Generally, up to a fifth of people with mild Covid-19 symptoms progress to severe disease. In the UWash trial, 6 of 72 patients (8.3 percent) in the placebo group deteriorated—as measured by indicators like shortness of breath, oxygen saturation dropping below 92 percent, or people being hospitalized to treat these conditions. However, as the researchers reported November 12 in the Journal of the American Medical Association, none of the 80 participants who took fluvoxamine worsened or went to the hospital during the study period. If the findings hold up in a larger study planned for later this year, they would suggest that fluvoxamine could “keep a lot of people out of the hospital, so that the hospitals won’t get overwhelmed while we wait for the vaccines to become widely available,” says Reiersen.
Just six patients reported episodes of nausea, a common side effect of the antidepressant—and five of those patients were in the placebo group. Plus, fluvoxamine is “an inexpensive, generic drug,” Lenze says. “A course like what we used in this study should cost about $10.”
The results are “extremely exciting,” says University of Virginia neuro-immunologist Alban Gaultier, whose lab published the 2019 mouse study that inspired the trial. At a recent lab meeting, Gaultier recalls, “I was telling my team that one of my dreams when I was a baby scientist was to make a discovery that could help human health. I’ve never been that close.”
But as the authors note, the study enrolled a relatively small number of patients in one geographical area. “I would emphasize that the finding is preliminary,” says Lenze.
Sandy McEwan, who served as an investigator for many clinical trials over decades as a physician at the University of Alberta, says the fluvoxamine data are “certainly very promising” and hopes the drug gets taken into “a UK-style dexamethasone study where it can be quickly and rigorously tested in a larger population with clear outcomes.” The United Kingdom’s Recovery Trial is a head-to-head trial of a half-dozen drugs, and was the first to show the utility of the older corticosteroid dexamethasone in reducing Covid-19 symptoms.
For now, CETF has pledged $500,000 of the $2 million needed for a larger confirmatory study of the antidepressant, which the WashU researchers are getting approval from their university’s review board to launch within a few weeks, using the same contactless format for 880 additional patients nationwide.
Some experts point out that the politicized debate over repurposing the antimalarial hydroxychloroquine, which gained early attention as a potential treatment but has since proven ineffective, has created a challenging backdrop for evaluating and repurposing existing medications for Covid-19. Yet this debacle “should not cow us into rejecting the results of evidence-based studies such as reported on fluvoxamine in JAMA,” says David Seftel, internist and CEO of the South San Francisco biotech company Enable Biosciences, which is developing ultrasensitive blood antibody tests for Covid-19.
But even if fluvoxamine does work, no one is quite sure why it might. The sigma-1 receptor—the ER molecule targeted by fluvoxamine and other SSRIs—also emerged as a promising target in an independent analysis designed to fight the pandemic with repurposed drugs. In that study, an international team led by UC San Francisco systems biologist Nevan Krogan exhaustively mapped interactions between human proteins and proteins in SARS-CoV-2, the virus that causes Covid-19. From those, the researchers identified 66 human proteins targeted by existing compounds, which then underwent further screens for antiviral properties.
Two sets of drugs emerged from this gauntlet of tests, and one set regulates sigma-1 and sigma-2 receptors. In follow-up experiments published in Science last month, Krogan and colleagues genetically deleted or knocked down the sigma-1 receptor in several types of cultured cells and found that this had a big effect on SARS-CoV-2 infection. Relative to normal cells, viral replication in infected cells was about 10 times lower in the knockdown group, says Krogan, whose team is also studying SSRI antiviral activity in a mouse model: “But clinical data trumps mice.”