Lithium, Inflammation and Neuroinflammation with Emphasis on Bipolar Disorder-A Narrative Review

Abstract

This narrative review examines lithium's effects on immune function, inflammation and cell survival, particularly in bipolar disorder (BD) in in vitro studies, animal models and clinical studies. In vitro studies show that high lithium concentrations (5 mM, beyond the therapeutic window) reduce interleukin (IL)-1β production in monocytes and enhance T-lymphocyte resistance, suggesting a protective role against cell death. Lithium modulates oxidative stress in lipopolysaccharide (LPS)-activated macrophages by inhibiting nuclear factor (NF)-ƙB activity and reducing nitric oxide production. At therapeutically relevant levels, lithium increased both pro-inflammatory [interferon (INF)-γ, IL-8 and tumor necrosis factor (TNF)-α)] and anti-inflammatory (IL-10) cytokines on whole blood supernatant culture in healthy volunteers, influencing the balance of pro- and anti-inflammatory responses. Animal models reveal lithium's potential to alleviate inflammatory diseases by reducing pro-inflammatory cytokines and enhancing anti-inflammatory responses. It also induces selective macrophage death in atherosclerotic plaques without harming other cells. In primary rat cerebellum cultures (ex vivo), lithium prevents neuronal loss and inhibits astroglial growth, impacting astrocytes and microglia. Clinical studies show that lithium alters cytokine profiles and reduces neuroinflammatory markers in BD patients. Chronic treatment decreases IL-2, IL-6, IL-10 and IFN-γ secretion from peripheral blood leukocytes. Lithium response correlates with TNF-α levels, with poor responders showing higher TNF-α. Overall, these findings elucidate lithium's diverse mechanisms in modulating immune responses, reducing inflammation and promoting cell survival, with significant implications for managing BD and other inflammation-related conditions. Yet, to better understand the drug's impact in BD and other inflammatory/neuroinflammatory conditions, further research is warranted to appreciate lithium's therapeutic potential and its role in immune regulation.

Keywords: animal models; clinical trials; lithium; neuroinflammation.

Figure 1

Lithium-induced effects on inflammation/neuroinflammation are not yet definite. This might be due to the variability in the methodology of the experiments. In vitro, animal and clinical studies report increased [43,54,58,64,68] anti-inflammatory cytokine levels. In animal models and in clinical trials decreased levels were also reported [27,60]. As for the levels of pro-inflammatory cytokines—either an increase [54,65,67,68] or a decrease [27,43,57,59,60,65] were found in all three paradigms.