2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)

Electroconvulsive therapy (ECT) is one of the most effective antidepressant non-invasive brain stimulation
therapies for adults with major depression. However, a number of patients fail to respond despite adequate trials,
and while clinically beneficial, ECT can produce adverse cognitive effects including amnesia, executive
dysfunction, and verbal dysfluency. Previous single- and multi-site ECT-imaging investigations have been limited
by insufficient sample size and/or non-standardization of methodology. Therefore, in answer to NIMH Strategic
Objective 3.2 “Develop strategies for tailoring existing interventions to optimize outcomes,” our investigative
teams have conducted clinical studies to develop standardized methods for acute ECT course administration,
antidepressant and cognitive measures for phenotyping, optimal neuroimaging protocols and E-field modeling,
and sophisticated analytic models to integrate and interpret the antidepressant-response and cognitive-
impairment biomarkers. In this prospective study we propose the first investigation integrating multiple units of
analysis including clinical and cognitive phenotyping, whole-brain neuroimaging, EEG, and E-field modeling to
establish the mechanisms underlying ECT-induced antidepressant response (response biomarkers) and
cognitive adverse effects (safety biomarkers), as well as to find the “sweet spot” of ECT dosing for optimal
antidepressant benefit and cognitive safety. Adult patients with major depressive disorder (n = 230) will receive
a standardized acute ECT course, complete clinical and cognitive measures and undergo structural and
functional MRI at three time points (baseline, after ECT #6, and following treatment completion) and one-month
naturalistic follow-up. All MRI data will be processed and harmonized identically at a central imaging core to
ensure uniformity. We have three primary aims: 1) Determine the relationships between E-field strength, ictal
power, and biomarkers; 2) Determine the relationships between E-field strength, biomarkers, and antidepressant
outcomes; and 3) Determine the relationships between E-field strength, biomarkers, and cognitive outcomes. An
exploratory aim will contrast antidepressant-response and cognitive-impairment biomarkers identified in the
current proposal with magnetic seizure therapy and healthy comparison subjects. The overarching hypothesis
of this investigation is that the E-field variability will explain antidepressant and cognitive outcomes.
Public Health Significance: Successful completion of this project will verify the optimal ECT dose (the “sweet
spot”) of 112 V/m within the right hippocampus which can then inform precision and individualization of ECT
amplitude with “E-field informed ECT”. The standardized algorithms for E-field modeling can be generalized and
widely disseminated. This proposal will result in a paradigm shift from “trial and error” approaches of ECT
parameter selection to individualized, precision dosing to improve patient outcomes.

Grant Number: 5R01MH128692-04
NIH Institute/Center: NIH
Principal Investigator: Christopher Abbott