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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores two non-invasive treatments for individuals experiencing a constant sense of unease or dissatisfaction, known as dysphoria. The trial tests Guided Meditation using Virtual Reality, which creates calming virtual environments, and Accelerated Transcranial Magnetic Stimulation (TMS), which uses magnetic pulses to improve brain function. The researchers aim to assess the effectiveness, tolerability, and feasibility of these treatments for mood disorders and related conditions. Individuals who have experienced mood, anxiety, trauma, or pain difficulties for over three months and have maintained a stable treatment routine may be suitable candidates for this trial. As an unphased trial, this study provides a unique opportunity to explore innovative treatments that could enhance well-being.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that both treatments in this trial are likely safe. For Accelerated Transcranial Magnetic Stimulation (TMS), past studies found it well-tolerated and safe. It has been used to help people with depression, significantly reducing their symptoms. Reports indicate it improves mood without causing serious side effects.

For Guided Meditation VR, studies suggest it helps reduce anxiety and stress. It is generally safe, with only minor side effects reported. Most people do not experience serious problems when using VR for meditation.

These findings suggest both treatments could be safe options for participants in this trial. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about these treatments for depression because they offer innovative approaches to tackling the condition. Unlike standard treatments like antidepressants or psychotherapy, the use of accelerated transcranial magnetic stimulation (TMS) in this trial is unique for its potential to rapidly alleviate symptoms. Treatment A uses intermittent theta-burst stimulation over the dorsolateral prefrontal cortex (dlPFC), while Treatment B employs intermittent theta-primed 10Hz stimulation over the medial prefrontal cortex (mPFC). These methods target specific brain areas linked to mood regulation, potentially offering faster relief than traditional approaches. Additionally, the use of guided meditation through virtual reality provides a novel, immersive way to enhance wellness, making treatment more engaging and accessible.

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

Research shows that Accelerated Transcranial Magnetic Stimulation (TMS), offered in this trial as either Treatment A or Treatment B, can significantly reduce depression symptoms. Studies have found that up to 43% of patients notice improvement after four weeks of treatment, meaning nearly half feel better. Another option in this trial is Guided Meditation using Virtual Reality (VR), which has also effectively reduced depression, anxiety, and stress. It provides an immersive experience that can enhance mood and well-being. Both treatments in this trial aim to offer non-drug options for managing low mood and related symptoms. ^{1 2 6 7 8}

Who Is on the Research Team?

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

Principal Investigator

Florida State University

Are You a Good Fit for This Trial?

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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) 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]

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]

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) 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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12090592/

Accelerated repetitive transcranial magnetic stimulation in ... Results indicated that accelerated rTMS is well-tolerated and safe, leading to a 33% response rate at week 1 and an increase to 43% at week 4 [ ...

2. bmcpsychiatry.biomedcentral.com bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-024-05545-1

Short-term and long-term efficacy of accelerated transcranial ... The aim of this study was to evaluate the efficacy and long-term maintenance effects of aTMS in patients with major depressive disorder (MDD).

3. sciencedirect.com sciencedirect.com/science/article/pii/S1876201825000632

Efficacy and safety of accelerated transcranial magnetic ... Accelerated TMS significantly reduced OCD and depressive symptoms, and increased response rate compared to sham aTMS.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38154411/

Evaluating real-world effectiveness of accelerated ... Results: Significant symptom reduction was found in the completer sample (N = 147), with 46.3 % of patients meeting post-treatment response ...

5. nature.com nature.com/articles/s41386-023-01599-z

Accelerated TMS - moving quickly into the future of ... Overall, accelerated TMS appears to hold promise to reduce treatment time and achieve rapid reduction in depressive symptoms, but at this time ...

6. brainstimjrnl.com brainstimjrnl.com/article/S1935-861X%2824%2900124-4/fulltext

A pilot study of safety and efficacy using a pragmatic protocol Transcranial magnetic stimulation (TMS) is an effective FDA-approved treatment for treatment-resistant major depressive disorder (MDD) [1.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06783361

Accelerated Transcranial Magnetic Stimulation in ... This study aims to monitor the change in neurocognitive functions of patients with moderate to severe depression diagnosed with major depression according to ...

8. 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.