Noradrenergic and dopaminergic mechanisms have been proposed for the pathophysiology of seasonal affective disorder (SAD). We investigated the effects of catecholamine depletion using alpha-methyl-para-tyrosine (AMPT), an inhibitor of tyrosine hydroxylase, in patients with SAD in natural summer remission. Nine drug-free patients with SAD by DSM-IV criteria, in summer remission for at least eight weeks, completed a double-blind, crossover study. Behavioral ratings and serum HVA and MHPG levels were obtained for 3-day sessions during which patients took AMPT or an active control drug, diphenhydramine. The active AMPT session significantly reduced serum levels of HVA and MHPG compared with the control diphenhydramine session. The AMPT session resulted in higher depression ratings with all nine patients having significant clinical relapse, compared with two patients during the diphenhydramine session. All patients returned to baseline scores after drug discontinuation. Catecholamine depletion results in significant clinical relapse in patients with SAD in the untreated, summer-remitted state. AMPT-induced depressive relapse may be a trait marker for SAD, and/or brain catecholamines may play a direct role in the pathogenesis of SAD.