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Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants

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To identify the key insights or developments described in this article
1 Credit CME
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 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.

Meaning  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.


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.

Objective  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.

Exposures  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  Death.

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 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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Article Information

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 (marina.sirota@ucsf.edu); David K. Stevenson, MD, Center for Academic Medicine, Stanford University School of Medicine, 453 Quarry Rd, Stanford, CA 94304 (dstevenson@stanford.edu).

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.

Hoertel  N , Sánchez-Rico  M , Vernet  R ,  et al.  Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study.   Mol Psychiatry. Published online February 4, 2021. doi:10.1038/s41380-021-01021-4Google Scholar
Lenze  EJ , Mattar  C , Zorumski  CF ,  et al.  Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial.   JAMA. 2020;324(22):2292-2300. doi:10.1001/jama.2020.22760 PubMedGoogle ScholarCrossref
Seftel  D , Boulware  DR .  Prospective cohort of fluvoxamine for early treatment of coronavirus disease 19.   Open Forum Infect Dis. 2021;8(2):b050. doi:10.1093/ofid/ofab050 PubMedGoogle ScholarCrossref
Dechaumes  A , Nekoua  MP , Belouzard  S ,  et al.  Fluoxetine can inhibit SARS-CoV-2 in vitro.   Microorganisms. 2021;9(2):339. doi:10.3390/microorganisms9020339 PubMedGoogle ScholarCrossref
Zimniak  M , Kirschner  L , Hilpert  H ,  et al.  The serotonin reuptake inhibitor fluoxetine inhibits SARS-CoV-2 in human lung tissue.   Sci Rep. 2021;11(1):5890. doi:10.1038/s41598-021-85049-0 PubMedGoogle ScholarCrossref
Creeden  JF , Imami  AS , Eby  HM ,  et al.  Fluoxetine as an anti-inflammatory therapy in SARS-CoV-2 infection.   Biomed Pharmacother. 2021;138:111437. doi:10.1016/j.biopha.2021.111437 PubMedGoogle Scholar
Costela-Ruiz  VJ , Illescas-Montes  R , Puerta-Puerta  JM , Ruiz  C , Melguizo-Rodríguez  L .  SARS-CoV-2 infection: the role of cytokines in COVID-19 disease.   Cytokine Growth Factor Rev. 2020;54:62-75. doi:10.1016/j.cytogfr.2020.06.001 PubMedGoogle ScholarCrossref
Pirraglia  PA , Stafford  RS , Singer  DE .  Trends in prescribing of selective serotonin reuptake inhibitors and other newer antidepressant agents in adult primary care.   Prim Care Companion J Clin Psychiatry. 2003;5(4):153-157. doi:10.4088/PCC.v05n0402 PubMedGoogle ScholarCrossref
Luo  Y , Kataoka  Y , Ostinelli  EG , Cipriani  A , Furukawa  TA .  National prescription patterns of antidepressants in the treatment of adults with major depression in the US between 1996 and 2015: a population representative survey based analysis.   Front Psychiatry. 2020;11:35. doi:10.3389/fpsyt.2020.00035 PubMedGoogle ScholarCrossref
Ravindran  LN , Stein  MB .  The pharmacologic treatment of anxiety disorders: a review of progress.   J Clin Psychiatry. 2010;71(7):839-854. doi:10.4088/JCP.10r06218bluPubMedGoogle ScholarCrossref
Hannestad  J , DellaGioia  N , Bloch  M .  The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis.   Neuropsychopharmacology. 2011;36(12):2452-2459. doi:10.1038/npp.2011.132 PubMedGoogle ScholarCrossref
Sacre  S , Medghalchi  M , Gregory  B , Brennan  F , Williams  R .  Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptors.   Arthritis Rheum. 2010;62(3):683-693. doi:10.1002/art.27304 PubMedGoogle ScholarCrossref
Carpinteiro  A , Edwards  MJ , Hoffmann  M ,  et al.  Pharmacological inhibition of acid sphingomyelinase prevents uptake of SARS-CoV-2 by epithelial cells.   Cell Rep Med. 2020;1(8):100142. doi:10.1016/j.xcrm.2020.100142 PubMedGoogle Scholar
Carpinteiro  A , Gripp  B , Hoffmann  M ,  et al.  Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells.   J Biol Chem. 2021;296:100701. doi:10.1016/j.jbc.2021.100701 PubMedGoogle Scholar
Marín-Corral  J , Rodríguez-Morató  J , Gomez-Gomez  A ,  et al.  Metabolic signatures associated with severity in hospitalized COVID-19 patients.   Int J Mol Sci. 2021;22(9):4794. doi:10.3390/ijms22094794 PubMedGoogle ScholarCrossref
Hoertel  N , Sánchez-Rico  M , Gulbins  E ,  et al; AP-HP / Université de Paris / INSERM COVID-19 research collaboration, AP-HP COVID CDR Initiative, “Entrepôt de Données de Santé” AP-HP Consortium.  Association between FIASMAs and reduced risk of intubation or death in individuals hospitalized for severe COVID-19: an observational multicenter study.   Clin Pharmacol Ther. Published online May 29, 2021. doi:10.1002/cpt.2317PubMedGoogle Scholar
Hoertel  N , Sánchez-Rico  M , Gulbins  E ,  et al.  Association between psychotropic medications functionally inhibiting acid sphingomyelinase and reduced risk of intubation or death among individuals with mental disorder and severe COVID-19: an observational study.   medRxiv. Preprint posted online February 20, 2021. doi:10.1101/2021.02.18.21251997Google Scholar
Wang QQ, Xu R, Volkow ND. Increased risk of COVID-19 infection and mortality in people with mental disorders: analysis from electronic health records in the United States. World Psychiatry. Published online October 7, 2020. Accessed September 3, 2021. https://onlinelibrary.wiley.com/doi/full/10.1002/wps.20806
Taquet  M , Luciano  S , Geddes  JR , Harrison  PJ .  Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA.   Lancet Psychiatry. 2021;8(2):130-140. doi:10.1016/S2215-0366(20)30462-4 PubMedGoogle ScholarCrossref
Diez-Quevedo  C , Iglesias-González  M , Giralt-López  M ,  et al.  Mental disorders, psychopharmacological treatments, and mortality in 2150 COVID-19 Spanish inpatients.   Acta Psychiatr Scand. 2021;143(6):526-534. doi:10.1111/acps.13304 PubMedGoogle ScholarCrossref
Günster  C , Busse  R , Spoden  M ,  et al.  6-Month follow up of 8679 hospitalized COVID-19 patients in Germany: a nationwide cohort study.   medRxiv. Preprint posted online April 24, 2012. doi:10.1101/2021.04.24.21256029Google Scholar
von Elm  E , Altman  DG , Egger  M , Pocock  SJ , Gøtzsche  PC , Vandenbroucke  JP ; STROBE Initiative.  The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.   Lancet. 2007;370(9596):1453-1457. doi:10.1016/S0140-6736(07)61602-X PubMedGoogle ScholarCrossref
ICD-10 Version:2019. Updated April 16, 2020. Accessed August 9, 2021. https://icd.who.int/browse10/2019/en#/U07.1
Austin  PC , Small  DS .  The use of bootstrapping when using propensity-score matching without replacement: a simulation study.   Stat Med. 2014;33(24):4306-4319. doi:10.1002/sim.6276 PubMedGoogle ScholarCrossref
Hayasaka  Y , Purgato  M , Magni  LR ,  et al.  Dose equivalents of antidepressants: evidence-based recommendations from randomized controlled trials.   J Affect Disord. 2015;180:179-184. doi:10.1016/j.jad.2015.03.021 PubMedGoogle ScholarCrossref
Furukawa  TA , Cipriani  A , Cowen  PJ , Leucht  S , Egger  M , Salanti  G .  Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis.   Lancet Psychiatry. 2019;6(7):601-609. doi:10.1016/S2215-0366(19)30217-2 PubMedGoogle ScholarCrossref
CDC/National Center for Health Statistics. Antidepressant use among adults: United States, 2015-2018. September 8, 2020. Accessed September 3, 2021. https://www.cdc.gov/nchs/products/databriefs/db377.htm
Hamed  MGM , Hagag  RS .  The possible immunoregulatory and anti-inflammatory effects of selective serotonin reuptake inhibitors in coronavirus disease patients.   Med Hypotheses. 2020;144:110140. doi:10.1016/j.mehy.2020.110140 PubMedGoogle Scholar
Pashaei  Y .  Drug repurposing of selective serotonin reuptake inhibitors: could these drugs help fight COVID-19 and save lives?   J Clin Neurosci. 2021;88(0):163-172. doi:10.1016/j.jocn.2021.03.010 PubMedGoogle Scholar
Ahern  GP .  5-HT and the immune system.   Curr Opin Pharmacol. 2011;11(1):29-33. doi:10.1016/j.coph.2011.02.004 PubMedGoogle ScholarCrossref
Köhler  CA , Freitas  TH , Stubbs  B ,  et al.  Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis.   Mol Neurobiol. 2018;55(5):4195-4206. doi:10.1007/s12035-017-0632-1PubMedGoogle Scholar
Słuzewska  A , Rybakowski  JK , Laciak  M , Mackiewicz  A , Sobieska  M , Wiktorowicz  K .  Interleukin-6 serum levels in depressed patients before and after treatment with fluoxetine.   Ann N Y Acad Sci. 1995;762(1):474-476. doi:10.1111/j.1749-6632.1995.tb32372.x PubMedGoogle ScholarCrossref
Ishima  T , Fujita  Y , Hashimoto  K .  Interaction of new antidepressants with sigma-1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells.   Eur J Pharmacol. 2014;727:167-173. doi:10.1016/j.ejphar.2014.01.064 PubMedGoogle ScholarCrossref
Kristiansen  JE , Hansen  JB .  Inhibition of HIV replication by neuroleptic agents and their potential use in HIV infected patients with AIDS related dementia.   Int J Antimicrob Agents. 2000;14(3):209-213. doi:10.1016/S0924-8579(99)00157-0 PubMedGoogle ScholarCrossref
Zuo  J , Quinn  KK , Kye  S , Cooper  P , Damoiseaux  R , Krogstad  P .  Fluoxetine is a potent inhibitor of coxsackievirus replication.   Antimicrob Agents Chemother. 2012;56(9):4838-4844. doi:10.1128/AAC.00983-12 PubMedGoogle ScholarCrossref
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