Abstract
BackgroundIn this study the predictive value of the combined dexamethasone/CRH test (DEX/CRH test) for acute antidepressant response was investigated.Methodology/Principal FindingsIn 114 depressed inpatients suffering from unipolar or bipolar depression (sample 1) the DEX/CRH test was performed at admission and shortly before discharge. During their stay in the hospital patients received different antidepressant treatment regimens. At admission, the rate of nonsuppression (basal cortisol levels >75.3 nmol/l) was 24.6% and was not related to the later therapeutic response. Moreover, 45 out of 114 (39.5%) patients showed an enhancement of HPA axis function at discharge in spite of clinical improvement. In a second sample, 40 depressed patients were treated either with reboxetine or mirtazapine for 5 weeks. The DEX/CRH test was performed before, after 1 week, and after 5 weeks of pharmacotherapy. Attenuation of HPA axis activity after 1 week was associated with a more pronounced alleviation of depressive symptoms after 5-week mirtazapine treatment, whereas downregulation of HPA system activity after 5 weeks was related to clinical response to reboxetine. However, early improvement of HPA axis dysregulation was not necessarily followed by a beneficial treatment outcome.Conclusions/SignificanceTaken together, performance of a single DEX/CRH test does not predict the therapeutic response. The best predictor for response seems to be an early attenuation of HPA axis activity within 1 or 2 weeks. However, early improvement of HPA system dysfunction is not a sufficient condition for a favourable response. Since a substantial part of depressive patients display a persistence of HPA axis hyperactivity at discharge, downregulation of HPA system function is not a necessary condition for acute clinical improvement either. Our data underline the importance of HPA axis dysregulation for treatment outcome in major depression, although restoration of HPA system dysfunction seems to be neither a necessary nor a sufficient determinant for acute treatment response.
Highlights
According to the corticosteroid-receptor hypothesis of depression hypothalamic-pituitary-adrenocortical (HPA) system dysregulation plays an important role in the pathophysiology of depression [1,2]
Further investigations using neuroendocrine challenge tests confirmed the hypothesis of a profound HPA axis dysregulation in depression: Several studies using the corticotropin-releasing hormone (CRH)-stimulation test reported a blunted adrenocorticotrophic hormone (ACTH) response whereas the COR stimulation was indistinguishable from normal controls [9,10]
We abstained from reporting the ACTH levels, since COR has been demonstrated to be the best parameter for analyzing DEX/CRH test results and since most established cut-off criterions are related to COR levels but not ACTH concentrations
Summary
According to the corticosteroid-receptor hypothesis of depression hypothalamic-pituitary-adrenocortical (HPA) system dysregulation plays an important role in the pathophysiology of depression [1,2]. Further investigations using neuroendocrine challenge tests confirmed the hypothesis of a profound HPA axis dysregulation in depression: Several studies using the corticotropin-releasing hormone (CRH)-stimulation test reported a blunted ACTH response whereas the COR stimulation was indistinguishable from normal controls [9,10]. Findings in depressed patients of increased CRH levels in the CSF [17] and elevated numbers of CRH [18] and argininevasopressin (AVP) [19] expressing neurons in the paraventricular nucleus of the hypothalamus as well as the observation of reduced CRH binding sites in the frontal cortex of suicide victims [20] gave reason to the assumption that depression is characterized by a hypothalamic overdrive of CRH and/or AVP which in consequence leads to receptor down-regulation in the corticotrophs of the pituitary gland. In this study the predictive value of the combined dexamethasone/CRH test (DEX/CRH test) for acute antidepressant response was investigated
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