Molecular Signatures of TMS Response in Treatment-Resistant Depression

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

NA

Total Enrollment

55 participants

Study Classification

INTERVENTIONAL

Study Start Date

2025-06-15

Study Completion Date

2027-06-01

Brief Summary

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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.

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Detailed Description

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This prospective cohort study aims to investigate the relationship between plasma proteomic and metabolomic profiles and the treatment response to transcranial magnetic stimulation (TMS) in patients with treatment-resistant depression (TRD). TRD is defined as a subtype of major depressive disorder (MDD), characterized by an inadequate response to at least two adequate trials of antidepressant therapy. Despite the clinical efficacy of TMS as a non-invasive neuromodulation treatment, the biological underpinnings that determine patient responsiveness remain unclear. This study addresses that gap by evaluating blood-based molecular biomarkers that may predict or reflect TMS treatment outcomes.

A total of 55 TRD patients, diagnosed according to DSM-5-TR criteria and confirmed through the SCID-5 structured clinical interview, will be enrolled. An additional 55 healthy individuals matched for age and sex will serve as a control group for baseline plasma comparisons. Patients will undergo a standardized TMS protocol using the MagVenture™ X100™ device. The protocol includes 20 treatment sessions over four weeks, with each session delivering 1,800 pulses of intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex (DLPFC). Motor threshold will be assessed weekly to calibrate treatment intensity to 90% of the resting motor threshold.

Blood samples will be collected from TRD patients prior to the first TMS session and after the 20th session, while healthy controls will provide samples at a single time point. Proteomic analysis will be conducted using LC-MS/MS following protein extraction, digestion, and purification. Metabolomic profiling will be carried out using LC-MS coupled with ion mobility spectrometry, enabling the identification of a wide range of plasma metabolites.

Psychiatric assessments, including the Hamilton Depression Rating Scale (HAM-D), Patient Health Questionnaire-9 (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), and the Clinical Global Impression (CGI) scale, will be administered at baseline and post-treatment to monitor clinical outcomes. Data integration and bioinformatics analyses will be performed using MaxQuant, Perseus, and MetaboAnalyst 6.0, enabling the identification of differentially expressed proteins and metabolites associated with treatment response.

The primary objective of the study is to determine whether plasma proteomic and metabolomic profiles differ significantly between TMS responders and non-responders. Secondary objectives include identifying predictive biomarkers for TMS efficacy and assessing biological changes correlated with clinical improvement.

Primary outcomes will focus on identifying molecular signatures that correlate with treatment responsiveness. Secondary outcomes will include changes in depression severity scores, documentation of any adverse effects related to TMS, and examination of correlations between biomarker expression and pharmacological history.

This study is crucial for advancing personalized treatment approaches in psychiatry. By identifying objective, blood-based biomarkers of TMS response, it may become possible to tailor treatment strategies, reduce unnecessary interventions, and improve therapeutic outcomes for individuals suffering from TRD.

Conditions

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Major Depression Disorder

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

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.

Primary Study Purpose

DIAGNOSTIC

Blinding Strategy

NONE

Study Groups

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Transcranial Magnetic Stimualtion Treatment Arm

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.

Group Type EXPERIMENTAL

TMS

Intervention Type 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.

Interventions

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TMS

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.

Intervention Type DEVICE

Eligibility Criteria

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Inclusion Criteria

* 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.

Exclusion Criteria

* 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.

Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes