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Psychiatry Research Review

Sanjay Gupta, MD
Released: December 22, 2021

Fluvoxamine in the Acute Treatment of COVID-19 and Risk of Emergency Care and Hospitalization: A Randomized Clinical Trial

Reis G, et al. Lancet Glob Health. 2021;S2214-109X(21)00448-4.

The TOGETHER trial compared fluvoxamine with placebo to determine whether it helps reduce hospitalization from COVID-19 when administered to patients while they are acutely ill.

This placebo-controlled, blinded, randomized trial screened 9803 people and ultimately enrolled 1497 adults with symptomatic COVID-19 from 11 clinical sites in Brazil. All patients had ≥1 risk factor for severe disease and were randomized 1:1 to receive 100-mg fluvoxamine twice daily for 10 days, placebo, or other treatments. The primary outcome was hospitalization in the intention-to-treat population, with hospitalization defined as retention in an emergency setting or transfer to a tertiary hospital within 28 days of randomization. Bayesian statistics were used to evaluate the effectiveness of fluvoxamine vs placebo.

Enrolled patients were a mean of 50 years of age, and 58% of the patients were female. In total, 741 patients were allocated to receive fluvoxamine, and 756 received placebo. Hospitalizations from COVID-19 were lower in the fluvoxamine arm (11%) vs the placebo arm (16%; risk ratio [RR]: 0.68), and there also were fewer deaths in the fluvoxamine arm (17 vs 25; odds ratio: 0.68). There were no significant differences in the rate of treatment-emergent AEs between fluvoxamine and placebo.

Outpatients acutely ill with COVID-19 at increased risk of severe disease who received fluvoxamine had reduced rates of hospitalization compared with patients who received placebo.

Clinical Commentary
The TOGETHER study was an adaptive platform trial (APT). Some questions about treatment interventions are difficult to answer in the context of a traditional randomized, controlled trial. In APTs, the research team can investigate multiple treatments in a disease state (COVID-19 in this case), and the focus is on the disease state rather than the experimental therapies, which enter and leave the platform using a predetermined algorithm. Effective treatments graduate to the clinical treatment phase, and ineffective treatments are dropped. Once a treatment is dropped, it can be replaced by another intervention. APTs could redefine clinical trials in the future and are less costly than randomized, controlled trials.

This is the first large trial examining fluvoxamine for the treatment of acute COVID-19. When given to patients acutely ill with COVID-19 with risk factors for severe disease, fluvoxamine reduced the hospitalization rate compared with placebo. These findings are consistent with the results of a previous trial that tested a higher dose of fluvoxamine (100 mg 3 times/day) in a smaller cohort of patients. One strength of this trial was the rapid recruitment and enrollment of patients acutely ill with COVID-19 at increased risk of severe disease. The main limitation is that the COVID-19 disease state is still not well characterized and is a fluid environment.

Clinical Insights

  • Fluvoxamine 100 mg twice daily (10-day course) reduces the risk of hospitalization in outpatients with symptomatic acute COVID-19 who have risk factors for severe disease. Of importance, this is consistent with a previous study.
  • It is unknown why fluvoxamine reduced the risk of COVID-19–related hospitalization. It may be due to anti-inflammatory effects through activation of the sigma-1 receptor, which regulates cytokine production.
  • A second mechanism might be the antiplatelet activity of fluvoxamine, which reduces the risk of thrombosis.
  • Treatment adherence was an important predictor of success. Patients with >80% adherence had the greatest benefit from fluvoxamine.
  • Fluvoxamine is metabolized in part by CYP2D6 and is a potent inhibitor of CYP1A2 and CYP2C19, so be aware of drug–drug interactions with other agents that affect these pathways.

There are now 2 studies supporting the use of fluvoxamine in patients with COVID-19 to prevent severe disease and hospitalization. Fluvoxamine is available as a generic, inexpensive, and easy to use. Of note is that drug–drug interactions should be considered. This trial raises questions about the potential of other serotonin reuptake inhibitors (SSRIs), including fluoxetine, to prevent severe disease and hospitalization from COVID-19.

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