Safety and efficacy of esketamine combined with propofol or ciprofol sedation for electroconvulsive therapy in patients with major depressive disorder: protocol for a randomized, double-blind, controlled trial with factorial design

Yuan Zhang¹De-zhen Su¹Rong Chen¹Zhong-yuan Xia¹Yan-ling Peng²Shen-hong Weng¹Qing-tao Meng^1*

• ¹Renmin Hospital of Wuhan University, Wuhan, China
• ²Qianjiang Central Hospital/Qianjiang Hospital Affiliated to Renmin Hospital of Wuhan University, Qianjiang, China

Introduction: Electroconvulsive therapy (ECT) is one of the main strategies for major depressive disorder (MDD). Recently, esketamine has been highlighted in the treatment of depression due to the rapid antidepressant effects. The present study hypothesizes that: (1) adjunctive esketamine during ECT will produce greater improvement in depressive symptoms compared to placebo; (2) esketamine-ciprofol combination will demonstrate superior antidepressant efficacy and fewer adverse events relative to esketamine-propofol combination.Methods and Analysis: This is a prospective, randomized, double-blind, placebo-controlled, repeated-measures trial with factorial design, planned to be conducted in Renmin hospital of Wuhan university from May 1st, 2024 to May 31st, 2025. A total of 168 cases with MDD undergoing scheduled ECT will be randomized in a ratio of 1:1:1:1 to receive propofol or ciprofol sedation with or without esketamine (0.25 mg/kg) treatment. Primary outcome is the changes from baseline to day 28 in HAMD-24. Secondary outcomes include the rate of response (a 50% or greater reduction in HAMD-24 total scores) and remission (a score of 8 or less in the HAMD-24 total scores), as well as the rate of reduction in the HAMD-24 total scores from baseline, at the end of trial. Besides, the incidence of adverse events and the details of ECT will also be recorded. Standard intention-to-treat (ITT) analyses will be performed after handling missing data via multiple imputation method. The predefined subgroup analysis on primary outcomes will be conducted according to age and sex. The generalized estimating equation (GEE) will be utilized to analyse the outcomes. This study will address two critical questions in ECT practice: whether ECT with adjunctive esketamine achieves clinically superior outcomes to ECT alone and anesthetic choice (ciprofol versus propofol) modulates the antidepressant efficacy of esketamine. The findings from this randomized controlled trial will provide novel evidence to optimize sedation regimens during ECT in patients with MDD, specifically addressing the risk-benefit ratio of adjunctive esketamine administration. Ethics and dissemination: This trial has been approved by the local Institutional Review Board (No. WDRY2024-K018) and conducted following the Declaration of Helsinki. Results of this trial will be publicly disclosed in a peer-reviewed journals. Trial Registration Number: ChiCTR2400083664.