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

This pooled analysis (n=456) of the two ASPIRE studies (comparing ketamine to placebo, both with standard care) finds significant improvements in depression scores immediately (4 & 24 hours) up to 25 days later (all similar reductions). The study also showed improvements on suicidal ideation (which all patients had), most for those with a history of suicide attempt.


“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.

Authors: Carla M. Canuso, Dawn F. Ionescu, Xiang Li, Xin Qiu, Rosanne Lane, Ibrahim Turkoz, Abigail I. Nash, Tricia J. Lopena & Dong-Jing Fu


This study is a follow-up to earlier analyses of the ASPIRE studies (e.g. Ionescu et al, 2020)

Study details

Compounds studied

Topics studied

Study characteristics
Placebo-Controlled Double-Blind Randomized



Institutes associated with this publication

Johnson & Johnson
One of the largest pharmaceutical companies in the world, Johnson & Johnson are responsible for bringing esketamine to market in the form of Spravato.

Linked Research Papers

Notable research papers that build on or are influenced by this paper

Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Plus a Newly Initiated Oral Antidepressant in Adult Patients with Treatment-Resistant Depression: A Randomized, Double-Blind, Multicenter, Active-Controlled Study Conducted in China and USA
This double-blind, randomized Phase III trial (n=227) finds no significant difference between esketamine plus a new antidepressant versus only the antidepressant (and a placebo) at day 28 on depression scores (MADRS). The study reports one death in the esketamine group. It also states esketamine to be "effective and safe" though only the first claim could be credibly made if one only looks at the immediate (24-hour) effects.

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