Vagal Nerve Stimulation for Treatment Resistant Major Depression

Study Overview
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Brief Summary
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The purpose of this study is to 1) explore whether vagal nerve stimulation (nVNS) using a hand- held non-invasive device (gammaCore™) works to treat depression and 2) to confirm gammaCore™'s safety profile.

Detailed Description
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The study will be up to 14 visits, which will occur for up to a 1 year period. The first visit is a screening visit, which will take about one hour to determine eligibility. If participants are eligible, participants will be scheduled for a baseline visit and 12 monthly visits to determine the antidepressant effects and possible side effects.

Official Title
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Vagal Nerve Stimulation for Treatment Resistant Major Depression

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Device: gammaCore™


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-75 years old Sufficient fluency in English to understand testing procedures and provide written informed consent A Hamilton Depression Rating Scale total score greater than or equal 18 A DSM 5 diagnosis of MDD based on the MINI Exclusion Criteria: Evidence of alcohol or other substance use disorder in the past 3 months For females: current pregnancy or lactation (women of reproductive potential must have a negative urine pregnancy test at screening). Depressed patients who have failed at least one adequate antidepressant trial during the current depressive episode based on the ATRQ. Diagnosis of other primary psychiatric disorder (defined in this case as being the main focus of treatment) as determined by the MINI, such as: bipolar disorder, personality disorders, psychotic disorders, post-traumatic stress disorder, obsessive-compulsive disorder, dissociative disorders, eating disorder, or cognitive task due to neurological conditions Systolic blood pressure < 150 and/or diastolic blood pressure < 90 at screening Post-partum state (being within 2 months of delivery or miscarriage) Imminent suicide or homicide risk as determined by the investigator Being treated with one of the following medications: benzodiazepines or other CNS depressants. No clinically significant neurological disease based on medical history (e.g., epilepsy) or significant head injury. Any of the following disorders are exclusionary: Rheumatoid arthritis; Lupus erythematosus; Autoimmune hepatitis; Autoimmune peripheral neuropathy; Autoimmune pancreatitis; Behcet's disease; Crohn's disease; Autoimmune glomerulonephritis; Grave's disease; Guillain-Barre syndrome; Hashimoto's thyroiditis; Autoimmune polymyositis or polymyalgia; Myasthenia gravis; Narcolepsy; Polyarteritis nodosa; Scleroderma; Sjogren's syndrome; Transverse myelitis; Wegener's granulomatosis; History of seizures (only childhood febrile seizures are allowed) The presence of clinically significant laboratory findings in the opinion of the investigator including, but not limited to, clinically significant anemia or transaminase elevation is considered exclusionary. If the UDS is positive, the subject would be excluded if, in the opinion of the investigator, the positive UDS meant the subject has an active substance use disorder. Patients with prior exposure to VNS therapy whether using an implantable or external device will be excluded. An active implantable medical device, such as a pacemaker, hearing aid implant, or any implanted electronic device A metallic device, such as a stent, bone plate, or bone screw, implanted at or near the neck An open wound, rash, infection, swelling, cut, sore, drug patch, or surgical scar(s) on the neck at the treatment location Patients diagnosed with narrowing of the arteries (carotid atherosclerosis) Patients who have had surgery to cut the vagus nerve in the neck (cervical vagotomy) Patients with clinically significant hypertension, hypotension, bradycardia, or tachycardia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention Group<br>Treatment effects will be measured using standard rating scales including the HDRS-17, MADRS, SF-36, CSSR-S, CGI-I, CGI-S, which will be completed at each visit. The following scales will be completed at every other visit following the screening visit: Social Anhedonia Scale, the Motivation and Energy Inventory and the Physical Anhedonia Scale. At each study visit safety assessments including vital sign assessment and adverse event assessment will be completed. Subjects will also undergo physical examination and an ECG for safety during screening, after 8 weeks of treatment and at the end of 12 weeks of treatment. | Device: gammaCore™<br>* Implantable VNS (iVNS), the electrical stimulation of the nervous system to modulate or modify function, has been FDA approved in the United States since the late 1990s. Implantable VNS therapy has been approved for use in epilepsy and depression. When treating major depression with implanted VNS, the widely held belief is that chronic stimulation is required for therapeutic effect. In trials of implantable VNS in major depression, more patients respond at 12 months than at 3 months. Once depressed patients respond to VNS, the effects have been demonstrated to continue for up to five years with continued stimulation. This finding suggests that VNS gradually changes brain function through neuroplasticity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antidepressant effects of nVNS in humans | Calculated by the Montgomery-Asberg Depression Rating Scale (MADRS): Each item has a severity scale from 0 to 6, with higher scores reflecting more severe symptoms. Ratings can be added to form an overall score (from 0 to 60). Snaith, Harrop, Newby, and Teale (1986) proposed the following cut-offs: scores of 0-6 indicate an absence of symptoms; 7-19 represent mild Depression; 20-34 moderate; 35-60 indicate severe Depression. | 3 months | 
| Incidence of gammaCore™ Adverse Events | gammaCore (nVNS) activates the vagus nerve with patented, gentle electrical stimulation. To assess potential changes in cognition, three computerized tests of cognition will the administered at baseline, Week 8, and Week 12. The Relational & Item Specific Encoding task (RISE) will probe any potential neural abnormalities. The Probabilistic Learning Task will be used to examine neural circuits related to reward processing in major depression disorder. For the working memory task, participants will be shown two images with objects and asked to decide whether the two images differ or not. | 3 months |