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

June 23, 2026 updated by: Beyazit Garip, Gulhane Training and Research Hospital

Relationship Between Response to Transcranial Magnetic Stimulation and Peripheral Inflammatory and Neuroprotective Biomarkers in Patients With Treatment-Resistant Depression

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

100

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Turkey (Türkiye)
    • Ankara
      • Ankara, Ankara, Turkey (Türkiye), 06000
        • Gulhane Training and Research Hospital
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

Yes

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Active iTBS Treatment
Participants with treatment-resistant depression will receive active intermittent theta burst stimulation (iTBS) over the left dorsolateral prefrontal cortex using a MagVenture X100 device. Treatment will be administered at 90% of the resting motor threshold, with 1800 pulses per session, 5 sessions per week, for a total of 20 sessions over 4 weeks. Participants will continue their routine pharmacological treatments throughout the study. Clinical assessments, neuropsychological testing, and peripheral biomarker analyses will be performed before and after treatment.
Device: Intermittent Theta Burst Stimulation (iTBS)
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Hamilton Depression Rating Scale (HAM-D-17) Total Score
Time Frame: Baseline and Week 4
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.
Baseline and Week 4

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Patient Health Questionnaire-9 (PHQ-9) Score
Time Frame: Baseline and Week 4
Change in depressive symptom severity measured by the Patient Health Questionnaire-9 (PHQ-9) following iTBS treatment.
Baseline and Week 4
Change in Insomnia Severity Index (ISI) Score
Time Frame: Baseline and Week 4
Change in insomnia severity following iTBS treatment.
Baseline and Week 4
Change in Wisconsin Card Sorting Test Performance
Time Frame: Baseline and Week 4
Change in executive function performance assessed using the Wisconsin Card Sorting Test
Baseline and Week 4
Change in Peripheral Inflammatory Biomarker Levels
Time Frame: Baseline and Week 4
Change in IL-1β, IL-6, IL-10, TNF-α, and high-sensitivity C-reactive protein (hs-CRP) levels following iTBS treatment.
Baseline and Week 4
Change in Neuroprotective Biomarker Levels
Time Frame: Baseline and Week 4
Change in BDNF, APOD, SAA1, and SAA2 levels following iTBS treatment
Baseline and Week 4
Change in Gene Expression Profiles
Time Frame: Baseline and Week 4
Change in gene expression levels of inflammatory and neuroprotective biomarkers measured by quantitative polymerase chain reaction (qPCR).
Baseline and Week 4

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Gulhane Training and Research Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

September 1, 2026

Primary Completion (Estimated)

September 1, 2027

Study Completion (Estimated)

September 1, 2027

Study Registration Dates

First Submitted

June 23, 2026

First Submitted That Met QC Criteria

June 23, 2026

First Posted (Actual)

June 29, 2026

Study Record Updates

Last Update Posted (Actual)

June 29, 2026

Last Update Submitted That Met QC Criteria

June 23, 2026

Last Verified

June 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GULHANE-TRD-TMS-BIOMARKER-2026

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

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.

IPD Sharing Time Frame

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

IPD Sharing Access Criteria

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.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF
  • ANALYTIC_CODE

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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