Heuser IJE, Yassouridis A, Holsboer F. The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. J Psychiatr Res 28: 341-356

Max Planck Institute of Psychiatry, Clinical Institute, Munich, Germany
Journal of Psychiatric Research (Impact Factor: 3.96). 07/1994; 28(4):341-356. DOI: 10.1016/0022-3956(94)90017-5


This report summarizes our extensive experience with the application of the DEX/CRH test to assess hypothalamic-pituitary-adrenal-system (HPA) alteration in patients with psychiatric disorders. The application of this combined dexamethasone suppression/CRH-challenge (DEX/CRH) test requires individuals to take 1.5 mg dexamethasone (DEX) at 23:00 h orally the previous night. On the day of the test, 100 μg human CRH are administered to the subjects under study at 15:00 h intravenously as a bolus, and blood samples for the determination of plasma cortisol and ACTH are drawn every 15 min from 14:00 h to 18:00 h. DEX/CRH-test results from 96 patients with major depression (MDE), 11 with a manic episode (MA), 9 with panic disorder (PD), 24 with a schizophrenic psychosis (SP), and 82 healthy control subjects served as the data base for this report. Three major conclusions can be drawn from statistical analysis of these data: 1. Psychiatric patients (n = 140), regardless of diagnostic classification, release significantly more cortisol and ACTH after DEX and additional CRH in comparison with age-matshed controls. This hormonal release pattern (DEX/CRH-test phenomenon) supports the assumption that psychiatric patients are prone to an altered glucocorticoid feedback regulation during the acute illness episode. This supports the notion that the DEX/CRH-test phenomenon constitutes a neuroendocrine sign of these various disorders and emphasizes the usefulness of the DEX/CRH test as a laboratory test to monitor the course of these disorders. 2. The sensitivity of the DEX/CRH test for MDE (about 80%) greatly exceeds that of the standard DST (1–2 mg of DEX), which has been reported to average about 44% in a meta-analysis of the literature data; in our sample the sensitivity of the DST was about 25%. 3. The sensitivity of the DEX/CRH test can be further increased to above 90% if subjects are clustered into four different age ranges: age < 35 years, age between 35 and 50 years, age between 50 and 70 years, and age above 70 years. 4. By reducing the time points of blood sampling for ACTH and cortisol to as few as five (15:00, 15:30, 15:45, 16:00, and 16:15 h), the DEX/CRH-test procedure becomes more convenient and more easily applicable without reducing its sensitivity.

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    • "However, more enduring HPA-axis hyperactivity is seen in approximately 73% of patients with Major Depressive Disorder (MDD) (Vreeburg et al., 2009; Holsboer, 2000). In general in MDD, HPA-axis alterations are found as (I) hyperactivity: increased cortisol in blood and cerebrospinal fluid, (II) non-suppression: higher rates of non-suppression to the dexamethasone suppression test and dexamethasone- CRH (DEX-CRH) test (Heuser et al., 1994; Stetler and Miller, 2011), and/or (III) decreased HPA-axis feedback inhibition . These factors can be integrated by the hypothesis that impaired glucocorticoid receptor (GR)-mediated feedback inhibition (non-suppression) leads to a higher baseline cortisol secretion (hyperactivity), which diminishes reactive capacity (Pariante, 2009). "
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    ABSTRACT: Hypothalamic-pituitary-adrenal (HPA)-axis dysregulation is a prominent finding in more severe Major Depressive Disorder (MDD), and is characterized by increased baseline cortisol levels at awakening (BCL), blunted cortisol awakening response (CAR) and increased area under the cortisol curve (AUC). Selective serotonin reuptake inhibitors (SSRIs) appear to normalize HPA-axis dysfunction, but this is hardly investigated longitudinally. We studied salivary BCL, CAR and AUC at awakening and 30min thereafter. We compared measurements in initially drug-free MDD-patients with healthy controls (HCs) at study-entry. In patients, we repeated measures after 6 and 12 weeks' treatment with the SSRI paroxetine. Non-responding patients received a randomized dose-escalation after six weeks' treatment. We found no significant study-entry differences in BLC, CAR or AUC between MDD-patients (n=70) and controls (n=51). In MDD-patients, we found general decreases of BCL and AUC during paroxetine treatment (p≤0.007), especially in late and non-responders. Importantly, while overall CAR did not change significantly over time, it robustly increased over 12 weeks especially when patients achieved remission (p≤0.041). The dose-escalation intervention did not significantly influence CAR or other cortisol parameters. In conclusion, paroxetine seems to interfere with HPA-axis dysregulation, reflected in significant overall decreases in BCL and AUC during treatment. Paroxetine appears to decrease HPA-axis set-point in MDD, which might result in increased HPA-axis activity over time, which is further improved when patients achieve remission (ISRCTN register nr. ISRCTN44111488). Copyright © 2014 Elsevier Ltd. All rights reserved.
    Psychoneuroendocrinology 11/2014; 52C(1):261-271. DOI:10.1016/j.psyneuen.2014.10.024 · 4.94 Impact Factor
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    • "These results suggest an interaction effect, in which the CRHR1 gene and childhood maltreatment impact on glucocorticoid-mediated inhibition of the HPA axis under challenge conditions, as tested by the specific test. Increased responsiveness in the dexamethasone/CRH test has long been known to be a potent risk marker for depression (87). Hence, this study provides important insight into the potential mechanism for a Gene × ELS interaction in depression. "
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    ABSTRACT: This review focuses on current research developments in the study of gene by early life stress (ELS) interactions and depression. ELS refers to aversive experiences during childhood and adolescence such as sexual, physical or emotional abuse, emotional or physical neglect as well as parental loss. Previous research has focused on investigating and characterizing the specific role of ELS within the pathogenesis of depression and linking these findings to neurobiological changes of the brain, especially the stress response system. The latest findings highlight the role of genetic factors that increase vulnerability or, likewise, promote resilience to depression after childhood trauma. Considering intermediate phenotypes has further increased our understanding of the complex relationship between early trauma and depression. Recent findings with regard to epigenetic changes resulting from adverse environmental events during childhood promote current endeavors to identify specific target areas for prevention and treatment schemes regarding the long-term impact of ELS. Taken together, the latest research findings have underscored the essential role of genotypes and epigenetic processes within the development of depression after childhood trauma, thereby building the basis for future research and clinical interventions.
    Frontiers in Endocrinology 02/2014; 5:14. DOI:10.3389/fendo.2014.00014
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    • "Most studies have demonstrated that severely depressed patients often show non-suppression and impaired feedback inhibition by dexamethasone, which is indicative for dysfunction of corticosteroid receptors, especially GR (34, 41–43). However, due to low sensitivity of the DST (20–50%) to distinguish between patients with major depression and patients with other psychiatric disorders or healthy subjects (39, 44), Holsboer et al. have developed a more sensitive neuroendocrine test (45, 46) that combines the DST and the corticotropin-releasing hormone (CRH) stimulation test, and it is called the dexamethasone/corticotrophin-releasing hormone (Dex/CRH) challenge test. A suppressive test using another synthetic glucocorticoid, prednisolone, has recently been developed. "
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    ABSTRACT: Background: Evidence indicates that early life stress (ELS) can induce persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis to respond to stress in the adult life that leads to depression. These appear to be related to the impairment of HPA hormones through binding to glucocorticoid (GR) and mineralocorticoid receptors (MR). The aim of this study was to evaluate the impact of ELS in HPA axis response to challenges with GR and MR agonists in depressed patients. Methods: We included 30 subjects, 20 patients with current major depression (HAM-D21 ≥ 17). Patients were recruited into two groups according to ELS history assessed by the Childhood Trauma Questionnaire (CTQ). The cortisol measures in the saliva and plasma were evaluated after using (at 10:00 p.m.) placebo, fludrocortisone (MR agonist), or dexamethasone (GR agonist). Results: Depressed patients showed a significantly lower salivary cortisol upon waking after placebo compared with controls. Moreover, cortisol awakening responses (CAR) after MR agonist were found to be lower in depressed patients than in controls. With CTQ scores, HAM-D21, body mass index and CAR after placebo, GR agonist, MR agonist we found in a Linear Regression model that depressive patients with ELS (p = 0.028) show differences between placebo vs. MR agonist (R = 0.51; p < 0.05) but not after GR agonist; in depressive patients, without ELS the data show differences between placebo vs. MR agonist (R = 0.69; p < 0.05); but now as well placebo vs. GR agonist (R = 0.53; p < 0.05). Conclusion: Our findings indicate that MR activity is impaired in depressed patients compared with controls. Furthermore, in spite of the previous limitations described, in depressed patients with ELS, there was suppression by MR agonist, indicating that patients with ELS are sensitive to MR agonists. In contrast with depressed patients without ELS, we find suppression after both MR and GR agonist. These data suggested that in ELS an imbalance exists between MR and GR with MR dysfunction.
    Frontiers in Psychiatry 01/2014; 5:2. DOI:10.3389/fpsyt.2014.00002
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