Sensitivity analyses of the randomised ESCAPE‑TRD trial confirmed that adjunctive esketamine nasal spray was consistently superior to quetiapine extended release for achieving remission at Week 8 and remaining relapse‑free to Week 32 (relative risks 1.46–1.84, all p<0.05). Esketamine also shortened time to first and confirmed remission (hazard ratios ≈1.66–1.71), supporting the robustness of the original findings.
Papers cited by this study that are also in Blossom
Background
In patients with treatment resistant depression (TRD), the ESCAPE-TRD study showed esketamine nasal spray was superior to quetiapine extended release.
Aims
To determine the robustness of the ESCAPE-TRD results and confirm the superiority of esketamine nasal spray over quetiapine extended release.
Method
ESCAPE-TRD was a randomised, open-label, rater-blinded, active-controlled phase IIIb trial. Patients had TRD (i.e. non-response to two or more antidepressive treatments within a major depressive episode). Patients were randomised 1:1 to flexibly dosed esketamine nasal spray or quetiapine extended release, while continuing an ongoing selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor. The primary end-point was achieving a Montgomery–Åsberg Depression Rating Scale score of ≤10 at Week 8, while the key secondary end-point was remaining relapse free through Week 32 after achieving remission at Week 8. Sensitivity analyses were performed on these end-points by varying the definition of remission based on timepoint, threshold and scale.
Results
Of 676 patients, 336 were randomised to esketamine nasal spray and 340 to quetiapine extended release. All sensitivity analyses on the primary and key secondary end-point favoured esketamine nasal spray over quetiapine extended release, with relative risks ranging from 1.462 to 1.737 and from 1.417 to 1.838, respectively (all p < 0.05). Treatment with esketamine nasal spray shortened time to first and confirmed remission (hazard ratio: 1.711 [95% confidence interval 1.402, 2.087], p < 0.001; 1.658 [1.337, 2.055], p < 0.001).
Conclusion
Esketamine nasal spray consistently demonstrated significant superiority over quetiapine extended release using all pre-specified definitions for remission and relapse. Sensitivity analyses supported the conclusions of the primary ESCAPE-TRD analysis and demonstrated robustness of the results.
Treatment-resistant depression (TRD) is commonly defined as failure to respond to two or more adequate pharmacological treatments during the same major depressive episode and affects an estimated 10-30% of people with major depressive disorder. Remission in the acute phase and prevention of relapse in the maintenance phase are the principal treatment goals for TRD, yet remission rates decline as the number of prior treatment failures increases and there is no single guideline-recommended strategy. Two treatments in current use are quetiapine extended release, a commonly used augmentation therapy, and esketamine nasal spray, which is approved specifically for TRD in Europe and has shown superiority versus placebo when added to a newly initiated SSRI or SNRI in previous trials. Young and colleagues report sensitivity analyses of the ESCAPE-TRD trial, a head-to-head, randomised, open-label, rater-blinded Phase IIIb study that originally demonstrated esketamine nasal spray was superior to quetiapine extended release when both were given with a continuing SSRI or SNRI. This paper examines the robustness of that finding by varying how remission and relapse are defined (timepoints, thresholds and scales) and by analysing additional outcomes such as remission over time and time to remission and response, with the aim of testing whether the main conclusions hold under alternative plausible definitions and analytic choices.
ESCAPE-TRD was a multicentre, randomised, open-label but rater-blinded Phase IIIb study (NCT04338321) comparing flexibly dosed esketamine nasal spray plus a continuing SSRI/SNRI versus quetiapine extended release plus a continuing SSRI/SNRI in adults with TRD. The extracted text does not list full inclusion/exclusion criteria here but defines TRD as non-response to at least two antidepressant treatments in the current episode. Ethics approvals and written informed consent were obtained. The primary end-point was remission at Week 8, defined in the main analysis as a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of ≤10. The key secondary end-point required patients to achieve remission at Week 8 and remain relapse-free through Week 32; relapse was principally defined using MADRS-based thresholds and clinical criteria (MADRS ≥22 at two consecutive assessments 5–15 days apart, hospital admission for worsening depression/suicide prevention, suicide attempt/completion, or other clinically relevant events as judged by the investigator). The sensitivity analyses reported here varied single elements of these definitions (timepoint, threshold or scale) in pre-specified ways to assess robustness. Alternative thresholds for remission at Week 8 included MADRS ≤8 and ≤12; an alternative relapse threshold used MADRS ≥18 and another used Clinical Global Impression–Severity (CGI‑S) ≥5 while keeping other relapse components the same. Timepoint variations redefined remission at Week 6, Week 10 or as remission at any visit at or before Week 8; the relapse observation window was also altered in one analysis to Weeks 8–24. Rates of remission over time were estimated at every on-treatment MADRS assessment. Because the trial took place during the COVID‑19 pandemic, some MADRS assessments were permitted remotely and the authors assessed the impact of remote versus in-person assessments. Binary end-points were analysed using non-responder imputation (NRI), where treatment discontinuation was treated as a negative outcome; missing Week 8 visits for patients still on treatment were imputed using last observation carried forward (LOCF). For binary comparisons the authors report odds ratios, risk differences, relative risks and numbers needed to treat (NNT) with 95% confidence intervals, using Cochran–Mantel–Haenszel chi-square tests adjusted for age strata (18–≤64 years; 65–≤74 years) and number of prior treatment failures (2; ≥3). Time-to-event outcomes (time to first and confirmed remission or response) were analysed with Kaplan–Meier estimates and compared by log‑rank test; hazard ratios were estimated from Cox proportional hazards models stratified by the same age and prior-failure categories. Patients who discontinued were effectively censored at an arbitrarily large time (set to 9999 days) and assumed never to have achieved the event, analogous to NRI for time-to-event analyses. All hypothesis tests were two-sided with alpha = 0.05 and no adjustment for multiple testing was applied.
Treatment resistant depression (TRD), most commonly defined as non-response to two or more pharmacological treatments of adequate duration and dose within the same major depressive episode (MDE), 1 affects 10-30% of patients with major depressive disorder (MDD).The two key treatment goals for patients with TRD are remission and prevention of relapse.Remission is the accepted short-term treatment goal, whilst prevention of relapse is a desired longer-term goal.Remission rates in patients with TRD who require three or more consecutive treatments are lower compared to patients who received fewer prior treatments.Therefore, a substantial unmet need exists for short-and longterm treatment of TRD.There is no one singular guideline-recommended strategy to treat patients with TRD;two currently available treatments are quetiapine extended release and esketamine nasal spray. Quetiapine extended release is one of the most commonly used augmentation therapies for TRD, and is approved for patients with MDD who have experienced a sub-optimal response to antidepressant monotherapy.Esketamine nasal spray, the only treatment specifically approved for TRD in Europe,has demonstrated a superior reduction of depressive symptoms compared with placebo when both were given in combination with a newly initiated selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI).ESCAPE-TRD was an open-label, rater-blinded, randomised clinical trial that compared flexibly dosed esketamine nasal spray with quetiapine extended release, both in combination with an ongoing SSRI/SNRI, in patients with TRD.It is one of the few existing head-to-head studies in TRD, and was the first head-to-head study comparing esketamine nasal spray with an augmentation strategy. The ESCAPE-TRD study demonstrated the superiority of esketamine nasal spray over quetiapine extended release over short-and long-term treatment periods.Esketamine nasal spray significantly increased the odds of achieving remission at Week 8 (primary end-point), and of being relapse-free through to Week 32 after achieving remission at Week 8 (key secondary end-point).
The primary and key secondary end-points are in line with the treatment goals in the acute and the maintenance periods and represent clinically meaningful outcomes for patients. Achieving the primary end-point requires meeting the treatment goal in the acute period, and achieving the key secondary end-point requires meeting the treatment goals in both acute and maintenance periods. There are no universally accepted definitions for remission or relapse; prior studies in the field have used different timeframes, scales and thresholds.The definitions chosen for the ESCAPE-TRD study are based on the Montgomery-Åsberg Depression Rating Scale (MADRS). As achieving remission without relapse is a goal for patients,examining the robustness of the primary and key secondary outcomes using different definitions of remission and relapse is important and will govern treatment decisions in a TRD treatment plan.
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Daly, E. J., Turkoz, I., Salvadore, G. et al. · Depression and Anxiety (2021)
Reif, A., Bitter, I., Buyze, J. et al. · New England Journal of Medicine (2023)
Papers in Blossom that reference this study
Cuomo, A., McIntyre, R., Koukouna, D. et al. · Therapeutic Advances in Psychopharmacology (2026)
A total of 676 patients were randomised: 336 to esketamine nasal spray plus SSRI/SNRI and 340 to quetiapine extended release plus SSRI/SNRI. Completion rates were 295 (esketamine) versus 250 (quetiapine) at the Week 8 acute phase, and 258 versus 203 at the end of the maintenance phase; the extracted text refers to supplementary material for further disposition and baseline adjunctive treatments. All pre-specified sensitivity analyses of the primary end-point (remission at Week 8) favoured esketamine nasal spray, with relative risks ranging from 1.462 to 1.737 and all p-values < 0.05. For example, using the more stringent remission threshold MADRS ≤8, 18.5% (62/336) of esketamine-treated patients were in remission at Week 8 versus 12.6% (43/340) with quetiapine (relative risk 1.462, 95% CI 1.017–2.100; p = 0.040; NNT 18, 95% CI 9–334). Using the more permissive threshold MADRS ≤12, remission rates at Week 8 were 38.7% (130/336) versus 22.9% (78/340) respectively (relative risk 1.695, 95% CI 1.338–2.149; p < 0.001; NNT 7, 95% CI 5–12). Analyses using LOCF produced similar conclusions. Sensitivity analyses of the key secondary end-point (remission at Week 8 and relapse-free through Week 32) also consistently favoured esketamine, with relative risks from 1.417 to 1.838 (all p < 0.05). Using the main definition, 21.7% (73/336) of esketamine-treated patients remained relapse-free through Week 32 after achieving remission at Week 8 versus 14.1% (48/340) with quetiapine (relative risk 1.552, 95% CI 1.115–2.160; p = 0.009; NNT 13, 95% CI 8–50). When the remission threshold was MADRS ≤8, relapse‑free rates were 15.2% versus 9.7% (relative risk 1.573, 95% CI 1.041–2.378; p = 0.032; NNT 19). With MADRS ≤12 the corresponding relapse‑free rates were 32.1% versus 17.6% (relative risk 1.838, 95% CI 1.396–2.419; p < 0.001; NNT 7). Time-to-event analyses showed faster clinical improvement with esketamine. Time to first remission was shorter with esketamine (hazard ratio 1.711, 95% CI 1.402–2.087; p < 0.001) and time to confirmed remission was similarly shortened (hazard ratio 1.658, 95% CI 1.337–2.055; p < 0.001). Time to first response and to confirmed response also favoured esketamine (HR 1.848, 95% CI 1.547–2.207; p < 0.001 and HR 1.809, 95% CI 1.505–2.174; p < 0.001, respectively). The authors report that remote versus in-person MADRS assessments had minimal impact on the estimated treatment differences in MADRS change from baseline.
Young and colleagues interpret these extensive sensitivity analyses as demonstrating that the superiority of esketamine nasal spray over quetiapine extended release is robust to a range of plausible definitions for remission and relapse, different assessment timepoints and analytic approaches. Across sensitivity analyses esketamine-treated patients were between 46.2% and 73.7% relatively more likely to achieve remission at Week 8 and between 41.7% and 83.8% relatively more likely to remain relapse-free after Week 8, compared with quetiapine-treated patients. The time-to-event results further indicate esketamine both increases the probability of remission and shortens the time required to reach remission and response, which the authors highlight as particularly relevant given the protracted suffering experienced by many with TRD. The authors acknowledge limitations that may influence interpretation. ESCAPE-TRD used an open-label, rater-blinded design that could introduce non-specific effects related to patient knowledge of treatment and to differential visit schedules; for example, esketamine administration required physician oversight and resulted in more clinic visits than self-administered quetiapine. Rapid titration of quetiapine may have affected tolerability. The study population may not generalise to hospital-based TRD populations where patients have undergone more prior treatment trials. The authors note that analyses were conducted with conservative imputation rules (NRI, censoring discontinuers at an arbitrarily large time) and that confidence intervals across sensitivity analyses largely overlapped with the main analysis, supporting consistency. Looking forward, the paper calls for additional research to determine whether continuing esketamine beyond Week 8 provides benefit for patients not in remission by that time, to establish optimal stopping and tapering strategies and to compare different maintenance dosing schedules. The investigators also propose further subgroup analyses and collection of patient-reported outcomes to better understand which patients derive the greatest benefit and how clinical improvements translate into patient-centred outcomes. Overall, the authors conclude the sensitivity analyses reinforce the original ESCAPE-TRD findings and provide additional evidence to guide clinicians about the use of esketamine nasal spray in both acute and maintenance phases of TRD.
Here, we explore the robustness of the main findings from the ESCAPE-TRD study through extensive sensitivity analyses. These sensitivity analyses incorporate alternative definitions of the primary and key secondary end-points, as well as additional outcomes such as remission over time and time to remission and response.
ESCAPE-TRD (NCT04338321) was a randomised, open-label, rater-blinded, active-controlled phase IIIb study that aimed to evaluate the efficacy and safety of esketamine nasal spray versus quetiapine extended release, both flexibly dosed according to their approved labels in combination with a continuing SSRI/SNRI, in patients with TRD. For further details concerning ESCAPE-TRD, please see Supplementary Appendix 1 available atand the previously published full methodology.The ESCAPE-TRD study was conducted in accordance with the Declaration of Helsinki; 21 country-specific ethics review boards provided approval. All patients provided written informed consent and the study was registered at ClinicalTrials.gov.
The primary end-point, assessing short-term efficacy, was the proportion of patients who achieved remission (defined as a MADRS total score of ≤10)at the Week 8 visit. The key secondary endpoint, assessing combined short-and long-term efficacy, was the proportion of patients who were relapse-free through to Week 32 after achieving remission at Week 8. As such, patients were required to satisfy both conditions (remission at Week 8 and no relapse from Week 8 to Week 32) to be considered as having a positive key secondary end-point; any deviation from these conditions (not achieving remission at Week 8 or experiencing relapse between Week 8 and Week 32) was considered a negative key secondary end-point. Outcomes from these end-points have been reported previously.Relapse was defined as any one of the following: a MADRS score of ≥22 at two consecutive assessments within 5-15 days of each other; admission to hospital for worsening depression, suicide prevention or suicide attempt; suicide attempt; completed suicide or any other clinically relevant event determined by the investigator's clinical judgement. However, throughout the trial, no patients were considered to have relapsed based on this clinical judgement criterion alone. Sensitivity analyses were pre-specified on the primary and key secondary end-points by varying parameters in their definitions, namely the timepoints, thresholds and scales used. A summary of all sensitivity analyses performed can be found in Supplementary Table. For analyses based on alternative thresholds, the threshold for remission at Week 8 was adjusted to MADRS total scores of ≤8 and ≤12, and the alternative threshold for relapse was adjusted to a MADRS total score of 18 or greater. An additional alternative for relapse used a Clinical Global Impression-Severity scale (CGI-S) score of ≥5 as a threshold for relapse, while keeping all other components of the definition unchanged. For analyses based on timepoints, the time to achieve remission was changed to Week 6, Week 10 and any point at or before Week 8. The timepoint for relapse was also changed; the key secondary end-point was redefined as relapse from Week 8 to Week 24 (4 months after remission) after remission at Week 8.Varying parameters related to the primary end-point affected outcomes for the key secondary end-point. For example, when the timepoint for remission was adjusted to Week 6, achieving the 'changed' key secondary end-point would be defined as remission at Week 6 and remaining relapse-free through Week 32. Alternative definitions for the key secondary end-point (i.e. the cut-off for relapse) did not affect the primary end-point. All sensitivity analyses differed from the main analysis by one element only (e.g. timepoint, threshold) to examine independently if this element influenced the result.
Rates of remission were estimated over time (all study visits where MADRS score was assessed) using the different remission cut-offs from previous analyses (MADRS ≤8, ≤10, ≤12).
Both remission and response were analysed as time to event endpoints. Time to first remission was defined as the duration of time elapsed from baseline to the visit at which a patient achieved a MADRS total score of ≤10, and first response was defined as the duration of time until a ≥50% improvement from baseline in MADRS total score, or MADRS ≤10, was reported. Time to confirmed remission and response were defined as the time to the first occurrence of achieving remission or response at two consecutive visits.
As the ESCAPE-TRD study was conducted during the coronavirus-19 (COVID-19) pandemic, additional flexibility (e.g. video assessments) had to be permitted to maintain follow-up of patients, and accommodate for the COVID-19 pandemic and related restrictions. An analysis providing an estimation of the impact of COVIDrelated additional flexibility on the MADRS results can be found in Supplementary Appendix 2.
All statistical tests were two-sided based on a significance level of 0.05. No adjustment for multiple testing was implemented.
The primary and key secondary end-points were analysed using non-responder imputation (NRI), whereby stopping treatment was considered a negative outcome. In addition, missing Week 8 visits for patients still on study treatment were imputed using last observation carried forward (LOCF). Sensitivity analyses for the primary and key secondary endpoints were conducted using the same methodology as those used in the primary publication.Odds ratios, risk differences, relative risks (here the term 'risk' is a generic term referring to the probability of experiencing a positive event under analysis, e.g. remission at Week 8) and the number needed to treat (NNT) are reported with 95% confidence intervals (CIs) for each sensitivity analysis, and were derived from Cochran-Mantel-Haenszel chisquare tests adjusted for age (18-≤64 years; 65-≤74 years) and total number of prior treatment failures (2; ≥3). Rates of remission over time were estimated based on on-treatment visits. Missing data were imputed using NRI or LOCF. Rates were compared using unadjusted relative risks.
Time to MADRS remission and response were analysed using the Kaplan-Meier method and study interventions were compared using a two-sided log-rank test for the full analysis set. Time to event parameters such as time to MADRS remission and response were summarised with median, 25th and 75th percentiles (if estimable). Hazard ratios with 95% CIs were estimated using Cox proportional hazard models stratified by age (18-≤64 years; 65-≤74 years) and total number of previous treatment failures (2; ≥3). Observed data from patients were included in the analyses for as long as patients remained on study intervention (esketamine nasal spray or quetiapine extended release). Patients that dropped out or discontinued study intervention were censored at an 'infinite' time (arbitrarily set at 9999 days) and assumed never to have achieved the event, similar to NRI.
Of 676 total patients, 336 were randomised to esketamine nasal spray + SSRI/SNRI and 340 were randomised to quetiapine extended release + SSRI/SNRI.Of all randomised patients, 295 and 250 esketamine nasal spray-treated and quetiapine extended release-treated patients completed the acute phase (Week 8), and 258 and 203 patients completed the maintenance phase, respectively. Further details can be found in Supplementary Table. Details concerning adjunctive antidepressant treatments at baseline can be found in Supplementary Figure.
All sensitivity analyses on the primary end-point (remission at Week 8) favoured esketamine nasal spray over quetiapine extended release, with relative risks ranging from 1.462 to 1.737 (all p < 0.05; Fig.). When the remission cut-off was reduced to a MADRS total score of 8, 18.5% (62/336) of esketamine nasal spray-treated patients achieved remission at Week 8 compared with 12.6% (43/340) of quetiapine extended release-treated patients (relative risk [95% CI]: 1.462 [1.017, 2.100]; p = 0.040; NNT [95% CI]: 18 [9, 334]; Fig.). When the remission cut-off was increased to a MADRS total score of 12, 38.7% (130/336) of esketamine nasal spraytreated patients achieved remission at Week 8 compared with 22.9% (78/340) of quetiapine extended release-treated patients (relative risk: 1.695 [1.338, 2.149]; p < 0.001; NNT: 7 [5, 12]; Fig.). A significantly greater proportion of esketamine nasal spraytreated patients remained relapse-free through Week 32 after achieving remission at Week 8 (21.7%; 73/336) compared with quetiapine extended release-treated patients (14.1%; 48/340; relative risk: 1.552 [1.115, 2.160]; p = 0.009; NNT: 13 [8, 50]).All sensitivity analyses for the key secondary end-point favoured esketamine nasal spray over quetiapine extended release, with relative risks ranging from 1.417 to 1.838 (all p < 0.05; Fig.). Where the remission cut-off was changed to a MADRS total score of 8, 15.2% (51/ 336) of esketamine nasal spray-treated patients remained relapsefree through to Week 32 after achieving remission at Week 8 compared with 9.7% (33/340) of quetiapine extended release-treated patients (relative risk: 1.573 [1.041, 2.378]; p = 0.032; NNT: 19 [10, 167]; Fig.). Where the remission cut-off was increased to a MADRS total score of 12, 32.1% (108/336) of esketamine nasal spray-treated patients remained relapse-free at Week 32 after achieving remission at Week 8 compared with 17.6% (60/340) of quetiapine extended release-treated patients (relative risk: 1.838 [1.396, 2.419]; p < 0.001; NNT: 7 [5, 13]; Fig.). Results using the LOCF approach were similar and demonstrated the superiority of esketamine nasal spray (Supplementary Figure).
Treatment with esketamine nasal spray shortened the time to first remission versus quetiapine extended release (hazard ratio: 1.711 [1.402, 2.087]; p < 0.001; Figs.) and 4(b)). The same result was seen in time to confirmed remission (hazard ratio: 1.658 [1.337, 2.055]; p < 0.001). Treatment with esketamine nasal spray also shortened the time to first response (hazard ratio: 1.848 [1.547, 2.207]; p < 0.001) and confirmed response (hazard ratio: 1.809 [1.505, 2.174]; p < 0.001) versus quetiapine extended release (Figs. 4
Hazard ratios displayed in a forest plot can be found in Supplementary Figure. There was minimal impact of remote versus in-person MADRS assessments on the estimated difference between esketamine nasal spray and quetiapine extended release on MADRS change from baseline at each visit (Supplementary Appendix 2, Supplementary Table).
Remission and prevention of relapse are well recognised as main treatment goals of treating depression. However, there is a lack of a consensus in the TRD field regarding how to best define remission and relapse. Varied definitions using different timelines, scales and thresholds are used in the literature,the most notable of which were used to define the sensitivity analyses reported here. Depending on the sensitivity analysis, esketamine nasal spray-treated patients were 46.2-73.7% relatively more likely to achieve remission at Week 8 (primary end-point), and 41.7-83.8% relatively more likely to be relapse-free after remission at Week 8 (key secondary end-point) than quetiapine extended release-treated patients. Additional analyses of remission over time and time to remission and response all significantly favoured esketamine nasal spray over quetiapine extended release. Even using the most conservative of the pre-specified cut-offs (MADRS score of ≤8), esketamine nasal spray still showed superiority over quetiapine extended release at Week 6 through Week 32. Confidence intervals were largely overlapping between all sensitivity analyses and with the main analysis; even if there were a difference in point estimates, the results remained highly consistent. These extensive sensitivity analyses show the conclusions of the study remain unchanged, thereby reinforcing the strength of the initial findings.MADRS cut-off scores of 8, 10 and 12 each demonstrate that remission rates continued to increase beyond Week 8 in both treatment arms. Esketamine nasal spray maintained superiority over Fig.Proportion of patients remaining relapse-free through Week 32 after achieving remission at Week 8 (key secondary end-point) per sensitivity analysis. The key secondary end-point was remaining relapse-free though to Week 32 after achieving remission at Week 8. CGI-S, Clinical Global Impression-Severity scale; CI, confidence interval; MADRS, Montgomery-Åsberg Depression Rating Scale; NNT, number needed to treat; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor. quetiapine extended release at each timepoint. By Week 32, there was a larger proportion of esketamine nasal spray patients, compared with quetiapine extended release, that achieved remission regardless of the MADRS cut-off score used. These data demonstrate that remission can be achieved after Week 8, and remission at a later timepoint is still beneficial to the patient. Whilst these analyses provide the overall remission rates at population level, it is not necessarily the same patients in remission from one visit to the next. To focus more on individual patient trajectories, time to remission and response analyses were conducted. These results also illustrate that esketamine nasal spray shortens time to remission and response compared with quetiapine extended release. Patients with TRD, for the most part, have endured long depressive episodes without relief, so enabling them to reach remission in a shorter amount of time is pertinent. In addition, these time to event analyses provide a time-based component to this analysis where before only binary end-points were reported for the ESCAPE-TRD study.Esketamine nasal spray not only increases the proportion of patients achieving remission at a specific time, but also decreases the time it takes to reach remission. Hazard ratios for time to remission and response both favoured esketamine nasal spray over quetiapine extended release.
To our knowledge, ESCAPE-TRD is the first randomised comparative study reporting long-term esketamine nasal spray use against an augmentation treatment for patients with TRD. To provide further evidence using various definitions of remission and relapse from the literature, these additional analyses of the primary and key secondary end-points support the overall superiority of esketamine nasal spray over quetiapine extended release. This study population reflects a patient population that may not be generalisable to the hospital-based population of patients with TRD, where more treatment trials may have occurred before initiation of esketamine nasal spray treatment. There are potential non-specific effects that were not equal between treatment groups. Given the single-blind (raters unaware of treatment assignment), open-label design of this study, this may have introduced some chance of premature discontinuation owing to patient knowledge of their study treatment. In addition, patients in the esketamine nasal spray arm had a higher number of clinic visits in the acute phase owing to the administration method, as esketamine nasal spray required physician oversight whilst quetiapine extended release was self-administered. Furthermore, quetiapine extended release was titrated rapidly to the final dose, which may have decreased tolerability. These elements of the study design were difficult to account for and may have influenced perceptions of efficacy; however, the treatment visit schedule did accurately reflect clinical practice for esketamine nasal spray treatment.
While additional study is required, these sensitivity analyses potentially further support the patient benefit of continuing use of esketamine nasal spray even if remission is not achieved by Week 8. Some current regulations recommend that esketamine nasal spray be discontinued if remission is not achieved before or by Week 8.Additional data should be collected to determine if longer treatment with esketamine nasal spray may be beneficial, or when esketamine nasal spray treatment should be stopped if remission is not achieved. These data could also explore how esketamine nasal spray should be tapered off, and if weekly or biweekly treatment is favourable. Further work could include analyses of patient-reported outcomes. Whilst improvements in TRD can be measured with clinical scores, it is important to consider improvements in measures that incorporate the patient experience and patient voice. In addition, further analyses could examine esketamine nasal spray versus quetiapine extended release in subgroups of patients, such as age, number of prior treatment failures or patients with generalised anxiety disorder, to determine the effect of esketamine nasal spray treatment in these groups. All sensitivity analyses favoured esketamine nasal spray over quetiapine extended release, which confirmed the robustness of the primary and key secondary results of the ESCAPE-TRD study.Additional analyses on remission beyond Week 8 provided additional perspective on the long-term benefit of esketamine nasal spray compared with quetiapine extended release. Furthermore, time to remission and response analyses demonstrated that esketamine nasal spray shortened time to remission and time to response. These findings all further support the superiority of esketamine nasal spray compared with quetiapine extended release in achieving treatment goals in both the acute and the maintenance phase in patients with TRD and provide guidance to clinicians about the use of esketamine nasal spray.