Innovative Esketamine Nasal Spray as Adjunctive Therapy for Treatment-Resistant Depression: Systematic Review and Meta-Analysis on Potential Use in Health Workers

Abstract

Introduction: Depression affects nearly 300 million people worldwide, making it a leading cause of disability.¹,² Treatment-Resistant Depression (TRD) exhibits ongoing symptoms despite sufficient treatment.³,⁴ Healthcare workers face a twofold higher risk from chronic stress, burnout, and sleep disruption, increasing relapse and resistance.⁵,6,⁷ About 30% fail to achieve remission after multiple antidepressant trials.⁸ Glutamatergic dysfunction, marked by abnormal NMDA receptor activity, reduces synaptogenesis and disrupts mood regulation.⁹,10,¹¹ Esketamine, an NMDA antagonist, restores glutamate signaling and boosts BDNF, addressing this unmet need.¹²,13,¹⁴ Unlike monoaminergic antidepressants with slow onset,¹⁵ it acts rapidly and may prevent relapse, suggesting potential benefits for healthcare workers under chronic stress.⁴,¹⁶

Objective: To systematically review and analyze the efficacy of esketamine nasal spray as an adjunctive therapy for treatment-resistant depression, emphasizing its potential future use among healthcare workers.

Method: A systematic search was conducted across Scopus, PubMed, Wiley, and ScienceDirect following PRISMA guidelines. Eligible randomized controlled trials compared esketamine nasal spray plus oral antidepressants with placebo plus antidepressants. Risk of bias was assessed using the Cochrane RoB 2.0 tool and data analyzed with Review Manager 5.4.1. Primary outcomes included MADRS, PHQ-9, and GAD-7 score changes.

Results and Discussion: Six RCTs (n = 2,205) were included. Esketamine adjunct therapy significantly improved depressive and anxiety symptoms versus placebo on depression patient: MADRS (MD = −3.71, 95% CI −5.07 to −2.35, p < 0.00001), PHQ-9 (MD = −2.11, 95% CI −2.90 to −1.31, p < 0.00001), and GAD-7 (MD = −1.08, 95% CI −1.79 to −0.37, p = 0.003). Studies showed low to moderate risk of bias. Studies showed low-to-moderate risk of bias. These findings highlight esketamine’s potential relevance for healthcare workers vulnerable to stress-related depression.

Conclusion: Esketamine nasal spray offers rapid, significant improvement in TRD symptoms and represents a promising adjunctive therapy, with potential application for healthcare workers under chronic stress.