Mood stabilizers and systemic inflammatory burden in euthymic patients with bipolar disorder: a comparative study of lithium and valproate

RATIONALE: Systemic inflammation is increasingly recognized as a key component of the pathophysiology and neuroprogression of bipolar disorder (BD). Novel hematologic indices, including the NLR, PLR, SII, SIRI, and PIV, provide accessible measures of the inflammatory burden. However, the impact of mood stabilizers on these indices in patients with BD remains insufficiently explored. OBJECTIVE: To investigate the association between mood stabilizer treatment (lithium and/or valproate [VPA]) and systemic inflammatory burden in euthymic patients with BD. METHODS: This study included 295 euthymic patients with BD who were followed up at a tertiary care center. Participants were categorized into four groups based on their current treatment: no lithium/VPA (n = 33), VPA (n = 102), lithium (n = 120), and lithium + VPA (n = 40). Sociodemographic and clinical variables, hematologic parameters, and derived inflammatory indices (NLR, PLR, SII, SIRI, and PIV) were compared between groups. Multiple linear regression analysis was performed to identify independent predictors of systemic inflammatory burden. RESULTS: Although most sociodemographic variables were comparable, patients receiving lithium + VPA exhibited a more severe illness course. The VPA group demonstrated significantly lower neutrophil counts and reduced NLR, PLR, SII, SIRI, and PIV values than the lithium and no lithium/VPA groups (all p<.001). In the regression analysis, VPA use independently associated lower SII levels (p=.021), whereas lithium use showed no significant association. Inflammatory indices were not correlated with the clinical course variables. CONCLUSION: VPA use was associated with lower systemic inflammatory indices in euthymic patients with BD, whereas lithium use showed no significant association with reduced inflammatory burden. These findings should be interpreted as preliminary and hypothesis-generating, and future studies are needed to clarify the direction, mechanisms, and clinical significance of these associations.