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.

Fig. 1. The clinical course of COVID-19 and early intervention by fluvoxamine.

The three escalating phases of COVID-19 progression, with associated symptoms. Approximately 80% of SARS-CoV-2-infected subjects is mild to moderate (stage I). The remaining 20% may convert to severe clinical stages in about 1 week (stage II). Subsequently, the part of stage II (~5% of total) may convert to stage III, ultimately resulting in intubation or death. Being a cheap antidepressant, fluvoxamine can be used in the early-stage of COVID-19. However, its use for COVID-19 was not yet approved. ARDS acute respiratory distress syndrome, SIRS systemic inflammatory response syndrome. A slight modification with Fig. 1 in the reference [1]. Some materials of the figure have been designated using resources from www.irasutoya.com.

Fig. 2. Proposed biological mechanisms of fluvoxamine in the treatment of COVID-19 patients.

SARS-CoV-2 binds to ACE2 receptor on the cells, resulting in acid sphingomyelinase (ASM) activation, converting sphingomyelin to ceramide. The ASM/ceramide system can facilitate viral entry. Antidepressants, such as fluvoxamine, inhibit ASM and ceramide-enriched membrane domain formation, resulting in decreased viral entry. Sigma-1 receptor plays a role in the SARS-CoV-2 replication. Through sigma-1 receptor chaperone activity, the sigma-1-receptor agonist fluvoxamine may attenuate SARS-CoV-2 replication and SARS-CoV-2 replication-induced ER stress in cells, resulting in a blockade against inflammatory events (i.e., cytokine storm). Moreover, fluvoxamine has anti-inflammatory effects by serotonin transporter inhibition in the body. Thus, early intervention using fluvoxamine may block or delay clinical deterioration in COVID-19 patients. A slight modification with Fig. 1 in the ref. [22]. Some materials of the figure have been designated using resources from Freepik.com.

Fig. 3. The risk for neuropsychiatric disorders in offspring after maternal COVID-19 infection.

Maternal infection by SARS-CoV-2 causes inflammatory events in pregnant women, resulting in higher levels of inflammatory biomarkers (i.e., CRP, IL-6, and TNF-α) in the blood and tissues. Given the role of maternal immune activation in the risk of neuropsychiatric disorders, such as ASD and schizophrenia in offspring, a follow-up study of COVID-19-infected pregnant women and their children is needed. Furthermore, early intervention using nutrition with anti-inflammatory actions may be needed to block the onset of neuropsychiatric disorders. A slight modification with Fig. 1 in the ref. [113]. Some materials of the figure have been designated using resources from Freepik.com and www.irasutoya.com.