The principal goal of the CNE is to study the long term medical consequences of major depression, to determine their pathophysiological mechanisms, and to develop improved means for their diagnosis and treatment. We study two main illnesses, coronary artery disease and osteoporosis, and, insofar as possible, focus on endocrine mediators that are common to the two illnesses. We have restored the NIMH Longitudinal Family Study, a study begun in 1979 consisting of 68 young mothers with major depression, two of their children between the ages of 2-6, and a group of matched controls (more than 400 subjects 90% of whom we have re-enrolled). These subjects represent an incomparable resource and are ideal for studying long-term medical consequences of depression. The mothers are now middle aged, an ideal age for demonstrating premature osteoporosis and coronary artery disease. The children are now young adults, and are old enough to begin showing stigmata suggestive of enhanced susceptibility to premature heart disease and osteoporosis. More than half of the children have already developed depression. We would like to emphasize that this cohort is a resource for the entire NIMH. In our studies this past year, we have found that patients with melancholic depression have increased around-the-clock levels of plasma and CSF norepinephrine that resolve after ECT. We also found that these patients were hypertensive while depressed and normotensive after recovery, in association with restoration of normal NE function. In addition, we found that moderately depressed outpatients with melancholic depression have significant increase in total body NE spillover at rest and in response to stressful stimuli. We have also found evidence of significant, interrelated decrements in insulin sensitivity, growth hormone deficiency, and increases in total body adiposity that correlates with their significant losses of bone mineral density. We have developed and deployed a non-peptide CRH type 1 receptor antagonist. Utilizing this compound, we have demonstrated that CRH plays a tonic role in the behavioral, autonomic, metabolic, and endocrine responses to stress in rhesus macaques, and in the rat, in the development as well as the expression of conditioned fear, peripheral inflammation, and susceptibility to stress ulcer.