We're unable to sign you in at this time. Please try again in a few minutes.
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

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

Joshua Chiappelli, MD1; Ana Pocivavsek, PhD1; Katie L. Nugent, PhD1; Francesca M. Notarangelo, PhD1; Peter Kochunov, PhD1; Laura M. Rowland, PhD1; Robert Schwarcz, PhD1; L. Elliot Hong, MD1
[+] Author Affiliations
1Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore
JAMA Psychiatry. 2014;71(7):761-768. doi:10.1001/jamapsychiatry.2014.243.
Text Size: A A A
Published online

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.

Figures in this Article

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?


Place holder to copy figure label and caption
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.

Graphic Jump Location
Place holder to copy figure label and caption
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).

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location




Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment


Some tools below are only available to our subscribers or users with an online account.

3 Citations

Sign in

Purchase Options

• Buy this article
• Subscribe to the journal
• Rent this article ?

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles