Jeffrey D. Baker

Divalproex ER Combined with Olanzapine or Risperidone for Treatment of Acute Exacerbations of Schizophrenia

The objective of this study was to evaluate the efficacy and safety of divalproex sodium extended release (divalproex ER) vs placebo in combination with olanzapine or risperidone for the treatment of acute exacerbations of schizophrenia. In this 12-week, randomized, double-blind, parallel-group, multi-center trial, a total of 402 patients were randomized and treated; 103 received olanzapine/placebo, 99 received olanzapine/divalproex ER, 101 received risperidone/placebo, and 99 received risperidone/divalproex ER. Divalproex ER was initiated on day 1 at 20 mg/kg per day q AM and was titrated to clinical effect on days 3, 7, and 10, not to exceed a maximum dosage of 35 mg/kg per day. Olanzapine and risperidone were initiated at 5 and 2 mg/day q PM, respectively, increased to 10 and 4 mg/day on day 3, and increased to fixed target doses of 15 and 6 mg/day on day 6. No significant treatment difference was demonstrated between the combination therapy and antipsychotic monotherapy groups on the primary efficacy variable of the mean change from baseline to day 14 last observation carried forward on the Positive and Negative Syndrome Scale (PANSS) total score, although antipsychotic monotherapy did demonstrate superiority to combination therapy on the PANSS Negative subscale at several time points. Combination therapy also failed to show an advantage over antipsychotic monotherapy at day 84 on the PANSS total score. Most adverse events observed in the study were mild to moderate in severity, and the overall number of adverse events did not differ significantly between the combination therapy groups and their corresponding antipsychotic monotherapy group.

A Randomized Trial to Assess the Efficacy and Safety of ABT-126, a Selective α7 Nicotinic Acetylcholine Receptor Agonist, in the Treatment of Cognitive Impairment in Schizophrenia

OBJECTIVE The authors sought to evaluate the efficacy and safety of ABT-126, a selective α7 nicotinic receptor partial agonist, in stable patients with schizophrenia. METHOD A 12-week, double-blind, placebo-controlled, parallel-group phase 2 study was conducted in 22 centers in the United States. Clinically stable patients with schizophrenia were randomly assigned to receive once-daily dosing with 10 mg of ABT-126, 25 mg of ABT-126, or placebo. The primary efficacy measure was change from baseline to week 12 on the MATRICS Consensus Cognitive Battery (MCCB) composite score compared with placebo, tested by a one-sided t test. Secondary measures included MCCB domain scores and UCSD Performance-Based Skills Assessment total score, each tested by two-sided t tests. RESULTS A total of 207 subjects were randomized, of whom 165 (81%) completed the study. ABT-126 showed an improvement that fell short of significance on the MCCB composite score at week 12 (least squares mean difference from placebo, 1.3 and 1.5 for the 10 mg and 25 mg groups, respectively). A significant treatment-by-smoking status interaction was observed on the mean change from baseline to final MCCB composite score: nonsmokers (N=69) demonstrated a difference from placebo of 2.9 (SE=1.4) in the 10 mg group and 5.2 (SE=1.6) in the 25 mg group, whereas no differences were observed in smokers (N=113). Among the nonsmokers in the ABT-126 25 mg group (N=19), significant improvements compared with placebo occurred at final assessment for verbal learning (least squares mean difference=5.5, SE=1.9), working memory (least squares mean difference=5.4, SE=2.0), and attention/vigilance (least squares mean difference=8.7, SE=2.5). The most frequently reported adverse events for ABT-126 were dizziness, diarrhea, and fatigue (all <8% incidence). CONCLUSIONS ABT-126 demonstrated a procognitive effect in nonsmoking subjects, particularly in verbal learning, working memory, and attention.

Relationship between serum valproate and lithium levels and efficacy and tolerability in bipolar maintenance therapy

Background. In spite of widespread recognition of the importance of maintenance treatment for bipolar disorder, there are relatively few available well-designed clinical trials that have provided rigorous evidence for the efficacy of specific agents. One approach used effectively in analyses of lithium studies has been the stratification of efficacy and tolerability results based on serum drug concentrations. Therefore, we conducted a similar analysis of the efficacy of divalproex or lithium, based on serum concentrations in the maintenance treatment of bipolar I disorder in a recent 12-month placebo-controlled trial. Methods. This was a post-hoc analysis of results obtained in a 12-month, double-blind, placebo-controlled trial of divalproex and lithium involving 372 patients (intent-to-treat). The patient set was stratified into four therapeutic drug concentration ranges (Non-therapeutic, Low Therapeutic, Medium Therapeutic, and High Therapeutic) for both divalproex and lithium. Efficacy measures were Kaplan–Meier survival analyses of time to discontinuation for any reason, time to discontinuation for a protocol-defined manic episode, and time to discontinuation for a manic or depressive episode. Results. Significant differences between divalproex at the Medium Therapeutic range (75–99.9 µg/ml) and placebo were demonstrated in Kaplan–Meier survival results for discontinuation for any reason (median survival time: divalproex, 8 months; placebo, 4 months; P<0.05) and for discontinuation for a manic or depressive episode (median survival time: divalproex, 8 months; placebo, 3 months, P=0.003). At 12 months, the proportion of divalproex-treated patients (Medium Therapeutic range) who did not discontinue for a protocol-defined manic episode (85%) was higher than the proportion of lithium (Medium Therapeutic range; 70%) or placebo-treated (83%) patients. Conclusions. Divalproex at the Medium Therapeutic range provided significantly better bipolar maintenance treatment response than placebo in survival analyses, suggesting a possible serum concentration target range for clinicians in providing optimal treatment response. The value of this analytic approach, used for the first time here for divalproex, is discussed, along with a call for further research into optimal therapeutic drug levels.

Erratum: Relationship between serum valproate and lithium levels and efficacy and tolerability in bipolar maintenance therapy (International Journal of Psychiatry in Clinical Practice (2005) 9,4 (271-277))

Around the world, people continue to harm themselves in substantial numbers. The retrospective study of almost 1000 presentations after non-fatal self-harm reported by Belgamwar and colleagues (Stoke, England) suggests that rates increased in men over an 8-year period, although the rate of completed suicide in the same geographical area decreased over the same time. The importance of establishing the presence of psychiatric illness in people presenting after self-harm is demonstrated by the consecutive case series (n /100) described by Rihmer and colleagues (Budapest, Hungary), in which at least one Axis I mental disorder was present in 92% of cases, 60% of patients having co-morbid conditions.