Relationship between neurotoxic kynurenine metabolites and reductions in right medial prefrontal cortical thickness in major depressive disorder
Open accessAbstract
Reductions in gray matter volume of the medial prefrontal cortex (mPFC), especially the rostral and subgenual anterior cingulate cortex (rACC, sgACC) are a widely reported finding in major depressive disorder (MDD). Inflammatory mediators, which are elevated in a subgroup of patients with MDD, activate the kynurenine metabolic pathway and increase production of neuroactive metabolites such as kynurenic acid (KynA), 3-hydroxykynurenine (3HK) and quinolinic acid (QA) which influence neuroplasticity. It is not known whether the alterations in brain structure and function observed in major depressive disorders are due to the direct effect of inflammatory mediators or the effects of neurotoxic kynurenine metabolites. Here, using partial posterior predictive distribution mediation analysis, we tested whether the serum concentrations of kynurenine pathway metabolites mediated reductions in cortical thickness in mPFC regions in MDD. Further, we tested whether any association between C-reactive protein (CRP) and cortical thickness would be mediated by kynurenine pathway metabolites. Seventy-three unmedicated subjects who met DSM-IV-TR criteria for MDD and 91 healthy controls (HC) completed MRI scanning using a pulse sequence optimized for tissue contrast resolution. Automated cortical parcellation was performed using the PALS-B12 Brodmann area atlas as implemented in FreeSurfer in order to compare the cortical thickness and cortical area of six PFC regions: Brodmann areas (BA) 9, 10, 11, 24, 25, and 32. Serum concentrations of kynurenine pathway metabolites were determined by high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) detection, while high-sensitivity CRP concentration was measured immunoturbidimetrically. Compared with HCs, the MDD group showed a reduction in cortical thickness of the right BA24 (p<0.01) and BA32 (p<0.05) regions and MDD patients with a greater number of depressive episodes displayed thinner cortex in BA32 (p<0.05). Consistent with our previous findings in an overlapping sample, the KynA/3HK ratio and the log KynA/QA were reduced in the MDD group relative to the HC group (p's<0.05) and symptoms of anhedonia were negatively correlated with log KynA/QA in the MDD group (p<0.05). Both KynA/3HK and log KynA/QA at least partially mediated the relationship between diagnosis and cortical thickness of right BA32 (p's<0.05). CRP was inversely associated with BA32 thickness (p<0.01) and KynA/3HK partially mediated the relationship between CRP and the thickness of right BA32 (p<0.05). The results raise the possibility that the relative imbalance between KynA and neurotoxic kynurenine metabolites may partially explain the reductions in mPFC thickness observed in MDD, and further that these changes are more strongly linked to the putative effects of neuroactive kynurenine metabolites than those of inflammatory mediators.
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A study found that a lower kynurenic acid to 3-hydroxykynurenine ratio correlated with smaller hippocampal volumes in major depressive disorder and partly mediated the link between major depressive disorder and medial prefrontal cortex cortical thinning.
“a study found that a lower KynA/3HK ratio correlated with reduced hippocampal volumes in MDD and partially mediated the relationship between MDD and mPFC cortical thinning (146,147).”
From The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology (2019) · cites this paper as [147]
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Piras, F., Salani, F., Bossù, P., Caltagirone, C., & Spalletta, G. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-42 · Cited by 10 · see citing works
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Neuroinflammation and depression: A review
Troubat, R., Barone, P., Leman, S., Desmidt, T., Cressant, A., Atanasova, B., Brizard, B., El Hage, W., Surget, A., Belzung, C., et al. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.14720 · Cited by 1,107 · see citing works
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Self-citationRescue of IL-1β-induced reduction of human neurogenesis by omega-3 fatty acids and antidepressants
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- Authors
- Meier, T. B., Drevets, W. C., Wurfel, B. E., Ford, B. N., Morris, H. M., Victor, T. A., Bodurka, J., Teague, T. K., Dantzer, R., & Savitz, J.
- Affiliations
- Medical College of Wisconsin (US)
- Laureate Institute for Brain Research (US)
- Oklahoma State University Center for Health Sciences (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Savitz, Jonathan
- ORCID
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 53
- Pages
- 39-48
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC4783304
- OpenAlex
- W2193977448
- Cited by
- 175
- References
- 84
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 16 · 2023: 23 · 2022: 18 · 2021: 21 · 2020: 18 · 2019: 18 · 2018: 19 · 2017: 8 · 2016: 13 · 2015: 1
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (K01MH096077)
- William K. Warren Foundation
- Mind Research Network/Lovelace Biomedical and Environmental Research Institute
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- major depressive disorder, kynurenine pathway metabolites, neurotoxicity, medial prefrontal cortex, cortical thickness, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, C-reactive protein, inflammation, mediation analysis, anhedonia, gray matter volume
- MeSH terms
- Adult, Brain, C-Reactive Protein, Cerebral Cortex, Major Depressive Disorder, Female, Humans, Kynurenic Acid, Kynurenine, Magnetic Resonance Imaging, Male, Tryptophan, Case-Control Studies, Quinolinic Acid, Prefrontal Cortex, Neurotoxicity Syndromes, Gray Matter
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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