Serotonin (5-HT) has been implicated in the pathophysiology of depressive syndromes and in the mechanism of antidepressant drug action. Rapid dietary depletion of tryptophan (TRP) provides a paradigm for studying the role of 5-HT in depressed patients. Drug-free depressed patients do not show mood changes during TRP depletion but about one third have a clinically apparent, transient improvement in mood on return to normal TRP intake. Depressed patients in clinical remission after 6 to 8 weeks of antidepressant therapy experience a transient depressive relapse during acute TRP depletion. The significance of these findings will be discussed. Tryptophan depletion in other psychiatric syndromes will also be reviewed.