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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., Competing Interests: 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., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Major Depressive Disorder (MDD) is an often-chronic condition with substantial molecular alterations and pathway dysregulations involved. Single metabolite, pathway and targeted metabolomics platforms have indeed 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 dysregulation 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 depression clinical phenotyping (1101 current MDD, 868 remitted MDD, 801 healthy controls) at baseline and 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 the 6-year follow-up. Metabolites consistently associated with MDD status or depression severity on both occasions were examined in Mendelian randomization (MR) analysis using metabolite (N=14,000) and MDD (N=800,000) GWAS results. At baseline, 139 and 126 metabolites were associated with current MDD status and depression severity, respectively, with 79 overlapping metabolites. Six years later, 34 out of the 79 metabolite associations were subsequently replicated. Downregulated metabolites were enriched with long-chain monounsaturated (P=6.7e-07) and saturated (P=3.2e-05) fatty acids and upregulated metabolites with lysophospholipids (P=3.4e-4). Adding BMI to the models changed results only marginally. MR analyses 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 (severity) 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., Competing Interests: Declaration of competing interest A. John Rush 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. R.R.K. is CEO of Rush University System for Health, Chairman of National Medical Research Council Ministry of Health Singapore, Chairman of Amyriad, BV Board member Community Health Systems, Advisory board SageRx, Verily Patents on Brain Computer Interface licensed to Psyber and ATAI, an inventor of Metabolomics patents in the CNS field including patents licensed to Chymia LLC and PsyProtix with royalties and ownership. R.K.D. is funded by National Institute on Aging [U01AG061359, R01AG057452, 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’s 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. B.W.D. 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.