{
  "abstract": "Dextromethorphan is extensively O-demethylated by cytochrome P450 2D6 (CYP2D6) to dextrorphan, and the two molecules do not share a target profile. Dextrorphan is the more potent N-methyl-D-aspartate (NMDA) channel blocker; the parent compound is the more potent serotonin transporter inhibitor; their sigma-1 affinities are comparable, so differences in sigma-1 engagement depend on exposure rather than intrinsic affinity. CYP2D6 activity therefore does not scale exposure to a fixed pharmacology; it determines which pharmacology is expressed. This review develops that principle and extends it to a three-agent system. From published unbound concentrations and functional potencies, we calculate a model-derived fractional-target-engagement index. Under the base-case inputs, CYP2D6 inhibition raises the serotonergic index approximately fourfold while reducing the NMDA channel index; deterministic sensitivity analysis shows that the direction is robust to one-at-a-time 0.5-fold to 2-fold perturbations but not to all joint extreme assumptions. Quinidine and bupropion are analyzed as mechanistically distinct proofs of concept, and quinidine-derived exposure estimates are not treated as quantitative surrogates for the dextromethorphan–bupropion steady state. The framework is then applied to the untested question of whether a boosted dextromethorphan combination and esketamine are redundant or complementary. The agents share an NMDA channel mechanism, while CYP2B6 pathway overlap remains a hypothesis-generating observation rather than evidence of clinically relevant competition. No controlled data on the three-agent combination exist, and no therapeutic recommendation is made.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Molecular and Developmental Medicine, University of Siena, Viale Bracci 16, 53100 Siena, Italy",
    "European Biomedical Research Institute of Salerno, EBRIS, Via Salvatore De Renzi 50, 84125 Salerno, Italy",
    "Mental Health and Addictions Research Group, Institut d’Investigació Biomèdica de Girona (IDIBGI-CERCA), Departament de Salut, Generalitat de Catalunya, Parc Hospitalari Martí i Julià, Edifici M2, 17190 Salt, Spain"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Andrea Fagiolini",
      "orcid": "0000-0001-5827-0853"
    },
    {
      "affs": [
        0
      ],
      "name": "Alessandro Cuomo",
      "orcid": "0000-0002-9211-5248"
    },
    {
      "affs": [
        1
      ],
      "name": "Giulio Corrivetti"
    },
    {
      "affs": [
        0
      ],
      "name": "Mario Pinzi",
      "orcid": "0009-0003-4229-8714"
    },
    {
      "affs": [
        0
      ],
      "name": "Pietro Carmellini"
    },
    {
      "affs": [
        1
      ],
      "name": "Alessandra Marenna",
      "orcid": "0000-0003-0960-2924"
    },
    {
      "affs": [
        1
      ],
      "name": "Francesco Monaco",
      "orcid": "0000-0002-1854-292X"
    },
    {
      "affs": [
        1
      ],
      "name": "Annarita Vignapiano",
      "orcid": "0009-0004-8301-3401"
    },
    {
      "affs": [
        2
      ],
      "name": "Eva Frigola-Capell",
      "orcid": "0000-0003-4758-0316"
    },
    {
      "name": "the OPADE Group"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/521trytj6zjta.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms272110036",
  "fulltext_url": null,
  "id": "521trytj6zjta",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/21/10036",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-09",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/521trytj6zjta.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:22:39Z",
      "native_id": "10.3390/ijms272110036",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/21/10036"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "issn:1422-0067",
      "subfield": "general"
    }
  ],
  "title": "Dextromethorphan-Bupropion-Esketamine Triadic Pharmacology: Molecular Targets, Enzymatic Interactions, and Risk-Benefit Assessment of a Three-Agent Combination for Treatment-Resistant Depression",
  "title_text": "Dextromethorphan-Bupropion-Esketamine Triadic Pharmacology: Molecular Targets, Enzymatic Interactions, and Risk-Benefit Assessment of a Three-Agent Combination for Treatment-Resistant Depression",
  "type": "peer-reviewed",
  "updated_at": "2026-11-10T00:21:27Z",
  "url": "https://research.draconitic.com/paper/521trytj6zjta",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}