tVNS for Depression

(tVNS_MDD_Sex Trial)

Overseen By Vitaly Napadow, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Massachusetts General Hospital

Must not be taking: Neuroleptics

Disqualifiers: Psychosis, Suicidal ideation, Substance use, Cardiovascular, CNS diseases, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 session

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores transcutaneous vagus nerve stimulation (tVNS) to assess its effects on stress response in individuals with major depressive disorder (MDD). Researchers aim to determine if this treatment alters how the brain and body manage stress and whether these changes vary between men and women. Participants will be randomly assigned to receive either the real tVNS treatment or a sham version during an MRI scan to measure these effects. The trial seeks individuals with recurring depression but no history of severe mental health issues, such as schizophrenia or recent substance abuse. As an unphased trial, this study provides a unique opportunity to contribute to groundbreaking research on stress and depression.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you have a history of using neuroleptic medications, you would not be eligible to participate.

What prior data suggests that this method is safe for treating depression?

Research has shown that transcutaneous vagus nerve stimulation (tVNS) is generally safe. Studies have found tVNS effective and safe for treating mild to moderate depression, often outperforming a placebo, which has no active effect.

Regarding safety, tVNS is usually well-tolerated. Most side effects are mild and short-lived, such as slight discomfort or tingling at the device site. Available studies have not linked tVNS to serious side effects.

Overall, current research suggests tVNS is a safe option for people with depression. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about tVNS (transcutaneous vagus nerve stimulation) for depression because it offers a non-invasive approach to treating this condition. Unlike traditional antidepressants, which often work by altering neurotransmitter levels in the brain, tVNS targets the vagus nerve through the skin on the left ear, potentially reducing side effects. This method provides a novel mechanism of action by stimulating nerve pathways that may improve mood and emotional regulation. Additionally, the use of a sham comparator arm in studies helps ensure the effectiveness of tVNS is accurately assessed, offering hope for a new option that could work faster or more efficiently than current treatments.

What evidence suggests that tVNS is effective for depression?

Research has shown that transcutaneous vagus nerve stimulation (tVNS) can help reduce symptoms of depression. In this trial, participants will receive either active tVNS or a sham tVNS treatment. Studies have found that active tVNS significantly improves scores on depression tests, such as the Hamilton Depression Scale and the Beck Depression Inventory, compared to sham treatments. Patients receiving active tVNS often achieve better results than those receiving the sham treatment, demonstrating its effectiveness. Early research suggests that tVNS is a safe and promising option for managing mild to moderate depression. Additionally, tVNS has been found to reduce anxiety symptoms, which often accompany depression. ^{1 2 6 7 8}

Who Is on the Research Team?

Ronald G Garcia, MD, PhD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for adults over 50 with a current or past diagnosis of recurrent Major Depressive Disorder. It's not suitable for those with traumatic brain injury, MRI/tVNS contraindications like claustrophobia or metallic implants, history of psychosis, recent severe substance use disorder, significant heart/cerebrovascular disease, CNS diseases (like MS or epilepsy), or pregnant women due to potential risks.

Inclusion Criteria

I have been diagnosed with Major Depressive Disorder more than once.

Exclusion Criteria

I have thinking or memory problems due to a head injury.

You have had a serious problem with drugs or alcohol in the past year.

I have taken medication for mental health issues.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive active or sham expiratory-gated transcutaneous vagus nerve stimulation during a functional magnetic resonance imaging (fMRI) session

1 session

1 visit (in-person)

Follow-up

Participants are monitored for changes in depressive symptoms, cardiac autonomic function, serum cortisol levels, and pro-inflammatory cytokines

2-4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• tVNS

Trial Overview

The study tests if transcutaneous vagus nerve stimulation (tVNS) can affect stress response in depression differently based on sex. Participants will be randomly assigned to receive either active tVNS or a sham treatment during an fMRI scan while mood and physiological responses are monitored.

How Is the Trial Designed?

Group I: Active tVNS Experimental Treatment 1 Intervention

Expiratory-gated transcutaneous vagus nerve stimulation on the left auricle

Group II: Sham tVNS Placebo Group 1 Intervention

Sham transcutaneous vagus nerve stimulation on the left auricle

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

Approved in European Union as Transcutaneous Vagus Nerve Stimulation for:

• Epilepsy
• Depression
• Chronic pain
• Migraines

Approved in United States as Transcutaneous Vagus Nerve Stimulation for:

• Epilepsy
• Depression
• Chronic pain

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

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]

Transcutaneous vagus nerve stimulation (tVNS) significantly reduced depression symptoms in patients with mild to moderate major depressive disorder (MDD), as evidenced by a notable decrease in Hamilton Depression Rating Scale scores after one month of treatment.

tVNS was found to modulate functional connectivity in the brain's default mode network, indicating potential mechanisms through which it may exert its antidepressant effects, particularly by altering connectivity with regions like the anterior insula and parahippocampus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous Vagus Nerve Stimulation Modulates Default Mode Network in Major Depressive Disorder. Fang, J., Rong, P., Hong, Y., et al.[2022]

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]

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]

Trans-auricular vagus nerve stimulation (taVNS) significantly reduced depression symptoms in 24 patients with treatment-resistant depression (TRD) over 8 weeks, with an average reduction of 66.95% in the Hamilton Rating Scale for Depression (HAMD-17) scores.

The efficacy of taVNS may be linked to changes in brain activity, particularly in the right insula and left frontal gyrus, as indicated by decreased regional homogeneity and functional connectivity, which correlated with improvements in depression symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Functional MRI-based study on neuromechanism of trans-auricular vagus nerve stimulation for treatment-resistant depression]. Chen, LM., Li, XJ., Xu, K., et al.[2021]

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 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 auricular vagus nerve stimulation (taVNS) significantly improved depressive behavior in rats, as evidenced by increased body weight and decreased immobility time in forced swimming tests after 21 days of treatment.

The mechanism of taVNS's effectiveness appears to involve the inhibition of the inflammatory response through the TLR4/MyD88 signaling pathway in the prefrontal cortex, suggesting a biological basis for its antidepressant effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of transcutaneous auricular vagus nerve stimulation on the expression of TLR4、MyD88、IL-18 protein in the prefrontal cortex of depression rats]. Wang, YF., Wang, Y., Zhang, Y., et al.[2022]

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]

A pilot study involving 37 patients with major depression showed that non-invasive auricular transcutaneous electric nerve stimulation (tVNS) resulted in a significant improvement in depression symptoms as measured by the Beck Depression Inventory, with an average score decrease of 12.6 points compared to 4.4 points in the sham group.

While the Hamilton Depression Rating Scale did not show significant changes, this study is the first to suggest an antidepressant effect of tVNS, indicating potential for further research despite limitations like small sample size and the need for more robust testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study. Hein, E., Nowak, M., Kiess, O., et al.[2021]

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