Hellings 2005.

Study characteristics
Methods	Parallel trial of valproate versus placebo
Participants	Inclusion criteria: aged 6‐20 years (mean age 9.46 +/‐ 2.46) comorbid DSM‐4 Axis I diagnoses, except Tourette’s Disorder significant aggression to self, others, or property at least 3 times/week presence of a PDD Exclusion criteria: previous adequate valproate trial for any indication or clinical seizures within the past year history of degenerative neurological changes or metabolic disorders Tourette’s Disorder history of thrombocytopenia, hepatitis, pancreatitis, pregnancy, or polycystic ovarian syndrome; concomitant psychotropic or antiseizure medications Location/setting: recruitment was through University of Kansas MR/Autism outpatient, USA Sample size: 30 in total (16 to valproate, 14 to placebo) Number of withdrawals/dropouts: 13/16 valproate participants completed the trial, 12/14 in placebo group completed the trial. 1 severely hyperactive and 1 spreading skin rash dropped out on advice from principal investigator and unblinded child psychiatrist, remaining 3 dropped out due to "manifested dangerous aggression". Gender: 20 boys, 10 girls Mean age: 11.2 years Mean IQ: 54 Baseline ABC‐I or other BoC: ABC‐I valproate 23.33, placebo 21.93; aggression valproate 10.05, placebo 10.50. Concomitant medications: psychotropic or anticonvulsant medications were not allowed to be taken concurrently. History of previous medications: details not provided
Interventions	Intervention (valproate acid 20 mg/kg/day) for 8 weeks: after an initial 1‐week placebo lead‐in phase, valproate liquid (250 mg/5 mL) was gradually introduced with an additional 250 mg added every 3rd day, replacing the equivalent amount of placebo liquid, to achieve a dosage of 20 mg/kg/day. Comparator (placebo) for 8 weeks: placebo administered in a liquid form resembling valproate for 8 weeks
Outcomes	Primary outcomes: ABC‐Irritability (Aman 1985) aggression, measured using the Parent Overt Aggression Scale (Yudofsky 2003) AEs Secondary outcomes: tolerability Timing of outcome assessments: weekly
Notes	Study start date: 1998 Study end date: 2003 Source of funding: "funding sources for this work were the National Institute of Mental Health (1K08MH01561‐01), National Institute of Child Health and Human Development (HD26927, HD02528), and Abbott Pharmaceuticals, Abbott Park, Illinois (Unrestricted $5,000 grant)." Conflicts of interest: none declared Trial registry: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "an 8‐week trial of two parallel groups of subjects, randomised to liquid VPA or placebo by the study pharmacist."
Allocation concealment (selection bias)	Unclear risk	Details not provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The investigators, parents, and teachers were blinded regarding medication or PBO [placebo] status"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "The investigators were blinded regarding medication or PBO [placebo] status"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	An ITT analysis was used however 1 participant is not accounted for LTFU: 1 in valproate group and 1 in placebo group discontinued due to AEs, and 1 in valproate group withdrew due to non‐efficacy
Selective reporting (reporting bias)	Low risk	The ABC‐I was measured and reported at baseline and endpoint.
Other bias	Unclear risk	Potential bias with pharmaceutical company funding but "unrestricted" implies no involvement beyond financial. No significant differences in age, gender, current placement home, day placement school, years in current placement, parental marriage status, and aggression as the worst presenting symptom.