A significant proportion of patients with primary depressive disorder show cortisol hypersecretion, flattened circadian periodicity, failure to suppress plasma cortisol with the overnight dexamethasone test, increased ACTH levels, and/or abnormalities in suppression of BLPH-BEndorphin by dexamethasone. Cushing's disease is the classic disease of hypothalamic-pituitary-adrenal axis activation: patients show elevated cortisol, ACTH and BLPH-BEndorphin levels. They also have a depressive syndrome, with mood, vegetative and cognitive symptoms that vary among patients with this disorder. We propose to study ACTH and BLPH-BEndorphin secretory profiles together with affective and cognitive symptoms and signs in patients with untreated Cushing's syndrome (CS) during baseline conditions and during metyrapone and dexamethasone challenge. Our hypothesis is that differences in degree of the depressive syndrome among patients with CS are related to heterogneity in the co-secretion profiles of these peptides. Since alterations in sleep are common in patients with CS, sleep EEGs and melatonin secretory profiles at baseline and with metyrapone and dexamethasone challenge testing will also be obtained. Metabolites of adrenal cortical steroids such as pregnenolone and deoxycorticosterone enchance or inhibit neuronal excitability via the GABA receptor in vitro. We propose to study in patients with CS the relationship between variabiility in the depressive syndrome and heterogenity in the urinary excretion profiles of 15 adrenal steroids. The clinical studies proposed will be the first to study simutaneously, under baseline conditions and with provocative testing, the association of depressive symptoms with the specific profiles of adrenal steroids and pituitary peptides. These studies should yield data which bear on the role of ACTH, BEndorphin, cortisol and other adrenal cortical steroids in the pathogenesis and symptomatology of primary affective disorder. In order to study the potential relevance of these concepts in primary depressive disorder, we propose to conduct preliminary studies investigating variability in the profile of 15 uncojugated urinary steroids in a group of patients with primary depressive disorder.
