# Protocol of the randomized double blind sham controlled AddVNS study of transcutaneous vagus nerve stimulation mechanisms in depression

## TL;DR

This study investigates how transcutaneous vagus nerve stimulation (tVNS) works in treating depression using a comprehensive, controlled trial with detailed biological and psychological measurements.

## Contribution

The AddVNS study is the most comprehensive investigation of tVNS effects in depression using a multimodal and longitudinal approach.

## Key findings

- tVNS is being tested as a non-invasive alternative to invasive vagus nerve stimulation for depression.
- The study uses deep phenotyping to explore biological and psychological effects of tVNS.
- Data collection includes neuroimaging, multiomic investigations, and continuous monitoring over six weeks.

## Abstract

Depression is among the most prevalent mental disorders worldwide, carrying one of the highest burden of disease among all mental disorders. While invasive vagus nerve stimulation has been approved for treatment-resistant depression for decades, its clinical use is limited by surgical risks and heterogeneous clinical efficacy. Transcutaneous auricular VNS (tVNS) may offer a non-invasive alternative, but to date it remains experimental due to limited high-quality evidence, unclear biological mechanisms of action, and rudimentary knowledge on optimal stimulation parameters. To address these gaps, we initiated the AddVNS study. The AddVNS study (Add-on tVNS in depression) is a monocentric, exploratory, prospective, randomized, double-blind, sham-controlled interventional trial conducted at the Max Planck Institute of Psychiatry’s research hospital. Adult patients with a depressive episode (ICD-10: F31–33) were assigned to receive active or sham transcutaneous vagus nerve stimulation (tVNS) in addition to treatment-as-usual (TAU) over a six-week period. Stimulation is administered three times daily (30 to 60 min each), five days per week. A deep phenotyping strategy is applied, including repeated psychophysiological measures (e.g., pupillometry, ECG, photoplethysmography, electrogastrogram) and neuroimaging (structural and functional MRI) at baseline and post-intervention, continuous actigraphy, repeated blood and stool sample acquisition (pre-, mid-, and post-intervention) for multiomic investigation, comprehensive neuropsychology including self-rated personality assessment, and closely monitored clinical evaluations. The patient-reported outcomes are collected weekly, the clinician-rated scales pre-, mid-, and post-intervention. In addition, follow-up self-ratings are obtained at 6 and 12 weeks post-tVNS. The main objective of AddVNS is to improve our understanding of the biological effects elicited by tVNS in depression. By combining rigorous methodology with an extensive and longitudinal multimodal approach, AddVNS represents the most comprehensive investigation of tVNS effects and markers in depression to date. We believe it to significantly advance our mechanistic understanding and subsequently clinical translation of this promising intervention.

The online version contains supplementary material available at 10.1038/s41598-026-42459-2.