Neuronavigated aiTBS for TRD

January 7, 2026 updated by: Andre Russowsky Brunoni, University of Texas Southwestern Medical Center

Neuronavigated and Non-Neuronavigated Accelerated Intermittent Theta-Burst Stimulation for Treatment-Resistant Depression A Sham-Controlled Randomized Controlled Trial

The purpose of this study is to confirm the efficacy of two recently introduced repetitive transcranial magnetic stimulation (rTMS) interventions - accelerated intermittent theta-burst stimulation (aiTBS) and individualized neuronavigation - in treatment-resistant depression (TRD). Using a three-arm design (neuronavigated aiTBS, non-neuronavigated aiTBS, and sham), this randomized controlled trial (RCT) is the first to specifically investigate the incremental benefit of neuronavigation within an accelerated stimulation protocol, as well as the first confirmatory RCT comparing the efficacy of each of these active treatments vs. sham, overcoming previous generalizability issues and being conducted in an independent, multicenter US TRD sample.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

247

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • San Diego, California, United States, 92127
        • University of California at San Diego (UCSD)
        • Contact:
        • Principal Investigator:
          • Greg Appelbaum, PhD
    • New York
      • New York, New York, United States, 10065
        • Cornell University
        • Contact:
          • Interventional Psychiatry Program Weill Cornell Medicine
          • Phone Number: 646-962-2900
          • Email: tmsinfo@med.cornell.edu
        • Principal Investigator:
          • Conor Liston, MD PhD
    • Texas
      • Dallas, Texas, United States, 75390
        • University of Texas Southwestern Medical Center
        • Contact:
        • Principal Investigator:
          • Andre Russowsky Brunoni, MD PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Age: 18 to 65 years at the time of consent
  2. Diagnosis: Current major depressive episode (MDE) in the context of unipolar major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), confirmed by clinical psychiatric interview

  3. Treatment Resistance: Documented failure to respond to at least two adequate antidepressant trials on the Antidepressant Treatment History Form-Short Form (ATHF-SF). An adequate trial is defined as:

    1. Antidepressant medication at the maximum tolerated dose for at least 6 weeks, OR
    2. Evidence-based psychotherapy consisting of at least 12 sessions
  4. Depression Severity: Montgomery-Åsberg Depression Rating Scale (MADRS) score >19 at screening, indicating moderate to severe depression
  5. Medication Stability: No changes in antidepressant medication type or dose for at least 6 weeks prior to randomization. Stable doses of permitted medications must be maintained throughout the trial
  6. Informed Consent: Demonstrated capacity to provide written informed consent and comply with study procedures
  7. Availability: Ability to attend treatment sessions for 15 consecutive workdays (approximately 90 minutes per day) and complete assessments including 4-hour evaluations at baseline and endpoint

Exclusion Criteria:

Psychiatric Exclusions:

  1. Any psychiatric disorder other than MDD and comorbid anxiety disorders, including but not limited to:

    (i) Bipolar disorder (Type I or II) (ii) Schizophrenia spectrum or other psychotic disorders (iii) Post-traumatic stress disorder (PTSD) (iv) Attention-deficit/hyperactivity disorder (ADHD) (v) Autism spectrum disorder (ASD) (vi) Obsessive-compulsive disorder (OCD) (vii) Current DSM-5 substance-use disorder (abuse or dependence) within the past 6 months, except nicotine dependence

  2. Personality disorder confirmed on clinical interview by an experienced study psychiatrist
  3. Severe suicidal ideation with structured plan (HDRS-17 item 3 score >2) or as determined by the evaluating psychiatrist
  4. Depressive symptoms better explained by another psychiatric condition, a medical condition, substance use, or use of medications

Medical and Neurological Exclusions:

  1. Any neurological disorder including but not limited to:

    (i) History of seizure disorder or epilepsy (ii) Family history of epilepsy (first-degree relatives) (iii) Significant head trauma with loss of consciousness >5 minutes (iv) Stroke or transient ischemic attack (v) Neurodegenerative disorders (e.g., Parkinson's disease, multiple sclerosis, dementia) (vi) Brain tumor or intracranial mass lesion

  2. Unstable medical condition, defined as any condition requiring acute medical intervention or hospitalization within the past 3 months, or any condition that in the investigator's judgment could affect participant safety or study outcomes

Contraindications to TMS/MRI:

  1. Presence of ferromagnetic material in or near the head, including:

    (i) Intracranial implants (e.g., aneurysm clips, shunts, stimulators) (ii) Cochlear implants or hearing aids (iii) Metallic facial tattoos or permanent makeup (iv) Other implanted medical devices deemed unsafe for MRI/TMS

  2. Inability to tolerate MRI scanning due to claustrophobia or other reasons

Medication Exclusions:

Current use of medications known to significantly alter cortical excitability:

  1. Anticonvulsants (including those used for mood stabilization)
  2. Psychostimulants
  3. Lithium
  4. Benzodiazepines exceeding 10mg diazepam-equivalent daily dose

Prior Treatment Exclusions:

  1. Electroconvulsive therapy (ECT) (≥ 6 sessions) in the current depressive episode
  2. Ketamine or esketamine treatment (≥ 6 sessions) in the current depressive episode
  3. Use of rTMS/iTBS (≥ 15 sessions) during the current depressive episode
  4. Vagus nerve stimulation (VNS) or deep brain stimulation (DBS) implantation

Psychotherapy:

• Concurrent evidence-based psychotherapy is permitted if initiated >4 weeks prior to enrollment and maintained at stable frequency throughout the tria

Other reasons:

  1. Unable to adhere to the study visit schedule
  2. Planning to relocate outside the study catchment area during the trial period
  3. No reliable transportation to attend study visits
  4. Current participation in another research study
  5. Current pregnancy (confirmed by in interview and clinical evaluation and, if deemed necessary, urine pregnancy test at screening)
  6. Currently breastfeeding

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Neuronavigated aiTBS
TBS device placement during treatment determined by MRI imaging
Device: aiTBS
Repetitive transcranial magnetic stimulation (rTMS) interventions - accelerated intermittent theta-burst stimulation (aiTBS) and individualized neuronavigation.
Active Comparator: Non-Neuronavigated aiTBS
Conventional device placement during treatment
Device: aiTBS
Repetitive transcranial magnetic stimulation (rTMS) interventions - accelerated intermittent theta-burst stimulation (aiTBS) and individualized neuronavigation.
Sham Comparator: Sham aiTBS
identical procedures as the other 2 groups but without turning on the device
Device: aiTBS
Repetitive transcranial magnetic stimulation (rTMS) interventions - accelerated intermittent theta-burst stimulation (aiTBS) and individualized neuronavigation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
HDRS-17 - Depression severity assessment
Time Frame: From Baseline visit until week 5 visit
depression severity as assessed by the Hamilton Depression Rating Scale-17 items (HDRS-17)
From Baseline visit until week 5 visit

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Montgomery-Åsberg Depression Rating Scale (MADRS)
Time Frame: From Baseline visit until week 5 visit.
From Baseline visit until week 5 visit.
Quick Inventory of Depressive Symptoms-Self Report (QIDS-SR)
Time Frame: From Baseline visit until week 5 visit
participant self-rated symptomatology
From Baseline visit until week 5 visit

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Texas Southwestern Medical Center

Collaborators

University of California, San Diego
Cornell University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

July 1, 2026

Primary Completion (Estimated)

June 1, 2031

Study Completion (Estimated)

September 1, 2031

Study Registration Dates

First Submitted

January 7, 2026

First Submitted That Met QC Criteria

January 7, 2026

First Posted (Actual)

January 9, 2026

Study Record Updates

Last Update Posted (Actual)

January 9, 2026

Last Update Submitted That Met QC Criteria

January 7, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STU-2025-1926

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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