Two 6-Week, Randomized, Double-Blind, Placebo-Controlled Studies of Ziprasidone in Outpatients With Bipolar I Depression

Abstract

Two randomized, double-blind, placebo-controlled, 6-week studies comparing ziprasidone versus placebo for treatment of bipolar depression (BPD) failed to meet their primary study objectives, indicating that either ziprasidone is ineffective in the treatment of BPD or the study failed. Adult outpatients with bipolar I depression with 17-item Hamilton Rating Scale for Depression total score more than 20 at screening and baseline received either ziprasidone 40 to 80 mg/d, 120 to 160 mg/d, or placebo (study 1), or ziprasidone 40 to 160 mg/d or placebo (study 2). Primary efficacy measure in both studies was change from baseline in Montgomery-Åsberg Depression Rating Scale total scores at week 6 (end of the study). Mixed-model repeated-measures methodology was used to analyze the primary efficacy measure in both studies. Secondary efficacy measures in both studies included Hamilton Rating Scale for Depression total score and Clinical Global Impression-Improvement score. Post hoc analyses were conducted for both studies to examine potential reasons for study failure. In both, ziprasidone treatment groups failed to separate statistically from placebo for change from baseline Montgomery-Åsberg Depression Rating Scale score at week 6. Response rates were 49%, 53%, and 46% for placebo, ziprasidone 40 to 80 mg/d, and ziprasidone 120 to 160 mg/d, respectively (study 1), and 51% and 53% for placebo and ziprasidone 40 to 160 mg/d, respectively (study 2). Ziprasidone 40 to 160 mg/d did not show superiority over placebo at week 6 in the treatment of BPD. Post hoc analyses revealed serious inconsistencies in subject rating that may have limited the ability to detect a difference between drug and placebo response. Rating reliability warrants further investigation to improve clinical trial methodology in psychiatry.

Lurasidone in the Long‐term Treatment of Patients With Bipolar Disorder: A 24‐week Open‐label Extension Study

“…Among atypical antipsychotics, quetiapine monotherapy,11, 12 and olanzapine in combination with fluoxetine (OFC),13 have demonstrated efficacy in the acute treatment of bipolar depression, whereas aripiprazole monotherapy,14 and ziprasidone monotherapy15 and adjunctive therapy (with lithium or divalproex)16 were not significantly different from placebo in controlled acute trials. Quetiapine monotherapy17 and adjunctive therapy (with lithium or divalproex)18, 19, 20 demonstrated significant efficacy in preventing recurrence of both manic and depressive episodes in bipolar populations.…”

Antidepressant Action of Atypical Antipsychotics

“…38 Finally, other atypical antipsychotics show antidepressant action despite boasting of less impressive putative antidepressant mechanisms than ziprasidone. Yet, ziprasidone showed no antidepressant advantage over placebo in the MDD 34 and bipolar depression 36,37 RCTs described in the earlier sections. Important take-home messages are that preclinical research and circumstantial evidence can only guide hypothesis generation, and antidepressant action is not a class action of atypical antipsychotic drugs.…”

“…Sachs et al 36 and Lombardo et al 37 reported serious inconsistencies in clinical ratings and recruitment matters that may have limited the ability of the RCTs to detect a difference between ziprasidone and placebo. It is therefore uncertain whether these RCTs can contribute meaningfully to decision-making on the use of ziprasidone in bipolar depression.…”

“…Sachs et al 36 described a 6-week RCT which found that ziprasidone (mean dose = 90 mg/d) augmentation of a mood stabilizer was ineffective in adults with bipolar depression. Lombardo et al 37 attempted to explain the failure of two 6-week RCTs comparing ziprasidone with placebo in adults with bipolar I depression. One of these studies examined 2 different doses of ziprasidone (40- In the ziprasidone group vs the placebo group, the dropout rates were 41% vs 16%, respectively, at the end of phase 1 and 33% vs 12% at the end of phase 2.…”

“…The ziprasidone bipolar depression studies 36,37 were considered flawed by their authors themselves and therefore should not be used as evidence to guide decision-making. So, if the ideal evidence is unavailable, the next best evidence that is available should be applied to the clinical problem at hand.…”