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Depression is a widespread mental disorder in which nearly half of the affected people have recurrent symptoms. Drug combinations may produce cumulative adverse effects, especially in elderly and physically ill patients. It was demonstrated that curcumin possesses antidepressive activity in various animal models of depression, and a combination of curcumin with some antidepressants potentiates the antidepressive effect of these agents. We sought to evaluate the efficacy of curcumin as an antidepressive agent in a combination with other antidepressants in patients with major depression.Forty patients with a first episode of depression participated in a 5-week, double-blind, randomized, placebo-controlled study. The subjects were treated with either 500-mg/d curcumin or placebo together with antidepressants (escitalopram or venlafaxine) during August 2010 until June 2011. The outcome measures were Clinical Global Impression—Severity Scale, Hamilton Depression Rating Scale, and Montgomery-Asberg Depression Rating Scale.Analysis of variance showed significant positive changes in both groups from baseline to the end of the study in all scales of measurement. These changes became significant from the first visit after 7 days of treatment. There was no difference between curcumin and placebo, which means negative results. However, the patients in the curcumin group demonstrated a trend to a more rapid relief of depressive symptoms in comparison to those in the placebo group. None of the patients complained of any adverse effect during the study.Although there is no definitive proof that curcumin can induce an earlier beneficial effect of antidepressive agents, it seems like an extended study is needed to prove it, using higher therapeutic doses of curcumin.