Study of the antidepressant mechanism of electroconvulsive therapy (ECT) is of particular importance because of its: efficacy; uniqueness as a nonchemical centrally-directed treatment; and rapid onset and offset of action. Animal studies have shown beta receptor downregulation after chronic tricylics or repeated ECS and 5-HT-2 receptor changes (downregulation by antidepressant drugs and upregulation by ECT). It has therefore been hypothesized that these effects may mediate the antidepressant effect of ECT. However, no such receptor studies have been reported to date in ECT-treated depressed patients. We have found changes in platelet 5-HT-2 binding sites and subsensitive beta-adrenergic responses in untreated depressed patients. The concept that the receptor systems through which ECT exerts its antidepressant effect are the same ones that are altered in depression is an exciting possibility. Our initial studies indicate that ECT causes an acute dose-dependent rise in plasma of NE that correlates with the rish in systolic blood pressure. A return of lymphocyte beta-adrenergic responsivity back to the normal range was found after a course of ECT which was comparable to the striking effects of tricyclics in the same system but in opposite direction to that seen in the brains of rodents. On the other hand platelet 5-HT-2 receptor indices appear to show increased 5-HT-2 sensitivity which parallels brain findings in rodents receiving ECS. We therefore propose to follow-up our results be a detailed neuroendocrinological study of ECT focused on the serotonergic system. A group of patients treated with tricyclics will serve as a contrast. We will study: 1) rise in plasma prolactin after fenfluramine (indirect agonist) and mCPP (direct agonist) challenges as measures of central 5-HT function; and 2) platelet 5-HT-2 receptor indices. Patients with a major depressive disorder, melancholic subtype will be compared at baseline to controls, and then studied longitudinally during a course of ECT or tricyclic treatment (nortriptyline, NT). Enduring ECT effects will be assessed by studying patients 5-7 days after the last ECT and compared to 4 weeks of NT. We hypothesize that both ECT and tricyclics will increase overall serotonin responses (fenfluramine challenge) but that whereas ECT may enhance receptor responses (mCPP), tricycles will depress receptor response (mCPP). These measures have a potential as predictors of monitors of clinical response, and may lead to better understanding of mechanisms of action of ECT and thereby to improved chemical antidepressants.
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