Major Depressive Disorder (MDD)Phase 1INSPiRE-DNCT07033780
Theta-Burst Stimulation to Treat Depression
A Phase 1 study testing Spaced iTBS and Compressed iTBS in people with Major Depressive Disorder (MDD), run by Centre for Addiction and Mental Health at 1 site in Canada.
Trial summary
The goal of this clinical trial is to explore the effects of non-invasive brain stimulation protocols using intermittent theta-burst stimulation (iTBS) on brain plasticity and depression severity in depressed individuals aged 18 to 50 years old. Read more about this study
- Who is it for?
- Ages 18 to 50 years
- Conditions the study is for
- Major Depressive Disorder (MDD)
- What is being tested?
- Spaced iTBS and Compressed iTBS
- Type of treatment
- Injection or infusion, Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 84 participants
- Where
- 1 siteCanada
- Study dates
- Jun 2025to Dec 2026
- Phase
- Phase 1
- 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 50 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Aged 18-50 years old;
- Must meet criteria for a current Major Depressive Episode (MDE) as ascertained using the Structured Clinical Interview for DSM 5 (SCID-5);
- Hamilton Rating Scale for Depression (HRSD-17) score > 7;
- Must be on a stable antidepressant regimen for a minimum of 4 weeks prior to enrollment, if currently taking antidepressants;
- Right handed or ambidextrous, assessed using the Edinburgh Handedness Inventory (EHI);
- Sufficiently proficient in English to complete the required study assessments, as per investigator judgement;
- Willingness and capacity to provide informed consent;
- Willingness to comply with all study procedures.
Who cannot join
- Age 17 years or less, or greater than 51 years old, as brain plasticity is known to be affected by age;
- Presence of any DSM-5 diagnosis (other than MDD), known to be associated with prefrontal cortical dysfunction, including lifetime diagnoses of bipolar disorder, intellectual disability, or a psychotic disorder, assessed using the SCID-5 and as per investigator judgement;
- Presence of acute suicidal intent, as determined by the Scale for Suicidal Ideation (SSI);
- Contradictions to MRI or TMS (e.g., cardiac pacemaker, acoustic device, history of seizures, pregnancy), assessed using the MRI Safety Form and TMS Adult Safety Screen (TASS) and as per investigator judgement;
- Left handed, assessed using the EHI, to minimize the heterogeneity in cortical excitability and plasticity;
- Current antipsychotic, antiepileptic, or benzodiazepine use given their potential effects on cortical plasticity, as ascertained through a medication review. An exception will be made if they are taking gabapentin or pregabalin prescribed only for chronic pain, and if the dose had been stable for at least 4 weeks prior to study enrollment.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Canada1 site, 1 recruiting
- Recruiting
Centre for Addiction and Mental Health
Toronto, Ontario, M6J 1H4
Christoph Zrenner, MD, (416) 535-8501 ext. 34319, christoph.zrenner@camh.ca
Dewi Clark, MHSc, (416) 535-8501 ext. 30409, dewi.clark@camh.ca
About this study
Official title: Optimization of Prefrontal Theta-Burst Stimulation to Treat Depression: A Bench to First-in-Human Study
The goal of this clinical trial is to explore the effects of non-invasive brain stimulation protocols using intermittent theta-burst stimulation (iTBS) on brain plasticity and depression severity in depressed individuals aged 18 to 50 years old. Brain plasticity is the brain's ability to change through growth or reorganization. iTBS is a form of transcranial magnetic stimulation (TMS), where magnetic pulses are applied to the scalp using a coil. These pulses pass through the scalp, and can alter brain activity in the area underneath the coil. Based on previous research conducted in animals and humans, researchers believe that iTBS can strengthen the connections between cells in the brain, leading to improved brain plasticity.
This trial will compare the effects of the compressed iTBS (iTBS-c) protocol, which is commonly used to treat depression, and the spaced iTBS (iTBS-s) protocol. Researchers want to find out which protocol is better able to produce changes in brain plasticity and improve symptoms of depression among individuals diagnosed with Major Depressive Disorder (MDD). In this trial, participants will be randomized to receive 3 sessions of iTBS-s or iTBS-c, undergo a washout period of at least 2 weeks, then complete 3 sessions of the opposite iTBS intervention.
Read more
Participants will complete 5 study visits within the span of 2-3 months, including:
- Screening assessments to determine eligibility \& 1 sham iTBS (iTBS-sh) session to assess tolerability of the brain stimulation (Visit 1);
- 1 Magnetic Resonance Imaging (MRI) brain scan and randomization (Visit 2);
- Safety and clinical assessments, iTBS-s or iTBS-c intervention, TMS evoked electroencephalography (TMS-EEG) measurements, and post-iTBS questionnaires (Visits 3-5) followed by a washout period of at least 2 weeks;
- Safety and clinical assessments, the opposite iTBS-s or iTBS-c intervention originally randomized to, TMS-EEG measurements, and post-iTBS questionnaires (Visits 6-8).
Read the detailed description
Major Depressive Disorder (MDD) is a mental illness affecting millions of individuals worldwide and in Canada, and is a leading cause of morbidity, mortality, and disability. While antidepressant medications are effective in treating MDD, their efficacy is moderate and systemic side-effects persist, such as sexual dysfunction, drowsiness, weight gain, and dry mouth. Thus, more effective treatments are needed for MDD.
Neuroimaging techniques have implicated the dysregulation of brain plasticity in depression. In particular, long-term potentiation (LTP)-like activity in the dorsolateral prefrontal cortex (DLPFC) and the motor cortex is known to be impaired in MDD. As such, transcranial magnetic stimulation (TMS)-based interventions, which aim to modify underlying cortical activity, are now established treatments of depression. Intermittent theta-burst stimulation (iTBS), a novel form of repetitive TMS (rTMS) approved by the US Food and Drug Administration (FDA) for the treatment of depression, delivers intermittent, high-frequency theta bursts. It has been demonstrated to induce sustained plasticity in the DLPFC and the motor cortex. Studies have shown that iTBS is equally effective as conventional rTMS in terms of response rates, and its adverse effects are comparable to iTBS-sh and active rTMS. One key advantage of iTBS over rTMS is its time efficiency, with each session lasting approximately 3 min compared to up to 40 min with rTMS. Notwithstanding its efficiency, systematic reviews of RCTs indicate no significant difference in remission rates - defined as a reduction in symptoms below a threshold indicating euthymic state - between iTBS (~26%) and iTBS-sh (~19%), or between iTBS (32%) and rTMS (27%). Thus, while iTBS is well tolerated, efficient and effective in reducing symptoms of MDD, its efficacy is still far from optimal as is the case for other treatments of depression.
Based on promising research conducted in the hippocampus of rodents, the investigators believe that modifying some parameters of the iTBS protocol may be more effective in inducing plasticity than the currently used iTBS protocol. Thus, in this trial researchers aim to determine whether an optimized iTBS protocol will result in better LTP-like activity in the DLPFC of adults with MDD.
The objectives and hypotheses of the study are as follows:
Objective 1: To compare the ability of iTBS-c vs. iTBS-s to induce DLPFC LTP-like activity in depressed adults as measured using TMS-electroencephalography (EEG).
Hypothesis 1a: iTBS-s will induce stronger DLPFC LTP-like activity compared to iTBS-c.
Hypothesis 1b: iTBS-s will induce longer-lasting DLPFC LTP-like activity compared to iTBS-c.
Objective 2: To evaluate the relationship between DLPFC LTP-like activity and changes in depression severity, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS).
Hypothesis 2a: DLPFC LTP-like activity will be inversely associated with baseline depressive symptoms.
Hypothesis 2b: DLPFC LTP-like activity will be associated with improvement in depressive symptoms on Visits 3 to 5.
Objective 3: To compare the effect of iTBS-c vs. iTBS-c within-subjects on DLPFC LTP-like activity in depressed adults as measured using TMS-EEG during the cross-over phase of the study.
Hypothesis 3: iTBS-s will induce stronger DLPFC LTP-like activity compared to iTBS-c within-subjects.
- Conditions
- Major Depressive Disorder (MDD)
- Being tested
- Spaced iTBS, Compressed iTBS
- Keywords
- TMS, TBS, iTBS, iTBS-sh, iTBS-c, iTBS-s, Sham iTBS, Spaced iTBS, Compressed iTBS, LTP, Long Term Potentiation, Theta-Burst Stimulation, Intermittent Theta Burst Stimulation, Transcranial Magnetic Stimulation, MDD, Major Depressive Disorder, Depression, Depressed individuals, Brain Plasticity, Dorsolateral Prefrontal Cortex
- Medical subject headings
- Depressive Disorder, Major, Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Spaced iTBSDevice
Also called iTBS-s
Intermittent Theta-Burst Stimulation (iTBS) is a form of non-invasive brain stimulation that uses magnetic pulses applied to the scalp using a coil. iTBS will be used to stimulate the left dorsolateral prefrontal cortex (DLPFC) to enhance long-term potentiation (LTP)-like activity, a physiological mechanism associated with brain plasticity. TMS-EEG will be performed to measure changes in brain plasticity throughout the trial. An EEG cap will be placed on the participant's head, and the electrodes on the cap will be filled with saline gel using a dull syringe.
During the intervention, the study team will conduct a baseline TMS-EEG measurement consisting of single TMS pulses. Participants will then complete iTBS-s (experimental study intervention), which will be delivered to the left DLPFC. Following iTBS-s, post-iTBS TMS-EEG measurements will be obtained consisting of 3 TMS trains delivered to the left DLPFC (Post-0, Post-20, and Post-60 minutes).
Compressed iTBSDevice
Also called iTBS-c
Intermittent Theta-Burst Stimulation (iTBS) is a form of non-invasive brain stimulation that uses magnetic pulses applied to the scalp using a coil. iTBS will be used to stimulate the left dorsolateral prefrontal cortex (DLPFC) to enhance long-term potentiation (LTP)-like activity, a physiological mechanism associated with brain plasticity. TMS-EEG will be performed to measure changes in brain plasticity throughout the trial. An EEG cap will be placed on the participant's head, and the electrodes on the cap will be filled with saline gel using a dull syringe.
During the intervention, the study team will conduct a baseline TMS-EEG measurement consisting of single TMS pulses. Participants will then complete iTBS-c (active comparator), which will be delivered to the left DLPFC. Following iTBS-c, post-iTBS TMS-EEG measurements will be obtained consisting of 3 TMS trains delivered to the left DLPFC (Post-0, Post-20, and Post-60 minutes).
| Study group | Role | What they receive |
|---|---|---|
| Spaced iTBS | Experimental | Upon completion of Visits 1-2 (Screening and MRI), participants randomized to iTBS-s will complete a baseline TMS-EEG measurement, one iTBS-s intervention session, and post-iTBS TMS-EEG measurements in each of Visits 3-5. Following this, participants will undergo a washout period of at least two weeks. Then, participants will return to complete the opposite iTBS intervention across Visits 6-8. The procedures and visits will be identical, but the participant will receive the other iTBS intervention that they were not initially randomized to. Receives: Device: Spaced iTBS |
| Compressed iTBS | Active comparator | Upon completion of Visits 1-2 (Screening and MRI), participants randomized to iTBS-c will complete a baseline TMS-EEG measurement, one iTBS-c intervention session, and post-iTBS TMS-EEG measurements in each of Visits 3-5. Following this, participants will undergo a washout period of at least two weeks. Then, participants will return to complete the opposite iTBS intervention across Visits 6-8. The procedures and visits will be identical, but the participant will receive the other iTBS intervention that they were not initially randomized to. Receives: Device: Compressed iTBS |
What is being measured
The primary outcome is the main question the study is designed to answer.
DLPFC LTP-like Activity - CEA Ratio at Visit 3
Cortical evoked activity (CEA) over the left DLPFC will be measured using TMS-EEG before the application of the iTBS condition and at 0, 20 and 60-minutes post-iTBS in Visit 3. The CEA ratio will be calculated by dividing the average post-iTBS CEA (across post-20 and post-60 minutes) by the pre-iTBS CEA. Hypothesis 1a will then be tested by comparing the CEA Ratio at Visit 3 between the group randomized to iTBS-s and the group randomized to iTBS-c.
Measured: Immediately before iTBS and at 20 and 60 minutes post-iTBS at Visit 3
DLPFC LTP-like Activity - Change in pre-iTBS CEA from Visit 3 to 4
Cortical evoked activity (CEA) over the left DLPFC will be measured using TMS-EEG before the application of the iTBS condition at Visit 3 (baseline), and again before iTBS at Visit 4 (24 hours post-baseline). Hypothesis 1b will be tested by comparing the change in pre-iTBS CEA from Visit 3 to Visit 4 between the group randomized to iTBS-s and the group randomized to iTBS-c.
Measured: Pre-iTBS at Baseline (Visit 3) and Pre-iTBS at 24 hours post-baseline (Visit 4)
DLPFC LTP-like Activity - Change in pre-iTBS CEA from Visit 4 to 5
Cortical evoked activity (CEA) over the left DLPFC will be measured using TMS-EEG before the application of the iTBS condition at Visit 4 (24 hours post-baseline) and again before iTBS at Visit 5 (6 days post-baseline). Hypothesis 1b will be tested by comparing the change in pre-iTBS CEA from Visit 4 to Visit 5 between the group randomized to iTBS-s and the group randomized to iTBS-c.
Measured: Pre-iTBS at 24 hours post-baseline (Visit 4) and Pre-iTBS at 6 days post-baseline (Visit 5)
Secondary outcomes (2)
MADRS Scores - Hypothesis 2a
Hypothesis 2a will be tested by comparing the association between the average CEA Ratio across Visits 3, 4, and 5 and baseline scores on the Montgomery-Åsberg Depression Rating Scale (MADRS), which ranges from 0 (minimum) to 60 (maximum), with higher scores reflecting greater depression severity.
Measured: Visit 3 (baseline), Visit 4 (24 hours post-baseline), and Visit 5 (6 days post-baseline)
MADRS Scores - Hypothesis 2b
Hypothesis 2b will be tested by comparing the association between the CEA Ratio at each of Visits 3, 4, and 5 and the corresponding change in MADRS scores from baseline to post-iTBS at each visit.
Measured: Visit 3 (baseline), Visit 4 (24 hours post-baseline), and Visit 5 (6 days post-baseline)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Jun 2025
- Study startJun 2025 (estimated)
- Primary completionJan 2026 (estimated)
- Study completionDec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Major Depressive Disorder (MDD)Studies of the same condition, open and under way.
- More trials run by Centre for Addiction and Mental HealthThe sponsor's other registered studies.
- 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 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- This phase I clinical trial will employ a double-blind, randomized controlled cross-over design with two experimental iTBS conditions (iTBS-c and iTBS-s).
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 84 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Centre for Addiction and Mental Health
- Sponsor type
- University, hospital or other
- Collaborators
- Brain Canada
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07033780
- Sponsor's protocol ID
- 2024/116-01
- Acronym
- INSPiRE-D
- Status last verified
- Feb 2025
- First submitted
- 6 Jan 2025
- Last updated
- 24 Jun 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 24 Jun 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Optimization of Prefrontal Theta-Burst Stimulation to Treat Depression: A Bench to First-in-Human Study
- ClinicalTrials.gov ID
- NCT07033780
- Acronym / sponsor ID
- INSPiRE-D / 2024/116-01
- Conditions
- Major Depressive Disorder (MDD)
- Keywords
- TMS, TBS, iTBS, iTBS-sh, iTBS-c, iTBS-s, Sham iTBS, Spaced iTBS
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 84 participants (estimated)
- Lead sponsor
- Centre for Addiction and Mental HealthUniversity, hospital or other
- Collaborators
- Brain Canada
- Study start
- Jun 2025 (estimated)
- Primary completion
- Jan 2026 (estimated)
- Study completion
- Dec 2026 (estimated)
- First posted
- 24 Jun 2025 (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.
The goal of this clinical trial is to explore the effects of non-invasive brain stimulation protocols using intermittent theta-burst stimulation (iTBS) on brain plasticity and depression severity in depressed individuals aged 18 to 50 years old. Brain plasticity is the brain's ability to change through growth or reorganization. iTBS is a form of transcranial magnetic stimulation (TMS), where magnetic pulses are applied to the scalp using a coil. These pulses pass through the scalp, and can alter brain activity in the area underneath the coil. Based on previous research conducted in animals and humans, researchers believe that iTBS can strengthen the connections between cells in the brain, leading to improved brain plasticity.
This trial will compare the effects of the compressed iTBS (iTBS-c) protocol, which is commonly used to treat depression, and the spaced iTBS (iTBS-s) protocol. Researchers want to find out which protocol is better able to produce changes in brain plasticity and improve symptoms of depression among individuals diagnosed with Major Depressive Disorder (MDD). In this trial, participants will be randomized to receive 3 sessions of iTBS-s or iTBS-c, undergo a washout period of at least 2 weeks, then complete 3 sessions of the opposite iTBS intervention.
Participants will complete 5 study visits within the span of 2-3 months, including:
- Screening assessments to determine eligibility \& 1 sham iTBS (iTBS-sh) session to assess tolerability of the brain stimulation (Visit 1);
- 1 Magnetic Resonance Imaging (MRI) brain scan and randomization (Visit 2);
- Safety and clinical assessments, iTBS-s or iTBS-c intervention, TMS evoked electroencephalography (TMS-EEG) measurements, and post-iTBS questionnaires (Visits 3-5) followed by a washout period of at least 2 weeks;
- Safety and clinical assessments, the opposite iTBS-s or iTBS-c intervention originally randomized to, TMS-EEG measurements, and post-iTBS questionnaires (Visits 6-8).
Detailed description
Major Depressive Disorder (MDD) is a mental illness affecting millions of individuals worldwide and in Canada, and is a leading cause of morbidity, mortality, and disability. While antidepressant medications are effective in treating MDD, their efficacy is moderate and systemic side-effects persist, such as sexual dysfunction, drowsiness, weight gain, and dry mouth. Thus, more effective treatments are needed for MDD.
Neuroimaging techniques have implicated the dysregulation of brain plasticity in depression. In particular, long-term potentiation (LTP)-like activity in the dorsolateral prefrontal cortex (DLPFC) and the motor cortex is known to be impaired in MDD. As such, transcranial magnetic stimulation (TMS)-based interventions, which aim to modify underlying cortical activity, are now established treatments of depression. Intermittent theta-burst stimulation (iTBS), a novel form of repetitive TMS (rTMS) approved by the US Food and Drug Administration (FDA) for the treatment of depression, delivers intermittent, high-frequency theta bursts. It has been demonstrated to induce sustained plasticity in the DLPFC and the motor cortex. Studies have shown that iTBS is equally effective as conventional rTMS in terms of response rates, and its adverse effects are comparable to iTBS-sh and active rTMS. One key advantage of iTBS over rTMS is its time efficiency, with each session lasting approximately 3 min compared to up to 40 min with rTMS. Notwithstanding its efficiency, systematic reviews of RCTs indicate no significant difference in remission rates - defined as a reduction in symptoms below a threshold indicating euthymic state - between iTBS (~26%) and iTBS-sh (~19%), or between iTBS (32%) and rTMS (27%). Thus, while iTBS is well tolerated, efficient and effective in reducing symptoms of MDD, its efficacy is still far from optimal as is the case for other treatments of depression.
Based on promising research conducted in the hippocampus of rodents, the investigators believe that modifying some parameters of the iTBS protocol may be more effective in inducing plasticity than the currently used iTBS protocol. Thus, in this trial researchers aim to determine whether an optimized iTBS protocol will result in better LTP-like activity in the DLPFC of adults with MDD.
The objectives and hypotheses of the study are as follows:
Objective 1: To compare the ability of iTBS-c vs. iTBS-s to induce DLPFC LTP-like activity in depressed adults as measured using TMS-electroencephalography (EEG).
Hypothesis 1a: iTBS-s will induce stronger DLPFC LTP-like activity compared to iTBS-c.
Hypothesis 1b: iTBS-s will induce longer-lasting DLPFC LTP-like activity compared to iTBS-c.
Objective 2: To evaluate the relationship between DLPFC LTP-like activity and changes in depression severity, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS).
Hypothesis 2a: DLPFC LTP-like activity will be inversely associated with baseline depressive symptoms.
Hypothesis 2b: DLPFC LTP-like activity will be associated with improvement in depressive symptoms on Visits 3 to 5.
Objective 3: To compare the effect of iTBS-c vs. iTBS-c within-subjects on DLPFC LTP-like activity in depressed adults as measured using TMS-EEG during the cross-over phase of the study.
Hypothesis 3: iTBS-s will induce stronger DLPFC LTP-like activity compared to iTBS-c within-subjects.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- This phase I clinical trial will employ a double-blind, randomized controlled cross-over design with two experimental iTBS conditions (iTBS-c and iTBS-s).
| Arm | Type | Receives |
|---|---|---|
| Spaced iTBS | Experimental | Device: Spaced iTBSUpon completion of Visits 1-2 (Screening and MRI), participants randomized to iTBS-s will complete a baseline TMS-EEG measurement, one iTBS-s intervention session, and post-iTBS TMS-EEG measurements in each of Visits 3-5. Following this, participants will undergo a washout period of at least two weeks. Then, participants will return to complete the opposite iTBS intervention across Visits 6-8. The procedures and visits will be identical, but the participant will receive the other iTBS intervention that they were not initially randomized to. |
| Compressed iTBS | Active comparator | Device: Compressed iTBSUpon completion of Visits 1-2 (Screening and MRI), participants randomized to iTBS-c will complete a baseline TMS-EEG measurement, one iTBS-c intervention session, and post-iTBS TMS-EEG measurements in each of Visits 3-5. Following this, participants will undergo a washout period of at least two weeks. Then, participants will return to complete the opposite iTBS intervention across Visits 6-8. The procedures and visits will be identical, but the participant will receive the other iTBS intervention that they were not initially randomized to. |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- Aged 18-50 years old;
- Must meet criteria for a current Major Depressive Episode (MDE) as ascertained using the Structured Clinical Interview for DSM 5 (SCID-5);
- Hamilton Rating Scale for Depression (HRSD-17) score > 7;
- Must be on a stable antidepressant regimen for a minimum of 4 weeks prior to enrollment, if currently taking antidepressants;
- Right handed or ambidextrous, assessed using the Edinburgh Handedness Inventory (EHI);
Key exclusion criteria (6 listed)
- Age 17 years or less, or greater than 51 years old, as brain plasticity is known to be affected by age;
- Presence of any DSM-5 diagnosis (other than MDD), known to be associated with prefrontal cortical dysfunction, including lifetime diagnoses of bipolar disorder, intellectual disability, or a psychotic disorder, assessed using the SCID-5 and as per investigator judgement;
- Presence of acute suicidal intent, as determined by the Scale for Suicidal Ideation (SSI);
- Contradictions to MRI or TMS (e.g., cardiac pacemaker, acoustic device, history of seizures, pregnancy), assessed using the MRI Safety Form and TMS Adult Safety Screen (TASS) and as per investigator judgement;
- Left handed, assessed using the EHI, to minimize the heterogeneity in cortical excitability and plasticity;
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 |
|---|---|---|
| Spaced iTBSAlso: iTBS-sIntermittent Theta-Burst Stimulation (iTBS) is a form of non-invasive brain stimulation that uses magnetic pulses applied to the scalp using a coil. iTBS will be used to stimulate the left dorsolateral prefrontal cortex (DLPFC) to enhance long-term potentiation (LTP)-like activity, a physiological mechanism associated with brain plasticity. TMS-EEG will be performed to measure changes in brain plasticity throughout the trial. An EEG cap will be placed on the participant's head, and the electrodes on the cap will be filled with saline gel using a dull syringe. During the intervention, the study team will conduct a baseline TMS-EEG measurement consisting of single TMS pulses. Participants will then complete iTBS-s (experimental study intervention), which will be delivered to the left DLPFC. Following iTBS-s, post-iTBS TMS-EEG measurements will be obtained consisting of 3 TMS trains delivered to the left DLPFC (Post-0, Post-20, and Post-60 minutes). | Device | Spaced iTBS |
| Compressed iTBSAlso: iTBS-cIntermittent Theta-Burst Stimulation (iTBS) is a form of non-invasive brain stimulation that uses magnetic pulses applied to the scalp using a coil. iTBS will be used to stimulate the left dorsolateral prefrontal cortex (DLPFC) to enhance long-term potentiation (LTP)-like activity, a physiological mechanism associated with brain plasticity. TMS-EEG will be performed to measure changes in brain plasticity throughout the trial. An EEG cap will be placed on the participant's head, and the electrodes on the cap will be filled with saline gel using a dull syringe. During the intervention, the study team will conduct a baseline TMS-EEG measurement consisting of single TMS pulses. Participants will then complete iTBS-c (active comparator), which will be delivered to the left DLPFC. Following iTBS-c, post-iTBS TMS-EEG measurements will be obtained consisting of 3 TMS trains delivered to the left DLPFC (Post-0, Post-20, and Post-60 minutes). | Device | Compressed iTBS |
Primary outcome
DLPFC LTP-like Activity - CEA Ratio at Visit 3
Time frame: Immediately before iTBS and at 20 and 60 minutes post-iTBS at Visit 3
Cortical evoked activity (CEA) over the left DLPFC will be measured using TMS-EEG before the application of the iTBS condition and at 0, 20 and 60-minutes post-iTBS in Visit 3. The CEA ratio will be calculated by dividing the average post-iTBS CEA (across post-20 and post-60 minutes) by the pre-iTBS CEA. Hypothesis 1a will then be tested by comparing the CEA Ratio at Visit 3 between the group randomized to iTBS-s and the group randomized to iTBS-c.
DLPFC LTP-like Activity - Change in pre-iTBS CEA from Visit 3 to 4
Time frame: Pre-iTBS at Baseline (Visit 3) and Pre-iTBS at 24 hours post-baseline (Visit 4)
Cortical evoked activity (CEA) over the left DLPFC will be measured using TMS-EEG before the application of the iTBS condition at Visit 3 (baseline), and again before iTBS at Visit 4 (24 hours post-baseline). Hypothesis 1b will be tested by comparing the change in pre-iTBS CEA from Visit 3 to Visit 4 between the group randomized to iTBS-s and the group randomized to iTBS-c.
DLPFC LTP-like Activity - Change in pre-iTBS CEA from Visit 4 to 5
Time frame: Pre-iTBS at 24 hours post-baseline (Visit 4) and Pre-iTBS at 6 days post-baseline (Visit 5)
Cortical evoked activity (CEA) over the left DLPFC will be measured using TMS-EEG before the application of the iTBS condition at Visit 4 (24 hours post-baseline) and again before iTBS at Visit 5 (6 days post-baseline). Hypothesis 1b will be tested by comparing the change in pre-iTBS CEA from Visit 4 to Visit 5 between the group randomized to iTBS-s and the group randomized to iTBS-c.
2 secondary outcomes
MADRS Scores - Hypothesis 2a
Time frame: Visit 3 (baseline), Visit 4 (24 hours post-baseline), and Visit 5 (6 days post-baseline)
MADRS Scores - Hypothesis 2b
Time frame: Visit 3 (baseline), Visit 4 (24 hours post-baseline), and Visit 5 (6 days post-baseline)
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 24 Jun 2025.
- Cortical Plasticity in DepressionLink provided by the sponsor.
- Pathophysiology of depression: the concept of synaptic plasticityLink provided by the sponsor.
- Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trialLink provided by the sponsor.
- The role of neural plasticity in depression: from hippocampus to prefrontal cortex. Neural plasticityLink provided by the sponsor.
- Impaired modulation of corticospinal excitability in drug-free patients with major depressive disorder: a theta-burst stimulation studyLink provided by the sponsor.
- Efficacy of theta burst stimulation (TBS) for major depression: an exploratory meta-analysis of randomized and sham-controlled trialsLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Recruiting
Targeting Network Dysfunction in Apathy of Late-life Depression Using Digital Therapeutics
Major Depressive Disorder, Apathy
Not yet recruiting
Acute Intermittent Hypoxia Therapy for Depression
Major Depressive Disorder (MDD)
RecruitingPhase 2
Psilocybin With Pimavanserin Compared to Psilocybin Alone for the Treatment of Major Depressive Disorder
Major Depressive Disorder
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.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Spaced iTBS and Compressed iTBS in people with Major Depressive Disorder (MDD), run by Centre for Addiction and Mental Health 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 8 inclusion and 6 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: looking for participants now, as of the sponsor's last update on 24 Jun 2025. 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.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
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 Christoph Zrenner, MD (416-535-8501 ext. 34319, christoph.zrenner@camh.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
DLPFC LTP-like Activity - CEA Ratio at Visit 3 (time frame: Immediately before iTBS and at 20 and 60 minutes post-iTBS at Visit 3). The study lists 3 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 24 Jun 2025.