Mattes 2008.

Methods	Design: placebo‐controlled parallel trial
Participants	Participants: adults meeting Coccaro‐revised criteria for intermittent explosive disorder (see note 1) Sex: mixed (35 men; 5 women) Age: mean 45.38 (SD 11.2) years; range 21 to 64 years Unit of allocation: individual participant Number randomised: 40 Number completing: 19 completed full 10 weeks; 34 completed first 4 weeks Setting: outpatient; USA Inclusion criteria: aged 18 to 65 years; in general good health; women of childbearing potential had to be practicing effective contraception; meeting Coccaro‐revised criteria for intermittent explosive disorder (see note 1): recurrent incidents of aggression manifest as verbal or physical aggression towards other people, animals or property occurring twice weekly on average for 1 month the degree of aggressiveness expressed is grossly out of proportion to the provocation or any precipitating psychosocial stressors the aggressive behaviour is generally not premeditated (e.g. is impulsive) and is not committed to achieve some tangible objective (e.g. money, power, intimidation etc) the aggressive behaviour causes either marked distress in the individual or impairment in occupational or interpersonal functioning the aggressive behaviour is not better accounted for by another mental disorder, a general medical condition, or the direct physiological effects of a substance Exclusion criteria: schizophrenia; bipolar disorder; epilepsy; dementia; mental retardation; substance abuse in last 6 months; need for treatment with antipsychotics, anticonvulsants or mood stabilisers, or any recent change (within 3 months); significant risk of severely injuring others or self; any current psychiatric or neurological conditions which required specific treatment Ethnicity: not reported Baseline characteristics: currently married (n = 23); never been married (n = 8); mean 12.9 (SD 2.2) years of education; history of perinatal trauma (n = 9); physically abused as a child (n = 13); history of ‘road rage’ (n = 34); arrested previously (n = 10); previously in jail because of aggressiveness (n = 9); restraining orders instituted against them (n = 10); prior psychiatric treatment (n = 30); attempted suicide (n = 2); in family history (first‐degree relatives), ‘a bad temper’ (n = 30), depression (n = 10), alcoholism (n = 9) Four diagnoses occurred frequently enough (at least 8 participants) to warrant analysis: ADHD (residual or in remission) (n = 13), prior alcohol or drug abuse/dependence (n = 12), prior major depression (n = 11), and intermittent explosive disorder by DSM‐IV criteria (n = 8)
Interventions	Two conditions: levetiracetam / placebo levetiracetam (n = 20 randomised); mean dosage 1738 (SD 1028) mg/day; mean 7.30 weeks on double‐blind medication placebo (n = 20 randomised); mean equivalent dosage 2313 (SD 854) mg/day;  mean 7.55 weeks on double‐blind medication Duration of intervention: 10 weeks Length of follow up: participants were not followed up beyond the end of the intervention period Dose adjustment: initial dose levetiracetam 250 mg twice daily, increased by 250 mg twice daily after 1 week of treatment with each dose to at least 1000 mg/day if tolerated, with a maximum of 3000 mg/day by week 6 if needed. Due to tolerability, the dose could be escalated more slowly, and more could be given at bedtime.
Outcomes	Primary outcomes Aggression (self‐reported): OAS‐M scores (see note 2); Relative Rating of Aggressive Behavior (see note 3) Secondary outcomes Hostility: BPRS hostility scale Non‐compliance: proportion of participants discontinuing treatment Adverse events: incidence of overall adverse events Other outcomes Patient‐rated global improvement
Notes	1. All participants met the Coccaro‐revised criteria for intermittent explosive, although only eight of the 49 randomised met DSM‐IV criteria for intermittent explosive disorder  2. The OAS‐M was “slightly revised”, in part to “improve face validity and limit variability and skewness” as described in Mattes (2005)  3. Derived from the rating Scale for Aggressive Behaviour in the Elderly
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Investigators report “at baseline, patients were randomly assigned to either levetiracetam or placebo in a 1:1 ratio” (p.312, col 1). Further details obtained from lead author indicated that sequence generation was achieved by the throwing of a dice.
Allocation concealment?	Low risk	Further details provided by lead author indicated that concealment achieved by use of, effectively, central allocation by a person not otherwise involved in the study, so that participants and any investigator enrolling participants could not foresee assignment
Blinding? of participants	Low risk	Information provided by lead author indicated that this was a double‐blind study. 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	Information provided by lead author indicated that this was a double‐blind study. 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	Information provided by lead author indicated that this was a double‐blind study. 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	Unclear risk	After 4 weeks of treatment (by which time trial investigators considered participants had received an 'adequate trial'): 5/20 missing from intervention (levetiracetam) group (suicidal ideation (n = 2), impaired co‐ordination (n = 1), increased irritability (n = 1), sedation and dizziness (n = 1); 1/20 missing from control (placebo) group (depressed mood). At completion of intervention (10 weeks), 21/40 missing (breakdown by treatment group not available). Unclear whether reasons for missing outcome data were likely to be related to true outcome. Trial investigators carried out intention‐to‐treat analysis. In this review, data from 40 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?	Unclear risk	Several small revisions to the OAS‐M instrument are described and justified, but it is unclear whether the revised scale has been formally tested for validity and reliability. The study is described as having funding support from UCB Pharma (the manufacturers of Keppra, the proprietary name for levetiracetam) but that “Dr Mattes reports no additional financial or other relationship relevant to the subject of this article” (p.310, col 1). The study appeared to be free of other sources of bias.