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.     

beta-Endorphin/beta-lipotropin immunoreactivity in endogenous depression. Effect of dexamethasone

This study addresses the question of whether pituitary peptides (ie, beta-endorphin) show regulatory disruption in endogenous depression and, if so, does it co-occur in the same subjects who show cortisol dysregulation. Endogenously depressed patients and psychiatric controls from three centers were evaluated, when not taking medications, and studied for plasma cortisol and beta-endorphin levels. Plasma samples were taken at four time points over one hour, on the basal day, and 16 hours after 1 mg of dexamethasone. From 33% to 69% of the endogenous patients were abnormal in their postdexamethasone cortisol levels, and from 50% to 69% were abnormal on postdexamethasone beta-endorphin values (vs 0% and 8%, respectively, for controls). When endogenous subjects were evaluated for abnormality on both cortisol and beta-endorphin, after dexamethasone, it was found that the two measures of hypothalamic-pituitary-adrenal dysfunction did not necessarily co-vary. In fact when having either abnormal beta-endorphin or cortisol levels (or both) was used as a biological marker a larger number of the endogenous patients were detected than with either measure alone. Our conclusions are as follows: Plasma beta-endorphin shows a circadian rhythm similar to that seen with corticotropin (ACTH) and is suppressable by dexamethasone. In many endogenous patients plasma beta-endorphin levels escape from dexamethasone suppression. Many of these subjects are not cortisol escapers. When abnormality of either the beta-endorphin or cortisol is considered it is clear that both levels of the hypothalamic-pituitary-adrenal axis can be dysregulated in endogenous depression.     

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.     

The dexamethasone suppression and metyrapone tests in depression

The dexamethasone suppression test (DST) and the metyrapone test (MT), a useful and reliable procedure for assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis, were performed in 28 patients suffering from major depressive illness with melancholia. The relationship between the DST and MT appeared to be complex. Patients who failed to suppress cortisol secretion after dexamethasone administration had higher postmetyrapone cortexolone levels and cortexolone/cortisol ratios than suppressors. However, there was a wide range of metyrapone responses in patients exhibiting abnormal DST results. This suggests that failure of adequate suppression after 1 mg of dexamethasone in depressed patients does not necessarily reflect homogeneity in the HPA axis disturbances of such patients.     

Neuroendocrine identification of depressed patients.

Recent studies of hypothalamo--pituitary--adrenal (HPA) suppression in depressed patients indicate that these subjects often show abnormal early escape of plasma cortisol levels following an initial suppression. Non-depressed psychiatric inpatients usually show normal sustained HPA suppression. The responses of 49 depressed and 30 non-depressed patients have been analysed to develop criteria which can make the dexamethasone suppression test suitable for outpatient studies. The cortisol levels measured in a 24-hour urine collection and a single blood sample post-dexamethasone were sufficient to enable 61% of the depressed patients to be identified correctly at a confidence level of 90%, on the basis of at least one abnormal cortisol value. When both cortisol values were abnormal 35% of the depressed patient were identified correctly at a confidence level of 100%. Patients with "endogenous" depressive profiles had the most abnormal results. A normal response to this test will not necessarily exclude the diagnosis of primary depressive illness. An abnormal response to the test may be of help in confirming the diagnosis. With the simplified procedure outpatient studies may become possible.     

Hypothalamic-pituitary-adrenocortical function in mixed and pure mania.

There is little information about hypothalamic-pituitary-adrenocortical (HPA) axis function in mania, particularly in mixed states. We therefore investigated HPA function and its relationship to clinical state in 19 hospitalized manic patients meeting Schedule for Affective Disorders and Schizophrenia - Research Diagnostic Criteria for acute manic episodes, compared patients with and without a mixed presentation, and examined correlations between HPA activity and behavior. Data were available from 13-16 patients. Behavioral and biochemical analyses were conducted during a 15-d placebo period. Patients with mania had elevated cerebrospinal fluid (CSF) and urinary free cortisol excretion compared with healthy subjects, and did not differ from depressed patients in any cortisol measures. Mixed manics had significantly higher morning plasma cortisol, postdexamethasone plasma cortisol and CSF cortisol than pure manics. Five of 7 mixed manics and 3 of 9 pure manics were dexamethasone suppression test (DST) nonsuppressors. Afternoon plasma cortisol and CSF cortisol correlated significantly with depressed mood; urinary free cortisol correlated with anxiety. None of the cortisol measures correlated with mania or agitation scores. These data suggest that increased cortisol secretion is a characteristic of the depressed state in mixed manics, although pure manics may also have increased DST nonsuppression.     

Hypercortisolemia decreases dexamethasone half-life in rabbit

The pharmacokinetics of dexamethasone have been found to be related to endogenous hypothalamic-pituitary-adrenal (HPA) axis activity. Lower plasma dexamethasone levels in psychiatric patients (especially depressed) who are dexamethasone suppression test (DST) nonsuppressors have previously been reported. Since DST nonsuppression is one measure of HPA axis hyperactivity and is usually associated with relatively increased plasma cortisol levels and lower post dose plasma dexamethasone levels, we hypothesized that hypercortisolemia can induce a more rapid disappearance of dexamethasone from plasma. We therefore studied the kinetics of dexamethasone in rabbits before and after a period of sustained hypercortisolemia produced by administration of IM hydrocortisone acetate, a slowly absorbed salt of cortisol. Mean dexamethasone half-life decreased significantly from baseline of 1.92 h on day zero in seven rabbits to 1.17 h on experimental day 17 of induced hypercortisolemia (P<0.001), while there was no significant change in saline treated controls (n=3). Dexamethasone half-life had returned to the baseline levels when retested 88 days later on experimental day 105. The results indicate that pronounced hypercortisolemia decreases dexamethasone half-life in rabbits, and support the concept that increased circulating cortisol levels induce hepatic enzymes that metabolize dexamethasone. Thus, the lower postdexamethasone plasma dexamethasone levels and decreased dexamethasone half-life in DST nonsuppressors may in part reflect the effect of prior or coincident hypercortisolemia.     

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.     

Inositol treatment has no effect on the dexamethasone suppression test.

The dexamethasone suppression test (DST) is a widely studied state marker for endogenous depression. Several drugs cause false positives or negatives in this test. Since inositol is a new treatment for depression it is important to determine if it causes artifacts in the DST. Five patients with major depression diagnosed according to DSM-IV underwent a dexamethasone suppression test before and after one and two weeks of 12 grams daily inositol treatment. Three normal subjects underwent the same procedure before and after one week of inositol treatment. Four depressed patients and all three normal subjects demonstrated pretreatment dexamethasone suppression of plasma cortisol. One or two weeks of inositol treatment had no effect on post-dexamethasone cortisol plasma levels in patients or subjects. One depressed patient was a non-suppressor before treatment and continued to show elevated post dexamethasone cortisol levels after one week of inositol treatment. However, after two weeks on inositol, when substantial clinical improvement was noted, he converted to a normal DST. Chronic inositol treatment does not seem to induce false positive DST results.     

A multivariate study of simultaneous escape from suppression by dexamethasone of urinary free cortisol, plasma cortisol, adrenocorticotropic hormone and beta-endorphin in melancholic patients.

To investigate the relationships between pre- and postdexamethasone hypothalamic-pituitary-adrenal (HPA) axis functioning in depression, we measured the levels of baseline and postdexamethasone urinary free cortisol (UFC), plasma cortisol, adrenocorticotropic hormone (ACTH) and beta-endorphin. We found that dexamethasone significantly suppressed all hormone levels. All 4 postdexamethasone hormones--but not their baseline levels--were significantly higher in melancholic subjects than in minor and simple major depressives. We have accumulated evidence that the melancholic and minor depression groups form discrete classes in postdexamethasone HPA axis hormone levels; this supports the biological heterogeneity hypothesis of melancholia. We found that a combination of the postdexamethasone UFC and beta-endorphin values yielded the most significant diagnostic tool for melancholia. Our results suggest that the measurements of both hormones may constitute the most accurate index reflecting the HPA axis escape from suppression by dexamethasone in melancholia. By means of pathway analysis, we determined the causal relationships between age, dexamethasone circulating levels, diagnostic depression classification and the various baseline and postdexamethasone hormone values.     

A novel prednisolone suppression test for the hypothalamic-pituitary-adrenal axis.

We have developed a suppressive test for the hypothalamic-pituitary-adrenal (HPA) axis using prednisolone, which is similar to endogenous glucocorticoids. We used a single-blind, repeated-measure design in healthy volunteers. In the first phase of the study, we compared placebo or prednisolone 2.5 mg, 5 mg, or 10 mg; in the second phase of the study, we compared placebo or prednisolone 5 mg or dexamethasone.5 mg. On the following day, we collected plasma and salivary cortisol levels from 9 AM to 5 PM. Maximal average prednisolone plasma levels (at 9 AM after the 10-mg dose) were 30 to 35 ng/mL. At all doses, prednisolone caused a larger suppression of salivary cortisol (approximately 20% after 2.5 mg, 30% to 35% after 5 mg, and 70% to 75% after 10 mg) than of plasma cortisol (approximately 5% after 2.5 mg, 10% after 5 mg, and 35% after 10 mg). Dexamethasone.5 mg gave 80% suppression of plasma cortisol and 90% suppression of salivary cortisol. Plasma and salivary cortisol levels were more consistently correlated in each subject after prednisolone than after dexamethasone. We propose that prednisolone at the 5-mg dosage (which gave partial HPA suppression), together with the assessment of salivary cortisol, can be used to investigate both impaired and enhanced glucocorticoid-mediated negative feedback in large samples of patients with psychiatric disorders.     

Neuroendocrine evidence of deranged noradrenergic activity in chronic migraine

Migraine is a psychobiological disorder in which a recurrent failure of opioid and adrenergic systems might occur, as plasma and CSF studies suggest. In order to elucidate the relationship between noradrenergic and opioidergic functions, the plasma beta-endorphin (beta-EP) response to clonidine and the cortisol response to dexamethasone were evaluated together in 25 patients suffering from migraine without aura, and with chronic tension headache (MTH). Baseline beta-EP plasma levels and beta-EP response to clonidine were significantly lower in MTH subjects than in controls, suggesting a postsynaptic hypothalamo-pituitary impairment. Forty-four percent of the MTH subjects showed either a lack of suppression of plasma cortisol following dexamethasone administration, or basal cortisol concentrations higher than controls and suppressors, suggesting a disinhibition of the hypothalamopituitary-adrenal (HPA) axis. An inverse correlation was found between pain severity and beta-EP secretion induced by clonidine (delta max), and no relationship was found between beta-EP and mood. These data suggest a failure of central noradrenergic activity, or perhaps an impaired secretion of beta-EP not related to HPA axis hyperactivity or to affective state.     

Corticotropin, cortisol and beta-endorphin responses to the human corticotropin-releasing hormone during melancholia and after unilateral electroconvulsive therapy

Previous research in neuroendocrinology has evidenced that hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA) depends on hypersecretion of corticotropin-releasing hormone (CRH). The aim of this study was to investigate the activity of HPA before and after recovery in depressed patients treated with electroconvulsive therapy (ECT). An h-CRH-stimulation test was performed on 2 occasions with examination of the HPA axis before ECT treatment during episodes of major depressive disorders with melancholia, and during the recovery phase after treatment. The results showed that patients during depression had significantly higher plasma levels of cortisol at 15 and 30 min after h-CRH-administration than after recovery. Depressed patients had significantly higher plasma levels of beta-endorphin 30 min after h-CRH-stimulation. The results are in agreement with previous studies, which have shown hypercortisolemia during depression. A possible hypersecretion of CRH may explain the effect on cortisol and beta-endorphin. No significant differences were found between cumulative responses of corticotropin, cortisol and beta-endorphin, calculated as the areas under the concentration curves.     

抑郁症伴或不伴糖尿病患者过夜小剂量地塞米松抑制试验的对照研究

目的 探讨下丘脑-垂体-肾上腺轴(HPA)功能异常在抑郁症患者伴发的糖尿病发病机制中的意义.方法 首次诊断为糖尿病的抑郁症患者(病例组)、正常血糖稳态的抑郁症患者(对照组)各40例,于药物治疗前测定空腹血糖、糖负荷后2 h血糖,并行过夜小剂量(1 mg)地塞米松抑制试验.结果 (1)病例组抑制前8:00、16:00及...     

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.     

Plasma levels of beta-endorphin, cortisol, prolactin and growth hormone in depressed patients

Basal serum cortisol, growth hormone, prolactin and immunoreactive (IR) plasma beta-endorphin levels were measured in 31 depressed patients (14 endogenous, 17 nonendogenous) undergoing the dexamethasone suppression test. The endogenously depressed patients had significantly higher (22.55 +/- 1.34 micrograms/dl) predexamethasone cortisol levels than the nonendogenous patients (16.34 +/- 1.93 micrograms/dl). The mean serum prolactin and growth hormone values of these two groups were not significantly different, while plasma IR-beta-endorphin levels of the endogenous group (40.11 +/- 3.57 pg/ml) were significantly lower than those of the nonendogenous group (120.33 +/- 27.98 pg/ml). Neither group showed a significant correlation between plasma IR-beta-endorphin and serum cortisol values. These results indicate that measurement of predexamethasone serum cortisol values and plasma IR-beta-endorphin could be valuable laboratory tests in the diagnosis of depression.     

Psychotic and nonpsychotic depressions: I. Comparison of plasma catecholamines and cortisol measures

Unconjugated plasma catecholamines and cortisol were measured before and after a 1 mg dose of dexamethasone in 22 medication-free depressed patients and 6 healthy, medication-free control subjects. Plasma dopamine (DA) levels in the psychotically depressed subgroup (n = 4) were significantly higher both before and after dexamethasone than those in the nonpsychotic depressed group and higher before dexamethasone than in the control group. Similarly, the psychotically depressed group exhibited significantly higher cortisol levels both before and after dexamethasone than the nonpsychotic depressed group or the control group. In contrast, the psychotically depressed group had significantly lower postdexamethasone plasma norepinephrine levels compared to the nonpsychotic depressed group. In both patients and controls, plasma DA was significantly higher after dexamethasone administration than before, but the magnitude of the increase was 10 times greater in controls than in patients.     

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.     

CSF corticotropin-releasing hormone in depressed patients and normal control subjects

The authors studied CSF corticotropin-releasing hormone (CRH) and plasma cortisol in 22 depressed patients and 18 normal control subjects. CRH levels were similar in the two groups. Depressed patients who were nonsuppressors on the dexamethasone suppression test had significantly higher levels of CRH than suppressors did. The depressed patients' CRH levels were significantly correlated with 4:00 p.m. postdexamethasone plasma cortisol levels. While the inclusion of a depressed patient with an outlier CRH value resulted in the loss of statistical significance for both of these findings, the authors suggest that these results support the hypothesis that hypercortisolism in depressed patients in part reflects a defect at or above the hypothalamus, resulting in hypersecretion of CRH.     

Specificity of plasma HVA response to dexamethasone in psychotic depression

Earlier reports have suggested that dexamethasone significantly increases levels of plasma homovanillic acid (HVA) in normal subjects, but that this effect may be altered in some depressed patients. To investigate the specificity of such alterations, we administered dexamethasone (1 mg p.o. at 11 p.m.) to 33 normal subjects, 27 depressed patients (8 with psychotic features), and 16 schizophrenic patients. Plasma for assay of cortisol and HVA was obtained at 4 p.m. before and on the day following dexamethasone administration. Dexamethasone induced significant increases in plasma HVA in the normal subjects and in the schizophrenic patients, but not in the depressed patients. Indeed, psychotically depressed patients tended to show a dexamethasone-associated decrease in plasma levels of HVA. In contrast to cortisol "suppression" or "nonsuppression," dexamethasone-induced changes in plasma levels of HVA (i.e., increases or decreases) sensitively and specifically discriminated between patients with affective and nonaffective psychoses.