Fluvoxamine: A cheap antidepressant reduced the need for hospitalization among high-risk adults with COVID-19

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A cheap antidepressant reduced the need for hospitalization among high-risk adults with COVID-19 in a study hunting for existing drugs that could be repurposed to treat coronavirus.

Researchers tested the pill used for depression and obsessive-compulsive disorder because it was known to reduce inflammation and looked promising in smaller studies.

They’ve shared the results with the U.S. National Institutes of Health, which publishes treatment guidelines, and they hope for a World Health Organization recommendation.

“If WHO recommends this, you will see it widely taken up,” said study co-author Dr. Edward Mills of McMaster University in Hamilton, Ontario, adding that many poor nations have the drug readily available. “We hope it will lead to a lot of lives saved.”

The pill, called fluvoxamine, would cost $4 for a course of COVID-19 treatment.

By comparison, antibody IV treatments cost about $2,000 and Merck’s experimental antiviral pill for COVID-19 is about $700 per course. Some experts predict various treatments eventually will be used in combination to fight the coronavirus.

Researchers tested the antidepressant in nearly 1,500 Brazilians recently infected with coronavirus who were at risk of severe illness because of other health problems, such as diabetes. About half took the antidepressant at home for 10 days, the rest got dummy pills. They were tracked for four weeks to see who landed in the hospital or spent extended time in an emergency room when hospitals were full.

In the group that took the drug, 11% needed hospitalization or an extended ER stay, compared to 16% of those on dummy pills.

The results, published Wednesday in the journal Lancet Global Health, were so strong that independent experts monitoring the study recommended stopping it early because the results were clear.

Questions remain about the best dosing, whether lower risk patients might also benefit and whether the pill should be combined with other treatments.

The larger project looked at eight existing drugs to see if they could work against the pandemic virus. The project is still testing a hepatitis drug, but all the others—including metformin, hydroxychloroquine and ivermectin—haven’t panned out.

The cheap generic and Merck’s COVID-19 pill work in different ways and “may be complementary,” said Dr. Paul Sax of Brigham and Women’s Hospital and Harvard Medical School, who was not involved in the study. Earlier this month, Merck asked regulators in the U.S. and Europe to authorize its antiviral pill.


Coronavirus disease 2019 (COVID-19), caused by infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can result in serious illness leading to hospitalization, intensive care unit admission, and death.1 Clinical deterioration typically occurs during the second week of illness.

Early studies of COVID-19 found that hospitalization most often occurs within 8 to 10 days of initially mild to moderate symptoms.2-4 Further evidence suggested that lung damage from COVID-19 was related to an excessive inflammatory response, prompting numerous trials of immunomodulatory drugs.5,6

A potential mechanism for immune modulation is σ-1 receptor (S1R) agonism.7 The S1R is an endoplasmic reticulum chaperone protein with various cellular functions, including regulation of cytokine production through its interaction with the endoplasmic reticulum stress sensor inositol-requiring enzyme 1α (IRE1).

Previous studies have shown that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) with high affinity for the S1R,8 reduced damaging aspects of the inflammatory response during sepsis through the S1R-IRE1 pathway, and decreased shock in murine sepsis models.9

Fluvoxamine is a strong S1R agonist,10,11 is highly lipophilic, and has rapid intracellular uptake.12 This study tested whether fluvoxamine, given as early treatment in individuals with mild COVID-19 illness, may prevent clinical deterioration.

Discussion

In this preliminary randomized clinical trial, fluvoxamine (an S1R agonist) was associated with a reduction in clinical deterioration in adult outpatients with COVID-19. No fluvoxamine-treated patients met criteria for clinical deterioration as defined in the study, whereas 8.3% of patients taking placebo met this end point. However, because of study limitations, these findings need to be interpreted as hypothesis generating rather than as a demonstration of efficacy.

This double-blind, placebo-controlled, randomized clinical trial demonstrated the feasibility of a fully remote (contactless) study during the COVID-19 pandemic. Adult outpatients with COVID-19 are in self-quarantine, but few studies have focused on the care of this vulnerable population.

This design included a short time from symptom onset to first dose of medication (median, 4 days), efficient study treatment initiation (92% took the first dose on the same day as they were contacted), and representative sample of race and sex.20 The study required approximately 4500 hours of staff time and 30 hours of time per participant.

If fluvoxamine is determined to be effective in treating COVID-19, the underlying mechanism needs further clarification. The study was prompted by a hypothesis involving the influence of fluvoxamine on the S1R-IRE1 pathway. Anti-inflammatory (cytokine reduction) actions resulting from S1R activation would fit with recent findings of benefits of other anti-inflammatory drugs, such as colchicine and corticosteroids, for COVID-19.21,22

However, a recent study found lower levels of cytokines in patients with severe COVID-19 vs patients with bacterial sepsis.23 Alternative mechanisms of a potential fluvoxamine benefit include direct antiviral effects via its lysosomotropic properties,24 modulation of the effect of IRE1 effects on autophagy,25 and SSRI inhibition of platelet activation.26

The potential advantages of fluvoxamine for outpatient treatment of COVID-19 include its safety,27 widespread availability, low cost, and oral administration. Fluvoxamine does not promote QT prolongation unlike other SSRIs.28 However, fluvoxamine has adverse effects and can cause drug-drug interactions, particularly via inhibition of cytochromes P450 1A2 and 2C19.29

reference link :https://jamanetwork.com/journals/jama/fullarticle/2773108?resultClick=1


More information: Gilmar Reis et al, Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial, The Lancet Global Health (2021). DOI: 10.1016/S2214-109X(21)00448-4

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