{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:53:57Z","timestamp":1785545637946,"version":"3.56.0"},"reference-count":116,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:00:00Z","timestamp":1772409600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":2,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Max Planck Institute of Psychiatry"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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 (\n                    <jats:bold>Add<\/jats:bold>\n                    -on t\n                    <jats:bold>VNS<\/jats:bold>\n                    in depression) is a monocentric, exploratory, prospective, randomized, double-blind, sham-controlled interventional trial conducted at the Max Planck Institute of Psychiatry\u2019s research hospital. Adult patients with a depressive episode (ICD-10: F31\u201333) 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\u00a0min 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.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-42459-2","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T18:24:50Z","timestamp":1772475890000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Protocol of the randomized double blind sham controlled AddVNS study of transcutaneous vagus nerve stimulation mechanisms in depression"],"prefix":"10.1038","volume":"16","author":[{"given":"Evangelos","family":"Kokolakis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iven-Alex","family":"von M\u00fccke-Heim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julius C.","family":"Pape","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norma C.","family":"Grandi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Erhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp G.","family":"S\u00e4mann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Spoormaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Gogolla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth B.","family":"Binder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Falkai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,2]]},"reference":[{"key":"42459_CR1","unstructured":"WHO. 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I-AMH nothing to disclose. JP nothing to disclose. NG nothing to disclose. AE nothing to disclose. PGS nothing to disclose. VS: patent applications PCT\/EP2024\/071376 and PCT\/EP2024\/071377, consultancy for Roche, Sony, Boehringer-Ingelheim, co-founder of Biomentric UG (entrepreneurial company), equity in Biomentric UG. EB nothing to disclose. NG nothing to disclose. PF gives payed talks and is partly a member of the advisory board at BMS, Richter, Johnson and Johnson and Otsuka.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"8149"}}