Efficacy and safety of adjunctive oral ziprasidone for acute treatment of depression in patients with bipolar I disorder: a randomized, double-blind, placebo-controlled trial.
Author(s): Sachs GS, Ice KS, Chappell PB, Schwartz JH, Gurtovaya O, Vanderburg DG, Kasuba B
Affiliation(s): Bipolar Clinic and Research Program, Massachusetts General Hospital, 50 Staniford St, 5th Floor, Boston MA 02114, USA. SachsG@aol.com.
Publication date & source: 2011-10, J Clin Psychiatry., 72(10):1413-22. Epub 2011 May 3.
OBJECTIVE: To assess efficacy and safety of adjunctive ziprasidone in subjects with bipolar depression treated with lithium, lamotrigine, or valproate. METHOD: 298 adult outpatients with bipolar I disorder (DSM-IV criteria) were randomized to receive ziprasidone, 20-80 mg twice a day, or placebo twice a day for 6 weeks plus their preexisting mood stabilizer. The primary efficacy variable was change in Montgomery-Asberg Depression Rating Scale (MADRS) total scores from baseline to 6 weeks. The key secondary efficacy endpoint was change from baseline to week 6 in Clinical Global Impressions-Severity (CGI-S) scores. Computer-administered assessments for diagnostic confidence were included for quality control and to evaluate study performance. The study was conducted between October 2007 and December 2008. RESULTS: The mean +/- SD daily dose of ziprasidone was 89.8 +/- 29.1 mg. Least squares mean +/- standard error changes from baseline to week 6 on MADRS total score for ziprasidone and placebo treatment groups were -13.2 +/- 1.2 and -12.9 +/- 1.1, respectively, with a 2-sided P value of .792. There was no significant difference on the key secondary variable (CGI-S). Adjunctive ziprasidone was well tolerated. Poor quality ratings at baseline were associated with a trend for better improvement on placebo than ziprasidone. Among 43 placebo-treated subjects with poor baseline quality ratings, 29 (67.4%) had baseline MADRS scores > 10 points higher on the computer-administered assessment than the MADRS administered by the site-based rater. The response favoring placebo over ziprasidone observed in this subgroup suggests that poor signal detection in some clinical trials can be a consequence of "subject inflation" as well as "rater inflation." CONCLUSIONS: Adjunctive ziprasidone treatment failed to separate from mood stabilizer alone on primary and secondary endpoints. Possible contributions to this result include enrollment of a substantial number of subjects with low diagnostic confidence, low quality ratings on the MADRS, and overzealous reporting of symptoms by subjects. TRIAL REGISTRATION: clinical trials.gov Identifier: NCT00483548. (c) Copyright 2011 Physicians Postgraduate Press, Inc.