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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)

Dawn F. Ionescu, Dong-Jing Fu, Xin Qiu, Rosanne Lane, Pilar Lim, Siegfried Kasper, David Hough, Wayne C. Drevets, Husseini Manji, Carla M. Canuso

The International Journal of Neuropsychopharmacology August 26, 2020 DOI: 10.1093/ijnp/pyaa068 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Randomized controlled trial Double-blind Peer reviewed
Sample size 227
Population Adults aged 18-64 years with major depressive disorder and active suicidal ideation with intent
Interventions Esketamine nasal spray Placebo nasal spray
Dose 84 mg
Duration 4-week double-blind treatment, with assessments at 4 hours and 24 hours post-first dose
Topics Depression Esketamine
Keywords Clinical global impression Placebo Randomized controlled trial Suicidal ideation Somnolence Adverse effect Poison control Injury prevention Cognition
Citations 411
Post-publication review 1 comment on PubPeer (opens in new tab) · last active August 2023
Registration NCT03097133
Key findings Esketamine plus standard of care reduced depressive symptoms more than placebo plus standard of care at 24 hours in severely ill patients with MDD and active suicidal ideation.

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.

In the evidence

This study is part of the evidence base for 2 syntheses in the library. Here is how each one recorded it.

  • State of the evidence: Esketamine for depression Supports

    Esketamine plus standard of care reduced MADRS scores more than placebo plus standard of care at 24 hours (LS mean difference -3.9), with no significant between-group difference in suicidality severity.

    Synthesized

  • State of the evidence: Esketamine Supports

    Esketamine plus standard of care reduced depressive symptoms more than placebo plus standard of care at 24 hours, but the between-group difference in severity of suicidality was not significant.

    Synthesized

Comparable studies

Other randomized controlled trials on esketamine for depression, most cited first.

Study Year Design Participants
Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study Adults with moderate to severe nonpsychotic depression and a history of nonresponse to... 2019 Phase 3, double-blind, active-controlled, multicenter randomized controlled trial n = 227
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression Adults with treatment-resistant depression who achieved stable remission or stable... 2019 Phase 3, multicenter, double-blind, randomized withdrawal study n = 297
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression Adults with DSM-IV-TR diagnosis of major depressive disorder and history of inadequate... 2017 Phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study n = 67
Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study Depressed patients at imminent risk for suicide 2018 Randomized controlled trial n = 68
Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) Adults with moderate-to-severe depression and nonresponse to at least two... 2019 Randomized controlled trial n = 346

Citations in the library

Cited by 125

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