Long-Term Efficacy of Intranasal Esketamine in Treatment-Resistant Major Depression: A Systematic Review

Int J Mol Sci. 2021 Aug 28;22(17):9338. doi: 10.3390/ijms22179338.


Esketamine (ESK) has been approved as a rapid-acting intranasal treatment for treatment-resistant depression (TRD). Although existing studies have investigated the efficacy of ESK in the 4-week induction phase, our knowledge about long-term ESK efficacy remains poor. The aim of this systematic review was to summarize the available data on long-term ESK efficacy for TRD. A systematic search was performed including articles in English, up to 31 March 2021. The search found 7 relevant studies, involving 1024 adult TRD patients. Continuing treatment with ESK after the 4-week induction phase may be associated with stable efficacy in relapse prevention among TRD patients. Conversely, the long-term antidepressant effectiveness upon discontinuation of ESK might be limited, although data from three studies had a moderate to high risk of bias. Overall, the results on the effectiveness of this compound in the long term are mixed. According to our findings, ESK treatment should be continued following the induction phase to reach a stable efficacy in relapse prevention, while the long-term antidepressant and anti-suicidal effects of ESK after discontinuation are inconsistent. Currently, the level of proof of ESK efficacy in long-term TRD treatment remains low and more RCTs with larger sample sizes and active comparators are needed.

Keywords: clinical trials; continuation; esketamine; systematic review; treatment-resistant depression.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Administration, Intranasal
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / pharmacology*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Depressive Disorder, Treatment-Resistant / pathology
  • Humans
  • Ketamine / administration & dosage
  • Ketamine / pharmacology*
  • Secondary Prevention


  • Antidepressive Agents
  • Esketamine
  • Ketamine