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Improvement under Fluoxetine and Moclobemide

Mechanisms of Action of Antidepressants

Decades of research into the putative mechanisms of action of antidepressant substances have not enhanced our understanding of the etiology of depressive disorders. In consequence, while having better tolerance and safety profiles, the newer anti- depressants do not offer an advantage over the first-generation agents (i.e., the tricyclic antidepressants and the monoamine oxidase inhibitors) neither with respect to the proportion of patients in whom they induce a therapeutic response nor in their ability to reduce residual symptoms. This raises the question of how effective antidepressants truly act. Investigations into the time characteristics of response under antidepressant treatment will certainly contribute to a better understanding of the mechanisms of action underlying effective drugs.

Differences Between Treatment Modalities

Our patient sample, provided by courtesy of F. Hoffmann-La Roche, Switzerland, consisted of 877 patients (307 males, 570 females, aged 18-86 years), diagnosed according to DSM-III criteria as suffering from major depressive disorders. To be included, patients were required to demonstrate a baseline score of at least 15 on the 17-item Hamilton Scale. Of this sample, 437 patients received the monoamine oxidase-A inhibitor moclobemide, and 440 patients the selective serotonin re-uptake inhibitor fluoxetine. Despite its cross-sectional design, the study allowed us to analyse the distribution of the time spans to onset of improvement at a one-day resolution because the "true" rating dates (calendar dates) varied by typically ±2 days around the pre-specified "design" days of the study protocol.

Early Improvement as Predictor of Later Response

Among responders to fluoxetine and moclobemide, the distributions of time spans to onset of improvement turned out to be virtually independent of treatment, as indicated by the cumulative percentage rates of improvers, regarded as a function of time (Table 12). These cumulative rates remained identical between treatment groups, even when the sustained relative improvement criterion was made successively more stringent from 20% to 60%. Most notably, the onset of improvement occurred in 57% of cases within the first two weeks, and in more than 70% of cases within the first three weeks, and was highly predictive of later outcome as more than 70% of "early" improvers became responders (50% sustained baseline score reduction). Inversely, of all responders of this study more than 80% had displayed "early" improvement.

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Onset of improvement
Table 12: Cumulative rates of improvers as a function of time under fluoxetine (n=440; 345 improvers [78%]) and moclobemide (n=437; 348 improvers [80%]). Improvement is defined as a 20% sustained baseline score reduction. It is worth noting that the time characteristics of improvement are virtually identical under pharmacologically very different antidepressants.
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