Zhen-Juan QIN, Xiao-Ming LI, Jia-Bao LI, Zhi LI, Xin WEI, Hui-Lin HU, Yu-Jiao CHEN, Su-Rong XU, Zhi-Yuan XIE, Xin-Hu YANG, Wen-Juan DAI, Yu-Hua WEI
Alpha Psychiatry - 2026;27(5):48866-0
Background: The therapeutic efficacy and safety of intravenous ketamine or esketamine in adolescents with major depressive disorder (MDD) remain insufficiently defined. This systematic review of randomized controlled trials (RCTs) aimed to evaluate the efficacy, safety, and tolerability of intravenous ketamine or esketamine in this population. Methods: A comprehensive search of four international databases (PubMed, EMBASE, PsycINFO, and the Cochrane Library) was conducted to identify RCTs comparing intravenous ketamine or esketamine with intravenous midazolam in adolescents with MDD. Results: Three RCTs involving a total of 134 adolescents with MDD were included. Two trials assessed the antidepressant effects of intravenous ketamine compared with intravenous midazolam, with inconsistent findings. No significant advantage of intravenous ketamine over intravenous midazolam was observed in reducing anxiety symptoms (1 RCT). One trial compared intravenous esketamine with intravenous midazolam and evaluated antidepressant, anti-suicidal, and neurocognitive outcomes, demonstrating the superiority of intravenous esketamine. Both intravenous ketamine and intravenous esketamine were associated with significantly higher rates of dissociative symptoms (1 RCT each), and intravenous esketamine was also linked to a higher incidence of psychopathological symptoms (1 RCT). Systematic reporting of adverse events was provided in only one of the three included RCTs. Conclusions: Given the limited number of studies, small sample sizes, and methodological heterogeneity of the available RCTs, the current evidence base remains preliminary and insufficient to support definitive conclusions regarding the efficacy and safety of intravenous ketamine/esketamine in adolescents with MDD. These findings highlight the need for further adequately powered RCTs to establish robust and clinically meaningful evidence.
