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The Esketamine multi-omic biomarker evaluation in MDD (EMBER-MDD) is a non-interventional, investigator-initiated, in-vitro study within the EU Psych-STRATA programme, analyzing biospecimens collected in the randomized INTENSIFY study and the mirror OBS-TR cohort after participants complete treatment. EMBER-MDD aims to discover individual-omic and integrated multi-omic (hypothesis-free) biomarkers and signatures associated with TR risk, and molecular correlates of clinical response to esketamine nasal spray versus treatment as usual (TAU). Biomaterials will derive from approximately 420 adults with MDD (estimated\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009210 esketamine;\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009210 TAU) and include whole blood, RNA-stabilized whole blood, plasma and serum, sampled at baseline and, when feasible, during and after treatment (up to ~\u20095,040 aliquots stored at \u2212\u200980\u00a0\u00b0C). Genomics will use baseline DNA genotyping on Illumina Infinium GSA v3.0+MD arrays; epigenomics will profile genome-wide DNA methylation across time points using MethylationEPIC v2.0; transcriptomics will employ mRNA-seq (NovaSeq X\/ X Plus); and proteomics\/ metabolomics will be generated using high-throughput Olink and\/ or Biocrates platforms. Each layer will undergo state-of-the-art preprocessing and analyses (e.g., GWAS\/ PRS, EWAS, differential expression, WGCNA, pathway and network analyses), followed by integrative strategies including QTL mapping (meQTL\/ eQTL\/ pQTL\/ mQTL) and intermediate-fusion machine learning with nested cross-validation, explainable AI (SHAP\/ LIME) and treatment-effect modelling. All outputs are research-only and will not support individual efficacy, tolerability, or clinical decision-making. The study will deliver robust biosignatures and mechanistic hypotheses to guide future validation and inform stratified, molecularly guided intervention strategies in subsequent prospective trials. Trial registration number: 2023-506617-21\u201300 and 2025-178-f-S.\n                  <\/jats:p>","DOI":"10.1007\/s00406-026-02306-x","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T13:06:11Z","timestamp":1782824771000},"page":"3469-3479","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Esketamine multi-omic biomarker evaluation in major depressive disorder (EMBER-MDD): concept, objectives and methodologies of a non-clinical investigator-initiated study"],"prefix":"10.1007","volume":"276","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3012-4840","authenticated-orcid":false,"given":"C.","family":"Hohoff","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0939-8062","authenticated-orcid":false,"given":"T.","family":"Lange","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7635-6217","authenticated-orcid":false,"given":"L.","family":"Steinbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3123-2233","authenticated-orcid":false,"given":"S. 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Janssen has no influence on the study design, biomarker selection, data evaluation, results and publication. Open Access funding enabled and organized by Projekt DEAL. This work of Psych-STRATA project was supported by funding from the European Union\u2019s Horizon Europe research and innovation programme under grant agreement No 101057454. BTB received speaker\/ consultation fees from: Angelini, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Meyers Squibb, Janssen, LivaNova, Lundbeck, Medscape, Neurotorium, Novartis, Otsuka, Pfizer, Recordati, Roche, Rovi, Sanofi, Servier, Teva. All other authors reported no conflicts of interest in relation to this project.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Analyses of biomaterials from INTENSIFY and OBS-TR will be performed in accordance with the ethical standards laid down in the Helsinki Declaration. Corresponding ethical approvals have been granted by the appropriate ethics committees \u201cEthik-Kommission der \u00c4rztekammer Nordrhein\u201d (MDD: 2023\u2013506617-21\u201300) and \u201cEthik-Kommission der \u00c4rztekammer Westfalen-Lippe\u201d and University of Muenster (2025-178-f-S; June 2025). All MDD patients gave their informed consent prior to their inclusion in INTENSIFY or OBS-TR.","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}}]}}