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

Abstract

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 pg 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 (14.5f4.3 ng x min x 1,00O/ml vs 3.1 k2.4 ng x min x 1,00O/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 pituitaryadrenocortical 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.Dysregulation of the limbic-hypothalamic-pituitary-adrenocortical (LHPA) axis as measured by an increased number of adrenocorticotrophin (ACTH) bursts, elevated amount of cortisol released per secretory burst, resistance of cortisol to the suppressive action of dexamethasone, and blunted ACTH response after human corticotrophin-releasing hormone (hCRH) are among the major findings in depression research (1). Although the initially propagated diagnostic specificity of the dexamethasone suppression test (DST) for the subgroup of endogenous depression (2) did not receive full acceptance (3,4), the DST has been established as a method of monitoring clinical treatment (5-7). Elucidation of pathology underlying LHPA dysregulation in affective disorders was facilitated after ovine and hCRH were sequenced and made available for clinical research (8, 9). Studies applying this key hormone for LHPA regulation to depressives suggested a suprapituitary mechanism driving excessive ACTH and cortisol secretion, because hypersecretion of cortisol was associated with blunted ACTH response to CRH probes in these patients (10)(11)(12)(13)(14)(15). This finding proved to be unspecific for depression, because patients with other psychiatric disorders associated with altered LHPA function such as alcoholism (16, 17), panic disorder (18, 19) and anorexia nervosa (20, 21) also responded with decreased ACTH to CRH challenge.In male controls pretreated with dexamethasone, hCRH failed to induce an escape of plasma ACTH and cortisol from suppression, which led us to speculate that endogenous hypersecretion of CRH alone might not explain DST nonsuppression among a subgroup of depressives (22). In a sample of four depressed patients, we...

Adiponectin is critical in determining susceptibility to depressive behaviors and has antidepressant-like activity

“…A hyperactive hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent features of major depression. Depressed patients show marked resistance to dexamethasone (DEX) suppression and exaggerated response to a combination of DEX suppression and corticotrophin releasing hormone (CRH) stimulation (30,31). Using the same tests, we measured the sensitivity of the HPA axis of Adipo +/− mice to glucocorticoidinduced negative feedback.…”

Update on stress and depression: the role of the hypothalamic-pituitary-adrenal (HPA) axis

“…[46][47][48] The test involves oral administration of a single dose of dexamethasone 1.5 mg at 11:00 p.m., followed the next day at 3:00 p.m. by an intravenous bolus of CRH 100 µg. Whereas previous studies using the CRH stimulus alone had found blunted ACTH responses in depressed patients, use of the dexamethasone/CRH test results in exaggerated ACTH responses in depressed patients compared with healthy controls.…”

Family-Based Study of AVPR1B Association and Interaction with Stressful Life Events on Depression and Anxiety in Suicide Attempts

“…Although corticotropin-releasing hormone (CRH) signaling via CRH receptor-1 (CRHR1) is the principal activation pathway of the stress-reactive hypothalamicpituitary-adrenal (HPA) axis, arginine vasopressin (AVP) signaling via AVP receptor-1B (AVPR1B) may act synergistically in response to certain stressors (Scott and Dinan 1998). Furthermore, CRH challenge combined with DEX (CRH/DEX), which is putatively more sensitive in detecting hypothalamic AVP dysregulation than DEX, has also been used in assessing stress-related disorders, eg, depression (Bardeleben and Holsboer 1989;Purba et al, 1996). Increased AVP signaling in HPA axis stress reactivity has additionally been shown to occur following exposure to chronic psychosocial stressors, which are commonly thought to underlie chronic stress-related disorders, eg, depression (Scott and Dinan 1998;Bao and Swaab 2010).…”