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Are selective serotonin reuptake inhibitors (SSRIs), specifically fluoxetine hydrochloride, associated with a lower mortality risk among patients with COVID-19?
In this multicenter cohort study analyzing electronic health records of 83 584 patients diagnosed with COVID-19, including 3401 patients who were prescribed SSRIs, a reduced relative risk of mortality was found to be associated with the use of SSRIs—specifically fluoxetine—compared with patients who were not prescribed SSRIs.
These findings suggest that SSRI use may reduce mortality among patients with COVID-19, although they may be subject to unaccounted confounding variables; further investigation via large, randomized clinical trials is needed.
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.
To investigate the association of SSRIs with outcomes in patients with COVID-19 by analyzing electronic health records (EHRs).
Design, Setting, and Participants
This retrospective cohort study used propensity score matching by demographic characteristics, comorbidities, and medication indication to compare SSRI-treated patients with matched control patients not treated with SSRIs within a large EHR database representing a diverse population of 83 584 patients diagnosed with COVID-19 from January to September 2020 and with a duration of follow-up of as long as 8 months in 87 health care centers across the US.
Selective serotonin reuptake inhibitors and specifically (1) fluoxetine, (2) fluoxetine or fluvoxamine, and (3) other SSRIs (ie, not fluoxetine or fluvoxamine).
Main Outcomes and Measures
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 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 or fluvoxamine and risk of death was not statistically significant (447 of 2898 [15.4%] vs 1474 of 8694 [17.0%]; RR, 0.92 [95% CI, 0.84-1.00]; adjusted P = .06).
Conclusions and Relevance
These results support evidence that SSRIs may be associated with reduced severity of COVID-19 reflected in the reduced RR of mortality. Further research and randomized clinical trials are needed to elucidate the effect of SSRIs generally, or more specifically of fluoxetine and fluvoxamine, on the severity of COVID-19 outcomes.
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: September 8, 2021.
Published: November 15, 2021. doi:10.1001/jamanetworkopen.2021.33090
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Oskotsky T et al. JAMA Network Open.
Corresponding Authors: Marina Sirota, PhD, Bakar Computational Health Sciences Institute, University of California, San Francisco, 490 Illinois St, 2nd Floor, PO Box 2933, San Francisco, CA 94143 (firstname.lastname@example.org); David K. Stevenson, MD, Center for Academic Medicine, Stanford University School of Medicine, 453 Quarry Rd, Stanford, CA 94304 (email@example.com).
Author Contributions: Dr T. Oskotsky had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs T. Oskotsky and Marić are co–first authors. Drs Sirota and Stevenson are co–senior authors.
Concept and design: T. Oskotsky, Marić, Wong, Sirota, Stevenson.
Acquisition, analysis, or interpretation of data: T. Oskotsky, Marić, Tang, B. Oskotsky, Aghaeepour, Sirota, Stevenson.
Drafting of the manuscript: T. Oskotsky, Marić, Sirota.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: T. Oskotsky, Tang, Aghaeepour, Sirota.
Obtained funding: Tang, Sirota, Stevenson.
Administrative, technical, or material support: T. Oskotsky, Marić, B. Oskotsky, Wong, Stevenson.
Supervision: T. Oskotsky, Sirota, Stevenson.
Conflict of Interest Disclosures: Dr Sirota reported serving as a scientific advisor at Aria Pharmaceuticals, Inc. No other disclosures were reported.
Funding/Support: This study was supported by the Christopher Hess Research Fund and in part by the University of California, San Francisco, Program for Breakthrough Biomedical Research grant, grant T32GM007618 from the Medical Scientist Training Program, and grant R35GM138353 from the National Institutes of Health.
Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank members of the Sirota Lab, University of California, San Francisco, for useful discussion. We also thank Cheryl Akridge, BA, Gary Gasperino, MS, Keenan Crane, BS, and Stacey Purinton, MSN, along with everyone on the Cerner Clinical Research Team, for providing access to the Cerner Real World COVID-19 deidentified database and technical assistance; these individuals were not compenstated for their contributions.
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