Combined dexamethasone suppression–corticotrophin-releasing hormone stimulation test in medication-free major depression and healthy volunteers

Background

The hypothalamic–pituitary–adrenal (HPA) axis is dysfunctional in a subgroup of mood disorders.

Methods

We compared cortisol and adrenocorticotropic hormone (ACTH) responses in major depression and healthy volunteers to the combined dexamethasone suppression–corticotrophin-releasing hormone stimulation (DEX–CRH) test. Unlike other published studies, the study patients were medication-free and the healthy volunteers did not have first-degree relatives with a mood or psychotic disorder. Demographics, DSM-IV diagnoses and other clinical parameters were evaluated in major depressive disorder (MDD) and healthy control groups. Participants received an oral dose of 1.5 mg dexamethasone at 11 pm the day before CRH administration. On the following day, at 3 pm, 100 µg of ovine CRH was infused. Blood samples for determination of cortisol and ACTH were collected every 15 min from 3 pm to 4:15 pm. Cortisol and ACTH responses were calculated as areas under the curve.

Results

Controlling for age, baseline (i.e., post-dexamethasone) ACTH levels were higher in depressed patients compared to controls (p=0.01). There was a trend for higher ACTH responses in depressed patients compared to the control group (p=0.08). In depressed patients, cortisol and ACTH responses correlated positively with age, duration of illness and number of hospitalizations.

Limitations

Because of the cross-sectional study design we can only evaluate the nature of potential HPA axis disturbances that were present in patients when they are acutely depressed.

Conclusions

Feedback inhibition of ACTH secretion by cortisol is compromised in MDD, and this is independent of an age effect on the HPA axis function.     

Effects of glucocorticoids on the regulation of the hypothalamic-pituitary-somatotropic system in depression

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.     

The interrelationship of beta endorphin, ACTH and cortisol in depressive illness: a controlled study

Plasma cortisol, ACTH and beta endorphin were measured before and after dexamethasone in 8 severely depressed patients and 8 age- and sex-matched controls to examine the relationship of ACTH and endogenous opioids to cortisol in depression. Despite having significantly higher plasma levels of cortisol than the controls, the depressed patients did not have correspondingly elevated plasma levels of ACTH. Beta-endorphin levels were also similar in the two groups. All three hormones suppressed to some degree after dexamethasone, but cortisol suppressed less in patients than controls. Our findings suggest that in severe depressive illness abnormalities exist in the hypothalamic-pituitary-adrenal axis peripherally as well as centrally.     

Seasonal variations of the dexamethasone suppression test in depression compared with schizophrenia: a gender effect.

The circannual results of the dexamethasone suppression test (DST) were compared in depressed and schizophrenic patients for the periods November-February and March-October. During the winter months, female depressive and schizophrenic patients had lower rates of DST nonsuppression as well as lower concentrations of post-dexamethasone plasma cortisol, compared to the March-October period, despite similar pre-dexamethasone cortisol levels. Male depressed patients had lower pre-dexamethasone cortisol levels during the winter months while male schizophrenics had higher pre- and post-dexamethasone cortisol levels and higher rates of DST nonsuppression. This may suggest less disturbance of HPA axis function in winter months in depressed patients, mostly females, and confirms findings from some previous studies. A gender effect of DST seasonality was also demonstrated, with male schizophrenic patients presenting a reverse DST nonsuppression pattern compared with female depressive and female schizophrenic patients.     

Tritiated imipramine binding sites in affective disorders and schizophrenia. Influence of circannual variation

We have investigated platelet [3H]imipramine binding in normal controls and patients with primary endogenous depression (unipolar and bipolar) or schizophrenia. Absolute Bmax values did not differ between subgroups. However, when circannual variation of binding was taken into account by expressing results as percentages of normalised values derived from the multiple linear regression of Bmax values as a function of time of sampling, schizophrenic patients were found to have higher Bmax than normal controls. There was no significant difference between depressed patients and controls, nor between patients exhibiting plasma cortisol suppression and non-suppression after the dexamethasone suppression test. A significant negative correlation was found between relative Bmax values and cerebrospinal 5-HIAA levels in depressed patients.     

Suppressive effects of dexamethasone on hypothalamic-pituitary-thyroid axis function in depressed patients

This study investigated the effects of dexamethasone (1 mg orally) on the function of the hypothalamic-pituitary-thyroid (HPT) axis. We determined pre- and post-dexamethasone thyroid-secreting hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), reverse T3 and cortisol levels in 61 depressed inpatients. Dexamethasone had a pronounced suppressive effect on basal TSH and FT3 levels. It had a significant stimulating effect on rT3 levels. No differences were found between melancholic and minor depressives in the effects of dexamethasone on basal TSH, FT3 and rT3. Cortisol non-suppressors were characterized by less suppression of basal TSH values.     

The relationship between age and post-dexamethasone cortisol: A test of three hypotheses

Previous studies report that DST nonsuppressors are older than normal suppressors. Data are presented on 188 primary unipolar major depressive inpatients and 35 healthy controls. In males, age appeared to correlate positively with post-dexamethasone cortisols in depressed patients and normal controls, although mean levels were higher in depressives. Female controls showed no consistent relationship between age and post-dexamethasone cortisol. A positive relationship did exist for depressed women. However, the association disappeared when age-of-onset was entered into the model, suggesting that in females early onset may identify a subtype of depression with normal DST suppression.     

Endocrine changes and clinical profiles in depression: I. The dexamethasone suppression test

Hypothalamic-pituitary-adrenal axis function was investigated in 72 patients with primary depression. Forty-four per cent of the patients demonstrated abnormal suppression of their cortisol levels after a 1 mg overnight dexamethasone suppression test. Patients with abnormal suppression ('non-suppressors') were not clearly distinguished from 'suppressors' by the commonly used diagnostic classifications. They did not appear to be more severely depressed, but they were more likely than the 'suppressors' to be in-patients. Multivariate analysis of the data suggested that two clinical features were independently associated with non-suppression: the PSE syndromes of Slowness and General Anxiety. However, the association of these syndromes with non-suppression was relatively weak, indicating that the clinical significance of the dexamethasone suppression test is, as yet, unclear. The results raise doubts about the validity of using the dexamethasone suppression test as a diagnostic marker for a specific depressive syndrome.     

Rhythm-related changes in pituitary-adrenal function in depression

We measured plasma ACTH and cortisol at 20-min intervals for 24 h in depressed patients and healthy control subjects. The data were analyzed by the PULSAR program to quantitate the number of hormone pulses, their amplitude, length, maximum and interval. We found that in both healthy and depressed subjects the circadian pattern of pituitary-adrenal activity is the result of significant time-related changes in pulse amplitude with no change in pulse frequency. Depressed patients who had an abnormal response to dexamethasone also had changes in pituitary-adrenal rhythm in the unmedicated state. These included ACTH and cortisol pulses whose amplitude, maximum and duration were greater than in the controls as well as a phase advance in the cortisol circadian rhythm. Some of those features were shared by patients who responded normally to dexamethasone suggesting that rhythm-related indices of pituitary-adrenal function may be a more sensitive index of disturbed pituitary adrenal regulation than the Dexamethasone Suppression Test.     

Hormonal differences between psychotic and non-psychotic melancholic depression

BACKGROUND: The dexamethasone suppression test (DST) is the main hormonal disturbance in psychotic depression compared to non-psychotic depression. However, although there have been many studies of individual hormonal axes in depression, few multi-axial studies have been reported. This study aims to examine hormonal differences between these groups of patients through three functional hormonal tests: DST, thyroid stimulating hormone response to thyroid releasing hormone (TSH-TRF) and growth hormone response to growth hormone releasing factor (GH-GRF). METHODS: Forty inpatients meeting DSM-III-R criteria for major depressive episode with melancholia (21 non-psychotic and 19 psychotic) were studied. Dexamethasone suppression test, TSH-TRF and GH-GRF tests were undertaken for all patients. RESULTS: In the whole melancholic sample, 80.0% showed disturbances in at least one hormonal axis, 40.0% in two axes and 5.0% in all three axes. Basal and post-dexamethasone cortisol levels were significantly higher in psychotic than in non-psychotic patients. An association between post-dexamethasone cortisol and blunted GH-GRF response was demonstrated in those with psychotic depression. In the whole sample, GH blunting was found in 62.5% of patients, DST non-suppression in 37.5% and TSH blunting in 25.0% (no differences were found between psychotic and non-psychotic patients). LIMITATIONS: Sample was restricted to melancholia and unknown factors may influence hormonal responses to stress. CONCLUSIONS: Hormonal disturbances in depression are more evident when studying several axes, being the HPA and the GH axes the most prominents. Psychotic depression showed more HPA disturbance than non-psychotic depression. Influence of the HPA on the GH axis is discussed.     

Seasonal variation of cortisol plasma levels in depressives

There is some evidence for a seasonal variation of plasma cortisol levels after administration of dexamethasone in depressed subjects. This variation is suspected to be associated with similar season-related changes in pre-dexamethasone cortisol levels. Therefore, cortisol plasma levels in depressed subjects before and after dexamethasone administration were investigated. No seasonal variation was found in pre- or post-dexamethasone cortisol levels.     

Allopregnanolone serum concentrations and diurnal cortisol secretion in women with premenstrual dysphoric disorder

Most prior studies in patients with premenstrual dysphoric disorder (PMDD) indicate a blunted hypothalamus–pituitary–adrenal axis function. However, the relationship between neuroactive progesterone metabolites, such as allopregnanolone, and hypothalamus–pituitary–adrenal (HPA) axis function in PMDD patients is relatively sparsely studied. The primary aims of this study were to assess diurnal variation in circulating cortisol and low-dose dexamethasone suppression in PMDD patients and healthy controls, and the relationship between these two HPA axis indices and allopregnanolone serum concentrations. Twenty-six women with prospectively defined PMDD and 30 healthy controls were recruited. Participants underwent diurnal sampling for cortisol serum concentrations and a low-dose dexamethasone suppression test. In addition, morning allopregnanolone serum concentrations were determined. There was no difference in diurnal secretion of cortisol and degree of dexamethasone suppression of cortisol between PMDD patients and healthy controls. However, PMDD patients with high allopregnanolone levels displayed blunted nocturnal cortisol levels in comparison with healthy controls who had low allopregnanolone serum concentrations. In women with PMDD, diurnal secretion of cortisol may be influenced by allopregnanolone levels of the luteal phase. This finding may be attributed to timing of blood sampling in the late luteal phase as well as the individual level of allopregnanolone but could potentially explain the discrepancies in results between studies examining HPA axis function in women with PMDD.     

Adrenocortical responsiveness to the ACTH stimulation test in depressed patients and healthy volunteers

Adrenocortical activation in depression has been postulated to result from overactivity of limbic system-hypothalamic function. However, some studies suggest the possibility that excessive secretion of cortisol might result, in part, from a heightened adrenocortical responsiveness to ACTH. To further examine this possibility, we utilized both the ACTH stimulation test and the overnight dexamethasone suppression test (DST) in 72 patients with major depression and 37 age- and gender-matched healthy volunteers. The melancholic/DST-nonsuppressor group had larger mean peak cortisol and cumulative cortisol responses (CCR) than any of the other patients groups or healthy controls. However, the differences failed to reach statistical significance as a result of a relatively large cortisol response variability. Nevertheless, the present findings are in general agreement with previous reports suggesting the possibility of an enhanced adrenocortical responsiveness to ACTH.     

The effects of dieting and weight loss upon the stimulation of thyrotropin (TSH) by thyrotropin-releasing hormone (TRH) and suppression of cortisol secretion by dexamethasone in men and women

The effects upon basal hormone levels and neuroendocrine responses of a weight reducing diet allowing 1200 kcal daily were determined in male and female volunteers. Thyrotropin (TSH) responses to thyrotropin-releasing hormone (TRH) were unchanged in men but attenuated in women; this effect was associated with a fall in basal TSH in women, not in men. Rates of non-suppression of cortisol in response to oral dexamethasone (1 mg) were unchanged during dieting although basal morning cortisol levels rose in males and females. The implications for the use of the TRH test and the dexamethasone suppression test (DST) in depressive illness are discussed.     

CSF 5-HIAA and DST non-suppression -independent biomarkers in suicide attempters?

BACKGROUND: Two major biomarkers of suicidal behaviour; low 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) and non-suppression in the dexamethasone suppression test (DST) have evidence for predictive power for suicide in mood disorders. Previous suicide attempt is the most robust clinical risk factor. PURPOSE OF STUDY: To study the interrelationship of suicide risk factors: low CSF 5-HIAA and the DST non-suppression in mood disorder patients with and without an index suicide attempt. METHODS: Fifty-eight hospitalised mood disorder patients (twenty-five with an index suicide attempt), who were not receiving any treatment with antidepressants, underwent lumbar puncture and DST. Plasma cortisol levels were determined from blood samples drawn the following day at 8:00 a.m., 4:00 p.m. and 11:00 p.m. and analysed in relation to CSF 5-HIAA. RESULTS: In the sample as a whole, the serum cortisol level at 4:00 p.m. showed a significant positive correlation to CSF 5-HIAA (r=0.3, p<0.02). In the patients with an index suicide attempt, the serum cortisol at 4.00 p.m. correlated positively with CSF 5-HIAA (r=0.65, p<0.0006), but not in the non-attempters (NS). CONCLUSION: The positive correlation means that low CSF 5-HIAA and DST non-suppression are relatively independent biomarkers of suicide risk in suicide attempters. The interrelation of the two systems seems to be different in suicide attempters compared to depressed inpatients without suicide attempt.     

Adrenocorticotropin hormone, beta-endorphin and cortisol responses to oCRF in melancholic patients.

Several authors have reported attenuated adrenocorticotropin hormone (ACTH) responses to corticotropin releasing factor (CRF) administration in melancholic patients as compared with healthy controls. In order to explore the integrity of the hypothalamic-pituitary-adrenal (HPA)-axis in melancholics, we examined the following parameters in 98 subjects: the ACTH; beta-endorphin; and cortisol responses to ovine CRF (oCRF) (100 micrograms/i.v.); and the postdexamethasone cortisol values. We found significant lower CRF-induced ACTH responses in melancholic patients as opposed to healthy controls and minor depressives, while major depressives occupied an intermediate position. The psychopathological correlates of the blunted CRF-induced ACTH responses were feelings of worthlessness, self-reproach, or excessive guilt. The CRF-stimulated beta-endorphin and cortisol response did not differ between the study samples. Higher baseline plasma cortisol was associated with attenuated CRF-induced ACTH responses, but these effects were not pertinent to melancholia. There were no relationships between the disordered oCRF test results, and postdexamethasone cortisol values, age, body size, sex and severity of illness. The diagnostic power of the oCRF and the dexamethasone suppression test for melancholia is enhanced when both test results are combined.     

Defining the boundaries of atypical depression: evidence from the HPA axis supports course of illness distinctions

BACKGROUND: Treatment outcome and brain laterality differ between early onset (<20 years) chronically (no well-being >2 months) depressed patients with atypical features (early/chronic atypical) and those with either later onset or less chronic illness (late/nonchronic atypical). Because hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been hypothesized to distinguish atypical depression from melancholia, we examined whether HPA measures would also differentiate these two groups of depressed patients with atypical features. METHODS: Three-hour afternoon cortisol levels, stimulation of cortisol by afternoon dextroamphetamine, and suppression of cortisol by dexamethasone were investigated in 85 depressed patients with atypical features. The latter group was divided into early/chronic atypical and late/nonchronic atypical based on chart review of course of illness. RESULTS: Patients with early/chronic atypical had significantly lower mean 3 h afternoon cortisol levels (N=21) and 4:00 p.m. post-dexamethasone cortisol levels (N=20) than did those with late/nonchronic atypical (N=43 with afternoon cortisol; N=26 with post-dexamethasone cortisol). Post-dextroamphetamine cortisol levels were numerically higher in the early/chronic atypical group (N=15 vs. 19), but this failed to reach conventional significance (0.05相似文献   

Hyperendorphinemia in obesity and relationships to affective state

Eight obese patients (exceeding ideal body weight by 50% or more) with no endocrinological or metabolic disorders and 8 healthy, age-matched, normal-weight volunteers were submitted to an overnight short dexamethasone (DXM) suppression test and to a psychological assessment through various psychometric scales. Plasma B-Endorphin (B-EP), B-Lipotropin (B-LPH), ACTH and cortisol concentrations were evaluated in basal conditions, as well as 9 and 17 hours after late night administration of 1 mg DXM in both groups. All hormones were measured by radioimmunoassay, either directly in the plasma (ACTH and cortisol) or after silicic acid extraction and Sephadex G-75 column chromatography (B-LPH and B-EP). In obese patients, plasma B-EP levels in basal conditions were three times higher than in normal weight controls and remained unaltered by DXM suppression. ACTH and B-LPH, in contrast, were within the normal range and were significantly reduced by DXM. In 3 of the 8 patients, plasma cortisol concentrations at 17 hours post-DXM were greater than 50 ng/ml indicating an early escape from the suppression. Psychometric evaluations revealed a prevalence of depressive personality in obese patients. These data indicate an hypersecretion of B-EP in obese patients, which is only partially dependent on hypothalamic control.     

The influences of dexamethasone levels on the predictive value of the DST for unipolar major depression and the relationships between post-dexamethasone cortisol and ACTH levels

To investigate the relationships between dexamethasone (DEX) and post-DEX cortisol and adrenocorticotropic hormone (ACTH) levels, the authors measured DEX at 8.00 a.m. and post-DEX cortisol and ACTH levels at 8.00 a.m. and 4.00 p.m. in 72 depressed patients categorized according to DSM-III. Cortisol non-suppressors exhibited significantly (P = 0.0006) decreased levels of DEX compared to suppressors. DEX levels at 8.00 a.m. explained 21.1% of the variance in the post-DEX cortisol values at 8.00 a.m. and 34.5% of those at 4.00 p.m. DEX levels were not significantly different among minor depressives (300.40, 309.00), major depressives without melancholia (296.X2) or with melancholia and/or psychotic features (296.X3, 296.X4). In the latter the post-DEX cortisol was significantly increased compared to all other depressives and these differences remained significant even after adjusting for the variations in DEX (by means of regression analysis). Also the diagnostic performance of the post-DEX cortisol values for major depression with associated features versus minor depression was not substantially affected when the DEX levels were accounted for. ACTH levels after DEX were shown to correlate significantly (P less than 0.05) and negatively with DEX. Although post-DEX ACTH levels did not differ among the DSM-III diagnostic categories, cortisol non-suppressors averaged significantly (P = 0.0004) higher ACTH levels than suppressors.     

Cortisol measures in primary major depressive disorder with hypersomnia or appetite increase

Morning plasma cortisol response to the 1 mg dexamethasone suppression test along with cortisol levels in blood, cerebrospinal fluid (CSF), and urine were measured in hospitalized male and female patients with primary major depressive disorder who reported hypersomnia (n = 23), or increase in appetite (n = 22). Comparisons were drawn to cortisol levels in patients with primary major depressive disorder who did not report hypersomnia or appetite increase (n = 23) and to normal controls (n = 23), all age- and sex-matched. Depressives with hypersomnia or increased appetite showed higher than normal 24-h urinary free cortisol concentrations. Depressed patients without hypersomnia or appetite increase had in addition to elevated free urinary cortisol concentrations higher than normal morning plasma cortisol levels before and after dexamethasone administration and a higher incidence of cortisol non-suppression after dexamethasone compared to normal subjects. The findings provide preliminary evidence that HPA activation in depression is diminished in the presence of hypersomnia and/or an increased appetite. Studies of the hypothalamic-pituitary-adrenal axis may be useful for differentiating subtypes of depression characterized by hypersomnia or enhanced appetite.