Peripheral S-(PGJ₂)-glutathione as a diagnostic biomarker for depression-anxiety comorbidity: development and...

Comorbidity of depression and anxiety disorders (DAs) is as high as 50%, and diagnosis remains heavily reliant on subjective symptomatic assessments due to the lack of validated objective biomarkers. Neuroinflammation and oxidative stress are well-recognized core pathophysiological features of DAs. Prostaglandins (PGs), a class of lipid mediators closely linked to neuroinflammation and oxidative stress, have been implicated as key mediators in the pathogenesis of mood and anxiety disorders. S-(PGJ₂)-glutathione, a covalent conjugate of 15d-PGJ₂ and glutathione (GSH), integrates PG-mediated inflammatory signaling and GSH-dependent antioxidant defense, suggesting its potential as a candidate biomarker for DAs.

The case-control study enrolled 77 participants, including 39 patients with comorbid depression and anxiety disorders (DAs) and 38 healthy controls (HCs) matched for gender, age, and body mass index (BMI). The cohort was randomly stratified into training and test sets at a 7:3 ratio. Serum levels of PG-related metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Univariate and multivariate logistic regression analyses were performed in the training set to identify independent biomarkers. Receiver operating characteristic (ROC) analysis was employed to assess diagnostic performance in the training cohort, test cohort, and overall population, while decision curve analysis (DCA) was used to evaluate clinical utility.

A total of 21 PG-related metabolites were detected, of which five were significantly dysregulated in DAs patients and remained significant after FDR correction for multiple testing. Multivariate logistic regression identified S-(PGJ₂)-glutathione as an independent biomarker associated with DAs, both before and after adjustment for confounding factors including education level, systolic blood pressure (SBP), and diastolic blood pressure (DBP). ROC analysis in the total cohort showed that S-(PGJ₂)-glutathione yielded an AUC of 0.949, with a sensitivity of 0.789 and specificity of 0.949. Consistent results were observed in the training and internal test sets. DCA suggested that using S-(PGJ₂)-glutathione for diagnosis may provide a higher net benefit than conventional "Treat All" or "Treat None" strategies over a wide range of threshold probabilities.

The PG metabolic pathway is dysregulated in patients with DAs. S-(PGJ₂)-glutathione is significantly downregulated and exhibits favorable preliminary diagnostic efficacy based on internal training and test set validation. Given the relatively small sample size and the absence of external cohort validation, these findings should be interpreted as preliminary.