AbstractAlterations in the kynurenine pathway of tryptophan metabolism have been implicated in the pathophysiology of schizophrenia. Here, we performed an in-depth analysis of all metabolites of the kynurenine pathway, i.e., tryptophan (TRY), kynurenic acid (KYNA), L-kynurenine (KYN), 3-hydroxykynurenine (3-HK), anthranylic acid (ANA), 3-hydroxyanthranylic acid (3-HANA), xanthurenic acid (XA) and quinolinic acid (QUINA), in postmortem samples of the dorsolateral prefrontal cortex (DLPFC, Brodmann area 46, 9) of individuals affected by schizophrenia and non-schizophrenic controls. The analysis was carried out in the gray and white matter. Levels of KYN, 3-HK, ANA, and 3-HANA were significantly increased in both the gray and white matter of the DLPFC of individuals affected by schizophrenia, whereas levels of TRY, KYNA, and QUINA were increased exclusively in the white matter and remained unchanged in the gray matter. These increases in kynurenine metabolites did not correlate with age, sex, duration of the disease, and duration and type of antipsychotic medication. These findings suggest that the two major branches of the kynurenine pathway, i.e., the transamination of KYN into KYNA, and hydroxylation of KYN into 3-HK are activated in the white matter of individuals affected by schizophrenia, perhaps as a result of neuroinflammation, and support the evidence that abnormalities of the white matter are consistenly associated with schizophrenia.