Comparing Outcomes of Theta Burst Stimulation in Depression Using Advanced PET Imaging

NCT07620288 | Not Yet Recruiting

• 1 other identifier: 0383
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

The proposed project will investigate the neurobiological mechanisms of accelerated intermittent Theta Burst Stimulation (iTBS) in major depressive disorder (MDD) using an advanced multimodal imaging approach. This single-arm, within-subject study will deliver one week of accelerated iTBS and use pre-/post-treatment PET/MRI to quantify changes in synaptic density, functional connectivity, and microstructural integrity. We will combine \[¹⁸F\]SynVesT-1 PET with functional, neurochemical and anatomical MRI, such as resting-state fMRI, magnetic resonance spectroscopy (MRS) and neurite orientation dispersion and density imaging (NODDI), to capture treatment-related plasticity. This integrated design will link molecular and network-level mechanisms to clinical improvement, providing an unprecedented mechanistic map of how accelerated iTBS restores brain function in depression.

Conditions

Depression; Depression - Major Depressive Disorder; Depressive Episode; Major Depressive Disorder (MDD)

Keywords

PET; iTBS; accelerated iTBS; rTMS; MRI

Outcome Measures

Primary Outcomes (1)

• Change in Synaptic Density Following iTBS Measured by [¹⁸F]SynVesT-1 PET

  We will quantify changes in synaptic density (expressed as non-displaceable binding potential (BPND)) within (a) the sgACC (primary ROI) and (b) the stimulated DLPFC (secondary ROI), with exploratory analyses in frontal, parietal and cerebellar regions identified in the seed dataset.

  Administered at baseline (prior to first iTBS treatment), and after the iTBS treatment course (i.e. one week later).

Secondary Outcomes (4)

• Change in Resting-State Functional Connectivity Following accelerated iTBS

  Administered at baseline (prior to first iTBS treatment) and after the iTBS treatment course (i.e. one week later).

• Change in Cortical Neurochemistry Following iTBS

  Administered at baseline (prior to first iTBS treatment) and after the iTBS treatment course (i.e. one week later).

• Change in Cerebral Perfusion Following iTBS

  Administered at baseline (prior to first iTBS treatment) and after the iTBS treatment course (i.e. one week later).

• Change in Neurite Microstructure Following iTBS

  Administered at baseline (prior to first iTBS treatment) and after the iTBS treatment course (i.e. one week later).

Other Outcomes (2)

• Incidence of Treatment-Emergent Adverse Events

  Daily Monday-Friday throughout treatment course (1 week).

• Side Effects

  Daily Monday-Friday throughout study (1 week).

Study Arms (1)

Accelerated iTBS

EXPERIMENTAL

One week of accelerated iTBS and use pre-/post-treatment PET/MRI to quantify changes in synaptic density, functional connectivity, and microstructural integrity.

Device: repetitive Transcranial Magnetic Stimulation

Interventions

repetitive Transcranial Magnetic Stimulation DEVICE

Repetitive transcranial magnetic stimulation (rTMS) is a Health Canada approved treatment for major depression. Typical treatments involve 30 to 45 minutes daily sessions delivered over 4 to 6 weeks. Recent technical advances allowed the development of theta burst stimulation (TBS), a novel rTMS paradigm that reduces daily sessions to 3 to 4 minutes while maintaining the same clinical efficacy. This study will specifically be administering intermittent TBS (iTBS), which is a novel refinement of conventional rTMS and consists of bursts of 3 stimulations at 50 Hz at theta frequency (5 Hz).

Also known as: rTMS, TMS, iTBS, TBS

Accelerated iTBS

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• to 55 years old.
• Competent to provide voluntary informed consent.
• English comprehension and verbal communication (participants must be able to both understand and speak English sufficiently to follow study procedures and be understood by study personnel
• Referred by their treating physician.
• Mini-International Neuropsychiatric Interview-confirmed diagnosis of MDD, as a single or recurring episode.
• Symptoms of MDD have not improved after ≥ 1 adequate antidepressant medication trial in the current depressive episode29.
• Baseline score of ≥18 on the 17-item Hamilton Rating Scale for Depression (HRSD-17).
• Maintained a stable treatment regimen for at least four weeks prior to entering the study, defined as being on a stable antidepressant regimen, a stable psychotherapy regimen, both, or neither (i.e., no treatment), with no changes during this period.

You may not qualify if:

• Participants fulfilling any of the following criteria will be excluded from the study:
• Any comorbid mental health disorders (including, but not limited to lifetime history of psychotic disorders, OCD, and/or bipolar I or II disorder) with the exception of anxiety/panic disorders, posttraumatic stress disorder and ADHD
• Current or past (\< 3 months) substance (including nicotine) or alcohol abuse/dependence, as defined in DSM-5 criteria.
• Positive urine test for illegal substances, cannabis, or cotinine.
• Significant unstable medical or neurologic illness confirmed by medical history (e.g. uncontrolled diabetes, or renal dysfunction).
• Breastfeeding or pregnant (confirmed via urine test).
• BMI \> 30 or BMI \< 18.
• Contraindication for TMS (e.g., personal history of epilepsy or convulsion, metallic head implant, pacemaker).
• Contraindication for MRI (e.g. metallic implant, claustrophobia).
• Have received a cumulative radioactivity dose \> 15.2mSv during the last 12 months.
• Have active malignancies (due to high chance of undergoing radiation therapy).
• Suicide attempt in the past three months and/or active suicidal intent.
• Failed (non-response) course of ECT or rTMS treatment in the current depressive episode.
• Benzodiazepine or lithium use. Other psychotropic medications (e.g. ADHD medications) are permitted, if stable in the 4 weeks prior to and during the treatment course)
• Any other condition that, in the opinion of the investigators, would adversely affect the participant's ability to complete the study.

Sponsors & Collaborators

• The Royal Ottawa Mental Health Centre: lead

Study Sites (1)

The Royal's Institute of Mental Health Research

Ottawa, Ontario, K1Z 7K4, Canada

Location

Related Publications (6)

• Cash RFH, Zalesky A, Thomson RH, Tian Y, Cocchi L, Fitzgerald PB. Subgenual Functional Connectivity Predicts Antidepressant Treatment Response to Transcranial Magnetic Stimulation: Independent Validation and Evaluation of Personalization. Biol Psychiatry. 2019 Jul 15;86(2):e5-e7. doi: 10.1016/j.biopsych.2018.12.002. Epub 2019 Jan 19. No abstract available.

  PMID: 30670304 BACKGROUND

• Baeken C, Marinazzo D, Everaert H, Wu GR, Van Hove C, Audenaert K, Goethals I, De Vos F, Peremans K, De Raedt R. The Impact of Accelerated HF-rTMS on the Subgenual Anterior Cingulate Cortex in Refractory Unipolar Major Depression: Insights From 18FDG PET Brain Imaging. Brain Stimul. 2015 Jul-Aug;8(4):808-15. doi: 10.1016/j.brs.2015.01.415. Epub 2015 Feb 7.

  PMID: 25744500 BACKGROUND

• Disner SG, Beevers CG, Haigh EA, Beck AT. Neural mechanisms of the cognitive model of depression. Nat Rev Neurosci. 2011 Jul 6;12(8):467-77. doi: 10.1038/nrn3027.

  PMID: 21731066 BACKGROUND

• Tremblay S, Tuominen L, Zayed V, Pascual-Leone A, Joutsa J. The study of noninvasive brain stimulation using molecular brain imaging: A systematic review. Neuroimage. 2020 Oct 1;219:117023. doi: 10.1016/j.neuroimage.2020.117023. Epub 2020 Jun 5.

  PMID: 32512125 BACKGROUND

• Kang SG, Cho SE. Neuroimaging Biomarkers for Predicting Treatment Response and Recurrence of Major Depressive Disorder. Int J Mol Sci. 2020 Mar 20;21(6):2148. doi: 10.3390/ijms21062148.

  PMID: 32245086 BACKGROUND

• Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, Knyahnytska Y, Kennedy SH, Lam RW, Daskalakis ZJ, Downar J. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018 Apr 28;391(10131):1683-1692. doi: 10.1016/S0140-6736(18)30295-2. Epub 2018 Apr 26.

  PMID: 29726344 BACKGROUND

MeSH Terms

Conditions

Depression; Depressive Disorder, Major

Interventions

Transcranial Magnetic Stimulation

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior; Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics

Study Officials

• Sara Tremblay

  The Royal's Institute of Mental Health Research

  PRINCIPAL INVESTIGATOR

• Lauri Tuominen

  The Royal's Institute of Mental Health Research

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Stacey Shim

CONTACT

613-722-6521; rtms@theroyal.ca

Emma Cummings

CONTACT

613-722-6521

Study Design

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

Study Record Dates

• First Submitted: May 13, 2026
• First Posted: June 2, 2026
• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): July 30, 2028
• Study Completion (Estimated): July 30, 2028
• Last Updated: June 9, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP
• Time Frame: Once data has been included in the OpenNeuro database, data cannot be removed or withdrawn as we will be unable to identify participant information to separate it from the database.
• Access Criteria: The shared data will be hosted on the OpenNeuro (https://openneuro.org/) platform. The dataset becomes publicly available under the Creative Commons Zero (CC0) Public Domain Dedication which places no restrictions on who can use the data or what can be done with them. The OpenNeuro is supported by the United States National Institutes of Mental Health BRAIN Initiative. The OpenNeuro follows the FAIR principles, which states that in order for shared data to be maximally useful for the scientific community, they need to be Findable, Accessible, Interoperable, and Reusable.

Locations

CA (1)