Esketamine Nasal Spray: Mechanism of Action, Clinical, and Translational Science.
Clinical and translational science April 1, 2026 Matthijs W Van Hoogdalem, Dong-Jing Fu, Wayne C Drevets et al.
Esketamine nasal spray is the first glutamate-modulating antidepressant approved as a monotherapy for adults with treatment-resistant depression. It acts rapidly by blocking NMDA receptors on inhibitory interneurons, which disinhibits glutamate release and alters synaptic plasticity. Administered at 56 mg or 84 mg, it reaches peak concentration in 20–40 minutes with about 50% bioavailability. This review covers its regulatory approval, mechanism of action, pharmacokinetics, and clinical trial data for efficacy and safety in treatment-resistant depression and major depressive disorder with acute suicidal ideation or behavior.