Electroconvulsive therapy amplitude titration for improved clinical outcomes in late-life depression

Electroconvulsive therapy (ECT) stimulation parameter selection reflects a balance between efficacy and
cognitive adverse effects. ECT stimulation parameters associated with more antidepressant efficacy (non-focal
electrode placement, longer pulse width) are associated with increased risk of cognitive adverse effects.
Amplitude is currently fixed at 800 or 900 milliamperes (mA) in standard clinical practice with no clinical or
scientific basis. Amplitude determines the intensity of the spatial distribution of the electric field (E-field). With a
fixed extracranial amplitude, the ECT “dose” as represented by the E-field is highly variable due to anatomic
differences in skin, skull, fluid, and brain tissue. This anatomic variability is prominent in older (age 50+)
depressed patients and can compromise both antidepressant efficacy (insufficient stimulation of mood-related
circuitry) and safety (inducing cognitive impairment due to excessive stimulation of cognitive related circuitry).
Amplitude titration, as proposed in this current proposal, can reduce the variability related to fixed amplitude
dosing and optimize clinical and cognitive outcomes. The goal of this project is to change standard ECT
parameter selection from a fixed amplitude to an individualized and empirically determined amplitude. To achieve
this goal, we will focus on the relationship between amplitude titration and treatment-responsive changes in
hippocampal neuroplasticity with RUL fixed amplitude ECT. Fixed amplitude ECT results in variable E-field or
ECT dose. Over the course of an ECT series, the variable ECT dose will result in inconsistent changes in
hippocampal neuroplasticity. In contrast, pre-translational investigations have demonstrated that amplitude
titration results in a consistent E-field or ECT “dose”. Seizure titration amplitudes (based on historic data, 233 to
544 mA) are below the amplitude range of FDA-approved ECT devices (500 to 900 mA) and will require an
adaptor to reduce the output amplitude (Investigational Device Exemption). Amplitude titration will also be below
the hippocampal neuroplasticity threshold and insufficient for antidepressant response. The difference between
RUL amplitude titration and RUL fixed amplitude (800 mA) ECT will determine the degree of target engagement
with the hippocampus. To illustrate, subjects with low amplitude titration of ~250 mA (800/250, high fixed/titration
amplitude ratio) will have significant changes in hippocampal neuroplasticity. Subjects with high amplitude
titration ~500 mA (800/500, low fixed/titration ratio) will have minimal changes in hippocampal neuroplasticity.
The relationship between amplitude titration and fixed amplitude hippocampal neuroplasticity will be used to
develop the amplitude multiplier required for consistent and clinically effective ECT dosing. A randomized
controlled trial will then compare hippocampal neuroplasticity, antidepressant, and cognitive outcomes between
amplitude titration with neuroplasticity multiplier (fixed pulse number) and traditional fixed amplitude ECT
(800 mA, variable pulse number) in older depressed subjects.

Grant Number: 5R33MH125126-05
NIH Institute/Center: NIH
Principal Investigator: Christopher Abbott