key: cord-0934035-krjtkqky
authors: Hashimoto, Yaeko; Suzuki, Takuji; Hashimoto, Kenji
title: Old drug fluvoxamine, new hope for COVID-19
date: 2021-09-02
journal: Eur Arch Psychiatry Clin Neurosci
DOI: 10.1007/s00406-021-01326-z
sha: f93b23b9a12937707f39f05782109ff807ceaa37
doc_id: 934035
cord_uid: krjtkqky

nan

On August 6, 2021, the interim results of TOGETHER trial (NCT04727424) by a multinational group in Canada and Brazil were presented at the NIH symposium. They compared three compounds, fluvoxamine, the antidiabetic drug metformin, and the antiparasitic drug ivermectin. Although metformin and ivermectin did not show beneficial effects, fluvoxamine was much more promising. Among the randomized participants (n = 1,480), fluvoxamine significantly reduced the risk of disease progression by 29% (95% confidence interval 0.54-0.93) [4] .

Detailed mechanisms of action of fluvoxamine for COVID-19 are currently unknown. In 1996, we reported that fluvoxamine binds to endoplasmic reticulum (ER) protein sigma-1 receptor with high affinity, suggesting a role of sigma-1 receptor in the mechanisms of its action [5] . Subsequent studies suggest that fluvoxamine is a potent agonist at sigma-1 receptor which plays a key role in inflammation [1, 5, 6] . Among the antidepressants, fluvoxamine was the most potent at sigma-1 receptor [1, 5, 6] . Furthermore, fluvoxamine has several beneficial effects, including reduction in platelet aggregation by serotonin transporter inhibition, decreased mast cell degranulation, interference with lysosomal trafficking of virus, inhibition of acid sphingomyelinase (ASM), and increased levels of metatonin by cytochrome P450 inhibition [7] .

In October 2020, Gordon et al. [8] identified the sigma-1 receptor (encoded by SIGMAR1) as a functional hostdependency factor for SARS-CoV-2. Knockout or knockdown of SIGMAR1 produced robust reductions in SARS-CoV-2 replication, indicating a key role of the sigma-1 receptor in SARS-CoV-2 replication (Fig. 1 ). In 2019, Rosen et al. [9] demonstrated that the sigma-1 receptor is essential for the cytokine production in a mouse model of septic shock, and that fluvoxamine could protect against inflammatory response and lethal septic shock. Taken together, it is likely that the potent sigma-1 receptor agonists, such as fluvoxamine, might ameliorate inflammatory events (i.e., cytokine storm) associated with ER stress due to SARS-CoV-2 replication (Fig. 1) [1] .

A recent observational multicenter study (n = 2846) showed association between the use of functional inhibitors of ASM and reduced risk of intubation or death in hospitalized patients with severe COVID-19 [10] . The functional inhibitors of ASM include the antidepressants such as fluvoxamine, fluoxetine, and escitalopram. Interestingly, fluoxetine and escitalopram are also sigma-1 receptor agonists although they are less potent than fluvoxamine [1] . Considering the role of sigma-1 receptor and ASM in biological actions of SARS-CoV-2 in cells (Fig. 1) , both fluoxetine and escitalopram may be prophylactic drugs for mild to moderate patients infected with SARS-CoV-2 although further clinical study is needed.

The advantages of fluvoxamine are favorable safety profiles, widespread availability, very low cost, oral administration and use for children and adolescents. If fluvoxamine is used in individuals with COVID-19 as quickly as possible after confirmation of SARS-CoV-2 infection, clinical deterioration might be prevented [1] . Importantly, fluvoxamine could be a prophylactic drug for COVID-19 in countries with low vaccination rates or low health system. Through sigma-1 receptor chaperone activity [1] , the sigma-1-receptor agonist fluvoxamine may attenuate ER stress due to SARS-CoV-2 replication in cells, thus resulting in a blockade against inflammatory events (i.e., cytokine storm). Thus, early intervention using fluvoxamine may block or delay clinical deterioration in individuals with SARS-CoV-2 infection. A slight modification with Fig. 1 in the reference [10] and Fig. 3 in the reference [1] 

Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor

Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19. A randomized clinical trial

Prospective cohort of fluvoxamine for early treatment of coronavirus disease 19

Could this be our first effective, inexpensive, widely available outpatient treatment for COVID-19?

Interaction of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain

Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication

Fluvoxamine: a review of its mechanisms of actions and its role in COVID-19

Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis

Entrepôt de Données de Santé" AP-HP Consortium (in press) Association between FIASMAs and reduced risk of intubation or death in individuals hospitalized for severe COVID-19: an observational multicenter study