A controlled trial of phenytoin in impulsive aggression. Oxcarbazepine in patients with impulsive aggression: a double-blind, placebo-controlled trial. The effects of phenytoin on impulsive and premeditated aggression: a controlled study. A double-blind, placebo-controlled study of valproate for aggression in youth with pervasive developmental disorders. Effects of diphenylhydantoin on child-abusing parents: a preliminary report. Positive effects of carbamazepine on behavioral dyscontrol in borderline personality disorder. Carbamazepine in aggressive children with conduct disorder: a double-blind and placebo-controlled study. Divalproex in the treatment of impulsive aggression: efficacy in cluster B personality disorders. Effects of diphenylhydantoin on anxiety and hostility in institutionalized prisoners. A double-blind placebo-controlled crossover study of phenytoin in individuals with impulsive aggression. Levetiracetam in patients with impulsive aggression: a double-blind, placebo-controlled trial. A comparison of anticonvulsants in the treatment of impulsive aggression. Treatment of young delinquent boys with diphenylhydantoin sodium and methyphenidate. A controlled comparison. Divalproex treatment for youth with explosive temper and mood lability: a double-blind, placebo-controlled crossover design.
nan Impulsive aggression is a common clinically significant symptom, but there are few controlled studies evaluating drug treatment. This study evaluated oxcarbazepine in patients with impulsive aggression and whether diagnosis or other baseline characteristics predict response.
                Eligible outpatients had clinically significant impulsive aggression, without other psychiatric symptoms clearly requiring treatment. Patients were randomized to oxcarbazepine or placebo, double-blind, for 10 weeks, at a variable dose increasing to 1200 mg/d if tolerated and to 2400 mg/d if aggression persisted. Primary outcome measures were (1) change in a Global Overt Aggression rating derived from the Overt Aggression Scale-Modified and (2) patient-rated global improvement.
                Of 48 patients, 24 per group, 9 dropped out due to adverse events, but 45 completed at least 4 weeks on double-blind medication. Analyses showed consistent evidence of benefit from oxcarbazepine, compared with placebo, on both primary efficacy measures and most secondary measures. There were no significant interactions between diagnosis or other baseline characteristics and differential response to oxcarbazepine or placebo.
                Oxcarbazepine appears to benefit adults with clinically significant impulsive aggression. Studies of the effects of phenytoin on aggression have produced equivocal results primarily because of a lack of (1) common objective criterion measures of aggressive acts across studies; (2) rigorous inclusion and exclusion criteria for selecting subjects; and (3) a nosologic basis for classifying different types of aggression. The current study was designed to remedy these deficiencies. Aggression was defined using a nosology that defines three types of aggression: (1) medically related; (2) premeditated; and (3) impulsive. The purpose of this study was to test the hypothesis that phenytoin will decrease impulsive aggressive acts but not have a significant influence on premeditated aggressive acts. Sixty inmates were divided into two groups on the basis of committing primarily impulsive aggressive acts or premeditated aggressive acts while in prison. Medical aggression was ruled-out by subject selection. The study used a double-blind, placebo-controlled, crossover design. As hypothesized, phenytoin (200 mg a.m. and 100 mg p.m.) significantly reduced impulsive aggressive acts but not premeditated aggressive acts. Event-related potentials (ERPs) measured information processing in the cortex during drug/placebo conditions. The amplitudes of P300 ERP waveforms among impulsive aggressive subjects were increased significantly during the phenytoin condition but not during the placebo condition. There were no significant changes in P300 ERP waveforms between drug/placebo conditions among nonimpulsive aggressive subjects. The aim of this study was to study valproate efficacy and safety for aggression in children and adolescents with pervasive developmental disorders (PDD).
                In this prospective double-blind, placebo-controlled study, 30 subjects (20 boys, 10 girls) 6-20 years of age with PDD and significant aggression were randomized and received treatment with valproate (VPA) or placebo (PBO) for 8 weeks as outpatients. Mean VPA trough blood levels were 75.5 mcg/mL at week 4 and 77.8 mcg/mL at week 8.
                No treatment difference was observed statistically between VPA and PBO groups. The Aberrant Behavior Checklist--Community Scale (ABC-C) Irritability subscale was the primary outcome measure (p = 0.65), and CGI--Improvement (p = 0.16) and OAS (p = 0.96) were secondary outcome measures. Increased appetite and skin rash were significant side effects. Only 1 subject was dropped from the study owing to side effects, notably a spreading skin rash, which then resolved spontaneously. Two subjects receiving VPA developed increased serum ammonia levels, one with an associated parent report of slurred speech and mild cognitive slowing. Poststudy, of 16 VPA and PBO subjects receiving VPA, 10 subjects demonstrated sustained response, 4 of whom later attempted taper, with significant relapse of aggression.
                The present negative findings cannot be viewed as conclusive, partly owing to the large placebo response, subject heterogeneity, and size of the groups. Larger studies are needed to expand upon these findings. nan In a double-blind crossover trial, carbamazepine, an anticonvulsant with primary effects on subcortical limbic structures, decreased the severity of behavioral dyscontrol in 11 women with borderline personality disorder significantly more than placebo. The authors emphasize the preliminary nature of their findings and discuss alternative hypotheses regarding mechanisms by which carbamazepine might influence behavioral dyscontrol. To assess critically the short-term efficacy and safety of carbamazepine in the reduction of aggressiveness in children with diagnosed conduct disorder.
                Subjects were children aged 5 to 12 years who were hospitalized for treatment-resistant aggressiveness and explosiveness and who had diagnosed conduct disorder. The study was double-blind and placebo-controlled, using a parallel-groups design. Following a 2-week placebo baseline period, children who met the aggression criteria were randomly assigned to treatments for 6 weeks; the study ended with a 1-week posttreatment placebo period. Multiple raters rated the children independently, using multiple rating scales under four conditions. The main outcome measures included the Overt Aggression Scale, the Global Clinical Judgments (Consensus) Scale, and the Children's Psychiatric Rating Scale.
                Twenty-two children, aged 5.33 to 11.7 years, completed the study. Carbamazepine was not superior to placebo at optimal daily doses ranging from 400 to 800 mg, mean 683 mg, at serum levels of 4.98 to 9.1 micrograms/mL. Untoward effects associated with administration of carbamazepine were common.
                In this modest sample of children, the superiority of carbamazepine over placebo in reducing aggressive behavior was not demonstrated. Impulsive aggressive behavior is common in psychiatric disorders and accounts for significant morbidity and mortality. However, little systematic treatment data exist from placebo-controlled trials for this symptom domain. This was a multicenter, randomized, double-blind, placebo-controlled study in which outpatients with a score of > or =15 on the Aggression scale of the Overt Aggression Scale-Modified (OAS-M) and who fulfilled DSM-IV criteria for Cluster B personality disorder (n=96), intermittent explosive disorder (n=116), or post-traumatic stress disorder (n=34) were randomized to divalproex sodium or placebo for 12 weeks duration. Based on average OAS-M Aggression scores over the last 4 weeks of treatment, a treatment effect was not observed in the intent-to-treat data set (combined across the three psychiatric disorders), but was observed in both intent-to-treat and evaluable data sets for patients with Cluster B personality disorders. In the Cluster B evaluable data set, statistically significant treatment differences favoring divalproex were also observed for component items of the OAS-M Aggression score, including verbal assault and assault against objects, as well as OAS-M Irritability score, and Clinical Global Impression (CGI)-Severity at multiple time points throughout the study. No treatment group difference was noted for overall premature discontinuation rate; however, across psychiatric diagnoses, 21 (17%) patients in the divalproex group prematurely discontinued because of an adverse event, as compared to 4 (3%) patients in the placebo group (p <0.001). While a treatment effect was not observed when all diagnostic groups were combined, in a large subgroup of patients with Cluster B disorders, divalproex was superior to placebo in the treatment of impulsive aggression, irritability, and global severity. nan The present study examines the behavioral and psychophysiological effects of phenytoin (PHT) in individuals who display impulsive-aggressive outbursts. In a double-blind placebo-controlled crossover design, individuals meeting previously established criteria for impulsive aggression were administered PHT and placebo during separate 6-week conditions. The efficacy measures used were the Overt Aggression Scale (OAS) and the Profile of Mood States (POMS). Psychophysiological measures (evoked potentials) were taken at baseline and at the end of each 6-week condition. Photic stimulation was used to evoke the mid-latency P1-N1-P2 waveform complex. Analysis indicated a significant decrease in the frequency of impulsive-aggressive outbursts during PHT administration compared to baseline and placebo. Analysis of the psychophysiological data showed significantly increased P1 amplitude and significantly longer N1 latency during PHT administration. In addition, a reduction in N1 amplitude during PHT administration was also suggested. These findings indicate reparation of physiological abnormalities previously observed in impulsive-aggressive individuals and imply more efficient sensory processing and effective orienting of attention. Taken together, these results provide insight as to the physiological mechanisms by which PHT serves to ameliorate impulsive-aggressive behavior. There are few controlled studies evaluating drug treatment for impulsive aggression. The objective of this study was to evaluate levetiracetam in patients with impulsive aggression, and whether diagnosis or other baseline characteristics predict response.
                Outpatients with clinically significant impulsive aggression (meeting Coccaro et al. revised criteria for intermittent explosive disorder), without other psychiatric symptomatology clearly requiring treatment, were randomly assigned to levetiracetam or placebo, double-blind, for 10 weeks, at a variable dose with a maximum dose of 3000 mg/day. The primary efficacy measure was change in the total aggression score from the revised Overt Aggression Scale-Modified. The study was conducted from September 2005 to July 2006.
                Of 40 patients (20 in each treatment group), 34 completed at least 4 weeks of treatment with double-blind medication. There was no overall statistical evidence of levetiracetam benefit, and no subgroup more responsive to levetiracetam could be identified.
                Levetiracetam was not as efficacious as oxcarbazepine was in a prior similar study. Additional studies of medications for impulsive aggression seem warranted. This study compared the behavioral effects of 3 anticonvulsants in impulsive aggressive men. In a double-blind, placebo-controlled, parallel groups design, participants were randomly assigned to 1 of 4 6-week treatments: phenytoin (n = 7), carbamazepine (n = 7), valproate (n = 7), or placebo (n = 8). The efficacy measure was the average aggression score, a global severity index from the Overt Aggression Scale (J. M. Silver & S. C. Yudofsky, 1991). Analysis showed a significant reduction in impulsive aggression during all 3 anticonvulsant conditions compared with placebo. However, the treatment effect during carbamazepine administration was slightly delayed compared with phenytoin and valproate. These findings suggest that increased use of anticonvulsants could make a significant impact in the control of impulsive aggression in both mental health and criminal justice settings. nan The authors sought to replicate open-label findings showing that specific criteria for explosive temper and mood lability identify disruptive youth who improve while receiving the anticonvulsant divalproex sodium.
                Twenty outpatient children and adolescents (ages 10-18) with a disruptive behavior disorder (oppositional defiant disorder or conduct disorder) met the specific criteria for explosive temper and mood lability. They received 6 weeks of divalproex treatment and 6 weeks of placebo by random assignment. Independent evaluators blind to group assignment assessed response at the end of each phase.
                At the end of phase 1, eight of 10 subjects had responded to divalproex; zero of 10 had responded to placebo. Of the 15 subjects who completed both phases, 12 has superior response taking divalproex.
                This preliminary study replicates open-label findings showing that divalproex is an efficacious treatment for explosive temper and mood lability in disruptive children and adolescents.
The authors consider that the body of evidence summarised in this review is insufficient to allow any firm conclusion to be drawn about the use of antiepileptic medication in the treatment of aggression and associated impulsivity. Four antiepileptics (valproate/divalproex, carbamazepine, oxcarbazepine and phenytoin) were effective, compared to placebo, in reducing aggression in at least one study, although for three drugs (valproate, carbamazepine and phenytoin) at least one other study showed no statistically significant difference between treatment and control conditions. Side effects were more commonly noted for the intervention group although adverse effects were not well reported. Absence of information does not necessarily mean that the treatment is safe, nor that the potential gains from the medication necessarily balance the risk of an adverse event occurring. Further research is needed.