Elevated serum kynurenic acid in individuals with first-episode psychosis and insufficient response to antipsychotics

Abstract

The tryptophan-metabolizing kynurenine pathway (KP) can be activated by enhanced inflammatory responses and has been implicated in the pathophysiology of schizophrenia. However, there is little evidence for KP dysregulation in the early course of psychotic illness. We aimed to investigate the potential immune-mediated hyperactivity of KP in individuals with first-episode psychosis (FEP) and the relationship with symptom severity and treatment response outcomes. Serum immunoassays were performed to measure peripheral levels of inflammatory cytokines (IL-1β, IL-10, TNF-a), KP rate-limiting enzymes (IDO/TDO), and kynurenic acid (KYNA) metabolite in 104 antipsychotic-naïve patients with FEP and 80 healthy controls (HC). The Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning Scale (GAF) were administered to assess psychopathology and functioning status at admission and following 4-week treatment with antipsychotics. Cytokine and KP components levels were substantially increased in FEP patients compared to HC, before and after antipsychotic treatment. A significant positive correlation between pro-inflammatory IL-1β and KYNA levels was observed among FEP patients, but not in HC. Importantly, within-patient analysis revealed that those with higher baseline KYNA experienced more severe negative symptoms and poorer clinical improvement at follow-up. These findings suggest that KP is upregulated in early psychosis, likely through the induction of IL-1β-dependent pathways, and raised peripheral KYNA might represent a promising indicator of non-response to antipsychotic medication in patients with FEP.

Fig. 1. Schematic representation of the tryptophan-metabolizing kynurenine pathway.

The key enzymes involved and main neuroactive metabolites are shown.

Fig. 2. Comparison of inflammatory cytokine and kynurenine pathway (KP) components serum levels in patients with first-episode psychosis (FEP) and heathy controls (HC).

Mean concentration values are shown at baseline and after 4-week treatment with antipsychotics. Error bars represent standard deviation (*FDR-adjusted p value < 0.05; ns non-significant).

Fig. 3. Pair-wise correlations between serum levels of inflammatory cytokines and KP components in healthy controls and individuals with first-episode psychosis (FEP).

Statistically significant Spearman's rho correlations are indicated with an asterisk (*FDR-adjusted p value < 0.05).

Fig. 4. Association between serum kynurenic acid (KYNA) levels and treatment response.

Box-plots depicting differences in mean serum KYNA concentration among FEP patients characterized as remitters/non-remitters following antipsychotic treatment based on the RSWG symptomatic criterion (left panel), and responders/non-responders based on the ≥50% PANSS reduction (right panel) at follow-up.