Search

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.

The authors measured pituitary adrenocortical responses to human corticotropin-releasing hormone (CRH) in 10 patients with a major depressive episode and 10 matched control subjects. Depressed patients had a significantly lower aldosterone and ACTH release, but cortisol and corticosterone responses were not different between groups.

After a dexamethasone suppression test (DST), cortisol, corticosterone, and the test substance were determined by a direct radioimmunoassay in 42 samples obtained from 22 depressed patients and 8 controls. The DST results of both glucocorticoids agreed in most of the tests. In all seven cases with elevated but not definitely abnormal post-DST (1600 hr) cortisol levels (transitional range 30-50 ng/ml) the concurrent determination of corticosterone indicated that this corticosteroid may serve as a potent additional discriminator. Dexamethasone plasma concentrations at 1600 hr after a 1-mg test dose of dexamethasone at 2300 hr were significantly (p less than 0.01) lower in cortisol and corticosterone nonsuppressors than in suppressors. Since these data were obtained 17 hr after ingestion of dexamethasone (half-life 3.5-5 hr) any conclusions about an inverse correlation between dexamethasone and corticosteroid plasma concentrations would be speculative. However, the dexamethasone pharmacokinetics might be an important variable and may contribute to some of the recent uncertainty about the DST.

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 mug 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 x min x 1,000/ml vs 3.1 +/- 2.4 ng x min x 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.

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.

Seventy-seven consecutively admitted inpatients with depressive syndromes were examined with the Present State Examination and classified according to eight different operational diagnoses of endogenous depression. All patients received a 1.5 mg dexamethasone suppression test (DST). Sensitivity, specificity and the corrected predictive values of DST nonsuppression (50 or more ng/ml at 0800 hr, 1600 hr, or 2300 hr), adjusted to a 50% prevalence of endogenous and nonendogenous depression, varied considerably depending on the diagnostic definition used. The highest predictive value (89.9%) was found with the Taylor-Abrams criteria (sensitivity = 43.9%, specificity = 95.0%), and the lowest predictive value (53.3%) with DSM-III (sensitivity = 37.7%, specificity = 68.1%). Eliminating the patients with dexamethasone levels of less than 2000 pg/ml improved the diagnostic specificity of the DST for most of the eight definitions of endogenous depression. This further indicates that plasma dexamethasone levels should be analyzed in studies designed to explore the diagnostic utility of the DST. A significant, chance-corrected association between DST nonsuppression and the diagnosis of endogenous depression was found with clinical diagnosis (according to the International Classification of Diseases), and for four out of eight operational diagnoses (Newcastle Scale I, Newcastle Scale II, Taylor-Abrams Criteria, and Vienna Research Criteria). For the other diagnoses (Research Diagnostic Criteria, DSM-III, Michigan Discriminant Index, and Hamilton Endogenomorphy Index), no significant association was found. The RDC criterion "early or intermittent awakening" was the only one out of 28 diagnostic criteria tested which was significantly associated with DST nonsuppression.

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.

Sleep EEG, nocturnal penile tumescence (NPT) and nocturnal endocrine activity were studied in 3 male control subjects during placebo, under trimipramine (TR) and after withdrawal. TR did not change the sleep structure. NPT activity tended to increase under TR. Nocturnal plasma cortisol levels decreased markedly while the early morning rise of cortisol appeared delayed under 200 mg TR. After withdrawal the changes of the cortisol secretion rebounded. Nocturnal secretion of GH, testosterone, LH and FSH remained unaffected, but plasma prolactin levels increased under TR and returned to normalcy after cessation. Our data illustrate that the neurobiological effects of TR are different from those of other antidepressants. We suggest that some of the psychotropic effects of TR are mediated by suppression of cortisol.

Alterations in baseline and challenged pituitary-adrenocortical function constitute the most extensively studied abnormalities in affective disorders. The recent availability of corticotropin-releasing hormone (CRH) for clinical studies opened the possibility to further investigate pathophysiology underlying aberrant ACTH and cortisol secretion. When injected to depressives CRH induces a blunted ACTH but normal cortisol release. Similar response patterns were observed among patients with panic disorder and alcoholism. In these diseases, enhanced baseline pituitary adrenocortical activity appears to be driven by a CNS disturbance resulting in overactive CRH secreting neurons. In addition to these endocrine findings we observed among normal controls suppressed nocturnal slow-wave sleep and growth hormone surges during infusions of CRH. Our clinical investigations with CRH support that this neuropeptide is involved in mediation of several neuroendocrine and behavioral changes frequently observed in depressive syndromes.

We examined the effect of 20 micrograms recombinant gamma-interferon (rec-gamma-IFN) upon corticotropin (ACTH) and cortisol secretion in 10 healthy male controls. We observed that rec-gamma-IFN enhances cortisol secretion with maxima around 3 hours after injection of the test dose. This effect was suppressible by a single dose of 1.5 mg dexamethasone and was not associated with increased ACTH secretion. Rec-gamma-IFN also failed to enhance ACTH secretion from a pituitary cell culture. From these data we conclude that rec-gamma-IFN acts on lymphoid cells which in turn release a yet unidentified substance that directly activates the adrenocortex in a feedback controlled manner.

Plasma ACTH levels after oral ingestion of 2 g metyrapone at 24.00 hours in six healthy subjects were higher after pretreatment with zimelidine (300 mg) in comparison to placebo. Since zimelidine is a relatively selective serotonin reuptake inhibitor its action on hypothalamic-pituitary-adrenal (HPA) activity suggests that serotonin is a potent stimulator of ACTH release. The ratio of cortisol to 11-deoxycortisol was taken as a measure of 11-hydroxylase activity, which indicates biological activity of secreted ACTH. These cortisol/11-deoxycortisol ratios were significantly increased after zimelidine treatment, when compared to placebo. Both the ACTH response and the cortisol/11-deoxycortisol ratios substantiate evidence derived from animal experiments, indicating a stimulatory influence of serotonin on HPA activity. No firm conclusion, however, may be drawn on by which mechanism zimelidine exerts its action on the HPA-axis. Moreover these findings provide no information on whether serotonin has a stimulatory role on ACTH production under physiological condition.

In an open clinical trial the authors treated 18 hospitalized patients suffering from endogenous depression with brofaromine (CGP 11305A), a competitive, selective, and short-acting inhibitor of type A monoamine oxidase (MAO). Four patients were defined as good responders, as they had a final HAMD score of between 0 and 7 points. Four patients were judged as improved, with final HAMD scores of between 8 and 15 points, while the remaining eight patients failed to respond (final HAMD score greater than or equal to 16 points). The major observations were a beneficial influence on drive in most patients, while paranoid symptoms worsened markedly, rendering the substance contraindicated in psychotic depression. Brofaromine appears to be safe and well tolerated and largely free of side effects. As objectified by the tyramine pressor test, dietary restrictions during brofaromine treatment require less stringency than is the case with conventional MAO inhibitors. The specificity of brofaromine to inhibit deamination is limited to MAO-A, since no reduction in platelet MAO activity was measurable. Sleep EEG recordings in a subset of patients reveals that the amount of rapid eye movement (REM) sleep is significantly reduced during brofaromine treatment.