Fluvoxamine: A Review of Its Mechanism of Action and Its Role in COVID-19

Sukhatme, Vikas P.; Reiersen, Angela M.; Vayttaden, Sharat J.; Sukhatme, Vidula

doi:10.3389/fphar.2021.652688

Cited by 162 publications

(170 citation statements)

References 107 publications

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“…Studies implemented in subjects with a recent infection requiring hospitalization should ideally consider FIASMA combining other mechanisms of action to reduce excessive inflammatory response during sepsis or to attenuate neurological complications. For example, amitriptyline exerts neuroprotection via tropomyosin receptor kinase [ 106 ], and fluvoxamine via the Sigma-1 receptor activity may modulate SARS-CoV-2 induced cytokine storm [ 107 ].…”

Section: Discussionmentioning

confidence: 99%

Update on Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) in SARS-CoV-2 Infection

Loas

Corre

2021

Pharmaceuticals

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The SARS-CoV-2 outbreak is characterized by the need of the search for curative drugs for treatment. In this paper, we present an update of knowledge about the interest of the functional inhibitors of acid sphingomyelinase (FIASMAs) in SARS-CoV-2 infection. Forty-nine FIASMAs have been suggested in the treatment of SARS-CoV-2 infection using in silico, in vitro or in vivo studies. Further studies using large-sized, randomized and double-blinded controlled clinical trials are needed to evaluate FIASMAs in SARS-CoV-2 infection as off-label therapy.

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Section: Discussionmentioning

confidence: 99%

Update on Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) in SARS-CoV-2 Infection

Loas

Corre

2021

Pharmaceuticals

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“…Fluvoxamine, an FDA-approved antidepressant, is an S1R agonist. Although fluvoxamine may inhibit SARS-CoV-2 by interfering with endosomal viral trafficking, most studies suggests that its main benefit is likely to be as an inhibitor of excess cytokine production ( 360 ). Indeed, fluvoxamine has also been shown to modulate the response to bacterial sepsis in a beneficial manner in a mouse model ( 361 ).…”

Section: Host-targeting Compoundsmentioning

confidence: 99%

SARS-CoV-2 Antiviral Therapy

et al. 2021

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The development of effective antiviral therapy for COVID-19 is critical for those awaiting vaccination, as well as for those who do not respond robustly to vaccination. This review summarizes 1 year of progress in the race to develop antiviral therapies for COVID-19, including research spanning preclinical and clinical drug development efforts, with an emphasis on antiviral compounds that are in clinical development or that are high priorities for clinical development.

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“…1 The underlying mechanism of fluvoxamine for COVID-19 disease remains uncertain. Although hypotheses include several potential mechanisms, 6 the main reason for the initial study of fluvoxamine as a treatment of COVID-19 was its anti-inflammatory action through activation of the σ -1 receptor (S1R). 12 S1R is an endoplasmic reticulum (ER) chaperone membrane protein involved in many cellular functions, 13 including regulation of ER stress response/unfolded protein response and regulation of cytokine production in response to inflammatory triggers.…”

Section: Comparison With Prior Evidencementioning

confidence: 99%

“…5 There are several potential mechanisms for fluvoxamine in treatment of COVID-19 illness, including anti-inflammatory and possible antiviral effects. 6 A small placebocontrolled randomized trial has raised the possibility that fluvoxamine may reduce the risk of clinical deterioration in outpatients with COVID-19, suggesting the need for larger randomized, placebo-controlled studies. 1,2 To evaluate the efficacy of fluvoxamine to prevent progression of COVID-19 and hospitalization among outpatients with laboratory-documented SARS-CoV-2, we conducted a randomized, placebo-controlled adaptive platform trial in Minas Gerais, Brazil.…”

Section: Introductionmentioning

confidence: 99%

Effect of Early Treatment with Fluvoxamine on Risk of Emergency Care and Hospitalization Among Patients with COVID-19: The TOGETHER Randomized Platform Clinical Trial

Reis

Silva

et al. 2021

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BackgroundRecent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER randomized platform clinical trial for acutely symptomatic patients with COVID-19, we assessed the efficacy of fluvoxamine vs. placebo in preventing either extended emergency room observation or hospitalization due to COVID-19. Herein, we report the preliminary findings.MethodsThis placebo-controlled, randomized, adaptive, platform trial conducted among symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients with a known risk factor for progression to severe disease. Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) or placebo. The primary endpoint was a composite outcome of emergency room observation for >6 hours or hospitalization from COVID-19 up to 28 days post randomization. Secondary outcomes included viral clearance at day 7, time to hospitalization, mortality, and adverse drug reactions. We used a Bayesian analytic framework to determine effects along with probability of success of intervention compared to placebo. The trial is registered at clinicaltrials.gov (NCT04727424) and is ongoing.ResultsThe study team screened 9020 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomization from January 15, 2021 to August 6th 2021, when the trial arms were stopped for superiority. A total of 3238 patients were allocated to fluvoxamine (n=739), placebo (n=733) and other treatments (n=1766). Herein, we report the effectiveness of fluvoxamine vs. a concurrent placebo control. The average age of participants was 50 years (range 18-102 years); 57% were female. The proportion of patients observed in an emergency room for >6 hours or admitted to hospital due to COVID-19 was lower for the fluvoxamine group compared to placebo (77/739 vs 108/733; Relative Risk [RR]: 0.71; 95% Bayesian Credible Interval [95% BCI]: 0.54 - 0.93), with a probability of superiority of 99.4% surpassing the prespecified superiority threshold of 97.6% (risk difference 4.3%). Of the composite primary outcome events, 88% were hospitalizations. We found no significant relative effects between the fluvoxamine and placebo groups on viral clearance at day 7 (Odds ratio [OR]: 0.75; 95% Confidence Intervals [95% CI]: 0.53 - 1.07), mortality (OR: 0.70; 95% CI: 0.36 - 1.30), time to death (Hazard ratio [HR]: 0.79; 95% CI: 0.58 - 1.08), days hospitalized (Mean Difference (MD) 1.22 days; 95% CI: 0.98 - 1.53), number of days ventilated (MD 1.10; 95% CI: 0.70 - 1.73) or other secondary outcomes. Data capturing all 28 days of follow-up will be reported after August 26th, 2021.ConclusionsTreatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19, reduced the need for extended emergency room observation or hospitalization.FundingThe trial was supported by FastGrants and The Rainwater Foundation.

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Fluvoxamine: A Review of Its Mechanism of Action and Its Role in COVID-19

Cited by 162 publications

References 107 publications

Update on Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) in SARS-CoV-2 Infection

Update on Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) in SARS-CoV-2 Infection

SARS-CoV-2 Antiviral Therapy

Effect of Early Treatment with Fluvoxamine on Risk of Emergency Care and Hospitalization Among Patients with COVID-19: The TOGETHER Randomized Platform Clinical Trial

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