The experiments proposed in this renewal application are designed to test the hypothesis that, within the same patient, plasma ACTH and cortisol hypersecretion are synonymous with dexamethasone (DEX) suppression test (DST) non-suppression using our modified (0.5 mg) DST protocol. It also is hypothesized that ACTH hypersecretion/DST non-suppression and reduced rapid eye movement (REM) latency are closely linked within subjects, possibly on the basis of a common central nervous system (CNS) abnormality underlying the dysregulation of both physiologic systems. With a simplified sleep-endocrine protocol, nocturnal secretion patterns of biologically and immunologically active plasma adrenocorticotropin (ACTH) and cortisol will be correlated with REM sleep measures. The CNS neurotransmitter systems which might regulate both the pituitary-adrenal axis and REM sleep parameters will be studied with pharmacologic challenges. Normal volunteers and then patients will be given cholinergic and serotonergic antagonists, and the expected reduction in nocturnal ACTH and cortisol secretion will be correlated with the degree of REM latency increase. The question of why only about 30-50% of endogenously depressed patients are DST non-suppressors will be explored, based on the hypothesis that patients who initially are non-suppressors on the DST are still less sensitive to DEX after clinical remission, even though their DST's have normalized. Preliminary data in normal volunteers indicate considerable inter-individual variability in sensitivity to DEX, suggesting that only those individuals who are inherently less sensitive to DEX will become non-suppressors when depressed. However, it also is conceivable that some ACTH hypersecretors might be DST suppressors because of their inherently increased sensitivity to the peripheral suppressive effects of DEX. Thus, in order to investigate potential peripheral sites of DEX action which might modulate the DST response, the effects of DEX pretreatment on the pituitary ACTH response to corticotropin releasing factor and the adrenocortical secretory response to ACTH administration will be measured. In addition, we will continue to compare our modified DST with the standard 1.0 mg DST. These studies should help elucidate why some patients with endogenous depression are DST non-suppressors and will more fully characterize the relationship between abnormalities of the CNS-pituitary adrenal axis and sleep EEG parameters. A companion grant renewal application (MH 28380) is being submitted by Dr. Robert Rubin, a co-investigator on this renewal application, for the study of the clinical utility of sleep EEG measures and endocrine tests to aid in the diagnosis of endogenous (endogenomorphic) depression and the following of treatment response.
Showing the most recent 10 out of 33 publications