Major depressive disorder (MDD) is a common and disabling psychiatric condition, and many patients do not achieve adequate response to standard antidepressant treatments. Accelerated intermittent theta burst stimulation (iTBS) is a promising neuromodulation approach that may provide rapid antidepressant effects. This prospective interventional study aims to evaluate the clinical effectiveness of accelerated bilateral dorsomedial prefrontal cortex iTBS in patients with MDD and to investigate treatment-related changes in neurobiological biomarkers, including cortisol, ACTH, BDNF, IL-1β, IL-6, TNF-α, and CRP. Associations between biomarker changes and treatment response will also be examined.

Major depressive disorder (MDD) is a highly prevalent and disabling psychiatric disorder. A substantial proportion of patients do not achieve sufficient improvement with conventional antidepressant treatments, resulting in treatment-resistant or difficult-to-treat depression. Noninvasive neuromodulation approaches such as transcranial magnetic stimulation (TMS) have emerged as effective alternatives for these patients. Accelerated intermittent theta burst stimulation (iTBS), delivered in multiple daily sessions over a short period, may provide faster clinical improvement compared with conventional protocols.

This prospective single-arm interventional study aims to evaluate the clinical efficacy and biological correlates of accelerated bilateral dorsomedial prefrontal cortex (DMPFC) iTBS in adults with MDD who have shown inadequate response to at least one adequate antidepressant treatment trial.

Participants aged 18 to 65 years will receive accelerated bilateral DMPFC iTBS for five consecutive days, with four sessions per day (20 total sessions). Participants demonstrating partial clinical improvement without remission after 20 sessions may receive an additional 10 sessions according to clinical evaluation.

Clinical assessments will be performed at baseline, during treatment, at the end of treatment, and at one-month follow-up. Outcome measures include Hamilton Depression Rating Scale (HAM-D), Beck Depression Inventory, Beck Anxiety Inventory, suicidal ideation measures, self-rated depressive symptom scales, and Clinical Global Impression ratings.

Blood samples will be collected at baseline and after treatment to evaluate neurobiological biomarkers, including cortisol, adrenocorticotropic hormone (ACTH), brain-derived neurotrophic factor (BDNF), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP).

The primary objective is to determine treatment response based on reduction in depressive symptom severity. Secondary objectives are to examine biomarker changes associated with treatment, identify predictors of response, and explore the relationship between early symptom improvement and final clinical outcomes.

Inclusion Criteria:

• Age between 18 and 65 years
• Diagnosis of Major Depressive Disorder according to DSM-5 criteria
• Inadequate response to at least one adequate antidepressant treatment trial
• Hamilton Depression Rating Scale (HAM-D) score ≥14 at baseline
• Stable dose of antidepressant medication for at least 4 weeks prior to study entry
• Ability to provide written informed consent

Exclusion Criteria:

• History of bipolar disorder, schizophrenia, schizoaffective disorder, or psychotic depression
• Current substance use disorder
• Neurological disorders that may affect brain function (e.g., epilepsy, multiple sclerosis, dementia, Parkinson's disease)
• History of epileptic seizures
• Severe head trauma
• Presence of metal implants in the head or neck region
• Cochlear implants
• Cardiac pacemaker or implanted electronic devices
• History of deep brain stimulation or vagus nerve stimulation
• Previous neurosurgical procedures
• Pregnancy or breastfeeding
• Use of medications that may significantly affect neuroendocrine or inflammatory markers (e.g., corticosteroids, immunomodulators)
• Endocrine disorders affecting the hypothalamic-pituitary-adrenal axis (e.g., Cushing's syndrome, Addison's disease, thyroid disorders)
• Autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, Hashimoto thyroiditis)
• Recent surgery or acute infection
• Active suicidal crisis, severe agitation, or inability to comply with study procedures

Individual participant data will not be publicly shared due to institutional and ethical considerations.