COVID-19: Antidepressant reduces risk of hospitalization and death

• A clinical trial has found that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) antidepressant, significantly reduces the chances of hospitalization and death in high-risk patients with COVID-19.
• Fluvoxamine is cheap, widely available, and has an established safety profile.
• If taken shortly after diagnosis, the drug may prevent the immune overreaction, or “cytokine storm,” often responsible for severe disease and death.
• The authors caution that other SSRI antidepressants, such as fluoxetine (Prozac), may not have the same anti-inflammatory effects in COVID-19.

In wealthy nations, vaccination programs have been turning the tide against COVID-19. However, many low and middle income countries still have very limited access to vaccines.

“Identifying inexpensive, widely available, and effective therapies against COVID-19 is therefore of great importance, and repurposing existing medications that are widely available and have well-understood safety profiles is of particular interest,” says Edward Mills, Ph.D., a health researcher at McMaster University in Ontario, Canada.

Doctors have therefore given a cautious welcome to the news that, at a cost of around $4, a 10-day course of an existing drug can significantly reduce the risk of hospitalization and death for outpatients at high risk of severe COVID-19.

The drug, an SSRI antidepressant called fluvoxamine, has been in use for decades to treat depression and obsessive-compulsive disorder. It also has an established safety record in these conditions.

The news came from a clinical trial in Brazil, which found that patients receiving the drug early in the course of the infection had a 32% reduced risk of hospitalization compared with those receiving a placebo.

The absolute reduction in risk was a more modest 5%. However, the researchers say this compares favorably with the benefits of more expensive outpatient treatments such as monoclonal antibodies.

Dr. Mills was co-principal investigator of the fluvoxamine study, which was part of the ongoing TOGETHER trial of repurposed treatments for COVID-19.

High risk of severe disease

The researchers recruited 1,497 patients in outpatient clinics who tested positive for SARS-CoV-2, the virus that causes COVID-19.

All the participants were at high risk of severe disease, for example, due to hypertension, diabetes, or obesity.

The researchers randomly assigned 741 patients to take fluvoxamine and 756 to take placebo pills that looked identical.

Overall, there were 17 deaths in the fluvoxamine group and 25 deaths in the placebo group, equating to a relative reduction in mortality of 32%.

However, for the subset of patients who took the medication as instructed (defined as taking at least 80% of the doses), there was only one death in the fluvoxamine group compared with 12 deaths in the placebo group.

The research appears in The Lancet Global Health.

The authors conclude:

“Given fluvoxamine’s safety, tolerability, ease of use, low cost, and widespread availability, these findings might influence national and international guidelines on the clinical management of COVID-19.”

Promising early research

Researchers carried out the clinical trial after a large observational study in France reported a significant association between antidepressant use and a reduced risk of intubation or death among patients hospitalized with COVID-19.

In addition, a small clinical trial in the United States found that COVID-19 outpatients receiving treatment with fluvoxamine were less likely to deteriorate in the following 15 days than those who received a placebo.

Several possible mechanisms, including antiviral activity, could explain the efficacy of fluvoxamine in COVID-19, but researchers believe the most likely contender is its anti-inflammatory action.

The greatest threat to the survival of individuals with severe COVID-19 may not be the virus itself but rather the overactivation of their immune systems, or cytokine storm.

Fluvoxamine is better than other SSRIs at activating a receptor known as sigma-1 that reduces the production of inflammatory signaling molecules called cytokines.

Angela Reiersen, M.D., Ph.D., associate professor of psychiatry at Washington University in St. Louis, MO, and one of the new clinical trial authors, wrote on Twitter that researchers do not know whether fluoxetine (Prozac) can treat COVID-19.

“It does not have as high affinity for the sigma-1 receptor, and no [randomized controlled trials] have been completed using fluoxetine for treatment of [COVID-19],” she wrote.

If fluvoxamine helps prevent the immune system from going into overdrive, early treatment — before hospitalization — is likely to be essential.

“I cannot say with any insight about whether this has a role in hospitalized patients, and I am inclined to think it probably does not,” said Edward Mills, Ph.D., the new study’s co-principal investigator.

“That would need to be evaluated in clinical trials,” he told Medical News Today.

According to Daniel Griffin, M.D., Ph.D., a virologist at Columbia University in New York, NY, fluvoxamine may be a better option for high-risk individuals early in the course of the disease than steroids such as dexamethasone.

Unlike steroids, fluvoxamine does not suppress the immune system’s antiviral activity.

“Think of it as being immune modulatory as opposed to being immune suppressive,” he told the podcast This Week in Virology.

“When you do this, you don’t have an adverse effect — you’re not allowing or facilitating viral replication that you might end up doing with steroids — but you have this selective modulation, what we think is preventing that cytokine storm,” he added.

Some unanswered questions

The new study’s authors note that 84 patients on fluvoxamine stopped taking the drug before the course was complete, compared with 64 of those who took a placebo for tolerability reasons.

Therefore, tolerability may reduce adherence to the treatment among people with relatively mild symptoms.

In addition, they highlight that most of the patients in the trial were unvaccinated, so further research will be necessary to assess any benefit among people who have had a COVID-19 vaccine.

Otavio Berwanger, M.D., Ph.D., a cardiologist and director of the Academic Research Organization at Hospital Israelita Albert Einstein in São Paulo, Brazil, who was not involved in the trial, says that some questions remain about the efficacy of fluvoxamine in COVID-19.

In an accompanying commentary, he concludes:

“[I]t is still unclear whether the results from the TOGETHER trial extend to other outpatient populations with COVID-19, including those without risk factors for disease progression, those who are fully vaccinated, and those [with infection of the] Delta variant or other variants.”

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