Clinical trial NCT07022171: Mechanisms of Transcutaneous Auricular Vagus Nerve Stimulation in Depression
Official title: Physiological and Molecular Mechanisms of Transcutaneous Auricular Vagus Nerve Stimulation in Depression
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Depressive Disorder
Bipolar Disorder
Keywords: transcutaneous
auricular
vagus nerve stimulation
biomarkers
depression
Lead sponsor: Max-Planck-Institute of Psychiatry
Sponsor class: OTHER
First posted: 2025-06-15
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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
Primary purpose: BASIC_SCIENCE

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:

Taken together, the main goal of the AddVNS 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. The strength of the study lies in its study design, as AddVNS is a randomized controlled trial combining a meticulous documentation of the tVNS procedure with a wide assessment of many different parameters. This makes the AddVNS study one of the most extensive studies of tVNS in depression to date.

Eligibility criteria: Inclusion Criteria:

1. age 18-65 years, legally competent and able to provide informed consent;
2. diagnosis of a depressive episode (MDD or bipolar disorder) according to DSM 4/DSM 5 or ICD-10/ICD-11;
3. signed informed consent documents for the AddVNS study;
4. signed informed consent and participation in the biobanking project of MPIP;
5. use of a safe contraceptive method

Exclusion Criteria:

1. age \< 18 years or age \> 65 years;
2. pregnancy or planning to get pregnant during the study period, breastfeeding;
3. legal supervision;
4. pervasive developmental disorders and/or intellectual disability;
5. acute substance abuse (e.g., alcohol, prescription or illicit drugs);
6. severe neurological disease;
7. technically or anatomically not possible tVNS (e.g., microtia or anotia, vagotomy);
8. current treatment with an established neurostimulation method (e.g., ECT, rTMS, VNS);
9. metallic foreign bodies, implanted intracranial devices or cerebral shunts;
10. severe general illness (e.g., relevant anemia requiring transfusion, high-grade cardiac arrythmia, severe cardiomyopathy);
11. active implants (e.g., cochlear implant, cardiac pacemaker, implantable cardioverter-defibrillator)

Primary outcomes:
measure: Change from baseline in pupillometry
timeFrame: Baseline, week 3, week 6
measure: Change from baseline in 3-channel ECG
timeFrame: Baseline, week 3, week 6
measure: Change from baseline in skin conductance level
timeFrame: Baseline, week 3, week 6
measure: Change from baseline in photoplethysmography
timeFrame: Baseline, week 3, week 6
measure: Change from baseline in electrogastrogram
timeFrame: Baseline, week 3, week 6
measure: Change from baseline in the functional status of brainstem nuclei
timeFrame: Baseline, week 6
measure: Change from baseline in the response patterns in the reward anticipation task
timeFrame: Baseline, week 6
measure: Change from baseline in motor activity
timeFrame: Continuously starting from baseline up to week 6
measure: Change from baseline in heart rate
timeFrame: Continuously starting from baseline up to week 6
measure: Change from baseline in heart rate variability
timeFrame: Continuously starting from baseline up to week 6
measure: Change from baseline in oxygen saturation
timeFrame: Continuously starting from baseline up to week 6
measure: Change from baseline in skin temperature
timeFrame: Continuously starting from baseline up to week 6
measure: Investigation of gene expression changes
timeFrame: Baseline, week 3, week 6
measure: Investigation of epigenetic changes
timeFrame: Baseline, week 3, week 6
measure: Investigation of protein changes
timeFrame: Baseline, week 3, week 6
measure: Investigation of lipid changes
timeFrame: Baseline, week 3, week 6
measure: Investigation of electrolyte changes
timeFrame: Baseline, week 3, week 6
measure: Investigation of immunophenotypic changes
timeFrame: Baseline, week 3, week 6
measure: Microbiome changes
timeFrame: Baseline, week 3, week 6
measure: Genetics
timeFrame: Baseline
Secondary outcomes:
measure: Change from baseline in the Hamilton Depression Rating Scale (HAM-D)
timeFrame: Baseline, week 3, week 6
measure: Change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS)
timeFrame: Baseline, week 3, week 6
measure: Change from baseline in the Global Assessment of Functioning (GAF)
timeFrame: Baseline, week 3, week 6
measure: Change from baseline in the Beck-Depression-Inventory II (BDI-II)
timeFrame: Weekly up to week 6, week 12, week 18
measure: Change from baseline in the Patient Health Questionnaire 9 (PHQ-9)
timeFrame: Weekly up to week 6, week 12, week 18
measure: Change from baseline in the Patient Health Questionnaire 15 (PHQ-15)
timeFrame: Weekly up to week 6, week 12, week 18
measure: Change from baseline in the Questionnaire on Mental Capacity (FLEI = Questionnaire for Complaints of Cognitive Disturbances )
timeFrame: Weekly up to week 6, week 12, week 18
measure: Change from baseline in the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0.) questionnaire
timeFrame: Baseline, week 6, week 12, week 18
measure: Change from baseline in the Rejection Sensitivity Questionnaire (RSQ)
timeFrame: Baseline, week 6, week 12, week 18
measure: Change from baseline in Snaith-Hamilton-Pleasure-Scale (SHAPS-D)
timeFrame: Weekly up to week 6, week 12, week 18
measure: Change from baseline in Hamilton Rating Scale for Anixety (HAM-A)
timeFrame: Baseline, week 3, week 6
measure: Change from baseline in Trail Making Test Version A (TMT-A) and B (TMT-B)
timeFrame: Baseline, week 6
measure: Change from baseline in TOL-F test (Tower of London - Freiburg version)
timeFrame: Baseline, week 6
measure: Change from baseline in Episodic memory test
timeFrame: Baseline, week 6
measure: Change from baseline in the INHIB test (Response inhibition)
timeFrame: Baseline, week 6
measure: Change from baseline in N-back-verbal test (NBV)
timeFrame: Baseline, week 6
measure: Change from baseline in WAF test (perception and attention functions battery )
timeFrame: Baseline, week 6
measure: Change from baseline in MWT-B test (multiple-choice vocabulary intelligence test B )
timeFrame: Baseline, week 6
Other outcomes:
measure: 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)
timeFrame: Baseline
measure: 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)
timeFrame: Baseline
measure: Sociodemographic variables (age, gender, marital status, income, education, occupation, family history of migration)
timeFrame: Baseline
measure: Medical history (psychiatric history, somatic medical history, family history, substance use history, medication history)
timeFrame: Baseline
measure: Actual medication
timeFrame: weekly up to week 6
Locations:
city: Munich
country: Germany
facility: Max Planck Institute of Psychiatry
Study officials:
affiliation: Max-Planck-Institute of Psychiatry
name: Peter Falkai, MD
role: PRINCIPAL_INVESTIGATOR
References: