By Vikas P. Sukhatme ~ Originally published in Frontiers in Pharmacology ~ April 20, 2021

Fluvoxamine is a well-tolerated, widely available, inexpensive selective serotonin reuptake inhibitor that has been shown in a small, double-blind, placebo-controlled, randomized study to prevent clinical deterioration of patients with mild coronavirus disease 2019 (COVID-19). Fluvoxamine is also an agonist for the sigma-1 receptor, through which it controls inflammation. We review here a body of literature that shows important mechanisms of action of fluvoxamine and other SSRIs that could play a role in COVID-19 treatment. These effects include: reduction in platelet aggregation, decreased mast cell degranulation, interference with endolysosomal viral trafficking, regulation of inositol-requiring enzyme 1α-driven inflammation and increased melatonin levels, which collectively have a direct antiviral effect, regulate coagulopathy or mitigate cytokine storm, which are known hallmarks of severe COVID-19.

Introduction

FLV and other SSRIs regulate inflammatory cytokine activity and gene expression in both cell and animal models of inflammation (Taler et al., 2007Tynan et al., 2012Rafiee et al., 2016Ghareghani et al., 2017Naji Esfahani et al., 2019Rosen et al., 2019). The potential of FLV to dampen cytokine storm has implications in COVID-19. COVID-19 severity is associated with an increased level of inflammatory mediators including cytokines and chemokines (Chen G. et al., 2020Chen N. et al., 2020Huang et al., 2020Tay et al., 2020). Other S1R agonists like fluoxetine have been reported to have antiviral activity (Zuo et al., 2012Bauer et al., 2019). These studies have raised interest in the potential therapeutic role of FLV and S1R agonists in COVID-19 (Vela, 2020Hashimoto, 2021).

This review illustrates mechanisms of action underlying anti-inflammatory and antiviral properties of FLV. It covers preclinical studies on effects of FLV and S1R agonists on inflammation, and summarizes currently available clinical data for FLV treatment in COVID-19.

Indications for Fluvoxamine

Fluvoxamine maleate is available as immediate release tablets and controlled-release capsules. FLV is indicated to treat obsessions and compulsions in patients with OCD. The half-life of FLV is 9–28 h depending on its formulation, and the recommended dosage is 100–300 mg/day (FDA, 2012).

Original Mechanism of Action

Serotonin Transporter Inhibition

FLV blocks reuptake of serotonin at the sodium-dependent serotonin transporter (SERT) of the neuronal membrane, enhancing actions of serotonin on 5HT1A autoreceptors (Dell’Osso et al., 2005FDA, 2012). FLV has negligible affinity for α1-, α2-, β-adrenergic, muscarinic, dopamine D2, histamine H1, GABA-benzodiazepine, opiate, 5-HT1, or 5-HT2 receptors (Irons, 2005).

Likely Mechanisms of Action in COVID-19

Platelet Aggregation

Platelets lack the enzyme to synthesize serotonin (Ni and Watts, 2006). A SERT enables rapid uptake of serotonin from plasma (Vanhoutte, 1991). During thrombosis platelets release serotonin, facilitating hemostasis through platelet aggregation (Berger et al., 2009) (Figure 1), and promotes recruitment of neutrophils (Duerschmied et al., 2013). SSRIs can therefore increase bleeding time (Leung and Shore, 1996) or reduce serum serotonin by >80% and reduce neutrophil recruitment (Duerschmied et al., 2013). Platelets from individuals treated with SSRIs, and platelets from SERT knockout mice, show decreased aggregation (Celada et al., 1992Carneiro et al., 2008McCloskey et al., 2008). Measures of coagulation and hemostasis were lower in patients with serotonergic antidepressant than in patients without serotonergic antidepressant (Geiser et al., 2011). A hyperserotonergic state distinguishes COVID-19 and non-COVID-19 acute respiratory distress syndrome, biochemically (Zaid et al., 2021) and clinically (Helms et al., 2020aHelms et al., 2020b). This is likely pathologic across a multitude of organs (akin to serotonin syndrome, F. Jalali—personal observation and communication) and may originate from an immune-mediated (Althaus et al., 2020Nazy et al., 2021) state of platelet hyperreactivity (Zaid et al., 2021), resulting in florid platelet degranulation of serotonin into plasma.

A concomitant impairment of serotonin reuptake may exacerbate this hyperserotonergic state. Serotonin clearance relies on a healthy pulmonary endothelium (Thomas and Vane, 1967Joseph et al., 2013), that is injured in COVID-19 (Ackermann et al., 2020). Platelet serotonin liberation can be reduced with chronic or early de novo SSRI use (Cloutier et al., 2018), since SSRIs deplete serotonin content of platelets (Narayan et al., 1998Javors et al., 2000). Initiation of de novo SSRIs at later stages of moderate to severe COVID-19, however, may be unpredictably harmful given the existing hyperserotonergic state (Zaid et al., 2021) unless counterbalanced by other beneficial effects of SSRIs. Indeed, direct serotonin antagonism specifically targeting the serotonin 2 A, B and C receptors with drugs such as cyproheptadine or mirtazapine in this stage may be beneficial and is being explored (F. Jalali—personal communication).

Three trials assessing benefit of anticoagulants to treat COVID-19 have paused enrollment of critically ill COVID-19 patients who require intensive care unit (ICU) support (NHLBI, 2020). Therapeutic blood thinners did not reduce need for ICU admission in this patient-group. Since full doses of therapeutic anticoagulants increase risk of internal bleeding, FLV could perhaps inhibit blood clotting more safely.

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