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.

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder associated with substantial functional impairment, reduced quality of life, increased suicide risk, and significant socioeconomic burden. Despite the availability of pharmacological, psychotherapeutic, and neuromodulation-based treatments, a considerable proportion of patients fail to achieve adequate clinical improvement and develop treatment-resistant depression (TRD).

Treatment-resistant depression is commonly defined as inadequate response to at least two antidepressant medications administered at adequate doses and durations. Patients with TRD frequently experience chronic symptoms, recurrent episodes, impaired psychosocial functioning, increased healthcare utilization, and poorer long-term outcomes.

Intermittent theta burst stimulation (iTBS) has emerged as an effective, non-invasive neuromodulation treatment for TRD. Compared with conventional high-frequency repetitive transcranial magnetic stimulation (rTMS), iTBS offers substantially shorter treatment sessions while maintaining comparable efficacy. However, the biological mechanisms underlying treatment response remain incompletely understood, and reliable biomarkers predicting therapeutic outcomes have not yet been established.

Accumulating evidence suggests that neuroinflammation, impaired neuroplasticity, oxidative stress, and altered immune regulation contribute to the pathophysiology of depression and may influence treatment response. Therefore, investigating biological changes associated with iTBS may improve the understanding of therapeutic mechanisms and facilitate the development of personalized treatment strategies.

This single-center, prospective, investigator-initiated clinical study aims to comprehensively evaluate clinical outcomes, executive functions, and peripheral inflammatory and neuroprotective biomarkers in patients with TRD receiving iTBS treatment.

A total of 100 participants will be enrolled, including 50 patients with treatment-resistant depression and 50 healthy controls. Patients will receive active iTBS over the left dorsolateral prefrontal cortex using a MagVenture X100 device for 20 sessions administered over four weeks. Healthy controls will not receive any intervention and will participate only in baseline assessments.

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 (WCST), Trail Making Test A and B (TMT-A and TMT-B), and verbal fluency tests.

Peripheral blood samples will be collected before and after treatment. Serum levels of 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) will be measured using enzyme-linked immunosorbent assays (ELISA). Gene expression analyses of relevant biomarkers will be performed using quantitative polymerase chain reaction (qPCR).

The primary outcome will be the change in HAM-D-17 scores from baseline to week 4. Secondary outcomes will include changes in clinical scales, executive function performance, biomarker levels, and gene expression profiles. Associations between biological markers, cognitive performance, and treatment response will also be examined.

The study seeks to identify potential biomarker signatures associated with iTBS response and contribute to the development of biomarker-guided, personalized neuromodulation strategies for treatment-resistant depression.

Inclusion Criteria:

Treatment-Resistant Depression Group:

Age between 18 and 55 years. Male or female participants. Diagnosis of Major Depressive Disorder according to DSM-5-TR criteria. Inadequate response to at least two antidepressant treatments administered at adequate doses and durations.

Eligible for transcranial magnetic stimulation (TMS) treatment. Able and willing to provide written informed consent. Able to complete neuropsychological assessments. Able to attend study visits and complete the treatment protocol.

Healthy Control Group:

Age between 18 and 55 years. Male or female participants. No current DSM-5-TR psychiatric disorder. Able and willing to provide written informed consent. Able to complete neuropsychological assessments.

Exclusion Criteria:

Schizophrenia, bipolar disorder, organic mental disorders, or other major psychiatric disorders.

History of epilepsy, brain tumor, severe head trauma, or significant neurological disease.

Any contraindication to TMS. Presence of intracranial metal implants, cardiac pacemakers, cochlear implants, or other incompatible implanted devices.

Active infection. Autoimmune disease or chronic inflammatory disease. Electroconvulsive therapy, deep brain stimulation, or vagus nerve stimulation within the previous 5 years.

Previous intravenous or intranasal ketamine treatment. Pregnancy or breastfeeding. Active alcohol or substance use disorder. Inability to comply with study procedures. Inability to tolerate the iTBS protocol. Withdrawal of informed consent at any stage of the study.

De-identified individual participant data (IPD) underlying the published results will be made available to qualified researchers upon reasonable request after publication of the primary study results. Data sharing will be subject to institutional approval and applicable ethical and legal regulations to protect participant confidentiality.

Beginning upon publication of the primary study results and ending 5 years after publication.

De-identified individual participant data and selected supporting documents will be available to qualified researchers upon reasonable request. Access will be granted after review and approval by the principal investigator and the sponsoring institution. Data will be shared for scientific research purposes only and will require compliance with applicable ethical, legal, and institutional regulations to protect participant confidentiality.