Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression

Andreas Reif; Istvan Bitter; Jozefien Buyze; Kerstin Cebulla; Richard Frey; Dong Jing Fu; Tetsuro Ito; Yerkebulan Kambarov; Pierre Michel Llorca; Albino J. Oliveira-Maia; Thomas Messer; Siobhán Mulhern-Haughey; Benoît Rive; Christian Von Holt; Allan H. Young; Yordan Godinov

doi:10.1056/NEJMoa2304145

Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression

Andreas Reif^*, Istvan Bitter, Jozefien Buyze, Kerstin Cebulla, Richard Frey, Dong Jing Fu, Tetsuro Ito, Yerkebulan Kambarov, Pierre Michel Llorca, Albino J. Oliveira-Maia, Thomas Messer, Siobhán Mulhern-Haughey, Benoît Rive, Christian Von Holt, Allan H. Young, Yordan Godinov

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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. (Funded by Janssen EMEA; ESCAPE-TRD ClinicalTrials.gov number, NCT04338321.).

Original language	English
Pages (from-to)	1298-1309
Number of pages	12
Journal	New England Journal of Medicine
Volume	389
Issue number	14
DOIs	https://doi.org/10.1056/NEJMoa2304145
Publication status	Published - 2023

Keywords

Clinical Medicine
Depression
Outpatient-Based Clinical Medicine
Psychiatry

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10.1056/NEJMoa2304145

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Reif, A., Bitter, I., Buyze, J., Cebulla, K., Frey, R., Fu, D. J., Ito, T., Kambarov, Y., Llorca, P. M., 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

@article{7b3345b01acd4e3e878191c5f90ef2fe,

title = "Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression",

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-{\AA}sberg 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. (Funded by Janssen EMEA; ESCAPE-TRD ClinicalTrials.gov number, NCT04338321.).",

keywords = "Clinical Medicine, Depression, Outpatient-Based Clinical Medicine, Psychiatry",

author = "Andreas Reif and Istvan Bitter and Jozefien Buyze and Kerstin Cebulla and Richard Frey and Fu, {Dong Jing} and Tetsuro Ito and Yerkebulan Kambarov and Llorca, {Pierre Michel} and Oliveira-Maia, {Albino J.} and Thomas Messer and Siobh{\'a}n Mulhern-Haughey and Beno{\^i}t Rive and {Von Holt}, Christian and Young, {Allan H.} and Yordan Godinov",

note = "Funding Information: This trial was conducted in accordance with the principles of the Declaration of Helsinki; country-specific ethics review boards approved the trial. All patients provided written informed consent. This trial was sponsored by Janssen EMEA. Janssen EMEA and a subgroup of investigators designed and coordinated the trial. A list of the investigators, the author contributions, and the medical writers who provided writing support in accordance with Good Publication Practice guidelines is provided in the (available with the full text of this article at NEJM.org). All the authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the (available at NEJM.org). All the authors contributed to the writing of the manuscript and to the decision to submit the manuscript for publication. Publisher Copyright: {\textcopyright} 2023 Massachusetts Medical Society.",

year = "2023",

doi = "10.1056/NEJMoa2304145",

language = "English",

volume = "389",

pages = "1298--1309",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "14",

}

Reif, A, Bitter, I, Buyze, J, Cebulla, K, Frey, R, Fu, DJ, Ito, T, Kambarov, Y, Llorca, PM, Oliveira-Maia, AJ, Messer, T, Mulhern-Haughey, S, Rive, B, Von Holt, C, Young, AH & Godinov, Y 2023, 'Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression', New England Journal of Medicine, vol. 389, no. 14, pp. 1298-1309. https://doi.org/10.1056/NEJMoa2304145

TY - JOUR

T1 - Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression

AU - Reif, Andreas

AU - Bitter, Istvan

AU - Buyze, Jozefien

AU - Cebulla, Kerstin

AU - Frey, Richard

AU - Fu, Dong Jing

AU - Ito, Tetsuro

AU - Kambarov, Yerkebulan

AU - Llorca, Pierre Michel

AU - Oliveira-Maia, Albino J.

AU - Messer, Thomas

AU - Mulhern-Haughey, Siobhán

AU - Rive, Benoît

AU - Von Holt, Christian

AU - Young, Allan H.

AU - Godinov, Yordan

N1 - Funding Information: This trial was conducted in accordance with the principles of the Declaration of Helsinki; country-specific ethics review boards approved the trial. All patients provided written informed consent. This trial was sponsored by Janssen EMEA. Janssen EMEA and a subgroup of investigators designed and coordinated the trial. A list of the investigators, the author contributions, and the medical writers who provided writing support in accordance with Good Publication Practice guidelines is provided in the (available with the full text of this article at NEJM.org). All the authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the (available at NEJM.org). All the authors contributed to the writing of the manuscript and to the decision to submit the manuscript for publication. Publisher Copyright: © 2023 Massachusetts Medical Society.

PY - 2023

Y1 - 2023

N2 - 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. (Funded by Janssen EMEA; ESCAPE-TRD ClinicalTrials.gov number, NCT04338321.).

AB - 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. (Funded by Janssen EMEA; ESCAPE-TRD ClinicalTrials.gov number, NCT04338321.).

KW - Clinical Medicine

KW - Depression

KW - Outpatient-Based Clinical Medicine

KW - Psychiatry

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U2 - 10.1056/NEJMoa2304145

DO - 10.1056/NEJMoa2304145

M3 - Article

C2 - 37792613

AN - SCOPUS:85173184069

SN - 0028-4793

VL - 389

SP - 1298

EP - 1309

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 14

ER -

Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression

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