Putative neuroprotective and neurotoxic kynurenine pathway metabolites are associated with hippocampal and amygdalar volumes in subjects with major depressive disorder
Open accessAbstract
Inflammation-related changes in the concentrations of kynurenine pathway metabolites occur in depression secondary to medical conditions but are not firmly established in primary mood disorders. Reductions in hippocampal and amygdalar volume that putatively reflect dendritic atrophy are widely reported in major depressive disorder (MDD). Here we tested whether the relative serum concentrations of putatively neuroprotective (kynurenic acid (KA)) and neurotoxic (3-hydroxykynurenine (3HK) and quinolinic acid (QA)) kynurenine pathway metabolites were altered in primary MDD and whether these metabolites were associated with hippocampal and amygdalar volume. A total of 29 moderately to severely depressed unmedicated subjects who met DSM-IV criteria for MDD and 20 healthy controls (HCs) completed a structural MRI scan and provided blood sample for kynurenine metabolite analysis, performed using high-performance liquid chromatography with tandem mass spectrometry. Cytokine concentrations were measured with ELISA and gray matter volumes were measured with the automated segmentation software, FreeSurfer. An a priori defined variable of interest, the KA/QA ratio, a putative neuroprotective index, trended lower in the MDD versus the HC group and correlated negatively with anhedonia but positively with the total hippocampal and amygdala volume in the MDD subjects. The post hoc data reduction methods yielded three principal components. Component 1 (interleukin-1 receptor antagonist, QA, and kynurenine) was significantly elevated in MDD participants versus the HCs, whereas component 2 (KA, tryptophan, and kynurenine) was positively correlated with hippocampal and amygdala volume within the MDD group. Our results raise the possibility that an immune-related imbalance in the relative metabolism of KA and QA predisposes to depression-associated dendritic atrophy and anhedonia.
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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 [146]
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- Authors
- Savitz, J., Drevets, W. C., Smith, C. M., Victor, T. A., Wurfel, B. E., Bellgowan, P. S., Bodurka, J., Teague, T. K., & Dantzer, R.
- Affiliations
- 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
- Neuropsychopharmacology
- Published
- 2014-07-30
- Volume
- 40
- Issue
- 2
- Pages
- 463-471
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4443961
- OpenAlex
- W2022766686
- Cited by
- 272
- References
- 61
- Citations by year
- 2026: 16 · 2025: 17 · 2024: 24 · 2023: 27 · 2022: 27 · 2021: 23 · 2020: 29 · 2019: 19 · 2018: 21 · 2017: 15 · 2016: 32 · 2015: 20 · 2014: 2
- FWCI
- 7.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- William K. Warren Foundation
- National Institute of Mental Health (K01MH096077)
- 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, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, hippocampal volume, amygdala volume, dendritic atrophy, anhedonia, interleukin-1 receptor antagonist, tryptophan metabolism, neuroinflammation, gray matter volume, cytokines
- MeSH terms
- Adult, Amygdala, C-Reactive Protein, Depressive Disorder, Major, Major Depressive Disorder, Female, Hippocampus, Humans, Kynurenic Acid, Kynurenine, Male, Organ Size, Psychiatric Status Rating Scales, Tryptophan, Signal Transduction, Quinolinic Acid, Receptors, Interleukin-1, Brain-Derived Neurotrophic Factor, Anhedonia, 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.
What counts as a claim ›How we measure confidence ›How we check this ›
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