Repurposing antidepressants inhibiting the sphingomyelinase acid/ceramide system against COVID-19: current evidence and potential mechanisms

Hoertel, Nicolas; Sánchez‐Rico, Marina; Cougoule, Céline; Gulbins, Erich; Kornhuber, Johannes; Carpinteiro, Alexander; Becker, Katrin Anne; Reiersen, Angela M.; Lenze, Eric J.; Seftel, David; Lemogne, Cédric; Limosin, Frédéric

doi:10.1038/s41380-021-01254-3

Cited by 46 publications

(67 citation statements)

References 16 publications

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“…In summary, the COVID-19-ASM/ceramide system helps us to understand (1) the entry of SARS-CoV-2 into cells; (2) hyperinflammation and increased levels of proinflammatory cytokines, such as IL-6; (3) mortality in severe sepsis; (4) risk factors for severe disease progression, such as age, hypertension and obesity; (5) thromboembolic complications; and (6) the beneficial effects of FIASMAs during both early and later stages of COVID-19. The COVID-19-ASM/ceramide system also supports the development of drugs against COVID-19, for example, by repurposing the FDAapproved FIASMAs fluoxetine or fluvoxamine, which display high in vitro inhibition effect on ASM, showed potential positive effects at usual antidepressant doses, and are easy to use, including high safety margins, good tolerability, widespread availability and low cost [80,122].…”

Section: Discussionmentioning

confidence: 92%

The acid sphingomyelinase/ceramide system in COVID-19

2021

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Acid sphingomyelinase (ASM) cleaves sphingomyelin into the highly lipophilic ceramide, which forms large gel-like rafts/platforms in the plasma membrane. We showed that SARS-CoV-2 uses these platforms for cell entry. Lowering the amount of ceramide or ceramide blockade due to inhibitors of ASM, genetic downregulation of ASM, anti-ceramide antibodies or degradation by neutral ceramidase protected against infection with SARS-CoV-2. The addition of ceramide restored infection with SARS-CoV-2. Many clinically approved medications functionally inhibit ASM and are called FIASMAs (functional inhibitors of acid sphingomyelinase). The FIASMA fluvoxamine showed beneficial effects on COVID-19 in a randomized prospective study and a prospective open-label real-world study. Retrospective and observational studies showed favorable effects of FIASMA antidepressants including fluoxetine, and the FIASMA hydroxyzine on the course of COVID-19. The ASM/ceramide system provides a framework for a better understanding of the infection of cells by SARS-CoV-2 and the clinical, antiviral, and anti-inflammatory effects of functional inhibitors of ASM. This framework also supports the development of new drugs or the repurposing of “old” drugs against COVID-19.

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Section: Discussionmentioning

confidence: 92%

The acid sphingomyelinase/ceramide system in COVID-19

2021

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“…In particular, the prevalence of any current mood disorder was 0.9% in our sample, contrasting with the rates observed in the European or French general population, estimated at 4.2% ( 36 ) and between 4.3% ( 37 ) and 6.7% ( 38 ), respectively. Because people with psychiatric disorders might be at higher risk of contracting COVID-19 ( 1 ), possibly because of lower adherence to barrier measures and socioeconomic and lifestyle factors, we can hypothesize that a substantial proportion of people with psychiatric disorders might have a reduced risk of severe COVID-19 requiring hospitalization, possibly thanks to certain psychotropic treatments such as antidepressants as previously suggested ( 18 , 27 , 30 , 33 , 34 ), whereas those with a high number of comorbid medical disorders and/or obesity could be at higher risk of developing severe COVID-19. However, an alternative explanation to these results includes a potential underreporting of the diagnoses of psychiatric disorders in patients hospitalized for COVID-19, for whom the clinical priority was the treatment of the infection, especially in a context of overwhelmed hospital units during the peak incidence.…”

Section: Discussionmentioning

confidence: 94%

“…One notable exception was that patients diagnosed with mood disorders, specifically those taking an antidepressant during the visit, showed a reduced risk of death than patients without psychiatric disorders, which was not explained by differences in medical risk factors or clinical severity at baseline. The hypothesis previously advanced of potential antiviral and anti-inflammatory effects of several psychotropic medications, especially certain antidepressants such as fluoxetine or fluvoxamine, which are taken by a substantial proportion of people with mood disorders, could be a promising avenue to explore further ( 27 , 41 ). For example, preclinical ( 30 , 31 , 32 , 42 , 43 ), observational ( 18 , 29 , 44 ) and clinical trial findings ( 33 , 34 ) support that fluvoxamine and fluoxetine may be associated with better outcomes in patients with COVID-19.…”

Section: Discussionmentioning

confidence: 99%

“…If any significant protective association was found following the same adjustments, we planned to further study it in the subpopulations of patients with and without antidepressant use, as these medications have been previously suggested to be potentially associated with reduced COVID-19-related mortality ( 27 ) in these data ( 18 , 28 ) and others ( 29 ), in several preclinical studies ( 30 , 31 , 32 ), and in two clinical trials ( 33 , 34 ).…”

Section: Methodsmentioning

confidence: 99%

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Risk of Death in Individuals Hospitalized for COVID-19 With and Without Psychiatric Disorders: An Observational Multicenter Study in France

Hoertel

Sánchez‐Rico

Muela

et al. 2023

Biological Psychiatry Global Open Science

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Background Prior research suggests that psychiatric disorders could be linked to increased mortality among patients with COVID-19. However, whether all or specific psychiatric disorders are intrinsic risk factors of death in COVID-19, or whether these associations reflect the greater prevalence of medical risk factors in people with psychiatric disorders, has yet to be evaluated. Methods We performed an observational multicenter retrospective cohort study to examine the association between psychiatric disorders and mortality among patients hospitalized for laboratory-confirmed COVID-19 at 36 Greater Paris University hospitals. Results Of 15,168 adult patients, 857 (5.7%) had an ICD-10 diagnosis of psychiatric disorder. Over a mean follow-up of 14.6 days (SD=17.9), death occurred in 326/857 (38.0%) patients with a diagnosis of psychiatric disorder versus 1,276/14,311 (8.9%) in patients without such a diagnosis (OR=6.27; 95%CI=5.40-7.28; p<0.01). When adjusting for age, sex, hospital, current smoking status, and medications according to compassionate use or as part of a clinical trial, this association remained significant (AOR=3.27; 95%CI=2.78-3.85; p<0.01). However, additional adjustments for obesity and number of medical conditions resulted in a non-significant association (AOR=1.02; 95%CI=0.84-1.23; p=0.86). Exploratory analyses following the same adjustments suggest that a diagnosis of mood disorders was significantly associated with reduced mortality, which might be explained by the use of antidepressants. Conclusions These findings suggest that the increased risk of COVID-19-related mortality in individuals with psychiatric disorders hospitalized for COVID-19 might be explained by the greater number of medical conditions and the higher prevalence of obesity in this population, but not by the underlying psychiatric disease.

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“…There are a number of plausible pathophysiological mechanisms that could explain the protective effects of antidepressant medication against COVID-19 infection. First, antidepressant use may directly impede viral host cell entry via inhibition of the ASM/ceramide system ( 20 , 21 and references therein). Specifically, the ASM enzyme, present in lysosomes and the cell membrane, cleaves ceramide from sphingomyelin, resulting in the formation of ceramide-enriched membrane domains in the outer cell membrane.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the impact of antidepressants and other medications on COVID-19 infection risk in a chronic psychiatric in-patient cohort

et al. 2021

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Background During the first wave of the coronavirus disease 2019 (COVID-19) pandemic, patients with confirmed cases in New York State accounted for roughly 25% of total US cases, with psychiatric hospital in-patients at particularly high risk for COVID-19 infection. Aims The beneficial effects of mental health medications, such as selective serotonin reuptake inhibitors (SSRIs), on the severity of COVID-19 disease outcomes have been documented. Protective effects against infection have also been suggested for these medications. We therefore tested the hypothesis that medication use modifies the risk of COVID-19 infection in a long-stay, chronic in-patient psychiatry setting, where the potential for exposure was likely uniform across the facility, and where these medications were routinely prescribed. Method This was a retrospective cohort study of an adult psychiatric facility operated by the New York State Office of Mental Health. Current medication information and COVID-19 status was collected from electronic medical records for 165 people who were in-patients during the period January to July 2020, and logistic regression was employed to model the main effects of medication use on COVID-19 infection. Results A significant protective association was observed between antidepressant use and COVID-19 infection (odds ratio (OR) = 0.33, 95% CI 0.15–0.70, adjusted P < 0.05). Analysis of individual antidepressant classes showed that SSRI, serotonin-norepinephrine reuptake inhibitor and the serotonin-2 antagonist reuptake inhibitor classes of antidepressants, drove this protective effect. Exploratory analyses of individual antidepressants demonstrated an association between lower risk of infection and fluoxetine use (P = 0.023), as well as trazodone use (P = 0.001). Conclusions The novel finding of reduced COVID-19 infection risk for psychiatric in-patients taking antidepressants, suggests that antidepressants may be an important weapon in the continued fight against COVID-19 disease. This finding may become particularly salient for in-patient settings if vaccine-resistant strains of the virus appear.

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Repurposing antidepressants inhibiting the sphingomyelinase acid/ceramide system against COVID-19: current evidence and potential mechanisms

Cited by 46 publications

References 16 publications

The acid sphingomyelinase/ceramide system in COVID-19

The acid sphingomyelinase/ceramide system in COVID-19

Risk of Death in Individuals Hospitalized for COVID-19 With and Without Psychiatric Disorders: An Observational Multicenter Study in France

Analysis of the impact of antidepressants and other medications on COVID-19 infection risk in a chronic psychiatric in-patient cohort

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