{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T05:03:20Z","timestamp":1768799000513,"version":"3.49.0"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T00:00:00Z","timestamp":1592524800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T00:00:00Z","timestamp":1592524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100006095","name":"Ministry of Health and Care Services | Helse S\u00f8r-\u00d8st RHF","doi-asserted-by":"publisher","award":["2016097"],"award-info":[{"award-number":["2016097"]}],"id":[{"id":"10.13039\/501100006095","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006095","name":"Ministry of Health and Care Services | Helse S\u00f8r-\u00d8st RHF","doi-asserted-by":"publisher","award":["2016097"],"award-info":[{"award-number":["2016097"]}],"id":[{"id":"10.13039\/501100006095","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006095","name":"Ministry of Health and Care Services | Helse S\u00f8r-\u00d8st RHF","doi-asserted-by":"publisher","award":["2013123"],"award-info":[{"award-number":["2013123"]}],"id":[{"id":"10.13039\/501100006095","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005416","name":"Norges Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["229129, 213837, 223273, 226971"],"award-info":[{"award-number":["229129, 213837, 223273, 226971"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["NS057198, EB00790"],"award-info":[{"award-number":["NS057198, EB00790"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Psychiatry"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Clozapine (CLZ) is the superior antipsychotic drug for treatment of schizophrenia, but exhibits an extensive interpatient pharmacokinetic variability. Here, we conducted a genome-wide association study (GWAS) of CLZ serum concentration adjusting for known smoking habits, which is a major nongenetic factor reducing CLZ levels. The study included 484 patients with 10,283 steady-state serum concentrations of CLZ and <jats:italic>N<\/jats:italic>-desmethylclozapine, prescribed dosing, co-medications and known smoking habits (<jats:italic>n<\/jats:italic>\u2009=\u2009422; 9284 serum samples) from a therapeutic drug monitoring (TDM) service. The GWAS analyses were performed with and without smoking habits as covariate, where possible hits were assessed in relation to the target CLZ concentration range applied in the TDM service (300\u20132500\u2009nmol\/L). The smoking-independent analysis of <jats:italic>N<\/jats:italic>-desmethylclozapine serum concentration and the CLZ-to-<jats:italic>N<\/jats:italic>-desmethylclozapine ratio replicated the previously identified locus on chromosome 4. After adjusting for smoking habits in patients confirmed as \u2018smokers\u2019 (61%) or \u2018nonsmokers\u2019 (39%), a novel variant (<jats:italic>rs28379954<\/jats:italic>; minor <jats:italic>T<\/jats:italic>&gt;<jats:italic>C<\/jats:italic> allele frequency 4.1%; 7.6% <jats:italic>CT<\/jats:italic> carriers in the population) within the gene encoding the nuclear factor 1 B-type (<jats:italic>NFIB<\/jats:italic>) was significantly associated with reduced CLZ serum concentration (<jats:italic>p<\/jats:italic>\u2009=\u20091.68\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>, beta\u2009=\u2009\u22120.376; explained variance 7.63%). There was no significant association between <jats:italic>rs28379954<\/jats:italic> and <jats:italic>N<\/jats:italic>-desmethylclozapine concentration in the GWAS analysis (<jats:italic>p<\/jats:italic>\u2009=\u20095.63\u2009\u00d7\u200910<jats:sup>\u22125<\/jats:sup>). The fraction of CLZ TDM samples below 300\u2009nmol\/L was significantly higher in carriers vs. noncarriers of the <jats:italic>rs28379954<\/jats:italic> minor <jats:italic>C<\/jats:italic> allele [12.0% (95% CI: 9.4\u201314.7) vs. 6.2% (95% CI: 5.7\u20136.8), <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001]. We identified a novel variant in the <jats:italic>NFIB<\/jats:italic> gene associated with reduced CLZ levels and increased risk of subtherapeutic serum concentrations. This warrants testing of clinical relevance of screening for this gene variant, and also experimental studies to investigate the biological mechanisms of NFIB involvement in CLZ pharmacokinetics.<\/jats:p>","DOI":"10.1038\/s41398-020-00888-1","type":"journal-article","created":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T03:57:36Z","timestamp":1592539056000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Identification of a novel polymorphism associated with reduced clozapine concentration in schizophrenia patients\u2014a genome-wide association study adjusting for smoking habits"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6789-7076","authenticated-orcid":false,"given":"Robert L\u00f8vsletten","family":"Smith","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6865-8795","authenticated-orcid":false,"given":"Kevin","family":"O\u2019Connell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3321-6997","authenticated-orcid":false,"given":"Lavinia","family":"Athanasiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8140-8061","authenticated-orcid":false,"given":"Srdjan","family":"Djurovic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4760-1693","authenticated-orcid":false,"given":"Marianne Kristiansen","family":"Kringen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ole A.","family":"Andreassen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6190-2751","authenticated-orcid":false,"given":"Espen","family":"Molden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,6,19]]},"reference":[{"key":"888_CR1","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1016\/S0140-6736(13)60733-3","volume":"382","author":"S Leucht","year":"2013","unstructured":"Leucht, S. et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382, 951\u2013962 (2013).","journal-title":"Lancet"},{"key":"888_CR2","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1503\/jpn.100055","volume":"35","author":"R Joober","year":"2010","unstructured":"Joober, R. & Boksa, P. Clozapine: a distinct, poorly understood and under-used molecule. J. Psychiatry Neurosci. 35, 147\u2013149 (2010).","journal-title":"J. Psychiatry Neurosci."},{"key":"888_CR3","unstructured":"FDA. U.S. Food and Drug Administration, Clozaril, label approval, NDA no. 019758 (FDA, 2014)."},{"key":"888_CR4","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1192\/bjp.169.4.483","volume":"169","author":"K Atkin","year":"1996","unstructured":"Atkin, K. et al. Neutropenia and agranulocytosis in patients receiving clozapine in the UK and Ireland. Br. J. Psychiatry 169, 483\u2013488 (1996).","journal-title":"Br. J. Psychiatry"},{"key":"888_CR5","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1056\/NEJM199307153290303","volume":"329","author":"JM Alvir","year":"1993","unstructured":"Alvir, J. M., Lieberman, J. A., Safferman, A. Z., Schwimmer, J. L. & Schaaf, J. A. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N. Engl. J. Med. 329, 162\u2013167 (1993).","journal-title":"N. Engl. J. Med."},{"key":"888_CR6","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1007\/s40263-017-0469-1","volume":"31","author":"RL Smith","year":"2017","unstructured":"Smith, R. L. et al. Correlation between serum concentrations of N-desmethylclozapine and granulocyte levels in patients with schizophrenia: a retrospective observational study. CNS Drugs 31, 991\u2013997 (2017).","journal-title":"CNS Drugs"},{"key":"888_CR7","doi-asserted-by":"crossref","unstructured":"Citrome L., McEvoy J. P., Saklad S. R. A guide to the management of clozapine-related tolerability and safety concerns. Clin Schizophr Relat Psychoses. 10, 163\u2013177 (2016).","DOI":"10.3371\/1935-1232.10.3.163"},{"key":"888_CR8","first-page":"603","volume":"25","author":"JG Dain","year":"1997","unstructured":"Dain, J. G., Nicoletti, J. & Ballard, F. Biotransformation of clozapine in humans. Drug Metab. Dispos. 25, 603\u2013609 (1997).","journal-title":"Drug Metab. Dispos."},{"key":"888_CR9","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1124\/dmd.112.050484","volume":"41","author":"S Dragovic","year":"2013","unstructured":"Dragovic, S., Gunness, P., Ingelman-Sundberg, M., Vermeulen, N. P. & Commandeur, J. N. Characterization of human cytochrome P450s involved in the bioactivation of clozapine. Drug Metab. Dispos. 41, 651\u2013658 (2013).","journal-title":"Drug Metab. Dispos."},{"key":"888_CR10","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1097\/MOH.0000000000000391","volume":"25","author":"M Wicinski","year":"2018","unstructured":"Wicinski, M. & Weclewicz, M. M. Clozapine-induced agranulocytosis\/granulocytopenia: mechanisms and monitoring. Curr. Opin. Hematol. 25, 22\u201328 (2018).","journal-title":"Curr. Opin. Hematol."},{"key":"888_CR11","doi-asserted-by":"publisher","first-page":"139","DOI":"10.2165\/00023210-199707020-00005","volume":"7","author":"M Pirmohamed","year":"1997","unstructured":"Pirmohamed, M. & Park, K. Mechanism of clozapine-induced agranulocytosis: current status of research and implications for drug development. CNS Drugs 7, 139\u2013158 (1997).","journal-title":"CNS Drugs"},{"key":"888_CR12","first-page":"984","volume":"272","author":"M Pirmohamed","year":"1995","unstructured":"Pirmohamed, M., Williams, D., Madden, S., Templeton, E. & Park, B. K. Metabolism and bioactivation of clozapine by human liver in vitro. J. Pharmacol. Exp. Ther. 272, 984\u2013990 (1995).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"888_CR13","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1097\/01.jcp.0000106221.36344.4d","volume":"24","author":"A Rostami-Hodjegan","year":"2004","unstructured":"Rostami-Hodjegan, A. et al. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J. Clin. Psychopharmacol. 24, 70\u201378 (2004).","journal-title":"J. Clin. Psychopharmacol."},{"key":"888_CR14","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1111\/j.1751-7893.2012.00374.x","volume":"7","author":"L Couchman","year":"2013","unstructured":"Couchman, L., Bowskill, S. V., Handley, S., Patel, M. X. & Flanagan, R. J. Plasma clozapine and norclozapine in relation to prescribed dose and other factors in patients aged <18 years: data from a therapeutic drug monitoring service, 1994-2010. Early Inter. Psychiatry 7, 122\u2013130 (2013).","journal-title":"Early Inter. Psychiatry"},{"key":"888_CR15","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1097\/YIC.0000000000000065","volume":"31","author":"A Krivoy","year":"2016","unstructured":"Krivoy, A., Gaughran, F., Weizman, A., Breen, G. & MacCabe, J. H. Gene polymorphisms potentially related to the pharmacokinetics of clozapine: a systematic review. Int Clin. Psychopharmacol. 31, 179\u2013184 (2016).","journal-title":"Int Clin. Psychopharmacol."},{"key":"888_CR16","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1176\/appi.ajp.2019.18050589","volume":"176","author":"AF Pardinas","year":"2019","unstructured":"Pardinas, A. F. et al. Pharmacogenomic variants and drug interactions identified through the genetic analysis of clozapine metabolism. Am. J. Psychiatry 176, 477\u2013486 (2019).","journal-title":"Am. J. Psychiatry"},{"key":"888_CR17","doi-asserted-by":"crossref","unstructured":"Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421\u2013427 (2014).","DOI":"10.1038\/nature13595"},{"key":"888_CR18","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1038\/nrg.2017.101","volume":"19","author":"NJ Timpson","year":"2018","unstructured":"Timpson, N. J., Greenwood, C. M. T., Soranzo, N., Lawson, D. J. & Richards, J. B. Genetic architecture: the shape of the genetic contribution to human traits and disease. Nat. Rev. Genet. 19, 110\u2013124 (2018).","journal-title":"Nat. Rev. Genet."},{"key":"888_CR19","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","volume":"138","author":"UM Zanger","year":"2013","unstructured":"Zanger, U. M. & Schwab, M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther. 138, 103\u2013141 (2013).","journal-title":"Pharmacol. Ther."},{"key":"888_CR20","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1186\/1479-7364-4-4-278","volume":"4","author":"SC Sim","year":"2010","unstructured":"Sim, S. C. & Ingelman-Sundberg, M. The Human Cytochrome P450 (CYP) Allele Nomenclature website: a peer-reviewed database of CYP variants and their associated effects. Hum. Genomics. 4, 278\u2013281 (2010).","journal-title":"Hum. Genomics."},{"key":"888_CR21","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5757","volume":"5","author":"JI Goldstein","year":"2014","unstructured":"Goldstein, J. I. et al. Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles. Nat. Commun. 5, 4757 (2014).","journal-title":"Nat. Commun."},{"key":"888_CR22","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.1038\/mp.2016.97","volume":"22","author":"SE Legge","year":"2017","unstructured":"Legge, S. E. et al. Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia. Mol. Psychiatry 22, 1502\u20131508 (2017).","journal-title":"Mol. Psychiatry"},{"key":"888_CR23","doi-asserted-by":"publisher","first-page":"23847","DOI":"10.1074\/jbc.R400004200","volume":"279","author":"DW Nebert","year":"2004","unstructured":"Nebert, D. W., Dalton, T. P., Okey, A. B. & Gonzalez, F. J. Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J. Biol. Chem. 279, 23847\u201323850 (2004).","journal-title":"J. Biol. Chem."},{"key":"888_CR24","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1097\/FTD.0000000000000619","volume":"41","author":"RL Smith","year":"2019","unstructured":"Smith, R. L., Kylleso, L., Haslemo, T., Andreassen, O. A. & Molden, E. Reduction in N-desmethylclozapine level is determined by daily dose but not serum concentration of valproic acid-indications of a presystemic interaction mechanism. Ther. Drug Monit. 41, 503\u2013508 (2019).","journal-title":"Ther. Drug Monit."},{"key":"888_CR25","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1007\/s00228-006-0209-9","volume":"62","author":"T Haslemo","year":"2006","unstructured":"Haslemo, T., Eikeseth, P. H., Tanum, L., Molden, E. & Refsum, H. The effect of variable cigarette consumption on the interaction with clozapine and olanzapine. Eur. J. Clin. Pharmacol. 62, 1049\u20131053 (2006).","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"888_CR26","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1055\/s-0031-1286287","volume":"44","author":"C Hiemke","year":"2011","unstructured":"Hiemke, C. et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry 44, 195\u2013235 (2011).","journal-title":"Pharmacopsychiatry"},{"key":"888_CR27","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1176\/ajp.148.10.1406-b","volume":"148","author":"PJ Perry","year":"1991","unstructured":"Perry, P. J., Miller, D. D., Arndt, S. V. & Cadoret, R. J. Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am. J. Psychiatry 148, 231\u2013235 (1991).","journal-title":"Am. J. Psychiatry"},{"key":"888_CR28","first-page":"117","volume":"55","author":"DD Miller","year":"1994","unstructured":"Miller, D. D., Fleming, F., Holman, T. L. & Perry, P. J. Plasma clozapine concentrations as a predictor of clinical response: a follow-up study. J. Clin. Psychiatry 55, 117\u2013121 (1994).","journal-title":"J. Clin. Psychiatry"},{"key":"888_CR29","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1021\/cn400189s","volume":"5","author":"P Seeman","year":"2014","unstructured":"Seeman, P. Clozapine, a fast-off-D2 antipsychotic. ACS Chem. Neurosci. 5, 24\u201329 (2014).","journal-title":"ACS Chem. Neurosci."},{"key":"888_CR30","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","volume":"81","author":"S Purcell","year":"2007","unstructured":"Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559\u2013575 (2007).","journal-title":"Am. J. Hum. Genet."},{"key":"888_CR31","doi-asserted-by":"publisher","DOI":"10.1186\/s13742-015-0047-8","volume":"4","author":"CC Chang","year":"2015","unstructured":"Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, 7 (2015).","journal-title":"Gigascience"},{"key":"888_CR32","doi-asserted-by":"publisher","first-page":"1443","DOI":"10.1038\/ng.3679","volume":"48","author":"PR Loh","year":"2016","unstructured":"Loh, P. R. et al. Reference-based phasing using the Haplotype Reference Consortium panel. Nat. Genet. 48, 1443\u20131448 (2016).","journal-title":"Nat. Genet."},{"key":"888_CR33","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1038\/ng.3571","volume":"48","author":"PR Loh","year":"2016","unstructured":"Loh, P. R., Palamara, P. F. & Price, A. L. Fast and accurate long-range phasing in a UK Biobank cohort. Nat. Genet. 48, 811\u2013816 (2016).","journal-title":"Nat. Genet."},{"key":"888_CR34","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1038\/ng.3656","volume":"48","author":"S Das","year":"2016","unstructured":"Das, S. et al. Next-generation genotype imputation service and methods. Nat. Genet. 48, 1284\u20131287 (2016).","journal-title":"Nat. Genet."},{"key":"888_CR35","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1001\/jama.2015.19394","volume":"315","author":"MA Detry","year":"2016","unstructured":"Detry, M. A. & Ma, Y. Analyzing repeated measurements using mixed models. JAMA 315, 407\u2013408 (2016).","journal-title":"JAMA"},{"key":"888_CR36","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.schres.2005.02.010","volume":"76","author":"J de Leon","year":"2005","unstructured":"de Leon, J. & Diaz, F. J. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophr. Res. 76, 135\u2013157 (2005).","journal-title":"Schizophr. Res."},{"key":"888_CR37","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1128\/MCB.25.2.685-698.2005","volume":"25","author":"G Steele-Perkins","year":"2005","unstructured":"Steele-Perkins, G. et al. The transcription factor gene Nfib is essential for both lung maturation and brain development. Mol. Cell Biol. 25, 685\u2013698 (2005).","journal-title":"Mol. Cell Biol."},{"key":"888_CR38","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1002\/(SICI)1097-0177(199703)208:3<313::AID-AJA3>3.0.CO;2-L","volume":"208","author":"AZ Chaudhry","year":"1997","unstructured":"Chaudhry, A. Z., Lyons, G. E. & Gronostajski, R. M. Expression patterns of the four nuclear factor I genes during mouse embryogenesis indicate a potential role in development. Dev. Dyn. 208, 313\u2013325 (1997).","journal-title":"Dev. Dyn."},{"key":"888_CR39","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1016\/j.jpba.2017.07.037","volume":"145","author":"D Lu","year":"2017","unstructured":"Lu, D., Xie, Q. & Wu, B. N-glucuronidation catalyzed by UGT1A4 and UGT2B10 in human liver microsomes: assay optimization and substrate identification. J. Pharm. Biomed. Anal. 145, 692\u2013703 (2017).","journal-title":"J. Pharm. Biomed. Anal."},{"key":"888_CR40","doi-asserted-by":"publisher","first-page":"13674","DOI":"10.1073\/pnas.1835612100","volume":"100","author":"C Sur","year":"2003","unstructured":"Sur, C. et al. N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. Proc. Natl Acad. Sci. USA 100, 13674\u201313679 (2003).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"888_CR41","first-page":"169","volume":"150","author":"V Raitasuo","year":"1993","unstructured":"Raitasuo, V., Lehtovaara, R. & Huttunen, M. O. Carbamazepine and plasma levels of clozapine. Am. J. Psychiatry 150, 169 (1993).","journal-title":"Am. J. Psychiatry"},{"key":"888_CR42","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1111\/j.1365-2125.2005.02529.x","volume":"61","author":"E Perucca","year":"2006","unstructured":"Perucca, E. Clinically relevant drug interactions with antiepileptic drugs. Br. J. Clin. Pharmacol. 61, 246\u2013255 (2006).","journal-title":"Br. J. Clin. Pharmacol."}],"updated-by":[{"DOI":"10.1038\/s41398-020-01061-4","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,11,2]],"date-time":"2020-11-02T00:00:00Z","timestamp":1604275200000}}],"container-title":["Translational Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41398-020-00888-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-020-00888-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-020-00888-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T14:01:30Z","timestamp":1670248890000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41398-020-00888-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,19]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["888"],"URL":"https:\/\/doi.org\/10.1038\/s41398-020-00888-1","relation":{"correction":[{"id-type":"doi","id":"10.1038\/s41398-020-01061-4","asserted-by":"object"}]},"ISSN":["2158-3188"],"issn-type":[{"value":"2158-3188","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,19]]},"assertion":[{"value":"20 December 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 June 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 June 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 June 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 November 2020","order":5,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":6,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"An amendment to this paper has been published and can be accessed via a link at the top of the paper.","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"O.A.A. has received a speaker\u2019s honorarium from Lundbeck and is a consultant for HealthLytix Inc. E.M. received speaker\u00b4s honorarium from Lilly, Lundbeck and Otsuka. The other authors have no conflicts of interest to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"198"}}