Intermittent Ketamine and Neuromodulation Treatment Evoke Synergistic Antidepressant-Relevant Action

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 led to a reconceptualization of 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 yielded mixed results.

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 dependent on dose and dose interval.

Repeated doses of ketamine, but not ECS, led to a metaplasticity characterized by an increased magnitude of synaptic potentiation at the hippocampal Schaffer collateral-CA1 synapse. Targeting ketamine-induced metaplasticity intermittently (i.e., 24-hour interval) by delivering individual, subeffective ketamine and ECS doses produced synergistic antidepressant-like synaptic and behavioral outcomes that resembled the actions of an effective ketamine dose. Unlike repeated ECS, intermittent ketamine and ECS administration yielded antidepressant-relevant synaptic and behavioral actions without impairing cognition. Antidepressant-like effects produced by ketamine alone were prolonged when intermittently administered with an individual ECS treatment. Synergistic effects were precluded when ketamine and ECS were delivered concurrently.

Ketamine and ECS exhibited time-sensitive, synergistic antidepressant-like actions, suggesting that strategies targeting metaplasticity at glutamatergic synapses can be used to reduce side effects while augmenting, accelerating, and prolonging antidepressant outcomes.