Major Depressive DisorderNCT05224206
Neural Mechanisms of Intermittent Theta Burst Stimulation in the Core Depression Network
A study testing Theta burst stimulation in people with Major Depressive Disorder, run by The Royal Ottawa Mental Health Centre at 1 site in Canada.
Trial summary
Repetitive Transcranial magnetic stimulation (TMS) uses magnetic fields to modulate brain activity. A novel form of repetitive TMS (rTMS), intermittent theta burst stimulation (iTBS), has emerged as a promising new treatment for depression. Read more about this study
- Who is it for?
- Ages 18 to 55 years
- Conditions the study is for
- Major Depressive Disorder
- What is being tested?
- Theta burst stimulation
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 22 participants
- Where
- 1 siteCanada
- Study dates
- 26 Apr 2023to 3 Jan 2027
- 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
- Men or women aged 18 to 55 years of age
- Mini-International Neuropsychiatric Interview-confirmed diagnosis of MDD, as a single or recurring episode
- Symptoms of MDD have not improved after ≥ 1 but ≤ 7 adequate dose(s) of antidepressant trial(s) in the current depressive episode
- A baseline score of ≥ 15 on the 17-item Hamilton Rating Scale for Depression (HRSD-17)
- Have received a stable antidepressant regimen for at least four weeks prior to entering trial
- Are voluntary and competent to consent to study
- Can speak and read English
Who cannot join
- 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
- Suicide attempt in the past three months and/or active suicidal intent
- Pregnancy (confirmed by urine test) and/or lactation
- Psychotic features in the current episode
- Any comorbid mental health disorders (including, but not limited to lifetime history of psychotic disorders, OCD, PTSD and/or bipolar I or II disorder) with the exception of anxiety/panic disorders and ADHD
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- Significant unstable medical or neurologic illness confirmed by medical history and blood test at baseline (e.g. uncontrolled diabetes, or renal dysfunction)
- Organic cause to the depressive symptoms (e.g. thyroid dysfunctions), as ruled out by the referring physician
- Contraindication for TMS (e.g., personal history of epilepsy or convulsion, metallic head implant, pacemaker)
- Contraindication for MRI (e.g. metallic implant, claustrophobia)
- Have undergone a prior PET or SPECT research study
- ECT or rTMS treatment in the current depressive episode
- Benzodiazepine use
- Have a body mass index (BMI) higher then 35 or lower then 18
- 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.
About this study
Repetitive Transcranial magnetic stimulation (TMS) uses magnetic fields to modulate brain activity. A novel form of repetitive TMS (rTMS), intermittent theta burst stimulation (iTBS), has emerged as a promising new treatment for depression. This technique may be advantageous due to its very short duration and potentially stronger effect on brain activity in comparison with standard rTMS. However, the exact effect of iTBS on the activity of the brain in clinical populations remains poorly understood. This project aims to improve understanding of the mechanisms of action of iTBS by comparing its neuronal effect to sham treatment in 22 individuals with a diagnosis of major depressive episode, using positron emission tomography (PET) and magnetic resonance imaging (MRI) in a double-blind cross-over experiment, followed by a 6-week daily treatment course of iTBS.
Read the detailed description
Repetitive transcranial magnetic stimulation (rTMS) is a Health Canada approved treatment for major depression. Typical clinical rTMS treatment is delivered on the left dorsolateral prefrontal cortex (DLPFC) at a 10 Hz frequency for 30-45 minutes to increase cortical excitability which will outlast the duration of stimulation. The treatment involves daily sessions that are applied over a four to six-week period. Intermittent theta burst stimulation (iTBS) is a novel refinement of conventional rTMS. iTBS consists of bursts of 3 stimulations at 50 Hz at theta frequency (5 Hz). However, instead of 30-min treatment sessions, iTBS has comparable clinical efficacy with only 3 minutes treatment sessions. Because iTBS is a novel technique, much of its effects on the brain are currently unknown. However, since it is a modified rTMS protocol, it is assumed that its neuronal effects are comparable.
Therapeutic effects of rTMS are thought to be related to its effects on the subgenual anterior cingulate cortex (sgACC; Broadman area 25). In depression, metabolic activity of the sgACC is increased (measured as increase of 18F-labeled fluorodeoxyglucose ([18F]FDG) uptake with positron emission tomography (PET)). Importantly, the metabolic activity of the sgACC appears to be a general marker for treatment response, e.g. [18F]FDG uptake is decreased in response to antidepressant medications or deep brain stimulation. In addition to resting state functional MRI, diffusion weighted imaging has been used to study TMS targets, but this technique has never been used for testing targets for treating depression.
Currently, the system level mechanisms of action of iTBS in depression patients are completely unexplored. Based on prior research the investigators hypothesize that 1) a single session of iTBS will decrease [18F]FDG uptake in the sgACC and 2) the magnitude of decrease is related to the connectivity between the target site and the sgACC. This study will establish the system level mechanisms of action of iTBS, paving a way to improve clinical treatment. This study will also develop connectivity measures that can be used to improve iTBS targeting (i.e. choose iTBS target based on sgACC connectivity) and predict treatment response (i.e. predict iTBS treatment response in patients based on sgACC connectivity).
- Conditions
- Major Depressive Disorder
- Being tested
- Theta burst stimulation
- Keywords
- iTBS, rTMS, positron emission tomography
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Theta burst stimulationDevice
Cool B65 active/placebo coil (left DLPFC) with X100 MagPro rTMS Device (Magventure A/S, Farum, Denmark)
Theta burst stimulationDevice
Cool B70 coil (left DLPFC), with X100 MagPro rTMS Device (Magventure A/S, Farum, Denmark)
| Study group | Role | What they receive |
|---|---|---|
| Sham iTBS/Active iTBS | Sham comparator | Intermittent Theta Burst Stimulation (iTBS) or realistic sham iTBS will be applied to the left DLPFC. Both sessions will be one week apart. Receives: Device: Theta burst stimulation |
| Active iTBS | Active comparator | Intermittent Theta Burst Stimulation (iTBS) will be applied to the left DLPFC. Participants will receive daily sessions (on weekdays) for 6 weeks. Receives: Device: Theta burst stimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Neural mechanisms of iTBS measured by [18F]FDG uptake in the sgACC
The primary outcome measure for Part I is the change in [18F]FDG uptake in the sgACC after iTBS.
Measured: 40 minutes after iTBS
Neuroimaging predictors of iTBS response to treatment - primary measures
The primary clinical outcome measures will be response to treatment and remission. Response to treatment will be defined as at least a 50% reduction in pre-treatment symptoms severity as measured by the mean HRSD-17 score at week 6. Remission will be defined as a HRSD-17 score lower or equal to 7 at week 6.
Measured: 6 weeks
Secondary outcomes (4)
Neuroimaging predictors of iTBS response to treatment - QIDS-SR16
For secondary analyses, improvement in symptoms will be defined as the percentage of change of symptoms at week 6 in comparison with pre-treatment symptoms severity. Response to treatment will be defined as a 50% reduction in pre-treatment symptoms severity as measured by the mean of the Quick Inventory of Depressive Symptomatology (16-item) (Self-Report) (QIDS-SR16). Remission will be defined as a QIDS-SR score ≤ 6.
Measured: 6 weeks
Neuroimaging predictors of iTBS response to treatment - Beck Anxiety Inventory (BAI)
For secondary analyses, improvement in symptoms will be defined as the percentage of change of symptoms at week 6 in comparison with pre-treatment symptoms severity. Response to treatment will be defined as a 50% reduction in pre-treatment symptoms severity. The Beck Anxiety Inventory (BAI) will be used to assess severity of patient anxiety. It is a structured 21-item self-report measure using a likert scale of 0-3. A total score of 0 - 7 is interpreted as a "Minimal" level of anxiety; 8 - 15 as "Mild"; 16 - 25 as "Moderate", and; 26 - 63 as "Severe".
Measured: 6 week
Neuroimaging predictors of iTBS response to treatment - Quality of life (Q-LES-Q-SF)
For secondary analyses, improvement in symptoms will be defined as the percentage of change of symptoms at week 6 in comparison with pre-treatment symptoms severity. Response to treatment will be defined as a 50% reduction in pre-treatment symptoms severity. The Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) will be used to assess response to iTBS treatment. The Q-LES-Q-SF is used to obtain sensitive measures of the degree of enjoyment and satisfaction experienced by subjects in various areas of daily functioning. It's a structured 16-item self-report measure where items are scored on a 5-point Likert scale, from Very Poor to Very Good.
Measured: 6 week
Neuroimaging predictors of iTBS response to treatment - Well-being (WEMWBS)
For secondary analyses, improvement in symptoms will be defined as the percentage of change of symptoms at week 6 in comparison with pre-treatment symptoms severity. Response to treatment will be defined as a 50% reduction in pre-treatment symptoms severity. The Short Warwick Edinburgh Mental Well-Being Scale (SWEMWBS) will be used to assess general overview of mental well-being. It's a self-rated; 7 questions; rated over the past 2 weeks. Scored: 1 (none of the time) to 5 (all of the time).
Measured: 6 week
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Feb 2022
- Study start26 Apr 2023
- Primary completion3 Jan 2027 (estimated)
- Study completion3 Jan 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 22 participants (estimated)
Sponsor and investigators
- Lead sponsor
- The Royal Ottawa Mental Health Centre
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Sara Tremblay, The Royal Ottawa Mental Health Centre
- Investigators
- Sara Tremblay, PhD, Principal investigator, The Royal Ottawa Mental Health Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05224206
- Sponsor's protocol ID
- 2021013
- Status last verified
- May 2026
- First submitted
- 13 Oct 2021
- Last updated
- 15 May 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: All Individual Participant Data collected from this study (IPD) will be de-identified for all parties who have permission to access it. This de-identified data may be shared with other researchers at the Royal's Institute of Mental Health Research. De-identified may be shared with the public only upon request. Please note that all data that has the potential of revealing participants' identity will NOT be used to shared.
Study at a glance
From the registry record, last updated by the sponsor on 15 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neural Mechanisms of Intermittent Theta Burst Stimulation in the Core Depression Network
- ClinicalTrials.gov ID
- NCT05224206
- Acronym / sponsor ID
- 2021013
- Conditions
- Major Depressive Disorder
- Keywords
- iTBS, rTMS, positron emission tomography
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 22 participants (estimated)
- Lead sponsor
- The Royal Ottawa Mental Health CentreUniversity, hospital or other
- Study start
- 26 Apr 2023 (actual)
- Primary completion
- 3 Jan 2027 (estimated)
- Study completion
- 3 Jan 2027 (estimated)
- First posted
- 4 Feb 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Repetitive Transcranial magnetic stimulation (TMS) uses magnetic fields to modulate brain activity. A novel form of repetitive TMS (rTMS), intermittent theta burst stimulation (iTBS), has emerged as a promising new treatment for depression. This technique may be advantageous due to its very short duration and potentially stronger effect on brain activity in comparison with standard rTMS. However, the exact effect of iTBS on the activity of the brain in clinical populations remains poorly understood. This project aims to improve understanding of the mechanisms of action of iTBS by comparing its neuronal effect to sham treatment in 22 individuals with a diagnosis of major depressive episode, using positron emission tomography (PET) and magnetic resonance imaging (MRI) in a double-blind cross-over experiment, followed by a 6-week daily treatment course of iTBS.
Detailed description
Repetitive transcranial magnetic stimulation (rTMS) is a Health Canada approved treatment for major depression. Typical clinical rTMS treatment is delivered on the left dorsolateral prefrontal cortex (DLPFC) at a 10 Hz frequency for 30-45 minutes to increase cortical excitability which will outlast the duration of stimulation. The treatment involves daily sessions that are applied over a four to six-week period. Intermittent theta burst stimulation (iTBS) is a novel refinement of conventional rTMS. iTBS consists of bursts of 3 stimulations at 50 Hz at theta frequency (5 Hz). However, instead of 30-min treatment sessions, iTBS has comparable clinical efficacy with only 3 minutes treatment sessions. Because iTBS is a novel technique, much of its effects on the brain are currently unknown. However, since it is a modified rTMS protocol, it is assumed that its neuronal effects are comparable.
Therapeutic effects of rTMS are thought to be related to its effects on the subgenual anterior cingulate cortex (sgACC; Broadman area 25). In depression, metabolic activity of the sgACC is increased (measured as increase of 18F-labeled fluorodeoxyglucose ([18F]FDG) uptake with positron emission tomography (PET)). Importantly, the metabolic activity of the sgACC appears to be a general marker for treatment response, e.g. [18F]FDG uptake is decreased in response to antidepressant medications or deep brain stimulation. In addition to resting state functional MRI, diffusion weighted imaging has been used to study TMS targets, but this technique has never been used for testing targets for treating depression.
Currently, the system level mechanisms of action of iTBS in depression patients are completely unexplored. Based on prior research the investigators hypothesize that 1) a single session of iTBS will decrease [18F]FDG uptake in the sgACC and 2) the magnitude of decrease is related to the connectivity between the target site and the sgACC. This study will establish the system level mechanisms of action of iTBS, paving a way to improve clinical treatment. This study will also develop connectivity measures that can be used to improve iTBS targeting (i.e. choose iTBS target based on sgACC connectivity) and predict treatment response (i.e. predict iTBS treatment response in patients based on sgACC connectivity).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Sham iTBS/Active iTBS | Sham comparator | Device: Theta burst stimulationIntermittent Theta Burst Stimulation (iTBS) or realistic sham iTBS will be applied to the left DLPFC. Both sessions will be one week apart. |
| Active iTBS | Active comparator | Device: Theta burst stimulationIntermittent Theta Burst Stimulation (iTBS) will be applied to the left DLPFC. Participants will receive daily sessions (on weekdays) for 6 weeks. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- Men or women aged 18 to 55 years of age
- Mini-International Neuropsychiatric Interview-confirmed diagnosis of MDD, as a single or recurring episode
- Symptoms of MDD have not improved after ≥ 1 but ≤ 7 adequate dose(s) of antidepressant trial(s) in the current depressive episode
- A baseline score of ≥ 15 on the 17-item Hamilton Rating Scale for Depression (HRSD-17)
- Have received a stable antidepressant regimen for at least four weeks prior to entering trial
Key exclusion criteria (15 listed)
- 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
- Suicide attempt in the past three months and/or active suicidal intent
- Pregnancy (confirmed by urine test) and/or lactation
- Psychotic features in the current episode
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Theta burst stimulationCool B65 active/placebo coil (left DLPFC) with X100 MagPro rTMS Device (Magventure A/S, Farum, Denmark) | Device | Sham iTBS/Active iTBS |
| Theta burst stimulationCool B70 coil (left DLPFC), with X100 MagPro rTMS Device (Magventure A/S, Farum, Denmark) | Device | Active iTBS |
Primary outcome
Neural mechanisms of iTBS measured by [18F]FDG uptake in the sgACC
Time frame: 40 minutes after iTBS
The primary outcome measure for Part I is the change in [18F]FDG uptake in the sgACC after iTBS.
Neuroimaging predictors of iTBS response to treatment - primary measures
Time frame: 6 weeks
The primary clinical outcome measures will be response to treatment and remission. Response to treatment will be defined as at least a 50% reduction in pre-treatment symptoms severity as measured by the mean HRSD-17 score at week 6. Remission will be defined as a HRSD-17 score lower or equal to 7 at week 6.
4 secondary outcomes
Neuroimaging predictors of iTBS response to treatment - QIDS-SR16
Time frame: 6 weeks
Neuroimaging predictors of iTBS response to treatment - Beck Anxiety Inventory (BAI)
Time frame: 6 week
Neuroimaging predictors of iTBS response to treatment - Quality of life (Q-LES-Q-SF)
Time frame: 6 week
Neuroimaging predictors of iTBS response to treatment - Well-being (WEMWBS)
Time frame: 6 week
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 May 2026.
- Individual participant dataSharing planned: Yes. All Individual Participant Data collected from this study (IPD) will be de-identified for all parties who have permission to access it. This de-identified data may be shared with other researchers at the Royal's Institute of Mental Health Research. De-identified may be shared with the public only upon request. Please note that all data that has the potential of revealing participants' identity will NOT be used to shared.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sara Tremblay, PhD principal investigator
The Royal Ottawa Mental Health Centre
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Theta burst stimulation in people with 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 7 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: under way, not looking for participants, as of the sponsor's last update on 15 May 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. Some participants in this study may receive a placebo. 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?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Neural mechanisms of iTBS measured by [18F]FDG uptake in the sgACC (time frame: 40 minutes after iTBS). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 15 May 2026; AzTrials last refreshed its copy on 7 Nov 2026.