Table 1 Characteristics of included Randomized Controlled Trials
Study, Year | Country | Diagnosis | Diagnostic criteria | Severity | Intervention (n) | Control(n) | Study design | Duration of intervention (wks) | Setting | Age mean (SD); range | Female (%) | Mental development | Outcomes | Funding |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Anderson, 1984 | USA | Autism | DSM-III | Not reported | Haloperidol 0.5 to 4.0 mg/day (20) | Placebo (20) | Crossover | 14 (2 weeks SB Placebo baseline, 12 weeks DB intervention: placebo/treatment/placebo or treatment/placebo/treatment) | Inpatient | 4.58 (NR); 2.3–6.9 | 27.5 | Not reported | Global changes (CGI-I, CGI-S), Behavior (CPRS), Social Interaction (CPTQ), discrimination learning, adverse events (DOTES), optimal dosages | McNeal Pharmaceuticals; NIMH |
Anderson, 1989 | USA | Autism | DSM-III | Not reported | Haloperidol 0.25 to 4.0 mg/day (15) | Placebo (30) | Crossover | 14 (2 weeks SB Placebo baseline, 12 weeks DB intervention: treatment/placebo/placebo or placebo/treatment/placebo or placebo/placebo/treatment) | Inpatient | 4.49 (1.16); 2.0–7.6 | 22.2 | Profound to borderline retardation | Global changes (CGI-I, CGI-S), Behavior (CPRS), Social Interaction (CPTQ), discrimination learning | McNeal Pharmaceuticals; NIMH; March of Dimes Birth Defects Foundation grant 12–108 |
Campbell, 1978 | USA | Autism | Not reported (Kanner and Rutter criteria) | Not reported | Haloperidol 0.5 to 4.0 mg/day, adaptive dose (21) | Placebo (21) | Parallel | 12 (2 weeks SB placebo, 3 weeks DB medication, 5 weeks DB medication plus behavioral therapy, 2 weeks SB placebo plus behavioral therapy) | Inpatient | 4.5 (NR); 2.6–7.2 | 20.0 | Not reported | McNeal Pharmaceutical; Behavior (CPRS, CBI, NGI), adverse events (DOTES), optimal dosages | NIHM |
Cohen, 1980 | USA | Autism | DSM-III | Not reported | Haloperidol 0.5 to 4.0 mg/day, adaptive dose (Not reported) | Placebo (Not reported) | Crossover | 10 (2 weeks SB placebo, 8 weeks intervention: placebo/Haldoperidol/placebo/Haldoperidol or vice-versa) | Inpatient | 4.7 (NR), 2.1–7.0 | 40.0 | Profound to mild retardation | Behavior, adverse events, optimal dosages | McNeal Pharmaceuticals; NIMH |
Findling, 2014 | USA | Autism | DSM-IV-TR; ADI-R | CGI-S ≥ 4; ABC-Irritability ≥ 18 | Aripiprazole 2 to 15 mg, adaptive dose (41) | Placebo (44) | Withdrawal | 30 (14 weeks open lable treatment, 16 weeks DB withdrawal) | Specialistic | 10.4 (2.8); 6.0–17.0 | 20.0 | MA ≥ 24 months | ABC, Global changes (CGI-I, CGI-S), quality of life (PedsQL), adverse events (AIMS, BARS, SAS) | Bristol-Myers Squibb; Otsuka Pharmaceuticals Co, Ltd |
Hellings, 2006 | USA | ASD | DSM-IV | ABC-I > 1SD above given norms for age, gender and setting | Risperidone 1.0 mg/day, fixed dose (NR); Risperidone 1.2 to 2.9 mg/day, adaptive dose (NR) | Placebo (NR) | Crossover | 22 weeks (4 weeks on average SB placebo, 2 weeks DB drug tapering, 4 weeks DB treatment, 2 weeks DB drug tapering, 4 weeks DB treatment, 2 weeks DB drug tapering, 4 weeks on average SB placebo) | Specialistic | 12.0 (2.8); 8.0–15.0 | 33.3 | IQ < 70 | ABC, adverse events (DISCUS) | Janssen Pharmaceutica |
Hollander, 2006 | USA | ASD | DSM-IV; ADI-R; ADOS | CGI-S ≥ 4 | Olanzapine 2.5 to 20 mg/day, adaptive dose (6) | Placebo (5) | Parallel | 8 | Specialistic | 9.1 (2.5); 6.0–14.8 | 18.1 | Profound retardation to normal | Global changes (CGI-I), compulsion (CY-BOCS), aggression (OASM), adverse events (AIMS, BAS, SAS) | Lilly Research Laboratories |
Ichikawa, 2017 | Japan | Autism | DSM-IV-TR; PARS | CGI-S ≥ 4; ABC-I ≥ 18 | Aripiprazole 1 to 15 mg/day, adaptive dose (47) | Placebo (45) | Parallel | 8 | Specialistic | 10.1 (3.2); 6.0–17.0 | 18.5 | IQ 20 to normal | Global changes, (CGI-S, CGAS), ABC, compulsion (CY-BOCS, compulsion scale only), adverse events (C-SSRS, AIMS, DIEPSS, BAS) | Otsuka Pharmaceutical Co., Ltd |
Kent, 2013 | USA | Autism | DSM-TR; ADI-R | CGI-S ≥ 4; ABC-I ≥ 18 | Risperidone 0.125 to 0.175 mg/day, fixed dose (30); Risperidone 1.25 to 1.75 mg/day, fixed dose (31) | Placebo (35) | Parallel | 32 (6 weeks DB treatment, 26 weeks open lable treatment) | Specialistic | 9.0 (3.1); 5.0–17.0 | 13.0 | MA ≥ 18 months | Global changes (CGI-S, CGI-I), ABC, compulsion (CY-BOCS), adverse events (EPS, SAS, BAS, AIMS) | Johnson & Johnson Pharmaceutical Research & Development, LLC |
Loebel, 2016 | USA | Autism | DSM-IV-TR; ADI-R | CGI-S ≥ 4; ABC-I ≥ 18 | Lurasidone 20 mg/day, fixed dose (49); Lurasidone 60 mg/day, fixed dose (51) | Placebo (49) | Parallel | 6 | Specialistic | 10.7 (3.0); 6.0–17.0 | 18.2 | Not reported | Global changes (CGI-I, CGI-S), ABC, compulsion (CY-BOCS), caregiver strain (CGSQ), adverse events (AIMS, SAS, BAS) | Sunovion Pharmaceuticals, Inc |
Luby, 2006 | USA | ASD | DSM-IV | CARS ≥ 30 | Risperidone 0.5 to 1.5 mg/day, adaptive dose (12) | Placebo (12) | Parallel | 26 | Specialistic | 4.0 (1.9); 2.5–6.0 | 26.1 | Not reported | CARS, GARS, adaptive behaviors (CBCL, VABS), communication (PLS-3) | Janssen Pharmaceutica |
Marcus, 2009 | USA | Autism | DSM-IV-TR; ADI-R | CGI-S ≥ 4; ABC-I ≥ 18 | Aripiprazole 5 mg/day, fixed dose (53); Aripiprazole 10 mg/day, fixed dose (59); Aripiprazole 15 mg/day (54) | Placebo (52) | Parallel | 8 | Specialistic | 9.7 (3.1), 6.0–17.0 | 10.6 | MA ≥ 18 months | CGI-S, ABC, quality of life (PedsQL), compulsion (CY-BOCS), caregiver strain (CGSQ), adverse events (EPS, SAS, BAS, AIMS) | Bristol-Myers Squibb; Otsuka Pharmaceutical Co., Ltd |
McCraken, 2002 | USA | Autism | DSM-IV; ADI-R | CGI-S ≥ 4; ABC-I ≥ 18 | Risperidone 0.25 to 2.5 (< 45 kg), 0.5 to 3.5 (≥ 45 kg) mg/day, adaptive dose (49) | Placebo (52) | Parallel | 8 | Specialistic | 8.8 (2.7); 5.0–17.0 | 18.8 | MA ≥ 18 months | Global changes (CGI-I), ABC, adverse events (SAS, AIMS) | NIMH; NIH; Korczak Foundation; Janssen Pharmaceutica |
Nagaraj, 2006 | India | Autism | DSM-IV | Not reported | Risperidone 1.0 mg/day, fixed dose (19) | Placebo (21) | Parallel | 26 | Specialistic | 5.1 (1.7); 2.0–9.0 | 12.8 | IQ ≥ 35 | Global changes (CGAS), CARS, social quotient (VSMS), adverse events (AIMS) | Sun Pharmaceuticals |
NCT00870727 | USA | PDD-NOS | DSM-IV-TR | CGI-S ≥ 4; ABC-I ≥ 18 | Aripiprazole 2.0 to 20.0 mg/ day, flexible dose (17) | Placebo (16) | Parallel | 8 | Specialistic | 9.6 (2.7); 5.0–17.0 | 21.2 | IQ ≥ 50 | Global changes (CGI-I), ABC, adverse wevents | Indiana University; NIMH; Bristol-Myers Squibb |
NCT01624675 | Japan | Autism | DSM-IV-TR | CGI-S ≥ 4; ABC-I ≥ 18 | Risperidone 1.0 (< 20 kg weight) or 2.5 (≥ 20 kg weight) mg/day (21) | Placebo (18) | Parallel | 8 | Specialistic | NR (NR); 5.0–17.0 | NR | IQ ≥ 35; MA ≥ 18 months | Global changes (CGI-I, CGI-S, CGAS), ABC, parents satisfaction (PSQ), adverse events | Janssen Pharmaceutical K.K |
Owen, 2009 | USA | Autism | DSM-IV; ADI-R | CGI-S ≥ 4; ABC-I ≥ 18 | Aripiprazole 2.0 to 15.0 mg/day, adaptive dose (47) | Placebo (51) | Parallel | 8 | Specialistic | 9.3 (3.0); 6.0–17.0 | 12.2 | MA ≥ 18 months | Global changes (CGI-I, CGI-S), ABC, compulsion (CY-BOCS), quality of life (PedsQL), caregiver strain (CGSQ), adverse events (AIMS, BAS, SAS) | Bristol-Myers Squibb; Otsuka Pharmaceutical Co, Ltd; Ogilvy Healthworld Medical Education |
Remington, 2001 | USA | Autism | DSM-IV | Not reported | Chlomipramine 100 to 150 mg/day (7); Haloperidol 1.0 to 1.5 mg/day (11) | Placebo (7) | Crossover | 22 (1 weeks SB placebo, 21 weeks DB intervention, 3 weeks each one: clomipramine/placebo/haloperidol, placebo/haloperidol/clomipramine, and haloperidol/clomipramine/placebo) | Specialistic | 12.8 (2.4); 10.0–17.0 | 12.0 | Not reported | CARS, adverse events (DOTES, EPS) | Ontario Mental Health Foundation |
RUPP, 2005 | USA | Autism | DSM-IV; ADI-R | CGI-S ≥ 4; ABC-I ≥ 18 | Risperidone 0.25 to 3.5 (< 45 kg), 0.5 to 4.5 (≥ 45 kg) mg/day, adaptive dose (16) | Placebo (16) | Withdrawal | 8 (3 weeks DB taper, 5 weeks DB placebo) | Specialistic | 9.0 (2.5); 5.0–17.0 | 13.2 | Profound retardation to normal | Relapse (ABC, CGI-I) | NIMH; NIH; Korczak Foundation; Janssen Pharmaceutica |
Shea, 2004 | Canada | PDD | DSM-IV-TR; CARS | CARS ≥ 30 | Risperidone 0.02 to 0.06 mg/kg/day, adaptive dose (41) | Placebo (39) | Parallel | 8 | Specialistic | 7.5 (2.3); 5.0–12.0 | 22.8 | IQ ≥ 35 | Global change (CGI-C), ABC, VAS, behavior (N-CBRF), adverse events (ESRS) | Janssen-Ortho, Inc., Canada; Johnson & Johnson Pharmaceuticals |
Troost, 2005 | Netherlands | PDD (Autism, Asperger, PDD-NOS) | DSM-IV-TR; ADI-R | CGI-S ≥ 4; ABC-Irritability ≥ 18 | Risperidone 0.5 to 6.0 mg/day, adaptive dose (12) | Placebo (12) | Withdrawal | 8 (3 weeks DB taper, 5 weeks DB placebo) | Specialistic | 9.1 (2.6); 5.0–17.0 | 8.3 | MA ≥ 18 months | Relapse (ABC, CGI-S) | Not reported |