Biol Psychiatry. 2025 Oct 17:S0006-3223(25)01529-X. doi: 10.1016/j.biopsych.2025.10.009. Online ahead of print.
ABSTRACT
BACKGROUND: Historically, the most effective antidepressant is electroconvulsive therapy (ECT). ECT induces cognitive side effects, and commonly requires numerous treatments over several weeks for robust symptom relief. The rapid response that can be observed following ketamine treatment has reconceptualized how pharmacotherapy can treat depression. One subanesthetic infusion can alleviate symptoms within hours; however, sustained relief also requires multiple doses. Clinical studies have combined ECT and ketamine to improve therapeutic outcomes, but have found mixed results.
METHODS: We used behavioral pharmacology and ex vivo hippocampal slice electrophysiology to test the hypothesis that a preclinical ECT model, electroconvulsive stimulation (ECS), and ketamine can exert synergistic antidepressant-relevant effects in adult mice if dose and dose interval are carefully considered.
RESULTS: We found that repeated doses of ketamine, but not ECS, lead to a metaplasticity characterized by an increased magnitude of synaptic potentiation at the hippocampal Schaffer collateral-CA1 synapse. We targeted ketamine-induced metaplasticity by intermittently (i.e., 24-hour interval) delivering individual, subeffective ketamine and ECS doses to produce synergistic antidepressant-like synaptic and behavioral outcomes that resembled the actions of an effective ketamine dose. Unlike repeated ECS, intermittent ketamine/ECS doses yielded antidepressant-relevant synaptic and behavioral actions without impairing cognition. Further, antidepressant-like effects produced by ketamine alone were prolonged when intermittently administered with an individual ECS treatment. Synergistic effects were precluded when ketamine/ECS were delivered concurrently.
CONCLUSIONS: Ketamine and ECS exhibited time-sensitive, synergistic antidepressant-like actions, suggesting that strategies targeting metaplasticity at glutamatergic synapses can be employed to reduce side effects while augmenting, accelerating, and prolonging antidepressant outcomes.
PMID:41110745 | DOI:10.1016/j.biopsych.2025.10.009
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