Neuropsychological Factors Drive Vitiligo Pathogenesis via Neuro-Endocrine-Immune-Cutaneous Axis

Vitiligo is a chronic autoimmune depigmenting disorder affecting 0.5%-2% of the global population, characterized by the loss of melanocytes. Current standard-of-care often overlooks the significant psychological burden and its direct mechanistic link to disease progression. This review highlights the critical, bidirectional interplay between psychological stress and vitiligo activity, emphasizing the central role of the neuro-endocrine-immune-cutaneous axis in its complex pathogenesis and identifying novel targets beyond traditional immunosuppression.

This comprehensive review synthesized current literature on the neuropsychological factors influencing vitiligo pathogenesis and their clinical applications. Researchers analyzed epidemiological data, mechanistic studies focusing on the functional 'neuro-pigment units' formed by melanocytes and intraepidermal nerve endings, and the roles of various neuropeptides and neurotransmitters. The review also evaluated the impact of sympathetic activation, dopamine metabolites, hypothalamic-pituitary-adrenal axis effects, and circadian disruption on melanocyte loss and immune dysregulation, identifying promising neuromodulatory interventions.

Epidemiological data indicate over half of vitiligo patients experience significant psychological stress prior to disease onset, establishing a self-amplifying pathogenic loop. Mechanistically, melanocytes form functional 'neuro-pigment units' with nerve endings, enabling bidirectional communication via neuropeptides including calcitonin gene-related peptide (CGRP) and substance P. Sympathetic activation drives melanocyte injury through norepinephrine-mediated β2-adrenergic receptor signaling, while dopamine metabolites exacerbate apoptosis via the oxidative stress-Akt-Bad axis. > Neuromodulatory approaches like transcutaneous auricular vagus nerve stimulation show therapeutic promise by attenuating oxidative stress and limiting pathogenic CD8⁺ T-cell infiltration. Context-dependent hypothalamic-pituitary-adrenal axis effects and light-melatonin-circadian clock disruption further promote immune dysregulation and melanocyte loss. These insights have fostered targeted strategies including CGRP receptor antagonists and dual antioxidant-neuroprotective natural compounds.