Does Fluvoxamine Work For COVID-19?

If you or a loved one are stuck in a hospital with COVID-19 there are not a lot of options outside of emergency use authorized therapeutics that lack long-term safety data. You can’t get ivermectin or hydroxychloroquine without a court order, and even then it is often too late. In fact, there is only one off-label drug with a 30+ year safety profile that is shown to work for COVID and that you could get a doctor to prescribe for you. 

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that has been used to treat depression and OCD for more than 30 years. Recently, fluvoxamine has been evaluated as a treatment for COVID-19. For psychiatric disease, fluvoxamine is given once daily and its effects take about 4-6 weeks to kick in, presumably due to changes in serotonin levels in the brain. In COVID-19 it is used for its short-term antiviral, anti-inflammatory, and blood-thinning effects. For COVID it is taken twice daily, usually only for 2 weeks. Side effects are primarily nausea, vomiting, diarrhea, headaches, and sleepiness. When used for depression it has been rarely linked to suicidal thoughts, especially in young adults, which are usually preceded by akathisia - a kind of fidgety, restless movement disorder. 

We will briefly review the evidence base and mechanisms of action and then discuss the official regulatory response to this cheap therapeutic option for COVID.

Evidence That Fluvoxamine Treats COVID-19

A prospective open-label study found that patients treated with fluvoxamine soon after diagnosis were less likely to require hospitalization (0%), compared to 12.5% hospitalized in the placebo group. Additionally, no patients treated with fluvoxamine experienced ongoing symptoms after 14 days, whereas 60% of untreated patients experienced ongoing, or long COVID symptoms. 

In a double-blind randomized phase 2 clinical trial, none of the fluvoxamine-treated patients experienced deteriorating symptoms. On the contrary, 8.3% of untreated patients experienced clinical deterioration. 

The TOGETHER phase 3 clinical trial, the largest trial of fluvoxamine for treating COVID-19 to date with 1497 participants, showed that fluvoxamine treatment prevented hospitalization of COVID-19 patients. In the ‘per protocol’ group that took at least 80% of the prescribed doses, there was a 12x lower rate of death compared to placebo (1 death in the fluvoxamine group and 12 in the placebo group). 

Most trials studied fluvoxamine as an early treatment for COVID-19, but there was a small open-label prospective cohort study in 102 critically ill ICU patients (51 in each arm) using either fluvoxamine or the standard of care. While there was no observed improvement in duration of ICU stay, ventilator use, or overall hospital stay with fluvoxamine treatment, there was a significant decrease in death, which is obviously the most important clinical endpoint. In the placebo arm there 76.5% died compared with only 58.8% in the fluvoxamine arm - a decrease of 23% with a p-value of 0.02 (anything under 0.05 is traditionally considered statistically significant) indicating the likelihood this result was due to chance alone was no more than 2%.

How Does Fluvoxamine Work for COVID?

Fluvoxamine has several possible mechanisms of action in COVID-19 patients. 

Fluvoxamine is known to stabilize platelets to prevent clotting and serotonin release. Platelet abnormalities, such as blood clots, which can cause heart attacks, strokes, deep vein thrombosis, and pulmonary embolism, are common serious pathologies triggered by the spike protein of COVID-19. Serotonin released by platelets into the bloodstream is a trigger for platelet aggregation - which is the mechanism of clot formation - and also has an inflammatory effect on vascular endothelium. All of these negative effects may be prevented by fluvoxamine. 

Fluvoxamine increases endogenous levels of melatonin, an important sleep hormone, which has powerful anti-inflammatory effects at higher concentrations. Melatonin is known to inhibit the signaling pathways associated with the COVID-19-mediated cytokine storm. In addition, melatonin treatment has been shown to improve survival of intubated COVID-19 patients.

Fluvoxamine also inhibits inflammatory cytokines and sepsis by activating the anti-inflammatory Sigma-1 receptor, and it may even block entry of COVID-19 into human cells. 

Regulatory Roadblocks and Some Acceptance

On January 22, 2021, before the phase 3 study or ICU study had been completed a panel of 30 key opinion leaders from the NIH, CDC and leading academic institutions spent 45 minutes reviewing the existing 2 early trials for Fluvoxamine, along with the proposed mechanisms of action. They voted 11 to 5 in favor of encouraging doctors to speak to their patients about the fluvoxamine in the context of a COVID-19 infection. The NIH soon added fluvoxamine to it’s COVID treatment page, but the official stance remained “neither for nor against” it’s use (the same stance they took at that time towards monoclonal antibodies, which were then being widely used). 

Encouragingly after the phase 3 trial results Johns Hopkins, a leading medical school began recommending fluvoxamine as a COVID therapy within seven days of symptom onset if monoclonal antibodies were unavailable.

However, in their most recent review of the evidence base for fluvoxamine on Jan 5, 2022, the NIH still does not find adequate evidence to recommend using it for COVID-19.

After Steve Kirsch had bankrolled the fluvoxamine trials he found the FDA would not accept an Emergency Use Authorization (EUA) application for fluvoxamine that was not submitted through a pharmaceutical company and there is no company willing to make the submission on behalf of the public, even if private parties pay the cost.

In hospitals it remains easy enough to obtain fluvoxamine when patients complain of depression, whether or not they are diagnosed with COVID-19, i.e. no one actually believes fluvoxamine is too dangerous to prescribe to a COVID-19 patient. Many physicians and researchers believe the evidence of benefit is clear and incontrovertible, despite some weaknesses. Either way, all medical interventions are a balance of risks and benefits. If the expected benefits of a drug outweigh its risks and the risk of untreated disease, then it should be considered.