Electroconvulsive therapy combined with esketamine improved depression through PI3K/AKT/GLT-1 pathway.
Xiangyang Zang, Jingting Zhang, Jingping Hu, Xingying Mo, Tingwei Zheng, Jiaming Ji, Jibin Xing, Chaojin Chen, Shaoli Zhou
Journal of Affective Disorders 2025 DOI: 10.1016/j.jad.2024.08.123 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial and animal study Peer reviewed |
|---|---|
| Sample size | 12 |
| Population | Human patients with severe depression and a rat model of depression |
| Interventions | Esketamine Electroconvulsive therapy |
| Dose | 5 mg/kg |
| Topics | Depression Esketamine |
| Keywords | Electroconvulsive therapy Glutamate transporter Psychiatric care Neurology Neural pathways Psychiatric medication psychopharmacology Antidepressants |
| Citations | 16 |
| Key findings | Esketamine plus ECT improves depression symptoms more than ECT alone, likely through activation of the PI3K/Akt/GLT-1 pathway. |
Abstract
Neuron excitotoxic damage induced by extracellular glutamate accumulation pathologically is one of the main mechanisms of depression. Glutamate transporter-1 (GLT-1) expressed in astrocyte is responsible for glutamate clearance to maintain glutamate balance. Electroconvulsive therapy (ECT) is prevalently recommended for severe depression due to its significant anti-depressant effect. Esketamine could offer advantages of rapid anti-depressant effect and neuron protection. The aim of this study is to investigate the anti-depressant efficacy of esketamine plus ECT, and further to explore the mechanism. Firstly, total 12 patients were randomized into anesthesia with propofol (P) or propofol+esketamine (PK) before ECT. 24-Hamilton Depression Scale (HAMD) was used to evaluate the severity of depression after each ECT. Then, depressive rat model was built using chronic unpredictable mild stress method, and subsequently received infusion of esketamine (5 mg/kg) or saline before ECT treatment (0.5 mA; 100 V) for consecutive 10 days. Tests including sucrose preference test, open field test and forced swimming test were used to evaluate depression-like behaviors. In next experiments, rats were injected with RIL, DHK or LY294002 intracerebroventricularly for continuous 10 days before individual treatment. After the fifth and sixth ECT, PK group displayed lower HAMD score compared to P group. In rat model, we found that esketamine plus ECT could significantly improve depression-like behaviors and decrease glutamate level. Esketamine and ECT could both activate PI3K/Akt/GLT-1 pathway. The GLT-1 agonist RIL made equivalent effect as esketamine plus ECT. Furthermore, after using PI3K/Akt inhibitor LY294002 and GLT-1 inhibitor DHK, esketamine plus ECT could neither improve depression-like symptoms, nor upregulate GLT-1 level. Our present study suggested that esketamine plus ECT could dramatically improve depression symptom. The activation of PI3K/Akt/GLT-1 pathway may be the potential mechanism.
Comparable studies
Other preclinical and animal studies on esketamine for depression, most cited first.
Citations in the library
Cited by 5
- Esketamine alleviates depressive-like behavior in neuropathic pain mice through the METTL3-GluA1 pathway. Cell Biology and Toxicology January 29, 2025
- Esketamine alleviates cognitive impairment signs induced by modified electroconvulsive therapy in a depression rat model via the KLF4/p38 MAPK pathway. Journal of Affective Disorders May 1, 2025
- Effects of Binaural Beat Music and Esketamine for ECT in the Treatment of Major Depressive Disorder: A Randomized Controlled Trial Protocol. Neuropsychiatric Disease and Treatment 2025
- Adverse drug events and toxicological mechanisms of esketamine: a study based on US Food and Drug Administration Adverse Event Reporting System and network toxicology analysis. Naunyn-Schmiedeberg's Archives of Pharmacology February 26, 2026
- Beyond surgery: Repurposing anesthetics for treatment of central nervous system disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry June 20, 2025
Cites 13
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Intravenous Ketamine as Adjunctive Therapy in Treatment-Resistant Depression (TRD) Molecular Psychiatry October 3, 2018
- Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. New England Journal of Medicine May 24, 2023
- Neural correlates of change in major depressive disorder anhedonia following open-label ketamine Journal of Psychopharmacology February 17, 2015
- Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study. Journal of Affective Disorders November 14, 2019
and 8 more in the library