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Background: In this study the predictive value of the combined dexamethasone/CRH test (DEX/CRH test) for acute antidepressant response was investigated., Methodology/principal Findings: In 114 depressed inpatients suffering from unipolar or bipolar depression (sample 1) the DEX/CRH test was performed at admission and shortly before discharge. During their stay in the hospital patients received different antidepressant treatment regimens. At admission, the rate of nonsuppression (basal cortisol levels >75.3 nmol/l) was 24.6% and was not related to the later therapeutic response. Moreover, 45 out of 114 (39.5%) patients showed an enhancement of HPA axis function at discharge in spite of clinical improvement. In a second sample, 40 depressed patients were treated either with reboxetine or mirtazapine for 5 weeks. The DEX/CRH test was performed before, after 1 week, and after 5 weeks of pharmacotherapy. Attenuation of HPA axis activity after 1 week was associated with a more pronounced alleviation of depressive symptoms after 5-week mirtazapine treatment, whereas downregulation of HPA system activity after 5 weeks was related to clinical response to reboxetine. However, early improvement of HPA axis dysregulation was not necessarily followed by a beneficial treatment outcome., Conclusions/significance: Taken together, performance of a single DEX/CRH test does not predict the therapeutic response. The best predictor for response seems to be an early attenuation of HPA axis activity within 1 or 2 weeks. However, early improvement of HPA system dysfunction is not a sufficient condition for a favourable response. Since a substantial part of depressive patients display a persistence of HPA axis hyperactivity at discharge, downregulation of HPA system function is not a necessary condition for acute clinical improvement either. Our data underline the importance of HPA axis dysregulation for treatment outcome in major depression, although restoration of HPA system dysfunction seems to be neither a necessary nor a sufficient determinant for acute treatment response.

Data suggest that both neurotrophic and hypothalamic-pituitary-adrenocortical (HPA) systems are involved in the pathophysiology of depression. The aim of the present study was to investigate whether the non-conservative brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has an impact on HPA axis activity in depressed patients. At admission, the dexamethasone/CRH (DEX/CRH) test was performed in 187 drug-free in-patients suffering from major depression or depressed state of bipolar disorder (DSM-IV criteria). Moreover, genotyping of BDNF Val66Met polymorphism was carried out using the fluorescence resonance energy transfer method (FRET). Homozygous carriers of the Met/Met genotype showed a significantly higher HPA axis activity during the DEX/CRH test than patients carrying the Val/Val or Val/Met genotype (ACTH, cortisol). Our results further contribute to the hypothesized association between HPA axis dysregulation and reduced neuroplasticity in depression and are consistent with the assumption that BDNF is a stress-responsive intercellular messenger modifying HPA axis activity.

The combined dexamethasone/corticotropin releasing hormone (Dex/CRH) test is one of the most reliable neuroendocrine function tests for investigation of hypothalamic-pituitary-adrenocortical (HPA) system dysregulation in depression. Persistent high HPA system activity reflected by an enhanced cortisol secretion during the Dex/CRH test after successful antidepressant treatment is correlated with an enhanced risk for relapse in remitted depressives. Thus, the Dex/CRH test might be a useful neuroendocrinological tool for treatment monitoring. However, the performance of the test requiring multiple blood samplings renders this test difficult for routine clinical use. Thus, a simplified test procedure using a saliva based test without the necessity of multiple blood samplings would be desirable.Therefore, we compared matched saliva and serum probes of Dex/CRH tests of 73 depressed patients who underwent a total of 157 tests. Both saliva and serum cortisol concentrations showed a significant stimulation pattern during the test and were highly correlated. This correlation was not influenced by either antidepressive treatment. In patients with high cortisol secretion patterns during the Dex/CRH test there was a decrease in HPA system activity after successful antidepressant treatment that was reflected by both the saliva and the serum Dex/CRH test.Thus, the saliva based combined Dex/CRH test appears to be a suitable tool for monitoring HPA system activity during the course of depressive illness. The easier performance of the saliva Dex/CRH test in comparison to the standard test procedure for both patients and hospital staff opens the door for routine clinical use of the Dex/CRH test for treatment monitoring and estimation of relapse risk.

In the present study we investigated HPA axis activity in depressed patients treated with partial sleep deprivation (PSD) in order to identify endocrinological characteristics related to PSD responsiveness. Thirty-three drug-free patients (14 men, 19 women) suffering from major depression according to DSM-IV criteria were treated with PSD. Response to PSD was defined as a reduction of at least 30% according to the 6-item version of the Hamilton Depression Scale (6-HAMD). Subsequently, the combined dexamethasone-suppression/CRH-stimulation test (DEX/CRH test) was performed. Patients were pretreated with 1.5 mg dexamethasone (DEX) at 23:00 h and challenged with 100 microg corticotropin-releasing hormone (CRH) the following day. Postdexamethasone cortisol concentrations (before CRH administration) served as parameters for the DST status (dexamethasone suppression test). The cortisol stimulation after CRH was used as measurement for the DEX/CRH test status. Of the depressive patients, 54.5% (18 out of 33) responded to PSD. DST suppressors (postdexamethasone cortisol levels < 15 ng/ml) showed a significantly greater reduction in 6-HAMD scores after PSD than DST nonsuppressors. Furthermore, a significant negative correlation between postdexamethasone cortisol levels and reduction in 6-HAMD scores after PSD could be established. However, there was no relationship between the cortisol stimulation following CRH challenge and response to PSD. Although the combined DEX/CRH challenge test is a more sensitive marker for HPA axis dysregulation in depression than the standard DST, the negative feedback of the HPA system reflected by the DST status is apparently more closely associated with response to partial sleep deprivation in major depressive disorder.

This follow-up study investigated lymphocyte blastogenesis induced by concanavalin A, phytohemagglutinin A, and pokeweed mitogen and their sensitivity to in vitro dexamethasone administration in 12 patients clinically recovered from severe major depression. Although cortisol-levels at 4.00 p.m. decreased significantly after clinical remission, mitogen-driven lymphocyte proliferative responses were unchanged when assessed intra-individually. No impairment of in vitro glucocorticoid-sensitivity of lectin-induced lymphocyte blastogenesis could be observed in clinically recovered patients. The inhibitory potency of in vitro dexamethasone was found to be inversely correlated with in vivo adrenal cortical hormone levels. There were no correlations with age, weight, sex, antidepressant medication, severity or duration of depression. No differences from age- and sex-matched healthy individuals were found. These results indicate that reduced glucocorticoid receptor sensitivity occurs only during the acute depressive illness.

The mitogen-induced lymphocyte proliferative response and its sensitivity to in vitro (10(-10)-10(-6) M) dexamethasone (DEX) administration were investigated in 12 severely depressed patients and 13 healthy controls. Patients with major depressive disorder exhibited no impairment of lectin-induced blastogenesis, but a significantly weaker suppressive effect of in vitro DEX on 1.0 microgram/ml phytohemagglutinin A-induced proliferation. The inhibitory potency of in vitro DEX was inversely correlated with in vivo adrenal cortical hormone levels at 4.00 p.m. These effects were not observed with pokeweed mitogen- and concanavalin A-stimulated cells. There were no correlations with age, weight, sex or severity of depression. These results do not support the hypothesis of a primarily impaired cell-mediated immunity, but might be indicative of reduced glucocorticoid receptor sensitivity in major depressive disorder.

We studied glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressed patients and controls, attempting to control for the confounding effect of endogenous glucocorticoids. After depletion of endogenous cortisol, depressed patients showed an attenuated suppressibility of corticotropin by dexamethasone in the face of unchanged dexamethasone plasma levels. Beta-endorphin levels were strongly correlated with adrenocorticotropic hormone (ACTH) concentrations. Although metyrapone administration resulted in a marked rise of glucocorticoid receptor sites per cell in controls, this effect was not present in depressives. These data support the hypothesis of a decreased glucocorticoid receptor plasticity and a partial steroid resistance in depression.

Although minor disturbances of the circadian serum cortisol rhythm and diminished excretion of steroid metabolites have been reported in patients with atopic dermatitis, test assays regarding subtle neuroendocrine alterations have not been employed so far. We therefore studied the serum concentrations of cortisol, prolactin and adrenocorticotropin under baseline conditions, after 1 mg dexamethasone and after a defined methylprednisolone treatment in 15 patients with atopic dermatitis, in comparison with 10 healthy controls. The assessment of the hormones revealed no remarkable differences between either group at any of the blood sampling time points. However, in 3 patients and 2 control subjects, though exhibiting no concomitant disease, we could find no suppression of endogenous cortisol to below 5 micrograms/dl after oral intake of 1 mg dexamethasone. These cortisol non-suppressors showed lower dexamethasone serum concentrations in the morning after its administration, as compared with the suppressors. Acute (1 mg dexamethasone) or prolonged (40 mg methylprednisolone over 6 days) intake of glucocorticoids suppressed prolactin levels in both groups, demonstrating that the effect of glucocorticoids on the hormone system is not restricted to the hypothalamic-pituitary-adrenal axis. Our results indicate an intact feedback response of this hormonal axis to 1 mg dexamethasone and the ability of long-term as well as acute glucocorticoid administration to influence the prolactin secretion in patients with atopic dermatitis.

Twelve severely depressed patients and 13 healthy controls were studied under baseline, metyrapone and metyrapone plus dexamethasone pretreated conditions. Lymphocyte proliferation data were obtained by concanavalin A, phytohaemagglutinin and pokeweed mitogen (PWM) stimulation. There was a decrease in PWM-induced B-cell proliferation and an increase in inhibition of spontaneous leucocyte proliferation by dexamethasone added in vitro following metyrapone administration in vivo, in healthy controls, which was not present in the depressed patients. These data support the concept of a decreased functional plasticity of the glucocorticoid receptor in depression also at the cellular level.

There is evidence that glucocorticoids may have a bimodal effect on growth hormone release in vitro and in vivo. To explore the influence of a single low dose administration of dexamethasone on the hypothalamic-pituitary-somatotropic system, 11 male healthy subjects received 50 micrograms synthetic human GHRH-44 amide as an i.v. bolus dose with and without pretreatment with orally administered 1 mg dexamethasone 9 hours prior to GHRH stimulation. Dexamethasone preparation did affect neither baseline levels of GH and IGF-I nor GHRH induced GH secretory patterns assessed by delta max and by the net area under the response curves. These results add to previous reports that corticosteroids may have different effects on GH secretory dynamics dependent on dose and duration of application.

Pre- and postdexamethasone triiodothyronine (T3), thyroxine (T4), and TSH levels of thirteen patients with psychogenic sexual dysfunction and thirteen controls were studied. Patients showed lowered T4 levels in comparison with the control group whereas T3 and TSH levels did not differ significantly. Dexamethasone had a suppressive effect on TSH in patients and in controls while T3 levels were suppressed in the control group only. Patients scored significantly higher on the Hamilton Depression Scale than controls. These results compared with results obtained in patients recovered from major depression might point to endocrinological as well as clinical interrelations between psychogenic sexual dysfunction and minor depression.

A study on 50 patients with endogenous and non-endogenous depression yielded a sensitivity of 64% and a specificity of 77% for the dexamethasone suppression test (DST). Endogenous depressive patients recovering from depression within one week mostly showed sufficient cortisol suppression. "Loss of feelings" was associated more frequently with cortisol nonsuppression, while a certain relationship between psychogenic induction of the present depressive episode and adequate suppression could be demonstrated. In conclusion, the diagnostic utility of the DST is of minor importance. However, in certain cases the DST could be recommended as a predictor of clinical course.

Psychoneuroendocrinology is of major importance in the biological research of depression. Most studies have focussed on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis but other endocrine systems such as the hypothalamic-pituitary-thyroid (HPT), hypothalamic-pituitary-somatotropic (HPS), and the hypothalamic-pituitary-gonadal (HPG) axis have also been shown to be involved in the psychobiology of depression. There are close interrelations between various endocrine axes which possibly are affected during depressive illness. A variety of neuroendocrine abnormalities has been detected in depressive disorder but the pathophysiology of these derangements remains still unclear. Although the currently used neuroendocrine tests are not of diagnostic validity they may help to clarify the pathophysiological significance of the complex regulatory mechanisms of different neuroendocrine axes in affective disorders. Neuroendocrine regulation is determined both by peripheral and central mechanisms which both have to be adequately considered as well as potent interactions between various endocrine systems in further neuroendocrine depression research.

In view of recent investigations concerning alterations of thyroid function in depression, the pre- and postdexamethasone levels of T3, T4, and TSH of 14 patients during depression and after recovery were studied, in addition to those of 27 healthy controls. A reduction of T3 and TSH levels was shown to be dependent on the depressive state, with a tendency to lower T4 levels after recovery. Dexamethasone had a pronounced suppressive effect on TSH levels in healthy controls and in patients after recovery, but not during the depressive episode. These results point to an inadequate suppressibility of the hypothalamo-pituitary-thyroid (HPT) axis to dexamethasone during depression. There are close interrelations between the hypothalamo-pituitary-adrenal (HPA) and the HPT axes that are possibly affected during depressive illness.

Pre- and post-dexamethasone prolactin and cortisol levels of 40 endogenous and non-endogenous depressive patients and of 20 controls were studied. Dexamethasone had a suppressive effect on prolactin levels, which was expressed more in normal controls and in non-endogenous depressive patients than in endogenous depression. A "prolactin suppression test" by dexamethasone was constructed and provided comparable results to the usual DST. However, it failed to be a specific marker for endogenous depression. There are close relationships between various endocrine axes, which might be altered in depression.

The 1 mg dexamethasone suppression test (DST) was performed in 50 depressive inpatients in order to investigate factors which might interfere with its sensitivity and specificity for endogenous depression: improvement within one week after the test, recent admission to a psychiatric ward, and weight loss. Four out of five endogenous depressive patients whose depression improved within one week after the test had normal suppression, thus supporting the assumption that normalization of the DST may precede the improvement in depression. Nonendogenous depressive patients had an accumulation of pathologic test results on the day after admission that may be due to "admission stress". However, in endogenous depressives this effect was not observed. An influence of weight loss on the percentage of suppressors and nonsuppressors was not demonstrable. It is concluded that in the evaluation of DST results time parameters should be considered to a greater degree.

In order to evaluate the possible effect of glucocorticoids as neuromodulators of the hypothalamic-pituitary-somatotropic system in depression, cortisol, growth hormone (GH), and insulin-like growth factor I (IGF-I) concentrations were studied before and after oral administration of 1 mg dexamethasone at 11 p.m. in 16 patients during depression and after recovery and in 28 healthy controls. While there were no significant differences in GH and IGF-I levels between depressed, recovered and control subjects, GH and IGF-I concentrations of cortisol non-suppressors were significantly elevated compared to suppressors. Moreover, post-dexamethasone cortisol, GH, and IGF-I levels were positively correlated. Dexamethasone had a stimulating effect on GH and IGF-I values in patients during depression and in cortisol non-suppressors only; this effect was absent in recovered and in control subjects and in cortisol suppressors. Thus, hypercortisolemia may be of great importance for the dysregulation of the hypothalamic-pituitary-somatotropic system reported in depression.

To explore corticosteroid-catecholamine interactions in depression, plasma dopamine, norepinephrine, and epinephrine concentrations were studied both before and after dexamethasone in 16 patients during depression and after recovery, and in 28 healthy controls. Dexamethasone had a significant suppressive effect on plasma epinephrine levels in depressed patients and controls, while dopamine and norepinephrine levels were not significantly affected following dexamethasone administration. Levels of norepinephrine, epinephrine, and cortisol were positively correlated, while dopamine showed no correlation with cortisol values. These findings point to differentiated interrelations between certain catecholamines and glucocorticoids which possibly are affected during depressive illness.

Numerous investigations have reported an alteration of hormonal response to dexamethasone in depressive disorder. No such data are available in psychogenic sexual dysfunction. Pre- and postdexamethasone levels of testosterone, estradiol, LH and FSH were studied in 20 male patients with sexual dysfunction and 20 male healthy controls. Dexamethasone had no influence on testosterone, estradiol, LH and FSH in normal controls. The patients showed an increase in testosterone and LH but not in FSH levels in the morning after dexamethasone administration. When compared with basal levels, the increase in postdexamethasone levels in sexual dysfunction was significant for testosterone (delta T) but not for LH (delta LH). The altered gonadal steroid and gonadotropin response to dexamethasone in sexual dysfunction might be due to disturbances of dexamethasone metabolism and glucocorticoid receptor density comparable to similar findings in depressive disorder.