fMRI-Guided rTMS for Depression

Overseen by Lauri Tuominen, MD PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: The Royal Ottawa Mental Health Centre

Must be taking: Antidepressants

Must not be taking: Illegal drugs, High-dose lorazepam

Disqualifiers: Bipolar, Substance use, Unstable illness, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

In this triple-blind randomized controlled trial, we ask if targeting intermittent theta burst stimulation (iTBS) based on individual resting state connectivity improves treatment outcomes in major depressive disorder (MDD). For the trial, we will recruit 210 patients with major depressive disorder. Each patient will undergo a 30-40-minute MRI scan, after which they will receive a 6-week standard iTBS treatment. Participants will be randomized to receive iTBS either to the standard neuronavigated target (a technique for treatment location targeting, based on group-average connectivity) or to a personalized connectivity-guided target selected based on individual functional connectivity scans. The main outcome of this trial is response rate as determined by ≥ 50% reduction in Grid HRSD-17 scores. Secondary outcomes include remission rate, change in depression, anxiety and anhedonia symptoms, quality of life, and biological measures of heart rate variability, objective sleep measures and daily activity as a proxy of anhedonia - defined as a reduced ability to experience pleasure.

Will I have to stop taking my current medications?

The trial requires that you have stable psychotropic medications (including prescribed cannabis) for at least four weeks before starting. You should not change your current antidepressant regimen during the trial.

What data supports the effectiveness of the treatment fMRI-Guided iTBS for depression?

Research shows that intermittent theta burst stimulation (iTBS) is as effective as the standard high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating depression, and it can be delivered in a much shorter time. Studies have demonstrated that iTBS is effective for treatment-resistant depression, providing similar outcomes to traditional rTMS. ^{1 2 3 4 5}

Is fMRI-Guided rTMS for Depression safe for humans?

Intermittent theta burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation (rTMS), is generally considered safe for treating depression, with studies showing it is as safe as traditional rTMS methods. Some participants may experience tolerability issues, but these are not common. The U.S. Food and Drug Administration has approved iTBS for treatment-resistant depression, indicating its safety profile is acceptable. ^{1 2 6 7 8}

How is the fMRI-Guided iTBS treatment for depression different from other treatments?

The fMRI-Guided iTBS treatment for depression is unique because it uses brain imaging to precisely target brain areas involved in depression, and it delivers stimulation in just over 3 minutes, which is much faster than traditional methods. This approach aims to improve the effectiveness and speed of treatment for those with treatment-resistant depression. ^{1 2 6 8 9}

Research Team

Sara Tremblay, PhD

Principal Investigator

The Royal's Institute of Mental Health Research

Lauri Tuominen, MD PhD

Principal Investigator

The Royal's Institute of Mental Health Research

Eligibility Criteria

This trial is for adults with major depression who haven't improved after trying at least one antidepressant. They must be over 18, speak English, and have moderate symptoms without psychotic features. People can't join if they have bipolar disorder, recent substance abuse (except mild cannabis or alcohol), are pregnant/breastfeeding, or have conditions like epilepsy that make TMS risky.

Inclusion Criteria

I have been diagnosed with major depression without psychosis.

My depression hasn't improved after trying at least one antidepressant.

I have chosen to undergo rTMS treatment after my doctor's recommendation.

Exclusion Criteria

Organic cause to the depressive symptoms (e.g. thyroid dysfunctions), as ruled out by the referring physician

Any other condition that, in the opinion of the investigators, would adversely affect the participant's ability to complete the study

Any contraindications for MRI

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

MRI Scan

Participants undergo a 30-40 minute MRI scan to determine treatment targeting

1 day

1 visit (in-person)

Treatment

Participants receive a 6-week iTBS treatment, either fMRI-guided or neuronavigation-guided

6 weeks

Daily visits Monday-Friday

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

1 visit (in-person)

Treatment Details

Interventions

• fMRI-Guided iTBS (Procedure)
• Standard iTBS (Procedure)

Trial Overview The study tests whether using fMRI to guide iTBS treatment improves outcomes in depression compared to standard iTBS targeting methods. Participants will undergo an MRI scan followed by a 6-week iTBS treatment, with their response measured by changes in depressive symptom scores.

Participant Groups

Group I: fMRI guided iTBS targetting Experimental Treatment 1 Intervention

The target selected is based on functional connectivity determined from the MRI scan.

Group II: Neuronavigation guided iTBS targetting Active Control 1 Intervention

A technique for treatment location targeting, based on structural images of the brain using standard coordinates.

Who Is Running the Clinical Trial?

The Royal Ottawa Mental Health Centre

Lead Sponsor

Trials

24

Recruited

2,300+

Findings from Research

Intermittent theta burst stimulation (iTBS) is as effective as standard high-frequency (10 Hz) rTMS for treating treatment-resistant depression, showing non-inferiority in improving depression scores over 4-6 weeks in a study with 414 participants.

Both iTBS and 10 Hz rTMS had similar safety profiles and dropout rates, with headaches being the most common side effect, indicating that iTBS can be a viable alternative that allows for more patients to be treated in a shorter time without losing effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Blumberger, DM., Vila-Rodriguez, F., Thorpe, KE., et al.[2022]

Intermittent theta-burst stimulation (iTBS) and high-frequency rTMS (HF-rTMS) show similar efficacy in treating treatment-resistant depression (TRD), with response rates of 48.0% for iTBS and 45.5% for HF-rTMS based on two high-quality randomized controlled trials involving 474 participants.

Both iTBS and HF-rTMS have comparable safety profiles, with similar rates of discontinuation and adverse events, such as headaches, indicating that iTBS is a safe alternative to HF-rTMS for patients with TRD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of intermittent theta burst stimulation versus high-frequency repetitive transcranial magnetic stimulation for patients with treatment-resistant depression: a systematic review. Lan, XJ., Yang, XH., Qin, ZJ., et al.[2023]

In a study of 60 patients with treatment-resistant unipolar depression, both intermittent theta burst stimulation (iTBS) and conventional 10 Hz rTMS showed similar efficacy in reducing depression scores and improving quality of life over a 6-month follow-up, with response rates of 36.7% for iTBS and 33.3% for rTMS.

iTBS is highlighted as a more time-efficient and cost-effective option compared to rTMS, suggesting it could be a valuable treatment alternative for patients with severe depression who have not responded to multiple antidepressant trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent theta burst stimulation (iTBS) versus 10 Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) to alleviate treatment-resistant unipolar depression: A randomized controlled trial (THETA-DEP). Bulteau, S., Laurin, A., Pere, M., et al.[2022]

Intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex significantly decreased the N100 amplitude in participants with treatment-resistant depression, indicating a neurophysiological response to the treatment.

Responders to iTBS showed a notable decrease in N100 amplitude and higher N45 amplitude post-treatment compared to nonresponders, suggesting that these TMS-EEG markers could help predict treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identifying Neurophysiological Markers of Intermittent Theta Burst Stimulation in Treatment-Resistant Depression Using Transcranial Magnetic Stimulation-Electroencephalography. Strafella, R., Momi, D., Zomorrodi, R., et al.[2023]

In a study of 105 participants with depression, early improvement after 10 sessions of either 10 Hz rTMS or iTBS was found to be a strong predictor of overall treatment response, with a negative predictive value (NPV) of around 70% for those showing less than 20% improvement.

There were no significant differences in predictive capacities between the two treatment modalities, suggesting that both iTBS and 10 Hz rTMS can be effectively used to identify patients at risk of non-response, allowing for timely adjustments in treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early Improvement Predicts Clinical Outcomes Similarly in 10 Hz rTMS and iTBS Therapy for Depression. Spitz, NA., Pace, BD., Ten Eyck, P., et al.[2023]

In a study of 22 participants with treatment-resistant depression, the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, which uses high-dose intermittent theta-burst stimulation (iTBS) guided by functional connectivity MRI, showed a remarkable remission rate of 90.5%.

The treatment was well tolerated with no negative cognitive side effects reported, suggesting that SAINT could be a safe and effective option for patients who have not responded to traditional antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. Cole, EJ., Stimpson, KH., Bentzley, BS., et al.[2020]

In a study of 27 participants, a prolonged intermittent theta burst stimulation (piTBS) protocol using 1,800 pulses showed limited effectiveness for major depressive disorder, with only 18.2% of participants achieving a response and 9.1% reaching remission.

Safety and tolerability were concerns, as 18.5% of participants experienced issues, suggesting that while piTBS is a promising approach, further research is needed to optimize its parameters and improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series. Richard, M., Noiseux, C., Desbeaumes Jodoin, V., et al.[2022]

A clinical trial involving 96 outpatients with moderate depression will investigate the effectiveness of intermittent theta burst stimulation (iTBS) on reducing depressive symptoms, comparing it to a sham treatment over ten sessions.

The study will also explore various factors, including genetic and neuropsychological measures, that may influence the response to iTBS, ensuring a thorough safety screening and adherence to ethical guidelines throughout the trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The antidepressant effect of intermittent theta burst stimulation (iTBS): study protocol for a randomized double-blind sham-controlled trial. Ørbo, MC., Grønli, OK., Larsen, C., et al.[2023]

In a study of 45 antidepressant-free patients with medication-resistant depression, accelerated intermittent Theta Burst Stimulation (aiTBS) led to significant changes in brain perfusion, particularly increasing blood flow in areas like the ventromedial prefrontal cortex, which are linked to mood regulation.

The findings suggest that active aiTBS not only improves depressive symptoms but also alters brain activity in regions associated with depression, while sham treatment showed different effects, indicating that the clinical benefits of aiTBS may be due to both direct stimulation and potential placebo responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated iTBS changes perfusion patterns in medication resistant depression. Wu, GR., Duprat, R., Baeken, C.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of intermittent theta burst stimulation versus high-frequency repetitive transcranial magnetic stimulation for patients with treatment-resistant depression: a systematic review. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Intermittent theta burst stimulation (iTBS) versus 10 Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) to alleviate treatment-resistant unipolar depression: A randomized controlled trial (THETA-DEP). [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Identifying Neurophysiological Markers of Intermittent Theta Burst Stimulation in Treatment-Resistant Depression Using Transcranial Magnetic Stimulation-Electroencephalography. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Early Improvement Predicts Clinical Outcomes Similarly in 10 Hz rTMS and iTBS Therapy for Depression. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. [2020]

7. Ireland pubmed.ncbi.nlm.nih.gov

Prolonged intermittent theta burst stimulation in the treatment of major depressive disorder: a case series. [2022]

8. England pubmed.ncbi.nlm.nih.gov

The antidepressant effect of intermittent theta burst stimulation (iTBS): study protocol for a randomized double-blind sham-controlled trial. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Accelerated iTBS changes perfusion patterns in medication resistant depression. [2022]