raj / Fluvoxamine for COVID-19 5d40903ba8b643b1c10582bc7f1032e6aefcc27a

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) which is being trialed for possible therapeutic use in COVID-19.

COVID-19 clinical trials

Fluvoxamine showed promise in a 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.

More on the Golden Gate Fields outbreak can be found in this Berkeleyside article.

Trials in progress 

• Fluvoxamine Administration in Moderate SARS-CoV-2 (COVID-19) Infected Patients - Randomized, double-blind, placebo-controlled trial in 100 moderate COVID-19 hospitalized patients.
• 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.
• Fluvoxamine for Adults With Mild to Moderate COVID-19 - Randomized control trial of 400 patients admitted to community treatment centers in South Korea. Mild to moderate symptoms.
• Repurposed Approved Therapies for Outpatient Treatment of Patients With Early-Onset COVID-19 and Mild Symptoms - Parallel assigment, 4-arm randomized control trial that includes a Fluvoxamine arm. Early treatment, outpatient. 2724 participants total across 4 arms.
  • Informational website on the TOGETHER trial.
  • Feb 9, 2021 news article about this trial.

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".

• "Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor"
• "Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?"

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 should 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 2021 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779245/

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

• Kaiser Health News - Scientists Seek Covid Treatment Answers in Cheap, Older Drugs
• 60 Minutes - Finding a possible early treatment for COVID-19 in a 40-year-old antidepressant
• Wired - How a Medication for OCD Ended Up in a Covid-19 Trial
• ScienceNews - The antidepressant fluvoxamine could keep mild COVID-19 from worsening
• Washington Post - Existing drugs could help treat covid-19. How do we know when to use them?
• Inverse.com - A surprising treatment for COVID-19 could be the key to stopping virants
• MSN-https://www.msn.com/en-us/health/medical/more-patients-take-anti-depressant-to-beat-covid-symptoms/ar-BB1eR8Dm
• LA Times: https://www.latimes.com/california/story/2021-02-03/can-common-antidepressant-help-covid-19-fight
• Science News: https://www.sciencenews.org/article/covid-19-coronavirus-antidepressant-fluvoxamine-treatment
• Health Affairs Blog: https://www.healthaffairs.org/do/10.1377/hblog20210208.174907/full/
• Scientific American: https://www.scientificamerican.com/article/these-drugs-might-prevent-severe-covid1/#:~:text=Fluvoxamine%2C%20a%20pill%20used%20for,the%20drug%20experienced%20worsening%20symptoms.
• STAT News: https://www.statnews.com/2020/11/12/pill-fluvoxamine-to-treat-ocd-anxiety-may-prevent-covid-19-from-worsening-preliminary-study-suggests/
• Elemental: https://elemental.medium.com/psychiatric-drugs-could-be-the-key-to-treating-covid-19-cb6d703e2d0f
• CNN: https://www.cnn.com/2021/01/11/health/fluvoxamine-covid-19-treatment-study/index.html
• CNN Health: https://www.cnn.com/2021/02/27/health/covid-19-drug-repurposing-gupta/index.html

• California Healthline- https://californiahealthline.org/news/article/fluvoxamine-antidepressant-covid-treatment-repurposed-drugs-generics/

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:

• "What we know about fluvoxamine for COVID-19 and how to prescribe. Providers thinking about using fluvoxamine will find this information helpful. " - Dr. Eric Lenze, one of the researchers who is running the fluvoxamine trials (above).
• Website dedicated to fluvoxamine & caffeine information.

See also

• COVID-19 therapeutics
• Fluvoxamine with Melatonin: The authors of this article suggest coadministration of Fluvoxamine and Melatonin can be beneficial. Fluvoxamine, Melatonin and COVID-19. Psychopharmacology, Jan 2021 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779245/
• Repurposing of psychiatric drugs: "What Were You Before the War?" Repurposing Psychiatry During the COVID-19 Pandemic https://pubmed.ncbi.nlm.nih.gov/32271506/
• STOP COVID 1 secondary analysis:  Acute-stage COVID19 symptom dynamics over ~15 days: https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab090/6154666?login=true 
•   Widely available lysosome targeting agents should be considered as potential therapy for COVID-19. https://pubmed.ncbi.nlm.nih.gov/32522674/