Glucocorticoid resistance in depression: the dexamethasone suppression test and lymphocyte sensitivity to dexamethasone

Approximately 50% of depressed patients are resistant to the cortisol-suppressing effect of dexamethasone. To determine if glucocorticoid resistance could be a more generalized phenomenon in depressed patients, mitogen stimulation tests were performed on lymphocytes from 12 depressed patients and 12 control subjects before and after dexamethasone administration. Suppression of serum cortisol following administration of 1 mg of dexamethasone in four depressed patients and 11 control subjects was associated with a decreased lymphoproliferative response, but no such change occurred in the eight depressed patients and the single control subject who did not suppress cortisol. The dexamethasone-induced changes in the mitogen responses were positively correlated with the highest postdexamethasone serum cortisol values.     

The low-dose dexamethasone suppression test in fibromyalgia

OBJECTIVE: Fibromyalgia syndrome (FMS) has been associated with decreased cortisol secretion. Patients with posttraumatic stress disorder (PTSD) exhibit similar hypocortisolism in the context of increased negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis. Because trauma and PTSD have been associated with fibromyalgia, we evaluated whether patients with fibromyalgia demonstrate increased HPA feedback sensitivity. METHOD: Baseline blood samples were obtained at 0800 h, and 0.5 mg of dexamethasone was administered to 15 female patients with FMS and 20 normal controls at 2300 h. Adrenocorticotropin (ACTH), cortisol, and dexamethasone levels were measured at 0800 h after dexamethasone intake. RESULTS: There were no group differences in mean ACTH or cortisol levels or in ACTH/cortisol ratio at baseline. After dexamethasone intake, patients with FMS exhibited more pronounced suppression of cortisol but not of ACTH, as well as increased ACTH/cortisol ratios compared with controls. Percent cortisol suppression was associated with pain and fatigue, while ACTH/cortisol ratio and dexamethasone availability were associated with stress and anxiety measures. CONCLUSION: Our results suggest increased sensitivity to glucocorticoid feedback, manifested at the adrenal level, in FMS.     

Glucocorticoid receptors in depression: relationship to the dexamethasone suppression test

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.     

Influences of cortisol on auditory evoked potentials (AEPs) and mood in humans

The present study was designed to investigate effects of cortisol on evoked potential indicators of sensory processing and on mood in 45 healthy human subjects. In order to determine the glucocorticoid effect to be primary excitatory or inhibitory, the vertex potential components. (P1, N1, P2) of the auditory evoked potential (AEP) were assessed, which also indicate a stimulus-induced cortical arousal response mediated by the nonspecific sensory system of the reticular formation. The AEPs were recorded while the subject performed a vigilance task containing 8 blocks of monotonous series of tone pips presented at different interstimulus intervals. Mood was assessed by an extensive adjective checklist. Experiments were held double-blind and designed as between-group comparison. Subjects received either 40 or 20 mg hydrocortisone (constantly infused between 35 min prior to testing till the end of the experiment), or placebo. Enhanced plasma cortisol levels were related to increased amplitudes of the AEP vertex response. Furthermore, cortisol augmented self-reported concentration and reduced tiredness during task performance. The glucocorticoid effects on both AEPs and self-report measures suggest an excitatory influence of cortisol on brainstem and thalamic mechanisms mediating the stimulus-induced cortical arousal.     

Lymphocyte glucocorticoid receptor binding in depressed patients with hypercortisolemia

Despite elevated levels of serum and urinary cortisol, patients with depressive illness manifest none of the clinical stigmata of glucocorticoid excess. This hypercortisolemia in the absence of clinical effects suggests a state of hormone resistance and could be mediated by alterations in the glucocorticoid receptor. Earlier studies have shown that small doses of glucocorticoids cause a decrease in glucocorticoid receptor binding in normal human lymphocytes. White cells from depressed patients with significant hypercortisolemia would be expected to show a similar change in receptor concentration if peripheral tissues are adequately exposed to and sensitive to the hormone. In this study we compared the binding of [³H]dexamethasone to lymphocytes from normal subjects and depressed patients with hypercortisolemia. Lymphocytes from normal subjects had a mean receptor concentration of 10.2 ± 0.66 fm/10⁶ cells (S.E.M.) and a dissociation constant of 4.8 ± 0.47 nM. Lymphocytes from depressed patients with abnormal 0800 h serum cortisol after dexamethasone had a mean receptor concentration of 8.8 ± 0.75 fm/10⁶ cells, which was not significantly different from that in lymphocytes from normal subjects or from depressed subjects with normal post-dexamethasone cortisol levels (9.4 ± 0.95 fm/10⁶ cells). Lymphocytes from depressed patients with elevated urinary free cortisol excretion (UFC) also had normal receptor concentration and binding affinity for dexamethasone. The lack of a change in lymphocyte glucocorticoid receptor concentration in the presence of cortisol excess suggests the possibility that hypercortisolemia in depressive illness represents a state of peripheral glucocorticoid resistance.     

Cortisol production during high dose dexamethasone therapy in neurological and neurosurgical patients.

Simultaneous plasma dexamethasone and cortisol levels were followed at intervals over 8 hour periods on 40 occasions in 19 subjects who received regular high dosage dexamethasone therapy (rarely less than 12 mg a day) for various neurological and neurosurgical conditions. Lower dexamethasone doses (for example 2 mg daily for 2 days) normally suppress adrenal cortical production of cortisol to below 50 micrograms/l for at least 8 hours. However, in 12 of the 35 studies that did not take place at the first steroid dose or in subjects taking second daily bolus steroid dosage such suppression was not present 8 to 12 hours after dexamethasone intake, though it was shown that dexamethasone could suppress cortisol production in all these cases. Failure of maintained suppression despite the high steroid dose appeared to be related to rapid elimination of dexamethasone. These findings may help explain the relative rarity of adrenal failure in clinical neurological practice after high dosage steroid therapy is ceased.     

The ACTH response to dexamethasone in PTSD

OBJECTIVE: Enhanced negative feedback and reduced adrenal output are two different models that have been put forth to explain the paradoxical observations of increased release of corticotropin-releasing factor in the face of low cortisol levels in posttraumatic stress disorder (PTSD). To discriminate between these models, the authors measured levels of adrenocorticopic hormone (ACTH) and cortisol at baseline and in response to dexamethasone in medically healthy subjects with and without PTSD. Under conditions of enhanced negative feedback inhibition, ACTH levels would not be altered relative to cortisol levels, but the ACTH response to dexamethasone would be augmented, in concert with the enhanced cortisol response to dexamethasone. In contrast, under conditions of reduced adrenal output, ACTH levels would be expected to be higher at baseline relative to cortisol levels, but the ACTH response to dexamethasone would be unchanged in PTSD relative to healthy comparison subjects. METHOD: The ACTH and cortisol responses to 0.50 mg of dexamethasone were assessed in 19 subjects (15 men and four women) with PTSD and 19 subjects (14 men and five women) without psychiatric disorder. RESULTS: The ACTH-to-cortisol ratio did not differ between groups before or after dexamethasone, but the subjects with PTSD showed greater suppression of ACTH (as well as cortisol) in response to dexamethasone. CONCLUSIONS: The data support the hypothesis of enhanced cortisol negative feedback inhibition of ACTH secretion at the level of the pituitary in PTSD. Pituitary glucocorticoid receptor binding, rather than low adrenal output, is implicated as a likely mechanism for this effect.     

The dexamethasone suppression test in normal control subjects: comparison of two assays and effect of age

he authors used competitive protein binding assay and radioimmunoassay to measure cortisol levels in 38 normal control subjects three times before and three times after administration of 1 mg of dexamethasone. They found significant interassay differences at 11:00 p.m. before dexamethasone and at all three postdexamethasone times. Analysis of variance revealed significant overall positive relationships between age and cortisol levels measured by both techniques. Age correlated significantly with postdexamethasone cortisol levels measured by radioimmunoassay but not when measured by competitive protein binding assay. Clinicians should obtain data from their laboratories as to appropriate cutoffs for cortisol suppression on the specific assay used.     

Differential effects to CCK-4-induced panic by dexamethasone and hydrocortisone

Abstract Objectives. Peripheral administration of the cholecystokinin (CCK) receptor agonist CCK-4 generates panic and activates the hypothalamic-pituitary-adrenal (HPA) axis. Direct effects at the pituitary and CCK-HPA interactions at higher regulatory sites have been suggested. According to preliminary data, ACTH response to CCK receptor agonists may differ from its response to exogenous CRH by its resistance to cortisol feedback inhibition. To further explore this resistance and to better characterize CCK-4 sites of action, the effects of different glucocorticoid pretreatments on CCK-4-induced panic were compared. Methods. Using a double-blind placebo-controlled design we pretreated healthy males with either dexamethasone (peripheral action) or hydrocortisone (central-peripheral action) each followed by a CCK-4 challenge. Blood levels of ACTH and cortisol were analyzed and panic symptoms were assessed. Results. We found a blunted response of ACTH release following CCK-4 injection only after hydrocortisone pretreatment. Dexamethasone however did not affect CCK-4-induced ACTH release relative to baseline. In contrast to dexamethasone, hydrocortisone reduced the severity of CCK-4-induced panic as measured by the Acute Panic Inventory on a trend level. Conclusions. Findings suggest that CCK-4-induced stress hormone release seems susceptible to cortisol-feedback inhibition and argues for a suprapituitary site of CCK action. Effects on panic anxiety were weak but congruent with studies showing that CCK-4-induced HPA axis inhibition is accompanied by a reduction of anxiety after CCK-4.     

Effects of glucocorticoids on declarative memory function in major depression.

BACKGROUND: Major depression has been associated with hypercortisolemia in a subset of patients with depression. Administration of exogenous cortisol and other glucocorticoids to healthy human subjects has been observed to result in a transient impairment in verbal declarative memory function. The purpose of this study was to assess the effects of the glucocorticoid, dexamethasone, on verbal declarative memory function in patients with untreated unipolar major depressive disorder (MDD). METHODS: Fifty two men and women with (n = 28) and without (n = 24) MDD received placebo or dexamethasone (1 mg and 2 mg on 2 successive days) in a double-blind, randomized fashion. Declarative memory was assessed with paragraph recall at baseline (day 1) and day 3. RESULTS: There was a significant interaction between diagnosis and drug (dexamethasone vs. placebo) on paragraph recall. In the healthy subjects, memory improved from baseline to day 3 with placebo and was unchanged with dexamethasone, whereas in MDD patients memory function showed a pattern of decreasing with placebo and improving with dexamethasone from baseline to day 3. CONCLUSIONS: These findings are consistent with an altered sensitivity of declarative memory function in MDD to regulation by glucocorticoids. Possible explanations of the findings include alterations in glucocorticoid receptors in the hippocampus or other brain regions mediating declarative memory, or differential sensitivity to dexamethasone-induced reductions in cortisol, in patients with MDD.     

Prediction of the DST results in depressives by means of urinary-free cortisol excretion, dexamethasone levels, and age

This study investigates the relationships between cortisol escape from suppression by dexamethasone during a depressive episode, and the baseline activity of the hypothalamic-pituitary-adrenal (HPA) axis, circulating dexamethasone levels, and age. To this end, we measured urinary-free cortisol (UFC) excretion in 24-hr urine samples and the 8 AM cortisol and dexamethasone levels after administration of 1 mg dexamethasone in 50 depressive patients. We found that up to 54% of the variance in the postdexamethasone cortisol values could be explained by the multiple regression on UFC, age, and dexamethasone levels. By utilizing these three parameters, the dexamethasone suppression test (DST) nonsuppressor/suppressor state was correctly identified in 92% of the subjects. It was shown that an important part of the variance in postdexamethasone cortisol is actually background variance, irrelevant to depression and produced by the cumulative effects of the three aforementioned parameters. Only a small part (less than 20%) of the variance in postdexamethasone cortisol is determined by the actual depressive state. It was concluded that (1) baseline hypersecretion of cortisol, (2) decrements in the bioavailability of the test substance, (3) increasing age, and (4) the depressive state per se--all of which are cumulative--contribute independently to cortisol escape from suppression by 1 mg dexamethasone.     

Pituitary-adrenal axis rhythm disturbances in psychiatric depression

We studied disturbances in the circadian pattern of plasma corticotropin and cortisol concentrations in 25 depressed patients (eight dexamethasone suppression test [DST] nonsuppressors and 17 suppressors) and 21 normal control subjects. Blood samples were drawn every 20 minutes for 24 hours before the administration of dexamethasone, and for a second 24 hours after the administration of 1 mg of dexamethasone. The corticotropin and cortisol level rhythms were examined using three different statistical methods. Nonsuppressors averaged greater elevations in plasma cortisol and corticotropin levels than did subjects in the other two groups, both before and after administration of the dexamethasone. The cortisol levels of the suppressors were virtually identical to those of the control subjects. However, the suppressors had significant elevations of corticotropin levels compared with normal control subjects, especially on the day before taking dexamethasone. Before taking dexamethasone, the depressed patients reached a daily nadir of cortisol concentration approximately two hours earlier than did the normal control subjects. The DST nonsuppressors also exhibited a blunting in the expected circadian rhythm of the corticotropin level.     

Effects of short-term stress-like cortisol on cerebral metabolism: A proton magnetic resonance spectroscopy study at 3.0 T

Preclinical and clinical studies suggest that glucocorticoids disturb cognitive performance and neuronal integrity. MR spectroscopy studies have tried to track these effects and correlate long-term effects of glucocorticoids with concentration changes of cerebral metabolites. However, a systematic spectroscopic study on short-term exposure to corticosteroids, in a dosage sufficient to impair memory performance, is lacking. Thus, it is not known when glucocorticoid effects become visible at 1H-MRS in vivo.Therefore, employing localized 1H-MRS at 3 T we quantitatively investigated the effects of a 4-day cortisol exposure (160 mg/d) on brain metabolites in vivo in a double blind and placebo-controlled cross-over study of 21 healthy subjects. Spectroscopic measurements were performed in four different brain regions, including the posterior cingulate gyrus, right frontal white matter, left and right anterior hippocampus using the PRESS method. Our results show, after 4 days of cortisol intake and despite a nearly 3-fold increase in serum cortisol concentration, for none of the investigated metabolites a significant corticosteroid-induced concentration change. Our results show that contrary to reported long-term effects, short-term hydrocortisone exposure at a stress-like dosage does not lead to changes of prominent cerebral metabolites, including N-acetylaspartate, creatine and phosphocreatine, choline-containing metabolites, myo-inositol and glutamate.     

The modulatory effects of corticosteroids on cognition: studies in young human populations

In the present article, we report on two studies performed in young human populations which tested the cognitive impact of glucocorticoids (GC) in situations of decreased or increased ratio of mineralocorticoid (MR) and glucocorticoid (GR) receptor occupation. In the first study, we used a hormone replacement protocol in which we pharmacologically decreased cortisol levels by administration of metyrapone and then restored baseline cortisol levels by a subsequent hydrocortisone replacement treatment. Memory function was tested after each pharmacological manipulation. We observed that metyrapone treatment significantly impaired delayed recall, while hydrocortisone replacement restored performance at placebo level. In the second study, we took advantage of the circadian variation of circulating levels in cortisol and tested the impact of a bolus injection of 35 mg of hydrocortisone in the late afternoon, at a time of very low cortisol concentrations. In a previous study with young normal controls, we injected a similar dose of hydrocortisone in the morning, at the time of the circadian peak, and reported detrimental effects of GC on cognitive function. Here, when we injected a similar dose of hydrocortisone in the afternoon, at the time of the circadian trough, we observed positive effects of GC on memory function. The results of these two studies provide evidence that GC are necessary for learning and memory in human populations.     

Differential effects to CCK-4-induced panic by dexamethasone and hydrocortisone

Abstract

Objectives. Peripheral administration of the cholecystokinin (CCK) receptor agonist CCK-4 generates panic and activates the hypothalamic–pituitary–adrenal (HPA) axis. Direct effects at the pituitary and CCK-HPA interactions at higher regulatory sites have been suggested. According to preliminary data, ACTH response to CCK receptor agonists may differ from its response to exogenous CRH by its resistance to cortisol feedback inhibition. To further explore this resistance and to better characterize CCK-4 sites of action, the effects of different glucocorticoid pretreatments on CCK-4-induced panic were compared. Methods. Using a double-blind placebo-controlled design we pretreated healthy males with either dexamethasone (peripheral action) or hydrocortisone (central-peripheral action) each followed by a CCK-4 challenge. Blood levels of ACTH and cortisol were analyzed and panic symptoms were assessed. Results. We found a blunted response of ACTH release following CCK-4 injection only after hydrocortisone pretreatment. Dexamethasone however did not affect CCK-4-induced ACTH release relative to baseline. In contrast to dexamethasone, hydrocortisone reduced the severity of CCK-4-induced panic as measured by the Acute Panic Inventory on a trend level. Conclusions. Findings suggest that CCK-4-induced stress hormone release seems susceptible to cortisol-feedback inhibition and argues for a suprapituitary site of CCK action. Effects on panic anxiety were weak but congruent with studies showing that CCK-4-induced HPA axis inhibition is accompanied by a reduction of anxiety after CCK-4.     

Incidence of hypercortisolism and dexamethasone resistance increases with age among wild baboons.

While many features of the adrenocortical axis are unchanged with age in humans, there is a pattern of senescent hypercortisolism. This occurs basally, following threshold doses of dexamethasone, and in synergy with depression or Alzheimer's disease. An understanding of neuroendocrine aging is important, for both its gerontological implications, and determination of normative values for comparison with neuropsychiatric states. We have investigated whether aging is associated with hypercortisolism in a population of wild primates. The subjects were 108 yellow baboons (Papio cynocephalus) that have been under long-term study of Amboseli National Park in Kenya. Animals were anesthetized by blowgun under similar circumstances that allow for determination of basal cortisol concentrations. Sixty minutes later, 5.0 mg dexamethasone was administered to each animal, and cortisol determinations were made on serum collected immediately before administration and 6 hr later. Basal cortisol concentrations rose with age (p less than 0.028; r = 0.23). This occurred in a nonprogressive manner, in that there were no differences in concentrations among the youngest three quartiles of animals, whereas animals in the oldest quartile (older than approximately 16 years) had significantly higher values. In addition, there was a significant increase in postdexamethasone cortical concentrations with age (p less than 0.01; r = 0.31). This feature emerged progressively with age in both sexes. A number of possible artifactual causes of this senescent pattern could be eliminated, including medication confound, coincident disease, and body weight. These findings suggest that hypercortisolism and glucocorticoid feedback resistance might be general features of primate aging.     

Comparison of in vivo and in vitro glucocorticoid sensitivity in depression: relationship to the dexamethasone suppression test

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 of in vitro dexamethasone on Con-A-stimulated lymphocytes was positively correlated with basal 4:00 PM cortisol values. In conclusion, in vitro techniques are useful probes to assess glucocorticoid sensitivity in depression. The present results also further support the hypothesis that glucocorticoid insensitivity is associated with DST nonsuppression.     

Cortisol, ACTH, and dexamethasone concentrations in a psychogeriatric population

Cortisol and adrenocorticotrophic hormone (ACTH) were measured at 2 time points before the administration of 1 mg of dexamethasone (day 1) and 1 time point on the following day (day 2). Thirteen severely depressed elderly patients, 15 patients with Alzheimer-type dementia (ATD), and 16 normal controls were studied. Cortisol was markedly elevated in depressed patients compared with the other subjects in day 1 samples. Following dexamethasone, both the depressed and ATD patients showed a similar elevation of cortisol compared with controls. ACTH concentrations were not significantly different between the groups before dexamethasone, but were significantly higher in both depressed and ATD patients after dexamethasone. More depressed patients than ATD patients exhibited hypersecretion of ACTH after dexamethasone. This implies that ACTH is less responsive to glucocorticoid feedback in elderly depressed patients, which may be a factor in causing hypercortisolemia.     

Increased saliva cortisol awakening response in patients with mild cognitive impairment

BACKGROUND: It is unknown whether HPA-axis dysfunction is present in patients with mild cognitive impairment (MCI). The aim of the present study was to investigate whether cortisol levels are elevated among patients with MCI and/or whether the individuals have adequate feedback control of their HPA axis. MATERIAL AND METHODS: 27 patients with MCI and 15 healthy controls were included in the study. Saliva samplings were performed 5 times a day before intake of 0.5 mg dexamethasone, and 5 times a day after intake of dexamethasone, respectively. RESULTS: Significantly higher cortisol levels were found 15 min after awakening among patients with MCI in comparison with the controls, both before and after dexamethasone administration (p<0.05). Also, the ratio between cortisol at awakening time and 15 min after awakening was lower in the patient group after dexamethasone administration (p<0.05). There were no significant differences in basal cortisol levels before or after dexamethasone between groups. CONCLUSION: The results indicate that there is an HPA-axis disturbance, with normal basal cortisol levels and increased awakening response among patients with MCI. The dissociation between basal values and the awakening response may be of pathophysiological importance for the cognitive impairment.     

Neuroendocrine aspects of primary endogenous depression. II. Serum dexamethasone concentrations and hypothalamic-pituitary-adrenal cortical activity as determinants of the dexamethasone suppression test response

To determine the contribution of serum dexamethasone concentrations and hypothalamic-pituitary-adrenal cortical activity before dexamethasone administration to the dexamethasone suppression test (DST) response, a series of stepwise discriminant function analyses were performed for 40 patients with definite endogenous depression and 40 matched normal control subjects. The 24-hour serum cortisol concentration before dexamethasone administration and the serum dexamethasone concentrations at 8, 16, and 24 hours after administration served as the independent variables, and the DST "escaper"/"suppressor" dichotomy served as the dependent variable. While both types of independent variables significantly influenced the DST response, the major factor that contributed to the discrimination of escapers from suppressors was the 24-hour cortisol concentration before dexamethasone administration. Sixteen hours after dexamethasone administration, when the DST had the highest positive predictive value, serum dexamethasone concentrations significantly influenced DST outcome only when they were below a certain threshold level. At this time, hypothalamic-pituitary-adrenal cortical hyperactivity before dexamethasone administration accounted for approximately two thirds of the incidence of DST nonsuppression.