Effect of Repeated Intravenous Esketamine on Adolescents With Major Depressive Disorder and Suicidal Ideation: A Randomized Active-Placebo-Controlled Trial

Objective Suicide is a major cause of death in adolescents with limited treatment options. Ketamine and its enantiomers have shown rapid anti-suicidal effects in adults with major depressive disorder (MDD), but their efficacy in adolescents is unknown. We conducted an active, placebo-controlled trial to determine the safety and efficacy of intravenous esketamine in this population. Method A total of 54 adolescents (aged 13-18 years) with MDD and suicidal ideation were included from an inpatient setting and randomly assigned (1:1) to receive 3 infusions of esketamine (0.25 mg/kg) or midazolam (0.02mg/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 the Montgomery–Åsberg Depression Rating Scale (MADRS, key secondary outcome) were analyzed using linear mixed models. In addition, 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 = .007; Intensity, −10.6 [SD = 8.4] vs −5.0 [SD = 7.4], p = .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 = .004). The rates of anti-suicidal and antidepressant responses at 4 weeks posttreatment were 69.2% and 61.5% after esketamine, and were 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 3-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. Clinical trial registration information The efficacy and safety of esketamine combined with oral antidepressants in the treatment of major depressive disorder with suicidal ideation. http://www.chictr.org.cn. Chinese Clinical Trial Registry: ChiCTR2000041232. Diversity & Inclusion Statement We worked to ensure that the study questionnaires were prepared in an inclusive way. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. We actively worked to promote sex and gender balance in our author group. Suicide is a major cause of death in adolescents with limited treatment options. Ketamine and its enantiomers have shown rapid anti-suicidal effects in adults with major depressive disorder (MDD), but their efficacy in adolescents is unknown. We conducted an active, placebo-controlled trial to determine the safety and efficacy of intravenous esketamine in this population. A total of 54 adolescents (aged 13-18 years) with MDD and suicidal ideation were included from an inpatient setting and randomly assigned (1:1) to receive 3 infusions of esketamine (0.25 mg/kg) or midazolam (0.02mg/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 the Montgomery–Åsberg Depression Rating Scale (MADRS, key secondary outcome) were analyzed using linear mixed models. In addition, the 4-week clinical treatment response was a key secondary outcome. 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 = .007; Intensity, −10.6 [SD = 8.4] vs −5.0 [SD = 7.4], p = .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 = .004). The rates of anti-suicidal and antidepressant responses at 4 weeks posttreatment were 69.2% and 61.5% after esketamine, and were 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. These preliminary findings indicate that 3-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.