There have been several reports indicating that schizophrenia is related to the activation of the inflammatory response system (IRS),characterized by increased serum concentrations of several cytokines,and that antipsychotic drugs may have immunosuppressive or immunoreg- ulatory effects.The aim of the present study was to examine the effects of neuroleptics on cytokine and reactive oxygen species production in vitro,in blood leukocytes. We studied the effect of haloperidol,chlorpromazine and clozapine on the unstimulated and stimulated (phytohemagglutinin+lipopolysaccharide ?PHA+LPS)production of some cytokines which are known to be mainly products of T lymphocytes and monocytes (IL-2, lymphotoxin,IFN-? ,IL-12,IL-4,IL-10 and TGF-? )in peripheral blood mononuclear cells (PBMC)of healthy subjects.We also compared the effect of neuroleptics on superoxide anion and hydrogen peroxide production in blood neutrophils. All three antipsychotic drugs significantly increased PHA+LPS-stimulated production of anti-inflammatory cytokines such as IL-10 and TGF-? as well as unstimulated production of IL-10,but they did not influence IL-12 production.In the same in vitroconditions they inhibited PHA+LPS-stimulated production of IL-2 and lymphotoxin.IL-4 production was inhibited by haloperidol and chlorpromazine,but not by clozapine.IFN-? production was inhibited by haloperidol and chlorpromazine,but stimulated by clozapine.All neuroleptics examined at a high (100 muM)concentration,but not at a 1 muM concentration,significantly inhibited superoxide anion production by phorbol ester (PMA)-stimulated neutrophils in vitro. The results indicate that in vitro typical antipsychotic drugs, such as haloperidol and chlor- promazine, and atypical ones, such as clozapine, modulate cytokines which are known to be produced by monocytes as well as by T helper (Th)1 and Th2 subpopulations.