Abstract
Antidepressant use may be associated with reduced levels of several proinflammatory cytokines suggested to be involved with the development of severe COVID-19. 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 size. To investigate the association of SSRIs with outcomes in patients with COVID-19 by analyzing electronic health records (EHRs). This retrospective cohort study used propensity score matching by demographic characteristics, comorbidities, and medication indication to compare SSRI-treated patients with matched control patients not treated with SSRIs within a large EHR database representing a diverse population of 83 584 patients diagnosed with COVID-19 from January to September 2020 and with a duration of follow-up of as long as 8 months in 87 health care centers across the US. Selective serotonin reuptake inhibitors and specifically (1) fluoxetine, (2) fluoxetine or fluvoxamine, and (3) other SSRIs (ie, not fluoxetine or fluvoxamine). Death. A total of 3401 adult patients with COVID-19 prescribed SSRIs (2033 women [59.8%]; mean [SD] age, 63.8 [18.1] years) were identified, with 470 receiving fluoxetine only (280 women [59.6%]; mean [SD] age, 58.5 [18.1] years), 481 receiving fluoxetine or fluvoxamine (285 women [59.3%]; mean [SD] age, 58.7 [18.0] years), and 2898 receiving other SSRIs (1733 women [59.8%]; mean [SD] age, 64.7 [18.0] years) within a defined time frame. When compared with matched untreated control patients, 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); 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). These results support evidence that SSRIs may be associated with reduced severity of COVID-19 reflected in the reduced RR of mortality. 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.
Highlights
As the world searches for effective treatments for COVID-19, evidence from recent studies has suggested that selective serotonin reuptake inhibitor (SSRI) antidepressants may be of benefit.[1,2,3,4,5,6] The severe respiratory illness of COVID-19 is primarily triggered by an intense proinflammatory host response.[7]
When compared with matched untreated control patients, 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); 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)
These results support evidence that SSRIs may be associated with reduced severity of COVID-19 reflected in the reduced RR of mortality
Summary
As the world searches for effective treatments for COVID-19, evidence from recent studies has suggested that selective serotonin reuptake inhibitor (SSRI) antidepressants may be of benefit.[1,2,3,4,5,6] The severe respiratory illness of COVID-19 is primarily triggered by an intense proinflammatory host response.[7] Selective serotonin reuptake inhibitors are one of the most prescribed, widely available classes of antidepressants used for treating psychological conditions, including depression and anxiety disorders.[8,9,10] It has been previously observed that SSRIs may have anti-inflammatory properties mediated through a reduction of several proinflammatory cytokines, including interleukin 6 and tumor necrosis factor.[11,12] Selective serotonin reuptake inhibitors may 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.[13,14,15] 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-19.16,17
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