Fluvoxamine improves fatigue and quality of life in long COVID

1. In this randomized controlled trial, fluvoxamine reduced fatigue, improved quality of life, and increased recovery frequency in adults with long COVID.

2. Metformin showed no significant effect on fatigue, provided only a modest short-term improvement in quality of life, and did not increase recovery frequency.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Over half a decade after the COVID-19 pandemic, long COVID continues to affect millions of people following acute infection. Fatigue is a common symptom that can persist for months and significantly impair quality of life. Current management remains largely supportive, with few effective therapeutic options. Metformin has shown promise in preventing the onset of long COVID, while fluvoxamine has demonstrated anti-inflammatory properties and reduced hospitalization in acute COVID-19. This study evaluated the efficacy of metformin and fluvoxamine in reducing fatigue among adults with long COVID. Fluvoxamine significantly reduced fatigue compared with placebo at 30, 60, and 90 days and also improved quality of life. Metformin produced a modest reduction in fatigue at 30 days but showed no benefit at later time points. Participants receiving fluvoxamine were more likely to experience recovery from long COVID, whereas metformin did not increase recovery frequency. Adverse events were less frequent with fluvoxamine, while metformin’s adverse event rate was similar to placebo; grade 3 or higher events were rare and comparable across all groups. The generalizability of these findings is limited by the short follow-up period, reliance on self-reported fatigue, and absence of inflammatory, metabolic, or depression-related measures. Nonetheless, the results suggest that fluvoxamine, but not metformin, may be an effective treatment for long COVID-related fatigue, providing a potential therapeutic option for a persistent and debilitating condition.

Click to read this study in AIM

Relevant Reading: Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19

In-Depth [randomized controlled trial]: This randomized controlled trial evaluated the efficacy of metformin and fluvoxamine in reducing fatigue among adults with long COVID. Participants were recruited from 22 outpatient sites in Brazil between October 2023 and February 2025. Eligible participants were adults (≥18 years) with a single episode of SARS-CoV-2 infection, confirmed by laboratory testing or, if unavailable, by clinician diagnosis or self-report, and with new or worsening moderate to severe fatigue lasting 90 to <365 days after acute illness, not attributable to another cause. Key exclusions included active COVID-19, pre-existing chronic fatigue syndromes or dysautonomia, diabetes, severe anemia, recent stroke or Lyme disease, illicit drug use, pregnancy or breastfeeding, current metformin use, contraindications to study medications, and uncontrolled psychiatric disorders. The primary outcome was change in Fatigue Severity Scale (FSS) score from baseline to day 60. Secondary outcomes included FSS at day 90, quality of life measured by EQ-5D-5L at days 30, 60, and 90, longitudinal FSS analysis, and recovery (FSS <3). A total of 399 participants were randomized to fluvoxamine (n = 150), metformin (n = 111), or placebo (n = 138). Median age was 44 years, and baseline FSS scores ranged from 5.6 to 5.9. At day 60, fluvoxamine reduced fatigue versus placebo (mean treatment effect -0.43 points; 95% credible interval [CrI], -0.80 to -0.07), with effects maintained at day 90 (-0.58; CrI, -0.98 to -0.16). Metformin showed no significant benefit. Fluvoxamine also improved EQ-5D-5L scores at all time points, whereas metformin showed only a small improvement at day 30. Recovery was more frequent with fluvoxamine (standardized risk ratios 1.48, 1.36, 1.19 at days 30, 60, and 90); metformin did not increase recovery. Subgroup and exploratory analyses showed consistent benefit for fluvoxamine, with no meaningful effect modification. Adverse events occurred in 20.0% of fluvoxamine, 28.8% of metformin, and 29.7% of placebo participants. Grade 3 or higher events were rare and comparable across groups. Serious adverse events were uncommon, with no treatment-related deaths. Overall, fluvoxamine, but not metformin, may reduce fatigue and improve quality of life in adults with long COVID.

Image: PD

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