The association between stage of treatment-resistant depression and clinical utility of ketamine/esketamine: A systematic review

J Affect Disord. 2022 Dec 1;318:139-149. doi: 10.1016/j.jad.2022.08.050. Epub 2022 Aug 29.


Objective: Ketamine has demonstrated rapid and significant antidepressant effects in patients with treatment resistant depression (TRD). Herein, we conducted a systematic review to determine ketamine's efficacy as a function of the stage of treatment resistance (e.g., number of failed treatments) among individuals with TRD.

Methods: A systematic search of PubMed and Scopus from inception to August 2021 was conducted. Where applicable, the studies were categorized into low and high stages of resistance, where low category included studies where the mean number of failed antidepressants was <3 or had a higher proportion of subjects with ≤2 antidepressant trials. Reported indicators of treatment resistance and efficacy were extracted from randomized-controlled trials (RCTs) assessing ketamine or esketamine for TRD.

Results: In total, 18 RCTs were included in the current review. There was variability across reported indicators of disease severity, definition of treatment resistance, as well as treatment protocols, preventing clear direct and indirect comparison of relative efficacy of ketamine at different stages of treatment resistance. Ketamine was effective in reducing depressive symptoms in RCTs at both lower and higher stages of treatment resistance; however, the effect size and duration of effects was greater in RCTs of lower stage of treatment resistance.

Conclusions: Our findings suggested that ketamine has antidepressant efficacy across all identified stages of treatment resistance, however with increasing failed treatment trials, treatment might be less efficacious. At this time, the comparative efficacy as a function of resistance stage remains to be well-established. Evaluation of participant level data is required to more clearly determine the association between level of treatment resistance and likelihood of response.

Keywords: Arketamine; BDNF; Bipolar; Glutamate; NMDA; Spravato.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Antidepressive Agents / therapeutic use
  • Depression / drug therapy
  • Depressive Disorder, Treatment-Resistant* / drug therapy
  • Humans
  • Ketamine* / therapeutic use


  • Antidepressive Agents
  • Esketamine
  • Ketamine