Hollander 2003.

Study characteristics
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: whole sample, including non‐AsPD participants, mean = 40.3 years (range = 19 to 67 years) Unit of allocation: individual participant 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; Stuctured Clinical Interview for DSM‐IV (SCID‐II)) or intermittent explosive disorder (IED), or post‐traumatic stress disorder (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 randomization; 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 Hamilton Depression Rating scale (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 selective serotonin reuptake inhibitors (SSRI), 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, monoamine oxidase inhibitors (MAOI) and antipsychotic agents (see note 2) Ethnicity: 195 Caucasian, 26 black, 12 other (whole sample, including non‐AsPD participants) Baseline characteristics: (for 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 (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 1 week tapering period) Length of follow‐up: participants were not followed up beyond the end of the intervention period Dose adjustment: initiated at 500 mg/day, and increased by 250 mg every 3 to 7 days during first 3 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 Timing of outcome assessments Blood assay at weeks 3, 6 and 12; OAS‐M at baseline then weekly (with telephone visits at weeks 5 and 7); CGI baseline and once a week, excluding weeks 5 and 7
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 Study funding: Abbott Laboratories, Abbott Park (Illinois, USA) Declaration of interests: The study authors report "Dr Hollander has received research grants from Abbott Laboratories, Bristol Myers Squibb, Eli Lilly and Company, Pfizer Laboratories, Solvay, and Wyeth‐Ayerst. He has served as a consultant to and member of the Speakers Bureau of Abbott Laboratories, Solvay, and Wyeth‐Ayerst. Dr Swann has received grant support from Abbott Laboratories, Glaxo SmithKline, UCB Pharma, Bristol Myers Squibb, Eli Lilly, and Shire Laboratories. He has served as a consultant for Abbott Laboratories, Pfizer Laboratories, Shire Laboratories, UCB Pharma, Glaxo SmithKline, Novartis, Eli Lilly, and Bristol Myers Squibb. He has served on Speakers’ Bureaus for Abbott Laboratories, Janssen Pharmaceuticals, Novartis, Glaxo SmithKline, and Pfizer Laboratories. Dr Coccaro is a consultant to Abbott Laboratories and to Eli Lilly Pharmaceuticals. He is a member of the Speakers Bureau for Abbott Laboratories, Eli Lilly Pharmaceuticals, Glaxo SmithKline, and Forest Pharmaceuticals and has received research grants from Abbott Laboratories and Eli Lilly Pharmaceuticals. Dr McElroy is a consultant to Abbott Laboratories and is a member of the company’s Speakers Bureau and Divalproex Advisory Board. She has also received research grants from Abbott Laboratories, and Eli Lilly and Company. Dr Nemeroff reports the following: Grants/Research: Abbott Laboratories; AstraZeneca; Bristol‐Myers‐Squibb; Forest Laboratories; Janssen Pharmaceutica; Eli Lilly; GlaxoSmithKline; NARSAD; NIMH; Organon; Pfizer Pharmaceuticals; Pharmacia‐Upjohn; Stanley Foundation/NAMI; and Wyeth‐Ayerst. Consultant: Abbott Laboratories; Acadia Pharmaceuticals; AstraZeneca; Bristol‐Myers‐Squibb; Cephalon Pharmaceuticals; Corcept; Cypress Biosciences; Forest Laboratories; GlaxoSmithKline; Janssen Pharmaceutica; Eli Lilly; Merck; Mindsense; Neurocrine Biosciences; Novartis; Organon; Otsuka; Pharmacia‐Upjohn; Sanofi; Somerset; Vela Pharmaceuticals; and Wyeth‐Ayerst. Speakers Bureau: Abbott Laboratories; AstraZeneca; Bristol‐ Myers‐Squibb; Eli Lilly; Forest Laboratories; GlaxoSmithKline; Janssen Pharmaceutica; Organon; Pfizer Pharmaceuticals; and Wyeth‐Ayerst. Stockholder: Corcept and applies only to Dr. Nemeroff Drs Tracy, Wozniak, and Sommerville are employees of Abbott Laboratories." (quote, p 1195‐6)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: 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 (selection bias)	Unclear risk	Comment: 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 (performance bias and detection bias) of participants	Low risk	Comment: 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 (performance bias and detection bias) of personnel	Low risk	Comment: 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 (performance bias and detection bias) of outcome assessors	Unclear risk	Comment: Insufficient information to permit judgement on adequacy of blinding of outcome assessors.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: 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.
Selective reporting (reporting bias)	Unclear risk	Comment: Study protocol is not available but it seems clear that the published report included all expected outcomes, including those that were pre‐specified.
Other bias	High risk	Comment: 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 authors declare multiple links to the funding source (Abbott Laboratories) and other pharmacy companies.