Immunomodulatory effects of lithium treatment in bipolar disorder: A prospective cohort study

Bipolar disorder pathophysiology remains incompletely understood but is thought to involve immune dysregulation and metabolic dysfunction. Although lithium is widely used in treatment, its biomolecular effects are not fully characterized, and no validated biomarker of treatment response exists. We conducted a prospective, longitudinal cohort study to investigate peripheral immune-related and cardiometabolic protein levels in 50 lithium-naïve patients with bipolar disorder, compared with 42 healthy controls, aiming to identify baseline differences, persistent proteomic changes during lithium treatment and potential markers of treatment response. Patients were assessed at baseline, at 2 weeks, 6 weeks, 12 months, and 24 months after achieving therapeutic serum lithium levels. For longitudinal analyses, patients served as their own controls. Plasma proteins were measured using Olink Target96-Inflammation and Target96-Cardiometabolic panels. Linear regression and mixed-effects models were applied, with analyses stratified by sex and treatment response defined by Alda score. At baseline, lithium-naïve patients exhibited upregulation of multiple chemokines (CXCL1, CXCL5, CCL5, MCP-3, MCP-4), CD40, and ST1A1, and downregulation of CA1, CA3, OSM, and 4E-BP1 compared with controls (all PFDR < 0.001). Following lithium initiation, dynamic proteomic changes were observed, with persistent upregulation of CCL18 (PFDR < 0.0001), which was associated with lithium response (Alda-A score) by 24 months (β = 1.94, 95% CI [0.29, 3.60]; std. β = 0.59). Sex-stratified analyses showed more pronounced changes in females. Our findings indicate coordinated chemokine upregulation and disrupted immune homeostasis in bipolar disorder and suggest that lithium exerts a complex immunomodulatory effect over time, with CCL18 representing a potential pharmacodynamic marker pending replication.