Rethinking Lithium Monitoring: Insights from a Comparative Analysis of Saliva, Plasma, and Erythrocytes

Background Lithium carbonate is a valuable and effective medication for treating and preventing mood disorders, especially bipolar disorder. Its narrow therapeutic window necessitates regular blood lithium monitoring. Existing literature does not conclusively support the reliability of salivary or erythrocyte lithium measurements. This study aimed to evaluate the predictive relationships between lithium concentrations in saliva, plasma, and erythrocytes at multiple time points during the day in patients receiving lithium carbonate treatment. The goal was to assess the temporal dynamics and relative utility of these biological matrices for therapeutic monitoring, while also considering the potential clinical advantages of non-invasive sampling methods. Methods Subjects were recruited from patients undergoing treatment at the Clinical Department of Psychiatry, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia during the period between August 2024 and December 2024. We measured lithium levels in saliva, erythrocytes and plasma of n = 77 participants with bipolar disorder or other psychiatric conditions at six time points during the day. A spectrophotometric method was used to determine lithium concentration. Results Regression analyses demonstrated that erythrocyte lithium concentration was the most consistent and robust predictor of plasma levels across most time points. Salivary lithium showed weaker and more variable performance, but was significantly associated with plasma levels at selected time points in univariate models. The strongest overall model fit in the multiple linear regression analysis was observed at 3:00 PM (r² = 0.665, p < 0.01), primarily driven by erythrocyte lithium. Conclusions These findings support the use of erythrocyte lithium as a reliable and robust biomarker for estimating plasma levels, particularly in complex clinical scenarios where intracellular lithium may better reflect treatment response or toxicity. While salivary lithium demonstrated weaker and more time-dependent predictive accuracy, it still holds conditional clinical value as a non-invasive alternative-particularly in outpatient, emergency, or resource-limited settings where individualized or more accessible monitoring may be beneficial.