Clinical Summary: Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent: Double-Blind, Randomized Study (ASPIRE I)
Patients with major depressive disorder and active suicidal ideation with intent need symptom relief within hours, not weeks, yet standard antidepressants typically require 4-6 weeks to exert their full effect. This study tests whether esketamine nasal spray can rapidly reduce depressive symptoms in a psychiatric emergency population already receiving hospitalization and intensive standard-of-care treatment.
Key Findings
- At 24 hours after the first dose, esketamine + standard-of-care produced greater improvement in depressive symptoms than placebo + standard-of-care on the MADRS total score, with a least-squares mean difference [SE] of -3.8 [1.39] (95% CI, -6.56 to -1.09; 2-sided P = .006).
- Both groups improved rapidly, but the mean [SD] change in MADRS total score from baseline to day 2 was -16.4 [11.95] with esketamine + standard-of-care versus -12.8 [10.73] with placebo + standard-of-care.
- Remission rates favored esketamine, with a treatment difference (95% CI) of 9.8% (0.87 to 18.77) 24 hours post-first dose and 16.1% (3.20 to 28.94) on day 25, 4 hours postdose.
- The key secondary outcome did not separate treatments at 24 hours: the Hodges-Lehmann estimate of the treatment difference (95% CI) for CGI-SS-r was 0.0 (-1.00 to 0.00; 2-sided P = .107).
- Sedation and tolerability effects were more frequent with esketamine: 21 patients (18.6%) had a dose reduction to 56 mg due to intolerance, and 13/113 (11.5%) had an MOAA/S score ≤ 3 during the double-blind phase versus 1/112 (0.9%) with placebo.
Esketamine nasal spray added to hospitalization and newly initiated or optimized oral antidepressant therapy delivers a rapid antidepressant effect in major depressive disorder with active suicidal ideation with intent. It did not show a statistically significant 24-hour advantage over placebo on clinician-rated suicidality severity, so its clearest practice value is fast reduction of depressive symptoms in this high-risk setting.
Practice Implications
- Consider esketamine when rapid reduction of depressive symptoms is needed in patients with major depressive disorder who have active suicidal ideation with intent and are already receiving comprehensive acute care.
- Do not expect a confirmed 24-hour advantage on CGI-SS-r suicidality severity over intensive standard-of-care alone; continue hospitalization, close observation, and full suicide-risk management even when depressive symptoms improve.
- Plan monitoring around dosing visits because 91.0% of adverse events in the esketamine group occurred on intranasal dosing days and 94.9% of those resolved on the same day.
- Be ready to adjust treatment for tolerability, as 21 patients (18.6%) required reduction from 84 mg to 56 mg due to intolerance, and moderate or greater sedation occurred in 13/113 (11.5%) of esketamine-treated patients.
