Results add to evidence linking SSRIs with better Covid-19 outcomes

Prescription of selective serotonin reuptake inhibitor (SSRI) antidepressants was associated with reduced mortality among Covid-19 patients in a retrospective electronic health record (EHR) analysis.

Death occurred in 14.6% of Covid-19 patients taking any SSRI compared with 16.3% of untreated controls (RR 0.92 95% CI 0.85-0.9; adjusted P=0.03), reported Marina Sirota, PhD, of the University of California, San Francisco, and co-authors in JAMA Network Open.

For Covid-19 patients prescribed fluoxetine, death occurred in 9.8%, compared with 13.3% of matched untreated controls (RR 0.72, 95% CI 0.54-0.97; adjusted P=0.03). For those prescribed either fluoxetine or fluvoxamine, death occurred in 10.0% versus 13.3% of matched untreated controls (RR 0.74, 95% CI 0.55-0.99; adjusted P=0.04).

SSRIs reduce proinflammatory cytokines, including interleukin 6 and tumor necrosis factor. “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 add to other evidence linking SSRIs to better Covid-19 outcomes. “Further research and large, 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,” Sirota and colleagues wrote.

“Over time, it is feasible that the difference in mortality or morbidity attributed to SSRI treatment compared with control patients not using SSRIs might lessen as the overall mortality and morbidity rates for Covid-19 decrease because of general improvement in care with other anti-inflammatory regimens or specific treatments,” they added.

In this analysis, Sirota and co-authors evaluated 83,584 patients diagnosed with Covid 19 from January to September 2020 in 87 U.S. health care centers identified in the Cerner Real World Data Covid-19 database. All were adult patients with laboratory confirmed Covid-19 infection and who were seen at an emergency department or urgent care center and admitted for observation or hospitalized.

Patients with an order for an SSRI within 10 days before and 7 days after first recorded Covid-19 diagnosis were included in the SSRI-treated group. Follow-up was as long as 8 months.

The analysis compared SSR- treated patients (n=3,401, 59.8% women, mean age 63.8) with propensity-matched controls who had Covid-19 but were not treated with SSRIs. SSRIs were categorized as fluoxetine, fluoxetine or fluvoxamine, and other. In addition to fluvoxamine and fluoxetine, SSRIs included escitalopram oxalate, paroxetine hydrochloride, paroxetine mesylate, sertraline hydrochloride, citalopram hydrobromide, vortioxetine hydrobromide, and vilazodone hydrochloride.

Of Covid-19 patients with an SSRI prescription, the fluoxetine group (n=470) included 59.6% women with mean age 58.5 and the fluoxetine or fluvoxamine group (n=481, with 11 patients on fluvoxamine) included 59.3% women with mean age 58.7. The other group (n=2,898) included 59.8% women with mean age 64.7.

For people receiving any SSRI, the mean fluoxetine-equivalent dose was 30.2 mg/day, while for those receiving fluoxetine, the mean dose was 28.2 mg/day. No association emerged between any non-fluoxetine, non-fluvoxamine SSRI, and mortality compared with non-SSRI-treated Covid-19 patients (15.4% versus 17.0, respectively; RR 0.92, 95% CI 0.84-1.00, adjusted P=0.06).

SSRIs may exert a salutary effect in COVID-19 infection through inhibition of the acid sphingomyelinase-ceramide system, noted Nicolas Hoertel, MD, MPH, PhD, of the Université de Paris of France, in an accompanying editorial. “Most SSRI antidepressants, including fluoxetine and fluvoxamine, belong to the group of functional inhibitors of acid sphingomyelinase (FIASMA),” he wrote.

“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 acid sphingomyelinase-ceramide system among SSRIs) and fluvoxamine (which has shown very encouraging results in three clinical trials) should be prioritized in large-scale phase III clinical trials at different stages of the disease, either alone or in combination with other medications,” Hoertel noted.

“This approach could enrich the current therapeutic arsenal with an inexpensive, well-tolerated, and easily administered medication in the global fight against Covid-19,” he observed.

Recent studies have shown suggestive associations between SSRIs and Covid-19 outcomes including mortality, but “these studies had limited power due to their small size,” Sirota and colleagues pointed out. An observational study (n=460) showed decreased mortality in hospitalized Covid-19 patients with prescribed antidepressants, they noted. A randomized clinical trial (n=52) indicated a decrease in Covid-19 severity with fluvoxamine over 30 day follow-up, and a prospective open label clinical trial (n=113) found that patients who received early treatment with fluvoxamine were not hospitalized (0%) compared to untreated patients (12.5%), with 14 day residual symptoms in 0% and 60%, respectively.

More recently, the TOGETHER trial looked at outpatients with Covid-19 in Brazil and found that fluvoxamine reduced the need for hospitalization (either retention in a Covid-19 emergency setting or transfer to a tertiary hospital due to Covid-19) with a RR of 0.68 compared with placebo.

A main limitation of the current analysis was “that its retrospective nature only allowed us to identify an association between SSRI treatment and Covid-19 mortality, but not causal effects,” Sirota and co-authors acknowledged. “Moreover, although records are available from 2015 and beyond for some individuals in this EHR database, this was not the case for all individuals; therefore, pertinent information such as previous medication use and comorbidities for certain individuals could be incomplete in this database.”

In addition, the number of patients using fluvoxamine in the EHR database was too small to assess this medication independently, they noted.

  1. Selective serotonin reuptake inhibitors (SSRI) prescription was associated with reduced mortality among Covid-19 patients in a retrospective analysis of electronic health records.

  2. Compared with matched controls, Covid-19 patients prescribed any kind of SSRI had 8% lower risk of mortality. Those taking fluoxetine had 28% lower mortality risk, and those taking either fluoxetine or fluvoxamine had 26% lower mortality risk.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This study was supported by the Christopher Hess Research Fund and in part by the University of California, San Francisco, Program for Breakthrough Biomedical Research grant, Medical Scientist Training Program, and National Institutes of Health.

Sirota reported serving as a scientific advisor at Aria Pharmaceuticals.

Hoertel reported being listed as an inventor on a patent application related to methods of treating Covid-19, filled by Assistance Publique–Hopitaux de Paris, and receiving consulting fees and nonfinancial support from Lundbeck.

Cat ID: 190

Topic ID: 79,190,730,933,190,926,192,927,146,55,151,928,925,934