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/ ).