Accelerated iTBS for Major Depression (AIM-D)

Investigation of the Relationship Between Changes in Neurobiological Biomarkers After Accelerated Transcranial Magnetic Stimulation Treatment and Treatment Response in Patients With Major Depressive Disorder

Major depressive disorder (MDD) is a common and disabling psychiatric condition, and many patients do not achieve adequate response to standard antidepressant treatments. Accelerated intermittent theta burst stimulation (iTBS) is a promising neuromodulation approach that may provide rapid antidepressant effects. This prospective interventional study aims to evaluate the clinical effectiveness of accelerated bilateral dorsomedial prefrontal cortex iTBS in patients with MDD and to investigate treatment-related changes in neurobiological biomarkers, including cortisol, ACTH, BDNF, IL-1β, IL-6, TNF-α, and CRP. Associations between biomarker changes and treatment response will also be examined.

Study Overview

• Status: Recruiting
• Conditions: Major Depressive Disorder (MDD); Treatment Resistant Depression (TRD)
• Intervention / Treatment: Device: Accelerated Intermittent Theta Burst Stimulation (iTBS)

Detailed Description

Major depressive disorder (MDD) is a highly prevalent and disabling psychiatric disorder. A substantial proportion of patients do not achieve sufficient improvement with conventional antidepressant treatments, resulting in treatment-resistant or difficult-to-treat depression. Noninvasive neuromodulation approaches such as transcranial magnetic stimulation (TMS) have emerged as effective alternatives for these patients. Accelerated intermittent theta burst stimulation (iTBS), delivered in multiple daily sessions over a short period, may provide faster clinical improvement compared with conventional protocols.

This prospective single-arm interventional study aims to evaluate the clinical efficacy and biological correlates of accelerated bilateral dorsomedial prefrontal cortex (DMPFC) iTBS in adults with MDD who have shown inadequate response to at least one adequate antidepressant treatment trial.

Participants aged 18 to 65 years will receive accelerated bilateral DMPFC iTBS for five consecutive days, with four sessions per day (20 total sessions). Participants demonstrating partial clinical improvement without remission after 20 sessions may receive an additional 10 sessions according to clinical evaluation.

Clinical assessments will be performed at baseline, during treatment, at the end of treatment, and at one-month follow-up. Outcome measures include Hamilton Depression Rating Scale (HAM-D), Beck Depression Inventory, Beck Anxiety Inventory, suicidal ideation measures, self-rated depressive symptom scales, and Clinical Global Impression ratings.

Blood samples will be collected at baseline and after treatment to evaluate neurobiological biomarkers, including cortisol, adrenocorticotropic hormone (ACTH), brain-derived neurotrophic factor (BDNF), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP).

The primary objective is to determine treatment response based on reduction in depressive symptom severity. Secondary objectives are to examine biomarker changes associated with treatment, identify predictors of response, and explore the relationship between early symptom improvement and final clinical outcomes.

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Merve rANA Altunel Ülkü, MD; Phone Number: +90 506 303 10 68; Email: ranaltunel@gmail.com

Study Locations

• Turkey (Türkiye)
  • Istanbul, Turkey (Türkiye), 34000
    • Recruiting
    • Istanbul University - Cerrahpasa
    • Contact: Merve rANA Altunel Ülkü, MD; Phone Number: +90 506 303 10 68; Email: ranaltunel@gmail.com
    • Contact: Cana Aksoy Poyraz, Prof. Dr.; Phone Number: +90 532 715 95 04; Email: aksoycana@gmail.com
    • Principal Investigator: Merve Rana Altunel Ülkü, MD
    • Sub-Investigator: Cana Aksoy Poyraz, Prof. Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age between 18 and 65 years
• Diagnosis of Major Depressive Disorder according to DSM-5 criteria
• Inadequate response to at least one adequate antidepressant treatment trial
• Hamilton Depression Rating Scale (HAM-D) score ≥14 at baseline
• Stable dose of antidepressant medication for at least 4 weeks prior to study entry
• Ability to provide written informed consent

Exclusion Criteria:

• History of bipolar disorder, schizophrenia, schizoaffective disorder, or psychotic depression
• Current substance use disorder
• Neurological disorders that may affect brain function (e.g., epilepsy, multiple sclerosis, dementia, Parkinson's disease)
• History of epileptic seizures
• Severe head trauma
• Presence of metal implants in the head or neck region
• Cochlear implants
• Cardiac pacemaker or implanted electronic devices
• History of deep brain stimulation or vagus nerve stimulation
• Previous neurosurgical procedures
• Pregnancy or breastfeeding
• Use of medications that may significantly affect neuroendocrine or inflammatory markers (e.g., corticosteroids, immunomodulators)
• Endocrine disorders affecting the hypothalamic-pituitary-adrenal axis (e.g., Cushing's syndrome, Addison's disease, thyroid disorders)
• Autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, Hashimoto thyroiditis)
• Recent surgery or acute infection
• Active suicidal crisis, severe agitation, or inability to comply with study procedures

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Accelerated iTBS; Participants receive accelerated bilateral dorsomedial prefrontal cortex intermittent theta burst stimulation (iTBS) administered over five consecutive days, with four sessions per day (20 sessions total). Participants with partial clinical response may receive an additional 10 sessions.

Device: Accelerated Intermittent Theta Burst Stimulation (iTBS); Accelerated intermittent theta burst stimulation (iTBS) is administered bilaterally to the dorsomedial prefrontal cortex using a double-cone coil, targeting the stimulation site based on anatomical landmarks. Treatment is delivered over five consecutive days with four sessions per day (total of 20 sessions). Each session consists of 600 pulses per hemisphere (1200 pulses total) at an intensity of 120% of the individual motor threshold. Participants with partial response may receive an additional 10 sessions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Hamilton Depression Rating Scale (HAM-D) Score	Change in depressive symptom severity measured by the 17-item Hamilton Depression Rating Scale (HAM-D-17). Scores range from 0 to 53, with higher scores indicating greater depression severity.	Baseline, within 3 days after completion of treatment and 1-month follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Response Rate Based on HAM-D	Proportion of participants achieving ≥50% reduction in HAM-D score from baseline.	within 3 days after completion of treatment
Remission Rate Based on HAM-D	Proportion of participants achieving remission defined as HAM-D score ≤7.	Within 3 days after completion of treatment
Sustained Treatment Response at 1-Month Follow-Up	Proportion of participants maintaining ≥50% reduction in HAM-D score at 1-month follow-up.	1 month after treatment completion
Sustained Remission at 1-Month Follow-Up	Proportion of participants maintaining remission, defined as HAM-D score ≤7, at 1-month follow-up.	1 month after treatment completion
Change in Serum Cortisol and ACTH Levels	Change in serum cortisol and adrenocorticotropic hormone (ACTH) levels following treatment.	Baseline, within 3 days after completion of treatment and 1-month follow-up
Change in Serum BDNF Levels	Change in serum brain-derived neurotrophic factor (BDNF) levels following treatment.	Baseline, within 3 days after completion of treatment, and 1-month follow-up
Change in Inflammatory Biomarkers	Change in serum IL-1β, IL-6, TNF-α, and C-reactive protein (CRP) levels following treatment.	Baseline, within 3 days after completion of treatment, and 1-month follow-up
Change in Beck Depression Inventory (BDI) Score	Change in depressive symptom severity measured by the Beck Depression Inventory(BDI). Scores range from 0 to 63, with higher scores indicating greater depressive symptom severity.	Baseline, within 3 days after completion of treatment, and 1-month follow-up
Change in Beck Anxiety Inventory (BAI) Score	Change in anxiety symptom severity measured by the Beck Anxiety Inventory (BAI). Scores range from 0 to 63, with higher scores indicating greater anxiety severity.	Baseline, end of treatment, and 1-month follow-up
Change in Clinical Global Impression (CGI) Score	The scale includes three clinician-rated dimensions assessing illness severity (1-7), clinical improvement (1-7), and side effect severity (1-4).	Baseline, within 3 days after completion of treatment and 1-month follow-up

Collaborators and Investigators

• Sponsor: Istanbul University - Cerrahpasa
• Investigators: Study Chair: Cana Aksoy Poyraz, Prof. Dr., Istanbul University - Cerrahpasa

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2026
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: April 30, 2026
• First Submitted That Met QC Criteria: May 21, 2026
• First Posted (Actual): May 22, 2026

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 21, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Depression; Neuroinflammation; Cortisol; Transcranial Magnetic Stimulation; Biomarkers; Major Depressive Disorder; Treatment Resistant Depression; BDNF; TMS; Intermittent Theta Burst Stimulation; ACTH; iTBS; Accelerated TMS; Accelerated iTBS; Dorsomedial Prefrontal Cortex
• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Pathologic Processes; Behavioral Symptoms; Inflammation; Mood Disorders; Depressive Disorder; Pathological Conditions, Signs and Symptoms; Behavior; Neuroinflammatory Diseases; Depression; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant
• Other Study ID Numbers: E-24687260-604.01-1433619; TTU-2025-38714 (Other Grant/Funding Number: IU-Cerrahpasa Scientific Research Projects Unit)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be publicly shared due to institutional and ethical considerations.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No