Cognitive and Neurophysiological Recovery Following Electroconvulsive Therapy: A Study Protocol

Abstract

Electroconvulsive therapy (ECT) employs the elective induction of generalizes seizures as a potent treatment for severe psychiatric illness. As such, ECT provides an opportunity to rigorously study the recovery of consciousness, reconstitution of cognition, and electroencephalographic (EEG) activity following seizures. Fifteen patients with major depressive disorder refractory to pharmacologic therapy will be enrolled (Clinicaltrials.gov, NCT02761330). Adequate seizure duration will be confirmed following right unilateral ECT under etomidate anesthesia. Patients will then undergo randomization for the order in which they will receive three sequential treatments: etomidate + ECT, ketamine + ECT, and ketamine + sham ECT. Sessions will be repeated in the same sequence for a total of six treatments. Before each session, sensorimotor speed, working memory, and executive function will be assessed through a standardized cognitive test battery. After each treatment, the return of purposeful responsiveness to verbal command will be determined. At this point, serial cognitive assessments will begin using the same standardized test battery. The presence of delirium and changes in depression severity will also be ascertained. Sixty-four channel EEG will be acquired throughout baseline, ictal, and postictal epochs. Mixed-effects models will correlate the trajectories of cognitive recovery, clinical outcomes, and EEG metrics over time. This innovative research design will answer whether: (1) time to return of responsiveness will be prolonged with ketamine + ECT compared with ketamine + sham ECT; (2) time of restoration to baseline function in each cognitive domain will take longer after ketamine + ECT than after ketamine + sham ECT; (3) postictal delirium is associated with delayed restoration of baseline function in all cognitive domains; and (4) the sequence of reconstitution of cognitive domains following the three treatments in this study is similar to that occurring after an isoflurane general anesthetic (NCT01911195). Sub-studies will assess the relationships of cognitive recovery to the EEG preceding, concurrent, and following individual ECT sessions. Overall, this study will lead the development of biomarkers for tailoring the cogno-affective recovery of patients undergoing ECT.

Keywords: anesthesia; consciousness; electroconvulsive therapy; electroencephalography; ketamine; major depressive disorder; neurocognitive disorders; seizures.

Figure 1

Overall study design. Patients are randomized to repeated testing on three different treatment (Tx) interventions: Etomidate + ECT (E + ECT), ketamine + ECT (K + ECT), and ketamine + sham ECT (K + Sham). These interventions occur over a 2-week period following a dose-charge titration session that determines the adequate ECT charge for treatment-resistant depression.

Figure 2

Timelines for dose-charge titration and treatment sessions. (A) Baseline cognitive assessments are acquired before the dose-charge titration session with etomidate general anesthesia. (B) Baseline cognitive assessments are acquired before each treatment session and serially from the return of responsiveness to verbal command (T = 0) and up to 90 min afterwards (T = 90). Continuous high-density EEG is acquired during baseline assessments and treatment sessions.