Stress-induced increase in kynurenic acid as a potential biomarker for patients with schizophrenia and distress intolerance

JAMA Psychiatry. 2014 Jul 1;71(7):761-8. doi: 10.1001/jamapsychiatry.2014.243.


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 [SEM], 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 (ρ = 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Biomarkers / metabolism
  • Female
  • Humans
  • Kynurenic Acid* / metabolism
  • Male
  • Middle Aged
  • Neuropsychological Tests
  • Neurotransmitter Agents / chemistry
  • Neurotransmitter Agents / physiology
  • Saliva / chemistry
  • Saliva / physiology
  • Schizophrenia / metabolism*
  • Schizophrenia / physiopathology
  • Stress, Psychological / metabolism*
  • Stress, Psychological / physiopathology


  • Biomarkers
  • Neurotransmitter Agents
  • Kynurenic Acid