Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
Janssen Research & Development, LLC., of Johnson & Johnson, Inc., Titusville, NJ, USA.
Brain Behav Immun. 2018 Jan;67:59-64. doi: 10.1016/j.bbi.2017.08.024. Epub 2017 Sep 1.
The incidence of depression is approximately 2-fold greater in women than men but the biological mechanisms underlying this phenomenon remain unclear. One potential mechanism that has been understudied is immune function, which is modulated by sex hormones and differs considerably between males and females. The immune-regulating kynurenine pathway previously has been implicated in the pathogenesis of mood disorders. In particular, a decreased ratio of neuroprotective (kynurenic acid; KynA) to neurotoxic (3-hydroxykynurenine; 3HK and quinolinic acid; QA) kynurenine pathway metabolites has been reported in several mood disorder subtypes. Yet there is a paucity of research investigating sex differences in the kynurenine pathway in the context of depression. Similarly, oral contraceptive (OC) use has been shown to be a risk factor for depression but to our knowledge this epidemiological relationship has not been considered within the framework of immune dysfunction. Here, we compared the concentrations of c-reactive protein (CRP) and kynurenine pathway metabolites in a combined sample of subjects with major depressive disorder (MDD), bipolar disorder (BD), and healthy controls (HC) comprising 130 men and 350 women. CRP was measured in a CLIA-certified hospital laboratory. Kynurenine metabolites were quantified using high performance liquid chromatography with tandem mass spectrometry. Estradiol and progesterone were quantified with the Mesoscale Discovery (MSD) platform. After controlling for diagnosis, age, sex, BMI, analysis batch, and self-reported childhood trauma we found that women had significantly lower KynA/3HK and KynA/QA ratios than men, and that these results were driven by a decrease in KynA. There was no significant difference between males and females in the concentration of CRP. Further, women taking OC showed significantly higher levels of CRP and lower ratios of KynA/3HK and KynA/QA compared with women on no form of contraception. Moreover, among women using OC, progesterone concentrations were positively correlated with KynA, KynA/3HK, and KynA/QA. Although preliminary, our results indicate that on average, healthy women show the same pattern of kynurenine pathway metabolism as that observed in subjects with depression. This finding raises the possibility that a reduction in KynA concentrations in women may constitute a vulnerability factor that partly explains the higher incidence of depression in females. Further, the significant association between OC use and reduced KynA as well as increased CRP, could conceivably partially account for the epidemiological association between OC use and depression. Nonetheless, because of the cross-sectional nature of this study, these hypotheses need to be more rigorously tested with longitudinal designs and/or large epidemiological studies.
抑郁症的发病率女性大约是男性的两倍，但这一现象的生物学机制仍不清楚。一个研究较少的潜在机制是免疫功能，它受性激素调节，男女之间有很大的差异。免疫调节的犬尿氨酸途径以前与心境障碍的发病机制有关。特别是，几种心境障碍亚型报告了神经保护（犬尿氨酸酸；KynA）与神经毒性（3-羟基犬尿氨酸；3HK 和喹啉酸；QA）犬尿氨酸途径代谢物比值降低。然而，在抑郁症的背景下，研究性别的犬尿氨酸途径差异的研究很少。同样，口服避孕药（OC）的使用已被证明是抑郁症的一个危险因素，但据我们所知，这种流行病学关系尚未在免疫功能障碍的框架内考虑。在这里，我们比较了包括 130 名男性和 350 名女性在内的重度抑郁症（MDD）、双相情感障碍（BD）和健康对照组（HC）患者的 C 反应蛋白（CRP）和犬尿氨酸途径代谢物的浓度。CRP 在 CLIA 认证的医院实验室中进行测量。使用高效液相色谱-串联质谱法定量犬尿氨酸代谢物。使用 Mesoscale Discovery（MSD）平台定量雌二醇和孕酮。在控制诊断、年龄、性别、BMI、分析批次和自我报告的儿童创伤后，我们发现女性的 KynA/3HK 和 KynA/QA 比值明显低于男性，这一结果是由于 KynA 减少所致。男性和女性之间 CRP 的浓度没有显著差异。此外，与未使用任何避孕形式的女性相比，服用 OC 的女性 CRP 水平显著升高，KynA/3HK 和 KynA/QA 比值降低。此外，在使用 OC 的女性中，孕酮浓度与 KynA、KynA/3HK 和 KynA/QA 呈正相关。尽管初步研究，但我们的结果表明，平均而言，健康女性表现出与抑郁症患者相同的犬尿氨酸途径代谢模式。这一发现提出了这样一种可能性，即女性 KynA 浓度的降低可能构成部分解释女性抑郁症发病率较高的脆弱因素。此外，OC 使用与 KynA 减少以及 CRP 增加之间的显著关联，可以部分解释 OC 使用与抑郁症之间的流行病学关联。然而，由于这项研究是横断面的，这些假设需要通过纵向设计和/或大型流行病学研究来更严格地检验。
