Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression

N Engl J Med. 2023 Oct 5;389(14):1298-1309. doi: 10.1056/NEJMoa2304145.


Background: In treatment-resistant depression, commonly defined as a lack of response to two or more consecutive treatments during the current depressive episode, the percentage of patients with remission is low and the percentage with relapse is high. The efficacy and safety of esketamine nasal spray as compared with extended-release quetiapine augmentation therapy, both in combination with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI), in patients with treatment-resistant depression are unknown.

Methods: In an open-label, single-blind (with raters unaware of group assignments), multicenter, phase 3b, randomized, active-controlled trial, we assigned patients, in a 1:1 ratio, to receive flexible doses (according to the summary of product characteristics) of esketamine nasal spray (esketamine group) or extended-release quetiapine (quetiapine group), both in combination with an SSRI or SNRI. The primary end point was remission, defined as a score of 10 or less on the Montgomery-Åsberg Depression Rating Scale (MADRS), at week 8 (scores range from 0 to 60, with higher scores indicating more severe depression). The key secondary end point was no relapse through week 32 after remission at week 8. All patients were included in the analysis; patients who discontinued the trial treatment were considered as having had an unfavorable outcome (i.e., they were grouped with patients who did not have remission or who had a relapse). Analyses of the primary and key secondary end points were adjusted for age and number of treatment failures.

Results: Overall, 336 patients were assigned to the esketamine group and 340 to the quetiapine group. More patients in the esketamine group than in the quetiapine group had remission at week 8 (91 of 336 patients [27.1%] vs. 60 of 340 patients [17.6%]; P = 0.003) and had no relapse through week 32 after remission at week 8 (73 of 336 patients [21.7%] vs. 48 of 340 patients [14.1%]). Over 32 weeks of follow-up, the percentage of patients with remission, the percentage of patients with a treatment response, and the change in the MADRS score from baseline favored esketamine nasal spray. The adverse events were consistent with the established safety profiles of the trial treatments.

Conclusions: In patients with treatment-resistant depression, esketamine nasal spray plus an SSRI or SNRI was superior to extended-release quetiapine plus an SSRI or SNRI with respect to remission at week 8. (Funded by Janssen EMEA; ESCAPE-TRD number, NCT04338321.).

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Antidepressive Agents* / administration & dosage
  • Antidepressive Agents* / adverse effects
  • Antidepressive Agents* / therapeutic use
  • Delayed-Action Preparations
  • Depression / drug therapy
  • Depressive Disorder, Treatment-Resistant* / drug therapy
  • Drug Therapy, Combination
  • Humans
  • Ketamine* / administration & dosage
  • Ketamine* / adverse effects
  • Ketamine* / therapeutic use
  • Nasal Sprays
  • Quetiapine Fumarate* / administration & dosage
  • Quetiapine Fumarate* / adverse effects
  • Quetiapine Fumarate* / therapeutic use
  • Recurrence
  • Selective Serotonin Reuptake Inhibitors* / administration & dosage
  • Selective Serotonin Reuptake Inhibitors* / adverse effects
  • Selective Serotonin Reuptake Inhibitors* / therapeutic use
  • Serotonin and Noradrenaline Reuptake Inhibitors* / administration & dosage
  • Serotonin and Noradrenaline Reuptake Inhibitors* / adverse effects
  • Serotonin and Noradrenaline Reuptake Inhibitors* / therapeutic use
  • Single-Blind Method
  • Treatment Outcome


  • Antidepressive Agents
  • Delayed-Action Preparations
  • Esketamine
  • Nasal Sprays
  • Quetiapine Fumarate
  • Selective Serotonin Reuptake Inhibitors
  • Serotonin and Noradrenaline Reuptake Inhibitors
  • Ketamine

Associated data