Contextual Regulation of the Kynurenine Pathway and Its Relevance for Personalized Psychiatry.

The kynurenine pathway (KP) is the primary route of tryptophan metabolism and a key interface linking immune activation, metabolic state, and neurochemical signaling. Although KP biomarkers are widely studied in psychiatric disorders, their interpretation remains inconsistent, in part due to biological context and compartmentalization. In this narrative review, we integrate evidence across peripheral and central systems to clarify how age, sex hormones, metabolic health, inflammation, and behavioral factors systematically bias KP flux and shape biomarker readouts. We re-examine the interpretation of the kynurenine/tryptophan ratio in light of differential IDO1 and TDO2 regulation, blood-brain barrier constraints, and cell-specific downstream metabolism that governs neuroprotective and neurotoxic outputs. We further synthesize clinical evidence linking KP alterations to symptom severity, cognitive dysfunction, treatment resistance, and suicidality, highlighting quinolinic acid as a mechanistic node connecting immune activation to glutamatergic dysregulation. Together, this framework reframes the kynurenine pathway not as a static biomarker of disease, but as a context-sensitive metabolic system with direct implications for study design, risk stratification, and personalized approaches in psychiatry.