Rajasekera Therese A, Joseph Anna, Pan Hui, Dreyfuss Jonathan M, Fida Doruntina, Wilson Julie, Behee Madeline, Fichorova Raina N, Cinar Resat, Spagnolo Primavera A
Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA.
Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Boston, MA, USA.
medRxiv. 2025 Jan 30:2025.01.13.25320467. doi: 10.1101/2025.01.13.25320467.
Posttraumatic stress disorder (PTSD) is one of the most sex-polarized psychiatric disorders, with women exhibiting twice the prevalence of men. The biological mechanisms underlying this sex disparity are not fully understood. Growing evidence suggests that alterations of the stress-buffering endocannabinoid (eCB) system and heightened inflammation are central to PTSD pathophysiology and may contribute to sex-biases in PTSD risk and severity. Here, we examined sex-differences in levels of circulating eCBs and peripheral pro-inflammatory markers in a cohort of men and women with PTSD and non-psychiatric controls.
88 individuals with PTSD and 85 sex- and age- matched controls (HC) were retrospectively selected from the Mass General Brigham Biobank. Serum was assayed to measure circulating eCBs [anandamide (AEA), 2-arachidonyl glycerol (2-AG), oleoylethanolamide (OEA), and arachidonic acid (AA] and inflammatory markers [interleukin-1β (IL-1β), IL-6, IL-8, IL-18, tumor necrosis factor-alpha (TNFα), and C-reactive Protein (CRP)]. Linear regression was used to predict differential abundance of each analyte by disease state (PTSD/HC) within the male and female subgroups. Two-sided t-tests with Benjamini-Hochberg correction were used to examine differences across subgroups. Analyses were repeated in those with comorbid major depressive disorder.
Male PTSD patients showed a significant decrease in AEA, AA and OEA levels compared to male controls ('s < .001) and to female subgroups (PTSD and HCs) (). In contrast, among females, PTSD patients showed elevated levels of IL-6 () and IL-8 (). Both male and female PTSD patients exhibited an increase in TNFα concentrations (), compared to HCs. Similar results were obtained in the subgroup of individuals with comorbid MDD and after controlling for the 385A genotype.
Our findings show for the first time that decrease in eCB levels is absent in women with PTSD, who in turn exhibit a broader increase in inflammatory markers, thus suggesting that biological perturbations underlying PTSD may vary by sex.
创伤后应激障碍（PTSD）是性别差异最为明显的精神疾病之一，女性患病率是男性的两倍。这种性别差异背后的生物学机制尚未完全明确。越来越多的证据表明，应激缓冲内源性大麻素（eCB）系统的改变和炎症加剧是PTSD病理生理学的核心，可能导致PTSD风险和严重程度的性别偏差。在此，我们研究了患有PTSD的男性和女性队列以及非精神疾病对照组中循环eCB水平和外周促炎标志物的性别差异。
从麻省总医院布莱根生物样本库中回顾性选取88例PTSD患者和85例性别及年龄匹配的对照（HC）。检测血清以测量循环eCBs[花生四烯乙醇胺（AEA）、2-花生四烯酸甘油酯（2-AG）、油酰乙醇胺（OEA）和花生四烯酸（AA）]以及炎症标志物[白细胞介素-1β（IL-1β）、IL-6、IL-8、IL-18、肿瘤坏死因子-α（TNFα）和C反应蛋白（CRP）]。采用线性回归预测男性和女性亚组中每种分析物在疾病状态（PTSD/HC）下的差异丰度。采用经Benjamini-Hochberg校正的双侧t检验来检验亚组间的差异。在患有共病重度抑郁症的患者中重复进行分析。
与男性对照组相比（P<0.001）以及与女性亚组（PTSD患者和HC）相比，男性PTSD患者的AEA、AA和OEA水平显著降低（P<0.001）。相比之下，在女性中，PTSD患者的IL-6（P<0.001）和IL-8（P<0.001）水平升高。与HC相比，男性和女性PTSD患者的TNFα浓度均升高（P<0.001）。在患有共病MDD的个体亚组以及在控制385A基因型后也获得了类似结果。
我们的研究结果首次表明，PTSD女性患者中eCB水平没有降低，反而炎症标志物有更广泛的升高，这表明PTSD潜在的生物学扰动可能因性别而异。
