Esketamine Nasal Spray: Mechanism of Action, Clinical, and Translational Science

ABSTRACT Major depressive disorder (MDD) imposes a substantial burden worldwide, with treatment‐resistant depression (TRD) and major depressive disorder with acute suicidal ideation or behavior (MDSI) representing two of the most severe clinical challenges. Conventional antidepressants often require several weeks to exert benefit, leaving patients symptomatic and at risk during this delay. Esketamine nasal spray was the first glutamate‐modulating antidepressant to enter clinical practice and was recently approved as the first and only monotherapy for adults with TRD. Administered at 56 mg or 84 mg, esketamine offers a rapid onset of action. Intranasal delivery yields approximately 50% bioavailability and peak concentrations within 20–40 min, correlating with early clinical effects. N‐methyl‐D‐aspartate (NMDA) receptor antagonism on inhibitory interneurons disinhibits glutamate release and modulates downstream synaptic plasticity pathways, providing a mechanistic basis for the rapid antidepressant effects of esketamine. This review summarizes the regulatory approval, mechanism of action, and pharmacokinetic/pharmacodynamic characteristics, together with key clinical trial efficacy and safety data for esketamine nasal spray in TRD and MDSI.