Fluvoxamine Significantly Reduces Long COVID Fatigue in Landmark Randomized Trial

A landmark international trial has identified fluvoxamine (Luvox; Jazz Pharmaceuticals), a widely available, low-cost selective serotonin reuptake inhibitor, as one of the first medications to meaningfully reduce fatigue in patients with postacute sequelae of SARS-CoV-2, or long COVID. The findings, published in Annals of Internal Medicine, represent a major step forward in the clinical management of a condition that has challenged health care teams since the early days of the pandemic.^1,2

Long COVID is defined by the World Health Organization as symptoms persisting at least 3 months after a confirmed SARS-CoV-2 infection and affects an estimated 6% to 7% of adults globally, although prevalence estimates vary widely across methodologies. Fatigue is the most reported and debilitating symptom, leaving many patients unable to work or care for themselves. Until now, medical guidelines have largely been limited to supportive care approaches such as activity pacing and symptom management, with no pharmacological therapies formally approved.^1,3

Trial Design and Patient Population

The phase 3 REVIVE-TOGETHER trial (NCT06128967), coled by researchers at McMaster University, the University of British Columbia, Stanford University, and several Brazilian institutions, enrolled 399 adults across 22 outpatient sites in Belo Horizonte and Minas Gerais, Brazil, between October 2023 and February 2025. Eligible participants had experienced new or worsening fatigue for at least 90 days—but no more than 1 year—following a confirmed COVID-19 infection. Fatigue severity had to meet or exceed a score of 4 on the validated 9-item Fatigue Severity Scale (FSS).²

Participants were randomly assigned to receive fluvoxamine 100 mg twice daily, metformin 750 mg twice daily, or matching placebo for 60 days. Individuals with a confirmed diagnosis of major depressive disorder were excluded, although patients with depressive symptoms were permitted to participate.²

“We wanted to test whether 2 existing, widely available, and affordable medications could help. Both had biological reasons to think they might work against long COVID fatigue, but neither had been rigorously tested for this purpose in a proper clinical trial,” Edward Mills, PhD, senior study author and professor in McMaster's Department of Health Research Methods, Evidence, and Impact, said in a news release.¹

Fluvoxamine Outperforms Placebo; Metformin Falls Short

The primary outcome, which was change in FSS score, favored fluvoxamine over placebo at day 60 (mean difference, −0.43; 95% credible interval [CrI], −0.80 to −0.07), a difference considered clinically meaningful. The benefit was sustained and deepened at day 90, a full 30 days after the treatment period ended (mean difference, −0.58; CrI, −0.98 to −0.16), suggesting a durable effect.²

At 30 days, participants on fluvoxamine were approximately 50% more likely than those on placebo to report a fatigue score below 3—a threshold considered indicative of recovery. Fluvoxamine also generated consistent improvements in quality-of-life measures, as assessed by the EQ-5D-5L instrument, and was associated with fewer adverse events than placebo.^2,4

In contrast, metformin demonstrated no significant benefit for established long COVID fatigue. The trial's monitoring board stopped the metformin arm early for futility. This finding is notable given prior data showing metformin reduces the risk of developing long COVID when taken during acute infection—a distinction investigators emphasize as clinically important.²

The evidence favoring fluvoxamine was strong, as the study reported a 99% probability that fluvoxamine outperformed placebo on the primary end point, meeting the prespecified Bayesian threshold for efficacy.²

"This is an important step forward for patients who have been desperate for evidence-based options,” Mills said. “Fluvoxamine showed consistent and meaningful benefits, and because it's already widely used and well understood, it has clear potential for clinical use."¹

Implications for Pharmacy Practice

For pharmacists, the emergence of an evidence-based pharmacological option for long COVID fatigue carries significant clinical implications. Available as a generic for less than $1 per tablet in many markets, fluvoxamine offers an accessible option for a patient population that has often resorted to costly and unproven remedies.¹

Pharmacists are well positioned to counsel patients on appropriate use; monitor for drug interactions—fluvoxamine is a potent CYP1A2 and CYP2C19 inhibitor—and assess for common adverse effects, including nausea, insomnia, and somnolence.

"This trial gives clinicians their first strong evidence for a medication that helps reduce long COVID fatigue. Patients want something they can try today—and this finding brings us closer to that reality,” Jamie Forrest, PhD, MPH, corresponding author and postdoctoral research fellow at the University of British Columbia, said in the news release.¹

The authors caution that long COVID is a complex, heterogeneous syndrome and that fluvoxamine should be considered one tool in a broader therapeutic approach. Further studies are needed to identify which patient subgroups benefit most, clarify the optimal duration of therapy, and explore potential combinations with emerging treatments.²

REFERENCES

1. Common antidepressant eases fatigue associated with long COVID, study finds. News release. McMaster University. March 30, 2026. Accessed March 31, 2026. https://www.eurekalert.org/news-releases/1121757

2. Reis G, Dos Santos Moreira Silva EA, Medeiros Silva DC, et al; REVIVE Investigators. The effect of fluvoxamine and metformin for fatigue in patients with long COVID: an adaptive randomized trial. Ann Intern Med. Published online March 31, 2026. doi:10.7326/ANNALS-25-03959

3. Hou Y, Gu T, Ni Z, Shi X, Ranney ML, Mukherjee B. Global prevalence of long COVID, its subtypes, and risk factors: an updated systematic review and meta-analysis. Open Forum Infect Dis. 2025;12(9):ofaf533. doi:10.1093/ofid/ofaf533