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 Mg 2+ concentrations ([Mg 2+ ] 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 + ] e ), Na + /Li + exchange parameters, membrane phospholipid levels, [Mg 2+ ] 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 [Mg 2+ ] 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 + /Mg 2+ 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.