Can an Antidepressant Help Long COVID Fatigue?

For many people living with long COVID, fatigue isn’t just feeling tired — it can be overwhelming, persistent and disruptive to daily life. In fact, fatigue is one of the most common and debilitating symptoms reported after a COVID-19 infection, sometimes lasting for months or even years.

A clinical trial published in Annals of Internal Medicine explored whether two existing medications, fluvoxamine and metformin, could help reduce this fatigue.

“We wanted to test whether two existing, widely available, and affordable medications could help,” explained co-lead investigator Edward J. Mills, Ph.D., a professor in McMaster University’s Department of Health Research Methods, Evidence and Impact. “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.”

What Was Studied?

A team of investigators conducted a randomized, placebo-controlled trial in Brazil involving 399 adults who had been experiencing fatigue for at least 90 days after a confirmed COVID-19 infection. This type of study is considered a gold standard for testing whether treatments are effective.

Participants were divided into three groups:

• One group received fluvoxamine (commonly used to treat depression and anxiety)
• One group received metformin (a medication often used for type 2 diabetes)
• One group received a placebo (an inactive pill)

Each participant took their assigned treatment for 60 days.

What Did Investigators Measure?

The main goal was to see whether fatigue improved over time. Investigators used a tool called the Fatigue Severity Scale (FSS), which measures how fatigue affects daily functioning. They also looked at quality of life and tracked any side effects.

What Were the Results?

• Fluvoxamine showed meaningful improvement. Patients taking fluvoxamine experienced a significant reduction in fatigue compared with those taking a placebo. This improvement was seen at 60 days and continued even after treatment ended, at the 90-day follow-up. In addition to reduced fatigue, patients also reported better overall quality of life, suggesting the benefits went beyond just feeling less tired.
• Metformin did not show benefit. Unlike fluvoxamine, metformin did not significantly improve fatigue symptoms compared with placebo.

Side effects were relatively similar across all groups, but fluvoxamine had fewer reported side effects (20%) compared with metformin and placebo groups (about 29%). Serious side effects were rare in all groups, which is reassuring for patients.

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

What Do These Findings Mean for Patients?

This study suggests that fluvoxamine, a medication already widely available, may help reduce fatigue in people with long COVID. That’s important because there are currently no widely approved treatments specifically for long COVID fatigue and many patients struggle to find relief through existing options.

However, the team noted it’s important to keep a few things in mind when evaluating the results. The study only followed patients for 90 days, so they don’t know how long the benefits last, and it focused only on fatigue, not other common long COVID symptoms like brain fog, shortness of breath. or pain. Therefore, more research is needed before this becomes a standard treatment

“This is an important step forward for patients who have been desperate for evidence‑based options,” said Mills. “Fluvoxamine showed consistent and meaningful benefits, and because it's already widely used and well understood, it has clear potential for clinical use.”