This research program will focus on the role of serotonin (5HT) in the pathogenesis of depression and mechanism of action of antidepressant treatment (ADT). A low tryptophan (TRP) diet and a TRP deficient amino acid drink (D-TFD) has been developed and used to evaluate the role of 5HT function in depression. In patients remitted on ADT, there is a rapid increase in depressive symptoms within 8 hours of the D-TFD which return to normal by 24-48 hours. This emphasizes the importance of intact presynpatic 5HT function for the efficacy of ADT. Approximately 50% of depressed patients off medication have a 1 to 4 day improvement in depressive symptoms with the D-TFD. The specificity of the D-TFD for producing changes in 5HT function will be evaluated by assessing the effects of rapid repletion of plasma TRP with a IV TRP infusion and by comparing the effects of the D-TFD to drinks deficient in other amino acids. The D-TFD will be given to recovered patients off treatment to see if it is a marker for state or trait. The effects of 7 days lithium treatment prior to the D-TFD as a protection against its effects of the D-TFD to drinks deficient in other amino acids. The D-TFD will be given to recovered patients off treatment to see if it is a marker for state or trait. The effects of 7 days lithium treatment prior to the D-TFD as a protection against its effects in remitted patients on ADT will be assessed. Lithium will be compared to placebo as a treatment to be used to maintain improvement in depressive symptoms of patients receiving the D-TFD while off medication. To better understand the role of 5HT function in the modulation of neuroendocrine abnormalities in depression, studies will be conducted in Rhesus monkeys using measures of 5HT receptor sensitivity and measures of neuroendocrine regulation similar to those made in patients. The effects of the D-TFD on these measures will be compared to parachlorophenylalanine, a drug that is known to impair 5HT synthesis. These studies will help clarify the role of presynaptic 5HT function in the pathogenesis and treatment of depression.
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