Plasma Sphingomyelin and Ceramide Profiles as Potential Biomarkers in Young Adults with Bipolar Depression: A Lipidomics Study

Background: Bipolar depression (BPD) lacks reliable peripheral biomarkers for early diagnosis. Sphingomyelin (SM) and ceramide (Cer) are bioactive lipids implicated in neuronal membrane signaling, yet their diagnostic utility in young adults with BPD remains unclear. Patients and Methods: We conducted a single-center exploratory untargeted lipidomics study focusing on SM and Cer species in plasma from 26 young adults (18– 26 years) with BPD at baseline and after three weeks of quetiapine and magnesium valproate treatment (BPD3w), alongside 27 sex- and age-matched healthy controls (HC). Group comparisons of total SM, total Cer, and SM/Cer ratio were performed; ROC curves assessed discriminative ability. A Venn diagram approach, followed by LASSO regression with bootstrap averaging, identified a refined candidate biomarker panel from 140 SM/Cer species. Results: Both BPD and BPD3w groups exhibited elevated total SM and Cer relative to HC, whereas the SM/Cer ratio was significantly reduced. Paired analysis revealed that total SM and the SM/Cer ratio decreased after treatment (both P < 0.05), while total Cer remained unchanged. Intersection analysis yielded 14 candidate lipids, which were further refined via LASSO regression (λ = 100) with bootstrap averaging to a 4-species panel: Cer(t20:1/24:3), Cer(d19:1/25:3), SM(t18:0/22:0), and Cer(t17:0/22:0), with an AUC of 0.975 (95% CI: 0.917– 1.000), representing an unvalidated internally derived estimate pending further validation. Correlation analysis revealed that Cer(d19:1/25:3), Cer(t17:0/22:0), and SM(t18:0/22:0) were positively correlated with depressive, anxiety, and manic symptom severity (HAMD, HAMA, and YMRS). Cer(t20:1/24:3) showed a modest negatively correlation with HAMD, but not with HAMA or YMRS. Additionally, Cer(t20:1/24:3) and SM(t18:0/22:0) exhibited sex-dependent differences. Conclusion: Plasma SM and Cer profiles are altered in young adults with BPD and show a partial trend toward normalization following short-term treatment. A refined 4-species panel showed promising but internally derived discriminative performance in this exploratory study. While peripheral sphingolipid signatures may serve as potential biomarkers for BPD, these findings require validation in independent cohorts before any clinical application. Keywords: bipolar disorder, depressive episodes, sphingolipids, lipidomics, biomarker