Theta-Burst Stimulation to Treat Depression (INSPiRE-D)

June 13, 2025 updated by: Centre for Addiction and Mental Health

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.

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).

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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 Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
84

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

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

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M6J 1H4
        • Recruiting
        • Centre for Addiction and Mental Health
        • Sub-Investigator:
          • Tarek Rajji, MD
        • Sub-Investigator:
          • Daniel Blumberger, MD
        • Contact:
        • Contact:
        • Principal Investigator:
          • Christoph Zrenner, MD
        • Sub-Investigator:
          • Heather Brooks, 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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.

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: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Spaced iTBS
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.
Device: Spaced iTBS

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).

Other Names:
  • iTBS-s
Active Comparator: Compressed iTBS
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.
Device: Compressed iTBS

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).

Other Names:
  • iTBS-c

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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.
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
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.
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
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.
Pre-iTBS at 24 hours post-baseline (Visit 4) and Pre-iTBS at 6 days post-baseline (Visit 5)

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
MADRS Scores - Hypothesis 2a
Time Frame: Visit 3 (baseline), Visit 4 (24 hours post-baseline), and Visit 5 (6 days post-baseline)
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.
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)
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.
Visit 3 (baseline), Visit 4 (24 hours post-baseline), and Visit 5 (6 days post-baseline)

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
DLPFC LTP-like activity (within subjects)
Time Frame: After Visits 3-5 (first iTBS condition) and Visits 6-8 (second iTBS condition)
To address Objective 3, the CEA Ratio will be calculated for each of Visits 3 through 8. The CEA ratios from Visits 3, 4, and 5 will be averaged to obtain the mean CEA Ratio for the first iTBS condition (iTBS-s or iTBS-c). Then, the CEA ratios from Visits 6, 7, and 8 will be averaged to determine the mean CEA Ratio for the other iTBS condition. The average CEA ratio of iTBS-s will be compared to the average CEA ratio of iTBS-c within subjects.
After Visits 3-5 (first iTBS condition) and Visits 6-8 (second iTBS condition)

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Centre for Addiction and Mental Health

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Brain Canada

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

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)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 1, 2025

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 1, 2026

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 6, 2025

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 13, 2025

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 24, 2025

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 24, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 13, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2024/116-01

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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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