Could antidepressants hold the key to treating long COVID? University of Pennsylvania researchers have uncovered a link between long COVID and levels of serotonin in the body that may offer a new explanation for the condition. The study even points to a possible treatment.

Serotonin is a neurotransmitter that has many functions in the body. It is the active ingredient in the most commonly prescribed antidepressants — the selective serotonin reuptake inhibitors (SSRIs), which include sertraline, fluoxetine, paroxetine, citalopram, and cscitalopram.

Serotonin is widely studied for its effects on the brain ― it regulates the messaging between neurons, affecting sleep, mood, and memory. It is present in the gut, is found in cells along the gastrointestinal tract, and is absorbed by blood platelets. Gut serotonin, known as circulating serotonin, is responsible for a host of other functions, including the regulation of blood flow, body temperature, and digestion.

Low levels of serotonin could result in any number of seemingly unrelated symptoms, as in the case of long COVID, experts say. The condition affects about 7% of Americans and is associated with a wide range of health problems, including fatigue, shortness of breath, neurologic symptoms, joint pain, blood clots, heart palpitations, and digestive problems.

Long COVID is difficult to treat because researchers haven’t been able to pinpoint the underlying mechanisms that cause prolonged illness after a SARS-CoV-2 infection, said study author Christoph A. Thaiss, PhD, an assistant professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania.

The hope is that this study could have implications for new treatments, he said.

“Long COVID can have manifestations not only in the brain but in many different parts of the body, so it’s possible that serotonin reductions are involved in many different aspects of the disease,” said Thaiss.

Thaiss’s study, published in the journal Cell, found lower serotonin levels in long COVID patients in comparison with patients who were diagnosed with acute COVID-19 but who fully recovered.

His team found that reductions in serotonin were driven by low levels of circulating SARS-CoV-2 virus that caused persistent inflammation as well as an inability of the body to absorb tryptophan, an amino acid that’s a precursor to serotonin. Overactive blood platelets were also shown to play a role; they serve as the primary means of serotonin absorption.

The study doesn’t make any recommendations for treatment, but understanding the role of serotonin in long COVID opens the door to a host of novel ideas that could set the stage for clinical trials and affect care.

“The study gives us a few possible targets that could be used in future clinical studies,” Thaiss said.

Persistent circulating virus is one of the drivers of low serotonin levels, said study author Michael Peluso, MD, an assistant research professor of infectious medicine at the University of California, San Francisco, School of Medicine. This points to the need to reduce viral load using antiviral medications like nirmatrelvir/ritonavir (Paxlovid), which is approved by the US Food and Drug Administration for the treatment of COVID-19, and VV116, which has not yet been approved for use against COVID.

Research published in the February 2023 issue of The New England Journal of Medicine found that the oral antiviral agent VV116 was as effective as nirmatrelvir/ritonavir in reducing the body’s viral load and aiding recovery from SARS-CoV-2 infection. Paxlovid has also been shown to reduce the likelihood of getting long COVID after an acute SARS-CoV-2 infection.

Researchers are investigating ways to target serotonin levels directly, potentially using SSRIs. But first they need to study whether improvement in serotonin level makes a difference.

“What we need now is a good clinical trial to see whether altering levels of serotonin in people with long COVID will lead to symptom relief,” Peluso said.

Indeed, the research did show that the SSRI fluoxetine as well as a glycine-tryptophan supplement improved cognitive function in SARS-CoV-2-infected rodent models, which were used in a portion of the study.

David F. Putrino, PhD, who runs the long COVID clinic at Mount Sinai Health System in New York City, said the research is helping “to paint a biological picture” that’s in line with other research on the mechanisms that cause long COVID symptoms.

But Putrino, who was not involved in the study, cautions against treating long COVID patients with SSRIs or any other treatment that increases serotonin before testing patients to determine whether their serotonin levels are actually lower than those of healthy persons.

“We don’t want to assume that every patient with long COVID is going to have lower serotonin levels,” said Putrino.

What’s more, researchers need to investigate whether SSRIs increase levels of circulating serotonin. It’s important to note that researchers found lower levels of circulating serotonin but that serotonin levels in the brain remained normal.

Traditionally, SSRIs are used clinically for increasing the levels of serotonin in the brain, not the body.

“Whether that’s going to contribute to an increase in systemic levels of serotonin, that’s something that needs to be tested,” said Akiko Iwasaki, PhD, co-lead investigator of the Yale School of Medicine COVID-19 Recovery Study, who was not involved in the research.

Thus far, investigators have not identified one unifying biomarker that seems to cause long COVID in all patients, said Iwasaki. Some research has found higher levels of certain immune cells and biomarkers, for example, monocytes and activated B lymphocytes, indicating a stronger and ongoing antibody response to the virus. Other recent research conducted by Iwasaki, Putrino, and others that was published in the journal Nature showed that long COVID patients tend to have lower levels of cortisol, which could be a factor in the extreme fatigue experienced by many who suffer from the condition.

The Cell study’s findings are promising, but they need to be replicated in more people, said Iwasaki. And even if they’re replicated in a larger study population, this would still be just one biomarker that is associated with one subtype of the disease. There is a need to better understand which biomarkers go with which symptoms so that the most effective treatments can be identified, she said.

Both Putrino and Iwasaki contended that there isn’t a single factor that can explain all of long COVID. It’s a complex disease caused by a host of different mechanisms.

Still, low levels of serotonin could be an important piece of the puzzle. The next step, said Iwasaki, is to uncover how many of the millions of Americans with long COVID have this biomarker.

“People working in the field of long COVID should now be considering this pathway and thinking of ways to measure serotonin in their patients.”

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