ECT Pulse Amplitude and Medial Temporal Lobe Engagement
Phase: PHASE4
Conditions: Major Depressive Disorder
Sponsor: University of New Mexico

Cover Page: ECT Current Amplitude and medial temporal lobe engagement (MH111826) 
 
ClinicalTrials.gov Identifier: NCT02999269 
 
Document Date: November 24, 2021 
 
Study Protocol and Statistical Analysis 
 
 

Study Protocol 
All subjects started the ECT series with right unilateral (d’Elia) electrode placement (28). Subjects were 
randomized and blinded to 600, 700, and 800 mA prior to the first ECT treatment. Subject randomization was 
completed with a random number generator prior to study initiation with a 1:1:1 ratio for each study arm. As 
determined by our preliminary data, 500 mA pulse amplitudes compromised efficacy. Subjects received clinical, 
neuropsychological, and imaging assessments pre- (V1), mid- (after the sixth ECT treatment, V2) and post-
ECT (within one week of finishing the ECT series, V3). If subjects were non-responsive to the assigned pulse 
amplitude (< 25% reduction in from baseline HDRS24 at the second visit), subjects then received bitemporal (BT) 
electrode placement (800 mA, 1.0 milliseconds (ms) pulse width) for the remainder of the ECT series (29). 
 
Subjects received ultrabrief pulse width (0.3 ms) until a planned interim data analysis (n = 47) to ensure 
that the experimental arms were equipoise with the active comparator. The analysis demonstrated a trend 
towards the lower efficacy of the 600 mA arm. We subsequently increased the pulse width from ultrabrief (0.3 ms) 
to brief (1.0 ms) all treatment arms for the remainder of the study (n = 15). The rationale for the increased pulse 
width, as approved by the National Institutes of Health (NIH) and the study Data Safety Monitoring Board 
(DSMB), was to improve the efficacy of the lower amplitude arm. The strength-duration curve established that 
lower pulse amplitudes required longer pulse widths to elicit neuronal activation potential (30, 31). Thus, we 
reasoned that the increased pulse width may improve the neuronal activation potential and the antidepressant 
efficacy of the 600 mA arm. 
 
The first ECT session determined individual seizure thresholds with subsequent treatments provided at 
six times the seizure threshold with similar adjustments to pulse train duration and frequency across all amplitude 
arms (32). Further adjustments to charge were permitted to ensure adequate seizure morphology and duration 
based on clinical judgment. Motor, electroencephalographic, and heart rate parameters were recorded for each 
treatment. The treating anesthesiologist determined the appropriate dose of methohexital, a general anesthetic, 
and succinylcholine, a depolarizing neuromuscular blocker.  
 
Statistical Analyses 
Clinical and demographic variables were assessed with chi-square or one-way analysis of variance. For the 
primary outcomes (change in HDRS24 and HVLT-R retention raw score), we performed a full longitudinal model 
with an unstructured repeated measures covariance matrix on subjects who completed the study in the assigned 
treatment arm. Missing values for the depression and cognitive variables (14% of values) were imputed using 
regression multiple imputation with five iterations (33). We completed imputation for seven subjects that did not 
complete the final post-ECT assessment and for sparse missing cognitive values. When a subject had all their 
values imputed for a variable, then that subject was removed from the analysis of that variable. In addition, we 
performed a separate analysis with subjects receiving bitemporal electrode placement between V2 and V3. For 
depression outcomes, the dependent variable was HDRS at each visit and the independent variables included 
progress (time within the ECT series: pre-, mid-, and post-ECT), amplitude, age, sex, pulse width and the 
following interactions: progress/amplitude, progress/sex, and progress/pulse width. For primary cognitive 
outcomes, the dependent variable was HVLT-R retention scores at each visit with the same model plus the Test 
of Premorbid Functioning Standard Scores as an additional covariate. In addition to our primary cognitive 
outcome, we assessed secondary outcomes for the additional cognitive measures using the same cognitive 
statistical model. Follow-up contrasts included the following: 1) longitudinal changes within each amplitude (e.g., 
HDRS24 differences in 600 mA subjects between V1 and V2); 2) amplitude contrasts during the mid- and post-
ECT assessments (e.g., HDRS24 differences 600 and 700 mA at V2); 3) sex differences; and 4) pulse width 
differences. The amplitude contrasts were averaged for sex and pulse width with Tukey’s method for multiple 
pairwise comparisons.