High-Dose rTMS for Depression

Overseen By Claire Cox, BA

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Medical University of South Carolina

Must not be taking: Stimulants, Theophylline, Bupropion

Disqualifiers: Schizophrenia, Bipolar I, Dementia, others

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

Compensation: Varies

Number of Visits: 41

Duration: 5 weeks

100 Participants Needed

Trial Summary

What is the purpose of this trial?

High frequency repetitive transcranial magnetic stimulation (rTMS) has been shown to be safe, feasible, and acceptable. Conventionally, rTMS investigations have relied on rational decision trees for dosage determination. The purpose of this study is to systematically examine an accelerated protocol of intermittent theta burst (iTBS). Study 1 aims to provide a quantifiable dose-response curve for iTBS and depressive symptom reduction in major depression. Study 2 aims to determine the role of individual variations of their functional networks compared to the site of stimulation and clinical outcomes.

Will I have to stop taking my current medications?

The trial requires that you stop taking medications with short half-lives that lower the seizure threshold and don't have proven antidepressant effects, like high-dose theophylline or certain stimulants. If you're taking bupropion, you must be on a stable dose of 300 mg/day or less.

What data supports the effectiveness of the treatment Brief, High-dose rTMS for depression?

Research shows that repetitive transcranial magnetic stimulation (rTMS), especially when applied to the left prefrontal cortex, is effective in treating depression, including cases that are resistant to other treatments. High-frequency rTMS has been linked to changes in brain function that help alleviate depressive symptoms. ^{1 2 3 4 5}

Is high-dose rTMS safe for humans?

High-dose rTMS is generally considered safe when used within recommended guidelines. Common side effects include minor issues like headaches, with a low risk of seizures and mood changes, which can be managed by screening for risk factors. ^{1 6 7 8 9}

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

High-dose rTMS (repetitive transcranial magnetic stimulation) for depression is unique because it involves delivering high-frequency magnetic pulses to the brain, specifically targeting the left dorsolateral prefrontal cortex, which is thought to be involved in mood regulation. This treatment can be administered in an accelerated schedule, allowing for multiple sessions per day, which may lead to faster improvement compared to traditional rTMS protocols. ^{10 11 12 13 14}

Eligibility Criteria

This trial is for individuals with depression who can speak English, consent to the study, and commit to regular visits. Pregnant women must have a negative pregnancy test. People with progressive CNS diseases, recent drug abuse (except nicotine/caffeine), or unstable medical conditions are excluded.

Inclusion Criteria

I am not pregnant.

After full explanation of the study, willingness of participant is demonstrated by signing the informed consent form

I can speak English, fill out forms, follow treatment plans, and attend regular visits.

Exclusion Criteria

I have a history of seizures or a seizure disorder.

I am on a stable dose of medication that doesn't lower seizure risk or act as an antidepressant.

Repeated abuse or dependence upon drugs (excluding nicotine and caffeine) within 6 days of study entry, with the exception of alcohol use disorder, which, at the discretion of the study team, may be permitted

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive accelerated rTMS with varying doses over multiple sessions

5 weeks

40 sessions (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Brief, High-dose rTMS

Trial Overview The trial tests an accelerated protocol of repetitive Transcranial Magnetic Stimulation (rTMS) called intermittent theta burst (iTBS). It aims to establish a dose-response curve for iTBS on depressive symptoms and explore individual variations in response based on functional networks.

Participant Groups

Group I: Study 2: 10 Active Doses Experimental Treatment 1 Intervention

All participants will be assigned to 10 sessions (per treatment day) of accelerated rTMS for 5 treatment days. All doses are active and within established therapeutic levels of rTMS. Dose 10 is 50 active sessions of 600 pulses at 120% of resting motor threshold. Intermittent theta burst triplets at 50 Hz for 2 seconds and repeated every 10 seconds for a total of 190 seconds.

Group II: Dose 9 Experimental Treatment 1 Intervention

All participants will be randomized to one of 10 doses of accelerated rTMS. All doses are active and within established therapeutic levels of rTMS. Dose 9 is 40 sessions of 600 pulses at 120% of resting motor threshold. Intermittent theta burst triplets at 50 Hz for 2 seconds and repeated every 10 seconds for a total of 190 seconds.

Group III: Dose 8 Experimental Treatment 1 Intervention

All participants will be randomized to one of 10 doses of accelerated rTMS. All doses are active and within established therapeutic levels of rTMS. Dose 8 is 35 sessions of 600 pulses at 120% of resting motor threshold. Intermittent theta burst triplets at 50 Hz for 2 seconds and repeated every 10 seconds for a total of 190 seconds.

Group IV: Dose 7 Experimental Treatment 1 Intervention

All participants will be randomized to one of 10 doses of accelerated rTMS. All doses are active and within established therapeutic levels of rTMS. Dose 7 is 30 sessions of 600 pulses at 120% of resting motor threshold. Intermittent theta burst triplets at 50 Hz for 2 seconds and repeated every 10 seconds for a total of 190 seconds.

Group V: Dose 6 Experimental Treatment 1 Intervention

All participants will be randomized to one of 10 doses of accelerated rTMS. All doses are active and within established therapeutic levels of rTMS. Dose 6 is 25 sessions of 600 pulses at 120% of resting motor threshold. Intermittent theta burst triplets at 50 Hz for 2 seconds and repeated every 10 seconds for a total of 190 seconds.

Group VI: Dose 5 Experimental Treatment 1 Intervention

All participants will be randomized to one of 10 doses of accelerated rTMS. All doses are active and within established therapeutic levels of rTMS. Dose 5 is 20 sessions of 600 pulses at 120% of resting motor threshold. Intermittent theta burst triplets at 50 Hz for 2 seconds and repeated every 10 seconds for a total of 190 seconds.

Group VII: Dose 4 Experimental Treatment 1 Intervention

All participants will be randomized to one of 10 doses of accelerated rTMS. All doses are active and within established therapeutic levels of rTMS. Dose 4 is 20 sessions of 600 pulses at 120% of resting motor threshold. Intermittent theta burst triplets at 50 Hz for 2 seconds and repeated every 10 seconds for a total of 190 seconds.

Group VIII: Dose 3 Experimental Treatment 1 Intervention

All participants will be randomized to one of 10 doses of accelerated rTMS. All doses are active and within established therapeutic levels of rTMS. Dose 3 is 15 sessions of 600 pulses at 120% of resting motor threshold. Intermittent theta burst triplets at 50 Hz for 2 seconds and repeated every 10 seconds for a total of 190 seconds.

Group IX: Dose 2 Experimental Treatment 1 Intervention

All participants will be randomized to one of 10 doses of accelerated rTMS. All doses are active and within established therapeutic levels of rTMS. Dose 2 is 10 sessions of 600 pulses at 120% of resting motor threshold. Intermittent theta burst triplets at 50 Hz for 2 seconds and repeated every 10 seconds for a total of 190 seconds.

Group X: Dose 10 Experimental Treatment 1 Intervention

All participants will be randomized to one of 10 doses of accelerated rTMS. All doses are active and within established therapeutic levels of rTMS. Dose 10 is 40 sessions of 600 pulses at 120% of resting motor threshold. Intermittent theta burst triplets at 50 Hz for 2 seconds and repeated every 10 seconds for a total of 190 seconds.

Group XI: Dose 1 Experimental Treatment 1 Intervention

All participants will be randomized to one of 10 doses of accelerated rTMS. All doses are active and within established therapeutic levels of rTMS. Dose 1 is five sessions of 600 pulses at 120% of resting motor threshold. Intermittent theta burst triplets at 50 Hz for 2 seconds and repeated every 10 seconds for a total of 190 seconds.

Who Is Running the Clinical Trial?

Medical University of South Carolina

Lead Sponsor

Trials

994

Recruited

7,408,000+

National Alliance for Research on Schizophrenia and Depression

Collaborator

Trials

97

Recruited

4,100+

National Alliance for Research on Schizophrenia & Depression

Collaborator

Trials

1

Recruited

100+

Findings from Research

Repetitive transcranial magnetic stimulation (rTMS) has shown statistical superiority over sham therapy for treating depression, particularly with left-prefrontal high frequency stimulation, but the actual clinical benefits are often marginal.

Factors such as younger age, absence of treatment-resistant depression, and no psychotic features are associated with a better response to rTMS, highlighting the need for further research to optimize treatment parameters and confirm its clinical utility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation for depression. Mitchell, PB., Loo, CK.[2017]

In a study involving 300 patients with treatment-resistant depression, different doses of repetitive transcranial magnetic stimulation (rTMS) did not show significant differences in response rates, with all groups exceeding a 45% response rate.

While increasing the number of TMS pulses did not correlate with better overall outcomes, higher doses of left-sided rTMS were associated with improved remission rates when considering the duration of illness, suggesting that other factors may influence treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pragmatic randomized controlled trial exploring the relationship between pulse number and response to repetitive transcranial magnetic stimulation treatment in depression. Fitzgerald, PB., Hoy, KE., Reynolds, J., et al.[2020]

In a preliminary study involving four patients with relapsed major depressive disorder, rapid transcranial magnetic stimulation (rTMS) showed significant improvement in depression ratings after treatment.

The results indicated that rTMS can be effectively used again in patients who had previously responded well to this therapy, suggesting its potential for repeated use in managing relapsed depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation is effective in the treatment of relapse of depression. Dannon, PN., Schreiber, S., Dolberg, OT., et al.[2022]

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]

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) 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 232 depressive patients, high-frequency repetitive transcranial magnetic stimulation (rTMS) was found to be a feasible and safe treatment option, with no severe side effects reported and only four patients discontinuing due to side effects.

Patients showed an average improvement of 9.0 points on the Hamilton Depression Rating Scale after receiving an average of 13 rTMS sessions, with 53 patients experiencing a 50% or greater reduction in their depression scores, indicating significant efficacy in a real-world clinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation for the treatment of depression: feasibility and results under naturalistic conditions: a retrospective analysis. Frank, E., Eichhammer, P., Burger, J., et al.[2021]

In a pilot study involving 7 treatment-resistant depression patients, accelerated low-frequency right-sided rTMS was found to be safe, with all participants completing the treatment without adverse effects.

While there were significant reductions in depression scores (MADRS and BDI-II) by the end of the 10-day treatment, no patients achieved full response or remission, indicating the need for further research to confirm efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot Study of Accelerated Low-Frequency Right-Sided Transcranial Magnetic Stimulation for Treatment-Resistant Depression. Tor, PC., Gálvez, V., Goldstein, J., et al.[2017]

Accelerated Deep TMS protocols, applied multiple times a day, demonstrated an impressive 80.2% response rate and 50.5% remission rate in 111 patients with major depressive disorder, indicating their efficacy as a treatment option.

The study found that these protocols were safe, with no serious adverse events reported, and showed long-term durability of effects, with 86.7% of patients maintaining benefits after 60 days and 92.9% after 180 days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real world efficacy and safety of various accelerated deep TMS protocols for major depression. Roth, Y., Hanlon, CA., Pell, G., et al.[2023]

In a study involving 115 outpatients with major depressive disorder, accelerated rTMS did not show significant differences in remission or response rates compared to standard rTMS, indicating similar efficacy between the two treatment schedules.

While accelerated rTMS was feasible, it was associated with a higher rate of treatment discomfort, suggesting that while it may be effective, patient comfort should be considered in treatment planning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated repetitive transcranial magnetic stimulation in the treatment of depression. Fitzgerald, PB., Hoy, KE., Elliot, D., et al.[2022]

References

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

Transcranial magnetic stimulation for depression. [2017]

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

Efficacy of adjunctive high frequency repetitive transcranial magnetic stimulation of left prefrontal cortex in depression: a randomized sham controlled study. [2022]

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

A pragmatic randomized controlled trial exploring the relationship between pulse number and response to repetitive transcranial magnetic stimulation treatment in depression. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation is effective in the treatment of relapse of depression. [2022]

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

Changes in regional cerebral blood flow after repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex in treatment-resistant depression. [2017]

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

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

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

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

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

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

9. 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]

10. Germany pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation for the treatment of depression: feasibility and results under naturalistic conditions: a retrospective analysis. [2021]

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

Pilot Study of Accelerated Low-Frequency Right-Sided Transcranial Magnetic Stimulation for Treatment-Resistant Depression. [2017]

12. Ireland pubmed.ncbi.nlm.nih.gov

Real world efficacy and safety of various accelerated deep TMS protocols for major depression. [2023]

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Ultra-high-frequency left prefrontal transcranial magnetic stimulation as augmentation in severely ill patients with depression: a naturalistic sham-controlled, double-blind, randomized trial. [2012]

14. England pubmed.ncbi.nlm.nih.gov

Accelerated repetitive transcranial magnetic stimulation in the treatment of depression. [2022]