The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies

Abstract

The importance of tryptophan as a precursor for neuroactive compounds has long been acknowledged. The metabolism of tryptophan along the kynurenine pathway and its involvement in mental disorders is an emerging area in psychiatry. We performed a meta-analysis to examine the differences in kynurenine metabolites in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). Electronic databases were searched for studies that assessed metabolites involved in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, and their associate ratios) in people with MDD, SZ, or BD, compared to controls. We computed the difference in metabolite concentrations between people with MDD, BD, or SZ, and controls, presented as Hedges’ g with 95% confidence intervals. A total of 101 studies with 10,912 participants were included. Tryptophan and kynurenine are decreased across MDD, BD, and SZ; kynurenic acid and the kynurenic acid to quinolinic acid ratio are decreased in mood disorders (i.e., MDD and BD), whereas kynurenic acid is not altered in SZ; kynurenic acid to 3-hydroxykynurenine ratio is decreased in MDD but not SZ. Kynurenic acid to kynurenine ratio is decreased in MDD and SZ, and the kynurenine to tryptophan ratio is increased in MDD and SZ. Our results suggest that there is a shift in the tryptophan metabolism from serotonin to the kynurenine pathway, across these psychiatric disorders. In addition, a differential pattern exists between mood disorders and SZ, with a preferential metabolism of kynurenine to the potentially neurotoxic quinolinic acid instead of the neuroprotective kynurenic acid in mood disorders but not in SZ.

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Fig. 1: PRISMA flow diagram of the included studies.
Fig. 2: Forest plots with the summary effect size (Hedge’s g) of kynurenine metabolites in people with Major Depressive Disorder, Bipolar Disorder, or Schizophrenia compared to healthy controls.
Fig. 3: Summary representation of the altered metabolites in the kynurenine pathway in Major Depressive Disorder, Bipolar Disorder, or Schizophrenia.

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Acknowledgements

WM is currently funded by an Alfred Deakin Postdoctoral Research Fellowship and a Multiple Sclerosis Research Australia early-career fellowship. WM has previously received funding from the Cancer Council Queensland and university grants/fellowships from La Trobe University, Deakin University, University of Queensland, and Bond University. WM has received industry funding and has attended events funded by Cobram Estate Pty. Ltd. WM has received travel funding from Nutrition Society of Australia. WM has received consultancy funding from Nutrition Research Australia. WM has received speakers honoraria from The Cancer Council Queensland and the Princess Alexandra Research Foundation. BS is supported by a Clinical Lectureship (ICA-CL-2017-03-001) jointly funded by Health Education England (HEE) and the National Institute for Health Research (NIHR). BS is partly funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust. BS also holds active grants with the Medical Research Council and Guys and St Thomas Charity (GSTT). JC has received research support from Deakin University. AJW is supported by a Deakin University Dean’s Research Postdoctoral Fellowship, and has received research support previously from the Trisno Family Gift, and Deakin University. MB is supported by a NHMRC Senior Principal Research Fellowship (1059660 and 1156072). MB has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical Research Council, Medical Research Futures Fund, Beyond Blue, Rotary Health, A2 milk company, Meat and Livestock Board, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Astra Zeneca, Lundbeck, Merck, Pfizer, and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Lundbeck Merck, Pfizer and Servier—all unrelated to this work. The views expressed are those of the author(s) and not necessarily those of the (partner organization), the NHS, the NIHR, the Department of Health and Social Care, the MRC, NHMRC, or GSTT. AO is supported by a Future Leader Fellowship (#101160) from the Heart Foundation Australia and Wilson Foundation. She has received research funding from National Health & Medical Research Council, Australian Research Council, University of Melbourne, Deakin University, Sanofi, Meat and Livestock Australia and Woolworths Limited and Honoraria from Novartis. The Food & Mood Centre has received funding from the Fernwood Foundation, the A2 Milk Company and Be Fit Foods – unrelated to this paper. ML is funded by a Deakin University PhD Scholarship and has received research support from BeFit Foods. SGC has received a grant for external rotation during psychiatry training period, from Fundación de Psiquiatría y Salud Mental. SGC has received CME-related honoraria, or consulting fees from Janssen-Cilag, Italfarmaco, Angelini and Lundbeck all unrelated to this work. APC Microbiome Ireland is funded by Science Foundation Ireland (SFI), through the Irish Government’s National Development Plan (grant number SFI/12/RC/2273 P2). GC is supported by the Health Research Board (HRB) (grant no ILP-POR-2017-013). AJM is funded by an Australian Rotary Health/Ten Island Tassie Tag Along Tour Funding Partner PhD Scholarship. TR has received grants, fellowships and research support from University of the Sunshine Coast, Australian Postgraduate Awards, Fernwood Foundation and Be Fit Food. TR received consultancy, honoraria and travel funds from Oxford University Press, the University of Melbourne, the University of Sydney, Bond University, University of Southern Queensland, Dietitians Association of Australia, Nutrition Society of Australia, The Royal Australian and New Zealand College of Psychiatrists, Academy of Nutrition and Dietetics, Black Dog Institute, Australian Rotary Health, Australian Disease Management Association, Department of Health and Human Services, Primary Health Networks, Barwon Health, West Gippsland Healthcare Group, Central West Gippsland Primary Care Partnership, Parkdale College, Positive Schools, City of Greater Geelong and Global Age.

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BSF, APD, AFC, BS, JC, MS, ML, SGC, PTT, WM, AJM, TR, AR, AJW, PYL, MB, AON, FJ, and JCS have no conflict of interest regarding this manuscript. GC from APC Microbiome Ireland has conducted studies in collaboration with several companies, including GSK, Pfizer, Cremo, Suntory, Wyeth, Mead Johnson, Nutricia, 4D Pharma, and DuPont. GC has been an invited speaker at meetings organized by Janssen and is receipt of research funding from Pharmavite. GC is not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this report.

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Marx, W., McGuinness, A.J., Rocks, T. et al. The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-00951-9

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