Cytotoxic effects of neuroleptic drugs

Agranulocytosis and the release of transaminase enzymes from liver cells are known consequences of neuroleptic drug use. These effects are most common with low potency neuroleptic drugs. It has been hypothesized that these effects are due to the direct toxic action of these drugs on blood and liver cells. The purpose of this study is to compare the cytotoxic effects of eight neuroleptic drugs in five different biological test systems. In all of the test systems, thioridazine, chlorpromazine, trifluoperazine, fluphenazine and thiothixene (group one drugs) were the most toxic drugs and molindone was the least toxic. Thioridazine was between 25 and 84 times more toxic than molindone. Loxapine was significantly more toxic than molindone, but less toxic than the group one drugs. Haloperidol was intermediate in toxicity between the group one drugs and loxapine. We conclude that the difference in cytotoxicity of the neuroleptic drugs observed in these experiments accounts in part for the increase in agranulocytosis and hepatotoxicity with thioridazine and chlorpromazine and for the lower incidence of these side effects with less toxic drugs. The possibility that tardive dyskinesia may be due to the cytotoxic effects of neuroleptic drugs is discussed and an experiment to test this hypothesis is suggested.