BJPsych Open (2021)

7, e179, 1–15. doi: 10.1192/bjo.2021.1003

Review

Randomised controlled trials of

antidepressant and anti-anxiety
medications for people with autism
spectrum disorder: systematic review
and meta-analysis
Shoumitro Deb, Meera Roy, Rachel Lee, Madiha Majid, Bharati Limbu, Jacopo Santambrogio, Ashok Roy
and Marco O. Bertelli

Background nine studies (60%) did not show any statistically significant inter-
Although widely used, the current evidence for the efficacy of group difference on either of the outcome measures. The
antidepressant and anti-anxiety medications for people with adverse effects reported were mild and, in most studies, their
autism spectrum disorder (ASD) is limited and conflicting. rates did not show any significant inter-group difference.

Aims Conclusions
We carried out a systematic review and meta-analysis of ran- Given the methodological flaws in the most included studies and
domised controlled trials that assessed the effectiveness of contradictory findings, it is difficult to draw any definitive con-
these medications in people with ASD. clusion about the effectiveness of either antidepressant or anti-
anxiety medications to treat either ASD core symptoms or
Method associated behaviours. Robust, large-scale, randomised con-
We searched the following databases: Cochrane Library, trolled trials are needed to address this issue.
Medline, EMBASE, CINAHL, PsycINFO, ERIC, DARE and
ClinicalTrials.gov. Additionally, we hand-searched 11 relevant Keywords
journals. We used the Cochrane risk-of-bias tool and Jadad score
Autism spectrum disorder; antidepressants; anti-anxiety medi-
to assess the quality of each included study. We carried out a
cations; systematic review; meta-analysis.
meta-analysis using a random effects model.

Results Copyright and usage

We included 15 randomised controlled trials (13 on antidepres- © The Author(s), 2021. Published by Cambridge University Press
sants and two on anti-anxiety medications) for a total of 958 on behalf of the Royal College of Psychiatrists. This is an Open
people with ASD. Data showed contradictory findings among the Access article, distributed under the terms of the Creative
studies, with larger studies mostly showing a non-significant Commons Attribution licence (http://creativecommons.org/
difference in outcomes between the treatment and the placebo licenses/by/4.0/), which permits unrestricted re-use, distribu-
groups. Meta-analysis of pooled Yale-Brown Obsessive tion, and reproduction in any medium, provided the original work
Compulsive Scale and Clinical Global Impression Scale data from is properly cited.

Autism spectrum disorder (ASD) is a neurodevelopmental dis- The prevalence of psychotropic medication use in ASD
order that starts in early childhood and often continues into A systematic review by Jobski et al5 included 47 studies of the preva-
adulthood. The condition is characterised by persistent deficits lence of psychotropic medication use in people with ASD (N > 300
in social communication and social interaction across multiple 000) published between 1976 and 2012. The overall median rate of
contexts, and restricted and repetitive patterns of behaviour psychotropic use was 45.7%, which was higher among adults
(RRB), interests or activities.1 The condition affects 1 in every (61.5%) than children (41.9%). Polypharmacy of psychotropic use
160 people.2 was reported on average among 23% of people with ASD. The most
commonly used psychotropics were antipsychotics (median 18.1%),
Psychiatric comorbidities in ASD antidepressants (median 17.2%) and psychostimulants (median
ASD is associated with considerable comorbidities with both 16.6%). The use of anti-anxiety medication is reported among 6.8%
other neurodevelopmental disorders such as intellectual and of children and adolescents.3 Psychotropic use in this population
developmental disabilities (IDD) and attention-deficit hyper- seems to have increased over the years.3,6 A longitudinal study
activity disorder (ADHD), and functional psychiatric disorders between 1998 and 2005 found that 57% of adolescents and adults
such as psychosis, depression and anxiety.1 One population- with ASD were taking one or more psychotropic medications at the
based German study reported depressive disorder in 8.3%, beginning of the study, which increased to 64% by the end of the
anxiety disorder in 11.1%, psychotic disorder in 1.6% and study (P < 0.05).7
sleep disorders in 4.9% of 1124 people (aged 0–24 years) with
ASD.3 In another community-based study of 112 children A systematic review of the efficacy of tricyclic
(aged 10–14 years), the overall rate of anxiety and phobic disor- antidepressants in ASD
ders was reported in 41.9% (social anxiety in 29.2%), ADHD in
28.2% and oppositional defiant disorder or conduct disorder in Hurwitz et al8 included only two small, crossover randomised con-
30% of the cohort.4 trolled trials (RCTs) on clomipramine with 12 children, and 31 chil-
dren and adults with ASD respectively, in a Cochrane review of the

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 Deb et al

effectiveness of tricyclic antidepressants. One study showed the strategy. We searched the following databases for English-language
superiority of clomipramine over placebo and the other study did publications between January 1985 and October 2020: Medline,
not show any significant inter-group difference. Another small EMBASE, PsycINFO, Cochrane Library, CINAHL, ERIC, DARE
RCT used tianeptine, which is now withdrawn from the market and ClinicalTrials.gov. Also, we cross-referenced pertinent reviews
because of its potential addictive effect. The authors concluded and articles. We hand-searched for relevant articles published
that ‘clinicians considering the use of tricyclic antidepressants between January 1990 and October 2020 in relevant journals in the
need to be aware of the limited and conflicting evidence of effect field of ASD (Journal of Autism and Developmental Disorders, Autism
and the side effect profile when discussing this treatment option Research, Journal of Autism Spectrum Disorder), IDD (Journal of
with people who have ASD and their carers. Further research is Intellectual Disability Research, Journal of Applied Research in
required before tricyclic antidepressants can be recommended for Intellectual Disabilities, Research in Developmental Disabilities) and psy-
treatment of individuals with ASD’. chopharmacology (Psychopharmacology, Neuropsychopharmacology,
International Journal of Neuropsychopharmacology, Journal of
Clinical Psychopharmacology, Human Psychopharmacology, Journal
A systematic review of the efficacy of selective
of Child and Adolescent Psychopharmacology), using relevant search
serotonin reuptake inhibitors in ASD
terms. Search terms are described in Supplementary Appendix 1
Williams et al9 published a Cochrane review on the effectiveness of available at https://doi.org/10.1192/bjo.2021.1003, and included
selective serotonin reuptake inhibitors (SSRIs) in people with ASD. terms like RCTs, depression, anxiety and anxiety disorder.
They included nine RCTs involving children (n = 5) and adults
(n = 4), assessing the effect of SSRIs on ASD core and associated
Selection criteria
symptoms: three on fluoxetine, two on fluvoxamine, two on fenflur-
amine (fenfluramine is withdrawn from the market now) and two on The titles, abstracts and full papers were screened independently by
citalopram. Most studies included a small number of participants, two authors (M.R. and J.S.), using pre-piloted eligibility criteria
but one parallel-design RCT of >100 children showed no superiority (Supplementary Appendix 2) designed as per Cochrane Library13
of citalopram over placebo. Of the four adult studies, one was based and PROSPERO11 guidelines. All RCTs in ASD involving antide-
on unpublished data and another included only six participants. The pressants and anti-anxiety medications were included. The list of
other two small studies (with 30 and 37 participants, respectively) excluded studies with reasons for exclusion is provided in
showed significant improvement in some behaviour in the medica- Supplementary Appendix 3.
tion groups (one study on fluoxetine and one study on fluvoxamine)
compared with the placebo. The authors concluded that ‘there is no Participants
evidence of effect of SSRIs in children and emerging evidence of Participants had a diagnosis of an ASD, defined using standardised
harm. There is limited evidence of the effectiveness of SSRIs in criteria such as the DSM or ICD, or based on a clinical assessment.
adults from small studies in which risk of bias is unclear’. The diagnosis may or may not have been made with a standardised
diagnostic instrument. No age limit was applied. Studies that
Justification for the current systematic review included people with IDD were included if the participants also
No systematic review exists on the efficacy of anti-anxiety medica- had a confirmed diagnosis of ASD. We excluded any RCT that
tion for people with ASD, although many SSRIs are used to treat included less than ten participants, in line with our previous
anxiety symptoms. One systematic review on the treatment of reviews.14–17
anxiety in people with ASD found nine studies on cognitive–behav-
iour therapy and four open-label studies involving fluvoxamine, Intervention
citalopram and buspirone.10 As several studies on antidepressants We included studies of both new- and old-generation antidepres-
have been published since the review by Williams et al,9 and there sants, including SSRIs, serotonin–noradrenaline reuptake inhibitor,
is no published systematic review on anti-anxiety medications, we tricyclics, any other types of antidepressants and any type of anti-
decided to carry out a systematic review and meta-analysis based anxiety medications such as benzodiazepines, buspirone, beta-
solely on RCTs (as non-RCTs are likely to produce bias) of anti- blockers and pregabalin, regardless of dosage used or frequency of
depressant (both old and new generation) and anti-anxiety (includ- administration.
ing benzodiazepines, buspirone and beta-blockers) medications for
people with ASD for any indication (ASD core symptoms, including Design and comparators
communication and language issues; associated behaviours, includ-
ing agitation and aggression; and/or psychiatric disorders such as Only RCTs that evaluated the effectiveness of antidepressants and
depression and anxiety). anti-anxiety medications on people with ASD of any age (including
children, adolescents and adults) were included in this review. The
control treatment could be a placebo or another medication.
Method
Outcome measures
Our objective was to determine the effectiveness of antidepressant Any standardised validated outcome measure to assess mental state,
and anti-anxiety medications in people with ASD for any indication. including symptoms of any psychiatric illness such as depression
The study was registered with International Prospective Register of and anxiety; ASD core symptoms such as language and communi-
Systematic Reviews (PROSPERO; identifier CRD42020210708) on cation impairment and RRB; and any other associated behaviours
16 October 2020. such as agitation, aggression, irritability, hyperactivity and any
other problem behaviour.
Search strategy
We followed PROSPERO guidelines11 and the Preferred Reporting Selection process
Items for Systematic Review and Meta-Analysis Protocols Any discrepancy in scoring was resolved by discussion and, if neces-
(PRISMA-P) checklist12 to develop our protocol and search sary, arbitration by a third author (S.D.). Data were organised with

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 Antidepressant and anti‐anxiety medications for autism spectrum disorder

Mendeley (Version 1.19.8 for Windows, Elsevier, Amsterdam, the studies in this review (see Fig. 1). Data were first extracted on the
Netherlands; see https://www. mendeley.com/download-desktop- 10 December 2020. We included 13 studies on antidepressants
new/)Reference Manager.18 (four on fluoxetine, two on clomipramine, two on fluvoxamine,
two on venlafaxine, one on citalopram, one on sertraline and one
Data extraction on agomelatine) and two on the anti-anxiety medication buspirone.
We did not find any RCT on the long-term use of beta-blockers or
Data were extracted independently by two authors (R.L. and M.M.),
benzodiazepines.
using a proforma modified from the Cochrane template19
(Supplementary Appendix 4). As people with ASD are likely to be
more sensitive to psychotropic medication, we have taken note of Description of the study population
the adverse effects described in the included studies20–34 and These studies included 958 participants in total. There was a male
presented the findings in Table 1. preponderance among the participants, reflecting the male prepon-
derance among people with ASD. Seven RCTs (53.85%) on antide-
Quality assessment of included studies pressants included children and adolescents only (age ranged from
2 to 18 years), four RCTs (30.76%) included adults only and another
The quality of the included RCTs was assessed independently by
two RCTs (15.38%) included both children and adults (age ranged
two authors (R.L. and M.M.), using the Cochrane risk-of-bias
from 6 to 36 years). All participants (adults) in two studies (15.38%)
tool35 (Supplementary Appendix 5) and the Jadad score.36 Any dis-
had IDD, in eight studies (61.53%) a high proportion had IDD and
crepancy in scores was resolved by discussion between the authors,
IQ was not reported in three studies (23.07%). Both RCTs on anti-
with arbitration from a third author (B.L.). Overall findings were
anxiety medications included children and adolescents only (age
presented in a narrative format, but a meta-analysis was also
starting from 2 years), and none reported participant IQ.
carried out where possible.
Information on the inclusion and exclusion criteria for each
study, along with comorbidities and funding source, is provided
Data synthesis in Supplementary Appendix 9.
A narrative synthesis of the findings is provided in Table 1.20–34
Where there were more than one studies, a meta-analysis was Outcome measures used in the included studies
carried out. A random-effects odds ratio or standardised mean dif-
We did not find any RCT that used outcome measures for anxiety
ference with 95% confidence interval meta-analysis was performed,
and depression. Instead, these RCTs assessed the effect of the
depending on the type of data gathered. Heterogeneity was tested
medications on ASD core symptoms such as RRB, and other
with the χ2-test and I2-statistic test of heterogeneity. If there was
associated behaviours such as irritability, hyperactivity and
substantial heterogeneity (I2 > 50%) as per the Cochrane guide, a
aggression. The two most common outcome measures used were
further sensitivity analysis was carried out.37
the ASD core symptom of RRB measured by the Yale-Brown
Obsessive Compulsive Scale (YBOCS)41 and Children-YBOCS
Meta-analysis (C-YBOCS),42 and the Clinical Global Impression-Improvement
We pooled data for meta-analysis only from those RCTs that pre- (CGI-I) Scale (National Institute of Mental Health).43 Both scales
sented data with the same outcome measure. A standardised were used in seven RCTs (46.66%). Some of the other outcome mea-
mean difference was calculated for those studies that presented sures included the Aberrant Behaviour Checklist-Community,44
means and s.d. for scores based on an outcome measure in the Repetitive Behaviours Scale,45 Children’s Global Assessment
two groups.37 RevMan version 5.3 (The Nordic Cochrane Centre, Scale46 and modified Children’s Psychiatric Rating Scale.47
The Cochrane Collaboration, Copenhagen, Denmark; see www.
training.cochrane.org) software for Windows 10 was used for A narrative synthesis of the data
random-effects meta-analysis, because of the heterogeneity.
Old generation of antidepressants
Clomipramine. The findings of the included studies are sum-
Meta-bias(es)
marised in Table 1.20–34 Two RCTs on old-generation antidepres-
Funnel plots38 were drawn, and an Egger’s value was calculated39 to sant tricyclics were on clomipramine, both of which were small
assess publication bias (Supplementary Appendices 6 and7). crossover trials (n = 24 and 36);24,25 one compared clomipramine
with desipramine and placebo,24 and the other with haloperidol
Confidence in cumulative estimate and placebo.25 One found clomipramine to be marginally signifi-
The quality of evidence was assessed across the risk-of-bias domains cantly better than placebo in treating ASD core symptoms like
of consistency, directness, precision and publication bias. Any RRB,24 but the other one did not show any significant inter-group
ambiguous studies that were deemed of low quality were excluded difference.25
from the review. The PRISMA-P checklist was completed, and the
overall quality of the systematic review and the meta-analysis was New generation of antidepressants, including SSRIs
assessed with the A Measurement Tool to Assess Systematic Fluoxetine. Among the new generation of antidepressants, most
Reviews 2 (AMSTAR 2) checklist (Supplementary Appendix 8).40 RCTs were on SSRIs. Four RCTs were on fluoxetine, one of which
No ethical approval was necessary for this review as no individual was a small crossover trial of 45 children and the rest were paral-
patient-related data were collected or analysed. lel-design RCTs involving 158 children, 146 children and 37
adults, respectively.26–29 Of the two larger RCTs, one26 showed no
statistically significant inter-group difference on RRB, but the
Results authors felt the overly cautious dosing regime and the
short follow-up may have prevented the therapeutic effect of fluox-
Search findings etine. The other large parallel-design RCT29 initially showed a sig-
Initially, we identified 2306 titles from the literature search and nificantly better outcome of fluoxetine compared with the
hand search of the relevant journals, and ultimately included 15 placebo, but the study evidenced a high drop-out rate (25%), the

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Deb et al
Table 1 Summary findings

Study type, Participants (N, Age

(methods used (mean ± s.d.), gender,
for ASD IQ (mean ± s.d.),
Study author and date diagnosis) Dose of medications Intervention, FU Outcome measures used Findings, Jadad score Comments
Agomelatine
Ballester et al, 201920 Crossover Agomelatine (25 mg/day) N = 23 TST, TiB, SoL, Number of Only night TST significantly increased (mean Small sample size risking type II error.
(DSM-V) Age: 18–65 years (53 ± awakenings during TiB, Wake 83 min) during agomelatine treatment The outcome is not directly related to
12 years) after sleep onset, Sleep (abnormal TST among 50% participants pre- ASD core symptoms, although sleep
Male: 83% efficiency treatment v. 16% post agomelatine problem is common in ASD. Only one
IQ: 100% IDD treatment) (P = 0.016). No significant change sleep parameter has shown
Agomelatine/Placebo: in other sleep parameters. improvement.
23 The authors reported only mild and
FU: 1 month transient adverse events associated with
the agomelatine treatment.
Jadad = 4
Buspirone
Chugani et al, 201621 Parallel design Buspirone 2.5 mg N = 166 (142 ADOS-CTS, ADOS-SA and A non-significant intergroup difference in Reasonable sample size but
(DSM-IV, ADI-R twice daily v. completed) ADOS-RRB, ABC, VABS, RBS, the primary outcome ADOS-CTS. RRB score contradictory findings based on
and ADOS) Buspirone 5 mg twice daily Age: 2–6 years SPS, C-YBOCS-PDD, CGI, Leiter as per CYBOCS-PDD showed a significant different dosages and outcome
Male: 82.5% Parent-Report difference from baseline to FU (P = 0.03) in measures.
IQ: Not reported 2.5 mg twice daily dose but not in the 5 mg
Buspirone 2.5 mg twice daily dose or the placebo group.
twice There was no significant intergroup
daily = 54 difference in the rate of adverse events.
Buspirone 5 mg twice Jadad = 5
daily = 55
Placebo = 57
FU: 24 weeks
Ghanizadeh & Parallel design Buspirone 10 mg/day (<40 kg) N = 40 (34 completed) ABC-Irritability subscale Thirteen (81.2%) in the buspirone group and Short study duration.
Ayoobzadehshirazi, 201522 (Clinical diagnosis) or 20 mg/day (>40 kg) Age: Mean: 7 years seven (38.9%) in the placebo group showed Small sample size risking a type II error.
Male: 82.5% a >30% decline in irritability score, although
IQ: Not reported total irritability score improved significantly
Buspirone: 16 from the baseline score in both groups (both
Placebo: 18 P < 0.001).
FU: 4 and 8 weeks No major adverse events are reported. The
most common adverse events associated
with buspirone treatment were increased
appetite (61%), drowsiness (11%), and
fatigue (11%).
Jadad = 5
Citalopram Parallel design Citalopram 10 mg/5 mL, N = 149 (123 C-YBOCS-PDD total score + No significant intergroup difference in C- A large sample is likely to have given
King et al, 200923 (DSM-IV-TR, ADI-R, 2.5 mg-20 mg/day completed) RRB, CGI-I, RBS, ABC YBOCS-PDD, RRB, and CGI-I scores. adequate power to the study but the
ADOS) Age: 5–17 years (9.4 ± Citalopram group showed more adverse overall dropout rate maybe a bit high.
3.1 years) effects such as increased energy, However, an ITT analysis should have
Male: 86% impulsiveness, decreased concentration, mitigated this.
IQ: 40% had a non- hyperactivity, stereotypy, diarrhoea,
verbal IQ <70 insomnia, and dry skin or pruritus.
Citalopram: 60 Jadad = 5
Placebo: 63
FU: 12 weeks
https://doi.org/10.1192/bjo.2021.1003 Published online by Cambridge University Press

Clomipramine Crossover Clomipramine v. desipramine N = 28 (24 completed) Modified CPRS OCD subscale, Clomipramine was superior to both placebo Small sample size risking a type II error.
Gordon et al, 199324 (DSM-III-R, ADI) 25 mg/day-250 mg/day (or 5 Age: 6–23 years (10.4 CGI (P ≤ 0.001) and desipramine (P ≤ 0.005) in A short washout period may have
mg/kg/day) ± 4.1 years) improving CPRS subscales and CGI scores. caused a carry-over effect on long-
Male: 62.5% There was no effect of age, gender, IQ level, standing behaviours.
IQ: 30–107 (n = 19; and dose of clomipramine on the outcome.
79.16% ≤70) The authors reported minor adverse effects
Clomipramine/ in all three groups without any significant
Placebo: 12 intergroup difference.
Clomipramine/ Jadad = 3
Desipramine: 12
FU: week 5
Remington et al, 200125 Crossover Latin Clomipramine (100–150 mg/ N = 36 Global ASD measures CARS, Clomipramine did not show any superiority Small sample size risking a type II error.
square day, mean: 128.4 mg/day); Age: 10–36 years, ESRS, DOTES, ABC- subscales over placebo, but haloperidol did (P < 0.05) A short washout period may have
(DSM-IV) Haloperidol (1–1.5 mg/day; (mean: 16.3) on the global measure of autistic symptoms, caused a carry-over effect on long-
mean: 1.3 mg/day) Male: 86% and ABC-irritability, hyperactivity, and standing behaviours. A complicated
IQ: Not stated stereotype subscale scores. study design has made the
Clomipramine/ Adverse events associated with interpretation of findings difficult.
Haloperidol/ clomipramine included fatigue (n = 4),
Placebo: 36 tremors (n = 2), tachycardia (n = 1), insomnia
FU: 7 weeks (n = 1), diaphoresis (n = 1), nausea or
vomiting (n = 1), and decreased appetite (n
= 1). Four of them also showed problem
behaviour.
Jadad = 4
Fluoxetine
Herscu et al, 202026 Parallel design Fluoxetine 2–18 mg/day N = 158 (121 CYBOCS-PDD total + RRB No significant intergroup difference in any of A large sample may have given
(SOFIA study) (DSM-IV-TR) (Mean: 11.8 mg/day) completed) score, CGI, CSQ the outcome measures. ‘Much improved’ adequate power, but the authors
Age: 5–17 years and ‘very much improved’ in 23% of suggested that a low starting dose may

Antidepressant and anti‐anxiety medications for autism spectrum disorder

Male: 85.5% fluoxetine and 34% placebo group as per have prevented a therapeutic effect.
IQ: Not reported CGI-I scores.
Fluoxetine: 56 The rate of adverse effects was similar in the
Placebo: 65 two groups and both groups showed a high
FU: 14 weeks rate of activation (fluoxetine: 42%, placebo:
45%).
Jadad = 5
Hollander et al, 200527 Crossover Fluoxetine 2.5 mg/day to N = 45 (39 completed) C-YBOCS RRB score, Autism Moderate to large effect size on C-YBOCS Small sample size risking a type II error.
(DSM-IV, 0.8 mg/kg/day Age: 5–17 years global symptoms, CGI RRB score (z = −2.075, SE = 0.407, P = 0.038). A short washout period may have
ADI-R, ADOS) Male: 76.9% No effect on CGI, speech, social interaction. caused a carry-over effect on long-
IQ: 30–132 (63.65 ± There was no significant intergroup standing behaviours.
27.9) difference in the rate of adverse effects. The
Fluoxetine/Placebo: fluoxetine group reported a numerically
39 lower rate of insomnia, anxiety, urinary
FU: 20 weeks incontinence, and mild weight gain but a
higher rate of sedation, agitation, diarrhoea,
and anorexia when compared with the
placebo group.
Jadad = 3
(Continued )
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Deb et al
Table 1 (Continued )
Study type, Participants (N, Age
(methods used (mean ± s.d.), gender,
for ASD IQ (mean ± s.d.),
Study author and date diagnosis) Dose of medications Intervention, FU Outcome measures used Findings, Jadad score Comments
Hollander et al, 201228 Parallel design Fluoxetine 10 mg/day starting N = 37 (34 completed) YBOCS RRB score, CGI, ABC, Fluoxetine was superior to placebo on Small sample size risking a type II error.
(DSM-IV, dose to maximum of Age: 18–60 years HAM-D YBOCS RRB score (F = 9.24, df = 1, 30.7, P =
ADI-R, ADOS) 80 mg/day (34.31 ± 14.26 years) 0.005, d = 0.53).
Male: 69% CGI improvement in obsessive-compulsive
IQ: 30–161 (103.25 ± symptoms (score 2 or less): 50% in the
28.45) fluoxetine group v. 8% in the placebo group
Fluoxetine: 21 (P = 0.03).
Placebo: 13 HAM-D scores were well under the
FU: 12 weeks threshold for a diagnosis of depressive
disorder in both groups.
A statistical comparison of intergroup
adverse effects was not possible. In the
fluoxetine group, 1.4 adverse effects per
patient were reported compared with 0.6 in
the placebo group. Adverse events
associated with the fluoxetine treatment
were mild to moderate and included bad
dreams (n = 3), mild insomnia (n = 3), mild
dry mouth (n = 3), and headaches (n = 3).
There was no statistically significant
intergroup difference in the rates of suicidal
ideation between the fluoxetine (6%) and
the placebo group (0%) (P = 1.00). No one in
either group reported suicidal gestures or
attempts.
Jadad = 3
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Reddihough et al, 201929 Multicentre, Fluoxetine: commencing at N = 146 (109 C-YBOCS-PDD, RBS, ABC, CGI The mean C-YBOCS-PDD score decreased in Initial analysis showed the superiority
parallel design 4 or 8 mg/day for the first completed) the fluoxetine group by 3.72 points (95% CI, of fluoxetine over placebo, but this
(DSM-IV-TR, ADI-R) week (4 mg if <40 kg; 8 mg if Age: 7.5–18 years −4.85 to −2.60) and in the placebo group by difference was not maintained when
≥40 kg) maximum dose was (11.2 ± 2.9 years) 2.53 points (95% CI, −3.86 to −1.19). The baseline imbalance in outcome scores
20 mg/day (participants <40 Male: 80% between-group mean difference at follow between two arms was adjusted for.
kg) or IQ: 30% IDD up was −2.01 (95% CI, −3.77 to −0.25; P = Also, the confidence interval of the
30 mg/day (participants ≥40 Fluoxetine: 54 0.03) (adjusted for stratification factors), and scores included a minimally clinically
kg). Placebo: 55 in the prespecified model with further important difference. High dropout rate
FU: 16 weeks adjustment, it was −1.17 (95% CI, −3.01 to (25%)
0.67; P = 0.21). The multiple imputation
analysis did not show any statistically
significant intergroup difference (mean
difference, −1.82; 95%CI, −3.71 to 0.06; P =
0.06).
The rate of commonly observed adverse
effects such as irritability, mood
disturbance, nausea, vomiting, and sleep
disorders did not show any significant
intergroup difference (fluoxetine, 45%, the
total number of events 2.5 (s.d. ± 1.6) and
placebo,
48%, the total number of events
2.6 (s.d. ± 2.1).
Jadad = 4
Fluvoxamine
McDougle et al, 199630 Parallel design Fluvoxamine: 50 mg/day, N = 30 (all completed) YBOCS, CGI, VABS A significantly higher proportion of the Small sample size risking a type II error.
(DSM-III-R, ICD-10) increased every 3 or 4 days to Age: 18–53 years maladaptive behavior fluvoxamine group (53%) was reported to be

Antidepressant and anti‐anxiety medications for autism spectrum disorder

a maximum of 300 mg/day as (30.1 ± 7.7 years) subscale, Brown Aggression responders to treatment compared with the
tolerated Male: 90% Scale, placebo group (0%). Fluvoxamine was
IQ: 25–114 (79.9 ± 29.7) Ritvo-Freeman Real-Life Rating superior in improving repetitive thoughts
Fluvoxamine: 15 Scale and behaviour (P < 0.001), problem
Placebo:15 behaviour (P < 0.001), aggression (P < 0.03),
FU: 12 weeks some aspects of social relatedness (P <
0.04), and language usage (P < 0.008). Age,
the severity of autism symptoms, and the
level of IQ did not influence the treatment
response.
Other than mild sedation and nausea in a
few cases, fluvoxamine was well tolerated.
No one reported dyskinesias, seizures,
electrocardiograph change, anticholinergic,
or adverse cardiovascular events.
Jadad = 3
(Continued )
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8

Deb et al
Table 1 (Continued )
Study type, Participants (N, Age
(methods used (mean ± s.d.), gender,
for ASD IQ (mean ± s.d.),
Study author and date diagnosis) Dose of medications Intervention, FU Outcome measures used Findings, Jadad score Comments
Sugie et al, 200531 A crossover study Fluvoxamine 1–3 mg/kg body N = 19 (18 completed) BAS, CGI Fluvoxamine showed a statistically Small sample size risking a type II error.
in the context of weight/day Age: 3 years - 8 years 5 significant improvement in two (flighty eye No adjustment is made for multiple
genetic evaluation months (mean: 5 years movements and delayed or peculiar or comparisons to avoid any type I error.
(DSM-IV) 4 months) inappropriate speech) of the 20 BAS items
Male: 79% compared with the placebo.
IQ: Not reported Fluvoxamine did not show any significant
Fluvoxamine/Placebo: adverse effects other than transient nausea
18 and hyperactivity.
FU: 12 weeks Jadad = 5
Sertraline
Potter et al, 201932 Parallel design Sertraline (20 mg/mL), under N = 58 (45 completed) MSEL (expressive language ITT analysis did not show any significant Small sample size risking a type II error.
(DSM-IV, ADOS) four years: 2.5 mg/day (0.125 Age: 2–6 years raw score and age equivalent intergroup difference in any outcome
mL); four years or older: 5 mg/ Male: 79.5% combined score), CGI, PVET, measure.
day (0.25 mL). IQ: (DQ: sertraline: VABS-II, ABC-C, PAS-R, SRS, No statistically significant intergroup
48.72 ± 28.46; SPM-P, PLS-5, Visual Analog difference in the rate of adverse effects. No
placebo: 50.63 ± Scale sertraline-associated serious adverse event
24.05) was reported.
Sertraline: 24 Jadad = 4
Placebo: 21
FU: 6 months
Venlafaxine
Carminati et al, 201633 Parallel design Venlafaxine 18.75 mg/day N = 13 ABC, BPI, CGI Reduction in Univariate analyses showed that the Small sample size. Very complicated
(ICD-10) Zuclopenthixol or clonazepam Age : venlafaxine : 18– usual doses of zuclopenthixol symptom of irritability improved in the entire design involving the use of additional
introduced or continued with 30 years (median : 22 or clonazepam, Simpson- sample (P = 0.061), although no difference medications, which makes
dose adjustment as necessary years); placebo: 19–32 Angus Rating Scale was observed between the venlafaxine and interpretation of the findings difficult.
years (median : the placebo group. No significant decrease Different results are shown depending
19 years) in hyperactivity/noncompliance was on the statistical analysis used
Male: 84.5% observed during the study. Global (univariate v. multivariate).
IQ: 100% IDD improvement was observed in 33% of
Venlafaxine: 6 participants treated with venlafaxine and in
Placebo: 7 71% of participants in the placebo group (P
FU: 8 weeks = 0.29). Decreased cumulative doses of
clonazepam and zuclopenthixol were
required for the venlafaxine group.
Multivariate analyses (principal component
analyses) with at least three combinations of
variables showed that the two populations
could be clearly separated (P < 0.05).
A few adverse effects in the venlafaxine
group included excessive salivation, slight
elbow stiffness, mild finger tremor, and
head dropping. No comparative data for the
placebo group is provided by the authors.
Jadad = 3
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Niederhofer, 200434 Crossover Venlafaxine: 30 mg/day N = 15 (14 completed) CGAS, CGI, ABC, Modified No statistically significant intergroup Very small all-male clinic sample, so the
(ICD-10) Age: 5.2–11.7 years CPRS difference in the clinician’s rating of generalisability of the findings is
(7.1 ± 3 years) videotaped behaviour according to CPRS, questionable.
Male: 100% CGAS, and CGI. Statistically significant better
IQ: 55-79 (67 ± 12) improvement in ABC sub scores of irritability
Venlafaxine/Placebo: (P = 0.04), inadequate eye contact (P =
14 0.042), hyperactivity (P = 0.035), and lethargy
FU: 6 weeks (P = 0.043) according to the teacher’s rating
during the venlafaxine treatment compared
with the placebo phase.
Adverse effects such as increased thirst,
drowsiness, sleep disturbance, sadness,
dizziness, irritability, decreased activity have
been reported in the venlafaxine treatment
group but without providing the number of
participants affected or any comparative
data in the placebo phase.
Jadad = 3

Antidepressant and anti‐anxiety medications for autism spectrum disorder

ABC, Aberrant Behaviour Checklist; ABC-C, Aberrant Behavior Checklist-Community version; ADI-R, Autism Diagnostic Interview-Revised; ADOS-CTS, Autism Diagnostic Observation Schedule-Composite Total Score; ADOS-SA, Autism Diagnostic Observation Schedule-Social
Affect; ADOS-RRB, Autism Diagnostic Observation Schedule-Restricted and Repetitive Behaviour; ASD, Autism Spectrum Disorder; BAS, Behaviour Assessment Scale; BPI, Behaviour Problems Inventory; CARS, Childhood Autism Rating Scale; CGAS, Children’s Global
Assessment Scale; CGI, Clinical Global Impressions Scale; CGI-I, Clinical Global Impressions-Improvement Scale; CI, Confidence Interval, CPRS OCD subscale, Comprehensive Psychological Rating Scale Obsessive Behaviour Disorder subscale; CSQ, Caregiver Strain
Questionnaire; C-YBOCS-PDD, Children’s Yale-Brown Obsessive Compulsive Scale-Modified for Pervasive Developmental Disorders; df, degree of freedom; DOTES, Dosage Treatment Emergent Symptom Scale; DSM-V, Diagnostic and Statistical Manual of Mental Disorders, 5th
Edition; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Text Revision; DSM-III-R, Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition-Revised; DQ,
Development Quotient; ESRS, Extrapyramidal Symptom Rating Scale; FU, Follow-up; ICD-10, International Classification of Diseases 10th Revision; HAM-D, Hamilton Depression Rating Scale; IDD, Intellectual and Developmental Disability; ITT, Intention to Treat; IQ, Intelligence
Quotient; MSEL, Mullen Scales of Early Learning; N, number; PAS-R, Preschool Anxiety Scale-Revised; PLS-5, Preschool Language Scales, 5th Edition; PVET, Passive-Viewing Eye Tracking Task; RBS, Repetitive Behavior Scale; RRB, Restrictive Repetitive Behaviors; SD, Standard
deviation; SE: Standard Error; SoL, Sleep onset Latency; SPM-P, Sensory Processing Measure-Preschool; SPS, Sensory Profile Scale; SRS, Social Responsiveness Scale; TiB, Time in Bed; TST, Total Sleep Time; VABS-II, Vineland-Adaptive Behaviour Scale-II (maladaptive behaviors);
YBOCS, Yale-Brown Obsessive Compulsive Scale.
9
 Deb et al

significant difference was not sustained when baseline imbalance Quality of the included papers
between the two groups was adjusted for, and the confidence inter- The Cochrane risk-of-bias analysis showed seven out of 15 studies
val of the difference in the outcome score included minimal clinic- (46.66%) scored a high risk in at least one item, of whom four
ally effective difference. The smaller crossover RCT27 and parallel- (26.66%) showed a high risk in two items (see Fig. 2). Ten out of
design28 RCT showed a significantly better efficacy of fluoxetine 15 studies (66.66%) received a Jaded score of <5.
over placebo.
Meta-analysis (RRB and CGI scores)
Fluvoxamine. In two small trials on fluvoxamine, one involved 19 Using YBOCS-/C-YBOCS-based RRB scores, we managed to pool
children in a crossover trial31 and the other involved 30 adults in a data for meta-analysis from seven (46.66%) out of 15 RCTs (four
parallel-design RCT.30 The parallel-design study30 showed a statis- on fluoxetine, one on fluvoxamine, one on citalopram and one on
tically significant better effect of fluvoxamine on RRB and social buspirone) (see Fig. 3). Similarly, using the CGI-I score, we were
communication and aggression. The crossover study31 was carried able to pool data from seven RCTs, all of which were on antidepres-
out in the context of a genetic study, which showed a significant sants (46.66%) (four on fluoxetine, one on citalopram, one on ser-
improvement in two of the 20 items (10%) in a behaviour scale traline and one on venlafaxine) (see Fig. 4). Altogether, it was
devised by the authors in the fluoxetine compared with the possible to pool data from nine (60%) RCTs. Fluoxetine and
placebo phase. citalopram did not show any significant inter-group difference,
but the fluvoxamine score was significantly better than the
Citalopram. One large-scale, parallel-design RCT involving 149 chil- placebo. Buspirone data could not be pooled together as there was
dren23 did not show any significant inter-group difference between the only one study that used RRB as an outcome, which showed a
citalopram and the placebo group in RRB and CGI-I score. significantly better effect of the medication when the two different
doses were combined (i.e. 5 mg and 2.5 mg twice daily dose, respect-
ively). The overall pooled data on antidepressants and anti-anxiety
Venlafaxine. There were two small RCTs involving venlafaxine: medication did not show any statistically significant inter-group
one included 14 male children in a crossover study34 and found con- difference, although the heterogeneity was high at I2 = 71 (see
flicting evidence depending on the outcome measure used, and Fig. 3). Neither the individual antidepressants nor the pooled
another study included3313 children in a parallel-design RCT and data on CGI-I showed any statistically significant inter-group
did not find any significant inter-group difference in efficacy. difference, and the heterogeneity was low at I2 = 0 (see Fig. 4).
Funnel plots did not show any publication bias for either
forest plot, and Egger’s test scores were P = 0.42 for the YBOCS
Sertraline. A parallel-design study involving 58 children did not
and P = 0.87 for the CGI-I forest plot, respectively. When the
show any significant inter-group difference in the efficacy
studies with a high risk of bias were removed from the meta-analysis,
between sertraline and the placebo.32
the medication group did not show any significant difference from
the placebo group.
Agomelatine. A crossover trial of 23 adults showed improvement
in night total sleep time but no other sleep parameters during ago-
melatine treatment, but not in the placebo phase.20 No ASD core Discussion
symptoms were assessed in this study.
We did not find any RCT involving paroxetine, escitalopram, Overall findings
mirtazapine, duloxetine or vortioxetine. Our systematic review found 13 RCTs involving antidepressants
clomipramine, fluvoxamine, fluoxetine, citalopram, sertraline, ven-
lafaxine and agomelatine, and two on the anti-anxiety medication
Anti-anxiety medication buspirone. The evidence for the efficacy of old-generation tricyclic
Buspirone. We found two parallel-design RCTs on buspirone, antidepressants in improving ASD symptoms and associated behav-
involving 40 and 166 children.21,22 The larger study21 did not show iour is lacking, based on only two small crossover trials with contra-
any significant inter-group difference in the primary outcome dictory results. Tricyclics are not recommended for use because of
measure of Autism Diagnostic Observation Schedule composite their anticholinergic and cardiac adverse effects, and the risk of
score48 at the 24-week follow-up. For RRB, 5 mg twice daily dose fatality associated with overdose. As for the new generation of anti-
and placebo did not show any significant change from baseline, but depressants (SSRIs and serotonin–noradrenaline reuptake inhibi-
2.5 mg twice daily dose showed a significant improvement. The tors), the evidence is non-conclusive. Only three studies included
smaller study22 showed a significant improvement in the Aberrant >100 participants (158 and 146 children for fluoxetine, and 149 chil-
Behaviour Checklist irritability subscale score44 in the buspirone dren for citalopram respectively). The citalopram study did not
compared with the placebo group. show a statistically significant inter-group difference. Of the two
large fluoxetine studies, one did not show any superiority over
placebo, and although the other one showed the superiority of flu-
Adverse effects oxetine in the initial analysis, this difference disappeared when
In most studies, there was no statistically significant inter-group dif- adjusted for baseline inter-group imbalance and the confidence
ference in the rate of medication-related adverse events, except for a intervals were taken into account. This study also had a high
large study of citalopram23 and a small study of clomipramine (see drop-out rate.
Table 1).25 In the large study, citalopram was more significantly The rest of the smaller studies showed contradictory results,
associated with adverse events, such as hyperactivity, decreased con- with some showing superiority of the medication over placebo
centration, impulsiveness and stereotype, compared with the and the others not. Only one of the two RCTs on buspirone included
placebo.23 In the other study, clomipramine25 was more signifi- >100 participants (166 children), which did not show any inter-
cantly associated with problem behaviour, fatigue, tremor and group difference in the primary outcome of Autism Diagnostic
cardiac problems, compared with the placebo. Observation Schedule-Composite Score but showed a statistically

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 Antidepressant and anti‐anxiety medications for autism spectrum disorder

Identification
Titles identified through database Additional titles identified through
searching other sources
(n = 2304) (n = 2)

Titles after duplicates removed

(n = 1949)
Screening

Abstracts screened Abstracts excluded

(n =1949) (n = 1925)

Full-text articles assessed for Full-text articles excluded

(n = 9)
Eligibility

eligibility
(n = 24)

Reasons for exclusion

Neuroimaging study, no clinical

Studies included in outcome data (n = 2)
qualitative synthesis
(n = 15) Single-dose administration of
propranolol (n = 4)
Included

Antidepressant was tianeptine,

which is withdrawn from the
Studies included in market (n = 1)
quantitative synthesis
(meta-analysis) Effect of tryptophan depletion
(n = 9) rather than any medication (n = 1)

Children with fragile X syndrome

were included but data on children
with ASD were incomplete (n = 1)

Fig. 1 Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) flow chart of paper selection. ASD, autism spectrum
disorder.

significant improvement in RRB only with the smaller daily dose Methodological issues
(2.5 mg twice daily), but not the higher dose (5 mg twice daily).
No RCT was found on any other anti-anxiety medications such as Most studies were on children, but some included data on adults with
benzodiazepines or beta-blockers (the only RCTs on beta-blockers ASD, and no specific age effect was observable from the data presented
were on a single-dose administration; see Supplementary in Table 1.20–34 Of the 15 RCTs, six (40%) used a crossover design.
Appendix 3). Benzodiazepines are not recommended for long- Crossover design may not be ideal to assess long-standing behaviour
term use because of their effect on cognition, paradoxical emergence outcomes, particularly if the washout period is relatively short, as is
of aggression, tolerance and addiction. Similarly, the administration the case in the included studies. Several studies recruited participants
of high doses of beta-blockers risks adverse effects such as lowering with ASD who also had IDD, but often did not present data separately
of blood pressure and respiratory failure. on those participants. Therefore, it is difficult to assess the influence of
Meta-analysis showed no statistically significant inter-group IQ on the outcome.
difference between antidepressants and the placebo. These findings The overall quantity and quality of the RCTs are, at best, poor.
are consistent with the previous Cochrane review.9 However, we However, our meta-analysis mitigates that to some extent. Based on
included additional RCTs that were not included in the previous the currently available weak and contradictory evidence, our sys-
Cochrane review.9 tematic review can neither support nor refute the use of antidepres-
We have also carried out a systematic review on the RCTs of sant and anti-anxiety medications for the treatment of ASD core
anti-anxiety medication on people with ASD, which was not done symptoms such as RRB, impaired social communication or asso-
before. ciated behaviour such as aggression, irritability and agitation,

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 Deb et al

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Random sequence generation (selection bias)

Incomplete outcome data (attrition bias)

Allocation concealment (selection bias)

Selective reporting (reporting bias)

Other bias
Ballester et al, 201920

Carminati et al, 201633

Chugani et al, 201621

Ghanizadeh and Ayoobzadehshirazi, 201522

Gordon et al, 199324

Herscu et al, 202026

Hollander et al, 200527

Hollander et al, 201228

King et al, 200923

McDougle et al, 199630

Niederhofer, 200434

Potter et al, 201932

Reddihough et al, 201929

Remington et al, 200125

Sugie et al, 200531

Fig. 2 Cochrane risk-of-bias summary scores.20–34

despite their widespread use in this population. However, this sys- any significant inter-group difference in the rate of adverse effects
tematic review does not answer the question of whether antidepres- in most studies, these medications have known adverse effects.
sants and anti-anxiety medications are effective in treating Therefore, the clinicians considering the use of these medications
depression and anxiety in people with ASD, as we did not find for people with ASD, particularly to treat ASD core symptoms
any RCTs involving these medications for the treatment of depres- and associated behaviours, should carefully weigh up the supporting
sion and anxiety in the ASD population. In fact, most included evidence (or lack of it) and the potential for adverse effects, which
RCTs excluded participants with a comorbid psychiatric disorder may be more pronounced in people with ASD.
(see Supplementary Appendix 9). Therefore, the evidence for this Information on funding was not available for three studies, but
has to be extrapolated from studies done on individuals without the available data shows that apart from possibly one exception, the
ASD. Although the RCTs included in our review did not show rest of the studies were not funded by any pharmaceutical company

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 Antidepressant and anti‐anxiety medications for autism spectrum disorder

Standardised mean Standardised mean

Medication Placebo difference difference
Study or subgroup Mean s.d. Total Mean s.d. Total Weight IV, random, 95% CI IV, random, 95% CI
1.1.1 Fluoxetine
Herscu et al, 202026 13.5 3.3 78 12.4 3.6 80 17.7% 0.32 [0.00−0.63]
Hollander et al, 200527 11.77 3.2 20 12.38 2.4 19 11.0% −0.21 [−0.84 to 0.42]
Hollander et al, 201228 10.48 3.92 21 11.15 3.05 13 10.0% −0.18 [−0.87 to 0.51]
Reddihough et al, 201929 9.02 4.84 75 10.89 4.29 71 17.4% −0.41 [−0.73 to −0.08]
Subtotal (95% Cl) 194 183 56.1% −0.10 [−0.52, to −0.31]
Heterogeneity: Tau2 = 0.12; Chi2 = 10.15, d.f. = 3 (P = 0.02); I2 = 70%
Test for overall effect: Z = 0.48 (P = 0.63)

1.1.2 Citalopram
King et al, 200923 13.1 3.7 73 13.1 3.2 76 17.5% 0.00 [−0.32 to 0.32]
Subtotal (95% Cl) 73 76 17.5% 0.00 [−0.32 to 0.32]
Heterogeneity: not applicable
Test for overall effect: Z = 0.00 (P = 1.00)

1.1.3 Fluvoxamine
McDougle et al, 199630 13.7 9.1 15 21.9 6.7 15 8.9% −1.00 [−0.76 to 0.23]
Subtotal (95% Cl) 15 15 8.9% −1.00 [−1.76 to 0.23]
Heterogeneity: not applicable
Test for overall effect: Z = 2.56 (P = 0.01)

1.1.4 Buspirone
Chugani et al, 201621 10.8982 0.6301 109 11.2 0.6 57 17.4% −0.48 [−0.81 to −0.16]
Subtotal (95% Cl) 109 57 17.4% −0.48 [−0.81 to −0.16]
Heterogeneity: not applicable
Test for overall effect: Z = 2.93 (P = 0.003)

Total (95% Cl) 391 331 100.0% −0.23 [−0.53 to 0.07]

Heterogeneity: Tau2 = 0.10; Chi2 = 20.43, d.f. = 6 (P = 0.002); I2 = 71%
Test for overall effect: Z = 1.52 (P = 0.13) −2 −1 0 1 2
Test for subgroup differences: Chi2 = 8.50, d.f. = 3 (P = 0.04), I2 = 64.7% Favours medication Favours placebo

Fig. 3 Forest plot based on the Children-Yale-Brown Obsessive Compulsive Scale (Y-BOCS) pooled data.

Standardised mean Standardised mean

Standardised mean difference difference
Study or subgroup difference s.e. Weight IV, random, 95% CI IV, random, 95% CI
1.1.1 Fluoxetine
Herscu et al, 202026 −0.29191 −0.19731 21.2% −0.29 [−0.68 to 0.09]
Hollander et al, 200527 −0.522 0.3264 7.7% −0.52 [−1.16 to 0.12]
Hollander et al, 201228 −0.3855 0.3598 6.4% −0.39 [−1.09 to 0.32]
Reddihough et al, 201929 −0.1434 0.1658 30.0% −0.14 [−0.47 to 0.18]
Subtotal (95% Cl) 65.3% −0.26 [−0.48 to −0.04]
Heterogeneity: Tau2 = 0.00; Chi2 = 1.29, d.f. = 3 (P = 0.73); I2 = 0%
Test for overall effect: Z = 2.31 (P = 0.02)

1.1.2 Venlafaxine
Carminati et al, 201633 0.38 0.5635 2.6% 0.38 [−0.72 to 1.48]
Subtotal (95% Cl) 2.6% −0.26 [−0.72 to 1.48]
Heterogeneity: not applicable
Test for overall effect: Z = 0.67 (P = 0.50)

1.1.3 Citalopram
King et al, 200923 −0.03297 0.191411 22.5% −0.03 [−0.41 to 0.34]
Subtotal (95% CI) 22.5% −0.03 [−0.41 to 0.34]
Heterogeneity: not applicable
Test for overall effect: Z = 0.17 (P = 0.86)

1.1.4 Sertraline
Potter et al, 201932 0.0846 0.2935 9.6% 0.08 [−0.49 to 0.66]
Subtotal (95% Cl) 9.6% 0.08 [−0.49 to 0.66]
Heterogeneity: not applicable
Test for overall effect: Z = 0.29 (P = 0.77)

Total (95% Cl) 100.0% −0.16 [−0.34 to 0.02]

Heterogeneity: Tau2 = 0.00; Chi2 = 4.13, d.f. = 6 (P = 0.66); I2 = 0%
−4 −2 0 2 4
Test for overall effect: Z = 1.75 (P = 0.08)
Favours medication Favours placebo
Test for subgroup differences: Chi2 = 2.85, d.f. = 3 (P = 0.42), I2 = 0%

Fig. 4 Forest plot based on the Clinical Global Impression-Improvement Scale (CGI-I) pooled data.

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 Deb et al

(see Supplementary Appendix 9). Therefore, the findings from these Medicine, Imperial College London, UK; Jacopo Santambrogio, MD, Clinical
studies could be considered independent and not influenced by the Neuroscience PhD program, Department of Medicine and Surgery, University of Milano-
Bicocca, Italy; Ashok Roy , MBBS, MA, FRCPsych, Warwick Medical School, University
funding organisations. of Warwick, UK; Marco O. Bertelli, MD, FISP, Research and Clinical Centre, San
Sebastiano Foundation of the Misericordia of Florence, Italy

Weakness Correspondence: Shoumitro Deb. Email: [email protected]

Several drawbacks have to be considered when interpreting the data First received 7 Apr 2021, final revision 27 Jul 2021, accepted 16 Aug 2021

of this systematic review. Different studies used different outcome

measures, which produced heterogeneity when the findings were
combined. As a result, we could only pool data for meta-analysis
Supplementary material
from those studies that used the same outcome measure, such as
the YBOCS/C-YOBCS and CGI-I, which were reported in only Supplementary material is available online at https://doi.org/10.1192/bjo.2021.1003

nine (60%) of the 15 RCTs. Although the meta-analysis of CGI-I

data showed no heterogeneity, the forest plot involving data from Data availability
YBOCS/C-YBOCS scores showed high heterogeneity. Another Data availability does not apply to this article as no new data were created or analysed in this
major problem is the small sample size in most studies. For study.

example, only four studies (26.7%) included >100 participants.

This makes the findings from most of these studies difficult to gen- Acknowledgements
eralise. Almost half of the studies have also shown at least one area We thank Andy Hough, the librarian at Brooklands Hospital, Coventry, UK, and Annalisa Bardelli,
of a high risk of bias according to the Cochrane risk-of-bias the Librarian at the University of Milano-Bicocca, Milan, Italy for carrying out the literature
search.
assessment.
Author contributions
Strengths
S.D., B.L., M.R., and J.S. conceptualised and designed the study. A.R., S.D. and M.O.B. carried out
Our review used a very stringent methodology, including hand- journal searches. M.R. and J.S. screened bibliographies and R.L. and M.M. extracted data and
completed risk-of-bias checklist. B.L. carried out the meta-analysis. All authors contributed
searching of 12 relevant journals, and should have captured the to manuscript writing and authorised the final version of the manuscript.
most relevant RCTs. This is reflected in the full score of the
AMSTAR 2, apart from one noncritical item for not including Funding
grey literature. It is still possible to miss relevant papers and we
B.L. is funded by the Research for Patient Benefit programme (grant number PBPG-0817-20010)
only included English-language papers. Another problem is that of the National Institute for Health Research. The Imperial Biomedical Research Centre Facility,
studies with positive findings tend to be published more often which is funded by the National Institute for Health Research, provided support for the study.
The views expressed in this article are those of the authors and not necessarily those of the
than studies with a negative finding, creating a publication bias. National Health Service, the National Institute for Health Research or the Department of Health.
However, the funnel plots in our review did not show any major
publication bias. Another strength of this review is that it is regis- Declaration of interest
tered on PROSPERO, so the study protocol is publicly available
None.
(www.crd.york.ac.uk/prospero).

Future direction References

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