Use of fluvoxamine appears to ease fatigue severity and improve quality of life (QoL) in patients with long COVID, as shown in a study.
“Fluvoxamine shows potential for improving long COVID–associated fatigue and QoL,” said the investigators, who conducted a randomized, placebo-controlled, adaptive trial in outpatient sites in Brazil to examine the efficacy of fluvoxamine and metformin in the treatment of long COVID fatigue.
A total of 399 adults with fatigue 90 days to 24 months after confirmed SARS-CoV-2 infection were randomly allocated to receive fluvoxamine 100 mg twice daily (BID), extended-release metformin (750 mg BID [n=71] from October 2023 to April 2024, reduced to 500 mg BID [n=40] in May 2024), or a matching placebo, each for 60 days, with follow-up to day 90.
The median baseline Fatigue Severity Scale (FSS) scores of the participants ranged from 5.6 to 5.9. Fluvoxamine improved the FSS score compared with placebo, with a mean difference of ‒0.43 at day 60 and ‒0.58 at day 90. Both had a 99-percent posterior probability of superiority. [Ann Intern Med 2026;doi:10.7326/ANNALS-26-02144]
Fluvoxamine also improved QoL scores with a high posterior probability of superiority. On the other hand, metformin results were deemed inconclusive.
“The results were inconclusive for metformin because of a dose change recommended by the data safety and monitoring committee due to adverse effects causing study withdrawal and early termination,” the investigators said.
Safety profile
The incidence of adverse events (AEs) was lower in the fluvoxamine group (24.0 percent) than in the two metformin dose groups (750 mg: 45.1 percent; 500 mg: 42.5 percent) and the placebo group (35.5 percent). Serious AEs (grade ≥3) rarely occurred (≤2.7 percent), with no treatment-related deaths.
“These findings suggest a role for fluvoxamine in the clinical management of fatigue in long COVID, recognizing that the condition encompasses a broad range of clinical manifestations in addition to fatigue,” the investigators said.
The findings also contribute to a growing body of evidence exploring therapeutic agents for long COVID. In trials of antiviral therapy, including nirmatrelvir‒ritonavir, the therapeutic effects on long COVID symptoms were inconsistent, as shown in the STOP-PASC study. [JAMA Intern Med 2024;184:1024-1034]
Other therapies, including low-dose naltrexone, aripiprazole, and sulodexide, are still on trial. Moreover, a recent study assessing nicotinamide riboside alongside placebo observed no marked improvements in fatigue, sleep, mood, or cognition. [EClinicalMedicine 2025;89:103633]
“These findings underscore the ongoing uncertainty surrounding effective treatments for long COVID and highlight the need for more rigorously designed randomized trials,” the investigators said.
“Future trials should also incorporate standardized assessments of depression, anxiety, and metabolic assessments at baseline and follow-up, alongside inflammatory and metabolic biomarkers, to clarify mechanisms and identify subgroups most likely to benefit,” they added.
The current study did not assess other long COVID symptoms, and the long-term benefit of fluvoxamine remains unknown.
Fluvoxamine is a selective serotonin reuptake inhibitor with σ-1 receptor agonism. It has anti-inflammatory properties and has been shown to lower hospitalization risk in acute COVID-19 across multiple trials. [JAMA 2020;324:2292-2300; Lancet Glob Health 2022;10:e42-e51]
“[The] central nervous system activity and immunomodulatory effects [of fluvoxamine] offer a possible mechanistic rationale for [its] use in neurocognitive and fatigue-related manifestations of long COVID,” the investigators said. [PLoS One 2024;19:e0300512]