Trial PaperDepressive DisordersSuicidalityAdolescentsMajor Depressive Disorder (MDD)Headache Disorders (Cluster & Migraine)Safety & Risk ManagementChronic PainEsketamineKetamine

Effect of Esketamine on Depressive Symptoms in Adolescents with Major Depressive Disorder at Imminent Suicide Risk: A Randomized Psychoactive-Controlled Study

This double-blind Phase IIb trial (n=147) evaluated the efficacy, safety, and tolerability of esketamine nasal spray versus midazolam in reducing depressive (MDD) symptoms in adolescents at imminent risk for suicide (SI). The study finds that pooled doses of esketamine (56 and 84 mg) significantly reduce depressive symptoms at 24 hours, with common side effects including dizziness, nausea, and dissociation.

Authors

  • Daniel Fu
  • William Drevets
  • Robert Lane

Published

Journal of the American Academy of Child & Adolescent Psychiatry
individual Study

Abstract

Objective

To evaluate the efficacy, safety, and tolerability of esketamine nasal spray versus psychoactive placebo (oral midazolam) in rapidly reducing depressive symptoms in adolescents with major depressive disorder at imminent risk for suicide.

Method

This double-blind, double-dummy, phase 2b study randomized (1:1:1:2) 147 adolescents (12 to <18 years old) to esketamine (28, 56, or 84 mg) or midazolam twice-weekly for 4 weeks. Participants concomitantly received comprehensive standard-of-care (SOC), including initial hospitalization, oral antidepressant, and evidenced-based psychotherapy. The primary efficacy endpoint - change in Children’s Depression Rating Scale-Revised (CDRS-R) total score from baseline to 24 hours post-first dose was analyzed using ANCOVA, according to a pooled sequential multiple-testing procedure.

Results

All participants were moderately-to-severely depressed at enrollment; approximately 95% were moderately-to-extremely suicidal. Pooled esketamine doses (56 and 84 mg) showed superiority over midazolam in reducing CDRS-R total score at 24 hours post-first dose (between-group difference of LS means [95% CI]: -5.8 [-11.19, -0.35]; p=0.037). The between-group differences for individual 84 mg and 56 mg esketamine doses versus midazolam were -5.7 ([-12.91, 1.55], p=0.123) and -5.9 ([-12.25, 0.53], p=0.072), respectively. Severity of suicidality, per Clinical Global Impression-Severity of Suicidality Revised, improved in all 4 groups (between-group difference of LS means [95% CI]: -0.2 [-0.90, 0.41], -0.3 [-0.93, 0.31], 0.0 [-0.69, 0.72] for esketamine 28, 56, and 84 mg, respectively, at 24 hours post-first dose). Common adverse events (incidence ≥20%) reported for esketamine were dizziness, nausea, dissociation, headache, dysgeusia, somnolence, vomiting, hypoesthesia, and intentional self-injury.

Conclusion

The primary efficacy endpoint of the study was met for the pooled esketamine doses (56 and 84 mg): Esketamine in conjunction with comprehensive SOC rapidly improved depressive symptoms among adolescents at imminent risk for suicide.

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Research Summary of 'Effect of Esketamine on Depressive Symptoms in Adolescents with Major Depressive Disorder at Imminent Suicide Risk: A Randomized Psychoactive-Controlled Study'

Introduction

Major depressive disorder (MDD) is highly prevalent in adolescents and is the psychiatric condition most commonly associated with suicide. Earlier research and clinical practice highlight that conventional oral antidepressants require several weeks to reach full effect and that adolescents with acute suicidal behaviour or intent are frequently excluded from antidepressant trials, leaving a gap in evidence-based, rapid pharmacological interventions for this high-risk group. Hospitalisation, psychotherapy and initiation or optimisation of oral antidepressants constitute the current standard-of-care (SOC), but each has limitations in speed of onset and durability of protection from suicide in the weeks after discharge. Kosik-Gonzalez and colleagues set out to evaluate whether intranasal esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, administered in addition to comprehensive SOC, can produce a rapid reduction in depressive symptoms in adolescents with MDD who are assessed to be at imminent risk for suicide. The trial compared three fixed doses of esketamine (28, 56, 84 mg) with an active psychoactive control (oral midazolam) given twice weekly for 4 weeks, with the primary endpoint focused on change in depressive symptoms 24 hours after the first dose. The study therefore addresses the question of rapid-onset antidepressant effect in a population typically excluded from registrational trials and conducted in the context of usual acute-care practices for suicidal adolescents.

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Study Details

References (2)

Papers cited by this study that are also in Blossom

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)

Ionescu, D. F., Lane, R., Lim, P. et al. · Journal of Clinical Psychiatry (2020)

174 cited
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)

Ionescu, D. F., Qiu, X., Lane, R. et al. · International Journal of Neuropsychopharmacology (2020)

205 cited

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Effect of Esketamine on Depressive Symptoms in... — Research Summary & Context | Blossom