This randomized, rater-blinded clinical trial aims to compare the effectiveness, safety, and tolerability of accelerated intermittent theta burst stimulation (iTBS) with standard iTBS in adults with major depressive disorder (MDD).
Participants will be randomly assigned in a 1:1 ratio to receive either accelerated or standard iTBS targeting the left dorsolateral prefrontal cortex. Participants may be psychotropic-medication naïve or may continue stable psychotropic medication according to the protocol-defined medication stability criteria. The accelerated iTBS group will receive 45 treatment sessions over approximately 15 treatment days, while the standard iTBS group will receive 20 treatment sessions over 4 weeks.
The primary objective is to compare changes in depressive symptom severity, measured using the 17-item Hamilton Depression Rating Scale (HAM-D17), from baseline to the end-of-treatment assessment. Secondary and exploratory assessments include treatment response and remission, sleep quality, quality of life, cognitive measures, safety and tolerability, resting electroencephalography (EEG), and transcranial magnetic stimulation combined with EEG (TMS-EEG).
Age 18 to 65 years.
Right-handed.
Diagnosis of major depressive disorder according to ICD-10 criteria (F32 or F33), confirmed by a psychiatrist.
17-item Hamilton Depression Rating Scale (HAM-D17) total score ≥18 at screening/baseline.
Intracranial or head/neck metallic foreign bodies or implants that constitute a contraindication to TMS or MRI.
Implanted electronic devices such as a cardiac pacemaker, implantable cardioverter-defibrillator, or deep brain stimulator.
Untreated or clinically unstable thyroid dysfunction based on abnormal TSH and/or free T4 levels.
Clinically significant intracranial structural abnormalities that may affect TMS safety, neuropsychiatric presentation, or study neurophysiological measures.
Parallel
Accelerated Intermittent Theta Burst Stimulation
DeviceIntermittent theta burst stimulation (iTBS) is delivered to the left dorsolateral prefrontal cortex using the Beam F3 approach. Stimulation consists of triplet bursts at 50 Hz repeated at 5 Hz, with 2 seconds on and 8 seconds off. Each session consists of 1,200 pulses delivered at 100% of the resting motor threshold. Participants receive three sessions per treatment day, separated by 30 ± 5-minute intervals, over 15 treatment days, for a total of 45 sessions.
Standard Intermittent Theta Burst Stimulation
DeviceIntermittent theta burst stimulation (iTBS) is delivered to the left dorsolateral prefrontal cortex using the Beam F3 approach. Stimulation consists of triplet bursts at 50 Hz repeated at 5 Hz, with 2 seconds on and 8 seconds off. Each session consists of 600 pulses delivered at 120% of the resting motor threshold. Participants receive one session per treatment day, 5 days per week for 4 weeks, for a total of 20 sessions.
Change in 17-Item Hamilton Depression Rating Scale (HAM-D17) Score From Baseline to End of Treatment
Depressive symptom severity will be assessed using the 17-item Hamilton Depression Rating Scale (HAM-D17). The total score ranges from 0 to 52, with higher scores indicating greater depressive symptom severity. The primary outcome is the change in HAM-D17 total score from baseline (T0) to the end-of-treatment assessment (T4).
Treatment Response Based on HAM-D17
Treatment response is defined as a reduction of at least 50% in the 17-item Hamilton Depression Rating Scale (HAM-D17) total score from baseline.
Remission Based on HAM-D17
Remission is defined as a 17-item Hamilton Depression Rating Scale (HAM-D17) total score of 7 or less at the end of treatment.
Change in Sleep Quality Assessed by the Pittsburgh Sleep Quality Index (PSQI)
Sleep quality is assessed using the Pittsburgh Sleep Quality Index (PSQI). The PSQI global score ranges from 0 to 21, with higher scores indicating poorer sleep quality. Change in PSQI global score from baseline to the end of treatment will be evaluated.
Change in Quality of Life Assessed by the WHOQOL-BREF
Quality of life is assessed using the World Health Organization Quality of Life-BREF (WHOQOL-BREF), which evaluates four domains: physical health, psychological health, social relationships, and environment. Each domain score is transformed to a 0-100 scale, with higher scores indicating better quality of life. Change in each domain score from baseline to the end-of-treatment assessment will be evaluated.
Change in Individual Alpha Frequency (IAF)
Individual alpha frequency (IAF) will be derived from resting-state electroencephalography (EEG). Change in IAF from baseline to the post-treatment neurophysiological assessment will be evaluated as an exploratory neurophysiological outcome.
Change in TMS-EEG TMS-Evoked Potential Amplitudes (N45, P60, and N100)
Transcranial magnetic stimulation-electroencephalography (TMS-EEG) will be used to assess neurophysiological changes. TMS-evoked potential amplitudes, including N45, P60, and N100, will be measured. Changes in N45, P60, and N100 amplitudes from baseline (T0) to the end-of-treatment assessment (T4) will be evaluated as exploratory neurophysiological outcomes.
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