Annals of Internal MedicineThe Effect of Fluvoxamine and Metformin for Fatigue in Patients With Long COVID

Fluvoxamine 100mg twice daily significantly reduced long COVID fatigue vs. placebo in 399 adults (mean FSS difference −0.43 at day 60, sustained at −0.58 at day 90). Metformin showed no benefit and was stopped early for futility.

Clinical Considerations

• Fluvoxamine’s fatigue benefit was independent of antidepressant effects; interaction analysis found no mood-mediated mechanism driving improvement
• 36% more patients reached FSS recovery scores at day 60 with fluvoxamine vs. placebo (RR 1.36)
• Fluvoxamine’s adverse event rate (20%) was lower than both metformin (28.8%) and placebo (29.7%), supporting tolerability
• Metformin’s prevention benefit during acute COVID infection does not extend to treating established long COVID fatigue

Practice Applications

• Consider fluvoxamine for long COVID fatigue persisting 90+ days when alternative causes are excluded
• Exclude active major depressive disorder before prescribing — diagnosed MDD was a trial exclusion criterion
• Set expectations: benefit is real but modest; a 0.43-point reduction on a 7-point scale
• Avoid metformin for long COVID fatigue regardless of metabolic comorbidities

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