Table 1

Characteristics of studies in the meta-analysis

Study	Diagnosis (criteria)	Exclusion criteria	Design	Intervention and comparator			Duration, wk	Outcome	IQ	CGI-S	Mean age, yr (range)	Female, %	Country

				Medication	DDD	n
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 behaviour	RCT	Fluoxetine 2–18 mg/d	NA	78	14	CY-BOCS-PDD	NA	4.87	9 (5–17)	14.55	United States
Herscu et al.30 (2020)	ASD (DSM-IV-TR)		RCT	Placebo	None	80		CY-BOCS-PDD
Potter et al.29 (2019)	ASD (DSM-5)	Fragile X syndrome full mutation; serious comorbid medical disorder affecting brain function	RCT	Sertraline 2.5–5 mg/d	NA	32	24	VAS (anxiety/ obsessive–compulsive behaviour, aggression/ hyperarousal/ hyperactivity, language/ communication); CGI-I; SRS; PARS-R	49.6	NA	4.03 (2–6)	20.7	United States
Potter et al.29 (2019)	ASD (DSM-5)		RCT	Placebo	None	26
Reddihough et al.41 (2019)	ASD (DSM-IV-TR)	Rett syndrome, childhood disintegrative disorder, schizophrenia or major depression; taking psychotropic medications; comorbid medical conditions	RCT	Fluoxetine 4–30 mg/d	NA	75	16	CY-BOCS-PDD; CGI-I; ABC (irritability, hyperactivity, social withdrawal, inappropriate speech); Spence children anxiety	NA	NA	11.2 (7.5–18)	15	Australia
Reddihough et al.41 (2019)	ASD (DSM-IV-TR)		RCT	Placebo	None	71
Sikich et al.44 (2014)^*	Autism (DSM-III-R)	AS, PDD-NOS, Rett syndrome, childhood disintegrative disorder	RCT	Fluoxetine 2–20 mg/d	NA	8	48	ABC (irritability)	NA	NA	3.62 (2.5–4.8)	0	United States
Sikich et al.44 (2014)^*	Autism (DSM-III-R)		RCT	Placebo	None	10		ABC (irritability)
Hollander et al.39 (2012)	ASD (DSM-IV); CGI-S ≥ 4	None	RCT	Fluoxetine 20–80 mg/d	3.24	22	12	Y-BOCS; CGI-I	103	4.39	34.31 (18–60)	31	United States
Hollander et al.39 (2012)	ASD (DSM-IV); CGI-S ≥ 4	None	RCT	Placebo	None	15		Y-BOCS; CGI-I
King et al.38 (2009)	AD, AS, PDD-NOS (DSM-IV-TR); CGI-S ≥ 4	Rett syndrome or childhood disintegrative disorder; seizure within the past 6 mo, weight < 15 kg; bipolar disorder or manic episode	RCT	Citalopram 10–20 mg/d	NA	73	12	CY-BOCS-PDD; ABC (irritability, hyperactivity, social withdrawal, inappropriate speech)	NA	4.94	9.36 (5–17)	14.1	United States
King et al.38 (2009)	AD, AS, PDD-NOS (DSM-IV-TR); CGI-S ≥ 4		RCT	Placebo	None	76
Hollander et al.36 (2005)	ASD (DSM-IV-TR)	Psychotic disorders, seizures; clinically significant medical illness	RCT/ cross-over	Fluoxetine 4.8–20 mg/d	NA	19	8	CY-BOCS; CGI-I	63.7	4.61	8.18 (5–17)	23.1	United States
Hollander et al.36 (2005)	ASD (DSM-IV-TR)		RCT/ cross-over	Placebo	None	20		CY-BOCS; CGI-I
Sugie et al.37 (2005)	Autism (DSM-IV)	Underlying diseases, such as chromosomal aberration; congenital rubella syndrome, apparent neurologic deficits	RCT/ cross-over	Fluvoxamine 1–3 mg/kg/d	NA	18	12	BAS (emotional instability, hyperactivity, social withdrawal, inappropriate speech)	NA	NA	5.33 (3–8.5)	26.7	Japan
Sugie et al.37 (2005)	Autism (DSM-IV)		RCT/ cross-over	Placebo	None	18
McDougle et al.34 (1996)	AD (DSM-III-R); CGI-S ≥ 4	Schizophrenia, psychotic symptoms, illicit substances within the previous 6 mo; notable medical condition, including seizure disorder; pregnancy	RCT	Fluvoxamine 50–300 mg/d	2.77	15	12	Y-BOCS; CGI-I; Brown Aggression Scale	79.9	4.12	30.1 (18–53)	10	United States
McDougle et al.34 (1996)	AD (DSM-III-R); CGI-S ≥ 4		RCT	Placebo	None	15		Y-BOCS; CGI-I; Brown Aggression Scale
SNRI versus placebo
Carminati et al.40 (2016)	PDD (ICD-10); mild to profound ID	Epilepsy or any indication against somatic–psychotropic treatments; pregnancy	RCT	Venlafaxine 18.75 mg/d	0.185	6	8	ABC (stereotype); CGI-I; ABC (irritability, hyperactivity, social withdrawal, inappropriate speech)	NA	NA	22 (18–30)	15.4	Switzerland
Carminati et al.40 (2016)	PDD (ICD-10); mild to profound ID		RCT	Placebo	None	7					Median: 19 (19–31)
Tricyclic antidepressant versus placebo
Remington et al.35 (2001)	Autism (DSM-IV)	NA	RCT/ cross-over	Clomipramine 100–150 mg/d	NA	36	7	ABC (repetitive behaviours, irritability, hyperactivity, social withdrawal, inappropriate speech); CARS	NA	NA	16.3 (10–36)	16.7	Canada
Remington et al.35 (2001)	Autism (DSM-IV)	NA	RCT/ cross-over	Placebo	None	36
Gordon et al.33 (1993)	AD (DSM-III-R)	Significant problems, including seizures	RCT/ cross-over	Clomipramine 25–250 mg/d	NA	12	10	Modified CPRS OCD subscale; CPRS autism-relevant subscale	57.1	NA	11.7 (6–23)	33.3	United States
Gordon et al.33 (1993)	AD (DSM-III-R)	Significant problems, including seizures	RCT/ cross-over	Placebo	None	12		Modified CPRS OCD subscale; CPRS autism-relevant subscale
Gordon et al.31 (1992)	AD (DSM-III-R)	Significant medical problems, including seizures	RCT/ cross-over	Clomipramine 25–250 mg/d	NA	7	5	NIMH-GOCS; CPRS	NA	NA	9.6 (6–18)	28.6	United States
				Desipramine 25–250 mg/d	NA	7
				Placebo	None	7
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 disorder	RCT	Mirtazapine 7.5–45 mg/d	NA	20	10	PARS	NA	NA	11 (5–17)	20	United States
McDougle et al.43 (2018)^*	AD, AS, PDD-NOS (DSM-IV)		RCT	Placebo		10		PARS
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 problems	RCT	Buspirone 5 mg/d	NA	54	24	CY-BOCS; ADOS-CTS; ABC (social withdrawal, inappropriate speech); anxiety composite score (ABC irritability + Leiter emotion regulation)	64.1	NA	3.62 (2–6)	17.5	United States
				Buspirone 10 mg/d	NA	55
				Placebo	None	57
Antidepressant versus antipsychotic
Sanchez et al.42 (1995)	AD (DSM-III-R; infantile autism (DSM-III)	Identifiable causes of autism; seizures or other systemic disease	RCT/ cross-over	Clomipramine 2.8–4.4 mg/kg/d	NA	8	4.5	CGI-S; CPRS (hyperactivity, speech deviance)	NA	NA	5.6 (2.3–7.8)	12.5	United States
Sanchez et al.42 (1995)	AD (DSM-III-R; infantile autism (DSM-III)		RCT/ cross-over	Haloperidol 0.02–0.05 mg/kg/d	NA	8		CGI-S; CPRS (hyperactivity, speech deviance)

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 ClinicalTrials.gov.