Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment

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.

Introduction

Hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis in patients with major depression is one of the most consistent findings in biological psychiatry. Specifically, patients with major depression have been shown to exhibit increased concentrations of cortisol in plasma, urine, and cerebrospinal fluid (CSF); an exaggerated cortisol response to adrenocorticotropic hormone (ACTH); and an enlargement of both the pituitary and the adrenal glands Gold et al 1988, Holsboer and Barden 1996, Nemeroff 1996, Owens and Nemeroff 1993.

These HPA axis alterations are believed to be secondary to hypersecretion of corticotropin-releasing hormone (CRH), which has behavioral effects in animals that are similar to those seen in depressed patients, including alterations in activity, appetite, and sleep (Owens and Nemeroff 1993). Moreover, depressed patients exhibit increased concentrations of CRH in the CSF, increased CRH messenger RNA (mRNA) and protein in the paraventricular nucleus (PVN) of the hypothalamus (postmortem samples), and a blunted ACTH response to a CRH challenge (likely reflecting downregulation of pituitary CRH receptors) Gold et al 1988, Nemeroff 1996. Finally, downregulation of CRH receptors in the frontal cortex of victims of suicide (many of whom were presumably depressed) has been described (Nemeroff 1996).

Although the mechanism by which extrahypothalamic CRH is elevated in depression has not been resolved, the increased levels of CRH in the hypothalamus are thought to be related, in part, to altered feedback inhibition by endogenous glucocorticoids. Through binding to their receptors in HPA axis tissues, endogenous glucocorticoids serve as potent negative regulators of HPA axis activity including the synthesis and release of CRH in the PVN Owens and Nemeroff 1993, Reul and de Kloet 1985. Data supporting the notion that glucocorticoid-mediated feedback inhibition is impaired in major depression come from a multitude of studies demonstrating nonsuppression of cortisol secretion following administration of the synthetic glucocorticoid dexamethasone and more recent studies showing a lack of inhibition of ACTH responses to CRH following dexamethasone pretreatment Gold et al 1988, Heuser et al 1994, Holsboer and Barden 1996, Nemeroff 1996, Owens and Nemeroff 1993. Although nonsuppression to dexamethasone in the dexamethasone suppression test (DST) and the dexamethasone–CRH test likely represent impaired feedback inhibition at the level of the pituitary de Kloet 1998, Miller et al 1992, impaired responsiveness to hydrocortisone challenge in depressed patients suggests these feedback alterations also occur in the brain (Young et al 1991). Furthermore, the existence of reduced HPA axis suppression by dexamethasone in first-degree relatives of depressed individuals suggests that altered feedback inhibition may represent a genetic (trait) vulnerability to the depressive disorders (Modell et al 1998).

Feedback regulation of the HPA axis by glucocorticoids is mediated through two distinct intracellular receptor subtypes referred to as the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) (Reul and de Kloet, 1985). The MR has a high affinity for endogenous corticosteroids and is believed to play a role in the regulation of circadian fluctuations in these hormones (especially the regulation of ACTH secretion during the diurnal trough in cortisol secretion). In contrast to the MR, the GR has a high affinity for dexamethasone and a lower affinity for endogenous corticosteroids. The GR is therefore believed to be more important in the regulation of the response to stress when endogenous levels of glucocorticoids are high. Recently, Spencer et al (1998) and de Kloet et al (1998) have clarified that GR activation is necessary for the HPA feedback regulation when levels of glucocorticoids are high (response to stress, circadian peak), but that the MR also plays an important role by modulating GR-dependent regulation. Because patients with major depression exhibit impaired HPA negative feedback in the context of elevated circulating levels of cortisol and because altered HPA axis responsiveness has been characterized with dexamethasone, which selectively binds GR in vivo, studies investigating corticosteroid receptors in major depression have logically focused on the expression and function of GR.