The combined dexamethasone/CRH test: A refined laboratory test for psychiatric disorders
ABSTRACT 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.
- SourceAvailable from: Henricus G Ruhé
[Show abstract] [Hide abstract]
- "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). "
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:261-271. DOI:10.1016/j.psyneuen.2014.10.024 · 5.59 Impact Factor
[Show abstract] [Hide abstract]
- "Stress, particularly in early life, is one of the strongest predictors of major depressive disorder (MDD; Green et al, 2010; Kessler and Magee, 2009) making it critical to understand the neurobiological mechanisms underlying this association. Early stress exposure (eg, Carpenter et al, 2007; Ouellet-Morin et al, 2011) and MDD (Heuser et al, 1994) are both associated with dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, the regulatory system for stress/cortisol responsivity. Accumulating evidence from animal models (eg, Conrad et al, 1999; Cui et al, 2008; Vyas et al, 2002; Watanabe et al, 1992) and humans (eg, Brown et al, 2008; Campbell et al, 2004; Sacher et al, 2012; Videbech and Ravnkilde, 2004) has shown that stress exposure, HPA axis dysregulation, excessive corticosteroid levels, and depression relate to structural alterations in the hippocampus and amygdala, brain regions important in HPA axis regulation (Jacobson and Sapolsky, 1991; Lupien et al, 2009). "
ABSTRACT: Depression has been linked to increased cortisol reactivity and differences in limbic brain volumes, yet the mechanisms underlying these alterations are unclear. One main hypothesis is that stress causes these effects. This is supported by animal studies showing that chronic stress or glucocorticoid administration can lead to alterations in hippocampal and amygdala structure. Relatedly, life stress is cited as one of the major risk factors for depression and candidate gene studies have related variation in stress-system genes to increased prevalence and severity of depression. The present study tested the hypothesis that genetic profile scores combining variance across 10 single nucleotide polymorphisms from four stress-system genes (CRHR1, NR3C2, NR3C1, FKBP5) and early life stress would predict increases in cortisol levels during laboratory stressors in 120 preschool-age children (3-5 years old), as well as hippocampal and amygdala volumes assessed with MRI in these same children at school age (7-12 years old). We found that stress-system genetic profile scores positively predicted cortisol levels while the number of stressful/traumatic life events experienced by 3-5 years old negatively predicted cortisol levels. The interaction of genetic profile scores and early life stress predicted left hippocampal and left amygdala volumes. Cortisol partially mediated the effects of genetic variation and life stress on limbic brain volumes, particularly on left amygdala volume. These results suggest that stress-related genetic and early environmental factors contribute to variation in stress cortisol reactivity and limbic brain volumes in children, phenotypes associated with depression in adulthood.Neuropsychopharmacology accepted article preview online, 25 November 2013. doi:10.1038/npp.2013.327.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2013; 39(5). DOI:10.1038/npp.2013.327 · 7.83 Impact Factor
[Show abstract] [Hide abstract]
- "In the combined DEX/CRH challenge test (Heuser et al., 1994), agents were given via intraperitoneal injection (i.p.). Dexamethasone (Dexa-ratiopharm 100 mg; "
ABSTRACT: Exposure to chronic stress during developmental periods is a risk factor for a number of psychiatric disorders. While the direct effects of stress exposure have been studied extensively, little is known about the long-lasting effects and the interaction with ageing. The same holds true for the treatment with selective serotonin reuptake inhibitors (SSRIs), which have been shown to prevent or reverse some stress-induced effects. Here, we studied the direct and long-lasting impact of chronic social stress during adolescence and the impact of chronic treatment with the SSRI paroxetine in adulthood and aged animals. Therefore, male CD1 mice at the age of 28 days were subjected to 7 weeks of chronic social stress. Treatment with paroxetine was performed per os with a dosage of 20 mg/g BW. We were able to reverse most of the effects of chronic social stress in adult mice (4 months old) and to some extend in aged animals (15 months old) with the SSRI treatment. Especially the regulation of the HPA axis seems to be affected in aged mice with a shift to the use of vasopressin. Our results demonstrate that chronic stress exposure and antidepressant treatment at the end of the developmental period can have a significant and long-lasting impact, highly relevant for healthy ageing.Neuropharmacology 04/2013; 72:38–46. DOI:10.1016/j.neuropharm.2013.03.035 · 4.82 Impact Factor