Although the efficacy of available antidepressants has been well established in the treatment of mild to moderate depression, clinical research literature on severe depression is more limited, due to lack of a standardized definition for the condition and the resulting inconsistent data. Given the heterogeneous nature of severe depression, reports suggesting noradrenergic as well as serotonergic system involvement in depressive disorders, and the substantive capability of both clomipramine and TCA-SSRI combination to treat severe depression, investigation of dual-action antidepressant agent efficacy in the treatment of severe depression is warranted. The merit of one such combined-action agent, venlafaxine, is reviewed. Efficacy findings from the limited number of comparative clinical trials conducted in the severely depressed patient population suggest that, while venlafaxine has been evaluated in a broad range of depressed patients, this compound may be particularly effective for the severely ill. Pharmacological features of venlafaxine, which may benefit the patient with severe depression, include the possibility of a rapid onset of action and a dose-response curve. Based upon studies comparing venlafaxine with both placebo and other first-line antidepressants, it is concluded that venlafaxine is safe, tolerable, and effective for the treatment of severe depression.