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Relationship of Peripheral Inflammatory and Neuroprotective Biomarkers With Response to Intermittent Theta Burst Stimulation in Treatment-Resistant Depression

Sponsor: Gulhane Training and Research Hospital • ClinicalTrials.gov ID: NCT07673913

Registry updated: 2026-09-14

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Description

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.

Interventions

Intermittent Theta Burst Stimulation (iTBS) (Device)
Intermittent 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.

Eligibility criteria

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.

Conditions

Treatment-resistant Depression (TRD) Major Depression

Locations

Gulhane Training and Research Hospital — Ankara, Ankara, Turkey (Türkiye)
Gulhane Training and Research Hospital — Ankara, Turkey (Türkiye)

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Official Source

Data sourced from ClinicalTrials.gov, a service of the U.S. National Institutes of Health.

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