The onset of action of antidepressant drugs was investigated on the basis of two independent, multicenter, double-blind studies, comparing amitriptyline (N = 120), oxaprotiline (N = 120), imipramine (N = 506) and moclobemide (N = 580) with placebo (N = 189/+191). Highly significant differences between the active drugs and placebo were found with respect to the total number of improvers and the total number of responders. In addition, significant differences between treatment modalities showed up in both the percentage rate and the time distribution of premature withdrawals. However, among improvers, the distribution of time spans to onset of improvement was found to be independent of treatment modality, indicated by virtually identical cumulative percentages of improvers over the whole observation period. This picture of treatment-independent improvement rates was essentially the same for the HAMD, HAMA and ZUNG assessments, except for a significant time lag between observerratings and self-ratings. Specifically, our analyses revealed no evidence for a delayed onset of action of various antidepressants with large biochemical and pharmacological differences when compared to placebo. The early onset of improvement was highly predictive of later outcome: on average, 70% of patients showing improvement within the first 14 days became responders. Differences between active treatments and placebo emerged within the first five days and reached a point of maximum distinction around day 14. After this time point, differences between treatment modalities remained constant until the end of the observation period. Not more than 20-25% of patients were, on average, "true" drug responders, thus suggesting that the therapeutic qualities of antidepressants do not lie in the suppression of symptoms, but rather relate to their ability to elicit and maintain certain conditions which enable recovery in a subgroup of patients who would otherwise remain nonresponders.