Ayatollahi 2020.

Study characteristics
Methods	10‐week parallel trial of pregnenolone + risperidone or placebo + risperidone
Participants	Inclusion criteria: "drug‐naive 11‐ to 17‐year‐old adolescents who had met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition' (DSM‐5 2013) who also display aggression, over‐reactivity or repetitive behaviours, ABC‐Irritability scores of at least 15 at screening" Exclusion criteria: any medical condition or disorder apart from psychiatric diagnosis or mild to moderate intellectual disability in receipt of any antipsychotic medications in the month prior to the trial severe hepatic disease, allergy or intolerance to risperidone history of seizures or taking anticonvulsant medications Location/setting: psychiatric hospital in Iran Sample size: 64 (32 to each group) Reason for dropouts/withdrawals: 5; 2 withdrew from pregnenolone group due to withdrawing consent (prior to week 5), 3 from placebo group withdrew consent prior to week 5 Gender: placebo = 10/19 male participants, pregnenolone = 13/17 male participants Mean age: 13.5 years IQ: not reported Baseline ABC‐I or other BoC scores: pregnenolone = 23.23 (4.88), placebo = 23.24 (6.0) Concomitant medications ‐ not reported Previous medications: not reported
Interventions	Intervention: pregnenolone 100 mg twice daily + risperidone 0.4 mg/day for those weighing 20‐45 kg, up to a maximum of 2.5 mg/day for 10 weeks. Participants weighing > 45 kg a maximum dose of 3.5 mg/day of risperidone Comparator: placebo capsules containing starch + risperidone 0.4 mg/day for those weighing 20‐45 kg, up to a maximum of 2.5 mg/day for 10 weeks. Participants weighing > 45 kg a maximum dose of 3.5 mg/day of risperidone
Outcomes	Primary outcomes: ABC‐Irritability (Aman 1985); AEs Secondary outcomes: tolerability
Notes	Study start date: August 2018 Study end date: January 2020 Funding: "This study was supported by a grant from Tehran University of Medical Sciences to S.A. (Grant Number: 38138)." Conflicts of interest: "The authors have no conflicts of interest to declare." Trial registry ‐ IRCT20090117001556N112
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Using a computer‐generated code, patients were randomly allocated to 2 treatment arms by the permuted randomisation block method in a 1:1 ratio.
Allocation concealment (selection bias)	Low risk	The assigned group number for each participant was kept hidden in a sealed opaque envelope until data analysis.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Pregnenolone and matching placebo capsules were identical in terms of shape, colour, size, and smell. All measures were under management of an independent group not involved elsewhere in the study. Both participants and the research team were blinded to the group assignments.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All measures were under management of an independent group not involved elsewhere in the study. Both participants and the research team were blinded to the group assignments."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Low attrition, no other obvious issues with outcome data reporting
Selective reporting (reporting bias)	High risk	CARS noted in registration but not reported
Other bias	High risk	The contact author is also on the ethics committee at the university funding the study. The contact author is a peer‐reviewer for one of the journals in which some of their studies are published.