Association between FIASMA psychotropic medications and reduced risk of intubation or death in individuals with psychiatric disorders hospitalized for severe COVID-19: an observational multicenter study

Abstract

The acid sphingomyelinase (ASM)/ceramide system may provide a useful framework for better understanding SARS-CoV-2 infection and the repurposing of psychotropic medications functionally inhibiting the acid sphingomyelinase/ceramide system (named FIASMA psychotropic medications) against COVID-19. We examined the potential usefulness of FIASMA psychotropic medications in patients with psychiatric disorders hospitalized for severe COVID-19, in an observational multicenter study conducted at Greater Paris University hospitals. Of 545 adult inpatients, 164 (30.1%) received a FIASMA psychotropic medication upon hospital admission for COVID-19. We compared the composite endpoint of intubation or death between patients who received a psychotropic FIASMA medication at baseline and those who did not in time-to-event analyses adjusted for sociodemographic characteristics, psychiatric and other medical comorbidity, and other medications. FIASMA psychotropic medication use at baseline was significantly associated with reduced risk of intubation or death in both crude (HR = 0.42; 95%CI = 0.31–0.57; p < 0.01) and primary inverse probability weighting (IPW) (HR = 0.50; 95%CI = 0.37–0.67; p < 0.01) analyses. This association was not specific to one FIASMA psychotropic class or medication. Patients taking a FIASMA antidepressant at baseline had a significantly reduced risk of intubation or death compared with those taking a non-FIASMA antidepressant at baseline in both crude (HR = 0.57; 95%CI = 0.38–0.86; p < 0.01) and primary IPW (HR = 0.57; 95%CI = 0.37–0.87; p < 0.01) analyses. These associations remained significant in multiple sensitivity analyses. Our results show the potential importance of the ASM/ceramide system framework in COVID-19 and support the continuation of FIASMA psychotropic medications in these patients and the need of large- scale clinical trials evaluating FIASMA medications, and particularly FIASMA antidepressants, against COVID-19.

Association between antidepressant use and ED or hospital visits in outpatients with SARS-CoV-2

“…Among individuals hospitalized with severe COVID-19, the use of a medication with FIASMA activity was associated with reduced hazards of intubation or death [ 35 ]. Similar results were observed in another cohort of individuals with psychiatric disorders hospitalized for severe COVID-19 [ 21 ]. In a retrospective cohort study conducted at an adult psychiatric facility, exposure to antidepressants was associated with a reduced incidence of COVID-19 infection [ 40 ], and a similar result was found for fluoxetine in a large pharmacopeia-wide association study [ 41 ].…”

“…Potential mechanisms of action include immunomodulatory activity via sigma-1 receptor (S1R) agonism and non-S1R pathways (e.g., NF-κB, inflammasomes, TLR4, PPARγ) [13][14][15], antiviral and antiinflammatory actions via functional inhibition of acid sphingomyelinase (FIASMA) activity [10,[16][17][18], as well as serotonin modulatory and anti-platelet activity of these agents. Among patients with COVID-19 treated in acute care settings, three large retrospective observational cohort studies have reported reduced death or mechanical ventilation among patients with antidepressant exposure [19][20][21]. In these studies, the association with improved outcomes appeared to be strongest among patients taking the SSRIs fluoxetine or fluvoxamine [19][20][21].…”

“…Among patients with COVID-19 treated in acute care settings, three large retrospective observational cohort studies have reported reduced death or mechanical ventilation among patients with antidepressant exposure [19][20][21]. In these studies, the association with improved outcomes appeared to be strongest among patients taking the SSRIs fluoxetine or fluvoxamine [19][20][21]. In the ambulatory setting, the use of fluvoxamine for 10-15 days was associated with a reduced risk of clinical deterioration in two randomized, placebo-controlled trials [22,23] as well as in one non-randomized observational study [24].…”

Antidepressant Drugs and COVID-19: A Review of Basic and Clinical Evidence

“…When taking SSRIs such as escitalopram and fluoxetine, or an SNRI such as venlafaxine, in all cases, a significantly lower risk of intubation or death was observed [ 78 ]. In the other study, a reduced risk of intubation or death was observed in those taking antidepressants [ 77 ]. The use of antidepressants was associated with positive but not significant results.…”

“…The association was not specific to one FIASMA psychotropic class or medication. Those taking FIASMA antidepressants at baseline had a reduced risk of intubation or death compared with those taking a non-FIASMA antidepressants at baseline (HR = 0.57; 95% CI = 0.38–0.86) [ 77 ].…”