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 is testing a treatment called trigeminal nerve stimulation, which involves sending electrical signals to a nerve in the face. It aims to help patients with panic disorder, generalized anxiety disorder, and social anxiety disorder. The treatment works by calming brain activity to reduce anxiety symptoms. Trigeminal nerve stimulation (TNS) is a promising strategy in treating diseases of the nervous system, including epilepsy and traumatic brain injury.

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.

Is trigeminal nerve stimulation (TNS) safe for humans?

Research on trigeminal nerve stimulation (TNS) for epilepsy shows it is generally safe and well tolerated in humans, with no significant issues related to heart rate or blood pressure. ^{1 2 3 4 5}

How does trigeminal nerve stimulation treatment differ from other treatments for anxiety disorders?

Trigeminal nerve stimulation (TNS) is unique because it is a non-invasive treatment that uses external electrodes to stimulate the trigeminal nerve, which may influence brain areas involved in mood and anxiety regulation. Unlike traditional medications, TNS does not involve taking drugs and has shown promise in improving mood and anxiety in conditions like epilepsy and depression. ^{1 3 4 6 7}

What data supports the effectiveness of the treatment Trigeminal Nerve Stimulation for anxiety disorders?

Research suggests that external trigeminal nerve stimulation (eTNS) is safe and may improve mood, as seen in studies with epilepsy and depression. It has shown potential in reducing seizure frequency and improving mood, which could indicate benefits for anxiety as well. ^{1 2 3 4 6}

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]

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]

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]

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]

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]

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

Acute and long-term safety of external trigeminal nerve stimulation for drug-resistant epilepsy. [2011]

2. England pubmed.ncbi.nlm.nih.gov

An audit of external trigeminal nerve stimulation (eTNS) in epilepsy. [2018]

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

External trigeminal nerve stimulation for drug resistant epilepsy: A randomized controlled trial. [2021]

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

Pilot study of trigeminal nerve stimulation (TNS) for epilepsy: a proof-of-concept trial. [2006]

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

Trigeminal Nerve Stimulation for Comorbid Posttraumatic Stress Disorder and Major Depressive Disorder. [2022]

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

The Effectiveness of Trigeminal Nerve Stimulation on Traumatic Brain Injury. [2023]

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

A prospective long-term study of external trigeminal nerve stimulation for drug-resistant epilepsy. [2018]