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DepressionNCT07620288

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

A study testing repetitive Transcranial Magnetic Stimulation in people with Depression and Depression - Major Depressive Disorder, run by The Royal Ottawa Mental Health Centre at 1 site in Canada.

Not yet recruiting

Opening soon. The study is approved but enrolment has not started yet. Sites may already take enquiries.

Sites and contacts
Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 55 years
What is being tested?
repetitive Transcranial Magnetic Stimulation
Type of treatment
Medical device
Could I receive a placebo?
No, everyone receives an active treatment
How many people
20 participants
Where
1 siteCanada
Study dates
1 Aug 2026to 30 Jul 2028
Phase
Interventional
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 55 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • For inclusion in the study, participants must fulfill all the following criteria:
  • 18 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.
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  • 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.

Who cannot join

  • 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).
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  • 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.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Emma Cummings contact

613-722-6521 ext. 6586

Canada1 site
  • The Royal's Institute of Mental Health Research

    Ottawa, Ontario, K1Z 7K4

    Sara Tremblay, PhD, 613-722-6521 ext. 6227, Sara.Tremblay@theroyal.ca

Other trials in Canada

About this study

Official title: Measuring Neuroplasticity Outcomes of Theta Burst Stimulation in Depression Using Advanced PET Imaging

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.

Read the detailed description

Major depressive disorder (MDD) is one of the most prevalent and disabling disorders worldwide, affecting approximately one in 20 Canadians at any given time and ranking among the leading causes of lost productivity, poor quality of life, and suicide. Despite major advances in pharmacological and psychotherapeutic interventions, only 40-60% of patients respond to first-line treatments. Theta Burst Stimulation (TBS) represents the next generation of rTMS technology: by delivering patterned bursts of magnetic pulses that mimic intrinsic theta-gamma coupling, TBS is thought to more efficiently engage synaptic plasticity mechanisms that underlie mood regulation. Clinically, iTBS achieves antidepressant efficacy comparable to conventional 10 Hz rTMS in one-tenth of the stimulation time, enabling faster, more accessible treatments. Yet, despite its growing clinical use and regulatory approval in multiple countries, the fundamental mechanisms by which iTBS modulates limbic-cortical networks to alleviate depressive symptoms remain poorly understood. Addressing this knowledge gap is essential to optimizing treatment protocols and advancing precision neuromodulation strategies.

Understanding how iTBS drives recovery thus requires moving beyond traditional symptom-based approaches toward multi-level indices of brain plasticity that capture functional, neurochemical, and microstructural change. Current evidence remains largely descriptive, with limited direct insight into the underlying synaptic or cellular mechanisms of iTBS-induced modulation. Integrating PET with high-resolution MRI techniques provides a unique window on these processes. We now have full capacity for in-house synthesis and imaging with [F18]SynVesT-1. Thus, this tracer quantifies synaptic density in vivo, providing a direct molecular measure of plasticity. The ability to pair [F18]SynVesT-1 PET simultaneously with MRI represents a transformative advance for mechanistic neuromodulation research.

Clinical trials show that accelerated TBS, individually targeted to the DLPFC region most anti-correlated to sgACC, can produce rapid symptom relief within days rather than weeks. However, the neurobiological mechanisms underlying these effects remain unknown. It is hypothesized that repeated stimulation sessions promote cumulative synaptic potentiation and large-scale network reorganization. Elucidating these processes is crucial to optimize dosing parameters, understand inter-individual variability in response, and guide the next generation of biologically informed treatment strategies.

The proposed project will investigate the neurobiological mechanisms of accelerated TBS in MDD using an advanced multimodal imaging approach. In this single-arm, within-subject study, participants will undergo one week of accelerated iTBS treatment while completing pre- and post-treatment positron emission tomography (PET) and magnetic resonance imaging (MRI). PET imaging with the synaptic vesicle tracer [¹⁸F]SynVesT-1 will quantify changes in synaptic density, while MRI sequences such as resting-state functional MRI, magnetic resonance spectroscopy, and neurite orientation dispersion and density imaging (NODDI) will assess functional connectivity and microstructural plasticity. By integrating molecular, functional, and structural measures of brain plasticity, the study will provide new insight into how accelerated iTBS alters brain circuits implicated in depression and how these changes relate to clinical improvement.

Being tested
repetitive Transcranial Magnetic Stimulation
Keywords
PET, iTBS, accelerated iTBS, rTMS, MRI
Medical subject headings
Depression, Depressive Disorder, Major

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • repetitive Transcranial Magnetic StimulationDevice

    Also called rTMS, TMS, iTBS, TBS

    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).

Study groups in NCT07620288
Study groupRoleWhat they receive
Accelerated iTBSExperimentalOne week of accelerated iTBS and use pre-/post-treatment PET/MRI to quantify changes in synaptic density, functional connectivity, and microstructural integrity.
Receives: Device: repetitive Transcranial Magnetic Stimulation

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

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

Secondary outcomes (4)
  1. Change in Resting-State Functional Connectivity Following accelerated iTBS

    Resting-state functional MRI (rs-fMRI) will be used to assess changes in functional connectivity (Fisher z-transformed correlation coefficients) within fronto-limbic networks following accelerated iTBS.

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

  2. Change in Cortical Neurochemistry Following iTBS

    Magnetic resonance spectroscopy (MRS) will be used to assess changes in cortical neurochemical metabolite concentrations or metabolite ratios (e.g., Glx, GABA+/Cr) following accelerated iTBS.

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

  3. Change in Cerebral Perfusion Following iTBS

    Arterial spin labelling (ASL) MRI will be used to assess changes in regional cerebral blood flow levels following accelerated iTBS.

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

  4. Change in Neurite Microstructure Following iTBS

    Neurite Orientation Dispersion and Density Imaging (NODDI) will be used to assess changes in neurite microstructure following accelerated iTBS, as measured by changes in neurite density index (NDI) and orientation dispersion index (ODI).

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Jun 2026
  2. Study start1 Aug 2026 (estimated)
  3. Primary completion30 Jul 2028 (estimated)
  4. Study completion30 Jul 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
20 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07620288
Sponsor's protocol ID
0383
Status last verified
Jun 2026
First submitted
13 May 2026
Last updated
9 Jun 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: After participants have completed their participation, we will ask them for informed consent for the storage of their de-identified data on OpenNeuro (an open access database) for the purpose of unspecified research for unspecified future research. If they do agree to participate, they will be given a unique study code (different from the participant ID used in the previous study) will be assigned to all of the study data instead of personal identifying information (ex. 'John Smith' replaced by the unique study code 'A283422'). This unique study code will be used in the Open Access database to ensure privacy and confidentiality (i.e. de-identified study data cannot be linked to participant in any way). In addition to an unique study code, their de-identified study data used in the Open Access database will include: age, sex, handedness, education level, medical diagnosis, medication, summary scores from clinical interviews, and MRI scans.

Publications

  • 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.

    PubMed 30670304
  • 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.

    PubMed 25744500
  • 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.

    PubMed 21731066
  • 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.

    PubMed 32512125
  • 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.

    PubMed 32245086
  • 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.

    PubMed 29726344

Questions about this trial

What is this clinical trial studying?

A study testing repetitive Transcranial Magnetic Stimulation in people with Depression and Depression - Major Depressive Disorder, run by The Royal Ottawa Mental Health Centre at 1 site in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: opening soon, as of the sponsor's last update on 9 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Stacey Shim (613-722-6521 ext. 6356, rtms@theroyal.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Synaptic Density Following iTBS Measured by [¹⁸F]SynVesT-1 PET (time frame: Administered at baseline (prior to first iTBS treatment), and after the iTBS treatment course (i.e. one week later).). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07620288, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jun 2026.

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