cortodoxone and Depressive-Disorder

To determine whether depressed patients demonstrate hypothalamic-pituitary-adrenal (HPA) axis activation during the late afternoon and evening, a time when the HPA axis is usually quiescent in normal subjects.. We administered metyrapone, an 11-beta-hydroxylase inhibitor of cortisol synthesis, to normal controls and depressed patients between 4 and 10 PM. Metyrapone blockade of cortisol secretion would amplify any HPA axis secretion.. In 10 normal control subjects, administration of metyrapone lowered plasma cortisol levels to a mean of 36 nmol/L. No rebound corticotropin or beta-endorphin secretion was seen in these normal controls between 4 and 10 PM, supporting the existence of a period of minimal endogenous corticotropin releasing factor drive. Compared with a group of placebo-treated depressed patients (n = 10), metyrapone-treated depressed subjects (n = 17) had significantly decreased plasma cortisol concentrations. However, in contrast to normal controls treated with metyrapone, metyrapone-treated depressed patients demonstrated rebound corticotroph secretion, particularly between 7:30 and 10 PM (P = .036 for patients vs normal controls for beta-endorphin secretion from 4:30 to 10 PM).. These data support the hypothesis of increased corticotropin releasing factor drive in the evening in depressed subjects and are in agreement with the longstanding observation of "early escape" from dexamethasone suppression between 4 and 11 PM in depressed patients.

Topics: Adrenocorticotropic Hormone; Adult; beta-Endorphin; beta-Lipotropin; Circadian Rhythm; Corticotropin-Releasing Hormone; Cortodoxone; Depressive Disorder; Dexamethasone; Female; Humans; Hydrocortisone; Male; Middle Aged; Placebos; Pyridines

Plasma cortisol and 11-deoxycortisol were measured in 30 depressed patients and 110 normal volunteers before and after a 1.0 mg dexamethasone suppression test (DST). Post-dexamethasone plasma cortisol, 11-deoxycortisol and the cortisol/11-deoxycortisol ratio were significantly higher in the depressives compared to the controls, even when age and sex were taken into account. Pre-dexamethasone plasma cortisol, post-dexamethasone cortisol, 11-deoxycortisol and their ratio were significantly higher in the cortisol nonsuppressors than in the suppressors. The measurement of post-dexamethasone 11-deoxycortisol and the ratio did not differentiate between endogenous and reactive depression. Using the normative data, we explored several methods for determining a criterion value to define abnormal post-dexamethasone plasma 11-deoxycortisol and the cortisol/11-deoxycortisol ratio in depressed patients. All showed poor sensitivity and a low positive predictive value for depression. The measurement of 11-deoxycortisol thus does not enhance the clinical utility of the DST.

Topics: Adult; Aged; Cortodoxone; Depressive Disorder; Dexamethasone; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Middle Aged; Pituitary-Adrenal System; Psychiatric Status Rating Scales; Reference Values

We studied pituitary corticotropin response to exogenous corticotropin-releasing hormone infusion and attempted to control for the confounding effect of variable serum cortisol levels between depressed and control subjects. If metyrapone was given during the time of day when hypothalamic pituitary adrenal activity was otherwise low, the relative increase in the corticotropin concentration was small. Pituitary response to exogenous corticotropin-releasing hormone can be defined under conditions in which the amount of glucocorticoid-mediated negative feedback present at the level of the pituitary gland is equal in all subjects. When the ambient cortisol level was equalized (and suppressed) in all subjects at the time of study with a threshold dosage of corticotropin-releasing hormone, we found an augmented response to corticotropin-releasing hormone in depressives. This raises the possibility that either increased pituitary sensitivity to corticotropin-releasing hormone or an increased intracellular pool of corticotropin is available for release in subjects with major depressive illness.

Topics: Adrenocorticotropic Hormone; Adult; Circadian Rhythm; Corticotropin-Releasing Hormone; Cortodoxone; Depressive Disorder; Dose-Response Relationship, Drug; Feedback; Female; Humans; Hydrocortisone; Hypothalamus; Male; Metyrapone

Eleven beta-hydroxylase activity was assessed by measuring the cortisol to 11-deoxycortisol ratio in 20 control subjects, 38 patients with major depression, and five patients with Cushing's disease before and after 1 mg of dexamethasone. The mean levels of 11 beta-hydroxylase activity did not differ among groups before dexamethasone. After dexamethasone patients with Cushing's disease showed a nonsignificant increase in 11 beta-hydroxylase activity while patients with major depression and controls subjects both showed a decrease. Endogenous depressive patients were no more likely to show high 11 beta-hydroxylase activity than neurotic depressive patients; however, depressed patients with cortisol nonsuppression after dexamethasone were. Post-dexamethasone 11 beta-hydroxylase activity is positively correlated with age in both control subjects and patients with depression.

Topics: Adult; Cortodoxone; Cushing Syndrome; Depressive Disorder; Dexamethasone; Female; Humans; Hydrocortisone; Male; Middle Aged; Steroid 11-beta-Hydroxylase; Steroid Hydroxylases

As it has been suggested that calculating the ratio of cortisol to its biosynthetic precursor, 11-deoxycortisol, may enhance the sensitivity of the dexamethasone suppression test (DST) for depression, cortisol and 11-deoxycortisol were measured in 90 subjects undergoing this test. Among these subjects, post-dexamethasone cortisol and 11-deoxycortisol levels were significantly correlated (r = 0.65, P less than 0.001) and evaluating the ratio of cortisol to 11-deoxycortisol decreased rather than enhanced sensitivity of the DST.

Topics: 17-Hydroxycorticosteroids; Bipolar Disorder; Cortodoxone; Depressive Disorder; Dexamethasone; Humans; Hydrocortisone; Middle Aged; Schizophrenia

Eleven-beta-hydroxylase activity was measured before and after acute adrenocorticotrophic hormone (ACTH) stimulation in 28 controls, 25 depressed Dexamethasone Suppression Test (DST) suppressors, 13 DST nonsuppressor patients, and 8 patients with Cushing's syndrome to investigate changes in states of cortisol hypersecretion. Eleven-beta-hydroxylase activity was equivalent among groups both before and after stimulation. Such 11-beta-hydroxylase stability, however, resulted in higher cortisol and 11-deoxycortisol poststimulation levels in both depressed DST nonsuppressors and Cushing's patients than in controls. Basal 11-beta-hydroxylase activity is positively correlated and 11-deoxycortisol is negatively correlated with age in controls and DST suppressors, but not in the patients tested with evidence of cortisol hypersecretion. These findings suggest that in vivo basal 11-beta-hydroxylase activity rises gradually with age, but does not rise after acute administration of exogenous ACTH. The age relationship is lost in states of cortisol hypersecretion, but the lack of response to acute exogenous ACTH is not affected.

Topics: Adrenocorticotropic Hormone; Adult; Aging; Cortodoxone; Cushing Syndrome; Depressive Disorder; Dexamethasone; Female; Humans; Hydrocortisone; Male; Middle Aged; Sex Factors; Steroid 11-beta-Hydroxylase; Steroid Hydroxylases

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Bipolar Disorder; Corticosterone; Corticotropin-Releasing Hormone; Cortodoxone; Depressive Disorder; Dexamethasone; Humans; Hydrocortisone; Metyrapone; Mineralocorticoids; Neurotransmitter Agents; Steroid 11-beta-Hydroxylase; Steroid Hydroxylases

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.

Topics: 17-Hydroxycorticosteroids; Adult; Cortodoxone; Depressive Disorder; Dexamethasone; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Metyrapone; Middle Aged; Pituitary-Adrenal System

Hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis in depression has received considerable attention, particularly in the now numerous studies utilizing the dexamethasone suppression test. The possibility of HPA axis hypoactivity in this population however has not been similarly explored. To examine this latter possibility, the metyrapone test, a well-established neuro-endocrine assay for determining pituitary reserve, was administered to ten endogenously depressed males and ten matched controls. Consistent with the findings of an earlier study on ten female depressives, one of the depressed males but none of the controls showed clear evidence of HPA axis hypoactivity. This suggests that HPA axis dysfunction in depressives may be more complex than originally anticipated. This finding also has implications for the psychiatric symptomatology classically associated with such illnesses as Addison's disease.

Topics: Addison Disease; Adult; Cortodoxone; Depressive Disorder; Dexamethasone; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Metyrapone; Middle Aged; Pituitary-Adrenal System

One hundred micrograms of ovine-corticotropin releasing factor (o-CRF) was administered intravenously to eight unmedicated patients with severe endogenous depression. Responses of immunoreactive (ir)-ACTH and the adrenal glucocorticosteroids corticosterone (B), 11-deoxycortisol (S), cortisol (F) and cortisone (E) were measured and compared with those following synthetic corticotropin stimulation and dexamethasone suppression. A comparative evaluation of the three pituitary--adrenal function tests suggests that hypersecretion of ir-ACTH and adrenal corticosteroids (B, S, F, and E) in depression reflects a central dysfunction rather than an altered responsiveness of the pituitary or adrenal glands. The data illustrate that the o-CRF paradigm is a valuable instrument to further support the hypothesis that a limbic--hypothalamic overdrive is the basic mechanism underlying exaggerated adrenocortical output in the endogenous subgroup of depressed patients.

Topics: 17-Hydroxycorticosteroids; Adrenocorticotropic Hormone; Adult; Aged; Corticosterone; Corticotropin-Releasing Hormone; Cortisone; Cortodoxone; Depressive Disorder; Dexamethasone; Female; Humans; Hydrocortisone; Male; Middle Aged; Radioimmunoassay

The metyrapone test was applied to groups of patients suffering from major depressive illness with melancholia, mania or schizophrenia, before and after treatment. There were interesting individual correlations between post-metyrapone cortexolone values, cortexolone/cortisol ratios and clinical improvement in depressives. Two patients who had exhibited abnormal metyrapone responses displayed a normalization of post-metyrapone cortexolone values upon clinical improvement, whereas the opposite trend was observed in a patient who did not improve and in another who became manic. These preliminary results may indicate that abnormal metyrapone responses in depression are state dependent.

Topics: Adult; Aged; Antidepressive Agents; Antipsychotic Agents; Bipolar Disorder; Cortodoxone; Depressive Disorder; Female; Humans; Hydrocortisone; Imipramine; Lithium; Male; Metyrapone; Middle Aged; Psychotic Disorders; Psychotropic Drugs; Schizophrenia

The metyrapone test was applied to patients suffering from major depressive illness with melancholia, from mania, and from schizophrenia. Hypoactivity of the HPA axis as assessed by the test appears to occur infrequently in affective disorders and schizophrenia. High normal or exaggerated responses to metyrapone, as observed in Cushing's disease, appear to be correlated to DST non-suppression in melancholia.

Topics: Adult; Aged; Bipolar Disorder; Cortodoxone; Depressive Disorder; Dexamethasone; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Metyrapone; Middle Aged; Pituitary-Adrenal System; Schizophrenia

The 1 mg dexamethasone suppression test was used to assess pituitary-adrenal activity in 23 depressed patients and 8 healthy volunteers. At 1600h, after administration of the test dose of dexamethasone at 2300h, levels of cortisol, 11-deoxycortisol, and corticotropin were determined following a chromatographic extraction step applying highly specific radioimmunoassay techniques. Cortisol nonsuppressors had significantly increased adrenocorticotropic hormone (ACTH) values and cortisol/11-deoxycortisol ratios. The cortisol/11-deoxycortisol ratio was regarded as a measure of biologically active ACTH. The present results, which indicate a concordance of corticotropin and corticosteroid response, suggest that the parent abnormality of dexamethasone-resistant cortisol concentrations is elevation of biologically active corticotropin.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Cortodoxone; Depressive Disorder; Dexamethasone; Female; Humans; Hydrocortisone; Male; Middle Aged; Pituitary-Adrenal Function Tests; Radioimmunoassay

Topics: 17-Hydroxycorticosteroids; Chromatography, High Pressure Liquid; Cortodoxone; Depressive Disorder; Humans; Hydrocortisone; Metyrapone

The dexamethasone suppression test (DST) based on multisteroid analysis was administered to 22 female patients with primary major depressive disorder (12 endogenous, 10 nonendogenous) and 12 healthy control subjects. Cortisol, its biosynthetic precursor 11-deoxycortisol, and cortisone were measured. Calculating cortisol/11-deoxycortisol ratios allows the assessment of the activity of 11 beta-hydroxylase, which depends on the mean secretion rate of adrenocorticotropic hormone. Preliminary findings indicate that the sensitivity of the DST is remarkably increased when based on a cortisol/11-deoxycortisol ratio instead of plasma cortisol or cortisone concentrations.

Topics: 17-Hydroxycorticosteroids; Adult; Cortisone; Cortodoxone; Depressive Disorder; Dexamethasone; Diagnosis, Differential; Female; Humans; Hydrocortisone; Middle Aged

Topics: 17-Hydroxycorticosteroids; Adult; Bipolar Disorder; Corticosterone; Cortisone; Cortodoxone; Depressive Disorder; Desoxycorticosterone; Dexamethasone; Female; Humans; Hydrocortisone; Middle Aged