Testing competing path models linking the biochemical variables in red blood cells from Li⁺ -treated bipolar patients

Objectives: Red blood cells (RBCs) from Li⁺-treated bipolar patients have shown abnormalities in intracellular Li⁺ concentration ([Li⁺]_i), Na⁺/Li⁺ exchange rates, and membrane phospholipid levels. Based on Li⁺-loaded RBC studies, we hypothesized that Li⁺-treated bipolar patients also have varied intracellular free Mg²⁺ concentrations ([Mg²⁺]_f) as compared with normotensive patients. We addressed how these experimentally determined values are intercorrelated. Assuming that Li⁺ treatment alters these biochemical parameters, we provide hypothetical pathways based upon structural equation modeling statistics. Methods: In RBCs from 30 Li⁺-treated bipolar patients, we determined [Li⁺]_i, serum [Li⁺] ([Li⁺]_c), Na⁺/Li⁺ exchange parameters, membrane phospholipid levels, [Mg²⁺]_f, and Li⁺ membrane binding affinities. Comprehensive statistical analyses assessed correlations among the biochemical data. We used path analysis statistics to propose potential pathways in which the data were correlated. Results: We found significant correlations within the three Na⁺/Li⁺ exchange parameters and percentage composition of the membrane phospholipids. Additional correlations existed between [Mg²⁺]_f and V_std, K_m, or phospholipid composition, between [Li⁺]_i and percentage of phosphatidylcholine, and between percentage of phosphatidylserine and K_m. Based on these findings, we hypothesized and statistically determined the most probable pathway through which these parameters were intercorrelated. Conclusions: Significant correlations existed between the biochemical parameters that describe the cell membrane abnormality and the Li⁺/Mg²⁺ competition hypotheses. Using path analysis statistics, we identified a biochemical pathway by which Li⁺ may assert its cellular effects. This study serves as an illustrative example how path analysis is a Valuable tool in determining the direction of a certain biochemical pathway.