Glucocorticoid receptors in major depression: Relevance to pathophysiologyand treatment

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been rel iably observed in patients with major depression. One of the primary featur es of this HPA axis hyperactivity is reduced sensitivity to the inhibitory effects of the glucocorticoid dexamethasone on the production of adrenocort icotropic hormone and cortisol during the dexamethasone suppression test an d, more recently, the dexamethasone-corticotropin-releasing hormone test. B ecause the effects of glucocorticoids are mediated by intracellular recepto rs including, most notably, the glucocorticoid receptor (GR), a number of s tudies have considered the possibility that the number and/or function of G Rs are reduced in depressed patients. Moreover, whether antidepressants act by reversing these putative GR changes has been examined. The extant liter ature on GR receptors in major depression was reviewed along with studies e xamining the impact of antidepressants on the GR. The data support the hypo thesis that the function of the GR is reduced in major depression in the ab sence of clear evidence of decreased GR expression. The data also indicate that some antidepressants have direct effects on the GR, leading to enhance d GR function and increased GR expression. Hypotheses regarding the mechani sm of these receptor changes involve relevant second messenger pathways tha t regulate GR function. The findings indicate that the GR is an important m olecular target in major depression. Further elucidation of the biochemical and molecular mechanisms involved in GR changes in major depression is an exciting frontier that will no doubt lead to new insights into the pathophy siology and treatment of affective disorders. Biol Psychiatry 2001;49:391-4 04 (C) 2001 Society of Biological Psychiatry.