Sex Differences in Serum Markers of Major Depressive Disorder in the Netherlands Study of Depression and Anxiety (NESDA)

Women have a consistently higher prevalence of major depressive disorder (MDD) than men. Hypotheses implicating hypothalamic-pituitary -adrenal, -gonadal, and -thyroid axes, immune response, genetic factors, and neurotransmitters have emerged to explain this difference. However, more evidence for these hypotheses is needed and new explanations must be explored. Here, we investigated sex differences in MDD markers using multiplex immunoassay measurements of 171 serum molecules in individuals enrolled in the Netherlands Study of Depression and Anxiety (NMDD = 231; Ncontrol = 365). We found 28 sex-dependent markers of MDD, as quantified by a significant interaction between sex and log2-transformed analyte concentration in a logistic regression with diagnosis (MDD/control) as the outcome variable (p0.05; q0.30). Among these were a number of male-specific associations between MDD and elevated levels of proteins involved in immune response, including C-reactive protein, trefoil factor 3, cystatin-C, fetuin-A, β2-microglobulin, CD5L, FASLG receptor, and tumor necrosis factor receptor 2. Furthermore, only male MDD could be classified with an accuracy greater than chance using the measured serum analytes (area under the ROC curve = 0.63). These findings may have consequences for the generalization of inflammatory hypotheses of depression to males and females and have important implications for the development of diagnostic biomarker tests for MDD. More studies are needed to validate these results, investigate a broader range of biological pathways, and integrate this data with brain imaging, genetic, and other relevant data.女性重性抑郁障碍（major depressive disorder, MDD）的患病率始终高于男性。目前已有诸多假说试图解释这一性别差异，涉及下丘脑-垂体-肾上腺轴、下丘脑-垂体-性腺轴、下丘脑-垂体-甲状腺轴、免疫应答、遗传因素以及神经递质等方向。然而，上述假说仍需更多实证支撑，全新的解释路径亦有待探索。本研究依托荷兰抑郁与焦虑研究队列中的受试者开展分析，其中重性抑郁障碍组（MDD组）231例、健康对照组365例，采用多重免疫分析法（multiplex immunoassay）对171种血清分子进行检测。本研究鉴定出28个与性别相关的MDD标志物，该结果通过以诊断状态（MDD/对照）为因变量的logistic回归分析得出：性别与经log₂转换的分析物浓度间存在显著交互作用（p<0.05；q<0.30）。其中存在多项男性特异性关联：男性MDD患者体内参与免疫应答的蛋白质水平升高，包括C反应蛋白、三叶因子3、胱抑素C、胎球蛋白A、β₂-微球蛋白、CD5L、FASLG受体以及肿瘤坏死因子受体2。此外，仅针对男性MDD患者，本研究基于检测到的血清分析物可实现高于随机猜测的分类准确率（受试者工作特征曲线（Receiver Operating Characteristic curve, ROC）下面积=0.63）。本研究结果或对抑郁炎症假说在两性中的推广应用产生影响，同时为重性抑郁障碍诊断性生物标志物检测的研发提供重要参考。未来仍需开展更多研究以验证本研究结果、探索更广泛的生物学通路，并将本数据集与脑影像、遗传学及其他相关数据进行整合分析。