Comparative efficacy and safety of intravenous racemic ketamine, repetitive transcranial magnetic stimulation and electroconvulsive therapy for Stage 2 or higher treatment-resistant depression: A systematic review and network meta-analysis.

Although electroconvulsive therapy (ECT) is the standard treatment for Stage 2 or higher treatment-resistant depression, it has several drawbacks. Repetitive transcranial magnetic stimulation (rTMS) and intravenous racemic ketamine (IV ketamine) have emerged as potential alternatives, but their comparative effectiveness and safety remain unclear due to limited evidence. We systematically searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and trial registries for randomized controlled trials (RCTs) up to 18 December 2023. Random-effects network meta-analyses were performed to compare the antidepressant efficacy, tolerability, and acceptability of ECT, IV ketamine, and rTMS. Thirty-five RCTs ( = 2109) were included. Most of the included studies had small sample sizes. There were no significant differences in response rate, remission rate, or tolerability of IV ketamine, rTMS, and ECT, while IV ketamine had significantly higher acceptability compared to rTMS and ECT. The confidence in the evidence for efficacy, tolerability, and acceptability was very low. IV ketamine and rTMS did not demonstrate apparent inferiority to ECT in terms of antidepressant efficacy and safety. Considering the various drawbacks of ECT, both treatments may have the potential to serve as viable alternatives. However, the confidence of the evidence in this study is rated as very low, possibly due to small-study bias, highlighting the need for further large-scale studies to strengthen the findings.