Altered Kynurenine Pathway Metabolism in Drug-naive Children and Adolescents with Generalized Anxiety Disorder

Generalized anxiety disorder (GAD) is among the most common psychiatric conditions in children and adolescents. Although its aetiology remains unclear, emerging evidence highlights the role of immune-metabolic pathways in its development. This study aimed to investigate alterations in the kynurenine pathway (KP) metabolites in drug-naive paediatric patients with GAD compared to healthy controls.

Twenty-six drug-naive children with GAD and thirty-two age- and sex-matched healthy controls were enrolled. Serum levels of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN) were measured using ELISA. Enzymatic activity indices, including KYN/TRP (IDO/TDO), KYNA/KYN (KAT), and QUIN/KYN (KMO), were calculated. Group differences and correlations with clinical anxiety scores were analysed. Additionally, ROC analysis was performed to evaluate the diagnostic performance of TRP levels in predicting GAD.

TRP levels were significantly elevated in the GAD group (median: 62.8 μmol/L) compared to controls (42.9 μmol/L, p < 0.001), while KYN (54.5 vs. 66.8 nmol/L, p = 0.042) and QUIN (9.9 vs. 11.9 μmol/L, p = 0.004) levels were reduced. The KYN/TRP ratio was positively correlated with RCADS-CV total anxiety scores (r = 0.430, p = 0.028). ROC analysis indicated that TRP had good diagnostic performance for GAD, with an AUC of 0.824, sensitivity of 73%, and specificity of 78%.

These findings suggest that disrupted tryptophan metabolism, characterized by reduced KP activation and altered neurotoxic metabolite levels, may contribute to the pathophysiology of paediatric GAD. The KP may represent a promising target for future biomarker and therapeutic research in anxiety disorders.