Common antidepressant eases fatigue associated with long COVID, study finds

A global research team co‑led by McMaster University has identified one of the first medications shown to meaningfully reduce fatigue in people living with long COVID—a breakthrough for millions still struggling with persistent symptoms years after the pandemic began.

The randomized, placebo‑controlled clinical trial found that fluvoxamine, a low‑cost and widely available antidepressant, significantly improved fatigue and quality of life among adults with long COVID. The findings were published in the Annals of Internal Medicine.

Fatigue is the most common and debilitating symptom of long COVID, leaving many people unable to work, care for their families, or resume their normal lives. Despite its global impact, few proven treatments exist.

“This is an important step forward for patients who have been desperate for evidence‑based options,” says Edward Mills, senior author, professor in McMaster’s Department of Health Research Methods, Evidence, and Impact, and co‑principal investigator of the trial.

“Fluvoxamine showed consistent and meaningful benefits, and because it’s already widely used and well understood, it has clear potential for clinical use.”

The study was co‑led by researchers in Canada, Brazil, and the United States, with clinical sites in the city of Belo Horizonte and across Minas Gerais, Brazil. The REVIVE-TOGETHER trial team included partners from McMaster University, the University of British Columbia, Stanford University, the University of Pittsburgh, Duke University, Georgetown University, and multiple Brazilian institutions.

The trial enrolled 399 adults in Brazil who continued to experience fatigue for at least 90 days after a confirmed SARS‑CoV‑2 infection. Participants were randomly assigned to receive fluvoxamine (sold under the brand name Luvox), metformin (a common diabetes medication), or placebo for 60 days.

“We wanted to test whether two existing, widely available, and affordable medications could help. Both had biological reasons to think they might work against long COVID fatigue, but neither had been rigorously tested for this purpose in a proper clinical trial,” says Mills.

The researchers found fluvoxamine reduced fatigue more than placebo, with evidence showing a 99 percent probability the drug outperformed the placebo. The medication also produced improvements in overall quality of life across multiple measures.

Previous research has showed metformin reduces the risk of developing long COVID when taken during the acute phase of infection, and this research showed it offers no meaningful benefit in helping people with fatigue symptoms of established long COVID.

The study used a sophisticated Bayesian adaptive design, allowing researchers to stop treatment arms early when results became clear—a method that accelerates evidence generation while maintaining scientific rigor.

“The trial used a sophisticated adaptive design that allowed it to reach conclusions more efficiently than traditional trials, stopping early when the evidence was clear enough—a design innovation as important as the findings themselves,” says Gilmar Reis, lead author, researcher with Cardresearch, a Brazilian clinical research center based in Belo Horizonte. Reis is also a part-time associate professor at McMaster.

Long COVID remains a major public health challenge, affecting an estimated 65 million people worldwide. Yet most medical guidelines still offer only supportive care, such as pacing and symptom management, due to the lack of proven treatments.

The researchers emphasize that while fluvoxamine offers a promising option for managing fatigue, long COVID is a complex condition with multiple symptoms and biological pathways. Further studies are needed to understand who benefits most, how the medication works, and how it might be combined with other emerging treatments.

“This trial gives clinicians their first strong evidence for a medication that helps reduce long COVID fatigue. Patients want something they can try today—and this finding brings us closer to that reality,” says Jamie Forrest, corresponding author and postdoctoral research fellow at the University of British Columbia.