raj / Fluvoxamine for COVID-19 7818805f019e3e8ffceb3752a9a9ae639ffe5636

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Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that has been trialed for possible therapeutic use in COVID-19 and is showing promising results.

Fluvoxamine, via agonism of the sigma-1 receptor, has shown benefit in animal models of septic shock.

COVID-19 clinical trials 

Trials that have been completed and published

STOP COVID: Fluvoxamine showed promise in a double-blinded, randomized, placebo-controlled trial of 152 COVID-19-positive outpatients.  In a paper published in November 2020 in the Journal of the American Medical Association:

Clinical deterioration occurred in 0 of 80 patients in the fluvoxamine group and in 6 of 72 patients in the placebo group (absolute difference, 8.7% [95% CI, 1.8%-16.4%] from survival analysis; log-rank P = .009). The fluvoxamine group had 1 serious adverse event and 11 other adverse events, whereas the placebo group had 6 serious adverse events and 12 other adverse events. -JAMA

In a prospective cohort study of fluvoxamine for an outbreak at the Golden Gate Fields racetrack:

Overall, 65 persons opted to receive fluvoxamine 50mg twice daily and 48 declined. Incidence of hospitalization was 0% (0/65) with fluvoxamine and 12.5% (6/48) with observation alone. At 14 days, residual symptoms persisted in 0% (0/65) with fluvoxamine and 60% (29/48) with observation.

TOGETHER TRIAL: Repurposed Approved Therapies for Outpatient Treatment of Patients With Early-Onset COVID-19 and Mild Symptoms - Parallel assignment, 4-arm randomized control trial that includes a Fluvoxaminearm.https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00448-4/fulltext

1497 Brazilian adults participated in the study looking at the effect of early treatment with fluvoxamine on the risk of emergency care and hospitalization among patients with COVID-19. They used Bayesian analysis, which showed Bayesian credible interval [95% BCI]: 0·52-0·88), with a probability of Fluvoxamine superiority of 99·8% over placebo in reducing the need for hospitalization. 

Informational website on the TOGETHER trial.

COVID-OUT TRIAL: Outpatient Treatment for SARS-CoV-2 Infection, a Factorial Randomized Trial, conducted bu the University of Minnesota.

The primary outcome measures of hypoxia, ER visits, and hospitalizations in participants who received Fluvoxamine 50mg BID showed no significant benefit. Presented at NIH Grand rounds.

STOP COVID-2 : Fluvoxamine for Early Treatment of Covid-19 (Stop Covid 2) - An expansion of the smaller contactless (telemedicine) randomized control trial above to 1100 participants. Early treatment, outpatient.

Trials in progress 

The skeletal formula of fluvoxamine.

Clinical Guidelines

Fluvoxamine in NIH CVOID-19 treatment guidelines.

https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/

Mechanism of possible benefit?

A review of all the mechanisms of action of Fluvoxamine and its role in COVID-19 

https://www.frontiersin.org/articles/10.3389/fphar.2021.652688/full

Sigma-1 receptor

Mechanisms of potential benefit in COVID-19 may include sigma-1 receptor agonism.  See "Fluvoxamine alleviates ER stress via induction of Sigma-1 receptor" and "Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis".

Possible mechanisms common with other antidepressants

The Enzyme Hypothesis: Fluvoxamine inhibits acid Sphingomyelinase which is needed for viruses to enter the cell -Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine. Emerging Microbes and infections vol 9, 2020. https://pubmed.ncbi.nlm.nih.gov/32975484/

Ceramide-door theory: Ceramides, which act as doors to let the virus enter the cells are also inhibited because of inhibition of enzyme Acid Sphingomyelinase by Fluvoxamine. Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells. Cell Reports Medicine Nov 2020. https://pubmed.ncbi.nlm.nih.gov/33163980/

The Lysosome theory: Fluvoxamine has lysosomotropic properties which inhibit movement and dissemination of virus particles in the lysosome pathway in the cells of the body. Widely available lysosome targeting agents can be considered as potential therapy for COVID-19. International Journal of Antimicrobial Agents. Aug 2020.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275137/

Increasing Melatonin levels in the brain. Fluvoxamine increases nighttime levels of melatonin 2-3 times through its inhibition of the melatonin-metabolizing liver enzymes CYP1A2 and CYP2C19.Fluvoxamine, Melatonin and COVID-19. Psychopharmacology, Jan https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779245/

Modulating endocytic trafficking of SARS-CoV-2 spike protein.  https://www.biorxiv.org/content/10.1101/2021.06.15.448391v1 

As an antidepressant

An observational study of 7,345 hospitalized COVID-19 patients hinted at possible benefit of prior antidepressant usage. 

As an anti-viral

In an October, 2020 preprint, fluoxetine, a related SSRI, showed in vitro anti-SARS-CoV-2 activity in Vero and Calu-3 cells.

Other methods of possible benefit

There is speculation that fluovamine may have benefits in COVID-19 by increasing nighttime plasma levels of melatonin.

News coverage

Notes on side effects & interactions

Fluvoxamine does not play well with caffeine — it makes a cup of coffee last 31-35 hours instead of 5 (see also and also). For more information on potential interactions see:

See also

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