Repurposing antidepressants inhibiting the sphingomyelinase acid/ceramide system against COVID-19: current evidence and potential mechanisms
Hoertel et al.,
Repurposing antidepressants inhibiting the sphingomyelinase acid/ceramide system against COVID-19: current..,
Molecular Psychiatry, doi:10.1038/s41380-021-01254-3 (Review)
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.
Hoertel et al., 12 Aug 2021, peer-reviewed, 12 authors.
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..
Please send us corrections, updates, or comments. Vaccines and
treatments are complementary. All practical, effective, and safe means should
be used based on risk/benefit analysis. No treatment, vaccine, or intervention
is 100% available and effective for all current and future variants. We do not
provide medical advice. Before taking any medication, consult a qualified
physician who can provide personalized advice and details of risks and
benefits based on your medical history and situation.
FLCCC and
WCH
provide treatment protocols.
Submit