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Clinical Trial
. 2025 Oct 14;68(1):e156.
doi: 10.1192/j.eurpsy.2025.10123.

Improvements in health-related quality of life with esketamine nasal spray versus quetiapine extended release

Andreas Reif  1   2 , Bernhard T Baune  3   4 , Jozefien Buyze  5 , Anthony J Cleare  6 , Shaun Johnson  7 , Yerkebulan Kambarov  5 , Nigel Olisa  7 , Falk Schuster  8 , Christian von Holt  9 , Tamara Werner-Kiechle  9 , Eduard Vieta  10
Affiliations
Clinical Trial

Improvements in health-related quality of life with esketamine nasal spray versus quetiapine extended release

Andreas Reif et al. Eur Psychiatry. .

Abstract

Background: Clinical response and remission may not fully reflect patient priorities in treatment-resistant depression (TRD). Health-related quality-of-life (HRQoL) outcomes should be assessed to comprehensively capture treatment benefits.

Methods: ESCAPE-TRD (NCT04338321) was a 32-week randomized, phase IIIb trial comparing esketamine nasal spray (NS) versus quetiapine extended release (XR), both alongside an ongoing selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor, in patients with TRD. Symptom and HRQoL improvements were assessed using the Patient Health Questionnaire-9 (PHQ-9), 36-Item Short Form Survey (SF-36), Quality of Life in Depression Scale (QLDS), and EuroQoL 5-Dimension 5-Level (EQ-5D-5L) measures.

Results: Esketamine NS-treated patients (N=336) reached PHQ-9 remission (score ≤4) quicker than quetiapine XR-treated patients (N=340), and more had remission by Week 32 (34.5% vs. 18.2%; odds ratio [OR]: 2.39 [1.67, 3.41], p<0.0001). "Role Emotional", "Mental Health", and "Social Functioning" SF-36 domains showed significantly greater improvements in esketamine NS-treated patients compared with quetiapine XR-treated patients at Week 32 (p<0.05), returning to levels close to general population norms. More esketamine NS-treated patients had a meaningful improvement in their QLDS score by Week 32 (60.7% vs. 41.8%; OR: 2.16 [1.59, 2.94], p<0.0001), and reached this improvement quicker than quetiapine XR-treated patients. Proportions of patients reporting an EQ-5D-5L score of 1 (no problems) were significantly higher across all domains with esketamine NS versus quetiapine XR at Week 32 (p<0.05).

Conclusions: Esketamine NS produced superior improvements in HRQoL compared with quetiapine XR, indicating positive impacts on aspects of patients' lives that matter to them, alongside clinical symptoms of TRD.

Keywords: clinical trial; esketamine; health-related quality of life; quetiapine; treatment-resistant depression.

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Conflict of interest statement

A.R.: Participated in advisory boards for and received speaker’s honoraria over the last 3 years from Boehringer Ingelheim, Compass, Cyclerion, Johnson & Johnson, LivaNova, Medice, MSD, Newron, SAGE/Biogen, and Shire/Takeda; received speaker’s honoraria from Das Fortbildungskolleg; received research grants from Johnson & Johnson and Medice; board member of DGBS, DGPPN, ECNP, and German Depression Foundation; aided in developing National Care Guidelines (NVL, S3) on ADHD, bipolar disorder, major depression, and suicidal behavior. B.T.B.: Received consulting fees for roles with the National Health and Medical Research Council, Australia; received honoraria from Angelini, AstraZeneca, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Johnson & Johnson, LivaNova, Lundbeck, Otsuka, Pfizer, Roche, Servier, Sumitomo Dainippon Pharma, Sunovion, and Wyeth; served on advisory boards for Biogen, Boehringer Ingelheim, Janssen-Cilag, LivaNova, Lundbeck, Novartis, and Otsuka; received research grants from private industries or nonprofit funds from AstraZeneca, Lundbeck, and Sanofi-Synthélabo; received research grants from the BMBF and BMG Germany, the DFG, Germany, the National Health and Medical Research Council, Australia, Horizon Europe 2021, and the Wellcome Trust (UK); received research grants from the Fay Fuller Foundation and James & Diana Ramsay Foundation, Adelaide. J.B., Y.K., C.H., and T.W.K.: Employees of Johnson & Johnson, and hold Johnson & Johnson company stock/stock options. A.J.C.: In the last 3 years, received grant funding from ADM Protexin Ltd, Beckley Psytech Ltd, European Union Horizon Europe/Innovate UK, the UK MRC, UK NIHR, and Wellcome Trust; received honoraria for presentations and/or consulting from COMPASS Pathways Plc, Janssen, Medscape, Otsuka, and Viatris; President of the International Society for Affective Disorders. S.J.: Board member of GAMIAN-Europe; Chair of the Lived Experience Advisory Board (LEAB) of Rethink Mental Illness; Chair and Trustee of Lamp, a charity providing mental health advocacy and support services. SJ receives no funding from, and holds no financial interest in, Johnson & Johnson. His contribution reflects an independent lived-experience perspective and does not imply endorsement of esketamine NS. F.S.: Member of Patients Advisory Boards of the EU-Horizon-funded projects PSY-PGx, TRUSTING, and ASPIRE; received consulting fees from Boehringer Ingelheim. N.O.: Patient Advocate and Executive Director of GAMIAN-Europe. E.V.: Received grants and served as consultant, advisor, or CME speaker for AB-Biotics, AbbVie, Adamed, Angelini, BeckleyPsych, Biogen, Boehringer Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, GSK, HMNC, Idorsia, Johnson & Johnson, Lundbeck, Medincell, Merck, Newron, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, Teva, and Viatris.

Figures

Figure 1.
Figure 1.
ESCAPE-TRD study design. (A) Esketamine NS was dosed twice weekly (56 mg on Day 1, 56/84 mg from Day 4) from Weeks 1–4, weekly (56/84 mg) from Weeks 5–8, and weekly or Q2W (56/84 mg) from Weeks 9–32, all in addition to an ongoing SSRI/SNRI that elicited nonresponse at baseline. (B) Quetiapine XR was flexibly dosed and administered daily, starting at 50 mg on Days 1–2, 150 mg/day on Days 3–4, and 300 mg/day from Day 5 onwards, all in addition to an ongoing SSRI/SNRI that elicited nonresponse at baseline. NS, nasal spray; Q2W, every 2 weeks; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; XR, extended release.
Figure 2.
Figure 2.
Proportion of patients achieving PHQ-9 remission over time. Full analysis set (includes all randomized patients). NRI was applied to treatment discontinuations. For patients who had a missing visit or a missing scale during a visit, but were still receiving study treatment, the missing score was imputed using LOCF. Tested at a two-sided 0.05 significance level without adjustment for multiple testing. Remission was defined as a PHQ-9 score ≤ 4. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. LOCF, last observation carried forward; NRI, nonresponder imputation; NS, nasal spray; PHQ-9, Patient Health Questionnaire-9; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; XR, extended release.
Figure 3.
Figure 3.
LS mean SF-36v2 domain scores by treatment arm. Full analysis set (includes all randomized patients). Gray dotted lines represent 2009 US population norms. LS means were based on MMRM (based on observed cases; on-treatment visits), adjusted for age and number of prior treatment failures. *p < 0.05, **p < 0.01, ***p < 0.001. ESK, esketamine; LS, least squares; MMRM, mixed model for repeated measures; NS, nasal spray; QTP, quetiapine; SF-36, 36-Item Short Form Survey; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; XR, extended release.
Figure 4.
Figure 4.
Time to a clinically meaningful improvement in QLDS. Full analysis set (includes all randomized patients). Patients discontinuing treatment were censored at an infinite (arbitrarily large) time and were assumed to never achieve clinically meaningful improvement. Time to first clinically meaningful improvement was defined as the first time a QLDS reduction of ≥8 points was reached. Shaded areas indicate 95% CIs. (A) Tested at a two-sided 0.05 significance level without adjustment for multiple testing. CI, confidence interval; ESK, esketamine; HR, hazard ratio; NS, nasal spray; QLDS, Quality of Life in Depression Scale; QTP, quetiapine; XR, extended release.
Figure 5.
Figure 5.
Proportion of patients reporting EQ-5D-5L domain score of 1 (no problems) by treatment arm. Full analysis set (includes all randomized patients). NRI was applied to treatment discontinuations. For patients who had a missing visit or a missing scale during a visit, but were still receiving study treatment, the missing score was imputed using LOCF. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. EQ-5D-5L, EuroQoL 5-Dimension 5-Level; ESK, esketamine; LOCF, last observation carried forward; NRI, nonresponder imputation; NS, nasal spray; QTP, quetiapine; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; XR, extended release.
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