Recruiting
Phase 1

iTBS-c & iTBS-s

Sponsor:

Centre for Addiction and Mental Health

Code:

NCT07033780

Conditions

Major Depressive Disorder (MDD)

Eligibility Criteria

Sex: All

Age: 18 - 50

Healthy Volunteers: Not accepted

Interventions

Spaced iTBS

Compressed iTBS

Study Details

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)

Study ID

NCT07033780

Start date

Jun, 2025

Status verified date

Feb, 2025

Completion date

Dec, 2026

Anticipated

Primary completion date

Jan, 2026

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18 - 50

Healthy Volunteers: Not accepted

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 Design

Enrollment

84 participants

Anticipated

Allocation

Randomized

Intervention Model

Crossover

Primary purpose

Basic Science

Interventions and Outcome Measures

Arms

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.

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.

Interventions

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).

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).

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 ]
  • 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) ]
  • 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) ]

Central Contacts and Locations

Central contacts

Christoph Zrenner, MD

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

Dewi Clark, MHSc

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

Locations

Centre for Addiction and Mental Health

Recruiting

Toronto, Ontario, Canada, M6J 1H4

Contacts

Christoph Zrenner, MD

(416) 535-8501christoph.zrenner@camh.ca

Dewi Clark, MHSc

(416) 535-8501dewi.clark@camh.ca

Principal Investigator:

Christoph Zrenner, MD

More Information

Sponsor

Centre for Addiction and Mental Health

Last update posted

Jun 24, 2025

Last verified

Feb, 2025

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

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by Centre for Addiction and Mental Health on 2025-06-24.