Researchers Try to Determine Why Patients on SSRIs Fare Better With COVID-19

A significant association has been found between use of SSRI depression drugs and a lower risk of dying from COVID-19. The question is why. Find out what researchers suggest could be behind the link, which they say needs to be proven by large randomized clinical trials.

SAN FRANCISCO – Do patients prescribed selective serotonin reuptake inhibitors (SSRIs) have a markedly lower risk of dying of COVID-19?

A large medical record analysis from 87 U.S. healthcare centers suggests that could be the case, especially with fluoxetine, which is marketed as Prozac.

The study, which was led by University of California San Francisco and Stanford University researchers and published in JAMA Network Open, suggests the results bolster growing evidence that SSRIs might have beneficial effects against the worst symptoms of COVID-19 but call for large randomized clinical trials to prove that. The authors caution that unaccounted confounding variables might be behind some of the findings.

"We can't tell if the drugs are causing these effects, but the statistical analysis is showing significant association," said Marina Sirota, PhD, associate professor of pediatrics and a member of the Bakar Computational Health Sciences Institute (BCHSI) at UC San Francisco. "There's power in the numbers."

Electronic health records of 83,584 patients diagnosed with COVID-19, including 3,401 patients who were prescribed SSRIs, were reviewed in the multicenter cohort study, which was conducted from January to September 2020 with follow-up of as long as 8 months.

“Antidepressant use may be associated with reduced levels of several proinflammatory cytokines suggested to be involved with the development of severe COVID-19,” researchers explain. “An association between the use of selective serotonin reuptake inhibitors (SSRIs)—specifically fluoxetine hydrochloride and fluvoxamine maleate—with decreased mortality among patients with COVID-19 has been reported in recent studies; however, these studies had limited power due to their small

Patients received either fluoxetine, fluoxetine or fluvoxamine, and other SSRIs that were not fluoxetine or fluvoxamine. Mortality was the primary outcome under investigation.

Of the 3,401 adults with COVID-19 prescribed SSRIs, 59.8% were women with a mean age of 63.8; 470 received fluoxetine only; 481 received fluoxetine or fluvoxamine and 2,898 were on other SSRIs.

When compared with matched untreated control patients, results indicate that relative risk (RR) of mortality was reduced among patients prescribed any SSRI (497 of 3401 [14.6%] vs. 1130 of 6802 [16.6%]; RR, 0.92 [95% CI, 0.85-0.99]; adjusted P = .03). That was especially the case with those receiving fluoxetine (46 of 470 [9.8%] vs 937 of 7050 [13.3%]; RR, 0.72 [95% CI, 0.54-0.97]; adjusted P = .03); and fluoxetine or fluvoxamine (48 of 481 [10.0%] vs 956 of 7215 [13.3%]; RR, 0.74 [95% CI, 0.55-0.99]; adjusted P = .04). “The association between receiving any SSRI that is not fluoxetine or fluvoxamine and risk of death was not statistically significant (447 of 2898 [15.4%] vs 1474 of 8694 [17.0%]; RR, 0.92 [95% CI, 0.84-1.00]; adjusted P = .06),” the authors point out.

“These results support evidence that SSRIs may be associated with reduced severity of COVID-19 reflected in the reduced RR of mortality,” researchers note. “Further research and randomized clinical trials are needed to elucidate the effect of SSRIs generally, or more specifically of fluoxetine and fluvoxamine, on the severity of COVID-19 outcomes.”

The authors recount that, based on previous research, SSRIs appear to have anti-inflammatory properties mediated through a reduction of several proinflammatory cytokines, including interleukin 6 and tumor necrosis factor. “Selective serotonin reuptake inhibitors may also be beneficial to patients with COVID-19 through their inhibiting effect on the acid sphingomyelinase/ceramide system, which may have an important role in SARS-CoV-2 infection,” according to the study. “In fact, an intake of functional inhibitors of acid sphingomyelinase activity medications, which inhibit the acid sphingomyelinase/ceramide system and include fluoxetine hydrochloride and fluvoxamine maleate (among other medications), was associated with substantially reduced likelihood of intubation or death among hospitalized patients with COVID-19.”

Another possibility, they said, is that psychiatric diagnosis, including mood and anxiety disorders, could be independent risk factors for COVID-19 infection, while others found an ameliorating effect for patients on antidepressants.

Essentially, the results of the most recent study suggest that patients taking fluoxetine were 28% less likely to die, those taking either fluoxetine or fluvoxamine, often used to treat obsessive-compulsive disorder, were 26% less likely to die; and the patients taking any kind of SSRI were 8 percent less likely to die than the matched patient controls.

"The results are encouraging," said first author Tomiko Oskotsky, MD, a research scientist at 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."