taVNS + TMS for Depression

Overseen By Mark George

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Medical University of South Carolina

Must be taking: Antidepressants

Disqualifiers: Neurological disorders, Dementia, Head trauma, others

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

Compensation: Varies

Number of Visits: 9

Duration: 2 weeks

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to treating depression by combining two types of brain stimulation: Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) through the ear and Transcranial Magnetic Stimulation (TMS) using magnets on the head. The researchers aim to determine if using both methods together reduces depression symptoms more effectively than either treatment alone. Participants will be randomly assigned to receive ear stimulation, magnetic head stimulation, or both, over six treatment days. Individuals who have tried at least two antidepressant medications without success or are currently using an ear stimulation device might be suitable for this trial.

As an unphased trial, this study provides a unique opportunity to explore innovative treatment combinations for depression.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you have a cervical VNS device, you will continue using it as part of the study.

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

Research shows that both treatments under study—taVNS and TMS—are generally safe. Studies have found taVNS effective and safe for treating mild to moderate depression, with most side effects being mild and temporary, such as slight tingling at the stimulation site.

TMS has also been well studied and is generally well tolerated. It uses magnetic fields to stimulate brain nerve cells, which can help alleviate depression symptoms. Major studies confirmed its safety, especially since it received FDA approval for treating depression.

Research suggests that combining these treatments, with synchronized VNS and TMS, is safe and well tolerated. Previous studies show that this combination can lead to a greater reduction in depression symptoms without adding significant risk.

Overall, trials have shown these treatments to be generally safe, with manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for depression because they offer innovative approaches beyond the typical medications like SSRIs or therapy sessions. Transcranial Magnetic Stimulation (TMS) uses magnetic fields to stimulate nerve cells in the brain, which can help alleviate depressive symptoms without the side effects associated with medications. Vagus Nerve Stimulation (VNS), on the other hand, targets the vagus nerve through electrical impulses, potentially improving mood regulation. The combination of synchronized VNS and TMS could amplify their effects, offering a new avenue for those who haven't responded well to traditional treatments.

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

Research has shown that transcutaneous auricular vagus nerve stimulation (taVNS) can help with depression. Studies have found that taVNS significantly improves depression symptoms, often outperforming placebo treatments. In this trial, some participants will receive only taVNS. Transcranial magnetic stimulation (TMS) has also proven effective, with about 30-60% of patients experiencing relief. Some participants in this trial will receive only TMS. Using both treatments together might be even more effective, as they address depression in different ways. Early studies suggest that this combined approach, which some participants in this trial will receive, may reduce symptoms more than using either method alone. ^{1 4 6 7 8}

Who Is on the Research Team?

Mark George, MD

Principal Investigator

Medical University of South Carolina

Are You a Good Fit for This Trial?

This trial is for adults aged 18-75 with severe depression, who haven't improved with talk therapy and have tried at least two antidepressants without success. It's also open to those already using cervical VNS. Participants must be able to consent, speak English, and not be pregnant or at high risk of suicide.

Inclusion Criteria

I am receiving VNS for my neck or have tried two antidepressants without success.

Able to provide informed consent

17-item Hamilton Depression Rating Scale (HAM-D) score ≥20

Exclusion Criteria

History of major head trauma

I need a legal guardian to make decisions for me due to cognitive issues.

Current active suicidal intent or plan, prior attempt within the last 6 months, or who in the judgment of the investigator would be at elevated risk for suicide will be excluded

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Treatment

Participants receive either VNS treatment alone, TMS treatment alone, or both at the same time over 6 treatment days

2 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 calls (virtual)

What Are the Treatments Tested in This Trial?

Interventions

• taVNS
• TMS

Trial Overview The study tests a combined depression treatment involving ear nerve stimulation (taVNS) and brain magnetic stimulation (TMS), separately or together. Over six sessions at the MUSC campus in Charleston, treatments are randomized across different days to assess which combination might best alleviate symptoms.

How Is the Trial Designed?

Group I: Vagus Nerve Stimulation (VNS) only Experimental Treatment 1 Intervention

Group II: Transcranial Magnetic Stimulation (TMS) only Experimental Treatment 1 Intervention

Group III: Synchronized VNS and TMS Experimental Treatment 2 Interventions

taVNS is already approved in United States, European Union for the following indications:

Approved in United States as Transcutaneous Auricular Vagus Nerve Stimulation for:

• Epilepsy
• Depression
• Obesity

Approved in European Union as Transcutaneous Auricular Vagus Nerve Stimulation for:

• Epilepsy
• Depression

Who Is Running the Clinical Trial?

Medical University of South Carolina

Lead Sponsor

Trials

994

Recruited

7,408,000+

Published Research Related to This Trial

Transcutaneous auricular vagus nerve stimulation (taVNS) significantly reduced depression symptoms in patients with major depressive disorder, outperforming sham treatments in multiple depression scales, including the 24-item HAMD and Self-Rating Depression Scale.

The study, which included 4 trials with a total of 222 participants, found no significant adverse effects associated with taVNS, suggesting it is a safe alternative treatment for depression, although further research with larger sample sizes is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulation in treating major depressive disorder: A systematic review and meta-analysis. Wu, C., Liu, P., Fu, H., et al.[2022]

Transcutaneous auricular vagus nerve stimulation (taVNS) is a safe and effective neuromodulation therapy for a variety of conditions, including epilepsy, depression, and anxiety, indicating its broad therapeutic potential.

Despite its effectiveness, there is currently no standardization among taVNS devices, and further research is needed to clarify the relationship between stimulation parameters and therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulators: a review of past, present, and future devices. Wang, L., Wang, Y., Wang, Y., et al.[2022]

Transcutaneous auricular vagus nerve stimulation (taVNS) has shown significant potential in reducing multiple symptoms of depression, including anxiety, sleep disturbances, and hopelessness, based on clinical studies and re-analysis of the Hamilton Depression Scale.

The proposed mechanisms of action for taVNS include modulating brain activity related to mood regulation, inhibiting neuro-inflammation, promoting neurogenesis in the hippocampus, and influencing the microbiome-brain-gut axis, highlighting its multifaceted approach to treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating Depression with Transcutaneous Auricular Vagus Nerve Stimulation: State of the Art and Future Perspectives. Kong, J., Fang, J., Park, J., et al.[2020]

Transcutaneous vagus nerve stimulation (taVNS) was assessed in a pilot study of 5 patients with treatment-resistant depression, showing substantial improvement in mental state for 2 participants after 12 weeks of treatment.

While taVNS is a non-invasive method that avoids surgical risks, 3 patients dropped out due to difficulties in using the device, highlighting a potential barrier to its broader application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of transcutaneous auricular vagus nerve stimulation (taVNS) in the treatment of drug-resistant depression - a pilot study, presentation of five clinical cases. Kaczmarczyk, M., Antosik-Wójcińska, A., Dominiak, M., et al.[2021]

Transcutaneous auricular vagus nerve stimulation (taVNS) has been shown to effectively modulate brain activity in patients with treatment-resistant depression (TRD), as evidenced by significant changes in brain regions such as the medial orbital frontal cortex after just 30 minutes of stimulation.

The study utilized rest-state functional magnetic resonance imaging (rs-fMRI) with 40 TRD patients and 40 healthy controls, revealing that taVNS may alter functional connectivity in key cortical areas, suggesting potential neural mechanisms for its therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve immediate stimulation treatment for treatment-resistant depression: A functional magnetic resonance imaging study. Ma, Y., Wang, Z., He, J., et al.[2022]

This study will investigate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on 15 patients with a minimally conscious state, using five different frequencies (1, 10, 25, 50, and 100 Hz) to determine the optimal stimulation parameters.

The goal is to achieve stable improvements in consciousness levels in patients with disorders of consciousness by optimizing the taVNS neuromodulation technique, with results measured through the coma recovery scale-revised (CRS-R) and resting EEG assessments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the modulation paradigm of transcutaneous auricular vagus nerve stimulation in patients with disorders of consciousness: A prospective exploratory pilot study protocol. Zhai, W., Jiao, H., Zhuang, Y., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (taVNS) significantly improves depression symptoms, as evidenced by reduced scores on the Hamilton Depression Scale in a review of 12 studies involving 838 participants.

taVNS shows comparable response rates to traditional antidepressants and has fewer side effects, suggesting it could be a safe alternative or complementary treatment for depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of transcutaneous auricular vagus nerve stimulation in the treatment of depressive disorder: A systematic review and meta-analysis of randomized controlled trials. Tan, C., Qiao, M., Ma, Y., et al.[2023]

This study will evaluate the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) in treating mild to moderate depression in adolescents aged 12-16, involving 120 participants in a randomized controlled trial comparing taVNS to sertraline, a common antidepressant.

The research will also explore the underlying neural mechanisms of taVNS using advanced MRI techniques, aiming to provide insights into how this non-invasive treatment can effectively alleviate depression symptoms without the severe side effects often associated with medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and brain mechanism of transcutaneous auricular vagus nerve stimulation for adolescents with mild to moderate depression: Study protocol for a randomized controlled trial. Xiao, X., Hou, X., Zhang, Z., et al.[2022]

Transcutaneous auricular vagus nerve stimulation (taVNS) is generally safe, with a low incidence of mild and transient adverse effects, such as ear pain, headache, and tingling, reported in only 24.86% of the studies analyzed.

In a systematic review of 177 studies involving 6322 subjects, there was no significant difference in the risk of adverse events between taVNS and control groups, indicating that taVNS is a feasible option for clinical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. Kim, AY., Marduy, A., de Melo, PS., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7970701/

Synchronized cervical VNS with accelerated theta burst ... Cervical VNS can effectively treat medication resistant epilepsy [2,3] and treatment resistant depression over the course of many years [4,5]. In some cases, ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S1094715925000327

Accelerated Transcutaneous Auricular Vagus Nerve ... In this open label study, taVNS significantly decreased depression and anxiety symptoms in patients admitted to the inpatient unit.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2990624/

Vagus Nerve Stimulation (VNS) and Treatment of Depression Outcomes. At the one-year mark, the TRD group who received adjunctive VNS had better outcomes compared to TAU only. On the HAM-D, the response ...

4. withpower.com withpower.com/trial/phase-depressive-disorder-2-2023-8a783

taVNS + TMS for Depression Transcutaneous auricular vagus nerve stimulation (taVNS) significantly reduced depression symptoms in patients with major depressive disorder, outperforming ...

5. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/46/NCT04130646/Prot_001.pdf

Version 3 This taVNS system can rapidly translate the promising basic animal studies revealing the neuroplasticity effects of paired-VNS, and a small open-label trial of ...

6. journals.lww.com journals.lww.com/ectjournal/fulltext/2024/03000/vagus_nerve_stimulation_combined_with_alternating.14.aspx

Vagus Nerve Stimulation Combined With Alternating... In our case, synchronized VNS led to stronger reduction in depression symptoms than nonsynchronized treatment. Treatment was safe and well tolerated. Data ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9094636/

Safety and recommendations for TMS use in healthy subjects ... Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines

8. brainstimjrnl.com brainstimjrnl.com/article/S1935-861X(24)01161-6/fulltext

Vagus nerve stimulation (VNS), repetitive transcranial ... Preliminary findings suggest that combining the two methods is safe and feasible, and 12 sessions of synchronized VNS and rTMS are more effective at acutely ...