Personalized Accelerated iTBS Versus Sham for Major Depressive Disorder (iTBS-MDD)

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.

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.

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.

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.

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

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

Proportion of participants achieving remission, defined as a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 10 or lower.

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 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.

Change in clinician-rated depressive symptom severity assessed using the HAM-D-17. The total score ranges from 0 to 52, with higher scores indicating greater depressive symptom severity. A greater reduction from pre-treatment baseline (Day -1) indicates greater improvement.

Change in SHAPS total score from baseline to each follow-up visit. The SHAPS is a 14-item self-reported measure of hedonic capacity and anhedonia. Higher scores indicate greater anhedonia, and a reduction from Pre-treatment baseline (Day -1) indicates improvement

The Clinical Global Impression (CGI) will be used to assess overall changes in participants' clinical condition and treatment response throughout the study.

Change in PSQI total score from baseline to each follow-up visit. The PSQI assesses subjective sleep quality and sleep disturbance. Total scores range from 0 to 21, with higher scores indicating poorer sleep quality. A reduction from baseline indicates improvement.

Change in the MCCB overall composite score and prespecified cognitive-domain scores from baseline. The MCCB assesses processing speed, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. Higher scores indicate better cognitive performance.

Relevant information will be collected through active inquiry, participant self-reports, clinical observation, and necessary medical examinations.

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.

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 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.

Changes in prespecified resting-state functional MRI-derived functional connectivity measures from baseline to each post-treatment assessment. These measures will include functional connectivity between the left dorsolateral prefrontal cortex target and the subgenual anterior cingulate cortex (sgACC), functional connectivity within the default mode network (DMN), functional connectivity between the sgACC and the DMN,and functional connectivity between the DLPFC and the DMN.

Changes in prespecified measures derived from resting-state electroencephalography (EEG). These measures will include frontal alpha asymmetry, alpha-band current source density, the aperiodic 1/f slope, and EEG spectral characteristics. These exploratory measures will be used to evaluate treatment-related changes in electrophysiological activity and their associations with clinical outcomes.