A New Era for Esketamine in Managing Treatment-Resistant Depression: A Systematic Review of Its Use From Adjunct to First-Line Therapy.

Treatment-resistant depression (TRD) remains a major clinical challenge, affecting nearly one-third of individuals with major depressive disorder (MDD) who fail to respond to standard antidepressant therapies. Esketamine, the S-enantiomer of ketamine, has emerged as a novel therapeutic option. Esketamine, initially introduced as an add-on therapy, has more recently also received recognition for use as a standalone treatment. This review aims to synthesize current clinical evidence on the efficacy and safety of esketamine monotherapy while exploring its molecular mechanisms and identifying research gaps. A systematic literature search was conducted across PubMed, Google Scholar, MedRxiv, and BioRxiv up to March 2025. Although designed as a systematic review, only one qualifying clinical trial was identified, limiting the feasibility of a meta-analysis and underscoring the scarcity of direct evidence. Despite this limitation, molecular insights suggest that TRD is associated with glutamatergic system dysfunction, impaired neuroplasticity, hypothalamic-pituitary-adrenal (HPA) axis abnormalities, and neuroinflammatory processes. Intranasal esketamine demonstrates potential as a rapid-acting and effective standalone therapy for TRD; nevertheless, further robust, large-scale randomized controlled trials are essential to confirm its therapeutic benefit, establish optimal dosing strategies, and overcome current research limitations.