Introduction
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Should antipsychotics be used for the treatment of children and adolescents with ASD?
Methods
Population
Intervention
Comparisons
Outcomes
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Restricted and repetitive interests and behavior,
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Hyperactivity, inattention, oppositional, disruptive behavior disorders,
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Self-harm,
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Insomnia,
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Social communication, social interaction,
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Serious adverse events,
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Emotional dysregulation/irritability,
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Anxiety,
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Adverse events,
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Global functioning, global improvement,
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Quality of life,
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Obsessions, compulsions,
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Dropout due to any cause,
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Dropout due to adverse events.
Subgroup analyses
Types of studies included
Literature search
Study selection and data extraction
Data analysis
Dealing with missing data
Risk of bias and overall certainty of evidence assessment
Results
Selected studies
Included studies characteristics
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 |
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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 |
Results and overall certainty of evidence
Antipsychotics versus no antipsychotics – continuous outcomes | ||||||
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Population: children and adolescents with ASD Setting: outpatients and inpatients Intervention: antipsychotics Comparator: no antipsychotics | ||||||
Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
Risk with no Antipsychotics | Risk with Antipsychotics | |||||
Restricted and repetitive interests and behaviors | – | SMD 0.21 SD lower (0.35 lower to 0.07 lower) | – | 823 (9 RCTs) | ⨁⨁⨁◯ MODERATE a | Antipsychotics probably slightly reduce restricted and repetitive interests and behaviors |
Hyperactivity, inattention, oppositional, disruptive behavior | – | SMD 0.67 SD lower (0.92 lower to 0.42 lower) | – | 783 (8 RCTs) | ⨁⨁⨁◯ MODERATE a | Antipsychotics probably reduce Hyperactivity, inattention, oppositional, disruptive behavior disorders |
Self-harm | – | SMD 0.14 SD lower (0.58 lower to 0.30 higher) | – | 77 (1 RCT) | ⨁◯◯◯ VERY LOW b,c | There are some uncertainties about the effect of Antipsychotics on self-harm |
Social communication, social interaction | – | SMD 0.38 SD lower (0.59 lower to 0.16 lower) | – | 854 (10 RCTs) | ⨁⨁⨁◯ MODERATE a | Antipsychotics probably slightly improve social communication, social interaction |
Emotional dysregulation/irritability | – | SMD 0.71 SD lower (0.98 lower to 0.43 lower) | – | 879 (9 RCTs) | ⨁⨁◯◯ LOW a,d | Antipsychotics administration may result in a large reduction of emotional dysregulation/irritability |
Anxiety | – | SMD 0.38 SD lower (0.82 lower to 0.07 higher) | – | 77 (1 RCT) | ⨁◯◯◯ VERY LOW b,c | There are some uncertainties about the effect of Antipsychotics on anxiety |
Global functioning, global improvement | – | SMD 0.64 SD lower (0.96 lower to 0.33 lower) | – | 839 (10 RCTs) | ⨁⨁◯◯ LOW e,f | Antipsychotics may influence positively Global functioning, global improvement |
Obsessions, compulsions | – | SMD 0.30 SD lower (0.55 lower to 0.06 lower) | – | 548 (4 RCTs) | ⨁⨁⨁◯ MODERATE g | Antipsychotics probably slightly reduce obsessions, compulsions |
Antipsychotics versus no antipsychotics – dichotomous outcomes | ||||||
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Population: children and adolescents with ASD Setting: outpatients and inpatients Intervention: Antipsychotics Comparator: no Antipsychotics | ||||||
Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
Risk with no Antipsychotics | Risk with Antipsychotics | |||||
Serious adverse events | 16 per 1.000 | 17 per 1.000 (8 to 39) | RR 1.07 (0.48 a 2.43) | 1057 (13 RCTs) | ⨁⨁◯◯ LOW a,b | Antipsychotics may increase the risk of severe adverse events slightly |
Adverse events | 657 per 1.000 | 781 per 1.000 (703 to 867) | RR 1.19 (1.07 a 1.32) | 924 (10 RCTs) | ⨁⨁⨁◯ MODERATE c | Antipsychotics probably increase the risk of adverse events |
Dropout due to any cause | 244 per 1.000 | 149 per 1.000 (117 to 190) | RR 0.61 (0.48 a 0.78) | 1124 (15 RCTs) | ⨁⨁⨁◯ MODERATE d | Antipsychotics probably reduce the risk of dropout due to any cause |
Drop-out due to adverse events | 39 per 1.000 | 39 per 1.000 (22 to 70) | RR 0.99 (0.55 to 1.79) | 1010 (12 RCTs) | ⨁⨁◯◯ LOW b,e | Antipsychotics may have little or no effect on the risk of dropouts due to adverse events |