Does pioglitazone improve depression through insulin-sensitization? Results of a randomized double-blind metformin-controlled trial in patients with polycystic ovarian syndrome and comorbid depression

Thiazolidinediones have shown beneficial effects in short-term treatment of depression. However, it is unclear whether the antidepressant efficacy of these agents is related to their insulin-sensitizing action. We conducted the present study to compare the antidepressant efficacy of pioglitazone with another insulin-sensitizer, metformin, in obese patients with concomitant polycystic ovarian syndrome (PCOS) and major depressive disorder (MDD). In a six-week double-blind study, 50 patients with PCOS and MDD (DSM-IV-TR criteria) with Hamilton depression rating scale (HDRS) score of <20, randomly received pioglitazone (15 mg twice daily; PO) or metformin (750 mg twice daily; PO). Assessment was done using HDRS (weeks 0, 3, 6) together with fasting Insulin, glucose, and lipid profile, liver enzymes, homeostatic model assessment of insulin resistance (HOMA-IR), anthropometric measures, and serum androgens (weeks 0 and 6). Pioglitazone was superior to metformin in reducing HDRS scores at the end of the study [38.3% versus 8.3% reduction from baseline scores, F(1, 37) = 73.513, P < 0.001]. Changes from baseline in HOMA-IR values at week 6 were not significantly different between the two groups (P = 0.888). Baseline (but not follow-up) HDRS and HOMA-IR values were significantly correlated (r = 0.393, P = 0.012). In multiple regression analysis, treatment with pioglitazone independent of HOMA-IR values predicted greater score reduction on HDRS at week 6 (standardized beta = 0.801, P < 0.001). Biochemical and hormonal profile did not differ between the two groups at week 6. Metformin was associated with higher frequency of gastrointestinal side effects (P = 0.014). In summary, we showed that pioglitazone improved depression with mechanisms largely unrelated to its insulin-sensitizing action (registration number: IRCT201106081556N23).