Esketamine's Therapeutic Effect on Anhedonia: A Post-hoc of a Randomized Controlled Trial
Qianqian Wu, Weicheng Li, Zhanjie Luo, Chengyu Wang, Xiaofeng Lan, Junhao Shen, Ziying Chen, Jincai Pan, Xuan Liu, Haobin Zhu, Yiyun Xue, Zitao Wu, Yuping Ning, Yanling Zhou
Research Square July 20, 2026 preprint DOI: 10.21203/rs.3.rs-10020524/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Double-blind |
|---|---|
| Sample size | 74 |
| Population | Adolescent patients aged 13-17 with moderate to severe depression |
| Interventions | Esketamine Midazolam |
| Dose | 0.25 mg/kg esketamine; 0.02 mg/kg midazolam |
| Duration | Three infusions every other day, each 40 minutes; follow-up to at least Day 12 |
| Measures | Montgomery-Asberg Depression Rating Scale (MADRS) anhedonia subscale |
| Topics | Esketamine |
| Key findings | Adjunctive esketamine showed no significant early advantage over midazolam, but from Day 12 onward significant drug-time interactions favored esketamine for reducing anhedonia. The authors report that esketamine improved anhedonia, depressive, and suicidal symptoms over the long term, with delayed efficacy, and suggest it may be an effective adjunctive treatment. |
Abstract
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 minutes, 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/).
Comparable studies
Other randomized controlled trials on esketamine, most cited first.
Citations in the library
Cites 22
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) The International Journal of Neuropsychopharmacology July 9, 2019
- Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II) The International Journal of Neuropsychopharmacology August 26, 2020
- Esketamine Nasal Spray for Rapid Reduction of Major Depressive Disorder Symptoms in Patients Who Have Active Suicidal Ideation With Intent The Journal of Clinical Psychiatry May 11, 2020
and 17 more in the library