Hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis and increased levels
of glucocorticoid hormones in patients with depression have mostly been ascribed to
impaired feedback regulation of the HPA axis, possibly caused by altered function
of the receptor for glucocorticoid hormones, the glucocorticoid receptor (GR). Antidepressants,
in turn, ameliorate many of the neurobiological disturbances in depression, including
HPA axis hyperactivity, and thereby alleviate depressive symptoms. There is strong
evidence for the notion that antidepressants exert these effects by modulating the
GR. Such modulations, however, can be manifold and range from regulation of receptor
expression to post-translational modifications, which may result in differences in
GR nuclear translocation and GR-dependent gene transcription. The idea that the therapeutic
action of antidepressants is mediated, at least in part, by restoring GR function,
is consistent with studies showing that decreased GR function contributes to HPA axis
hyperactivity and to the development of depressive symptoms. Conversely, excessive
glucocorticoid signalling, which requires an active GR, is associated with functional
impairments in the depressed brain, especially in the hippocampus, where it results
in reduced neurogenesis and impaired neuroplasticity. In this review, we will focus
on the GR as a key player in the precipitation, development and resolution of depression.
We will discuss potential explanations for the apparent controversy between glucocorticoid
resistance and the detrimental effects of excessive glucocorticoid signalling. We
will review some of the evidence for modulation of the GR by antidepressants and we
will provide further insight into how antidepressants may regulate the GR to overcome
depressive symptoms.
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