Frontostriatal circuitry and the tryptophan kynurenine pathway in major psychiatric disorders

Rationale An imbalance of the tryptophan kynurenine pathway (KP) commonly occurs in psychiatric disorders, though the neurocognitive and network-level effects of this aberration are unclear. Objectives In this study, we examined the connection between dysfunction in the frontostriatal brain circuits, imbalances in the tryptophan kynurenine pathway (KP), and neurocognition in major psychiatric disorders. Methods Forty first-episode medication-naive patients with schizophrenia (SCZ), fifty patients with bipolar disorder (BD), fifty patients with major depressive disorder (MDD), and forty-two healthy controls underwent resting-state functional magnetic resonance imaging. Plasma levels of KP metabolites were measured, and neurocognitive function was evaluated. Frontostriatal connectivity and KP metabolites were compared between groups while controlling for demographic and clinical characteristics. Canonical correlation analyses were conducted to explore multidimensional relationships between frontostriatal circuits-KP and KP-cognitive features. Results Patient groups shared hypoconnectivity between bilateral ventrolateral prefrontal cortex (vlPFC) and left insula, with disorder-specific dysconnectivity in SCZ related to PFC, left dorsal striatum hypoconnectivity. The BD group had higher anthranilic acid and lower xanthurenic acid levels than the other groups. KP metabolites and ratios related to disrupted frontostriatal dysconnectivity in a transdiagnostic manner. The SCZ group and MDD group separately had high-dimensional associations between KP metabolites and cognitive measures. Conclusions The findings suggest that KP may influence cognitive performance across psychiatric conditions via frontostriatal dysfunction.