The application of a tryptophan-free amino acid mixture (tryptophan depletion test) induces a rapid and substantial lowering of both total and free plasma tryptophan. Consequently, the brain serotonin content and also cerebral serotonin function are decreased. This method provides a paradigm to study the role of serotonin in the pathobiology of depressive disorders and their treatment modalities. Untreated depressed patients show few behavioral effects during tryptophan depletion. In depressed patients during an antidepressant or light-therapy-induced stable remission, a transient depressive relapse was induced by tryptophan depletion. Healthy subjects with a genetic risk for affective disorder show worsening of their condition induced by tryptophan depletion. These findings indicate the relevance of altered brain serotonin function in the pathophysiology of affective disorders and strengthen the importance of serotonin in the mechanism of action of antidepressants. Since recently published studies revealed some evidence that the serotonergic system is directly involved in the pathophysiology of various psychiatric syndromes besides depression, it seems to be reasonable to evaluate the validity of the tryptophan depletion test also in non-depressed patients.