Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II)

Abstract

Background: Patients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment.

Methods: This double-blind study (ASPIRE II) randomized adults (aged 18-64 years) with MDD having active suicidal ideation with intent to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks, given with comprehensive standard of care (hospitalization ≥5 days and newly initiated or optimized oral antidepressant[s]). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale total score (primary efficacy endpoint) was analyzed using ANCOVA. Clinical Global Impression-Severity of Suicidality-revised (key secondary endpoint) was analyzed using ANCOVA on ranks of change.

Results: Of 230 patients who were randomized (115 per arm), 227 received study drug and were included in efficacy/safety analyses; 184 (80.0%) completed double-blind treatment. Greater improvement in Montgomery-Asberg Depression Rating Scale total score was observed with esketamine (mean [SD]: -15.7 [11.56]) vs placebo (-12.4 [10.43]), each with standard of care, at 24 hours (least-squares mean difference [SE]: -3.9 [1.39], 95% CI: -6.60, -1.11; 2-sided P = .006). This was also noted at the earlier (4-hour) timepoint (least-squares mean difference -4.2, 95% CI: -6.38, -1.94). Patients in both treatment groups experienced rapid reduction in Clinical Global Impression-Severity of Suicidality-revised score; the between-group difference was not statistically significant. The most common adverse events among esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia.

Conclusion: This study confirmed rapid and robust reduction of depressive symptoms with esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent. Trial Registration: Clinical Trials.gov identifier: NCT03097133.

Keywords: Esketamine; depression; suicidal ideation; suicide risk.

Figure 1.

Study design and disposition of patients. ^aStandard antidepressant treatment was initiated or optimized on day 1.  ^bPatients who completed the double-blind phase and either entered the follow-up phase or had adverse events evaluated after the double-blind treatment phase. Note: Three patients were not included in the efficacy analysis dataset due to discontinuing prior to receiving study drug or not providing postbaseline efficacy data.

Figure 2.

Least-square mean changes (±SE) from baseline for Montgomery-Asberg Depression Rating Scale (MADRS) total score during the double-blind treatment phase (mixed-effects model using repeated measures [MMRM]; observed cases). ^aIncludes patients who had their dose reduced due to tolerability issues. Note: Negative change in score indicates improvement.

Figure 3.

Montgomery-Asberg Depression Rating Scale (MADRS) remission rate over time during the double-blind treatment phase. ^aIncludes patients who had their dose reduced due to tolerability issues. Note: Remission was based on a MADRS total score of ≤12. Patients who did not meet such criterion or discontinued prior to the time point for any reason were not be considered to be in remission.

Figure 4.

Frequency distribution of Clinical Global Impression-Severity of Suicidality-Revised (CGI-SS-r) score at baseline, 4 and 24 hours post-first dose, and day 25 (observed cases). SOC, standard of care. ^aIncludes patients who had their dose reduced due to tolerability issues.