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Previous genomic evidence identified four ACs potentially linked to depression risk. We carried forward these ACs and tested the association of their circulating levels with Major Depressive Disorder (MDD) diagnosis, overall depression severity and specific symptom profiles. The sample from the Netherlands Study of Depression and Anxiety included participants with current (n\u2009=\u20091035) or remitted (n\u2009=\u2009739) MDD and healthy controls (n\u2009=\u2009800). Plasma levels of four ACs (short-chain: acetylcarnitine C2 and propionylcarnitine C3; medium-chain: octanoylcarnitine C8 and decanoylcarnitine C10) were measured. Overall depression severity as well as atypical\/energy-related (AES), anhedonic and melancholic symptom profiles were derived from the Inventory of Depressive Symptomatology. As compared to healthy controls, subjects with current or remitted MDD presented similarly lower mean C2 levels (Cohen\u2019s d\u2009=\u20090.2, p\u2009\u2264\u20091e-4). Higher overall depression severity was significantly associated with higher C3 levels (\u00df\u2009=\u20090.06, SE\u2009=\u20090.02, p\u2009=\u20091.21e-3). No associations were found for C8 and C10. Focusing on symptom profiles, only higher AES scores were linked to lower C2 (\u00df\u2009=\u2009\u22120.05, SE\u2009=\u20090.02, p\u2009=\u20091.85e-2) and higher C3 (\u00df\u2009=\u20090.08, SE\u2009=\u20090.02, p\u2009=\u20093.41e-5) levels. Results were confirmed in analyses pooling data with an additional internal replication sample from the same subjects measured at 6-year follow-up (totaling 4141 observations). Small alterations in levels of short-chain acylcarnitine levels were related to the presence and severity of depression, especially for symptoms reflecting altered energy homeostasis. Cellular metabolic dysfunctions may represent a key pathway in depression pathophysiology potentially accessible through AC metabolism.<\/jats:p>","DOI":"10.1038\/s41398-025-03274-x","type":"journal-article","created":{"date-parts":[[2025,2,23]],"date-time":"2025-02-23T04:20:21Z","timestamp":1740284421000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Acylcarnitines metabolism in depression: association with diagnostic status, depression severity and symptom profile in the NESDA cohort"],"prefix":"10.1038","volume":"15","author":[{"given":"Silvia","family":"Montanari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3333-6737","authenticated-orcid":false,"given":"Rick","family":"Jansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Schranner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabi","family":"Kastenm\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4666-0923","authenticated-orcid":false,"given":"Matthias","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delfina","family":"Janiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9767-8752","authenticated-orcid":false,"given":"Gabriele","family":"Sani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3493-6029","authenticated-orcid":false,"given":"Sudeepa","family":"Bhattacharyya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siamak","family":"Mahmoudian Dehkordi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4653-0483","authenticated-orcid":false,"given":"Boadie W.","family":"Dunlop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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Milaneschi has received consulting fees from Noema Pharma. A. John Rush 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. M. Arnold and G. Kastenm\u00fcller are co-inventors (through Duke University\/Helmholtz Zentrum M\u00fcnchen) 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 treatment-resistant depression. B. Dunlop 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, Myriad Neuroscience, NRx Pharmaceuticals, Otsuka, and Sage. R. Kaddurah-Daouk 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. All the other authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"NESDA\u2019s research protocol was approved by the ethical review board of each participating research center in Amsterdam, Leiden, and Groningen (METC number 2003-183). All participants provided written informed consent after having received detailed verbal and printed study information.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"65"}}