Delta sleep-inducing peptide response to human corticotropin-releasing hormone (CRH) in major depressive disorder. Comparison with CRH-induced corticotropin and cortisol secretion

Twenty-four subjects (12 patients with major depressive disorder and 12 controls matched for sex and age) received 100 micrograms synthetic human corticotropin-releasing hormone (hCRH) as an iv bolus dose. Healthy subjects exhibited a slight, but sustained, increase of plasma delta sleep-inducing peptide (DSIP) concentrations, whereas a marked reduction of DSIP levels was found in depressives. Compared to controls, depressed patients showed a significant attenuation of corticotropin (ACTH) responses, whereas cortisol secretion in response to hCRH was normal. Basal DSIP and cortisol concentrations were highly correlated and were higher in depressives than in controls. Both were negatively correlated with the DSIP responses to hCRH. These findings are compatible with the hypothesis that hypothalamic-pituitary-adrenal (HPA) overactivity in the depressive state is primarily due to central hypersecretion of CRH and support the view of a modulatory function of DSIP in the complex regulatory mechanism of the HPA system and of its pathophysiological significance for aberrant HPA axis function in major depressive disorder.     

Corticotropin and cortisol response to human CRH as a probe for HPA system integrity in major depressive disorder

To explore the integrity of the hypothalamic-pituitary-adrenal (HPA) system in major depressive disorder, 12 patients and normal controls matched for sex, age, and body weight received 100 micrograms synthetic human corticotropin-releasing hormone (hCRH) as an i.v. bolus dose. Compared to controls, depressed patients showed an elevation in baseline cortisol and a significant attenuation of net adrenocorticotropin (ACTH) responses, while cortisol secretion in response to hCRH was normal. These abnormalities in HPA axis function and apparent discordances in the interrelationships of ACTH and cortisol baseline and net stimulation responses between depressed patients and normal controls indicate, at least in part, a derangement of the glucocorticoid-dependent negative feedback circuitry and support the hypothesis that HPA hyperactivity in depression involves neurotransmitter-mediated hypothalamic hypersecretion of CRH.     

Endocrine responses to growth hormone-releasing hormone, thyrotropin-releasing hormone and corticotropin-releasing hormone in depression

To explore and to compare hypothalamic-pituitary-somatotropic (HPS), hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-adrenocortical (HPA) axis function in depression, 30 subjects (15 patients with a major depressive episode and individually matched controls) received 50 micrograms growth hormone-releasing hormone-44 amide at 9:00, 200 micrograms thyrotropin-releasing hormone (TRH) at 9:00 and 100 micrograms human corticotropin-releasing hormone (CRH) at 18:00 on consecutive days as an i.v. bolus dose. Compared with controls, depressed patients showed blunted growth hormone (GH) responses to GHRH, decreased TRH-induced thyrotropin (TSH) release and reduced corticotropin (ACTH) but normal cortisol secretion following CRH. ACTH secretion following CRH and TRH-induced TSH release were positively correlated across depressed patients and controls but no significant correlations between GH responses to GHRH and TRH-induced TSH release or ACTH and cortisol secretion following CRH administration were demonstrated. Our findings suggest that altered HPT and HPA axis function associated with depression are triggered by factors that are at least partly different from those that cause HPS system dysfunction. We conclude that the pathophysiological process resulting in aberrant neuroendocrine secretory dynamics associated with depression may primarily occur at a suprapituitary site, and that HPS, HPT and HPA axis dysfunction may be precipitated by complex central and peripheral regulatory mechanisms involving largely independent factors.     

Hypothalamic-pituitary-adrenal-cortical activity in anorexia nervosa and bulimia

We studied hypothalamic-pituitary-adrenal-cortical (HPA) activity in nine underweight women with anorexia nervosa, 12 women of normal body weight with bulimia, and nine control subjects. The measures of HPA activity were the pattern of plasma cortisol secretion over 24 hr and the responses of plasma cortisol to dexamethasone suppression and to low dose ACTH stimulation. The patients with anorexia nervosa had significantly elevated 24 hr concentrations of plasma cortisol compared to the controls and showed significantly less cortisol suppression following dexamethasone. There was no difference between patients with anorexia nervosa and controls in the rise in plasma cortisol following ACTH. On most measures of HPA activity, the normal weight patients with bulimia were indistinguishable from the controls. These results suggest that HPA activity is normal in most patients of normal body weight with bulimia and that the psychological and behavioral disturbances common to both anorexia nervosa and bulimia are, in the absence of significant weight loss, insufficient to produce major alterations in HPA activity.     

Pituitary and adrenocortical responses to the ovine corticotropin releasing hormone in depressed patients and healthy volunteers

It has been suggested that limbic system-hypothalamic "overdrive" may be the underlying mechanism causing an augmented secretion of corticotropin releasing hormone (CRH), heightened adrenocortical responsiveness to corticotropin (adrenocorticotropic hormone) (ACTH), and alteration in cortisol feedback regulatory mechanisms as demonstrated by the dexamethasone suppression test. We examined pituitary and adrenocortical responses after morning administration of ovine CRH (oCRH) in 26 depressed patients and 11 healthy volunteers. Basal plasma ACTH concentrations were similar in both groups, whereas patients had a significantly diminished cumulative ACTH response after administration of oCRH. In contrast, basal total cortisol concentrations and cumulative cortisol responses to oCRH were similar in depressed patients and controls. Patients with melancholic features demonstrated the most profound ACTH blunting after oCRH, whereas patients separated according to dexamethasone suppression test results had similar ACTH and cortisol responses to oCRH. The present results extend data from prior studies utilizing oCRH in the evening and demonstrate a dysregulation of the functional integrity of the hypothalamic-pituitary-adrenocortical axis in depressive illness after a morning oCRH test at both central and peripheral hypothalamic-pituitary-adrenocortical axis sites.     

Sex differences in the ACTH response to 24H metyrapone in depression

Increased hypothalamic-pituitary-adrenal (HPA) axis activation has been observed in major depression. Increased corticotropin-releasing hormone (CRH) is hypothesized to drive corticotropin (ACTH) secretion leading to increased ACTH and cortisol secretion throughout 24H. Contradicting data exist as to whether the increased drive is present throughout the day or is restricted to the late afternoon and evening. To determine if increased HPA axis activation occurs during a specific circadian phase or is found throughout the 24H, we studied 26 healthy drug-free depressed patients and 26 healthy age- and sex-matched control subjects under metyrapone inhibition of cortisol synthesis for 24H beginning at 4 PM. Blood was drawn every 10 min for 24H and assayed for ACTH and cortisol. Gender differences in response to metyrapone were seen in both patients and controls. Depressed women demonstrated increased ACTH concentrations between 4 PM and 10 PM compared to control women. Maximal ACTH response over time was identical between depressed and control women. Depressed men demonstrated significantly decreased ACTH secretion between 4 and 10 PM as well as decreased maximal ACTH response compared to control men or depressed women. These data support an increased evening CRH drive in depressed women, but overall decreased CRH drive in depressed men.     

Cortisol response to ACTH infusion in depressed patients: comparison with age-, sex-, and weight-matched normal subjects

Adrenal responsiveness to Cosyntropin (synthetic ACTH_1–24) was investigated in five patients with major depression and five individually matched normal subjects. Three hours following suppression of endogenous ACTH secretion with dexamethasone (1 mg orally), the adrenal response to a 10-min infusion of Cosyntropin (0.05 μg/kg body weight) was monitored for hr by plasma cortisol measured at 15-min intervals. The depressed patients had significantly higher baseline plasma cortisol, but not higher baseline ACTH, than the controls. During the 3-hr post-dexamethasone (and prior to Cosyntropin infusion), the depressed patients maintained significantly higher cortisol secretion, but not higher ACTH secretion, than the controls. After Cosyntropin infusion, there were no differences in ACTH and cortisol increases between the two groups. These findings stand in contrast to previous reports of enhanced adrenal responsiveness to the administration of much larger amounts of Cosyntropin in major depression.     

Blunting of ACTH response to human CRH in depressed patients is avoided by metyrapone pretreatment

The current concept that blunted adrenocorticotropic hormone (ACTH) response to human corticotropin-releasing-hormone (h-CRH) in depression is primarily determined by elevated circulating plasma cortisol levels is still unproven. We tested this hypothesis by comparing ACTH release following intravenous administration of 100 micrograms h-CRH in 10 normal controls and in 21 inpatients with a major depressive episode. Eleven of these depressed patients were pretreated with an oral dose of 2 g metyrapone, which inhibits cortisol biosynthesis by blocking C-11 beta-steroid-hydroxylase. This intervention deprives the entire system of cortisol, which is the major feedback signal for the regulation of ACTH secretion at various pituitary and limbic sites. ACTH responses, assessed as areas-under-time-course-curves, were: in normal controls, 6.8 +/- 2.4 (SD) pg/ml/min x 10(3); in unmedicated patients, 2.6 +/- 1.1 pg/ml/min x 10(3); and in metyrapone pretreated patients, 9.0 +/- 6.7 pg/ml/min x 10(3). Thus, ACTH release in unmedicated depressed patients was significantly (p less than 0.001, Mann-Whitney U-test) blunted when compared with normal controls. In contrast, this blunting was completely avoided after metyrapone pretreatment, which resulted in net ACTH responses that were indistinguishable from those of the controls.     

Function of the adrenal cortex in patients with major depression

Failure to suppress cortisol secretion after administration of dexamethasone occurs in up to 50% of depressed patients. To test whether this hypothalamic-pituitary-adrenal (HPA) overactivity is associated with adrenocortical hyperresponsiveness, we performed dexamethasone suppression tests (DSTs) and adrenocorticotropic hormone (ACTH) stimulation tests in depressed subjects and subjects with other psychiatric disorders. Three groups were defined: depressed nonsuppressors, depressed suppressors, and other suppressors. While predexamethasone and postdexamethasone cortisol concentrations were greater in the depressed nonsuppressor group, ACTH concentrations did not differ among groups. After receiving alpha-ACTH[1-24] (4.2 micrograms/kg), depressed nonsuppressors had greater increases in stimulated cortisol secretion than the other groups. These results demonstrate that in a subgroup of depressed patients, HPA overactivity is associated with adrenocortical hyperresponsiveness.     

Cortisol Response to a Combined Dexamethasone-Human Corticotrophin-Releasing Hormone Challenge in Patients with Depression

We administered a combined dexamethasone-human corticotrophin-releasing hormone (hCRH) challenge test to 14 in-patients with a major depressive episode and to 14 age-matched controls. After pretreatment with 1.5 mg dexamethasone at 2300 h the day before, 100 μg hCRH was administered iv at 1500 h. Blood samples for cortisol determinations by radioimmunoassay were drawn at 1400 h, 1430 h and 1500 h before infusion of hCRH and thereafter every 15 min until 1700 h. Cortisol secretion after injection of hCRH assessed as area under the curve was significantly increased in patients with depression when compared to controls (14.5 ± 4.3 ng × min × 1,000/ml vs 3.1 ± 2.4 ng × min × 1,000/ml). Multiple regression analysis among patients revealed a significant impact of age and severity of depression upon hCRH-induced cortisol secretion, whereas in normal controls no significant influence of age on cortisol secretion after hCRH emerged.
Our data show that in depressed patients hCRH evokes an escape from dexamethasone-induced suppression of the pituitary-adrenocortical activity, whereas it fails to do so among controls. This finding suggests that at the pituitary level the action of hCRH is enhanced by a factor that is less sensitive to dexamethasone suppression in depression. We postulate that this factor is vasopressin.     

Combined DEX/CRH test among Japanese patients with major depression

There is compelling evidence for an important role of the hypothalamus-pituitary-adrenal (HPA) axis abnormalities in the pathophysiology of major depressive disorder. Growing evidence has suggested that the combined dexamethasone (DEX)/CRH test is much more sensitive than the conventional DEX suppression test in order to detect HPA axis abnormalities. However, little data is currently available on DEX/CRH results for Asian populations, which prompted us to examine the sensitivity of the DEX/CRH test among Japanese subjects with major depression. The DEX/CRH test was administered in 20 inpatients with major depressive episode and 30 healthy controls. Significantly increased cortisol responses were observed for the patients, compared to the controls. There was a substantial difference in the distribution of non-suppressor, intermediate suppressor, and suppressor, which were defined in terms of cortisol response, was observed between the patients and controls (10, 60, and 30% in the patients vs. 0, 27, and 73% in the controls, P<0.01). Responses of ACTH showed a trend in the same direction. Within the depressed patients, individuals with a history of attempted suicide, in particular, tended to have enhanced responses to the DEX/CRH test, compared to those without such a history. Our results confirmed that the DEX/CRH test is a sensitive test to detect HPA axis abnormalities among Japanese patients with major depression. In addition, a possible relationship between suicidal acts and enhanced HPA axis abnormalities was suggested.     

Immune-endocrine host response to endotoxin in major depression

OBJECTIVE: An impaired hypothalamic-pituitary-adrenocortical (HPA) function is a well-established finding in major depression (MD), but it is still unclear how this dysfunction affects immune responses in this disorder. METHOD: To further examine the relationship between immune and endocrine responses in MD, 0.4ng/kg body weight endotoxin [LPS] or 100mug hCRH were sequentially applied to 12 patients with MD and to 12 age- and gender-matched healthy controls after pre-treatment with 1.5mg dexamethasone (DEX). Immune (TNF-alpha, IL-6, rectal temperature) and endocrine (ACTH, cortisol) parameters were examined as area under the curve (AUC) levels. RESULTS: After pre-treatment with DEX, LPS evoked an immune response in all participants of the study with most immune parameters significantly related to the endotoxin challenge. However, only a marked immune response resulted in an additional endocrine reaction. Subsequently, the quantitative extent of the endocrine reaction was related to the extent of the immune response after DEX/LPS challenge. Pre-LPS AUC levels of cortisol, ACTH and post-LPS levels of IL-6 as well as the post-CRH AUC levels of cortisol and ACTH were related to the depressive symptomatology as measured by the Beck depression inventory (BDI). In depressive patients who showed increased cortisol plasma levels before LPS, the later increase in IL-6 was reduced. CONCLUSIONS: The challenge with DEX/LPS did not reveal major impairments of evoked immune functions in MD. Only the endocrine parameters and the IL-6 response were related to the depressive symptomatology, suggesting a limited interaction between immune and endocrine dysfunctions in MD.     

Enhanced adrenal sensitivity to exogenous cosyntropin (ACTH alpha 1-24) stimulation in major depression. Relationship to dexamethasone suppression test results

ACTH alpha 1-24 (cosyntropin) (250 micrograms by intravenous bolus) was given to 38 medicated patients with major depressive disorder (MDD) and to 34 normal control subjects. Patients with MDD had significantly higher plasma cortisol concentrations and significantly higher increases in plasma cortisol levels 60 minutes after cosyntropin infusion than did control subjects. Patients who were nonsuppressors in the dexamethasone suppression test had significantly higher 60-minute cortisol concentrations and cortisol increases than did normal subjects and patients with MDD who were suppressors. There were significant, strongly positive correlations between cortisol secretory responses to cosyntropin and postdexamethasone cortisol concentrations in patients with MDD. These findings confirm that adrenal sensitivity to corticotropin (ACTH) is enhanced in MDD and suggest that this endocrine abnormality may be related pathophysiologically to the resistance of cortisol secretion to dexamethasone suppression.     

Immunoendocrine aspects of major depression

Recently, a complete bidirectional circuit between the immune and neuroendocrine systems has been documented. Previous reports from this laboratory have shown that there are complex reciprocal relationships between immune and hypothalamic-pituitary-adrenal (HPA)-axis function in major depression. To further examine the immune-endocrine relationships, this study investigates plasma baseline cortisol and prolactin secretion in relation to plasma interleukin-6 (IL-6) and soluble IL-2 receptor (sIL-2R) levels in 34 healthy controls and 56 major depressed patients. There were significant positive correlations between IL-6 or sIL-2R and plasma cortisol in major depressed subjects and in the combined group of major depressed and healthy subjects. There were also significant positive correlations between plasma prolactin and sIL-2R concentrations in major depressed subjects and in the combined groups of normal and major depressed subjects.     

Process irregularity of cortisol and adrenocorticotropin secretion in men with major depressive disorder

Although evidence suggests that major depressive disorder (MDD) is associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, research on basal HPA axis hormone levels in MDD patients has been inconclusive. Definitive characterization of basal cortisol and adrenocorticotropin (ACTH) secretion may be important for understanding the pathophysiology of this disorder. In recent years, a new approach to the analysis of basal hormone secretion has been developed involving the approximate entropy (ApEn) statistic, which represents the degree of disorderliness or serial irregularity in a time series of hormone levels. ApEn has been shown to reflect the degree of coordination in integrated network systems and has provided new insights into the pathophysiology of a number of endocrine conditions. In the study reported here, 15 medication-free men with MDD and 15 healthy control men were admitted to a General Clinical Research Center and had blood sampled for cortisol and ACTH determinations every hour over a 24-h period. The cortisol and ACTH time series were characterized with a cosinor analysis and with analysis of ApEn. Depressed patients and control subjects did not differ significantly on any parameter derived from the cosinor analysis or on several other standard indices of basal hormone secretion. However, the depressed men had significantly increased cortisol ApEn and significantly decreased ACTH ApEn compared with the healthy subjects. The ApEn findings suggest a loss of regulatory control over cortisol secretion, and possibly increased cortisol feedback on the pituitary in the depressed patients. Together, these results are most consistent with a primary abnormality of the adrenal gland and suggest that further investigation of adrenal gland physiology may be informative for the pathophysiology of depression.     

Abnormal growth hormone and cortisol, but not thyroid-stimulating hormone, responses to an intravenous glucose tolerance test in normal-weight, bulimic women

Abnormal growth hormone (GH) and adrenocorticotropic hormone (ACTH)/cortisol secretory patterns in response to a glucose load have been observed in underweight anorectic women. The present study was performed in an attempt to establish whether changes in the hypothalamic/pituitary sensitivity to hyperglycemia occur in bulimia in the absence of weight disturbance. Therefore, serum GH, plasma cortisol, and plasma insulin concentrations were measured in eight women with normal weight bulimia and in eight normal women during an intravenous glucose (0.33 g/kg as an bolus) tolerance test (IGTT). In addition, since abnormal pituitary hormone responses to a glucose load might reflect alterations in somatostatin (SRIH) release, TSH secretion also was measured, in view of its sensitivity to SRIH inhibition.

Both GH and cortisol levels progressively and significantly declined during IGTT in the normal subjects. In the bulimic women, cortisol levels remained unchanged, whereas GH concentrations rose significantly after glucose injection. Plasma cortisol and serum GH levels were significantly higher in the bulimic than in the control subjects. No significant differences between groups were observed in hyperglycemia-induced insulin increments or in TSH decrements.

These data indicate that an altered sensitivity to hyperglycemia affects the hypothalamic/pituitary centers controlling the secretion of the counterregulatory hormones GH and ACTH/cortisol in bulimia nervosa. The lack of a simultaneous change in the TSH secretory pattern argues against a possible involvement of SRIH in the pathophysiology of this disorder.     

Melatonin, cortisol and ACTH in patients with major depressive disorder and healthy humans with special reference to the outcome of the dexamethasone suppression test

The 24 hr profiles of melatonin and cortisol in serum, morning levels of ACTH in plasma, and the dexamethasone suppression test (DST) were investigated in 32 acutely ill patients with a RDC diagnosis of major depressive disorder, 24 patients with a history of longlasting unipolar or bipolar major depressive disorder studied in remission, and 33 healthy subjects. A significant decrease in maximum nocturnal melatonin level (MTmax) was found in the acutely ill depressed patients with abnormal DST compared to both those with normal DSTs and the healthy subjects. The MTmax levels were unaltered when these patients were reinvestigated in remission. A decrease of MTmax was also seen in the group of unipolar and bipolar patients studied in remission. Low nocturnal melatonin is proposed to be a trait marker for major depressive disorder and depressive states with abnormalities in the hypothalamic--pituitary--adrenal (HPA) axis. A significant decrease of ACTH levels at 0800 hr after dexamethasone administration the preceding evening was found in the healthy subjects, the unipolar--bipolar patients in remission, and the acutely ill depressed patients with normal DSTs, but was not found in the acutely ill depressed patients with abnormal DSTs. These findings support the hypothesis that pituitary ACTH regulation is altered in depressed patients with abnormal DST. Morning plasma ACTH before the administration of dexamethasone did not significantly differ between the acutely ill depressed patients with abnormal DSTs, normal DSTs, the patients with unipolar--bipolar disease in remission, or the healthy subjects. Thus, the abnormalities in the HPA axis in depresséd patients are proposed to be due to a hypersecretion of corticotrophin releasing factor (CRF) with a subsequent stimulus-induced pituitary desensitization. A significant decrease of melatonin after dexamethasone was seen at 0800 hr in the unipolar--bipolar patients in remission as well as in the healthy subjects, at 1600 hr and 2200 hr in the acutely ill depressed patients in remission, but not at 0800 hr in the acutely ill depressed patients in relapse. A significant regression was found between MTmax levels and the degree of non-suppression of cortisol at 0800 hr in the DST in the acutely ill depressed patients both in relapse and in remission. Melatonin thus is proposed to be an inhibiting factor for CRF during depression. A trend to a phase-advance of cortisol nadir and melatonin peak was seen in the acutely ill depressed patients with abnormal DST, possibly indicating an involvement of the suprachiasmatic nuclei in the hypothalamus.     

Plasma ACTH and cortisol concentrations before and after dexamethasone

Alteration in the hypothalamic-pituitary-adrenal (HPA) axis occurs in up to 50% of depressed patients and is demonstrated by the failure to suppress cortisol concentrations after dexamethasone administration. Evidence suggesting that these cortisol abnormalities reflect hypothalamic-pituitary dysfunction has been inconsistent. We administered the dexamethasone suppression test to 28 psychiatric inpatients, including 17 cortisol suppressors and 11 nonsuppressors. Adrenocorticotropic hormone (ACTH) concentrations at 8 a.m. pre- and postdexamethasone were significantly greater in cortisol nonsuppressors than in suppressors. Our data support the hypothesis that pituitary ACTH secretion is altered in depressed patients who have HPA axis abnormalities demonstrated by plasma cortisol measurements.     

Human CRH stimulation response during acute withdrawal and after medium-term abstention from alcohol abuse

We compared the baseline cortisol secretory pattern and ACTH and cortisol responses to hCRH (100 μg) in eight patients acutely withdrawn from ethanol and 12 patients who abstained from ethanol for two to six weeks. Acute withdrawal from ethanol was characterized by elevated baseline cortisol and blunted ACTH release after hCRH, while medium-term abstention was associated with normalized cortisol secretion but persistence of decreased ACTH output following stimulation. These findings support an altered corticotrophic CRH receptor function in detoxified sober alcoholics. The pathophysiology underlying the blunted ACTH response to hCRH in medium-term ethanol abstention appears to be different from that in acute alcohol withdrawal and hypercortisolemic depression.     

5-HT1A receptor responsivity in unipolar depression. Evaluation of ipsapirone-induced ACTH and cortisol secretion in patients and controls

The selective 5-HT1A receptor ligand ipsapirone (IPS) induces corticotropin (ACTH) and cortisol secretion in humans. To explore 5-HT1A receptor-mediated hypothalamic-pituitary-adrenal (HPA) system activation in depression, 24 subjects (12 patients with unipolar depression and 12 individually matched controls) were given 0.3 mg/kg IPS or placebo in random order. Compared with controls, the depressed patients exhibited significantly decreased ACTH and cortisol responses to IPS in association with increased basal cortisol secretion. The impaired HPA response following 5-HT1A receptor challenge in unipolar depression could have resulted from glucocorticoid-dependent subsensitivity of the (post-synaptic) 5-HT1A receptor itself and/or from a defective postreceptor signaling pathway [inhibitory guanine nucleotide-binding protein (Gi)-adenylate cyclase complex function], thus supporting the hypothesis that a disintegrated 5-HT and HPA system interaction may be present in depression. Future studies of the HPA response to direct-acting 5-HT1A ligands, such as IPS, should facilitate the assessment of 5-HT/HPA system integrity in various affective disorders and its involvement in psychotropic drug effects.