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Hypercortisolemia and Depression

From the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.

Address correspondence and reprint requests to Charles B. Nemeroff, MD, PhD, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 101 Woodruff Circle, Suite 4000 WMRB, Atlanta, GA 30322. E-mail: cnemero{at}emory.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION TESTS OF HPA AXIS... STATE-DEPENDENT FINDINGS IN... NOTES REFERENCES

 
Hypercortisolemia and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis are often found in severe forms of depression. The authors review the history of techniques used to assess the functions of the HPA axis, evidence for hypercortisolemia as a state rather than trait component of depression, and treatment implications.

Key Words: depression • hypercortisolemia • cortisol • corticotropin-releasing factor • dexamethasone

Abbreviations: HPA = hypothalamic-pituitary-adrenal; DST = dexamethasone suppression test; ACTH = adrenocorticotropic hormone; NS = nonsuppression; CRF = corticotropin-releasing factor.

	INTRODUCTION

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More than 40 years ago, a significant number of patients with depression were noted to exhibit both hypersecretion of cortisol (1,2) and its metabolites (3). The observation that patients with Cushing’s disease or syndrome often experienced severe depression and anxiety, and the increased production and secretion of glucocorticoids such as cortisol in healthy people exposed to stress, in part contributed to the modern stress-diathesis hypothesis of depression in which excess secretion of cortisol is thought to play a significant pathophysiologic role in the etiology of depression.

A variety of methods are now available to measure the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Concurrent with the development of sensitive measures of HPA axis activity has been an increase in understanding the nature of its alterations in affective disorders.

	TESTS OF HPA AXIS FUNCTION

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One of the first endocrine challenge tests to be studied in psychiatric patients was the dexamethasone suppression test (DST), which was originally designed to aid in the diagnosis of Cushing’s syndrome. Small (1 mg) doses of the synthetic glucocorticoid, dexamethasone, are orally administered at 2300 hours, and plasma cortisol concentrations are measured at 2 or 3 time points on the following day. Dexamethasone acts at the level of the anterior pituitary corticotrophs to reduce the secretion of adrenocorticotropic hormone (ACTH), resulting in a decrease in the synthesis and release of cortisol from the adrenal cortex. Failure to suppress plasma cortisol concentrations after dexamethasone administration suggests impaired feedback regulation and hyperactivity of the HPA axis.

Carroll (4) demonstrated that a large percentage of drug-free patients with depression exhibit failure to suppress secretion of cortisol following administration of dexamethasone, a finding known as dexamethasone nonsuppression, and suggested that DST nonsuppression (NS) was a biological marker for depression (5). Thus, DST-NS status and hypercortisolemia are both common in depression but certainly not universal. In a comprehensive analysis of more than 150 reports, Arana et al. (6) concluded that: 1) DST-NS status was most commonly found in patients with psychotic depression or mixed states, as previously reported by several investigators (7,8); and 2) DST-NS status generally predicted a more severe course of illness. A meta-analytic study conducted by Ribeiro et al. (9) concluded that 1) baseline DST status was not predictive of response to treatment; 2) NS status was associated with poor response to placebo; and 3) identified post-treatment DST-NS as a significant risk factor for relapse and poor outcome as initially reported by Greden et al. (10) with subsequent confirmation by Nemeroff and Evans (11). Additional data from a meta-analysis performed by Nelson and Davis (12) further supported the relationship between hypercortisolemia and psychotic depression as assessed with the DST. The prognostic utility of the DST with respect to suicide remains unclear. Some data suggest that DST-NS is predictive of future completed suicide (13), whereas other data are discordant (14).

The greatest criticism of the DST was its suggested use as a diagnostic test for depression. Indeed, substantial rates of DST-NS were reported in patients with eating disorders and a variety of other Axis I diagnoses (15), calling into question its specificity as a diagnostic test. However, its greatest contribution was to serve as an impetus for subsequent studies exploring the underlying pathophysiology of the HPA axis in depression.

In 1981, the long sought after hypothalamic releasing hormone, corticotropin-releasing factor (CRF), was discovered (16) and this finding greatly accelerated research on the HPA axis, and on stress and depression. Neurons of the paraventricular nuclei of the hypothalamus project to the median eminence where they secrete CRF into the hypophyseal portal system. CRF is then transported to the anterior pituitary and acts on corticotrophs to increase ACTH secretion thereby controlling HPA axis activity (17). CRF is also widely distributed in extrahypothalamic brain areas where it functions, in concert with the hypothalamic CRF system, as a neurotransmitter in coordinating the behavioral, autonomic, endocrine, and immune responses to stress (18).

The availability of synthetic CRF allowed for the development and standardization of the CRF stimulation test. In this test, CRF is administered intravenously at a dose of 1 µg/kg or 100 µg and ACTH and cortisol are measured at 30-minute intervals over a 2- to 3-hour period (19,20). Healthy control subjects respond to CRF infusion with increased secretion of ACTH, whereas depressed patients exhibit a blunted ACTH, but normal cortisol response (21–23). Not surprisingly, the blunted ACTH response to CRF occurs in depressed DST-NS patients but not in depressed patients with normal DST suppression (24).

Holsboer et al. (25,26) developed a more sensitive variant of the CRF stimulation test in which patients are pretreated with oral dexamethasone (1 mg) at 2300 hours and given a 100-µg infusion of CRF on the following day. In this paradigm, depressed patients exhibit enhanced (as opposed to blunted) secretion of ACTH and cortisol compared with normal volunteers. Interestingly, asymptomatic first-degree relatives of depressed patients show abnormalities of this sensitive measure of HPA axis activity (27) that are maintained over time (28) suggesting the presence of a heritable vulnerability to HPA axis dysregulation that may be relevant in the pathophysiology of depression.

Blunting of the ACTH response to exogenous CRF may in part be secondary to down-regulation of pituitary CRF receptors as a result of chronic CRF hypersecretion. Consistent with this hypothesis, depressed patients have repeatedly been found to exhibit elevated CSF CRF concentrations (29). Further, postmortem studies of people who have committed suicide have revealed a decreased density of CRF receptors in the frontal cortex (30), decreased expression of CRF receptor mRNA and increased CRF concentrations in frontal cortex when compared with controls (31), and increased concentrations of CSF CRF (32).

	STATE-DEPENDENT FINDINGS IN DEPRESSION AND IMPLICATIONS FOR TREATMENT

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The etiology of depressive illness is complex. Approximately 30% to 40% of the risk for development of depression is thought to be heritable, with the remaining variability imparted by the environment (33,34). Exposure to stress, particularly during neurobiologically vulnerable periods of development, may be one means whereby the environment influences the development of depression (35). Depressed women with a history of prepubertal sexual abuse exhibit persistently increased HPA axis activity in adulthood as evidenced by a blunted ACTH response to CRF infusion (23), and both hypercortisolemia and increased ACTH secretion in response to a standardized laboratory stressor (36).

Thus, a large body of data has accumulated suggesting that the hyperactivity of the HPA axis in depressed patients (37) is due in part to CRF hypersecretion (18). Considerable data support the hypothesis that the dysregulation of the HPA axis observed in depression is a state, rather than a trait, phenomenon. In this context, state dependence implies the presence of pathobiologic phenomena that are related to a particular phase of illness rather than being constitutively present, i.e., trait-based. In depressed hypercortisolemic patients, plasma cortisol levels (3), DST-NS status (6), blunting of the ACTH response to CRF infusion (38), hypersecretion of CRF (39), and adrenal hypertrophy (40) all normalize following resolution of clinical symptoms.

Successful treatment of depression using either electroconvulsive therapy (39) or fluoxetine (41) has been shown to result in a reduction in the high pretreatment concentrations of cerebrospinal fluid CRF. However, persistently elevated cerebrospinal fluid CRF in symptomatically improved depressed patients is associated with early relapse of depression (42), suggesting that elevated cerebrospinal fluid CRF may be a state marker for depressive vulnerability.

Currently, several novel approaches to the treatment of depression are being evaluated based on the present understanding of HPA axis dysregulation in mood disorders. The CRF-1 receptor antagonist R121919 has shown promise in the treatment of depression (43) but was subsequently withdrawn from clinical trials due to hepatotoxicity. More recently, the glucocorticoid receptor antagonist, mifepristone (RU486), has been reported to be effective in the treatment of psychotic depression (44). These compounds may be effective in treating depression through the interruption of reverberating neuroendocrine loops involving the HPA axis and several areas of the brain (prefrontal cortex, amygdala, hippocampus, and hypothalamus) that become excessively activated in response to stress driven perhaps by hypersecretion of CRF. Such interruption of a positive feedback loop may allow the system to return to a more adaptive set point associated with remission of depression (45).

	NOTES

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In accordance with CME accreditation guidelines, author Charles B. Nemeroff disclosed that he has received research support from, served as a consultant for, and/or served on the speakers’ bureau for Acadia Pharmaceuticals, AFSP, AstraZeneca, Bristol-Myers-Squibb, Corcept, Cyberonics, Cypress Biosciences, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Merck, NARSAD, Neurocrine Biosciences, NIMH, Organon, Otsuka, Pfizer Pharmaceuticals, Sanofi, Somerset, Stanley Foundation/NAMI, Wyeth-Ayerst, and Abbott Laboratories. He is a stockholder in Corcept and Neurocrine Biosciences. He is on the board of directors for American Foundation for Suicide Prevention (AFSP), Cypress Biosciences, George West Mental Health Foundation, Novadel Pharma, and the Heinz C. Prechter Fund for Manic Depression. He is supported by NIH grants MH-42088 MH-52899 and NCRR MOI-RR00039. The other author of this article disclosed no real or potential conflicts of interest.

DOI:10.1097/01.psy.0000163456.22154.d2

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