Intermittent Ketamine and Neuromodulation Treatment Evoke Synergistic Antidepressant-Relevant Action

Area of Science:

• Neuroscience
• Pharmacology
• Psychiatry

Background:

• Electroconvulsive therapy (ECT) is a highly effective antidepressant but causes cognitive side effects and requires multiple sessions.
• Ketamine offers rapid symptom relief for depression within hours, but sustained effects necessitate repeated doses.
• Combining ECT and ketamine has shown mixed results in clinical settings.

Purpose of the Study:

• To investigate the synergistic antidepressant effects of electroconvulsive stimulation (ECS), a preclinical model of ECT, and ketamine in mice.
• To determine if the dose and interval of ketamine and ECS administration influence their combined efficacy.
• To explore the impact of ECS and ketamine on synaptic plasticity and cognitive function.

Main Methods:

• Utilized behavioral pharmacology and ex vivo hippocampal slice electrophysiology in adult mice.
• Tested the hypothesis that ECS and ketamine can produce synergistic antidepressant-like effects.
• Administered varying doses and intervals of ECS and ketamine.

Main Results:

• Intermittent administration (24-hour interval) of subeffective doses of ketamine and ECS produced synergistic antidepressant-like synaptic and behavioral effects.
• Ketamine alone induced metaplasticity at hippocampal synapses; intermittent ECS enhanced this effect.
• Combined intermittent ketamine and ECS improved outcomes without cognitive impairment, unlike repeated ECS.
• Concurrent administration of ketamine and ECS precluded synergistic effects.

Conclusions:

• Ketamine and ECS exhibit time-sensitive synergistic antidepressant actions.
• Targeting metaplasticity at glutamatergic synapses can enhance, accelerate, and prolong antidepressant outcomes.
• Intermittent administration strategies may reduce side effects associated with combined ketamine and ECS therapy.