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 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.