Perhaps the HAM-D as administered across the CO-MED sites did not adequately capture the element of symptom severity most relevant to the emergence of clear drug effects. The CO-MED study group contained far fewer subjects with melancholia than did either of the groups of Blier et al., and depressed patients with melancholic features have been shown to have higher severity ratings on global and other symptom-based measures in comparison to those without melancholia, despite having nearly identical HAM-D scores (9). Group differences were only somewhat larger in the CO-MED subset with melancholic features than in the patients without them. The performance of melancholia as a response predictor, though, varies considerably by how its components are defined and applied (10), and the CO-MED report does not state how melancholic symptoms were assessed. The relative scarcity of melancholia in the CO-MED patients nevertheless indicates a correspondingly lower severity level on some dimension.
A particularly striking feature of the CO-MED study group is the coexistence of the absence of treatment resistance, as specified by the entry criteria, and a high rate of chronicity. Although none of the participants had had an adequate monotherapy trial of an FDA-approved antidepressant within the current episode, over one-half of the group had a depressive episode that had been fully syndromal for at least the preceding 2 years. Why had they not undergone even one adequate antidepressant trial before the CO-MED effort came to pass? Whatever the answer, it seems likely that the average interval between episode onset and the receipt of first treatment was quite long. A number of prospective studies of major depressive disorder have shown the no-treatment interval to be as robust a predictor of poor outcome with treatment as neuroticism (11). Why this is so is a matter of speculation, but the measure's association with poorer treatment response generally may well have narrowed differences between the regimens applied here.
The Search for Improved Antidepressant Strategies: Is Bigger Better?
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