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Psychiatry Research Review

Sanjay Gupta, MD
Released: December 22, 2021
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Selective Serotonin Reuptake Inhibitors and COVID-19 Mortality Risk

Oskotsky T, et al. JAMA Netw Open. 2021;4:e2133090.

As we saw in the previous article (Reis and colleagues), the SSRI fluvoxamine reduces the risk of hospitalization from COVID-19. Other studies have found a similar benefit with fluoxetine and other SSRIs but were limited in statistical power. In this retrospective study, electronic health records were used to examine the association between SSRIs and COVID-19 outcomes.

This study matched 3401 adult patients receiving SSRIs to control patients not receiving SSRIs using demographic characteristics, comorbidities, and medication indication from a database of 83,584 patients diagnosed with COVID-19. The duration of follow-up was up to 8 months, and patients were seen in 87 healthcare centers across the United States. Patients received fluoxetine, fluoxetine or fluvoxamine, or other SSRIs. The main outcome was patient death.

Patients were a mean 63.8 years of age, and 59.8% were female. Most patients (n = 2898) received SSRIs other than fluoxetine or fluvoxamine, 470 patients received fluoxetine only, and 481 patients received fluoxetine or fluvoxamine. The relative risk of mortality was significantly reduced in patients who received fluoxetine (RR: 0.72; P = .03) and in patients who received fluoxetine or fluvoxamine (RR: 0.74; P = .04). However, there was not a significant reduction in the mortality risk among patients receiving other SSRIs (RR: 0.92; P = .06).

These results support previous trials that found an association between SSRIs and a reduction in severity and mortality from COVID-19. 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.

Clinical Commentary
This retrospective study revealed that fluoxetine and fluvoxamine reduce mortality from COVID-19, with a 28% reduction with fluoxetine and 26% reduction with fluoxetine or fluvoxamine. The fluvoxamine group was too small to be independently assessed, but—as I noted for the previous article (Reis and colleagues)—2 randomized, controlled trials have found that fluvoxamine reduces the risk for severe complications from COVID-19. The current study had a large sample size but had the limitations of a retrospective study. The limitations of retrospective studies are that they provide less robust evidence compared with prospective studies, less control over confounding variables, there is convenience sampling for the control groups, and they are prone to recall bias and misclassification.

  • Mortality risk among patients with COVID-19 was significantly reduced with fluoxetine or fluvoxamine but not with other SSRIs.
  • Fluoxetine and fluvoxamine may improve patient outcomes by reducing the production of proinflammatory cytokines that contribute to the cytokine storm that is linked to the severe respiratory distress caused by COVID-19. Fluoxetine and fluvoxamine also may directly inhibit signaling pathways and enzymes that contribute to the inflammatory response or viral entry.

This is an interesting trial with a definite signal—especially for fluvoxamine, whose effects have been replicated in other studies. We should stay tuned and follow this story. Although these medications are already approved by the FDA for other indications and available as generics, I believe these findings deserve comment from the FDA and the CDC. Much of the world remains unvaccinated, so inexpensive, well-tolerated, and effective treatments are useful.

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