The Multidimensional Pathogenesis of Susceptibility to Depression in Sjögren’s Syndrome: An Integrated Approach from Immune–Inflammatory to Psychosocial Factors

Sjögren’s syndrome is a chronic systemic autoimmune disease with primary (pSS) and secondary forms. Epidemiological evidence suggests a higher prevalence of depressive symptoms and depression in pSS than in the general population, indicating possible disease-specific susceptibility. The underlying mechanisms remain unclear, limiting early identification and targeted intervention. This narrative review examines five domains of depression susceptibility in pSS: inflammatory pathways, neuroendocrine regulation, the gut–brain axis, medication effects, and psychosocial factors. Interleukin-6, tumor necrosis factor-α, and interferon-α may contribute by activating the indoleamine 2,3-dioxygenase–kynurenine pathway, downregulating brain-derived neurotrophic factor, and inhibiting hippocampal neurogenesis. Hypothalamic–pituitary–adrenal axis dysfunction may provide a neuroendocrine link, whereas gut microbial imbalance may affect emotional regulation through immune and neural signaling. Glucocorticoids, hydroxychloroquine, and calcineurin inhibitors may increase neuropsychiatric risk through multiple pathways. Somatic symptoms and social stress may reinforce a psychosocial vicious cycle. Much of the mechanistic evidence comes from major depressive disorder, animal models, or in vitro studies; causality has not been established in pSS. The proposed multidimensional model is hypothetical and offers a framework for early screening and targeted intervention in pSS with depression.