Page - (000139) - in Biomedical Chemistry: Current Trends and Developments

dysfunction in MDD, melancholic subtype, which is not conditional on the conscious awareness of stress (Wong, 2000). Circadian measures of CSF NE and CSF CRH and peripheral cortisol suggest mutually reinforcing bidirectional relationships between brain NE and CRH pathways that promotes increased central noradrenergic, adrenomedullary, and adrenocortical secretion, which promote a state of hyperarousal and anxiety found in MDD (Gold, 2005; Wong, 2000). In MDD, atypical subtype, patients display fatigue, lethargy, hypersomnia, and hyperphagia, which are related to suppression of the stress system mediators (Chrousos & Gold, 1992; Gold, 1988a, 1988b). Patients with atypical features have been reported to be eucortisolemic and have low CSF CRH levels (Geracioti, 1997; Gold, 1995). However, detecting decrement in HPA axis is challenging. In response to synthetic CRH, these patients show delays in peripheral ACTH response and very attenuated cortisol responses (Schulte, 1984). We have reported the involvement of the CRHR1 gene in antidepressant response; anxious patients homozygous for the GAG haplotype of CRHR1 gene had a better antidepressant response (Licinio, 2004); as pre-clinical studies suggested that antidepressants suppress CRH gene expression (Brady, 1992; 1991; Reul, 1993) and clinical studies reported that antidepressants reduce CSF CRH concentrations (De Bellis, 1993; Heuser, 1998; Veith, 1993), downregulation of CRH activity could be a common pathway for the therapeutic actions of antidepressants. Chronic stress can also result in dysregulation with activation or suppression of the immune system; clinical and pre-clinical research support a role of immune system dysregulation in MDD with activation of the cellular and humoral immune responses (Kronfol & Remick, 2000; Licinio & Wong, 1999). Increased circulating lymphocytes and monocytes have been described (Herbert & Cohen, 1993; Rothermundt, 2001; Seidel, 1996). Increased circulating IL-6 levels have been described in MDD and these levels were significantly correlated with self-reported mood ratings (Alesci, 2005). Pro-inflammatory cytokines, such as IL-1ß and IL-6, stimulate the HPA axis (Plata-Salaman, 1991). Stress-induced depressive-like behaviours also increase peripheral IL-6 levels in rodents (Himmerich, 2013), and recently brain IL-6 has been implicated in