PATHOPHYSIOLOGY OF MOOD DISORDERS: NEUROENDOCRINE MECHANISMS

We review the major findings of the Hypothalamic-Pituatary-Adrenal (HPA) axis and depression. We give an overview of the HPA axis organization and its component parts, including cortisol, CRF and CRFBP, and interpret findings from the dexamethasone suppression test, dex/CRF and CRF-provocation tests in relation to depression. CRF appears to mediate the neuroendocrine, autonomic, immune and behavioral responses to stress; the CRF1 Receptor (CRF1R) plays a central role in the stress response, while CRF2R exerts a modulating effect on the CRF1R. The CRF hypothesis of depression suggests that CRF is hypersecreted in depressed subjects and persistently elevated CSF CRF may serve as a marker for depressive vulnerability and early relapse. Pharmacological data support the view that chronic antidepressant treatment may decrease CRF sensitivity to stress. Our group’s findings, and others’, on the nexus of childhood trauma, depression and HPA axis disruption are explored; data are highly suggestive of far-reaching CNS changes associated with a history of childhood trauma that may underlie increased vulnerability to future depression. A distinct biological subtype of depression with a history of childhood trauma is proposed for future investigation. Gender differences in response to the triad of early life trauma, depression and HPA axis disruption are reviewed, as are gene studies for the CRF1R, CRHBP and FKBP5. A variant of the CRF1R gene may exert a protective effect in men. Studies of CRF1R antagonists as novel antidepressants have been inconclusive, yet the studies haven’t sub-typed the depressed patients with a history of childhood trauma. Mefipristone and other glucocorticoid receptor antagonists may be effective in the treatment of psychotic depression.

Keywords: hypothalamic-pituitary-adrenal (HPA) axis, corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), paraventricular nucleus (PVN) of hypothalamus, childhood trauma, stress response, psychotic and atypical depression, antidepressant drugs, alcohol dependence and withdrawal.