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Cited by 69Tryptophan and brain disordersTreatment of Major DepressionMetabolomics and Mass Spectrometry Studies

Tryptophan-kynurenine and lipid related metabolites as blood biomarkers for first-episode drug-naïve patients with major depressive disorder: An exploratory pilot case-control study

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Kuwano, Nobuki, Kato, Takahiro A., Setoyama, Daiki, Sato-Kasai, Mina, Shimokawa, Norihiro, Hayakawa, Kohei, Ohgidani, Masahiro, Sagata, Noriaki +4 more·2018·Journal of Affective Disorders
DOI 10.1016/j.jad.2018.01.014
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Abstract

Background Early intervention in depression has been critical to prevent its negative impact including suicide. Recent blood biomarker studies for major depressive disorder (MDD) have suggested that tryptophan-kynurenine and lipid related metabolites are involved in the pathophysiology of MDD. However, there have been limited studies investigating these blood biomarkers in first-episode drug-naïve MDD, which are particularly important for early intervention in depression.Methods As an exploratory pilot case-control study, we examined the above blood biomarkers, and analyzed how these biomarkers are associated with clinical variables in first-episode drug-naïve MDD patients, based on metabolome/lipidome analysis.Results Plasma tryptophan and kynurenine levels were significantly lower in MDD group (N = 15) compared to healthy controls (HC) group (N = 19), and plasma tryptophan was the significant biomarker to identify MDD group (area under the curve = 0.740). Lower serum high density lipoprotein-cholesterol (HDL-C) was the predictive biomarker for severity of depression in MDD group (R 2 = 0.444). Interestingly, depressive symptoms were variously correlated with plasma tryptophan-kynurenine and lipid related metabolites. Moreover, plasma tryptophan-kynurenine metabolites and cholesteryl esters (CEs) were significantly correlated in MDD group, but not in HC group.Limitations This study had small sample size, and we did not use the multiple test correction.Conclusions This is the first study to suggest that not only tryptophan-kynurenine metabolites but also HDL-C and CEs are important blood biomarkers for first-episode drug-naïve MDD patients. The present study sheds new light on early intervention in clinical practice in depression, and further clinical studies especially large-scale prospective studies are warranted.

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Crossref · 10.1016/j.jad.2018.01.014

Cites

98 of 98 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 48 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In first-episode drug-naïve MDD patients, serum HDL-C was negatively correlated with BDI-II total score (r=-0.666, P=.007).

    “As shown in Table S2, serum HDL-C was negatively correlated with BDI-II total score (r = -0.666,P = .007).”
    Quote in the paperSubstantial claim
  • Findingown data

    There was no significant difference in plasma kynurenine/tryptophan ratio between healthy controls and MDD patients.

    “In the present study, there has been no significant difference in the plasma kynurenine/tryptophan ratio, an indicator for the activity of TDO and IDO, between HC and MDD group.”
    Quote in the paperSubstantial claim
  • Findingown data

    In healthy controls, the significant correlation between plasma tryptophan-kynurenine metabolites and lipid species seen in MDD patients was not detected.

    “On the other hand, the above significant correlation between plasma tryptophan-kynurenine metabolites and lipid species in MDD group was not detected in HC group (Fig. S2 and Table S6).”
    Quote in the paperSubstantial claim
  • Findingown data

    In first-episode drug-naïve MDD patients, plasma tryptophan levels were significantly lower than in healthy controls.

    “Plasma tryptophan and kynurenine levels were significantly lower in MDD group compared to HC group (P = .010,P = .018,respectively).”
    • Also stated in: § Abstract · plain
      “Plasma tryptophan and kynurenine levels were significantly lower in MDD group (N = 15) compared to healthy controls (HC) group (N = 19), and plasma tryptophan was the significant biomarker to identify MDD group (area under the curve = 0.740).”
    Quote in the paperSubstantial claim
  • Findingown data

    Plasma tryptophan was selected by stepwise discriminant analysis as a biomarker significantly associated with MDD diagnosis.

    “Plasma tryptophan was selected as the biomarker significantly associated with MDD diagnosis through the stepwise selection (P = .010).”
    Quote in the paperSubstantial claim
  • May combine two claims. 8
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 21

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    Findingown data

    The discriminant analysis using plasma tryptophan correctly classified 76.5% of participants, with 80.0% sensitivity and 73.7% specificity.

    “The correct classification rate obtained from discriminant analysis between HC and MDD group was 76.5%, with a sensitivity and specificity of 80.0% and 73.7%, respectively.”
    Quote in the paperSubstantial claim

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    Findingown data

    After adjustment for age and sex, serum HDL-C retained a significant predictive association with BDI-II total score in MDD patients (partial r=-0.619, t=-2.611, P=.024).

    “After control by age and sex, serum HDL-C still exhibited a significant predictive ability of SOD (partial correlation coefficient = -0.619,t = -2.611,P = .024).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    There were no significant differences in sex and age between healthy controls and MDD patients.

    “There were no significant differences in sex and age between HC and MDD group.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    The tryptophan-kynurenine pathway has recently been highlighted in the pathophysiological understanding of MDD beyond the traditional serotonin hypothesis.

    “The tryptophan-kynurenine pathway has recently been highlighted in pathophysiological understanding of MDD beyond the traditional”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Dantzer, 2017

      Not checked in the free run.

    • cites Dantzer et al., 2008 source

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    • cites Dantzer et al., 2011 source

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    Study design and conductreasoning

    The study had a small sample size, which restricts drawing conclusive findings and makes the findings preliminary.

    “First, the main limitation is sample size.Small sample size has its restriction in drawing conclusive findings, and the present findings are preliminary.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    This was the first blood biomarker study combining tryptophan metabolites, routine biochemical markers, and lipid species in first-episode drug-naïve MDD patients.

    “This is the first blood biomarker study combining tryptophan metabolites, routine biochemical markers, and lipid species in first-episode drug-naïve MDD patients.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Blood biomarker studies combining tryptophan metabolites, routine biochemical markers, and lipid species in first-episode drug-naïve MDD patients had not existed before this study.

  • May combine two claims.

    Premisecitation

    Tryptophan, kynurenine metabolites, and cholesteryl esters are involved not only in major depressive disorder but also in various psychiatric disorders (schizophrenia, bipolar disorder) and physical disorders (inflammatory bowel diseases, infectious diseases, heart diseases).

    “Tryptophan, kynurenine metabolites, and CEs have been reported to be involved not only with MDD but also with various psychiatric disorders such as schizophrenia and bipolar disorder and physical disorders such as inflammatory bowel diseases, infectious diseases, and heart diseases (Choi et al., 2017;Dantzer et al., 2011;Halaris, 2013Halaris, , 2017;;Maes et al., 2011b;Martin-Subero et al., 2016;M”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Choi et al., 2017

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    • cites Dantzer et al., 2011 source

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    • cites Halaris, 2013

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Both tryptophan-kynurenine metabolites and cholesterol have been suggested to be involved in inflammation.

    “Both tryptophan-kynurenine metabolites and cholesterol have been suggested to be involved in inflammation (Dantzer, 2017;Dantzer et al., 2011;Halaris et al., 2015;Maes et al., 2012;Maes et al., 2011b;Myint, 2012;Myint et al., 2012;Parekh et al., 2017).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Dantzer, 2017

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    • cites Dantzer et al., 2011 source

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    • cites Halaris et al., 2015

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    Premisecitation

    Brain inflammation induced by microglial activation is highlighted in various psychiatric disorders including MDD.

    “Brain inflammation induced by microglial activation is now highlighted in various psychiatric disorders including MDD (Hayakawa et al., 2014;Horikawa et al., 2010;Kato et al., 2011a;Kato et al., 2013;Monji et al., 2009;Ohgidani et al., 2016;Sato-Kasai et al., 2016).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hayakawa et al., 2014

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    • cites Horikawa et al., 2010

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    • cites Kato et al., 2011a

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  • May combine two claims.

    Interpretationown data

    Not only tryptophan-kynurenine metabolites but also HDL-C and CEs are important blood biomarkers for first-episode drug-naïve MDD patients.

    “In the present study, we have shown the first findings that not only tryptophan-kynurenine metabolites but also HDL-C and CEs are important blood biomarkers for first-episode drug-naïve MDD patients.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    A recent rodent study showed that serum lipid species are involved with altered function of tryptophan metabolites.

    “Moreover, a recent rodent study has shown that serum lipid species are involved with altered function of tryptophan metabolites (Weng et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Weng et al., 2016

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    Study design and conductcitation

    The disease specificity of biomarkers is a critical issue in the present study.

    “Second, the disease specificity of biomarkers is a critical issue in the present study.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Depression or some depressive symptoms also occur in the psychiatric and physical disorders mentioned.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    The present study has shed new light on the role of tryptophan-kynurenine and lipid related metabolites in the pathophysiology of MDD.

    “The present study has shed new light on the role of tryptophan-kynurenine and lipid related metabolites in the pathophysiology of MDD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study did not assess body mass index (BMI) and diet conditions.

    “Third, we did not assess body mass index (BMI) and diet conditions.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Blood biomarker levels are influenced by BMI and diet.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Xanthurenic acid is involved in psychiatric disorders, including depression, through an anti-inflammatory effect.

    “have suggested that xanthurenic acid is involved with psychiatric disorders including depression through an anti-inflammatory effect (Kanchanatawan et al., 2017;Maes et al., 1986;Maes et al., 2007).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Kanchanatawan et al., 2017

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    • cites Maes et al., 1986

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    • cites Maes et al., 2007

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    Premisecitation

    Many studies have shown elevated oxidative stress in patients with MDD.

    “Many studies have shown elevated oxidative stress in patients with MDD (Herken et al., 2007;Liu et al., 2015a;Maes et al., 2010), thus oxidative stress is regarded to be involved in the pathophysiology of MDD (de Melo et al., 2017;Maes et al., 2011a;Michel et al., 2012).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Herken et al., 2007

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    • cites Liu et al., 2015a

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    • cites Maes et al., 2010

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A tryptophan hydroxylase-2 knockout mouse study showed that serotonin deficiency is caused by elevated oxidative stress associated with altered metabolism of serum lipid species.

    “A recent study, using tryptophan hydroxylase-2 knockout mouse, has shown that serotonin deficiency is caused by elevated oxidative stress associated with altered metabolism of serum lipid species (Weng et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Weng et al., 2016

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    Study design and conductreasoning

    The present findings are preliminary because the small sample size makes conclusive findings difficult.

    “However, as mentioned above, the present findings are preliminary, since drawing conclusive findings is difficult due to small sample size.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CRP is higher in patients with MDD.

    “One of these substances is CRP with accumulated evidence that CRP is higher in patients with MDD (Haapakoski et al., 2015;Howren et al., 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Haapakoski et al., 2015 source

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    • cites Howren et al., 2009 source

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    Study design and conductown data

    In the exclusion criteria of healthy controls, the study did not check psychiatric and physical disorders in first-degree relatives.

    “Fourth, in the exclusion criteria of HC, we did not check psychiatric and physical disorders in first degree relatives.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Blood biomarker levels may be influenced by family history, particularly for diseases with genetic predisposition.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    The levels of some blood biomarkers may change according to the stage of major depressive disorder.

    “In addition, the levels of some blood biomarkers may change according to the stage of MDD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The blood biomarkers proposed in the present study are possible objective diagnostic indicators for first-episode drug-naïve patients with depression, particularly useful for early detection in psychiatric settings, primary care, and corporate health settings.

    “The blood biomarkers proposed in the present study are possible objective diagnostic indicators for first-episode drugnaïve patients with depression, which are particularly important and useful for early detection not only in psychiatric settings but also primary care and corporate health settings.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Diagnosis and symptom evaluation of MDD in clinical practice rely on physicians' clinical experience and patients' self-assessments.
    • Rests on an assumption: This reliance leads to many delayed consultations and treatments and misdiagnoses.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several studies have reported that serum HDL-C is negatively correlated with severity of depression in patients with MDD.

    “Supporting the present study, several studies have reported that serum HDL-C is negatively correlated with SOD in patients with MDD (Lucka et al., 2017;Shin et al., 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Lucka et al., 2017

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    • cites Shin et al., 2008

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    Study design and conductown data

    There were no significant differences in age and sex between healthy controls and first-episode drug-naïve MDD patients.

    “Age (year) | 30.2 | 6.8 | 30.1 | 7.6 | t = 0.058 | 32 | 0.954”
    • Also stated in: § 4.2. Conclusion · plain
      “N (Male/Female) | 19 (10/9) | | 15 (9/6) | | χ 2 = 0.185 | 1 | 0.667”
    Quote in the paperNot a substantial claim

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    Study design and conductreasoning

    Blood samples were not checked for fasting or non-fasting conditions.

    “We did not check as to whether blood samples were collected under fasting or non-fasting conditions, since blood collection of first-episode drug-naïve MDD patients was performed according to the voluntary time when the patients consulted.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Blood cholesterols such as HDL-C and LDL-C have been suggested to be involved in the pathophysiology of MDD.

    “Blood cholesterols such as HDL-C and LDL-C have been suggested to be involved in the pathophysiology of MDD (Parekh et al., 2017;Shelton and Miller, 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Parekh et al., 2017

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    • cites Shelton and Miller, 2010

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    Premisecitation

    Cholesteryl esters play an important part in cholesterol transportation and homeostasis.

    “CEs, formed by the esterification of cholesterol, play an important part in cholesterol transportation and homeostasis (Tosi and Tugnoli, 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tosi and Tugnoli, 2005

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  • Classified as probably not a substantial claim.

    Premisecitation

    A recent clinical study showed that cholesterol-lowering treatment leads to downregulation of the tryptophan-kynurenine pathway paralleled by oxidative stress improvement in patients with chronic kidney disease.

    “On the other hand, a recent clinical study has shown that cholesterol-lowering treatment leads to downregulation of tryptophankynurenine pathway paralleled by oxidative stress improvement in patients with chronic kidney disease (Zinellu et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zinellu et al., 2015

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    Premisecitation

    A previous study showed that plasma tryptophan levels and TDO/IDO activity are elevated in MDD patients with a history of suicide attempts.

    “On the other hand, a previous study has shown that plasma tryptophan levels and activity of TDO and IDO are elevated in MDD patients with a history of suicide attempts (Sublette et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sublette et al., 2011 source

      Not checked in the free run.

29 of 29

  • The paper relies on this without support.

    Blood biomarker studies combining tryptophan metabolites, routine biochemical markers, and lipid species in first-episode drug-naïve MDD patients had not existed before this study.

    “To our knowledge, blood biomarker studies combining tryptophan metabolites, routine biochemical markers, and lipid species especially focusing on first-episode drug-naïve MDD patients have not existed until now.”

  • The paper relies on this without support.

    Blood biomarkers in practical use for depression have been very limited until now.

    “However, to our knowledge, blood biomarkers in practical use for depression have been very limited until now.”

  • The paper relies on this without support.

    Many previous studies have included patients under medication and patients with recurrent episodes of MDD.

    “yet, many previous studies have included patients under medication and patients with recurrent episodes of MDD.”

  • The paper relies on this without support.

    Present MDD diagnostic and severity-of-depression evaluation systems including SCID and BDI-II completely rely on persons' subjective descriptions, spoken information, and attitudes.

    “Present MDD diagnostic and SOD evaluation systems including SCID and BDI-II completely rely on persons' subjective descriptions, spoken information, and attitudes.”

  • The paper relies on this without support.

    Depression or some depressive symptoms also occur in the psychiatric and physical disorders mentioned.

    “Interestingly, depression, or at least some depressive symptoms, also occur in the above disorders.”

  • The paper relies on this without support.

    Blood biomarker levels are influenced by BMI and diet.

    “Levels of some blood biomarkers are affected by BMI and diet.”

  • The paper relies on this without support.

    Blood biomarker levels may be influenced by family history, particularly for diseases with genetic predisposition.

    “Levels of some blood biomarkers may be affected by family history, especially by family history of diseases with genetic predisposition.”

  • The paper relies on this without support.

    Diagnosis and symptom evaluation of MDD in clinical practice rely on physicians' clinical experience and patients' self-assessments.

    “The diagnosis and symptom evaluation of MDD in clinical practice has depended on physician's clinical experiences and patient's self-assessments.”

  • The paper relies on this without support.

    This reliance leads to many delayed consultations and treatments and misdiagnoses.

    “As a result, there are many delayed consultations and treatments, and misdiagnoses.”
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Authors
Kuwano, N., Kato, T. A., Setoyama, D., Sato-Kasai, M., Shimokawa, N., Hayakawa, K., Ohgidani, M., Sagata, N., Kubo, H., Kishimoto, J., Kang, D., & Kanba, S.
Affiliations
Kyushu University (JP)
Corresponding author
Kato, Takahiro A.
ORCID
Venue
Journal of Affective Disorders
Publisher
Elsevier BV
Published
2018-04
Volume
231
Pages
74-82
ISSN
0165-0327 (ISSN-L)
DOI
10.1016/j.jad.2018.01.014
OpenAlex
W2793738947
Cited by
69
References
99
Citations by year
2026: 10 · 2025: 7 · 2024: 7 · 2023: 6 · 2022: 10 · 2021: 8 · 2020: 9 · 2019: 10 · 2018: 2
FWCI
2.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Affective Disorders (publishedVersion)
  • PubMed (publishedVersion)
  • Kyushu University Institutional Repository (QIR) (Kyushu University) (submittedVersion, other-oa)
Funders
  • SENSHIN Medical Research Foundation
  • Japan Agency for Medical Research and Development (16dk0307047h0002, 16dm0107095h0001)
  • Japan Society for the Promotion of Science (JP15K15431, JP16H02666, JP16H03741, JP26713039)
  • Ministry of Education, Culture, Sports, Science and Technology (JP16H06403, JP25117011)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
Keywords
major depressive disorder, first-episode drug-naive depression, blood biomarkers, kynurenine pathway, plasma tryptophan, kynurenine, HDL cholesterol, cholesterol esters, lipid metabolism, depression severity
MeSH terms
Adult, Major Depressive Disorder, Female, Humans, Kynurenine, Lipids, Male, Middle Aged, Pilot Projects, Predictive Value of Tests, Prospective Studies, Severity of Illness Index, Tryptophan, Biomarkers, Case-Control Studies

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