Armand Gerken

ACTH and multisteroid responses to corticotropin-releasing factor in depressive illness: Relationship to multisteroid responses after ACTH stimulation and dexamethasone suppression ☆

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.

Human corticotropin-releasing hormone in depression--correlation with thyrotropin secretion following thyrotropin-releasing hormone.

Twenty-two subjects (11 patients with major endogenous depression and 11 controls) received an intravenous test dose of 100 micrograms human corticotropin-releasing hormone (h-CRH). Corticotropin (ACTH), but not cortisol, responses were blunted in depressives. Basal cortisol secretion was higher in depressives than in controls and was negatively correlated to the corticotropin response following h-CRH. This finding indicates the integrity of the glucocorticoid-dependent negative feedback regulation in depression and supports the view that hypercortisolism in depression is primarily due to a suprapituitary disturbance. Comparison of ACTH responses after h-CRH with thyrotropin (TSH) output following thyrotropin-releasing hormone (TRH) revealed a positive correlation (r = 0.65, p less than 0.001). The concordance between ACTH and TSH responses after specific challenges suggests that regulation of both systems is at least in part under a common control.

ACTH, cortisol, and corticosterone output after ovine corticotropin-releasing factor challenge during depression and after recovery☆

Synthetic ovine corticotropin releasing factor (o-CRF) was administered as an intravenous bolus (100 micrograms) to eight patients suffering from a major depressive disorder, endogenous subtype. All patients showed inadequately suppressed cortisol levels after 1 mg dexamethasone. After clinical remission and normalized dexamethasone responses, these patients were reinvestigated with o-CRF stimulation. The mean adrenocorticotropic hormone (ACTH) release from the pituitary corticotroph cells was indiscriminate at both test sessions. Cortisol and corticosterone output after o-CRF tended to be higher during depression than after recovery. The o-CRF-induced increments observed with corticosterone were more marked in comparison with cortisol. Within the limitations of the current protocol, our preliminary data lend support to the view that an increased pituitary ACTH reserve or adrenocortical steroid reserve is not likely to be responsible for the defective pituitary-adrenal regulation in some dexamethasone-resistant depressives.

Cortisol, 11-deoxycortisol, and ACTH concentrations after dexamethasone in depressed patients and healthy volunteers

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.

The plasma dexamethasone variable in depression: Test- retest studies and early biophase kinetics

A dexamethasone suppression test (DST) was performed in 45 patients during depressive illness and after recovery. Thirty-one samples from patients in whom plasma cortisol was resistant to the suppressive action of dexamethasone contained significantly lower mean (+/- SD) concentrations of the test drug (0.63 +/- 0.39 ng/ml vs 1.10 +/- 0.53 ng/ml) during illness than after recovery and normalization of the DST. In a control group of 14 patients who exhibited adequate DST suppression during the depressive state and after recovery, the dexamethasone concentrations were unchanged (1.54 +/- 0.91 ng/ml vs. 1.30 +/- 0.92 ng/ml). To investigate further the influence of bioavailability or pharmacokinetics of the test drug on DST results, we conducted a catheter study during sleep in 11 endogenously depressed patients who received an oral 1.5 mg dose of dexamethasone at 11 p.m. The half-life of dexamethasone was markedly lower in five DST nonsuppressors (t1/2 = 160 +/- 33 minutes) than in six DST suppressors (t1/2 = 422 +/- 172 minutes). These preliminary results indicate that metabolism of dexamethasone should be controlled in studies evaluating the clinical utility of the DST.

Weekly monitoring of dexamethasone suppression response in depression: its relationship to change of body weight and psychopathology

Weekly dexamethasone suppression tests (DST) were performed in 19 hospitalized patients with major depressive disorder, endogenous subtype, and who had an abnormal DST at admission. Depression scores (Hamilton Rating Scale) and weight changes were collected by investigators who were blind to the test results. Major findings were: (1) the DST gradually normalized 3-4 weeks prior to full resolution of clinical symptomatology; (2) weight loss was an important patient variable which may have contributed to false positive DST results; however, the positive correlation between changes in DST results and changes in depression scores in all our patients with or without weight loss suggests that psychopathological factors other than weight change participate in the development of dexamethasone resistance in depression; (3) the low dose (1 mg) version of the test requires careful control of minor medical disturbances, which can make the test result ambiguous. The data suggest that after resolution of some methodological issues the DST may serve as a valuable laboratory test to monitor clinical progress during drug treatment.

Mean 14.00–17.00 h plasma cortisol concentration and its relationship to the 1 mg‐dexamethasone suppression response in depressives and controls

ABSTRACT– Three‐hour cortisol‐profiles and cortisol responses to a 1 mg dose of dexamethasone were recorded in 31 depressed patients and nine controls. The data indicate that the likelihood of detecting non‐suppressible cortisol concentrations after dexamethasone is significantly increased in depressed patients with a hypersecretion of cortisol. However, a considerable subsample of normosecretors shows abnormal DST results. Conversely, hypersecretion is often associated with dexamethasone suppression. In this study a 1 mg‐DST did not reflect the adrenocortical activity with ultimate accuracy. Therefore any attempts which correlate psychopathological or biological data with pituitary‐adrenal activity and use a DST‐result as measure are criticizable. Data derived from volunteers illustrate that medical factors such as weight‐loss, steroid‐containing contraceptives and sleep deprivation can make a pituitary‐adrenal activity test ambiguous.

Cortisol and corticosterone response after syn-corticotropin in relationship to dexamethasone suppressibility of cortisol

The current study was designed to investigate whether glucocorticoid output after syn-ACTH stimulation is different in depression associated with dexamethasone suppression test (DST) nonsuppression from the euthymic state and DST suppression. We gave 28 depressives a DST and an adrenocortical challenge with synthetic ACTH. Fourteen patients were nonsuppressors on the DST. After successful drug treatment, the subjects were reinvestigated by both tests; all DSTs revealed plasma cortisol concentrations below the criterion value of 50 ng/ml. Cortisol and corticosterone responses after syn-ACTH tended to be higher during depression. After clinical remission, higher cortisol and corticosterone responses occurred in those patients who were DST nonsuppressors during depression. This finding suggests that patients who suffer from a depression which is linked to an abnormal pituitary--adrenocortical regulation develop an enhanced sensitivity of the adrenal cortex to ACTH.

Multisteroid analysis after DST in depressed patients — A controlled study

111 consecutively admitted in-patients with a depressive syndrome received a dexamethasone suppression test (DST) after all known factors which might confound the test results had been carefully excluded. Plasma concentrations of cortisol, corticosterone and dexamethasone were compared with several diagnostic evaluations (RDC, DSM-III, ICD-9) in a controlled study. The positive predictive value of nonsuppressed corticosteroid levels was only moderate for each diagnostic category. Diagnostic specificities were 84.6% for major depression, endogenous subtype (RDC), 71.2% for melancholia (DSM-III) and 86.8% for endogenous depression (IDC-9) when using a post-DST cortisol value above 50 ng/ml (5 micrograms/dl) as the referent value to define DST nonsuppression. Combined determination of cortisol and corticosterone as an index of dexamethasone-induced suppression raised the sensitivity rate considerably at the cost of the predictive value for major diagnostic categories. Dexamethasone plasma levels were reciprocally correlated with cortisol levels and neglect of samples with low plasma dexamethasone contents improved the diagnostic performance for endogenous depression according to RDC and ICD-9, but not for DSM-III melancholia. Although it would be speculative to suppose that the observed low dexamethasone levels are involved in DST nonsuppression, the present findings emphasize that multisteroid analysis which includes dexamethasone is important in future studies designed to explore the clinical utility of the DST.

Differential effects of the enantiomers R(−) and S(+) oxaprotiline on major endogenous depression, the sleep EEG and neuroendocrine secretion: Studies on depressed patients and normal controls

The effects of the optically active enantiomers of oxaprotiline (OXP), R(-) OXP and S(+) OXP, on depressive symptomatology and the sleep EEG were investigated in two separate exploratory studies. In addition, the neuroendocrine profile of both compounds was characterized in normal controls. In the patients treated with a daily oral dose of 150 mg S(+) OXP we found a Hamilton depression score that decreased from 29.1 +/- 1.8 (SEM) on day 0 to 14.7 +/- 3.2 on day 28 (P < 0.01). Six patients were judged to be full responders (HAMD score 0-7 points), three were improved (HAMD score 8-15) and four were nonresponders (HAMD score > 16). The therapeutic effect achieved with 150 mg R(-) OXP daily was less pronounced: the HAMD score decreased from 27.8 +/- 2.5 on day 0 to 19.4 +/- 3.2 on day 28 (P < 0.05). There were two full responders, one improved patient and seven nonresponders. The sleep EEG scoring revealed a marked suppression of REM sleep among patients treated with S(+) OXP but not with R(-) OXP. In the normal controls, a single oral dose of 75 mg S(+) OXP prompted an increase in the secretion of cortisol and growth hormone, whereas 75 mg R(-) OXP did not. Neither enantiomer influenced the secretion of testosterone or prolactin.