If you remember those colorful pictures of the cell from grade school biology, you might recall that the main job of the maze-like structure called the endoplasmic reticulum (ER) is to manufacture proteins—the cell’s workhorse molecules. Some of those molecules promote inflammation, and one protein in the ER that keeps a lid on their production is the sigma-1 receptor.
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By Eve Sneider
Several years ago, Angela Reiersen, a psychiatrist at Washington University School of Medicine in St. Louis, stumbled upon this receptor in a different context—as an alternate molecular target for the drug fluvoxamine and other antidepressants. Fluvoxamine is a selective serotonin reuptake inhibitor, or SSRI, and it’s typically prescribed for obsessive-compulsive disorder.
Fast forward to March. As the pandemic rolled in, Reiersen came across early research suggesting that some people with Covid-19 got sicker not due to the virus itself but because of an out-of-control inflammatory response that can produce severe respiratory and blood-clotting problems. Immediately, she recalled a paper she’d read last year that seemed to bridge the disparate realms. In that 2019 study, researchers at the University of Virginia had injected fluvoxamine into mice to prevent complications and death from ER-driven inflammation. Reiersen connected the dots. “I thought, ‘Well, I wonder if we could use this for Covid?’” she recalls.
She brought the idea to her department chair, who connected her with a WashU psychiatrist named Eric Lenze who has plenty of experience designing clinical trials. Over a couple of emails and Zoom calls, the two wrote up a protocol for a study to test if fluvoxamine could be repurposed to treat people with mild Covid-19 symptoms. They wanted to see if the drug could slow the immune system inflammation linked to more severe symptoms. Within a few weeks, they secured $20,000 from an internal fund at their university to start a double-blind, placebo-controlled, randomized trial—the type of study that’s considered the gold standard to gauge a treatment’s effectiveness.
Recruitment took longer than expected, but just as research money was running dry, Lenze read a New York Times op-ed about the Covid-19 Early Treatment Fund. Launched in May by Steve Kirsch, a tech entrepreneur who invented an early version of the optical mouse, the group’s mission is to find existing drugs that can keep people with mild symptoms out of the hospital. “Early treatment is the key to getting the pandemic under control until a vaccine is widely available,” says Carolyn Machamer, a Johns Hopkins Medicine cell biologist who studies coronaviruses. She’s among the dozen experts on the fund’s advisory board; they review proposals for outpatient trials of repurposed drugs to decide which will get support from millions of CETF dollars donated by individuals and foundations.
Right after seeing the op-ed, Lenze went to the CETF website and submitted an application. An hour later he got a call from Kirsch, and within a week the fund committed about $67,000 toward the fluvoxamine trial. Lenze called it “a real lifeline for us.”
From April to early August, his team enrolled 152 people with mild Covid-19 symptoms, all recently diagnosed and self-isolating at home in the St. Louis metropolitan area. To protect everyone, the trial was fully remote. The team placed supplies and instructions into brown paper bags and dropped them off on the participants’ porches, “like the Domino’s pizza delivery man does now,” Lenze says. Inside each bag was a fingertip pulse oximeter, an automated blood pressure monitor, a thermometer, and two bottles of purple capsules containing fluvoxamine or a placebo.
Participants took their pills three times a day for 15 days, starting within a week of first symptoms. Twice a day over email or phone, they logged their blood pressure, pulse rate, and oxygen saturation, as well as possible symptoms.
Generally, up to a fifth of people with mild Covid-19 symptoms progress to severe disease. In the WashU 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.”
In the Science paper, Krogan’s team took a stab at correlating their molecular findings with previously reported clinical outcomes. Combing through medical billing data for some 28,000 people hospitalized for Covid-19 in the United States, they focused on people who also happened to be taking antipsychotic drugs. Patients treated with antipsychotics that target the sigma-1 receptor were half as likely as those taking other types of antipsychotics to require mechanical ventilation, the researchers found.
The mouse study by Gaultier and colleagues suggests that drugs like fluvoxamine could stave off Covid-19 symptoms by tamping down inflammation. The researchers found that the sigma-1 receptor blocks a molecular pathway in the ER that controls inflammation. When they studied mice that genetically lack the sigma-1 receptor, they saw that this arm of inflammation “gets unshackled and you have what we call a ‘cytokine storm,’” says Gaultier. However, despite earlier research that suggested a connection between cytokine storms and severe Covid-19 disease, recent studies such as this one published last week in Science Advances call into question whether elevated cytokines are truly a hallmark of Covid-19 disease progression.
The biology of the sigma-1 receptor itself also remains somewhat of a mystery. “It’s a bit more complicated than other things we call ‘receptors,’” says Reiersen. Rather than being embedded in the ER membrane, a sigma-1 receptor can detach itself, acting as a chaperone ferrying other proteins through the ER. Plus, SSRIs can inhibit the activity of platelets, tiny blood cells that help form clots to stop bleeding but can also drive up inflammation through other pathways. SSRIs also accumulate in structures called lysosomes, which act as the cell’s trash disposal system. Last month, researchers showed that coronaviruses can hijack lysosomes to leave cells and spread through the body. There are “a lot of different things that could be going on,” Reiersen says.
And there are still other questions for researchers to untangle. It’s unclear, for instance, whether other psychiatric drugs could have similar benefits for people with Covid-19. Among sigma-1 receptor-activating SSRIs, fluvoxamine binds most strongly. So if these medications’ disease-fighting effects directly stem from shutting down inflammation through sigma-1 receptor’s actions at the ER, “we would expect fluvoxamine to have a stronger effect” than other SSRIs, says Reiersen. But, she adds, “we haven’t proven that’s the mechanism that provided the benefit.”
Still, fluvoxamine is a cheap, safe and widely available drug that “could have enormous positive impact,” says Lenze. “Our goal right now is to confirm or refute these findings as soon as possible.”