Abstract: Open Forum Infectious Diseases MAJOR ARTICLE Screening Large Population Health Databases for Potential Coronavirus Disease 2019 Therapeutics: A PharmacopeiaWide Association Study of Commonly Prescribed Medications Derek R. MacFadden,1,2 Kevin Brown,2,3,4 Sarah A. Buchan,2,3,4, Hannah Chung,2, Rob Kozak,5,6 Jeffrey C. Kwong,2,3,4,7 Doug Manuel,1,2 Samira Mubareka,5,6 and Nick Daneman2,4,5,6 Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, 2ICES, Toronto, Ontario, Canada, 3Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada, 4Public Health Ontario, Toronto, Ontario, Canada, 5Sunnybrook Research Institute, Toronto, Ontario, Canada 6Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada, and 7Department of Family and Community Medicine, University of Toronto, Ontario, Canada Background. For both the current and future pandemics, there is a need for high-throughput drug screening methods to identify existing drugs with potential preventive and/or therapeutic activity. Epidemiologic studies could complement laboratory-focused efforts to identify possible therapeutic agents. Methods. We performed a pharmacopeia-wide association study (PWAS) to identify commonly prescribed medications and medication classes that are associated with the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older individuals (≥65 years) in long-term care homes (LTCHs) and the community, between 15 January 2020 and 31 December 2020, across the province of Ontario, Canada. Results. A total of 26 121 cases and 2 369 020 controls from LTCHs and the community were included in this analysis. Many of the drugs and drug classes evaluated did not yield significant associations with SARS-CoV-2 detection. However, some drugs and drug classes appeared to be significantly associated with reduced SARS-CoV-2 detection, including cardioprotective drug classes such as statins (weighted odds ratio [OR], 0.91; standard P < .01, adjusted P < .01) and β-blockers (weighted OR, 0.87; standard P < .01, adjusted P = .01), along with individual agents ranging from levetiracetam (weighted OR, 0.70; standard P < .01, adjusted P < .01) to fluoxetine (weighted OR, 0.86; standard P = .013, adjusted P = .198) to digoxin (weighted OR, 0.89; standard P < .01, adjusted P = .02). Conclusions. Using this epidemiologic approach, which can be applied to current and future pandemics, we have identified a variety of target drugs and drug classes that could offer therapeutic benefit in coronavirus disease 2019 (COVID-19) and may warrant further validation. Some of these agents (eg, fluoxetine) have already been identified for their therapeutic potential. Keywords. case-control; COVID-19; drug screening; epidemiology; SARS-CoV-2. Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), the agent of coronavirus disease 2019 (COVID-19), has caused substantial morbidity and mortality since its recognition in China in December 2019 [1]. Hundreds of millions of COVID-19 cases and millions of attributable deaths have been documented worldwide [2]. Mortality has been particularly high in elderly patients and those with comorbid Received 18 November 2021; editorial decision 17 March 2022; accepted 24 March 2022; published online 29 March 2022. Correspondence: Derek MacFadden, MD, ScD,The Ottawa Hospital, Civic Campus–CPC 214, 1053 Carling Ave, Ottawa ON, Canada K1Y 4E9..