The proposed study is a revised version of a prospective, cross-sectional investigation of individuals who do not manifest any psychiatric disorder but demonstrate an exaggerated cortisol response to the dexamethasone/corticotropin releasing hormone (DEX/CRH) stimulation test. The DEX/CRH is the most sensitive test of human hypothalamus-pituitary-adrenal (HPA) axis function available. A pattern of HPA dysfunction, as detected by this standardized laboratory test, may signal a stable endophenotype of mood and anxiety disorders. A growing body of preclinical literature, describing persistent neuroendocrine and behavioral consequences of exposure to stress during early development, provides a conceptual mechanism by which such HPA hyperactivity may be present in adult humans who were exposed to adversity during early life. Our preliminary data suggest that self-reported ratings of severity of stress during childhood predict cortisol response to the DEX/CRH test in healthy adults without current psychopathology. The presence of DEX/CRH cortisol hyperresponsivity, taken together with certain known risk factors, such as exposure to significant stressors during early life, positive family history of mood disorder, and having a certain cognitive style, may eventually be used to identify individuals at high risk for development of mood and anxiety disorders or other adverse health outcomes, and aid in their prevention. The proposed investigation will generate critical data about the clinical characteristics of nondepressed, healthy individuals who have the HPA hyperactivity endophenotype as measured by """"""""high"""""""" cortisol response (HCR) to the DEX/CRH test. A group of HCR individuals will be compared with a group of DEX/CRH """"""""low"""""""" cortisol responders (LCR) on a number of relevant assessments. We will answer key questions about the proposed HCR endophenotype, including: What is the nature of its relationship to perceived childhood adversity and recent stressors? Does it predict autonomic, behavioral and neuroendocrine response to a standardized psychological stress test? Is it associated with certain temperament or personality features? Is it associated with medical morbidity or quality of life? Is it stable over time? Such information provides the groundwork for a longitudinal study to assess the predictive utility of a potential biomarker for affective illness. ? ?
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