A prospective multicentre double-blind randomized controlled trial evaluating clinical, cognitive and neural effects of potentiation of electroconvulsive therapy by repetitive transcranial magnetic stimulation in patients with treatment-resistant depression (STIMAGNECT 2)

Background: Major depressive disorder is a leading cause of disability worldwide, with treatment-resistant depression (TRD) affecting approximately one-third of patients and leading to increased morbidity and healthcare costs. Electroconvulsive therapy (ECT) remains a key treatment for TRD, but its efficacy is limited, and it is associated with cognitive side effects and delayed symptom relief. Repetitive transcranial magnetic stimulation (rTMS) shares action mechanisms with ECT and has shown potential in enhancing ECT efficacy in a previous trial. The STIMAGNECT 2 trial aims to evaluate whether an rTMS add-on protocol can improve ECT outcomes in TRD patients after 10 ECT sessions. Methods: Eighty patients with TRD will be enrolled in a prospective multicentric double-blind randomized controlled trial. All patients will receive a total of 10 ECT sessions. Patients will be randomly assigned to an active or sham rTMS arm. The rTMS protocol (either active of sham) consists of 5 rTMS sessions over 4 days before the beginning of the ECT protocol, with an additional rTMS session the day before each ECT session from the 6 ^th ECT session onward. The main outcome is the response rate following 10 ECT sessions, defined as the proportion of patients achieving a ≥ 50% reduction in their Hamilton Depression Rating Scale (HAMD, 21 items). Secondary outcomes include changes in depression severity (HAMD and QIDS-SR-16) at baseline, during the protocol (Day 4, Day 19, Day 26) and at the end of the protocol, as well as assessment of side effects (adapted UKU), cognitive function (memory, attention, visuospatial abilities, subjective cognitive complaint), autobiographical memory (TEMPau) and ECT session parameters such as seizure characteristics and anesthetic doses. Additionally, potential changes in regional grey matter density, cortical thickness, brain connectivity and GABA levels will be compared between groups using several magnetic resonance imaging (MRI) sequences (3D, resting-state functional MRI, magnetic resonance spectroscopy). Discussion: The aim of this trial is to optimize neurostimulation protocols using the synergistic effects of rTMS and ECT in order to improve the treatment of TRD. Trial registration: ClinicalTrials.gov NCT06391723 Id RCB: 2023-A01813-42/1