Esketamine Nasal Spray Improves Rate and Time to Remission Versus Quetiapine Extended Release in Subgroups of Patients With Treatment Resistant Depression and Two or Three Plus Prior Treatment Failures: Results From ESCAPE-TRD, a Randomised Phase IIIb Trial

Among people with treatment-resistant depression, those who had failed three or more prior treatments were more likely to achieve remission after eight weeks of esketamine nasal spray (28.0%) than after quetiapine extended release (10.9%). For those with only two prior treatment failures, remission rates were similar between the two treatments (26.5% vs. 21.8%). Esketamine also led to faster remission in both subgroups. The results suggest esketamine may be especially effective for patients with more extensive treatment histories.

Study at a glance

Abstract

Aims For patients with depression, the likelihood of remission decreases with each subsequent treatment failure. Per European Medicines Agency guidance, treatment resistant depression (TRD) is defined as nonresponse to ≥2 consecutive treatments at adequate dosage and duration in the current depressive episode. In ESCAPE-TRD (NCT04338321), esketamine nasal spray (NS) increased the probability of achieving remission and remaining relapsefree, compared with quetiapine extended release (QXR) in patients with TRD. Here, we report the efficacy of esketamine NS vs QXR in patient subgroups with 2 or ≥3 consecutive prior treatment failures (PTFs). Methods ESCAPETRD was a phase IIIb trial comparing the efficacy of esketamine NS with QXR in patients with TRD. Patients (N = 676) were randomised 1:1 to esketamine NS (n = 336; 56/84 mg; twice weekly, weekly, or every 2 weeks [wks]) or QXR (n = 340; 150–300 mg daily, both in combination with an ongoing selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor. Randomisation was stratified by age (18-64 years; 65–74 years) and PTFs (2; ≥3). The primary endpoint of remission (Montgomery-Åsberg Depression Rating Scale total score ≤10) at Wk8 and the secondary endpoint of remaining relapse-free through Wk32 after remission at Wk8, were analysed in PTF patient subgroups and compared between study arms, with treatment discontinuation considered as a negative outcome. The effect on time to remission was assessed using hazard ratios (HR) from a Cox regression model. Results Of the randomised patients, 415 (61.4%; esketamine NS: 204, QXR: 211) had experienced 2 PTFs and 261 (38.6%; esketamine NS: 132, QXR: 129) had experienced ≥3. Of patients with 2 PTFs, 54/204 (26.5%) esketamine NS-treated patients and 46/211 (21.8%) Q-XR-treated patients achieved remission at Wk8 (p = 0.267). Of patients with ≥3 PTFs, 37/132 (28.0%) and 14/129 (10.9%) patients achieved remission at Wk8 in esketamine NS and Q-XR arms, respectively (p < 0.001). Of patients with 2 and ≥3 PTFs, 49/204 (24.0%) and 24/132 (18.2%) of esketamine NS-treated patients and 38/211 (18.0%) and 10/129 (7.8%) of Q-XR-treated patients achieved remission at Wk8 without relapse to Wk32 (p = 0.133 and p = 0.013), respectively. Esketamine NS significantly improved time to remission, with a greater effect in the ≥3 PTF subgroup (2 PTFs: HR = 1.547 [95% confidence interval (CI) 1.210–1.976]; p < 0.001 vs ≥3 PTFs: HR = 2.066 [95% CI 1.469–2.907]; p < 0.001). Conclusion Esketamine NS demonstrated a significantly superior remission rate versus QXR at Wk8 in patients with ≥3 PTFs, and significantly shorter time to remission versus Q-XR in both subgroups.