Erythrocyte membrane Na+,K(+)-ATPase activity was studied in drug naive patients with bipolar (BP) mania (n = 62) and unipolar (UP) depression (n = 60) and normal controls (n = 66). Compared to controls there was a significantly decreased Na+,K(+)-ATPase activity in UP depressives but no change in BP manics. However, lithium treatment caused a significant increase in Na+,K(+)-ATPase activity although there was no correlation between plasma lithium levels and enzyme activity. Plasma cortisol correlated inversely with Na+,K(+)-ATPase in UP depressives. Interestingly, the lithium responders [less than 50% Beck Rafaelson's Mania Rating Scale (BRMS) score] showed a significant increase in Na+,K(+)-ATPase activity compared to lithium nonresponders (greater than 50% BRMS score). These observations indicate that monitoring of Na+,K(+)-ATPase activity during lithium therapy is useful to predict a therapeutic response.