Hellings 2005.

Methods	Design: placebo‐controlled parallel trial
Participants	Participants: children and adolescents with pervasive developmental disorder and significant aggressive behaviour Sex: mixed; 12 boys, 6 girls (valproate group); 14 boys, 4 girls (placebo group) Age: mean 10.3 (SD 3.7) years (valproate group); mean 12.1 (SD 4.8) years (placebo group) Unit of allocation: individual participant Number randomised: 30 (20 boys; 10 girls) Number completing: 25 Setting: outpatient; USA (Kansas) Inclusion criteria: aged 6 to 20 years; significant aggression to self, others, or property at least 3 times a week; presence of a pervasive developmental disorder (PDD) Exclusion criteria: Tourette’s Disorder (DSM‐IV); previous adequate trial of valproate within past year for any indication or for clinical seizures; history of degenerative neurological changes or metabolic disorders; history of thrombocytopenia, hepatitis, pancreatitis, pregnancy or polycystic ovarian syndrome; concomitant psychotropic or antiseizure medication (see note 1) Ethnicity: 27 Caucasian, 2 African‐American, 1 Hispanic Baseline characteristics: autistic disorder (n = 27); pervasive developmental disorder NOS (n = 1); Asperger’s disorder (n = 2); mean IQ = 54 (range 20 to 137); average or above‐average IQ (n = 2); borderline intellectual functioning (n = 2); mental retardation (n = 26)
Interventions	Two conditions: valproate / placebo valproate (n = 16 randomised); as liquid; target dose 20 mg/kg/day; mean blood levels: 75.5 mcg/dL at week 4, 77.7 mcg/dL at week 8 placebo (n = 14 randomised); as liquid Duration of intervention: 8 weeks Duration of trial: 11 to 13 weeks (treatment preceded by washout period of 2 weeks (for tricyclics) or 4 weeks (for all other psychotropic medication) plus 1‐week placebo run‐in prior to randomisation) Length of follow up: participants were not followed up beyond the end of the intervention period Dose adjustment: valproate gradually introduced from day 1 adding 250 mg every third day, replacing the equivalent amount of placebo liquid, to achieve a dosage of 20 mg/kg/day. Adequate blood levels within the therapeutic range were achieved and maintained from at least week 4 to week 8.
Outcomes	Primary outcomes Aggression (observer‐reported): Overt Aggression Scale(OAS) completed by parents and teachers for each aggressive outburst. Aggression recurring after 30 minutes of non‐aggressive behaviour was documented as a separate episode. Secondary outcomes Non‐compliance: proportion of participants discontinuing treatment Adverse events: rated via checklist derived from the Physicians’ Desk Reference Other outcomes Clinical Global Impressions‐Improvement subscale (CGI‐I); Aberrant Behavior Checklist‐Community scale (ABC‐C) ‐ irritability subscale
Notes	1. Stimulant medications stopped the day before placebo run‐in commenced
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Investigators report "two parallel groups of subjects, randomized to VPA or PBO by the study pharmacist" (p.685, col 1). No further details given. Insufficient information to permit judgement on adequacy of sequence generation. Clarification has been requested from the trial investigators, but no further information was available at the time this review was prepared.
Allocation concealment?	Unclear risk	No details reported. Clarification has been requested from the trial investigators, but no further information was available at the time this review was prepared.
Blinding? of participants	Low risk	Investigators report that participants and parents were blinded regarding allocation status and that “mock dosage adjustment was made for the placebo group” (p.685, col 2). Appropriate care appears to have been taken to ensure blinding of participants. Unlikely that this blinding could have been broken.
Blinding? of personnel	Low risk	Investigators report that “investigators, parents and teachers were blinded regarding medication or PBO status” (p.685, col 2). Appropriate care appears to have been taken to ensure blinding of personnel. Unlikely that this blinding could have been broken.
Blinding? of outcome assessors	Low risk	Investigators report that “investigators, parents and teachers were blinded regarding medication or PBO status” (p.685, col 2). Appropriate care appears to have been taken to ensure blinding of outcome assessors. Unlikely that this blinding could have been broken.
Incomplete outcome data addressed? All outcomes	Low risk	At completion of intervention (8 weeks): 3/16 missing from intervention (valproate) group; 2/14 missing from control (placebo) group. Investigators do not provide a breakdown by intervention group of reasons for non‐completion. However, review authors judge that missing outcome data was balanced in numbers across intervention groups and reasons for missing outcome data were unlikely to be related to true outcome. Trial investigators provided an intention‐to‐treat analysis. In this review, data from 30 participants were included in the analysis.
Free of selective reporting?	Low risk	Study protocol is not available but it seems clear that the published report includes all expected outcomes, including those that were pre‐specified
Free of other bias?	Low risk	The study appeared to be free of other sources of bias. It would however have been helpful if the investigators had clarified whether the use of diphenhydramine as a ‘rescue medication’ was a possible confounder.