Repurposing Selective Serotonin Reuptake Inhibitors for COVID-19: Rationale and Concerns

With a global count of more than 28 million cases and 921,801 deaths till September 14, 2020, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV2) remains a challenge for health professionals. Though more than 500 trials (clinicaltrials.gov) are ongoing, none of the agents has been officially approved to treat the infection. Despite the preliminary favorable results of certain antiviral drugs, the research is curtailed by the risk of their toxicity and methodological flaws.¹ Though psychotropics are placed far away from antimicrobial and antiviral drugs in the taxonomy, antimicrobial and antiviral properties of various psychotropics have been documented.² With this background, we would like to discuss the potential role of selective serotonin reuptake inhibitors (SSRIs) in SARS-COV2 pathology.

Among those infected, only 5%–15% progress to severe acute respiratory syndrome. This is mediated through dysregulated immune response involving activation of nuclear factor kappa B (NF-kB), signal transducer activator of transcription (STAT 3), and inflammatory cytokines. This eventually establishes an inflammatory feedback loop, leading to a state of hypercytokinemia, known as “cytokine storm,” which is implicated in multiple organ dysfunction.³ Though agents with a potential action at virus-entry-level can help in preventing the infection, there is a vital need to investigate therapies that reduce dysregulated immune cascade. If successful, this could substantially reduce mortality.

Though there has been no systematic study of the antiviral property of SSRIs on SARS-COV-2, their antiviral property—especially that of fluoxetine—for Hepatitis C, Enteroviruses, and Coxsackievirus has been reported. As STAT3 plays a vital role in the inflammatory loop, drugs that inhibit this pathway need consideration. Sertraline and paroxetine have been shown to attenuate mitogen-stimulated increases of STAT3 and Cyclooxygenases-2, which is also implicated in SARS-COV2 immunopathology.^{4, 5} This action has been reported to be more pronounced than that of dexamethasone, another keystone in SARS-COV2 treatment.⁵ Secretion of cytokines is a crucial step in organ damage, and SSRIs have been known to reduce their levels.⁶ Likewise, Interleukin-6 (IL-6) being a major cytokine of the inflammatory loop, there has been an ample number of studies showing a reduction of IL-6 levels with SSRI treatment.⁶ Furthermore, SSRIs may have a potential role in regulating the release of tumor necrosis factor—α, IL-6, IL-10, and Interferon-ϒ—since they require intracellular serotonin that is transported through a serotonin transporter—the target site of SSRIs.

Interestingly, the SARS-COV2 targets sigma receptors that mediate autophagosome–lysosome fusion in the endoplasmic reticulum. In line with this finding, preliminary research on molecules with sigma receptor activity displayed antiviral properties.⁷ With this background, fluvoxamine, a potent sigma-1 receptor agonist with immunomodulatory properties in animal studies, is being employed in trials to investigate the potential antiviral property (clinicaltrials.gov).

In addition, we know that stress by itself can produce alterations in the immune system, which may increase the risk of infection. In animal models, fluoxetine has been shown to reverse stress-induced immune dysfunction.⁸ However, further studies are needed before we can translate it into clinical practice.

Considering the mentioned factors and owing to their relatively better safety and tolerability profile, SSRIs merit further investigation for their role in treating SARS-COV-2 infection. Encouraging preliminary evidence is available from research using in vitro human cell culture models^{9, 10} as well as hospitalized patients¹¹ with COVID-19, all of which point to a beneficial role for SSRIs in treating the condition through mechanisms such as reducing virus entry and propagation. Nevertheless, researchers have also highlighted the potential risks with SSRI in SARS-COV2, such as impaired coagulation, risk of arrhythmias, liver injury, and cytochrome-mediated drug interactions, which can potentially limit the use of SSRI in such patients. Future research must balance these safety considerations against potential benefits of SSRIs in SARS-COV-2 and identify the right candidates who may benefit optimally from add-on SSRI.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors