OBJECTIVE: Brain serotonin systems might be involved in the pathophysiology of seasonal affective disorder. The authors tested whether tryptophan depletion alters the mood of depressed patients with seasonal affective disorder. METHOD: Eleven drug-free depressed patients with seasonal affective disorder underwent tryptophan depletion in a placebo-controlled, double-blind crossover study. Tryptophan depletion was induced by a 24-hour low-tryptophan diet and by ingestion of a tryptophan-free amino acid beverage. During control testing the diet and the beverage were supplemented with tryptophan. Behavioral ratings and plasma total and free tryptophan levels were obtained before the diet started and several times after administration of the beverages. RESULTS: The diet and the tryptophan-free amino acid drink reduced plasma total and free tryptophan levels by 79.0% and 87.5%, respectively. Both levels increased during control testing. No significant behavioral changes were induced by tryptophan depletion or control testing. CONCLUSIONS: The failure of tryptophan depletion to exacerbate the depressive syndrome suggests that dysfunctional serotonergic activity does not play a primary, direct role in the pathogenesis of winter depression.