Potential Role of the Antidepressants Fluoxetine and Fluvoxamine in the Treatment of COVID-19

Abstract

Mapping non-canonical cellular pathways affected by approved medications can accelerate drug repurposing efforts, which are crucial in situations with a global impact such as the COVID-19 pandemic. Fluoxetine and fluvoxamine are well-established and widely-used antidepressive agents that act as serotonin reuptake inhibitors (SSRI-s). Interestingly, these drugs have been reported earlier to act as lysosomotropic agents, inhibitors of acid sphingomyelinase in the lysosomes, and as ligands of sigma-1 receptors, mechanisms that might be used to fight severe outcomes of COVID-19. In certain cases, these drugs were administered for selected COVID-19 patients because of their antidepressive effects, while in other cases, clinical studies were performed to assess the effect of these drugs on treating COVID-19 patients. Clinical studies produced promising data that encourage the further investigation of fluoxetine and fluvoxamine regarding their use in COVID-19. In this review, we summarize experimental data and the results of the performed clinical studies. We also provide an overview of previous knowledge on the tissue distribution of these drugs and by integrating this information with the published experimental results, we highlight the real opportunity of using these drugs in our fight against COVID-19.

Outpatients prescribed with fluvoxamine around the time of COVID-19 diagnosis are not at a reduced risk of unfavorable COVID-19 course compared to their non-prescribed peers: a nationwide matched cohort study

“…In this context, "not prescribed" fluvoxamine implies being prescribed with some other treatment for the underlying psychiatric condition, and the contrast between "prescribed" and "non-prescribed" patients regarding COVID-19 outcomes would be informative about fluvoxamine only if "not prescribed fluvoxamine" means also "not being treated for COVID-19" in the sense implied for fluvoxamine. Fluoxetine is another serotonine selective reuptake inhibitor (SSRI) that shows some antiviral and anti-inflammatory activity in non-clinical models 9 . One observational study 10 included laboratory confirmed COVID-19 adult outpatients in the pre-vaccination era: a cohort of patients prescribed fluoxetine (n=470) at a critical peridiagnostic period were matched (propensity-score based, 1:15) to patients not prescribed any SSRI or a related treatment (i.e., vilazodone, vortioxetine) -and yielded a relatively 25% lower mortality.…”

Outpatients prescribed with fluvoxamine around the time of COVID-19 diagnosis are not at a reduced risk of unfavorable COVID-19 course compared to their non-prescribed peers: population-based matched cohort study

“…People suffering conditions requiring antidepressant/anxiolytic treatment not treated with fluvoxamine are likely exposed to other treatments. Biological (mechanistic) rationale to support their use in COVID-19 has been argued for a range of antidepressants/anxiolytics not only for SSRIs [8,9], with, seemingly, an emphasis on fluvoxamine and fluoxetine [15]. One early observational study based on administrative data on COVID-19 patients identfied based on the fact of emergency department vistis of hospitalizations suggested that those prescribed fluoxetine (n=470) had by 28% lower mortality than propensity score-matched controls not prescribed with any SSRI [16].…”

Dissecting Physiopathology of COVID-19

“…The articles included in this Special Issue are focused on prevention, diagnostics, signatures of the disease course, molecules involved, vaccine-related adverse effects, potential treatments, and short- and long-term consequences. There are 3 original research papers [ 2 , 3 , 4 ] and 11 review articles [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ].…”

“…Paulina Niedźwiedzka-Rystwej and colleagues [ 5 ] discuss whether the cytokine storm results from immune system suppression or if it is a positive reaction necessary to clear the virus from the infected organism. The hope of finding new drugs acting against COVID-19 is sustained by the article by Mahdi et al [ 6 ] who present an overview of fluoxetine and fluvoxamine regarding their use in COVID-19. The two drugs are antidepressive agents that were also reported to act as lysosomotropic agents, inhibitors of acid sphingomyelinase in the lysosomes, and ligands of sigma-1 receptors.…”