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.
Papers cited by this study that are also in Blossom
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.
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.
ESCAPE-TRD was a randomised, open-label, rater-blinded, long-term Phase 3b trial conducted across 171 sites in 24 countries. An open-label pragmatic design was used because the administration routes and dosing schedules of ESK and quetiapine XR differ; however, Montgomery-Åsberg Depression Rating Scale (MADRS) assessments were performed by independent on-site raters blinded to treatment. Eligible patients had current MDD and demonstrated inadequate response (<25% improvement) to at least two consecutive, adequately dosed antidepressant treatments from two different pharmacologic classes during the current episode. Randomisation used a computer-generated schedule with randomly permuted blocks and was stratified by age and number of prior treatment failures. This secondary analysis included patients aged 18–64 years who were randomised 1:1 to ESK + OAD or quetiapine XR + OAD and who received dosing consistent with USPI (patients who received 28 mg ESK were excluded). ESK was administered intranasally: twice weekly in week 1–4 (56 mg on day 1, with possible increase to 84 mg from day 4), weekly in weeks 5–8 (56 or 84 mg), and weekly or every two weeks in weeks 9–32 (56 or 84 mg). Quetiapine XR was administered orally, starting at 50 mg/day and titrated to ≥150 mg/day by end of week 2, then flexibly dosed at 150–300 mg/day from week 3–32. Both arms continued an ongoing selective serotonin reuptake inhibitor or serotonin–noradrenaline reuptake inhibitor. The primary endpoint was remission at week 8, defined as MADRS total score ≤10; the key secondary endpoint was being relapse-free through week 32 after achieving remission at week 8. Relapse was prespecified as MADRS ≥22 confirmed by a second assessment within 5–15 days, psychiatric hospitalisation for worsening depression or suicide prevention, suicide attempt/completed suicide, or other investigator-determined clinically relevant worsening. Analyses of the primary and key secondary endpoints used a Cochran–Mantel–Haenszel test adjusted for number of prior treatment failures (2 versus ≥3); patients who discontinued were counted as negative for those endpoints. Remission and response at on-treatment visits were analysed using a last-observation-carried-forward (LOCF) approach with Cochran–Mantel–Haenszel tests. Change from baseline in MADRS was analysed with mixed models for repeated measures (MMRM) including baseline MADRS as covariate and treatment, stratification factors, visit and visit-by-treatment interaction as fixed effects (unstructured covariance). Time-to-event outcomes (time to first and to confirmed remission/response) used Kaplan–Meier methods with censoring at treatment discontinuation. Prespecified sensitivity analyses varied remission/relapse thresholds (e.g. MADRS ≤12 or ≤8; relapse defined as MADRS ≥18 or CGI-S ≥5) and timepoints (week 6, week 10, any point within 8 weeks). Safety analyses included all patients who received at least one dose and used standard definitions for treatment-emergent adverse events (TEAEs) and serious TEAEs.
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)
Papers in Blossom that reference this study
Clemens, K., Teeple, A., Rive, B. et al. · Journal of Comparative Effectiveness Research (2025)
Of 676 patients enrolled in the overall trial, 636 met criteria for this secondary analysis (ESK n = 316; quetiapine XR n = 320). The safety analysis set comprised 314 patients in the ESK arm and 316 in the quetiapine XR arm. Baseline characteristics were reported as comparable between arms (mean age 43.7 years; 65.9% female), with moderate-to-severe baseline symptom severity on average. Primary and key secondary outcomes: Using the prespecified definition (MADRS ≤10) and counting discontinuations as negative, remission without treatment discontinuation at week 8 was significantly higher with ESK versus quetiapine XR (26.6% versus 18.1%; P = 0.009). The odds of remission at week 8 were 1.65 times higher with ESK + OAD compared with quetiapine XR + OAD (OR 1.65; 95% CI 1.13–2.41). Among patients who achieved remission at week 8, a greater proportion receiving ESK remained relapse-free through week 32 (21.2% versus 14.4%; P = 0.020). Approximately 80% of patients in both treatment arms who achieved remission at week 8 remained relapse-free through week 32 (ESK 79.8%; quetiapine XR 79.3%). Remission and response over time: In analyses of remission and response over visits, ESK produced earlier and larger effects. Response rates were higher with ESK starting at week 2 (16.6% versus 8.4%; P = 0.002) and at all subsequent timepoints through week 32 (75.9% versus 55.0%; P < 0.001). The odds of response at week 32 were higher with ESK (OR 2.58; 95% CI 1.83–3.64). Using observed rates, absolute remission rates at week 8 were reported as 28.3% (ESK) versus 18.6% (quetiapine XR; P = 0.005), and at week 32 were 55.7% versus 36.3% (P < 0.001), with an odds ratio for remission at week 32 of 2.20 (95% CI 1.60–3.04). Change from baseline in MADRS was greater with ESK at each visit from day 8 onward; the average least-squares mean difference over time in MADRS change-from-baseline was −2.5 (95% CI −3.5 to −1.4), favouring ESK. Sensitivity analyses: Across prespecified sensitivity analyses that varied remission thresholds and timepoints, ESK consistently showed higher proportions achieving remission than quetiapine XR. For MADRS ≤12, week-8 remission rates were 38.3% (ESK) versus 23.4% (quetiapine XR; P < 0.001); for MADRS ≤8 at week 8 rates were 17.4% versus 13.1% (P = 0.131). Considering remission at any point within the first 8 weeks, 34.5% of ESK patients versus 20.9% of quetiapine XR patients achieved remission. When alternative relapse definitions were used (e.g. CGI-S ≥5), the proportion remaining relapse-free through week 32 after week-8 remission remained higher with ESK (22.8% versus 14.7%; P = 0.008). Time-to-event outcomes: Treatment with ESK shortened time to first remission and time to confirmed remission (two consecutive visits), and likewise shortened time to first and confirmed response, versus quetiapine XR (Kaplan–Meier analyses reported; exact medians not provided in the extracted text). Safety: In the safety set, 92.0% of patients in the ESK arm and 78.5% in the quetiapine XR arm experienced at least one TEAE. Overall, 5.4% of patients (n = 34) experienced at least one serious TEAE. The most frequently reported TEAEs (≥10%) included dizziness, headache, somnolence, nausea, dissociation and vertigo. Treatment discontinuation occurred in 22.2% of ESK-treated patients and 40.0% of quetiapine XR–treated patients. Discontinuations due to TEAEs were less common with ESK (4.5%) than with quetiapine XR (10.1%). TEAEs most commonly leading to discontinuation included sedation and weight increase in the quetiapine XR arm and dizziness in both arms. Weight increase occurred more often with quetiapine XR (12.3%) than with ESK (2.9%). The authors note that many ESK-associated TEAEs (dizziness, nausea, dissociation, vertigo) were transient and resolved on the dosing day while patients were still under supervision.
The researchers interpret these secondary-analysis results as supporting a clinical advantage for ESK plus an OAD over quetiapine XR plus an OAD in adult patients with TRD treated in accordance with US prescribing information. Findings were consistent with the trial's primary analysis and showed higher remission and response rates with ESK, earlier onset of benefit, greater reductions in MADRS scores over time, and shorter times to first and confirmed remission/response. Safety findings were described as consistent with known profiles for each medication. Although TEAEs were reported more frequently with ESK, discontinuations due to TEAEs were lower than with quetiapine XR; many ESK-associated events were transient and resolved the same day under clinical supervision, whereas quetiapine-associated TEAEs such as fatigue and weight gain tended to be more chronic and may have contributed to higher discontinuation. The authors also relate the results to real-world evidence (ICEBERG), which they state supported long-term benefit of ESK versus routine real-world treatment. The authors acknowledge limitations that could affect interpretation. The open-label design was necessary because of differing administration routes but may introduce bias related to treatment adherence and differing visit schedules; patients receiving ESK had more frequent visits early in treatment (twice weekly weeks 1–4) because supervised administration is required, whereas quetiapine XR patients had once-weekly visits during that period (more frequent than typical practice). Overall engagement with healthcare professionals in both arms was higher than with OADs alone in routine care, which may limit generalisability. The authors conclude that, within these constraints, no new safety signals were identified and that ESK improved short- and long-term outcomes compared with quetiapine XR when administered according to US prescribing information.