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)

• Published in: The international journal of neuropsychopharmacology Vol. 24; no. 1; pp. 22 - 31
• Main Authors: Ionescu, Dawn F, Fu, Dong-Jing, Qiu, Xin, Lane, Rosanne, Lim, Pilar, Kasper, Siegfried, Hough, David, Drevets, Wayne C, Manji, Husseini, Canuso, Carla M
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01-01-2021
• Subjects: Administration, Intranasal; Adolescent; Adult; Antidepressive Agents - administration & dosage; Antidepressive Agents - pharmacology; Depressive Disorder, Major - drug therapy; Double-Blind Method; Drug therapy; Female; Health aspects; Humans; Intranasal medication; Ketamine - administration & dosage; Ketamine - pharmacology; Major depressive disorder; Male; Middle Aged; Nasal Sprays; Outcome Assessment, Health Care; Patient Acuity; Regular s; Suicidal Ideation; Testing; Young Adult; United States; Esketamine; suicidal ideation; depression; suicide risk
• ISSN: 1461-1457; 1469-5111
• DOI: 10.1093/ijnp/pyaa068

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