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An Exciting Prospect for an Old SSRI in the COVID-19 Pandemic

An Exciting Prospect for an Old SSRI in the COVID-19 Pandemic

Can an old selective serotonin reuptake inhibitor (SSRI), fluvoxamine, prevent individuals infected with COVID-19 from severe clinical decompensation? This 40-year-old, inexpensive drug is currently indicated for obsessive compulsive disorder/social anxiety, but recently has been looked at in 3 different types of studies for COVID-19: a retrospective observational study looking at hospitalized patients in France published in August 2020; a randomized, double-blind, placebo-controlled trial published in JAMA in November 2020; and a prospective cohort study which has not yet been published.

We think of SSRIs through their principal mechanism of action: blocking the reuptake of serotonin, thereby increasing serotonin levels in those with clinical depression. However, a little-known mechanism for some SSRIs includes binding to the Sigma-1 receptor (S1R) in cells. When S1R is bound by fluvoxamine—the most potent SSRI binder of this receptor—it prevents cytokine release known as a "cytokine storm," which, when activated, can injure multiple organs and cause death. Other SSRIs, including sertraline and fluoxetine, bind less tightly to S1R. Interestingly, no S1R activity is seen with citalopram or paroxetine. This mechanism is hypothesized to be an effective target for preventing severe COVID-19 in already-infected patients.

Fluvoxamine will be looked at as a candidate drug as a part of Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partnership overseen by the NIH. In the ACTIV-6 trials, FDA-approved drugs for indications other than COVID-19 will be looked at for "drug repurposing" and emergency use authorization (EUA) in the outpatient setting for patients with mild to moderate COVID-19. Up to 7 OTC and prescription drugs will be investigated in these phase 3 trials. The NIH's National Center for Advancing Translational Sciences (NCATS) will oversee the trials. These "repurposed" medication trials (not yet recruiting) will fill a need for adults with risk factors for progressing to severe disease (ie, older age, comorbid conditions) who cannot or will not get monoclonal antibody infusions—2 of which, bamlanivimab and casirivimab/imdevimab, are currently approved under EUA for outpatient treatment of adults with mild to moderate COVID-19.

With all this important information, how can you help? There is currently a contactless clinical trial of fluvoxamine in COVID-19 recruiting online. As of this writing, a PA or NP in primary care can assist by enrolling anyone over the age of 30 who is positive for COVID-19, and not yet vaccinated, through this link: The patient must be within 6 days of symptomatic infection and have 1 or more of the comorbid risk factors listed on the site.

It is my firm belief that with a larger and longer study, fluvoxamine could prove to be a great option for the outpatient population. COVID-19 and its variants will likely be with us for some time, and it appears that the S1R mechanism has promise to offer protection against severe disease going forward. As practitioners, we can play a small part in moving this ball forward, and I would encourage you to consider enrolling your patients with COVID-19 in this important study at the Washington University School of Medicine site linked above.


Filed under: Infectious Diseases, Miscellaneous

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