Longitudinal Study on the Sustainability of Transcranial Magnetic Stimulation Protocols - Biomarkers

Обзор

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.

Вмешательства

• Другое Repetitive transcranial magnetic stimulation
  Participants receive a conventional 20Hz TMS protocol as per standard clinical care. During the 20Hz protocol, participants receive 10 daily sessions of 20 Hz rTMS (one per day over 2 weeks), each consisting of 75 trains of 40 pulses (2s per train) with a 10 seconds inter-train interval (ITI), totaling 3,000 pulses per session and 30,000 pulses over the full course. The intensity is 120% of the participant's motor threshold (MT).

Первичные конечные точки

• The sustainability of the antidepressant effect of a conventional 20 Hz rTMS course targeting the left left dorsolateral prefrontal cortex. [Срок оценки: From enrollment until last assessment : 12 months]

Вторичные конечные точки (7)

• Evaluation of sociodemographic determinants associated with durability. [Срок оценки: From enrollment until last assessment : 12 months]
• Evaluation of clinical determinants associated with durability. [Срок оценки: From enrollment until last assessment : 12 months]
• Evaluation of therapeutic determinants associated with durability. [Срок оценки: From enrollment until last assessment : 12 months]
• Evaluation of neuroplasticity as a surrogate of durability. [Срок оценки: From enrollment until last assessment : 12 months]
• Evaluation of heart-brain coupling associated with durability. [Срок оценки: From enrollment until last assessment : 12 months]
• Evaluation of inflammation associated with durability. [Срок оценки: From enrollment until last assessment : 12 months]
• Assessment of TMS-induced changes in MRI-derived metrics of neuroplasticity and its correlation with treatment outcomes. [Срок оценки: From enrollment until last assessment : 12 months]

Критерии участия

Критерии включения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Только случаи

Центры проведения

Франция · 1 центр

• Centre Hospitalier Guillaume Régnier — Rennes

Публикации

• Wilkening, J., Jungeblut, H. M., Adamovic, I., Belov, V., Dechent, P., Eicke, L., Hansen, N., Kozyrev, V., Marten, L. E., Muschke, Y., Riemer, C., Schnell, K., Tura, A., Wilke, M., Witteler, F., Wiltfang, J., Wunderlich, A., Zimmeck, V., Zobott, A., … Goya-Maldonado, R. (2025). Heart rate modulation and clinical improvement in major depression: A randomized clinical trial with accelerated intermit
• Wilkening J, Goya-Maldonado R. White matter tracts associated with iTBS-induced heart rate deceleration and treatment response in major depressive disorder. Transl Psychiatry. 2025 Oct 20;15(1):424. doi: 10.1038/s41398-025-03646-3. PMID 41115869
• Voineskos D, Daskalakis ZJ, Blumberger DM. Management of Treatment-Resistant Depression: Challenges and Strategies. Neuropsychiatr Dis Treat. 2020 Jan 21;16:221-234. doi: 10.2147/NDT.S198774. eCollection 2020. PMID 32021216
• van Rooij SJH, Arulpragasam AR, McDonald WM, Philip NS. Accelerated TMS - moving quickly into the future of depression treatment. Neuropsychopharmacology. 2024 Jan;49(1):128-137. doi: 10.1038/s41386-023-01599-z. Epub 2023 May 22. PMID 37217771
• Suneson K, Lindahl J, Chamli Harsmar S, Soderberg G, Lindqvist D. Inflammatory Depression-Mechanisms and Non-Pharmacological Interventions. Int J Mol Sci. 2021 Feb 6;22(4):1640. doi: 10.3390/ijms22041640. PMID 33561973
• Senova S, Cotovio G, Pascual-Leone A, Oliveira-Maia AJ. Durability of antidepressant response to repetitive transcranial magnetic stimulation: Systematic review and meta-analysis. Brain Stimul. 2019 Jan-Feb;12(1):119-128. doi: 10.1016/j.brs.2018.10.001. Epub 2018 Oct 2. PMID 30344109
• Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006 Nov;163(11):1905-17. doi: 10.1176/ajp.2006.163.11.1905. PMID 17074942
• Popovic D, Dragic M. Repetitive transcranial magnetic stimulation as a universal modulator of synaptic plasticity: Bridging the gap between functional and structural plasticity. Neurochem Int. 2025 Sep;188:106021. doi: 10.1016/j.neuint.2025.106021. Epub 2025 Jul 8. PMID 40639590

Идентификаторы

NCT: NCT07684911 · RC25_01_JMB · 2025-A02833-46

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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