Improvement under Imipramine and Moclobemide versus Placebo

The onset of action of antidepressant drugs was investigated on the basis of two independent multicenter, double-blind efficacy studies comparing amitriptyline (N=120), oxaprotiline (N=120), imipramine (N=506) and moclobemide (N=580) with placebo (N=189+191). The samples consisted of in- and out-patients diagnosed, according to DSM-III criteria, as suffering from major depressive disorder. Measures of efficacy were the Hamilton Depression (HAMD), Hamilton Anxiety (HAMA) and Zung Self-Rating scales. By using the "sustained relative improvement" criterion, onset of action was determined in each individual patient as that time point in the 30 day observation period, at which a 20% baseline score reduction was achieved without subsequent deterioration beyond achieved improvement score. Analogously, response to treatment was defined as sustained 50% baseline score reduction. Highly significant differences between active drugs and placebo were found with respect to the total number of improvers and responders.

Differences Between Treatment Modalities

Significant differences between treatment modalities surfaced in the percentage rate as well as the time distribution of premature withdrawals. Yet unexpectedly, among improvers, the time spans to onset of improvement turned out to be independent of treatment modality as indicated by virtually identical cumulative percentages of improvers over the full observation period. The picture was essentially the same for the HAMA and ZUNG assessments, except for a significant time lag between observer- and self-ratings. In particular, our analyses revealed no evidence for a delayed onset of action under various antidepressants with large biochemical and pharmacological differences in comparison to placebo. Moreover, 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.

Therapeutic Qualities of Antidepressants

Applying survical-analytical methods, we found that differences between active treatments and placebo emerged within the first 5 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. According to our data, 20-25% of patients were, on average, "true" drug responders, thus suggesting that the therapeutic qualities of antidepressants does not lie in the suppression of symptoms, but rather related to their ability to elicit and maintain certain conditions which enable recovery in a subgroup of patients who would otherwise remain non-responders.

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