The results from these and other studies provide an opportunity to critically re-examine the role of brain monoamine function in the pathophysiology of depression and the mechanism of action of antidepressant drugs. The following observations are most salient: 1. Tryptophan depletion, which reduces brain serotonin function, reverses the therapeutic effects of specific serotonin reuptake inhibitors (SSRIs) but not drugs which potently inhibit noradrenaline reuptake. In contrast, depletion of noradrenaline and dopamine, as a consequence of AMPT administration, reverses the remission induced by noradrenaline (desipramine) and dopamine (mazindol) reuptake inhibitors, but not SSRIs. These data suggest that the efficacy of antidepressant drugs may not be due to a common mechanism involving a single monoamine system. SSRIs and noradrenaline reuptake inhibitors may work via primary actions on serotonin and noradrenaline function, respectively. Alternatively, these two classes of antidepressant drugs may exert their therapeutic properties by affecting the function of an, as yet, unknown neuronal system that is regulated by these monoamine systems; 2. In both drug-free depressed patients and healthy subjects, tryptophan depletion and AMPT do not produce marked alterations in depressed mood. These results suggest that alterations in serotonin, dopamine, and noradrenaline systems may not reflect the primary pathology causing depressive illness. An alternative explanation is that in depressed patients these systems are maximally dysfunctional such that further manipulations do not worsen depressive systems. 3. Clinical experience and the results from several controlled studies indicate that the efficacy of SSRIs and noradrenaline inhibiting drugs are approximately equal.(ABSTRACT TRUNCATED AT 250 WORDS)