We study the neurobiology of major depression. The fundamental central nervous system pathophysiological changes that underlie the core affective and cognitive symptoms of major depression also play a role in the fact that patients with major depression have twice the expected death rate at any age, independent of suicide. In addition, patients with major depression show a marked increase in the incidence of premature ischemic heart disease and osteoporosis. Our work consists of designing and performing studies to elucidate fundamental central nervous system mechanisms that contribute both to the affective and cognitive symptoms of major depression as well as their long-term medical consequences. As a corollary, our goal is to develop improved means for the diagnosis, treatment,, and prevention of the psychological and medical components of depressive disorders. Our clinical studies proceed predominantly in a group of 100 families studied longitudinally at the NIH for over twenty years. In 60 families the mother entered the study with a diagnosis of major depression and two children between the ages of 2 and 4. This population represents an ideal group for prospective studies in the years to come. In the past year, we have begun to elucidate the pathophysiology of the significant loss of bone mineral density we first described in patients with major depression via biospy of the anterior iliac crest. To date, we note decreased bone turnover and a marked decrease in the bone mineralization rate. We have also found that patients with major depression (matched closely with volunteers with respect to height, weight, and gender) show a significant decrement in lean body mass that correlates with bone mineral density. We have also found that patients with melancholic depression show profound, around-the-clock increases in CSF NE levels, that NE and the hypercortisolism mutually reinforce one another, and that these defects are closely related to defects in specific components of the central CRH system. We have developed and deployed a non-peptide CRH type 1 receptor antagonist. Utilizing this compound, we have demonstrated that CRHplays a tonic role in the behavioral, autonomic, metabolic, and endocrine responses to stress in rhesus macaques. These studies are premonitory to introducing this compound for study in human subjects.