Use of antidepressants is associated with less risk of mortality in patients with COVID-19 infections, new research shows.

The findings, gleaned from a study of the health records of over 80,000 patients who contracted COVID-19 in the US last year, indicate that people taking selective serotonin reuptake inhibitors (SSRIs) had a significantly better chance of survival than matched patients not using the medications.

"Our subgroup analysis found a statistically significant reduction of 28 percent in the relative risk of mortality for the patients treated with fluoxetine and 26 percent for the patients treated with fluoxetine or fluvoxamine," researchers explain in the new study, authored by a team from the University of California, San Francisco (UCSF) and Stanford University.

While the findings only show a correlation in the data – not proof of a causative effect – it isn't the first time this link has been seen.

A number of studies have observed that antidepressant use is somehow associated with better outcomes for COVID-19 patients, although the precise mechanisms behind the phenomenon are not yet fully understood.

Nonetheless, scientists are making progress with each new analysis, and have plenty of ideas as to why SSRIs might be able help to protect people from succumbing to severe or deadly cases of COVID-19 – and it's likely to be more than just one channel that's involved.

"It has been previously observed that SSRIs may have anti-inflammatory properties mediated through a reduction of several proinflammatory cytokines, including interleukin 6 and tumor necrosis factor," the team, led by first author and computational health scientist Tomiko Oskotsky from UCSF, writes in the new study.

Beyond anti-inflammatory effects, it's also possible that SSRIs might be working against processes that help the coronavirus to take hold in the body.

SSRI antidepressants, including fluoxetine and fluvoxamine, belong to the group of pharmacological compounds called functional inhibitors of acid sphingomyelinase (FIASMA).

These compounds inhibit an enzyme called acid sphingomyelinase (ASM), which breaks down sphingomyelin, a lipid in cell membranes, into other molecules, including one called ceramide.

"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," psychiatrist Nicolas Hoertel from the University of Paris, who wasn't involved with the study, explains in a perspective article on the new research.

In other words, it's possible that SSRIs, amongst other things, are making it harder for SARS-CoV-2 to infect cells, by disrupting the molecules the virus uses as anchor points.

"Importantly, the reconstitution of ceramides in cells treated with these antidepressants restores the infection," Hoertel writes.

"Taken together, these results show the potentially crucial importance of the ASM-ceramide system as a treatment target in COVID-19."

As promising as it is, however, more research is needed, and the researchers emphasize that their own analysis doesn't bring us closer to understanding any causal effects.

What it does do, though, is help us understand the level of reduced mortality risk SSRIs seem to offer to patients with COVID-19.

From a vast cohort of 490,373 deidentified COVID-19 patients in the Cerner Real-World Data database, the researchers drilled down to 83,584 patients who met their study criteria.

Of these, 3,401 patients took SSRIs during the study timeframe (January to September 2020), and were compared to a control group of matched patients that didn't take SSRIs in the same period.

Overall, patients taking any SSRI had a lower mortality rate (14.6 percent) than those who didn't (16.3 percent), with the lowest mortality rates seen in patients taking fluoxetine only (9.8 percent, compared to controls at 13.3 percent) and patients taking fluoxetine or fluvoxamine (10 percent, compared to 13.3 percent).

SSRIs that weren't fluoxetine or fluvoxamine also appeared to show a small protective benefit, but the data were not statistically significant, the researchers say.

While there's still much we don't know for sure about how fluoxetine or fluvoxamine might bring about these improved outcomes, in a time of pandemic, any link this promising needs to be chased up further, as it could ultimately have life-saving consequences.

"Because most of the world's population is currently unvaccinated and the COVID-19 pandemic is still active, effective treatments of COVID-19 – especially those that are easy to use, show good tolerability, can be administered orally, and have widespread availability at low cost to allow their use in resource-poor countries – are urgently needed to reduce COVID-19-related mortality and morbidity," Hoertel writes.

"In this context, short-term use of fluoxetine or fluvoxamine, if proven effective, should be considered as a potential means of reaching this goal."

The findings are reported in JAMA Network Open.