Potential Psychosis Biomarker Found in Saliva

Nancy A. Melville

July 10, 2014

Kynurenic acid (KYNA), detected in saliva, represents a potentially important biomarker identifying acute stress in patients with schizophrenia who may not report stress.

"These findings are the first to directly demonstrate that KYNA increases in response to stress in humans and that this increase can be measured in a noninvasive manner," first author Joshua Chiappelli, MD, told Medscape Medical News.

"The finding that KYNA levels are elevated in a subset of individuals with schizophrenia who have a poor capacity for tolerating stress suggests the kynurenine pathway may be involved in the mechanisms by which stress contributes to the development of psychosis," said Dr. Chiappelli, of the Maryland Psychiatric Research Center, at the University of Maryland School of Medicine, in Baltimore.

The study was published in the July issue of JAMA Psychiatry.

Stress Intolerance

KYNA, an endogenous neuromodulator, has been previously linked with schizophrenia, with increased concentrations of kynurenine pathway metabolites and KYNA found in the postmortem brain tissue and cerebrospinal fluid of people with schizophrenia.

Research is lacking, however, on the extent of the role of kynurenergic abnormalities in schizophrenia.

For the study, Dr. Chiappelli and colleagues enrolled 128 participants, including 64 outpatients with schizophrenia and 64 healthy control individuals.

Participants were given laboratory-based computer stress challenges involving 2 mirror drawing and mental arithmetic tasks. As an incentive, the participants were told they would receive a monetary reward based on completion of the tasks, but they were not told the maximum time allowed for completion.

Participants' salivary KYNA levels were measured at baseline, at 20 minutes, and then 40 minutes following the completion or failure to complete the second task.

The results showed that patients with schizophrenia had a significantly higher rate of distress intolerance, defined as quitting the stress task early, compared with healthy control participants (P = .003).

Patients with schizophrenia also had higher mean salivary KYNA levels at baseline, and although the KYNA levels increased by an average of about 40% between baseline and 20 minutes following the stress task in both groups (P = .007), levels were significantly higher among those who were unable to tolerate the tasks, compared with those who finished the stress tasks (P = .02).

In both groups, KYNA elevation was still higher at 40 minutes after the test compared with baseline (P = .03).

"These results demonstrate a transient increase in salivary KYNA following a stressful task that was similar in patients with schizophrenia and healthy controls when not accounting for distress intolerance," the authors write.

Importantly, although KYNA levels significantly correlated with the severity of clinical symptoms assessed by repeated measures analysis of variance (ANOVA) among those with distress intolerance (P = .008), the elevation did not correlate with subjective reports of distress, rated by participants on a 5-point Likert scale.

"[This suggests] that the elevated KYNA levels primarily marked an inability to persist in tasks while stressed rather than the subjective experience of stress," the investigators note.

"Therefore, in individuals with schizophrenia, elevated salivary KYNA levels may provide a quantitative biomarker indexing an inability to persist in tasks under stressful conditions," they add.

The authors note that they unexpectedly did not find a correlation between KYNA and cortisol levels, suggesting a distinct difference in the mechanisms behind how the 2 respond to acute stress.

There was also no significant association between KYNA levels and medication use, including use of antipsychotics or antidepressants.

Dr. Chiappelli underscored the fact that the findings, if replicated, could have important clinical implications for several reasons.

"If further studies show that the kynurenine pathway is involved in how stress contributes to symptom increases, this would underscore the importance of developing medications to target tryptophan metabolism," he said.

"And if KYNA levels indicate susceptibility to stress-induced clinical exacerbations, then KYNA could be useful as a biomarker to identify individuals who would be most likely to benefit from psychosocial treatment strategies aimed at stress reduction."

Treatment Target

Daniel C. Javitt, MD, PhD, author of an accompanying editorial, told Medscape Medical News that the findings shed light on KYNA as an important piece of the puzzle in the broader issue of N-methyl-D-aspartate (NMDA) receptor function.

"We have known for over 20 years that disturbances of NMDA receptor function produce psychosis that closely resembles schizophrenia," said Dr. Javitt, of the Division of Experimental Therapeutics at Columbia University College of Physicians and Surgeons in New York City.

"An important focus of research has been to identify the causes of disturbance, [and] causes likely differ across individuals."

"This paper shows that stress-related accumulation of the kynurenic acid is another potential cause of NMDA receptor dysfunction and, if true, that treatments aimed at reduced kynurenic acid levels in the brain could be effective."

KYNA is intriguing because of its potentially beneficial "druggability," Dr. Javitt added.

"A current disconnect in psychiatric research is that even though many genes are being linked to schizophrenia, many of them code for structural proteins. Therefore, even if they are abnormal, there is no easy way to target them for new treatment development."

"Classic cases are disorders such as sickle cell anemia or Huntington's disease, in which the responsible gene has been known for a long time, but there is nothing a drug could do to reverse the abnormality."

"Given the nature of the enzymes involved in kynurenine metabolism, it should be possible to develop very specific drugs that will have predictable effects on the system," he said. "Whether or not this will lead to beneficial clinical effects, however, still needs to be determined."

In the meantime, the findings suggest benefits even from KYNA monitoring, Dr. Javitt noted.

"Patients are often very bad at reporting when they are stressed ― they may not be consciously aware of the stress (alexithymia) or may not be able to articulate their experience," he explained.

"If KYNA can be reliably detected from saliva, it might be worth measuring as part of routine examination."

The study was supported by grants from the National Institutes of Health. Coauthors Robert Schwarcz, PhD, and Elliott Hong, MD, have submitted a patent application for the use of salivary KYNA as a biomarker. Dr Javitt has consulted for Eli Lilly, Takeda, Omeros, SK Biopharmaceuticals, Otsuka, Sunovion, and Envivo; he has received grant support from Pfizer and Roche; he holds equity in GlyTech; and he has intellectual property rights in glycine, D-serine, and glycine transport inhibitors for schizophrenia and related conditions.

JAMA Psychiatry. 2014;71:761-768, 749-750. Abstract, Editorial

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