A corollary of the hypothesis that desensitization of beta- adrenergic binding or responsiveness represents a final common pathway for generating an antidepressant effect is that the pathogenesis of depressive disorders involves the beta-adrenergic receptor complex. We have found a) diminished responsiveness of the lymphocyte beta-adrenergic receptor complex in drug-free inpatients with endogenous depression. Subsensitive beta- responses were associated with a more severe, recurrent form of depression and nonsuppression on the DST; b) treatment with tricyclic antidepressants resulted in resensitization of beta- adrenergic receptor complexes. It is proposed to extend these studies by: (1) further defining clinical, neuroendocrine and biochemical correlates of blunted lymphocyte beta-adrenergic responsiveness in depressed patients; (2) clarifying the mechanism of abnormalities in beta-receptor function in depressed patients at the receptor level by (i) agonist binding studies to assess receptor function, (ii) assays of the Ns and Ni coupling proteins and (iii) measurement of in vitro and in vivo downregulability of synapse independent lymphocyte beta- receptors; (3) indirectly assessing postsynaptic beta 1 - adrenergic receptors by measurement of heart rate change after an increase in catecholamine levels; (4) studies of factors that regulate the receptor including (i) plasma NE and EPI while supine and after a postural challenge test as well as 24 hour urinary excretion levels of CAs and (ii) plasma and urinary cortisol levels before and after dexamethasone; (5) studying patients longitudinally both during the inpatient phase and six months as an outpatient to determine treatment effects (nortriptyline). Testing will be carried out after 6 months of treatment is completed in drug-free euthymic patients and controls to permit a distinction to be made between state-and- trait dependent as well as drug-induced biological differences. Preliminary data suggest resensitization of lymphocyte beta- adrenergic responsiveness in depressed patients after tricyclic treatment is partly dependent on normalization of dexa- methasone resistance. The basis for resensitization will be studied and relationships to cardiac beta-adrenergic responsivity, NT drug level, clinical improvement, HYPAC status, plasma CAs levels will be determined. These studies should provide new insights into potential neurobiological subtypes of unipolar endogenous depression, the role of beta-adrenergic receptors in the pathophysiology of depression, and the mechanism of action of tricyclic antidepressants.
