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)

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) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article 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(STIMAGNECT 2) Léa Clabeau, Virginie Moulier, Bastien Kaczmarek, Marine Dalmont, and 28 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7213949/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Jan, 2026 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract 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 Electroconvulsive therapy Repetitive Transcranial Magnetic Stimulation Treatment-resistant Depression Neuromodulation Combined Brain Stimulation Randomized controlled trial Figures Figure 1 Figure 2 Administrative information Title {1}: A prospective multicentre double-blind randomized controlled trial evaluating clinical, cognitive and neural effects of potentiation of ECT by rTMS in patients with treatment-resistant depression (STIMAGNECT 2) Trial registration {2a and 2b}: ClinicalTrials.gov NCT06391723 Id RCB: 2023-A01813-42/1 Protocol version {3}: Protocol version number 2 (22/03/2024) Funding {4}: This study was financed by the Neuromodulation Institute (INM) of GHU Paris Psychiatry and Neuroscience Author details {5a} ¹ Centre Hospitalier du Rouvray, Service Hospitalo-Universitaire de Psychiatrie, Centre d’Excellence Thérapeutique, Sotteville-lès-Rouen, France ; ² INSERM U 1245, University of Rouen, Rouen, France ; ³ Etablissement Public de Santé (EPS) Ville Evrard, Centre de Recherche Clinique, Neuilly-sur-Marne, France ; ⁴ Department of Radiology, Centre Hospitalier Universitaire de Rouen, Rouen, France ; ⁵ Brain Stimulation Lab, Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA ; ⁶ Pôle Hospitalo-Universitaire de Psychiatrie Adulte, Centre Hospitalier Guillaume Régnier, Rennes, France ; ⁷ EPS Ville Evrard, Pôle 93G03, Centre de Recherche Clinique, Neuilly-sur-Marne, France ; ⁸ La Fondation FondaMental, F-94010 Créteil, France ; ⁹ Research and Innovation Unit, Esquirol Hospital, 15 rue du Docteur Marcland, Limoges cedex, 87025, France ; ¹⁰ EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Tropical Neurology, Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, OmegaHealth, Limoges, France ; ¹¹ Université de Bordeaux, 33000 Bordeaux, France ; ¹² Clinique Mirambeau, 64600 Anglet ; ¹³ Inserm UMR-S 1237 PhIND, Presage team, GIP Cyceron, Caen, France ; ¹⁴ Normandie Univ, Université de Caen Normandie (UNICAEN), UFR de Médecine, Caen, France ; ¹⁵ CHU de Caen, Service de Psychiatrie, Caen, France ; ¹⁶ Fédération Hospitalo-Universitaire (FHU) A2M2P- CHU, Caen, France ; ¹⁷ Department of Psychiatry, Service Hospitalo-Universitaire, Groupe Hospitalier Universitaire (GHU) Paris Psychiatrie et Neurosciences, Site Sainte-Anne, Paris, France ; ¹⁸ Institut de Neuromodulation, Groupe Hospitalier Universitaire (GHU) Paris, Psychiatrie et Neurosciences, Centre Hospitalier Sainte-Anne, Pôle Hospitalo-universitaire 15, Université Paris Cité, Paris, France ; ¹⁹ Cognitive Neuroimaging Unit, NeuroSpin Institut national de la santé et de la recherche médicale - Commissariat à l'énergie atomique et aux énergies alternatives (INSERM-CEA), Gif-sur-Yvette, France ; ²⁰ Centre d'Investigation Clinique INSERM 1414, équipe neuropsychiatrie du développement et du comportement, Université de Rennes, Rennes, France ; ²¹ Centre Hospitalier Le Vinatier, Bron, France ; ²² Service de Psychiatrie Adulte et d'Addictologie, CHU d'Angers, Angers, France ; ²³ Université Angers, Faculté de Santé, Angers, France ; ²⁴ Unité de Recherche Clinique Intersectorielle en Psychiatrie, CH Henri Laborit, Poitiers, France ; ²⁵ Université de Poitiers, Poitiers, France ; ²⁶ Centre de Recherches sur la Cognition et l'Apprentissage, CNRS UMR 7295, Université de Poitiers, France ; ²⁷ Service de Psychiatrie de l'Adulte, Centre Expert Dépression Résistante FondaMental, CHU de Grenoble, Hôpital Nord, Grenoble, France ; ²⁸ Service Hospitalo-Universitaire de Psychiatrie et de Psychologie Médicale, CH Henri Laborit, Poitiers, France ; ²⁹ Université Clermont Auvergne, INP, CNRS, Institut Pascal, Clermont-Ferrand, France ; ³⁰ Service de Psychiatrie de l'Adulte et Psychologie Médicale, CHU Clermont-Ferrand, France ; ³¹ UMR 1253 Imaging and Brain, Université de Tours, INSERM, Tours, France ; ³² Université de Nantes, CHU Nantes, UR MIP 4334, Nantes, France ; ³³ Université Grenoble Alpes, Grenoble, France ; ³⁴ INSERM U1216, Grenoble, France ; ³⁵ Département de Psychiatrie, CHU Grenoble Alpes, France ; 36 CHU de Nantes, Addictologie et Psychiatrie de Liaison, Nantes, France ; 37 Nantes Université, CHU Nantes, UR MIP EA 4334, Nantes, France ; 38 Centre Hospitalier Princesse Grace, Unité Neuromodulation, Service de Psychiatrie, Monaco ; 39 Motivation, Brain and Behavior (MBB) Lab, Paris Brain Institute (ICM), Hôpital Pitié-Salpêtrière, Paris, France ; 40 Sorbonne Université, Inserm U1127, CNRS U7225, Paris, France ; 41 Université Paris Cité, Paris, France ; 42 Département de Psychiatrie, SHU, GHU Paris Psychiatrie et Neurosciences, Paris, France ; 43 Département de Biostatistiques, Université de Rouen, CHU Rouen, France ; 44 Faculté de Médecine, Normandie Université, Rouen, France ; 45 Département d’Anesthésie-Réanimation, CHU Rouen, France ; 46 Département de Psychiatrie, CHU de Rouen, France Name and contact information for the trial sponsor {5b}: This study was financed by the Neuromodulation Institute (INM) of GHU Paris Psychiatry and Neuroscience, 1 rue Cabanis, 75014 Paris, France +331 45 65 63 90 Role of sponsor {5c}: Sponsor only has a financial role. It has no authority over analysis, interpretation and writing of the report. Introduction Background and rationale {6a} Major depressive disorder (MDD) is currently the leading cause of morbidity and disability in the world. According to the last 2015 estimates of the World Health Organization (WHO) (1), approximately 332 million people suffer from MDD. In France, the annual prevalence of MDD was estimated in 2010 at 7.5% among individuals aged 15 to 85 years, with a prevalence approximately twice as high in women compared to men, according to the Institut National de Prévention et d'Éducation pour la Santé (INPES, (2)). More than one-third of MDD patients fail to achieve remission despite adequate treatment, and are considered to have treatment resistant depression (TRD) (3). TRD is associated with a greater impairment of quality of life, higher mortality rates and an increased risk of relapse (4). Moreover, TRD leads to additional healthcare costs, with an increased rate of hospitalisation (5). Electroconvulsive Therapy (ECT) is recognized as an effective treatment for TRD, although its efficacy is only partial, as demonstrated in a meta-analysis where 48% of TRD patients achieved remission following an ECT protocol (6). In addition, there is a delay between the beginning of ECT sessions and symptom relief, and ECT is associated with cognitive side effects. The mechanism of action of ECT remain incompletely understood, though multiple biological pathways appear to be involved, including activation of the hypothalamic-pituitary-adrenal (HPA) axis (7,8) , inflammation (9,10), neurotrophic factor modulation (11), and changes in excitatory (glutamatergic) (12) and inhibitory (GABAergic) pathways (13). Structural changes in specific brain regions, such as the hippocampus and amygdala, have also been implicated (14) (15). Repetitive transcranial magnetic stimulation (rTMS) is another neurostimulation technique that offers practical advantages over ECT, being non-invasive, less costly, easier to administer, and not associated with anaesthetic risks. It uses electromagnetic pulses to induce electrical current in the underlying brain area. Repetitive application of the stimulation affects cortical activity (inhibition or excitation) within the target region and its associated network (16). A recent umbrella meta-analysis including 13 meta-analyses about TRD demonstrated the effectiveness of rTMS for depressive symptom reduction (17). rTMS is generally well tolerated, and associated with minimal side effects (18). However, rTMS has shown lower efficacy in comparison with ECT, particularly in MDD with psychotic features (19). rTMS and ECT seem to share action mechanisms (20) (21) and literature suggests they both increase gamma-aminobutyric acid (GABA) levels (22) (23). Literature suggests they both increase the cortical silence period and intra-cortical inhibition (24,25) (26), and we therefore hypothesize that a priming high frequency rTMS protocol aiming at the left dorsolateral prefrontal cortex could help raise GABA levels faster during the ECT protocol compared to using ECT alone. In the initial STIMAGNECT trial (27), we investigated the potentiating effect of five high-frequency active rTMS sessions targeting the left dorsolateral prefrontal cortex (DLPFC) on ECT response, compared to a sham rTMS group, in 52 TRD patients. The response rate was 43.4% (±28.6%) in the active rTMS group versus 25.4% (±17.2%) in the sham rTMS group. Additionally, the active rTMS group reported fewer subjective cognitive side effects, and lower electrical charges were required to induce effective seizures. This preliminary study suggests a potential additive effect of rTMS on ECT efficacy. However, in the open follow-up phase of STIMAGNECT, we observed a possible attenuation of the rTMS effect after 8–12 ECT sessions. We therefore designed STIMAGNECT 2 to evaluate the response to a longer ECT protocol (10 sessions) comparatively between a group receiving an active vs sham rTMS protocol. The rTMS protocol (either active or sham), consists of the same priming protocol, i.e. 5 rTMS sessions prior to the beginning of the ECT protocol, followed by an additional rTMS session the day before each ECT session from the 6 th to the 10 th ECT session. This second series of rTMS aimed to avoid the attenuation of potential effects. To explore the underlying physiological mechanisms, patients will undergo MRI at baseline and after 10 ECT sessions. Imaging will include anatomical sequences, resting-state functional MRI, and magnetic resonance spectroscopy to assess GABA levels in the left DLPFC. Explanation for the choice of comparators {6b} In this trial, the primary intervention under investigation is the rTMS add-on protocol, which will be administered as either active rTMS or sham rTMS. Objectives {7} Our primary objective is to evaluate the effect of adjunctive rTMS in a 10-session ECT protocol on therapeutic response in patients with treatment-resistant depression. The rTMS protocol consists of five sessions administered before the initiation of ECT, followed by one rTMS session the day before each ECT session from the 6th ECT session onward. Additionally, we aim to assess: Patients’ perceived efficacy of the rTMS-ECT combination on depressive symptoms. The impact of rTMS-ECT on brain anatomy, functional brain activity, and cerebral chemistry *. The effect of rTMS-ECT on ECT side effects. The effect of rTMS-ECT on cognition. The influence of rTMS on ECT parameters. *These assessments are optional, as they are not available in all clinical centers. Trial design {8} STIMAGNECT 2 is a prospective, multicenter, double-blind, randomized controlled trial. All participants will follow a 10 sessions ECT protocol. Randomization will be conducted using block randomization with a 1:1 allocation to either the rTMS arm or the sham rTMS arm. Methods: participants, interventions, and outcomes The study protocol follows the SPIRIT recommendations. Study setting {9} This trial will be conducted by the Research Department of the Centre Hospitalier du Rouvray (Sotteville-les-Rouen, France), in collaboration with 12 French clinical centers and one clinical center located in the Principality of Monaco. Eligibility criteria {10} Patients eligible for the study must be adults (≥ 18 years) diagnosed with resistant depression. Inclusion criteria · Age 18 to 70 years · Ongoing diagnosis of major depressive disorder (MDD) as defined by DSM-5 criteria · Depression severity assessed with a Hamilton depression scale (HAMD) ≥ 15 · For unipolar depression: lack of remission of current episode after at least two different antidepressant trials at an adequate dose and duration · For bipolar depression: lack of remission of current episode despite lithium at an adequate level (0,80 mEq/L) combined with lamotrigine (50-200mg per day), or despite full dose quetiapine monotherapy (300-600 mg per day) · No modifications in antidepressant or mood-stabilizing treatment within the last 15 days · No prior exposure to rTMS · Patient affiliated to a social security system · No benzodiazepine or antiepileptic treatment (including lamotrigine) within the last 15 days · Ability to understand both spoken and written French · Written informed consent from the patient and, if applicable, legal guardian consent for patients under guardianship Non-inclusion criteria · Prior ECT for the current depressive episode · Contraindications to ECT or anaesthesia, including: o Intracranial hypertension o Recent myocardial infarction o Severe coronary failure o Thrombotic disease o Severe cardiac or respiratory failure o Recent brain haemorrhage o Expansive brain lesions o Brain aneurysms or vascular abnormalities with a risk of haemorrhage o Aortic aneurysm o Retinal detachment o Pheochromocytoma · Contraindications to rTMS, including: o Presence of any implanted electronic device o Any metallic intracranial foreign body · Contraindications to MRI, including: o Pacemaker, neurosensory stimulator, or implanted defibrillator o Cochlear implants o Cerebral or ocular metallic foreign objects near nervous structures o Metallic prostheses o Ventriculoperitoneal shunt valves o Tattoos containing iron particles o Claustrophobia · Patients with a severe substance use disorder (excluding nicotine or caffeine) as defined by DSM-5 criteria · Pregnant or lactating women and women of child-bearing age without adequate contraception · Contraindications to propofol or neuromuscular blocking agents · Dementia or a history of epilepsy · Presence of a cerebral lesion (post-traumatic, vascular, tumoral) · Ongoing exposure to electrical or magnetic stimulating therapies, including transcutaneous electrical nerve stimulation (TENS) · Severe hearing impairment · Patients under freedom restriction as imposed by an administrative or judiciary decision · Patients participating, or having participated in another interventional clinical trial within 30 days prior to study inclusion Randomization criteria · No change in antidepressant or mood-stabilizing treatment since the last visit Who will take informed consent? {26a} Potential participants will receive comprehensive and detailed information about the study protocol. They will be given a minimum reflection period of 7 days before signing the informed consent form in the presence of the investigators. For patients under legal guardianship, written agreement from their legal guardians must also be obtained. Additional consent provisions for collection and use of participant data and biological specimens {26b} Written information will be given to inform the participant of their right to withdraw their consent regarding the use of their data for research purposes. This trial does not involve the collection or storage of biological specimens. Interventions Patients will be randomized to receive either an active rTMS protocol or a sham rTMS protocol. All patients will receive active ECT. Active rTMS protocol: Patients in the active rTMS arm will first receive 5 sessions of active rTMS, administered over 4 consecutive days. On day 5, they will receive the first ECT session as part of a 10 sessions ECT protocol (administered twice per week). Additional active rTMS sessions will be administered the day before the 6 th , 7 th , 8 th , 9 th and 10 th ECT sessions. Sham rTMS protocol: Patients in the sham rTMS arm will undergo an identical schedule, receiving 5 sessions of sham rTMS, administered over 4 consecutive days. On day 5, they will receive the first ECT session as part of a 10 sessions ECT protocol (administered twice per week). Additional sham rTMS sessions will be administered the day before the 6 th , 7 th , 8 th , 9 th and 10 th ECT sessions. Intervention description {11a} ECT equipment and procedure The ECT devices used in this study will be spECTrum 5000Q (MECTA/Micromed 7015 SW Mc Ewan Rd, Lac Oswego, OR 97035, USA) or the Thymatron System IV (Somatics, LC. 910 Sherwood Drive, Lake Bluff IL 60044, USA). All patients will receive active right unilateral ultra brief pulse stimulation. One electrode will be placed on the right temporal region, and the other will be placed at the vertex. The seizure threshold will be determined using the titration method during the first ECT session (28). The operator will gradually increase the stimulation intensity until an EEG-confirmed seizure is achieved, meeting the following criteria: · Seizure duration on EEG of at least 20 seconds · Generalization of the seizure to both hemispheres Once the epileptic threshold is determined, the first therapeutic stimulation will be administered either on the same session or on the next one. The dose delivered for therapeutic stimulation will be set at 6 times the seizure threshold. As recommended, this dose may be increased if the seizure does not meet the effectiveness criteria. ECT sessions will take place twice a week, with a total of 10 sessions. If, after 5 effective unilateral ECT sessions, the patient’s clinical presentation worsens, with a life-threatening risk for the patient, the clinician is authorized to switch to bitemporal ECT after performing a new titration. Anaesthesia procedure Patient must undergo a pre-anaesthesia assessment within one month prior to starting ECT. A consultation with the anaesthetist will also be conducted before ECT session. Patients must refrain from eating or drinking for 12 hours before each ECT session, except in cases requiring premedication. All administered pharmacological agents will be recorded on the anaesthesia sheet. Infusion therapy will be provided. Vital signs monitoring will include blood pressure, heart rate and oxygen saturation. An emergency medication kit will be available and checked before each session to manage potential cardiovascular effects. Loss of consciousness will be induced with propofol (1 to 2 mg/kg). Muscle relaxation will be achieved using suxamethonium chloride (0.3 to 0.8mg/kg), a short-acting neuromuscular blocker that reduces muscle contraction while ensuring spontaneous breathing recovery within 3 to 5 minutes at this dose. The anaesthetist will adjust doses based on individual patient needs. Oxygen-enriched ventilation will be provided via a mask until spontaneous breathing resumes. Patients will remain under medical supervision in the recovery room for one hour. Resumption of normal eating is expected 1.5 to 2 hours after recovery. Each ECT session will be conducted by a multidisciplinary team, including a psychiatrist who is responsible for administering ECT, an anaesthetist, and a nurse anaesthetist. Active rTMS Each center will be using its own rTMS device and coil, ensuring consistency in CE certification and technical specifications, regardless of the brand differences. Regarding the rTMS device, centers will use the MagPro X100 from MagVenture (Tonica Elektronik A/S, Lucernemarken 15, DK-3520 Farum, Denmark) (n=7), the MagPro R30 from MagVenture (n=4), the PowerMag device from MAG & More (GmbH Machtlfingerstr. 13 81379 Munich, Germany) (n=1) and the DuoMag XT100 from Deymed (Kudrnáčova 533 549 31 Hronov, Czech Republic). (n=1). Regarding the coil, 12 centers will be using the Cool-B65 coil (MagVenture). This figure-eight coil is equipped with a temperature sensor that deactivates the device if the coil temperature exceeds 41°C. One center will be using the PMD70-pCool coil (MAG & More) and 1 center will be using the D70BF-LQC coil (DEYMED). Patients may eat and drink before rTMS sessions. Patients must remove any jewellery, hearing aids, dentures, or other prosthesis, and will be provided earplugs. The procedure will take place in a ventilated room to dissipate heat generated by the device. The resting motor threshold (RMT), defined as the minimal intensity to elicit a motor evoked potential exceeding 50µV in at least 50% of the trials, will be measured in the resting abductor pollicis brevis muscle. The left dorsolateral prefrontal cortex (DLPFC) will be localized using a neuronavigation system and the 3D reconstruction of the cerebral MRI obtained at baseline. The left DLPFC stimulation target was selected based on literature indicating that the frontal region whose activity is the most anticorrelated with the subgenual cingulate cortex activity is optimal for depression treatment (29). A resting-state fMRI study of 1,000 participants identified the Montreal Neurological Institute (MNI) coordinates of this region as x = -41, y = 43, z = 27 (30). The rTMS coil will be positioned accordingly using an anatomical MRI and a neuronavigation system (either Localite, Syneika or Nexstim eXimia, depending on the clinical center). The rTMS parameters were chosen because they were considered effective in the previous study (Stimagnect, Rothärmel et al., 2021). The rTMS parameters are defined as follows: · Frequency: 20Hz · Stimulation intensity: 90% of the resting motor threshold · Train duration: 2 seconds · Intertrain interval: 60 seconds · Number of trains per session: 20 · Total pulses per session: 800 Each patient will receive 10 rTMS sessions in total. The first five sessions will occur over four consecutive days (D1, D2, D3, D4), with at least one hour between multiple sessions on the same day. The remaining five sessions will be administered the day before each electroconvulsive therapy (ECT) session, from the 6th to the 10th ECT session. No specific post-rTMS monitoring is required, as existing literature reports an extremely low incidence of adverse effects (18,31). Sham rTMS The sham rTMS sessions will be administered using the same rTMS devices, except a using sham coil instead of an active one. These sham coils reproduce the auditive artefact of an active rTMS coil while preventing the delivery of magnetic stimulation to the scalp. They therefore do not produce the characteristic sensory effects of active rTMS. A significant challenge in rTMS research is the lack of a perfect placebo alternative, as no sham condition can entirely replicate the sensory and auditory experience of active rTMS while remaining physiologically inactive. In this study, we will use a standard rTMS coil positioned upside down, allowing patients to hear the acoustic effects of stimulation without actual magnetic field transmission to the scalp. We opted not to use scalp electrical stimulation to mimic the tactile sensation of active rTMS, as this could introduce additional confounding factors. The sham rTMS method we opted for was found to lead to acceptable levels of blinding integrity in a 2013 meta-analysis (32). To further ensure effective blinding, only patients with no prior exposure to magnetic stimulation therapies will be included, minimizing the risk of unblinding due to prior familiarity with rTMS sensations. The rTMS operator will be blinded to treatment condition, and the rTMS settings will be pre-programmed by an informed research technician before each session. MRI data acquisition For patients from all participating centers, structural T1-weighted scans will be obtained before and after treatment for rTMS neuronavigation, Voxel-Based Morphometry (VBM) and cortical thickness analyses. For patients included by Centre Hospitalier du Rouvray (Sotteville-les-Rouen, France), MRI scans will be obtained on a 3 Tesla SIGNA Premier scanner (General Electric HealthCare, Waukesha, USA) at CHU Charles Nicolle University Hospital in Rouen, France. Three-dimensional, T1-weighted brain volumes were acquired with the following parameters: 176 contiguous slices, slice thickness= 0.5 mm, field of view= 256 mm, repetition time (TR)= 6.2 ms and echo time (TE)= 2.5 ms. For patients in Rouen and Paris, additional imaging assessments will be conducted at V0 (baseline) and after 10 ECT: · Resting-state functional MRI (fMRI) will be performed to assess functional connectivity. We will record a Bold MRI sequence applied with the following parameters: 40 slices, slice thickness= 3.5 mm, flip angle = 66°, TR= 1200 ms, TE= 27 ms. Patients are instructed to relax, remain still, and keep their eyes closed without falling asleep. · Proton magnetic resonance spectroscopy (¹H-MRS) will be performed with a MEGA-PRESS sequence for GABA detection. The sequence parameters were determined as follows: TR of 2000 ms and TE of 68 ms. The voxel size is set to 20 × 20 × 20 mm³ (8 cm³), positioned manually within the left dorsolateral prefrontal cortex (DLPFC) (figure 1). The acquisition time is 9 minutes and 20 seconds. Imagery data analysis Regarding structural T1-weighted MRI, the assessment of changes in grey matter regional density will be conducted with Whole brain voxel-based morphometry using SPM 25 (Wellcome Department of Cognitive Neurology, London, UK). Potential cortical thickness changes will also be assessed using the FreeSurfer software (https://surfer.nmr.mgh.harvard.edu). Regarding resting-state functional MRI (fMRI), functional connectivity will be assessed using the CONN toolbox (33). Regarding Magnetic resonance spectroscopy (MRS), the GABA levels will be measured using the GANNET software (34). Criteria for discontinuing or modifying allocated interventions {11b} Patients will be withdrawn from the study under the following circumstances: · Withdrawal of patient consent or legal guardian agreement, in which case patient is to be definitively excluded from the study and data will not be included in the analysis · Discontinuation without formal withdrawal of consent, in which case data will be included in the analysis · Investigator’s decision due to clinical deterioration, occurrence of significant adverse effects, necessity to change the background pharmacological treatment, or inability for the patient to follow the established protocol · Death of the patient · Loss to follow-up, defined as failure to establish contact with the patient after three attempts, made at 1-week intervals Strategies to improve adherence to interventions {11c} Throughout the trial, adherence to interventions will be enhanced through frequent visits and scheduled appointments, ensuring regular monitoring and patient engagement. Additionally, study staff will provide reminders and follow-up communications to reinforce compliance and address any concerns or barriers to participation. Relevant concomitant care permitted or prohibited during the trial {11d} Patients will continue their usual medication as prescribed by their psychiatrist or primary care physician. However, the following conditions apply: · Antidepressant and mood-stabilizing treatments must remain at a stable dose starting 15 days before the trial and throughout its duration. Only the lithium dosage (if maintained during the trial) may be adjusted within the 15 days before randomization and during the study period, to ensure a lithium level within the lower limit. · Benzodiazepines and antiepileptic medications (including lamotrigine) should be discontinued at least 15 days before the trial whenever possible. If discontinuation is not feasible, the dosage should be reduced to the lowest possible level and maintained at a constant dose throughout the trial. · During the trial, patients must not receive any other electrical or magnetic stimulation therapies (e.g., transcutaneous electrical nerve stimulation). Provisions for post-trial care {30} After completing the trial, patients will resume their regular follow-up care as prescribed by their treating psychiatrist or primary care physician. Those requiring further ECT will continue treatment until remission. For patients attaining remission, maintenance ECT will be considered. Outcomes {12} Main outcome The primary outcome of the trial 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) score between Visit 1 (Day 1) and Visit 5 (Day 38) (35). Secondary outcomes The secondary outcomes are defined as follow: - The relative change in the Hamilton depression scale (HAMD, 21 items) and Quick Inventory of Depressive Symptomatology (QIDS-SR-16) between V1 (Day 1) and after rTMS (V2 = day 4), after 5 ECT sessions (V3, day 19), after 7 ECT sessions (V4, day 26), after 10 ECT sessions (V5, day 40) (35). - rTMS-adapted UKU side effect scale score (adapted UKU) at V2, V3, V4 and V5 (36). - Squire Subjective Memory Questionnaire (SSMQ) score and the Cognitive Failures Questionnaire (CFQ) score at V2, V3, V4 and V5 (37). - The change in the Mini Mental Status Examination (MMSE) score (38), RL/RI-16 score (39), D2 attention test score (40), Rey Osterrieth complex figures test score (41) at V0 (at baseline) and after 10 ECT sessions (V5, D40). - ECT session parameters: seizure threshold, seizure duration, postictal suppression on the EEG, administered anaesthetic drugs doses at each session. - The change in the gray matter density and cortical thickness, measured in T1-weighted 3D anatomical MRI at baseline and after 10 ECT sessions (V5, D40). - Blinding efficacy: patient assessment of perceived treatment condition (active vs sham rTMS). The facultative secondary outcomes are defined as follows: - The change in the Autobiographical memory performance: TEMPau score at baseline and after 10 ECT sessions (V5, D40) in centers where trained professionals are available (42). - The change in the GABA rate at baseline and after 10 ECT sessions (V5, D40) in centers equipped for these assessments (GABA magnetic resonance spectroscopy) - The change in the brain activity at baseline and after 10 ECT sessions (V5, D40) in centers equipped for these assessments (resting-state fMRI) Participant timeline {13} In addition to the rTMS and ECT sessions, participants will undergo several visits to assess the primary and secondary outcomes and to ensure proper application of the protocol. At the inclusion visit V0 (M-1), the investigator will obtain informed consent from the participant, after addressing any questions about the research protocol, its aims and its potential risks. The participant will be reminded of their rights in relation to the research and given a copy of the consent form. If applicable, guardian agreement will also be obtained. The investigating clinician will check for contraindications to ECT, rTMS or MRI, and ensure that the pre-ECT workup is complete. A cerebral MRI and pregnancy test (if applicable) will be prescribed, along with fMRI and magnetic resonance spectroscopy for participants recruited in Rouen or Paris. A physical exam will be performed and sociodemographic data will be collected. The following assessments will also be conducted: · MINI (Mini International Neuropsychiatric Interview) · HAMD-21 and QIDS-SR-16 · Neuropsychological assessment: MMSE, RL/RI-16, d2 attention test, Rey-Osterrieth complex figures test · TEMPau autobiographical memory questionnaire (if trained professional is available) On randomization day (V1, D1), an investigator will proceed to randomization via the Ennov Clinical software. Treatment allocation will be sent to informed investigators, who must be distinct from the investigators conducting rTMS or outcomes assessments. A physical exam and vital sign assessment will be performed, along with HAMD-21 and QIDS-SR-16. The first rTMS session will take place on V1. Follow-up visits will contain the following assessments: · V2 (D4, post-5 rTMS sessions, pre-ECT): physical examination, vital signs assessment, HAMD-21, QIDS-SR-16, adapted UKU, SSMQ, CFQ · V3 (D19, post-5 ECT sessions): physical examination, vital signs assessment, HAMD-21, QIDS-SR-16 · V4 (D26, post-7 ECT sessions): physical examination, vital signs assessment, HAMD-21, QIDS-SR-16 At the end-of-study visit after 10 ECT sessions (V5, D40), a physical examination and vital sign assessment will be performed, as well as the HAMD-21, QIDS-SR-16, adapted-UKU, SSMQ, CFQ, MMSE, RL/RI-16 test, d2 attention test, Rey-Osterrieth complex figures test, TEMPau (if trained professional is available). Patients will also undergo anatomical MRI, with fMRI and magnetic resonance spectroscopy for those recruited in Paris or Rouen. The experimental design, intervention and assessment schedule are presented in Fig 2 as well as in the following SPIRIT figure. Participant timeline: Schedule of enrollment, interventions, and assessments. Sample size {14} A previous randomized, double-blind, placebo-controlled trial (Rothärmel et al., 2021) including 56 patients with treatment-resistant depression (TRD) demonstrated that the proportion of patients responding to treatment after 5 active/sham priming rTMS sessions and 5 active ECT sessions and was three times higher in the active rTMS arm compared to the sham rTMS arm. For the present study, we assume that after 10 ECT sessions, the response ratio will be 1.5:1 between the active rTMS arm and the sham rTMS arm. Furthermore, by administering rTMS the day before ECT sessions from the 6th to the 10th session, we anticipate that the response rate observed after 5 ECT sessions will be maintained. According to the meta-analysis by Haq et al. (2015), the response rate to ECT in patients with TRD is 58%. Based on our assumed ratio (1.5 × 58%), we estimate a response rate of 87% in the active rTMS arm. With an alpha risk of 0.05 and a statistical power of 0.80, our calculation indicates that 37 patients per group are required. To account for an estimated 10% dropout rate, the sample size is increased to 40 patients per arm, resulting in a total of 80 patients for the study. Recruitment {15} Enrolment will take place in 14 clinical centers (see Table 1) over a period of 26 months, corresponding to an average of approximately 2.5 patients per center per year. Participants will be patients for who ECT is indicated, with treatment-resistant depression being the main indication in the participating centers. After an assessment of the patients file and a psychiatric evaluation, eligible patients will be invited to participate in the study. Prior to enrolment, patients will be fully informed about the STIMAGNECT 2 protocol, including its objectives, potential risks, and expected benefits. Patients may be hospitalized for the initial treatment sessions and later managed on an outpatient basis if their clinical condition allows. During hospitalization, a comprehensive pre-ECT assessment will be performed—including at least an electrocardiogram (ECG), standard blood tests, and a pre-anaesthesia evaluation—to screen for any contraindications to the protocol. Patients meeting the inclusion criteria during this assessment will be enrolled in the study upon providing their consent and after signing an informed consent form. Assignment of interventions: allocation Sequence generation {16a} Patients will be randomly assigned to either the active rTMS or sham rTMS group using a web-based randomization system in a 1:1 ratio, with balanced blocks of undisclosed size to ensure allocation concealment. Stratification by clinical center will be performed to account for potential site-specific variations. The details of the randomization procedure are confidential and securely stored within the Research Department of the Centre Hospitalier du Rouvray. Concealment mechanism {16b} On demand, the informed investigator will obtain the patient number and the arm in which the latter has been assigned on the Ennov Clinical software. Implementation {16c} The allocation sequence was generated by an engineer from the Research Department of the Centre Hospitalier du Rouvray and securely uploaded to the Ennov Clinical software. Participants will be enrolled by investigators at each participating clinical center (Table 1). To ensure blinding, an informed technician (distinct from the technician administering rTMS) will configure the rTMS device according to the patient's assigned group (active or sham rTMS). This setup ensures that the rTMS operator remains blinded to the treatment allocation. Assignment of interventions: blinding Who will be blinded {17a} The following individuals will be blinded to the treatment allocation: · Investigators conducting clinical assessments · Psychologists administering cognitive tests · rTMS technicians performing the stimulation · Patients receiving the treatment · Data analysts, who will remain blinded until the entire analysis is completed Procedure for unblinding if needed {17b} In the event of a major adverse event or if the patient’s safety is compromised, the investigator will be able to access the patient’s allocation via the electronic case report form (eCRF). Data collection and management Plan for assessment and collection of outcomes {18a} Since the mandatory clinical scales used in the study are routinely employed in clinical practice and administered by experienced psychiatrists and psychologists, no additional training was required. For the optional TEMPau scale, specific neuropsychological training is necessary to ensure proper administration and scoring. The validity and reliability of all scales used in the study are detailed in Table 2. Plans to promote participant retention and complete follow-up {18b} To promote participant retention and ensure complete follow-up, patients will receive regular reminders of upcoming visits, and in the event of a missed appointment, they will be promptly contacted to reschedule. Data management {19} All required information specified in the protocol will be accurately recorded on the case report forms (CRFs), with clear explanations provided for any missing data. Data will be collected immediately upon availability and transcribed clearly from these forms into the electronic system. In the case of errors or discrepancies, the investigator or an authorized individual will correct the mistaken data. Since the data are collected through an electronic case report form (eCRF), audit-trail functionality ensures automatic traceability of all amendments and updates, maintaining transparency and accountability. Confidentiality {27} All data collected in the electronic case report form (eCRF) will be anonymized. Each patient will be assigned a unique code name based on their inclusion center and randomization number. Only the patient’s initials and month and year of birth will be recorded. All documentation related to the study (e.g., protocol, consent forms, case report forms, investigator folders) as well as original documents (such as laboratory results, neuroimaging data, consultation reports, clinical examination reports) will be stored securely and treated as confidential material. The investigator will be responsible for data archiving and must comply with applicable legal requirements. The investigator will retain the data and the patient identification list for a minimum of 15 years after the end of the study. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial / future use {33} None of these procedures is planned in the study. Statistical methods Statistical methods for the primary and secondary outcomes {20a} Patient characteristics will be described both overall and by treatment arm (active rTMS or sham rTMS) using the usual parameters: mean, standard deviation, median, interquartile range, and range for quantitative variables as well as frequences for categorical variables. The percentage of responding patients, defined as those showing a 50% or more reduction of the Hamilton depression scale (HAMD-21) score, between the two groups (active vs. sham rTMS) from V1 (at baseline) to V5 (after 10 ECT sessions) will be compared using the chi-square test. This analysis will be completed by a comparison of the relative HAMD-21 score using the Student’s t-test for normally distributed data with equal variance, or using the Mann-Whitney non parametric test if the assumptions of normality and homogeneity of variances are not met. The same strategy will be chosen for the other quantitative secondary outcomes. These analyses might be adjusted for prognostic factors and clinical centers using a regression model. For the qualitative outcomes, the comparison of the two groups will be done with the chi-square test, and if the sample size requires it, on the Fisher exact test. A difference will be considered statistically significant if the p-value is inferior to 0.05 (alpha risk = 5%). Interim analysis {21b} No interim analyses are planned. Methods for additional analysis (e.g. subgroup analyses) {20b} The analysis will be completed by a comparison using the logistic regression model to adjust for centers and possible prognostic characteristics. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} Comparison of the two arms will be based on the intention-to-treat principle. The maximum bias hypothesis will be applied for patients lost to follow-up. Those patients, if in the group with the most favorable evolution, shall be considered as having not responded. On the contrary, those patients, if in the group with the most unfavorable evolution, shall be considered as responding to treatment. The aim is to reduce the gap between both to a minimum. By doing so, a robust conclusion is expected. Two additional sensitivity analyses will be performed: a per-protocol analysis excluding patients lost to follow-up and an imputation analysis using the “last observation carried forward” (LOCF) method to impute missing data. Plans to give access to the full protocol, participant level-data, and statistical code {31c} The datasets analysed during the current study are available from the corresponding author on reasonable request. Oversight and monitoring Composition of the coordinating center and trial steering committee {5d} The research department of the Rouvray Hospital coordinates the trial. The department consists of 5 psychiatrists, 1 clinical research associate, 1 project manager, 1 engineer, and 2 research technicians. Composition of the data monitoring committee, its role, and reporting structure {21a} The clinical research associate appointed by the promoter shall regularly visit the center in which the trial is led: · At trial implementation · During the trial · At the end of the trial The clinical research associate shall ensure that the participants’ fundamental rights and safety are respected, as well as reliability, quality and traceability of the transmitted data. The clinical research associate shall check that the study is led in compliance with the protocol, in good clinical practice, and within the legal regulatory framework. The purpose of the visits is to validate the following: - Patient eligibility: respect of inclusion/exclusion criteria - Compliance with the procedures of information sharing with patients and consent collection - Compliance with the specific procedures of the protocol, trial schedule, and patient follow-up - Data Quality: Data recorded in the case report forms (CRF) are accurate, complete, and consistent - Compliance with the procedures reporting serious adverse event (SAE) - Treatment/Device Management: The handling and traceability of treatments/devices (including pharmacy visits, storage, and accounting) are appropriately managed. At the end of each visit, a standardized monitoring report must be drafted by the clinical research associate. This report is reviewed by the study promoter. Adverse event reporting and harms {22} The investigator is responsible for assessing each adverse event (AE) for its seriousness. All adverse events must be recorded in the AE section of the case report form (CRF). Whenever possible, symptoms should be grouped as a single syndrome or diagnosis. The investigator must document the date of onset, intensity, actions taken, outcome of the event, and their assessment as to whether the event is related to the study procedure. Any event meeting one or more criteria of seriousness must be reported as serious adverse events. In case of a serious adverse event, the investigator should immediately (within 1 working day) do the following: - Send the complete SAE form to the sponsor by fax: Ms. Graziella Guesdon, Centre Hospitalier du Rouvray, Fax : +33 02 32 95 18 56. All SAE forms should be dated and signed by the investigator. - Specify the SAE diagnosis, describe the event, and detail any actions taken. If the diagnosis is unknown at the time of the report or later changes, a detailed written follow-up should be sent to inform the sponsor of the final diagnosis. - Attach copies of all examinations carried out along with the dates on which these examinations were performed. Care should be taken to ensure that the patient’s identity is protected, and that trial identifiers are properly mentioned on any copy of the source document. For laboratory results, it must include relevant negative results and the laboratory’s normal ranges. - Joint report of hospitalization related to SAE, if applicable - Assess the causality between the study procedures and the SAE - Ensure that relevant information is communicated to the sponsor as it becomes available - Monitor the patient until the SAE resolves, stabilizes, or the patient returns to their pre-event state, even if the patient has left the trial, and update the sponsor on the SAE evolution. Frequency and plans for auditing trial conduct {23} Audits may be conducted at any time by individuals appointed by the promoter, the Centre Hospitalier du Rouvray. Auditors are independent of the research team. The objective is to ensure the quality of the research, the validity of its results, and the respect of the law. The investigators agree to adhere to the requirements set by the promoter and the Competent Authority regarding audits or inspections at any stage of the study. Plans for communicating important protocol amendments to relevant parties (eg : trial participants, ethical committees) {25} Any modification to the protocol should be approved by the Independent Ethics Committee (art. L1123-6 of French Public Health Code) that authorized the start of the trial. Approved modification are also communicated to the ANSM (French Competent Authority) as per art L 1123-8 of the French Public Health Code. Once modifications are accepted, the new version of the protocol is sent to all the investigative centers, and modifications are applied. Updates will also be made on ClinicalTrials.gov. Dissemination plans {31a} Analysis of the results will be presented in conferences and scientific publications. Publication texts and communications will be discussed with all the participating investigators. The order of the co-authors considers the participation of different investigators to the trial. Discussion The STIMAGNECT 2 trial aims to build upon previous findings that suggest an additive effect of repetitive transcranial magnetic stimulation (rTMS) on electroconvulsive therapy (ECT) efficacy in treatment-resistant depression (TRD). Given the limited response rates to ECT alone, particularly in individuals with chronic and severe depression, this study seeks to confirm the effect of add-on rTMS on clinical outcome and determine whether a prolonged rTMS protocol can help maintain this effect after 5 ECT sessions. Additionally, the use of multimodal neuroimaging techniques, assessment of grey matter regional density, cortical thickness, brain connectivity, and measure of gamma-aminobutyric acid (GABA) levels, provides insights into the neural changes induced by the rTMS-ECT combination. In designing STIMAGNECT 2, several key modifications were made compared to the original STIMAGNECT study. These adjustments were implemented to address limitations identified in the first study and to improve the robustness and applicability of the findings. In the original STIMAGNECT study, the efficacy of rTMS and ECT combination was assessed after the first five ECT sessions. In STIMAGNECT 2, we increased the length of the efficacy assessment ECT to 10 ECT sessions, to study the effects of this combination over a longer duration. Additionally, based on findings from the initial STIMAGNECT study indicating a decrease in the priming effect of rTMS on ECT efficacy over time, we introduced additional rTMS sessions on the day prior to the ECT sessions from the sixth ECT session onward. This modification aims to sustain the priming effect throughout the full duration of the ECT protocol. Another change in STIMAGNECT 2 was an increase in sample size to enhance statistical power and improve the generalizability of the results. The first STIMAGNECT study had a relatively small cohort, which limited the ability to detect subtle effects. By increasing the sample size, STIMAGNECT 2 aimed to produce more reliable and reproducible findings. In the initial STIMAGNECT study, ECT electrode placement was bitemporal. Our results suggested that priming ECT with rTMS could lower the seizure threshold, as the required ECT dosage was found to be twice as low in the active rTMS group compared to the sham group ( 27 ). This finding is supported by Buday et al (2020)’s study, which reported a 34.55% average reduction in seizure threshold following rTMS priming ( 43 ). However, the first STIMAGNECT protocol did not demonstrate improved cognitive tolerance of bitemporal ECT with the rTMS add-on. Literature indicates that unilateral ultra brief pulse ECT has a lesser impact on retrograde autobiographical memory and cognitive function in general ( 44 , 45 ). Unilateral ECT shows better efficacy at a high dosage relative to seizure threshold ( 46 , 47 ), making seizure threshold reduction particularly relevant, as it may allow for a lower overall ECT dose, and potentially reduce cognitive side effects ( 47 – 49 ). Therefore, in STIMAGNECT 2, we opted for high-intensity ultra-brief pulse unilateral ECT, in the hope of lowering the seizure threshold through rTMS, thereby reducing the electrical charge required to achieve effective ECT and potentially reducing cognitive side effects. Regarding rTMS, in the initial STIMAGNECT study, the target was defined as the middle part of the middle frontal gyrus, at the intersection of Brodmann areas 9 and 46, guided by neuronavigation, in accordance with previous literature ( 50 ). More recent studies have explored the use of fMRI to optimize rTMS targeting for depression, and suggest that the antidepressant efficacy of the different left DLPFC rTMS targets is associated with their functional anticorrelation to the subgenual cingulate cortex (SGC) ( 29 , 51 ). Although it would have been ideal to personalize the rTMS target for each patient using resting-state fMRI, this technique is not yet widely available in clinical practice and was not accessible in most of our participating centers. We therefore opted to use the standardized MNI coordinates described in Cash’s 2020 study ( 30 ), which reflect the average location of maximal anticorrelation with the SGC across a sample of 1,000 participants. A major methodological challenge was the choice of the comparator. No sham condition can entirely replicate the sensory and auditory experience of active rTMS while remaining physiologically inactive. We chose not to use scalp electrical stimulation in the sham group to mimic the tactile sensation of active rTMS and therefore excluded from the trial patients with prior experience of magnetic stimulation therapies. To assess the success of blinding, STIMAGNECT 2 includes an evaluation of patients' ability to discern their treatment group, allowing for a better interpretation of the study results. One of the key strengths of our study is therefore its rigorous design, including a multicenter, double-blind, randomized controlled methodology. Perspectives The results of this trial are expected to bring answers about rTMS and ECT combination in treatment resistant depression. If rTMS proves to enhance ECT efficacy, accelerate symptom relief, and reduce cognitive side effects, it could improve the acceptability and feasibility of ECT as a treatment option. Future research should explore the long-term effects of the rTMS-ECT combination beyond the acute treatment phase, to assess the durability of response and potential relapse rates. Additionally, investigating alternative rTMS protocols, including different stimulation frequencies and coil configurations, may further optimize efficacy and tolerability. Conclusion The STIMAGNECT 2 trial will investigate the effect of rTMS as an adjunct to an ECT protocol in treatment resistant depression. Depressive symptoms intensity will be compared after 10 ECT sessions between the active and sham rTMS groups. By investigating the synergistic effects of rTMS and ECT, this study will provide new insight into TRD treatment, potentially paving the way for new neurostimulation strategies that optimize both efficacy and tolerability, ultimately improving the quality of life for individuals suffering from TRD. Trial status This is the 2.0 of the protocol dated march the 22nd, 2024. Recruitment is set to start on September 15th 2025, for a duration of 26 months (until November 2027). Abbreviations ANSM Agence Nationale de Sécurité du Médicament et des Produits de Santé (French National Agency for Medicines and Health Products Safety) CFQ Cognitive Failures Questionnaire DSM-V Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ECT Electroconvulsive Therapy eCRF Electronic Case Report Form GABA Gamma-Aminobutyric Acid GHU Groupement Hospitalier Universitaire HAMD Hamilton Depression Rating Scale HPA Hypothalamic-Pituitary-Adrenal ICC Intra-class Correlation Coefficient INM Neuromodulation Institute INPES Institut National de Prévention et d'Éducation pour la Santé LOCF Last Observation Carried Forward MDD Major Depressive Disorder MINI Mini International Neuropsychiatric Interview MNI Montreal Neurological Institute MRI Magnetic Resonance Imaging QIDS-SR-16 Quick Inventory of Depressive Symptomatology RL/RI-16 Rey-Lesniak/Raymond-Izard 16-item test rTMS Repetitive Transcranial Magnetic Stimulation SAE Serious Adverse Event SGC Subgenual Cingulate Cortex SPIRIT Standard Protocol Items:Recommendations for Interventional Trials SSMQ Squire Subjective Memory Questionnaire TEMPau Test of Memory and Learning TRD Treatment-Resistant Depression UKU Udvalg for Kliniske Undersøgelser (Committee for Clinical Investigations) Declarations Acknowledgements We would like to thank Graziella Guesdon, Amel Zettili, Frédérique Caillot, Sébastien Normant for their assistance in this project. Author’s contributions {31b} Maud Rothärmel, Virginie Moulier, Olivier Guillin, Pierre Quesada have developed the clinical trial methodology, Bastien Kaczmarek, Emmanuel Gérardin and Virginie Moulier have developed the neuroimaging methodology. Virginie Moulier and Léa Clabeau were major contributors in writing the manuscript. All authors read and approved the final manuscript. Funding {4} This study was financed by the Neuromodulation Institute (INM) of GHU Paris Psychiatry and Neuroscience. Sponsor only has a financial role. It has no authority over analysis, interpretation and writing of the report. Availability of data and materials {29} Any data required to support the protocol can be supplied on request Declarations Ethics approval and consent to participate {24} This study will be conducted in accordance with legal and regulatory requirements, as well as the general principles set forth in the International Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences, 2002), Guidelines for Good Clinical Practice (International Conference on Harmonization, 1996), and the Declaration of Helsinki (World Medical Association 1996 and 2008). In addition, the study will be conducted in accordance with the protocol, the International Conference on Harmonization Guideline on Good Clinical Practice, and applicable local regulatory requirements and laws (law n°2004-806, august 9 th 2004). This protocol obtained a favorable opinion of the Independent Ethics Committee (art. L1123-6 of French Public Health Code), and the National Agency for the Safety of Medicines and Health Products (ANSM) was informed. All participants in the study will sign an informed consent form. Agreement of their legal guardian for patients under guardianship will be asked. The promotor of this research, the Centre Hospitalier du Rouvray, 4 rue Paul Eluard, 76300 Sotteville-lès-Rouen, France, has purchased civil liability insurance from the Société Hospitalière d’Assurance Mutuelle. Consent for publication {32} Not applicable Competing interests {28} The authors declare that they have no competing interests. Author details ¹ Centre Hospitalier du Rouvray, Service Hospitalo-Universitaire de Psychiatrie, Centre d’Excellence Thérapeutique, Sotteville-lès-Rouen, France ; ² INSERM U 1245, University of Rouen, Rouen, France ; ³ Etablissement Public de Santé (EPS) Ville Evrard, Centre de Recherche Clinique, Neuilly-sur-Marne, France ; ⁴ Department of Radiology, Centre Hospitalier Universitaire de Rouen, Rouen, France ; ⁵ Brain Stimulation Lab, Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA ; ⁶ Pôle Hospitalo-Universitaire de Psychiatrie Adulte, Centre Hospitalier Guillaume Régnier, Rennes, France ; ⁷ EPS Ville Evrard, Pôle 93G03, Centre de Recherche Clinique, Neuilly-sur-Marne, France ; ⁸ La Fondation FondaMental, F-94010 Créteil, France ; ⁹ Research and Innovation Unit, Esquirol Hospital, 15 rue du Docteur Marcland, Limoges cedex, 87025, France ; ¹⁰ EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Tropical Neurology, Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, OmegaHealth, Limoges, France ; ¹¹ Université de Bordeaux, 33000 Bordeaux, France ; ¹² Clinique Mirambeau, 64600 Anglet ; ¹³ Inserm UMR-S 1237 PhIND, Presage team, GIP Cyceron, Caen, France ; ¹⁴ Normandie Univ, Université de Caen Normandie (UNICAEN), UFR de Médecine, Caen, France ; ¹⁵ CHU de Caen, Service de Psychiatrie, Caen, France ; ¹⁶ Fédération Hospitalo-Universitaire (FHU) A2M2P- CHU, Caen, France ; ¹⁷ Department of Psychiatry, Service Hospitalo-Universitaire, Groupe Hospitalier Universitaire (GHU) Paris Psychiatrie et Neurosciences, Site Sainte-Anne, Paris, France ; ¹⁸ Institut de Neuromodulation, Groupe Hospitalier Universitaire (GHU) Paris, Psychiatrie et Neurosciences, Centre Hospitalier Sainte-Anne, Pôle Hospitalo-universitaire 15, Université Paris Cité, Paris, France ; ¹⁹ Cognitive Neuroimaging Unit, NeuroSpin Institut national de la santé et de la recherche médicale - Commissariat à l'énergie atomique et aux énergies alternatives (INSERM-CEA), Gif-sur-Yvette, France ; ²⁰ Centre d'Investigation Clinique INSERM 1414, équipe neuropsychiatrie du développement et du comportement, Université de Rennes, Rennes, France ; ²¹ Centre Hospitalier Le Vinatier, Bron, France ; ²² Service de Psychiatrie Adulte et d'Addictologie, CHU d'Angers, Angers, France ; ²³ Université Angers, Faculté de Santé, Angers, France ; ²⁴ Unité de Recherche Clinique Intersectorielle en Psychiatrie, CH Henri Laborit, Poitiers, France ; ²⁵ Université de Poitiers, Poitiers, France ; ²⁶ Centre de Recherches sur la Cognition et l'Apprentissage, CNRS UMR 7295, Université de Poitiers, France ; ²⁷ Service de Psychiatrie de l'Adulte, Centre Expert Dépression Résistante FondaMental, CHU de Grenoble, Hôpital Nord, Grenoble, France ; ²⁸ Service Hospitalo-Universitaire de Psychiatrie et de Psychologie Médicale, CH Henri Laborit, Poitiers, France ; ²⁹ Université Clermont Auvergne, INP, CNRS, Institut Pascal, Clermont-Ferrand, France ; ³⁰ Service de Psychiatrie de l'Adulte et Psychologie Médicale, CHU Clermont-Ferrand, France ; ³¹ UMR 1253 Imaging and Brain, Université de Tours, INSERM, Tours, France ; ³² Université de Nantes, CHU Nantes, UR MIP 4334, Nantes, France ; ³³ Université Grenoble Alpes, Grenoble, France ; ³⁴ INSERM U1216, Grenoble, France ; ³⁵ Département de Psychiatrie, CHU Grenoble Alpes, France ; 36 CHU de Nantes, Addictologie et Psychiatrie de Liaison, Nantes, France ; 37 Nantes Université, CHU Nantes, UR MIP EA 4334, Nantes, France ; 38 Centre Hospitalier Princesse Grace, Unité Neuromodulation, Service de Psychiatrie, Monaco ; 39 Motivation, Brain and Behavior (MBB) Lab, Paris Brain Institute (ICM), Hôpital Pitié-Salpêtrière, Paris, France ; 40 Sorbonne Université, Inserm U1127, CNRS U7225, Paris, France ; 41 Université Paris Cité, Paris, France ; 42 Département de Psychiatrie, SHU, GHU Paris Psychiatrie et Neurosciences, Paris, France ; 43 Département de Biostatistiques, Université de Rouen, CHU Rouen, France ; 44 Faculté de Médecine, Normandie Université, Rouen, France ; 45 Département d’Anesthésie-Réanimation, CHU Rouen, France ; 46 Département de Psychiatrie, CHU de Rouen, France References Organization WH. 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Tables Table 1 : List of the centers and investigators Investigators Center/department Dr Maud Rothärmel Centre Hospitalier du Rouvray, Sotteville-lès-Rouen Pr Fabien Vinckier / Pr Philippe Domenech Centre Hospitalier Sainte Anne, Paris Dr Christophe Daudet Clinique Mirambeau, Anglet Pr Dominique Drapier / Dr Jean-Marie Batail Centre Hospitalier Guillaume Régnier, Rennes Pr Anne Sauvaget / Dr Andrew Laurin Nantes University Hospital, Nantes Pr Nemat Jaafari / Dr Ghina Harika-Germaneau Centre Hospitalier Henri Laborit, Poitiers Pr Dominique Januel / Dr Noomane Bouaziz EPS Ville Evrard, Neuilly-sur-Marne Pr Sonia Dollfus / Dr Florian Letourneur Centre Esquirol, Caen University Hospital, Caen Pr Isabelle Jalenques / Pr Ludovic Samalin Clermont Ferrand University Hospital, Clermont Ferrand Dr Benjamin Calvet Centre Hospitalier Esquirol, Limoges Pr Bénédicte Gohier / Dr François Kazour Angers University Hospital, Angers Dr Jérôme Holtzmann / Dr Arnaud Pouchon Grenoble University Hospital, Grenoble Dr Filipe Galvao / Dr Jerome Brunelin Centre Hospitalier Vinatier, Bron Dr David Szekely Centre Hospitalier Princesse Grasse, Principality of Monaco Table 2 : Validity and reliability of the main and secondary outcomes Validity Test-retest reliability and/or sensitivity to change Inter-rater reliability Main Outcome Hamilton Depression Rating Scale 21 items (35) Good internal consistency with a pooled mean alpha coefficient = 0.78 (52) High test-retest reliability, with pooled mean reliability figures = 0.93 (52) Pooled mean intraclass correlation coefficient (ICC) for interrater reliability = 0.94 (52) Secondary Outcomes Quick Inventory of Depressive Symptomatology (QIDS-RS) (53) Good concurrent validity, with moderate to high correlations (0.68–0.96) with established depression scales such as the HRSD, MADRS, PHQ-9, BDI-II, and Carroll Rating Scale (53) (54) - - rTMS side effects scale (adapted U.K.U) (36) ICC = 0.49–0.92 for the original U.K.U scale (55) - - Squire Subjective Memory Questionnaire (SSMQ) (37) Good construct validity, correlates significantly with the Rey Auditory Verbal Learning Test (56) (r = 0.31) and Cognitive Failures Questionnaire in the expected directions. (57) High test-retest reliability, with Pearson correlation coefficients = 0.87 (3-month interval) and 0.90 (6-week interval) in separate samples. (57) - Cognitive Failures Questionnaire (CFQ) (58) Cronbach’s alpha = 0.94 (59) - - Mini-Mental State Examination (MMSE) (38) Convergent validity: r = 0.7 to 0.9 with other cognitive screening tests (60) Test-retest reliability coefficients = 0.80 to 0.95 (60) High inter-rater reliability (mean kappa value = 0.97) (61) RL/RI-16 Test (39) Sensitive enough to differentiate patients with Alzheimer’s disease from those with mild cognitive impairment (62), vascular dementia (63) and fronto-temporal dementia (64) Use of a parallel form which performances are not different from the basic list except for free recall 2 and delayed free recall (parallel form > basic list) - d2 attention test (40) Internal consistency: Cronbach’s alpha = 0.97 for total score (65) The ICCs for the seven subscores of the d2 between successive sessions were between 0.78 and 0.94 (66) - Rey-Osterrieth complex figures test (41) - Test-retest reliability coefficients = 0.60 to 0.76 (67) Inter-rater reliability for direct copying scores was r = 0.96 (p < 0.0001) (68) TEMPau (42) Effectively differentiates between autobiographical memories of different life periods, assessing both semantic and episodic aspects of memory using standardized scoring criteria (69) Structured 4-point rating system ICC = Intra-class correlation coefficient Cite Share Download PDF Status: Published Journal Publication published 26 Jan, 2026 Read the published version in Trials → Version 1 posted Reviewers agreed at journal 17 Sep, 2025 Reviewers invited by journal 02 Sep, 2025 Editor assigned by journal 02 Sep, 2025 First submitted to journal 01 Sep, 2025 Editorial decision: Major revision 21 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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11:42:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7213949/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7213949/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-025-09406-4","type":"published","date":"2026-01-26T15:58:16+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":90904534,"identity":"07bb5d57-f495-4d8d-bcf8-eb79de613a16","added_by":"auto","created_at":"2025-09-09 12:55:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":141791,"visible":true,"origin":"","legend":"\u003cp\u003eAxial, sagittal, and coronal sections showing the GABA analysis region in proton magnetic resonance spectroscopy (H-MRS).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7213949/v1/f7ad314cd27102e82a28ef66.png"},{"id":90903177,"identity":"85d9a324-201b-497c-9fa8-fc9a59105acb","added_by":"auto","created_at":"2025-09-09 12:47:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":75010,"visible":true,"origin":"","legend":"\u003cp\u003eChart of the study protocol\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7213949/v1/2ddcc196e1c3bdc399579356.png"},{"id":101690438,"identity":"7cda1405-560a-49f1-8814-e6e5616947ae","added_by":"auto","created_at":"2026-02-02 16:02:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1286918,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7213949/v1/8fbad4a3-bd7a-4656-bdc5-dd63d15e4634.pdf"}],"financialInterests":"","formattedTitle":"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)","fulltext":[{"header":"Administrative information","content":"\u003cp\u003e\u003cstrong\u003eTitle {1}:\u0026nbsp;\u003c/strong\u003eA prospective multicentre double-blind randomized controlled trial evaluating clinical, cognitive and neural effects of potentiation of ECT by rTMS in patients with treatment-resistant depression (STIMAGNECT 2)\u003c/p\u003e\n\u003cp\u003eTrial registration {2a and 2b}: ClinicalTrials.gov NCT06391723 Id RCB: 2023-A01813-42/1\u003c/p\u003e\n\u003cp\u003eProtocol version {3}: Protocol version number 2 (22/03/2024)\u003c/p\u003e\n\u003cp\u003eFunding {4}: This study was financed by the Neuromodulation Institute (INM) of GHU Paris Psychiatry and Neuroscience\u003c/p\u003e\n\u003cp\u003eAuthor details {5a}\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e¹ Centre Hospitalier du Rouvray, Service Hospitalo-Universitaire de Psychiatrie, Centre d’Excellence Thérapeutique, Sotteville-lès-Rouen, France ; ² INSERM U 1245, University of Rouen, Rouen, France ; ³ Etablissement Public de Santé (EPS) Ville Evrard, Centre de Recherche Clinique, Neuilly-sur-Marne, France ; ⁴ Department of Radiology, Centre Hospitalier Universitaire de Rouen, Rouen, France ; ⁵ Brain Stimulation Lab, Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA ; ⁶ Pôle Hospitalo-Universitaire de Psychiatrie Adulte, Centre Hospitalier Guillaume Régnier, Rennes, France ; ⁷ EPS Ville Evrard, Pôle 93G03, Centre de Recherche Clinique, Neuilly-sur-Marne, France ; ⁸ La Fondation FondaMental, F-94010 Créteil, France ; ⁹ Research and Innovation Unit, Esquirol Hospital, 15 rue du Docteur Marcland, Limoges cedex, 87025, France ; ¹⁰ EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Tropical Neurology, Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, OmegaHealth, Limoges, France ; ¹¹ Université de Bordeaux, 33000 Bordeaux, France ; ¹² Clinique Mirambeau, 64600 Anglet ; ¹³ Inserm UMR-S 1237 PhIND, Presage team, GIP Cyceron, Caen, France ; ¹⁴ Normandie Univ, Université de Caen Normandie (UNICAEN), UFR de Médecine, Caen, France ; ¹⁵ CHU de Caen, Service de Psychiatrie, Caen, France ; ¹⁶ Fédération Hospitalo-Universitaire (FHU) A2M2P- CHU, Caen, France ; ¹⁷ Department of Psychiatry, Service Hospitalo-Universitaire, Groupe Hospitalier Universitaire (GHU) Paris Psychiatrie et Neurosciences, Site Sainte-Anne, Paris, France ; ¹⁸ Institut de Neuromodulation, Groupe Hospitalier Universitaire (GHU) Paris, Psychiatrie et Neurosciences, Centre Hospitalier Sainte-Anne, Pôle Hospitalo-universitaire 15, Université Paris Cité, Paris, France ; ¹⁹ Cognitive Neuroimaging Unit, NeuroSpin Institut national de la santé et de la recherche médicale - Commissariat à l'énergie atomique et aux énergies alternatives (INSERM-CEA), Gif-sur-Yvette, France ; ²⁰ Centre d'Investigation Clinique INSERM 1414, équipe neuropsychiatrie du développement et du comportement, Université de Rennes, Rennes, France ; ²¹ Centre Hospitalier Le Vinatier, Bron, France ; ²² Service de Psychiatrie Adulte et d'Addictologie, CHU d'Angers, Angers, France ; ²³ Université Angers, Faculté de Santé, Angers, France ; ²⁴ Unité de Recherche Clinique Intersectorielle en Psychiatrie, CH Henri Laborit, Poitiers, France ; ²⁵ Université de Poitiers, Poitiers, France ; ²⁶ Centre de Recherches sur la Cognition et l'Apprentissage, CNRS UMR 7295, Université de Poitiers, France ; ²⁷ Service de Psychiatrie de l'Adulte, Centre Expert Dépression Résistante FondaMental, CHU de Grenoble, Hôpital Nord, Grenoble, France ; ²⁸ Service Hospitalo-Universitaire de Psychiatrie et de Psychologie Médicale, CH Henri Laborit, Poitiers, France ; ²⁹ Université Clermont Auvergne, INP, CNRS, Institut Pascal, Clermont-Ferrand, France ; ³⁰ Service de Psychiatrie de l'Adulte et Psychologie Médicale, CHU Clermont-Ferrand, France ; ³¹ UMR 1253 Imaging and Brain, Université de Tours, INSERM, Tours, France ; ³² Université de Nantes, CHU Nantes, UR MIP 4334, Nantes, France ; ³³ Université Grenoble Alpes, Grenoble, France ; ³⁴ INSERM U1216, Grenoble, France ; ³⁵ Département de Psychiatrie, CHU Grenoble Alpes, France ; \u003csup\u003e36\u003c/sup\u003e CHU de Nantes, Addictologie et Psychiatrie de Liaison, Nantes, France ; \u003csup\u003e37\u003c/sup\u003e Nantes Université, CHU Nantes, UR MIP EA 4334, Nantes, France ; \u003csup\u003e38\u003c/sup\u003e Centre Hospitalier Princesse Grace, Unité Neuromodulation, Service de Psychiatrie, Monaco ; \u003csup\u003e39\u003c/sup\u003e Motivation, Brain and Behavior (MBB) Lab, Paris Brain Institute (ICM), Hôpital Pitié-Salpêtrière, Paris, France ; \u003csup\u003e40\u003c/sup\u003e Sorbonne Université, Inserm U1127, CNRS U7225, Paris, France ; \u003csup\u003e41\u003c/sup\u003e Université Paris Cité, Paris, France ; \u003csup\u003e42\u003c/sup\u003e Département de Psychiatrie, SHU, GHU Paris Psychiatrie et Neurosciences, Paris, France ; \u003csup\u003e43\u003c/sup\u003e Département de Biostatistiques, Université de Rouen, CHU Rouen, France ; \u003csup\u003e44\u003c/sup\u003e Faculté de Médecine, Normandie Université, Rouen, France ; \u003csup\u003e45\u003c/sup\u003e Département d’Anesthésie-Réanimation, CHU Rouen, France ; \u003csup\u003e46\u003c/sup\u003e Département de Psychiatrie, CHU de Rouen, France\u003c/p\u003e\n\u003cp\u003eName and contact information for the trial sponsor {5b}: This study was financed by the Neuromodulation Institute (INM) of GHU Paris Psychiatry and Neuroscience, 1 rue Cabanis, 75014 Paris, France +331 45 65 63 90\u003c/p\u003e\n\u003cp\u003eRole of sponsor {5c}: Sponsor only has a financial role. It has no authority over analysis, interpretation and writing of the report.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eBackground and rationale {6a}\u003c/p\u003e\n\u003cp\u003eMajor depressive disorder (MDD) is currently the leading cause of morbidity and disability in the world. According to the last 2015 estimates of the World Health Organization (WHO)\u0026nbsp;(1), approximately 332 million people suffer from MDD. In France, the annual prevalence of MDD was estimated in 2010 at 7.5% among individuals aged 15 to 85 years, with a prevalence approximately twice as high in women compared to men, according to the Institut National de Prévention et d'Éducation pour la Santé (INPES,\u0026nbsp;(2)). More than one-third of MDD patients fail to achieve remission despite adequate treatment, and are considered to have treatment resistant depression (TRD)\u0026nbsp;(3). TRD is associated with a greater impairment of quality of life, higher mortality rates and an increased risk of relapse\u0026nbsp;(4). Moreover, TRD leads to additional healthcare costs, with an increased rate of hospitalisation\u0026nbsp;(5).\u003c/p\u003e\n\u003cp\u003eElectroconvulsive Therapy (ECT) is recognized as an effective treatment for TRD, although its efficacy is only partial, as demonstrated in a meta-analysis where 48% of TRD patients achieved remission following an ECT protocol\u0026nbsp;(6). In addition, there is a delay between the beginning of ECT sessions and symptom relief, and ECT is associated with cognitive side effects. The mechanism of action of ECT remain incompletely understood, though multiple biological pathways appear to be involved, including activation of the hypothalamic-pituitary-adrenal (HPA) axis\u0026nbsp;(7,8)\u0026nbsp;, inflammation\u0026nbsp;(9,10), neurotrophic factor modulation\u0026nbsp;(11), and changes in excitatory (glutamatergic)\u0026nbsp;(12)\u0026nbsp;and inhibitory (GABAergic) pathways\u0026nbsp;(13).\u0026nbsp;Structural changes in specific brain regions, such as the hippocampus and amygdala, have also been implicated\u0026nbsp;(14)\u0026nbsp;(15).\u003c/p\u003e\n\u003cp\u003eRepetitive transcranial magnetic stimulation (rTMS) is another neurostimulation technique that offers practical advantages over ECT, being non-invasive, less costly, easier to administer, and not associated with anaesthetic risks. It uses electromagnetic pulses to induce electrical current in the underlying brain area. Repetitive application of the stimulation affects cortical activity (inhibition or excitation) within the target region and its associated network\u0026nbsp;(16). A recent umbrella meta-analysis including 13 meta-analyses about TRD demonstrated the effectiveness of rTMS for depressive symptom reduction\u0026nbsp;(17). rTMS is generally well tolerated, and associated with minimal side effects\u0026nbsp;(18). However, rTMS has shown lower efficacy in comparison with ECT, particularly in MDD with psychotic features\u0026nbsp;(19).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003erTMS and ECT seem to share action mechanisms\u0026nbsp;(20)\u0026nbsp;(21)\u0026nbsp;and literature suggests they both increase gamma-aminobutyric acid (GABA) levels\u0026nbsp;(22)\u0026nbsp;(23). Literature suggests they both increase the cortical silence period and intra-cortical inhibition\u0026nbsp;(24,25)\u0026nbsp;(26), and we therefore hypothesize that a priming high frequency rTMS protocol aiming at the left dorsolateral prefrontal cortex could help raise GABA levels faster during the ECT protocol compared to using ECT alone.\u003c/p\u003e\n\u003cp\u003eIn the initial STIMAGNECT trial\u0026nbsp;(27), we investigated the potentiating effect of five high-frequency active rTMS sessions targeting the left dorsolateral prefrontal cortex (DLPFC) on ECT response, compared to a sham rTMS group, in 52 TRD patients. The response rate was 43.4% (±28.6%) in the active rTMS group versus 25.4% (±17.2%) in the sham rTMS group. Additionally, the active rTMS group reported fewer subjective cognitive side effects, and lower electrical charges were required to induce effective seizures. This preliminary study suggests a potential additive effect of rTMS on ECT efficacy. However, in the open follow-up phase of STIMAGNECT, we observed a possible attenuation of the rTMS effect after 8–12 ECT sessions.\u003c/p\u003e\n\u003cp\u003eWe therefore designed STIMAGNECT 2 to evaluate the response to a longer ECT protocol (10 sessions) comparatively between a group receiving an active vs sham rTMS protocol. The rTMS protocol (either active or sham), consists of the same priming protocol, i.e. 5 rTMS sessions prior to the beginning of the ECT protocol, followed by an additional rTMS session the day before each ECT session from the 6\u003csup\u003eth\u003c/sup\u003e to the 10\u003csup\u003eth\u003c/sup\u003e ECT session. This second series of rTMS aimed to avoid the attenuation of potential effects.\u003c/p\u003e\n\u003cp\u003eTo explore the underlying physiological mechanisms, patients will undergo MRI at baseline and after 10 ECT sessions. Imaging will include anatomical sequences, resting-state functional MRI, and magnetic resonance spectroscopy to assess GABA levels in the left DLPFC.\u003c/p\u003e\n\u003cp\u003eExplanation for the choice of comparators {6b}\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn this trial, the primary intervention under investigation is the rTMS add-on protocol, which will be administered as either active rTMS or sham rTMS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eObjectives {7}\u003c/p\u003e\n\u003cp\u003eOur primary objective is to evaluate the effect of adjunctive rTMS in a 10-session ECT protocol on therapeutic response in patients with treatment-resistant depression. The rTMS protocol consists of five sessions administered before the initiation of ECT, followed by one rTMS session the day before each ECT session from the 6th ECT session onward.\u003c/p\u003e\n\u003cp\u003eAdditionally, we aim to assess:\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003ePatients’ perceived efficacy of the rTMS-ECT combination on depressive symptoms.\u003c/li\u003e\n \u003cli\u003eThe impact of rTMS-ECT on brain anatomy, \u003cem\u003efunctional brain activity, and cerebral chemistry\u003c/em\u003e*.\u003c/li\u003e\n \u003cli\u003eThe effect of rTMS-ECT on ECT side effects.\u003c/li\u003e\n \u003cli\u003eThe effect of rTMS-ECT on cognition.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe influence of rTMS on ECT parameters.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e*These assessments are optional, as they are not available in all clinical centers.\u003c/p\u003e\n\u003cp\u003eTrial design {8}\u003c/p\u003e\n\u003cp\u003eSTIMAGNECT 2 is a prospective, multicenter, double-blind, randomized controlled trial. All participants will follow a 10 sessions ECT protocol. Randomization will be conducted using block randomization with a 1:1 allocation to either the rTMS arm or the sham rTMS arm.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods: participants, interventions, and outcomes","content":"\u003cp\u003eThe study protocol follows the SPIRIT recommendations.\u003c/p\u003e\n\u003cp\u003eStudy setting {9}\u003c/p\u003e\n\u003cp\u003eThis trial will be conducted by the Research Department of the Centre Hospitalier du Rouvray (Sotteville-les-Rouen, France), in collaboration with 12 French clinical centers and one clinical center located in the Principality of Monaco.\u003c/p\u003e\n\u003cp\u003eEligibility criteria {10}\u003c/p\u003e\n\u003cp\u003ePatients eligible for the study must be adults (\u0026ge; 18 years) diagnosed with resistant depression.\u003c/p\u003e\n\u003cp\u003eInclusion criteria\u003c/p\u003e\n\u003cp\u003e\u0026middot; Age 18 to 70 years\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026middot; Ongoing diagnosis of major depressive disorder (MDD) as defined by DSM-5 criteria\u003c/p\u003e\n\u003cp\u003e\u0026middot; Depression severity assessed with a Hamilton depression scale (HAMD) \u0026ge; 15\u003c/p\u003e\n\u003cp\u003e\u0026middot; For unipolar depression: lack of remission of current episode after at least two different antidepressant trials at an adequate dose and duration\u003c/p\u003e\n\u003cp\u003e\u0026middot; For bipolar depression: lack of remission of current episode despite lithium at an adequate level (0,80 mEq/L) combined with lamotrigine (50-200mg per day), or despite full dose quetiapine monotherapy (300-600 mg per day)\u003c/p\u003e\n\u003cp\u003e\u0026middot; No modifications in antidepressant or mood-stabilizing treatment within the last 15 days\u003c/p\u003e\n\u003cp\u003e\u0026middot; No prior exposure to rTMS\u003c/p\u003e\n\u003cp\u003e\u0026middot; Patient affiliated to a social security system\u003c/p\u003e\n\u003cp\u003e\u0026middot; No benzodiazepine or antiepileptic treatment (including lamotrigine) within the last 15 days\u003c/p\u003e\n\u003cp\u003e\u0026middot; Ability to understand both spoken and written French\u003c/p\u003e\n\u003cp\u003e\u0026middot; Written informed consent from the patient and, if applicable, legal guardian consent for patients under guardianship\u003c/p\u003e\n\u003cp\u003eNon-inclusion criteria\u003c/p\u003e\n\u003cp\u003e\u0026middot; Prior ECT for the current depressive episode\u003c/p\u003e\n\u003cp\u003e\u0026middot; Contraindications to ECT or anaesthesia, including:\u003c/p\u003e\n\u003cp\u003eo Intracranial hypertension\u003c/p\u003e\n\u003cp\u003eo Recent myocardial infarction\u003c/p\u003e\n\u003cp\u003eo Severe coronary failure\u003c/p\u003e\n\u003cp\u003eo Thrombotic disease\u003c/p\u003e\n\u003cp\u003eo Severe cardiac or respiratory failure\u003c/p\u003e\n\u003cp\u003eo Recent brain haemorrhage\u003c/p\u003e\n\u003cp\u003eo Expansive brain lesions\u003c/p\u003e\n\u003cp\u003eo Brain aneurysms or vascular abnormalities with a risk of haemorrhage\u003c/p\u003e\n\u003cp\u003eo Aortic aneurysm\u003c/p\u003e\n\u003cp\u003eo Retinal detachment\u003c/p\u003e\n\u003cp\u003eo Pheochromocytoma\u003c/p\u003e\n\u003cp\u003e\u0026middot; Contraindications to rTMS, including:\u003c/p\u003e\n\u003cp\u003eo Presence of any implanted electronic device\u003c/p\u003e\n\u003cp\u003eo Any metallic intracranial foreign body\u003c/p\u003e\n\u003cp\u003e\u0026middot; Contraindications to MRI, including:\u003c/p\u003e\n\u003cp\u003eo Pacemaker, neurosensory stimulator, or implanted defibrillator\u003c/p\u003e\n\u003cp\u003eo Cochlear implants\u003c/p\u003e\n\u003cp\u003eo Cerebral or ocular metallic foreign objects near nervous structures\u003c/p\u003e\n\u003cp\u003eo Metallic prostheses\u003c/p\u003e\n\u003cp\u003eo Ventriculoperitoneal shunt valves\u003c/p\u003e\n\u003cp\u003eo Tattoos containing iron particles\u003c/p\u003e\n\u003cp\u003eo Claustrophobia\u003c/p\u003e\n\u003cp\u003e\u0026middot; Patients with a severe substance use disorder (excluding nicotine or caffeine) as defined by DSM-5 criteria\u003c/p\u003e\n\u003cp\u003e\u0026middot; Pregnant or lactating women and women of child-bearing age without adequate contraception\u003c/p\u003e\n\u003cp\u003e\u0026middot; Contraindications to propofol or neuromuscular blocking agents\u003c/p\u003e\n\u003cp\u003e\u0026middot; Dementia or a history of epilepsy\u003c/p\u003e\n\u003cp\u003e\u0026middot; Presence of a cerebral lesion (post-traumatic, vascular, tumoral)\u003c/p\u003e\n\u003cp\u003e\u0026middot; Ongoing exposure to electrical or magnetic stimulating therapies, including transcutaneous electrical nerve stimulation (TENS)\u003c/p\u003e\n\u003cp\u003e\u0026middot; Severe hearing impairment\u003c/p\u003e\n\u003cp\u003e\u0026middot; Patients under freedom restriction as imposed by an administrative or judiciary decision\u003c/p\u003e\n\u003cp\u003e\u0026middot; Patients participating, or having participated in another interventional clinical trial within 30 days prior to study inclusion\u003c/p\u003e\n\u003cp\u003eRandomization criteria\u003c/p\u003e\n\u003cp\u003e\u0026middot; No change in antidepressant or mood-stabilizing treatment since the last visit\u003c/p\u003e\n\u003cp\u003eWho will take informed consent? {26a}\u003c/p\u003e\n\u003cp\u003ePotential participants will receive comprehensive and detailed information about the study protocol. They will be given a minimum reflection period of 7 days before signing the informed consent form in the presence of the investigators. For patients under legal guardianship, written agreement from their legal guardians must also be obtained.\u003c/p\u003e\n\u003cp\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/p\u003e\n\u003cp\u003eWritten information will be given to inform the participant of their right to withdraw their consent regarding the use of their data for research purposes. This trial does not involve the collection or storage of biological specimens.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eInterventions\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients will be randomized to receive either an active rTMS protocol or a sham rTMS protocol. All patients will receive active ECT.\u003c/p\u003e\n\u003cp\u003eActive rTMS protocol: Patients in the active rTMS arm will first receive 5 sessions of active rTMS, administered over 4 consecutive days. On day 5, they will receive the first ECT session as part of a 10 sessions ECT protocol (administered twice per week). Additional active rTMS sessions will be administered the day before the 6\u003csup\u003eth\u003c/sup\u003e, 7\u003csup\u003eth\u003c/sup\u003e, 8\u003csup\u003eth\u003c/sup\u003e, 9\u003csup\u003eth\u003c/sup\u003e and 10\u003csup\u003eth\u003c/sup\u003e ECT sessions.\u003c/p\u003e\n\u003cp\u003eSham rTMS protocol: Patients in the sham rTMS arm will undergo an identical schedule, receiving 5 sessions of sham rTMS, administered over 4 consecutive days. On day 5, they will receive the first ECT session as part of a 10 sessions ECT protocol (administered twice per week). Additional sham rTMS sessions will be administered the day before the 6\u003csup\u003eth\u003c/sup\u003e, 7\u003csup\u003eth\u003c/sup\u003e, 8\u003csup\u003eth\u003c/sup\u003e, 9\u003csup\u003eth\u003c/sup\u003e and 10\u003csup\u003eth\u003c/sup\u003e ECT sessions.\u003c/p\u003e\n\u003cp\u003eIntervention description {11a}\u003c/p\u003e\n\u003cp\u003eECT equipment and procedure\u003c/p\u003e\n\u003cp\u003eThe ECT devices used in this study will be spECTrum 5000Q (MECTA/Micromed 7015 SW Mc Ewan Rd, Lac Oswego, OR 97035, USA) or the Thymatron System IV (Somatics, LC. 910 Sherwood Drive, Lake Bluff IL 60044, USA).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll patients will receive active right unilateral ultra brief pulse stimulation. One electrode will be placed on the right temporal region, and the other will be placed at the vertex.\u003c/p\u003e\n\u003cp\u003eThe seizure threshold will be determined using the titration method during the first ECT session\u0026nbsp;(28). The operator will gradually increase the stimulation intensity until an EEG-confirmed seizure is achieved, meeting the following criteria:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026middot; Seizure duration on EEG of at least 20 seconds\u003c/p\u003e\n\u003cp\u003e\u0026middot; Generalization of the seizure to both hemispheres\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOnce the epileptic threshold is determined, the first therapeutic stimulation will be administered either on the same session or on the next one. The dose delivered for therapeutic stimulation will be set at 6 times the seizure threshold. As recommended, this dose may be increased if the seizure does not meet the effectiveness criteria.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eECT sessions will take place twice a week, with a total of 10 sessions.\u003c/p\u003e\n\u003cp\u003eIf, after 5 effective unilateral ECT sessions, the patient\u0026rsquo;s clinical presentation worsens, with a life-threatening risk for the patient, the clinician is authorized to switch to bitemporal ECT after performing a new titration.\u003c/p\u003e\n\u003cp\u003eAnaesthesia procedure\u003c/p\u003e\n\u003cp\u003ePatient must undergo a pre-anaesthesia assessment within one month prior to starting ECT. A consultation with the anaesthetist will also be conducted before ECT session.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients must refrain from eating or drinking for 12 hours before each ECT session, except in cases requiring premedication. All administered pharmacological agents will be recorded on the anaesthesia sheet. Infusion therapy will be provided. Vital signs monitoring will include blood pressure, heart rate and oxygen saturation. An emergency medication kit will be available and checked before each session to manage potential cardiovascular effects.\u003c/p\u003e\n\u003cp\u003eLoss of consciousness will be induced with propofol (1 to 2 mg/kg). Muscle relaxation will be achieved using suxamethonium chloride (0.3 to 0.8mg/kg), a short-acting neuromuscular blocker that reduces muscle contraction while ensuring spontaneous breathing recovery within 3 to 5 minutes at this dose. The anaesthetist will adjust doses based on individual patient needs.\u003c/p\u003e\n\u003cp\u003eOxygen-enriched ventilation will be provided via a mask until spontaneous breathing resumes. Patients will remain under medical supervision in the recovery room for one hour. Resumption of normal eating is expected 1.5 to 2 hours after recovery. Each ECT session will be conducted by a multidisciplinary team, including a psychiatrist who is responsible for administering ECT, an anaesthetist, and a nurse anaesthetist.\u003c/p\u003e\n\u003cp\u003eActive rTMS\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEach center will be using its own rTMS device and coil, ensuring consistency in CE certification and technical specifications, regardless of the brand differences.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRegarding the rTMS device, centers will use the MagPro X100 from MagVenture (Tonica Elektronik A/S, Lucernemarken 15, DK-3520 Farum, Denmark) (n=7), the MagPro R30 from MagVenture (n=4), the PowerMag device from MAG \u0026amp; More (GmbH Machtlfingerstr. 13 81379 Munich, Germany) (n=1) and the DuoMag XT100 from Deymed (Kudrn\u0026aacute;čova 533 549 31 Hronov, Czech Republic). (n=1).\u003c/p\u003e\n\u003cp\u003eRegarding the coil, 12 centers will be using the Cool-B65 coil (MagVenture). This figure-eight coil is equipped with a temperature sensor that deactivates the device if the coil temperature exceeds 41\u0026deg;C. One center will be using the PMD70-pCool coil (MAG \u0026amp; More) and 1 center will be using the D70BF-LQC coil (DEYMED).\u003c/p\u003e\n\u003cp\u003ePatients may eat and drink before rTMS sessions. Patients must remove any jewellery, hearing aids, dentures, or other prosthesis, and will be provided earplugs. The procedure will take place in a ventilated room to dissipate heat generated by the device.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe resting motor threshold (RMT), defined as the minimal intensity to elicit a motor evoked potential exceeding 50\u0026micro;V in at least 50% of the trials, will be measured in the resting abductor pollicis brevis muscle.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe left dorsolateral prefrontal cortex (DLPFC) will be localized using a neuronavigation system and the 3D reconstruction of the cerebral MRI obtained at baseline.\u003c/p\u003e\n\u003cp\u003eThe left DLPFC stimulation target was selected based on literature indicating that the frontal region whose activity is the most anticorrelated with the subgenual cingulate cortex activity is optimal for depression treatment\u0026nbsp;(29). A resting-state fMRI study of 1,000 participants identified the Montreal Neurological Institute (MNI) coordinates of this region as \u003cstrong\u003ex = -41, y = 43, z = 27\u003c/strong\u003e (30). The rTMS coil will be positioned accordingly using an anatomical MRI and a neuronavigation system (either Localite, Syneika or Nexstim eXimia, depending on the clinical center).\u003c/p\u003e\n\u003cp\u003eThe rTMS parameters were chosen because they were considered effective in the previous study (Stimagnect, Roth\u0026auml;rmel et al., 2021). The rTMS parameters are defined as follows:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026middot; Frequency: 20Hz\u003c/p\u003e\n\u003cp\u003e\u0026middot; Stimulation intensity: 90% of the resting motor threshold\u003c/p\u003e\n\u003cp\u003e\u0026middot; Train duration: 2 seconds\u003c/p\u003e\n\u003cp\u003e\u0026middot; Intertrain interval: 60 seconds\u003c/p\u003e\n\u003cp\u003e\u0026middot; Number of trains per session: 20\u003c/p\u003e\n\u003cp\u003e\u0026middot; Total pulses per session: 800\u003c/p\u003e\n\u003cp\u003eEach patient will receive 10 rTMS sessions in total. The first five sessions will occur over four consecutive days (D1, D2, D3, D4), with at least one hour between multiple sessions on the same day. The remaining five sessions will be administered the day before each electroconvulsive therapy (ECT) session, from the 6th to the 10th ECT session.\u003c/p\u003e\n\u003cp\u003eNo specific post-rTMS monitoring is required, as existing literature reports an extremely low incidence of adverse effects\u0026nbsp;(18,31).\u003c/p\u003e\n\u003cp\u003eSham rTMS\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe sham rTMS sessions will be administered using the same rTMS devices, except a using sham coil instead of an active one. These sham coils reproduce the auditive artefact of an active rTMS coil while preventing the delivery of magnetic stimulation to the scalp. They therefore do not produce the characteristic sensory effects of active rTMS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA significant challenge in rTMS research is the lack of a perfect placebo alternative, as no sham condition can entirely replicate the sensory and auditory experience of active rTMS while remaining physiologically inactive. In this study, we will use a standard rTMS coil positioned upside down, allowing patients to hear the acoustic effects of stimulation without actual magnetic field transmission to the scalp. We opted not to use scalp electrical stimulation to mimic the tactile sensation of active rTMS, as this could introduce additional confounding factors. The sham rTMS method we opted for was found to lead to acceptable levels of blinding integrity in a 2013 meta-analysis\u0026nbsp;(32). To further ensure effective blinding, only patients with no prior exposure to magnetic stimulation therapies will be included, minimizing the risk of unblinding due to prior familiarity with rTMS sensations.\u003c/p\u003e\n\u003cp\u003eThe rTMS operator will be blinded to treatment condition, and the rTMS settings will be pre-programmed by an informed research technician before each session.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMRI data acquisition\u003c/p\u003e\n\u003cp\u003eFor patients from all participating centers, structural T1-weighted scans will be obtained before and after treatment for rTMS neuronavigation, Voxel-Based Morphometry (VBM) and cortical thickness analyses.\u003c/p\u003e\n\u003cp\u003eFor patients included by Centre Hospitalier du Rouvray (Sotteville-les-Rouen, France), MRI scans will be obtained on a 3 Tesla SIGNA Premier scanner (General Electric HealthCare, Waukesha, USA) at CHU Charles Nicolle University Hospital in Rouen, France. Three-dimensional, T1-weighted brain volumes were acquired with the following parameters: 176 contiguous slices, slice thickness= 0.5 mm, field of view= 256 mm, repetition time (TR)= 6.2 ms and echo time (TE)= 2.5 ms.\u003c/p\u003e\n\u003cp\u003eFor patients in Rouen and Paris, additional imaging assessments will be conducted at V0 (baseline) and after 10 ECT:\u003c/p\u003e\n\u003cp\u003e\u0026middot; Resting-state functional MRI (fMRI) will be performed to assess functional connectivity. We will record a Bold MRI sequence applied with the following parameters: 40 slices, slice thickness= 3.5 mm, flip angle = 66\u0026deg;, TR= 1200 ms, TE= 27 ms. Patients are instructed to relax, remain still, and keep their eyes closed without falling asleep.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Proton magnetic resonance spectroscopy (\u0026sup1;H-MRS) will be performed with a MEGA-PRESS sequence for GABA detection. The sequence parameters were determined as follows: TR of 2000 ms and TE of 68 ms. The voxel size is set to 20 \u0026times; 20 \u0026times; 20 mm\u0026sup3; (8 cm\u0026sup3;), positioned manually within the left dorsolateral prefrontal cortex (DLPFC) (figure 1). The acquisition time is 9 minutes and 20 seconds.\u003c/p\u003e\n\u003cp\u003eImagery data analysis\u003c/p\u003e\n\u003cp\u003eRegarding structural T1-weighted MRI, the assessment of changes in grey matter regional density will be conducted with Whole brain voxel-based morphometry using SPM 25 (Wellcome Department of Cognitive Neurology, London, UK). Potential cortical thickness changes will also be assessed using the FreeSurfer software (https://surfer.nmr.mgh.harvard.edu).\u003c/p\u003e\n\u003cp\u003eRegarding resting-state functional MRI (fMRI), functional connectivity will be assessed using the CONN toolbox\u0026nbsp;(33).\u003c/p\u003e\n\u003cp\u003eRegarding Magnetic resonance spectroscopy (MRS), the GABA levels will be measured using the GANNET software\u0026nbsp;(34).\u003c/p\u003e\n\u003cp\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/p\u003e\n\u003cp\u003ePatients will be withdrawn from the study under the following circumstances:\u003c/p\u003e\n\u003cp\u003e\u0026middot; Withdrawal of patient consent or legal guardian agreement, in which case patient is to be definitively excluded from the study and data will not be included in the analysis\u003c/p\u003e\n\u003cp\u003e\u0026middot; Discontinuation without formal withdrawal of consent, in which case data will be included in the analysis\u003c/p\u003e\n\u003cp\u003e\u0026middot; Investigator\u0026rsquo;s decision due to clinical deterioration, occurrence of significant adverse effects, necessity to change the background pharmacological treatment, or inability for the patient to follow the established protocol\u003c/p\u003e\n\u003cp\u003e\u0026middot; Death of the patient\u003c/p\u003e\n\u003cp\u003e\u0026middot; Loss to follow-up, defined as failure to establish contact with the patient after three attempts, made at 1-week intervals\u003c/p\u003e\n\u003cp\u003eStrategies to improve adherence to interventions {11c}\u003c/p\u003e\n\u003cp\u003eThroughout the trial, adherence to interventions will be enhanced through frequent visits and scheduled appointments, ensuring regular monitoring and patient engagement. Additionally, study staff will provide reminders and follow-up communications to reinforce compliance and address any concerns or barriers to participation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/p\u003e\n\u003cp\u003ePatients will continue their usual medication as prescribed by their psychiatrist or primary care physician. However, the following conditions apply:\u003c/p\u003e\n\u003cp\u003e\u0026middot; Antidepressant and mood-stabilizing treatments must remain at a stable dose starting 15 days before the trial and throughout its duration. Only the lithium dosage (if maintained during the trial) may be adjusted within the 15 days before randomization and during the study period, to ensure a lithium level within the lower limit.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Benzodiazepines and antiepileptic medications (including lamotrigine) should be discontinued at least 15 days before the trial whenever possible. If discontinuation is not feasible, the dosage should be reduced to the lowest possible level and maintained at a constant dose throughout the trial.\u003c/p\u003e\n\u003cp\u003e\u0026middot; During the trial, patients must not receive any other electrical or magnetic stimulation therapies (e.g., transcutaneous electrical nerve stimulation).\u003c/p\u003e\n\u003cp\u003eProvisions for post-trial care {30}\u003c/p\u003e\n\u003cp\u003eAfter completing the trial, patients will resume their regular follow-up care as prescribed by their treating psychiatrist or primary care physician. Those requiring further ECT will continue treatment until remission. For patients attaining remission, maintenance ECT will be considered.\u003c/p\u003e\n\u003cp\u003eOutcomes {12}\u003c/p\u003e\n\u003cp\u003eMain outcome\u003c/p\u003e\n\u003cp\u003eThe primary outcome of the trial is the response rate following 10 ECT sessions, defined as the proportion of patients achieving a \u0026ge;50% reduction in their Hamilton Depression Rating Scale (HAMD, 21 items) score between Visit 1 (Day 1) and Visit 5 (Day 38)\u0026nbsp;(35).\u003c/p\u003e\n\u003cp\u003eSecondary outcomes\u003c/p\u003e\n\u003cp\u003eThe secondary outcomes are defined as follow:\u003c/p\u003e\n\u003cp\u003e- The relative change in the Hamilton depression scale (HAMD, 21 items) and Quick Inventory of Depressive Symptomatology (QIDS-SR-16) between V1 (Day 1) and after rTMS (V2 = day 4), after 5 ECT sessions (V3, day 19), after 7 ECT sessions (V4, day 26), after 10 ECT sessions (V5, day 40)\u0026nbsp;(35).\u003c/p\u003e\n\u003cp\u003e- rTMS-adapted UKU side effect scale score (adapted UKU) at V2, V3, V4 and V5\u0026nbsp;(36).\u003c/p\u003e\n\u003cp\u003e- Squire Subjective Memory Questionnaire (SSMQ) score and the Cognitive Failures Questionnaire (CFQ) score at V2, V3, V4 and V5\u0026nbsp;(37).\u003c/p\u003e\n\u003cp\u003e- The change in the Mini Mental Status Examination (MMSE) score\u0026nbsp;(38), RL/RI-16 score\u0026nbsp;(39), D2 attention test score\u0026nbsp;(40), Rey Osterrieth complex figures test score\u0026nbsp;(41)\u0026nbsp;at V0 (at baseline) and after 10 ECT sessions (V5, D40).\u003c/p\u003e\n\u003cp\u003e- ECT session parameters: seizure threshold, seizure duration, postictal suppression on the EEG, administered anaesthetic drugs doses at each session.\u003c/p\u003e\n\u003cp\u003e- The change in the gray matter density and cortical thickness, measured in T1-weighted 3D anatomical MRI at baseline and after 10 ECT sessions (V5, D40).\u003c/p\u003e\n\u003cp\u003e- Blinding efficacy: patient assessment of perceived treatment condition (active vs sham rTMS).\u003c/p\u003e\n\u003cp\u003eThe facultative secondary outcomes are defined as follows:\u003c/p\u003e\n\u003cp\u003e- The change in the Autobiographical memory performance: TEMPau score at baseline and after 10 ECT sessions (V5, D40) in centers where trained professionals are available\u0026nbsp;(42).\u003c/p\u003e\n\u003cp\u003e- The change in the GABA rate at baseline and after 10 ECT sessions (V5, D40) in centers equipped for these assessments (GABA magnetic resonance spectroscopy)\u003c/p\u003e\n\u003cp\u003e- The change in the brain activity at baseline and after 10 ECT sessions (V5, D40) in centers equipped for these assessments (resting-state fMRI)\u003c/p\u003e\n\u003cp\u003eParticipant timeline {13}\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn addition to the rTMS and ECT sessions, participants will undergo several visits to assess the primary and secondary outcomes and to ensure proper application of the protocol.\u003c/p\u003e\n\u003cp\u003eAt the inclusion visit V0 (M-1), the investigator will obtain informed consent from the participant, after addressing any questions about the research protocol, its aims and its potential risks. The participant will be reminded of their rights in relation to the research and given a copy of the consent form. If applicable, guardian agreement will also be obtained. The investigating clinician will check for contraindications to ECT, rTMS or MRI, and ensure that the pre-ECT workup is complete. A cerebral MRI and pregnancy test (if applicable) will be prescribed, along with fMRI and magnetic resonance spectroscopy for participants recruited in Rouen or Paris. A physical exam will be performed and sociodemographic data will be collected. The following assessments will also be conducted:\u003c/p\u003e\n\u003cp\u003e\u0026middot; MINI (Mini International Neuropsychiatric Interview)\u003c/p\u003e\n\u003cp\u003e\u0026middot; HAMD-21 and QIDS-SR-16\u003c/p\u003e\n\u003cp\u003e\u0026middot; Neuropsychological assessment: MMSE, RL/RI-16, d2 attention test, Rey-Osterrieth complex figures test\u003c/p\u003e\n\u003cp\u003e\u0026middot; TEMPau autobiographical memory questionnaire (if trained professional is available)\u003c/p\u003e\n\u003cp\u003eOn randomization day (V1, D1), an investigator will proceed to randomization via the Ennov Clinical software. Treatment allocation will be sent to informed investigators, who must be distinct from the investigators conducting rTMS or outcomes assessments. A physical exam and vital sign assessment will be performed, along with HAMD-21 and QIDS-SR-16. The first rTMS session will take place on V1.\u003c/p\u003e\n\u003cp\u003eFollow-up visits will contain the following assessments:\u003c/p\u003e\n\u003cp\u003e\u0026middot; V2 (D4, post-5 rTMS sessions, pre-ECT): physical examination, vital signs assessment, HAMD-21, QIDS-SR-16, adapted UKU, SSMQ, CFQ\u003c/p\u003e\n\u003cp\u003e\u0026middot; V3 (D19, post-5 ECT sessions): physical examination, vital signs assessment, HAMD-21, QIDS-SR-16\u003c/p\u003e\n\u003cp\u003e\u0026middot; V4 (D26, post-7 ECT sessions): physical examination, vital signs assessment, HAMD-21, QIDS-SR-16\u003c/p\u003e\n\u003cp\u003eAt the end-of-study visit after 10 ECT sessions (V5, D40), a physical examination and vital sign assessment will be performed, as well as the HAMD-21, QIDS-SR-16, adapted-UKU, SSMQ, CFQ, MMSE, RL/RI-16 test, d2 attention test, Rey-Osterrieth complex figures test, TEMPau (if trained professional is available). Patients will also undergo anatomical MRI, with fMRI and magnetic resonance spectroscopy for those recruited in Paris or Rouen.\u003c/p\u003e\n\u003cp\u003eThe experimental design, intervention and assessment schedule are presented in Fig 2 as well as in the following SPIRIT figure.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eParticipant timeline: Schedule of enrollment, interventions, and assessments.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cimg 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\"\u003e\u003c/strong\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eSample size {14}\u003c/p\u003e\n\u003cp\u003eA previous randomized, double-blind, placebo-controlled trial (Roth\u0026auml;rmel et al., 2021) including 56 patients with treatment-resistant depression (TRD) demonstrated that the proportion of patients responding to treatment after 5 active/sham priming rTMS sessions and 5 active ECT sessions and was three times higher in the active rTMS arm compared to the sham rTMS arm.\u003c/p\u003e\n\u003cp\u003eFor the present study, we assume that after 10 ECT sessions, the response ratio will be 1.5:1 between the active rTMS arm and the sham rTMS arm. Furthermore, by administering rTMS the day before ECT sessions from the 6th to the 10th session, we anticipate that the response rate observed after 5 ECT sessions will be maintained.\u003c/p\u003e\n\u003cp\u003eAccording to the meta-analysis by Haq et al. (2015), the response rate to ECT in patients with TRD is 58%. Based on our assumed ratio (1.5 \u0026times; 58%), we estimate a response rate of 87% in the active rTMS arm.\u003c/p\u003e\n\u003cp\u003eWith an alpha risk of 0.05 and a statistical power of 0.80, our calculation indicates that 37 patients per group are required. To account for an estimated 10% dropout rate, the sample size is increased to 40 patients per arm, resulting in a total of 80 patients for the study.\u003c/p\u003e\n\u003cp\u003eRecruitment {15}\u003c/p\u003e\n\u003cp\u003eEnrolment will take place in 14 clinical centers (see Table 1) over a period of 26 months, corresponding to an average of approximately 2.5 patients per center per year. Participants will be patients for who ECT is indicated, with treatment-resistant depression being the main indication in the participating centers.\u003c/p\u003e\n\u003cp\u003eAfter an assessment of the patients file and a psychiatric evaluation, eligible patients will be invited to participate in the study. Prior to enrolment, patients will be fully informed about the STIMAGNECT 2 protocol, including its objectives, potential risks, and expected benefits.\u003c/p\u003e\n\u003cp\u003ePatients may be hospitalized for the initial treatment sessions and later managed on an outpatient basis if their clinical condition allows. During hospitalization, a comprehensive pre-ECT assessment will be performed\u0026mdash;including at least an electrocardiogram (ECG), standard blood tests, and a pre-anaesthesia evaluation\u0026mdash;to screen for any contraindications to the protocol. Patients meeting the inclusion criteria during this assessment will be enrolled in the study upon providing their consent and after signing an informed consent form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAssignment of interventions: allocation\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSequence generation {16a}\u003c/p\u003e\n\u003cp\u003ePatients will be randomly assigned to either the active rTMS or sham rTMS group using a web-based randomization system in a 1:1 ratio, with balanced blocks of undisclosed size to ensure allocation concealment. Stratification by clinical center will be performed to account for potential site-specific variations.\u003c/p\u003e\n\u003cp\u003eThe details of the randomization procedure are confidential and securely stored within the Research Department of the Centre Hospitalier du Rouvray.\u003c/p\u003e\n\u003cp\u003eConcealment mechanism {16b}\u003c/p\u003e\n\u003cp\u003eOn demand, the informed investigator will obtain the patient number and the arm in which the latter has been assigned on the Ennov Clinical software.\u003c/p\u003e\n\u003cp\u003eImplementation {16c}\u003c/p\u003e\n\u003cp\u003eThe allocation sequence was generated by an engineer from the Research Department of the Centre Hospitalier du Rouvray and securely uploaded to the Ennov Clinical software.\u003c/p\u003e\n\u003cp\u003eParticipants will be enrolled by investigators at each participating clinical center (Table 1). To ensure blinding, an informed technician (distinct from the technician administering rTMS) will configure the rTMS device according to the patient\u0026apos;s assigned group (active or sham rTMS). This setup ensures that the rTMS operator remains blinded to the treatment allocation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAssignment of interventions: blinding\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWho will be blinded {17a}\u003c/p\u003e\n\u003cp\u003eThe following individuals will be blinded to the treatment allocation:\u003c/p\u003e\n\u003cp\u003e\u0026middot; Investigators conducting clinical assessments\u003c/p\u003e\n\u003cp\u003e\u0026middot; Psychologists administering cognitive tests\u003c/p\u003e\n\u003cp\u003e\u0026middot; rTMS technicians performing the stimulation\u003c/p\u003e\n\u003cp\u003e\u0026middot; Patients receiving the treatment\u003c/p\u003e\n\u003cp\u003e\u0026middot; Data analysts, who will remain blinded until the entire analysis is completed\u003c/p\u003e\n\u003cp\u003eProcedure for unblinding if needed {17b}\u003c/p\u003e\n\u003cp\u003eIn the event of a major adverse event or if the patient\u0026rsquo;s safety is compromised, the investigator will be able to access the patient\u0026rsquo;s allocation via the electronic case report form (eCRF).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eData collection and management\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePlan for assessment and collection of outcomes {18a}\u003c/p\u003e\n\u003cp\u003eSince the mandatory clinical scales used in the study are routinely employed in clinical practice and administered by experienced psychiatrists and psychologists, no additional training was required.\u003c/p\u003e\n\u003cp\u003eFor the optional TEMPau scale, specific neuropsychological training is necessary to ensure proper administration and scoring.\u003c/p\u003e\n\u003cp\u003eThe validity and reliability of all scales used in the study are detailed in Table 2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/p\u003e\n\u003cp\u003eTo promote participant retention and ensure complete follow-up, patients will receive regular reminders of upcoming visits, and in the event of a missed appointment, they will be promptly contacted to reschedule.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData management {19}\u003c/p\u003e\n\u003cp\u003eAll required information specified in the protocol will be accurately recorded on the case report forms (CRFs), with clear explanations provided for any missing data. Data will be collected immediately upon availability and transcribed clearly from these forms into the electronic system.\u003c/p\u003e\n\u003cp\u003eIn the case of errors or discrepancies, the investigator or an authorized individual will correct the mistaken data. Since the data are collected through an electronic case report form (eCRF), audit-trail functionality ensures automatic traceability of all amendments and updates, maintaining transparency and accountability.\u003c/p\u003e\n\u003cp\u003eConfidentiality {27}\u003c/p\u003e\n\u003cp\u003eAll data collected in the electronic case report form (eCRF) will be anonymized. Each patient will be assigned a unique code name based on their inclusion center and randomization number. Only the patient\u0026rsquo;s initials and month and year of birth will be recorded.\u003c/p\u003e\n\u003cp\u003eAll documentation related to the study (e.g., protocol, consent forms, case report forms, investigator folders) as well as original documents (such as laboratory results, neuroimaging data, consultation reports, clinical examination reports) will be stored securely and treated as confidential material.\u003c/p\u003e\n\u003cp\u003eThe investigator will be responsible for data archiving and must comply with applicable legal requirements. The investigator will retain the data and the patient identification list for a minimum of 15 years after the end of the study.\u003c/p\u003e\n\u003cp\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial / future use {33}\u003c/p\u003e\n\u003cp\u003eNone of these procedures is planned in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eStatistical methods\u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical methods for the primary and secondary outcomes {20a}\u003c/p\u003e\n\u003cp\u003ePatient characteristics will be described both overall and by treatment arm (active rTMS or sham rTMS) using the usual parameters: mean, standard deviation, median, interquartile range, and range for quantitative variables as well as frequences for categorical variables.\u003c/p\u003e\n\u003cp\u003eThe percentage of responding patients, defined as those showing a 50% or more reduction of the Hamilton depression scale (HAMD-21) score, between the two groups (active vs. sham rTMS) from V1 (at baseline) to V5 (after 10 ECT sessions) will be compared using the chi-square test.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis analysis will be completed by a comparison of the relative HAMD-21 score using the Student\u0026rsquo;s t-test for normally distributed data with equal variance, or using the Mann-Whitney non parametric test if the assumptions of normality and homogeneity of variances are not met. The same strategy will be chosen for the other quantitative secondary outcomes. These analyses might be adjusted for prognostic factors and clinical centers using a regression model.\u003c/p\u003e\n\u003cp\u003eFor the qualitative outcomes, the comparison of the two groups will be done with the chi-square test, and if the sample size requires it, on the Fisher exact test.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA difference will be considered statistically significant if the p-value is inferior to 0.05 (alpha risk = 5%).\u003c/p\u003e\n\u003cp\u003eInterim analysis {21b}\u003c/p\u003e\n\u003cp\u003eNo interim analyses are planned.\u003c/p\u003e\n\u003cp\u003eMethods for additional analysis (e.g. subgroup analyses) {20b}\u003c/p\u003e\n\u003cp\u003eThe analysis will be completed by a comparison using the logistic regression model to adjust for centers and possible prognostic characteristics.\u003c/p\u003e\n\u003cp\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}\u003c/p\u003e\n\u003cp\u003eComparison of the two arms will be based on the intention-to-treat principle. The maximum bias hypothesis will be applied for patients lost to follow-up. Those patients, if in the group with the most favorable evolution, shall be considered as having not responded. On the contrary, those patients, if in the group with the most unfavorable evolution, shall be considered as responding to treatment. The aim is to reduce the gap between both to a minimum. By doing so, a robust conclusion is expected. Two additional sensitivity analyses will be performed: a per-protocol analysis excluding patients lost to follow-up and an imputation analysis using the \u0026ldquo;last observation carried forward\u0026rdquo; (LOCF) method to impute missing data.\u003c/p\u003e\n\u003cp\u003ePlans to give access to the full protocol, participant level-data, and statistical code {31c}\u003c/p\u003e\n\u003cp\u003eThe datasets analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eOversight and monitoring\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComposition of the coordinating center and trial steering committee {5d}\u003c/p\u003e\n\u003cp\u003eThe research department of the Rouvray Hospital coordinates the trial. The department consists of 5 psychiatrists, 1 clinical research associate, 1 project manager, 1 engineer, and 2 research technicians.\u003c/p\u003e\n\u003cp\u003eComposition of the data monitoring committee, its role, and reporting structure {21a}\u003c/p\u003e\n\u003cp\u003eThe clinical research associate appointed by the promoter shall regularly visit the center in which the trial is led:\u003c/p\u003e\n\u003cp\u003e\u0026middot; At trial implementation\u003c/p\u003e\n\u003cp\u003e\u0026middot; During the trial\u003c/p\u003e\n\u003cp\u003e\u0026middot; At the end of the trial\u003c/p\u003e\n\u003cp\u003eThe clinical research associate shall ensure that the participants\u0026rsquo; fundamental rights and safety are respected, as well as reliability, quality and traceability of the transmitted data. The clinical research associate shall check that the study is led in compliance with the protocol, in good clinical practice, and within the legal regulatory framework.\u003c/p\u003e\n\u003cp\u003eThe purpose of the visits is to validate the following:\u003c/p\u003e\n\u003cp\u003e- Patient eligibility: respect of inclusion/exclusion criteria\u003c/p\u003e\n\u003cp\u003e- Compliance with the procedures of information sharing with patients and consent collection\u003c/p\u003e\n\u003cp\u003e- Compliance with the specific procedures of the protocol, trial schedule, and patient follow-up\u003c/p\u003e\n\u003cp\u003e- Data Quality: Data recorded in the case report forms (CRF) are accurate, complete, and consistent\u003c/p\u003e\n\u003cp\u003e- Compliance with the procedures reporting serious adverse event (SAE)\u003c/p\u003e\n\u003cp\u003e- Treatment/Device Management: The handling and traceability of treatments/devices (including pharmacy visits, storage, and accounting) are appropriately managed.\u003c/p\u003e\n\u003cp\u003eAt the end of each visit, a standardized monitoring report must be drafted by the clinical research associate. This report is reviewed by the study promoter.\u003c/p\u003e\n\u003cp\u003eAdverse event reporting and harms {22}\u003c/p\u003e\n\u003cp\u003eThe investigator is responsible for assessing each adverse event (AE) for its seriousness. All adverse events must be recorded in the AE section of the case report form (CRF). Whenever possible, symptoms should be grouped as a single syndrome or diagnosis. The investigator must document the date of onset, intensity, actions taken, outcome of the event, and their assessment as to whether the event is related to the study procedure.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAny event meeting one or more criteria of seriousness must be reported as serious adverse events. In case of a serious adverse event, the investigator should immediately (within 1 working day) do the following:\u003c/p\u003e\n\u003cp\u003e- Send the complete SAE form to the sponsor by fax: Ms. Graziella Guesdon, Centre Hospitalier du Rouvray, Fax : +33 02 32 95 18 56. All SAE forms should be dated and signed by the investigator.\u003c/p\u003e\n\u003cp\u003e- Specify the SAE diagnosis, describe the event, and detail any actions taken. If the diagnosis is unknown at the time of the report or later changes, a detailed written follow-up should be sent to inform the sponsor of the final diagnosis.\u003c/p\u003e\n\u003cp\u003e- Attach copies of all examinations carried out along with the dates on which these examinations were performed. Care should be taken to ensure that the patient\u0026rsquo;s identity is protected, and that trial identifiers are properly mentioned on any copy of the source document. For laboratory results, it must include relevant negative results and the laboratory\u0026rsquo;s normal ranges.\u003c/p\u003e\n\u003cp\u003e- Joint report of hospitalization related to SAE, if applicable\u003c/p\u003e\n\u003cp\u003e- Assess the causality between the study procedures and the SAE\u003c/p\u003e\n\u003cp\u003e- Ensure that relevant information is communicated to the sponsor as it becomes available\u003c/p\u003e\n\u003cp\u003e- Monitor the patient until the SAE resolves, stabilizes, or the patient returns to their pre-event state, even if the patient has left the trial, and update the sponsor on the SAE evolution.\u003c/p\u003e\n\u003cp\u003eFrequency and plans for auditing trial conduct {23}\u003c/p\u003e\n\u003cp\u003eAudits may be conducted at any time by individuals appointed by the promoter, the Centre Hospitalier du Rouvray. Auditors are independent of the research team. The objective is to ensure the quality of the research, the validity of its results, and the respect of the law. The investigators agree to adhere to the requirements set by the promoter and the Competent Authority regarding audits or inspections at any stage of the study.\u003c/p\u003e\n\u003cp\u003ePlans for communicating important protocol amendments to relevant parties (eg\u0026nbsp;: trial participants, ethical committees) {25}\u003c/p\u003e\n\u003cp\u003eAny modification to the protocol should be approved by the Independent Ethics Committee (art. L1123-6 of French Public Health Code) that authorized the start of the trial. Approved modification are also communicated to the ANSM (French Competent Authority) as per art L 1123-8 of the French Public Health Code.\u003c/p\u003e\n\u003cp\u003eOnce modifications are accepted, the new version of the protocol is sent to all the investigative centers, and modifications are applied. Updates will also be made on ClinicalTrials.gov.\u003c/p\u003e\n\u003cp\u003eDissemination plans {31a}\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnalysis of the results will be presented in conferences and scientific publications. Publication texts and communications will be discussed with all the participating investigators. The order of the co-authors considers the participation of different investigators to the trial.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe STIMAGNECT 2 trial aims to build upon previous findings that suggest an additive effect of repetitive transcranial magnetic stimulation (rTMS) on electroconvulsive therapy (ECT) efficacy in treatment-resistant depression (TRD). Given the limited response rates to ECT alone, particularly in individuals with chronic and severe depression, this study seeks to confirm the effect of add-on rTMS on clinical outcome and determine whether a prolonged rTMS protocol can help maintain this effect after 5 ECT sessions. Additionally, the use of multimodal neuroimaging techniques, assessment of grey matter regional density, cortical thickness, brain connectivity, and measure of gamma-aminobutyric acid (GABA) levels, provides insights into the neural changes induced by the rTMS-ECT combination.\u003c/p\u003e\u003cp\u003eIn designing STIMAGNECT 2, several key modifications were made compared to the original STIMAGNECT study. These adjustments were implemented to address limitations identified in the first study and to improve the robustness and applicability of the findings.\u003c/p\u003e\u003cp\u003eIn the original STIMAGNECT study, the efficacy of rTMS and ECT combination was assessed after the first five ECT sessions. In STIMAGNECT 2, we increased the length of the efficacy assessment ECT to 10 ECT sessions, to study the effects of this combination over a longer duration. Additionally, based on findings from the initial STIMAGNECT study indicating a decrease in the priming effect of rTMS on ECT efficacy over time, we introduced additional rTMS sessions on the day prior to the ECT sessions from the sixth ECT session onward. This modification aims to sustain the priming effect throughout the full duration of the ECT protocol.\u003c/p\u003e\u003cp\u003eAnother change in STIMAGNECT 2 was an increase in sample size to enhance statistical power and improve the generalizability of the results. The first STIMAGNECT study had a relatively small cohort, which limited the ability to detect subtle effects. By increasing the sample size, STIMAGNECT 2 aimed to produce more reliable and reproducible findings.\u003c/p\u003e\u003cp\u003eIn the initial STIMAGNECT study, ECT electrode placement was bitemporal. Our results suggested that priming ECT with rTMS could lower the seizure threshold, as the required ECT dosage was found to be twice as low in the active rTMS group compared to the sham group (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). This finding is supported by Buday et al (2020)\u0026rsquo;s study, which reported a 34.55% average reduction in seizure threshold following rTMS priming (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). However, the first STIMAGNECT protocol did not demonstrate improved cognitive tolerance of bitemporal ECT with the rTMS add-on. Literature indicates that unilateral ultra brief pulse ECT has a lesser impact on retrograde autobiographical memory and cognitive function in general (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). Unilateral ECT shows better efficacy at a high dosage relative to seizure threshold (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e), making seizure threshold reduction particularly relevant, as it may allow for a lower overall ECT dose, and potentially reduce cognitive side effects (\u003cspan additionalcitationids=\"CR48\" citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e). Therefore, in STIMAGNECT 2, we opted for high-intensity ultra-brief pulse unilateral ECT, in the hope of lowering the seizure threshold through rTMS, thereby reducing the electrical charge required to achieve effective ECT and potentially reducing cognitive side effects.\u003c/p\u003e\u003cp\u003eRegarding rTMS, in the initial STIMAGNECT study, the target was defined as the middle part of the middle frontal gyrus, at the intersection of Brodmann areas 9 and 46, guided by neuronavigation, in accordance with previous literature (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e). More recent studies have explored the use of fMRI to optimize rTMS targeting for depression, and suggest that the antidepressant efficacy of the different left DLPFC rTMS targets is associated with their functional anticorrelation to the subgenual cingulate cortex (SGC) (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e). Although it would have been ideal to personalize the rTMS target for each patient using resting-state fMRI, this technique is not yet widely available in clinical practice and was not accessible in most of our participating centers. We therefore opted to use the standardized MNI coordinates described in Cash\u0026rsquo;s 2020 study (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), which reflect the average location of maximal anticorrelation with the SGC across a sample of 1,000 participants.\u003c/p\u003e\u003cp\u003eA major methodological challenge was the choice of the comparator. No sham condition can entirely replicate the sensory and auditory experience of active rTMS while remaining physiologically inactive. We chose not to use scalp electrical stimulation in the sham group to mimic the tactile sensation of active rTMS and therefore excluded from the trial patients with prior experience of magnetic stimulation therapies. To assess the success of blinding, STIMAGNECT 2 includes an evaluation of patients' ability to discern their treatment group, allowing for a better interpretation of the study results.\u003c/p\u003e\u003cp\u003eOne of the key strengths of our study is therefore its rigorous design, including a multicenter, double-blind, randomized controlled methodology.\u003c/p\u003e\n\u003ch3\u003ePerspectives\u003c/h3\u003e\n\u003cp\u003eThe results of this trial are expected to bring answers about rTMS and ECT combination in treatment resistant depression. If rTMS proves to enhance ECT efficacy, accelerate symptom relief, and reduce cognitive side effects, it could improve the acceptability and feasibility of ECT as a treatment option.\u003c/p\u003e\u003cp\u003eFuture research should explore the long-term effects of the rTMS-ECT combination beyond the acute treatment phase, to assess the durability of response and potential relapse rates. Additionally, investigating alternative rTMS protocols, including different stimulation frequencies and coil configurations, may further optimize efficacy and tolerability.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe STIMAGNECT 2 trial will investigate the effect of rTMS as an adjunct to an ECT protocol in treatment resistant depression. Depressive symptoms intensity will be compared after 10 ECT sessions between the active and sham rTMS groups. By investigating the synergistic effects of rTMS and ECT, this study will provide new insight into TRD treatment, potentially paving the way for new neurostimulation strategies that optimize both efficacy and tolerability, ultimately improving the quality of life for individuals suffering from TRD.\u003c/p\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eTrial status\u003c/h2\u003e\u003cp\u003eThis is the 2.0 of the protocol dated march the 22nd, 2024. Recruitment is set to start on September 15th 2025, for a duration of 26 months (until November 2027).\u003c/p\u003e\u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eANSM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAgence Nationale de S\u0026eacute;curit\u0026eacute; du M\u0026eacute;dicament et des Produits de Sant\u0026eacute; (French National Agency for Medicines and Health Products Safety)\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCFQ\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCognitive Failures Questionnaire\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDSM-V\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDiagnostic and Statistical Manual of Mental Disorders, Fifth Edition\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eECT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eElectroconvulsive Therapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eeCRF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eElectronic Case Report Form\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGABA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eGamma-Aminobutyric Acid\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGHU\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eGroupement Hospitalier Universitaire\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHAMD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHamilton Depression Rating Scale\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHPA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHypothalamic-Pituitary-Adrenal\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eICC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIntra-class Correlation Coefficient\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eINM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNeuromodulation Institute\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eINPES\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInstitut National de Pr\u0026eacute;vention et d'\u0026Eacute;ducation pour la Sant\u0026eacute;\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLOCF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLast Observation Carried Forward\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMDD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMajor Depressive Disorder\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMINI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMini International Neuropsychiatric Interview\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMNI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMontreal Neurological Institute\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMagnetic Resonance Imaging\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eQIDS-SR-16\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eQuick Inventory of Depressive Symptomatology\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRL/RI-16\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRey-Lesniak/Raymond-Izard 16-item test\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003erTMS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRepetitive Transcranial Magnetic Stimulation\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSAE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSerious Adverse Event\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSGC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSubgenual Cingulate Cortex\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSPIRIT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eStandard Protocol Items:Recommendations for Interventional Trials\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSSMQ\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSquire Subjective Memory Questionnaire\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTEMPau\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTest of Memory and Learning\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTRD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTreatment-Resistant Depression\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eUKU\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eUdvalg for Kliniske Unders\u0026oslash;gelser (Committee for Clinical Investigations)\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eWe would like to thank Graziella Guesdon, Amel Zettili, Frédérique Caillot, Sébastien Normant for their assistance in this project.\u003c/p\u003e\n\u003cp\u003eAuthor’s contributions {31b}\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMaud Rothärmel, Virginie Moulier, Olivier Guillin, Pierre Quesada have developed the clinical trial methodology, Bastien Kaczmarek, Emmanuel Gérardin and Virginie Moulier have developed the neuroimaging methodology.\u003c/p\u003e\n\u003cp\u003eVirginie Moulier and Léa Clabeau were major contributors in writing the manuscript.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eFunding {4}\u003c/p\u003e\n\u003cp\u003eThis study was financed by the Neuromodulation Institute (INM) of GHU Paris Psychiatry and Neuroscience. Sponsor only has a financial role. It has no authority over analysis, interpretation and writing of the report.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials {29}\u003c/p\u003e\n\u003cp\u003eAny data required to support the protocol can be supplied on request\u003c/p\u003e\n\u003cp\u003eDeclarations\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate {24}\u003c/p\u003e\n\u003cp\u003eThis study will be conducted in accordance with legal and regulatory requirements, as well as the general principles set forth in the International Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences, 2002), Guidelines for Good Clinical Practice (International Conference on Harmonization, 1996), and the Declaration of Helsinki (World Medical Association 1996 and 2008). In addition, the study will be conducted in accordance with the protocol, the International Conference on Harmonization Guideline on Good Clinical Practice, and applicable local regulatory requirements and laws (law n°2004-806, august 9\u003csup\u003eth\u003c/sup\u003e 2004). This protocol obtained a favorable opinion of the Independent Ethics Committee (art. L1123-6 of French Public Health Code), and the National Agency for the Safety of Medicines and Health Products (ANSM) was informed. All participants in the study will sign an informed consent form. Agreement of their legal guardian for patients under guardianship will be asked. The promotor of this research, the Centre Hospitalier du Rouvray, 4 rue Paul Eluard, 76300 Sotteville-lès-Rouen, France, has purchased civil liability insurance from the Société Hospitalière d’Assurance Mutuelle.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication {32}\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eCompeting interests {28}\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eAuthor details\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e¹ Centre Hospitalier du Rouvray, Service Hospitalo-Universitaire de Psychiatrie, Centre d’Excellence Thérapeutique, Sotteville-lès-Rouen, France ; ² INSERM U 1245, University of Rouen, Rouen, France ; ³ Etablissement Public de Santé (EPS) Ville Evrard, Centre de Recherche Clinique, Neuilly-sur-Marne, France ; ⁴ Department of Radiology, Centre Hospitalier Universitaire de Rouen, Rouen, France ; ⁵ Brain Stimulation Lab, Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA ; ⁶ Pôle Hospitalo-Universitaire de Psychiatrie Adulte, Centre Hospitalier Guillaume Régnier, Rennes, France ; ⁷ EPS Ville Evrard, Pôle 93G03, Centre de Recherche Clinique, Neuilly-sur-Marne, France ; ⁸ La Fondation FondaMental, F-94010 Créteil, France ; ⁹ Research and Innovation Unit, Esquirol Hospital, 15 rue du Docteur Marcland, Limoges cedex, 87025, France ; ¹⁰ EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Tropical Neurology, Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, OmegaHealth, Limoges, France ; ¹¹ Université de Bordeaux, 33000 Bordeaux, France ; ¹² Clinique Mirambeau, 64600 Anglet ; ¹³ Inserm UMR-S 1237 PhIND, Presage team, GIP Cyceron, Caen, France ; ¹⁴ Normandie Univ, Université de Caen Normandie (UNICAEN), UFR de Médecine, Caen, France ; ¹⁵ CHU de Caen, Service de Psychiatrie, Caen, France ; ¹⁶ Fédération Hospitalo-Universitaire (FHU) A2M2P- CHU, Caen, France ; ¹⁷ Department of Psychiatry, Service Hospitalo-Universitaire, Groupe Hospitalier Universitaire (GHU) Paris Psychiatrie et Neurosciences, Site Sainte-Anne, Paris, France ; ¹⁸ Institut de Neuromodulation, Groupe Hospitalier Universitaire (GHU) Paris, Psychiatrie et Neurosciences, Centre Hospitalier Sainte-Anne, Pôle Hospitalo-universitaire 15, Université Paris Cité, Paris, France ; ¹⁹ Cognitive Neuroimaging Unit, NeuroSpin Institut national de la santé et de la recherche médicale - Commissariat à l'énergie atomique et aux énergies alternatives (INSERM-CEA), Gif-sur-Yvette, France ; ²⁰ Centre d'Investigation Clinique INSERM 1414, équipe neuropsychiatrie du développement et du comportement, Université de Rennes, Rennes, France ; ²¹ Centre Hospitalier Le Vinatier, Bron, France ; ²² Service de Psychiatrie Adulte et d'Addictologie, CHU d'Angers, Angers, France ; ²³ Université Angers, Faculté de Santé, Angers, France ; ²⁴ Unité de Recherche Clinique Intersectorielle en Psychiatrie, CH Henri Laborit, Poitiers, France ; ²⁵ Université de Poitiers, Poitiers, France ; ²⁶ Centre de Recherches sur la Cognition et l'Apprentissage, CNRS UMR 7295, Université de Poitiers, France ; ²⁷ Service de Psychiatrie de l'Adulte, Centre Expert Dépression Résistante FondaMental, CHU de Grenoble, Hôpital Nord, Grenoble, France ; ²⁸ Service Hospitalo-Universitaire de Psychiatrie et de Psychologie Médicale, CH Henri Laborit, Poitiers, France ; ²⁹ Université Clermont Auvergne, INP, CNRS, Institut Pascal, Clermont-Ferrand, France ; ³⁰ Service de Psychiatrie de l'Adulte et Psychologie Médicale, CHU Clermont-Ferrand, France ; ³¹ UMR 1253 Imaging and Brain, Université de Tours, INSERM, Tours, France ; ³² Université de Nantes, CHU Nantes, UR MIP 4334, Nantes, France ; ³³ Université Grenoble Alpes, Grenoble, France ; ³⁴ INSERM U1216, Grenoble, France ; ³⁵ Département de Psychiatrie, CHU Grenoble Alpes, France ; \u003csup\u003e36\u003c/sup\u003e CHU de Nantes, Addictologie et Psychiatrie de Liaison, Nantes, France ; \u003csup\u003e37\u003c/sup\u003e Nantes Université, CHU Nantes, UR MIP EA 4334, Nantes, France ; \u003csup\u003e38\u003c/sup\u003e Centre Hospitalier Princesse Grace, Unité Neuromodulation, Service de Psychiatrie, Monaco ; \u003csup\u003e39\u003c/sup\u003e Motivation, Brain and Behavior (MBB) Lab, Paris Brain Institute (ICM), Hôpital Pitié-Salpêtrière, Paris, France ; \u003csup\u003e40\u003c/sup\u003e Sorbonne Université, Inserm U1127, CNRS U7225, Paris, France ; \u003csup\u003e41\u003c/sup\u003e Université Paris Cité, Paris, France ; \u003csup\u003e42\u003c/sup\u003e Département de Psychiatrie, SHU, GHU Paris Psychiatrie et Neurosciences, Paris, France ; \u003csup\u003e43\u003c/sup\u003e Département de Biostatistiques, Université de Rouen, CHU Rouen, France ; \u003csup\u003e44\u003c/sup\u003e Faculté de Médecine, Normandie Université, Rouen, France ; \u003csup\u003e45\u003c/sup\u003e Département d’Anesthésie-Réanimation, CHU Rouen, France ; \u003csup\u003e46\u003c/sup\u003e Département de Psychiatrie, CHU de Rouen, France\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOrganization WH. 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Test-Retest Reliability and Minimal Detectable Change of the D2 Test of Attention in Patients with Schizophrenia. Arch Clin Neuropsychol 1 d\u0026eacute;c. 2018;33(8):1060\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBerry DT, Allen RS, Schmitt FA. Rey-Osterrieth Complex Figure: Psychometric characteristics in a geriatric sample. Clin Neuropsychologist. 1991;5(2):143\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCaffarra P, Vezzadini G, Dieci F, Zonato F, Venneri A. Rey-Osterrieth complex figure: normative values in an Italian population sample. Neurol Sci mars. 2002;22(6):443\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePiolino P. La m\u0026eacute;moire autobiographique: Th\u0026eacute;orie et pratique en neuropsychologie. Revue Qu\u0026eacute;b\u0026eacute;coise de Psychologie 1 janv. 2006;27:1\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 : List of the centers and investigators\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"622\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 321px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInvestigators\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCenter/department\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 321px;\"\u003e\n \u003cp\u003eDr Maud Roth\u0026auml;rmel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003eCentre Hospitalier du Rouvray, Sotteville-l\u0026egrave;s-Rouen\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 321px;\"\u003e\n \u003cp\u003ePr Fabien Vinckier / Pr Philippe Domenech\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003eCentre Hospitalier Sainte Anne, Paris\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 321px;\"\u003e\n \u003cp\u003eDr Christophe Daudet\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003eClinique Mirambeau, Anglet\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 321px;\"\u003e\n \u003cp\u003ePr Dominique Drapier / Dr Jean-Marie Batail\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003eCentre Hospitalier Guillaume R\u0026eacute;gnier, Rennes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 321px;\"\u003e\n \u003cp\u003ePr Anne Sauvaget / Dr Andrew Laurin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003eNantes University Hospital, Nantes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 321px;\"\u003e\n \u003cp\u003ePr Nemat Jaafari / Dr Ghina Harika-Germaneau\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003eCentre Hospitalier Henri Laborit, Poitiers\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 321px;\"\u003e\n \u003cp\u003ePr Dominique Januel / Dr Noomane Bouaziz\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003eEPS Ville Evrard, Neuilly-sur-Marne\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 321px;\"\u003e\n \u003cp\u003ePr Sonia Dollfus / Dr Florian Letourneur\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003eCentre Esquirol, Caen University Hospital, Caen\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 321px;\"\u003e\n \u003cp\u003ePr Isabelle Jalenques / Pr Ludovic Samalin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003eClermont Ferrand University Hospital, Clermont Ferrand\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 321px;\"\u003e\n \u003cp\u003eDr Benjamin Calvet\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003eCentre Hospitalier Esquirol, Limoges\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 321px;\"\u003e\n \u003cp\u003ePr B\u0026eacute;n\u0026eacute;dicte Gohier / Dr Fran\u0026ccedil;ois Kazour\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003eAngers University Hospital, Angers\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 321px;\"\u003e\n \u003cp\u003eDr J\u0026eacute;r\u0026ocirc;me Holtzmann / Dr Arnaud Pouchon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003eGrenoble University Hospital, Grenoble\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 321px;\"\u003e\n \u003cp\u003eDr Filipe Galvao / Dr Jerome Brunelin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003eCentre Hospitalier Vinatier, Bron\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 321px;\"\u003e\n \u003cp\u003eDr David Szekely\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 301px;\"\u003e\n \u003cp\u003eCentre Hospitalier Princesse Grasse, Principality of Monaco\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;Table 2 : Validity and reliability of the main and secondary outcomes\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eValidity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eTest-retest reliability and/or sensitivity to change\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eInter-rater reliability\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 601px;\"\u003e\n \u003cp\u003eMain Outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eHamilton Depression Rating Scale 21 items\u0026nbsp;(35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eGood internal consistency with a pooled mean alpha coefficient = 0.78\u0026nbsp;(52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eHigh test-retest reliability, with pooled mean reliability figures = 0.93 \u0026nbsp;(52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003ePooled mean intraclass correlation coefficient (ICC) for interrater reliability = 0.94\u0026nbsp;(52)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 601px;\"\u003e\n \u003cp\u003eSecondary Outcomes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eQuick Inventory of Depressive Symptomatology (QIDS-RS)\u0026nbsp;(53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eGood concurrent validity, with moderate to high correlations (0.68\u0026ndash;0.96) with established depression scales such as the HRSD, MADRS, PHQ-9, BDI-II, and Carroll Rating Scale\u0026nbsp;(53)\u0026nbsp;(54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003erTMS side effects scale (adapted U.K.U)\u0026nbsp;(36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eICC = 0.49\u0026ndash;0.92 for the original U.K.U scale\u0026nbsp;(55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eSquire Subjective Memory Questionnaire (SSMQ)\u0026nbsp;(37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eGood construct validity, correlates significantly with the Rey Auditory Verbal Learning Test\u0026nbsp;(56)\u0026nbsp;(r = 0.31) and Cognitive Failures Questionnaire in the expected directions.\u0026nbsp;(57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eHigh test-retest reliability, with Pearson correlation coefficients = 0.87 (3-month interval) and 0.90 (6-week interval) in separate samples.\u0026nbsp;(57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eCognitive Failures Questionnaire (CFQ)\u0026nbsp;(58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eCronbach\u0026rsquo;s alpha = 0.94\u0026nbsp;(59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eMini-Mental State Examination (MMSE)\u0026nbsp;(38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eConvergent validity: r = 0.7 to 0.9 with other cognitive screening tests\u0026nbsp;(60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eTest-retest reliability coefficients = 0.80 to 0.95\u0026nbsp;(60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eHigh inter-rater reliability (mean kappa value = 0.97)\u0026nbsp;(61)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eRL/RI-16 Test\u0026nbsp;(39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eSensitive enough to differentiate patients with Alzheimer\u0026rsquo;s disease from those with mild cognitive impairment\u0026nbsp;(62), vascular dementia\u0026nbsp;(63)\u0026nbsp;and fronto-temporal dementia\u0026nbsp;(64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eUse of a parallel form which performances are not different from the basic list except for free recall 2 and delayed free recall (parallel form \u0026gt; basic list)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003ed2 attention test\u0026nbsp;(40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eInternal consistency: Cronbach\u0026rsquo;s alpha = 0.97 for total score\u0026nbsp;(65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eThe ICCs for the seven subscores of the d2 between successive sessions were between 0.78 and 0.94\u0026nbsp;(66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eRey-Osterrieth complex figures test\u0026nbsp;(41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eTest-retest reliability coefficients = 0.60 to 0.76\u0026nbsp;(67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eInter-rater reliability for direct copying scores was r = 0.96 (p \u0026lt; 0.0001)\u0026nbsp;(68)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eTEMPau\u0026nbsp;(42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eEffectively differentiates between autobiographical memories of different life periods, assessing both semantic and episodic aspects of memory using standardized scoring criteria\u0026nbsp;(69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 150px;\"\u003e\n \u003cp\u003eStructured 4-point rating system\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eICC = Intra-class correlation coefficient\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Electroconvulsive therapy, Repetitive Transcranial Magnetic Stimulation, Treatment-resistant Depression, Neuromodulation, Combined Brain Stimulation, Randomized controlled trial","lastPublishedDoi":"10.21203/rs.3.rs-7213949/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7213949/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: 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.\u003c/p\u003e\n\u003cp\u003eMethods: 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\u003csup\u003eth\u003c/sup\u003e 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).\u003c/p\u003e\n\u003cp\u003eDiscussion: 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.\u003c/p\u003e\n\u003cp\u003eTrial registration: ClinicalTrials.gov NCT06391723 Id RCB: 2023-A01813-42/1\u003c/p\u003e","manuscriptTitle":"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)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-09 12:47:34","doi":"10.21203/rs.3.rs-7213949/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-09-17T07:11:22+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-02T11:08:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-02T06:46:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-09-01T06:08:41+00:00","index":"","fulltext":""},{"type":"decision","content":"Major revision","date":"2025-08-21T04:17:25+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9a4aee56-1c6a-4487-a524-f827803b0b25","owner":[],"postedDate":"September 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-02T16:00:33+00:00","versionOfRecord":{"articleIdentity":"rs-7213949","link":"https://doi.org/10.1186/s13063-025-09406-4","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2026-01-26 15:58:16","publishedOnDateReadable":"January 26th, 2026"},"versionCreatedAt":"2025-09-09 12:47:34","video":"","vorDoi":"10.1186/s13063-025-09406-4","vorDoiUrl":"https://doi.org/10.1186/s13063-025-09406-4","workflowStages":[]},"version":"v1","identity":"rs-7213949","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7213949","identity":"rs-7213949","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}