FLUVOXAMINE for long COVID fatigue may offer a new treatment avenue, with trial data showing reduced fatigue severity and improved quality of life in affected adults.

Long COVID, a condition characterised by persistent symptoms following acute SARS-CoV-2 infection, poses a substantial clinical challenge. Fatigue is among its most common and debilitating features, often lasting months and limiting daily function. Despite its growing burden, treatment options remain largely supportive.

Why Long Covid Fatigue Remains Difficult to Treat

The biological drivers of long COVID are complex, including persistent viral material, immune dysregulation, endothelial dysfunction, and mitochondrial impairment. These overlapping mechanisms may explain why targeted treatments have been limited.

Both fluvoxamine and metformin have been considered potential candidates.

Fluvoxamine, a selective serotonin reuptake inhibitor with σ-1 receptor activity, has demonstrated anti-inflammatory effects and central nervous system activity.

Metformin, widely used in diabetes management, has anti-inflammatory and mitochondrial-modulating properties and has shown potential in preventing long COVID when used during acute infection.

Trial Design and Key Findings

In a randomised, placebo-controlled adaptive trial conducted across 22 outpatient sites in Brazil, 399 adults with fatigue persisting at least 90 days after confirmed infection were enrolled. Participants received fluvoxamine (100 mg twice daily), metformin (750 mg twice daily), or placebo for 60 days.

The primary outcome was change in Fatigue Severity Scale (FSS) score. Fluvoxamine produced a statistically significant reduction in fatigue at day 60 compared with placebo, with sustained improvement at day 90. Quality of life measures also improved consistently across all time points.

By contrast, metformin showed no meaningful benefit on fatigue at either time point. The metformin arm was stopped early for futility – although some participants had already completed treatment at the time of stopping. The fluvoxamine arm was stopped for superiority following interim analysis.

Adverse events were less frequent with fluvoxamine (20.0%) than with metformin (28.8%) or placebo (29.7%), with serious events rare across all groups.

Interpreting the Findings with Caution

Several limitations temper interpretation. Follow-up was limited to 90 days, restricting conclusions on durability. Fatigue was assessed using a self-reported scale, which may be influenced by subjective factors. The study also focused solely on fatigue, leaving broader symptom effects unclear.

Participants with major depressive disorder were excluded, but those with depressive symptoms were included, leaving it unclear if fatigue improvements reflect direct benefit or secondary mood effects. Other long COVID symptoms were not assessed.

Additionally, all participants were recruited in Brazil, potentially limiting generalisability, and early stopping may have reduced precision, particularly for metformin.

What This Means for Clinical Practice

The findings suggest fluvoxamine may help reduce fatigue and improve overall well-being in long COVID, although causality and mechanisms remain uncertain. The absence of benefit with metformin does not support its use for this indication based on current evidence.

Further studies incorporating biological markers and broader symptom assessment will be needed to clarify which patients are most likely to benefit and how these effects are mediated.

Reference

Reis G et al. The Effect of Fluvoxamine and Metformin for Fatigue in Patients With Long COVID : An Adaptive Randomized Trial. Ann Intern Med. 2026.;DOI:10.7326/ANNALS-25-03959.

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