Glucocorticoid Resistance: Is It a Requisite for Increased Cytokine Production in Depression? A Systematic Review and Meta-Analysis

Abstract

Background: Glucocorticoid resistance—reduced function of the glucocorticoid receptor (GR)—is seen in many depressed patients. It is argued that this resistance to glucocorticoids leads to failure of normal feedback regulation on the immune system. High levels of pro-inflammatory cytokines result. Purpose: We sought to identify evidence supporting or refuting a link between glucocorticoid resistance and immune dysregulation in depression and to summarize retrieved evidence in aggregate form. Methods: We systematically reviewed and meta-analyzed studies that examined cytokine levels in depressed patients compared with controls and that also reported a measure of glucocorticoid resistance. These measures included plasma cortisol, the dexamethasone suppression test (DST), GR expression levels, and the results of in vitro assays of GR function. We conducted four separate meta-analyses to test for moderating effects of glucocorticoid resistance on cytokine production in depression. Results: After sub-grouping 32 studies by the ratio of cortisol levels in patients compared with controls, we observed a trend for increasing glucocorticoid resistance (i.e., the most hypercortisolemic patients) to be associated with increased production of interleukin (IL)-6 [ d = 0.94; 95% CI (0.29, 1.59)] and tumour necrosis factor (TNF)-α [ d = 0.46; 95% CI (0.12, 0.79)]. We stratified nine studies that reported DST results by relative glucocorticoid resistance between patients and controls, identifying a trend for higher glucocorticoid resistance in patients, compared with controls, to be associated with higher cytokine production in patients (170 patients and 187 controls). This was particularly evident when studies were sub-grouped by source of cytokine—plasma ( d = 1.04; 95% CI, 0.57–1.50) versus in vitro ( d = 0.24; 95% CI, −0.20 to 0.67). Stratifying the four studies (147 patients and 118 controls) that used in vitro assays of GR function or GR expression to quantify glucocorticoid resistance revealed variable contributions to cytokine production in patients compared with controls (overall effect size: d = 1.35; 95% CI 0.53–2.18). Combining our analyses of studies that reported DST results with those that used in vitro assays of GR function or GR expression to quantify glucocorticoid resistance (302 patients and 277 controls), we noted that although depressed patients produced more cytokines than controls ( d = 1.02; 95% CI, 0.55–1.49), there was no evident positive correlation between glucocorticoid resistance and inflammation. Conclusions: Our work provides some support for a model conceptualizing glucocorticoid resistance...

Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study

“…While the concept of reduced GR function and expression leading to 'glucocorticoid resistance' in depression has been extensively discussed before [51][52][53][54][55] , including for TRD patients [56][57][58] , the present study shows that reduced GR mRNA expression alone cannot fully explain the increased inflammation. Indeed the aforementioned study by Mellon et al 21 found upregulation of immune pathways in mononuclear cells from depressed patients in the absence of changes in GR function, and our own clinical meta-analysis on this topic has found only limited evidence linking 'glucocorticoid resistance' to inflammation 59 . Furthermore, it is important to emphasise here the additional confounding effects of antidepressant treatment.…”

Neuroimmune Mechanisms and Sex/Gender-Dependent Effects in the Pathophysiology of Mental Disorders

“…In support of that, elevated cortisol levels, GR insensitivity and dysregulation of the HPA axis have been consistently correlated with the inflammatory manifestations during MDD (Turecki and Meaney, 2016). In a recent single-nucleus RNA sequencing study of PFC in patients with MDD, co-chaperones of GRs (Heat shock protein 90 and FKBP5) were downregulated (Nagy et al, 2020), whereas in a systematic meta-analysis, it was demonstrated that increased inflammation (TNF-a, IL-6) is correlated with glucocorticoid resistance and elevated levels of cortisol in patients with MDD (Perrin et al, 2019).…”

The Microbiota-gut-immune-glia (MGIG) Axis in Major Depression<strong> </strong>

“…Moreover, disruption of the intestinal barrier and its increased permeability may be caused by broad range of other stressors including immune, intestinal microbiota-related and environmental factors namely, pro-inflammatory cytokines, i.e., IFN-γ (113), TNF-α (114,115), IL-1β (116), further, NF-κB (117), O&NS (112,118), infections (119,120), abnormalities in gut flora composition such as dysbiosis and small intestine bacterial overgrowth (SIBO) (47,121,122), alcohol (47,(123)(124)(125), heat stress (126), food additives and pesticides (127)(128)(129)(130)(131)(132), prolonged strenuous exercise (133,134), specific medication including non-steroidal anti-inflammatory drugs (NSAID) (135,136) or antibiotics (137-140) ( Figure 1). Furthermore, psychological stress, MDD and chronic inflammatory disorders are often accompanied by hypercortisolemia which when prolonged, may lead to glucocorticoid (GKK) receptors resistance (141). This might be another crucial aspect in the context of increased intestinal permeability in MDD since it has been demonstrated that GKK…”