Association between SSRI Antidepressant Use and Reduced Risk of Intubation or Death in Hospitalized Patients with Coronavirus Disease 2019: a Multicenter Retrospective Observational Study

Objective

To examine the association between antidepressant use and the risk of intubation or death in hospitalized patients with COVID-19.

Design

Multicenter observational retrospective cohort study.

Setting

Greater Paris University hospitals, France.

Participants

7,345 adults hospitalized with COVID-19 between 24 January and 1 April 2020, including 460 patients (6.3%) who received an antidepressant during the visit.

Data source

Assistance Publique-Hôpitaux de Paris Health Data Warehouse.

Main outcome measures

The primary endpoint was a composite of intubation or death. We compared this endpoint between patients who received antidepressants and those who did not in time-to-event analyses adjusting for patient characteristics (such as age, sex, and comorbidities), disease severity and other psychotropic medications. The primary analyses were multivariable Cox models with inverse probability weighting.

Results

Over a mean follow-up of 18.5 days (SD=27.1), 1,331 patients (18.1%) had a primary end-point event. Unadjusted hazard ratio estimates of the association between antidepressant use and the primary outcome stratified by age (i.e., 18-50, 51-70, 71-80, and 81+) were non-significant (all p>0.072), except in the group of patients aged 71-80 years (HR, 0.66; 95% CI, 0.45 to 0.98; p=0.041). Following adjustments, the primary analyses showed a significant association between use of any antidepressant (HR, 0.64; 95% CI, 0.51 to 0.80; p<0.001), SSRI (HR, 0.56; 95% CI, 0.42 to 0.75; p<0.001), and SNRI (HR, 0.57; 95% CI, 0.34 to 0.96; p=0.034), and reduced risk of intubation or death. Specifically, exposures to escitalopram, fluoxetine, and venlafaxine were significantly associated with lower risk of intubation or death (all p<0.05). These associations remain significant in multiple sensitivity analyses, except for the association between SNRI use and the outcome.

Conclusions

SSRI use could be associated with lower risk of death or intubation in hospitalized patients with COVID-19. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.

What is already known on this topic

• A prior meta-analysis, mainly including studies on selective serotonin reuptake inhibitors (SSRIs), showed that antidepressant use in major depressive disorder was associated with reduced levels of several pro-inflammatory cytokines, including IL-6, TNF-α, and CCL-2, which have been suggested to be associated with severe COVID-19.

• A recent in-vitro study supports antiviral effects of the SSRI fluoxetine on SARS-CoV-2.

• To our knowledge, no study has examined the efficacy of antidepressants in patients with COVID-19.

What this study adds

• In a multicenter observational retrospective study, we examined the association between antidepressant use and the risk of intubation or death in hospitalized patients with COVID-19, adjusting for patient characteristics, disease severity and other psychotropic medications.

• Antidepressant use was significantly and substantially associated with reduced risk of intubation or death.

• At the level of antidepressant classes, SSRI use was significantly and substantially associated with reduced risk of intubation or death, but not other antidepressant classes.

• At the level of antidepressant medications, exposures to the SSRIs fluoxetine and escitalopram, and the SNRI venlafaxine were significantly associated with lower risk of intubation or death.

• Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.