Metabolic Fingerprints of Effective Fluoxetine Treatment in the Prefrontal Cortex of Chronically Socially Isolated Rats: Marker Candidates and Predictive Metabolites

Abstract

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.

Prefrontal Cortex Cytosolic Proteome and Machine Learning-Based Predictors of Resilience toward Chronic Social Isolation in Rats

“…In support of this, downregulated Impa1, responsible for the production of inositol and essential for the synthesis of phosphatidylinositol, was found. Moreover, a recent metabolomic study demonstrated increased levels of the components of phosphatidylinositol, such as myo-inositol, following CSIS (referred to as CSIS-susceptible rats) in the PFC as one of the most interesting variables for stratifying CSIS-susceptible vs. control rats [ 33 ]. Downregulated proteins involved in the Ras subfamily of GTPases, such as Rap1b, Rab1A, Rab2a, and Rab1b, were identified as predictive proteins using ML algorithms.…”