The purpose of this study is to determine whether HPA activity, as measured by ACTH release, is higher in depressed than control subjects and to describe the circadian nature of this difference. As ACTH is subject to negative glucocorticoid feedback on the pituitary, accurate measurement of HPA activity requires removal of the negative feedback by blocking adrenal production of cortisol with metyrapone. This protocol calls for 25 depressed and 25 control subjects, ages 18-75. Blood samples for cortisol and ACTH assays are obtained every 10 minutes, first under a 24 hour baseline condition, then for 24 hours when the pituitary is """"""""unmasked"""""""" from glucocorticoid feedback by the oral administration of metyrapone (1g p.o. beginning at midnight on Day 2 and continuing q 2 hours through 2200h). The significance of this study is that the procedure of unmasking the pituitary from negative glucocorticoid feedback should provide a more accurate picture of the true extent of HPA overdrive in depression, which we believe to be much more severe than has been thought to date. The plan for the future is to establish clinical-pathological correlates. After approval of this protocol we learned that Ciba-Geigy was no longer distributing metyrapone and we obtained permission from the Duke IRB to substitute ketoconazole for the adrenal enzyme inhibitor. Three subjects were tested on the GCRC under this revised protocol (Duke IRB Registry #1100-95-8). The cortisol and ACTH assays from these three runs showed that ketoconazole failed to consistently suppress cortisol below the 3.5 ug/dL required to ensure maximum endogenous stimulation of pituitary ACTH secretion. We have since learned that we can obtain metyrapone from the world headquarters of Ciba-Geigy in Basle, Switzerland, who are making the drug available for special uses. This protocol has now been renewed under its current registry number, returning to metyrapone as the adrenal enzyme inhibitor and we are awaiting Ciba-Geigy's promised release of the drug in order to implement this protocol as originally designed.
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