Fluvoxamine may have a beneficial role in the clinical management of long COVID fatigue.The antidepressant fluvoxamine reduces long COVID fatigue, whereas the antidiabetic agent metformin fails to outperform placebo in the randomized REVIVE-TOGETHER trial.
At day 60, adults receiving fluvoxamine had a significant reduction in fatigue, as measured by the Fatigue Severity Scale (FSS), compared with placebo (mean difference -0.43, 95 percent credible interval [CrI] -0.80 to -0.07), with a 99 percent posterior probability of superiority. This effect was sustained at day 90 (mean difference -0.58, 95 percent CrI - 0.98 to -0.16), with a 99.7 percent probability of superiority, said investigator Dr Jamie Forrest from the University of British Columbia in Vancouver, Canada. [Ann Intern Med 2026;179:621-628]
“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,” he added. “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.”
Among those receiving metformin, the mean difference in FSS scores at 60 days was only 0.03 points lower than placebo (95 percent CrI, -0.42 to 0.37), with a 56 percent probability that metformin was superior to placebo. The treatment effect at 90 days was marginally better (-0.04, 95 percent CrI -0.47 to 0.38).
Fluvoxamine, metformin, or placebo
Patients enrolled in the trial (n=399) had a single episode of COVID-19 and new or worsening fatigue lasting 90 to 364 days. The median age was 44 years, and most patients were women. They received oral fluvoxamine 100 mg twice daily (n=150), oral extended-release metformin 750 mg twice daily (n=111), or placebo (n=138). Those with diabetes on long-term metformin therapy were enrolled only in the fluvoxamine or placebo groups and were not compared with the metformin group.
Median FSS screening scores across the three groups ranged from 5.6 to 5.9. A score of 4 or higher indicates moderate-to-severe fatigue.
Treatment effects
At day 60, the treatment effect of fluvoxamine on the 5-level EuroQol 5-dimensional questionnaire (EQ-5D-5L) was 0.06 (95 percent CrI 0.01-0.11) vs 0.01 (95 percent CrI -0.04 to 0.07) for metformin. By day 90, the treatment effects were 0.07 and -0.03, respectively. By day 90, fluvoxamine’s probability of superiority to placebo was 98.2 percent vs 20 percent for metformin.
Recovery, defined as an FSS score <3, was more likely with fluvoxamine than with placebo, with a 48 percent increase at day 30, 36 percent at day 60, and 19 percent at day 90. By contrast, metformin showed no advantage over placebo at 30, 60, or 90 days.
Safety was comparable among the three treatment groups. Adverse events occurred in 20 percent of patients in the fluvoxamine group, 28.8 percent of those taking metformin, and 29.7 percent of those on placebo.
The 90-day follow-up period limits conclusions about the durability of treatment effects, and focusing solely on fatigue as the primary outcome does not address other common long COVID symptoms.
While fluvoxamine may be a safe, effective, and affordable option for treating fatigue linked to long COVID, Forrest pointed out that it is not a cure for long COVID.