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.
Study 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.
Eligibility
Sex
ALL
Min age
18 Years
Max age
65 Years
Healthy volunteers
Accepted
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.
Primary outcome measure(s)
Plasma Proteomic Profile Changes After TMS in Patients with Treatment-Resistant Depression — From enrollment to end of treatment at 4 weeks 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.
Plasma Metabolomic Profile Changes After TMS in Patients with Treatment-Resistant Depression — From enrollment to end of treatment at 4 weeks 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.
Fold Change in Baseline Proteomic Markers Between Treatment Responders and Non-Responders — From enrollment to end of the treatment at 4 weeks 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.
Variable Importance in Projection Scores of Predictive Proteins — Baseline and End of 4-week treatment 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.
Area Under the ROC Curve for Predictive Proteomic Markers Between Treatment Responders and Non-Responders — Baseline and End of 4-week treatment 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.
Fold Change in Baseline Plasma Metabolomic Markers Between TMS Responders and Non-Responders — Baseline 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.
Variable Importance in Projection Scores of Baseline Plasma Metabolomic Markers Between TMS Responders and Non-Responders — Baseline and End of 4-week treatment 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
Area Under the ROC Curve of Baseline Plasma Metabolomic Markers Between TMS Responders and Non-Responders — Baseline and End of 4-week treatment 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)
Trial sites (2)
Facility
City
Region
Status
Gulhane Training and Research Hospital
Ankara
Ankara
Recruiting
Gulhane Training and Research Hospital
Ankara
Ankara
Recruiting
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This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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