Ketamine/esketamine treatment for resistant depression in children and adolescents: a PRISMA systematic review

Ketamine and esketamine have been approved as an adjunctive therapy for treatment-resistant major depressive disorder with acute suicidal ideation and behavior in adults. The current paper aimed to systematically review the available data on their efficacy in children and adolescents. The MEDLINE was searched with the keyword 'esketamine' on July 5th, 2024 (by following the PRISMA statement). The review has been registered in PROSPERO for ketamine and esketamine separately (CRD42024552011 and CRD42024516053). Out of 5131 articles originally identified, 29 were included for analysis and discussion. There is only one double-blind RCT with ketamine and another one with esketamine. The ketamine trial tested the effects at 24 h of a single dose with a crossover design and reported that the therapeutic effect lasted for at least two weeks. No effect on suicidality was reported. The esketamine trial reported that mood and suicidality improved after the three infusions were completed. The improvement in depressive symptoms persisted until the end of the study, but the improvement in suicidality did not. ketamine attenuated the negativity bias and reduced depressive cognitive style. Esketamine did not harm cognition, but instead, it improved processing speed. The current systematic review found only positive reports in the literature, but the scarcity of data suggests there is no definitively convincing evidence concerning the usefulness of ketamine and esketamine in the treatment of paediatric resistant depression. More research is needed, both in light of the problematic data in adults as well as in the light of the problems this kind of substance could cause in brain development and maturation.