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.
