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  • The role of the ER EK variant which is

    2021-09-23

    The role of the ER22/23EK variant which is associated with relative resistance to GC, as shown by a reduction of transactivating capacity in vitro and less suppression of Calcium Colorimetric Assay Kit levels after 1mg DST in vivo. Relative GC resistance associated with the ER22/23EK polymorphism might protect from the development of dementia or cognitive decline with aging. Dementia and white matter lesions were less frequent in older (over 55 years) carriers of the ER22/23EK variant [62]. In addition, carriers of the ER22/23EK variant had better cognitive speed tasks and less progression of subcortical lesions. In a study of patients with depression, carrier of the ER22/23EK polymorphism had higher rates of recurrent major depression episodes and responded faster to treatment with antidepressants [63], [64]. A possible explanation could be the higher concentration of the less active GR variant which could lead to GC resistance [65]. An association between the BclI polymorphism and major depression has been found in several studies. This variant is associated with increased sensitivity to GC. The frequency of the BclI variant was higher in patients with major depression and carriers were found to have higher ACTH levels and a worse response to antidepressant therapy [59], [66]. The 9β polymorphism of the GR gene has been linked with a lower incidence of bipolar disorder compared to healthy subjects. A higher incidence of the 9β polymorphism has been linked with a lower frequency of hypomanic episodes in patients with bipolar disorder, suggesting a protective effect of this polymorphism [67]. As mentioned before, this variation results in increased expression and stability of GRβ, functioning as a dominant negative inhibitor of the active receptor GRα. The role of FKBP5, an important factor that controls GR sensitivity and signaling, has been increasingly recognized. The FKBP5 is a HSP90 co-chaperone that binds to GR in the cytosol and decreases the affinity of the GR for its ligand as well as the probability of the translocation of the GR-ligand complex into the nucleus. FKBP5 SNPs have been linked to a variety of psychiatric disorders including dissociative symptoms after trauma, a predictor of PTSD development in children and adult [68]. In addition, FKBP5 SNPs have been linked to recurrence of major depression and the response to antidepressants. The rs9296158 SNP has been found to be associated with a significant risk for PTSD development in subjects traumatized as children. The mechanism by which FKBP5 SNPs alter the function of the HPA axis in PTSD patients is by selectively changing cellular expression of FKBP5 and sensitivity of GR signaling. The reduction of STAT5B mRNA levels found in blood cells from PTSD patients carrying the rs9296158 SNP provides another mechanism of altered GR sensitivity [69]. Docking of the GR to a binding site on the STAT5B N-terminus inhibits GR nuclear translocation. Thereby, STAT5B deficiency could induce excessive GR signal transduction and GR-mediated transcription of target genes. Understanding that polymorphisms of the GR can lead to variable effects on psychiatric diseases, several studies have set out to evaluate a potent antagonist of GR, mifepristone, for the reduction of the psychotic symptoms of psychotic depression [70], [71]. A consistent observation from these studies reveal that 7-day administration of mifepristone appears to be effective in reducing psychotic symptoms but only when sufficient plasma levels of mifepristone are reached. Because there is significant inter-individual variability in plasma mifepristone levels due to complex pharmacokinetics, not every patient can achieve therapeutic mifepristone plasma level at a specific dose level of mifepristone. While approximately 50% of patients administered mifepristone 600mg daily for 7days will achieve this plasma threshold after 7 days, approximately 66% of the patients will surpass the threshold with dosing of 1200mg for 7days [72]. Both dosing regimens appear to be safe and well tolerated. Of note, there is also a relationship between increases in cortisol and ACTH levels after seven days of dosing and response. While mifepristone plasma levels are a predictor of response, cortisol and ACTH levels are a mediator of response to treatment (publication in press), signifying a biologically targeted therapy for the HPA dysregulation of PD.