{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T13:44:41Z","timestamp":1793281481829,"version":"4.5.0"},"reference-count":22,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T00:00:00Z","timestamp":1766620800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T00:00:00Z","timestamp":1766620800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["accpjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacotherapy"],"published-print":{"date-parts":[[2026,2]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Clozapine initiation often triggers inflammatory responses that can alter metabolism via Cytochrome P450 1A2 (CYP1A2) suppression. Although C\u2010reactive protein (CRP) is the recommended marker, it may be unavailable in community settings. Neutrophil\u2010to\u2010lymphocyte ratio (NLR), routinely measured, could serve as a surrogate, though its value in detecting clozapine\u2010related inflammation and metabolic changes remains unclear.<\/jats:p>\n <\/jats:sec>\n \n Aims<\/jats:title>\n This study aimed to assess the relationship between CRP and NLR in individuals treated with clozapine, evaluate whether NLR can act as a proxy for elevated CRP (>\u20095\u2009mg\/L), and determine whether NLR, like CRP, explains variability in clozapine metabolism (concentration to dose (C\/D) ratios) after adjusting for covariates.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We performed a retrospective cohort study of clozapine\u2010treated inpatients at the British Columbia Psychosis Program (2012\u20132021). Patients with clozapine levels and matched complete blood counts (CBCs) (\u00b17\u2009days) were included, with CRP added when available. Multivariate mixed models assessed associations between CRP, NLR, and clozapine C\/D ratios, while receiver operating characteristic (ROC) analyses evaluated NLR as a proxy for elevated CRP.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among 150 patients, 760 clozapine serum\/CBC pairs and 212 CRP measurements met eligibility criteria. NLR was modestly associated with CRP (estimate\u2009=\u20090.027,\n p<\/jats:italic>\n \u2009<\u20090.001). ROC analysis indicated that NLR had limited predictive utility, with an area under the curve (AUC) of 0.640 for detecting CRP\u2009>\u20095\u2009mg\/L. Subsequent analyses for higher CRP thresholds (>\u200910 and >\u200920\u2009mg\/L) produced comparable NLR AUC values of 0.621 and 0.669, respectively. Neutrophil count alone demonstrated marginally better performance but remained similarly limited in predictive value. In multivariate models, CRP but not NLR, was independently associated with clozapine C\/D ratios.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n Our findings indicate that although NLR and other hematological indices are easily accessible and may provide some indication of inflammation, they cannot substitute for CRP in guiding clozapine titration decisions. Where CRP is unavailable, NLR\u2009>\u20093 may be cautiously informative, though CRP remains the preferred marker for early detection and dose adjustment to optimize tolerability, adherence, and safety during clozapine initiation.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/phar.70094","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T05:12:49Z","timestamp":1766725969000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["C\u2010Reactive Protein and Neutrophil\u2010To\u2010Lymphocyte Ratio: Can They Be Used Interchangeably in Tracking Clozapine\u2010Related Inflammation?"],"prefix":"10.1002","volume":"46","author":[{"given":"Nicoline","family":"Bihelek","sequence":"first","affiliation":[{"name":"Lower Mainland Pharmacy Services Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6303-8696","authenticated-orcid":false,"given":"Chad A.","family":"Bousman","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry, Medical Genetics, Physiology & Pharmacology, and Community Health Sciences University of Calgary Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William G.","family":"Honer","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of British Columbia Vancouver British Columbia Canada"},{"name":"BC Psychosis Program, UBC Hospital Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4163-8241","authenticated-orcid":false,"given":"Reza","family":"Rafizadeh","sequence":"additional","affiliation":[{"name":"Lower Mainland Pharmacy Services Vancouver British Columbia Canada"},{"name":"Department of Psychiatry University of British Columbia Vancouver British Columbia Canada"},{"name":"BC Psychosis Program, UBC Hospital Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,25]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2024.111104"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/phar.2887"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2023.04.003"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2023.06.003"},{"key":"e_1_2_11_6_1","first-page":"1","article-title":"Multidisciplinary Consensus on Prevention, Screening and Monitoring of Clozapine\u2010Associated Myocarditis and Clozapine Rechallenge After Myocarditis","volume":"2","author":"Wagner E.","year":"2025","journal-title":"British Journal of Psychiatry"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-022-01173-8"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes11121509"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(25)24566-9"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/02698811241241394"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0000000000001987"},{"key":"e_1_2_11_12_1","volume-title":"StatPearls","author":"Singh B.","year":"2025"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200318921"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofv098"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1055\/a-1625-6388"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2023.1258868"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2017.08.010"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2018.01.007"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.4149\/BLL_2021_078"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2024.12.010"},{"key":"e_1_2_11_21_1","first-page":"293","article-title":"Exploring Low Clozapine C\/D Ratios, Inverted Clozapine\u2010Norclozapine Ratios and Undetectable Concentrations as Measures of Non\u2010Adherence in Clozapine Patients: A Literature Review and a Case Series of 17 Patients From 3 Studies","volume":"268","author":"Ruan C. J.","year":"2024","journal-title":"Schizophrenia Research"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2215-0366(24)00097-X"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41537-025-00648-4"}],"container-title":["Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/accpjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/phar.70094","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accpjournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/phar.70094","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accpjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/phar.70094","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T06:49:14Z","timestamp":1770446954000},"score":1,"resource":{"primary":{"URL":"https:\/\/accpjournals.onlinelibrary.wiley.com\/doi\/10.1002\/phar.70094"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,25]]},"references-count":22,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1002\/phar.70094"],"URL":"https:\/\/doi.org\/10.1002\/phar.70094","archive":["Portico"],"relation":{},"ISSN":["0277-0008","1875-9114"],"issn-type":[{"value":"0277-0008","type":"print"},{"value":"1875-9114","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,25]]},"assertion":[{"value":"2025-09-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70094"}}