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.