SSRIs

Clarissa Chan, PharmD

A new study conducted by Oskotsky and colleagues in JAMA Network Open’s November 2021 issue found an association suggesting that patients with COVID-19 who take selective serotonin reuptake inhibitor (SSRI) antidepressants—specifically fluoxetine hydrochloride and fluvoxamine maleate—are less likely to experience severe forms of COVID-19 requiring hospitalizations resulting in death.

SSRIs have long been used to treat psychological disorders like depression and anxiety.

Since COVID-19 currently has no cure, researchers are investigating trends and repurposing drugs to prevent, treat, and manage symptomes of COVID-19.

Epidemiologists had previously noticed associations between patients with major depression and a reduction in mortality from COVID-19, suggesting protective effects from antidepressant use in this population.

Retrospective data analysis

Previous studies with small samples sizes have found an association between SSRI use and reduction in COVID-19–related mortality.

Oskotsky and colleagues set out to perform a large retrospective cohort study leveraging a combined clinical dataset from the Cerner Real World Data COVID-19 deidentified electronic health record database of 490,373 patients with COVID-19 across 87 health care centers.

After standardizing the dataset based on time of SSRI exposure, comorbidities, and demographic characteristics to reduce confounding variables, 83,584 patients who were 18 years or older were included in the analysis, with 3,401 of those patients receiving an SSRI medication order at least once within 10 days before and 7 days after their first recorded COVID-19 diagnosis.

Data from patients taking an SSRI from January to September 2020 were compared to patients with COVID-19 who did not have SSRI orders.

Associations, not conclusions

Patients taking fluoxetine were 28% less likely to experience COVID-19–related mortality and others taking fluoxetine or fluvoxamine were 26% less likely to experience COVID-19–related mortality compared to matched control groups not taking SSRIs.

The investigators also found patients with COVID-19 taking SSRIs other than fluoxetine and fluvoxamine were 8% less likely to experience COVID-19–related mortality than matched controls.

“We observed a statistically significant reduction in mortality of COVID-19 patients who were already taking SSRIs,” said Marina Sirota, PhD, associate professor and associate director of Advocacy and Outreach of Bakar Computational Health Sciences Institute at University of California in San Francisco (UCSF) and one of the study’s authors. “This is a demonstration of a data-driven approach for identifying new uses for existing drugs.”

Tomiko Oskotsky, MD, who was also involved in the study, said for the statistically significant reduction in mortality that they observed for patients with COVID-19 who were already taking SSRIs, the reduction in mortality appeared to be greater for those who were already taking fluoxetine.

This analysis of electronic health records data can only show association and not cause,” said Oskotsky, a research scientist of Sirota Lab at UCSF. “As for the clinical implications, additional studies—including large, randomized clinical trials—are needed to further investigate these drugs as a potential treatment for COVID-19.”

Possible implications

Results from the JAMA Network Open study support previous findings and add to the body of research that points to an association between SSRI use—specifically fluoxetine hydrochloride and fluvoxamine maleate—and better outcomes in patients with COVID-19. While the study simply shows an association between SSRIs and COVID-19 outcomes and doesn’t investigate the mechanism of action as to why these drugs might work, Sirota said there are multiple proposed mechanisms SSRIs play in reducing the severity of COVID-19.

One mechanism has to do with the anti-inflammatory properties of SSRIs. Severe COVID-19 outcomes have been associated with several proinflammatory cytokines, which can trigger a cytokine storm. Some SSRIs such as fluoxetine and fluvoxamine may modulate the sigma-1 receptor-IRE1 pathway, thereby reducing damaging aspects of the inflammatory response, as hypothesized by Oskotsky and colleagues.

“Because most of the world’s population is currently unvaccinated and the COVID-19 pandemic is still active, effective treatments of COVID-19–especially those that are easy to use, show good tolerability, can be administered orally, and have widespread availability at low cost to allow their use in resource-poor countries—are urgently needed to reduce COVID-19–related mortality and morbidity,” said Nicolas Hoertel, MD, PhD, MPH from Université de Paris and Corentin-Celton Hospital in France, who wrote an accompanying editorial to the study.

Hoertel said that if more robust data support the use of fluoxetine or fluvoxamine—an inexpensive, well-tolerated, and easily administered medication—in the treatment of COVID-19, hospitalization and global death rates from COVID-19 could be minimized in the worldwide fight against COVID-19. ■