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Tryptophan challenge in individuals with schizophrenia and healthy controls: acute effects on circulating kynurenine and kynurenic acid, cognition and cerebral blood flow

Neuropsychopharmacology volume 48, pages 1594–1601 (2023)Cite this article

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Abstract

Cognitive impairments predict poor functional outcomes in people with schizophrenia. These impairments may be causally related to increased levels of kynurenic acid (KYNA), a major metabolic product of tryptophan (TRYP). In the brain, KYNA acts as an antagonist of the of α7-nicotinic acetylcholine and NMDA receptors, both of which are involved in cognitive processes. To examine whether KYNA plays a role in the pathophysiology of schizophrenia, we compared the acute effects of a single oral dose of TRYP (6 g) in 32 healthy controls (HC) and 37 people with either schizophrenia (Sz), schizoaffective or schizophreniform disorder, in a placebo-controlled, randomized crossover study. We examined plasma levels of KYNA and its precursor kynurenine; selected cognitive measures from the MATRICS Consensus Cognitive Battery; and resting cerebral blood flow (CBF) using arterial spin labeling imaging. In both cohorts, the TRYP challenge produced significant, time-dependent elevations in plasma kynurenine and KYNA. The resting CBF signal (averaged across all gray matter) was affected differentially, such that TRYP was associated with higher CBF in HC, but not in participants with a Sz-related disorder. While TRYP did not significantly impair cognitive test performance, there was a trend for TRYP to worsen visuospatial memory task performance in HC. Our results demonstrate that oral TRYP challenge substantially increases plasma levels of kynurenine and KYNA in both groups, but exerts differential group effects on CBF. Future studies are required to investigate the mechanisms underlying these CBF findings, and to evaluate the impact of KYNA fluctuations on brain function and behavior. (Clinicaltrials.gov: NCT02067975).

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Fig. 1: Effects of tryptophan (TRYP) administration on plasma levels of kynurenine and kynurenic acid.
Fig. 2: Effect of tryptophan (TRYP) administration on cerebral blood flow (CBF) in healthy controls and participants with a schizophrenia-related disorder (PSz).

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Acknowledgements

We thank the participants, especially those with schizophrenia, who graciously gave their time and effort to undergo the medical, imaging, and cognitive procedures in this project. We acknowledge the effort and contribution of many individuals to this project including Dr. Heather Adams, Pat Ball, Frank Blatt, Hongji Chen, Amber Earl, Frank Gaston, Matthew Glassman, Dr. David Gorelick, Katherine Kilday, Sharon Pugh, Marian Thomas, Samantha Trikeriotis, Dr. Gopal Vyas, and the Spring Grove Hospital Center Treatment Research Unit.

Funding

This study was supported by NIMH grant P50-MH103222 (Conte Center for Translational Neuroscience Research).

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Author notes

  1. These author contributed equally: Laura M. Rowland, Robert W. Buchanan.

Authors and Affiliations

  1. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Stephanie M. Hare, Bhim M. Adhikari, Shuo Chen, S. Andrea Wijtenburg, Samuel Kane-Gerard, Korrapati V. Sathyasaikumar, Francesca M. Notarangelo, Robert Schwarcz, Deanna L. Kelly, Laura M. Rowland & Robert W. Buchanan

  2. Harvard Medical School, Boston, MA, 02115, USA

    Chen Mo

  3. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Chamindi Seneviratne

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Contributions

Conceptualization: DLK, LMR, RWB and RS; funding acquisition: RWB and RS; methodology, data collection, quality control and analysis: SMH, BMA, SC, CM, SAW, CS, SKG, KVS, FMN, and LMR; writing (original draft preparation): SMH; writing (review and editing): SMH, BMA, CM, SC, SAW, CS, SKG, KVS, FMN, RS, LMR, DLK, and RWB; supervision: DLK, LMR, RWB and RS. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Stephanie M. Hare.

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Competing interests

RS is co-founder of KyNexis AB, which develops novel drugs targeting kynurenine pathway metabolism. RWB performs consultation for Boehringer-Ingelheim and serves on the Data Safety and Monitoring Boards of Roche, Merck and Newron; and on the Advisory Boards of Merck, Acadia, and Neurocrine. DLK is a consultant for Janseen, Alkermes and Sunovion. All other authors declare no competing interests.

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Hare, S.M., Adhikari, B.M., Mo, C. et al. Tryptophan challenge in individuals with schizophrenia and healthy controls: acute effects on circulating kynurenine and kynurenic acid, cognition and cerebral blood flow. Neuropsychopharmacol. 48, 1594–1601 (2023). https://doi.org/10.1038/s41386-023-01587-3

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