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The article you requested is

Olanzapine-Divalproex Combination Versus Divalproex Monotherapy in the Treatment of Bipolar Mixed Episodes: A Double-Blind, Placebo-Controlled Study

J Clin Psychiatry 2009;70(11):1540-1547
Copyright 2009 Physicians Postgraduate Press, Inc.

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Objective: This 6-week, randomized, double-blind, placebo-controlled trial used simultaneous depression and mania criteria to compare a single mood stabilizer, divalproex, with and without adjunctive olanzapine in patients with bipolar I disorder experiencing acute mixed episodes.

Method: Two hundred two adults, aged 18 to 60 years, who met DSM-IV-TR criteria for bipolar disorder with a current mixed episode and had been taking divalproex for ≥14 days at levels of 75 to 125 µg/mL with inadequate efficacy (21-item Hamilton Depression Rating Scale [HDRS-21] and Young Mania Rating Scale [YMRS] scores ≥16) were randomly assigned to olanzapine 5 to 20 mg/d versus placebo augmentation. HDRS-21, YMRS, Clinical Global Impressions for Bipolar Disorder (CGI-BP), hospitalizations, concomitant medications, and adverse events were assessed. Comparisons included changes in both HDRS-21 and YMRS (primary outcome measure), time to partial response and time to response, CGI-BP improvement, hospitalizations, and safety (secondary outcome measures). The study was conducted from December 2006 to February 2008.

Results: Mean (SD) baseline HDRS-21 and YMRS scores were 22.2 (4.5) and 20.9 (4.4), respectively, with 59% female and 51% white subjects. Mean±SE score changes from baseline across the 6-week treatment period for adjunctive olanzapine (n=100) versus adjunctive placebo (n=101) arms, respectively, were −9.37± 0.55 versus −7.69± 0.54, P=.022, on the HDRS-21 and −10.15± 0.44 versus −7.68± 0.44 P<.001, on the YMRS. Mean±SE score changes from baseline to last observation carried forward for CGI-BP measures were −1.34± 0.11 for adjunctive olanzapine versus −1.06± 0.11 for adjunctive placebo, P=.056. Time to partial response (≥25% HDRS-21 and YMRS decreases, median 7 versus 14 days) and time to response (≥50% HDRS-21 and YMRS decreases, median 25 versus 49 days) were significantly shorter with adjunctive olanzapine. Increases in weight (total and ≥7%) and fasting blood glucose were significantly greater with adjunctive olanzapine.

Conclusion: Adjunctive olanzapine yielded greater and earlier reduction of manic and depressive symptoms in mixed-episode patients with inadequate response to at least 2 weeks of divalproex.

Trial Registration: clinicaltrials.gov Identifier: NCT00402324

See also Commentary on page 1548.

Submitted: November 24, 2008; accepted March 6, 2009.

Online ahead of print: September 22, 2009.

Corresponding author: John P. Houston, MD, PhD, Lilly USA, LLC, Drop Code 4133, Indianapolis, IN 46285 (houstonjp@lilly.com).