Numerous psychiatric disorders are associated with dysregulation of stress responses. A substantial subpopulation of depressed individuals exhibit glucocorticoid dyshomeostasis, manifest primarily as disrupted cortisol rhythms and resistance to negative feedback (Sachar et al., 1973; Carroll, 1982; Wong et al., 2000). In fact, depression is associated with long-term HPA axis activation, manifest as adrenal hypertrophy (Amsterdam et al., 1987, 1989) as well as somatic changes indicative of increased glucocorticoid burden [e.g., accelerated bone loss (Gold and Chrousos, 2002)]. It is postulated that depression-related hypercortisolemia causes glucocorticoid “resistance” by down-regulating GRs, thereby “freeing” the HPA axis from feedback control of down-stream stress effectors (Pariante, 2004). Accordingly, depression may be an example of “out of context” corticosteroid secretion, wherein hormone release is not aligned with a true threat and is increased out of proportion with the actual objective impact of the stressor (relative to non-depressed individuals). Thus, to some extent, depression shares attributes with what may be considered a disorder of chronic stress regulation.
