A 6 Week Randomized Double-Blind Placebo-Controlled Trial of Ziprasidone for the Acute Depressive Mixed State

OBJECTIVE: To examine the efficacy of ziprasidone vs. placebo for the depressive mixed state in patients with bipolar disorder type II or major depressive disorder (MDD). METHODS: 73 patients were randomized in a double-blinded, placebo-controlled study to ziprasidone (40-160 mg/d) or placebo for 6 weeks. They met DSM-IV criteria for a major depressive episode (MDE), while also meeting 2 or 3 (but not more nor less) DSM-IV manic criteria. They did not meet DSM-IV criteria for a mixed or manic episode. Baseline psychotropic drugs were continued unchanged. The primary endpoint measured was Montgomery-Åsberg Depression Rating Scale (MADRS) scores over time. The mean dose of ziprasidone was 129.7±45.3 mg/day and 126.1±47.1 mg/day for placebo. RESULTS: The primary outcome analysis indicated efficacy of ziprasidone versus placebo (p = 0.0038). Efficacy was more pronounced in type II bipolar disorder than in MDD (p = 0.036). Overall ziprasidone was well tolerated, without notable worsening of weight or extrapyramidal symptoms. CONCLUSIONS: There was a statistically significant benefit with ziprasidone versus placebo in this first RCT of any medication for the provisional diagnostic concept of the depressive mixed state. TRIAL REGISTRATION: Clinicaltrials.gov NCT00490542

Antidepressants worsen rapid-cycling course in bipolar depression: A STEP-BD randomized clinical trial.

Artículo de publicación ISIBackground: The use of antidepressants in rapid-cycling bipolar disorder has been controversial. We report the first randomized clinical trial with modern antidepressants on this topic. Methods: As part of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, we analyzed, as an a priori secondary outcome, rapid cycling as a predictor of response in 68 patients randomized to continue vs. discontinue antidepressant treatment, after initial response for an acute major depressive episode. Outcomes assessed were percent time well and total number of episodes. All patients received standard mood stabilizers. Results: In those continued on antidepressants (AD), rapid cycling (RC) subjects experienced 268% (3.14/1.17) more total mood episodes/year, and 293% (1.29/0.44) more depressive episodes/year, compared with non-rapid cycling (NRC) subjects (mean difference in depressive episodes per year RC vs. NRC was 0.85 +/- 0.37 (SE), df=28, p=0.03). In the AD continuation group, RC patients also had 28.8% less time in remission than NRC patients (95% confidence intervals (9.9%, 46.5%), p=0.004). No such differences between RC and NRC subjects were seen in the AD discontinuation group (Table 1). Analyses within the rapid-cycling subgroup alone were consistent with the above comparisons between RC and NRC subjects, stratified by maintenance antidepressant treatment, though limited by sample size. Conclusions: In an a priori analysis, despite preselection for good antidepressant response and concurrent mood stabilizer treatment, antidepressant continuation in rapid-cycling was associated with worsened maintenance outcomes, especially for depressive morbidity, vs. antidepressant discontinuation.NIMH, United State

Ziprasidone vs Placebo: 6 week change in MADRS (SD) from baseline.

<p>Ziprasidone vs Placebo: 6 week change in MADRS (SD) from baseline.</p

Clinical Response of the Sample.

<p>SD = Standard deviation, MADRS = Montgomery-Åsberg Depression Rating Scale, MRS = Mania Rating Scale, CGI = Clinical Global Impressions Scale, GAF = Global Assessment of Functioning Scale.</p>*<p>p<0.05.</p>†<p>Outcome change = Change of each measure from baseline to endpoint.</p>‡<p>F = 8.273.</p

Clinical and Demographic Characteristics of the Sample.

<p>SD = standard deviation, MDD = major depressive disorder, BD = bipolar disorder.</p

Ziprasidone vs Placebo: 6 week change in MRS (SD) from baseline.

<p>Ziprasidone vs Placebo: 6 week change in MRS (SD) from baseline.</p

Final ANOVA table of model without baseline adjustments.

<p>DF =  degrees of freedom, ANOVA = Analysis of variance, β = effect estimate.</p