Adjunctive intranasal esketamine for major depressive disorder: A systematic review of randomized double-blind controlled-placebo studies

J Affect Disord. 2020 Mar 15;265:63-70. doi: 10.1016/j.jad.2020.01.002. Epub 2020 Jan 3.


Objectives: This is a meta-analysis of randomized double-blind controlled-placebo trials (RCTs) examining the effectiveness, tolerability, and safety of intranasal esketamine in treating major depressive disorder (MDD).

Methods: Standardized mean difference (SMD), risk ratio (RR) and their 95% confidence intervals (CIs) were calculated using RevMan version 5.3.

Results: Four RCTs with 7 active arms covering 708 patients with MDD on intranasal esketamine (n = 419) and placebo (n = 289) were included. Compared with placebo, adjunctive intranasal esketamine was associated with significantly greater study-defined response (RR=1.39, 95%CI: 1.18 to 1.64, P<0.0001) and remission (RR=1.42, 95%CI: 1.17 to 1.72, P = 0.0004) at endpoint assessment. Intranasal esketamine had greater study-defined response starting at 2 h (RR= 2.77, 95%CI: 1.62 to 4.76, P = 0.0002), peaking at 24 h (RR=5.42, 95%CI: 1.38 to 21.20, P = 0.02), and at least lasting for 28 days (RR=1.36, 95%CI: 1.16 to 1.58, P = 0.0001). Similarly, intranasal esketamine had significantly greater study-defined remission starting at 2 h (RR=7.71, 95%CI: 2.16 to 27.55, P = 0.002), peaking at 24 h (RR=6.87, 95%CI: 1.55 to 30.35, P = 0.01), and lasting for 28 days (RR=1.38, 95%CI: 1.11 to 1.72, P = 0.004). Intranasal esketamine had a significantly higher rate of discontinuation due to intolerability (RR=3.50, 95%CI: 1.38 to 8.86, P = 0.008). Discontinuation due to any reasons and inefficacy were similar between the two groups.

Conclusion: Intranasal esketamine appears to have an ultra-rapid antidepressant effect for MDD, at least lasting for 28 days. The long-term therapeutic effect and safety of intranasal esketamine need to be further examined in large-scale RCTs.

Keywords: Depression; Intranasal esketamine; Meta-analysis; Remission; Response.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Administration, Intranasal
  • Antidepressive Agents / therapeutic use
  • Depressive Disorder, Major* / drug therapy
  • Humans
  • Ketamine* / therapeutic use
  • Randomized Controlled Trials as Topic


  • Antidepressive Agents
  • Esketamine
  • Ketamine