Comparing the Cognitive Effects of Repeated Intravenous Ketamine and Electroconvulsive Therapy in Patients With Treatment-Resistant Depression: A Secondary Analysis of the ELEKT-D Trial

Kristina T. Kumpf, MA; Samuel T. Wilkinson, MD; Bo Hu, PhD; Ruoying Chen, PhD; Kamini Krishnan, PhD; Shinjon Chakrabarti, BS; Taeho Greg Rhee, PhD; Tiffany Grezmak, MA; Sanjay J. Mathew, MD; Gerard Sanacora, MD, PhD; James W. Murrough, MD, PhD; Fernando S. Goes, MD; Katherine A. Collins, PhD; LCSW; Brian S. Barnett, MD; Amit Anand, MD

J Clin Psychiatry 2025;86(4):25m15781

Abstract

Objective: Electroconvulsive therapy (ECT) has potent antidepressant effects yet can lead to neurocognitive side effects. Ketamine is a rapid-acting antidepressant, which may be an alternative to ECT. Few have directly compared the cognitive effects of ECT and ketamine treatment.

Methods: We compared cognitive effects of intravenous ketamine and ECT in patients with treatment-resistant depression (TRD), collected through a multisite, randomized trial conducted between April 2017 and November 2022 (the ELEKT-D study). Participants received 6 IV ketamine treatments or 9 ECT sessions. Cognitive functioning was assessed through 4 validated cognitive tasks at pre- and posttreatment visits. The Squire Memory Complaint Questionnaire (SMCQ) and Global Self-Evaluation of Memory (GSE-My) were used to measure changes in memory functioning. Responders (those who achieved ≥50% reduction in depressive symptoms) were evaluated again at 1-, 3-, and 6-month follow-up visits.

Results: In the intent-to-treat sample (N = 365), ECT recipients performed significantly worse than ketamine recipients on all cognitive tasks at end of treatment (P < .001), with no significant differences in task performance associated with response to either treatment. Among responders, we observed no significant group differences at 1-, 3-, and 6-month follow-up. Analyses of subjective memory questionnaires were mixed. SMCQ scores improved for both groups with ketamine recipients reporting greater functional gains; ketamine-treated patients reported improvements in GSE-My scores while ECT-treated patients reported a decline in GSE-My scores. Within-group analyses in the ketamine group found improvements in executive functioning and cognitive flexibility. This survived adjustments for changes in depression, suggesting partial independence of cognitive and mood effects.

Conclusions: Patients treated with ketamine demonstrated superior cognitive functioning compared with those treated with ECT following a 3-week treatment course, with no differences between treatments observed among responders in follow-up. Findings support the short-term superiority of ketamine on cognitive functioning and the long-term cognitive safety of both treatments for TRD.

Trial Registration: ClinicalTrials.gov identifier: NCT03113968.

J Clin Psychiatry 2025;86(4):25m15781

Author affiliations are listed at the end of this article.

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