Brain serotonin (5-HT) content is dependent on plasma levels of the essential amino acid, tryptophan (TRP). We have previously reported on the effects of rapid dietary TRP depletion in psychiatric patients; this study extends those reports and summarizes the effects of rapid TRP depletion on mood in depressed patients. One hundred and fifteen depressed (according to DSM-III-R) patients (69 drug free and symptomatic; 46 in clinical remission after antidepressant treatment) received tryptophan depletion testing in a double-blind, placebo-controlled, crossover fashion. Of 69 symptomatic, drug-free, depressed patients, 30 percent were unchanged the day of the tryptophan-free drink (TFD), but became clinically less depressed the day after the TFD. Although 80 percent of monoamine oxidase inhibitor- or fluvoxamine-treated patients experienced a depressive relapse during TRP depletion testing, only 18 percent of desipramine-treated patients relapsed. Brain 5-HT function may be intimately involved in the modulation of some affective states and in the mechanism of action of some antidepressant medications.