21 No heritability data are available for the combined dex/CRH test. However, In the Munich Vulnerability Study,22,23 the combined dex/CRH test was conducted In healthy selleck first-degree relatives of patients with a major depressive disorder, who are assumed to carry a genetic vulnerability for affective disorders. These so-called high-risk probands (HRPs) are

characterized by a moderately elevated hormonal response to the combined dex/CRH test, which was significantly higher compared with controls without a personal or familial history of psychiatric disorders, Inhibitors,research,lifescience,medical but less pronounced compared with the response in acutely depressed patients. Modell and coworkers24 replicated these findings In Inhibitors,research,lifescience,medical still unaffected HRPs who were re-examined in a follow-up Investigation about 4 years later (Figure 3), suggesting that this trait-like impaired regulation of the HPA system could reflect the genetic vulnerability for affective disorders in these

subjects. Figure 3. Cortisol response to the combined dex/CRH test is moderately elevated in high risk probands for affective disorders Inhibitors,research,lifescience,medical (AUC, P<.05), which was stable over time at the group level (AUC, P=.758) as well as at the individual level (Pearson correlation, ... Despite the statistical evidence for a considerable heritability of the stress response, the number of significant genetic findings Is small, and the conclusiveness Inhibitors,research,lifescience,medical rather limited. The findings are summarized in Table I. Due to the Importance of the HPA system for the stress response, which is primarily regulated by GR, the GR gene has been proposed as the primary candidate Inhibitors,research,lifescience,medical for the genetic association studies. Significant associations between GR and psychosocial stress response were reported, but only when a haplotype approach is applied25

or when male subjects are separately analyzed (Kumsta and Wust, 2006; personal communication). Further genetic associations, not yet replicated, are reported for the γ-aminobutyric acid (GABA) A 6 receptor subunit gene26 and for an nonsynonymous exon single-nucleotide polymorphism (SNP) of the micro-opiold receptor 1 (MOR) gene.27 Table I. Genetic associations and with stress response in human paradigms. GABA, γ-aminobutyric acid; ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; HPA, hypothalamic-pituitary-adrenal Additional evidence for an Involvement of the GR gene in the genetics of the stress response has been provided by two other studies (Table I) employing a low-dose dex suppression test In elderly subjects.