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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method of using high-dose repetitive transcranial magnetic stimulation (rTMS) to help individuals with major depression. The researchers aim to determine the optimal dose to effectively reduce depression symptoms. Participants will receive different doses to observe changes in their symptoms. This study suits those with major depression who can commit to treatment sessions. As an unphased trial, it offers a unique opportunity for participants to explore innovative treatment options for depression.

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 prior data suggests that this protocol is safe for treating depression?

Research has shown that repetitive transcranial magnetic stimulation (rTMS) is generally safe and well-tolerated. This non-invasive treatment uses magnetic fields to stimulate nerve cells and can help improve symptoms of major depression. A study of 7,215 patients with major depressive disorder (MDD) found a strong connection between the number of TMS sessions and positive results.

When used according to guidelines, rTMS is considered safe. Serious side effects are rare, and most people experience only mild and temporary effects, such as slight headaches or scalp discomfort. This makes rTMS a good option for those considering participation in a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about high-dose rTMS for depression because it offers a potentially faster and more efficient treatment option compared to traditional methods like medication and psychotherapy. Unlike standard treatments that often take weeks to show effects, high-dose rTMS can potentially deliver noticeable improvements in just a few days. This technique uses accelerated sessions of magnetic pulses that target specific brain areas associated with mood regulation, providing a non-invasive and drug-free alternative. The ability to tailor doses and intensify treatment sessions is a key feature that sets this approach apart from existing options.

What evidence suggests that this trial's treatments could be effective for depression?

Research has shown that high-dose repetitive transcranial magnetic stimulation (rTMS) can help treat major depressive disorder (MDD). In one study with 7,215 patients, more TMS sessions led to better results. Another study found that rTMS matched lithium, a common depression medication, in preventing relapse for those with treatment-resistant depression. This trial will explore the effects of different doses of accelerated rTMS, with all participants randomized to one of 10 active doses. Although rTMS is approved for MDD, results can vary among individuals. Overall, these findings suggest that rTMS is a promising option for reducing symptoms of depression. ^{1 3 4 6 7}

Are You a Good Fit for This Trial?

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

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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 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 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]

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]

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]

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]

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]

Citations

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Repetitive transcranial magnetic stimulation treatment for ... dTMS moreover appears to be well tolerated and efficacious in late-life depression [21], and showed to be potentially effective as add-on treatment in resistant ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S1935861X23019265

Dosing transcranial magnetic stimulation in major ... In a study of 7215 MDD patients, there were powerful associations between number of TMS sessions and effectiveness.

3. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2835319

Repetitive Transcranial Magnetic Stimulation as ... This randomized clinical trial of 75 participants with TRD showed that rTMS and lithium had comparable efficacy in preventing TRD relapse.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10095476/

Effectiveness of Repetitive Transcranial Magnetic Stimulation ... Results from this pilot study suggested that rTMS might be routinely applied in persons with MS displaying symptoms of depression and fatigue.

5. cell.com cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00475-6

A sequential dual-site repetitive transcranial magnetic ... Repetitive transcranial magnetic stimulation (rTMS) is approved for major depressive disorder (MDD), but it is limited by variable efficacy.

6. mayoclinic.org mayoclinic.org/tests-procedures/transcranial-magnetic-stimulation/about/pac-20384625

Transcranial magnetic stimulation Transcranial magnetic stimulation (TMS) is a procedure that uses magnetic fields to stimulate nerve cells in the brain to improve symptoms of major depression.

7. academic.oup.com academic.oup.com/ijnp/article/11/1/131/647218

A review of the safety of repetitive transcranial magnetic ... When given within recommended guidelines, the overall safety profile of rTMS is good, and supports its further development as a clinical treatment. Clinical ...