Stress-Induced Increase in Kynurenic Acid as a Potential Biomarker for Patients With Schizophrenia and Distress Intolerance

IMPORTANCE Several lines of evidence have linked the endogenous neuromodulator kynurenic acid (KYNA) to schizophrenia. The pathophysiology of schizophrenia is commonly associated with stress, and stress plays a key regulatory role in the first, rate-limiting step of the kynurenine pathway, which produces KYNA. OBJECTIVE To determine whether the level of KYNA changes following psychological stress and whether this change is associated with stress-related behavior. DESIGN, SETTING, AND PARTICIPANTS The KYNA level was measured in saliva samples taken at baseline and at 2 times following a laboratory-based psychological stress challenge in 128 participants (64 patients with schizophrenia from outpatient clinics and 64 healthy controls from the community). EXPOSURE Laboratory-based psychological stress challenge. MAIN OUTCOMES AND MEASURES Quitting the stressful task early was used as a behavioral marker of distress intolerance. RESULTS Patients with schizophrenia showed a significantly higher rate of distress intolerance compared with healthy controls (P = .003). Salivary KYNA levels increased significantly between baseline and 20 minutes following the stress task in both patients and controls (mean [SEMI, 6.72nM [0.65nM] vs 8.43nM [1.05nM], respectively; P = .007). Patients who were unable to tolerate the stressful tasks and quit early showed significantly higher levels of KYNA than patients who tolerated the psychological stressor (P = .02) or healthy controls (P = .02). In patients with distress intolerance, KYNA elevation significantly correlated with the severity of clinical symptoms (p = 0.64; P = .008). CONCLUSIONS AND RELEVANCE Distress intolerance is more common in patients with schizophrenia. Patients with this behavioral phenotype have elevated salivary KYNA levels. This stress response behavior-linked biomarker may aid heterogeneity reduction in schizophrenia and other stress-related psychiatric conditions.