Efficacy of esketamine nasal spray over quetiapine extended release over the short and long term: sensitivity analyses of ESCAPE-TRD, a randomised phase IIIb clinical trial
Sensitivity analyses of the randomised ESCAPE‑TRD trial confirmed that adjunctive esketamine nasal spray was consistently superior to quetiapine extended release for achieving remission at Week 8 and remaining relapse‑free to Week 32 (relative risks 1.46–1.84, all p<0.05). Esketamine also shortened time to first and confirmed remission (hazard ratios ≈1.66–1.71), supporting the robustness of the original findings.
Authors
- Allan Young
- Andrea Fagiolini
Published
Abstract
Background
In patients with treatment resistant depression (TRD), the ESCAPE-TRD study showed esketamine nasal spray was superior to quetiapine extended release.
Aims
To determine the robustness of the ESCAPE-TRD results and confirm the superiority of esketamine nasal spray over quetiapine extended release.
Method
ESCAPE-TRD was a randomised, open-label, rater-blinded, active-controlled phase IIIb trial. Patients had TRD (i.e. non-response to two or more antidepressive treatments within a major depressive episode). Patients were randomised 1:1 to flexibly dosed esketamine nasal spray or quetiapine extended release, while continuing an ongoing selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor. The primary end-point was achieving a Montgomery–Åsberg Depression Rating Scale score of ≤10 at Week 8, while the key secondary end-point was remaining relapse free through Week 32 after achieving remission at Week 8. Sensitivity analyses were performed on these end-points by varying the definition of remission based on timepoint, threshold and scale.
Results
Of 676 patients, 336 were randomised to esketamine nasal spray and 340 to quetiapine extended release. All sensitivity analyses on the primary and key secondary end-point favoured esketamine nasal spray over quetiapine extended release, with relative risks ranging from 1.462 to 1.737 and from 1.417 to 1.838, respectively (all p < 0.05). Treatment with esketamine nasal spray shortened time to first and confirmed remission (hazard ratio: 1.711 [95% confidence interval 1.402, 2.087], p < 0.001; 1.658 [1.337, 2.055], p < 0.001).
Conclusion
Esketamine nasal spray consistently demonstrated significant superiority over quetiapine extended release using all pre-specified definitions for remission and relapse. Sensitivity analyses supported the conclusions of the primary ESCAPE-TRD analysis and demonstrated robustness of the results.
Research Summary of 'Efficacy of esketamine nasal spray over quetiapine extended release over the short and long term: sensitivity analyses of ESCAPE-TRD, a randomised phase IIIb clinical trial'
Introduction
Treatment-resistant depression (TRD) is commonly defined as failure to respond to two or more adequate pharmacological treatments during the same major depressive episode and affects an estimated 10-30% of people with major depressive disorder. Remission in the acute phase and prevention of relapse in the maintenance phase are the principal treatment goals for TRD, yet remission rates decline as the number of prior treatment failures increases and there is no single guideline-recommended strategy. Two treatments in current use are quetiapine extended release, a commonly used augmentation therapy, and esketamine nasal spray, which is approved specifically for TRD in Europe and has shown superiority versus placebo when added to a newly initiated SSRI or SNRI in previous trials. Young and colleagues report sensitivity analyses of the ESCAPE-TRD trial, a head-to-head, randomised, open-label, rater-blinded Phase IIIb study that originally demonstrated esketamine nasal spray was superior to quetiapine extended release when both were given with a continuing SSRI or SNRI. This paper examines the robustness of that finding by varying how remission and relapse are defined (timepoints, thresholds and scales) and by analysing additional outcomes such as remission over time and time to remission and response, with the aim of testing whether the main conclusions hold under alternative plausible definitions and analytic choices.
Expert Research Summaries
Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.
Full Text PDF
Full Paper PDF
Pro members can view the original manuscript directly in the browser.
Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Authors
- APA Citation
Young, A. H., Llorca, P., Fagiolini, A., Falkai, P., Cardoner, N., Nielsen, R. E., Blomqvist, O., Godinov, Y., Rive, B., Diels, J., Mulhern-Haughey, S., & Reif, A. (2025). Efficacy of esketamine nasal spray over quetiapine extended release over the short and long term: sensitivity analyses of ESCAPE-TRD, a randomised phase IIIb clinical trial. The British Journal of Psychiatry, 226(2), 72-78. https://doi.org/10.1192/bjp.2024.124
References (2)
Papers cited by this study that are also in Blossom
Daly, E. J., Turkoz, I., Salvadore, G. et al. · Depression and Anxiety (2021)
Reif, A., Bitter, I., Buyze, J. et al. · New England Journal of Medicine (2023)
Your Personal Research Library
Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.