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The effectiveness of the newer antidepressants in comparison to that of the more established agents is frequently questioned.Although selective serotonin reuptake inhibitors (SSRIs) show a high degree of pharmacologic selectivity, this does not seem to translate into improved clinical efficacy. Instead, the clinical effectiveness of the tricyclic agents may be attributable to their dual inhibitory effects on both noradrenergic and serotonergic systems. Accordingly, newer antidepressants with multiple modes of action may prove more effective than serotonin-selective compounds.To assess the relative merits of older and newer antidepressant drugs in severe depression, efficacy findings from the limited number of comparative clinical trials conducted in this patient population were reviewed.A systematic approach was taken, with studies being grouped according to the various characteristics that, in conjunction with standard DSM-IV and International Classification of Diseases, 10th revision, diagnostic criteria, define severe depression, viz. a 17-item Hamilton Rating Scale for Depression score greater or equal to 25, hospitalization, and the presence of psychotic (delusional), melancholic, and endogenous features. The contention that tricyclic antidepressants offer superior efficacy to the SSRIs and the reversible monoamine oxidase inhibitors in the treatment of severe depression is supported by several comparisons of clomipramine with fluoxetine, paroxetine, citalopram, and moclobemide. Venlafaxine also seems to be more effective than fluoxetine in hospitalized patients with melancholic depression. Mirtazapine, a noradrenergic and specific serotonergic antidepressant, displays comparable antidepressant efficacy to clomipramine and amitriptyline in severe depression and seems to be a useful option in this patient population. (J Clin Psychopharmacol 1997;17[suppl 1]:19S-28S).