Alterations in serum nudifloramide associated with response to diverse pharmacological treatments in major depressive disorder: a preliminary study.

Pharmacological treatments for major depressive disorder (MDD) have limited efficacy, underscoring the need for biomarkers to assess treatment response. Metabolomics enables characterization of metabolic alterations associated with antidepressant effectiveness. This cross-sectional study aimed to discover and validate metabolite biomarkers that can be used to screen responses to drug treatment in MDD through a metabolomics-based approach. Serum samples from drug-treated MDD patients with persistent depression (D-MDD), patients in remission (R-MDD), and healthy controls were divided into discovery (D-MDD: n=19, R-MDD: n=17, control: n=25) and validation (D-MDD: n=36, R-MDD: n=30, control: n=65) sets. Untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis identified candidate metabolites, which were validated using multiple reaction monitoring. L-histidine and nudifloramide were identified in the discovery phase. L-histidine increased stepwise from D-MDD to R-MDD to controls, but significance was lost in validation. Nudifloramide showed a similar trend; in validation, its concentration was significantly higher in controls than in D-MDD, with R-MDD at intermediate levels approaching controls. Alterations in nudifloramide suggest involvement of the tryptophan-kynurenine pathway and NAD⁺ homeostasis in MDD pathophysiology and treatment response. Nudifloramide may serve as a biomarker for distinguishing depressed from healthy states in treated patients. Further pathway-focused studies are warranted.