Esketamine nasal spray versus quetiapine XR in adults with treatment-resistant depression: a secondary analysis of the ESCAPE-TRD randomized clinical trial
In a secondary analysis of ESCAPE-TRD (n=636), esketamine nasal spray plus an oral antidepressant, dosed according to US prescribing information, produced significantly higher remission rates from week 8 to week 32 and greater, earlier reductions in MADRS scores (from day 8) than quetiapine XR, with fewer discontinuations due to adverse events.
Abstract
Objective
Esketamine nasal spray (ESK) is approved in combination with an oral antidepressant (OAD) for the treatment of adults with treatment-resistant depression (TRD); however, direct comparisons with atypical antipsychotics for TRD are limited. This secondary analysis of the ESCAPE-TRD study compared rates of remission and response, and improvements in depressive symptoms over time, between ESK and quetiapine extended-release (XR) in patients with TRD treated in accordance with US prescribing information (USPI).
Methods
ESCAPE-TRD (NCT04338321) was a randomized, open-label, rater-blinded phase 3b trial investigating ESK versus quetiapine XR for acute and maintenance treatment of patients with TRD. This secondary analysis included patients aged 18–64 years who were treated/dosed according to USPI. The primary endpoint was remission, defined as Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≤ 10. Treatment-emergent adverse events (TEAEs) leading to discontinuation were summarized descriptively.
Results
Among 636 patients in this secondary analysis (ESK, n = 316; quetiapine XR, n = 320), significantly more ESK-treated patients achieved remission starting at week 8 (28.3% versus 18.6%; P = 0.005) through week 32 (55.7% versus 36.3%; P < 0.001), compared with quetiapine XR–treated patients. There were clinically and statistically significant improvements in MADRS scores with ESK versus quetiapine XR at each visit from day 8 onwards. Fewer patients discontinued treatment because of TEAEs with ESK (4.5%) versus quetiapine XR (10.1%).
Conclusions
Consistent with the primary analysis, this secondary analysis demonstrated that ESK improves short- and long-term outcomes compared with quetiapine XR in patients with TRD treated according to USPI.
Research Summary of 'Esketamine nasal spray versus quetiapine XR in adults with treatment-resistant depression: a secondary analysis of the ESCAPE-TRD randomized clinical trial'
Introduction
Major depressive disorder (MDD) is common, often chronic, and carries substantial clinical and economic burden. A substantial subset of patients fail to respond adequately to multiple oral antidepressants (OADs) and are classified as having treatment-resistant depression (TRD), commonly defined as insufficient response to two or more adequately dosed antidepressants. TRD is associated with greater morbidity, hospitalisation and suicide risk, and achieving remission early in the treatment sequence is important because the probability of remission decreases with successive treatment steps. Esketamine nasal spray (ESK), an N-methyl-D-aspartate receptor antagonist, is approved in combination with an OAD for adults with TRD and has demonstrated efficacy versus placebo in prior trials. Quetiapine extended-release (XR) is an atypical antipsychotic indicated as an adjunctive treatment for major depression. Head-to-head comparisons between ESK and other active TRD treatments are limited, and most prior comparative analyses have been retrospective. The ESCAPE-TRD trial was a randomised, open-label, rater-blinded Phase 3b study designed to compare ESK versus quetiapine XR in TRD. This paper reports a preplanned secondary analysis restricted to patients treated according to US prescribing information (USPI)—excluding lower 28 mg ESK dosing—to reassess remission, relapse and response outcomes (including several sensitivity analyses) in a population more directly applicable to US clinical practice.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Author
- APA Citation
McIntyre, R. S., Mattingly, G., Godinov, Y., Buyze, J., Turkoz, I., Cabrera, P., Patel, M., Martinez, L., Himedan, M., & Lopena, O. (2025). Esketamine nasal spray versus quetiapine XR in adults with treatment-resistant depression: a secondary analysis of the ESCAPE-TRD randomized clinical trial. CNS Spectrums, 30(1). https://doi.org/10.1017/s1092852924002451
References (4)
Papers cited by this study that are also in Blossom
Daly, E. J., Turkoz, I., Salvadore, G. et al. · Depression and Anxiety (2021)
Brendle, M., Ahuja, S., Della Valle, M. et al. · Future Medicine (2022)
D'Andrea, G., Pettorruso, M., Di Lorenzo, G. et al. · Journal of Affective Disorders (2023)
Reif, A., Bitter, I., Buyze, J. et al. · New England Journal of Medicine (2023)
Cited By (1)
Papers in Blossom that reference this study
Clemens, K., Teeple, A., Rive, B. et al. · Journal of Comparative Effectiveness Research (2025)
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