Mechanisms of Transcutaneous Auricular Vagus Nerve Stimulation in Depression

NCT07022171 | Recruiting

• 1 other identifier: 24-0985
• Study Type: interventional
• Target: 86
• Locations: 1 country
• Sites: 1

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.

Conditions

Depressive Disorder; Bipolar Disorder

Keywords

transcutaneous; auricular; vagus nerve stimulation; biomarkers; depression

Outcome Measures

Primary Outcomes (20)

• Change from baseline in pupillometry

  Pupil diameter associated with the clinical response to tVNS

  Baseline, week 3, week 6

• Change from baseline in 3-channel ECG

  3-channel ECG associated with the clinical response to tVNS

  Baseline, week 3, week 6

• Change from baseline in skin conductance level

  Skin conductance level associated with the clinical response to tVNS

  Baseline, week 3, week 6

• Change from baseline in photoplethysmography

  Photoplethysmography associated with the clinical response to tVNS

  Baseline, week 3, week 6

• Change from baseline in electrogastrogram

  Electrogastrogram associated with the clinical response to tVNS

  Baseline, week 3, week 6

• Change from baseline in the functional status of brainstem nuclei

  Functional status of selected brainstem nuclei (by fMRI) associated with the clinical response to tVNS

  Baseline, week 6

• Change from baseline in the response patterns in the reward anticipation task

  Response patterns in the reward anticipation task (by fMRI) with the clinical response to tVNS

  Baseline, week 6

• Change from baseline in motor activity

  Motor activity changes, measured by actigraph, associated with the clinical response to tVNS

  Continuously starting from baseline up to week 6

• Change from baseline in heart rate

  Heart rate, measured by actigraph, associated with the clinical response to tVNS

  Continuously starting from baseline up to week 6

• Change from baseline in heart rate variability

  Heart rate variability, measured by actigraph, associated with the clinical response to tVNS

  Continuously starting from baseline up to week 6

• Change from baseline in oxygen saturation

  Oxygen saturation, measured by actigraph, associated with the clinical response to tVNS

  Continuously starting from baseline up to week 6

• Change from baseline in skin temperature

  Skin temperature, measured by actigraph, associated with the clinical response to tVNS

  Continuously starting from baseline up to week 6

• Investigation of gene expression changes

  Gene expression changes over time (based on material extracted from peripheral blood)

  Baseline, week 3, week 6

• Investigation of epigenetic changes

  Epigenetic changes over time (based on material extracted from peripheral blood)

  Baseline, week 3, week 6

• Investigation of protein changes

  Protein changes over time (based on material extracted from peripheral blood)

  Baseline, week 3, week 6

• Investigation of lipid changes

  Lipid changes over time (based on material extracted from peripheral blood)

  Baseline, week 3, week 6

• Investigation of electrolyte changes

  Electrolyte changes over time (based on material extracted from peripheral blood)

  Baseline, week 3, week 6

• Investigation of immunophenotypic changes

  Immunophenotypic changes over time (based on material extracted from peripheral blood)

  Baseline, week 3, week 6

• Microbiome changes

  Microbiome changes (bacteria strains and metabolites) over time

  Baseline, week 3, week 6

• Genetics

  Genotyping based on material extracted from peripheral blood

  Baseline

Secondary Outcomes (18)

• 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

Other Outcomes (5)

• Identification of clinical predictors of treatment response namely maladaptive personality traits measured by the German version of the Personality Inventory for DSM-5 and ICD-11 - brief form -version 1.1 (self-rating)

  Baseline

• Identification of clinical predictors of treatment response namely maladaptive personality traits measured by the Levels of Personality Functioning Scale-Brief Form 2.0 (self-rating)

  Baseline

• Sociodemographic variables (age, gender, marital status, income, education, occupation, family history of migration)

  Baseline

Study Arms (2)

tVNS-arm (transcutaneous auricular vagus nerve stimulation)

EXPERIMENTAL

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

Device: transcutaneous auricular vagus nerve stimulation

sham tVNS-arm (sham transcutaneous auricular vagus nerve stimulation)

SHAM COMPARATOR

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

Device: sham transcutaneous auricular vagus nerve stimulation

Interventions

transcutaneous auricular vagus nerve stimulation DEVICE

Half of the patients are randomized to the arm receiving transcutaneous auricular vagus nerve stimulation for a period of six weeks. Transcutaneous auricular vagus nerve stimulation 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.

tVNS-arm (transcutaneous auricular vagus nerve stimulation)

sham transcutaneous auricular vagus nerve stimulation DEVICE

Half of the patients are randomized to the arm receiving sham transcutaneous auricular vagus nerve stimulation for a period of six weeks. Sham transcutaneous auricular vagus nerve stimulation 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. 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

sham tVNS-arm (sham transcutaneous auricular vagus nerve stimulation)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Max-Planck-Institute of Psychiatry: lead

Study Sites (1)

Max Planck Institute of Psychiatry

Munich, 80804, Germany

RECRUITING

MeSH Terms

Conditions

Depressive Disorder; Bipolar Disorder; Depression

Condition Hierarchy (Ancestors)

Mood Disorders; Mental Disorders; Bipolar and Related Disorders; Behavioral Symptoms; Behavior

Study Officials

• Peter Falkai, MD

  Max-Planck-Institute of Psychiatry

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Evangelos Kokolakis, MD

CONTACT

0049-89-30622-1000; ambulanz@psych.mpg.de

Iven-Alex von Mücke-Heim, MD, MSc

CONTACT

0049-89-30622-1000; ambulanz@psych.mpg.de

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients from the clinic of Max-Planck-Institute of Psychiatry are block wise randomly assigned to one of 2 study arms (transcutaneous auricular vagus nerve stimulation, sham transcutaneous auricular vagus nerve stimulation) after they have given informed consent

Study Record Dates

• First Submitted: May 9, 2025
• First Posted: June 15, 2025
• Study Start: March 18, 2025
• Primary Completion (Estimated): March 17, 2030
• Study Completion (Estimated): March 17, 2030
• Last Updated: June 15, 2025

Record last verified: 2025-04

Locations

DE (1)