The efficacy of tianeptine in the treatment of major depressive episodes was assessed in three double-blind placebo-controlled studies. In a first double-blind study comparing tianeptine (37.5 mg/day) with placebo, 126 patients with Major Depression or a Depressed Bipolar Disorder were treated for 42 days; 60% of these patients fulfilled DSM-III-R criteria for melancholia. Final MADRS scores showed the efficacy of tianeptine in comparison with placebo (P = 0.007). This result was confirmed by the time course of the Severity of Illness (CGI item 1) (P = 0.015). 58% of the patients responded to tianeptine versus 41% to placebo. In another study comparing tianeptine (37.5 mg/day), imipramine (150 mg/day), and placebo, 186 depressed patients were treated for 42 days. The patients had either Major Depression or Depressed Bipolar Disorder, without melancholia (DSM III-R). In the intention-to-treat analysis, final MADRS scores showed a better efficacy of tianeptine and imipramine than placebo (P = 0.012 and P = 0.034, respectively). There were 56% responders on tianeptine vs 48% on imipramine, and 32% on placebo. A third study involved 244 patients with Major Depression with or without melancholia (DSM-III-R). They were treated in a parallel group design with tianeptine (37.5 mg/day) or tianeptine (75 mg/day) or placebo for 42 days. The high rate of placebo-responders (> 65%) did not allow any conclusion about the efficacy of tianeptine. Altogether, tianeptine was shown to be an effective and safe medication for the treatment of major depressive episodes. However, a controlled study in endogenous depression would be useful to determine the position of tianeptine among the other antidepressants in this indication.