The vagus nerve has emerged as central hub of brain–body communication and a promising target for psychiatric research. Across a range of mental disorders, including depression, anxiety, and stress-related conditions, alterations in autonomic regulation and vagal functioning have been linked to symptom expression, disease trajectories, and treatment outcomes. At the same time, vagus nerve stimulation has attracted growing interest as a therapeutic approach capable of modulating neural circuits implicated in affective and cognitive processes. In this talk, I will trace the emergence of the vagus nerve as a focus of psychiatric research, from early theoretical accounts of autonomic regulation and emotion to contemporary investigations of vagal biomarkers and neuromodulation-based interventions. Drawing on evidence accumulated over the past decades, I will examine how findings from human studies have shaped our understanding of vagal functioning across development and psychopathology, and how these observations have informed the development of invasive and non-invasive treatment approaches. Particular attention will be given to the promises, limitations, and evolving mechanistic frameworks that have accompanied this progression. I will argue that future progress requires a stronger reverse-translational framework that moves beyond largely correlational biomarker research in humans. Clinical observations in patients should increasingly guide mechanistic investigations in experimental models, while insights from basic neuroscience can inform hypothesis-driven studies in humans. At the same time, advancing the field will require novel methodological approaches that move beyond the current reliance on proximal and indirect indices of vagal function. Such an iterative exchange between clinical psychiatry and basic neuroscience, may provide a more mechanistic understanding of vagal signaling in mental health and support the development of targeted and personalized interventions.
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