Trigeminal Nerve Stimulation for Generalized Anxiety Disorder

Overseen By Rafael Freire, MD PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Dr. Rafael Freire

Must be taking: SSRIs, SNRIs

Disqualifiers: Depression, Suicidality, OCD, 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: 4

Duration: 8 weeks

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to assist individuals with generalized anxiety disorder (GAD) who haven't found success with standard medications. It uses trigeminal nerve stimulation (TNS), which involves mild electrical pulses to the forehead, to determine if it can safely reduce anxiety symptoms. Individuals with GAD who have been on a stable dose of certain medications for at least 8 weeks and haven't responded to at least two different treatments may be suitable for this trial. The results will guide the planning of a larger study in the future. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research that could lead to new treatment options for GAD.

Will I have to stop taking my current medications?

The trial does not require you to stop your current medications. In fact, participants need to be on a stable dose of an SSRI or SNRI for at least 8 weeks to join the study.

What prior data suggests that trigeminal nerve stimulation is safe for patients with treatment-resistant generalized anxiety disorder?

Research has shown that trigeminal nerve stimulation (TNS) is generally safe for people. Studies have found it to be well-tolerated, with few reports of side effects. For example, one study found that using TNS to treat conditions like ADHD (Attention Deficit Hyperactivity Disorder) caused minimal side effects. Another study suggested that TNS could safely improve mood and reduce seizures in conditions like epilepsy and depression. While this does not guarantee the same results for generalized anxiety disorder, it suggests that TNS is safe for humans. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Trigeminal nerve stimulation is unique because it targets the trigeminal nerve directly through non-invasive electrical stimulation on the forehead. Unlike standard anxiety treatments, such as medications and talk therapy, which can take time to work and may have side effects, this method could offer a quicker route to relief with fewer side effects. Researchers are excited about this approach because it involves a novel mechanism that could benefit patients who haven't found success with traditional treatments.

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

Research has shown that trigeminal nerve stimulation (TNS) can effectively treat certain conditions, such as ADHD, with few side effects. In studies, TNS improved ADHD symptoms more than a placebo, indicating a real therapeutic effect. Most people tolerate the TNS device well, experiencing few negative reactions. This trial will provide participants with active stimulation using TNS to explore its potential benefits for generalized anxiety disorder (GAD). Although TNS has not been widely tested for GAD, its success with other conditions suggests it might also help with GAD. TNS works by stimulating nerves on the forehead, which may help control brain activity related to anxiety. ^{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 with generalized anxiety disorder (GAD) who haven't had success with standard treatments. It's a small study, aiming to include just ten participants.

Inclusion Criteria

Meet DSM5 criteria for generalized anxiety disorder

I have been on a steady dose of depression/anxiety medication for at least 8 weeks.

My anxiety hasn't improved after trying two different types of medication for at least 8 weeks each.

Exclusion Criteria

Pregnant or breastfeeding women

I have been diagnosed with major depression that is moderate to severe.

Moderate to high suicidality

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 (TNS) for 8 weeks as an augmentation strategy to pharmacological treatment for generalized anxiety disorder

8 weeks

Baseline visit, 4-week visit, 8-week visit

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Trigeminal Nerve Stimulation

Trial Overview

The study is testing trigeminal nerve stimulation (TNS) as an add-on to usual drug treatment for GAD over 8 weeks. The main goal is to check if TNS is safe and tolerable, while also watching for any changes in the severity of anxiety symptoms.

How Is the Trial Designed?

Group I: Active stimulation Experimental Treatment 1 Intervention

Trigeminal nerve stimulation will occur by placement of electrodes (1.25" silver electrodes Bio-Flex BF4, Biotens/Vermed, Buffalo, New York, 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 milliampere (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.

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) 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]

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]

Trigeminal nerve stimulation (TNS) and transcutaneous vagus nerve stimulation (tVNS) show preliminary promise in treating neuropsychiatric disorders like depression, but the results are mixed and based on small, open-label studies, limiting their reliability.

The systematic review included four studies on TNS and four on tVNS, indicating that while these techniques may improve treatment outcomes, their modest impact in clinical practice is due to the small sample sizes and lack of robust data.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus and trigeminal nerve stimulation for neuropsychiatric disorders: a systematic review. Shiozawa, P., Silva, ME., Carvalho, TC., et al.[2019]

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 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) 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]

Citations

1.

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.

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.

pmc.ncbi.nlm.nih.gov

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

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

62 children with ADHD showing improvement of ADHD symptoms after 4 weeks of nightly real versus sham eTNS with minimal side effects.

4.

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.

5.

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 ...

6.

withpower.com

withpower.com/trial/phase-anxiety-disorders-2024-0e0cc

Trigeminal Nerve Stimulation for Generalized Anxiety ...

Research on trigeminal nerve stimulation (TNS) shows it is safe and may improve mood and reduce seizures in epilepsy and depression. This suggests it might also ...