Neuromodulation for Depression

Overseen By F. Andrew Kozel, M.D., M.S.C.R.

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Florida State University

Must not be taking: Tricyclics, Stimulants, Clozapine

Disqualifiers: Schizophrenia, Substance use, Dementia, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

100 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open label prospective pilot study of two neuromodulation interventions for patients suffering from dysphoria. Dysphoria is a transdiagnostic symptom of unease or dissatisfaction experienced across a range of diagnoses, including mood disorders and pain. There is a significant gap of treatment options across conditions with dysphoria, particularly non-medicated and self-care alternatives. Many neuromodulation therapies require extensive medical resources or time to deliver. Thus, the investigators will test two non-invasive technologies administered in a manner that would reduce resources and/or time. Virtual Reality (VR) overlays the sensory system to block the external environment and provide vast range of meaningful sensory experiences. Transcranial Magnetic Stimulation (TMS) involves a magnetic pulse passing through the scalp to depolarize neurons in the outer cortex of the brain, and daily treatments over 6 weeks are currently FDA indicated for the treatment of major depressive disorder. Accelerated TMS is the delivery of treatment in a shorter period of time. The primary objective of this study to demonstrate the preliminary effectiveness, tolerability, and feasibility of these two interventions: Guided Meditation VR for Wellness and Accelerated Transcranial Magnetic Stimulation.

Will I have to stop taking my current medications?

The trial requires that you do not change your psychotropic medication (if you are taking any) for 1 month before starting and during the trial. However, you must stop taking any medication that significantly affects brain activity, like tricyclic antidepressants or stimulants.

What data supports the effectiveness of the treatment Accelerated Transcranial Magnetic Stimulation for depression?

Accelerated Transcranial Magnetic Stimulation (aTMS) has been shown to improve depressive symptoms, with studies indicating it is effective for treatment-resistant depression and can reduce the time needed for treatment compared to traditional methods. A meta-analysis found that aTMS improves depressive symptom severity, and another study reported high response and remission rates in patients using a similar TMS method. ^{1 2 3 4 5}

Is repetitive transcranial magnetic stimulation (rTMS) safe for humans?

Repetitive transcranial magnetic stimulation (rTMS) is generally considered safe for humans, with most studies showing a reassuring safety profile. However, there have been rare cases of seizures and other mild adverse events, so guidelines have been developed to ensure its safe use. ^{6 7 8 9 10}

How is Accelerated Transcranial Magnetic Stimulation (Accelerated TMS) different from other treatments for depression?

Accelerated Transcranial Magnetic Stimulation (Accelerated TMS) is unique because it delivers all treatments over a few days instead of the typical 4-6 weeks, making it more accessible and potentially more acceptable to patients. It is particularly beneficial for those with treatment-resistant depression who have not responded to standard antidepressant medications. ^{3 11 12 13 14}

Research Team

F. Andrew Kozel, M.D., M.S.C.R.

Principal Investigator

Florida State University

Eligibility Criteria

This trial is for adults over 18 with dysphoria, which can be part of depression or pain conditions. Participants must have stable medication and therapy for a month before the study and not change them during it. They need to be able to consent and follow the study's procedures. Excluded are those at suicide risk, with severe mental disorders like schizophrenia, significant hearing or vision loss, unstable medical conditions, substance abuse issues, non-English speakers, pregnant women, prisoners.

Inclusion Criteria

I am 18 years old or older.

My mental health medication and therapy have been stable for the last month.

I understand the study details and can follow its requirements.

Exclusion Criteria

Suicidal risk that precludes safe participation defined as clinical impression that the participant is at significant risk for suicide

Significant auditory or visual impairment that prevents participants from using Virtual Reality headset

Unstable medical conditions or any current medical condition that could preclude being able to safely participate in this phase of the study (e.g., unstable metabolic abnormality, unstable angina, etc.)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Guided Meditation VR for Wellness and Accelerated Transcranial Magnetic Stimulation over a period of 6 weeks

6 weeks

Daily treatments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Accelerated Transcranial Magnetic Stimulation: Treatment A
• Accelerated Transcranial Magnetic Stimulation: Treatment B
• Guided Meditation VR for Wellness

Trial Overview The trial tests two neuromodulation treatments: Guided Meditation using Virtual Reality (VR) to provide sensory experiences that may ease dysphoria; Accelerated Transcranial Magnetic Stimulation (TMS), where magnetic pulses stimulate brain neurons quickly compared to traditional TMS schedules. The goal is to see if these treatments are effective and practical.

Participant Groups

Group I: Guided Meditation VR for Wellness Active Control 1 Intervention

Selected modules of commercially available meditation VR

Group II: Accelerated Transcranial Magnetic Stimulation: Treatment A Active Control 1 Intervention

Intermittent theta-burst over dlPFC

Group III: Accelerated Transcranial Magnetic Stimulation: Treatment B Active Control 1 Intervention

Intermittent theta-primed 10Hz over mPFC

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

Approved in United States as Transcranial Magnetic Stimulation for:

• Major Depressive Disorder

Approved in European Union as Transcranial Magnetic Stimulation for:

• Major Depressive Disorder

Approved in Canada as Transcranial Magnetic Stimulation for:

• Major Depressive Disorder

Who Is Running the Clinical Trial?

Florida State University

Lead Sponsor

Trials

234

Recruited

41,100+

Findings from Research

A meta-analysis of 24 studies involving 911 patients found that maintenance rTMS can help stabilize mood symptoms for up to 5 months after an initial acute rTMS treatment for depression.

Patients receiving monthly or more frequent maintenance rTMS experienced sustained benefits for up to 6-12 months, while those without maintenance showed only minor changes in mood symptoms over the same period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trajectory of changes in depressive symptoms after acute repetitive transcranial magnetic stimulation: A meta-analysis of follow-up effects. Brian Chen, YC., Chou, PH., Tu, YK., et al.[2023]

Accelerated transcranial magnetic stimulation (aTMS) has been shown to significantly improve depressive symptoms, with a cumulative effect size of 0.39 from randomized control trials and an even higher effect size of 1.27 when including open-label trials.

The review analyzed 18 articles from 11 distinct studies, indicating that while the methodologies were generally acceptable, there is room for improvement in sham techniques and blinding to enhance the reliability of future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated TMS for Depression: A systematic review and meta-analysis. Sonmez, AI., Camsari, DD., Nandakumar, AL., et al.[2020]

Accelerated transcranial magnetic stimulation (aTMS) is safe and effective for treating treatment-resistant depression, with no seizures reported and only one serious adverse event in a study of 14 patients.

Patients experienced significant reductions in depression and anxiety after aTMS, with response rates of 43% immediately after treatment and 36% at 3 and 6 weeks, indicating that the benefits of treatment can persist over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated repetitive transcranial magnetic stimulation for treatment-resistant depression. Holtzheimer, PE., McDonald, WM., Mufti, M., et al.[2022]

In a Phase IV study involving 1753 patients across 21 sites, Deep TMS treatment for major depression showed an impressive 81.6% response rate and a 65.3% remission rate after 30 sessions, indicating its efficacy in real-world settings.

The study found that higher stimulation intensity correlated with better clinical outcomes, and most patients experienced sustained improvement within 20 sessions, although some may require extended treatment for optimal results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep TMS H1 Coil treatment for depression: Results from a large post marketing data analysis. Tendler, A., Goerigk, S., Zibman, S., et al.[2023]

Accelerated repetitive transcranial magnetic stimulation (rTMS) is a well-tolerated and effective treatment for major depressive disorder, showing comparable antidepressant efficacy to conventional rTMS protocols, which typically involve 20-30 sessions over 4-6 weeks.

The use of high pulse doses and multiple daily sessions in accelerated rTMS may enhance treatment efficiency and potentially lead to faster onset of effects, although the certainty of quicker antidepressant effects remains unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated Repetitive Transcranial Magnetic Stimulation to Treat Major Depression: The Past, Present, and Future. Chen, L., Klooster, DCW., Tik, M., et al.[2023]

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 gained popularity for its ability to modulate brain activity, but safety considerations are crucial, especially with the recent updates to safety guidelines published in 2021.

The guidelines emphasize the importance of screening for risks, monitoring for adverse events, and specific safety measures when using rTMS, particularly in patients with conditions like stroke and traumatic brain injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. Kim, WS., Paik, NJ.[2023]

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]

In a study of 63 obese individuals undergoing a 5-week rTMS treatment for weight control, the treatment showed a reassuring safety profile with no unexpected adverse events reported up to one year after treatment.

The most common side effects were moderate headaches (40.4%) and local pain/discomfort (19.2%), particularly more frequent in the high-frequency rTMS group, but overall, rTMS was well tolerated in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of repeated sessions of deep transcranial magnetic stimulation in obesity. Ferrulli, A., Massarini, S., Macrì, C., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) is a powerful tool that can effectively treat clinical depression and potentially other brain disorders, but it carries risks, including the potential to induce seizures, as evidenced by 7 known cases by 1996.

A workshop established safety guidelines for rTMS, emphasizing the importance of monitoring, ethical considerations, and the expertise required for its administration to minimize risks and enhance therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Wassermann, EM.[2022]

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a potential treatment for major depressive disorder, particularly for patients who do not respond to traditional antidepressants, with the FDA approving the NeuroStar TMS Therapy System in 2008 for this purpose.

Despite nearly two decades of research, the effectiveness of rTMS in clinical practice remains uncertain due to the variability in study designs and small sample sizes, highlighting the need for larger multicenter trials to better assess its antidepressant effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation in depression--lessons from the multicentre trials. Schönfeldt-Lecuona, C., Cárdenas-Morales, L., Freudenmann, RW., et al.[2021]

A study of 77 military patients receiving rTMS treatment showed significant reductions in depression and PTSD symptoms, with over 44% of patients experiencing a notable decrease in depression scores after treatment.

Most patients had previously tried multiple antidepressants (average of 2.7 trials), indicating that rTMS may be an effective alternative for those with treatment-resistant depression and comorbid PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impacts of rTMS on Refractory Depression and Comorbid PTSD Symptoms at a Military Treatment Facility. Wilkes, S., Ona, C., Yang, M., et al.[2021]

Repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved treatment for medication-resistant depression, but the standard high-frequency protocol has a modest average response rate of only 29.3%.

Newer rTMS paradigms, such as theta burst stimulation and deep TMS, are being explored to enhance the effectiveness of treatment, particularly for patients who do not respond to traditional antidepressant therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Updates on Newer Forms of Transcranial Magnetic Stimulation in Major Depression. Cheng, CM., Li, CT., Tsai, SJ.[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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Trajectory of changes in depressive symptoms after acute repetitive transcranial magnetic stimulation: A meta-analysis of follow-up effects. [2023]

2. Ireland pubmed.ncbi.nlm.nih.gov

Accelerated TMS for Depression: A systematic review and meta-analysis. [2020]

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

Accelerated repetitive transcranial magnetic stimulation for treatment-resistant depression. [2022]

4. Ireland pubmed.ncbi.nlm.nih.gov

Deep TMS H1 Coil treatment for depression: Results from a large post marketing data analysis. [2023]

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

Accelerated Repetitive Transcranial Magnetic Stimulation to Treat Major Depression: The Past, Present, and Future. [2023]

6. 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]

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

Safety Review for Clinical Application of Repetitive Transcranial Magnetic Stimulation. [2023]

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

Safety and tolerability of repeated sessions of deep transcranial magnetic stimulation in obesity. [2021]

10. Ireland pubmed.ncbi.nlm.nih.gov

Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. [2022]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Transcranial magnetic stimulation in depression--lessons from the multicentre trials. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Impacts of rTMS on Refractory Depression and Comorbid PTSD Symptoms at a Military Treatment Facility. [2021]

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

Current Updates on Newer Forms of Transcranial Magnetic Stimulation in Major Depression. [2022]

14. Netherlands pubmed.ncbi.nlm.nih.gov

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