Dehydroepiandosterone (DHEA) is produced in the adrenal glands from cholesterol and, in its sulphated form, it is the most abundant circulating steroid in humans. It has antiglucocorticoid properties and thus the ratio of cortisol to DHEA has been used as a measure of functional hypercortisolaemia [Young et al. 2002]. The hypothalamic–pituitary–adrenal axis in depression It has been repeatedly shown that there is dysregulation of the HPA axis in depression [Cowen, 2010; McAllister-Williams

et al. 1998]. As early as the 1950s, reports of higher peripheral Inhibitors,research,lifescience,medical concentrations of cortisol in depression emerged, with levels typically normalizing as depressive symptoms remitted [Quarton et al. 1955]. There is evidence of a blunted ACTH response to CRH and of an increased cortisol

Inhibitors,research,lifescience,medical response to ACTH in depression [Kellner et al. 1983]. The volume of pituitary and adrenal glands has also been shown to be increased in patients with depression [Kessing et al. 2011]. An increased cortisol/DHEA ratio Inhibitors,research,lifescience,medical is seen in adults and adolescents with depression and appears to be an indicator of poor prognosis [Markopoulou et al. 2009]. Studies have also shown altered feedback inhibition by corticosteroids as measured by the dexamethasone suppression test or the combined dexamethasone/CRH test [Heuser et al. 1994]. These tests measure the ability of the axis to suppress cortisol release in the presence of the synthetic steroid dexamethasone, a process reliant on the functional integrity of GRs. Is the hypothalamic–pituitary–adrenal axis implicated in the pathogenesis and treatment of depression? Inhibitors,research,lifescience,medical An aetiological role of HPA axis dysregulation in depression is supported by the findings that depression is common in patients with primary abnormalities of cortisol production, such as Cushing’s disease and that depression in these patients is most effectively done treated by normalization of steroid levels [McFarland, 1963; Sonino et al. 1998]. Moreover, exogenous corticosteroid administration is associated Inhibitors,research,lifescience,medical with increased rates of depression, mood Brefeldin_A lability,

cognitive impairment and psychosis [Hall et al. 1979; Rome and Braceland, 1952; Sprague et al. 1950; Wolkowitz et al. 1990a, 1990b] Genes regulating HPA axis function contribute to the genetic vulnerability for depression. The heritability of the level of basal cortisol secretion is estimated to be 60% [Bartels et al. 2003]. HPA feedback disturbance has been observed in otherwise healthy people with a first-degree relative with an affective disorder [Holsboer et al. 1995]. The binding protein FKBP5 is an selleck chemicals llc important modulator of the function of the GR and polymorphisms of genes encoding the GR and FKBP5 have been associated with variations in peripheral cortisol levels and have been implicated in the pathogenesis of stress-related disorders [Velders et al. 2011; Zimmermann et al. 2011].