“Our subgroup analysis found a statistically significant reduction of 28 percent in the relative risk of mortality for the patients treated with fluoxetine and 26 percent for the patients treated with fluoxetine or fluvoxamine,” researchers explain in the new study, authored by a team from the University of California, San Francisco (UCSF) and Stanford University.
Antidepressant use is linked to better outcomes for COVID-19 patients, although the precise mechanisms behind the phenomenon are not yet fully understood.
“It has been previously observed that SSRIs may have anti-inflammatory properties mediated through a reduction of several proinflammatory cytokines, including interleukin 6 and tumor necrosis factor,” the team, led by first author and computational health scientist Tomiko Oskotsky from UCSF, writes in the new study.
SSRIs include fluoxetine and fluvoxamine, belong to the group of pharmacological compounds called functional inhibitors of acid sphingomyelinase (FIASMA). They inhibit an enzyme called acid sphingomyelinase (ASM), which breaks down sphingomyelin, a lipid in cell membranes, into other molecules, including one called ceramide.
“Preclinical data indicate that SARS-CoV-2 activates the ASM-ceramide system, resulting in the formation of ceramide-enriched membrane domains that facilitate viral entry and infection by clustering ACE2, the cellular receptor of SARS-CoV-2, and the release of proinflammatory cytokines,” psychiatrist Nicolas Hoertel from the University of Paris, who wasn’t involved with the study, explains in a perspective article on the new research.
SSRIs are making it harder for SARS-CoV-2 to infect cells, by disrupting the molecules the virus uses as anchor points.
“Importantly, the reconstitution of ceramides in cells treated with these antidepressants restores the infection,” Hoertel writes.
“Taken together, these results show the potentially crucial importance of the ASM-ceramide system as a treatment target in COVID-19.”
More research is needed, and the researchers emphasize that their own analysis doesn’t bring us closer to understanding any causal effects.
From a cohort of 490,373 deidentified COVID-19 patients in the Cerner Real-World Data database, the researchers drilled down to 83,584 patients who met their study criteria.
3,401 patients took SSRIs during the study timeframe (January to September 2020), and were compared to a control group of matched patients that didn’t take SSRIs in the same period.
Patients taking any SSRI had a lower mortality rate (14.6 percent) than those who didn’t (16.3 percent), with the lowest mortality rates seen in patients taking fluoxetine only.
SSRIs that weren’t fluoxetine or fluvoxamine also appeared to show a small protective benefit, but the data were not statistically significant, the researchers say.
While there’s still much we don’t know for sure about how fluoxetine or fluvoxamine might bring about these improved outcomes, in a time of pandemic, any link this promising needs to be chased up further, as it could ultimately have life-saving consequences.
“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,” Hoertel writes.
“In this context, short-term use of fluoxetine or fluvoxamine, if proven effective, should be considered as a potential means of reaching this goal.”