Beta-adrenergic-mediated cyclic AMP accumulation was reduced in lymphocytes obtained from depressed patients from that observed in an age- and sex-matched group of control subjects. Among the depressed patients, those not responding to treatment showed significantly lower pretreatment responses to isoproterenol compared with patients who exhibited significant clinical improvement during antidepressant treatment. Late-night (terminal) insomnia was significantly associated with the blunted response to beta-adrenergic stimulation. In depressed patients with the lowest isoproterenol response, the effect of forskolin (which acts distal to the receptor and directly stimulates the catalytic subunit) on cyclic AMP accumulation was also significantly decreased. This suggests that post-receptor modulations of signal amplification also play a role in the reduced response to beta-adrenergic stimulation in depression.