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

Abstract

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.

Figure 1. Schematic Illustration of the Experimental Procedure

The stress challenge consisted of the Paced Auditory Serial Addition Task (PASAT) and the Mirror-Tracing Persistence Task (MTPT). The order of the tasks was randomized across participants. Subjective feeling of negative affect was measured using the Positive and Negative Affect Schedule at 3 points during the study session (arrowheads). Saliva was collected at baseline and then again at 20 and 40 minutes after the end of the stress challenge. The duration of the stress challenge varied between participants depending on whether a participant quit 2, 1, or 0 tasks.

Figure 2. Distress Tolerance and Intolerance of Patients With Schizophrenia and Healthy Controls

In performing 2 psychological stress challenge tasks, patients with schizophrenia were significantly more likely to be distress intolerant than healthy controls. A χ² test was used to examine the frequency of distress-tolerant vs distress-intolerant participants across patients with schizophrenia and healthy controls (P = .003).

Figure 3. Salivary Kynurenic Acid (KYNA) Levels in Distress-Tolerant and Distress-Intolerant Participants and Negative Affect

A, All subgroups showed increased salivary KYNA levels 20 minutes after the stressor. However, in participants who tolerated 1 or both tasks, the KYNA response was similar in patients with schizophrenia and healthy controls. “Stress duration” bar indicates the timing of the stress task relative to sample collection. B, In participants showing distress intolerance, the KYNA response significantly separated patients with schizophrenia from healthy controls (P = .04 for interaction effect) such that only patients with distress intolerance had higher baseline KYNA levels and KYNA response to stress. “Stress duration” bar indicates the timing of the stress task relative to sample collection. C, Subjectively experienced maximum negative affect during the psychological stress challenge (stress) was substantially higher compared with baseline (P < .001). Patients with schizophrenia generally had higher negative affect at baseline than healthy controls. Error bars indicate standard error of the mean. D, However, there was no difference in the magnitude of negative affect change between patients with schizophrenia and healthy controls (P = .36). Error bars indicate standard error of the mean.