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

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

J Clin Psychiatry

Submitted: December 22, 2009; accepted August 19, 2010.

Online ahead of print: May 3, 2011 (doi:10.4088/JCP.09m05934).

Corresponding author: Gary S. Sachs, MD, Bipolar Clinic and Research Program, Massachusetts General Hospital, 50 Staniford St, 5th Floor, Boston MA 02114 ([email protected]).