BACKGROUND: The efficacy of esketamine nasal spray for treatment-resistant depression remains controversial. This systematic review and meta-analysis was conducted to explore the influence of esketamine nasal spray on treatment efficacy for treatment-resistant depression. METHODS: We conducted a comprehensive search across multiple databases, including PubMed, EMbase, Web of Science, EBSCO, and Cochrane library through March 2024 for randomized controlled trials (RCTs) assessing the effect of esketamine nasal spray on the treatment efficacy of depression. This meta-analysis was performed using the random-effect model. RESULTS: Five RCTs are included in the meta-analysis. Overall, compared with control group treatment-resistant depression, esketamine nasal spray is associated with significantly reduced MADRS scores (SMD = -3.88
95% confidence interval [CI] = -5.71 to -2.05
P <
.0002), increased response rates (RR = 1.99
95% CI = 1.28-3.10
P = .002), decreased Sheehan Disability Scale (SMD = -3.01
95% CI = -4.39 to -1.64
P <
.0002) and PHQ-9 scores (SMD = -2.32
95% CI = -3.51 to -1.13
P = .0002), but leads to the increase in dizziness (RR = 3.55
95% CI = 2.37-5.32
P <
.00002) and nausea (RR = 3.88
95% CI = 2.10-7.18
P <
.0002). CONCLUSION: Esketamine nasal spray is beneficial to improve the efficacy of treatment-resistant depression.