Major depression represents a major public health problem worldwide and in the U.S. Fifteen percent of the U.S. population has depression at some point in life (40 million individuals), with a female to male ratio 5:2. Presently, 6-8% of all outpatients in primary care meet diagnostic criteria for major depression. Fifteen percent of untreated depressed patients commit suicide-most suicides have depression. In the U.S., in the year 2020 suicide will be the 10th cause of death. In addition to mortality due to suicide, major depression is associated with severe morbidity, that includes decreased hippocampal volume, cardiovascular illness, and decreased bone mineral density. Moreover, after myocardial infarction, patients with depression have a higher mortality rate than those without depression (adjusted risk ratio 4:29). Because such morbidity can be differentially affected either by increased or decreased levels of hypothalamic-pituitary-adrenal (HPA) function, it is necessary to study HPA function in our populations. Additionally, based on our previous data, we have hypothesized that depressed patients with melancholic features would have increase HPA function, while those with atypical features would have decreased HPA function. Using this protocol, over the past four years we have developed, refined, and repeatedly conducted detailed patient-oriented studies that have expanded the frontiers of existing knowledge on HPA regulation in healthy humans and depressed subjects. This protocol has already demonstrated the existence of two distinct biological subtypes of major depression, with the important finding of a decrement of HPA function in patients with atypical features. Thus, the atypical classification is not restricted to phenotype but represents a subtype with specific biological characteristics. This finding shows that there are unique strategies, targets, and potential interventional approaches to patients with either atypical or melancholic features. The elucidation of the neuroendocrinology of major depression has been a key goal of our branch, and this protocol offers the potential to unravel the biology of phenotypically distinct subtypes of major depression. Moreover, the elucidation of the medical consequences of major depression requires the precise longitudinal characterization of HPA function that is accomplished by this study.