Combined treatment with haloperidol and lithium is a frequently employed strategy for the treatment of acute psychoses. Although this combination regime is safe in most clinical situations, under certain circumstances it has resulted in neurotoxicity, with organic brain syndrome, and ultimately, in some patients, irreversible brain damage and death. Plasma lithium levels in these neurotoxic patients are generally within the clinically acceptable range of 0.7 - 1.5 mEq/l, but RBC-lithium levels, when reported are abnormally elevated. To account for these observations we hypothesized that in vivo haloperidol will alter the transport of lithium across the RBC membrane and thus cause an increase in RBC lithium levels. We report preliminary results from a study that tested this hypothesis by measuring RBC lithium transport in vitro, in patients treated with a) haloperidol only, b) haloperidol, followed by haloperidol and lithium, c) combined haloperidol and lithium. In eight manic depressive patients in vivo haloperidol alone, or in combination with lithium resulted in a statistically significant (p less than 0.0001) reduction of the in vitro RBC Li+ uptake values. These results are interpreted as supportive of our hypothesis, that in vivo haloperidol alters the transport of lithium across the RBC membrane, and this effect can be detected by the use of a sensitive in vitro test. Work is currently in progress to evaluate, whether the RBC Li+ transport alteration is due to a direct effect of the drug on the cell membrane or secondary to some circulating factor, and to extend these findings to a larger sample of patients.