 (23) 85 (36) 0 (0) 11 (6) 9 (16)b 0 (0) 9 (15)
CDD 0 (0) 0 (0) 0 (0) 1 (1) 0 (0)b 0 (0) 0 (0)
No ASD 2 (2) 2 (1) 0 (0) 0 (0) 1 (2)b 0 (0) 0 (0)
IQ, mean (SD) 68.6 (31.0)c 86.3 (20.5) Not reported Not reported Not reported Not reported Not reported
Average, n (%) 1 (8)d Not reported 34 (37) 19 (12) 21 (34)
Borderline, n (%) 1 (8)d 22 (14)
Mild, n (%) 3 (23)d 32 (35)e 85 (54) 39 (63)
Moderate, n (%) 5 (38)d 14 (15)e
Severe, n (%) 3 (23)d 12 (13)e 31 (20)

ASD, autism spectrum disorder; CDD childhood disintegrative disorder; PDD-NOS, pervasive developmental disorder not otherwise specified; RCT, randomized controlled trial.
a
Pooled from 3/4 RCTs (Handen et al., 2015; Harfterkamp et al., 2012; McDougle et al., 2017) – Arnold et al., 2006 reported dose in mg/day (mean [standard deviation] final dose was 44.2
[21.9] mg/day).
b
Estimates include 1 of 2 RCTs (Ghanizadeh et al.2014).
c
Mean from 2 RCTs (RUPP2005 and Pearson et al.2013).
d
From 1 RCT (Handen et al., 2000).
e
1 of 3 RCTs reported IQ (Ichikawa et al.2017).

© 2020 Association for Child and Adolescent Mental Health

 Treating ADHD symptoms in autism 7

Figure 2 Effect sizes (pooled and individual studies) and quality of evidence for the effects of each intervention on ADHD symptoms. RCT
indicates randomized controlled trial; SMD standardized mean difference; CI confidence interval. aSMD not estimable due to reporting of
postintervention and change from baseline findings in each study, however, mean difference (MD) findings significant on the Aberrant
Behavior Checklist hyperactivity subscale (MD = 8.98, 95%CI = 12.02, 5.94, I2 = 20%, very low quality of evidence)

dose for these studies (Handen et al., 2000; Pearson
et al., 2013; RUPP, 2005). Methylphenidate reduced
hyperactivity compared to placebo, with medium to
large effect sizes (parent-rated: SMD = .63, 95%CI
.95, .30, I2 = 60%, low quality of evidence;
teacher-rated: SMD = .81, 95%CI 1.43, .19,
I2 = 86%, very low quality of evidence), and had
small effects on inattention (parent-rated:
SMD = .36, 95%CI .64, .07, I2 = 67%, low qual-
ity of evidence; teacher-rated: SMD = .30, 95%CI
.49, .10, I2 = 57%, low quality of evidence).
Methylphenidate also had medium-sized effects on
total ADHD symptoms (parent-rated: SMD = .60,
95%CI .96, .23, I2 = 72%, very low quality of
evidence; teacher-rated: SMD = .55, 95%CI 1.11,
0.00, I2 = 92%, very low quality of evidence). Sub-
group analysis indicated that effect sizes were
consistently lower with low (as opposed to medium
or high-dose treatment; low = .11 to .21 mg/kg/
dose, medium = .22 to .36 mg/kg/dose, high = .43
to .6 mg/kg/dose; Figures S6-S8). In addition,
methylphenidate was associated with small improve-
ments in ODD symptoms, though the 95%CI indi-
cated a range of possible effects that crossed the line
of no effect (Figure S9), and large effects on CGI-I
and CGI-S scores (Figure S10).
Atomoxetine
Four studies (6–10 weeks duration) compared the
effects of atomoxetine versus placebo on ADHD
symptoms (Arnold et al., 2006; Handen et al.,
2015; Harfterkamp et al., 2012, 2014; McDougle,
2017). Atomoxetine improved hyperactivity with

© 2020 Association for Child and Adolescent Mental Health

8 Rebecca Rodrigues et al.
small to medium effect sizes (parent-rated:
SMD = .49, 95%CI .76, .23, I2 = 0%, low quality
of evidence; teacher-rated: SMD = .43, 95%CI
.92, .06, I2 = 65%, low quality of evidence). Ato-
moxetine improved inattention with small to med-
ium-sized effects shown (parent-rated: SMD = .54,
95%CI .98, .09, I2 = 0%, low quality of evidence;
teacher/investigator-rated: SMD = .38, 95%CI
.75, .01, I2 = 40%, low quality of evidence). For
total ADHD symptoms, parent ratings from a single
study demonstrated a medium to large effect
(SMD = .71, 95%CI 1.29, .13, I2 = N/A, low
quality of evidence) and pooled teacher/investigator
ratings showed a small effect of atomoxetine
(SMD = .44, 95%CI .93, .06, I2 = 66%, very low
quality of evidence). Removal of the crossover study
from the pooled analysis did not change our findings
(Table S24). In a double-blind extension, no signif-
icant difference was observed with atomoxetine
compared to placebo at 24 weeks, likely due to the
inclusion of only placebo responders in the compar-
ison group (Smith et al., 2016). Atomoxetine did not
improve ODD symptoms (parent-rated SMD = .07,
95%CI .41, .27; teacher-rated SMD = .1, 95%
CI .32, .13, Figure S11). A small effect of atomox-
etine compared to placebo on the rate of positive
response on the CGI-I (very much or much improved)
was found (SMD = .19, 95%CI .05, .33, Figure S12).
In cognitive tests assessing response inhibition,
atomoxetine showed a small effect in improving
errors of commission (SMD = .36, 95%CI .74,
.02), but not omission (Figure S13).
Alpha-2 agonists
In one available study (8 weeks duration; Scahill
et al., 2015), treatment with guanfacine immediate
release resulted in large effects on hyperactivity
(parent-rated: SMD = .93, 95%CI 1.45, .40,
I2 = N/A, very low quality of evidence; investigator-
rated: SMD = 1.35, 95%CI 1.91, .80, I2 = N/A,
very low quality of evidence), inattention (parent-
rated: not measured; investigator-rated:
SMD = .81, 95%CI 1.33, .29, I2 = N/A, very
low quality of evidence), and total ADHD symptoms
(parent-rated: not measured; investigator-rated:
SMD = 1.20, 95%CI 1.75, .66, I2 = N/A, very
low quality of evidence). Guanfacine improved CGI-I
response compared to placebo (RD = .41, 95%CI .2,
.61, and small effects were seen on some cognitive
measures (Table S20).
Second-generation antipsychotics
With the exception of one trial of aripiprazole versus
risperidone (Lamberti et al., 2016), all antipsychotic
studies were designed to evaluate the treatment of
significant irritability in children with ASD; hyper-
activity was a secondary outcome and inattention
was not evaluated.
Two aripiprazole studies used flexible dosing
(Ichikawa et al., 2017; Owen et al., 2009), and one
had three fixed dose groups (Marcus et al., 2009);
therefore, we calculated a combined treatment effect
across the three dose groups for this study. Pooled
findings from three studies of aripiprazole versus
placebo (Ichikawa et al., 2017; Marcus et al., 2009;
Owen et al., 2009) showed that patients treated with
aripiprazole experienced a decrease, with a medium
to large effect size, in parent-rated hyperactivity on
the Aberrant Behavior Checklist (ABC) subscale
(SMD = .73, 95%CI .95, .51, I2 = 0%;
MD = 7.96, 95%CI 10.26, 5.66, I = 0%, low 2
quality of evidence). A randomized discontinuation
study included children with ASD and irritability
that were responders to aripiprazole on irritability
outcomes. In this study, a decrease in ABC hyper-
activity over 6–9 months was found in children who
were randomized to ongoing aripiprazole treatment
compared to a switch to placebo (MD = 5.20, 95%
CI 10.20, .20, I2 = N/A; Findling et al., 2014).
Aripiprazole treatment also improved emotional and
cognitive functioning on pediatric QoL scales; how-
ever, no effect was observed on social functioning or
total scores (Figure S14). Aripiprazole treatment also
reduced caregiver strain (Figure S15).
Risperidone improved parent-rated ABC hyperac-
tivity in pooled findings from two studies (SMD = not
estimable; MD = 8.98, 95%CI 12.01, 5.94,
I2 = 20%, very low quality of evidence; RUPP, 2002;
Shea et al., 2004). We were unable to include three
similar studies in the meta-analysis because of
reporting differences; however, descriptive findings
indicated a significant improvement in hyperactivity
with risperidone (Janssen Pharmaceutical K.K.,
2015; Kent et al., 2013; Nagaraj et al., 2006). Long-
term findings from a double-blind discontinuation
study in risperidone responders following a 24-week
open-label trial showed no difference in hyperactivity
scores in participants randomized to risperidone
continuation (n = 12) versus placebo (n = 12) at
32 weeks (Troost et al., 2005). We were unable to
pool available secondary outcomes (cognitive and
adaptive functioning); see supplement for findings
(Table S20).
Individual studies that were limited in sample size
(i.e., n = 59, 44, respectively) compared aripiprazole
versus risperidone (Ghanizadeh et al., 2014; Lam-
berti et al., 2016) and lurasidone versus placebo
(Loebel et al., 2016). No significant difference was
observed on any ADHD outcome for either compar-
ison (very low quality of evidence; Figure 2).
Adverse events
In pooled findings from four studies (Ghuman et al.,
2009; B L Handen et al., 2000; Pearson et al., 2013;
RUPP, 2005), methylphenidate was associated with
an increased risk of dropout due to AEs (RD = .08,
95%CI .02, .17, I2 = 30%). No other drug was
© 2020 Association for Child and Adolescent Mental Health

associated with increased risk of discontinuation. No
serious AEs were reported with methylphenidate.
Serious AEs were reported with atomoxetine (1
event; hospitalization for aggression; Arnold et al.,
2006), guanfacine (1 event; hospitalization for
aggression; Scahill et al., 2015), aripiprazole (2
events; 1 presyncope, 1 aggression; Marcus et al.,
2009), and lurasidone (5 events; 3 arm fractures, 1
irritability, 1 appendicitis; Loebel et al., 2016). No
serious AEs were reported with risperidone; how-
ever, there were 5 events reported as severe (1
hyperkinesia, 1 weight gain, 2 somnolence, 1 aggres-
sive reaction with impaired concentration, and 1
extrapyramidal disorder as a result of accidental
overdose; Shea et al., 2004).
Statistically significant findings from pooled and
individual studies for specific AEs are summarized in
Table 2. Complete findings for all AEs are available
in Tables S26–S32. Methylphenidate was associated
with a higher risk of decreased appetite, sleep
disturbance, and risk was higher with medium and
high doses. Atomoxetine was associated with a
higher risk of decreased appetite (RD = .21, 95%CI
.12, .31, I2 = 0%) and of abdominal discomfort
(RD = .11, 95%CI .01, .22, I2 = 59%) and nausea
(RD = .12, 95%CI .02, .25, I2 = 60%). A number of
statistically significant AEs were observed with
guanfacine (Table 2), however, the largest effects
were observed for drowsiness (RD = .77, 95%CI .61,
.93, I2 = N/A) and fatigue (RD = .54, 95%CI .34, .74,
I2 = N/A). Second-generation antipsychotics were
associated with a number of adverse events, includ-
ing gastrointestinal effects (vomiting, changes in
appetite), drowsiness, tremor, drooling, and weight
gain (Table 2, Tables S29-S32).
Discussion
We present an updated systematic review and meta-
analysis of the evidence for efficacy and tolerability of
all pharmacological agents studied in RCTs for the
treatment of ADHD symptoms in children and youth
with ASD. Our work is the first to synthesize the
evidence across different medication classes using a
meta-analytic approach. With respect to efficacy, we
examined not only symptomatic improvement in
inattention and hyperactivity, but also relevant
functional outcomes.
Summary of systematic review and meta-analysis
results
Current (low to very low quality) evidence, from
studies of short duration (1–2 weeks), indicates that
short-term methylphenidate treatment may have a
clinically meaningful effect on parent and teacher-
rated hyperactivity symptoms in school-age children
with ASD and variable IQ. Subgroup analysis by
dose indicates lower effect sizes with low dose
treatment. Observed effect sizes are larger for high
© 2020 Association for Child and Adolescent Mental Health
Treating ADHD symptoms in autism 9
dose (.43–.6 mg/kg/dose) compared to medium
(.22–.36 mg/kg/dose) dose treatment. Uncertainty
and heterogeneity in the effect estimates highlight
the need for further research to determine superior-
ity for high-dose treatment. Our findings are similar
to those in the recent Cochrane review of methyl-
phenidate treatment in ASD (Sturman et al., 2017).
In comparison with children with ADHD without
ASD, the magnitude of methylphenidate effects on
total ADHD symptom scores may be lower in chil-
dren with ASD (Storebø et al., 2015). Consistent with
a prior systematic review (Mahajan et al., 2012), the
current literature suggests that children with ASD
may be more likely to discontinue short-term
methylphenidate treatment compared to placebo
treatment. It is also important to note that AEs in
reviewed studies may be underestimated compared
to everyday practice as some trials excluded partic-
ipants that could not tolerate test doses of methyl-
phenidate.
Recently published studies examining efficacy of
atomoxetine in ASD enabled meta-analysis of the
same (or greater, depending on the examined out-
come) number of studies for atomoxetine compared
to methylphenidate and including more participants.
However, the overall quality of available evidence for
atomoxetine remains low. Our results were consis-
tent with those of Patra et al. (2019) showing
medium effects of atomoxetine on parent-rated inat-
tention. In contrast, effects on parent-rated hyper-
activity were smaller in the current study compared
to the previously published meta-analysis on this
topic (Patra et al., 2019). This difference may be due
to the inclusion of two additional studies in our
meta-analysis of atomoxetine effects on parent-rated
hyperactivity in ASD (Harfterkamp et al., 2012,
2014; McDougle, 2017), whereas our meta-analysis
of parent-rated inattention included the same stud-
ies submitted to meta-analysis previously (Patra
et al., 2019). Based on available evidence, effect
sizes for treatment efficacy with atomoxetine were
slightly smaller compared to methylphenidate and
perhaps less clinically meaningful based on avail-
able CGI-I data. One available study with a reason-
able sample size, relative to other studies published
across the ASD treatment literature (Ameis et al.,
2018), provides support for the efficacy of guanfacine
treatment on ADHD symptoms in children with
autism (Scahill et al., 2015).
Randomized, controlled data on the effects of
risperidone or aripiprazole versus placebo on hyper-
activity are limited to studies focused on treatment of
significant irritability in children with ASD, where
hyperactivity was a secondary outcome; therefore,
results are exploratory and may not generalize to
children with ASD and ADHD symptoms without
significant irritability. Concerning metabolic, neuro-
logical, and other side effects are also reasons for
caution regarding the use of antipsychotic medica-
tions for treatment of ADHD symptoms (Ameis et al.,
10 Rebecca Rodrigues et al.

Table 2 Summary of statistically significant adverse events from pooled and individual RCTs

Comparison Outcome No. RCTs and sample size RD (95% CI)a I2

Methylphenidate vs. placebo
Atomoxetine vs. placebo
Guanfacine vs. placebo
Aripiprazole vs. placebo
Risperidone vs. placebo
Lurasidone vs. placebo
Decreased appetite 2 RCTs (90 patients) Low dose: 0.12 ( 0.15, 0.38) 84%
2 RCTs (101 patients) Medium dose: 0.23 (0.13, 0.33) 0%
2 RCTs (101 patients) High dose: 0.23 (0.11, 0.35) 14%
Sleep disturbance 2 RCTs (90 patients) Low dose: 0.09 (0.01, 0.17) 0%
2 RCTs (90 patients) Medium dose: 0.18 (0.09, 0.27) 0%
2 RCTs (74 patients) High dose: 0.15 (0.05, 0.25) 0%
Decreased appetite 4 RCTs (301 patients) 0.21 (0.12, 0.31) 0%
Drowsiness 1 RCT (62 patients) 0.77 (0.61, 0.93) N/A
Fatigue 1 RCT (62 patients) 0.54 (0.34, 0.74) N/A
Decreased appetite 1 RCT (62 patients) 0.37 (0.17, 0.57) N/A
Emotional/tearful 1 RCT (62 patients) 0.31 (0.10, 0.51) N/A
Dry mouth 1 RCT (62 patients) 0.37 (0.18, 0.55) N/A
Irritability 1 RCT (62 patients) 0.27 (0.07, 0.47) N/A
Anxiety 1 RCT (62 patients) 0.27 (0.09, 0.44) N/A
Mid-sleep awakening 1 RCT (62 patients) 0.24 (0.05, 0.42) N/A
10-point drop in systolic BP 1 RCT (62 patients) 0.25 (0.02, 0.49) N/A
Vomiting 3 RCTs (405 patients) 0.06 (0.00, 0.11) 0%
Decreased appetite 2 RCTs (308 patients) 0.07 (0.02, 0.12) 0%
Increased appetite 2 RCTs (313 patients) 0.07 (0.01, 0.14) 0%
EPS-related AEs 3 RCTs (405 patients) 0.07 (0.01, 0.12) 0%
Tremor 2 RCTs (313 patients) 0.10 (0.05, 0.14) 0%
Drooling 2 RCTs (313 patients) 0.09 (0.05, 0.13) 0%
Pyrexia 2 RCTs (313 patients) 0.08 (0.04, 0.13) 0%
Weight change (kg) 3 RCTs (405 patients) MD: 0.97 (0.54, 1.40) 0%
BMI change (kg/m2) 3 RCTs (405 patients) MD: 0.40 (0.18, 0.63) 0%
Increased appetite 4 RCTs (314 patients) 0.25 (0.12, 0.38) 61%
Drowsiness 4 RCTs (314 patients) 0.38 (0.07, 0.68) 93%
Tremor 2 RCTs (179 patients) 0.11 (0.04, 0.18) 0%
Tachycardia 2 RCTs (179 patients) 0.11 (0.04, 0.19) 0%
Weight gain 3 RCTs (214 patients) 0.10 (0.03, 0.17) 0%
Weight change (kg) 3 RCTs (274 patients) MD: 1.45 (0.97, 1.93) 16%
Vomiting 1 RCT (148 patients) 0.14 (0.05, 0.23) N/A
Nasopharyngitis 1 RCT (148 patients) 0.08 (0.02, 0.14) N/A
Akathisia 1 RCT (148 patients) 0.06 (0.00, 0.12) N/A
Weight gain (kg) 1 RCT (148 patients) MD: 0.80 (0.25, 1.35) N/A

BMI, body mass index; BP, blood pressure; CI, confidence interval; EPS, extrapyramidal symptoms; MD, mean difference; RCT,
randomized controlled trial; RD, risk difference.
a
Positive risk difference favors intervention.

2013; Pagsberg et al., 2017). Nonetheless, pooled
findings from available data indicate large effects of
treatment on parent-rated hyperactivity.
Limitations of our systematic review and meta-
analysis
We observed substantial heterogeneity in the meta-
analysis of methylphenidate studies; however, inves-
tigation of dose and rating scales suggests that the
heterogeneity may be partially explained by these
factors. For continuous outcomes from crossover
studies, we imputed correlation coefficients to calcu-
late SMDs and standard errors. Since imputed cor-
relation coefficients can impact the magnitude of
SMDs, use of this method could impact our findings.
However, results from our sensitivity analyses exam-
ining the impact of different correlation coefficient
values (r = 0, .5, .8) did not change our findings. We
were unable to impute correlation coefficients for
binary outcomes and analyzed these data as inde-
pendent groups; as a result, we likely underesti-
mated AEs with methylphenidate and atomoxetine.
For risperidone, we were unable to include three
studies of similar design in the meta-analysis
because of missing data. Given the small number of
studies in each intervention and outcome group, we
were unable to assess publication bias with funnel
plots and therefore cannot rule it out. In interpreting
findings from studies including parent and teacher-
based outcomes, it is notable that although point
estimates for SMD were overall similar between
parent and teacher-based outcomes, precision was
consistently lower for teacher-based outcomes and
the range of potential effects measured by the confi-
dence interval crossed the line of no effect.
Evidence gaps and implications for future research
Taken together, the quality of evidence is low to very
low for ADHD treatment studies in ASD. Evidence for
long-term medication treatment is limited, and evi-
dence for effects on real-world function (e.g., adaptive,
cognitive, academic) is minimal or altogether lacking
in the current literature. As well, future studies
should evaluate the impact of pharmacotherapy on

© 2020 Association for Child and Adolescent Mental Health


academic performance and school adjustment, as this
is an important outcome for children and families that
has been overlooked in studies to date.
A number of the available atomoxetine and
antipsychotic studies were industry supported.
Although we included industry funding in the
‘other’ domain of the risk-of-bias assessment, a
recent review concluded that industry funding
results in bias that cannot be explained (or
accounted for) by standard risk-of-bias tools (Lundh
et al., 2017). Future long-term efficacy studies that
can provide information on whether initial treatment
effects are maintained or enhanced in children with
ASD with longer-term treatment are needed. Exam-
ination of whether clinical effects translate into
improvement in real-world functioning is also criti-
cal. Core outcome sets that include measures that
track functional impact (e.g., adaptive, executive
functioning) are needed to compare results across
studies and the impact of treatment on functional
outcome (McConachie et al., 2015). As further trials
become available (which are needed across more
pharmacological agents, e.g., amphetamines), net-
work meta-analysis may help to guide clinical deci-
sion-making by providing comparisons of different
interventions that have not been previously studied
using head-to-head comparison trials (Cortese et al.,
2018; Tonin et al., 2018).
Practical guidance I: Clinical interpretation of
the synthesized evidence base
The current recommendations are based on a con-
sensus among coauthors that integrates (a) the
expanded empirical literature focused on medication
treatment of ADHD symptoms in ASD included in
our systematic review and meta-analysis, (b) evi-
dence from clinical guidelines and treatment studies
of ADHD without ASD to support guidance when
there are less/poor data to draw from in the ASD
literature, and (c) clinical experience from expert
members of our research team (M-CL, DAG, EA, PS,
SHA). While the quality of the evidence for ADHD
treatment studies in ASD (based on our evidence
synthesis) remains low to very low, it is important to
note the advances that have been made in the
literature since the publication of the 2012 ATN
Clinical Practice Pathways that provide clinical
guidance for assessment and treatment of ADHD
symptoms in ASD (Mahajan et al., 2012). For exam-
ple, the 2012 ATN Practice Pathways were based on
expert opinion, the general ADHD treatment litera-
ture, and a systematic review of five RCTs examining
efficacy of medication treatments on ADHD symp-
toms in ASD as a primary outcome (Mahajan et al.,
2012). This included just one study (exploring effects
of methylphenidate) with a participant sample
greater than twenty (Posey et al., 2007). We now
have meta-analytic level evidence from eight different
RCTs evaluating the efficacy of two different
© 2020 Association for Child and Adolescent Mental Health
Treating ADHD symptoms in autism 11
medication classes on ADHD symptoms as primary
outcome in ASD (and five of the total available RCTs
examine three different medication classes, all of
which include samples of >60 participants; Posey
et al., 2007; Harfterkamp et al., 2012; Handen et al.,
2015; Scahill et al., 2015; McDougle 2017). Nonethe-
less, as the overall quality of the evidence base
remains low, clinical opinions will differ on how
much to lean on the limited data available in the ASD
population versus the much larger evidence base in
the non-ASD, ADHD population. Here, we provide a
stepwise visual practical clinical guide to accompany
the current resource outlining baseline symptom
evaluation, implementation of behavioral interven-
tions, and subsequent medication treatment choice,
if a medication is determined to be indicated by the
treating clinician (Figure 3). The provided pathway
offers guidance for medication choice across chil-
dren and youth with co-occurring ASD and ADHD.
Of note, although the mean age for participants
included in RCTs reviewed above was 8–10 years,
many studies (across medication classes) included
adolescent participants (e.g., oldest participants
ranged from 12 to 18 years of age, Tables S1–S5).
The provided pathway is not meant to take the place
of other ADHD assessment and care guidelines. It
does not list all clinical precautions requiring careful
evaluation prior to initiating a medication treatment
for ADHD symptoms, nor adverse effects experienced
with listed medication treatments. Rather, the path-
way aims to provide a visual guide to accompany in
text suggestions regarding medication choice.
Evaluation of best practices for ADHD symptom
assessment in ASD was beyond the scope of our
synthesis of the treatment literature. Here, we
provide a brief summary of recommendations
regarding evaluation of ADHD symptoms in ASD
but refer the reader to the 2012 ATN Symptom
Evaluation Practice Pathway for further guidance
(Mahajan et al., 2012) as well as to a recent publi-
cation from the United Kingdom ADHD Partnership
summarizing consensus opinion focused on assess-
ment of ASD and ADHD and nonpharmacological
intervention approaches (Young et al., 2020). These
references provide clear, stepwise clinical guidance
on best practices for assessing ADHD symptoms in
ASD, evaluation of medical and academic problems
that may contribute to ADHD symptoms, and edu-
cational/behavioral interventions that should be
implemented (particularly in the school setting) prior
to initiating medication treatment (Mahajan et al.,
2012; Young et al., 2020). These references are also
in line with the 2018 NICE guidance for ADHD
medication management in children and youth in
the general population (5 years or older), with
respect to moving toward medication management
only when significant ADHD symptoms persist fol-
lowing environmental modifications (National Insti-
tute for Health & Care Excellence, 2018).
Environmental modifications for ADHD symptoms
12 Rebecca Rodrigues et al.

include strategies such as selection of seating in
class to optimize engagement and reduce distrac-
tion, reducing distraction through the use of head-
phones/ear plugs or other personalized strategies
helpful to the individual, appropriate access to
teaching assistants to help with schoolwork, fre-
quent breaks for physical movement paired with
shorter duration of focus, and relaying expectations
using both verbal and visual or written supports
(National Institute for Health & Care Excellence,
2018). Recent evidence in children with ADHD in the
general population indicates that functional out-
come may be better when treatment is initiated with
behavioral intervention, followed by medication, as
opposed to the other way around (Pelham et al.,
2016). Although studies that combine behavioral
interventions with medication treatment did not
meet the inclusion criteria for our systematic review,
such studies are of interest for clinical practice. We
are aware of two clinical trials that compared the
effect of treatment with behavioral interventions plus
medication versus medication treatment alone on
ADHD and noncompliance symptoms in ASD (Aman
et al., 2009; Handen et al., 2015). The study by
Aman and others compared the effect of combined
treatment with manualized parent training plus
risperidone to risperidone treatment alone on every-
day noncompliant behavior in children with ASD and
significant irritability (n = 124). Parent training con-
sisted of 11, 60–90 min treatment sessions, deliv-
ered individually to parents and focused on the use
of visual schedules, positive reinforcement, teaching
functional communication, and adaptive skills.
Combined treatment was superior to risperidone
treatment alone on the ABC hyperactivity/noncom-
pliance scale (effect size, d = 0.55) with larger effect
sizes found by treatment week 24 (compared to week
16; Aman et al., 2009; Handen et al., 2013). The
study by Handen et al. (2015) that was included in
our quantitative synthesis, based on comparison of
atomoxetine to placebo treatment (Handen et al.,
2015), also included combined parent training plus
atomoxetine and parent training plus placebo arms
(using the same manualized approach as in Aman
et al., 2009). While this study did not find a bene-
ficial effect of atomoxetine plus parent training
compared to atomoxetine treatment alone, parent
training plus placebo was beneficial over placebo
alone for the treatment of ADHD symptoms and
noncompliance at week 10 of the double-blind RCT
(effect size range = 0.46–0.6; Handen et al., 2015). In
addition, combined treatment with parent training
and atomoxetine was also superior to the beneficial
effects of atomoxetine alone on ADHD symptoms and
noncompliance, following an open-label extension of
the double-blind atomoxetine study (Smith et al.,
2016). Thus, the available literature suggests that
psychosocial interventions can have a meaningful
impact on ADHD symptoms and noncompliance in
ASD, as in the general ADHD population.
Practical guidance II: Clinical pathway
recommendations
First, given the quality of the available evidence base,
a shared decision-making model between clinicians,
patients, and their caregivers/families is encouraged
that adjusts the pathway for a given child/youth
(including the order of medication class/preparation
chosen) to best support the patient and accommo-
date the approach to fit their socio-ecological con-
texts (i.e., familial/caregiving factors, school setting,
etc.). The first phase of intervention begins with
evaluation of ADHD symptoms using structured
questionnaires [e.g., Connor’s Rating Scale (Wolraich
et al., 2003), SWAN rating scale (Brites, Salgado-
Azoni, Ferreira, Lima, & Ciasca, 2015)]. Additional
use of a structured measure such as the Clinical
Global Impression (CGI) Scale provides an easily
implemented baseline measure of a patient’s global
functioning prior to initiating a medication treatment
(using the CGI-Severity, CGI-S) that can also be used
to track progress in later phases of the pathway
(using the CGI-Improvement, CGI-I, version of the
scale (Busner & Targum, 2007). Medical evaluation
to assess for clinical conditions suggestive of the
need for consultation from other health profession-
als (e.g., cardiology, based on the presence of base-
line cardiovascular risk prior to initiating medication
treatment) is essential (Subcommittee on Attention-
Deficit/Hyperactivity Disorder et al., 2011; Warren
et al., 2009). Baseline documentation of vital signs
and symptoms that can be exacerbated with ADHD
medication treatment or experienced as side effects

Figure 3 Medication choice pathway for children and youth with ADHD and ASD. (1) Is clinically significant ADHD present using
structured questionnaires?: for example, Connor’s Rating Scale, SWAN, etc (reference: Wolraich et al., 2003; https://www.ncbi.nlm.
nih.gov/pubmed/23363973); Clinical Global Impressions-Severity (CGI-S) to measure baseline symptom severity (https://www.ncbi.nlm.
nih.gov/pmc/articles/PMC2880930/); (2) Evaluate baseline symptoms, co-occuring diagnoses, medical conditions. Document baseline
symptoms: sleep, appetite, any symptoms of psychosis, tics, mood lability, other psychiatric diagnoses. Document blood pressure, heart
rate, height, weight. Document/address medical conditions as per Warren et al., 2009 (https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC2776560/) AAP 2011 Guidelines for ADHD (https://pediatrics.aappublications.org/content/pediatrics/128/5/1007.full.pdf) and Mahajan
et al., 2012 (https://www.ncbi.nlm.nih.gov/pubmed/?term=23118243); (3) Quick assessment and evaluation every 2 weeks: for example,
ADHD assessment—structured questionnaires; vital signs: heart rate, blood pressure, height, weight, sleep, appetite, mood, GI effects,
tics, medication compliance, side effects (note 4); Clinical Global Impressions-Improvement (CGI-I) guidelines (https://www.ncbi.nlm.
nih.gov/pmc/articles/PMC2880930/); (4) Intolerable side effects: for example, hypertension, tachycardia, extreme weight loss or gain,
insomnia, suicidal ideation, extreme mood swings

© 2020 Association for Child and Adolescent Mental Health

 Treating ADHD symptoms in autism 13

Figure 3. Medication Choice Pathway for Children and Youth with ADHD and ASD

Evaluate:
Baseline symptoms, co- Behavioural
Evaluate: Yes occuring diagnoses, Supports: Yes
Screening Phase
Is clinically significant
medical conditions, Are recommended
(~0-8 Weeks)
ADHD present on clinical Medication
contraindications to behavioural supports Choice Pathway
assessment & structured
medication treatment in place?
questionnaires?
(1) (2)

No
No 8 Week
Behavioural
Exit Pathway Intervention If clinically significant ADHD symptoms persist, consider:

if ADHD symptoms disappear

Start First-line Treatment with

Stimulant Monotherapy
1st choice: methylphenidate
monotherapy (immediate or extended
release)

Quick Assessment and

Evaluation, every 2 weeks
e.g CGI-I >= 3 e.g. CGI-I = 1 or 2
(3)
(~8-23 Weeks)
First -Line
Treatment

Partial or No Response
Side Effects Limit Ongoing
Full Response
Treatment [consider (4)]

consider monotherapy with

Second-line treatment option: Continuation of dosage and
atomoxetine, alpha-2 agonist behavioural supports;
Switch to another (guanfacine or clonidine, consider switching to less
methylphenidate preparation, immediate or extended frequent follow-up
Titrate
release) or amphetamine
to effective dose
(when inadequate response or
mild-to-moderate side effects
limit first-line methylphenidate
treatment). Choice based on
patient/family/environment/
context of care factors

Quick Assessment and

Evaluation, every 2 weeks e.g. CGI-I= 1 or 2
e.g. CGI-I>= 3
(3)
(~23-38 Weeks)

Side Effects Limit Ongoing

Second-Line

Partial or No Response Full Response

Treatment

Treatment [consider (4)]

Continuation of dosage
Switch to another second- and behavioural supports;
Titrate
line option not previously consider switching to less
to effective dose
used frequent follow-up

Quick Assessment and

Evaluation, every 2 weeks
e.g. CGI-I >=3 (3) e.g. CGI-I= 1 or 2
(~32+ Weeks)
Final Phase

Partial or No Response Side Effects Limit Ongoing

Treatment [consider (4)]

Full Response
Reassessment, Need
for Complex Care

© 2020 Association for Child and Adolescent Mental Health

14 Rebecca Rodrigues et al.
of treatment is critical for later evaluation of tolera-
bility of a given medication, once initiated (i.e., sleep,
appetite, presence of tics, psychosis, suicidality,
mood dysregulation/irritability, blood pressure,
heart rate, weight, height; Storebø et al., 2015).
Based on the present updated systematic review and
meta-analysis, and consistent with prior guidance,
the current evidence base supports first-line methyl-
phenidate monotherapy, based on efficacy evidence
in ASD as well as general ADHD treatment guidance
(Cortese et al., 2018; Mahajan et al., 2012; National
Institute for Health & Care Excellence, 2018; Padilha
et al., 2018). As recommended previously, system-
atic and cautious titration by small increments with
frequent reassessment and dose adjustment and
more frequent monitoring for treatment of ADHD
symptoms may improve tolerability in children and
youth with ASD (Mahajan et al., 2012; National
Institute for Health & Care Excellence, 2018). The
optimal dose level will aim to maximize therapeutic
benefits while producing minimal adverse events.
Although more evidence is available for short than
long-acting methylphenidate in the ASD population,
preparation choice may be tailored to practical
needs, such as the patient’s and family’s prefer-
ences, the need for increased flexibility with short-
acting or dosing convenience with longer-acting
preparations (National Institute for Health & Care
Excellence, 2018).
For the general management of ADHD, a trial of
amphetamines (specifically Lisdexamphetamine) is
recommended following inadequate response to a 6-
week trial of methylphenidate (National Institute for
Health & Care Excellence, 2018). As yet, there are no
RCT data supporting the use of amphetamines for
management of ADHD in children/youth with ASD. In
children with ADHD without ASD, the evidence base
indicates that amphetamine treatment has large
effects on ADHD symptoms, and moderate effects on
academic performance and similar side effect profiles
as with methylphenidate (Cortese et al., 2018; Padilha
et al., 2018; Punja et al., 2016). While monotherapy
with amphetamines may be considered in ASD, it is
important for clinicians to be aware that network
meta-analyses comparing ADHD treatments in the
ADHD without ASD literature suggest that overall
tolerability is lower with amphetamines compared to
methylphenidate (Cortese et al., 2018; Padilha et al.,
2018), particularly for sleep disturbance, appetite
disturbance, and irritability (Padilha et al., 2018).
This needs to be considered alongside indication from
the current evidence base that tolerability to methyl-
phenidate is lower in ASD than in the ADHD without
ASD population (McCracken, 2004). In addition,
although higher rates of serious side effects with
stimulant treatments have not been shown consis-
tently in RCTs (Punja et al., 2016; Storebø et al., 2018;
Storebø et al., 2015), in general, stimulants have been
found to be associated with a small risk of psychotic
symptoms in children with ADHD (Mosholder et al.,
2009). One study found that this risk is greater with
amphetamines than methylphenidate (2.83 episodes
per 1,000 person-years vs. 1.78 episodes per 1000
person-years, hazard ratio = 1.65 [95%CI 1.31–2.09];
Moran et al., 2019). The evidence is mixed, however,
with other studies finding that methylphenidate is not
associated with an increased risk of psychosis in
ADHD and may even have a protective effect (Hollis
et al., 2019; Man et al., 2016). As ASD itself is an
independent risk factor for later psychotic disorders
in youth and adulthood (Lai et al., 2019), clinicians
should be aware of the potential risk for psychosis
with stimulant treatment and carefully document risk
for psychosis at baseline (e.g., individual and family
history of psychosis or mania/hypomania).
Previous guidance for treatment of ADHD symp-
toms in ASD has suggested that when inadequate
response or mild-to-moderate side effects limit ongo-
ing treatment with methylphenidate preparations, an
amphetamine preparation is recommended as the
next medication choice (Mahajan et al., 2012). It is
important to note that expert opinion may differ at
this decision point regarding the next best medica-
tion choice after a failed methylphenidate trial (i.e.,
when treatment with methylphenidate is not effective
or side effects preclude continued use). The current
resource considered (a) potential for reduced tolera-
bility to stimulants in children and youth with ASD
and ADHD (compared to ADHD alone), (b) increased
evidence of efficacy for other medication classes
(atomoxetine and alpha-2 agonist) in children and
youth with ASD and ADHD since the prior medication
choice pathway (Mahajan et al., 2012) was published
(though evidence quality remains low to very low),
and (c) lack of studies examining efficacy and toler-
ability of amphetamines in children and youth with
ASD and ADHD balanced with evidence of efficacy
but reduced tolerability in the non-ASD, ADHD
population (Cortese et al., 2018; Padilha et al.,
2018). Based on these considerations, it is our expert
consensus opinion that second-line treatment
options for children and youth with ASD and ADHD
include both nonstimulant medication treatment
options with atomoxetine or an alpha-2 agonist or a
trial of amphetamine treatment (when inadequate
response or mild-to-moderate side effects limit ongo-
ing treatment with methylphenidate preparations).
Updated evidence provides more confidence in
choosing a trial of either monotherapy with atomox-
etine or guanfacine as a second-line option following
a failed methylphenidate trial. Although head-to-
head comparison trials of guanfacine and atomox-
etine are not available in the ADHD and ASD
population, drawing from one head-to-head trial
and network meta-analysis from the ADHD without
ASD literature, tolerability may be lower with guan-
facine (including with the extended release prepara-
tion) or amphetamine treatment than with
atomoxetine (Cortese et al., 2018). A prior network
meta-analysis comparing different ADHD
© 2020 Association for Child and Adolescent Mental Health

medications on a variety of safety outcomes (e.g.,
sleep, decreased appetite, and behavior events such
as irritability, anxiety, aggression) provides helpful
clinical information regarding which medication may
be the best choice for a given child based on their
particular circumstance or side effect sensitivity
Padilha et al.,2018. Clinicians will need to evaluate
the current evidence base with families, consider
personalized child, familial and environmental (e.g.,
school) factors, the context of care (e.g., ability to
monitor response and tolerability with frequent
follow-ups), side effect, administration and discon-
tinuation profiles of each second-line option and
ultimately undertake a shared decision-making pro-
cess to support choice among second-line options for
a given patient.
Of note, second-line options from the ATN medica-
tion choice pathway (Mahajan et al., 2012) include
atomoxetine and either guanfacine or clonidine as
second-line alpha-2 adrenergic agonists. There are no
trials of clonidine in children with both ADHD and
ASD. Although selectivity for alpha-2 adrenergic sub-
types differs with clonidine versus guanfacine, based
on the general ADHD literature, these medications
may have similar efficacy and tolerability (Hirota,
Schwartz, & Correll, 2014; with increased risk for
sedation, somnolence and fatigue, hypotension and
bradycardia with immediate or extended release ver-
sions of either medication), though hypotension and
bradycardia may be more common with immediate
release clonidine, and QTc prolongation with extended
release guanfacine (Hirota et al., 2014). Therefore, if
guanfacine is not available, or an extended release
formulation of either alpha-2 agonists are not avail-
able (for easier administration), or cost prohibits the
use of one formulation, clonidine could be used as a
second-line treatment option, in place of guanfacine.
Given risk of rebound hypertension, tachycardia, and
arrhythmias with abrupt discontinuation, alpha-2
agonists should be tapered gradually prior to discon-
tinuation (Scahill et al., 2015).
Importantly, as there is limited evidence with
respect to the risk and benefit of long-term mainte-
nance, careful evaluation of the clinical impact of
treatment on ADHD symptoms, global functioning,
and quality of life across settings (e.g., school, home,
community) is required. Therefore, ongoing evalua-
tion of the need for continuous pharmacological
treatment has to be an integral component of ongoing
care of children and youth with ASD and ADHD with
careful consideration of the potential benefits weighed
against the limitations of safety/efficacy data.
Supporting information
Additional supporting information may be found online
in the Supporting Information section at the end of the
article:
Appendix S1. Medline search strategy.
© 2020 Association for Child and Adolescent Mental Health
Treating ADHD symptoms in autism 15
Appendix S2. Methods for data synthesis and analysis.
Table S1. Attempts to contact study authors for
unpublished or missing data and outcomes.
Table S2. Characteristics of included studies compar-
ing methylphenidate vs. placebo.
Table S3. Characteristics of included studies compar-
ing atomoxetine vs. placebo.
Table S4. Characteristics of the included alpha-2
agonist study.
Table S5. Characteristics of included antipsychotic
studies.
Table S6. Characteristics of included small, single
studies.
Table S7. Summary of results for the effect of olanza-
pine, tianeptine, and venlafaxine on ADHD symptoms.
Table S8. Summary of findings for olanzapine vs.
haloperidol.
Table S9. Summary of findings for tianeptine vs.
placebo.
Table S10. Summary of findings for venlafaxine vs.
placebo.
Table S11. Adverse events from small, single studies
(olanzapine vs. haloperidol, tianeptine vs. placebo, and
venlafaxine vs. placebo).
Table S12. Sensitivity analysis for different correlation
coefficient values for ADHD outcomes from the individ-
ual tianeptine and venlafaxine studies.
Table S13. Summary of findings for methylphenidate
vs. placebo.
Table S14. Summary of findings for atomoxetine vs.
placebo.
Table S15. Summary of findings for guanfacine vs.
placebo.
Table S16. Summary of findings for aripiprazole vs.
placebo.
Table S17. Summary of findings for risperidone vs.
placebo.
Table S18. Summary of findings for aripiprazole vs.
risperidone.
Table S19. Summary of findings for lurasidone vs.
placebo.
Table S20. Summary of findings for secondary out-
comes from single studies.
Table S21. Summary of results for ADHD symptoms
measured on the same scale.
Table S22. Sensitivity analysis of different correlation
coefficient values for outcomes from methylphenidate
studies.
Table S23. Sensitivity analysis for pooled atomoxetine
ADHD findings, in which the teacher-rated outcomes
(from Handen et al.10) were removed from the teacher/
investigator-rated ADHD outcomes.
Table S24. Sensitivity analysis for pooled atomoxetine
ADHD findings, in which the crossover study (Arnold
et al.9) was removed.
Table S25. Sensitivity analysis for different correlation
coefficient values for outcomes including the atomox-
etine crossover study9.
Table S26. Adverse events with methylphenidate ver-
sus placebo.
Table S27. Adverse events with atomoxetine versus
placebo.
16 Rebecca Rodrigues et al.

Table S28. Adverse events with guanfacine versus
placebo.
Table S29. Adverse events with aripiprazole versus
placebo.
Table S30. Adverse events with risperidone versus
placebo.
Table S31. Adverse events with aripiprazole versus
risperidone.
Table S32. Adverse events with lurasidone versus
placebo.
Figure S1. Review authors’ judgments about each risk-
of-bias item, presented as percentages across all
included studies.
Figure S2. Review authors’ judgments about each risk-
of-bias item for each included study.
Figure S3. Forest plots for meta-analysis of the effects
of methylphenidate on ADHD symptoms, including (A)
hyperactivity, (B) inattention, and (C) total ADHD
symptoms.
Figure S4. Forest plots for meta-analysis of the effects
of atomoxetine on ADHD symptoms, including (A)
hyperactivity, (B) inattention, and (C) total ADHD
symptoms.
Figure S5. Forest plots for meta-analysis of the effects
of antipsychotics on hyperactivity, including aripipra-
zole, (A) standardized mean difference and (B) mean
difference, and (C) risperidone, mean difference.
Figure S6. Subgroup analysis of parent- and teacher-
rated hyperactivity by methylphenidate dose.
Figure S7. Subgroup analysis of parent- and teacher-
rated inattention by methylphenidate dose.
Figure S8. Subgroup analysis of parent- and teacher-
rated total ADHD symptoms by methylphenidate dose.
Figure S9. Forest plot for meta-analysis of the effects of
methylphenidate on oppositional defiant disorder
(ODD) symptoms.
Figure S10. Forest plots for meta-analysis of the effect
of methylphenidate on Clinical Global Impression
(CGI)-Improvement (CGI-I) and CGI-Severity (CGI-S),
including (A) standardized mean difference and (B)
mean difference.
Figure S11. Forest plots for meta-analysis of the effect
of atomoxetine on oppositional defiant disorder (ODD)
symptoms.
Figure S12. Forest plot for meta-analysis of the effect of
atomoxetine on obtaining a positive responses on the
Clinical Global Impression-Improvement (CGI-I) scale.
Figure S13. Forest plot for meta-analysis of effects of
atomoxetine on cognitive tasks assessing response
inhibition including the continuous performance task.
(A) Errors of commission and (B) errors of omission.
Figure S14. Forest plot for meta-analysis of the effect of
aripiprazole on pediatric quality of life.
Figure S15. Forest plot for meta-analysis of the effect of
aripiprazole on caregiver strain, measured with the
Caregiver Strain Questionnaire.
Acknowledgements
This work was supported in part by two Academic
Scholars Awards from the Department of Psychiatry,
University of Toronto (to S.H.A. and M-C.L.), by the
O’Brien Scholars Program, Slaight Family Child and
Youth Mental Health Innovation Fund and The Cather-
ine and Maxwell Meighen Foundation via the CAMH
Foundation (to S.H.A. and M-C.L.), and an Ontario
Mental Health Foundation New Investigator Fellowship
(to S.H.A.). E.A. is supported by funding from CIHR,
NIH, DoD, Ontario Brain Institute, Brain Canada,
Genome Canada, Ontario Research Fund, Azrieli Foun-
dation, Autism Speaks, HRSA, Canada Research Chairs
Program, and Dr. Sims Chair in Autism. The authors
thank John Costella, Associate Librarian at Western
University, for his guidance in developing the search
strategy. The authors also thank Caroline Kassee and
Dr. Amanda Sawyer for their help with developing the
medication choice pathway figure. E.A. has received
consultation fees from Roche, in kind support from
AMO Pharma, and editorial honorarium from Wiley. The
remaining authors have declared that they have no
competing or potential conflicts of interest.
Correspondence
Stephanie H. Ameis, Centre for Addiction and Mental
Health, 80 Workman Way, Toronto, ON, M6J 1H4, USA;
Email: Stephanie.ameis@camh.ca

Key points

 Clinically significant attention-deficit/hyperactivity disorder (ADHD) symptoms are common and impairing in
children and youth with autism spectrum disorder (ASD).
 This systematic review and meta-analysis sought to update and integrate the available evidence regarding
the pharmacological treatment of ADHD in ASD.
 Methylphenidate, atomoxetine, and guanfacine had small to large effects on hyperactivity and inattention
in children with autism spectrum disorder, based on low/very low quality of evidence.
 Indirect, low quality evidence indicated aripiprazole and risperidone were efficacious in reducing hyperactive
symptoms.
 Current evidence for treatment of ADHD symptoms in ASD is limited; however, methylphenidate remains the
first-line treatment option and emerging evidence for atomoxetine and guanfacine indicates these
treatments may reduce ADHD symptoms in ASD.

© 2020 Association for Child and Adolescent Mental Health


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