Treatment Response of Add-On Esketamine Nasal Spray in Resistant Major Depression in Relation to Add-On Second-Generation Antipsychotic Treatment

Int J Neuropsychopharmacol. 2020 Jul 29;23(7):440-445. doi: 10.1093/ijnp/pyaa034.


In this meta-analysis, we aimed to estimate and compare the efficacy of add-on treatment of antidepressants with esketamine nasal spray and second-generation antipsychotics in patients with nonpsychotic major depressive disorder and inadequate response to antidepressants. Searching for acute-phase, double-blind, placebo-controlled, randomized trials, we found 22 second-generation antipsychotic (n = 8363) and 3 intranasal esketamine (n = 641) studies. Mean change in the Montgomery Åsberg Depression Rating Scale total score served as outcome. We determined a higher mean difference (vs placebo) for the pooled esketamine nasal spray trials (mean difference = 4.09, 95% confidence interval: 2.01 to 6.17) than for the pooled second-generation antipsychotic augmentation trials (mean difference = 2.05, 95% confidence interval: 1.51 to 2.59). Thus, the effect size for intranasal esketamine was nearly twice as high as those for the second-generation antipsychotics. This indicates high efficacy of add-on esketamine nasal spray in treatment-resistant major depressive disorder compared with other well-established, evidence-based pharmacological options such as augmentation with second-generation antipsychotics.

Keywords: add-on treatment; esketamine nasal spray; major depressive disorder; second-generation antipsychotics; treatment resistance.

Publication types

  • Systematic Review

MeSH terms

  • Administration, Intranasal
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / therapeutic use*
  • Antipsychotic Agents / therapeutic use*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Drug Therapy, Combination
  • Humans
  • Ketamine / administration & dosage
  • Ketamine / therapeutic use*
  • Nasal Sprays
  • Randomized Controlled Trials as Topic
  • Treatment Outcome


  • Antidepressive Agents
  • Antipsychotic Agents
  • Nasal Sprays
  • Esketamine
  • Ketamine