European Journal of Psychotraumatology (Sep 2012)
Genetic variation and HPA axis activity: implications for diagnosis and treatment
Abstract
Background : Hypothalamic–pituitary–adrenal (HPA) axis activity remains a major focus for the study of the pathophysiology of anxiety and depressive disorders. Recent developments in genetics allow for potential new avenues for assessing risk and for developing new treatments. We will address recent studies on genetics of HPA axis dysregulation in a preclinical model of anxiety/depression, the brains of suicide victims, and severely ill delusional and nondelusional depressives. Last, the development of new glucocorticoid receptor (GR) antagonists that may prove useful as therapeutics in major psychiatric disorders is reviewed. Methods : Ned Kalin will first present data on a stress model of anxiety/depression in rhesus monkeys. Over 400 monkeys were characterized on behavior and positron emission tomography imaging in response to an intruder and were genotyped for alleles for both corticotropin-releasing hormone receptors (CRH-R1 and CRH-R2). Shyam Pandey will report on gene expression for CRH-R1, CRH-R2, GR, and the mineralocorticoid receptor (MR) in multiple brain regions of adolescents who committed suicide and in matched controls who did not. In a sample of 122 subjects, Alan Schatzberg will present data on genetic variation differences in GR and CRH-R1 between severely depressed patients (delusional and nondelusional) and healthy controls as well as on the relationship of CRH and GR alleles to mean cortisol activity collected hourly from 6 PM to 1 AM as well as from 1 AM to 9 AM. Finally, Joseph Belanoff of Corcept Therapeutics will discuss the application of medicinal stereochemistry in the development of GR antagonists with greater GR specificity and organ selectivity than those currently available. Results : Associations between allelic variations in HPA axis genes and behavior were observed for CRH-R1 and CRH-R2 alleles in the rhesus monkey. Decreased message expression for GR and CRH-R1 was observed in key brain regions in suicide victims. Allelic variation for CRH_R1 and GR was associated with risk for severe depression and psychosis, and GR alleles were associated with elevated cortisol levels. A number of nonsteroidal GR antagonists have been synthesized and are active in various animal models. Conclusions : HPA axis remains a potential source of diagnostic tests and innovative treatment.
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