{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T20:33:22Z","timestamp":1778704402589,"version":"3.51.4"},"reference-count":34,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,10,7]],"date-time":"2022-10-07T00:00:00Z","timestamp":1665100800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2021\u201002732"],"award-info":[{"award-number":["2021\u201002732"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006095","name":"Helse S\u00f8r-\u00d8st RHF","doi-asserted-by":"publisher","award":["2020019"],"award-info":[{"award-number":["2020019"]}],"id":[{"id":"10.13039\/501100006095","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Clinical response of clozapine is closely associated with serum concentration. Although tobacco smoking is the key environmental factor underlying interindividual variability in clozapine metabolism, recent genome\u2010wide studies suggest that <jats:italic>CYP1A<\/jats:italic> and <jats:italic>NFIB<\/jats:italic> genetic variants may also be of significant importance, but their quantitative impact is unclear. We investigated the effects of the <jats:italic>rs2472297 C&gt;T<\/jats:italic> (<jats:italic>CYP1A<\/jats:italic>) and <jats:italic>rs28379954 T&gt;C<\/jats:italic> (<jats:italic>NFIB<\/jats:italic>) polymorphisms on serum concentrations in smokers and nonsmokers. The study retrospectively included 526 patients with known smoking habits (63.7% smokers) from a therapeutic drug monitoring service in Norway. Clozapine dose\u2010adjusted concentrations (C\/D) and patient proportions with subtherapeutic levels (&lt;1070\u2009nmol\/L) were compared between <jats:italic>CYP1A<\/jats:italic>\/<jats:italic>NFIB<\/jats:italic> variant allele carriers and homozygous wild\u2010type carriers (noncarriers), in both smokers and nonsmokers. Clozapine C\/D was reduced in patients carrying <jats:italic>CYP1A\u2010T<\/jats:italic> and <jats:italic>NFIB\u2010C<\/jats:italic> variants versus noncarriers, both among smokers (\u221248%; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) and nonsmokers (\u221235%; <jats:italic>p<\/jats:italic>\u00a0=\u00a00.028). Patients who smoke carrying <jats:italic>CYP1A\u2010T<\/jats:italic> and <jats:italic>NFIB\u2010C<\/jats:italic> variants had a 66% reduction in clozapine C\/D versus nonsmoking noncarriers (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). The patient proportion with subtherapeutic levels was 2.9\u2010fold higher in patients who smoke carrying <jats:italic>NFIB\u2010C<\/jats:italic> and <jats:italic>CYP1A\u2010T<\/jats:italic> variants versus nonsmoking noncarriers (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). In conclusion, <jats:italic>CYP1A<\/jats:italic> and <jats:italic>NFIB<\/jats:italic> variants have significant and additive impact on clozapine dose requirements for reaching target serum concentrations. Patients who smoke carrying the studied <jats:italic>CYP1A<\/jats:italic> and <jats:italic>NFIB<\/jats:italic> variants, comprising 2.5% of the study population, may need threefold higher doses to prevent risk of clozapine undertreatment. The results suggest that pre\u2010emptive genotyping of <jats:italic>NFIB<\/jats:italic> and <jats:italic>CYP1A<\/jats:italic> may be utilized to guide clozapine dosing and improve clinical outcomes in patients with treatment\u2010resistant schizophrenia.<\/jats:p>","DOI":"10.1111\/cts.13422","type":"journal-article","created":{"date-parts":[[2022,9,24]],"date-time":"2022-09-24T17:59:15Z","timestamp":1664042355000},"page":"62-72","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Impact of <scp>NFIB<\/scp> and <scp>CYP1A<\/scp> variants on clozapine serum concentration\u2014A retrospective naturalistic cohort study on 526 patients with known smoking habits"],"prefix":"10.1111","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4724-7396","authenticated-orcid":false,"given":"Hasan \u00c7a\u011f\u0131n","family":"Lenk","sequence":"first","affiliation":[{"name":"Center for Psychopharmacology Diakonhjemmet Hospital  Oslo Norway"},{"name":"Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy University of Oslo  Oslo Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6789-7076","authenticated-orcid":false,"given":"Robert","family":"L\u00f8vsletten Smith","sequence":"additional","affiliation":[{"name":"Center for Psychopharmacology Diakonhjemmet Hospital  Oslo Norway"},{"name":"Division of Mental Health and Addiction, NORMENT Centre Oslo University Hospital  Oslo Norway"},{"name":"Institute of Clinical Medicine University of Oslo  Oslo Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6865-8795","authenticated-orcid":false,"given":"Kevin S.","family":"O'Connell","sequence":"additional","affiliation":[{"name":"Division of Mental Health and Addiction, NORMENT Centre Oslo University Hospital  Oslo Norway"},{"name":"Institute of Clinical Medicine University of Oslo  Oslo Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5296-4245","authenticated-orcid":false,"given":"Marin M.","family":"Juki\u0107","sequence":"additional","affiliation":[{"name":"Section of Pharmacogenetics, Department of Physiology and Pharmacology Karolinska Institutet  Stockholm Sweden"},{"name":"Department of Physiology, Faculty of Pharmacy University of Belgrade  Belgrade Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianne Kristiansen","family":"Kringen","sequence":"additional","affiliation":[{"name":"Center for Psychopharmacology Diakonhjemmet Hospital  Oslo Norway"},{"name":"Department of Life Sciences and Health Oslo Metropolitan University  Oslo Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4461-3568","authenticated-orcid":false,"given":"Ole A.","family":"Andreassen","sequence":"additional","affiliation":[{"name":"Division of Mental 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