Personalized Accelerated iTBS Versus Sham for Major Depressive Disorder

NCT07843875 | Not Yet Recruiting DMC

• 2 other identifiers: 2026(43)YG202603, 3-1-99-2026-pt22
• Study Type: interventional
• Target: 90
• Locations: 0 countries
• Sites: N/A

Brief Summary

This randomized, double-blind, sham-controlled, parallel-group clinical trial will evaluate the efficacy and safety of individualized functional connectivity-guided accelerated intermittent theta-burst stimulation (iTBS) in adults with major depressive disorder (MDD). A total of 90 participants will be randomly assigned in a 1:1 ratio to receive either active iTBS or matched sham stimulation. Treatment will be administered over 5 consecutive days, with 10 stimulation sessions per day. For each participant, an individualized stimulation target within the left dorsolateral prefrontal cortex will be identified using resting-state functional magnetic resonance imaging (MRI). The primary objective is to compare the change in depressive symptoms, measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), from pre-treatment baseline (Day -1) to 4 weeks post-treatment (Week 4; Day 34) between the active and sham groups. Changes in other clinical symptoms, treatment response, remission, and safety will also be assessed during follow-up through 8 weeks after treatment. Multimodal MRI, resting-state electroencephalography (EEG), and transcranial magnetic stimulation combined with EEG (TMS-EEG) will be collected at prespecified time points. These measures will be used to explore treatment-related changes in brain function and connectivity and to identify potential neuroimaging and neurophysiological biomarkers associated with clinical improvement and the maintenance of treatment effects.

Conditions

Major Depressive Disorder (MDD)

Keywords

accelerated iTBS; functional connectivity targeting; DLPFC; personalized neuromodulation

Outcome Measures

Primary Outcomes (1)

• Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score From pre-treatment baseline (Day -1) to 4 weeks post-treatment (Week 4; Day 34, corresponding to 28 days after the first post-treatment assessment visit)

  Change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline (Day -1) to 4 weeks post-treatment (Week 4; Day 34, corresponding to 28 days after the first post-treatment assessment visit). The MADRS assesses the severity of depressive symptoms, with higher scores indicating greater severity. A greater reduction indicates greater improvement in depressive symptoms

  Pre-treatment baseline (Day -1) to 4 weeks post-treatment (Week 4; Day 34)

Secondary Outcomes (9)

• Montgomery-Åsberg Depression Rating Scale (MADRS) Response Rate

  Pre-treatment baseline (Day -1), 1 day post-treatment (Day 6), 1 week post-treatment (Week 1; Day 13), 4 weeks post-treatment (Week 4; Day 34), 6 weeks post-treatment (Week 6; Day 48), and 8 weeks post-treatment (Week 8; Day 62).

• Montgomery-Åsberg Depression Rating Scale (MADRS) Remission Rate

  1 day post-treatment (Day 6), 1 week post-treatment (Week 1; Day 13), 4 weeks post-treatment (Week 4; Day 34), 6 weeks post-treatment (Week 6; Day 48), and 8 weeks post-treatment (Week 8; Day 62).

• Change From Pre-treatment baseline (Day -1) in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Follow-up Visits

  Pre-treatment baseline (Day -1), 1 day post-treatment (Day 6), 1 week post-treatment (Week 1; Day 13), 6 weeks post-treatment (Week 6; Day 48), and 8 weeks post-treatment (Week 8; Day 62).

• Change in the 30-Item Inventory of Depressive Symptomatology-Self-Report (IDS-SR30) Total Score

  Screening (Day -8), pre-treatment baseline (Day -1), 1 day post-treatment (Day 6), 1 week post-treatment (Week 1; Day 13), 4 weeks post-treatment (Week 4; Day 34), 6 weeks post-treatment (Week 6; Day 48), and 8 weeks post-treatment (Week 8; Day 62).

• Change in 17-item Hamilton Depression Rating Scale (HAM-D-17) Total Score

  Screening (Day -8), pre-treatment baseline (Day -1), 1 day post-treatment (Day 6), 1 week post-treatment (Week 1; Day 13), 4 weeks post-treatment (Week 4; Day 34), 6 weeks post-treatment (Week 6; Day 48), and 8 weeks post-treatment (Week 8; Day 62).

Other Outcomes (6)

• Incidence of Adverse Events and Serious Adverse Events

  From the first stimulation session on Treatment Day 1 through 8 weeks post-treatment (Week 8; Day 62).

• Emergence or Worsening of Suicidal Ideation or Suicidal Behavior Assessed Using the Columbia-Suicide Severity Rating Scale

  Screening (Day -8), pre-treatment baseline (Day -1), 1 day post-treatment (Day 6), 1 week post-treatment (Week 1; Day 13), 4 weeks post-treatment (Week 4; Day 34), 6 weeks post-treatment (Week 6; Day 48), and 8 weeks post-treatment (Week 8; Day 62).

• Emergence or Worsening of Manic Symptoms Assessed by the Young Mania Rating Scale

  Pre-treatment baseline (Day -1), 1 day post-treatment (Day 6), 1 week post-treatment (Week 1; Day 13), 4 weeks post-treatment (Week 4; Day 34), 6 weeks post-treatment (Week 6; Day 48), and 8 weeks post-treatment (Week 8; Day 62).

Study Arms (2)

Active: Accelerated iTBS

EXPERIMENTAL

Participants in this arm will receive personalized functional-connectivity-targeted accelerated intermittent theta-burst stimulation to the left dorsolateral prefrontal cortex. The treatment consists of 10 sessions per day for 5 consecutive days, with 1,800 pulses per session, 90,000 pulses total, 90% resting motor threshold with depth adjustment, and a 50-minute inter-session interval.

Device: Personalized Functional-Connectivity-Targeted Accelerated iTBS

Sham: Accelerated iTBS

SHAM COMPARATOR

Participants in this arm will receive sham accelerated intermittent theta-burst stimulation using the same imaging-based targeting workflow and the same 10 sessions per day for 5 consecutive days schedule. The sham system is designed to match coil positioning, sound, and scalp sensation, while delivering no effective cortical magnetic field.

Device: Sham Accelerated iTBS

Interventions

Sham Accelerated iTBS DEVICE

Sham accelerated intermittent theta-burst stimulation delivered using the same imaging-based targeting workflow and the same 10 sessions per day for 5 consecutive days schedule as the active intervention. The sham system is designed to match coil positioning, acoustic click, and scalp sensation, while delivering no effective cortical magnetic field.

Sham: Accelerated iTBS

Personalized Functional-Connectivity-Targeted Accelerated iTBS DEVICE

Personalized functional-connectivity-targeted accelerated intermittent theta-burst stimulation delivered to the left dorsolateral prefrontal cortex. The stimulation target is individualized using resting-state functional MRI. The active treatment consists of 10 sessions per day for 5 consecutive days, with 1,800 pulses per session, 90,000 total pulses, 90% resting motor threshold with depth adjustment, and a 50-minute inter-session interval.

Active: Accelerated iTBS

Eligibility Criteria

• Age: 22 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Aged 22 to 65 years, regardless of sex. Right-handed.
• Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for major depressive disorder, confirmed using the Mini International Neuropsychiatric Interview (MINI), version 7.0.The current major depressive episode has lasted for at least 4 weeks.
• Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 20 or greater at both screening and baseline.
• Stable depressive symptoms, defined as a difference in MADRS total score between screening and baseline of no more than 20%.
• Currently medication-free or receiving a stable dose of psychiatric medication for at least 4 weeks before enrollment, with agreement to maintain the same medication regimen through the Week 4 follow-up.
• Able to provide a complete and verifiable history of previous antidepressant treatments.
• Eligible to undergo magnetic resonance imaging (MRI).
• Able to complete all protocol-specified resting-state electroencephalography (EEG) and transcranial magnetic stimulation-electroencephalography (TMS-EEG) assessments.
• Able to understand and comply with the study procedures and provide written informed consent.

You may not qualify if:

• Current or previous diagnosis of bipolar disorder, a psychotic disorder, primary obsessive-compulsive disorder, post-traumatic stress disorder, or another psychiatric disorder considered incompatible with study participation.
• A response of "yes" to Item 4 or Item 5 of the suicidal ideation section of the Columbia-Suicide Severity Rating Scale (C-SSRS) during the current depressive episode; suicidal behavior within the 6 months before screening; or current high suicide risk as determined by the investigator.
• A change of more than 20% in MADRS total score between screening and baseline.
• A skull defect or fracture, treatment-resistant epilepsy, brain tumor, stroke, or another serious medical or neurological condition that may affect study participation or safety.
• A cardiac pacemaker, cochlear implant, MRI-incompatible metallic foreign body, implanted electronic device, claustrophobia, or another contraindication to MRI or transcranial magnetic stimulation.
• Pregnant or breastfeeding.
• Participation in another drug or medical-device clinical trial within 1 month before screening.
• Receipt of electroconvulsive therapy, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, vagus nerve stimulation, deep brain stimulation, light therapy, or another systematic neuromodulation treatment within 1 month before screening.
• Any other condition that, in the investigator's judgment, makes the individual unsuitable for participation in the study.

Sponsors & Collaborators

• Capital Medical University: lead

Related Publications (6)

• Rossi S, Antal A, Bestmann S, Bikson M, Brewer C, Brockmoller J, Carpenter LL, Cincotta M, Chen R, Daskalakis JD, Di Lazzaro V, Fox MD, George MS, Gilbert D, Kimiskidis VK, Koch G, Ilmoniemi RJ, Lefaucheur JP, Leocani L, Lisanby SH, Miniussi C, Padberg F, Pascual-Leone A, Paulus W, Peterchev AV, Quartarone A, Rotenberg A, Rothwell J, Rossini PM, Santarnecchi E, Shafi MM, Siebner HR, Ugawa Y, Wassermann EM, Zangen A, Ziemann U, Hallett M; basis of this article began with a Consensus Statement from the IFCN Workshop on "Present, Future of TMS: Safety, Ethical Guidelines", Siena, October 17-20, 2018, updating through April 2020. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines. Clin Neurophysiol. 2021 Jan;132(1):269-306. doi: 10.1016/j.clinph.2020.10.003. Epub 2020 Oct 24.

  PMID: 33243615 BACKGROUND

• Fox MD, Buckner RL, White MP, Greicius MD, Pascual-Leone A. Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate. Biol Psychiatry. 2012 Oct 1;72(7):595-603. doi: 10.1016/j.biopsych.2012.04.028. Epub 2012 Jun 1.

  PMID: 22658708 BACKGROUND

• Cash RFH, Cocchi L, Lv J, Wu Y, Fitzgerald PB, Zalesky A. Personalized connectivity-guided DLPFC-TMS for depression: Advancing computational feasibility, precision and reproducibility. Hum Brain Mapp. 2021 Sep;42(13):4155-4172. doi: 10.1002/hbm.25330. Epub 2021 Feb 5.

  PMID: 33544411 BACKGROUND

• Taylor JJ, Kare MR, Haj-Darwish D, Jones E, Sanderson L, Khosravani S, Leach J, Bomer L, Hall N, Chiulli N, Steuber E, Lin C, Drew W, Palm ST, Chandra A, Frandsen SB, Bekou A, Barbour T, Baratono SR, Gonsalvez I, Lyndon S, Schaper FLWVJ, Wang W, Silbersweig D, Siddiqi SH, Fox MD. Connectivity- vs Scalp-Based Targeting of Accelerated Transcranial Magnetic Stimulation for Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2026 Aug 1;83(8):807-817. doi: 10.1001/jamapsychiatry.2026.1100.

  PMID: 42340706 BACKGROUND

• Cole EJ, Phillips AL, Bentzley BS, Stimpson KH, Nejad R, Barmak F, Veerapal C, Khan N, Cherian K, Felber E, Brown R, Choi E, King S, Pankow H, Bishop JH, Azeez A, Coetzee J, Rapier R, Odenwald N, Carreon D, Hawkins J, Chang M, Keller J, Raj K, DeBattista C, Jo B, Espil FM, Schatzberg AF, Sudheimer KD, Williams NR. Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. Am J Psychiatry. 2022 Feb;179(2):132-141. doi: 10.1176/appi.ajp.2021.20101429. Epub 2021 Oct 29.

  PMID: 34711062 BACKGROUND

• Cole EJ, Stimpson KH, Bentzley BS, Gulser M, Cherian K, Tischler C, Nejad R, Pankow H, Choi E, Aaron H, Espil FM, Pannu J, Xiao X, Duvio D, Solvason HB, Hawkins J, Guerra A, Jo B, Raj KS, Phillips AL, Barmak F, Bishop JH, Coetzee JP, DeBattista C, Keller J, Schatzberg AF, Sudheimer KD, Williams NR. Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. Am J Psychiatry. 2020 Aug 1;177(8):716-726. doi: 10.1176/appi.ajp.2019.19070720. Epub 2020 Apr 7.

  PMID: 32252538 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Major

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Central Study Contacts

Adam Williamson, PhD

CONTACT

8615026544105; full.field.hammer@gmail.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof.

Study Record Dates

• First Submitted: July 12, 2026
• First Posted: September 28, 2026
• Study Start: September 1, 2026
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: September 28, 2026

Record last verified: 2026-09