Table 1

Characteristics of studies in the meta-analysis

StudyDiagnosis (criteria)Exclusion criteriaDesignIntervention and comparatorDuration, wkOutcomeIQCGI-SMean age, yr (range)Female, %Country
SSRI versus placebo
 Herscu et al.30 (2020)ASD (DSM-IV-TR)AS, PDD-NOS, Rett syndrome, childhood disintegrative disorder, active seizure disorder; taking psychotropic medication; high levels of aggression or self-injurious behaviourRCTFluoxetine 2–18 mg/dNA7814CY-BOCS-PDDNA4.879 (5–17)14.55United States
 Potter et al.29 (2019)ASD (DSM-5)Fragile X syndrome full mutation; serious comorbid medical disorder affecting brain functionRCTSertraline 2.5–5 mg/dNA3224VAS (anxiety/ obsessive–compulsive behaviour, aggression/ hyperarousal/ hyperactivity, language/ communication); CGI-I; SRS; PARS-R49.6NA4.03 (2–6)20.7United States
 Reddihough et al.41 (2019)ASD (DSM-IV-TR)Rett syndrome, childhood disintegrative disorder, schizophrenia or major depression; taking psychotropic medications; comorbid medical conditionsRCTFluoxetine 4–30 mg/dNA7516CY-BOCS-PDD; CGI-I; ABC (irritability, hyperactivity, social withdrawal, inappropriate speech); Spence children anxietyNANA11.2 (7.5–18)15Australia
 Sikich et al.44 (2014)*Autism (DSM-III-R)AS, PDD-NOS, Rett syndrome, childhood disintegrative disorderRCTFluoxetine 2–20 mg/dNA848ABC (irritability)NANA3.62 (2.5–4.8)0United States
 Hollander et al.39 (2012)ASD (DSM-IV); CGI-S ≥ 4NoneRCTFluoxetine 20–80 mg/d3.242212Y-BOCS; CGI-I1034.3934.31 (18–60)31United States
 King et al.38 (2009)AD, AS, PDD-NOS (DSM-IV-TR); CGI-S ≥ 4Rett syndrome or childhood disintegrative disorder; seizure within the past 6 mo, weight < 15 kg; bipolar disorder or manic episodeRCTCitalopram 10–20 mg/dNA7312CY-BOCS-PDD; ABC (irritability, hyperactivity, social withdrawal, inappropriate speech)NA4.949.36 (5–17)14.1United States
 Hollander et al.36 (2005)ASD (DSM-IV-TR)Psychotic disorders, seizures; clinically significant medical illnessRCT/ cross-overFluoxetine 4.8–20 mg/dNA198CY-BOCS; CGI-I63.74.618.18 (5–17)23.1United States
 Sugie et al.37 (2005)Autism (DSM-IV)Underlying diseases, such as chromosomal aberration; congenital rubella syndrome, apparent neurologic deficitsRCT/ cross-overFluvoxamine 1–3 mg/kg/dNA1812BAS (emotional instability, hyperactivity, social withdrawal, inappropriate speech)NANA5.33 (3–8.5)26.7Japan
 McDougle et al.34 (1996)AD (DSM-III-R); CGI-S ≥ 4Schizophrenia, psychotic symptoms, illicit substances within the previous 6 mo; notable medical condition, including seizure disorder; pregnancyRCTFluvoxamine 50–300 mg/d2.771512Y-BOCS; CGI-I; Brown Aggression Scale79.94.1230.1 (18–53)10United States
SNRI versus placebo
 Carminati et al.40 (2016)PDD (ICD-10); mild to profound IDEpilepsy or any indication against somatic–psychotropic treatments; pregnancyRCTVenlafaxine 18.75 mg/d0.18568ABC (stereotype); CGI-I; ABC (irritability, hyperactivity, social withdrawal, inappropriate speech)NANA22 (18–30)15.4Switzerland
PlaceboNone7Median: 19 (19–31)
Tricyclic antidepressant versus placebo
 Remington et al.35 (2001)Autism (DSM-IV)NARCT/ cross-overClomipramine 100–150 mg/dNA367ABC (repetitive behaviours, irritability, hyperactivity, social withdrawal, inappropriate speech); CARSNANA16.3 (10–36)16.7Canada
 Gordon et al.33 (1993)AD (DSM-III-R)Significant problems, including seizuresRCT/ cross-overClomipramine 25–250 mg/dNA1210Modified CPRS OCD subscale; CPRS autism-relevant subscale57.1NA11.7 (6–23)33.3United States
 Gordon et al.31 (1992)AD (DSM-III-R)Significant medical problems, including seizuresRCT/ cross-overClomipramine 25–250 mg/dNA75NIMH-GOCS; CPRSNANA9.6 (6–18)28.6United States
Desipramine 25–250 mg/dNA7
Other antidepressant versus placebo
 McDougle et al.43 (2018)*AD, AS, PDD-NOS (DSM-IV)Rett syndrome, childhood integrative disorder, OCD, post-traumatic stress disorder, major mood disorder, psychotic disorder, substance use disorderRCTMirtazapine 7.5–45 mg/dNA2010PARSNANA11 (5–17)20United States
 Chugani et al.32 (2016)ASD (DSM-IV-TR)Neurologic disorders, phenylketonuria, tuberous sclerosis complex, Rett syndrome, Fragile X syndrome; Down syndrome; traumatic brain injury or other medical or behavioural problemsRCTBuspirone 5 mg/dNA5424CY-BOCS; ADOS-CTS; ABC (social withdrawal, inappropriate speech); anxiety composite score (ABC irritability + Leiter emotion regulation)64.1NA3.62 (2–6)17.5United States
Buspirone 10 mg/dNA55
Antidepressant versus antipsychotic
 Sanchez et al.42 (1995)AD (DSM-III-R; infantile autism (DSM-III)Identifiable causes of autism; seizures or other systemic diseaseRCT/ cross-overClomipramine 2.8–4.4 mg/kg/dNA84.5CGI-S; CPRS (hyperactivity, speech deviance)NANA5.6 (2.3–7.8)12.5United States
Haloperidol 0.02–0.05 mg/kg/dNA8
  • ABC = Aberrant Behavior Checklist; AD = autistic disorder; ADOS-CTS = Autism Diagnostic Observation Schedule Composite Total Score; AS = Asperger syndrome; ASD = autism spectrum disorder; BAS = Behavioural Assessment Scale; CARS = Childhood Autism Rating Scale; CGI-I = Clinical Global Impression–Improvement; CGI-S = Clinical Global Impression–Severity; CPRS = Children’s Psychiatric Rating Scale; CY-BOCS = Children’s Yale–Brown Obsessive–Compulsive Scale; CY-BOCS-PDD = Children’s Yale–Brown Obsessive–Compulsive Scale modified for pervasive developmental disorder; DDD = defined daily dose; DSM-III = Diagnostic and Statistical Manual of Mental Disorders, 3rd edition; DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised; 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-5 = Diagnostic and Statistical Manual of Mental Disorders, 5th edition; ICD-10 = International Statistical Classification of Diseases and Related Health Problems, 10th revision; ID = intellectual disability; NA = not available; NIMH-GOCS = National Institute of Mental Health Global Obsessive–Compulsive Scale; OCD = obsessive–compulsive disorder; PARS = Pediatric Anxiety Rating Scale; PARS-R = Pediatric Anxiety Rating Scale revised; PDD = pervasive developmental disorder; PDD-NOS = pervasive developmental disorder, not otherwise specified; RCT = randomized controlled trial; SNRI = serotonin and norepinephrine reuptake inhibitor; SRS = Social Responsiveness Scale; SSRI = selective serotonin reuptake inhibitor; VAS = visual analogue scale; Y-BOCS = Yale–Brown Obsessive–Compulsive Scale.

  • * Study identified from