The proposed studies will attempt to investigate the effects of serotonin depletion on mood, nocturnal polygraphic sleep measures, and neuroendocrine secretion in (a) normal volunteer, (b) patients with Major Depressive Disorder before and during double-blind antidepressant treatment with either sertraline or bupropion, and (c) nonaffected individuals who are at high genetic risk for the development of a mood disorder. The investigator will experimentally induce serotonin depletion with the tryptophan-free amino acid drink (TFD), which has been reported to reduce brain serotonin or its metabolites in animals and humans and to briefly reverse the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) in euthymic patients. Based upon his pilot data, the investigator hopes to refine the current methodology with (a) the development of a new control drink which contains tryptophan but does not alter plasma tryptophan levels and (b) a lower dose of amino acids in the TFD which avoid side effects, such as nausea and vomiting in women, but still significantly and substantially reduces plasma tryptophan concentrations. We predict that the TFD, compared with the control drink, will significantly induce depressive symptoms in sertraline-but not bupropion-treated euthymic patients, but only at about 4-6 weeks rather than 4-6 months of treatment. In addition, he predicts that the TFD will reverse the rapid eye movement (REM) sleep suppressing effects of sertraline at both time points. He predicts that morning administration of TFD will increase midafternoon mean secretion of cortisol and prolactin 5-7 hours later in normal controls and depressed patients, with a greater increase in depressed patients. Finally, he hopes to extend and confirm the hypothesis that the TFD induces depressogenic symptoms and signs (greater shortening of REM latency, increased REM percentage and REM Density, and cortisol and prolactin secretion in unaffected individuals from family positive than from family negative homes.
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