Impact of Fluvoxamine on Quality of Life and Fatigue Severity in Long COVID

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Summary of  Annals of Internal Medicine https://doi.org/10.7326/ANNALS-25-03959 
Dr. Gilmar Reis et al.

Points

Researchers evaluated three hundred ninety-nine participants at twenty-two sites in Brazil to determine if fluvoxamine or metformin could effectively treat chronic fatigue caused by post-acute COVID-19 infection.
The study found that fluvoxamine significantly reduced fatigue levels by day sixty and continued to provide symptomatic relief through a ninety-day follow-up period for the treated patient population.
Patients taking fluvoxamine reported a measurable boost in their overall quality-of-life scores and experienced fewer adverse side effects than those who were assigned to the placebo group.
The diabetes medication metformin failed to show any statistically significant clinical benefit in reducing fatigue or improving the functional status of patients during the trial observation period.
Investigators noted that the lack of baseline depression screening remains a limitation in determining whether the drug directly targeted long COVID or provided relief through its primary antidepressant mechanisms.

Summary

This research evaluated the efficacy of fluvoxamine and metformin for the treatment of persistent fatigue in patients with post-acute sequelae of SARS-CoV-2 (long COVID). Fatigue remains a primary contributor to functional impairment in this population, and the study sought to determine if these repurposed medications could modulate the underlying inflammatory or neuropsychiatric pathways of the condition. Conducted across 22 outpatient sites in Brazil, the trial assessed 399 participants who had experienced debilitating fatigue for at least 90 days following acute infection.

Participants were randomized to receive 60 days of fluvoxamine, metformin, or a placebo, with longitudinal assessments performed at 60 and 90 days using a standardized fatigue severity scale. The results demonstrated that fluvoxamine produced a statistically significant reduction in fatigue scores by day 60, with therapeutic benefits continuing through day 90. Additionally, the fluvoxamine cohort showed marked improvements in overall quality-of-life scores. Conversely, metformin demonstrated no clinical or statistical benefit over placebo in mitigating fatigue symptoms, despite its established safety profile in other long COVID contexts.

The study concluded that fluvoxamine is a safe and potentially effective intervention for long COVID-related fatigue, reporting fewer adverse events than the placebo group. However, investigators noted a significant limitation: the study did not formally screen for baseline depression. This introduces uncertainty regarding whether the observed improvement resulted from a direct effect on long COVID pathophysiology or a secondary antidepressant effect. Further research is required to differentiate these mechanisms and to evaluate the long-term durability of the treatment beyond the 90-day observation window.

Link to the article: https://www.acpjournals.org/doi/10.7326/ANNALS-25-03959

References

Reis, G., Dos Santos Moreira Silva, E. A., Medeiros Silva, D. C., Thabane, L., Ferreira, T. S., Reis, L. L. F., Figueiredo Guimaraes Almeida, A. P., Menezes Amaral, M., Savassi, L. C. M., De Souza Campos, V. H., Campos Simplicio, M. I., Barra Ribeiro, L., De Souza Medeiros, T., Campos Siqueira, T., Vieira, T. S., Drumond Rausse, N., Garofolo, T. C., Fagundes Silva, E. C., Harari, O., … Resende Do Nascimento, G. (2026). The effect of fluvoxamine and metformin for fatigue in patients with long covid: An adaptive randomized trial. Annals of Internal Medicine, ANNALS-25-03959. https://doi.org/10.7326/ANNALS-25-03959