Trigeminal Nerve Stimulation in Treatment-resistant Generalized Anxiety Disorder: a Feasibility Study

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.

Study Overview

• Status: Recruiting
• Conditions: Generalized Anxiety Disorder
• Intervention / Treatment: Device: Trigeminal Nerve Stimulation

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yan Deng; Phone Number: +1 613-548-7839; Email: yan.deng@queensu.ca
• Study Contact Backup: Name: Rafael Freire, MD PhD; Phone Number: +1 613-548-7839; Email: rafael.freire@queensu.ca

Study Locations

• Canada
  • Ontario
    • Kingston, Ontario, Canada
      • Recruiting
      • Kingston Health Sciences Centre
      • Contact: Yan Deng; Phone Number: +1-613-548-7839; Email: yan.deng@queensu.ca
      • Contact: Rafael Freire, MD PhD
      • Contact: Elisa Brietzke, MD PhD
      • Contact: Claudio Soares, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Meet the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM5) criteria for generalized anxiety disorder.
• Subjects on a stable dose of an selective serotonin reuptake inhibitor (SSRI) or serotonin and noradrenaline reuptake inhibitor (SNRI) for at least 8 weeks.
• Treatment-resistant - treatment resistance will be defined as lack of response to at least two drugs, from two different classes of drugs considered first-line or second-line for GAD. Only trials lasting at least 8 weeks, and with at least the minimum effective dose of the given medication will be considered failed trials.

Exclusion Criteria:

• Moderate to severe major depressive disorder
• Moderate to high suicidality
• Diagnosis of obsessive compulsive disorder (OCD), PTSD, bipolar disorder, schizophrenia, schizoaffective disorder, personality disorders, substance use disorders, intellectual disabilities and dementia or other neurological diseases including trigeminal neuralgia
• Pregnant or breastfeeding women
• Participants who are experiencing seizures
• Implanted vagal nerve stimulation (VNS) or other electrical devices
• Participants who are already undergoing transcutaneous electrical nerve stimulation
• Consumption of cannabis, any cannabis by-products, illicit drugs, or alcohol above 3 drinks per week
• Consumption of natural health products that may affect anxiety or depression symptoms

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Active stimulation; 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.

Device: Trigeminal Nerve Stimulation; Active trigeminal nerve stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-emergent adverse events	Monitor participants for treatment-emergent adverse events and serious adverse events.	Throughout the study, 8 weeks
Response to treatment defined by CGI-I score below 3	Response to treatment, which will be defined as a score of 1 or 2 on the Clinical Global Impression - Improvement (CGI-I) scale. CGI-I is a clinician administered one-item clinical scale rated from 1 (very much improved) to 7 (very much worse). Not assessed would confer score 0.	4-week visit and 8-week visit.
Incidence of treatment-emergent side effects measured with the NSEC	Monitor participants for minor treatment-emergent side effects measured with the Neurostimulation Side-Effect Checklist (NSEC). NSEC is a list of 31 possible side effects from neurostimulation or from antidepressants. Each item is rated from 0 (absent) to 3 (severe).	Baseline visit, 4-week visit and 8-week visit.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Remission defined by CGI-S score below 3	Remission will be defined as a score of 1 or 2 on the Clinical Global Impression - Severity (CGI-S) scale. CGI-S is a clinician administered one-item clinical scale rated from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). Not assessed would confer score 0.	4-week visit and 8-week visit.
Change in anxiety severity measured by CGI-S	Changes in scores for CGI-S by comparing the scores in each visit. CGI-S is a clinician administered one-item clinical scale rated from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). Not assessed would confer score 0.	Baseline visit, 4-week visit and 8-week visit.
Change of anxiety symptoms measured with GAD-7	Changes in scores for Generalized Anxiety Disorder 7-item scale (GAD-7) by comparing the scores in each visit. GAD-7 is a self-rated 7-item scale, each item is rated from 0 (not at all) to 3 (nearly every day).	Baseline visit, 4-week visit and 8-week visit.
Change of anxiety symptoms measured with PSWQ	Changes in scores for Penn State Worry Questionnaire (PSWQ) by comparing the scores in each visit. PSWQ is a self-rated 16-item scale, each item is rated from 1 (not at all typical of me) to 5 (very typical of me).	Baseline visit, 4-week visit and 8-week visit.
Change of anxiety symptoms measured with BAI	Changes in scores for Beck Anxiety Inventory (BAI) by comparing the scores in each visit. BAI is a self-rated 21-item scale, each item is rated from 0 (not at all) to 3 (severely - it bothered me a lot).	Baseline visit, 4-week visit and 8-week visit.

Collaborators and Investigators

• Sponsor: Dr. Rafael Freire
• Investigators: Principal Investigator: Rafael Freire, MD PhD, Department of Psychiatry, Queen's University

Publications and helpful links

General Publications

• Cook IA, Schrader LM, Degiorgio CM, Miller PR, Maremont ER, Leuchter AF. Trigeminal nerve stimulation in major depressive disorder: acute outcomes in an open pilot study. Epilepsy Behav. 2013 Aug;28(2):221-6. doi: 10.1016/j.yebeh.2013.05.008. Epub 2013 Jun 14.
• Cook IA, Abrams M, Leuchter AF. Trigeminal Nerve Stimulation for Comorbid Posttraumatic Stress Disorder and Major Depressive Disorder. Neuromodulation. 2016 Apr;19(3):299-305. doi: 10.1111/ner.12399. Epub 2016 Jan 28.
• Freire RC, Cabrera-Abreu C, Milev R. Neurostimulation in Anxiety Disorders, Post-traumatic Stress Disorder, and Obsessive-Compulsive Disorder. Adv Exp Med Biol. 2020;1191:331-346. doi: 10.1007/978-981-32-9705-0_18.
• Trevizol AP, Shiozawa P, Sato IA, Calfat EL, Alberto RL, Cook IA, Medeiros HH, Cordeiro Q. Trigeminal Nerve Stimulation (TNS) for Generalized Anxiety Disorder: A Case Study. Brain Stimul. 2015 May-Jun;8(3):659-60. doi: 10.1016/j.brs.2014.12.009. Epub 2014 Dec 31. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2024
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: February 9, 2024
• First Submitted That Met QC Criteria: February 23, 2024
• First Posted (Actual): February 26, 2024

Study Record Updates

• Last Update Posted (Actual): April 8, 2025
• Last Update Submitted That Met QC Criteria: April 4, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Anxiety Disorders
• Other Study ID Numbers: 6036699

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes