Treatment Database

An SSRI and potent sigma-1 receptor (S1R) agonist with positive randomized trial evidence for Long COVID fatigue. REVIVE-TOGETHER, an adaptive placebo-controlled RCT (Reis et al., Annals of Internal Medicine 2026; n=399; outpatient sites in Brazil; corrected and republished in October 2026), randomized adults with new or worsened fatigue lasting 90 days to 24 months after COVID-19 to fluvoxamine 100 mg twice daily, metformin (750 mg, later lowered to 500 mg, twice daily), or placebo for 60 days. Fluvoxamine reduced Fatigue Severity Scale scores vs. placebo at day 60 (mean difference −0.43 on the 1–7 scale; 95% CrI −0.80 to −0.07) and at day 90, 30 days after stopping (−0.58; 95% CrI −0.98 to −0.16), and improved quality of life. Adverse events were less frequent than with placebo (24.0% vs. 35.5%). Results for metformin were inconclusive, and its arm was stopped for futility. Caveats: the effect is modest, the trial was conducted in one country with 90-day follow-up, and people with major depressive disorder or already taking antidepressants were excluded. Whether early treatment prevents Long COVID is unclear: in COVID-OUT (Lancet Infect Dis 2023), it did not reduce Long COVID incidence (HR 1.36; 95% CI 0.78–2.34), while a smaller Iranian trial (BMC Infect Dis 2023; n=85) found less fatigue 12 weeks after a 10-day course but no difference in other symptoms. For acute COVID-19, results are mixed: TOGETHER (Lancet Glob Health 2022, n=1,497) found fewer emergency-care stays over 6 hours or transfers to a tertiary hospital (RR 0.68), a small JAMA 2020 trial (n=152) found less clinical deterioration, and ACTIV-6 (JAMA 2023, n=1,175 analyzed) found no faster recovery. Fluvoxamine is a potent CYP1A2 inhibitor and also inhibits CYP2C19, CYP2C9 and CYP3A4, so interactions (e.g. tizanidine, which is contraindicated, theophylline, clozapine) should be reviewed with a prescriber.