Abstract: Molecular Psychiatry www.nature.com/mp CORRESPONDENCE Repurposing antidepressants inhibiting the sphingomyelinase acid/ceramide system against COVID-19: current evidence and potential mechanisms © The Author(s), under exclusive licence to Springer Nature Limited 2021 Molecular Psychiatry; https://doi.org/10.1038/s41380-021-01254-3 TO THE EDITOR: We read with great interest the correspondence letters of Salles et al. [1] and Stip et al. [2], following our multicenter observational retrospective study that showed a substantial association between antidepressant use and reduced risk of intubation or death in 7230 patients hospitalized for COVID-19 [3]. Salles et al. suggest that combining an antidepressant such as fluoxetine with rimonabant, an inverse agonist of CB1 cannabinoid receptor, may be useful against COVID-19, thanks to the antiviral and anti-inflammatory effects of the former and the potentially complementary antiinflammatory properties of the later. Stip et al. significantly summarized the growing body of evidence of the potential benefit of different psychotropic medications in COVID-19 and their possible underlying mechanisms. They suggested further elucidation of ways that certain antidepressants may be acting in this indication. These two letters challenge us on the potential mechanisms that may underlie the potential positive effect of certain antidepressants on the course of COVID-19. This knowledge is crucial to help identify the more promising molecules for COVID-19 and help design trials evaluating these molecules. Since the initial release of our results in July, 2020 [4], several important studies have led to a substantially improved understanding of the mechanisms that may underlie the potential positive effect of certain antidepressants. First, molecules such as fluoxetine, fluvoxamine, paroxetine, escitalopram, or amitriptyline are antidepressants that belong to the group of functional inhibitors of acid sphingomyelinase (ASM), called FIASMA [5–7], that also comprises other medications commonly used in clinical practice, such as antihistamine medications (e.g., hydroxyzine, promethazine), calcium channel blockers (e.g., amlodipine, bepridil), and mucolytics (e.g., ambroxol [7]). These pharmacological compounds in vitro and in vivo inhibit ASM, an enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine [5–7]. Preclinical evidence indicates that SARS-CoV-2 activates the ASM/ceramide system, resulting in the formation of ceramide-enriched membrane domains that facilitate viral entry and infection by clustering ACE2, the cellular receptor of SARS-CoV-2 [6, 7]. The inhibition of the ASM/ceramide system by FIASMA antidepressants prevented infection of Vero E6 cells with SARS-CoV-2. Importantly, the reconstitution of ceramides in cells treated with these antidepressants restored the infection [6]. In healthy volunteers, oral Received: 30 June 2021 Revised: 26 July 2021 Accepted: 29 July 2021 administration of a low dose of the FIASMA antidepressant amitriptyline prevented infection of freshly isolated nasal epithelial cells with SARS-CoV-2 spike protein pseudotyped particles within 2 h, which was also restored after the reconstitution of ceramides in these cells [6]. These preclinical data were confirmed by another study that demonstrated an inhibition by fluoxetine of SARS-CoV-2 infection in cultured epithelial cells [8]. The potential benefit of FIASMA treatments among patients..