ECT AMPLITUDE AND CLINICAL OUTCOMES

Introduction ECT is recognized for its efficacy in the treatment of depressive disorders, however neurocognitive impairment remains a major concern of treatment. Demographic factors, depression severity, and ECT treatment parameters influence neurocognitive outcomes. Studies examining ECT electrode placement and pulse width find that more focal stimulus delivery with right unilateral placement or ultrabrief pulse width can reduce cognitive side effects, however are associated with less efficacy than standard treatments. Pulse amplitude, which determines the induced electric field strength in the brain, is currently set at 800-900?mA on modern ECT devices without any clinical or scientific rationale. Lower pulse amplitudes also produce more focal electric fields and potentially reduce neurocognitive impairment. Recent small studies have demonstrated that low amplitude ECT can generate seizure induction, may improve depression severity, and result in fewer cognitive side effects. There are not yet prospective randomized studies examining the antidepressant and neurocognitive dose-response relationship relative of ECT pulse amplitude. The present study compares three different pulse amplitudes during an ECT series. We hypothesize that the lower amplitudes will maintain the antidepressant efficacy of the standard treatment and reduce the risk of neurocognitive impairment. Methods The present study (ClinicalTrials.gov identifier NCT0299929) prospectively randomized subjects to three treatment arms: 600mA, 700mA, and 800mA (active comparator). Clinical, neuropsychological, and imaging assessments were conducted pre-, mid- (after the sixth ECT treatment) and post-ECT (within one week of finishing the ECT series). Subjects had a diagnosis of major depressive disorder, met the clinical indication for ECT, were between 50 and 80?years of age, and right-handed. Depression severity was tracked using the Hamilton Depression Rating Scale 24-item (HDRS-24). The neuropsychological battery is focused on detecting longitudinal differences in hippocampal-dependent changes in cognitive performance. Our primary outcome measure was the Hopkins Verbal Learning Test-Revised (HVLT-R) raw retention score. All subjects were treated with right unilateral electrode placements with either ultrabrief pulse width (0.3 ms) or brief pulse widths (1.0ms, used for the last 14 subjects following interim data analysis). Treatments were individually titrated to supra-threshold, with subsequent treatments given at 6x seizure threshold. Results For this analysis, we focused on subjects that completed all three time points with RUL electrode placement. 62 patients were randomized to the three different pulse amplitude groups and completed at least the first and mid- visits. Demographics, including age, sex, duration of depressive episode, number of lifetime episodes, and baseline cognitive status were not significantly different between groups. Initial HDRS-24 scores were similar. The lowest amplitude group (600 mA) in our study showed significantly less antidepressant effect compared to the higher amplitudes (700mA and 800mA). The amplitude groups did not have significant differences in our primary cognitive outcome, the HVLT-R retention score. Several of the secondary cognitive outcomes were more sensitive to detecting cognitive impairment than the Hopkins Verbal Learning Test, revealing that subjects receiving 800?mA demonstrated greater impairment effects compared to the lower amplitude. This was most sensitive in the Delis Kaplan Executive Function System (DKEFS)-Verbal Fluency subset, DKEFS-Color Word Interference, and Dot Counting Test. Conclusions This study used a blinded randomized design to examine dose-dependent effects of pulse amplitude on depression response and neurocognitive measures. Despite seizure induction, treatment with the 600mA pulse amplitude did not achieve clinical efficacy in comparison to higher amplitudes. These findings support the concept that seizure is necessary but not sufficient for treatment response. The primary cognitive outcome, the Hopkins Verbal Learning Test-Revised (HVLT-R) raw retention score, did not show significant difference between amplitudes. However, neurocognitive battery outcomes of verbal fluency, color-word interference, and dot counting showed sensitivity in the secondary analyses. Focal electric field exposure through reduction of pulse amplitude may be beneficial in limiting the effects of some aspects of cognitive impairment. Limitations of our study include attrition and missing data from for some subjects who could not complete the full neurocognitive battery. Further work on understanding ECT treatment parameters can optimize and individualize care for patients undergoing ECT, maximizing benefit and reducing cognitive risk. This research was funded by: BRAIN Initiative U01 MH111826