McCracken 2002.

Study characteristics
Methods	Parallel trial of risperidone versus placebo
Participants	Inclusion criteria: age 5‐17 years weight ≥ 15 kg a mental age of ≥ 18 months diagnosis of ASD according to the DSM‐4 criteria with 1 or a combination of tantrums, aggression or self‐injurious behaviour no seizures for at least 6 months prior to the trial withdrawn from ineffective psychotropic medication for the treatment of aggression, tantrums, or self‐injurious behaviour 7‐28 days prior to enrolment free of all psychotropic drugs at least 2 weeks prior to randomisation (4 weeks for antipsychotics and fluoxetine) ABC‐I score of ≥ 18 at baseline Exclusion criteria: any serious medical disorders or other psychiatric disorders requiring medications receiving psychotropic drugs that were considered effective for the treatment of aggression, tantrums or self‐injurious behaviour. Location/setting: University of California at Los Angeles, Ohio State University, Indiana University, Yale University, and the Kennedy Krieger Institute at Johns Hopkins University, USA Sample size: 101: 49 risperidone group, 51 placebo Number of withdrawals/dropouts: risperidone 3/49; placebo 18/52 (risperidone: 3 lack of efficacy; placebo: severe headache and seizure (1); withdrawal of consent (1); LTFU (3); non‐compliance (1); lack of efficacy (12)). Gender: 82 boys, 19 girls Mean age: 8.6 years IQ: 13/101 had profound intellectual disability, 18/101 had severe intellectual disability, 18/101 had a moderate intellectual disability, 25/101 had a mild intellectual disability Baseline ABC‐I or other BoC: ABC‐I risperidone 26.2, placebo 25.5 Concomitant medications: participants had to be free of all psychotropic drugs at least 2 weeks prior to randomisation (4 weeks for antipsychotics and fluoxetine). History of previous medications: antipsychotics 5/101, SSRIs 16/101, stimulant 21/101, alpha‐2‐agonist 16/101
Interventions	Risperidone for 8 weeks: children who weigh 20‐45 kg commenced on 0.5 mg at bedtime, increased to 0.5 mg twice daily on day 4. The dose was gradually increased in 0.5 mg increments of 2.5 mg/day (1.0 mg in the morning and 1.5 mg at bedtime) by day 29. Children weighing > 45 kg had a maximum dose of 1.5 mg in the morning and 2.0 mg at bedtime. Children weighing < 20 kg were given an initial dose of 0.25 mg/ day. Dose increases could be delayed because of adverse effects or significant improvement on lower doses. No dose increases after day 29. Mean daily dose of 1.8 mg/day or maximum daily dose of 2.5 mg/day children < 45 kg or 3.5 mg/day children > 45 kg Placebo for 8 weeks: placebo equivalent of 2.4 ± 0.6 mg/day
Outcomes	Primary outcomes Irritability (ABC‐I) (Aman 1985) Improvement in irritability (defined as a minimum 25% improvement in ABC‐Irritability scores) Relapse in Irritability (defined as a minimum 25% increase, or deterioration in ABC‐Irritability scores) AEs Secondary outcomes: none reported Timing of outcome assessments: weekly for 8 weeks
Notes	Study start date: June 1999 Study end date: April 2001 Source of funding: "supported by contracts from the National Institute of Mental Health (N01MH70009), to Dr Scahill; N01MH70010 to Dr McCracken; N01MH70001 to Dr McDougle ; and N01MH80011 to Dr Aman, General Clinical Research Centre grants from the National Institute of Health (M01 RR00750 to Indiana University; M01 RR00052 to Johns Hopkins University; M01 RR00034 to Ohio State University; and M01 RR06022 to Yale University, and a grant from the Korczak Foundation to Dr Scahill". Conflicts of interest: none declared
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient details
Allocation concealment (selection bias)	Unclear risk	Insufficient details
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Each child was seen weekly by two clinicians who were unaware of the treatment assignment."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Each child was seen weekly by two clinicians who were unaware of the treatment assignment: a primary clinician, who reviewed side effects and adjusted the dose of medication, and a clinical evaluator, who assessed the response to treatment."
Incomplete outcome data (attrition bias) All outcomes	Low risk	LTFU risperidone: treatment ineffective (3) 46 of original 49 in risperidone group completed trial (3 withdrew "because the study was not effective") 18 children in placebo group withdrew: severe headaches and a seizure (1); withdrawal of consent (1); nonadherence (1); LTFU (3) and lack of efficacy (12) 4 were identified as having an ABC‐I that fell below the ABC‐I score of 18 and were included in theITT analysis. Authors noted that zero participants withdrew from study due to AEs. An ITT analysis was used, and all participants were included in the analysis.
Selective reporting (reporting bias)	High risk	Sedation not reported as an AE
Other bias	Low risk	No concerns