Esketamine versus placebo on time to remission in major depressive disorder with acute suicidality

Abstract

Background: Esketamine (ESK) nasal spray, taken with oral antidepressant therapy, is approved for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior. In pooled analyses of two pivotal phase 3 studies, ASPIRE I and II, remission rates were consistently higher among patients with MDD with active suicidality who were treated with ESK + standard of care (SOC) versus placebo (PBO) + SOC at all time points in the double-blind and most time points in the follow-up phases. The current analysis of the ASPIRE data sets assessed the effect of ESK + SOC versus PBO + SOC on additional remission-related endpoints: time to achieving remission and consistent remission, proportion of patients in remission and consistent remission, and days in remission.

Methods: Post hoc analysis of pooled data from ASPIRE I and II (N = 451). Remission and consistent remission were defined as Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≤ 12 at any given visit or two consecutive visits, respectively. Combined endpoints utilizing Clinical Global Impression-Severity of Suicidality-revised version [CGI-SS-r] ≤ 1 (i.e., not suicidal/questionably suicidal) along with the remission and consistent remission definitions (i.e., MADRS total score ≤ 12) were also examined.

Results: The median times to remission and consistent remission of MDD were significantly shorter in ESK + SOC versus PBO + SOC (15 versus 23 [p = 0.005] and 23 versus 50 days [p = 0.007], respectively) and a greater proportion of patients in ESK + SOC achieved remission and consistent remission by Day 25 (65.2% versus 55.5% and 54.2% versus 39.8%, respectively). Similar results were obtained using the combined endpoint for both remission definitions. The median percent of days in remission during the double-blind treatment phase was significantly greater in ESK + SOC (27.1% or 5 days) versus PBO + SOC (8.3% or 2 days; p = 0.006), and the significant difference was maintained during follow-up.

Conclusion: Treatment with ESK + SOC versus PBO + SOC resulted in significantly shorter time to remission, greater proportion of patients in remission, and greater percent of days in remission using increasingly rigorous definitions of remission. These findings underscore the clinical benefits of ESK for adults with MDD with suicidality.

Trial registration: ClinicalTrials.gov registry NCT03039192 (registered February 1, 2017) and NCT03097133 (registered March 31, 2017).

Keywords: Antidepressant agents; Depressive disorder; Esketamine nasal spray; Remission; Suicidal ideation.

Fig. 1

Study design of ASPIRE I and ASPIRE II. Two patients in each treatment group were excluded from these analyses because they did not receive a dose of intranasal study drug after randomization. Changes in MADRS total score and CGI-SS-r were assessed at 4 and 24 h post first dose, twice per week pre-dose during the double-blind phase, and at varied time intervals during the follow-up phase (days 28–39: twice weekly; days 46–53: weekly; days 67–90: biweekly). AD, antidepressant; ESK, esketamine; MDD, major depressive disorder; PBO, placebo; SOC, standard of care

Fig. 2

Kaplan–Meier curves of (A) time to remission of MDD based on MADRS and (B) time to remission of MDD based on the combined endpoint of MADRS and CGI-SS-r for the ESK + SOC and PBO + SOC groups. Cumulative probability of remission is the cumulative probability of achieving remission by criterion (A) or (B) by a given time. The numbers of patients at risk (ie, who have not yet remitted) for each of the groups are shown below the survival curves. CGI-SS-r, Clinical Global Impression-Severity of Suicidality-revised version; ESK, esketamine; MADRS, Montgomery-Åsberg Depression Rating Scale; PBO, placebo; SOC, standard of care

Fig. 3

Kaplan–Meier curves of (A) time to consistent remission of MDD based on MADRS and (B) time to consistent remission of MDD based on the combined endpoint of MADRS and CGI-SS-r for the ESK + SOC and PBO + SOC groups. Cumulative probability of remission is the cumulative probability of achieving remission by criterion (A) or (B) by a given time. The numbers of patients at risk (ie, who have not yet remitted) for each of the groups are shown below the survival curves. CGI-SS-r, Clinical Global Impression-Severity of Suicidality-revised version; ESK, esketamine; MADRS, Montgomery-Åsberg Depression Rating Scale; PBO, placebo; SOC, standard of care