Olanzapine-divalproex combination versus divalproex monotherapy in the treatment of bipolar mixed episodes: a double-blind, placebo-controlled study.
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.


METHODS
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 >or=14 days at levels of 75 to 125 microg/mL with inadequate efficacy (21-item Hamilton Depression Rating Scale [HDRS-21] and Young Mania Rating Scale [YMRS] scores >or=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 (>or=25% HDRS-21 and YMRS decreases, median 7 versus 14 days) and time to response (>or=50% HDRS-21 and YMRS decreases, median 25 versus 49 days) were significantly shorter with adjunctive olanzapine. Increases in weight (total and >or=7%) and fasting blood glucose were significantly greater with adjunctive olanzapine.


CONCLUSIONS
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00402324.
Houston
John P
JP
Lilly USA, LLC, Drop Code 4133, Indianapolis, IN 46285, USA. houstonjp@lilly.com
Tohen
Mauricio
M
Degenhardt
Elisabeth K
EK
Jamal
Hassan H
HH
Liu
Lin L L
LL
Ketter
Terence A
TA
D000328:Adult; D018692:Antimanic Agents / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000523:psychology; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000077152:Olanzapine; D010919:Placebos; D011569:Psychiatric Status Rating Scales; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires; D016896:Treatment Outcome; D014635:Valproic Acid / Q000627:therapeutic use*
D018692:Antimanic Agents; D014150:Antipsychotic Agents; D010919:Placebos; D001569:Benzodiazepines; D014635:Valproic Acid; D000077152:Olanzapine