How a cheap antidepressant emerged as a promising Covid-19 treatment

Since Covid-19 patients started showing up at clinics and hospitals a year and a half ago, doctors and researchers have been hard at work trying to figure out how to treat them. Most drugs and treatments haven’t panned out, producing either no results or small ones in large-scale clinical trials. Many of the few that work are expensive and difficult to administer.

Hydroxychloroquine, enthusiastically endorsed by President Trump last year, has been shown to have no measurable benefits. New drugs like monoclonal antibodies — proteins meant to imitate the immune system’s response to the disease — have been approved by regulators but must be administered by a doctor through an IV or series of injections.

But scientists haven’t stopped searching, and the results of a new massive clinical trial suggest they’re getting somewhere. In a large, randomized clinical trial conducted with thousands of patients over the past six months, researchers at McMaster University tested eight different Covid-19 treatments against a control group to figure out what works.

One drug stood out: fluvoxamine, an antidepressant that the Food and Drug Administration has already found to be safe and that’s cheap to produce as a generic drug.

These new results follow some promising findings in small-scale trials last year. In those smaller studies, researchers found that fluvoxamine was strikingly good at reducing hospitalization for Covid-19 patients — but small-scale trials can sometimes turn up spurious good results, so those findings were obviously tempered by a lot of caveats.

This study, called the TOGETHER study, is a lot bigger — more than 3,000 patients across the whole study, with 800 in the fluvoxamine group — and supports the promising results from those previous studies. The authors released it this week as a preprint, meaning that it is still under peer review.

Patients given fluvoxamine within a few days after testing positive for Covid-19 were 31 percent less likely to end up hospitalized and similarly less likely to end up on a ventilator. (Death from Covid-19 is rare enough that the study has wide error bars when it comes to how much fluvoxamine reduces death, meaning it’s much harder to draw conclusions.) It’s a much larger effect than any that has been found for an outpatient Covid-19 treatment so far.

“This is a huge finding,” study co-author Ed Mills, a professor of health sciences at McMaster University, told me. “The game changers are things we already had in the cupboards.”

What makes this result potentially such a big deal is that fluvoxamine is inexpensive and has already been FDA approved for obsessive-compulsive disorder (OCD), so any doctor can prescribe it for Covid-19 using their clinical judgment (what’s called “off-label” prescribing). It’s a pill, which means it doesn’t need to be administered in a hospital or by a medical professional.

To be clear, these results have just been released, and clinicians around the world will want to take a close look at them as they decide whether or not to prescribe fluvoxamine. Future research could also moderate this exciting result.

Here’s what we know: This is a large and well-designed study that affirms previous studies that pointed in the same direction. More research is needed, but the results from this trial might already start changing how we treat Covid-19. And the way researchers stumbled upon the drug as a potential treatment is a worthwhile story in itself about the scientific process and the unseen and often unheralded work that’s helping humanity fight the pandemic.

The shifting landscape of Covid-19 treatment

Covid-19 treatments fall into two categories: treatment for severe illness, generally administered in the hospital to reduce the risk of death; and treatment for the onset of illness, which hopefully reduces the odds that a patient will need to be hospitalized at all.

The FDA has granted emergency authorization to a variety of Covid-19 treatments, but the evidence base for many is limited and the effect sizes have tended to be small. Hopes were high for repurposed antiviral drugs, for instance. Many of them are routinely administered and at least one was shown to reduce the length of hospital stays, but some studies have found no effect on mortality.

The same is true of convalescent plasma, transfusions of blood proteins from people who recovered from Covid-19. After more than a year of research, it mostly looks like these treatments aren’t effective, though there’s still lots we don’t know.

The FDA has issued emergency use authorization for monoclonal antibody treatments — proteins that mimic the ones the immune system would produce to fight off the virus — for those at severe risk from Covid-19. Monoclonal antibodies are also infused intravenously or as a series of four injections. They cost $2,100 a dose, which in the US is paid by the federal government so they are free to patients. They seem to work best when given early, pre-hospitalization, and while under those conditions they appear to be highly effective. However, getting people who recently tested positive for Covid-19 and still have mild symptoms to a medical setting for an intravenous infusion or four injections is a logistical challenge — and the cost and the difficulty of delivery mean monoclonal antibodies will never be an option in much of the world.

Corticosteroids, which are powerful anti-inflammatory medicines, have a solid track record. Studies have found that administering the cheap steroid dexamethasone, which can be given as a pill or an infusion, to patients hospitalized with Covid-19 reduces their risk of death. But because it can constrain the immune system, it isn’t recommended early in the course of the disease, when the main concern is the direct damage from the virus.

That leaves a glaring hole: Where are cheap, outpatient treatments that can reduce the risk of hospitalization in the first place and don’t require a medical professional to administer in a medical setting? Fluvoxamine could hopefully fill that gap.

Fluvoxamine’s journey, explained

Fluvoxamine is an antidepressant, and in the US, it’s mostly prescribed for treating OCD. It is what is known as an SSRI, short for selective serotonin reuptake inhibitor — the same class of drugs as popular antidepressants like Zoloft, Prozac, and Lexapro.

Through an unusual journey, it ended up on scientists’ radars as a potential Covid-19 treatment — and subsequent research seems to bear that out.

Years ago, before the novel coronavirus had infected its first patient, Angela Reiersen, a psychiatrist at Washington University in St. Louis, was studying patients with a rare genetic disorder called Wolfram syndrome, which affects cellular stress responses. She noticed that they seemed to tolerate some SSRIs well and others poorly and dove into the differences in SSRI chemistry to figure out why.

It turned out that one of the SSRIs that worked well, fluvoxamine, binds to a receptor in cells that regulates cellular stress response and the production of cytokines, proteins that tell the body something is wrong and cause inflammation. Researchers at the University of Virginia found that fluvoxamine reduced inflammation in animals. Reiersen wondered if that was why it worked well for her patients.

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Then the pandemic hit. One leading theory of what happens when patients suffer through Covid-19 is that cells damaged by the disease release tons of cytokines, which then causes inflammation in the lungs that can make it hard to breathe and cause lasting tissue damage. Early in the pandemic, Reiersen went to her colleagues at the Washington University School of Medicine in St. Louis with a wild idea: Fluvoxamine might help Covid-19 patients.

Eric Lenze, a leading clinical researcher, agreed they should test it with a randomized controlled trial. “I emailed him on March 25, 2020. We got the trial started by April 10,” Reiersen told me.

They spent the spring and summer recruiting and treating Covid-19 patients. By the fall, they had results: Of the 152 participants, half in the placebo group (receiving a sugar pill rather than active medication) and half in the fluvoxamine group, six patients in the placebo group had met their study’s threshold for respiratory difficulties. None in the fluvoxamine group had.

The results were published in the Journal of the American Medical Association. “What I think is the most supported mechanism is an anti-inflammatory effect,” Reiersen told me. “Fluvoxamine can reduce the level of these chemicals called cytokines, which are involved in inflammation, so you’d get less damage in the lungs.”

The results were promising, but 152 patients isn’t that many. Reiersen and Lenze started recruiting for a larger-scale trial, looking for more evidence that fluvoxamine could be a first-line Covid-19 treatment.

In the meantime, evidence was coming in from other angles, too. After a mass outbreak in California, researchers gave affected people the option to take fluvoxamine; 65 people opted to take it and 48 declined. None of those who took it required hospitalization, while six did among those who declined it.

In France, Nicolas Hoertel, a psychiatry researcher at the University of Paris who is not affiliated with the TOGETHER study, had conducted and published an observational study finding that patients on certain antidepressants were less likely to have severe Covid-19. “This effect is not just fluvoxamine, but it’s not all antidepressants,” he told me.

Observational studies don’t assign patients a specific treatment but just record what treatment they receive and how well they do. They don’t involve randomization, so they can be misleading if, say, people on antidepressants are systemically different from people not on antidepressants or if people who agree to try an experimental medication are healthier than people who refuse. So the results from these studies couldn’t be taken as definitive — but it was additional data.

The limited, promising literature around fluvoxamine prompted its inclusion in the large-scale study of treatments for Covid-19 run by Ed Mills at McMaster University and primarily conducted in Brazil. Dubbed the TOGETHER study after other prominent mega-clinical trials like RECOVERY and SOLIDARITY by other organizations, it randomized patients across eight prospective treatments, including metformin (a diabetes medication), hydroxychloroquine (an antimalarial), and ivermectin (an antiparasite).

The team announced their results at an August 6 symposium that was sponsored by the National Institutes of Health. Most of the treatments failed: Their study couldn’t detect an effect. “A lot of drugs against Covid just don’t work very well,” Mills told me. Two other treatments were still in progress, and it was too early to rule out the chance that they’ll work.

But fluvoxamine was a different story. In the trial, it improved patient outcomes substantially — and while it’s not the first drug to do that, ease of delivery and price give it the potential to have an outsized impact on patient care, especially outside the rich world.

Do we know enough to recommend fluvoxamine to Covid-19 patients?

In the research conducted so far, fluvoxamine was prescribed to patients who started experiencing Covid-19 symptoms.

In the TOGETHER study, they typically visited a doctor to enroll in the trial — and start taking medication or a placebo — three days after their symptoms began.

The results of the study are strong enough that researchers are suggesting changing clinical practice to recommend fluvoxamine to people with symptomatic Covid-19.

“We have now growing evidence from different kinds of research — technical, clinical — indicating that [treatment with certain antidepressants] is very likely to be effective in Covid,” Hoertel said. “The likelihood of benefits is very high.”

Critical to changing clinical recommendations is having enough information about the risks and benefits of a treatment. Since fluvoxamine is decades old, its risks are already well understood.

“We know a great deal about the safety and tolerability of fluvoxamine,” Lenze told me. “It can cause in about one-quarter of people some nausea, which is usually mild. It’s not fatal even in overdose, it’s been around for over a quarter of a century so there’s not going to be any unpleasant surprises about safety issues, and it’s really easy to use — it’s just a pill. I don’t see anything that should stop people from taking it.”

There are still things scientists want to know about fluvoxamine, including exactly how it works within the body. And pinning down precisely how much the drug reduces hospitalization and death will definitely take more evidence — though from the 31 percent reduction in hospitalizations in the McMaster study, the researchers who spoke to Vox think it’s likely that the effect is real and sizable.

The TOGETHER trial hasn’t yet been peer-reviewed, though I spoke with numerous unaffiliated researchers who’d seen the results and found them convincing.

“Bottom line, in my opinion at least, Ed [Mills]’s finding proves that the drug works,” Lenze told me.

“We’ve all been burned by promising studies of these repurposed drugs, and it’s quite reasonable to reserve final judgment until we see the complete data, and even other studies. … But this already feels different from hydroxychloroquine and company given the high quality of the research,” Paul Sax argued in NEJM Journal Watch Infectious Diseases. “We might finally be onto something.”

Another possibility to account for when looking at clinical trial data is publication bias — studies that find results get published, while those that find null results often don’t. Lenze is attempting a large-scale replication of his small-scale fluvoxamine study from last year, and so far hasn’t been able to validate the huge reduction in hospitalizations he found the first time around — mainly because recruiting for Covid-19 clinical trials in the US has gotten increasingly difficult as most high-risk people are vaccinated and not at risk of hospitalization, and unvaccinated people are less likely to enroll in clinical trials or adhere to a recommended course of medication. (The TOGETHER study got around this problem by recruiting in Brazil.)

Another worry is that variants will make our understanding of Covid-19 treatments obsolete as soon as we develop one. The TOGETHER study was mostly conducted before the delta variant predominated in Brazil. There’s no strong reason to think fluvoxamine wouldn’t work against delta, but we’ll need additional research to see if the effect size remains the same.

But crucially, we don’t have to answer every unanswered question for doctors to prescribe fluvoxamine to patients. Researchers do have answers to the questions of “Is the drug safe?” and “Does the balance of evidence suggest significant improvement in patient outcomes?” The evidence on those two points looks convincing, so even though there’s lots more to learn, the researchers and clinicians studying fluvoxamine feel ready to say that the drug is a good idea.

One question lots of doctors and patients have about a Covid-19 treatment, of course, is: “Is it FDA-approved?” Fluvoxamine is FDA-approved — but for OCD, not for Covid-19. In fact, Lenze told me, ”I don’t think the FDA ever will approve it for Covid. The reason the FDA will never approve it for Covid is exactly the reason it’s so useful for Covid, namely it’s cheap and it’s widely available. No one can make any money off it, so no one is going to spend the money to appeal to the FDA to approve it.”

Doctors can prescribe drugs the FDA has approved as a treatment for one condition to treat another condition off-label, using their clinical judgment. Doctors may vary in how comfortable they feel with it, but it is common and fully permitted by US regulations.

How Covid-19 is changing the process of clinical trials

One other thing about the emergence of fluvoxamine worth discussing is the process by which it happened: a new approach to clinical trials that is changing how we find new treatments.

Conducting clinical trials takes a long time. Most people will not be eligible to join a given trial. Finding the eligible ones and recruiting and enrolling them is time- and labor-intensive.

In order to find moderate-effect sizes and be confident in the results, a clinical trial needs to enlist thousands of patients, but that also means it will take much longer to recruit for and conduct — and with Covid-19, delays have costs in human lives. Clinical trials on this scale are expensive, too. TOGETHER is funded by private philanthropists, including Fast Grants, an initiative by Silicon Valley billionaire Patrick Collison and economist Tyler Cowen to speed pandemic response by getting grant money out rapidly.

For the past year, Mills has been using a new approach to clinical trials in order to test potential Covid-19 treatments faster. The key thing was to conduct them in parallel using what’s called an adaptive platform trial. “They’re multi-armed, so you’re testing lots of substances at a time, which allows you to only have one control group,” Mills told me. “What all of the useful trials in Covid have in common is that they’re an adaptive platform trial.”

Running, say, eight clinical trials, with eight control groups, requires many thousands of patients to get an informative sample, which can take a long time. Having eight experimental groups sharing a single control group cuts the number of patients required nearly in half.

This study model reallocates patients among treatment groups once a given treatment has been demonstrated not to work. That leads them to have larger, more convincing sample sizes for the most promising treatments. “You make decisions based on the data that emerges early,” Mills said. “After you have randomized 200 patients to the drug, if you can’t tell that it’s working, it’s probably not a very good drug. Every drug that’s not showing effects is a waste of patients.”

Fluvoxamine was one of eight treatments Mills and colleagues tested. Over time, as other treatments showed no effect, more patients got randomized to the fluvoxamine arm of the trial — letting the researchers learn more about the drug that seemed the most promising.

Mills says that played a huge role in their ability to quickly figure out what worked and what didn’t. “Prior to Covid, it was really just MD Anderson [the cancer hospital in Houston] doing this design. I think it’s going to be how almost all clinical trials happen going forward.”

Vaccines are great — but treatments are as badly needed as ever

Now that there are Covid-19 vaccines, the race for a treatment might seem less urgent than it was last year. But researchers say that mindset would be a mistake.

Vaccine uptake has stalled in most rich countries around 60 to 70 percent, and the delta variant means that the virus is still spreading. Effective treatments could mean dramatically fewer people hospitalized in places where hospitals are overwhelmed.

In poor countries, the situation is starker. Vaccines are not yet widely available, and the prospects for mass vaccinations are grim. And many existing treatments for Covid-19 are unaffordable for the global poor. That’s where fluvoxamine’s promise really comes in.

“It’s $2,000 for a dose for a monoclonal antibody,” Mills told me. “Our drug costs $4.” The supply chain, too, is simpler. Fluvoxamine doesn’t need to be kept in a freezer, doesn’t expire quickly, and can be mass-manufactured cheaply. If it continues to show health benefits for Covid-19 patients, making it widely available in poor countries could help them weather delta.

The fight to discover new treatments isn’t over, either. When I talked with Mills, he was excited about research in the UK finding that steroid inhalers — another cheap, widely available medication — reduced Covid-19 hospitalizations. Mills is also in the process of enrolling patients for a study of both steroids and fluvoxamine, to see whether the benefits are greater when patients take both drugs. “We go from having no drugs for early treatment that are cheap and widely available to having two,” he told me. “What does it look like if we use them together?”

The world is still months of research away from an answer to that question. But even the partial answers available today might make all the difference for some patients.