Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1)

Int J Neuropsychopharmacol. 2019 Oct 1;22(10):616-630. doi: 10.1093/ijnp/pyz039.


Background: About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression.

Methods: This Phase 3, double-blind, multicenter study enrolled adults with moderate-to-severe depression and nonresponse to ≥2 antidepressants in the current depression episode. Eligible patients (N = 346) were randomized (1:1:1) to twice-weekly nasal spray treatment (esketamine [56 or 84 mg] or placebo) plus a newly initiated, open-label, oral antidepressant taken daily for 4 weeks. The primary efficacy endpoint was change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score, performed by blinded, remote raters. Based on the predefined statistical testing sequence, esketamine 84 mg/antidepressant had to be significant for esketamine 56 mg/antidepressant to be formally tested.

Results: Statistical significance was not achieved with esketamine 84 mg/antidepressant compared with antidepressant/placebo (least squares [LS] means difference [95% CI]: -3.2 [-6.88, 0.45]; 2-sided P value = .088). Although esketamine 56 mg/antidepressant could not be formally tested, the LS means difference was -4.1 [-7.67, -0.49] (nominal 2-sided P value = .027). The most common (>20%) adverse events reported for esketamine/antidepressant were nausea, dissociation, dizziness, vertigo, and headache.

Conclusions: Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between esketamine/antidepressant groups and no new dose-related safety concerns were identified. This study provides supportive evidence for the safety and efficacy of esketamine nasal spray as a new, rapid-acting antidepressant for patients with treatment-resistant depression.

Trial registration: ClinicalTrials.gov identifier: NCT02417064.

Keywords: esketamine; ketamine; s-ketamine; treatment-resistant depression.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intranasal
  • Administration, Oral
  • Adolescent
  • Adult
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / adverse effects*
  • Antidepressive Agents / therapeutic use*
  • Citalopram / therapeutic use
  • Delayed-Action Preparations / therapeutic use
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Double-Blind Method
  • Drug Therapy, Combination / adverse effects
  • Duloxetine Hydrochloride / therapeutic use
  • Female
  • Humans
  • Ketamine / administration & dosage
  • Ketamine / adverse effects*
  • Ketamine / therapeutic use*
  • Male
  • Middle Aged
  • Sertraline / therapeutic use
  • Treatment Outcome
  • Venlafaxine Hydrochloride / therapeutic use
  • Young Adult


  • Antidepressive Agents
  • Delayed-Action Preparations
  • Citalopram
  • Esketamine
  • Ketamine
  • Venlafaxine Hydrochloride
  • Duloxetine Hydrochloride
  • Sertraline

Associated data

  • ClinicalTrials.gov/NCT02417064