A technique has been developed for the study of in vitro lithium accumulation by erythrocytes (RBCs). Preliminary studies with normal volunteers have demonstrated a significant correlation between in vitro and in vivo RBC lithium uptake, suggesting that this in vitro method reliably reflects in vivo events. We now propose to apply this technique to the study of RBCs from depressed psychiatric patients, in order to determine: (1) whether the amount of RBC lithium accumulation in vitro can be used as an aid in the differential diagnosis of depression; (2) whether in vitro RBC lithium accumulation can serve as a predictor of therapeutic response in depressed patients; and (3) whether in vitro incubation of RBCs with lithium can be used to simulate the changes in RBC sodium and potassium metabolism which occur in vivo when patients are treated with lithium. In order to address these problems, RBC lithium, sodium, and potassium concentrations, as well as membrane Na-K ATPase activity will be measured during in vitro incubation of RBCs obtained from depressed patients. These individuals will subsequently be treated with lithium carbonate. During the course of this treatment, we will perform longitudinal measurements of: clinical state; plasma and RBC concentrations of sodium, postassium, and lithium; and RBC membrane Na-K ATPase activity. Correlations of in vitro findings with clinical and in vivo biochemical data will be sought. Such relationships, if present, could support the use of in vitro studies as a means for increasing our knowledge of differential diagnostic and prognostic factors in depressive illness, and as a potentially useful tool for study of the cellular mechanisms by which lithium affects sodium and potassium metabolism in depressed patients.