Effect of Repeated Intravenous Esketamine on Adolescents With Major Depressive Disorder and Suicidal Ideation: A Randomized Active-Placebo-Controlled Trial
Chao, Z., Fu, L., Hu, Z., Lan, X-F., Li, W., Liu, H., Ning, Y-P., Wang, C., Ye, Y., Zhang, F., Zhou, Y.
This placebo-controlled trial (n=54) investigates the efficacy and safety of esketamine (iv, 17.5mg, 3x) in adolescents suffering from depression (MDD) and suicidal ideation (SI). It shows significant reductions in Columbia Suicide Severity Rating Scale (C-SSRS) Ideation and Intensity scores and Montgomery-Åsberg Depression Rating Scale (MADRS) scores in the esketamine group compared to the midazolam (placebo) group at day six, with maintained antisuicidal and antidepressant responses at four weeks post-treatment.
Abstract
Objective Suicide is a major cause of death in adolescents with limited treatment options. Ketamine and its enantiomers have shown rapid antisuicidal effects in adults with major depressive disorder (MDD), but their efficacy in adolescents is unknown. We conducted an active, placebo-controlled trial of intravenous esketamine��s safety and efficacy in this population.Method A total of 54 adolescents (aged 13-18) with MDD and suicidal ideation were included from an inpatient setting and randomly assigned (1:1) to receive three infusions of esketamine (0.25 mg/kg) or midazolam (0.045 mg/kg) over 5 days, with routine inpatient care and treatment. Changes from baseline to 24 hours after the final infusion (Day 6) in the scores of the Columbia Suicide Severity Rating Scale (C-SSRS) Ideation and Intensity (primary outcome) and Montgomery-Åsberg Depression Rating Scale (MADRS, key secondary outcome) were analyzed using linear mixed models. Additionally, the 4-week clinical treatment response was a key secondary outcome.Results The mean changes in C-SSRS Ideation and Intensity scores from baseline to Day 6 were significantly greater in the esketamine group than in the midazolam group (Ideation, -2.6 [SD=2.0] vs. -1.7 [SD=2.2], P=0.007; Intensity, -10.6 [SD=8.4] vs. -5.0 [SD=7.4], P=0.002), and the changes in MADRS scores from baseline to Day 6 were significantly greater in the esketamine group than in the midazolam group (-15.3 [SD=11.2] vs. -8.8 [SD=9.4], P=0.004). The rates of antisuicidal and antidepressant responses at 4 weeks posttreatment were 69.2% and 61.5% after esketamine, and 52.5% and 52.5% after midazolam, respectively. The most common adverse events in the esketamine group were nausea, dissociation, dry mouth, sedation, headache and dizziness.Conclusion These preliminary findings indicate that three-dose intravenous esketamine, added to routine inpatient care and treatment, was an effective and well-tolerated therapy for treating adolescents with MDD and suicidal ideation.