title: 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.
abstract: OBJECTIVE
  To assess efficacy and safety of adjunctive ziprasidone in subjects with bipolar depression treated with lithium, lamotrigine, or valproate.
  
  
  METHODS
  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.
  
  
  BACKGROUND
  clinical trials.gov Identifier: NCT00483548.
authors.affiliation: Bipolar Clinic and Research Program, Massachusetts General Hospital, Boston MA 02114, USA. SachsG@aol.com
authors.forename: Gary S
authors.initials: GS
authors.lastname: Sachs
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Ice
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Chappell
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Schwartz
authors.forename: Oksana
authors.initials: O
authors.lastname: Gurtovaya
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Vanderburg
authors.forename: Bryce
authors.initials: B
authors.lastname: Kasuba
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D018692:Antimanic Agents / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008094:Lithium / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D012702:Serotonin Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014227:Triazines / Q000627:therapeutic use; D014635:Valproic Acid / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D018692:Antimanic Agents; D010879:Piperazines; D012702:Serotonin Antagonists; D013844:Thiazoles; D014227:Triazines; D014635:Valproic Acid; C092292:ziprasidone; D008094:Lithium; D000077213:Lamotrigine