Willemsen‐Swinkels 1996.

Study characteristics
Methods	Cross‐over trial of naltrexone versus placebo
Participants	Inclusion criteria: children aged 3‐7 years either outpatients of the Department of Child Psychiatry of the Utrecht University or members of the Dutch Autism Association met the DSM‐III‐R criteria for autistic disorder Exclusion criteria: details not provided Location/ Setting: the Netherlands Sample size: 20 total (23 originally randomised) Number of withdrawals/dropouts: 2 children were excluded from analysis because "they had taken up the habit of chewing the capsules", and 1 participant dropped out after the first treatment due to parents withdrawing consent. Gender: 16 male, 4 female Mean age: 5.5 years IQ: details not provided Baseline ABC‐I or other BoC: naltrexone ABC‐I 18.5, placebo 14 Concomitant medications: participants were free of psychotropic drugs for at least 6 weeks before the study. 1 participant with epilepsy was treated with carbamazepine in a fixed dosage during the study period. None of the participants had previously been treated with psychotropic drugs. History of previous medications: details not provided
Interventions	Intervention (single‐dose naltrexone) for 4 weeks: naltrexone was given at 40 mg (approximately 2 mg/kg) in a single‐dose capsule. After 11 weeks, this group was given a placebo in a matched capsule. Long‐term daily dose study 1996: after a 2‐week baseline period, naltrexone was given at 20 mg per day (approximately 1 mg/kg) over 4 weeks, with the exception of 1 participant with the weight of 42 kg who was given 40 mg per day over 4 weeks. Comparator (placebo) for 4 weeks: matching placebo tablet was given daily over 4 weeks
Outcomes	Primary outcomes: irritability, measured using the ABC‐Irritability subscale (Aman 1985) Secondary outcomes: none reported Timing of outcome assessments: 2 weeks before baseline, baseline, day 1 and day 2 (for each phase)
Notes	Study start date: details not reported Study end date: details not reported Source of funding: supported by Janusz Korczak Foundation. Du Pont Pharma supplied part of the drug required. Conflicts of interest: none declared
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Further details not provided
Allocation concealment (selection bias)	Unclear risk	Further details not provided
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Details not provided
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Details not provided
Incomplete outcome data (attrition bias) All outcomes	High risk	Baseline ABC‐I scores were significantly higher in the naltrexone group compared to placebo.
Selective reporting (reporting bias)	Unclear risk	Results only graphically presented
Other bias	High risk	Only single dosage used. Active treatment supplied in part by pharmaceutical company. The nature of foundation support is unclear.