Multi-omics integration of inflammation, immunity, and metabolism identifies depression subtypes associated with...

Accumulating evidence indicates that inflammation, immune dysfunction, and metabolic disturbances are associated with major depressive disorder (MDD). Subtype analysis can reduce disease heterogeneity in MDD, significantly improving response prediction and personalized treatment. However, there is still a lack of robust strategies to effectively integrate diverse multi-omics data for subtype analysis. Therefore, multi-omics data (mass cytometry by time-of-flight [CyTOF], cytokine, and metabolomics) were used for depression subtype analysis, with the goal of explaining the heterogeneity of MDD and predicting treatment response.

134 adult patients with MDD were enrolled according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Of these, 83 patients underwent CyTOF, cytokine, and metabolomics testing, and were included for subsequent subtype analysis. The 17-item Hamilton depression rating scale (HAMD-17) score was used to assess the severity of depressive symptoms at baseline (w0), 4 weeks (w4), and 8 weeks (w8). Multiomics subtypes (MoSs) for MDD patients were identified using 10 state-of-the-art algorithms from the R package "MOVICS".

Three MoS subtypes (MoS1-3) were found in this study. MoS2 was associated with a poorer response, whereas MoS1 and MoS3 demonstrated better efficacy at 8 weeks (χ² = 8.03, p = 0.020). Multivariable logistic regression analysis was performed on both weighted and unweighted samples, confirming that the MoS subtype was an independent predictor of treatment outcome. Compared with MoS1, the patients in MoS2 had a significantly reduced likelihood of treatment response (IPW weighted: OR = 0.09, 95% CI: 0.02-0.34, p < 0.001; Unweighted: OR = 0.14, 95% CI: 0.03-0.53, p = 0.005), while no significant difference was found in MoS3. Biologically, MoS2 was characterized by significantly elevated triglycerides and an increase in regulatory T-cell subsets; MoS1 was characterized by enhanced T-cell activity and elevated growth factors (e.g., bFGF); and MoS3 was characterized by elevated monocytes, reduced T-cell and Treg levels, and modest cytokine levels.

This exploratory study identified three subtypes of MDD with distinct biological profiles and differential treatment responses-most notably poorer outcomes in the MoS2 subgroup. Although this classification could help explain some of the heterogeneity in depression and might be associated with different antidepressant treatment outcomes, these preliminary findings require validation in independent cohorts.