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Abstract
Hyperactivity of the hypothalamic--pituitary--adrenal (HPA) axis has been reliably
observed in patients with major depression. One of the primary features of this HPA
axis hyperactivity is reduced sensitivity to the inhibitory effects of the glucocorticoid
dexamethasone on the production of adrenocorticotropic hormone and cortisol during
the dexamethasone suppression test and, more recently, the dexamethasone--corticotropin-releasing
hormone test. Because the effects of glucocorticoids are mediated by intracellular
receptors including, most notably, the glucocorticoid receptor (GR), a number of studies
have considered the possibility that the number and/or function of GRs are reduced
in depressed patients. Moreover, whether antidepressants act by reversing these putative
GR changes has been examined. The extant literature on GR receptors in major depression
was reviewed along with studies examining the impact of antidepressants on the GR.
The data support the hypothesis that the function of the GR is reduced in major depression
in the absence of clear evidence of decreased GR expression. The data also indicate
that some antidepressants have direct effects on the GR, leading to enhanced GR function
and increased GR expression. Hypotheses regarding the mechanism of these receptor
changes involve relevant second messenger pathways that regulate GR function. The
findings indicate that the GR is an important molecular 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 pathophysiology and treatment of affective disorders.