Treatment effects on sphingosine-1-phosphate and its receptors in major depressive disorder: implications for biomarkers

Abstract

The diagnosis of major depressive disorder (MDD) currently relies on subjective clinical assessments, highlighting a critical need for objective biological markers. The sphingosine-1-phosphate (S1P) signaling pathway, a pivotal regulator of neuro-immune interactions, has emerged as a potential contributor to MDD pathophysiology, yet its role remains incompletely understood. This study aimed to investigate plasma levels of S1P and its key receptors, S1PR1 and S1PR3, as potential diagnostic and predictive biomarkers for MDD, with a specific focus on sex differences and treatment effects. Patients with MDD (n = 56) underwent an 8-week treatment protocol were enrolled, alongside 42 healthy controls (HCs). Depression severity was evaluated using the Hamilton Depression Rating Scale (HAMD-24) and Patient Health Questionnaire (PHQ-9) at baseline and 8-week visit. The plasma levels of S1P, S1PR1 and S1PR3 were measured at baseline and week 8. At baseline, plasma concentrations of S1P, S1PR1, and S1PR3 were significantly elevated in patients with MDD compared to HCs. All three markers significantly decreased and trended toward normal levels after 8 weeks of antidepressant treatment. Notably, a significant sex-specific difference was observed for the receptors, baseline elevations of S1PR1 and S1PR3 were more obvious in female patients than in male patients. Furthermore, baseline S1P levels significantly predicted symptom improvement—as measured by changes in both HAMD-24 and PHQ-9 scores—whereas baseline S1PR levels alone did not. In addition, a combined panel of S1P, S1PR1, and S1PR3 yielded high diagnostic accuracy, with an area under the receiver operating characteristic curve (AUC) of 0.9575. Our data demonstrate a significant, sex-dependent dysregulation of the peripheral S1P signaling pathway in MDD, which is responsive to antidepressant treatment. The ability of baseline S1P to predict clinical outcomes and the encouraging diagnostic precision of the S1P-S1PR1-S1PR3 panel strongly support their potential as clinically applicable biomarkers. These results imply that the S1P pathway plays a crucial role in the pathophysiology of depression, offering new possibilities for diagnosis and personalized treatment strategies in psychiatry.