A substantial body of data suggests that excessive cortisol secretion in depression may result from dysregulation at several sites within the hypothalamic-pituitary-adrenocortical (HPA) axis. The alterations in regulatory mechanisms are thought to result from a limbic system-hypothalamic "overdrive" of corticotropin-releasing hormone (CRH). We also have demonstrated that excessive secretion of cortisol may result from an abnormal adrenocortical responsiveness to adrenocorticotropic hormone (ACTH), and we have postulated that corticotropic cells within the pituitary mediate between excessive secretion of CRH from the hypothalamus and hypercortisolemia secondary to adrenocortical hyperplasia and enhanced sensitivity to ACTH at the adrenal cortex. The present report describes a series of clinical experiments utilizing several neuroendocrine probes, as well as computer-assisted tomography, to examine the complexities of the HPA axis dysregulation in depression. These studies support the hypothesis that a limbic system-hypothalamic disturbance results in excessive CRH secretion as well as enhanced adrenocortical activity, and that these factors contribute to excessive cortisol secretion in patients with depression. These data further support the hypothesis that endogenous affective disorders are best characterized in the framework of a generalized biological disturbance of HPA axis function which involves both central and peripheral endocrine sites.