Highlights
- Fluvoxamine demonstrated significant reduction in fatigue severity at both 60 days and 90 days compared to placebo in patients with long COVID fatigue.
- Metformin showed no significant benefit for fatigue improvement in the same patient population.
- Fluvoxamine was associated with fewer adverse events (20.0%) compared to metformin (28.8%) and placebo (29.7%).
Background: The Burden of Long COVID Fatigue
Postacute sequelae of SARS-CoV-2 infection, commonly known as long COVID, has emerged as a major therapeutic challenge in modern medicine. Among the constellation of symptoms affecting millions worldwide, fatigue stands out as one of the most prevalent and debilitating manifestations, significantly impacting quality of life and functional capacity. Despite the widespread prevalence of this condition, treatment options remain limited, creating an urgent unmet medical need for evidence-based therapeutic interventions.
The persistence of fatigue beyond 90 days following acute SARS-CoV-2 infection represents a significant clinical challenge. Healthcare providers have struggled to offer patients effective pharmacological options, often relying on supportive measures and lifestyle modifications with variable success. This gap in therapeutic options has prompted researchers to investigate repurposed medications that may target underlying mechanisms of post-viral fatigue.
Study Design
The trial was designed as a randomized, placebo-controlled, adaptive study conducted across outpatient sites in Brazil. The research team enrolled 399 adults who met inclusion criteria of fatigue persisting 90 or more days after laboratory-confirmed SARS-CoV-2 infection. Participants were randomly assigned to one of three treatment arms: fluvoxamine at a dose of 100 mg administered twice daily, metformin at a dose of 750 mg twice daily, or matching placebo. Treatment duration extended for 60 days, with follow-up assessments at both 60 and 90 days to evaluate durability of any observed effects.
The primary outcome measure was change in Fatigue Severity Scale (FSS) score, a validated instrument that quantifies the impact of fatigue on daily functioning. Secondary endpoints included quality-of-life assessments and safety monitoring throughout the study period. The trial was registered under ClinicalTrials.gov identifier NCT06128967.
Key Findings
Primary Efficacy Results
Fluvoxamine demonstrated statistically significant and clinically meaningful reduction in fatigue compared with placebo at day 60, with a mean difference of -0.43 (95% credible interval [CrI], -0.80 to -0.07). Importantly, the treatment effect appeared to strengthen over time, with an even more robust benefit observed at day 90 (mean difference, -0.58 [CrI, -0.98 to -0.16]). These findings suggest not only immediate symptomatic improvement but also potential sustained benefit beyond the active treatment period.
In contrast, metformin failed to demonstrate significant benefit for fatigue reduction at either assessment timepoint. The absence of effect was consistent across analyses, indicating that this particular therapeutic approach, despite some theoretical basis for investigation, does not appear to address long COVID fatigue effectively.
Secondary Outcomes and Quality of Life
Beyond the primary fatigue endpoint, fluvoxamine-treated participants showed improvements in quality-of-life scores with high posterior probability, suggesting broad beneficial effects on overall well-being rather than isolated symptom reduction. This finding is particularly significant given the profound impact that persistent fatigue has on multiple domains of life functioning, including work capacity, social relationships, and mental health.
Safety Profile
Adverse event monitoring revealed an encouraging safety profile for fluvoxamine. Treatment-emergent adverse events occurred in 20.0% of participants receiving fluvoxamine, compared with 28.8% in the metformin group and 29.7% in the placebo group. Notably, grade 3 and higher adverse events were rare across all treatment arms, indicating that even active treatment with fluvoxamine was generally well-tolerated in this patient population.
Expert Commentary
The results of this trial represent an important contribution to the limited body of evidence for treating long COVID symptoms. Fluvoxamine, traditionally used as a selective serotonin reuptake inhibitor for depression and anxiety disorders, has previously shown promise in early outpatient COVID-19 treatment trials, potentially through anti-inflammatory or antiviral mechanisms. The current findings extend this research into the post-acute sequelae phase, suggesting a role for this medication in addressing persistent symptoms.
Several mechanistic hypotheses may explain fluvoxamine’s apparent efficacy. The medication’s anti-inflammatory properties, particularly its sigma-1 receptor agonism, could theoretically address the immune dysregulation thought to underlie long COVID pathophysiology. Additionally, fluvoxamine’s effects on platelet function and potential antiviral properties remain areas of active investigation.
Limitations and Considerations
The authors appropriately acknowledge several limitations that should be considered when interpreting these findings. The 90-day follow-up period limits conclusions about the long-term durability of treatment effects, leaving unanswered questions about optimal treatment duration and potential need for maintenance therapy. Furthermore, the exclusive focus on fatigue as the primary outcome does not address other prevalent long COVID symptoms such as cognitive dysfunction, dyspnea, or autonomic dysfunction, leaving fluvoxamine’s broader therapeutic utility uncertain.
Generalizability considerations include the study’s geographic location (Brazil) and the requirement for confirmed SARS-CoV-2 infection, which may not reflect the full spectrum of post-viral syndromes encountered in clinical practice. Additionally, the adaptive trial design, while methodologically rigorous, introduces some complexity in interpretation.
Conclusion
This adaptive randomized trial provides compelling evidence that fluvoxamine may be an effective treatment for reducing fatigue and improving quality of life in patients with long COVID. The magnitude of effect observed, combined with a favorable safety profile, positions fluvoxamine as a promising therapeutic option that warrants further investigation and consideration in clinical management algorithms.
While metformin demonstrated no significant benefit in this study, the successful identification of an effective treatment for long COVID fatigue represents a significant advance for patients and clinicians alike. Future research should focus on confirming these findings in diverse populations, investigating optimal dosing and treatment duration, and exploring combination approaches for patients with multiple long COVID symptoms.
The burden of long COVID fatigue extends beyond individual patients to impact families, workplaces, and healthcare systems. Effective treatments have the potential to restore functional capacity and quality of life for millions affected by this condition. The fluvoxamine findings offer renewed hope and a foundation for building more comprehensive treatment strategies.
Funding and ClinicalTrials.gov
Primary Funding Source: The Latona Foundation
Trial Registration: ClinicalTrials.gov NCT06128967
References
1. Reis G, Dos Santos Moreira Silva EA, Medeiros Silva DC, et al. The Effect of Fluvoxamine and Metformin for Fatigue in Patients With Long COVID: An Adaptive Randomized Trial. Ann Intern Med. 2026 Mar 31. PMID: 41911553.
