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COVID-19 patients on an antidepressant were less likely to die from the infection, a retrospective study found.

Compared with patients not on an antidepressant, patients with COVID-19 who were taking a selective serotonin reuptake inhibitor (SSRI) had a modest but significant 8% reduced risk of death (relative risk 0.92, 95% CI 0.85-0.99, P=0.03), reported Marina Sirota, PhD, of the University of California, San Francisco (UCSF), and colleagues.

Overall, 14.6% of patients (497 of 3,401) on an SSRI died from COVID-19 versus 16.6% (1,130 of 6,802) of patients who never had a history of taking an SSRI, the researchers wrote in the study online in .

Interestingly, though, this protective mortality benefit was more pronounced when the team looked specifically at patients on fluoxetine (Prozac). COVID-19 patients treated only with fluoxetine had a 28% reduced risk of death compared with non-treated controls (9.8% vs 13.3%, RR 0.72, 95% CI 0.54-0.97).

Similarly, there was a 26% lower risk of death among patients taking either fluoxetine or fluvoxamine during their COVID-19 infection compared with untreated controls (10% vs 13.3%; RR 0.74, 95% CI 0.55-0.99, P=0.04).

"We can't tell if the drugs are causing these effects, but the statistical analysis is showing significant association," Sirota said in a statement. "There's power in the numbers."

"The results are encouraging," added co-study author Tomiko Oskotsky, MD, also of UCSF. "It's important to find as many options as possible for treating any condition. A particular drug or treatment may not work or be well tolerated by everyone."

"Data from electronic medical records allow us to quickly look into existing drugs that could be repurposed for treating COVID-19 or other conditions."

For this retrospective cohort study, the research group looked at a large electronic health record database containing data on 83,584 patients diagnosed with laboratory-confirmed COVID-19 between January to September 2020 from 87 U.S. healthcare centers.

Sirota's group narrowed down the patient population to 3,401 adults with COVID-19 who were prescribed an SSRI: 470 receiving fluoxetine only, 481 receiving fluoxetine or fluvoxamine, and 2,898 receiving other SSRIs. Using propensity score matching, the team matched these patients with untreated COVID-19 patients for demographic factors, comorbidities, and medication indications.

In addition to fluoxetine and fluvoxamine, SSRI exposure in this study included citalopram (Celexa), escitalopram (Lexapro), paroxetine (Pexeva, Paxil), vilazodone (Viibryd), vortioxetine (Trintellix), and sertraline (Zoloft) as the most popular SSRI.

These findings come on the heels of the randomized TOGETHER trial, published last month, which found a 32% reduced risk for a composite endpoint of hospitalization -- defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19 up to 28 days post-random assignment on the basis of intention to treat -- among patients treated with fluvoxamine versus placebo.

"Convergent results from observational, preclinical, and clinical studies performed by different research teams call into question the mechanisms that underlie this potential positive effect of certain antidepressants against COVID-19," wrote the author of an , Nicolas Hoertel, MD, MPH, PhD, of the Université de Paris in France.

Hoertel added that this mortality protection is likely due to the fact that most SSRI antidepressants belong to the group of functional inhibitors of acid sphingomyelinase (FIASMA).

"Preclinical data indicate that SARS-CoV-2 activates the ASM-ceramide system, resulting in the formation of ceramide-enriched membrane domains that facilitate viral entry and infection by clustering ACE2, the cellular receptor of SARS-CoV-2, and the release of proinflammatory cytokines," he explained. "The inhibition of the ASM-ceramide system by FIASMA antidepressants prevents infection of Vero E6 cells with SARS-CoV-2."

It's also possible that the anti-inflammatory properties of SSRIs could help fight against COVID-19, as well as some other possible mechanisms of action, Hoertel added.

Sirota's group and Hoertel both called for large, randomized trials looking at SSRIs on COVID-19 outcomes.

"Given the urgent need for an easily administered, effective treatment against COVID-19, especially in resource-poor countries, and increasing evidence of efficacy of these medications for this indication, both fluoxetine (which is on the World Health Organization's Model List of Essential Medicines and has the greatest in vitro inhibitory effect on the ASM-ceramide system among SSRIs) and fluvoxamine (which has shown very encouraging results in 3 clinical trials) should be prioritized in large-scale phase 3 clinical trials at different stages of the disease, either alone or in combination with other medications," Hoertel wrote.

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