Enhancement of Local Retionic Acid Signaling: A Pivotal Mechanism in Fluoxetine's Pleiotropic Actions

Abstract

Major depression (MDD) is one of the leading global causes of all non-fatal burden of disease. Involving monoaminergic imbalances, but also hormonal, structural and inflammatory alterations, the underlying pathogenesis remains incompletely understood. The antidepressant drug fluoxetine, which may be considered the "prototype" of all selective serotonin reuptake inhibitors (SSRI), appears to affect all of these processes. Interestingly, this is also the case for retinoic acid (RA), the highly potent active metabolite of vitamin A. In this review, we discuss RA signaling as a central mechanism of action -and missing link -for the multiple, pleiotropic effects of fluoxetine in the CNS, suggesting that direct inhibition of CYP-450-mediated RA catabolism by fluoxetine results in increased local concentration, and enhanced paracrine RA signaling in the CNS.