Selective serotonin reuptake inhibitor use may be associated with reduced mortality from COVID-19 infection

1. The relative risk of death for patients prescribed a selective serotonin reuptake inhibitor (SSRI) was reduced compared to matched controls who were not using SSRIs in this retrospective cohort study.

2. Fluoxetine and fluvoxamine users in particular were found to have a lower risk of death from COVID-19 compared to SSRI non-users.

Level of Evidence: 2 (Good)

Study Rundown: Selective serotonin reuptake inhibitors (SSRIs) are a widely-used class of antidepressant medications. The anti-inflammatory properties of SSRIs are well-described and early evidence suggests they may have a role to play in decreasing the severity of COVID-19 infection through inhibition of certain proinflammatory cytokines.  Few clinical studies have examined this relationship thus far. The present study by Oskotsky et al sought to understand whether SSRI use was associated with decreased severity of COVID-19 infection in a population of American adults. A retrospective cohort study was performed using data from a deidentified Electronic Health Records database of COVID-19 infections, which tracked 83,584 patients. 3401 patients (4.1%) were found to have been exposed to SSRIs, the most common of which was fluoxetine. The relative risk of mortality amongst patients taking any SSRI was significantly lower than control (14.6% vs. 16.3-16.6%). The mortality rate for patients taking fluoxetine only was 9.8%, and ranged from 13.3-13.4% in the corresponding matched control group. The risk of mortality was not significantly different between patients taking SSRIs other than fluoxetine or fluvoxamine and matched controls. Ostkotsky et al concluded that SSRIs, particularly fluoxetine and fluvoxamine, demonstrated a statistically significant protective association with regards to death from COVID-19. Some strengths of this report include the relatively large sample size and clear definition of variables and outcomes. This is one of the first studies to clinically assess the notion that SSRIs may benefit patients with COVID-19; further research should be done to better delineate these findings. Drawbacks of this work include its retrospective nature which does not control for confounding factors, as well as the selection of relatively healthy patients which reduces the external validity of the study. These conclusions should be interpreted with caution as a point of interest and further study.

Click to read the study in JAMA Network Open

Click to read an accompanying editorial in JAMA Network Open

Relevant Reading: The anti-inflammatory mechanism of anti-depressants: SSRIs, SNRIs

In-Depth [retrospective cohort study]: Data from patients who had visited the emergency department or had been hospitalized due to laboratory-confirmed COVID-19 were included. Linked demographic data were used to identify SSRI use as well as other baseline characteristics. Patients were considered SSRI-users if they had an active prescription for one of the following SSRIs within 10 days retrospectively, or 7 days prospectively, of their COVID-19 diagnosis: escitalopram oxalate, paroxetine hydrochloride, paroxetine mesylate, sertraline hydrochloride, fluoxetine, citalopram hydrobromide, vortioxetine hydrobromide, fluvoxamine, and vilazodone hydrochloride. Patients with comorbidities including diabetes, hypertension, chronic obstructive pulmonary disease cardiovascular or cerebrovascular disease, chronic kidney disease and cancer were excluded. Ten iterations of propensity score matching were performed to generate controls matched on age, sex, race, ethnicity, comorbidities and SSRI indication. The most commonly prescribed SSRIs were as follows: fluoxetine only (470 patients, women [59.6%], men [40.4%]), fluvoxamine only (11 patients, women [45.5%], men [54.5%]), other SSRIs (2898 patients, women [59.8%], men [40.2%]). The relative risk of mortality for the SSRI group compared to controls was 0.92 (95% confidence interval 0.85-093); the adjusted p-value was 0.03, which was considered statistically significant. The risk difference was 8% between SSRI users and controls. The relative risk of mortality amongst the fluoxetine group compared to matched controls was 0.72 (95% confidence interval 0.54-0.97, adjusted p=0.03). This was also statistically significant. The relative risk of mortality for patients taking SSRIs other than fluoxetine or fluvoxamine compared with matched controls was 0.92 (95% confidence interval 0.84-1.00), which was not statistically significant.

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