Kynurenine Pathway Metabolite Levels in Drug Naïve and Risperidone Treated Schizophrenia: Insights From Systemic and Post‐Mortem Brain Tissue Analysis

ABSTRACT

Kynurenine pathway (KP), the principal route of tryptophan (TRY) metabolism, is implicated in schizophrenia (SCZ), but findings remain inconsistent, particularly regarding peripheral‐central associations and links to immune dysregulation. We measured KP metabolites, cytokines, and metabolic risk factors in serum from drug‐naïve (DN) and risperidone‐treated (RT) SCZ patients versus healthy controls (HC) as well as in post‐mortem brain tissue from an independent cohort by assessing KP metabolites, enzyme expression (mRNA, protein) and cytokine profiles. We recruited a total of 227 participants from the clinical services of a large neuropsychiatric hospital, which included DN SCZ ( n  = 66), RT SCZ ( n  = 87), and HC ( n  = 74). Additionally, brain KP metabolite levels and the mRNA and protein expression of key enzymes and cytokines were evaluated in the dorsolateral prefrontal cortex (DLPFC) samples from the post‐mortem cohort of 10 SCZ patients and 17 controls. KP metabolites were measured using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Both DN and RT groups exhibited significantly reduced TRY ( p  < 0.05), elevated kynurenine (KYN), kynurenic acid (KYNA), KYN/TRY ratio and serotonin (SER) in serum ( p  < 0.001), alongside higher TNF‐α, and IFN‐γ and lower IL‐10 ( p  < 0.001 for both). These alterations were correlated with metabolic risk factors, symptom severity of SCZ, and immune markers, and these remained associated with disease status after adjusting for confounders. Post‐mortem analyses confirmed increased brain KYN ( p  < 0.05) and KYNA ( p  < 0.001) in the DLPFC of SCZ, accompanied by upregulation of Tryptophan 2,3‐dioxygenase (TDO2) ( p  < 0.001) and Kynurenine aminotransferase II (KAT II) ( p  < 0.05) expression and elevated pro‐inflammatory cytokines. Our findings provide convergent evidence for KP dysregulation in SCZ, linking immune activation with enhanced change toward KYNA synthesis both systemically and centrally. The observed alterations across independent serum and post‐mortem brain cohorts support the potential relevance of these molecular signatures to SCZ pathophysiology and their possible therapeutic implications.

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