Esketamine nasal spray versus quetiapine XR in adults with treatment-resistant depression: a secondary analysis of the ESCAPE-TRD randomized clinical trial

Treatment-resistant depression (TRD), commonly defined as failure to respond to two or more adequate pharmacologic treatments during the same major depressive episode, is associated with low rates of remission, high relapse rates, and substantial clinical and economic burden. Previous trials have shown that esketamine nasal spray, given with a newly initiated SSRI or SNRI, reduces depressive symptoms and lowers relapse risk versus placebo; however, direct comparisons between esketamine and active pharmacologic augmentation strategies commonly used in clinical practice are limited. Extended-release quetiapine is a guideline-supported antipsychotic augmentation agent frequently used in TRD, but its comparative efficacy and safety relative to esketamine have not been established. Cebulla and colleagues report a randomised, active-controlled trial that aimed to compare esketamine nasal spray plus a continuing SSRI or SNRI with extended-release quetiapine plus a continuing SSRI or SNRI in adults with TRD. The prespecified primary outcome was remission at week 8 (defined as a Montgomery-Åsberg Depression Rating Scale [MADRS] score of ≤10), and the key secondary outcome was freedom from relapse through week 32 after remission at week 8. The trial was designed to address both short-term remission and longer-term maintenance outcomes in a TRD population receiving real-world-like antidepressant continuation.

The ESCAPE-TRD trial was a multicentre, phase 3b, randomised, open-label study with blinded outcome raters (single-blind with raters unaware of group assignment) conducted at 171 sites in 24 countries. Adults 18 to 74 years old meeting DSM-5 criteria for major depressive disorder and having treatment-resistant depression (two to six consecutive failed antidepressant treatments in the current episode, including the current treatment) were eligible. Patients had a score of 34 or higher on the 30-item Inventory of Depressive Symptomatology–Clinician-Rated scale at screening and were maintained on a continuing SSRI or SNRI; other antidepressants and augmentation agents were discontinued. Patients receiving ≤50 mg/day quetiapine at screening could enter after a washout of at least 7 days. Participants were randomised 1:1 to flexible-dose esketamine nasal spray plus the continuing SSRI or SNRI (esketamine group) or to flexible-dose extended-release quetiapine plus the continuing SSRI or SNRI (quetiapine group). Dosing was flexible and followed the respective product summaries of characteristics; specific dosing and administration details were reported in the trial supplement and are not fully presented in the extracted text. The trial comprised up to 14 days of screening, an initial 8-week treatment phase, a 24-week maintenance phase, and a 2-week safety follow-up after the last dose. Efficacy analyses used an intention-to-treat approach including all randomised patients. The primary end point was remission at week 8 (MADRS ≤10). The key secondary end point was no relapse through week 32 among those remitting at week 8; relapse was defined by prespecified clinical and MADRS-based criteria (MADRS ≥22 at two consecutive assessments 5–15 days apart, hospitalisation for worsening depression, suicide-related events, or investigator-assessed relapse). The primary and key secondary analyses applied a nonresponder imputation strategy (patients who discontinued trial treatment were counted as unfavorable outcomes), with last-observation-carried-forward (LOCF) used to impute week-8 missing data for patients who had not discontinued. Cochran–Mantel–Haenszel chi-square tests adjusted for age group (18 to ≤64 years vs. 65 to ≤74 years) and number of past failed treatments (2 vs. ≥3) were used to estimate adjusted odds ratios, relative risks, and risk differences. Change in MADRS over time was analysed with a mixed model for repeated measures (MMRM) including baseline MADRS, treatment, stratification factors, time, and time-by-treatment interaction. Safety analyses included all patients who received at least one dose; adverse events were coded per MedDRA versions 23–25. A retrieved-dropout sensitivity analysis was also performed to assess the impact of discontinuations.

A total of 676 patients were randomised: 336 to esketamine and 340 to quetiapine. Baseline demographic and clinical characteristics were generally similar between groups. More patients discontinued the trial treatment in the quetiapine group (137 patients, 40.3%) than in the esketamine group (78 patients, 23.2%); discontinuations in the quetiapine group were more often attributed to adverse events or lack of efficacy. Primary outcome: Remission at week 8 (MADRS ≤10) occurred in 91 of 336 patients (27.1%) in the esketamine group and in 60 of 340 patients (17.6%) in the quetiapine group. The adjusted between-group difference favoured esketamine (adjusted P = 0.003); the adjusted odds ratio was 1.74 (95% confidence interval [CI], 1.20 to 2.52). Sensitivity analyses produced consistent findings. Key secondary outcome: Among the full analysis set, 73 of 336 patients (21.7%) in the esketamine group and 48 of 340 patients (14.1%) in the quetiapine group had no relapse through week 32 after remission at week 8. The adjusted odds ratio was 1.72 (95% CI, 1.15 to 2.57) and the adjusted relative risk was 1.55 (95% CI, 1.12 to 2.16), both favouring esketamine. Other efficacy outcomes: Remission and response rates increased over time in both groups but consistently favoured esketamine. Using nonresponder imputation, remission at week 32 occurred in 49.1% of esketamine-treated patients versus 32.9% of quetiapine-treated patients; using LOCF these figures were 55.0% and 37.0%, respectively. Treatment response at week 32 (nonresponder imputation) occurred in 65.5% versus 47.1% (odds ratio 2.13; 95% CI, 1.57 to 2.91) and (LOCF) in 75.5% versus 55.5% (odds ratio 2.48; 95% CI, 1.78 to 3.46), favouring esketamine. The decrease in MADRS score from baseline was greater at each time point in the esketamine group; at week 32 the least-squares mean difference in change from baseline was −2.2 (95% CI, −3.6 to −0.8) in favour of esketamine. Safety: Adverse events during the treatment period were reported in 307 patients (91.9%) in the esketamine group and in 262 patients (78.0%) in the quetiapine group. Serious adverse events occurred in 19 patients (5.7%) versus 17 patients (5.1%), respectively. Adverse events leading to discontinuation occurred in 14 patients (4.2%) in the esketamine group and in 37 patients (11.0%) in the quetiapine group. Two serious adverse events were judged by investigators to be related to esketamine (acute coronary syndrome after 21 weeks and dizziness after 2 weeks); no quetiapine-related serious adverse events were identified. Suicide attempts were reported in two esketamine-treated patients and in one quetiapine-treated patient; investigators judged none to be related to trial treatment. Two deaths occurred during the trial (one esketamine-treated patient in week 9 with undetermined cause, one quetiapine-treated patient in week 17 due to cerebrovascular accident); neither was considered related to trial treatment. The investigators noted that adverse events with esketamine were generally transient, mild, and occurred on dosing days, and that although dizziness was more common with esketamine, discontinuation for dizziness was more frequent in the quetiapine group.

The investigators interpret their findings as evidence that esketamine nasal spray, administered with a continuing SSRI or SNRI, was superior to extended-release quetiapine plus a continuing SSRI or SNRI for achieving remission at week 8 and for preventing relapse through week 32 among adults with treatment-resistant depression. They report that patients treated with esketamine were approximately 1.5 times as likely to remit by week 8 and to remain relapse-free through week 32, and that odds ratios favouring esketamine were consistent across multiple time points and measures, including response rates and continuous MADRS change. Cebulla and colleagues position these results in the context of prior phase 3 trials that compared esketamine with placebo augmentation; the current head-to-head comparison with an active augmentation agent extends the evidence base for esketamine in TRD. They emphasise that esketamine produced earlier symptom reduction, and note that early improvement is a known predictor of subsequent remission, supporting the clinical value of continuing esketamine treatment when initial remission is not achieved. The authors acknowledge several limitations. The open-label design was chosen because the different routes of administration would have required a burdensome double-dummy design; this choice introduces the potential for functional unmasking and for differential patient behaviour, including discontinuation. To mitigate bias, MADRS assessments were performed by independent raters who were unaware of treatment assignment, and a retrieved-dropout sensitivity analysis suggested that between-group differences in discontinuation had minimal impact on the primary and key secondary results. Generalisability may be limited because real-world treatment strategies are heterogeneous and the trial compared esketamine with a single augmentation agent. Safety findings were consistent with the known profiles of the two treatments; although adverse events were more frequent with esketamine, they were typically transient and related to dosing days, and overall discontinuation due to adverse events was lower with esketamine than with quetiapine. The investigators conclude that, within the constraints of the trial design, their data support the use of esketamine nasal spray as an effective option for patients with treatment-resistant depression and that these findings may inform future treatment guidelines.