Frequently Asked Questions

Esketamine nasal spray added to comprehensive standard-of-care improved depressive symptoms rapidly, with a treatment effect observed starting at 4 hours after the first dose and confirmed at 24 hours. At 24 hours, the least-squares mean difference in MADRS total score versus placebo was -3.8 (SE 1.39; 95% CI, -6.56 to -1.09; 2-sided P = .006). Mean change from baseline to 24 hours was -16.4 (SD 11.95) with esketamine plus standard-of-care versus -12.8 (SD 10.73) with placebo plus standard-of-care.

No statistically significant between-group difference was shown at 24 hours on the study's key secondary measure of suicidality severity. Both groups improved on the Clinical Global Impression of Severity of Suicidality Revised version (CGI-SS-r), but the Hodges-Lehmann estimate of the treatment difference was 0.0 (95% CI, -1.00 to 0.00; 2-sided P = .107).

ASPIRE I enrolled adults aged 18 to 64 years with major depressive disorder without psychotic features, active suicidal ideation with intent, and a clinical need for acute psychiatric hospitalization due to imminent suicide risk. Patients had to answer yes to MINI questions about thinking about suicide and intending to act on those thoughts within the past 24 hours, and they also needed a baseline MADRS total score greater than 28. All patients had to agree to comprehensive standard-of-care treatment, including hospitalization and newly initiated or optimized oral antidepressant therapy.

All patients received comprehensive standard-of-care in addition to double-blind intranasal treatment. This included an initial psychiatric hospitalization, recommended for 5 days but adjustable based on clinical need, plus newly initiated or optimized oral antidepressant treatment chosen by the investigator; augmentation could include a second antidepressant, an atypical antipsychotic, or a mood stabilizer. Approximately three-fourths of patients also received at least 1 concomitant benzodiazepine during the double-blind phase.

Patients were randomized to esketamine 84 mg nasal spray twice weekly for 4 weeks or matching placebo, both added to standard-of-care. After day 1, one dose reduction from 84 mg to 56 mg was allowed for intolerance, and if reduced, the 56-mg dose was continued thereafter.

Yes. Remission, defined as a MADRS total score of 12 or lower, was more common with esketamine than placebo. The treatment difference in remission rates was 9.8% (95% CI, 0.87 to 18.77) at 24 hours after the first dose and 16.1% (95% CI, 3.20 to 28.94) on day 25, 4 hours postdose.

The most commonly reported adverse events with esketamine were dizziness, dissociation, headache, nausea, and somnolence. Most adverse events in the esketamine group occurred on intranasal dosing days (91.0%), and 94.9% of those resolved on the same day.

Moderate or greater sedation was more frequent with esketamine than placebo. An MOAA/S score of 3 or lower occurred at any time during the double-blind phase in 13 of 113 patients (11.5%) receiving esketamine versus 1 of 112 (0.9%) receiving placebo, and none required medical intervention. In addition, 21 patients (18.6%) in the esketamine group had their dose reduced to 56 mg because of intolerance, primarily on the second dosing session.

ASPIRE I was a phase 3, double-blind, randomized, placebo-controlled, multicenter trial conducted at 51 sites globally. A total of 226 adults were randomized 1:1 to esketamine or placebo nasal spray twice weekly for 4 weeks, with both groups also receiving hospitalization and newly initiated or optimized antidepressant treatment. This design supports a controlled comparison of esketamine versus placebo, but the strong background intervention means the results reflect esketamine as an add-on to intensive acute care rather than as a standalone treatment.

The authors noted several limitations. In this high-risk population, it is difficult to separate the effects of esketamine from the benefits of hospitalization, intensive clinical attention, and expectancy effects that can accompany trial participation. They also noted potential regional differences in standard-of-care across the global study and the possibility that patients may have been unblinded because esketamine has known transient sedative and dissociative effects, although separate raters were used for efficacy and safety assessments to help preserve blinding.