{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T14:34:05Z","timestamp":1792852445956,"version":"4.5.0"},"reference-count":52,"publisher":"BMJ","issue":"3","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2014,2,10]]},"published-print":{"date-parts":[[2014,3]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To clarify the effects of smoking on the disposition of two commonly used antipsychotics, olanzapine and clozapine, and to create standards to adjust the doses of these drugs in clinical practice based on the smoking status.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>A meta-analysis was conducted by searching MEDLINE, Scopus and the Cochrane Library for relevant prospective and retrospective studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Included studies<\/jats:title>\n                    <jats:p>We included the studies that investigated the effects of smoking on the concentration to dose (C\/D) ratio of olanzapine or clozapine.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Primary outcome measure<\/jats:title>\n                    <jats:p>The weighted mean difference was calculated using a DerSimonian-Laird random effects model, along with 95% CI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Seven association studies, comprising 1094 patients (652 smokers and 442 non-smokers) with schizophrenia or other psychiatric disorders, were included in the meta-analysis of olanzapine. The C\/D ratio was significantly lower in smokers than in non-smokers (p&lt;0.00001), and the mean difference was \u22120.75 (ng\/mL)\/(mg\/day) (95% CI \u22120.89 to \u22120.61). Therefore, it was estimated that if 10 and 20\u2005mg\/day of olanzapine would be administered to smokers, about 7 and 14\u2005mg\/day, respectively, should be administered to non-smokers in order to obtain the equivalent olanzapine concentration. Four association studies of clozapine were included in the meta-analysis of clozapine, comprising 196 patients (120 smokers and 76 non-smokers) with schizophrenia or other psychiatric disorders. The C\/D ratio was significantly lower in smokers than in non-smokers (p&lt;0.00001), and the mean difference was \u22121.11 (ng\/mL)\/(mg\/day) (95% CI \u22121.53 to \u22120.70). Therefore, it was estimated that if 200 and 400\u2005mg\/day of clozapine would be administered to smokers, about 100 and 200\u2005mg\/day, respectively, should be administered to non-smokers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We suggest that the doses of olanzapine and clozapine should be reduced by 30% and 50%, respectively, in non-smokers compared with smokers in order to obtain an equivalent olanzapine or clozapine concentration.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2013-004216","type":"journal-article","created":{"date-parts":[[2014,3,4]],"date-time":"2014-03-04T21:50:19Z","timestamp":1393969819000},"page":"e004216","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":113,"title":["Meta-analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine"],"prefix":"10.1136","volume":"4","author":[{"given":"Yoshiyuki","family":"Tsuda","sequence":"first","affiliation":[{"name":"Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junji","family":"Saruwatari","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Yasui-Furukori","sequence":"additional","affiliation":[{"name":"Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2014,3,4]]},"reference":[{"key":"2025121422143756000_4.3.e004216.1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200746050-00001"},{"key":"2025121422143756000_4.3.e004216.2","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1097\/JCP.0b013e31828b28d5","article-title":"Olanzapine: a systematic review and meta-regression of the relationships between dose, plasma concentration, receptor occupancy, and response","volume":"33","author":"Bishara","year":"2013","journal-title":"J Clin Psychopharmacol"},{"key":"2025121422143756000_4.3.e004216.3","doi-asserted-by":"crossref","first-page":"99","DOI":"10.9758\/cpn.2012.10.2.99","article-title":"Use of clozapine for the treatment of schizophrenia: findings of the 2006 research on the china psychotropic prescription studies","volume":"10","author":"Si","year":"2012","journal-title":"Clin Psychopharmacol Neurosci"},{"key":"2025121422143756000_4.3.e004216.4","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/hup.1191","article-title":"Factors affecting interindividual differences in clozapine response: a review and case report","volume":"26","author":"Bersani","year":"2011","journal-title":"Hum Psychopharmacol"},{"key":"2025121422143756000_4.3.e004216.5","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1111\/j.1521-0391.2013.00313.x","article-title":"Effects of tobacco smoking on neuropsychological function in schizophrenia in comparison to other psychiatric disorders and non-psychiatric controls","volume":"22","author":"Morisano","year":"2013","journal-title":"Am J Addict"},{"key":"2025121422143756000_4.3.e004216.6","first-page":"371","article-title":"Smoking and schizophrenia","volume":"21","author":"Sagud","year":"2009","journal-title":"Psychiatr Danub"},{"key":"2025121422143756000_4.3.e004216.7","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0b013e3181a289cb"},{"key":"2025121422143756000_4.3.e004216.8","doi-asserted-by":"publisher","DOI":"10.1097\/00004714-200304000-00003"},{"key":"2025121422143756000_4.3.e004216.9","doi-asserted-by":"crossref","first-page":"415","DOI":"10.2165\/11587240-000000000-00000","article-title":"Does olanzapine warrant clinical pharmacokinetic monitoring in schizophrenia?","volume":"50","author":"Schwenger","year":"2011","journal-title":"Clin Pharmacokinet"},{"key":"2025121422143756000_4.3.e004216.10","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-199604000-00015"},{"key":"2025121422143756000_4.3.e004216.11","doi-asserted-by":"publisher","DOI":"10.1007\/s002130050028"},{"key":"2025121422143756000_4.3.e004216.12","doi-asserted-by":"publisher","DOI":"10.1016\/S0920-9964(03)00159-2"},{"key":"2025121422143756000_4.3.e004216.13","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1055\/s-2007-1014307","article-title":"Seizures following smoking cessation in a clozapine responder","volume":"27","author":"McCarthy","year":"1994","journal-title":"Pharmacopsychiatry"},{"key":"2025121422143756000_4.3.e004216.14","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-199910000-00016"},{"key":"2025121422143756000_4.3.e004216.15","doi-asserted-by":"publisher","DOI":"10.1097\/00004850-200205000-00008"},{"key":"2025121422143756000_4.3.e004216.16","doi-asserted-by":"publisher","DOI":"10.1176\/appi.psy.49.2.176"},{"key":"2025121422143756000_4.3.e004216.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcms.2010.11.001"},{"key":"2025121422143756000_4.3.e004216.18","doi-asserted-by":"publisher","DOI":"10.1001\/jama.283.15.2008"},{"key":"2025121422143756000_4.3.e004216.19","doi-asserted-by":"publisher","DOI":"10.1016\/0197-2456(86)90046-2"},{"key":"2025121422143756000_4.3.e004216.20","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.315.7109.629"},{"key":"2025121422143756000_4.3.e004216.21","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-006-0209-9"},{"key":"2025121422143756000_4.3.e004216.22","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1097\/FTD.0b013e31816336fd","article-title":"The relationship between the response of clinical symptoms and plasma olanzapine concentration, based on pharmacogenetics: Juntendo University Schizophrenia Projects (JUSP)","volume":"30","author":"Nozawa","year":"2008","journal-title":"Ther Drug Monit"},{"key":"2025121422143756000_4.3.e004216.23","doi-asserted-by":"publisher","DOI":"10.1177\/0091270007310385"},{"key":"2025121422143756000_4.3.e004216.24","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/tpj.2009.32","article-title":"Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome","volume":"10","author":"Laika","year":"2009","journal-title":"Pharmacogenomics J"},{"key":"2025121422143756000_4.3.e004216.25","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1097\/FTD.0b013e3181c0590e","article-title":"Effect of valproate on olanzapine plasma concentrations in patients with bipolar or schizoaffective disorder","volume":"31","author":"Spina","year":"2009","journal-title":"Ther Drug Monit"},{"key":"2025121422143756000_4.3.e004216.26","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1097\/JCP.0b013e318204d9e2","article-title":"High correlation between serum and cerebrospinal fluid olanzapine concentrations in patients with schizophrenia or schizoaffective disorder medicating with oral olanzapine as the only antipsychotic drug","volume":"31","author":"Skogh","year":"2011","journal-title":"J Clin Psychopharmacol"},{"key":"2025121422143756000_4.3.e004216.27","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1111\/j.1365-2125.2010.03880.x","article-title":"The effect of ethinylestradiol-containing contraceptives on the serum concentration of olanzapine and N-desmethyl olanzapine","volume":"71","author":"Haslemo","year":"2011","journal-title":"Br J Clin Pharmacol"},{"key":"2025121422143756000_4.3.e004216.28","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1007\/s002130000503","article-title":"Long-term therapeutic drug monitoring of clozapine and metabolites in psychiatric in- and outpatients","volume":"152","author":"Dettling","year":"2000","journal-title":"Psychopharmacology (Berl)"},{"key":"2025121422143756000_4.3.e004216.29","doi-asserted-by":"publisher","DOI":"10.1016\/S0278-5846(01)00291-3"},{"key":"2025121422143756000_4.3.e004216.30","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-200303000-00006"},{"key":"2025121422143756000_4.3.e004216.31","doi-asserted-by":"publisher","DOI":"10.2165\/11539240-000000000-00000"},{"key":"2025121422143756000_4.3.e004216.32","doi-asserted-by":"publisher","DOI":"10.1378\/chest.10-0777"},{"key":"2025121422143756000_4.3.e004216.33","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1P759"},{"key":"2025121422143756000_4.3.e004216.34","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1220919110"},{"key":"2025121422143756000_4.3.e004216.35","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199937030-00001"},{"key":"2025121422143756000_4.3.e004216.36","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/s00213-012-2922-7","article-title":"Clozapine and therapeutic drug monitoring: is there sufficient evidence for an upper threshold?","volume":"225","author":"Remington","year":"2013","journal-title":"Psychopharmacology (Berl)"},{"key":"2025121422143756000_4.3.e004216.37","doi-asserted-by":"crossref","unstructured":"Li LJ , Shang DW, Li WB, et al. Population pharmacokinetics of clozapine and its primary metabolite norclozapine in Chinese patients with schizophrenia. Acta Pharmacol Sin 2012;33:1409\u201316.","DOI":"10.1038\/aps.2012.71"},{"key":"2025121422143756000_4.3.e004216.38","doi-asserted-by":"publisher","DOI":"10.1097\/01.jcp.0000185427.08268.db"},{"key":"2025121422143756000_4.3.e004216.39","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1176\/ajp.147.11.1471","article-title":"Influence of patient-related variables on clozapine plasma levels","volume":"147","author":"Haring","year":"1990","journal-title":"Am J Psychiatry"},{"key":"2025121422143756000_4.3.e004216.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2004.03.017"},{"key":"2025121422143756000_4.3.e004216.41","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1055\/s-2007-1004591","article-title":"Estimating the size of the effects of co-medications on plasma clozapine concentrations using a model that controls for clozapine doses and confounding variables","volume":"41","author":"Diaz","year":"2008","journal-title":"Pharmacopsychiatry"},{"key":"2025121422143756000_4.3.e004216.42","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1097\/FTD.0b013e31819c7037","article-title":"Clozapine exposure and the impact of smoking and gender: a population pharmacokinetic study","volume":"31","author":"Ng","year":"2009","journal-title":"Ther Drug Monit"},{"key":"2025121422143756000_4.3.e004216.43","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-200302000-00007"},{"key":"2025121422143756000_4.3.e004216.44","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1097\/JCP.0b013e31825ac35c","article-title":"Association study of 27 annotated genes for clozapine pharmacogenetics: validation of preexisting studies and identification of a new candidate gene, ABCB1, for treatment response","volume":"32","author":"Lee","year":"2012","journal-title":"J Clin Psychopharmacol"},{"key":"2025121422143756000_4.3.e004216.45","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1097\/01.ftd.0000249950.75462.7f","article-title":"Serum levels of olanzapine and its N-desmethyl and 2-hydroxymethyl metabolites in child and adolescent psychiatric disorders: effects of dose, diagnosis, age, sex, smoking, and comedication","volume":"28","author":"Theisen","year":"2006","journal-title":"Ther Drug Monit"},{"key":"2025121422143756000_4.3.e004216.46","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0b013e318221b408"},{"key":"2025121422143756000_4.3.e004216.47","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/tpj.2012.47","article-title":"Influence of FMO1 and 3 polymorphisms on serum olanzapine and its N-oxide metabolite in psychiatric patients","volume":"13","author":"Soderberg","year":"2013","journal-title":"Pharmacogenomics J"},{"key":"2025121422143756000_4.3.e004216.48","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/j.pnpbp.2008.04.018","article-title":"Estimating the effects of co-medications on plasma olanzapine concentrations by using a mixed model","volume":"32","author":"Botts","year":"2008","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"2025121422143756000_4.3.e004216.49","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1055\/s-2004-815527","article-title":"Olanzapine plasma concentration, average daily dose, and interaction with co-medication in schizophrenic patients","volume":"37","author":"Bergemann","year":"2004","journal-title":"Pharmacopsychiatry"},{"key":"2025121422143756000_4.3.e004216.50","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.2217\/pgs.13.120","article-title":"Pharmacogenetics of olanzapine metabolism","volume":"14","author":"Soderberg","year":"2013","journal-title":"Pharmacogenomics"},{"key":"2025121422143756000_4.3.e004216.51","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-011-1189-y"},{"key":"2025121422143756000_4.3.e004216.52","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291709005455"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2013-004216","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T06:14:47Z","timestamp":1765779287000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2013-004216"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,3]]},"references-count":52,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2014,3,4]]},"published-print":{"date-parts":[[2014,3]]}},"alternative-id":["10.1136\/bmjopen-2013-004216"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2013-004216","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,3]]}}}