Effect of Esketamine on Depressive Symptoms in Adolescents with Major Depressive Disorder at Imminent Suicide Risk: A Randomized Psychoactive-Controlled Study
Bloch, M. H., Canuso, C. M., Chen, L. N., DelBello, M., Drevets, W. C., Fu, D. J., Kosik-Gonzalez, C., Lane, R., Moreno, C.
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
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.