Esketamine Nasal Spray for the Rapid Reduction of Depressive Symptoms in Major Depressive Disorder With Acute Suicidal Ideation or Behavior

Abstract

Purpose/background: Numerous health authority approvals of esketamine nasal spray, combined with oral antidepressant, to treat depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior were based on 2 identically designed, double-blind, phase 3 studies.

Methods/procedures: Across both ASPIRE studies (NCT03039192, NCT03097133), patients (N = 456) were randomized to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks plus comprehensive standard of care, including hospitalization and newly initiated or optimized antidepressant(s). In post hoc analyses of pooled data, changes from baseline at 24 hours after the first dose in Montgomery-Åsberg Depression Rating Scale total score and Clinical Global Impression-Severity of Suicidality-Revised, in the full cohort and in subgroups, were analyzed using analysis of covariance.

Findings/results: Esketamine plus standard of care demonstrated significantly greater improvement in Montgomery-Åsberg Depression Rating Scale total score versus placebo plus standard of care at 24 hours (least square mean difference [95% confidence interval], -3.8 [-5.75 to -1.89]) and at earlier (4 hours: -3.4 [-5.05 to -1.71]) and later time points (day 25: -3.4 [-5.36 to -1.36]). The between-group difference (95% confidence interval) for change in Clinical Global Impression-Severity of Suicidality-Revised at 24 hours was -0.20 (-0.43 to 0.04) for all patients and -0.31 (-0.61 to -0.01) for those with a history of suicide attempt. Common adverse events (≥20%) during esketamine treatment were dizziness, dissociation, nausea, somnolence, and headache.

Implications/conclusions: Esketamine plus comprehensive standard of care rapidly reduces depressive symptoms in patients with major depressive disorder who have acute suicidal ideation or behavior, especially in those with a history of suicide attempt, providing a new treatment option for this particularly ill and vulnerable population.

FIGURE 1

Least squares mean (95% CI) treatment difference of change in the MADRS total score from baseline to 24 hours after the first dose by subgroup^a. ^a Change in the MADRS total score was analyzed using ANCOVA with LOCF. Negative change in score indicates improvement. Patients were hospitalized at the time of the primary end point; therefore, missing data were infrequent. ^b Includes patients who had their dose reduced because of tolerability issues. ^c One patient in the esketamine 84 mg + standard-of-care group had missing MADRS data at baseline. One additional patient in esketamine 84 mg + standard-of-care group was missing both the day 1, 4 hour, and day 2 values and therefore was excluded from subgroup analyses.

FIGURE 2

Least squares mean (± SE) change in the MADRS total score from baseline during the double-blind treatment phase^a. MMRM, mixed-effects model using repeated measures; SE, standard error. ^a MMRM analysis with observed cases. Negative change in score indicates improvement. ^b Includes patients who had their dose reduced because of tolerability issues. ^c One patient in the esketamine 84 mg + standard-of-care group had missing MADRS data at baseline.

FIGURE 3

Odds ratios (95% CI) for a ≥2-point improvement in the MADRS item scores during the double-blind treatment phase. ^a Includes patients who had their dose reduced because of tolerability issues. Notes: MADRS items are rated on a scale of 0 to 6 where 0 indicates no abnormality and 6 indicates severe. The reduced sleep item was not assessed at the 4-hour post–first dose time point.

FIGURE 4

Frequency distribution of CGI-SS-r score at baseline, 4, and 24 hours after the first dose, and day 25 (observed cases). ^a Includes patients who had their dose reduced because of tolerability issues.