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, doubleblind, placebo-controlled study in which outpatients with a score of X15 on the Aggression scale of the Overt Aggression ScaleModified (OAS-M) and who fulfilled DSM-IV criteria for Cluster B personality disorder (n ¼ 96), intermittent explosive disorder (n ¼ 116), or post-traumatic stress disorder (n ¼ 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 (po0.001). 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.

and yyOvation Pharmaceuticals, Inc., Deerfield, Illinois, U.S.A. SUMMARYPurpose: This randomized, double-blind, doseranging study evaluated safety and efficacy of clobazam (CLB) as adjunctive therapy for drop seizures in patients with Lennox-Gastaut syndrome (LGS). Methods: Sixty-eight patients with LGS aged 2-26 years were administered CLB (low dose = target 0.25 mg/kg/day; high dose = target 1.0 mg/kg/ day). The study consisted of 4-week baseline, 3-week titration, and 4-week maintenance periods, followed by a 3-week taper or continuation in an open-label study. Seizure frequency was recorded in a diary by the parent/caregiver throughout the study. Results: Weekly drop seizure rates were significantly reduced from baseline in both the high-dose and low-dose groups; the reduction was significantly greater in the high-dose group. A significantly greater proportion of patients in the high-dose group experienced reductions in drop seizures of ‡25%, ‡50%, and ‡75% compared to the low-dose group; more patients in the high-dose group experienced a 100% reduction, but the difference was not significant. Nondrop seizures were also reduced in a dose-dependent manner. In both investigator and parent/caregiver global evaluations, patients in the high-dose group showed significantly greater improvements in overall symptoms compared to low-dose CLB. Adverse events were generally mild or moderate, and were similar between dose groups. Five serious adverse events were reported in four patients, but in no case was CLB discontinued. Conclusions: Clobazam was well tolerated and reduced drop seizure rates; high-dose CLB was more effective than low-dose CLB. Other seizure types were also reduced. KEY WORDS: Childhood epilepsy, Drop seizure, Atonic seizure, Akinetic seizure, Catastrophic epilepsy.Lennox-Gastaut syndrome (LGS) is a catastrophic childhood epilepsy characterized by multiple types of seizures and developmental delay. Onset of LGS usually occurs between 3 and 10 years of age, and affects boys more often than girls (Beaumanoir & Dravet, 1992). Typical LGS is described by the presence of the characteristic triad of: (1) tonic axial, atonic, and/or atypical absence seizures; (2) electroencephalography (EEG) abnormalities with bursts of diffuse slow spike-wave pattern of 1.5-2.5 Hz; and (3) impaired intellectual growth (Beaumanoir & Blume, 2002;Crumrine, 2002). Atonic or drop seizures are frequent in LGS and are responsible for most injuries associated with falls. The prognosis for LGS is poor, since the seizures tend to be medically refractory, with only 10% of cases experiencing full seizure remission with available therapies. Most patients experience ongoing cognitive impairment and refractory epilepsy, and some patients experience frequent episodes of status epilepticus (Crumrine, 2002;Markand, 2003 (Markand, 2003).Clobazam (CLB) is a novel 1,5-benzodiazepine that was initially developed as an antianxiety treatment designed to decrease AEs associated with 1,4-benzodiazepines while maintaining efficacy (Chapman et al., 1...

This double-blind, randomized, multicenter study investigated the use of divalproex with an antipsychotic agent in patients hospitalized for acute exacerbation of schizophrenia. Patients (n = 249) who met DSM-IV criteria for schizophrenia were randomly assigned to receive olanzapine monotherapy, risperidone monotherapy, divalproex plus olanzapine, or divalproex plus risperidone for 28 days. Divalproex was initiated at 15 mg/kg/day and titrated over 12 days to a maximum dosage of 30 mg/kg/day. Olanzapine and risperidone, were, respectively, initiated at 5 and 2 mg/day and were titrated over the first 6 days to respective target fixed daily dosages of 15 and 6 mg/day. Improvements from baseline were observed at all evaluation points throughout the 28-day treatment period in the two combination therapy and the two antipsychotic monotherapy groups, with statistically significant treatment differences favoring combination therapy as soon as day 3 for Positive and Negative Syndrome Scale (PANSS) total score, derived Brief Psychiatric Rating Scale (BPRSd) total score, as well as PANSS and BPRSd subscales. These findings were confirmed in post hoc repeated-measures analyses of variance in which treatment differences favoring combination therapy were observed for PANSS total (p = 0.020) and PANSS positive scale scores (p = 0.002). Both combination therapy and antipsychotic monotherapy were well tolerated. Treatment with divalproex in combination with an atypical antipsychotic agent resulted in earlier improvements in a range of psychotic symptoms among acutely hospitalized patients with schizophrenia. Further evaluation is warranted to confirm these findings.