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

Trial Summary

What is the purpose of this trial?

This is a feasibility study for trigeminal nerve stimulation (TNS) in patients with treatment-resistant generalized anxiety disorder (TR-GAD). Ten participants will receive TNS for 8 weeks as an augmentation strategy to pharmacological treatment for generalized anxiety disorder (GAD). * The primary objective is to ascertain if TNS is a safe and well-tolerated treatment for patients with TR-GAD. * The secondary objective will be to monitor changes in GAD symptom severity throughout the study. Results from this study will inform a randomized controlled trial to be conducted in the future.

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 data supports the effectiveness of the treatment Trigeminal Nerve Stimulation for Generalized Anxiety Disorder?

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 help with anxiety, as it affects brain areas involved in mood and anxiety regulation. ^{1 2 3 4 5}

Is trigeminal nerve stimulation safe for humans?

Research on trigeminal nerve stimulation (TNS) for epilepsy shows it is generally safe and well tolerated, with no significant issues related to heart rate or blood pressure. ^{1 2 3 5 6}

How is trigeminal nerve stimulation different from other treatments for generalized anxiety disorder?

Trigeminal nerve stimulation (TNS) is unique because it is a non-invasive treatment that uses external electrodes to stimulate the trigeminal nerve, potentially affecting brain areas involved in mood and anxiety regulation. Unlike medications, it does not involve taking drugs and has shown promise in improving mood and anxiety in other conditions like epilepsy and depression. ^{1 2 3 4 7}

Research Team

Rafael Freire, MD PhD

Principal Investigator

Department of Psychiatry, Queen's University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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) 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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

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

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

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

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

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

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

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

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

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

7. Germany pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus and trigeminal nerve stimulation for neuropsychiatric disorders: a systematic review. [2019]