fMRI-Guided rTMS for Depression

Overseen By Emma Cummings, BA

Age: 18+

Sex: Any

Trial Phase: Academic

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 All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

Duration: 6 weeks

210 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method for treating major depressive disorder (MDD) using intermittent theta burst stimulation (iTBS). Researchers aim to determine if customizing the treatment based on individual brain scans is more effective than the standard approach. Participants will undergo a 6-week iTBS treatment, guided either by their own brain activity from an MRI scan (fMRI-Guided iTBS) or by a typical targeting method (Standard iTBS). Suitable candidates have major depressive disorder that hasn't improved with medication and are seeking new treatment options. As an unphased trial, this study provides a unique opportunity to explore personalized treatment alternatives to traditional methods.

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 prior data suggests that these techniques are safe for treating major depressive disorder?

Research shows that both fMRI-guided intermittent theta burst stimulation (iTBS) and standard iTBS are generally safe for treating major depressive disorder.

Studies have found fMRI-guided iTBS to be well-tolerated, with no serious side effects reported. Participants did not experience significant issues, and most found the treatment easy to handle.

Research found standard iTBS effective and safe, with improvements in depression symptoms and no major side effects. Compared to a sham (fake) treatment, it showed better results, confirming its safety.

Overall, current research indicates that both treatments are safe options for people with depression. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using fMRI-guided iTBS (intermittent Theta Burst Stimulation) for depression because it offers a more personalized approach than standard treatments. Unlike common antidepressants or standard iTBS, which often take a one-size-fits-all approach, fMRI-guided iTBS uses brain connectivity patterns to tailor the treatment to each individual's unique brain activity. This method could potentially enhance the precision and effectiveness of the treatment, leading to better outcomes for patients with depression.

What evidence suggests that this trial's treatments could be effective for major depressive disorder?

Research has shown that iTBS, a type of brain stimulation, can effectively treat major depressive disorder (MDD). In this trial, participants will receive either fMRI-guided iTBS, which targets specific brain areas based on individual brain scans, or neuronavigation-guided iTBS, which uses standard coordinates for treatment location targeting. Studies have found that fMRI-guided iTBS can lead to lasting reductions in depression symptoms by focusing on each person's unique brain activity. Other research suggests that iTBS can quickly relieve depression and might work better than traditional treatments. Overall, these findings support the potential of iTBS to effectively reduce symptoms of depression in people with MDD. ^{6 7 8 9 10}

Who Is on the 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

Are You a Good Fit for This Trial?

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

Current use of illegal substances or cannabis (unless medical use, see note below), confirmed by urine drug screen

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

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• fMRI-Guided iTBS
• Standard iTBS

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.

How Is the Trial Designed?

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.

fMRI-Guided iTBS is already approved in United States, European Union for the following indications:

Approved in United States as iTBS for:

• Major Depressive Disorder

Approved in European Union as iTBS for:

• Major Depressive Disorder

Who Is Running the Clinical Trial?

The Royal Ottawa Mental Health Centre

Lead Sponsor

Trials

24

Recruited

2,300+

Published Research Related to This Trial

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 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]

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 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 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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10878976/

Connectivity-guided intermittent theta burst versus repetitive ... Persistent decreases in depressive symptoms were seen over 26 weeks, with no differences between arms on the primary outcome GRID Hamilton Depression Rating ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06152705

Comparing the Efficacy of FMRI-Guided Vs. Standard ITBS ... Secondary outcomes include remission rate, change in depression, anxiety and anhedonia symptoms, quality of life, and biological measures of heart rate ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0165178123003797

Accelerated intermittent theta burst stimulation in major ... aiTBS is a promising form of non-invasive brain stimulation [NIBS] with rapid antidepressant and antisuicidal effects in major depressive disorder [MDD].

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12047393/

The effects of intermittent theta burst stimulation (iTBS) on ... Subthreshold stimulation intensity is associated with greater clinical efficacy of intermittent theta-burst stimulation priming for Major Depressive Disorder.

5. nature.com nature.com/articles/s41380-024-02630-5

Theta burst stimulation for depression: a systematic review ... Theta burst stimulation (TBS) presents as a more efficient and potentially more effective therapeutic modality than conventional repetitive transcranial ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11609094/

Theta burst stimulation for depression: a systematic review ... A randomized controlled trial (RCT) of SNT demonstrated that iTBS (L-DLPFC) outperformed sham in depressive symptom improvement with a large ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006322325013563

Efficacy and Safety of Accelerated Intermittent Theta-burst ... In this trial, a-iTBS, administered five sessions per day for ten days, is effective and safe for adolescents with non-treatment-resistant MDD.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT07033780

NCT07033780 | Theta-Burst Stimulation to Treat Depression The goal of this clinical trial is to explore the effects of non-invasive brain stimulation protocols using intermittent theta-burst stimulation (iTBS) on ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10423820/

Efficacy and safety of intermittent theta burst stimulation ... Similarly, a recently published study showed similar response rates (36.7% versus 33.3%) and remission rates (18.5% versus 14.8%) as evaluated ...

10. sciencedirect.com sciencedirect.com/science/article/pii/S0166432824005175

Four weeks standard vs. one week accelerated intermittent ... aiTBS with 1200 pulses and five daily sessions lead to amelioration of symptoms within one week. But benefit, satisfaction, tolerability was slightly lower.