Figure 1.

Possible mechanisms underlying depression in primary Sjögren's syndrome (pSS). (1) General psychological distress and specific personality traits like neuroticism, psychoticism, and obsessiveness might reduce stress tolerance and lead to depression. (2) Physical discomfort of pSS including fatigue, cognitive symptoms, sicca symptoms, and autonomic nervous system issues could contribute to depressive symptoms. (3) Elevated serum antibodies against N-methyl aspartate receptor (NMDAR) subtype NR2 found in pSS patients are associated with hippocampal atrophy, contributing to cognitive impairment and mood disorders in these patients. (4) Elevated levels of cytokines such as interferon-γ (IFN-γ), interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) in pSS can trigger the overproduction of kynurenine and its metabolites from tryptophan through the indoleamine 2,3-dioxygenase (IDO) enzyme, diverting tryptophan away from serotonin production in the central nervous system (CNS). This imbalance in the hippocampus leads to depression, slower cognitive function, and other cognitive disorders. (5) Frequent central nervous system (CNS) white matter lesions (WML) were found in pSS, which can be linked to depression. Moreover, microstructural changes and decreased functional connectivity in the somatosensory cortex and corticospinal tract, as well as microvascular and ischemic lesions causing functional impairment in brain regions, have been observed in pSS. (6) Negative social and environmental factors, such as increased economic burden and lack of social support, may exacerbate depressive tendencies. Abbreviations: pSS: primary Sjögren's syndrome; TNF-α: tumor necrosis factor alpha; IL-6: interleukin 6; IL-1: interleukin 1; IFN- γ: interferon-γ; Anti-NR2: serum antibodies against N-methyl aspartate receptor (NMDAR) subtype NR2; IDO: indoleamine 2,3-dioxygenase enzyme; CNS: central nervous system. (This figure is created by Bioreneder.com).