Confirmatory efficacy and safety trial of magnetic seizure therapy versus right unilateral ultra-brief electroconvulsive therapy in depression (CREST–MST): a randomised, double-blind, non-inferiority trial in Canada and the USA

BACKGROUND: Magnetic seizure therapy (MST) is an innovative convulsive therapy that is clinically beneficial for patients with depression and has fewer cognitive adverse effects. This trial aimed to confirm the efficacy, tolerability, and cognitive safety of MST compared with right unilateral ultra-brief pulse-width (RUL-UB) electroconvulsive therapy (ECT). METHODS: This multisite randomised, double-blind, parallel-group, non-inferiority trial was conducted at three academic centres across Canada and the USA. Participants aged 18 years and older with major depressive disorder (MDD) received treatment until they achieved remission, dropped out, or up to 21 total treatments. MST was delivered using a twin coil in a midline frontal position. Remission of depression on the Hamilton Rating Scale for Depression-24 item and worsening of autobiographical memory on the Autobiographical Memory Test (AMT) were the coprimary outcomes. The non-inferiority margin was 15% absolute difference in remission rates and AMT worsening was defined as 25% reduction, corresponding to one standard deviation reduction in performance. People with lived experience were not directly involved; the study was informed by indirect feedback from previous trials and clinical discussions with people with depression who declined ECT. The trial is registered with ClinicalTrials.gov, NCT03191058. FINDINGS: Between June 26, 2018 and March 1, 2024, 292 participants were enrolled, of whom 239 were randomly assigned and three withdrew before treatment across study sites (RUL-UB ECT: mean age 45·5 years [SD 14·8, range 18-78], 80% White, 65 [55%] female, 54 [45%] male; MST: mean age 44·5 years [SD 13·8, range 18-75], 100 [85%] White, 70 [60%] female, 47 [40%] male). Enrolment concluded before reaching the intended sample size. The difference in remission rates was 5·3% in favour of RUL-UB ECT (27·8%) compared with MST (22·5%), establishing non-inferiority of MST (Z-test p=0·048 [95% CI -4·4 to 14·9]). More RUL-UB ECT participants had worsening autobiographical memory (17·3%) compared with MST participants (2·7%; p=0·0003). 12 participants in the RUL-UB ECT group and three participants in the MST group withdrew from treatment due to non-serious adverse events. INTERPRETATION: MST showed non-inferior efficacy relative to RUL-UB ECT in achieving remission of depression, and a more favourable cognitive safety profile. Collectively, the overall risk-benefit profile of MST supports its consideration as a first-line convulsive therapy in MDD, particularly in those who refuse RUL-UB ECT. FUNDING: National Institutes of Mental Health.