{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T19:06:22Z","timestamp":1782846382785,"version":"3.54.5"},"reference-count":55,"publisher":"JMIR Publications Inc.","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JMIR Public Health Surveill"],"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n \n Drug-induced parkinsonism (DIP) predominantly occurs due to antipsychotic drugs (APDs) blocking dopamine D2 receptors (D\n 2<\/jats:sub>\n Rs). However, in vitro assays often fail to fully reflect real-world variability in clinical outcomes.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n This study aimed to evaluate whether in vitro pharmacological metrics correspond to real-world risk of DIP associated with APD use.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n For 8 commonly used APDs, key in vitro parameters\u2014including inhibition constants (K\n i<\/jats:sub>\n ) of D\n 2<\/jats:sub>\n Rs and the serotonin 2A receptor, reversal rate (K\n r<\/jats:sub>\n ) of D\n 2<\/jats:sub>\n Rs, and blood-brain barrier (BBB) penetration rate\n \n \u2014were compiled to construct 6 composite DIP risk metrics. The real-world DIP risk was assessed using the Seoul National University Hospital common data model (2002\u20102021). APD users were matched 1:1 to selective serotonin reuptake inhibitor users using propensity score matching, and Cox proportional hazard regression was performed to estimate the hazard ratios (HRs) for DIP risk. Correlation between each in vitro metric and real-world DIP risk was evaluated using logarithmic regression models.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among 44,664 patients from 8 matched cohorts, haloperidol showed the highest DIP risk (HR=4.56, 95% CI 2.29\u20109.07), whereas aripiprazole exhibited the lowest risk (HR=2.11, 95% CI 1.56\u20102.86). Metric 4 (pK\n r<\/jats:sub>\n \u00d7 BBB penetration rate\n \n ) exhibited the strongest correlation with real-world DIP risk (\n R<\/jats:italic>\n 2<\/jats:sup>\n =0.95). The correlation decreased when aripiprazole, a partial D\n 2<\/jats:sub>\n R agonist, was included in the analysis (\n R<\/jats:italic>\n 2<\/jats:sup>\n =0.58).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Integrating receptor-binding kinetics with BBB penetration may provide an in vitro framework that reflects real-world variation in DIP risk among D\n 2<\/jats:sub>\n R-antagonizing APDs. These findings support the relevance of combining kinetic and central nervous system exposure parameters for early safety evaluation.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.2196\/81876","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T15:30:07Z","timestamp":1767108607000},"page":"e81876-e81876","source":"Crossref","is-referenced-by-count":0,"title":["Comparison of In Vitro Metrics With Real-World Risk of Drug-Induced Parkinsonism Due to Antipsychotic Drugs: Retrospective Cohort Study"],"prefix":"10.2196","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7533-6184","authenticated-orcid":false,"given":"Woo-Taek","family":"Lim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5676-3846","authenticated-orcid":false,"given":"Hyun Woo","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3327-3534","authenticated-orcid":false,"given":"Seungyeon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4586-5062","authenticated-orcid":false,"given":"Kwangsoo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4458-797X","authenticated-orcid":false,"given":"Yong Min","family":"Ahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6028-8286","authenticated-orcid":false,"given":"Minseok","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8267-9453","authenticated-orcid":false,"given":"Yun Mi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4752-1300","authenticated-orcid":false,"given":"Ha Young","family":"Jang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1010","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"issue":"7403","key":"R1","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/nature11159","article-title":"Large-scale prediction and testing of drug activity on side-effect targets","volume":"486","author":"Lounkine","journal-title":"Nature New Biol"},{"issue":"3","key":"R2","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1038\/nrd3681","article-title":"Diagnosing the decline in pharmaceutical R&D efficiency","volume":"11","author":"Scannell","journal-title":"Nat Rev Drug Discov"},{"issue":"10","key":"R3","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1124\/dmd.119.088708","article-title":"Pharmacokinetic and drug metabolism properties of novel therapeutic modalities","volume":"47","author":"Rock","journal-title":"Drug Metab Dispos"},{"issue":"1","key":"R4","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3988\/jcn.2012.8.1.15","article-title":"Drug-induced parkinsonism","volume":"8","author":"Shin","journal-title":"J Clin Neurol"},{"issue":"212","key":"R5","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/978-3-642-25761-2_2","article-title":"Role of dopamine D(2) receptors for antipsychotic activity","volume":"2012","author":"Ginovart","journal-title":"Handb Exp Pharmacol"},{"issue":"12","key":"R6","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.1038\/mp.2012.47","article-title":"Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents","volume":"17","author":"Miyamoto","journal-title":"Mol Psychiatry"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-050911-161504","article-title":"Update on typical and atypical antipsychotic drugs","volume":"64","author":"Meltzer","journal-title":"Annu Rev Med"},{"issue":"9657","key":"R8","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/S0140-6736(08)61764-X","article-title":"Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis","volume":"373","author":"Leucht","journal-title":"Lancet"},{"issue":"7","key":"R9","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1001\/archpsyc.1992.01820070032005","article-title":"Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. 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