Abstract: Original Investigation | Infectious Diseases Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants Tomiko Oskotsky, MD; Ivana Marić, PhD; Alice Tang, BS; Boris Oskotsky, PhD; Ronald J. Wong, PhD; Nima Aghaeepour, PhD; Marina Sirota, PhD; David K. Stevenson, MD Abstract IMPORTANCE Antidepressant use may be associated with reduced levels of several proinflammatory cytokines suggested to be involved with the development of severe COVID-19. An association between the use of selective serotonin reuptake inhibitors (SSRIs)—specifically fluoxetine hydrochloride and fluvoxamine maleate—with decreased mortality among patients with COVID-19 has been reported in recent studies; however, these studies had limited power due to their small size. Key Points Question Are selective serotonin reuptake inhibitors (SSRIs), specifically fluoxetine hydrochloride, associated with a lower mortality risk among patients with COVID-19? Findings In this multicenter cohort OBJECTIVE To investigate the association of SSRIs with outcomes in patients with COVID-19 by study analyzing electronic health analyzing electronic health records (EHRs). records of 83 584 patients diagnosed with COVID-19, including 3401 patients DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study used propensity score who were prescribed SSRIs, a reduced matching by demographic characteristics, comorbidities, and medication indication to compare SSRI- relative risk of mortality was found to be treated patients with matched control patients not treated with SSRIs within a large EHR database associated with the use of SSRIs— representing a diverse population of 83 584 patients diagnosed with COVID-19 from January to specifically fluoxetine—compared with September 2020 and with a duration of follow-up of as long as 8 months in 87 health care centers patients who were not prescribed SSRIs. across the US. Meaning These findings suggest that SSRI use may reduce mortality among EXPOSURES Selective serotonin reuptake inhibitors and specifically (1) fluoxetine, (2) fluoxetine or fluvoxamine, and (3) other SSRIs (ie, not fluoxetine or fluvoxamine). patients with COVID-19, although they may be subject to unaccounted confounding variables; further MAIN OUTCOMES AND MEASURES Death. investigation via large, randomized clinical trials is needed. RESULTS A total of 3401 adult patients with COVID-19 prescribed SSRIs (2033 women [59.8%]; mean [SD] age, 63.8 [18.1] years) were identified, with 470 receiving fluoxetine only (280 women [59.6%]; mean [SD] age, 58.5 [18.1] years), 481 receiving fluoxetine or fluvoxamine (285 women [59.3%]; mean [SD] age, 58.7 [18.0] years), and 2898 receiving other SSRIs (1733 women [59.8%]; mean [SD] age, 64.7 [18.0] years) within a defined time frame. When compared with matched untreated control patients, relative risk (RR) of mortality was reduced among patients prescribed any + Invited Commentary + Supplemental content Author affiliations and article information are listed at the end of this article. SSRI (497 of 3401 [14.6%] vs 1130 of 6802 [16.6%]; RR, 0.92 [95% CI, 0.85-0.99]; adjusted P = .03); fluoxetine (46 of 470 [9.8%] vs 937 of 7050 [13.3%]; RR, 0.72 [95% CI, 0.54-0.97]; adjusted P = .03); and fluoxetine or fluvoxamine (48 of 481 [10.0%] vs 956 of 7215 [13.3%]; RR, 0.74 [95% CI, 0.55-0.99]; adjusted P = .04). The association between receiving any SSRI that is not fluoxetine..