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

Abstract

Objective: To evaluate the efficacy, safety, and tolerability of esketamine nasal spray vs 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, including initial hospitalization, oral antidepressant, and evidenced-based psychotherapy. The primary efficacy end point-change in Children's Depression Rating Scale-Revised (CDRS-R) total score from baseline to 24 hours post first dose-was analyzed using analysis of covariance, 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 least squares means [95% CI]: -5.8 [-11.19, -0.35], p = .037). The between-group differences for individual esketamine 84 mg and 56 mg doses vs midazolam were -5.7 ([-12.91, 1.55], p = .123) and -5.9 ([-12.25, 0.53], p = .072), respectively. Severity of suicidality, per Clinical Global Impression of Severity of Suicidality-revised (CGI-SS-R), improved in all 4 groups (between-group difference of least squares 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 end point of the study was met for the pooled esketamine doses (56 and 84 mg). Esketamine in conjunction with comprehensive standard of care rapidly improved depressive symptoms among adolescents at imminent risk for suicide.

Clinical trial registration information: Study to Evaluate the Efficacy and Safety of 3 Fixed Doses of Intranasal Esketamine in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Pediatric Participants Assessed to Be at Imminent Risk for Suicide; https://clinicaltrials.gov/study/NCT03185819.