Minelli Alessandra, Meloni Anna, Bortolomasi Marco, Pisanu Claudia, Zampieri Elisa, Congiu Donatella, Lana Beatrice, Manchia Mirko, Meattini Mattia, Paribello Pasquale, Baune Bernhard T, Gennarelli Massimo, Squassina Alessio
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Neurosci Appl. 2024 Oct 23;4:104095. doi: 10.1016/j.nsa.2024.104095. eCollection 2025.
Early life adversities (ELA) have been linked to a greater risk for major depressive disorder (MDD) and treatment-resistant depression (TRD). The molecular mechanisms underlying the link between ELA and MDD and/or TRD are yet unknown. It has been suggested that ELA induces an allostatic burden, which in turn promotes oxidative stress and an inflammatory response that are further intensified by the influence of maladaptive coping behaviour. In this study we explored the role of two markers of cellular aging and oxidative stress (leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn)) in TRD and in response to trauma-focused psychotherapies. The study comprised 30 TRD patients receiving trauma-focused psychotherapies and 65 healthy controls. LTL and mtDNAcn were measured at baseline and four weeks after the end of the psychotherapy sessions. Response was defined based on reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS). In the case control analysis, the logistic regression model showed that mtDNAcn but not LTL was a significant predictor of diagnosis (chi-square 92.108, p = 7.72e-20; contribution of mtDNAcn, B = -9-297, p = 0.00009). In the TRD sample, LTL and mtDNAcn were inversely correlated with MADRS score at baseline (LTL, Pearson's r = -0.478, p = 0.008; mtDNAcn, Pearson's r = -0.656, p = 0.00008), but there was no difference in either LTL or mtDNAcn between responders and non-responders. In conclusion, our findings support an involvement of cellular aging in TRD, and suggest that LTL and mtDNAcn are not predictors or mediators of response to trauma-focused psychotherapies.
早年生活逆境（ELA）与患重度抑郁症（MDD）和难治性抑郁症（TRD）的风险增加有关。ELA与MDD和/或TRD之间联系的分子机制尚不清楚。有人提出，ELA会引发一种适应性负荷，进而促进氧化应激和炎症反应，而适应不良的应对行为会进一步加剧这种反应。在本研究中，我们探讨了细胞衰老和氧化应激的两个标志物（白细胞端粒长度（LTL）和线粒体DNA拷贝数（mtDNAcn））在TRD以及对以创伤为重点的心理治疗反应中的作用。该研究包括30名接受以创伤为重点的心理治疗的TRD患者和65名健康对照者。在基线和心理治疗结束四周后测量LTL和mtDNAcn。根据蒙哥马利-Åsberg抑郁评定量表（MADRS）的降低情况来定义反应。在病例对照分析中，逻辑回归模型显示，mtDNAcn而非LTL是诊断的显著预测指标（卡方=92.108，p = 7.72e-20；mtDNAcn的贡献，B = -9-297，p = 0.00009）。在TRD样本中，LTL和mtDNAcn在基线时与MADRS评分呈负相关（LTL，皮尔逊r = -0.478，p = 0.008；mtDNAcn，皮尔逊r = -0.656，p = 0.00008），但反应者和无反应者之间的LTL或mtDNAcn均无差异。总之，我们的研究结果支持细胞衰老参与TRD，并表明LTL和mtDNAcn不是对以创伤为重点的心理治疗反应的预测指标或介导因素。
