Intranasal esketamine effectively treats treatment-resistant depression in adults regardless of baseline irritability

J Affect Disord. 2023 Jan 15:321:153-160. doi: 10.1016/j.jad.2022.10.020. Epub 2022 Oct 20.


Objective: To evaluate the impact of baseline irritability on clinical outcomes in adults with treatment-resistant depression (TRD) treated with fixed or flexible doses of esketamine nasal spray plus a newly initiated oral antidepressant (ESK+AD) and to explore whether treatment with ESK affects irritability symptoms over time.

Methods: This was a post hoc analysis of pooled data from two 4-week, double-blind, phase 3 studies: TRANSFORM-1 (NCT02417064) and TRANSFORM-2 (NCT02418585). Adults with TRD (n = 560) were randomly assigned to ESK+AD or placebo nasal spray plus oral antidepressant (AD+PBO). Irritability was assessed with Item 6 of the 7-item Generalized Anxiety Disorder scale at screening and baseline. Changes in depression severity (Montgomery-Åsberg Depression Rating Scale [MADRS] total score) were evaluated by analysis of covariance (ANCOVA) models. Rates of MADRS response (≥50 % decrease from baseline total score) and remission (total score ≤ 12) were examined using multiple logistic regression models.

Results: Of 560 participants with TRD, 52.9 %, 23.2 %, and 23.9 % had high, low, and varying levels of irritability, respectively. No significant interaction between baseline irritability and treatment group was observed for change in MADRS total score, treatment response, or remission at day 28; numerically greater improvement was observed on all outcomes with ESK+AD versus AD+PBO at day 28 regardless of baseline irritability level. Percentages of patients reporting adverse events were similar across the three baseline irritability groups.

Limitations: TRANSFORM-1 and TRANSFORM-2 were not designed to prospectively evaluate predetermined irritability outcomes.

Conclusions: These post hoc results support efficacy of ESK+AD in patients with TRD, regardless of baseline irritability.

Trial registration: identifiers: NCT02417064 (TRANSFORM-1), NCT02418585 (TRANSFORM-2).

Keywords: Antidepressant; Depression; Esketamine; Irritability; Major depressive disorder; Treatment-resistant depression.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antidepressive Agents / adverse effects
  • Depression
  • Depressive Disorder, Treatment-Resistant* / drug therapy
  • Double-Blind Method
  • Humans
  • Nasal Sprays*
  • Treatment Outcome


  • Esketamine
  • Nasal Sprays
  • Antidepressive Agents

Associated data