Mechanisms of action of fluvoxamine for COVID-19: a historical review

Abstract

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) accelerates the discovery of prophylactic and therapeutic drugs for persons infected with the virus. Drug repurposing for the COVID-19 pandemic has received particular attention. Increasing clinical data suggest that antidepressant use in early-stage subjects with COVID-19 might be associated with a reduced risk of intubation or death. Among the antidepressants, fluvoxamine is the most attractive drug for mild to moderate subjects with COVID-19. In this article, we review the mechanisms of action (i.e., serotonin transporter, sigma-1 receptor, and acid sphingomyelinase) of fluvoxamine for COVID-19. Furthermore, we discuss a possible link between maternal COVID-19 infection and a risk for neuropsychiatric disorders (i.e., autism spectrum disorder and schizophrenia) in offspring.

COVID-19 and its clinical severity are associated with alterations of plasma sphingolipids and enzyme activities of sphingomyelinase and ceramidase

“…There is an urgent need for a better understanding of underlying mechanisms, diagnostic markers and highly effective treatments. Our data support the use of FIASMA drugs such as fluoxetine and fluvoxamine, well-tolerated, widely available, orally administered and inexpensive SSRIs in the fight against the COVID-19 pandemic (Hashimoto et al 2022). They not only reduce Cer levels and thus potentially SARS-CoV-2 entry by functionally inhibiting ASM but -as shown for these and other SSRIs -have also direct effects in controlling inflammation, coagulopathy and the cytokine storm as hallmarks of severe COVID-19 disease (Creeden et al 2021;Sukhatme et al 2021).…”

The effect of antidepressants on severity of COVID-19 in hospitalized patients: A systematic review and meta-analysis

“…(11, 29, 30) this might be owing to serotonin transporter inhibition. (31) Serotonin is involved in anti-inflammatory cytokine production. (32) For example, it can increase the release of the IL-10, which is a potent cytokine with reputable anti-inflammatory assets (33) IL-10 also moderates the levels of TNF-α and IL-6(34).…”

“…Considering that other antidepressants with the ability to block serotonin transporters did not show similar beneficial effects for COVID-19 patients, it is unlikely that serotonin transporter inhibition may play a significant role in SSRIs’ beneficial effects for COVID-19 patients. However, the anti-inflammatory effects of serotonin transporter inhibition may be a factor for the beneficial effects of SSRIs such as fluoxetine and fluvoxamine (31).…”

Difficulty in Repurposing Selective Serotonin Reuptake Inhibitors and Other Antidepressants with Functional Inhibition of Acid Sphingomyelinase in COVID-19 Infection

“…These favorable effects of SSRIs have been linked to several potential underlying mechanisms of action including anti-inflammatory properties, agonist sigma-1 receptor (S1R) properties, as well as inhibition of acid sphingomyelinase/ceramide system. Within antidepressants with SIR agonist properties, fluvoxamine is the most powerful with a low nanomolar affinity (around 10-times more potent than fluoxetine), and early intervention of fluvoxamine (i.e., in the early infection and pulmonary stage) has been proposed ( Hashimoto et al, 2022 ). Furthermore, taking into account that hypoxia could be a strong factor in COVID-19 progression, the use of fluvoxamine in the early phase of COVID-19 has been suggested in order to counteract some early posthypoxic events ( Grieb et al, 2021 ; Grieb and Rejdak, 2021 ; Rejdak and Grieb, 2021 ).…”