Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression

Treatment-resistant depression, commonly defined as failure to respond to two or more adequate pharmacologic treatments during the same depressive episode, is associated with low rates of remission, high relapse rates, and substantial morbidity and economic burden. Earlier clinical trials showed that esketamine nasal spray, when added to a newly initiated SSRI or SNRI, reduced depressive symptoms and lowered relapse risk versus placebo nasal spray plus oral antidepressant, but head-to-head data comparing esketamine with an active augmentation strategy in patients already receiving an SSRI or SNRI were limited. Extended-release quetiapine is a guideline-supported antipsychotic augmentation agent commonly used in practice, yet direct comparative efficacy and safety versus esketamine in treatment-resistant depression had not been established. Cebulla and colleagues conducted the ESCAPE-TRD trial to address this gap. The trial tested the hypothesis that, among adults with treatment-resistant major depressive disorder who continued treatment with an SSRI or SNRI, esketamine nasal spray plus that antidepressant would lead to higher rates of remission at week 8 and greater freedom from relapse through week 32 after remission than extended-release quetiapine plus the same antidepressant. The study therefore sought to compare short-term remission and longer-term relapse prevention, together with safety, in a pragmatic, head-to-head setting.

ESCAPE-TRD was a phase 3b, randomised, open-label, single-blind (independent raters unaware of group assignments), active-controlled multicentre trial conducted at 171 sites in 24 countries. After screening, adults aged 18 to 74 years with DSM-5 major depressive disorder and treatment-resistant depression were randomised 1:1 to receive either esketamine nasal spray or extended-release quetiapine, each in combination with the patient’s ongoing SSRI or SNRI. Randomisation used computer-generated permuted blocks with stratification by age group (18 to ≤64 years vs. 65 to ≤74 years) and number of past failed treatments (2 vs. ≥3). The trial comprised an 8-week initial treatment phase, a 24-week maintenance phase (total follow-up 32 weeks after remission at week 8), and safety follow-up 2 weeks after the last dose. Eligibility required adults with a current major depressive episode who had failed two to six consecutive treatments (including the current treatment) from at least two antidepressant classes, with limited improvement on the current SSRI or SNRI despite at least 6 weeks at an adequate dose; other antidepressants and augmentation agents were washed out. Dosing for both trial agents was flexible and followed each product’s summary of product characteristics; specific dosing details are reported in the Supplementary Appendix (not provided in the extracted text). Patients receiving ≤50 mg/day quetiapine at screening required a ≥7-day washout before randomisation. Efficacy analyses used an intention-to-treat approach including all randomised patients. The primary end point was remission at week 8, defined as a Montgomery-Åsberg Depression Rating Scale (MADRS) score of ≤10. The key secondary end point was no relapse through week 32 after remission at week 8; relapse was defined by a MADRS score worsening to ≥22 on two consecutive assessments 5–15 days apart, hospitalisation for worsening depression or suicide prevention, suicide attempt or completion, or other investigator-assessed indicators of relapse. Additional analyses reported remission and response using a MADRS threshold of ≤12 to align with prior registrational trials. MADRS assessments were conducted on site by independent raters blinded to treatment assignment. The primary and key secondary end points were analysed using nonresponder imputation (patients who discontinued trial treatment were counted as having an unfavorable outcome). For missing week-8 data in patients who remained on treatment, last-observation-carried-forward (LOCF) was used. Cochran–Mantel–Haenszel chi-square tests adjusted for stratification factors (age group and number of prior failed treatments) estimated adjusted odds ratios, relative risks, and risk differences. Change in MADRS over time was analysed with a mixed model for repeated measures (unstructured covariance) including baseline MADRS, treatment, stratification factors, time, and time-by-treatment interaction. The trial was sized to provide 90% power for the primary end point and 80% power for the key secondary end point. Safety analyses included all patients who received at least one dose, with adverse events classified per MedDRA and counted if occurring from first dose through safety follow-up (14 days after last dose) or up to 30 days for serious adverse events.

Between 26 August 2020 and 5 November 2021, 811 patients were screened and 676 were randomised: 336 to esketamine plus an SSRI or SNRI and 340 to extended-release quetiapine plus an SSRI or SNRI. Baseline demographic and clinical characteristics were reported as generally similar between groups and representative of the broader treatment-resistant depression population. More patients discontinued the trial treatment in the quetiapine group than in the esketamine group (137 of 340 [40.3%] vs. 78 of 336 [23.2%]); discontinuations for adverse events or lack of efficacy were more frequent in the quetiapine group. For the primary end point, remission at week 8 (MADRS ≤10) occurred in 91 of 336 patients (27.1%) in the esketamine group versus 60 of 340 patients (17.6%) in the quetiapine group; the adjusted P value was 0.003. The adjusted odds ratio for remission at week 8 was 1.74 (95% CI, 1.20 to 2.52), favouring esketamine; results were consistent in unadjusted sensitivity analyses. Regarding the key secondary end point, no relapse through week 32 after remission at week 8 was observed in 73 of 336 patients (21.7%) in the esketamine group compared with 48 of 340 patients (14.1%) in the quetiapine group. The adjusted odds ratio for freedom from relapse 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 also favoured esketamine. Using nonresponder imputation, remission at week 32 was observed in 49.1% of esketamine-treated patients versus 32.9% of quetiapine-treated patients (LOCF estimates 55.0% vs. 37.0%). Treatment response at week 32 (≥50% improvement in MADRS or MADRS ≤10) occurred in 65.5% versus 47.1% by nonresponder imputation (LOCF: 75.5% vs. 55.5%); the odds ratios favoured esketamine across time points. The MADRS score decreased in both groups over time, with a greater reduction at each time point in the esketamine group; at week 32 the least-squares mean difference in change from baseline was −2.2 points (95% CI, −3.6 to −0.8), favouring esketamine. Adverse events during the treatment period were reported in 307 of 334 patients (91.9%) in the esketamine group and in 262 of 336 patients (78.0%) in the quetiapine group (safety-analysis denominators reflect those who received at least one dose). Serious adverse events occurred in 19 patients (5.7%) receiving esketamine and in 17 patients (5.1%) receiving quetiapine. Two serious adverse events in esketamine-treated patients were judged by investigators to be related to treatment (acute coronary syndrome after 21 weeks and dizziness after 2 weeks); no serious adverse events in the quetiapine group were considered related. Adverse-event–related discontinuations occurred in 14 patients (4.2%) in the esketamine group and in 37 patients (11.0%) in the quetiapine group. Suicide attempts were reported in two esketamine-treated patients and one quetiapine-treated patient; none were judged related to trial treatment. Two deaths occurred during the trial (one esketamine-treated patient in week 9 with undetermined cause, and one quetiapine-treated patient in week 17 due to cerebrovascular accident); investigators did not consider either death to be related to trial treatment.

The investigators interpret the trial as demonstrating that esketamine nasal spray, when continued in combination with an ongoing SSRI or SNRI, was superior to extended-release quetiapine plus an SSRI or SNRI for the primary clinical goal of remission at week 8 and for reduced relapse through week 32 in patients with treatment-resistant depression. They note that patients receiving esketamine were approximately 1.54 times as likely to achieve remission at week 8 and 1.55 times as likely to remain free from relapse through week 32 after remission, with consistent odds ratios favouring esketamine across the 32-week period. The authors also highlight that esketamine produced earlier symptom reductions and that early improvement is predictive of subsequent remission; by week 32 roughly half of esketamine-treated patients were in remission and about two thirds had a treatment response. In positioning these findings relative to earlier research, the discussion contrasts this head-to-head result with prior placebo-controlled trials of esketamine, and reports supplementary analyses using a MADRS threshold of ≤12 to align with earlier registrational trials. Those analyses produced higher remission percentages but retained the pattern favouring esketamine, which the authors suggest helps contextualise the current results within the phase 3 programme. Safety findings were described as consistent with known profiles for each agent, with adverse events more frequent but generally transient and dose-day–limited in the esketamine group; nevertheless, discontinuations due to adverse events were more common with quetiapine, suggesting the burden of adverse effects may differ between treatments. The investigators acknowledge limitations inherent to the open-label design, including potential functional unmasking and differences in patient contact frequency between groups. They justify the non-double-dummy approach on pragmatic grounds, noting that routes of administration differed and a double-dummy design would have increased participant burden; to mitigate bias, MADRS assessments were performed by independent raters blinded to treatment assignment. The authors report that a retrieved-dropout sensitivity analysis showed that differences in discontinuation had minimal impact on the primary and key secondary results. Finally, they caution that generalisability is limited by heterogeneity in real-world treatment histories and patterns, but conclude that the trial provides evidence supporting the use of esketamine nasal spray as an effective option for patients with treatment-resistant depression and may inform future guideline recommendations.