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.
Abstract of Effect of Esketamine on Depressive Symptoms in Adolescents with Major Depressive Disorder at Imminent Suicide Risk
“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.“
Authors: Colette Kosik-Gonzalez, Dong-Jing Fu, Li Nancy Chen, Rosanne Lane, Michael H. Bloch, Melissa DelBello, Carmen Moreno, Wayne C. Drevets & Carla M. Canuso
Summary of Effect of Esketamine on Depressive Symptoms in Adolescents with Major Depressive Disorder at Imminent Suicide Risk
Major depressive disorder (MDD) is one of the most common psychiatric conditions in adolescents and is a significant risk factor for suicide. Adolescents diagnosed with MDD are at a substantially higher risk of attempting suicide, with research indicating that up to 80% of those who attempt suicide meet the criteria for depression at the time of the attempt. Similarly, a large proportion of adolescents who die by suicide had MDD at the time of death.
The urgency of intervention is critical, as suicidal ideation can rapidly escalate to suicide attempts. However, there are currently no pharmacological treatments approved by regulatory authorities specifically for adolescents with MDD at imminent risk of suicide. Traditional treatments for MDD, such as antidepressants and psychotherapy, have notable limitations. Antidepressants often take several weeks to become fully effective, while psychotherapy requires significant time and resources that may not be readily available. Even hospitalisation, which is the standard intervention for suicidal adolescents, does not entirely eliminate the risk of suicide following discharge.
Esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has demonstrated rapid antidepressant effects in adults with MDD and acute suicidal ideation or behaviour. In the United States, esketamine nasal spray is approved for use in adults with MDD experiencing acute suicidal thoughts, and it is also approved in the European Union for the rapid reduction of depressive symptoms in psychiatric emergencies. Given these findings in adults, the current study aimed to evaluate the efficacy and safety of esketamine nasal spray in adolescents with MDD who were at imminent risk for suicide.
Methods
Find this paper
https://doi.org/10.1016/j.jaac.2025.02.015
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Cite this paper (APA)
Kosik-Gonzalez, C., Fu, D. J., Chen, L. N., Lane, R., Bloch, M. H., DelBello, M., ... & Canuso, C. M. (2025). Effect of Esketamine on Depressive Symptoms in Adolescents with Major Depressive Disorder at Imminent Suicide Risk: A Randomized Psychoactive-Controlled Study. Journal of the American Academy of Child & Adolescent Psychiatry.
Study details
Compounds studied
Ketamine
Topics studied
Depression
Suicidality
Study characteristics
Placebo-Controlled
Active Placebo
Double-Blind
Randomized
Participants
147
Humans
Compound Details
The psychedelics given at which dose and how many times
Ketamine 28 - 84mg | 8x