The hypothesis that depressive illness is related to supersensitive alpha 2-adrenoceptors in the brain has been tested indirectly in blood platelets. The binding of tritiated clonidine hydrochloride to platelet membranes, a ligand that labels only the high-affinity state of the alpha 2-adrenoceptor that is coupled with cell functions, and the aggregation response induced by epinephrine hydrochloride, which is the result of the activation of the high-affinity state, were measured and correlated in 13 patients with major affective disorder. Both the number of high-affinity binding sites and the aggregation response were increased in depressed patients. There was a negative and significant correlation between both measures in the same depressed patients. Treatment with lithium carbonate (Plenur [Spain]; Linthane, comparable US product) was associated with a decrease in the high-affinity state and with an increase in the aggregation response. Thus, major effective disorder may be related to a dysfunction of the high-affinity state of the alpha 2-adrenoceptor that recognizes agonists and mediates physiological effects.