Electroconvulsive therapy (ECT) is the most effective therapy for adults with major depression; however, some patients fail to respond despite an adequate trial, and ECT can produce negative cognitive effects. In this revised four site, prospective study we propose the first investigation of ECT outcome integrating multiple types of data including clinical and cognitive measures, whole-brain neuroimaging, EEG, and E-field modeling to establish the mechanisms underlying ECT-induced antidepressant response (response biomarkers) and negative cognitive effects (safety biomarkers). Using this approach in patients with major depressive disorder (n = 230), we will confirm the “sweet spot” of ECT dosing in order to maximize antidepressant benefit and cognitive safety.