Department of Molecular Biology and Endocrinology, "VINČA" Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia.
Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, 23562 Lübeck, Germany.
Int J Mol Sci. 2023 Jun 30;24(13):10957. doi: 10.3390/ijms241310957.
The increasing prevalence of depression requires more effective therapy and the understanding of antidepressants' mode of action. We carried out untargeted metabolomics of the prefrontal cortex of rats exposed to chronic social isolation (CSIS), a rat model of depression, and/or fluoxetine treatment using liquid chromatography-high resolution mass spectrometry. The behavioral phenotype was assessed by the forced swim test. To analyze the metabolomics data, we employed univariate and multivariate analysis and biomarker capacity assessment using the receiver operating characteristic (ROC) curve. We also identified the most predictive biomarkers using a support vector machine with linear kernel (SVM-LK). Upregulated myo-inositol following CSIS may represent a potential marker of depressive phenotype. Effective fluoxetine treatment reversed depressive-like behavior and increased sedoheptulose 7-phosphate, hypotaurine, and acetyl-L-carnitine contents, which were identified as marker candidates for fluoxetine efficacy. ROC analysis revealed 4 significant marker candidates for CSIS group discrimination, and 10 for fluoxetine efficacy. SVM-LK with accuracies of 61.50% or 93.30% identified a panel of 7 or 25 predictive metabolites for depressive-like behavior or fluoxetine effectiveness, respectively. Overall, metabolic fingerprints combined with the ROC curve and SVM-LK may represent a new approach to identifying marker candidates or predictive metabolites for ongoing disease or disease risk and treatment outcome.
抑郁症的患病率不断上升，这就需要更有效的治疗方法和对抗抑郁药作用模式的理解。我们使用液相色谱-高分辨率质谱法对慢性社会隔离（CSIS）暴露的大鼠前额叶进行了非靶向代谢组学研究，CSIS 是一种大鼠抑郁症模型，以及/或氟西汀治疗。行为表型通过强迫游泳试验进行评估。为了分析代谢组学数据，我们采用了单变量和多变量分析以及使用接收者操作特征（ROC）曲线进行生物标志物能力评估。我们还使用具有线性核的支持向量机（SVM-LK）来识别最具预测性的生物标志物。CSIS 后肌醇的上调可能代表抑郁表型的潜在标志物。有效的氟西汀治疗可逆转抑郁样行为，并增加 sedoheptulose 7-phosphate、hypotaurine 和乙酰-L-肉碱的含量，这些物质被鉴定为氟西汀疗效的候选标志物。ROC 分析显示，CSIS 组有 4 个显著的候选标志物，氟西汀疗效有 10 个。具有 61.50%或 93.30%准确度的 SVM-LK 分别确定了 7 个或 25 个预测抑郁样行为或氟西汀有效性的预测代谢物的面板。总的来说，代谢指纹图谱结合 ROC 曲线和 SVM-LK 可能代表一种识别正在进行的疾病或疾病风险以及治疗结果的候选标志物或预测代谢物的新方法。
