Glucocorticoid Signaling in Stress-Related Psychiatric Disorders Uncovered by Dexamethasone-Induced Gene Expression

Major depressive disorder (MDD) is a common, serious and in some cases life‐threatening condition and affects approximately 350 million people globally (Otte et al., 2016). The magnitude of the clinical burden reflects the limited effectiveness of current available therapies. The current prescribed antidepressants are based on modulating monoaminergic neurotransmission, i.e. they improve central availability of serotonin, norepinephrine and dopamine. However, they are associated with a high rate of partial or non-response, delayed response onset and limited duration. Actually more than 50% of the patients fail to respond to their first antidepressant they receive. Therefore there is a need of new treatment approaches targeting other systems than the monoaminergic pathway. One of the most robust findings in biological psychiatry is a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in major depression (Holsboer, 2000). Many studies observed an increased production of the corticotropin-releasing hormone (CRH) in the hypothalamus, leading to an increased release of adrenocorticotropic hormone (ACTH) from the pituitary and subsequently to an enhanced production of cortisol in the adrenal cortex. Due to an impaired sensitivity of the glucocorticoid receptor (GR) the negative feedback mechanisms usually restoring homeostasis after a stress triggered cortisol release are not functioning properly (Holsboer, 2000, Pariante and Miller, 2001). However, treatment strategies targeting the GR or the CRH receptors have not been successful for a general patient population. Selecting the right patients for these treatment alternatives may improve therapy outcome, since a dysregulation of the HPA axis affects only 40-60 % of the depressed patients. Thus, patients with a dysregulated HPA axis have first to be identified and then allocated to a specific treatment regime. Tests like the dexamethasone-suppression-test (DST) or the dex-CRH test have been shown to uncover GR sensitivity deficits, but are not routinely applied in the clinical setting. Recently, the dexamethasone-induced gene expression could uncover GR alterations in participants suffering from major depression and job-related exhaustion (Menke et al., 2012, Menke et al., 2013, Menke et al., 2014, Menke et al., 2016). Actually, by applying the dexamethasone-stimulation test we found a GR hyposensitivity in depressed patients (Menke et al., 2012) and a GR hypersensitivity in subjects with job-related exhaustion (Menke et al., 2014). These alterations normalized after clinical recovery (Menke et al., 2014). Interestingly, the dexamethasone-stimulation test also uncovered FKBP5 genotype dependent alterations in FKBP5 mRNA expression in depressed patients and healthy controls (Menke et al., 2013). FKBP5 is a co-chaperone which modulates the sensitivity of the GR (Binder, 2009). In addition, the dexamethasone-stimulation test provided evidence of common genetic variants that modulate the immediate transcriptional response to GR activation in peripheral human blood cells and increase the risk for depression and co-heritable psychiatric disorders (Arloth et al., 2015). In conclusion, the molecular dexamethasone-stimulation test may thus help to characterize subgroups of subjects suffering from stress-related conditions and in the long-run may be helpful to guide treatment regime as well as prevention strategies.   References: Arloth J, Bogdan R, Weber P, Frishman G, Menke A, Wagner KV, Balsevich G, Schmidt MV, Karbalai N, Czamara D, Altmann A, Trumbach D, Wurst W, Mehta D, Uhr M, Klengel T, Erhardt A, Carey CE, Conley ED, Major Depressive Disorder Working Group of the Psychiatric Genomics C, Ruepp A, Muller-Myhsok B, Hariri AR, Binder EB, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium PGC (2015) Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders. Neuron 86:1189-1202. Binder EB (2009) The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology 34 Suppl 1:S186-195. Holsboer F (2000) The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23:477-501. Menke A, Arloth J, Best J, Namendorf C, Gerlach T, Czamara D, Lucae S, Dunlop BW, Crowe TM, Garlow SJ, Nemeroff CB, Ritchie JC, Craighead WE, Mayberg HS, Rex-Haffner M, Binder EB, Uhr M (2016) Time-dependent effects of dexamethasone plasma concentrations on glucocorticoid receptor challenge tests. Psychoneuroendocrinology 69:161-171. Menke A, Arloth J, Gerber M, Rex-Haffner M, Uhr M, Holsboer F, Binder EB, Holsboer-Trachsler E, Beck J (2014) Dexamethasone stimulated gene expression in peripheral blood indicates glucocorticoid-receptor hypersensitivity in job-related exhaustion. Psychoneuroendocrinology 44:35-46. Menke A, Arloth J, Putz B, Weber P, Klengel T, Mehta D, Gonik M, Rex-Haffner M, Rubel J, Uhr M, Lucae S, Deussing JM, Muller-Myhsok B, Holsboer F, Binder EB (2012) Dexamethasone Stimulated Gene Expression in Peripheral Blood is a Sensitive Marker for Glucocorticoid Receptor Resistance in Depressed Patients. Neuropsychopharmacology 37:1455-1464. Menke A, Klengel T, Rubel J, Bruckl T, Pfister H, Lucae S, Uhr M, Holsboer F, Binder EB (2013) Genetic variation in FKBP5 associated with the extent of stress hormone dysregulation in major depression. Genes Brain Behav  12:289-296. Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, Mohr DC, Schatzberg AF (2016) Major depressive disorder. Nature reviews Disease primers 2:16065. Pariante CM, Miller AH (2001) Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biological psychiatry 49:391-404.