To examine whether alpha 2-adrenergic receptor function is altered in affective and schizophrenic disorders, we determined 3H-clonidine binding in platelets obtained from 33 normal control subjects and from 24 patients with depressive, 22 patients with schizophrenic, 18 with bipolar, and 8 patients with schizoaffective disorders during a drug-free period. The maximum number of binding sites (Bmax) and apparent dissociation constant (Kd) for high affinity 3H-clonidine binding was computed by Scatchard analysis. Comparison of the diagnostic groups indicated that the Bmax in depressed, schizophrenic, and schizoaffective patients was significantly higher than in normal controls, but there were no significant Bmax differences between bipolar patients and controls. Comparison of the Kd among the diagnostic groups indicated no significant differences among the groups or between patient diagnostic groups and normal controls. Baseline Bmax in schizophrenic patients was significantly correlated with the decrease in Brief Psychiatric Rating Scale (BPRS) scores after treatment, suggesting a relationship between baseline Bmax and clinical response. Treatment with lithium caused a significant decrease in the baseline Bmax, whereas treatment with desipramine or trifluoperazine did not cause significant changes in the baseline Bmax. Our results thus indicate an increase in the number of alpha 2-adrenergic receptors in depressed and schizophrenic patients as compared to normal controls.