Can Red Blood Cell Membrane Fatty Acids Predict Intracellular Lithium Concentration in Bipolar Disorder? A Cross-Sectional Study

Bipolar disorder is a chronic psychiatric condition that requires long-term treatment. Lithium remains the gold standard for mood stabilization; yet, its therapeutic response is highly variable and unpredictable due to the lack of reliable biomarkers. As lithium may exert its effect through interactions with neuronal membranes, particularly their lipid composition, red blood cell membranes have been proposed as a peripheral model to investigate this relationship. We conducted a monocentric, cross-sectional study involving 30 patients with bipolar disorder receiving a stable dose of lithium. Clinical and sociodemographic characteristics were assessed alongside plasma lithium and red blood cell lithium levels. Fatty acid profiles of red blood cell membranes were analyzed. The cohort was divided into three groups based on the red blood cell lithium/plasma lithium ratio to explore potential associations with fatty acid profiles. Additionally, an unsupervised clustering approach was used to identify patient subgroups based on fatty acid profiles and clinical characteristics, and their lithium levels were compared. No significant differences in fatty acid composition were found across the red blood cell lithium/plasma lithium ratio groups. However, older age was associated with higher red blood cell lithium/plasma lithium ratios. No clear association was found between fatty acid concentrations and intracellular lithium. Cluster analysis based on clinical data revealed two clinical subgroups, with the less severe group exhibiting significantly higher plasma lithium and higher omega-6 fatty acid levels. While no direct relationship was observed between fatty acid composition and lithium distribution, this study suggests that the lithium's action may involve other membrane components. Future longitudinal studies with larger samples and advanced lipidomic profiling are needed to identify potential composite biomarkers of lithium response.