Translational development strategy for magnetic seizure therapy.

Electroconvulsive therapy (ECT) has unparalleled antidepressant efficacy, but its cognitive side effects may be persistent. Research suggests that the side effects may be at least partially dissociable from the therapeutic effects of ECT, suggesting that distinct cortical networks may underlie them and introducing a role for focal seizure induction as a means of minimizing side effects. In magnetic seizure therapy (MST), magnetic fields avoid tissue impedance and induce electrical currents confined to superficial cortex, facilitating focal seizure induction. The translational development strategy for MST has included: (1) device development, (2) feasibility in animals and initial human trials, (3) testing in nonhuman primates on safety and mechanisms of action (with neuroanatomical, neurophysiological and cognitive endpoints), (4) safety testing in patients, (5) initial efficacy testing in patients, (6) dosage optimization, and (7) randomized comparison with ECT. These stages have been iterative, with results of early clinical testing prompting device enhancements that were, in turn, tested in nonhuman primates prior to human trials. Safety testing was aided by development of a nonhuman primate model of human ECT, and the validation of a cognitive battery for the monkey that is sensitive to the range of effects of ECT on human memory. Human testing has been facilitated by the development of an international consortium of centers addressing various aspects of technique and dose/response relationships. Challenges facing MST are common to other device-based therapies: characterizing dose/response relationships, optimizing efficacy, and developing efficient and reliable methods to induce lasting therapeutic change in the circuitry underlying depression.