Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression
This open-label Phase IIIb trial (n=676) compared the efficacy of esketamine nasal spray and extended-release quetiapine, combined with an SSRI or SNRI, in patients with treatment-resistant depression (TRD). The study found that a significantly higher percentage of patients in the esketamine group achieved remission at week 8 (27.1% vs 17.6%) and had no relapse through week 32 after remission at week 8 (21.7% vs 14.1%). Adverse events were consistent with the established safety profiles of the trial treatments.
Authors
- Daniel Fu
Published
Abstract
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.
Research Summary of 'Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression'
Introduction
Treatment-resistant depression, commonly defined as failure to respond to two or more adequate pharmacologic treatments during the same depressive episode, is associated with low rates of remission, high relapse rates, and substantial morbidity and economic burden. Earlier clinical trials showed that esketamine nasal spray, when added to a newly initiated SSRI or SNRI, reduced depressive symptoms and lowered relapse risk versus placebo nasal spray plus oral antidepressant, but head-to-head data comparing esketamine with an active augmentation strategy in patients already receiving an SSRI or SNRI were limited. Extended-release quetiapine is a guideline-supported antipsychotic augmentation agent commonly used in practice, yet direct comparative efficacy and safety versus esketamine in treatment-resistant depression had not been established. Cebulla and colleagues conducted the ESCAPE-TRD trial to address this gap. The trial tested the hypothesis that, among adults with treatment-resistant major depressive disorder who continued treatment with an SSRI or SNRI, esketamine nasal spray plus that antidepressant would lead to higher rates of remission at week 8 and greater freedom from relapse through week 32 after remission than extended-release quetiapine plus the same antidepressant. The study therefore sought to compare short-term remission and longer-term relapse prevention, together with safety, in a pragmatic, head-to-head setting.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Author
- APA Citation
Reif, A., Bitter, I., Buyze, J., Cebulla, K., Frey, R., Fu, D., Ito, T., Kambarov, Y., Llorca, P., Oliveira-Maia, A. J., Messer, T., Mulhern-Haughey, S., Rive, B., von Holt, C., Young, A. H., & Godinov, Y. (2023). Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression. New England Journal of Medicine, 389(14), 1298-1309. https://doi.org/10.1056/nejmoa2304145
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)
Jha, M. K., Williamson, D. J., Magharehabed, G. et al. · Journal of Affective Disorders (2022)
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Samalin, L., Rothärmel, M., Mekaoui, L. et al. · Journal of Psychiatric Research (2026)
Reif, A., Anıl, Y. A., Bitter, I. et al. · European Neuropsychopharmacology (2026)
Gründer, G., Mertens, L. J., Spangemacher, M. et al. · European Neuropsychopharmacology (2026)
Hong, C. J. · Journal of Affective Disorders (2025)
Tylš, F., Páleníček, T., Klučková, T. et al. · Pharmacological Reports (2025)
Clemens, K., Teeple, A., Rive, B. et al. · Journal of Comparative Effectiveness Research (2025)
Veraart, J. K. E., Smith-Apeldoorn, S. Y., van der Meij, A. et al. · Journal of Psychopharmacology (2025)
Harding, L., Zhdanava, M., Teeple, A. et al. · Clinical Therapeutics (2025)
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McIntyre, R. S., Mattingly, G., Godinov, Y. et al. · CNS Spectrums (2025)
Young, A. H., Llorca, P. M., Fagiolini, A. et al. · British Journal of Psychiatry (2024)
Gründer, G., Brand, M., Mertens, L. J. et al. · Lancet Psychiatry (2024)
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