{
  "abstract": "Clozapine is the most effective antipsychotic drug, while also causing the most severe metabolic side effects. The underlying mechanisms of these side effects appear multifactorial and are not entirely understood. We hypothesized that liver sinusoidal endothelial cells (LSEC) dysfunction is linked to the metabolic side effects of clozapine, based on known association between reduced LSEC porosity, hypertriglyceridemia and insulin resistance. Accordingly, we conducted a translational study by assessing the porosity of murine LSECs following clozapine exposure in vitro and correlating serum clozapine concentrations with metabolic parameters in routine human blood samples. The patient data showed a correlation for clozapine serum concentrations with both triglycerides (Spearman's ρ = 0.47, P = 0.00024) and glucose levels (ρ = 0.24, P = 0.034), but no correlation with LDL cholesterol (ρ = -0.04, P = 0.82) or HDL cholesterol (ρ = -0.22, P = 0.088). The in vitro experiments showed a concentration-dependent reduction in murine LSEC porosity (P for trend = 0.00036). Together, these findings support a link between clozapine exposure and reduced LSEC porosity. This represents a promising point of intervention that potentially could expand safe access to clozapine as a highly effective antipsychotic treatment for a broader population, also in individuals at high risk for metabolic and cardiovascular side effects.",
  "abstract_shown": true,
  "affiliations": [
    "Vascular Biology Research Group, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway.",
    "Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.",
    "Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.",
    "Translational Vascular Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway.",
    "The Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.",
    "ANZAC Research Institute, Concord Hospital, Sydney Local Health District and Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.",
    "Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.",
    "Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway. eriksdi@uio.no.",
    "Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway. eriksdi@uio.no."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Tetyana Voloshyna"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Øyvind V Svendsen",
      "orcid": "0000-0001-5665-6904"
    },
    {
      "affs": [
        0
      ],
      "name": "Karolina Szafranska"
    },
    {
      "affs": [
        0
      ],
      "name": "Jakub Pospíšil"
    },
    {
      "affs": [
        3
      ],
      "name": "Eike C Struck"
    },
    {
      "affs": [
        2
      ],
      "name": "Elisabet Størset"
    },
    {
      "affs": [
        2
      ],
      "name": "Robert L Smith"
    },
    {
      "affs": [
        2,
        4
      ],
      "name": "Espen Molden",
      "orcid": "0000-0001-6190-2751"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "David G Le Couteur"
    },
    {
      "affs": [
        5
      ],
      "name": "Victoria C Cogger"
    },
    {
      "affs": [
        0
      ],
      "name": "Peter A G McCourt",
      "orcid": "0000-0001-5072-4590"
    },
    {
      "affs": [
        7,
        8
      ],
      "name": "Erik S Dietrichs",
      "orcid": "0000-0002-5679-9937"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/d0e1nj1qm2ka7.bib",
  "cited_by": 0,
  "doi": "10.1038/s41398-026-04328-4",
  "fulltext_url": "https://europepmc.org/articles/PMC13683405",
  "id": "d0e1nj1qm2ka7",
  "issns": [
    "2158-3188"
  ],
  "landing_url": "https://europepmc.org/article/MED/42901887",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "RC321-571"
    ],
    [
      "openalex",
      "2738|Schizophrenia research and treatment"
    ]
  ],
  "openalex": "W7196946930",
  "pdf_url": "https://europepmc.org/articles/PMC13683405?pdf=render",
  "pmcid": "PMC13683405",
  "pmid": "42901887",
  "published": "2026-08-01",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/d0e1nj1qm2ka7.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:41Z",
      "native_id": "MED:42901887",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42901887"
    },
    {
      "first_seen": "2026-10-30T13:46:25Z",
      "native_id": "a454fdb576ea4a45bf11e4f51c8caa63",
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      "url": "https://doi.org/10.1038/s41398-026-04328-4"
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2738|Schizophrenia research and treatment",
      "subfield": "psychiatry"
    }
  ],
  "title": "Association between clozapine-induced hypertriglyceridemia and defenestration of liver sinusoidal endothelial cells.",
  "title_text": "Association between clozapine-induced hypertriglyceridemia and defenestration of liver sinusoidal endothelial cells.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:46:25Z",
  "url": "https://research.draconitic.com/paper/d0e1nj1qm2ka7",
  "venue": "Translational psychiatry",
  "versions": []
}