Methods	Design: placebo-controlled parallel trial
Participants	Participants: adults with impulsive aggression (subgroup with AsPD; see note 1) Sex: mixed (72.5% men in whole sample including non-AsPD participants) Age: mean 40.3 years; range 19 to 67 years (whole sample including non-AsPD participants) Unit of allocation: individual participant Length of followup: Number randomised: 233 in whole sample; 9 with AsPD (see note 1; breakdown by treatment condition not reported) Number completing: not reported Setting: outpatient; 19 sites; USA Inclusion criteria: aged 18 to 65 years; diagnosis of cluster B personality disorder (DSM-IV; SCID-II) or intermittent explosive disorder (IED), or PTSD; average of two episodes of physical or verbal aggressive outbursts per week for at least a month prior to screening, causing marked distress or impairment in occupational or interpersonal function where the aggressive behaviour was judged to be neither premeditated nor committed to achieve a tangible objective; minimum score of 15 on OAS at first screening visit and at either the second screening visit or at randomisation; if receiving psychotherapy, have a stable psychotherapy schedule for at least 3 months prior to screening and maintained throughout the study Exclusion criteria: lifetime bipolar I disorder; bipolar II disorder with hypomania in the last year or a baseline Mania Syndrome Scale Score >= 12; major depressive disorder > 15 on HAM-D; history of schizophrenia or other psychotic disorder; symptoms of dementia; serious homicidal or suicidal ideation; impulsive aggression resulting from previous head trauma or other medical condition; pregnant or lactating females; clinically abnormal laboratory data; unstable medical condition; any underlying condition that would confound the interpretation of study results; concurrent use of psychotropic medication, with exception of SSRIs, tricyclic antidepressants and stimulants if taken at a stable dose for at least 2 months prior to screening and continued at same dose throughout the study; participants specifically prohibited from use of benzodiazepines, mood stabilisers, anticonvulsants, MAOIs and antipsychotic agents (see note 2) Ethnicity: 195 Caucasian, 26 black, 12 other (whole sample including non-AsPD participants) Baseline characteristics: (whole sample including non-AsPD): at least one psychiatric hospitalisation (n = 36); history of alcohol misuse/dependence (n = 75); history of drug misuse/dependence (n = 38); history of incarceration (n = 52)
Interventions	Two conditions: divalproex sodium / placebo divalproex sodium (number randomised not reported); delayed-release tablets; administered twice daily; target valproate serum level 80 to 120 μg/ml by week 3; Maximum dose 30 mg/kg/day placebo (number randomised not reported); in matching tablets Duration of intervention: 12 weeks Duration of trial: 15 weeks (treatment preceded by screening period not exceeding 14 days and followed by one-week tapering period) Length offollow up: participants were not followed up beyond the end ofthe intervention period Dose adjustment: initiated at 500 mg/day, and increased by 250 mg every 3 to 7 days during first three weeks of treatment, based on individual clinical response and tolerance. Maximum dose 30 mg/kg/day
Outcomes	Primary outcomes Aggression (self-reported): Overt Aggression Scale-Modified (OAS-M) scores Global state/functioning: Clinical Global Impression (CGI) scores Adverse events: assessment by attending physician Secondary outcomes Leaving the study early: proportion of participants discontinuing treatment Other outcomes None
Notes	10% of 91 participants with cluster B personality disorder had AsPD (n = 9). Data from this subgroup not reported Zolpidem tartrate (up to 10 mg/day up to 4 days/week) allowed for control of insomnia but not within 8 hours prior to efficacy ratings
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	Investigators reported “patients were randomised in equal numbers, within each of the three diagnostic groups, to receive either divalproex sodium delayed-release tablets … or matching placebo” (col 1, page 1188). 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	Insufficient information to permit judgement on adequacy of allocation concealment. Clarification has been requested from the trial investigators, but no further information was available at the time this review was prepared
Blinding? of participants	Yes	Investigators describe study throughout as “double-blind” and that participants received a “matching placebo”. Review authors judged that blinding of participants was adequate and that it was unlikely that this blinding could have been broken
Blinding? of personnel	Yes	Investigators reported “An unblinded person from the central laboratory reported serum valproate levels … to the investigators, so that the dose of the study drug could be adjusted appropriately. In order to preserve the study blind, sham valproate levels were reported for selected placebo patients” (p.1188, col 1). Review authors judged that blinding of personnel was adequate and that it was unlikely that this blinding could have been broken
Blinding? of outcome assessors	Unclear	Insufficient information to permit judgement on adequacy of blinding of outcome assessors
Incomplete outcome data addressed? All outcomes	Unclear	Incomplete outcome data arise from participants not completing the study and applies to all measured outcomes. Overall, 54/124 (44%) of the treatment group and 47/122 (39%) of the control group discontinued prematurely, with reasons for non-completion approximately balanced between conditions. Review authors unable to make a judgement unless data from the (small) AsPD subgroup (n = 9) become available
Free of selective reporting?	Yes	Study protocol is not available but it seems clear that the published report included all expected outcomes, including those that were pre-specified
Free of other bias?	Yes	The investigators note that the mean final valproate serum level was 64.2 μg/ml, which is well below possible therapeutic range (80-120 μg/ml) based on previous studies. The study appeared to be free of other sources of bias