Abstract
Directly measuring hypothalamic pituitary adrenal (HPA) axis function, an important player in affective disorders, is intensive and invasive. A crucial component of this system, the activity of the glucocorticoid receptor (GR), can be assessed ex vivo instead. Here, we investigated GR sensitivity in patients with major depressive disorder (MDD) to determine its predictive potential. Psychometric data and blood samples were collected from patients experiencing a major depressive episode (MDE, n = 87), healthy control subjects (n = 49), and patients with remitted MDD (n = 31) at baseline and (for patients) after median 20 days of follow-up after treatment as usual. Blood cells were stimulated ex vivo with lipopolysaccharide and the effect was suppressed by increasing dexamethasone (DEX) concentrations. The resultant cytokine secretion profile (for IL-6, IL-10, and TNF-α) was considered indicative of GR activity. Higher baseline scores of the Montgomery–Åsberg Depression Rating Scale (MADRS) were associated with a stronger decrease of logIC IL-6 (indicating an increase of GR sensitivity). Higher baseline logEC IL-10 (indicating a lower GR sensitivity) and a stronger reduction of logEC IL-10 (indicating a stronger increase in GR sensitivity) were associated with a stronger decrease in the MADRS score. Patients with remitted MDD showed higher logIC TNF-α values (indicating lower GR sensitivity) in comparison to patients with a current MDD at baseline and follow-up. Initially low GR sensitivity measured ex vivo in peripheral blood cells that increases over the course of treatment could serve as a predictive marker for stronger improvement in depression severity.
Highlights
Major depressive disorder (MDD) is an important public health issue and one of the five leading reasons that caused people to live with a disability in 2016 (GBD 2016 disease and injury incidence and prevalence collaborators 2017)
LPS can modulate the production of the antiinflammatory cytokine IL-10 (Saraiva and O’Garra 2010; van den Bosch et al 2014) and measuring LPS-induced IL-10 response has been shown to be a sensitive marker for disturbed glucocorticoid regulation at least in patients with chronic fatigue syndrome (Visser et al 2001)
We investigated an applicable, less burdensome ex vivo stimulation method to measure glucocorticoid receptor (GR) sensitivity alterations in patients with depression based on published protocols (Bellingrath et al 2013; Burnsides et al 2012; Smits et al 1998; ter Wolbeek et al 2008)
Summary
Major depressive disorder (MDD) is an important public health issue and one of the five leading reasons that caused people to live with a disability in 2016 (GBD 2016 disease and injury incidence and prevalence collaborators 2017). The combined dexamethasone–corticotropin-releasing hormone (DEX/CRH) test, a measure of HPA axis (dys)regulation, is altered in 24–35% of patients with acute depression (Schüle et al 2009). TNF-α seems to be sensitive to suppression by DEX, at least in patients with chronic fatigue syndrome (Lynn et al 2018) This could be due to stronger inhibition of Th1 over Th2 CD4 + T cells through glucocorticoids (Lynn et al 2018; Visser et al 2000). LPS can modulate the production of the antiinflammatory cytokine IL-10 (Saraiva and O’Garra 2010; van den Bosch et al 2014) and measuring LPS-induced IL-10 response has been shown to be a sensitive marker for disturbed glucocorticoid regulation at least in patients with chronic fatigue syndrome (Visser et al 2001). Whole blood was stimulated with LPS and the production of the cytokines IL-6, IL-10, and TNF-α as well as suppression of this effect by increasing concentrations of DEX has been measured
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