Fluvoxamine, a low-cost and widely available antidepressant, has demonstrated a significant ability to reduce fatigue and improve the quality of life for adults suffering from long COVID. In a randomized clinical trial, the medication provided one of the first pieces of strong evidence for a pharmacological treatment targeting the persistent, debilitating exhaustion that often leaves patients unable to work or resume normal daily activities.
A Targeted Approach to Debilitating Fatigue
Fatigue is among the most common and challenging features of post-acute sequelae of SARS-CoV-2 (long COVID), often persisting for months and resisting standard supportive care. The biological drivers are complex, involving a combination of immune dysregulation, mitochondrial impairment, endothelial dysfunction, and the presence of persistent viral material. Because these mechanisms overlap, finding a single targeted treatment has proven difficult.
Researchers sought to determine if fluvoxamine—a selective serotonin reuptake inhibitor (SSRI) known for its $sigma$-1 receptor activity and anti-inflammatory effects—could meaningfully alleviate these symptoms. The study, co-led by McMaster University and published March 31, 2026, in the Annals of Internal Medicine, compared the drug against both a placebo and metformin, a common diabetes medication with known mitochondrial-modulating properties.
Trial Parameters: The study enrolled 399 adults in Brazil (specifically Belo Horizonte and Minas Gerais) who had experienced fatigue for at least 90 days following a confirmed SARS-CoV-2 infection. Participants were assigned to 60 days of either fluvoxamine (100 mg twice daily), metformin (750 mg twice daily), or a matching placebo.
Comparing Fluvoxamine and Metformin
The trial utilized an adaptive design, meaning the researchers could adjust the study based on interim results. The findings revealed a clear divergence in efficacy between the two candidate drugs.
- Fluvoxamine: Participants saw a statistically significant reduction in fatigue by day 60, as measured by the Fatigue Severity Scale (mean difference of -0.43 compared to placebo). This improvement was sustained through day 90, with a mean difference of -0.58. Quality of life scores also showed consistent improvement.
- Metformin: The drug showed no meaningful benefit in reducing fatigue at either the 60-day or 90-day mark. The metformin arm of the trial was stopped early for futility.
Safety profiles were also notable. Adverse events occurred less frequently in the fluvoxamine group (20.0%) than in either the metformin group (28.8%) or the placebo group (29.7%). Across all three cohorts, serious adverse events (grade 3 and higher) remained rare.
Necessary Cautions in Interpretation
While the results offer a potential path forward for clinicians and patients, several limitations temper the findings. The study relied on a self-reported scale to assess fatigue, which can be influenced by subjective factors. Because the trial focused exclusively on fatigue, it remains unclear how fluvoxamine affects other complex long COVID symptoms.
There is also a question of causality regarding mood. While patients with major depressive disorder were excluded from the trial, those experiencing general depressive symptoms were included. This makes it difficult to determine if the reduction in fatigue was a direct physiological result of the medication or a secondary effect of improved mood.
Finally, the study’s geographic limitation—all participants were recruited in Brazil—may affect how these results generalize to global populations. The early stopping of the fluvoxamine arm for superiority and the metformin arm for futility may have also reduced the precision of the data for those specific groups.
Implications for Clinical Practice
For the millions of people still struggling with post-pandemic exhaustion, these findings suggest that fluvoxamine may be a viable option for improving overall well-being and reducing fatigue severity. However, the evidence does not currently support the use of metformin for this specific indication.
Moving forward, the medical community requires studies that incorporate biological markers and broader symptom assessments. Such data will be essential to identify which specific patient profiles are most likely to respond to fluvoxamine and to clarify the exact mechanisms by which the drug eases long COVID fatigue.
Common Questions About the Study
Was the improvement in fatigue permanent?
The study tracked participants up to 90 days. While the effect was sustained from day 60 to day 90, the limited follow-up period means the long-term durability of the treatment is not yet known.
Is fluvoxamine safe for everyone with long COVID?
The trial showed a low rate of serious adverse events, but fluvoxamine is a prescription medication. Its use should be managed by a healthcare provider who can evaluate individual risk factors and potential drug interactions.
How should the medical community balance the use of antidepressants for physiological fatigue versus psychiatric symptoms in long COVID patients?
