[See also CRF and Unipolar Depression.]

Peeters F, Nicolson NA, Berkhof J.
Levels and variability of daily life cortisol secretion in major depression.
Psychiatry Res. 2004 Apr 15;126(1):1-13.
"Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is an important feature of major depressive disorder (MDD), but relatively little attention has been given to within-person variability of hormone secretion over time. Because most studies have been conducted in hospital settings, little information is available about naturally occurring patterns of cortisol secretion throughout the day in depressed outpatients. Multiple salivary cortisol samples were obtained over a 6-day period from 47 outpatients with MDD and 39 healthy controls in their everyday environment. We used multilevel regression analysis to estimate the effects of MDD and associated clinical characteristics on cortisol levels and intraindividual variability. Although more severe symptoms were associated with small elevations in cortisol levels, we found no clear evidence for hypercortisolism in the MDD group as a whole. However, cortisol output in MDD outpatients was less stable from sample to sample, as evidenced by a significantly lower autocorrelation than that observed in controls. Secretory patterns were particularly erratic in patients with more severe or recurrent episodes. Findings suggest that erratic cortisol secretion may be a more characteristic feature of HPA axis dysregulation in MDD than hypercortisolism, especially in outpatient populations." [Abstract]

Raison, Charles L., Miller, Andrew H.
When Not Enough Is Too Much: The Role of Insufficient Glucocorticoid Signaling in the Pathophysiology of Stress-Related Disorders
Am J Psychiatry 2003 160: 1554-1565
"OBJECTIVE: Previous theories have emphasized the role of excessive glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH). METHOD: The literature on neuroendocrine function and glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed. RESULTS: Although not occurring together, both hypocortisolism and reduced responsiveness to glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychiatric disorders were also associated with immune system activation/inflammation, high SNS tone, and CRH hypersecretion, which are all consistent with insufficient glucocorticoid-mediated regulation of stress hyperresponsiveness. Finally, antidepressants, a mainstay in the treatment of stress-related disorders, were regularly associated with evidence of enhanced glucocorticoid signaling. CONCLUSIONS: Neuroendocrine data provide evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders. Impaired feedback regulation of relevant stress responses, especially immune activation/inflammation, may, in turn, contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism, and acquired immune responses. From an evolutionary perspective, reduced glucocorticoid signaling, whether achieved at the level of the hormone or its receptor, may foster immune readiness and increase arousal. Emphasis on insufficient glucocorticoid signaling in stress-related pathology encourages development of therapeutic strategies to enhance glucocorticoid signaling pathways." [Abstract]

Pariante CM, Miller AH.
Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment.
Biol Psychiatry 2001 Mar 1;49(5):391-404
"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." [Abstract]

Webster MJ, Knable MB, O'Grady J, Orthmann J, Weickert CS.
Regional specificity of brain glucocorticoid receptor mRNA alterations in subjects with schizophrenia and mood disorders.
Mol Psychiatry 2002;7(9):985-94, 924
"Glucocorticoid receptors (GR) mediate the direct effects of glucocorticoids released in response to stress and the regulation of the hypothalamic-pituitary-adrenocortical (HPA) system through a negative feedback mechanism. Individuals with major mental illness, who often exhibit hypercortisolemia, may have down-regulated levels of GR mRNA. In situ hybridization for GR mRNA was performed on post-mortem specimens from patients suffering from depression, bipolar disorder, schizophrenia and from normal controls (n = 15 per group). In frontal cortex, GR mRNA levels were decreased in layers III-VI in the subjects with depression and schizophrenia. In inferior temporal cortex, GR mRNA levels were decreased in layer IV in all three diagnostic groups. In the entorhinal cortex, GR mRNA levels were decreased in layers III and VI in the bipolar group. In hippocampus, GR mRNA levels were reduced in the dentate gyrus, CA(4), CA(3) and CA(1) in the schizophrenia group. In the subiculum, GR mRNA levels were reduced in the bipolar group. These results suggest that GR dysregulation occurs in all three major psychiatric illnesses with variability according to anatomical site. The severity and heterogeneity of this reduction may underlie some of the clinical heterogeneity seen in these disorders." [Abstract]

Kling MA, Whitfield HJ Jr, Brandt HA, Demitrack MA, Kalogeras K, Geracioti TD, Perini GI, Calabrese JR, Chrousos GP, Gold PW.
Effects of glucocorticoid antagonism with RU 486 on pituitary-adrenal function in patients with major depression: time-dependent enhancement of plasma ACTH secretion.
Psychopharmacol Bull 1989;25(3):466-72
"Data from our group and others suggest that pituitary-adrenal activation in major depression reflects a defect at or above the hypothalamus which results in the hypersecretion of corticotropin-releasing hormone (CRH); some have suggested, however, that elevated indices of cortisol secretion and lack of suppressibility to dexamethasone may be a manifestation of a primary defect in glucocorticoid receptor activation. We report here a study of early morning pituitary-adrenal responses to the glucocorticoid antagonist RU 486 in patients with major depression and healthy volunteers. Previous data suggested that the response to RU 486 could represent an index of endogenous CRH secretory activity. RU 486 produced a robust increase in plasma corticotropin (ACTH) and cortisol secretion in both control subjects and depressed patients. In the controls, however, the increase was confined to the last 2 hours of sampling (6 to 8 am), whereas in the depressed patients the increase occurred throughout the sampling period (3 to 8 am). The ACTH response in the depressed patients exceeded that in the controls during most of the sampling period, including a significant (p less than .005) increase between 3 and 4:30 am. These results are compatible with the idea that hypercortisolism in major depression represents an alteration in the overall set point for hypothalamic CRH secretion rather than a primary alteration at the level of the glucocorticoid receptor." [Abstract]

Holsboer F.
Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy.
J Affect Disord 2001 Jan;62(1-2):77-91
"Clinical and preclinical studies have gathered substantial evidence that alterations of the stress hormone system play a major, causal role in the development of depression. In this review article, a summary of studies sustaining that view is given and data are presented which demonstrate that depression is associated with an impairment of corticosteroid receptor function that gives rise to an excessive release of neurohormones to which a number of signs and symptoms characteristic of depression can be attributed. The studies referred to in the following unanimously support the concept of an antidepressant mechanism of action that exerts its effects beyond the cell membrane receptors of biogenic amines and particularly includes the improvement of corticosteroid receptor function. When activated by ligands, corticosteroid receptors act as transcription factors in correspondence with numerous other transcription factors already known to be activated by antidepressants. Furthermore, the potential of drugs that interfere more directly with stress hormone regulation, such as corticosteroid receptor antagonists and corticotropin-releasing hormone receptor antagonists, is discussed." [Abstract]

Holsboer F.
The corticosteroid receptor hypothesis of depression.
Neuropsychopharmacology 2000 Nov;23(5):477-501
"Signs and symptoms that are characteristic for depression include changes in the setpoint of the hypothalamic-pituitary-adrenocortical (HPA) system, which in the majority of these patients result in altered regulation of corticotropin (ACTH) and cortisol secretory activity. More refined analysis of the HPA system revealed that corticosteroid receptor (CR) signaling is impaired in major depression, resulting among other changes, in increased production and secretion of corticotropin-releasing hormone (CRH, also frequently abbreviated CRF) in various brain regions postulated to be involved in the causality of depression. This article summarizes the clinical and preclinical data, supporting the concept that impaired CR signaling is a key mechanism in the pathogenesis of depression. Mouse genetics, allowing for selective inactivation of genes relevant for HPA regulation and molecular pharmacology, dissecting the intracellular cascade of CR signaling, are the most promising future research fields, suited for identifying genes predisposing to depression. Focusing on these two research lines may also allow to gain insight into understanding how current antidepressants work and further, how more specific targets for future antidepressant drugs can be identified." [Abstract]

Hugin-Flores ME, Steimer T, Schulz P, Vallotton MB, Aubert ML.
Chronic corticotropin-releasing hormone and vasopressin regulate corticosteroid receptors in rat hippocampus and anterior pituitary.
Brain Res 2003 Jun 27;976(2):159-170
"Corticotropin-releasing hormone (CRH) and vasopressin (AVP) participate in the endocrine, autonomic, immunological and behavioral response to stress. CRH and AVP receptors are found in hippocampus and anterior pituitary, where mineralocorticoid (MR) and glucocorticoid (GR) receptors are abundant. We investigated the possible influence of CRH and AVP on the regulation of MR and GR in both tissues. CRH, AVP, or their antagonists were administered to adrenalectomized rats substituted with corticosterone, to avoid interference with adrenal secretion. Repeated i.c.v. oCRH injections (10 &mgr;g) for 5 days significantly decreased MR and GR mRNA in hippocampus and MR mRNA in anterior pituitary. AVP significantly increased both corticosteroid receptor mRNAs, as repeated i.c.v. injections (5 &mgr;g) for 5 days in hippocampus, and as continuous i.c.v. infusion (10 ng/h/5 days) in anterior pituitary. The i.c.v. infusion of 5 or 10 &mgr;g/day of the alpha-helical CRH antagonist during intermittent restraint stress (5 days), induced a significant decrease in hippocampal MR binding. In anterior pituitary, 5 &mgr;g/day significantly decreased MR binding, while 10 &mgr;g/day significantly increased GR binding. Under the same conditions of stress, the infusion of 15 &mgr;g/day of the vasopressin V1a/1b receptor antagonist [dP Tyr (Me)(2)AVP] significantly increased MR and GR binding in hippocampus and anterior pituitary; 5 &mgr;g/day significantly decreased pituitary MR binding. Our results show that CRH and AVP regulate MR and GR in hippocampus and anterior pituitary. This reveals another important function of CRH and AVP, which could be relevant to understand stress adaptation and the pathophysiology of stress-related disorders like major depression." [Abstract]

van Haarst AD, Oitzl MS, Workel JO, de Kloet ER.
Chronic brain glucocorticoid receptor blockade enhances the rise in circadian and stress-induced pituitary-adrenal activity.
Endocrinology 1996 Nov;137(11):4935-43
"This study examined the hypothesis that experimentally induced corticosteroid resistance in the brain would lead to adaptations in the activity of the hypothalamic-pituitary-adrenal (HPA) axis similar to the endocrine features of the endogenous resistance accompanying the pathogenesis of depression. For this purpose, the glucocorticoid antagonist RU 38486 (aGC) was infused intracerebroventricularly (i.c.v.) (100 ng/h) via Alzet minipumps for several days. During this chronic receptor blockade, parameters for basal and stress-induced HPA activity were measured in a longitudinal study design. Chronic i.c.v. infusion of the aGC did not affect basal morning levels of ACTH and corticosterone. During the afternoon phase of the circadian cycle, the aGC caused gradual and sequential changes in the HPA axis. After aGC infusion, the circadian rise of ACTH levels was enhanced in the afternoon of day 1, but was normal on subsequent days. For corticosterone, basal afternoon levels towards the diurnal peak were increased at days 1, 3, and 4 in aGC-treated rats. On day 2, in contrast, corticosterone levels did not differ from vehicle-infused controls. Paraventricular CRH messenger RNA, as measured at day 4, was not altered by aGC treatment. After 10 days of aGC treatment, the adrenal weight was increased, and the sensitivity of adrenocortical cells in vitro to ACTH was enhanced. Corticosteroid receptor binding in vitro in hippocampus, hypothalamus, and pituitary was not different between the aGC and vehicle-treated rats. In a second series of experiments, the HPA responsiveness to the stress of a novel environment at day 2 in the morning was increased after chronic aGC infusion, at a time basal hormone levels were not affected. The data show that 1) chronic i.c.v. infusion of aGC readily enhances the amplitude of circadian corticosterone changes, presumably by increasing the adrenocortical sensitivity to ACTH; 2) chronic aGC-treated animals show an enhanced ACTH and corticosterone response to stress, which is delayed in termination; 3) corticosteroid receptor expression, basal CRH messenger RNA, and ACTH levels are not altered after prolonged chronic aGC treatment. It is concluded that, over a period of a few days, aGC-induced corticosteroid resistance triggers a sequelae of pituitary-adrenal adaptations ultimately resulting in hypercorticism. Paradoxically, however, this hypercorticism develops because of increased peak levels of corticosteroid hormone rather than through elevated trough levels as is commonly observed during depressive illness." [Abstract]

Dijkstra, Ivar, Tilders, Fred J. H., Aguilera, Greti, Kiss, Alexander, Rabadan-Diehl, Cristina, Barden, Nicholas, Karanth, Sharada, Holsboer, Florian, Reul, Johannes M. H. M.
Reduced Activity of Hypothalamic Corticotropin-Releasing Hormone Neurons in Transgenic Mice with Impaired Glucocorticoid Receptor Function
J. Neurosci. 1998 18: 3909-3918
"Loss of central glucocorticoid receptor (GR) function is thought to be involved in the development of neuroendocrine and psychiatric disorders associated with corticotropin-releasing hormone (CRH) hyperactivity. The possible causal relationship between defective GR function and altered activity of CRH neurons was studied in transgenic mice (TG) expressing antisense RNA against GR. Immunocytochemical studies showed significant reductions in CRH immunoreactive neurons in the paraventricular nucleus (PVN) and in CRH and vasopressin (AVP) stores in the external zone of the median eminence. Concomitantly, stimulus-evoked CRH secretion from mediobasal hypothalami of TG mice in vitro was reduced significantly. However, CRH mRNA levels in the PVN of TG mice were marginally lower than those in wild-type (WT) mice. 125I-CRH binding autoradiography revealed no differences between WT and TG animals in any of the brain regions that were studied. Basal plasma corticosterone (cort) levels and 125I-CRH binding, CRH-R1 mRNA, POMC mRNA, and POMC hnRNA levels in the anterior pituitary gland were similar in WT and TG mice. Intraperitoneal injection of interleukin-1beta (IL-1beta) increased plasma cort levels, CRH mRNA in the PVN, and anterior pituitary POMC hnRNA similarly in WT and TG mice. The injection of saline significantly reduced anterior pituitary CRH-R1 mRNA levels in WT mice, but not in TG mice, whereas IL-1beta produced a decrease in these mRNA levels in both strains. The data show that long-term GR dysfunction can be associated with reduced activity of CRH neurons in the PVN and decreased sensitivity of pituitary CRH-R1 mRNA to stimulus-induced downregulation. Moreover, the hypothalamic changes observed in this model suggest that impaired GR function, at least if present since early embryonic life, does not necessarily result in CRH hyperexpression characteristics of disorders such as major depression." [Full Text]

Sharada Karanth, Astrid C. E. Linthorst, Günther K. Stalla, Nicholas Barden, Florian Holsboer, and Johannes M. H. M. Reul
Hypothalamic-Pituitary-Adrenocortical Axis Changes in a Transgenic Mouse with Impaired Glucocorticoid Receptor Function
Endocrinology 138: 3476-3485
"Recently, a transgenic mouse with impaired glucocorticoid receptor (GR) function was created to serve as an animal model for the study of neuroendocrine changes occurring in stress-related disorders, such as major depression. Here, we investigated the hypothalamic-pituitary-adrenocortical (HPA) axis changes in these transgenic mice. There were no significant differences between basal early morning plasma ACTH and corticosterone levels in normal and transgenic mice. When animals were exposed to a mild stressor, an enhanced response in plasma ACTH was observed in the transgenic mice, whereas plasma corticosterone responses were not different. In view of these differences in plasma ACTH and corticosterone responses, we directed our studies toward the regulation of ACTH secretion on the hypothalamic-hypophyseal level in vitro. Therefore, an in vitro model, the pituitary-hypothalamic complex (PHc) was developed and its ACTH release profile was compared with that of the pituitary (PI) alone. The basal ACTH release by PHc and PI from normal and transgenic mice was similar. Regardless of the strain under study, the basal ACTH release by PI was significantly lower than the release by PHc. Stimulation of tissues with either high K+ (56 mM) or CRH (10 or 20 nM) produced an enhanced ACTH release from both PHc and PI, whereas the response in PI was larger than that in PHC. Moreover, the responses to these stimuli were markedly enhanced in tissues from transgenic mice. In tissues of normal mice, corticosterone inhibited both basal and CRH-stimulated ACTH release more potently in PHc than in PI. Furthermore, the feedback capacity of corticosterone to restrain both basal and CRH-stimulated ACTH release was highly impaired in tissues of transgenic mice, whereas the feedback in PHc appeared to be more affected than that in the PI of these animals.

In conclusion, the in vitro data on PHc and PI revealed intrahypothalamic mechanisms operating 1) to fine-tune stimulus-evoked ACTH responses; and 2) to facilitate the negative feedback action of glucocorticoids. Moreover, in the transgenic tissues, the impaired GR function was found to cause augmented stimulus-evoked ACTH responses and an impaired glucocorticoid feedback efficacy which appeared to be mainly defective at the hypothalamic level. Thus, in the transgenic mice with life-long central GR dysfunction we found impaired negative feedback combined with "normal" (i.e. noncompensated) in vivo plasma corticosterone responses. This is a condition with potentially grave pathophysiological consequences and, therefore, this transgenic animal may be regarded as a valuable model for the study of functional glucocorticoid insufficiency at the central nervous system level." [Full Text]

Heuser I.
Anna-Monika-Prize paper. The hypothalamic-pituitary-adrenal system in depression.
Pharmacopsychiatry 1998 Jan;31(1):10-3
"Patients with depression frequently have symptom clusters which point strongly to involvement of the hypothalamic-pituitary-adrenal (HPA) system as a relay station between neurocircuitries in the brain and peripheral hormone and autonomic nervous function. It has been proposed that this increased, state-dependent hyperactivity of the HPA-system in depression is probably initiated and/or maintained by the combination of enhanced central production of CRH and desensitization of the binary, glucocorticoid receptor binding system in the hippocampus, which is the central regulator of HPA system activity. In a first series of studies a refined neuroendocrine test to probe the integrity of HPA system status--the combined dexamethasone suppression/CRH challenge (DEX/CRH) test--was developed and the differential effects of aging and depressed psychopathology on DEX/CRH test outcome were described. In a second set of studies, the chronological relationship between improvement of psychopathology in depressed patients treated with antidepressants and normalization of the disturbed HPA system function in these patients was further elucidated. Given the evidence from animal studies, we conclude that antidepressants induce an up-regulation of hippocampal glucocorticoid receptor mRNA concentration, thus amplifying the negative feedback effect of glucocorticoids. This then results in the normalization of DEX/CRH test results observed in the depressed patients in our study. We further conclude that dampening of HPA system hyperactivity in depression by means of antidepressants is a conditio sine qua non for successful improvement of psychopathology." [Abstract]

Montkowski A, Barden N, Wotjak C, Stec I, Ganster J, Meaney M, Engelmann M, Reul JM, Landgraf R, Holsboer F.
Long-term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function.
J Neuroendocrinol 1995 Nov;7(11):841-5
"Impaired cognitive function and enhanced activity of the hypothalamic-pituitary-adrenocortical system are among the cardinal symptoms of major depression in humans that resolve after successful antidepressant treatment. We used a transgenic mouse model expressing antisense RNA complementary to that of glucocorticoid receptor (GR) mRNA to test the hypothesis that reduced GR function can cause these clinical disturbances. The transgenic mice show profound behavioural changes in a number of animal tests that are indicative of cognitive impairment. These mice also have elevated plasma corticotropin concentrations in response to stress. After long-term treatment with moclobemide, a reversible inhibitor of monoamine oxidase type A that acts clinically as an antidepressant, both the behavioural deficits and the hormonal alterations disappeared. These observations suggest that a transgenic mouse with GR dysfunction may be a useful model for investigation of drug effects on the cognitive and neuroendocrine aspects of depression." [Abstract]

Pepin MC, Pothier F, Barden N.
Antidepressant drug action in a transgenic mouse model of the endocrine changes seen in depression.
Mol Pharmacol 1992 Dec;42(6):991-5
"We have created transgenic mouse lines with impaired glucocorticoid receptor function by expression of a type II glucocorticoid receptor antisense RNA in brain tissues. These animals have endocrinological characteristics similar to those seen in depression, including a hyperactive hypothalamic-pituitary-adrenal axis as indicated by elevated plasma corticosterone and adrenocorticotropin hormone levels. Treatment of transgenic animals with the tricyclic antidepressant desipramine increased hypothalamic glucocorticoid receptor mRNA concentration and dexamethasone-binding activity while decreasing plasma adrenocorticotropin hormone concentration and corticosterone levels. These results support the hypothesis that antidepressants exert action on the hypothalamic-pituitary-adrenal axis through modulation of glucocorticoid receptor gene expression." [Abstract]

Barden N.
Regulation of corticosteroid receptor gene expression in depression and antidepressant action.
J Psychiatry Neurosci 1999 Jan;24(1):25-39
"OBJECTIVE: Major alterations of the hypothalamic-pituitary-adrenocortical (HPA) system are often seen in patients with depression, and can be reversed by successful antidepressant therapy. Persuasive evidence points to the involvement of a dysfunctional glucocorticoid receptor system in these changes. The authors developed a transgenic mouse to determine the mechanism for these changes. DESIGN: In vivo and in vitro animal experiments. ANIMALS: Transgenic mice expressing glucocorticoid receptor antisense RNA and control mice. INTERVENTIONS: In vivo: hormone assays and dexamethasone suppression tests; in vitro: cell transfection, chloramphenicol acetyl transferase assay, Northern blot analysis, binding assays of cytosolic receptor. OUTCOME MEASURES: Indicators of depressive disorder in transgenic mice, effect of antidepressant therapy on dexamethasone binding in transgenic mouse hippocampus, mouse behaviour, and glucocorticoid receptor activity. RESULTS: Transgenic mice showed no suppression of corticosterone with a dose of 2 mg per 100 g body weight dexamethasone. Treatment with amitriptyline reduced levels of corticotropin and corticosterone, increased glucocorticoid receptor mRNA concentrations and glucocorticoid binding capacity of several brain areas, and reversed behavioural changes. In vitro experiments also showed that desipramine increased glucocorticoid receptor mRNA. CONCLUSION: These transgenic mice have numerous neuroendocrine characteristics of human depression as well as altered behaviour. Many of these neuroendocrinologic and behavioural characteristics are reversed by antidepressants. The antidepressant-induced increase in glucocorticoid receptor activity may render the HPA axis more sensitive to glucocorticoid feedback. This new insight into antidepressant drug action suggests a novel approach to the development of new antidepressant drugs." [Abstract]

Okugawa G, Omori K, Suzukawa J, Fujiseki Y, Kinoshita T, Inagaki C.
Long-term treatment with antidepressants increases glucocorticoid receptor binding and gene expression in cultured rat hippocampal neurones.
J Neuroendocrinol 1999 Nov;11(11):887-95
"Since the glucocorticoid receptor (GR) and/or mineralocorticoid receptor (MR) in the hippocampus have been implicated in cortisol feedback of the hypothalamus-pituitary-adrenal (HPA) axis, abnormalities in those receptors might underlie the hyperactivity of the HPA axis described in patients with major depression. Animal studies have shown that long-term in-vivo treatment with antidepressants up-regulates hippocampal GR and/or MR, but it is not clear whether this up-regulation is evoked through a direct action of antidepressants on these receptors. We therefore examined the direct effects of long-term antidepressant treatment on GR binding and the levels of GR messenger RNA (mRNA) in primary cultures of rat hippocampal neurones. The time course of the effects of the tricyclic antidepressants desipramine and amitriptyline on GR binding, as assessed by [3H]dexamethasone binding using RU 28362, a specific agonist for GR, showed a biphasic mode of stimulation: desipramine significantly increased the GR binding with 2-day exposure by 36% over that in controls and by 99% and 60% with 10- and 14-day exposures, respectively. Amitriptyline also led to a significant increase in GR binding, with peaks at 2 (by 60%) and 14 days of exposure (by 60%). The effects of 14-day treatment with desipramine required at least the first 4-day exposure, and the first 10-day exposure was required for the full effect. Northern blot analysis demonstrated that the GR mRNA level was significantly increased by 14-day treatment with desipramine (+142% over control), amitriptyline (+108%), mianserin (+124%), paroxetine (+42%) and sulpiride (+92%), but not with haloperidol. Immunocytochemistry for GR revealed that 2- or 14-day treatment with desipramine significantly increased the number of GR-positive cells with dominant immunoreactivity in the nuclei of granule cell-like neurones or in perikarya of pyramidal cell- and granule cell-like neurones. These findings suggest that tricyclic antidepressants directly increase hippocampal GR by short-term (2-day) and long-term (14-day) exposure, and that the increase by long-term exposure is evoked commonly with different classes of antidepressants through transcriptional up-regulation of GR expression." [Abstract]

Brady LS, Gold PW, Herkenham M, Lynn AB, Whitfield HJ Jr.
The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications.
Brain Res 1992 Feb 14;572(1-2):117-25
"Various classes of antidepressant drugs with distinct pharmacologic actions are differentially effective in the treatment of classic melancholic depression--characterized by pathological hyperarousal and atypical depression--associated with lethargy, hypersomnia, and hyperphagia. All antidepressant agents exert their therapeutic efficacy only after prolonged administration. In situ hybridization histochemistry was used to examine in rats the effects of short-term (2 weeks) and long-term (8 weeks) administration of 3 different classes of activating antidepressant drugs which tend to be preferentially effective in treating atypical depressions, on the expression of central nervous system genes thought to be dysregulated in major depression. Daily administration (5 mg/kg, i.p.) of the selective 5-hydroxytryptophan (5-HT) reuptake inhibitor fluoxetine, the selective alpha 2-adrenergic receptor antagonist idazoxan, and the nonspecific monoamine oxidase A and B inhibitor phenelzine increased tyrosine hydroxylase mRNA levels by 70-150% in the locus coeruleus after 2 weeks of drug and by 71-115% after 8 weeks. The 3 drugs decreased corticotropin-releasing hormone mRNA levels by 30-48% in the paraventricular nucleus of the hypothalamus. The decreases occurred at 8 weeks but not at 2 weeks. No consistent change in steroid hormone receptor mRNA levels was seen in the hippocampus with the 3 drugs, but fluoxetine and idazoxan increased the level of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA, respectively, after 8 weeks of drug administration. Proopiomelanocortin (POMC) mRNA levels in the anterior pituitary and plasma adrenocorticotropic-hormone (ACTH) levels were not altered after 2 or 8 weeks of drug treatment." [Abstract]

Brady LS, Whitfield HJ Jr, Fox RJ, Gold PW, Herkenham M.
Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications.
J Clin Invest 1991 Mar;87(3):831-7
"Imipramine is the prototypic tricyclic antidepressant utilized in the treatment of major depression and exerts its therapeutic efficacy only after prolonged administration. We report a study of the effects of short-term (2 wk) and long-term (8 wk) administration of imipramine on the expression of central nervous system genes among those thought to be dysregulated in imipramine-responsive major depression. As assessed by in situ hybridization, 8 wk of daily imipramine treatment (5 mg/kg, i.p.) in rats decreased corticotropin-releasing hormone (CRH) mRNA levels by 37% in the paraventricular nucleus (PVN) of the hypothalamus and decreased tyrosine hydroxylase (TH) mRNA levels by 40% in the locus coeruleus (LC). These changes were associated with a 70% increase in mRNA levels of the hippocampal mineralocorticoid receptor (MR, type I) that is thought to play an important role in mediating the negative feedback effects of low levels of steroids on the hypothalamic-pituitary-adrenal (HPA) axis. Imipramine also decreased proopiomelanocortin (POMC) mRNA levels by 38% and glucocorticoid receptor (GR, type II) mRNA levels by 51% in the anterior pituitary. With the exception of a 20% decrease in TH mRNA in the LC after 2 wk of imipramine administration, none of these changes in gene expression were evident as a consequence of short-term administration of the drug. In the light of data that major depression is associated with an activation of brain CRH and LC-NE systems, the time-dependent effect of long-term imipramine administration on decreasing the gene expression of CRH in the hypothalamus and TH in the LC may be relevant to the therapeutic efficacy of this agent in depression." [Abstract]

Okuyama-Tamura M, Mikuni M, Kojima I.
Modulation of the human glucocorticoid receptor function by antidepressive compounds.
Neurosci Lett 2003 May 22;342(3):206-10
"Hyperactivity of the hypothalamic-pituitary-adrenal axis is associated with depression. We investigated the effect of various types of antidepressant agents in vitro on the function of glucocorticoid receptor (GR). Desipramine, clomiplamine, fluoxetine, milnacipran and clorgyline all induced rapid and sustained translocation of GR into the nucleus of human lymphocytes. In contrast, major and minor tranquilizers, lithium and verapamil, a blocker of membrane steroid transporter, were without effect. These antidepressants did not affect GR-mediated transcription by themselves, but significantly inhibited dexamethasone-induced transcription. These results indicate that structurally different antidepressants induce translocation of GR and inhibit GR-mediated transcription." [Abstract]

Carmine M. Pariante, Andrew Makoff, Simon Lovestone, Susan Feroli, Alexandra Heyden, Andrew H. Miller, and Robert W. Kerwin
Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters
Br J Pharmacol 2001 134: 1335-1343
"1. Previous data demonstrate that the tricyclic antidepressant, desipramine, induces glucocorticoid receptor (GR) translocation from the cytoplasm to the nucleus in L929 cells and increases dexamethasone-induced GR-mediated gene transcription in L929 cells stably transfected with the mouse mammary tumour virus-chloramphenicol acetyltransferase (MMTV-CAT) reporter gene (LMCAT cells) (Pariante et al., 1997). 2. To extend these findings, the present study has investigated the effects of 24 h coincubation of LMCAT cells with dexamethasone and amitriptyline, clomipramine, paroxetine, citalopram or fluoxetine. 3. All antidepressants, except fluoxetine, enhanced GR-mediated gene transcription, with clomipramine having the greatest effect (10 fold increase). Twenty-four hours coincubation of cells with desipramine, clomipramine or paroxetine, also enhanced GR function in the presence of cortisol, but not of corticosterone. 4. It is proposed that these effects are due to the antidepressants inhibiting the L929 membrane steroid transporter, which actively extrudes dexamethasone and cortisol from the cell, but not corticosterone. This is further confirmed by the fact that clomipramine failed to enhance GR-mediated gene transcription in the presence of dexamethasone when the membrane steroid transporter was blocked by verapamil. 5. The membrane steroid transporters that regulate access of glucocorticoids to the brain in vivo, like the multiple drug resistance p-glycoprotein, could be a fundamental target for antidepressant action." [Abstract]

Rossby SP, Nalepa I, Huang M, Perrin C, Burt AM, Schmidt DE, Gillespie DD, Sulser F.
Norepinephrine-independent regulation of GRII mRNA in vivo by a tricyclic antidepressant.
Brain Res 1995 Jul 31;687(1-2):79-82
"Desipramine (DMI), a tricyclic antidepressant drug used in the treatment of depression, has been shown to increase steady-state levels of glucocorticoid receptor type II (GRII) mRNA in vitro and in vivo. To determine whether this effect is secondary to norepinephrine (NE) reuptake inhibition i.e., increases in synaptic NE induced by DMI, GRII mRNA levels were assayed in rat hippocampus following neurotoxic lesioning of NE neurons with DSP4. Chronic DMI treatment significantly increased GRII mRNA levels to the same degree in lesioned and non-lesioned animals. In contrast to DMI, the non-tricyclic antidepressant fluoxetine had no effect on GRII mRNA. These results provide evidence which demonstrates that a tricyclic antidepressant can regulate steady-state mRNA levels in vivo by a mechanism which is independent of its effects on synaptic monoamine levels." [Abstract]

Pariante, Carmine M., Pearce, Bradley D., Pisell, Tracy L., Owens, Michael J., Miller, Andrew H.
Steroid-Independent Translocation of the Glucocorticoid Receptor by the Antidepressant Desipramine
Mol Pharmacol 1997 52: 571-581
"The glucocorticoid receptor (GR) is a ligand-regulated transcription factor that in its unactivated form resides primarily in the cytoplasm. After being bound by steroid, the GR undergoes a conformational change and translocates to the nucleus, where it influences gene transcription. Because the GR mediates negative feedback exerted by circulating glucocorticoid hormones on the hypothalamic-pituitary-adrenal (HPA) axis, it has been hypothesized that abnormalities in GR expression and/or function may underlie the HPA axis hyperactivity described in patients with major depression. In further support of this hypothesis, animal studies have shown that long term in vivo treatment with antidepressants enhances glucocorticoid feedback inhibition, possibly through a direct effect on the GR. To examine this latter possibility, we evaluated translocation of the GR from the cytoplasm to the nucleus after 24-hr in vitro treatment of L929 cells (mouse fibroblasts) with the tricyclic antidepressant desipramine (0.1-10 microM) in the presence or absence of the synthetic steroid dexamethasone. In addition, GR-mediated gene transcription was measured with the use of L929 cells stably transfected with the mouse mammary tumor virus-chloramphenicol acetyltransferase reporter gene. Desipramine was found to (i) induce GR translocation from the cytoplasm to the nucleus in the absence of steroids (with no effect alone on GR-mediated gene transcription) and (ii) potentiate dexamethasone-induced GR translocation and dexamethasone-induced GR-mediated gene transcription. Treatment with desipramine for 24-96 hr had no effect on the expression of GR protein as measured by cytosolic radioligand receptor binding. We suggest that one important aspect of the effects of antidepressants in vivo may be to facilitate GR-mediated feedback inhibition on the HPA axis, by facilitating GR translocation and function, and thereby reverse glucocorticoid hypersecretion in depression." [Full Text]

Hatzinger M.
Neuropeptides and the hypothalamic-pituitary-adrenocortical (HPA) system: review of recent research strategies in depression.
World J Biol Psychiatry 2000 Apr;1(2):105-11
"Depressed patients show a variety of alterations in hypothalamic-pituitary-adrenocortical (HPA) system regulation which is reflected by increased pituitary-adrenocortical hormone secretion at baseline and a number of aberrant neuroendocrine function tests. The latter include the combined dexamethasone (DEX) suppression/corticotropin-releasing hormone (CRH) challenge test, in which CRH was able to override DEX induced suppression of ACTH and cortisol secretion. Whereas the abnormal HPA activation in these patients improved in parallel with clinical remission, persistent HPA dysregulation was associated with an increased risk of relapse. Moreover, healthy subjects at high genetic risk for depression also showed this phenomenon as a trait marker. In consequence, it has been concluded that HPA alteration and developmen as well as course of depression may be causally related. As evidenced from clinical and preclinical studies, underlying mechanisms of these abnormalities involve impairment of central corticosteroid receptor function which leads to enhanced activity of hypothalamic neurons synthesising and releasing vasopressin and CRH. These neuropeptides mediate not only neuroendocrine but also behavioural effects. Recent research provided evidence that CRH can induce depression-like symptoms in animals and that these signs are mediated through the CRH1 receptor subtype. Hence, therapeutical application of new compounds acting more specifically on the HPA system such as CRH1 receptor antagonists appear to be a promising approach for future treatment options of depression. In conclusion, research in neuroendocrinology provided new insights into the underlying pathophysiology of depression and, in consequence, may lead to the development of new therapeutic tools." [Abstract]

Muller M, Holsboer F, Keck ME.
Genetic modification of corticosteroid receptor signalling: novel insights into pathophysiology and treatment strategies of human affective disorders.
Neuropeptides 2002 Apr-Jun;36(2-3):117-31
"Every disturbance of the body, either real or imagined, evokes a stress response. Essential to this stress response is the activation of the hypothalamic-pituitary-adrenocortical (HPA) system, finally resulting in the release of glucocorticoid hormones from the adrenal cortex. Glucocorticoid hormones, in turn, feed back to this system by central activation of two types of corticosteroid receptors: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) which markedly differ in their neuroanatomical distribution and ligand affinity. Whereas a brief period of controllable stress, experienced with general arousal and excitement, can be a challenge and might thus be beneficial, chronically elevated levels of circulating corticosteroids are believed to enhance vulnerability to a variety of diseases, including affective disorders. Corticosteroids are known to influence emotions and cognitive processes, such as learning and memory. In addition, corticosteroids play extremely important roles in modulating fear and anxiety-related behaviour. The mechanisms by which corticosteroids exert their effects on behaviour are often indirect, by modulating particular sets of neurons or neurotransmitter systems. In addition, the timing of corticosteroid increase (before, during or after exposure to a stressor) determines whether and how behaviour is affected.The cumulative evidence makes a strong case implicating corticosteroid receptor dysfunction in the pathogenesis of affective disorders. Although definitive controlled trials remain to be conducted, there is evidence indicating that cortisol-lowering or corticosteroid receptor antagonist treatments may be of clinical benefit in selected individuals with major depression. A more detailed knowledge of the GR signalling pathways therefore opens up the possibility to specifically target GR function.In recent years, refined molecular technologies and the generation of genetically engineered mice (e.g. "conventional" and "conditional" knock-outs) have allowed to specifically target individual genes involved in corticosteroid receptor signalling and stress hormone regulation. Given the fundamental role of corticosteroid receptors in hippocampal integrity and mental performance during aging and psychiatric disorders, the identification and detailed characterization of these molecular pathways will ultimately lead to the development of novel neuropharmacological intervention strategies." [Abstract]

Barden N.
Modulation of glucocorticoid receptor gene expression by antidepressant drugs.
Pharmacopsychiatry 1996 Jan;29(1):12-22
"Through expression of a glucocorticoid receptor (GR) antisense RNA in brain, we have produced transgenic mice with an hyperactive hypothalamic-pituitary-adrenocortical (HPA) system similar to that seen in depressed patients. This model supports the hypothesis that disturbed corticosteroid receptor regulation could be the primary factor responsible for both the CRH/AVP hyperdrive that leads to increased activity of the HPA system, and the premature escape from the cortisol suppressant action of dexamethasone seen in affective disorders. Although normalisation of the hyperactive HPA system occurs during successful antidepressant therapy of depressive illness, these improvements do not correlate with changes in monoaminergic neurotransmitter systems, suggesting that unknown mechanisms of action may be operative. Work from my laboratory was the first to show that different types of antidepressants increased glucocorticoid receptor (GR) mRNA. We found increased GR mRNA levels irrespective of the preferential inhibitory action of antidepressant on the monoamine neurotransmitter re-uptake and showed increased GR gene transcription in antidepressant-treated mouse fibroblast cells that do not possess monoamine re-uptake mechanisms. We measured changes in glucocorticoid response in cells transfected with a glucocorticoid-sensitive reporter plasmid (MMTV-CAT) and observed increased glucocorticoid-stimulated CAT activity when the cells were treated with antidepressant. A different chimaeric gene construct consisting of a fragment of the GR gene promoter region fused to the CAT gene allowed more direct measurement of antidepressant action and increased CAT activity was also seen when cells transfected with this construct were treated with antidepressant. Finally, GR mRNA concentration and glucocorticoid binding activity were increased in brain tissues of animals chronically treated with antidepressant. The time course of antidepressant actions on corticosteroid receptors coincides with their long-term actions on HPA system activity and follows closely that of clinical improvement of depression. This suggests that antidepressant-induced changes in brain corticosteroid receptors may underlie the observed simultaneous decrease in circulating ACTH and corticosterone levels and the decreased adrenal size. Some of these effects may be mediated through CRH since, in antidepressant-treated transgenic mice hypothalamic CRH mRNA levels were decreased. From this work we have formulated the hypothesis that a primary action of antidepressants could be the stimulation of corticosteroid receptor gene expression that renders the HPA system more susceptible to feedback inhibition by cortisol. The resultant decrease in HPA system activity could induce secondary changes in glucocorticoid-sensitive gene expression and lead to redressment of neurotransmitter imbalance. This work opens up a completely new insight into antidepressant drug action and suggests a line of approach to the development of new drugs by focusing on this action." [Abstract]

Post A, Ohl F, Almeida OF, Binder EB, Rucker M, Welt S, Binder E, Holsboer F, Sillaber I.
Identification of molecules potentially involved in mediating the in vivo actions of the corticotropin-releasing hormone receptor 1 antagonist, NBI30775 (R121919).
Psychopharmacology (Berl). 2005 Jan 29; [Epub ahead of print]
RATIONALE: The neuropeptide corticotropin-releasing hormone (CRH) plays a central role in the regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis. The view that CRH hypersecretion underlies anxiety and mood disorders was recently supported by preclinical and clinical data obtained after application of the CRH receptor (CRH-R1) antagonist NBI30775 (R121919). Despite its therapeutic efficacy, there is only little information about its mechanisms of action on cellular and molecular targets. OBJECTIVE: To identify some of the intracellular substrates mediating the actions of NBI30775 after its acute administration in a stress-independent animal model. RESULTS: Of the different doses of NBI30775 tested (0.5, 1, 5 and 30 mg/kg), the 1-mg/kg dose proved behaviorally active insofar that it reduced anxiety-like behavior in mice under basal conditions. Subsequent analysis of brain tissues revealed NBI30775-induced increases in the nuclear translocation of glucocorticoid receptors (GR) and BAG-1, an upregulation of mRNA transcripts encoding GR, mineralocorticoid receptors (MR) and CRH-R1, and a suppression of the DNA-binding activity of the transcription factor AP-1. These changes were significant at a dose of 1 mg/kg of NBI30775. CONCLUSION: NBI30775 reduces levels of anxiety in mice (under basal conditions) with a steep dose-response curve. Molecules such as GR, MR, BAG-1 and AP-1 have been identified as some of the drug's intracellular targets; interestingly, changes in these molecules have also been seen in response to conventional antidepressants, showing that structurally and mechanistically unrelated anxiolytic and antidepressant drugs can influence common downstream pathways. [Abstract]

Modell S, Yassouridis A, Huber J, Holsboer F.
Corticosteroid receptor function is decreased in depressed patients.
Neuroendocrinology 1997 Mar;65(3):216-22
"Decreased feedback control of the hypothalamic-pituitary-adrenocortical (HPA) system as revealed by the combined dexamethasone and corticotropin-releasing hormone (DEX-CRH) test has been documented in the vast majority of patients with affective disorders. This finding was interpreted as a failure at the level of the glucocorticoid receptor (GR)-mediated feedback action, which apparently fails to restrain HPA activity in the presence of elevated plasma corticosteroid levels. To test this hypothesis we conducted the DEX/CRH test using increasing doses of DEX in order to establish a dose-response relationship. We used three different DEX doses (0.75, 1.5, 3.0 mg) in three groups of depressed patients and controls. As expected, increasing DEX doses were associated with decreasing amounts of adrenocorticotropin (ACTH) and cortisol being released after CRH injection. However, dose-response curves for both plasma ACTH and cortisol concentrations were shifted to higher area under the curve (AUC) values among patients compared to controls. Pretreatment with 0.75 and 1.5 mg DEX produced significantly higher AUC values for both plasma ACTH and cortisol values among patients. These differences became less obvious with the higher DEX doses, indicating that the dose of 1.5 mg used in the majority of clinical studies so far is well suited to differentiate between healthy controls and patients. The reported data here are consistent with the hypothesis that an altered GR capacity or function underlies the exaggerated HPA activity in depression." [Abstract]

Michael Deuschle, Ulrich Schweiger, Bettina Weber, Ulrike Gotthardt, Andreas Körner, Jurgen Schmider, Harald Standhardt, Claas-Hinrich Lammers, and Isabella Heuser
Diurnal Activity and Pulsatility of the Hypothalamus-Pituitary-Adrenal System in Male Depressed Patients and Healthy Controls
J. Clin. Endocrinol. Metab. 82: 234-238
"There is only sparse and ambiguous information about circadian and pulsatile secretion features of the hypothalamus-pituitary-adrenocortical system in depression. We studied 15 severely depressed (Hamilton Depression Scale 30.4 +/- 6.7) male patients (age 22-72 yr; mean, 47.7 +/- 14.8) and 22 age-matched male controls (age 23-85 yr; mean, 53.1 +/- 18.2). Twenty-four-hour blood sampling from 0800-0800 h with 30-min sampling intervals was performed; from 1800-2400 h, blood was drawn every 10 min. Multivariate analysis of covariance, with the covariate being age, revealed mean 24-h cortisol (315.9 +/- 58.5 vs. 188.2 +/- 27.3 nmol/L) and mean ACTH (7.82 +/- 1.94 vs. 5.79 +/- 1.28 pmol/L) to be significantly increased in depressed patients. The frequency of cortisol (2.6 +/- 0.7 vs. 1.3 +/- 1.0 pulses/6 h) and ACTH (2.6 +/- 1.6 vs. 1.6 +/- 1.4 pulses/6 h) pulses during the evening were higher in patients compared to controls. The flattened circadian cortisol variation and reduced time of quiescence of cortisol secretory activity (140 +/- 116 vs. 305 +/- 184 min) in patients suggest disturbances of circadian functions. We conclude that increased hypothalamus-pituitary-adrenocortical activity in depression is related to a greater frequency of episodic hormone release, and we hypothesize that the observed circadian changes might be partly due to altered mineralocorticoid and glucocorticoid receptor capacity and function." [Full Text]

Calfa G, Kademian S, Ceschin D, Vega G, Rabinovich GA, Volosin M.
Characterization and functional significance of glucocorticoid receptors in patients with major depression: modulation by antidepressant treatment.
Psychoneuroendocrinology. 2003 Jul; 28(5): 687-701.
"Hyperactivity of the hypothalamic pituitary adrenal (HPA) axis in patients with major depression is one of the most consistent findings in biological psychiatry. Experimental data support the idea that glucocorticoid-mediated feedback via glucocorticoid receptors (GR) is impaired in major depression. The aim of the present work was to assess the putative changes in GR density of peripheral blood mononuclear cells (PBMCs) in a group of patients with major depression and to determine modulation of these GR sites by antidepressant treatment. In addition, susceptibility of PBMCs to glucocorticoid effects was also studied using a functional end-point analysis in vitro, such as cortisol inhibition of mitogen-induced lymphocyte proliferation. Cortisol levels were also measured before and after dexamethasone suppression test (DST). The results showed a decrease in GR density in depressed patients compared with healthy subjects, mainly in those patients that showed basal cortisol levels in the upper normal range and were refractory to DST. Regarding the functional significance of this variation, two representative groups emerged from our study: a) free-medication patients with GR function comparable to healthy controls, and b) patients showing diminished GR activity. These results suggest a lack of relationship between GR density and cortisol-induced inhibition of lymphocyte proliferation. Patients treated with different antidepressant drugs showed a marked increase in the number of GR sites per cell compared to non-treated. Interestingly, this increase was even higher than in normal subjects. Hence, restoration of GR density after an efficient antidepressant treatment could be an index of an effective modulatory action of drugs on GR expression and highlights the possibility that GR levels might be used as markers of a successful treatment." [Abstract]

Yehuda R, Boisoneau D, Mason JW, Giller EL.
Glucocorticoid receptor number and cortisol excretion in mood, anxiety, and psychotic disorders.
Biol Psychiatry 1993 Jul 1-15;34(1-2):18-25
"In the present study, we measured cytosolic lymphocyte glucocorticoid receptor and 24-hour urinary cortisol excretion in patients with major depressive disorder, bipolar mania, posttraumatic stress disorder, panic disorder, and schizophrenia. Patients with major depression had the smallest, and posttraumatic stress disordered patients the largest, mean number of glucocorticoid receptors per cell compared to patients in the other groups. Bipolar manic and panic patients did not differ from each other in regard to the number of lymphocyte glucocorticoid receptors. Bipolar manic and panic patients did have significantly more glucocorticoid receptors/cell than schizophrenic patients. The mean 24-hour urinary cortisol excretion was significantly higher in patients with major depression and bipolar mania than in those in the other diagnostic groups. Lymphocyte glucocorticoid receptor number and cortisol excretion tended to be inversely related, when the entire sample was considered as a whole, but this effect did not reach statistical significance. It is concluded that lymphocyte glucocorticoid receptors may be modulated by multiple influences, not just ambient cortisol levels. These preliminary data suggest that the assessment of lymphocyte glucocorticoid receptor number in tandem with cortisol levels may provide a more meaningful estimate of hypothalamic-pituitary-adrenal axis activity than is achieved using cortisol alone." [Abstract]

Rupprecht R, Kornhuber J, Wodarz N, Lugauer J, Gobel C, Riederer P, Beckmann H.
Lymphocyte glucocorticoid receptor binding during depression and after clinical recovery.
J Affect Disord 1991 May-Jun;22(1-2):31-5
"Lymphocyte glucocorticoid receptor binding parameters were studied in 15 severely depressed patients during depression and after clinical recovery, and in 15 healthy controls. There was no difference in glucocorticoid receptor number or affinity between depressed patients and recovered or control subjects. Afternoon ACTH and cortisol concentrations did not differ significantly between the three groups. No relationship could be established between glucocorticoid receptor binding and antidepressant medication. These data support the view of an impaired ligand-induced plasticity of glucocorticoid receptor regulation rather than the hypothesis of decreased glucocorticoid receptor numbers during depression." [Abstract]

Whalley LJ, Borthwick N, Copolov D, Dick H, Christie JE, Fink G.
Glucocorticoid receptors and depression.
Br Med J (Clin Res Ed) 1986 Mar 29;292(6524):859-61
"The number of glucocorticoid receptor sites in lymphocytes was estimated and plasma cortisol concentrations measured in 17 depressed patients, 12 patients with chronic schizophrenia, and 31 healthy control subjects. The number of receptor sites was significantly lower in the depressed patients than in either the controls or the patients with chronic schizophrenia, but there were no differences between the groups in the dissociation constants of the glucocorticoid receptors or the plasma cortisol concentrations. When two control subjects were studied intensively over 28 hours a slight diurnal variation in the number of glucocorticoid receptors was detected. The lower numbers of glucocorticoid receptors in the lymphocytes of depressed patients may explain why such patients, who often have hypercortisolaemia, do not show the clinical features of excess production of cortisol." [Abstract]

Gormley GJ, Lowy MT, Reder AT, Hospelhorn VD, Antel JP, Meltzer HY.
Glucocorticoid receptors in depression: relationship to the dexamethasone suppression test.
Am J Psychiatry 1985 Nov;142(11):1278-84
"Cytoplasmic glucocorticoid receptor content wa quantitated in lymphocytes from unmedicated depressed patients and control subjects before and after a standardized dexamethasone suppression test. Depressed patients (N = 11) had significantly lower (32%) basal cytoplasmic glucocorticoid receptor content than the control group (N = 14). Suppression of serum cortisol (5.0 micrograms/dl or less) in both control and depressed subjects (N = 16) following dexamethasone (1 mg) was associated with a decrease in lymphocyte cytoplasmic glucocorticoid receptor number, whereas no such change occurred in cortisol nonsuppressors (N = 9). Changes in receptor concentration were positively correlated with postdexamethasone serum cortisol levels and with the inhibitory effect of dexamethasone on mitogen-induced lymphocyte proliferation." [Abstract]

Wassef A, Smith EM, Rose RM, Gardner R, Nguyen H, Meyer WJ.
Mononuclear leukocyte glucocorticoid receptor binding characteristics and down-regulation in major depression.
Psychoneuroendocrinology 1990;15(1):59-68
"Some patients with major depressive disorder (MDD) have elevated plasma cortisol concentrations and show failure to suppress cortisol secretion upon administration of dexamethasone (DEX), yet they do not have Cushingoid features. To study whether this represents glucocorticoid (GC) resistance, [3H]-DEX-binding assays were used to measure, in vitro, the GC receptor affinity (1/Kd) and number (Bmax) in mononuclear leukocytes of 11 MDD patients and 15 control subjects. No receptor abnormalities were detected in the MDD group; thus any cellular defect leading to a lack of responsiveness to GC in the MDD patients, if present, probably lies beyond the initial receptor binding. DEX (1.0 mg orally) was administered to study in vivo GC receptor down-regulation. Compared to the control group, fewer depressed subjects down-regulated Bmax after DEX. By paired t-test, Bmax decreased significantly in the control group but not in the depressed group. Receptor number on the control day did not correlate significantly with the degree of receptor down-regulation, severity of depression or cortisol concentrations across all the subjects. These results do not lend support to previous reports suggesting that GC resistance in MDD results from a GC receptor-binding abnormality, and they emphasize the importance of considering receptor studies in the context of GC-mediated cell processes in order to identify the exact cellular defect(s) leading to GC resistance." [Abstract]

McQUADE, RICHARD, YOUNG, ALLAN H. Y.
Future therapeutic targets in mood disorders: the glucocorticoid receptor
Br J Psychiatry 2000 177: 390-395
"BACKGROUND: The hypercortisolaemia and dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis associated with mood disorders have been attributed to a breakdown in the glucocorticoid-receptor-mediated negative feedback mechanism regulating HPA activity. Reinstating normal feedback may be therapeutic in mood disorders. AIMS: To review the evidence for the involvement of the glucocorticoid receptor in the pathogenesis and treatment of mood disorders. METHOD: Medline and hand searches were carried out, selecting literature relevant to psychiatrists and psychopharmacologists. RESULTS: A dysfunction in glucocorticoid receptors is integral to the HPA abnormalities of mood disorders. Antidepressant and mood-stabilising drugs can up-regulate glucocorticoid receptors, restoring glucocorticoid function. Preliminary clinical studies targeting the glucocorticoid receptor are encouraging. CONCLUSIONS: Drugs designed specifically to up-regulate glucocorticoid receptors may be integral to future strategies in treating mood disorders." [Full Text]

Wolkowitz, Owen M., Reus, Victor I.
Treatment of Depression With Antiglucocorticoid Drugs
Psychosom Med 1999 61: 698-711
"OBJECTIVE: The theoretical and empirical rationales for the potential therapeutic use of antiglucocorticoid agents in the treatment of depression are reviewed. METHOD: Individual case reports, case series, open-label, and double-blind, controlled trials of the usage of cortisol-lowering treatments in Cushing's syndrome and major depression are evaluated and critiqued. RESULTS: In each of the 28 reports of antiglucocorticoid treatment of Cushing's syndrome, antidepressant effects were noted in some patients; the largest two series document a response rate of 70% to 73%. Full response, however, was at times erratic and delayed. Across the 11 studies of antiglucocorticoid treatment of major depression, some degree of antidepressant response was noted in 67% to 77% of patients. Antidepressant or antiobsessional effects of antiglucocorticoid augmentation of other psychotropic medications have also been noted in small studies of patients with treatment-resistant depression, obsessive-compulsive disorder, and schizoaffective disorder or schizophrenia. CONCLUSIONS: These promising results with antiglucocorticoid treatment must be interpreted cautiously because of the small sample sizes and heterogeneity of the studies reviewed, the bias favoring publication of positive results, and the open-label nature of most of the studies. Although definitive controlled trials remain to be conducted, there is a consistent body of evidence indicating that cortisol-lowering treatments may be of clinical benefit in select individuals with major depression and other hypercortisolemic conditions." [Full Text]

Lowy MT, Reder AT, Gormley GJ, Meltzer HY.
Comparison of in vivo and in vitro glucocorticoid sensitivity in depression: relationship to the dexamethasone suppression test.
Biol Psychiatry 1988 Oct;24(6):619-30
"The effect of in vivo (1 mg) and in vitro (10(-7)-10(-10) M) dexamethasone administration on mitogen-induced lymphocyte proliferation was examined in drug-free depressed patients, nondepressed psychiatric patients, as well as normal controls, and was related to the results of a standard overnight Dexamethasone Suppression Test (DST). The effect of oral dexamethasone administration was also examined for its effect on lymphocyte cytosolic glucocorticoid receptor content. Oral dexamethasone administration significantly decreased both phytohemagglutinin (PHA) and concanavalin A (Con-A) induced lymphocyte proliferation, as well as glucocorticoid receptor number in suppressors, whereas dexamethasone failed to decrease these responses in nonsuppressors. Nonsuppressors had significantly lower serum dexamethasone levels compared to suppressors at both 8:00 AM and 4:00 PM. However, when differences in serum dexamethasone levels were covaried out, there were still significant differences between suppressors and nonsuppressors on the dexamethasone-induced mitogen changes, but the changes in glucocorticoid receptor content were no longer significant. In vitro incubation of lymphocytes with dexamethasone produced a dose-related decrease in mitogenesis, which was not different between the depressed and nondepressed groups. However, at physiologically relevant concentrations of dexamethasone (10(-9)-10(-10) M), nonsuppressors as compared to suppressors were more resistant to the immunosuppressive effects of in vitro dexamethasone on the Con-A response. The inhibitory effect