Perrin Andrew J, Horowitz Mark A, Roelofs Jacob, Zunszain Patricia A, Pariante Carmine M
Stress, Psychiatry and Immunology Laboratory, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
Clinician Investigator Program and Department of Psychiatry, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
Front Psychiatry. 2019 Jun 28;10:423. doi: 10.3389/fpsyt.2019.00423. eCollection 2019.
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. 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. 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), expression levels, and the results of assays of GR function. We conducted four separate meta-analyses to test for moderating effects of glucocorticoid resistance on cytokine production in depression. 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 [ = 0.94; 95% CI (0.29, 1.59)] and tumour necrosis factor (TNF)-α [ = 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 ( = 1.04; 95% CI, 0.57-1.50) versus ( = 0.24; 95% CI, -0.20 to 0.67). Stratifying the four studies (147 patients and 118 controls) that used assays of GR function or expression to quantify glucocorticoid resistance revealed variable contributions to cytokine production in patients compared with controls (overall effect size: = 1.35; 95% CI 0.53-2.18). Combining our analyses of studies that reported DST results with those that used assays of GR function or expression to quantify glucocorticoid resistance (302 patients and 277 controls), we noted that although depressed patients produced more cytokines than controls ( = 1.02; 95% CI, 0.55-1.49), there was no evident positive correlation between glucocorticoid resistance and inflammation. 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.
许多抑郁症患者存在糖皮质激素抵抗，即糖皮质激素受体（GR）功能降低。有人认为，这种对糖皮质激素的抵抗会导致免疫系统正常反馈调节失效。进而产生高水平的促炎细胞因子。我们试图找出支持或反驳抑郁症中糖皮质激素抵抗与免疫失调之间联系的证据，并以汇总形式总结检索到的证据。我们系统地回顾并荟萃分析了相关研究，这些研究检测了抑郁症患者与对照组的细胞因子水平，同时也报告了糖皮质激素抵抗的一项指标。这些指标包括血浆皮质醇、地塞米松抑制试验（DST）、表达水平以及GR功能检测结果。我们进行了四项独立的荟萃分析，以检验糖皮质激素抵抗对抑郁症中细胞因子产生的调节作用。在根据患者与对照组皮质醇水平之比对32项研究进行亚组分析后，我们观察到糖皮质激素抵抗增加（即皮质醇水平最高的患者）与白细胞介素（IL）-6[效应量 = 0.94；95%置信区间（0.29，1.59）]和肿瘤坏死因子（TNF）-α[效应量 = 0.46；95%置信区间（0.12，0.79）]产生增加之间存在一种趋势。我们根据患者与对照组之间的相对糖皮质激素抵抗对九项报告了DST结果的研究进行分层，发现与对照组相比，患者中较高的糖皮质激素抵抗与患者中较高的细胞因子产生相关（170例患者和187例对照）。当根据细胞因子来源（血浆）对研究进行亚组分析时，这种情况尤为明显（效应量 = 1.04；95%置信区间，0.57 - 1.50），而（效应量 = 0.24；95%置信区间，-0.20至0.67）。对四项使用GR功能检测或表达来量化糖皮质激素抵抗的研究（147例患者和118例对照）进行分层分析，结果显示与对照组相比，患者中对细胞因子产生的贡献各不相同（总体效应量：效应量 = 1.35；95%置信区间0.53 - 2.18）。将我们对报告DST结果的研究分析与使用GR功能检测或表达来量化糖皮质激素抵抗的研究分析相结合（302例患者和277例对照），我们注意到尽管抑郁症患者比对照组产生更多的细胞因子（效应量 = 1.02；95%置信区间，0.55 - 1.49），但糖皮质激素抵抗与炎症之间没有明显的正相关。我们的研究为将糖皮质激素抵抗概念化为抑郁症炎症增加的必要条件的模型提供了一些支持。已确定的研究数量有限，这突出表明需要进行专门设计的调查，以直接研究抑郁症中糖皮质激素抵抗与细胞因子产生之间的关系。
