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| |  Divalproex Augmentation With Olanzapine Reduces Mania and Depression in Patients With Mixed Episodes of Bipolar I Disorder: Presented at EPA By Chris Berrie LISBON, Portugal -- January 26, 2009 -- Augmentation of divalproex monotherapy with olanzapine appears to reduce both mania and depression in patients with mixed-episode bipolar I disorder, according to a multicentre, randomised, double-blind, placebo-controlled trial presented here at the 17th European Congress of Psychiatry, organised by the European Psychiatric Association (EPA). Coinvestigator John P. Houston, MD, PhD, US Medical Division, Lilly Research Laboratories, Indianapolis, Indiana, presented this study on January 25. Olanzapine is already approved for treatment of bipolar mania and mixed mania in combination with lithium and divalproex, Dr. Houston stated, adding, "this expands our database for mixed response … while also looking at earlier time points for response, as early as 2 days." For the study, the researchers enrolled adults aged 18 to 60 years with a diagnosis of bipolar I disorder and current mixed episodes. They also had a Hamilton Depression Rating Scale (HDRS) score of 16 or greater, a Young Mania Rating Scale (YMRS) of 16 or greater, no active substance abuse/dependence within previous 6 months, no suicidal risk, and lack of response to divalproex treatment for 2 weeks or more. The primary objectives were mean changes in both HDRS and YMRS total scores from baseline to 6 weeks of treatment. Secondary objectives were HDRS and YMRS times to partial response (25% or greater reduction in both) and response (50% or greater reduction in both), Clinical Global Impression for Bipolar Disorder (CGI-BP) changes from baseline, hospitalisation rates, and safety and tolerability. Among the 202 nonresponding patients on open-label divalproex (target serum levels, 75-125 mcg/mL), 101 were randomised to addition of placebo and 101 to addition of olanzapine 15 mg/day, with flexible dosing of 5, 10, 15, or 20 mg/day. Mean age in the 2 groups was 39 years; males made up 42.6% and 39.6% of each group, respectively. There were no significant differences across placebo and olanzapine groups for mean baseline illness severity, as determined by scores on the HDRS (21.87 vs 22.45, respectively), YMRS (20.40 vs 21.42), and CGI-BP (4.26 vs 4.33). The same was seen for clinical history (hospitalised, 15.8% vs 13.9%; mean mania episodes, 0.85 vs 0.65; mean depression episodes, 1.14 vs 0.91; mean mixed episodes, 1.61 vs 1.82). Significant improvements were seen over 6 weeks of treatment for olanzapine over control in mean change from baseline for (respectively) both HDRS (-9.37 vs -7.69; P = .022) and YMRS (-10.15 vs -7.68; P < .001). These changes were significant (P < .05) from days 7 and 6 onwards, respectively. Significant benefits for olanzapine treatment versus placebo were seen in median number of days for partial responses (mania, 3 vs 7, P = .002; depression, 5 vs 7, P = .004; mixed, 7 vs 14, P < .001) and for most responses (mania, 10 vs 22, P = .011; depression, 15 vs 29, P = .065; mixed, 25 vs 49, P = .020). A beneficial trend was also seen for olanzapine over placebo in mean CGI-BP changes from baseline (-1.34 vs -1.06; P = .056). Treatment emergent adverse events saw significant increases (P < .02) with olanzapine treatment over control for sedation (23.8% vs 4.0%), somnolence (20.8% vs 5.9%), weight increase (20.8% vs 4.0%), dry mouth (12.9% vs 3.0%), and tremor (8.9% vs 0.0%). Olanzapine reduces the time to onset of response in patients who did not show a response after the first 2 weeks of treatment with divalproex, Dr. Houston noted. In this study, greater and earlier reductions in both mania and depression were observed with olanzapine augmentation over placebo. Funding for this study was provided by Eli Lilly and Company.
[Presentation title: A Double-Blind, Placebo-Controlled Trial of Olanzapine Augmentation in Bipolar I Disorder, Mixed Episode. Abstract P1146]
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