An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation
Open accessAbstract
Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N-methyl-d-aspartate receptor agonist, are increased. The enzyme amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Åsberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single-nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (P<0.001) and blood (P=0.001 and P<0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.
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Quinolinic and kynurenic acids are related to suicidal behavior.
“Quinolinic and kynurenic acids (which serve as an agonist and an antagonist of the excitotoxic glutamate receptors, respectively) are related to suicidal behavior (205-207).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [207]
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- Authors
- Brundin, L., Sellgren, C. M., Lim, C. K., Grit, J., Pålsson, E., Landén, M., Samuelsson, M., Lundgren, K., Brundin, P., Fuchs, D., Postolache, T. T., Traskman-Bendz, L., Guillemin, G. J., & Erhardt, S.
- Affiliations
- Van Andel Institute (US)
- Broad Institute (US)
- Macquarie University (AU)
- University of Gothenburg (SE)
- Linköping University (SE)
- Innsbruck Medical University (AT)
- University of Maryland, Baltimore (US)
- National Health and Medical Research Council (AU)
- Karolinska Institutet (SE)
- Corresponding author
- Grit, J
- ORCID
- Venue
- Translational Psychiatry
- Published
- 2016-08-02
- Volume
- 6
- Issue
- 8
- Pages
- e865-e865
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC5022080
- OpenAlex
- W2504229998
- Cited by
- 195
- References
- 51
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 20 · 2023: 17 · 2022: 28 · 2021: 25 · 2020: 24 · 2019: 18 · 2018: 16 · 2017: 15 · 2016: 2
- FWCI
- 5.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DiVA (Linkoping University) (submittedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 CX001310)
- American Foundation for Suicide Prevention (DIG-1-162-12)
- Van Andel Research Institute (2011-4787)
- Michigan State University (2009-4284)
- Australian Government
- Vetenskapsrådet (2011-04787, 2008-02922, 2002-5297, K2014‐62X‐14647‐12‐51, 2009-04284, 2009-07052, 2013-02838)
- National Institutes of Health
- College of Engineering, Michigan State University
- Joint Institute for Food Safety and Applied Nutrition, University of Maryland (001418)
- Medical Research Council
- Australian Research Council
- National Health and Medical Research Council
- National Institute of Mental Health (R01MH104622)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Social Sciences › Psychology › Clinical Psychology › Suicide and Self-Harm Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- kynurenine pathway, suicidal behavior, quinolinic acid, picolinic acid, neuroinflammation, excitotoxicity, NMDA receptor, depression, suicide attempters, cerebrospinal fluid biomarkers, single nucleotide polymorphisms, glutamate metabolism
- MeSH terms
- Adolescent, Adult, Aged, Alleles, Carboxy-Lyases, Child, Female, Humans, Inflammation, Kynurenine, Male, Middle Aged, Picolinic Acids, Suicide, Attempted, Case-Control Studies, Self-Injurious Behavior, Quinolinic Acid, Polymorphism, Single Nucleotide, Young Adult, Suicidal Ideation
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