Esketamine in Treatment-Resistant Depression: Clinical and Translational Perspectives

Esketamine, an intranasally administered N-methyl-D-aspartate (NMDA) receptor antagonist, represents a significant advancement in the treatment of Major Depressive Disorder (MDD), particularly among patients with Treatment-Resistant Depression (TRD). Its therapeutic effects are associated with rapid enhancement of glutamatergic neurotransmission and downstream activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-Brain-Derived Neurotrophic Factor (BDNF)-mechanistic Target Of Rapamycin (mTOR) signaling pathway, which is implicated in synaptic plasticity. This mini-review aims to synthesize current clinical and translational evidence on intranasal esketamine in TRD.

This mini-review provides an integrative overview of clinically relevant and translational studies on intranasal esketamine, based on a focused search of the PubMed and Scopus databases. Peer-reviewed clinical trials, meta-analyses, mechanistic studies, and regulatory documents were included.

Evidence from randomized controlled trials demonstrates a rapid onset of antidepressant effects, often within hours of administration, with consistent reductions in depressive symptom severity. Effects on clinician-rated suicidality were variable across studies. The most common adverse events include transient dissociation, dizziness, and modest increases in blood pressure, which are generally self-limiting.

Overall, the available evidence supports intranasal esketamine as an effective rapid-acting treatment for TRD, with a favorable benefit-risk profile under supervised clinical use. However, important considerations remain regarding optimal patient selection, maintenance strategies, and long-term outcomes.

Esketamine offers a clinically meaningful option for patients unresponsive to conventional monoaminergic treatments. Key unresolved issues include the development of predictive biomarkers, optimization of maintenance regimens, integration with psychotherapy, and evaluation of long-term cognitive and functional outcomes.