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

NCT07673913 | Not Yet Recruiting

• 1 other identifier: GULHANE-TRD-TMS-BIOMARKER-2026
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Treatment-resistant Depression (TRD); Major Depression

Keywords

Treatment-Resistant Depression; Transcranial Magnetic Stimulation; Biomarkers; Personalized Psychiatry; Neuromodulation

Outcome Measures

Primary Outcomes (1)

• 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.

  Baseline and Week 4

Secondary Outcomes (6)

• Change in Patient Health Questionnaire-9 (PHQ-9) Score

  Baseline and Week 4

• Change in Insomnia Severity Index (ISI) Score

  Baseline and Week 4

• Change in Wisconsin Card Sorting Test Performance

  Baseline and Week 4

• Change in Peripheral Inflammatory Biomarker Levels

  Baseline and Week 4

• Change in Neuroprotective Biomarker Levels

  Baseline and Week 4

Study Arms (1)

Active iTBS Treatment

EXPERIMENTAL

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)

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.

Active iTBS Treatment

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Gulhane Training and Research Hospital: lead

Study Sites (1)

Gulhane Training and Research Hospital

Ankara, Ankara, 06000, Turkey (Türkiye)

Location

Related Publications (4)

• Fyfe-Desmarais G, Desmarais F, Rassart E, Mounier C. Apolipoprotein D in Oxidative Stress and Inflammation. Antioxidants (Basel). 2023 Apr 28;12(5):1027. doi: 10.3390/antiox12051027.

  PMID: 37237893 BACKGROUND

• Lee H, Rhee SJ, Kim J, Lee Y, Kim H, Lee J, Lee K, Shin H, Kim H, Lee TY, Kim M, Kim EY, Kim SH, Ahn YM, Kwon JS, Han D, Ha K. Plasma proteomic data in bipolar II disorders and major depressive disorders. Data Brief. 2021 Oct 17;39:107495. doi: 10.1016/j.dib.2021.107495. eCollection 2021 Dec.

  PMID: 34825021 BACKGROUND

• Perera T, George MS, Grammer G, Janicak PG, Pascual-Leone A, Wirecki TS. The Clinical TMS Society Consensus Review and Treatment Recommendations for TMS Therapy for Major Depressive Disorder. Brain Stimul. 2016 May-Jun;9(3):336-346. doi: 10.1016/j.brs.2016.03.010. Epub 2016 Mar 16.

  PMID: 27090022 BACKGROUND

• Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, Knyahnytska Y, Kennedy SH, Lam RW, Daskalakis ZJ, Downar J. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018 Apr 28;391(10131):1683-1692. doi: 10.1016/S0140-6736(18)30295-2. Epub 2018 Apr 26.

  PMID: 29726344 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant; Depressive Disorder, Major

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Central Study Contacts

BEYAZIT GARİP, Principal Investigator

CONTACT

+903123044512; beyazitgarip@gmail.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Psychiatry, MD, PhD Candidate

Model Details: Participants with treatment-resistant depression will receive active intermittent theta burst stimulation (iTBS) administered over the left dorsolateral prefrontal cortex for 20 sessions during a 4-week treatment period. Healthy control participants will not receive any intervention and will undergo baseline clinical, cognitive, and biological assessments for comparative analyses.

Study Record Dates

• First Submitted: June 23, 2026
• First Posted: June 29, 2026
• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): September 1, 2027
• Last Updated: June 29, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF, ANALYTIC CODE
• Time Frame: Beginning upon publication of the primary study results and ending 5 years after publication.
• 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.

Locations

TU (1)