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Jansen, R.* ; Milaneschi, Y.* ; Schranner, D. ; Kastenmüller, G. ; Arnold, M. ; Han, X.* ; Dunlop, B.W.* ; Rush, A.J.* ; Kaddurah-Daouk, R.* ; Penninx, B.W.J.H.*

The metabolome-wide signature of major depressive disorder.

Mol. Psychiatry, DOI: 10.1038/s41380-024-02613-6 (2024)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Major Depressive Disorder (MDD) is a common, frequently chronic condition characterized by substantial molecular alterations and pathway dysregulations. Single metabolite and targeted metabolomics platforms have revealed several metabolic alterations in depression, including energy metabolism, neurotransmission, and lipid metabolism. More comprehensive coverage of the metabolome is needed to further specify metabolic dysregulations in depression and reveal previously untargeted mechanisms. Here, we measured 820 metabolites using the metabolome-wide Metabolon platform in 2770 subjects from a large Dutch clinical cohort with extensive clinical phenotyping (1101 current MDD, 868 remitted MDD, 801 healthy controls) at baseline, which were repeated in 1805 subjects at 6-year follow up (327 current MDD, 1045 remitted MDD, 433 healthy controls). MDD diagnosis was based on DSM-IV psychiatric interviews. Depression severity was measured with the Inventory of Depressive Symptomatology Self-report. Associations between metabolites and MDD status and depression severity were assessed at baseline and at 6-year follow-up. At baseline, 139 and 126 metabolites were associated with current MDD status and depression severity, respectively, with 79 overlapping metabolites. Adding body mass index and lipid-lowering medication to the models changed results only marginally. Among the overlapping metabolites, 34 were confirmed in internal replication analyses using 6-year follow-up data. Downregulated metabolites were enriched with long-chain monounsaturated (P = 6.7e-07) and saturated (P = 3.2e-05) fatty acids; upregulated metabolites were enriched with lysophospholipids (P = 3.4e-4). Mendelian randomization analyses using genetic instruments for metabolites (N = 14,000) and MDD (N = 800,000) showed that genetically predicted higher levels of the lysophospholipid 1-linoleoyl-GPE (18:2) were associated with greater risk of depression. The identified metabolome-wide profile of depression indicated altered lipid metabolism with downregulation of long-chain fatty acids and upregulation of lysophospholipids, for which causal involvement was suggested using genetic tools. This metabolomics signature offers a window on depression pathophysiology and a potential access point for the development of novel therapeutic approaches.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Mendelian Randomization; Anxiety Nesda; Supplementation; Metaanalysis; Netherlands; Symptoms; Diseases; Risk; Bias
ISSN (print) / ISBN 1359-4184
e-ISSN 1476-5578
Journal Molecular Psychiatry
Publisher Nature Publishing Group
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
Grants Netherlands Organisation for Health Research and Development (ZonMw)
NIA
NIMH
European Union
ZonMw: The Netherlands Organization for Health Research and Development
Neurocrine Biosciences Inc.
Compass Inc.
Myriad Neuroscience
Sage, Usona Institute
Otsuka
Compass Pathways, NIMH
Boehringer Ingelheim
National Institutes of Health/National Institute on Aging
ZonMw (Netherlands Organisation for Health Research and Development)