A recent meta-analysis of a small number of fluvoxamine efficacy trials enrolling just over 2,000 patients found that fluvoxamine reduces the chances of severe hospitalization by up to 95%. If this efficacy is maintained in larger studies, fluvoxamine could be an important component of the Test-to-Treat strategy that the US is in the process of rolling out.

Fluvoxamine was not developed as an anti-COVID drug. It has long been used as a mood-stabilizing selective serotonin reuptake inhibitor (SSRI) and is now available as an inexpensive generic drug worldwide.

Hallmarks of Severe Covid

The apparent effectiveness of fluvoxamine raises the question of how it might act independently of its use as a mood stabilizer. The following review by Sukhatme et al. provides details of the potential mechanisms by which fluvoxamine has the potential to interfere with the most severe consequences of COVID 19 infection, including cytokine storms, coagulation, and hyperinflammation.

FIGURE 1: Fluvoxamine acts independently to inhibit several of the pathways that are characteristic of severe COVID-19.ACCESS HEALTH INTERNATIONAL

There are six known mechanisms, potentially more, by which fluvoxamine may act to treat late-stage Covid and prevent late-stage sequela: reduction In platelet aggregation, decreased mast cell degranulation, interference with endolysosomal viral trafficking and membrane binding, sigma-1 receptor activity, and increased melatonin levels.

FIGURE 2: Potential anti-COVID-19 mechanisms of action of fluvoxamine, including reduction of serotonin uptake by platelets, reduction of histamine release from mast cells, interference with lysosomal trafficking and binding, inhibition of melatonin SUKHATME ET AL.

Inhibition of Cytokine Storm: Decreased Mast Cell Degranulation

The cytokine storm is a life-threatening systemic inflammatory syndrome involving elevated levels of circulating cytokines and immune-cell hyperactivation. Essentially, this is the alarm bell in your immune system once a dangerous pathogen is detected, sending immune defenses to fight off the invader and resulting in severe symptoms.

One of the primary triggers of the cytokine storm is the interaction between SARS-CoV-2 and human mast cells, which are often viral reservoirs for RNA viruses. Pulmonary tissues in the lungs of deceased Covid patients are often linked to activated mast cells, which are degranulated by viruses upon infection.

Fluvoxamine also interacts with mast cells, decreasing mRNA levels of protease-1, which promotes mucosal permeability in intestinal allergic hypersensitivity reactions. This likely impacts the efficiency of interaction between the virus and mast cells, leading to less severe cytokine storm responses and symptoms. Therefore, fluvoxamine has the potential to reduce the cytokine storm pathway of severe SARS-CoV-2 infection.

Inhibition of Coagulation: Reduction In Platelet Aggregation

Coagulation is the thickening of the blood as a result of blood platelets aggregating. This may lead to bloodstream issues like hypertension. Although platelets do not produce serotonin, they do absorb and contain high concentrations of the chemical. When aggregating in the bloodstream, platelets release serotonin to facilitate hemostasis.

Fluvoxamine inhibits the uptake of serotonin from platelets and therefore inhibits platelet aggregation. Fluvoxamine is a serotonin uptake inhibitor and inhibits serotonin concentration in platelets prior to clot formation. A 2011 study showed that patients taking SSRIs measured lower levels of coagulation than those that were not taking the drugs. Therefore, fluvoxamine has the potential to reduce the coagulation pathway of severe SARS-CoV-2 infection.

Inhibition of Hyperinflammation: Sigma-1 Receptor Activity

Hyperinflammation following coagulation causes a number of health issues, including joint pain, gastrointestinal issues, and in some cases, brain injury. One player in inflammation is the sigma-1 receptor, which regulates endoplasmic reticulum mitochondrial calcium ion signaling, resulting in pro-inflammatory responses in higher concentrations.

Fluvoxamine upregulates interleukin-10 (IL-10), which is an anti-inflammatory protein. The sigma-1 receptor downregulates other interleukins, such as IL-6 and IL-8, but not IL-10. Therefore high levels of IL-10 can inhibit the sigma-1 receptor and its hyperinflammatory processes. In other words, fluvoxamine may reduce Covid-related hyperinflammation.

Indirect Mechanisms: Endolysosomal Viral Trafficking And Membrane Binding

SARS-CoV-2, along with other beta-coronaviruses, use lysosomal trafficking to escape infected cells. Lysosomes break down worn-out cell structures in a process called apoptosis, which the virus uses as a means of leaving one infected cell to find another.

Basic SSRIs like fluvoxamine actually hinder lysosomes by interfering with their charge and reducing their membrane-crossing efficiency. This may not impact the virus itself, but it impedes one of its major routes of escape, resulting in antiviral effects that could make extended infections more difficult.

We also note that lysosomotropic drugs also impact viral entry of the SARS-CoV-2. While fluvoxamine has not been tested specifically for this feature, it has an anti-lysosome function, meaning it may also impact viral entry.

Inhibition of Hyperinflammation: Increased Melatonin Levels

Fluvoxamine elevates melatonin levels by the inhibition of the enzyme CYP1A2, which is involved in the metabolization of polyunsaturated fatty acids. Some CYP1A2 reactions result in elevated blood pressure and promoted inflammation responses. Melatonin mitigates inflammation from the NLRP3 pathway, a common tool for SARS-CoV-2. Fluvoxamine, therefore, may reduce Covid-related hyperinflammation.

Although it is still early days, given the relatively limited trials fluvoxamine has been shown prevention of serious COVID, the results already look promising. Moreover, the study by Sukhatme et al. finds that there are many independent biochemical pathways that may explain how these drugs, given earlier in infection, may prevent serious disease. Although fluvoxamine does not seem to have a direct antiviral effect other than effective endosomal viral entry into the cell, it does have a number of activities that fortuitously inhibit precisely those pathways that are characteristic of the most serious forms of COVID-19. We can only hope that these promising results hold up against further investigation.