Rapid Onset of Intranasal Esketamine in Patients with Treatment Resistant Depression and Major Depression with Suicide Ideation: A Meta-Analysis

Objective: We performed a meta-analysis of randomized double-blinded placebo controlled trials (DB-RCTs) to inves-tigate efficacy and safety of intranasal esketamine in treating major depressive disorder (MDD) including treatment re-sistant depression (TRD) and major depression with suicide ideation (MDSI). Methods: Mean change in total scores on Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to differ-ent time-points were our primary outcome measure. Secondary efficacy measures included rate of remission of depres-sion and resolution of suicidality. Results: Eight DB-RCTs (seven published and one un-published) covering 1,488 patients with MDD were included. Esketamine more significantly improved MADRS total scores than placebo starting from 2−4 hours after the first admin-istration (standardized mean difference, −0.41 [95% CI, −0.58 to −0.25], p ＜ 0.00001), and this superiority main-tained until end of double-blinded period (28 days). Sub-group analysis showed that superior antidepressant effects of esketamine over placebo in TRD and MDSI was observed from 2−4 hours, which was maintained until 28 days. Resolution of suicide in MDSI was also greater for esketamine than for placebo at 2−4 hours (OR of 2.04, 95% CIs, 1.37 to 3.05, p = 0.0005), but two groups did not statistically differ at 24 hours and day 28. Total adverse events (AEs), and other common AEs including dissociation, blood pressure increment, nausea, vertigo, dysgeusia, dizziness, and somnolence were more frequent in esketamine than in placebo group. Conclusion: Esketamine showed rapid antidepressant effects in patients with MDD, including TRD and MDSI. The study also suggested that esketamine might be associated with rapid anti-suicidal effects for patients with MDSI.