Back in early 2020, as the then-novel SARS-CoV-2 spread across Earth, doctors began to notice a phenomenon only seen previously in a lab: specific types of antidepressants appeared to help people heal from inflammation caused by an infection.
As bodies filled emergency rooms and intensive care beds, people who took common antidepressants appeared to be healing better than those who were not.
Since then, scientists have been fine-tuning our understanding of how selective serotonin reuptake inhibitors (SSRIs), which include household name antidepressants like Prozac (fluoxetine) and Luvox (fluvoxamine), influence the body’s response to infection.
A new study adds to a growing body of evidence that suggests SSRIs could be an effective treatment for Covid-19.
“It’s been proposed that certain SSRIs might be used for sepsis in hospitalized patients, so I do think it would make sense based on those animal studies to test this in other types of infection,” says Angela Reiersen, an associate professor of psychiatry at Washington University School of Medicine in St. Louis. Reiersen is currently working on a clinical trial that studies whether or not fluvoxamine can produce better outcomes for people with Covid-19, and was not involved in this study.
What’s new — The team behind the study, published Monday in JAMA Network Open, collected health records from more than 83,000 patients from across the United States who had been diagnosed with Covid-19, including roughly 3,400 patients who were prescribed SSRIs.
They found that people who took any SSRI were 8 percent less likely to die of Covid-19.
“After your body has been fighting Covid-19, sometimes the inflammation doesn’t turn off the way it’s supposed to.”
Those odds jumped to 28 percent among those prescribed fluoxetine.
A growing body of research, including a randomized clinical trial, is showing that fluvoxamine appears to have a positive effect on the body’s ability to heal from — and potentially stave off — Covid-19 infection. The new observational study suggests that the same could be true for fluoxetine.
“These observational studies are good and give us hypotheses. Now we need to make sure with a controlled trial that these drugs really work when you intervene and give them as a treatment,” says Reiersen.
The study’s huge cohort gives it weight, indicating that although the findings were based on observation rather than intervention, there seems to be a significant connection between specific SSRIs and the body’s ability to recover from Covid-19.
How it works — Researchers studying the link suggest several mechanisms explain these results, but Reiersen's own research suggests it mostly comes down to inflammation and a receptor called sigma-1 (SRI-1).
SRI-1 is a protein inside cells that’s located mostly in the membrane and some SSRIs bind to this receptor. Fluvoxamine is particularly good at binding, followed by fluoxetine, which doesn’t bind quite as well. The receptor plays a key role in regulating the body’s inflammatory response.
When Covid-19 first breaks into your cells, it sets off a chain reaction that throws your cells into fight mode. Cells produce tiny proteins called cytokines, which cause inflammation. Inflammation can stop an infection, but if it goes on for too long, it can wreak havoc in the body.
“After your body has been fighting Covid-19, sometimes the inflammation doesn’t turn off the way it’s supposed to,” Reiersen explains. “You can have continued excessive inflammation which seems to be what is causing people to develop severe respiratory problems. It’s not the virus itself, but the body’s response to the virus not shutting down or turning off. SSRIs can turn off that inflammation.”
They do this by activating the SR-1 receptor. When it’s active, the SR-1 receptor stops the chain reaction that prompts cells to produce cytokines.
Since fluoxetine doesn’t bind to these receptors as well as fluvoxamine does, it may work against infection by stopping blood cells from hoarding serotonin and then releasing it all at once when the body becomes infected, which also stimulates cytokine production.
This is significant because serotonin isn’t just in the brain.
“If the serotonin transporter is important in the treatment of Covid-19, it is probably because the serotonin transporter protein is located on the cell membranes of platelets, not because of its presence in the brain,” says Reiersen.
Fluoxetine may also stop the virus from getting into cells in the first place.
What it means for the future — Researchers still need to confirm with controlled clinical trials whether or not fluoxetine, or a confounding factor, is responsible for lower mortality rates due to Covid-19.
But clinical trials have shown sufficient evidence that fluvoxamine is associated with lower mortality rates and a smaller risk of severe illness in people infected with Covid-19. (The NIH, however, still states “there is insufficient evidence” for recommending “either for or against the use of fluvoxamine” as a Covid-19 treatment.)
The results of the TOGETHER trial, published in October in the journal The Lancet, found intervening early with fluvoxamine reduced the risk of death from Covid-19 by 90 percent and the need for intensive medical care by 65 percent.
About 1 in 7 adults in the U.S. have taken an SSRI in the past 30 days. According to Reiersen, the fact that fluvoxamine is already widely produced and approved for use gives it an edge over novel Covid-19 treatments that will take more time to be approved, produced, and distributed around the world.
“It’s not yet clear that fluoxetine works the way fluvoxamine does, but with the two controlled trials we have on fluvoxamine, I think many physicians will feel there is enough evidence to prescribe fluvoxamine for Covid-19, especially in high-risk patients who have no contradictions to this particular treatment,” says Reiersen.
The World Health Organization doesn’t currently have a stance on whether or not either drug should be used as part of a Covid-19 treatment. But as the pandemic extends, scientists continue to develop more easily accessible treatments. It’s possible more research will prove these already exist.
Importance: Antidepressant use may be associated with reduced levels of several proinflammatory cytokines suggested to be involved with the development of severe COVID-19. An association between the use of selective serotonin reuptake inhibitors (SSRIs)—specifically fluoxetine hydrochloride and fluvoxamine maleate—with decreased mortality among patients with COVID-19 has been reported in recent studies; however, these studies had limited power due to their small size.
Conclusions and Relevance: These results support evidence that SSRIs may be associated with reduced severity of COVID-19 reflected in the reduced RR of mortality. Further research and randomized clinical trials are needed to elucidate the effect of SSRIs generally, or more specifically of fluoxetine and fluvoxamine, on the severity of COVID-19 outcomes.