The quercetin-serotonin transporter (SERT) connection: a new hope for depression therapy?

Quercetin, a naturally occurring flavonoid, has been found to be a potential agent for the treatment of major depressive disorder (MDD), given the complexity of its interaction with the serotonin transporter (SERT). Clinically, quercetin has direct and indirect modulatory effects as opposed to conventional selective serotonin reuptake inhibitors (SSRI), which act mainly by inhibiting SERT after a time delay and communicate with SERT through possible binding location preferences and allosteric processing, while simultaneously controlling its definite expression through anti-inflammatory and antioxidant pathways, such as the NF-kB, AMPK/SIRT-1, and Nrf2-ARE cascades. These processes assist in modifying serotonergic neurotransmission and minimizing oxidative and inflammatory strains, which are the major contributors to the pathophysiology of depression. Quercetin positively affects neuroplasticity and regulates the gut-to-brain axis, which affirms its antidepressant effects. Preclinical evidence indicates that quercetin can cause more rapid and extensive effects than SSRIs. However, translation issues include poor bioavailability and interindividual variation. Future trials should focus on inflammatory markers and individual quercetin formulations to maximize therapeutic effects in the depressed state.