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The metabolome-wide signature of major depressive disorder

Molecular Psychiatry volume 29, pages 3722–3733 (2024)Cite this article

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Abstract

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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Fig. 1: Forest plot of the 34 internally replicated metabolites.

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Data availability

The data used to support the findings of this study are available upon reasonable request from NESDA, Amsterdam: nesda@amsterdamumc.nl. Information on how to request the study data, including the data sharing policy, can be found at https://www.nesda.nl/nesda-english/.

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Acknowledgements

RJ received funding from ZonMw: The Netherlands Organization for Health Research and Development (project number: 636310017, research program GGZ). This project is partially supported by funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 848146. In addition, the work was funded through NIMH grant number R01MH108348 and through a series of grants issued to Dr. KaddurahDaouk (PI) through NIA including U01AG061359, RF1AG057452, and RF1AG051550 that supported large number of scientists working on metabolomics and neuropsychiatric disorders and role for acylcarnitines. MA and GK received funding (through their institutions) from the National Institutes of Health/National Institute on Aging through grants RF1AG058942, RF1AG059093, U01AG061359, U19AG063744, and R01AG069901. We would like to thank the Psychiatric Genomics Consortium and 23andMe, including its research participants and employees, for making this work possible by sharing GWAS summary statistics. BWD has received research support from Boehringer Ingelheim, Compass Pathways, NIMH, Otsuka, Sage, Usona Institute, and Takeda and has served as a consultant for Biohaven, Cerebral Therapeutics, Greenwich Biosciences, Myriad Neuroscience, NRx Pharmaceuticals, Otsuka, Sage, and Sophren Therapeutics. AJR has received consulting fees from Compass Inc., Curbstone Consultant LLC, Emmes Corp., Evecxia Therapeutics, Inc., Holmusk Technologies, Inc., ICON, PLC, Johnson and Johnson (Janssen), Liva-Nova, MindStreet, Inc., Neurocrine Biosciences Inc., Otsuka-US; speaking fees from Liva-Nova, Johnson and Johnson (Janssen); and royalties from Wolters Kluwer Health, Guilford Press and the University of Texas Southwestern Medical Center, Dallas, TX (for the Inventory of Depressive Symptoms and its derivatives). He is also named co-inventor on two patents: U.S. Patent No. 7,795,033: Methods to Predict the Outcome of Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S, Wilson AS; and U.S. Patent No. 7,906,283: Methods to Identify Patients at Risk of Developing Adverse Events During Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S. The infrastructure for the NESDA study (http://www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw, grant number 10-000-1002) and financial contributions by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Rob Giel Onderzoekscentrum). We thank Dr. Najaf Amin for sharing results.

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Author notes

  1. These authors contributed equally: Rick Jansen, Yuri Milaneschi.

  2. A list of members and their affiliations appears in the Supplementary Information.

Authors and Affiliations

  1. Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands

    Rick Jansen, Yuri Milaneschi & Brenda W. J. H. Penninx

  2. Amsterdam Public Health, Mental Health Program, Amsterdam, the Netherlands

    Rick Jansen, Yuri Milaneschi & Brenda W. J. H. Penninx

  3. Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program, Amsterdam, the Netherlands

    Rick Jansen, Yuri Milaneschi & Brenda W. J. H. Penninx

  4. Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany

    Daniela Schranner, Gabi Kastenmuller & Matthias Arnold

  5. Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA

    Matthias Arnold, A. John Rush & Rima Kaddurah-Daouk

  6. Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Xianlin Han

  7. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    Boadie W. Dunlop

  8. Duke National University of Singapore, Singapore, Singapore

    A. John Rush

  9. Department of Medicine, Duke University, Durham, NC, USA

    Rima Kaddurah-Daouk

  10. Duke Institute of Brain Sciences, Duke University, Durham, NC, USA

    Rima Kaddurah-Daouk

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Mood Disorder Precision Medicine Consortium

Contributions

RJ and YM performed analysis and wrote the manuscript. DS, GK and MA performed pre processing of the metabolite data. XH, BD, AR, RK and BP designed the study and helped writing and interpreting.

Corresponding authors

Correspondence to Rick Jansen or Rima Kaddurah-Daouk.

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Competing interests

AJR has received consulting fees from Compass Inc., Curbstone Consultant LLC, Emmes Corp., Evecxia Therapeutics, Inc., Holmusk, Johnson and Johnson (Janssen), Liva-Nova, Neurocrine Biosciences Inc., Otsuka-US; speaking fees from Liva-Nova, Johnson and Johnson (Janssen); and royalties from Guilford Press and the University of Texas Southwestern Medical Center, Dallas, TX (for the Inventory of Depressive Symptoms and its derivatives). He is also named co-inventor on two patents: U.S. Patent No. 7,795,033: Methods to Predict the Outcome of Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S, Wilson AS; and U.S. Patent No. 7,906,283: Methods to Identify Patients at Risk of Developing Adverse Events During Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S. M.A. and G.K. are co-inventors (through Duke University/Helmholtz Zentrum München) on patents on applications of metabolomics in diseases of the central nervous system and hold equity in Chymia LLC and IP in PsyProtix and Atai that are exploring the potential for therapeutic applications targeting mitochondrial metabolism in depression. RKD is funded by National Institute on Aging [U19AG063744, U01AG061359, 1RF1AG058942, 1RF1AG057452, RF1AG051550, and R01AG046171] and National Institute of Mental Health [R01MH108348]. This funding enabled consortia that she leads including the Mood Disorder Precision Medicine Consortium, the Alzheimer’s Disease Metabolomics Consortium, and the Alzheimer Gut Microbiome Project that contributed to acylcarnitine discoveries. She is an inventor on key patents in the field of Metabolomics and hold equity in Metabolon, a biotech company in North Carolina. In addition, she holds patents licensed to Chymia LLC and PsyProtix with royalties and ownership. The funders listed above had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the paper; and decision to submit the paper for publication. BWD has received research support from Acadia, Compass, Aptinyx, NIMH, Sage, Otsuka, and Takeda, and has served as a consultant to Greenwich Biosciences, Myriad Neuroscience, Otsuka, Sage, and Sophren Therapeutics. All the other authors declare no conflict of interest.

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Jansen, R., Milaneschi, Y., Schranner, D. et al. The metabolome-wide signature of major depressive disorder. Mol Psychiatry 29, 3722–3733 (2024). https://doi.org/10.1038/s41380-024-02613-6

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