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.
Highlights
Global spread of the novel coronavirus SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), has created an unprecedented infectious disease crisis worldwide [1–5]
In the matched analytic sample using a 1:1 ratio, sex and the number of medical conditions differed between groups (Table 1). In this multicenter retrospective observational study involving 545 adult patients with psychiatric disorders hospitalized for severe COVID-19 (N = 545), we found that FIASMA psychotropic medication use at study baseline was significantly and substantially associated with reduced risk of intubation or death, independently of sociodemographic characteristics, psychiatric and other medical comorbidity, and other medications
They indicate that patients taking a FIASMA antidepressant may have a significantly reduced risk of intubation or death compared with those taking a non-FIASMA antidepressant
Summary
Global spread of the novel coronavirus SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), has created an unprecedented infectious disease crisis worldwide [1–5]. Prior preclinical evidence supports that SARS-CoV-2 activates the acid sphingomyelinase (ASM)/ceramide system, resulting in the formation of ceramide-enriched membrane domains that serve viral entry and infection by clustering ACE2, the cellular receptor of SARS-CoV-2 [8–10]. An in vitro study [8] showed that several FIASMA Activity) [11] antidepressant medications, including amitriptyline, 0.04), while the association between receiving any SSRI that were imipramine, desipramine, fluoxetine, sertraline, escitalopram, and not fluoxetine and fluvoxamine, and reduced mortality showed a maprotiline, inhibited ASM and the formation of ceramide- non-significant trend (447 of 2898 [15.4%] vs 1474 of 8694 [17.0%]; enriched membrane domains and prevented Vero E6 cells from RR, 0.92 [95% CI, 0.84–1.00]; adjusted p = 0.06) [26]. Reconstitution of from these observational studies might be biased due to possible ceramides in cells treated with these FIASMA antidepressants confounding by indication or unmeasured confounding [25]
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