Trigeminal Nerve Stimulation for Anxiety Disorders

Overseen By Roumen Milev, MD PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Dr. Rafael Freire

Must not be taking: Antidepressants, Benzodiazepines

Disqualifiers: Depression, Suicidality, Bipolar, Schizophrenia, 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: Unknown

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called trigeminal nerve stimulation to determine its effectiveness for anxiety disorders such as panic disorder, generalized anxiety disorder, and social anxiety disorder. The treatment uses gentle electrical currents on the forehead to stimulate the trigeminal nerve, potentially reducing anxiety symptoms. Participants will receive either the active treatment or a placebo-like version for comparison. The trial seeks individuals with one of these anxiety disorders who are not currently undergoing other treatments like cognitive behavioral therapy or medication. As an unphased trial, this study provides a unique opportunity to explore a novel approach to managing anxiety symptoms.

Will I have to stop taking my current medications?

Yes, you will need to stop taking medications for anxiety disorders, antidepressants, and benzodiazepines to participate in this trial.

What prior data suggests that trigeminal nerve stimulation is safe for anxiety disorders?

Research has shown that trigeminal nerve stimulation (TNS) is generally safe. One study noted only a few mild side effects: skin irritation on the forehead in about 15% of participants, headaches in 20%, and increased anxiety in 10%. Importantly, no serious side effects occurred. Other studies support these findings, indicating that TNS is used safely for various conditions with few negative effects. Overall, TNS appears to be a safe option for many people. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about trigeminal nerve stimulation (TNS) for anxiety disorders because it offers a non-invasive and potentially more convenient alternative to current treatments like medication and psychotherapy. Unlike medications, which can have significant side effects and take time to work, TNS may provide relief by directly stimulating the trigeminal nerve, possibly leading to quicker symptom reduction. Moreover, TNS is administered at home using a small device, offering a flexible treatment option that fits easily into daily routines. This approach could be a game-changer for those who struggle with the traditional methods' limitations or side effects.

What evidence suggests that trigeminal nerve stimulation is effective for anxiety disorders?

Research shows that trigeminal nerve stimulation (TNS) can help treat various conditions. Studies have found that TNS significantly improves symptoms of depression and ADHD. In these cases, patients generally tolerate TNS well, with few side effects. While research on TNS for anxiety disorders continues, its success with other conditions is encouraging. In this trial, participants will receive either active or sham TNS treatment. The treatment uses a non-invasive device that gently stimulates the trigeminal nerve through the forehead, potentially helping to balance brain activity. Early results suggest this method could be especially promising for people with anxiety disorders. ^{2 3 5 6 7}

Who Is on the Research Team?

Rafael Freire, MD PhD

Principal Investigator

Department of Psychiatry, Queen's University

Are You a Good Fit for This Trial?

This trial is for individuals who have been diagnosed with panic disorder, social anxiety disorder, or generalized anxiety disorder according to DSM5 criteria. It's not specified who can't join the trial.

Inclusion Criteria

I have been diagnosed with panic, social anxiety, or generalized anxiety disorder.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive trigeminal nerve stimulation or sham stimulation at home for 8 hours per night, 7 days a week for 8 weeks

8 weeks

Follow-up

Participants are monitored for sustained response and remission two weeks after the end of treatment

2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Trigeminal Nerve Stimulation

Trial Overview

The study is testing trigeminal nerve stimulation (TNS) as a treatment for various anxiety disorders. Participants will receive either active TNS or a sham (placebo) version to compare effectiveness and tolerability.

How Is the Trial Designed?

Group I: Active stimulation Experimental Treatment 1 Intervention

Active or sham TNS treatment will be performed at the patients' home for approximately 8 hours per night 7 days a week for 8 consecutive weeks. Trigeminal nerve stimulation will occur by placement of electrodes (1.25" silver electrodes Bio-Flex BF4, Biotens/Vermed, Buffalo, NY, USA) bilaterally on the V1 branches of the trigeminal nerve (CNV) located on the forehead. Current will be generated from the EMS 7500 stimulator (TENS Products, Inc., Granby, CO) (Class II medical device) and will be set to a level that is clearly perceptible by each patient (i.e. tingling sensation) but not uncomfortable or painful. Current level will be determined for each patient at baseline and will likely be between 4-6 mA. Active stimulation will occur at 120 Hz with a 250 µs pulse width and with a duty cycle of 30 seconds on to 30 seconds off.

Group II: Sham stimulation Placebo Group 1 Intervention

Active or sham TNS treatment will be performed at the patients' home for approximately 8 hours per night 7 days a week for 8 consecutive weeks. Sham stimulation will occur by placement of electrodes (1.25" silver electrodes Bio-Flex BF4, Biotens/Vermed, Buffalo, NY, USA) bilaterally on the V1 branches of the trigeminal nerve (CNV) located on the forehead. Current will be generated from the EMS 7500 stimulator (TENS Products, Inc., Granby, CO) (Class II medical device) and will be set to a level that is clearly perceptible by each patient (i.e. tingling sensation) but not uncomfortable or painful. Current level will be determined for each patient at baseline and will likely be between 4-6 mA. Sham stimulation will use the same parameters of active stimulation, but after 60 seconds the stimulator will turn off.

Trigeminal Nerve Stimulation is already approved in United States, European Union for the following indications:

Approved in United States as Monarch eTNS System for:

• Attention Deficit Hyperactivity Disorder (ADHD) in children aged 7-12

Approved in European Union as Cefaly for:

• Migraine prevention and treatment

Who Is Running the Clinical Trial?

Dr. Rafael Freire

Lead Sponsor

Trials

2

Recruited

10+

Dr. Rafael Freire

Lead Sponsor

Trials

2

Recruited

10+

Published Research Related to This Trial

External trigeminal nerve stimulation (eTNS) is a safe and well-tolerated therapy for patients with drug-resistant epilepsy, as shown in a pilot feasibility study.

The study specifically monitored heart rate and blood pressure responses to eTNS, indicating no significant adverse effects on these vital signs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute and long-term safety of external trigeminal nerve stimulation for drug-resistant epilepsy. Pop, J., Murray, D., Markovic, D., et al.[2011]

Trigeminal nerve stimulation (TNS) was found to be well tolerated in a pilot study involving seven subjects with epilepsy, indicating a favorable safety profile.

Among the participants who completed at least three months of treatment, 57% experienced a significant reduction of 50% or more in seizure frequency, suggesting preliminary efficacy and warranting further research into TNS for epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot study of trigeminal nerve stimulation (TNS) for epilepsy: a proof-of-concept trial. DeGiorgio, CM., Shewmon, A., Murray, D., et al.[2006]

Trigeminal nerve stimulation (TNS) significantly improves neurological function and reduces brain edema in a mouse model of traumatic brain injury (TBI), suggesting its potential as a therapeutic intervention.

TNS also lowers inflammatory markers like tumor necrosis factor-α and interleukin 6, and modulates the cleaved caspase-3 pathway, indicating a mechanism that may protect against secondary brain injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effectiveness of Trigeminal Nerve Stimulation on Traumatic Brain Injury. Yang, Q., Zhang, S., Xu, Z., et al.[2023]

In a study of 42 patients with drug refractory epilepsy, external trigeminal nerve stimulation (eTNS) showed a significant improvement in quality of life and mood for patients without intellectual disabilities, suggesting its potential benefits beyond seizure control.

While there was a decrease in seizure frequency of 11% among participants, this change was not statistically significant, indicating that more controlled studies are needed to fully assess the efficacy of eTNS as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An audit of external trigeminal nerve stimulation (eTNS) in epilepsy. Slaght, SJ., Nashef, L.[2018]

External trigeminal nerve stimulation (ETNS) significantly reduced seizure frequency in patients with focal drug-resistant epilepsy (DRE), with a 50% response rate compared to 0% in the control group after 12 months.

ETNS was well-tolerated with no relevant adverse events, and it improved quality of life without affecting mood or cognitive function, indicating its potential as a safe long-term treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

External trigeminal nerve stimulation for drug resistant epilepsy: A randomized controlled trial. Gil-López, F., Boget, T., Manzanares, I., et al.[2021]

In a proof-of-concept trial involving 12 adults with PTSD and major depressive disorder, external trigeminal nerve stimulation (eTNS) significantly reduced symptoms of both conditions over eight weeks, showing a median decrease of 15 points in PTSD scores and a 42% response rate in depression scores.

eTNS was well tolerated with minimal adverse effects, suggesting it could be a safe and effective adjunct therapy for individuals with PTSD and depression when combined with standard pharmacotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trigeminal Nerve Stimulation for Comorbid Posttraumatic Stress Disorder and Major Depressive Disorder. Cook, IA., Abrams, M., Leuchter, AF.[2022]

External trigeminal nerve stimulation (eTNS) is a safe and well-tolerated long-term treatment for drug-resistant epilepsy, with no serious device-related adverse events reported over 12 months.

In a follow-up study of 35 participants, eTNS significantly reduced median seizure frequency by 27.4% at 6 months and 34.8% at 12 months, demonstrating its efficacy as a promising therapy for patients with epilepsy who do not respond to medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective long-term study of external trigeminal nerve stimulation for drug-resistant epilepsy. Soss, J., Heck, C., Murray, D., et al.[2018]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11059677/

The efficacy of real versus sham external Trigeminal Nerve ...

External trigeminal nerve stimulation (eTNS) is a minimal risk, non-invasive neuromodulation device, targeting the trigeminal system. It was approved for ADHD ...

2.

sciencedirect.com

sciencedirect.com/science/article/pii/S2773021223000524

The use of external Trigeminal Nerve Stimulation as an ...

Previous research into the use of eTNS to treat other psychiatric and neurological disorders has shown the device to be well-tolerated with few adverse events.

3.

nature.com

nature.com/articles/s41380-023-02227-4

Clinical and cognitive effects of external trigeminal nerve ...

In summary, eTNS has been shown to significantly improve depression symptoms at first end-point and one-month after stimulation cessation (with ...

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6481187/

Double-Blind, Sham-Controlled, Pilot Study of Trigeminal ...

This study demonstrates TNS efficacy for ADHD in a blinded sham-controlled trial, with estimated treatment effect size similar to non-stimulants.

5.

clinicaltrials.gov

clinicaltrials.gov/study/NCT02155608

NCT02155608 | Trigeminal Nerve Stimulation for ADHD

This three-year developmental study is a double-blind randomized trial of active vs. inactive sham eTNS for ADHD, with four weeks acute treatment.

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10827664/

Clinical and cognitive effects of external trigeminal nerve ...

Forehead skin irritation was observed in 3 patients (15%), headache in 4 (20%) and anxiety in 2 (10%). Olivie et al. (2019), eTNS was well tolerated. No serious ...

7.

accessdata.fda.gov

accessdata.fda.gov/cdrh_docs/reviews/DEN180041.pdf

De Novo Summary (DEN180041) Page 1 of 1 FDA identifies ...

The Monarch external Trigeminal Nerve Stimulation (eTNS) System is a non-invasive device that uses electrical signals to therapeutically ...