Coronavirus particle

Breakthrough

A surprising treatment for Covid-19 could be the key to stopping variants

Household name antidepressants may be helping some patients survive.

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When France had its first wave of Covid-19 in February 2020, Nicolas Hoertel worried about his patients.

Hoertel is an associate professor of psychiatry at Paris University and a psychiatrist at Corentin Celton Hospital, which specializes in older adult psychiatry. Information coming out of China made it clear that the risk of severe disease or death from Covid-19 increases dramatically over the age of 65. At least half all of the patients in the 90-bed facility where Hoertel is a psychiatrist were very high risk.

However, as the surge peaked, he noticed that the patients in his facility almost never had symptoms severe enough to warrant hospitalization. In fact, between February 2020 and March 2021, only four of his patients required hospitalization for Covid-19.

Over 90 percent of France's 88,933 deaths in the past year occurred in people ages 65 and older. And yet, at the psychiatric hospital filled with antidepressant-taking patients, many of whom were in that high-risk age group, only one died. A genuinely shocking contrast when you compare it with any other facilities with older adults.

The antidepressants, evidence suggests, were helping these patients survive.

Intrigued by this revelation, from January to April 2020, Hoertel worked with a total of 39 hospitals (23 acute, 20 adult, 3 pediatric) in and around Paris to develop a multicenter observational retrospective study examining outcomes for Covid-19 patients. What he and his team found was remarkable: While some antidepressants appeared to have no effect on outcomes, several did to an astonishing degree.

They found cases of Covid-19 resulting in intubation or death could be reduced by as much as 72 percent. The antidepressants that were the most promising? They’re household names among those who struggle with treatment-resistant depression: venlafaxine, mirtazapine, escitalopram, paroxetine, and fluoxetine.

Antidepressants and Covid-19

While Hoertel was working in France, Angela Reiersen, a psychiatrist at the Washington University School of Medicine in St. Louis, had seen research that indicated fluvoxamine could be useful in treating sepsis, a condition that releases cytokines into the bloodstream and is often fatal.

Knowing that “cytokine storms” are associated with severe cases of Covid-19, Reiersen contacted her colleague Eric Lenze about doing a study together. The pair conducted a double-blind, placebo-controlled study to determine if early use of the antidepressant fluvoxamine by Covid-19 patients could reduce severe outcomes. The researchers found that clinical deterioration occurred in 0 of 80 patients in the fluvoxamine and in 6 of 72 in the placebo group.

Now, studies in at least three countries — France, the United States, and Germany — support the idea that certain antidepressants can be an effective early treatment for Covid-19.

Not only does it appear to be effective, but it’s also fairly safe and cheap — millions of people are already taking the drugs. And compared to the only other real early Covid-19 treatment, monoclonal antibodies, a two-week course of antidepressants is wildly affordable.

Perhaps most excitingly, if more studies confirm these initial findings, experts Inverse spoke to say it’s very likely that antidepressants will be just as effective in combating severe outcomes from variants of the virus as they were in the study.

The precise mechanism by which these antidepressants are mitigating severe effects of Covid-19 is still unclear, though there are three compelling hypotheses:

  1. The anti-inflammatory properties of the drugs reduce the inflammation that is often associated with severe Covid outcomes like cytokine storms
  2. That these drugs have some antiviral properties
  3. That they inhibit an enzyme that allows the virus to enter a cell

There’s compelling evidence for all of the above. And it may turn out to be some combination of the three.

Antidepressants can be anti-inflammatory

When Hoertel first started hypothesizing he, like Lenze and Reiersen, thought the anti-inflammatory hypothesis was the most likely answer because of something called the Sigma 1 Receptor (S1R). Activation of S1R is common with antidepressants and that activation can produce anti-inflammatory effects. But as the study progressed, the French psychiatrist thought that was less likely.

“Some of the antidepressants that target Sigma 1 we had very good results with and others that target the same receptor, not so much,” Hoertel tells Inverse. “So, for us, this explanation doesn’t work.”

He says it’s possible that there’s some positive effect from this anti-inflammatory, but it's not the answer his team has been looking for. “It’s not satisfying,” he says. “It’s not about to explain all our findings.”

The explanation he found most compelling is number three — the enzyme hypothesis. It was posited to him by a German physician and researcher, Erich Gulbins. Instead of focusing on the spike protein on the virus that allows it to penetrate and consequently replicate in a human cell, Gulbins wanted to know what was happening in the host cell.

Based on his research into waxy lipid molecules called ceramides — as well as the work of researchers like Hoertel — Gulbins hypothesizes that when the novel coronavirus enters the cell, it activates an enzyme called acid sphingomyelinase (ASM). When that enzyme is activated, ceramides are produced.

Ceramides function as the open door that lets the virus into the cell, where it can reproduce. What these antidepressants do is inhibit those enzymes. Fewer enzymes mean fewer ceramides and fewer open doors for the virus to stroll through into a human cell.

When a viral particle enters your body, the virus immediately starts looking for cells where it can reproduce. But if the “ceramide-door” theory is correct, the cells of people taking ASM inhibitors are little fortresses and the virus can’t find a way in.

Protection from Covid-19 variants

What is especially thrilling about this possibility — this is all in the process of being reviewed and replicated — is not just that it would offer an inexpensive, readily available, and effective treatment for Covid-19, but what it might mean for the variants.

Vaccines teach the body what to look for and protect against. The coronavirus enters cells through its spike protein. So the vaccine gives your body a picture of the spike protein and says “create antibodies that attack and kill the thing attached to this spike.”

The coronavirus enters cells through its spike protein.Getty Images

While some vaccines are proving to be very effective against some variants, other variants may pose more of a challenge. The reason that some vaccines may be less effective against some of the variants is because of spike protein mutations. When a virus mutates, and those mutations affect the thing your antibodies have been trained to look for, they might miss it — it depends on how different the mutation looks compared to what the antibodies have been trained to fight.

If the virus simply runs out of doors to go through, it can’t find a cell and replicate no matter what mutation disguise it might be wearing. It could be dressed up as a Girl Scout selling Thin Mints and the door still wouldn’t open.

Lenze cautions not to get too bogged down in which of the three mechanisms is at work — stressing that whatever the mechanism is causing the antidepressants to help, “they should work regardless of variants,” he tells Inverse.

What’s important, he stresses, is that these are effective, cheap, safe medications, that if taken early, can prevent severe Covid-19 outcomes. Determining which mechanism is at work will happen eventually (and probably not too far in the future) through more clinical trials and double-blind studies, like the at-home study he is conducting called Stop Covid 2.

While more research and clinical trials need to be done to confirm what the initial data show, Hoertel is hopeful. But he wants to be clear: the likelihood that some of these antidepressants provide a measure of protection against severe disease shouldn’t stop anyone from getting a vaccine or feeling overconfident about their level of protection — there’s still too much that needs to be replicated and confirmed.

Instead, he says, we should follow his lead: “Be hopeful but cautious.”

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