Association Between SSRIs and Reduced COVID-19 Mortality Rate

A new study published in JAMA Network reports an observed association between selective serotonin reuptake inhibitor (SSRI) prescription and reduced COVID-19 mortality. The study is retrospective and observational in nature, meaning it does not prove causation. However, the researchers believe that the study warrants replication analyses in larger populations worldwide.

COVID-19 drug discovery landscape

Almost two years after the SARS-CoV-2 virus emerged, we are still searching for effective therapeutics that can prevent and/or treat COVID-19. Across the globe, research efforts continue, exploring both the potential of novel drugs, and the repurposing of current drugs that are being used for different indications.

One approach to identify potential COVID-19 drugs is to look retrospectively for associations between certain prescribed medications, COVID-19 infections and severity of illness.

A new study has adopted this method, using an electronic health record database that represents a population of 83,84 participants that received a diagnosis of COVID-19 between January and September 2020.

Selective serotonin reuptake inhibitors and COVID-19

The study is a collaborative effort from researchers at the University of California San Francisco (UCSF) and Stanford University. The research team wanted to explore whether any associations exist between the use of selective serotonin reuptake inhibitors (SSRIs) and COVID-19 mortality rate.

SSRIs are one of the most prescribed classes of antidepressants. There are several different types, including citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil, Pexeva) and sertraline (Zoloft).

"Per the name of this type of antidepressant, SSRIs work to treat depression by selectively inhibiting the reuptake of serotonin by neurons, resulting in increased serotonin levels in the brain. Serotonin is a hormone responsible for stabilizing our mood, feelings of well-being and happiness," explained Dr. Tomiko Oskotsky, research scientist at the UCSF school of medicine and co-author of the study.

SSRIs have been reported to show anti-inflammatory capabilities that occur via a reduction in proinflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor (TNF). For some patients, COVID-19 presents as an asymptomatic illness, while for others, it proves fatal. Severe COVID-9 illness occurs in many cases as a result of overdrive of the host's proinflammatory immune response. "Previous, smaller studies observed a decreased mortality rate among hospitalized patients with COVID-19 taking SSRIs," said Ivana Marić, senior research scientist at Stanford and one of the study's co-authors.

The objective of this study was to therefore investigate the association of SSRIs with COVID-19 outcomes in patients, using the electronic health record database. From the sample of 83,584 people, 3,401 adult patients had been prescribed SSRIs, including 2,033 women and 1,368 men. The SSRIs prescribed included, along others, fluoxetine and fluvoxamine.

"Patients with COVID-19 and a medication order for an SSRI with an order status of active or completed and without a designation of as needed (i.e., medication taken only when needed) at least once within a period of 10 days before and 7 days after their first recorded COVID-19 diagnosis were compared with patients with COVID-19 and no SSRI orders," the authors write in the paper.

"After identifying [in our database] patients diagnosed with COVID-19 who had taken SSRI antidepressants, we used a statistical method to identify other patients in this database who had not taken SSRI antidepressants yet had features, including demographic characteristics and medical conditions associated with severe COVID-19, that were the same as the treated patients."

Lower mortality rate in patients prescribed certain SSRIs

The study's key findings include that, for patients who had COVID-19, the risk of death for those taking either fluoxetine or fluvoxamine, and for those taking specifically fluoxetine, was 26% and 28% lower, respectively, when compared with those who were not taking any SSRI. "For patients with COVID-19 taking SSRIs other than fluoxetine or fluvoxamine, their risk of death was 8% lower than those who were not taking any SSRI," Ostotsky added.

Association does not mean causation

Due to the design of the study being observational and retrospective in nature, it cannot determine causation. Therefore, the associated reduction in mortality does not prove that SSRIs indeed protect against severe COVID-19 illness. "The data leveraged here is from the US, and additional replication analyses should be carried out in similar clinical datasets worldwide," said Marina Sirota, associate professor at the Bakar Computational Health Sciences Institute at UCSF, and co-author of the study.

Sirota added, "Further studies investigating the mechanism of action of these drugs, as well as clinical trials, will need to be carried out before they would be used in patients moving forward."

In addition, the research team are also interesting in using the clinical data to identify and test novel hypotheses about other classes of drugs that may be efficacious against COVID-19.

Tomiko Oskotsky, Ivana Marić and Marina Sirota were speaking to Molly Campbell, Science Writer for Technology Networks.

Reference: Oskotsky T, Marić I, Tang A, et al. Mortality risk among patients with COVID-19 prescribed selective serotonin reuptake inhibitor antidepressants. JAMA Net. 2021;4(11):e2133090-e2133090. doi: 10.1001/jamanetworkopen.2021.33090.