Immuno-kynurenine shifts track cognitive change in antipsychotic-naive first-episode schizophrenia

ObjectiveTo delineate the longitudinal relationships among peripheral inflammation, kynurenine pathway (KP) dysregulation, immune-cell redistribution, and cognitive performance in antipsychotic-naïve first-episode schizophrenia (FES).MethodsAntipsychotic-naïve FES patients (n = 136) and healthy controls (HC; n = 136) were enrolled. FES received aripiprazole monotherapy through week 6, followed by naturalistic treatment through month 6. Cognition was assessed with the MATRICS Consensus Cognitive Battery (MCCB). Plasma KP metabolites were quantified by LC–MS/MS, inflammatory markers by high-sensitivity ELISA, and immune-cell subsets by flow cytometry.ResultsFES showed marked baseline cognitive impairment with stepwise improvement by week 6 and month 6. At baseline, FES demonstrated a KP shift toward a relatively more neurotoxic profile (lower TRP and KYNA, higher KYN/TRP, 3-HK, and QA, with elevated QA/KYNA and reduced KYNA/3-HK), heightened inflammation (higher hs-CRP and pro-inflammatory cytokines with lower IL-10), and monocyte-skewed redistribution (higher CD14+ and CD16+ monocyte measures). Over follow-up, KP and inflammatory markers partially normalized and immune-cell distributions shifted toward the HC baseline profile. In FDR-adjusted longitudinal models, higher between-person inflammation and monocyte burden were associated with lower MCCB scores, whereas IL-10 and a more protective KP profile (higher KYNA, KYNA/KYN, and KYNA/3-HK) were associated with better cognition. In change-score analyses, ΔMCCB tracked KP remodeling—positively with ΔKYNA and ΔKYNA/KYN at both intervals and with ΔKYNA/3-HK at month 6, and inversely with Δ3-HK.ConclusionsAntipsychotic-naïve FES shows marked cognitive impairment with heightened inflammation, monocyte shifts, and KP dysregulation. Over follow-up, cognitive performance was more closely aligned with stable between-person immuno-KP differences, while cognitive improvement most consistently tracked KP remodeling rather than broad inflammatory or cellular change.