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.
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%.
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.
Parallel
Personalized Functional-Connectivity-Targeted Accelerated iTBS
DevicePersonalized 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.
Sham Accelerated iTBS
DeviceSham 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.
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
Montgomery-Åsberg Depression Rating Scale (MADRS) Response Rate
Proportion of participants with a clinical response, defined as a 50% or greater reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from pre-treatment baseline
Montgomery-Åsberg Depression Rating Scale (MADRS) Remission Rate
Proportion of participants achieving remission, defined as a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 10 or lower.
Change From Pre-treatment baseline (Day -1) in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Follow-up Visits
Change in MADRS total score from Pre-treatment baseline (Day -1) to each specified follow-up visit. The MADRS total score ranges from 0 to 60, with higher scores indicating more severe depressive symptoms. A greater reduction from baseline indicates greater improvement.
Change in the 30-Item Inventory of Depressive Symptomatology-Self-Report (IDS-SR30) Total Score
Change in self-reported depressive symptom severity assessed using the IDS-SR30. Higher scores indicate greater depressive symptom severity. A greater reduction from pre-treatment baseline (Day -1) indicates greater improvement.
Incidence of Adverse Events and Serious Adverse Events
Relevant information will be collected through active inquiry, participant self-reports, clinical observation, and necessary medical examinations.
Emergence or Worsening of Suicidal Ideation or Suicidal Behavior Assessed Using the Columbia-Suicide Severity Rating Scale
Occurrence or worsening of suicidal ideation or suicidal behavior assessed using the Columbia-Suicide Severity Rating Scale. Outcomes include newly emergent or increased suicidal ideation, suicidal intent, suicidal planning, suicidal behavior, or an increased level of suicide risk compared with baseline.
Emergence or Worsening of Manic Symptoms Assessed by the Young Mania Rating Scale
The Young Mania Rating Scale (YMRS) will be used as a safety measure to monitor the emergence or worsening of manic symptoms during and after treatment. The total score ranges from 0 to 60, with higher scores indicating greater severity of manic symptoms.
Change in Transcranial Magnetic Stimulation-Evoked Potentials
Change in the amplitude and latency of transcranial magnetic stimulation-evoked electroencephalographic potential components, including the N45 and N100 components, following stimulation of the left dorsolateral prefrontal cortex. These measures assess cortical excitation-inhibition balance and neuroplasticity.
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