Efficacy of esketamine nasal spray over quetiapine extended release over the short and long term: sensitivity analyses of ESCAPE-TRD, a randomised phase IIIb clinical trial

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.

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.