Molecular Signatures of TMS Response in Treatment-Resistant Depression

NCT07039370 | Recruiting

• 1 other identifier: 2025/245 / 46418926
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 2

Brief Summary

Transcranial Magnetic Stimulation (TMS) therapy is an approved and effective treatment option for treatment-resistant depression (TRD). This study aims to identify biomarkers that predict TMS treatment response in TRD, provide insights into the neurobiological mechanisms underlying TMS efficacy, and contribute to personalized treatment strategies. By establishing proteomic and metabolomic signatures, this research seeks to enhance clinical decision-making, reduce healthcare costs, and improve patient outcomes in TRD. The findings will align with the precision medicine movement in psychiatry, advancing biomarker-driven therapeutic approaches for treatment-resistant depression.

Conditions

Major Depression Disorder

Keywords

TMS; Metabolomics; Proteomics; Treatment Resistance; Molecular Signuture

Outcome Measures

Primary Outcomes (8)

• Plasma Proteomic Profile Changes After TMS in Patients with Treatment-Resistant Depression

  Assessment of differences in plasma proteomic profiles in treatment-resistant depression (TRD) patients before and after transcranial magnetic stimulation (TMS), using high-resolution liquid chromatography-mass spectrometry (LC-MS/MS) analysis. Changes in protein expression will be used to identify potential biomarkers of treatment response.

  From enrollment to end of treatment at 4 weeks

• Plasma Metabolomic Profile Changes After TMS in Patients with Treatment-Resistant Depression

  Evaluation of global metabolomic changes in plasma of TRD patients pre- and post-TMS therapy. Analysis will be conducted via liquid chromatography-mass spectrometry with ion mobility separation (LC-TIMS-TOF-MS), enabling identification of differential metabolites associated with clinical outcomes.

  From enrollment to end of treatment at 4 weeks

• Fold Change in Baseline Proteomic Markers Between Treatment Responders and Non-Responders

  Differences in baseline proteomic markers between treatment responders and non-responders will be assessed using LC-MS/MS. Fold change values will be calculated to identify proteins with significant differential expression between the two groups.

  From enrollment to end of the treatment at 4 weeks

• Variable Importance in Projection Scores of Predictive Proteins

  Variable Importance in Projection scores will be calculated using multivariate statistical analysis (e.g., PLS-DA) to rank the importance of baseline proteomic markers in distinguishing treatment responders from non-responders.

  Baseline and End of 4-week treatment

• Area Under the ROC Curve for Predictive Proteomic Markers Between Treatment Responders and Non-Responders

  Receiver Operating Characteristic (ROC) curve analysis will be performed to evaluate the predictive performance of baseline and end-of-treatment proteomic markers in distinguishing treatment responders from non-responders. Area Under the Curve (AUC) values will be calculated to assess discriminative ability.

  Baseline and End of 4-week treatment

• Fold Change in Baseline Plasma Metabolomic Markers Between TMS Responders and Non-Responders

  Fold change in baseline plasma metabolomic expression levels will be assessed between TMS treatment responders and non-responders using LC-MS/MS. The analysis aims to identify significantly altered metabolites that may predict treatment response.

  Baseline

• Variable Importance in Projection Scores of Baseline Plasma Metabolomic Markers Between TMS Responders and Non-Responders

  Variable Importance in Projection scores will be calculated using multivariate statistical models (e.g., PLS-DA) to rank baseline plasma metabolomic markers according to their importance in differentiating TMS treatment responders from non-responders. Unitless

  Baseline and End of 4-week treatment

• Area Under the ROC Curve of Baseline Plasma Metabolomic Markers Between TMS Responders and Non-Responders

  Receiver Operating Characteristic curve analysis will be conducted to evaluate the predictive accuracy of baseline plasma metabolomic markers in distinguishing TMS treatment responders from non-responders. The Area Under Curve (AUC)will quantify each marker's discriminative ability. Measurement Tool: ROC curve analysis Unit of Measure: AUC (0-1 scale)

  Baseline and End of 4-week treatment

Secondary Outcomes (6)

• Change in Depression Severity Based on Hamilton Depression Rating Scale (HAM-D, 17-item)

  From enrollment to the end of the treatment at 4 weeks

• Change in Depression Severity Based on Patient Health Questionnaire-9 (PHQ-9)

  From enrollment to the end of the treatment at 4 weeks

• Change in Subjective Sleep Quality Measured by Pittsburgh Sleep Quality Index [Sleep Quality]

  From enrollment to end of the treatment 4 weeks

• Correlation Between Antidepressant Medication Use and Clinical Response to TMS Measured by Hamilton Depression Rating Scale-17

  From enrollment to end of the treatment at 4 weeks

• Change in Headache and Scalp Pain Severity Measured by Visual Analog Scale (VAS) [Tolerability]

  Baseline and End of 4-week treatment

Study Arms (1)

Transcranial Magnetic Stimualtion Treatment Arm

EXPERIMENTAL

This arm includes participants diagnosed with treatment-resistant depression (TRD) who will receive transcranial magnetic stimulation (TMS) therapy. TMS will be delivered using the MagVenture™ X100™ device. The treatment protocol consists of 20 sessions over a 4-week period (5 sessions per week). Stimulation will target the left dorsolateral prefrontal cortex (DLPFC) using intermittent theta burst stimulation (iTBS). Motor threshold will be determined at baseline and reassessed weekly to calibrate stimulation intensity at 90% of the resting motor threshold. Blood samples will be collected from participants at two time points: prior to the first TMS session (pre-treatment) and following the final (20th) session (post-treatment). Proteomic and metabolomic analyses will be performed using high-resolution liquid chromatography-mass spectrometry (LC-MS). The goal is to identify differentially expressed proteins and metabolites associated with clinical response to TMS.

Device: TMS

Interventions

TMS DEVICE

Transcranial Magnetic Stimulation (TMS) is a non-invasive brain stimulation technique approved for the treatment of major depressive disorder (MDD), particularly in individuals with treatment-resistant depression (TRD). TMS targets the left dorsolateral prefrontal cortex (DLPFC), a brain region often underactive in depression, and modulates neural activity through magnetic pulses. This study aims to evaluate the effects of TMS on plasma proteomic and metabolomic profiles in patients with TRD. Participants will undergo 20 sessions of intermittent theta burst stimulation (iTBS) over four weeks. Blood samples will be collected before and after treatment to identify molecular changes associated with clinical response. Healthy controls will provide single-time-point blood samples for baseline comparison. Findings may support the development of biomarker-based strategies for personalized treatment in psychiatry.

Transcranial Magnetic Stimualtion Treatment Arm

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of Major Depressive Disorder (MDD) according to DSM-5-TR criteria.
• Inadequate clinical response to at least two different antidepressants and/or anti-obsessive agents administered at therapeutic doses and durations.
• Clinical symptoms not better explained by metabolic or organic medical conditions.
• No epileptic activity detected on routine electroencephalography (EEG) prior to TMS initiation.
• Routine pre-TMS laboratory tests reveal no abnormalities that may significantly affect treatment response, including:
• Normal thyroid hormone profile
• No significant vitamin deficiencies
• No markedly elevated inflammatory markers
• No history or current evidence of hearing loss on clinical evaluation; if present, evaluation by an otolaryngologist will be obtained.
• Age 18 years and older.
• Ability to provide written informed consent.

You may not qualify if:

• Any contraindication to TMS as identified in the standardized pre-TMS risk assessment form.
• Presence of epileptic focus detected on pre-TMS EEG.
• History of significant head trauma, loss of consciousness, or intracranial surgery.
• Presence of metal implants or foreign bodies incompatible with TMS (e.g., aneurysm clips, surgical clamps, metallic fragments).
• Abnormal thyroid hormone levels in pre-TMS laboratory testing.
• Significantly elevated inflammation markers (e.g., CRP) in pre-TMS bloodwork.
• Vitamin deficiencies associated with cognitive impairment (e.g., B12, folate) in pre-TMS labs.
• Electrolyte imbalances on pre-TMS blood testing.
• History of psychotic disorder or bipolar I/II disorder.
• History of substance-induced psychosis or bipolar disorder.
• Current or past substance use disorder (including alcohol, stimulants, or illicit drugs), unless abstinent from substances (excluding alcohol) for a minimum of 12 months.
• Voluntary discontinuation of TMS during the treatment course.
• Any serious adverse event or unexpected clinical condition during treatment that necessitates discontinuation of TMS.

Sponsors & Collaborators

• Gulhane Training and Research Hospital: lead

Study Sites (2)

Gulhane Training and Research Hospital

Ankara, Ankara, 06000, Turkey (Türkiye)

RECRUITING

Gulhane Training and Research Hospital

Ankara, Ankara, 06300, Turkey (Türkiye)

RECRUITING

Central Study Contacts

BEYAZIT GARİP, Medical Doctor

CONTACT

+903123044512; beyazitgarip@gmail.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: This is a prospective, single-group, open-label cohort study designed to evaluate the association between plasma proteomic and metabolomic profiles and clinical response to transcranial magnetic stimulation (TMS) in patients with treatment-resistant depression (TRD). All participants in the intervention arm will receive a standardized TMS protocol targeting the left dorsolateral prefrontal cortex. A group of age- and sex-matched healthy individuals will serve as a non-randomized control group for baseline biomarker comparison. No randomization or blinding will be employed.

Study Record Dates

• First Submitted: May 31, 2025
• First Posted: June 26, 2025
• Study Start: June 15, 2025
• Primary Completion (Estimated): December 15, 2026
• Study Completion (Estimated): June 1, 2027
• Last Updated: June 26, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF, CSR
• Time Frame: The data will be made available immediately after the publication, and will remain available for at least 5 years.
• Access Criteria: Anyone who wishes to access the data

Locations

TU (2)