rTMS for Depression

(NCP Trial)

Overseen By Jessica Layton

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of British Columbia

Must be taking: Antidepressants

Must not be taking: Anticonvulsants, Lorazepam

Disqualifiers: Substance use, Unstable illness, Suicidal, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 33

Duration: 6 weeks

110 Participants Needed

Trial Summary

What is the purpose of this trial?

Heartbeat is controlled by the brain and is regular but flexible to change in response to environmental and internal stimuli. This feature is known as heart rate variability (HRV). Major depressive disorder (MDD) has been associated with diminished HRV and this is a reflection of abnormal brain function caused by MDD. Repetitive transcranial magnetic stimulation (rTMS) is a treatment that stimulates specific areas of the brain. The goal of this study is to test the hypothesis that rTMS induces changes in connectivity between the area of the brain stimulated with rTMS and deeper areas in the brain associated to heart rate regulation. 110 patients with TRD will be recruited and will undergo a concurrent TMS-fMRI session before receiving a course of iTBS to the L-DLPFC for 30 sessions at 120% rMT.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not have started or increased any psychotropic medication in the 4 weeks before screening. Also, you cannot take more than 2 mg of lorazepam daily or any anticonvulsant.

What data supports the effectiveness of the treatment Repetitive Transcranial Magnetic Stimulation (rTMS) for depression?

Research over the past 20 years shows that rTMS is increasingly used and effective for treating depression, with recent studies indicating improved results with new stimulation methods. A study also found that rTMS was more effective than a placebo treatment in patients with depression, including those who had not responded to other treatments. ^{1 2 3 4 5}

Is rTMS safe for treating depression?

Repetitive transcranial magnetic stimulation (rTMS) is generally considered safe for treating depression, with common side effects being minor, such as headaches. There is a low risk of seizures and mood changes, but these are rare and can often be avoided by screening for risk factors. Long-term effects are not fully known, but when used according to guidelines, rTMS has a good safety profile. ^{6 7 8 9 10}

How is the treatment rTMS for depression different from other treatments?

Repetitive transcranial magnetic stimulation (rTMS) is unique because it uses magnetic fields to stimulate nerve cells in the brain, which can help improve symptoms of depression. Unlike medications, it is non-invasive and does not require surgery or drugs, making it a novel option for those who haven't responded to traditional treatments. ^{1 2 11 12 13}

Research Team

Fidel Vila-Rodriguez, M.D., Ph.D.

Principal Investigator

Department of Psychiatry, UBC

Eligibility Criteria

This trial is for adults aged 18-65 with Major Depressive Disorder (MDD) who haven't responded to antidepressants, as shown by a score ≥ 18 on the HDRS-17. Participants must be able to follow the treatment schedule and have not had any psychotropic medication changes in the last four weeks. Exclusions include pregnancy, previous rTMS treatment, certain medications like high-dose lorazepam or anticonvulsants, substance use within three months, major medical illnesses, primary anxiety or personality disorders causing more impairment than MDD, history of seizure or significant neurological issues.

Inclusion Criteria

I haven't started or increased any mental health medication in the last month.

My depression hasn't improved after trying enough of at least one antidepressant, or I couldn't tolerate two different ones.

Patients must have a score ≥ 18 on the Hamilton Depression Rating Scale (HDRS-17 item)

Exclusion Criteria

I have not had significant neurological issues, seizures (except from ECT), or major head injuries.

Patients with a MINI anxiety disorder or personality disorder assessed by a study investigator to be primary and causing greater impairment than MDD

I do not have any major unstable illnesses.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants undergo a concurrent TMS-fMRI session to establish baseline measurements

1 week

1 visit (in-person)

Treatment

Participants receive a course of iTBS to the L-DLPFC for 30 sessions at 120% rMT

6 weeks

30 visits (in-person)

Follow-up

Participants are monitored for changes in heart rate variability and depressive symptoms

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Repetitive Transcranial Magnetic Stimulation

Trial Overview The study tests if Repetitive Transcranial Magnetic Stimulation (rTMS) can change brain connectivity related to heart rate regulation in those with depression. It involves stimulating specific brain areas using rTMS while monitoring changes through fMRI before and after a course of iTBS treatments over 30 sessions.

Participant Groups

Group I: Active iTBS Experimental Treatment 1 Intervention

Active intermittent theta-burst stimulation (iTBS) rTMS session on the left dorsolateral prefrontal cortex (L-DLPFC)

Repetitive Transcranial Magnetic Stimulation is already approved in United States, European Union, Canada for the following indications:

Approved in United States as rTMS for:

• Major depressive disorder
• Obsessive-compulsive disorder
• Migraines

Approved in European Union as rTMS for:

• Major depressive disorder
• Obsessive-compulsive disorder
• Anxiety disorders

Approved in Canada as rTMS for:

• Major depressive disorder
• Obsessive-compulsive disorder

Who Is Running the Clinical Trial?

University of British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Findings from Research

In a study involving 19 patients who had previously responded to rTMS, treatment for 30 episodes of depressive relapse showed significant improvement in symptoms, indicating its effectiveness for recurring depression.

The results suggest that rTMS maintains its efficacy over time, with patients benefiting from both low-frequency right-sided and high-frequency left-sided stimulation during their treatment courses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naturalistic study of the use of transcranial magnetic stimulation in the treatment of depressive relapse. Fitzgerald, PB., Benitez, J., de Castella, AR., et al.[2022]

High-frequency rTMS targeting the left dorsolateral prefrontal cortex is an effective treatment for acute episodes of major depressive disorder, supported by over 20 years of clinical trials.

While rTMS is effective for unipolar and likely bipolar depression, there is limited evidence for its effectiveness in the maintenance phase of treatment, indicating a need for ongoing research and practitioner education.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the clinical use of repetitive transcranial magnetic stimulation in the treatment of depression. Fitzgerald, PB.[2021]

Recent studies on repetitive transcranial magnetic stimulation (rTMS) for depression have demonstrated significantly improved clinical outcomes, with a pooled effect size of -0.76 from 5 studies involving 274 patients, compared to -0.35 from earlier studies.

The findings indicate that new parameters of rTMS stimulation may enhance its antidepressant effects, suggesting a potential advancement in treatment strategies for depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Has repetitive transcranial magnetic stimulation (rTMS) treatment for depression improved? A systematic review and meta-analysis comparing the recent vs. the earlier rTMS studies. Gross, M., Nakamura, L., Pascual-Leone, A., et al.[2018]

In a 6-month follow-up study of 31 patients with major depression who completed a 4-week rTMS trial, 63.64% of those who initially did not respond to treatment became late responders, indicating potential for continued improvement after treatment ends.

The study also found a low relapse rate of only 10% among those who initially responded to rTMS, with an overall high rate of maintained response at 90%, suggesting that rTMS can have lasting effects in treating major depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 6-month follow-up study on response and relapse rates following an acute trial of repetitive transcranial magnetic stimulation in patients with major depression. Arici, C., Benatti, B., Cafaro, R., et al.[2022]

In a sham-controlled study involving 29 patients with depression (79% treatment-resistant), fast, left frontal repetitive transcranial magnetic stimulation (rTMS) was found to be more effective than sham treatment, with a response rate of 77% compared to 55% (P<0.05).

The treatment was generally well tolerated, and the improvements in depression symptoms were maintained for up to 12 weeks, suggesting that rTMS could be a valuable addition to existing depression therapies, although further research is needed to optimize treatment parameters.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive fast repetitive transcranial magnetic stimulation in depression. Anderson, IM., Delvai, NA., Ashim, B., et al.[2018]

Repetitive transcranial magnetic stimulation (rTMS) is generally a well-tolerated treatment for depression, with mild side effects like headaches being the most common, while severe adverse effects are rare.

Special precautions are necessary for certain groups, such as adolescents, pregnant women, and individuals with metal implants, but with proper assessment and monitoring, rTMS can be safely administered to many patients with depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation (TMS) safety: a practical guide for psychiatrists. Taylor, R., Galvez, V., Loo, C.[2019]

Repetitive transcranial magnetic stimulation (rTMS) is generally safe for older adults with late-life depression, with only 12.4% reporting any adverse events and serious adverse events occurring in just 1.5% of cases, based on a review of 11 studies involving 353 patients.

The most common adverse events were mild, such as headaches (6.9%) and discomfort at the stimulation site (2.7%), although some serious adverse events, including psychiatric hospitalization and increased suicidal ideation, were noted in case reports, highlighting the need for further research to ensure safety in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events of repetitive transcranial magnetic stimulation in older adults with depression, a systematic review of the literature. Overvliet, GM., Jansen, RAC., van Balkom, AJLM., et al.[2021]

In a study involving 18 subjects with major depression, repetitive transcranial magnetic stimulation (rTMS) for up to 4 weeks was found to be generally safe, with no significant mean deficits in neuropsychologic function or auditory thresholds.

However, two patients experienced mild high-frequency hearing loss, indicating that while rTMS is safe for most, individual responses may vary and warrant further investigation into long-term safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of a 2- to 4-week course of repetitive transcranial magnetic stimulation (rTMS) on neuropsychologic functioning, electroencephalogram, and auditory threshold in depressed patients. Loo, C., Sachdev, P., Elsayed, H., et al.[2019]

A patient with treatment-resistant depression (TRD) showed unexpected improvement after experiencing a seizure during repetitive transcranial magnetic stimulation (rTMS), suggesting a potential link between seizure activity and therapeutic effects in TRD.

While rTMS is generally safe, known adverse events include headaches and seizures; this case highlights an unusual outcome where a seizure may have contributed to the patient's improvement, warranting further investigation into the mechanisms of rTMS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-Resistant Depression Entering Remission Following a Seizure during the Course of Repetitive Transcranial Magnetic Stimulation. Kim, JW., Bae, KY., Kim, SW., et al.[2020]

Repetitive Transcranial Magnetic Stimulation (rTMS) has a good overall safety profile for treating depression, with common side effects like headaches being minor and manageable.

While there is a low incidence of serious side effects such as seizures and hypomania, these are linked to specific risk factors, suggesting that proper screening can enhance patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of the safety of repetitive transcranial magnetic stimulation as a clinical treatment for depression. Loo, CK., McFarquhar, TF., Mitchell, PB.[2021]

High-frequency rTMS targeting the left dorsolateral prefrontal cortex is an effective treatment for major depressive disorder, supported by over 15 years of research and the authors' 10 years of clinical experience.

While other rTMS techniques, such as low-frequency stimulation to the right prefrontal cortex, show potential, they need further evaluation in larger trials to confirm their efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A practical guide to the use of repetitive transcranial magnetic stimulation in the treatment of depression. Fitzgerald, PB., Daskalakis, ZJ.[2022]

Repetitive transcranial magnetic stimulation (rTMS) has shown statistically significant effects in treating major depression, with 29 studies reviewed indicating that factors like high treatment resistance and advanced age negatively predict treatment response.

Effective rTMS treatment parameters include using stimulation intensity above 100% of the motor threshold and more than 1000 stimulations per session, with older patients requiring higher intensity due to cortical atrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Repetitive transcranial magnetic stimulation in major depression: response factor]. Dumas, R., Padovani, R., Richieri, R., et al.[2012]

References

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

Naturalistic study of the use of transcranial magnetic stimulation in the treatment of depressive relapse. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

An update on the clinical use of repetitive transcranial magnetic stimulation in the treatment of depression. [2021]

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

Has repetitive transcranial magnetic stimulation (rTMS) treatment for depression improved? A systematic review and meta-analysis comparing the recent vs. the earlier rTMS studies. [2018]

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

A 6-month follow-up study on response and relapse rates following an acute trial of repetitive transcranial magnetic stimulation in patients with major depression. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Adjunctive fast repetitive transcranial magnetic stimulation in depression. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation (TMS) safety: a practical guide for psychiatrists. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Adverse events of repetitive transcranial magnetic stimulation in older adults with depression, a systematic review of the literature. [2021]

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

Effects of a 2- to 4-week course of repetitive transcranial magnetic stimulation (rTMS) on neuropsychologic functioning, electroencephalogram, and auditory threshold in depressed patients. [2019]

9. Korea (South) pubmed.ncbi.nlm.nih.gov

Treatment-Resistant Depression Entering Remission Following a Seizure during the Course of Repetitive Transcranial Magnetic Stimulation. [2020]

10. England pubmed.ncbi.nlm.nih.gov

A review of the safety of repetitive transcranial magnetic stimulation as a clinical treatment for depression. [2021]

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

A practical guide to the use of repetitive transcranial magnetic stimulation in the treatment of depression. [2022]

12. France pubmed.ncbi.nlm.nih.gov

[Repetitive transcranial magnetic stimulation in major depression: response factor]. [2012]

13. Thailand pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation for treatment resistant depression: six case reports and review. [2010]