Kynurenine Pathway Metabolites and Executive Function Impairments in Generalized Anxiety Disorder: A Case Control Study.

Generalized anxiety disorder (GAD) is marked by excessive worry and cognitive difficulties, yet its neurometabolic mechanisms remain unclear. 41patients with GAD and 41 healthy controls (HC) were assessed using neuropsychological tests: Wisconsin Card Sorting Test (WCST), Trail Making Test (TMT-A/B), Digit Span Test (DST), Verbal Fluency Test (VFT), Stroop Test, and State-Trait Anxiety Inventory (STAI). Blood samples were analyzed for kynurenine pathway metabolites including kynurenic acid (KYNA), quinolinic acid (QUIN), tryptophan (TRP), 3-hydroxykynurenine (3-HK), kynurenine (KYN), and 3-hydroxyanthranilic acid (3-HAA) via liquid chromatography-mass spectrometry (LC-MS). Patients with GAD performed significantly worse than healthy controls on executive function and attention tasks, including WCST (p = 0.014), TMT-A (p < 0.001), TMT-B (p = 0.015), and Stroop tests (p < 0.001). Patients with GAD showed elevated QUIN levels and reduced KYNA/QUIN ratios (p < 0.001), while HC group had higher 3-HK/KYN ratios (p = 0.008) than the patient group. Among anxiety measures, only state anxiety was positively correlated with KYN levels (r = 0.34, p = 0.032) in the patient group. Notably, a higher KYNA/QUIN ratio was independently associated with lower odds of GAD (p = 0.001; OR = 0.531), suggesting a potential neuroprotective role of this balance. Dysregulation in kynurenine pathway, particularly elevated neurotoxic QUIN and reduced KYNA/QUIN ratio, may lead to executive dysfunction in GAD. The KYNA/QUIN ratio emerges as a potential biomarker and therapeutic target in GAD.