AUTHOR=Perrin Andrew J. , Horowitz Mark A. , Roelofs Jacob , Zunszain Patricia A. , Pariante Carmine M. 

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

JOURNAL=Frontiers in Psychiatry

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2019.00423

DOI=10.3389/fpsyt.2019.00423

ISSN=1664-0640

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Purpose:</bold> 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.</p><p><bold>Methods:</bold> 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), <italic>GR</italic> expression levels, and the results of <italic>in vitro</italic> assays of GR function. We conducted four separate meta-analyses to test for moderating effects of glucocorticoid resistance on cytokine production in depression.</p><p><bold>Results:</bold> 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 [<italic>d</italic> = 0.94; 95% CI (0.29, 1.59)] and tumour necrosis factor (TNF)-α [<italic>d</italic> = 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 (<italic>d</italic> = 1.04; 95% CI, 0.57–1.50) versus <italic>in vitro</italic> (<italic>d</italic> = 0.24; 95% CI, −0.20 to 0.67). Stratifying the four studies (147 patients and 118 controls) that used <italic>in vitro</italic> assays of GR function or <italic>GR</italic> expression to quantify glucocorticoid resistance revealed variable contributions to cytokine production in patients compared with controls (overall effect size: <italic>d</italic> = 1.35; 95% CI 0.53–2.18). Combining our analyses of studies that reported DST results with those that used <italic>in vitro</italic> assays of GR function or <italic>GR</italic> expression to quantify glucocorticoid resistance (302 patients and 277 controls), we noted that although depressed patients produced more cytokines than controls (<italic>d</italic> = 1.02; 95% CI, 0.55–1.49), there was no evident positive correlation between glucocorticoid resistance and inflammation.</p><p><bold>Conclusions:</bold> Our work provides some support for a model conceptualizing glucocorticoid resistance as a requisite for increased inflammation in depression. The limited number of studies identified highlights the need for purpose-designed investigations that directly examine the relationship between glucocorticoid resistance and cytokine production in depression.</p>