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

Hoertel et al., Molecular Psychiatry, doi:10.1038/s41380-021-01254-3
Aug 2021  
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Review of the mechanisms of action and clinical studies for the treatment of COVID-19 with FIASMA antidepressants such as fluoxetine, fluvoxamine, paroxetine, escitalopram, or amitriptyline.
Reviews covering fluvoxamine for COVID-19 include Hashimoto, Hashimoto (B), Hashimoto (C), Hoertel, Kirsch, Scheim, Sukhatme.
Hoertel et al., 12 Aug 2021, peer-reviewed, 12 authors.
This PaperFluvoxamineAll
Repurposing antidepressants inhibiting the sphingomyelinase acid/ceramide system against COVID-19: current evidence and potential mechanisms
Nicolas Hoertel, Marina Sánchez-Rico, Céline Cougoule, Erich Gulbins, Johannes Kornhuber, Alexander Carpinteiro, Katrin Anne Becker, Angela M Reiersen, Eric J Lenze, David Seftel, Cédric Lemogne, Frédéric Limosin
Molecular Psychiatry, doi:10.1038/s41380-021-01254-3
Molecular Psychiatry might collectively lead to anti-SARS-COV-2 effects while diminishing coagulopathy and cytokine storm consequences, which are known hallmarks of severe COVID-19. Following these preclinical, observational and clinical converging findings, and as stated by Salles et al. [1] and Stip et al. [2], large-scale double-blind placebo-controlled randomized clinical trials of FIASMA antidepressants for COVID-19 at different stages of the disease, either alone or combined with medications that have shown preliminary evidence of potential efficacy and good tolerability, are urgently needed. Fluoxetine and 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, should be considered compelling treatments to prioritize for phase 3 trials against .
AUTHOR CONTRIBUTIONS Writing-original draft: NH; Writing-review & editing: MS-R, CG, EG, JK, AC, KAB, AMR, EJL, DS, CL, FL. COMPETING INTERESTS ADDITIONAL INFORMATION Correspondence and requests for materials should be addressed to N.H. Reprints and permission information is available at http://www.nature.com/ reprints Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
Carpinteiro, Edwards, Hoffmann, Kochs, Gripp et al., Pharmacological inhibition of acid sphingomyelinase prevents uptake of SARS-CoV-2 by epithelial cells, Cell Rep Med, doi:10.1016/j.xcrm.2020.100142
Carpinteiro, Gripp, Hoffmann, Pöhlmann, Hoertel et al., Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells, J Biol Chem, doi:10.1016/j.jbc.2021.100701
Darquennes, Corre, Moine, Loas, Association between functional inhibitors of acid sphingomyelinase (Fiasmas) and reduced risk of death in covid-19 patients: a retrospective cohort study, Pharmaceuticals
Fred, Kuivanen, Ugurlu, Casarotto, Levanov et al., Antidepressant and antipsychotic drugs reduce viral infection by SARS-CoV-2 and fluoxetine show antiviral activity against the novel variants in vitro, bioRxiv, doi:10.1101/2021.03.22.436379
Hoertel, Sánchez-Rico, Gulbins, Kornhuber, Carpinteiro et al., Association between FIASMAs and Reduced Risk of Intubation or Death in Individuals Hospitalized for Severe COVID-19: an observational multicenter study, Clin Pharmacol Ther, doi:10.1002/cpt.2317
Hoertel, Sánchez-Rico, Gulbins, Kornhuber, Carpinteiro et al., Association between Psychotropic Medications Functionally Inhibiting Acid Sphingomyelinase and reduced risk of Intubation or Death among Individuals with Mental Disorder and Severe COVID-19: an Observational Study, medRxiv, doi:10.1101/2021.02.18.21251997
Hoertel, Sánchez-Rico, Vernet, Beeker, Jannot et al., Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study, Mol Psychiatry, doi:10.1038/s41380-021-01021-4
Hoertel, Sánchez-Rico, Vernet, Beeker, Jannot et al., SSRIs and SNRIs and Risk of Death or Intubation in COVID-19: Results from an Observational Study, medRxiv, doi:10.1101/2020.07.09.20143339
Kornhuber, Tripal, Reichel, Mühle, Rhein et al., Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications, Cell Physiol Biochem
Lenze, Mattar, Zorumski, Stevens, Schweiger et al., Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: a Randomized Clinical Trial, JAMA
Marín-Corral, Rodríguez-Morató, Gomez-Gomez, Pascual-Guardia, Muñoz-Bermúdez et al., Metabolic Signatures Associated with Severity in Hospitalized COVID-19 Patients, Int J Mol Sci
Salles, Briand-Mésange, Trudel, Ausseil, Salles et al., Can antidepressants unlock prescription of rimonabant in the fight against COVID-19?, Mol Psychiatry, doi:10.1038/s41380-021-01221-y
Schloer, Brunotte, Goretzko, Mecate-Zambrano, Korthals et al., Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine, Emerg Microbes Infect
Seftel, Boulware, Prospective Cohort of Fluvoxamine for Early Treatment of Coronavirus Disease 19, Open Forum Infect Dis
Stip, Arnone, Aziz, Javaid, Diversity of mechanism of action of psychotropic drugs in their anti-COVID-19 properties, Mol Psychiatry, doi:10.1038/s41380-021-01222-x
Sukhatme, Reiersen, Vayttaden, Sukhatme, Fluvoxamine: a Review of Its Mechanism of Action and Its Role in COVID-19, Molecular Psychiatry
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