raj / Fluvoxamine for COVID-19 b98bd26a68bd8e2b3b8917098b2fefdb8a982728

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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

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 by 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.

Fluvoxamine in the ICU: Safety and efficacy of fluvoxamine in COVID-19 ICU patients: An open-label, prospective cohort trial with matched controls among 51 ICU COVID-19 patients hospitalized in the University Hospital Dubrava and University Hospital Centre Zagreb, Croatia. 

No statistically significant differences between groups were observed regarding the number of days on ventilator support, duration of ICU, or total hospital stay. However, overall mortality was lower in the fluvoxamine group, 58.8% (n = 30/51), than in the control group, 76.5% (n = 39/51), HR 0.58, 95% CI (0.36-0.94, P=.027). It appears fluvoxamine treatment in hospitalised ICU COVID-19 patients could have had a positive effect on mortality. https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15126

STOP COVID-2 (NCT04668950): Fluvoxamine for Early Treatment of Covid-19 (Stop Covid 2) - A decentralized, hub-and-spoke clinical trial conducted across the US and two provinces of Canada. The Data Safety Monitoring Board(DSMB) for the study recommended an early stop for futility due to a low case rate and difficulty recruiting patients, and treatment effects were observed.

South Korean trial(NCTO4711863): Fluvoxamine for Adults With Mild to Moderate COVID-19. A randomized, single-blind placebo control study of adult patients with symptomatic COVID-19 admitted to the community treatment center showed no significant differences in clinical deterioration between patients treated with fluvoxamine and placebo. https://icjournal.org/DOIx.php?id=10.3947/ic.2021.0142

Trials in progress 

The skeletal formula of fluvoxamine.
  • Fluvoxamine for Moderate SARS-CoV-2 (COVID-19) Infected Patients in Hungary(NCT04718480): A randomized, double-blind, placebo-controlled, adaptive two-stage design, human phase 2 study, with add-on treatment arrangement of fluvoxamine or placebo on top of standard of care, including antiviral and immunomodulant therapy and convalescent plasma therapy in serious cases as indicated by the investigator.
  • Thailand Study(NCT05087381): Randomized-controlled Trial of the Effectiveness of COVID-19 Early Treatment in Community used biomarkers to evaluate effectiveness. However, the study has been currently discontinued.

Clinical Guidelines

NIH: Fluvoxamine in NIH CVOID-19 treatment guidelines. There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of fluvoxamine for the treatment of COVID-19.https://www.covid19treatmentguidelines.nih.gov/therapies/immunomodulators/fluvoxamine/

FDA: FDA rejects antidepressant, fluvoxamine seen as possible Covid-19 treatment. https://www.statnews.com/2022/05/16/fda-rejects-antidepressant-seen-as-possible-covid-19-treatment/

IDSA Infectious Diseases Society of America: IDSA Guidelines on the Treatment and Management of Patients with COVID-19- Recommendation 28. The guideline panel recommends fluvoxamine only in the context of a clinical trial to better delineate the effects of fluvoxamine on disease progression, such as the need for hospital admission, ICU care, and ultimately, mortality.

The hypothesized mechanisms of action

Published reviews & commentary discussing fluvoxamine mechanisms

https://link.springer.com/article/10.1007/s40265-021-01636-5

https://www.nature.com/articles/s41380-021-01254-3

https://onlinelibrary.wiley.com/doi/10.1002/wps.20983

https://link.springer.com/article/10.1007/s40265-022-01681-8

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

https://www.psychiatrist.com/jcp/covid-19/repurposing-psychiatry-during-covid/

https://link.springer.com/article/10.1007/s00406-021-01326-z

https://www.psychiatria-danubina.com/UserDocsImages/pdf/dnb_vol34_no1/dnb_vol34_no1_171.pdf

https://www.nature.com/articles/s41380-021-01432-3

https://link.springer.com/article/10.1007/s00406-020-01231-x

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".

Functional Inhibition of Acid Sphingomyelinase (FIASMA)

According to 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 the inhibition of the 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/

Lysosomal Tropism 

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

Interference with Melatonin metabolism

Fluvoxamine increases melatonin levels 2-3 times by inhibiting the melatonin-metabolizing liver enzymes CYP1A2 and CYP2C19. Fluvoxamine, Melatonin and COVID-19. Psychopharmacology, Jan https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779245/

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 possible mechanisms 

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

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

Fluvoxamine side effects & drug-drug 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:

News coverage

See Also

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