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Cardiac metrics such as respiratory sinus arrythmia (RSA) and vagal efficiency (VE) can noninvasively assess parasympathetic output. Commonly used antidepressant drugs inhibit vagal signaling and may interfere with PENFS. This study examined immediate effects of active compared to sham PENFS on cardiac vagal function in adolescents with chronic nausea with and without concurrent drug therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>Participants (<jats:italic>n<\/jats:italic>\u2009=\u200984) were randomized to active (3.2\u2009V, 1\u201310\u2009Hz) or sham PENFS within an 8\u2010week prospective, double\u2010blind clinical trial. Subjects underwent posture challenges to elicit a vagal response before and after PENFS device placement mid\u2010way through the study. RSA, mean heart period (HP), and VE were calculated from electrocardiogram recordings. Exposure to antidepressant drugs was recorded.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The mean (SD) age was 15.61 (2.07) years (83% female). Fifty percent were treated with antidepressants. PENFS neurostimulation enhanced VE in patients without antidepressant exposure (mean increase after PENFS stimulation =7.56 [95% CI: 0.26, 14.86], <jats:italic>d<\/jats:italic>\u2009=\u20090.30, 17% increase) but not in those treated with antidepressants (mean change\u2009=\u2009\u22125.30 [95% CI:\u221214.28, 3.68]). Sham PENFS did not produce significant VE changes regardless of medication use (both <jats:italic>p<\/jats:italic>\u2009&gt;\u20090.40). There were no significant effects on RSA or HP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Acute enhancement of cardiac VE is demonstrated with PENFS in patients not exposed to chronic antidepressant drug therapy. Findings indicate that VE is a sensitive metric for rapid assessment of PENFS effects but raise concern for possible interaction or interference by standard of care medications.<\/jats:p><jats:p><jats:bold>Trial Registration:<\/jats:bold> <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">Clinicaltrials.gov<\/jats:ext-link> #: 1064187\u20132<\/jats:p><\/jats:sec>","DOI":"10.1111\/nmo.15007","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T08:14:52Z","timestamp":1738224892000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cardiac Vagal Efficiency Is Enhanced by Percutaneous Auricular Neurostimulation in Adolescents With Nausea: Moderation by Antidepressant Drug Exposure"],"prefix":"10.1111","volume":"37","author":[{"given":"Jacek","family":"Kolacz","sequence":"first","affiliation":[{"name":"Department of Psychiatry and 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