Treatment-resistant depression (TRD) is a major clinical challenge affecting a substantial proportion of patients with major depressive disorder who do not adequately respond to conventional antidepressant treatments. Intermittent theta burst stimulation (iTBS), a non-invasive neuromodulation technique targeting the left dorsolateral prefrontal cortex, has emerged as an effective treatment option for these patients. However, the biological mechanisms underlying treatment response remain poorly understood.
This single-center, prospective, investigator-initiated clinical study aims to investigate the effects of iTBS on clinical symptoms, executive functions, and peripheral inflammatory and neuroprotective biomarkers in patients with treatment-resistant depression.
Fifty patients with treatment-resistant depression and fifty healthy control participants will be enrolled. Patients will receive active iTBS treatment for four weeks (20 sessions), while healthy controls will undergo baseline clinical, cognitive, and biological assessments without receiving any intervention.
Clinical outcomes will be evaluated using the 17-item Hamilton Depression Rating Scale (HAM-D-17), Patient Health Questionnaire-9 (PHQ-9), Clinical Global Impression (CGI), and Insomnia Severity Index (ISI). Executive functions will be assessed using the Wisconsin Card Sorting Test, Trail Making Test A and B, and verbal fluency tests.
Peripheral blood samples will be collected before and after treatment to measure inflammatory, neuroplasticity, and neuroprotective biomarkers, including IL-1β, IL-6, IL-10, TNF-α, high-sensitivity C-reactive protein (hs-CRP), brain-derived neurotrophic factor (BDNF), apolipoprotein D (APOD), serum amyloid A1 (SAA1), and serum amyloid A2 (SAA2). Gene expression analyses will also be performed using quantitative polymerase chain reaction (qPCR).
The study aims to identify biological mechanisms associated with iTBS treatment response and to explore potential biomarkers that may predict clinical improvement in patients with treatment-resistant depression. The findings may contribute to the development of personalized neuromodulation strategies and biomarker-guided treatment approaches for depression.
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Single group
Intermittent Theta Burst Stimulation (iTBS)
DeviceIntermittent theta burst stimulation (iTBS) will be administered over the left dorsolateral prefrontal cortex using a CE-marked MagVenture X100 transcranial magnetic stimulation device. Stimulation intensity will be set at 90% of each participant's resting motor threshold. The protocol will consist of bursts of three pulses delivered at 50 Hz, repeated at a frequency of 5 Hz, with 2-second stimulation trains followed by 8-second intertrain intervals. Participants will receive 1800 pulses per session, five sessions per week, for a total of 20 sessions over four weeks (36,000 pulses in total). Participants will continue their routine pharmacological treatments throughout the study, and no investigational medicinal products will be initiated as part of the research protocol.
Change in Hamilton Depression Rating Scale (HAM-D-17) Total Score
The primary outcome is the change in the 17-item Hamilton Depression Rating Scale (HAM-D-17) total score between baseline and week 4 following intermittent theta burst stimulation (iTBS) treatment. Clinical response will be defined as a reduction of 50% or greater from baseline, and remission will be defined as a HAM-D-17 total score of 7 or lower.
Change in Patient Health Questionnaire-9 (PHQ-9) Score
Change in depressive symptom severity measured by the Patient Health Questionnaire-9 (PHQ-9) following iTBS treatment.
Change in Insomnia Severity Index (ISI) Score
Change in insomnia severity following iTBS treatment.
Change in Wisconsin Card Sorting Test Performance
Change in executive function performance assessed using the Wisconsin Card Sorting Test
Change in Peripheral Inflammatory Biomarker Levels
Change in IL-1β, IL-6, IL-10, TNF-α, and high-sensitivity C-reactive protein (hs-CRP) levels following iTBS treatment.
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