The kynurenine pathway in depression and schizophrenia: convergent signals, divergent states, and clinical signatures.

Abstract

Chronic low-grade inflammation (LGI) is increasingly recognized as a biologically meaningful contributor to heterogeneity in major psychiatric disorders. The tryptophan (Trp)-kynurenine (KYN) metabolic pathway is a leading candidate mechanism because immune and stress-related signals can redirect Trp metabolism toward bioactive KYNs that influence glutamatergic signaling, redox balance, energetics, and immune feedback. In treatment-resistant depression and schizophrenia spectrum psychosis, this pathway is especially relevant because inflammatory burden often coexists with anhedonia, fatigue, cognitive dysfunction, and negative symptoms. Yet the literature remains difficult to integrate. Studies often rely on shallow biomarker panels, inconsistent inflammatory phenotyping, mixed matrices, and incomplete handling of major confounders, including smoking, adiposity, sleep disruption, infection timing, and medication exposure. Interpretation is further complicated by the kynurenic acid (KYNA) paradox and by central-peripheral discrepancies, as KYNA-related findings are strongly shaped by biological context and compartment, with blood measures often diverging from cerebrospinal fluid profiles and therefore not reliably reflecting central branch balance. This review therefore aimed to identify the Trp-KYN nodes most relevant to chronic LGI in psychiatry, synthesize clinical and preclinical evidence by disorder and symptom module, and define realistic near- and long-term research priorities. Here we highlight that Trp-KYN findings become more coherent when interpreted as context-dependent branch-balance signatures rather than standalone biomarkers. This framework can improve comparability, sharpen stratification, and support biomarker-enriched translational psychiatry. More broadly, it offers a practical model for linking immune biology to symptom dimensions across heterogeneous brain disorders. See also the graphical abstract(Fig. 1).