Hui Song,1,* Yang Luo,2,* Lingzhi Fang1 

1The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, People’s Republic of China; 2Jiang You Third People Hospital, Mianyang, Sichuan, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Hui Song, Email 182321767@qq.com

Abstract: Esketamine nasal spray has emerged as a promising rapid-relief therapy for treatment-resistant depression (TRD) and suicide prevention. This review examines the chemical structure and pharmacodynamics of esketamine, highlighting its primary action on NMDA receptors and additional effects on AMPA receptors, opioid receptors, monoaminergic receptors, and inflammatory pathways. Despite the synergistic mechanisms contributing to its clinical benefits not being fully understood, future studies are essential to refine our understanding and optimize clinical use. Clinical research indicates that esketamine effectively alleviates depressive symptoms and prevents suicidal behavior in TRD patients, demonstrating good safety and efficacy over extended periods. Specifically, multiple randomized controlled trials have shown that esketamine reduces depressive symptoms within hours and maintains these benefits over several weeks, with a favorable safety profile and minimal side effects observed in long-term use. The approval of esketamine for TRD has significant implications for healthcare practices and policies, offering a new therapeutic option that addresses the urgent needs of patients with severe depression.

Keywords: esketamine, treatment-resistant depression, TRD, NMDA receptors, pharmacodynamics, clinical benefits, safety and efficacy