Esketamine’s therapeutic effect on anhedonia in adolescents: a post-hoc of a randomized controlled trial

Abstract Background Anhedonia, a prominent symptom of major depressive disorder (MDD), severely impairs patients’ quality of life and is challenging to treat. Although esketamine has shown potential in treating anhedonia in adult treatment-resistant MDD, its effects on adolescents remain under-explored. Methods In this study, a prospective, randomized, double-blind, controlled trial was conducted involving 74 adolescent patients aged 13–17 with moderate to severe depression. These patients were randomly assigned to either the esketamine group (receiving 0.25 mg/kg esketamine) or the midazolam group (receiving 0.02 mg/kg midazolam) as an adjunct to ongoing antidepressant medications. Infusions were administered every other day for 40 min, with a total of three sessions. The level of anhedonia was evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS) anhedonia subscale at specific time points after treatment, and statistical analysis was performed using mixed-effects models. Results No significant drug-time interaction was found between groups in early follow-up, while significant interactions favoring esketamine appeared from Day 12 onward (all P < 0.05). The results indicated that esketamine injections could significantly improve anhedonia in adolescent MDD patients over the long term, suggesting its potential as an effective adjunctive treatment. Conclusions Adjunctive esketamine relieves anhedonia, depressive and suicidal symptoms in adolescents with moderate-severe MDD with delayed efficacy. Further large, long-term studies with neurobiological tests are needed to verify its effects and mechanisms. Trial registration Registered on 2020-12-22 at the Chinese Clinical Trial Registry, registration number ChiCTR2000041232 ( https://www.chictr.org.cn/ ).