Despite advances in the effective treatment of major depressive disorder using repetitive transcranial magnetic stimulation (rTMS), the processes that determine a patient's response trajectory remain poorly understood.

Currently, there are no validated clinical or neurophysiological markers that can identify factors predicting the durability of the response to rTMS at the individual level. This constitutes a major limitation for planning individualised treatments and highlights the need for precision medicine approaches and reliable biomarkers to predict the long-term efficacy of TMS-based interventions, thereby enabling more informed clinical decisions and optimised resource allocation.

rTMS is assumed to work by inducing neuroplasticity on multiple levels of the nervous system, ranging from modulating neurotransmitter release to changing structural and functional brain circuits. While rTMS likely acts as a universal modulator of neuroplasticity, the exact mechanisms are not fully established, especially regarding long-term durability.

The LONGISTIM-BIO study ("Longitudinal Study on the Durability of Transcranial Magnetic Stimulation Protocols - Biomarkers") aims to explore the duration of the treatment effect following an initial response to a course of TMS treatment and examines potential neurophysiological and clinical/sociodemographic predictors associated with the trajectories of the treatment effect. More explicitly, it examines neuroplasticity as a biomarker of treatment response durability, and explores its association with heart-brain-coupling (HBC), a physiological marker of rTMS target engagement, as well as inflammation, as measured by a blood test (white blood cells, C-reactive protein (CRP)).

During this study, participants undergo an rTMS treatment as per standard clinical care. They receive daily sessions of 20Hz rTMS targeting the left dorsolateral prefrontal cortex during which the heart rate will be recorded. Before the first rTMS session, after the last session, and one month after the last session, the severity of depression is evaluated using both the MADRS and the PHQ-8 questionnaire. At the one-month follow-up, the effectiveness of the course is determined by a 50% improvement in the MADRS score. Following the 1-month follow-up visit, if meeting the inclusion criteria, patients will receive bi-weekly assessments of depression severity (PHQ-8 as primary and MADRS self-rated questionnaire as secondary outcome). If two consecutive PHQ-8 questionnaires are pathological (score ≥10), a new rTMS course is scheduled with the shortest delay possible.

During this new course of treatment, participation in the study includes:

• a blood draw prior to the first TMS session
• 4 magnetic resonance imaging (MRI) scans: #1 before the course of treatment, #2 at the end of the course, #3 one month after the end of the treatment, and #4 upon the expected date of relapse.

Patients will again be monitored using self-report questionnaires (PHQ-8 and MADRS-SR) every 2 weeks until a relapse occurs.

Inclusion Criteria:

• Patients aged 18 or older.
• Patients who have experienced treatment-resistant unipolar or bipolar depression and responded to a previous TMS course (response defined by a 50% reduction in MADRS score).
• Sufficient command of French to complete questionnaires and follow instructions during MRI assessments and TMS treatments.
• Willingness to comply with all study procedures, including availability for the duration of the study, and to communicate with study staff about adverse events and other clinically relevant information.
• Patients who have expressed their informed written consent to participate in the study.
• Person affiliated with a social welfare scheme or other scheme.

Non-inclusion Criteria:

• Current psychiatric comorbidity (suicidal risk, psychotic episode).
• Unstable somatic pathology: active cancer, unstabilized endocrinological pathology, untreated sleep apnea.
• For neuroimaging: Contraindications to magnetic resonance imaging (MRI) such as ferromagnetic metal in the body or severe claustrophobia
• Adults under legal protection (legal guardianship, conservatorship, trusteeship), persons deprived of their liberty
• Pregnancy or breast-feeding.

Patients undergoing a TMS course as part of clinical care at the Adult Psychiatry University Hospital Unit of the Guillaume Régnier Hospital Center.

Data about study protocol and clinical information will be available on request from other researchers.