Abstract: OBJECTIVE To evaluate the safety of esketamine nasal spray add-on therapy for treatment-resistant depression by meta analysis. METHODS Randomized controlled trials(RCTs) of esketamine nasal spray+oral antidepressants were searched and meta-analysis was conducted. RESULTS Five RCTs and 1 019 patients were included in the study. Compared with contrast group, treatment group had more adverse reacions, such as dissociation(RR=6.35, 95%CI, 2.84-14.23, P<0.000 01); sedation(RR=5.47, 95%CI, 2.05-14.57, P=0.000 7); somnolence(RR=2.66, 95%CI, 1.30-5.44, P=0.007); headache(RR=1.38, 95%CI, 1.05-1.83, P=0.02); vertigo(RR=5.87, 95%CI, 3.30-69.79, P<0.000 01; diziness(RR=2.98, 95%CI, 1.33-6.68, P=0.008); hypoesthesia(RR=10.25, 95%CI, 3.65-28.83, P<0.000 1); anxiety(RR=2.01, 95%CI, 1.20-3.37, P=0.008); paresthesia(RR=6.62, 95%CI, 2.75-15.98, P<0.000 1); nausea(RR=4.05, 95%CI, 2.71-6.05, P<0.000 01); dysguesia(RR=1.81, 95%CI, 1.35-2.42, P<0.000 1). At the same time, compared with contrast group, in esketamine nasal spray 28 mg subgroup, it had no significant difference in adverse effects; while in 56, 84 mg subgroup, there was significant difference besides of somnolence, headache, dysguesia. CONCLUSION It is showed that the appearance of adverse events has increased, but it is very light in esketamine nasal spray add-on therapy for treatment-resistant depression.