Double-blind, placebo-controlled trial of pioglitazone for bipolar depression.

Background: Objective of the present study was to conduct an 8-week double-blind, randomized, placebo-controlled trial to test the efficacy of pioglitazone in the treatment of bipolar depression. Methods: 38 outpatients with bipolar disorder and current major depressive episode were randomized to pioglitazone (15-45 mg/day) or placebo. The use of concomitant mood stabilizers, antipsychotics, and antidepressants was permitted. The primary outcome measure was the 30-item Inventory of Depressive Symptomatology, Clinician Rated (IDS-C30) total score change from baseline to endpoint. Laboratory evaluations, including serum level of inflammatory and metabolic biomarkers, were conducted. Results: 37 subjects were analyzed for efficacy (1 subject had no follow-up data). Mean reduction from baseline to week 8 in IDS-C30 score was -6.59 for pioglitazone and -11.63 for placebo. Mixed effects modeling indicated borderline statistically significant difference between the two groups (p = 0.056) in favor of placebo. On analysis of inflammatory and metabolic markers, a statistically significant negative correlation was noted between change in leptin levels and change in depression scores in the pioglitazone group (r=-0.61, p = 0.047) but not in the placebo group, the significance of which is unclear as the study failed to demonstrate antidepressant efficacy of pioglitazone over placebo. No serious adverse effects were reported, and pioglitazone was well-tolerated. Limitations: small sample size with inadequate power, concomitant use of other psychotropic medications, and lack of statistical adjustment for multiple testing. Conclusion: Current study does not support the antidepressant efficacy of pioglitazone in the treatment of bipolar depression. (240 words)