Effects of Respiratory-Gated Transcutaneous Vagal Nerve Stimulation in Major Depression (Phase 1)

Study Overview
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Brief Summary
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This study will evaluate the short term effects of respiratory-gated transcutaneous vagus nerve stimulation on the regulation of cardiovagal activity, depressive symptomatology and immune function in subjects with major depression and determine the optimal stimulation frequency for this population.

Detailed Description
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This study will compare the acute effects of respiratory-gated transcutaneous vagus nerve stimulation (tVNS) at different stimulation frequencies and sham stimulation during five sessions within a 2 week period. Heart rate variability (HRV) point process adaptive filtering estimation algorithms will be used to evaluate changes in cardiac autonomic physiology in subjects with major depression in response to tVNS. The effects of tVNS on cardiovagal regulation will be evaluated at rest and in response to an emotion reactivity task. Depression rating scales (Beck's Depression Inventory) will be used to evaluate short term effects of tVNS on depressive symptoms in these subjects. In addition, the study will evaluate the acute effects of the stimulation on serum levels of pro-inflammatory cytokines. The stimulation frequency that produces the greatest regulatory effects on depressive symptoms and physiological variables in this population will be used in a second longitudinal phase of the study.

Official Title
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A Translational Approach to Cardiorespiratory-Gated Stimulation of the Auricular Branch of the Vagus Nerve for the Treatment of Major Depression

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Other: Active transcutaneous vagus nerve stimulation
* Other: Sham transcutaneous vagus nerve stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of recurrent Major Depressive Disorder with a current active depressive episode Currently not taking psychiatric medications or on a stable therapeutic dose of psychiatric medication for at least 30 days prior to entering the study Exclusion Criteria: History of cardio-, cerebro-, or peripheral vascular disease, diabetes mellitus, morbid obesity (BMI > 40 kg/m2), kidney or liver failure, history of unexplained fainting spells Any psychiatric disorder involving a history of psychosis (e.g. schizophrenia, bipolar disorders, severe personality disorders) Any chronic condition affecting movement, speech and/or ability to read or follow written instructions Substance use disorder, either mild, moderate, or severe within the past 12 months (excludes nicotine) History of suicide attempt within the last year or current active suicidal ideation History of a clinically defined neurological disorder including, but not limited to: Any condition likely to be associated with increased intracranial pressure; space occupying brain lesion; History of cerebrovascular accident; Transient ischemic attack within two years; Cerebral aneurysm; Dementia; Parkinson's Disease; Huntington's chorea; or Multiple sclerosis. Pregnant or nursing Metallic implants or devices contraindicating tVNS

Ages Eligible for Study
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Minimum Age: 24 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active tVNS - 2 Hz<br>Expiratory-gated transcutaneous vagus nerve stimulation on the left auricle with 2 Hz stimulation frequency | Other: Active transcutaneous vagus nerve stimulation<br>* respiratory-gated non-painful electrical stimulation of the auricle for 30 minutes<br>* Other names: transcutaneous vagus nerve stimulation;|
| Experimental: Active tVNS - 8 Hz<br>Expiratory-gated transcutaneous vagus nerve stimulation on the left auricle with 8 Hz stimulation frequency | Other: Active transcutaneous vagus nerve stimulation<br>* respiratory-gated non-painful electrical stimulation of the auricle for 30 minutes<br>* Other names: transcutaneous vagus nerve stimulation;|
| Experimental: Active tVNS - 30 Hz<br>Expiratory-gated transcutaneous vagus nerve stimulation on the left auricle with 30 Hz stimulation frequency | Other: Active transcutaneous vagus nerve stimulation<br>* respiratory-gated non-painful electrical stimulation of the auricle for 30 minutes<br>* Other names: transcutaneous vagus nerve stimulation;|
| Experimental: Active tVNS - 100 Hz<br>Expiratory-gated transcutaneous vagus nerve stimulation on the left auricle with 100 Hz stimulation frequency | Other: Active transcutaneous vagus nerve stimulation<br>* respiratory-gated non-painful electrical stimulation of the auricle for 30 minutes<br>* Other names: transcutaneous vagus nerve stimulation;|
| Sham Comparator: Sham tVNS<br>Sham transcutaneous vagus nerve stimulation on the left auricle | Other: Sham transcutaneous vagus nerve stimulation<br>* stimulation of the auricle for 30 minutes<br>* Other names: transcutaneous vagus nerve stimulation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac autonomic function | Changes in cardiac autonomic function (High Frequency power-Heart Rate Variability) between active and sham tVNS. | 1 hour | 
| Change in depressive symptoms assessed by the Beck Depression Inventory | Changes from baseline to post-stimulation in the score of the Beck Depression Inventory will be compared between active and sham tVNS. (Beck depression inventory minimum score= 0, maximum score= 63; higher total scores indicate more severe depressive symptoms) | 1 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in serum levels of pro-inflammatory cytokines | Changes in serum levels of proinflammatory cytokines (Interleukin 1B, Interleukin 6, Tumor necrosis factor alfa) from baseline to post-stimulation will be assessed and compared between active and sham tVNS | 2 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transcutaneous Vagus Nerve Stimulation, Cardiac autonomic function, Depressive symptomatology