Major depression is hypothesized to be associated with reduced serotonergic function. Animal and clinical studies suggest that ECT and antidepressant mediations such as SSRIs enhance overall serotonergic transmission. Serotonin depletion reverses the antidepressant effect of SSRIs. The investigators hypothesize that enhance serotonin effects are central to the antidepressant action of SSRIs and ECT, but that these two treatments achieve this enhancement by different mechanisms. In the last funding period, the investigators developed and implemented a method for assessing central serotonergic function by a fenfluramine (indirect serotonin agonist) challenge using positron emission tomography (PET) to image regional cerebral glucose uptake (18FDG). The investigators found blunted responses to fenfluramine in the prefrontal cortex of untreated depressed patients using this method. ECT and paroxetine had different effects on relative regional brain glucose uptake following placebo or fenfluramine. Whereas SSRIs altered rCMRglu during fenfluramine challenge, ECT treatment had its main effect on relative regional metabolism in the placebo condition. The investigators now propose an imaging approach that is more specific fpr the serotonergic system in order to test a major hypothesis regarding the therapeutic mechanism of action of antidepressants that has been generated from animal studies. Animal studies have found that chronic SSRI administration downregulates somatodendritics 5-HT1A autoreceptors, and ECS upregulates 5-HT1A hippocampal postsynaptic receptors. Both these effects should enhance serotonergic transmission. Neuroendocrine challenge studies have suggested that both 5-HT1A autoreceptors and 5-HT1A peripheral field receptors generate blunted responses in untreated depressed patients. The investigators propose to use PET and [ I IC]WAY-10 0635 to evaluate 5-HTIA receptor populations (somatodendritic autoreceptor and distal postsynaptic receptor) in untreated depressed patients compared to healthy volunteers, and then again after a course of paroxetine (an SSRI) or ECT to evaluate treatment effects. An initial series of baboon and then human studies will refine and validate the methodology including evaluation of the effects of modifying binding through manipulatingrelease of endogenous serotonin. Thus. The investigators will measure regional correspondence of the brain serotonin deficits in depression and the effect of a course of ECT or SSRI drugs upon the serotonergic system. Elucidation of the mechanism and locus of antidepressant action of ECT compared to SSRIs may ultimately lead to improved antidepressant mediation and better understanding of the pathophysiology of depression.
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