Discovery of Rapid-Acting, Orally Available Antidepressants by Activating TrkB Signaling

Major depressive disorder (MDD) remains a significant global health burden, and its current treatments are limited by the delayed onset of efficacy weeks after dosing. While esketamine and psychedelics were clinically successful as rapid-acting antidepressants in recent years, these molecules are heavily associated with psychotic side effects and the risks of substance abuse. In this study, we identified a rapid-acting antidepressant B11 through phenotypic screening and pharmacophore-oriented lead optimization. Unlike the existing fast-onset antidepressants, B11 showed minimal interference with targets associated with psychotic side effects while demonstrating potent antidepressant effects through activation of the TrkB-CREB signaling axis in preclinical models. Besides, B11 readily penetrates the blood–brain barrier and possesses a favorable pharmacokinetic profile that enables oral administration. Our findings highlight the potential of optimized fast-onset therapeutics for addressing unmet clinical needs in depression treatment and underscore the importance of neuroplasticity modulation in drug discovery efforts for MDD.