Theta-Burst Stimulation to Treat Depression

NCT07033780 | Recruiting Phase 1

• 1 other identifier: 2024/116-01
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 1

Brief 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. 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).

Conditions

Major Depressive Disorder (MDD)

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; DLPFC; Motor Cortex; Neuroplasticity

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

  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.

  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

  Visit 3 (baseline), Visit 4 (24 hours post-baseline), and Visit 5 (6 days post-baseline)

• MADRS Scores - Hypothesis 2b

  Visit 3 (baseline), Visit 4 (24 hours post-baseline), and Visit 5 (6 days post-baseline)

Other Outcomes (1)

• DLPFC LTP-like activity (within subjects)

  After Visits 3-5 (first iTBS condition) and Visits 6-8 (second iTBS condition)

Study Arms (2)

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.

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.

Device: Compressed iTBS

Interventions

Spaced iTBS DEVICE

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).

Also known as: iTBS-s

Spaced iTBS

Compressed iTBS DEVICE

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).

Also known as: iTBS-c

Compressed iTBS

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Centre for Addiction and Mental Health: lead
• Brain Canada: collaborator

Study Sites (1)

Centre for Addiction and Mental Health

Toronto, Ontario, M6J 1H4, Canada

RECRUITING

Related Links

• Pathophysiology of depression: the concept of synaptic plasticity
• Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial
• The role of neural plasticity in depression: from hippocampus to prefrontal cortex. Neural plasticity
• Impaired modulation of corticospinal excitability in drug-free patients with major depressive disorder: a theta-burst stimulation study
• Efficacy of theta burst stimulation (TBS) for major depression: an exploratory meta-analysis of randomized and sham-controlled trials
• Theta-burst stimulation: A new form of TMS treatment for depression? Depression and anxiety
• Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression
• Theta burst stimulation for the acute treatment of major depressive disorder: a systematic review and meta-analysis
• Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial

MeSH Terms

Conditions

Depressive Disorder, Major; Depression

Condition Hierarchy (Ancestors)

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

Central Study Contacts

Christoph Zrenner, MD

CONTACT

416-535-8501; christoph.zrenner@camh.ca

Dewi Clark, MHSc

CONTACT

416-535-8501; dewi.clark@camh.ca

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The study will be completed under double-blind conditions: (1) Participants will be blind to the hypothesis and potential differences in outcomes between iTBS-c and iTBS-s; (2) The research staff conducting the clinical and TMS-EEG assessments will be blind to group assignment. Trained personnel administering iTBS (i.e., the interventionist) will not be blinded to the iTBS condition being administered. Therefore, trained personnel who administer iTBS will not be permitted to complete any study assessments following the intervention.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: January 6, 2025
• First Posted: June 24, 2025
• Study Start: June 1, 2025
• Primary Completion: January 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: June 24, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)