One Drug Wins and Another Fails for Long COVID Fatigue

The antidepressant fluvoxamine delivered clinically relevant reductions in long COVID fatigue, but the diabetes drug metformin didn’t outdo placebo, according to the randomized REVIVE-TOGETHER trial.

Among 399 adults with long COVID, those receiving fluvoxamine had a significant reduction in fatigue as measured by the Fatigue Severity Scale (FSS) compared with placebo at day 60 (mean difference – 0.43, 95% credible interval [CrI] -0.80 to -0.07), with a 99% posterior probability of superiority, reported Jamie Forrest, PhD, MPH, of the University of British Columbia in Vancouver, and colleagues.

This effect was sustained at day 90 (mean difference -0.58, 95% CrI – 0.98 to -0.16), with a 99.7% probability of superiority.

Among those receiving metformin, however, the mean difference in FSS scores at 60 days was only 0.03 points lower than placebo scores (95% CrI -0.42 to 0.37), with a 56% probability that metformin was superior to placebo, they noted in the Annals of Internal Medicine. The treatment effect at 90 days was barely better (-0.04, 95% CrI -0.47 to 0.38).

“These findings suggest that fluvoxamine may have a beneficial role in the clinical management of fatigue in long COVID, although the condition encompasses a broad range of clinical manifestations beyond fatigue alone,” Forrest and colleagues wrote. “The concordance between the disease-specific fatigue reduction and broader health-related quality-of-life improvement supports the clinical relevance of the observed treatment effects.”

Fatigue is one of the most common symptoms of long COVID, also known as post-acute sequelae of SARS-CoV-2 infection. Fluvoxamine and metformin have demonstrated anti-inflammatory and immunomodulatory properties beyond their primary therapeutic uses. Those effects have led researchers to test their ability to prevent and treat long COVID and its symptoms.

For example, the COVID-OUT trial showed that metformin, but not fluvoxamine, significantly reduced long COVID risk in outpatients with COVID.

The REVIVE-TOGETHER researchers enrolled 399 adults at 22 outpatient sites in Brazil between October 2023 and February 2025. Participants had a single index episode of COVID and new or worsening fatigue that lasted 90 to 364 days after the acute illness. Exclusion criteria included active acute COVID, pre-existing myalgic encephalomyelitis or chronic fatigue syndrome, current metformin use, diabetes with severe anemia, or uncontrolled psychiatric disorders such as anxiety or depression.

Participants received oral fluvoxamine 100 mg twice daily (150 people), oral extended-release metformin 750 mg twice daily (111 people), or placebo (138 people). Participants with diabetes who were on long-term metformin therapy were enrolled only in either the fluvoxamine or placebo groups, and long-term metformin users in the placebo group weren’t compared with the metformin group.

Median age was 44 years, and most participants were women. The median screening FSS scores across the three groups ranged from 5.6 to 5.9. A score of 4 or higher indicates moderate to severe fatigue.

At day 60, the treatment effect with fluvoxamine on the 5-level EuroQol 5-dimensional questionnaire (EQ-5D-5L) was 0.06 (95% CrI 0.01-0.11) versus 0.01 (95% CrI -0.04 to 0.07) with metformin. By day 90, treatment effects were 0.07 and -0.03, respectively. Fluvoxamine’s probability of superiority to placebo was 98.2% by day 90, compared with 20% for metformin.

Recovery defined by an FSS score less than 3 was more likely with fluvoxamine than placebo — 48% more likely at day 30, 36% at day 60, and 19% at day 90. In contrast, metformin showed no advantage over placebo at 30, 60, or 90 days.

Safety was similar across the three treatment groups. Adverse events occurred in 20% of those in the fluvoxamine group, 28.8% of those taking metformin, and 29.7% of those receiving placebo.

Study limitations included the enrollment of participants only in Brazil, which may limit the findings’ generalizability. Subjective factors may affect the self-reported FSS. In addition, while common, fatigue is just one of many symptoms of long COVID.

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