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RESEARCH WEEKLY: 2022 Brain & Behavior Research Foundation Symposium
By Elizabeth Sinclair Hancq
(November 9, 2022) On October 28, 2022, the Brain and Behavior Research Foundation held their annual research symposium, spotlighting advances in mental illness research in the past year. The Brain and Behavior Research Foundation was established in 1987 and has awarded over $440 million to fund innovative research in the neuroscience and psychiatry fields.
At this year’s symposium, there were two presentations on the role of kynurenic acid in schizophrenia. Kynurenic acid, an organic compound found in the human body, was first discovered in 1853 but didn’t begin to be understood until the 1950s. Today, it is clear this compound has a role in the development and treatment of mental illness.
Amino acids are molecules in the human body that combine to form proteins. There are 22 amino acids that form these protein building blocks and nine of those are considered ‘essential’ because the human body cannot synthesize them itself but requires consumption of them in our diets. Tryptophan is one of the nine essential amino acids.
Tryptophan is metabolized in the human body by two main pathways. The first, which constitutes the vast majority of its metabolism, is a pathway in which tryptophan is broken down to produce kynurenic acid. In the second pathway, tryptophan is metabolized into serotonin, another important brain molecule that has known implications in mental health and mental illness.
Below is a summary of the two presentations on kynurenic acid in schizophrenia:
From Obscurity to Hot Topic: The Kynurenic Acid Story, Robert Schwarcz, Ph.D.
Dr. Schwarcz presented on his decades-long work examining the role of kynurenic acid in symptoms of severe mental illness and his work developing the foundational science for potential drug targets. Utilizing brain tissue from deceased individuals with schizophrenia who donated their brains for science, his research found that people with schizophrenia have higher levels of kynurenic acid in the prefrontal cortex region of their brains compared to controls with no mental illness. They also found that schizophrenia patients have higher levels of kynurenic acid in their cerebral spinal fluid. Research further found that people with schizophrenia have lower levels of activity from an enzyme that breaks down kynurenic acid in the brain. The decreased activity of this enzyme is thought to cause higher levels of kynurenic acid in people with schizophrenia.
In fact, Dr. Schwarcz’s research on mice has shown that mice with lower levels of enzyme activity have similar cognitive issues to people with schizophrenia. According to his research, mice with too much kynurenic acid have cognitive deficits, while, on the other hand, decreased kynurenic acid appears to improve mice's cognitive and memory.
New Evidence for Translationally Relevant Roles of Kynurenic Acid in Schizophrenia, Sophie Erhardt, Ph.D.
Dr. Erhardt then presented her work examining how this science of kynurenic acid could be translated into clinically meaningful results for patients with schizophrenia.
She presented how her research has shown that kynurenic acid is not only elevated in patients with schizophrenia, but also in people with infectious disorders including Tuberculosis, HIV, and Malaria, all of which also have neurocognitive symptoms. In fact, HIV patients who also developed psychosis had even higher levels of kynurenic acid in their brains than HIV patients who did not experience psychosis. More recently, her work has shown that patients hospitalized for COVID-19 also have elevated levels of kynurenic acid in their brains. Therefore, the neurocognitive effects of COVID-19 and long-COVID such as brain fog or even psychosis could be due to elevated brain kynurenic acid levels.
Her further research has shown that kynurenic acid is also elevated in patients with bipolar disorder, but only those who have psychotic features. In patients with bipolar disorder and no psychotic symptoms, their brain kynurenic acid levels are like those of people with no mental illness. Completing the picture, her research suggests that the immune system activates the kynurenic acid metabolism pathway of tryptophan.
She is currently working on drug discovery for a molecule that selectively reduces kynurenic acid in human cells. This type of drug only works in immune activated cells and has no impact on kynurenic acid in cells that do not have immune activity. Therefore, this drug could work for schizophrenia and bipolar disorder, but also patients that have cognitive deficits due to immune activation. Dr. Erhardt believes this type of drug could have positive impacts on cognition but also in reducing psychotic symptoms, but a biomarker for immune activation is needed as it will only work for those patients.
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