The Unexpected Story of Fluvoxamine
In the frantic search for COVID-19 treatments, a decades-old antidepressant offered a surprising glimmer of hope.
Explore the StoryWhen the COVID-19 pandemic began, scientists launched a global race to find effective treatments. They looked not only to new drugs but also to existing medications that could be repurposed against the virus. One of the most surprising candidates was fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) used since the 1980s to treat depression and obsessive-compulsive disorder.
This article explores the compelling science and clinical evidence behind this unlikely contender, a journey that shows how sometimes, help can come from the most unexpected places.
An existing antidepressant explored for COVID-19 treatment
Multiple trials investigated its effectiveness
Potential treatment for resource-limited settings
Fluvoxamine is a well-established antidepressant that functions as a selective serotonin reuptake inhibitor (SSRI). It works primarily by increasing levels of serotonin, a key neurotransmitter in the brain, by blocking its reabsorption into neurons 7 .
For decades, its use was confined to psychiatry. However, fluvoxamine has another, less prominent property that would later catch the attention of COVID-19 researchers: it is a potent agonist of the sigma-1 receptor 1 4 . This receptor plays a key role in regulating the body's inflammatory response, a feature that would become central to the drug's proposed new use.
The theory that fluvoxamine could help COVID-19 patients is not as far-fetched as it might seem. Researchers identified several mechanisms through which the drug might combat the severe effects of the disease.
The most severe stages of COVID-19 are often driven not by the virus itself, but by the immune system's overreaction, a destructive phenomenon known as a "cytokine storm." Fluvoxamine's ability to stimulate the sigma-1 receptor is believed to help control this dangerous inflammation 1 4 .
Reducing platelet aggregation: COVID-19 can cause abnormal blood clotting. SSRIs like fluvoxamine are known to reduce platelet aggregation, potentially mitigating this risk 4 .
Interfering with viral trafficking: As a lysosomotropic drug, fluvoxamine can accumulate in cellular components called lysosomes. Some researchers suggest this could disrupt the pathway some coronaviruses use to exit infected cells 4 .
Regulating mast cell degranulation: Mast cells are part of the immune system and can contribute to the inflammatory cascade in COVID-19. Antidepressants have been shown to stabilize these cells, reducing the release of inflammatory substances 4 .
These diverse mechanisms positioned fluvoxamine as a promising, affordable, and widely available drug worthy of urgent investigation.
Among the many studies conducted, the TOGETHER Trial stands out as a pivotal investigation that provided strong, high-quality evidence for fluvoxamine's effectiveness. This large-scale study was designed to cut through the noise and definitively test several repurposed drugs for early COVID-19 treatment.
The TOGETHER Trial was a randomized, double-blind, placebo-controlled platform trial conducted in Brazil 1 2 . This is considered the gold standard in clinical research.
The trial enrolled 1,497 symptomatic, high-risk adult outpatients with a confirmed COVID-19 diagnosis. All participants had at least one additional risk factor for severe disease, and they were enrolled within seven days of showing symptoms 2 .
Participants were randomly assigned to receive either fluvoxamine (100 mg twice daily for 10 days) or a matching placebo.
The main goal was to determine whether the treatment reduced the number of patients who required emergency care for over 6 hours or hospitalization due to COVID-19 over a 28-day period 2 .
The results, published in 2021, were striking. They demonstrated that fluvoxamine provided a significant clinical benefit for high-risk patients early in their illness.
| Group | Number of Patients | Patients with Primary Outcome (Hospitalization or >6h ER Observation) | Percentage |
|---|---|---|---|
| Fluvoxamine | 741 | 79 | 10.7% |
| Placebo | 756 | 119 | 15.7% |
The data showed a relative risk reduction of 32% for the primary outcome in the fluvoxamine group 1 . Perhaps even more impressive was the finding on mortality: there was one death in the fluvoxamine group compared to 12 in the placebo group, suggesting the drug might have a powerful effect on preventing the most tragic outcomes 1 .
Within the context of the larger TOGETHER Trial, which tested multiple drugs like hydroxychloroquine and ivermectin, fluvoxamine was the only treatment to show a clear positive effect at the time .
in hospitalization/ER retention for high-risk COVID-19 patients
Science advances not through a single study, but through the consensus of multiple investigations. A meta-analysis published in 2022 combined the results of three randomized trials, including the TOGETHER Trial and the STOP COVID 1 & 2 studies. This analysis, encompassing over 2,100 patients, concluded that fluvoxamine led to a 31% reduction in clinical deterioration or hospitalization compared to a placebo 2 .
| Trial | Location | Sample Size | Key Finding |
|---|---|---|---|
| STOP COVID 1 | USA | 152 | 0% clinical deterioration in fluvoxamine group vs. 8.7% in placebo group 1 |
| STOP COVID 2 | USA & Canada | 547 | No significant difference in clinical deterioration 2 |
| TOGETHER Trial | Brazil | 1,497 | 32% relative risk reduction in hospitalization/ER retention 1 |
However, the story is not one of unanimous success. The ACTIV-6 trial, a large U.S. study, found that fluvoxamine at doses of 50 mg and 100 mg twice daily did not speed up recovery from mild-to-moderate COVID-19 compared to a placebo 8 .
Similarly, a real-world study found that patients taking fluvoxamine did not see a significant benefit in preventing deterioration and had higher rates of pneumonia and hospitalization, though no difference in survival was observed 9 .
This mix of positive and negative results highlights that the effectiveness of fluvoxamine may depend on factors like patient population, timing of treatment, and disease severity.
The conflicting evidence suggests that while fluvoxamine may be beneficial for certain high-risk groups when administered early, its effectiveness may vary across different populations and treatment protocols.
To understand how these clinical trials were conducted, it's helpful to know the essential tools researchers used to measure fluvoxamine's effects.
| Tool | Function in Research | Example from Fluvoxamine Trials |
|---|---|---|
| Placebo | An inactive substance that looks identical to the drug being tested, allowing for blinded comparison. | The control groups in the TOGETHER and STOP COVID trials received placebo pills 1 2 . |
| Pulse Oximeter | A device that measures oxygen saturation in the blood, a key indicator of respiratory distress in COVID-19. | Provided to participants in the STOP COVID trials for daily monitoring of oxygen levels 6 . |
| Electronic Data Capture (EDC) | A secure system for collecting and managing patient data from clinical trials. | The STOP COVID trials used REDCap surveys to collect vital signs and symptom data remotely 6 . |
| Automated Blood Pressure Cuff | Allows for at-home monitoring of vital signs, which is crucial for fully-remote trials. | Used in the STOP COVID trials to track safety metrics like pulse and blood pressure daily 6 . |
| Ecological Momentary Assessment (EMA) | A method where participants report symptoms in real-time via smartphone, providing high-frequency data. | STOP COVID 1 used EMA to track nausea, anxiety, and concentration twice daily 6 . |
Gold standard methodology to eliminate bias
Advanced tools for at-home patient tracking
Real-time symptom reporting via smartphones
The story of fluvoxamine and COVID-19 is a fascinating chapter in the history of pandemic science. The evidence, particularly from the well-designed TOGETHER Trial, strongly suggests that this cheap, widely available, and well-understood drug can reduce hospitalizations and save lives when given early to high-risk individuals. It represents a powerful tool, especially for resource-limited settings that lack access to more expensive therapies.
The fluvoxamine story underscores a powerful idea: in the face of a new threat, innovative thinking and the willingness to repurpose old tools can sometimes yield surprising and life-saving victories.
Yet, the conflicting results from other studies remind us that medical science is a process of continual inquiry. Major health bodies like the WHO and NIH have reviewed the same data and arrived at different conclusions regarding its recommendation.
Low-cost option for resource-limited settings
Decades of safety data from psychiatric use
Already approved in many countries worldwide