The interaction between the immune system and the autonomic nervous system in the pathophysiology of major depressive disorder: a scoping review

Abstract

Major depressive disorder (MDD) has been associated with both immune dysregulation and autonomic nervous system (ANS) dysfunction, and growing evidence suggests that bidirectional interactions between these systems may contribute to depression pathophysiology. However, the existing evidence has not yet been comprehensively synthesized, limiting understanding of the ANS–immune axis in MDD. This scoping review aimed to map the literature investigating interactions between the ANS and immune system in MDD, identify methods assessing this relationship, and explore implications for stratification. Following PRISMA-ScR and Joanna Briggs Institute guidelines, a systematic search of 12 databases and trial registers was conducted through January 2026. Eligible studies included human studies examining both ANS functioning and immune markers in MDD. Data were synthesized across three ANS domains: catecholaminergic signaling, cardiac autonomic measures, and vagus nerve functioning. Twenty-five studies published between 1989 and 2025 were included. Studies on catecholamine–immune interactions reported both positive associations and null findings between catecholamines and inflammatory markers, while in vitro studies showed both suppressive and enhancing immune effects. Several studies investigating heart rate variability (HRV) have reported inverse associations between inflammatory markers and vagally mediated HRV indices, although many of these studies lacked covariate adjustment. Studies investigating vagal function and vagus nerve stimulation reported immunomodulatory effects, but these varied according to stimulation modality, duration, and participant stratification. Current evidence suggests that altered ANS functioning may be associated with immune dysregulation in MDD, but findings remain heterogeneous. Larger longitudinal studies with standardized methods are needed to clarify these ANS–immune interactions.