Dynamic metabolic reconfiguration accompanies treatment response in MDD in children and adolescents: A longitudinal plasma metabolomics study

Background The metabolic underpinnings of treatment response in adolescent major depressive disorder (MDD) remain poorly characterized. This longitudinal study examined whether clinical improvement is accompanied by dynamic reconfiguration of the plasma metabolome, and whether such changes reflect state-dependent modulation rather than fixed trait pathology. Methods We employed a longitudinal case-control design enrolling 30 first-episode MDD adolescents (aged 6–18 years) and 30 healthy controls (HC). Plasma untargeted metabolomics profiling and standardized clinical assessments were conducted at both hospital admission and discharge. Differential analysis and pathway enrichment identified metabolites associated with diagnosis and treatment response, with post-treatment profiles systematically positioned relative to baseline MDD and HC states to assess normalization trajectories. Results MDD adolescents exhibited widespread metabolic dysregulation at baseline compared to HC. Clinical improvement was accompanied by significant shifts in primary bile acid biosynthesis, steroid hormone metabolism, and tryptophan catabolism, alongside treatment-modulated caffeine metabolism reflecting pharmacokinetic adaptation. Post-treatment metabolic profiles occupied an intermediate position between baseline MDD and HC states, consistent with partial, state-dependent reorganization rather than complete metabolic normalization. Conclusion Effective treatment in adolescent MDD is associated with dynamic, partially reversible metabolic reconfiguration centered on bile acid, steroid, and tryptophan pathways. These findings support the state-dependent nature of metabolic disturbances in this developmental population and prioritize these specific pathways for future mechanistic validation. However, clinical translation remains premature pending replication in larger, demographically balanced cohorts with rigorous control of dietary and medication-related confounding factors. Trial registration: Not applicable.