{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T06:08:04Z","timestamp":1788934084819,"version":"build-2803163510"},"reference-count":72,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T00:00:00Z","timestamp":1607385600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Objective<\/jats:title>\n<jats:p>Mining the data contained within Electronic Health Records (EHRs) can potentially generate a greater understanding of medication effects in the real world, complementing what we know from Randomised control trials (RCTs). We Propose a text mining approach to detect adverse events and medication episodes from the clinical text to enhance our understanding of adverse effects related to Clozapine, the most effective antipsychotic drug for the management of treatment-resistant schizophrenia, but underutilised due to concerns over its side effects.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Material and methods<\/jats:title>\n<jats:p>We used data from de-identified EHRs of three mental health trusts in the UK (&gt;50 million documents, over 500,000 patients, 2835 of which were prescribed Clozapine). We explored the prevalence of 33 adverse effects by age, gender, ethnicity, smoking status and admission type three months before and after the patients started Clozapine treatment. Where possible, we compared the prevalence of adverse effects with those reported in the Side Effects Resource (SIDER).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Sedation, fatigue, agitation, dizziness, hypersalivation, weight gain, tachycardia, headache, constipation and confusion were amongst the highest recorded Clozapine adverse effect in the three months following the start of treatment. Higher percentages of all adverse effects were found in the first month of Clozapine therapy. Using a significance level of (p&lt; 0.05) our chi-square tests show a significant association between most of the ADRs and smoking status and hospital admission, and some in gender, ethnicity and age groups in all trusts hospitals. Later we combined the data from the three trusts hospitals to estimate the average effect of ADRs in each monthly interval. In gender and ethnicity, the results show significant association in 7 out of 33 ADRs, smoking status shows significant association in 21 out of 33 ADRs and hospital admission shows the significant association in 30 out of 33 ADRs.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>A better understanding of how drugs work in the real world can complement clinical trials.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0243437","type":"journal-article","created":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T21:06:25Z","timestamp":1607461585000},"page":"e0243437","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":60,"title":["The side effect profile of Clozapine in real world data of three large mental health hospitals"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9477-9745","authenticated-orcid":true,"given":"Ehtesham","family":"Iqbal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9925-7866","authenticated-orcid":true,"given":"Risha","family":"Govind","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvin","family":"Romero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3878-2143","authenticated-orcid":true,"given":"Olubanke","family":"Dzahini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Broadbent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Hun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nomi","family":"Werbeloff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James H.","family":"MacCabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J. B.","family":"Dobson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zina M.","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,12,8]]},"reference":[{"issue":"7456","key":"pone.0243437.ref001","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1136\/bmj.329.7456.15","article-title":"Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients","volume":"329","author":"M Pirmohamed","year":"2004","journal-title":"Bmj"},{"issue":"4","key":"pone.0243437.ref002","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1377\/hlthaff.2011.0190","article-title":"\u2018Global trigger tool\u2019shows that adverse events in hospitals may be ten times greater than previously measured","volume":"30","author":"DC Classen","year":"2011","journal-title":"Health affairs"},{"issue":"15","key":"pone.0243437.ref003","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1001\/jama.279.15.1200","article-title":"Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies","volume":"279","author":"J Lazarou","year":"1998","journal-title":"Jama"},{"key":"pone.0243437.ref004","unstructured":"U.S. Food and Drug Administration [Available from: https:\/\/www.fda.gov\/Drugs\/GuidanceComplianceRegulatoryInformation\/Surveillance\/AdverseDrugEffects\/ucm082193.htm."},{"issue":"125","key":"pone.0243437.ref005","doi-asserted-by":"crossref","first-page":"125ra31","DOI":"10.1126\/scitranslmed.3003377","article-title":"Data-driven prediction of drug effects and interactions","volume":"4","author":"NP Tatonetti","year":"2012","journal-title":"Science translational medicine"},{"issue":"7","key":"pone.0243437.ref006","doi-asserted-by":"crossref","first-page":"607","DOI":"10.2165\/00003088-200342070-00001","article-title":"What is an adequate trial with clozapine?","volume":"42","author":"PF Schulte","year":"2003","journal-title":"Clinical pharmacokinetics"},{"key":"pone.0243437.ref007","volume-title":"Essential psychopharmacology: Neuroscientific basis and practical applications:","author":"SM Stahl","year":"2000"},{"issue":"4","key":"pone.0243437.ref008","doi-asserted-by":"crossref","first-page":"323","DOI":"10.9758\/cpn.2016.14.4.323","article-title":"Clozapine monitoring in clinical practice: beyond the mandatory requirement","volume":"14","author":"N Kar","year":"2016","journal-title":"Clinical Psychopharmacology and Neuroscience"},{"issue":"1","key":"pone.0243437.ref009","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3371\/CSRP.4.1.4","article-title":"Clozapine for treatment-resistant schizophrenia: National Institute of Clinical Excellence (NICE) guidance in the real world","volume":"4","author":"A Mortimer","year":"2010","journal-title":"Clinical schizophrenia & related psychoses"},{"key":"pone.0243437.ref010","article-title":"Clozapine-associated agranulocytosis: risk and aetiology","author":"P Krupp","year":"1992","journal-title":"The British Journal of Psychiatry"},{"issue":"10","key":"pone.0243437.ref011","doi-asserted-by":"crossref","first-page":"920","DOI":"10.4088\/JCP.v63n1010","article-title":"Wang R-h, Nasrallah HA. Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database","volume":"63","author":"FD Gianfrancesco","year":"2002","journal-title":"The Journal of clinical psychiatry"},{"issue":"9","key":"pone.0243437.ref012","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1038\/npp.2010.78","article-title":"Antipsychotics associated with the development of type 2 diabetes in antipsychotic-na\u00efve schizophrenia patients","volume":"35","author":"J Nielsen","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"pone.0243437.ref013","first-page":"S197","article-title":"Side effects of clozapine and their relationship with clinical variables in patients with schizophrenia","volume":"41","author":"G G\u00fcrcan","year":"2017","journal-title":"European Psychiatry"},{"issue":"2","key":"pone.0243437.ref014","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1093\/schbul\/17.2.247","article-title":"Update on the clinical efficacy and side effects of clozapine","volume":"17","author":"A Safferman","year":"1991","journal-title":"Schizophrenia bulletin"},{"key":"pone.0243437.ref015","article-title":"Review and management of clozapine side effects","author":"DD Miller","year":"2000","journal-title":"Journal of Clinical Psychiatry"},{"issue":"3","key":"pone.0243437.ref016","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1093\/oxfordjournals.schbul.a033333","article-title":"Management of the adverse effects of clozapine.","volume":"24","author":"CR Young","year":"1998","journal-title":"Schizophrenia Bulletin"},{"issue":"2","key":"pone.0243437.ref017","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1192\/bjp.bp.108.051979","article-title":"Reasons for discontinuing clozapine: matched, case\u2013control comparison with risperidone long-acting injection","volume":"194","author":"DM Taylor","year":"2009","journal-title":"The British Journal of Psychiatry"},{"issue":"2","key":"pone.0243437.ref018","doi-asserted-by":"crossref","first-page":"115","DOI":"10.2174\/157488608784529251","article-title":"Side effects of clozapine and some other psychoactive drugs","volume":"3","author":"RJ Flanagan","year":"2008","journal-title":"Current drug safety"},{"issue":"3","key":"pone.0243437.ref019","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/BF00606409","article-title":"Agranulocytosis during treatment with clozapine","volume":"11","author":"J Id\u00e4np\u00e4\u00e4n-Heikkil\u00e4","year":"1977","journal-title":"European journal of clinical pharmacology"},{"issue":"4","key":"pone.0243437.ref020","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/j.1600-0447.1977.tb00224.x","article-title":"Agranulocytosis in patients treated with clozapine","volume":"56","author":"HA Amsler","year":"1977","journal-title":"Acta Psychiatrica Scandinavica"},{"issue":"3","key":"pone.0243437.ref021","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1056\/NEJM199307153290303","article-title":"Clozapine-induced agranulocytosis\u2014incidence and risk factors in the United States","volume":"329","author":"JMJ Alvir","year":"1993","journal-title":"New England Journal of Medicine"},{"key":"pone.0243437.ref022","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.2147\/NDT.S83989","article-title":"Rare and very rare adverse effects of clozapine","volume":"11","author":"P De Fazio","year":"2015","journal-title":"Neuropsychiatric disease and treatment"},{"issue":"1","key":"pone.0243437.ref023","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.eurpsy.2013.08.001","article-title":"Systematic review of the efficacy and tolerability of clozapine in the treatment of youth with early onset schizophrenia","volume":"29","author":"C Schneider","year":"2014","journal-title":"European Psychiatry"},{"issue":"1","key":"pone.0243437.ref024","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.schres.2015.07.052","article-title":"Glasgow antipsychotic side-effects scale for clozapine\u2014development and validation of a clozapine-specific side-effects scale","volume":"168","author":"C Hynes","year":"2015","journal-title":"Schizophrenia research"},{"issue":"1\u20133","key":"pone.0243437.ref025","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.schres.2016.04.005","article-title":"Consistency between clinician and patient ratings of clozapine-induced side effects","volume":"174","author":"H Takeuchi","year":"2016","journal-title":"Schizophrenia research"},{"issue":"1","key":"pone.0243437.ref026","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/BF01064682","article-title":"Clinical profile of clozapine: adverse reactions and agranulocytosis","volume":"63","author":"JA Lieberman","year":"1992","journal-title":"Psychiatric Quarterly"},{"issue":"1","key":"pone.0243437.ref027","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/j.1447-0349.2007.00506.x","article-title":"Side\u2010effects and treatment with clozapine: a comparison between the views of consumers and their clinicians","volume":"17","author":"K Hodge","year":"2008","journal-title":"International Journal of Mental Health Nursing"},{"issue":"3","key":"pone.0243437.ref028","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1017\/S0033291701003749","article-title":"Patients' and relatives' assessment of clozapine treatment","volume":"31","author":"M Angermeyer","year":"2001","journal-title":"Psychological Medicine"},{"issue":"1","key":"pone.0243437.ref029","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1176\/ajp.149.1.68","article-title":"Clozapine-induced weight gain: prevalence and clinical relevance","volume":"149","author":"R Leadbetter","year":"1992","journal-title":"The American journal of psychiatry"},{"issue":"1","key":"pone.0243437.ref030","doi-asserted-by":"crossref","first-page":"47","DOI":"10.2165\/00002018-200730010-00005","article-title":"Clozapine-associated myocarditis","volume":"30","author":"SJ Haas","year":"2007","journal-title":"Drug Safety"},{"issue":"12","key":"pone.0243437.ref031","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1001\/archpsyc.1996.01830120020005","article-title":"Childhood-onset schizophrenia: a double-blind clozapine-haloperidol comparison","volume":"53","author":"S Kumra","year":"1996","journal-title":"Archives of general psychiatry"},{"issue":"4","key":"pone.0243437.ref032","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1089\/cap.1999.9.239","article-title":"Elevated prolactin in pediatric patients on typical and atypical antipsychotics","volume":"9","author":"M Wudarsky","year":"1999","journal-title":"Journal of child and adolescent psychopharmacology"},{"issue":"5","key":"pone.0243437.ref033","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1097\/00004583-199406000-00006","article-title":"An open trial of clozapine in 11 adolescents with childhood-onset schizophrenia","volume":"33","author":"JA Frazier","year":"1994","journal-title":"Journal of the American Academy of Child & Adolescent Psychiatry"},{"issue":"10","key":"pone.0243437.ref034","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1097\/01.chi.0000171904.23947.54","article-title":"Hematological adverse events in clozapine-treated children and adolescents.","volume":"44","author":"G Gerbino-Rosen","year":"2005","journal-title":"Journal of the American Academy of Child & Adolescent Psychiatry"},{"issue":"10","key":"pone.0243437.ref035","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1097\/chi.0b013e31812eed10","article-title":"Clozapine treatment of childhood-onset schizophrenia: evaluation of effectiveness, adverse effects, and long-term outcome.","volume":"46","author":"AL Sporn","year":"2007","journal-title":"Journal of the American Academy of Child & Adolescent Psychiatry"},{"issue":"6","key":"pone.0243437.ref036","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1192\/bjp.170.6.507","article-title":"An open trial of clozapine in neuroleptic-resistant childhood-onset schizophrenia","volume":"170","author":"M Turetz","year":"1997","journal-title":"The British Journal of Psychiatry"},{"issue":"2","key":"pone.0243437.ref037","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1089\/1044546041648977","article-title":"Chart review for potential features of myocarditis, pericarditis, and cardiomyopathy in children and adolescents treated with clozapine","volume":"14","author":"PM Wehmeier","year":"2004","journal-title":"Journal of child and adolescent psychopharmacology"},{"issue":"11","key":"pone.0243437.ref038","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1007\/s00702-008-0105-9","article-title":"Weight gain in children and adolescents during 45 weeks treatment with clozapine, olanzapine and risperidone","volume":"115","author":"C Fleischhaker","year":"2008","journal-title":"Journal of Neural Transmission"},{"issue":"3","key":"pone.0243437.ref039","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1089\/cap.2006.16.308","article-title":"Clinical drug monitoring in child and adolescent psychiatry: side effects of atypical neuroleptics. Journal of Child &","volume":"16","author":"C Fleischhaker","year":"2006","journal-title":"Adolescent Psychopharmacology"},{"issue":"1","key":"pone.0243437.ref040","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1176\/appi.ps.201200143","article-title":"Cigarette smoking among persons with schizophrenia or bipolar disorder in routine clinical settings, 1999\u20132011","volume":"64","author":"F Dickerson","year":"2013","journal-title":"Psychiatric Services"},{"issue":"5","key":"pone.0243437.ref041","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1192\/apt.6.5.327","article-title":"Cigarette smoking and schizophrenia","volume":"6","author":"C Kelly","year":"2000","journal-title":"Advances in Psychiatric Treatment"},{"issue":"2","key":"pone.0243437.ref042","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/0920-9964(92)90024-Y","article-title":"Smoking and schizophrenia","volume":"8","author":"JB Lohr","year":"1992","journal-title":"Schizophrenia research"},{"issue":"3","key":"pone.0243437.ref043","first-page":"102","volume":"36","author":"C Lucas","year":"2013","journal-title":"Smoking and drug"},{"issue":"3","key":"pone.0243437.ref044","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1208\/s12248-009-9127-y","article-title":"Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2","volume":"11","author":"S-F Zhou","year":"2009","journal-title":"The AAPS journal"},{"issue":"7","key":"pone.0243437.ref045","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1089\/152460902760360559","article-title":"Biologic and molecular mechanisms for sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics: Part I","volume":"11","author":"M Anthony","year":"2002","journal-title":"Journal of women's health & gender-based medicine"},{"issue":"6","key":"pone.0243437.ref046","doi-asserted-by":"crossref","first-page":"349","DOI":"10.2165\/00128071-200102060-00001","article-title":"Do women have more adverse drug reactions?","volume":"2","author":"M. Rademaker","year":"2001","journal-title":"American journal of clinical dermatology"},{"issue":"10","key":"pone.0243437.ref047","doi-asserted-by":"crossref","first-page":"577","DOI":"10.5414\/CP201514","article-title":"Adverse drug reactions (ADRs) associated with hospital admissions\u2014elderly female patients are at highest risk","volume":"49","author":"C Hofer-Dueckelmann","year":"2011","journal-title":"International Journal of Clinical Pharmacologyand Therapeutics"},{"issue":"1","key":"pone.0243437.ref048","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1111\/j.1365-2125.2010.03811.x","article-title":"Sex\u2010related differences in hospital admissions attributed to adverse drug reactions in the Netherlands","volume":"71","author":"EM Rodenburg","year":"2011","journal-title":"British journal of clinical pharmacology"},{"issue":"1","key":"pone.0243437.ref049","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.pharmthera.2007.04.008","article-title":"Regulation of cardiac ion channels via non-genomic action of sex steroid hormones: implication for the gender difference in cardiac arrhythmias","volume":"115","author":"T Furukawa","year":"2007","journal-title":"Pharmacology & therapeutics"},{"issue":"12","key":"pone.0243437.ref050","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/j.lfs.2007.08.009","article-title":"Effect of chronic infusion of olanzapine and clozapine on food intake and body weight gain in male and female rats","volume":"81","author":"S Choi","year":"2007","journal-title":"Life sciences"},{"issue":"2","key":"pone.0243437.ref051","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/BF00156581","article-title":"Ethnicity and psychopharmacology","volume":"10","author":"K-M Lin","year":"1986","journal-title":"Culture, medicine and psychiatry"},{"issue":"6","key":"pone.0243437.ref052","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1177\/0269881107082105","article-title":"Ethnicity and psychopharmacology","volume":"22","author":"IB Chaudhry","year":"2008","journal-title":"Journal of Psychopharmacology"},{"issue":"5","key":"pone.0243437.ref053","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1093\/schbul\/sbl068","article-title":"Clozapine underutilization and discontinuation in African Americans due to leucopenia","volume":"33","author":"DL Kelly","year":"2006","journal-title":"Schizophrenia bulletin"},{"issue":"5","key":"pone.0243437.ref054","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1358\/dot.2004.40.5.850492","article-title":"The increase in risk of diabetes mellitus from exposure to second-generation antipsychotic agents","volume":"40","author":"LL Citrome","year":"2004","journal-title":"Drugs of Today"},{"issue":"01","key":"pone.0243437.ref055","first-page":"1","article-title":"Atypical antipsychotics and new onset diabetes mellitus","volume":"38","author":"D. Cohen","year":"2004","journal-title":"Pharmacopsychiatry"},{"issue":"11","key":"pone.0243437.ref056","doi-asserted-by":"crossref","first-page":"e0187121","DOI":"10.1371\/journal.pone.0187121","article-title":"ADEPt, a semantically-enriched pipeline for extracting adverse drug events from free-text electronic health records","volume":"12","author":"E Iqbal","year":"2017","journal-title":"PloS one"},{"issue":"D1","key":"pone.0243437.ref057","doi-asserted-by":"crossref","first-page":"D1075","DOI":"10.1093\/nar\/gkv1075","article-title":"The SIDER database of drugs and side effects","volume":"44","author":"M Kuhn","year":"2015","journal-title":"Nucleic acids research"},{"issue":"1","key":"pone.0243437.ref058","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/1471-244X-9-51","article-title":"The South London and Maudsley NHS foundation trust biomedical research centre (SLAM BRC) case register: development and descriptive data","volume":"9","author":"R Stewart","year":"2009","journal-title":"BMC psychiatry"},{"issue":"3","key":"pone.0243437.ref059","doi-asserted-by":"crossref","first-page":"e008721","DOI":"10.1136\/bmjopen-2015-008721","article-title":"Cohort profile of the south london and maudsley nhs foundation trust biomedical research centre (slam brc) case register: current status and recent enhancement of an electronic mental health record-derived data resource","volume":"6","author":"G Perera","year":"2016","journal-title":"BMJ open"},{"key":"pone.0243437.ref060","unstructured":"Camden and Islington NHS Foundation Trust. Camden and Islington NHS Foundation Trust 2017 [Available from: http:\/\/www.candi.nhs.uk\/."},{"issue":"1","key":"pone.0243437.ref061","doi-asserted-by":"crossref","first-page":"e0190703","DOI":"10.1371\/journal.pone.0190703","article-title":"The Camden & Islington Research Database: Using electronic mental health records for research","volume":"13","author":"N Werbeloff","year":"2018","journal-title":"PloS one"},{"key":"pone.0243437.ref062","unstructured":"Oxford Health NHS Foundation Trust. Oxford Health NHS Foundation Trust 2018 [Available from: https:\/\/www.oxfordhealth.nhs.uk\/."},{"issue":"1","key":"pone.0243437.ref063","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.schres.2016.04.010","article-title":"antipsychotic polypharmacy prescribing in secondary mental healthcare","volume":"174","author":"G Kadra","year":"2016","journal-title":"Schizophrenia research"},{"issue":"3","key":"pone.0243437.ref064","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1093\/schbul\/sbu120","article-title":"The effect of clozapine on premature mortality: an assessment of clinical monitoring and other potential confounders","volume":"41","author":"RD Hayes","year":"2014","journal-title":"Schizophrenia bulletin"},{"key":"pone.0243437.ref065","unstructured":"Joint Formulary Committee. British national formulary (BNF) 72: Pharmaceutical Press; 2016."},{"key":"pone.0243437.ref066","unstructured":"Datapharm Communications Ltd. electronic Medicines Compendium (eMC) 2017 [Available from: https:\/\/www.medicines.org.uk\/emc\/."},{"issue":"6","key":"pone.0243437.ref067","doi-asserted-by":"crossref","first-page":"e0178562","DOI":"10.1371\/journal.pone.0178562","article-title":"Trajectories of dementia-related cognitive decline in a large mental health records derived patient cohort","volume":"12","author":"E Baker","year":"2017","journal-title":"PLoS One"},{"key":"pone.0243437.ref068","author":"MM Iqbal","journal-title":"Most Common Side Effects of Clozapine and Their Management"},{"issue":"9","key":"pone.0243437.ref069","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1017\/S146114571100201X","article-title":"A systematic review of the evidence of clozapine's anti-aggressive effects","volume":"15","author":"C Frogley","year":"2012","journal-title":"International Journal of Neuropsychopharmacology"},{"issue":"5","key":"pone.0243437.ref070","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1517\/14740338.7.5.525","article-title":"The safety of clozapine in the elderly","volume":"7","author":"P Gareri","year":"2008","journal-title":"Expert opinion on drug safety"},{"issue":"3","key":"pone.0243437.ref071","doi-asserted-by":"crossref","first-page":"164","DOI":"10.2174\/157488611797579230","article-title":"Clozapine safety, 35 years later","volume":"6","author":"M. Raja","year":"2011","journal-title":"Current drug safety"},{"issue":"3","key":"pone.0243437.ref072","doi-asserted-by":"crossref","first-page":"163","DOI":"10.2174\/1574886309666140428115040","article-title":"Clozapine safety, 40 years later","volume":"9","author":"M Raja","year":"2014","journal-title":"Current drug safety"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0243437","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T21:07:53Z","timestamp":1607461673000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0243437"}},"subtitle":[],"editor":[{"given":"Vincenzo","family":"De Luca","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2020,12,8]]},"references-count":72,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0243437","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,8]]}}}