Physiological and Molecular Mechanisms of Transcutaneous Auricular Vagus Nerve Stimulation in Depression
Trial Snapshot
- Phase
- Not Applicable
- Status
- Recruiting
- Sponsor
- Enrollment
- 86
- Locations
- 1
- Primary Endpoint
- Investigation of protein changes
Study Overview
Brief Summary
Invasive vagus nerve stimulation (VNS) is an approved treatment of treatment-resistant depression (TRD) in Europe and in USA. Because of the associated possible surgical complications as well as side effects, invasive VNS is applied limitedly in the treatment of depression. Transcutaneous auricular VNS (tVNS), on the other hand, is a non-invasive alternative to traditional invasive VNS. tVNS is still considered an experimental treatment for depression. This is due to the limited high-quality evidence from randomized clinical studies, the not yet fully understood biological mechanisms of action, along with overall limited knowledge about the optimal stimulation parameters. To address these issues, the AddVNS study was initiated. The AddVNS study intends to recruit n=86 patients of the Max Planck Institute of Psychiatry with depression. The patients participating in the AddVNS study are going to receive either tVNS or sham tVNS for a period of 6 weeks. The primary objective of the study is to identify biological, psychological, socio-economic, and clinical biomarkers associated with treatment progression and response to treatment in patients with depression undergoing tVNS. To achieve this, an exploratory design with an assessment of many different parameters including psychophysiology, imaging, blood-based multi-omics, microbiome, psychometrics and neuropsychology will be used.
Detailed Description
Background:
Depression is one of the most prevalent mental disorders worldwide and is associated with the highest burden of disease among all psychiatric disorders. Invasive vagus nerve stimulation (VNS) has been approved for the treatment of treatment-resistant depression (TRD). However, invasive VNS is applied limitedly in the treatment of depression due to the associated possible surgical complications and side effects. Transcutaneous auricular VNS (tVNS), on the other hand, is a non-invasive alternative to invasive VNS. During the last decade, the effects of tVNS have been examined in an increasing number of clinical trials across many different disorders, with depression being one of the most prominent areas of interest. Nevertheless, tVNS is still considered an experimental treatment for depression. Reasons for this categorization come from the limited high-quality evidence from randomized clinical studies, the not yet fully understood biological mechanisms of action, along with overall limited knowledge about the optimal stimulation parameters. To address these issues, we initiated the AddVNS study. The primary objective of the study is to identify biomarkers of tVNS and to better understand its biological mechanisms of action in the treatment of depression.
Material and methods:
The AddVNS is a monocentric, exploratory-prospective, randomized, double-blind, sham-controlled interventional study that recruits adult and legally competent patients with current MDD or bipolar disorder with current depression who are treated in MPIP (either inpatient or day clinic treatment). The participants are going to receive either tVNS or sham tVNS for a period of 6 weeks. Both tVNS and sham tVNS will be carried out as an adjuvant, i.e. in addition to the regular treatment of the participants. The intervention will take place three times a day from Monday to Friday. Each of the three daily sessions is going to last 30-60 minutes, depending on patient tolerance. The procedures for sham tVNS will be identical to tVNS, with the only exception that the sham tVNS will be performed with no current output. Participants and investigators are blinded to the assignment of participants to a study arm, except for the investigators responsible for the stimulation. The AddVNS study includes a wide range of assessments, which will be identical for both study arms. Psychophysiological measurements (pupillometry, respiratory rate, 3-channel ECG, skin conductance level, photoplethysmography and an electrogastrogram) will be conducted at baseline, after 3 weeks of intervention and at the end of the 6-week intervention (for a small number of patients, two additional psychophysiological measurements are planed). Actigraphy will take place throughout the 6-week intervention. Two MRI scans are planned over the course of the AddVNS study; one scan is scheduled at baseline and one after the 6-week intervention. Participants will have a total of three venous blood samples taken over the course of the 6-week intervention. They will be asked to collect stool samples that will be used for microbiome analysis at baseline, after 3 weeks of intervention and at the end of the 6-week intervention. Participants will be also asked to fill out self-rating questionnaires (patient health questionnaire 9 and 15, Beck Depression Inventory II, Snaith-Hamilton-Pleasure-Scale, Questionnaire for complaints of cognitive disturbances) once a week, while two further questionnaires will be obtained at baseline and after the 6-week intervention (Rejection Sensitivity Questionnaire, World Health Organization Disability Assessment Schedule questionnaire). During a clinical interview at baseline, after 3 weeks of intervention and after 6 weeks of intervention, clinician-rating scales (Montgomery-Åsberg Depression Rating Scale, Hamilton Rating Scale for Depression with 21 items, Hamilton Rating Scale for Anxiety, Global Assessment of Functioning) will be obtained. Furthermore, a neuropsychological assessment is carried out at baseline and after the 6-week intervention, while a personality assessment will be performed at baseline. To assess the longitudinal effects of tVNS, we will ask the patients to fill out self-rating questionnaires (patient health questionnaire 9 and 15, Beck Depression Inventory II, Snaith-Hamilton-Pleasure-Scale, Questionnaire for complaints of cognitive disturbances, Rejection Sensitivity Questionnaire, World Health Organization Disability Assessment Schedule questionnaire) 6 and 12 weeks after the end of the intervention.
Discussion:
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Basic Science
- Masking
- Triple (Participant, Care Provider, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •age 18-65 years, legally competent and able to provide informed consent;
- •diagnosis of a depressive episode (MDD or bipolar disorder) according to DSM 4/DSM 5 or ICD-10/ICD-11;
- •signed informed consent documents for the AddVNS study;
- •signed informed consent and participation in the biobanking project of MPIP;
- •use of a safe contraceptive method
Exclusion Criteria
- •age < 18 years or age > 65 years;
- •pregnancy or planning to get pregnant during the study period, breastfeeding;
- •legal supervision;
- •pervasive developmental disorders and/or intellectual disability;
- •acute substance abuse (e.g., alcohol, prescription or illicit drugs);
- •severe neurological disease;
- •technically or anatomically not possible tVNS (e.g., microtia or anotia, vagotomy);
- •current treatment with an established neurostimulation method (e.g., ECT, rTMS, VNS);
- •metallic foreign bodies, implanted intracranial devices or cerebral shunts;
- •severe general illness (e.g., relevant anemia requiring transfusion, high-grade cardiac arrythmia, severe cardiomyopathy);
- •active implants (e.g., cochlear implant, cardiac pacemaker, implantable cardioverter-defibrillator)
Arms & Interventions
tVNS-arm (transcutaneous auricular vagus nerve stimulation)
Half of the patients are randomized to the arm receiving transcutaneous auricular vagus nerve stimulation in addition to their regular treatment for a period of six weeks
Intervention: transcutaneous auricular vagus nerve stimulation (Device)
sham tVNS-arm (sham transcutaneous auricular vagus nerve stimulation)
Half of the patients are randomized to the arm receiving sham transcutaneous auricular vagus nerve stimulation in addition to their regular treatment for a period of six weeks. The procedures for sham tVNS will be identical to tVNS, with the only exception that the sham tVNS will be performed with no current output
Intervention: sham transcutaneous auricular vagus nerve stimulation (Device)
Outcomes
Primary Outcomes
Investigation of protein changes
Time Frame: Baseline, week 3, week 6
Protein changes over time (based on material extracted from peripheral blood)
Investigation of lipid changes
Time Frame: Baseline, week 3, week 6
Lipid changes over time (based on material extracted from peripheral blood)
Investigation of electrolyte changes
Time Frame: Baseline, week 3, week 6
Electrolyte changes over time (based on material extracted from peripheral blood)
Investigation of gene expression changes
Time Frame: Baseline, week 3, week 6
Gene expression changes over time (based on material extracted from peripheral blood)
Investigation of epigenetic changes
Time Frame: Baseline, week 3, week 6
Epigenetic changes over time (based on material extracted from peripheral blood)
Change from baseline in pupillometry
Time Frame: Baseline, week 3, week 6
Pupil diameter associated with the clinical response to tVNS
Change from baseline in 3-channel ECG
Time Frame: Baseline, week 3, week 6
3-channel ECG associated with the clinical response to tVNS
Change from baseline in skin conductance level
Time Frame: Baseline, week 3, week 6
Skin conductance level associated with the clinical response to tVNS
Change from baseline in photoplethysmography
Time Frame: Baseline, week 3, week 6
Photoplethysmography associated with the clinical response to tVNS
Change from baseline in electrogastrogram
Time Frame: Baseline, week 3, week 6
Electrogastrogram associated with the clinical response to tVNS
Change from baseline in the functional status of brainstem nuclei
Time Frame: Baseline, week 6
Functional status of selected brainstem nuclei (by fMRI) associated with the clinical response to tVNS
Change from baseline in the response patterns in the reward anticipation task
Time Frame: Baseline, week 6
Response patterns in the reward anticipation task (by fMRI) with the clinical response to tVNS
Change from baseline in motor activity
Time Frame: Continuously starting from baseline up to week 6
Motor activity changes, measured by actigraph, associated with the clinical response to tVNS
Change from baseline in heart rate
Time Frame: Continuously starting from baseline up to week 6
Heart rate, measured by actigraph, associated with the clinical response to tVNS
Change from baseline in heart rate variability
Time Frame: Continuously starting from baseline up to week 6
Heart rate variability, measured by actigraph, associated with the clinical response to tVNS
Change from baseline in oxygen saturation
Time Frame: Continuously starting from baseline up to week 6
Oxygen saturation, measured by actigraph, associated with the clinical response to tVNS
Change from baseline in skin temperature
Time Frame: Continuously starting from baseline up to week 6
Skin temperature, measured by actigraph, associated with the clinical response to tVNS
Investigation of immunophenotypic changes
Time Frame: Baseline, week 3, week 6
Immunophenotypic changes over time (based on material extracted from peripheral blood)
Microbiome changes
Time Frame: Baseline, week 3, week 6
Microbiome changes (bacteria strains and metabolites) over time
Genetics
Time Frame: Baseline
Genotyping based on material extracted from peripheral blood
Secondary Outcomes
- Change from baseline in the Hamilton Depression Rating Scale (HAM-D)(Baseline, week 3, week 6)
- Change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS)(Baseline, week 3, week 6)
- Change from baseline in the Global Assessment of Functioning (GAF)(Baseline, week 3, week 6)
- Change from baseline in the Beck-Depression-Inventory II (BDI-II)(Weekly up to week 6, week 12, week 18)
- Change from baseline in the Patient Health Questionnaire 9 (PHQ-9)(Weekly up to week 6, week 12, week 18)
- Change from baseline in the Patient Health Questionnaire 15 (PHQ-15)(Weekly up to week 6, week 12, week 18)
- Change from baseline in the Questionnaire on Mental Capacity (FLEI = Questionnaire for Complaints of Cognitive Disturbances )(Weekly up to week 6, week 12, week 18)
- Change from baseline in the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0.) questionnaire(Baseline, week 6, week 12, week 18)
- Change from baseline in the Rejection Sensitivity Questionnaire (RSQ)(Baseline, week 6, week 12, week 18)
- Change from baseline in Snaith-Hamilton-Pleasure-Scale (SHAPS-D)(Weekly up to week 6, week 12, week 18)
- Change from baseline in Hamilton Rating Scale for Anixety (HAM-A)(Baseline, week 3, week 6)
- Change from baseline in Trail Making Test Version A (TMT-A) and B (TMT-B)(Baseline, week 6)
- Change from baseline in TOL-F test (Tower of London - Freiburg version)(Baseline, week 6)
- Change from baseline in Episodic memory test(Baseline, week 6)
- Change from baseline in the INHIB test (Response inhibition)(Baseline, week 6)
- Change from baseline in N-back-verbal test (NBV)(Baseline, week 6)
- Change from baseline in WAF test (perception and attention functions battery )(Baseline, week 6)
- Change from baseline in MWT-B test (multiple-choice vocabulary intelligence test B )(Baseline, week 6)