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 |
| Placebo | None | 80 | |||||||||||
| 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 |
| 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 |
| 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 |
| Placebo | None | 10 | |||||||||||
| 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 |
| Placebo | None | 15 | |||||||||||
| 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 |
| 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 |
| Placebo | None | 20 | |||||||||||
| 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 |
| 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 |
| Placebo | None | 15 | |||||||||||
| 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 |
| 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 |
| 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 |
| Placebo | None | 12 | |||||||||||
| 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 |
| Placebo | 10 | ||||||||||||
| 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 |
| Haloperidol 0.02–0.05 mg/kg/d | NA | 8 | |||||||||||
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.