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However, there is no evidence that machine learning approaches combining multi-omics measures (e.g., genomics and plasma metabolomics) can achieve clinically meaningful predictions of outcomes to combination pharmacotherapy. This study examined data from 264 MDD outpatients treated with citalopram or escitalopram in the Mayo Clinic Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) and 111 MDD outpatients treated with combination pharmacotherapies in the Combined Medications to Enhance Outcomes of Antidepressant Therapy (CO-MED) study to predict response to combination antidepressant therapies. To assess whether metabolomics with functionally validated single-nucleotide polymorphisms (SNPs) improves predictability over metabolomics alone, models were trained\/tested with and without SNPs. Models trained with PGRN-AMPS\u2019 and CO-MED\u2019s escitalopram\/citalopram patients predicted response in CO-MED\u2019s combination pharmacotherapy patients with accuracies of 76.6% (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01; AUC: 0.85) without and 77.5% (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01; AUC: 0.86) with SNPs. Then, models trained solely with PGRN-AMPS\u2019 escitalopram\/citalopram patients predicted response in CO-MED\u2019s combination pharmacotherapy patients with accuracies of 75.3% (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05; AUC: 0.84) without and 77.5% (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01; AUC: 0.86) with SNPs, demonstrating cross-trial replication of predictions. Plasma hydroxylated sphingomyelins were prominent predictors of treatment outcomes. To explore the relationship between SNPs and hydroxylated sphingomyelins, we conducted multi-omics integration network analysis. Sphingomyelins clustered with SNPs and metabolites related to monoamine neurotransmission, suggesting a potential functional relationship. These results suggest that integrating specific metabolites and SNPs achieves accurate predictions of treatment response across classes of antidepressants. Finally, these results motivate functional investigation into how sphingomyelins might influence MDD pathophysiology, antidepressant response, or both.<\/jats:p>","DOI":"10.1038\/s41398-021-01632-z","type":"journal-article","created":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T13:21:55Z","timestamp":1633612915000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Multi-omics driven predictions of response to acute phase combination antidepressant therapy: a machine learning approach with cross-trial replication"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4367-6380","authenticated-orcid":false,"given":"Jeremiah B.","family":"Joyce","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline W.","family":"Grant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1065-246X","authenticated-orcid":false,"given":"Duan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siamak","family":"MahmoudianDehkordi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rima","family":"Kaddurah-Daouk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Skime","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9350-4440","authenticated-orcid":false,"given":"Joanna","family":"Biernacka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6997-4215","authenticated-orcid":false,"given":"Mark A.","family":"Frye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5992-6081","authenticated-orcid":false,"given":"Taryn","family":"Mayes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Carmody","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6843-6503","authenticated-orcid":false,"given":"Paul E.","family":"Croarkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3818-8531","authenticated-orcid":false,"given":"Liewei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4911-7985","authenticated-orcid":false,"given":"Richard","family":"Weinshilboum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William V.","family":"Bobo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2983-1110","authenticated-orcid":false,"given":"Madhukar H.","family":"Trivedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9764-1768","authenticated-orcid":false,"given":"Arjun P.","family":"Athreya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,7]]},"reference":[{"key":"1632_CR1","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1001\/jamapsychiatry.2017.4602.","volume":"75","author":"DS Hasin","year":"2018","unstructured":"Hasin DS, Sarvet AL, Meyers JL, Saha TD, Ruan WJ, Stohl M, et al. 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Dr. WV Bobo\u2019s research has been supported by the National Institute of Mental Health, the Agency for Healthcare Quality and Research, the National Science Foundation, the Myocarditis Foundation, and the Mayo Foundation for Medical Education and Research. He has contributed chapters to UpToDate concerning the pharmacological treatment of adults with bipolar major depression. Dr. PE Croarkin has received research grant support from Neuronetics, Inc., NeoSync, Inc., and Pfizer, Inc. He has received grant in-kind (equipment and supply support for research studies) from Assurex Health, Neuronetics, Inc., and MagVenture, Inc. Dr. PE Croarkin has served as a consultant for Engrail Therapeutics, Myriad Neuroscience, Procter & Gamble, and Sunovion. Dr. MH Trivedi has provided consulting services to Acadia Pharmaceuticals, Inc., Alkermes, Inc., Alto Neuroscience, Inc., Axsome Therapeutics, GH Research Limited, GreenLight VitalSign6, Inc., Janssen, Merck Sharp & Dohme Corp., Neurocrine Biosciences, Inc., Orexo US, Inc., Otsuka, SAGE Therapeutics, Signant Health, Titan Pharmaceuticals, Inc. He has received grant\/research funding from NIMH, NIDA, Patient-Centered Outcomes Research Institute (PCORI), and Cancer Prevention Research Institute of Texas (CPRIT). In addition, he has received editorial compensation from Oxford University Press. Dr. T Carmody has provided consulting services to Alkermes, Inc. Dr. R Kaddurah-Daouk is an inventor on key patents in the field of metabolomics in the study of CNS diseases and holds equity in Metabolon, Inc., a biotechnology company that provides metabolic profiling capabilities. Dr. MA Frye has received research support from Assurex Health, Myriad, Mayo Foundation, and Medibio; he has served as a consultant for Actify Neurotherapies, Allergan, Intra-Cellular Therapies, Inc., Janssen, Myriad, Neuralstem, Inc., Sanofi, Takeda, Teva Pharmaceuticals; he has received CME Travel\/Honoraria from American Physician Institute, CME Outfitters, Global Academy for Medical Education. All other authors declared no competing interests for this work.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"513"}}