Search

Antipsychotic drugs (APDs) have been used to ease clinical psychotic symptoms. APDs have also been recently discovered to induce immune regulation. Our previous studies found that atypical APDs risperidone and clozapine could inhibit INF-γ production of human peripheral blood mononuclear cells (PBMC) and could inhibit Th1 differentiation. This study further investigates APD effects on monocyte-derived macrophages, which are the major antigen-presenting cells in PBMC. Our data suggest that adhesion, phagocytosis and reactive oxygen species production of monocytic cell lines would be inhibited by haloperidol, risperidone or clozapine. Also, that APDs inhibited the production of LPS-stimulated macrophages IL-6 and IL-8 suggests that risperidone and clozapine may inhibit inflammation. We further discovered that risperidone and clozapine could inhibit IL-12 production and increase IL-10 production of LPS-stimulated macrophages. These results indicated that risperidone and clozapine could inhibit Th1 differentiation not only by increasing INF-γ production of PBMC but by inhibiting the release of Th1-inducing cytokines and increasing Th2-inducing cytokines of LPS-stimulated macrophages to modulate and regulate immune responses.

Antipsychotic drugs (APDs) are widely used to alleviate a number of psychic disorders and may have immunomodulatory effects. However, the previous studies of cytokine and immune regulation in APDs are quite inconsistent. The aim of this study was to examine the in vitro effects of different ADPs on cytokine production by peripheral blood mononuclear cells (PBMCs). We examined the effects of risperidone, clozapine, and haloperidol on the production of phorbol myristate acetate and ionomycin-induced interferon-γ (IFN-γ)/interleukin (IL)-4 in PBMCs by using intracellular staining. Real-time quantitative PCR and Western blot were used to further examine the expression changes of some critical transcription factors related to T-cell differentiation in antipsychotic-treated PBMCs. Our results indicated that clozapine can suppress the stimulated production of IFN-γ by 30.62%, whereas haloperidol weakly enhances the expression of IFN-γ. Differences in IL-4 production or in the number of CD4+ T cells were not observed in cells treated with different APDs. Furthermore, clozapine and risperidone inhibited the T-bet mRNA and protein expression, which are critical to Th1 differentiation. Also, clozapine can enhance the expression of Signal Transducer and Activator of Transcription 6 and GATA3, which are critical for the differentiation of Th2 cells. The results suggested that clozapine and haloperidol may induce different immunomodulatory effects on the immune system.

Antipsychotic drugs (APDs) used to treat clinical psychotic syndromes cause a variety of blood dyscrasias. APDs suppress the aggregation of platelets; however, the underlying mechanism remains unknown. We first analyzed platelet aggregation and clot formation in platelets treated with APDs, risperidone, clozapine, or haloperidol, using an aggregometer and rotational thromboelastometry (ROTEM). Our data indicated that platelet aggregation was inhibited, that clot formation time was increased, and that clot firmness was decreased in platelets pretreated with APDs. We also examined the role two major adenosine diphosphate (ADP) receptors, P2Y1 and P2Y12, play in ADP-mediated platelet activation and APD-mediated suppression of platelet aggregation. Our results show that P2Y1 receptor stimulation with ADP-induced calcium influx was inhibited by APDs in human and rats’ platelets, as assessed by in vitro or ex vivo approach, respectively. In contrast, APDs, risperidone and clozapine, alleviated P2Y12-mediated cAMP suppression, and the release of thromboxane A2 and arachidonic acid by activated platelets decreased after APD treatment in human and rats’ platelets. Our data demonstrate that each APD tested significantly suppressed platelet aggregation via different mechanisms. [ABSTRACT FROM AUTHOR]

Antipsychotic drugs (APDs) have been used to ease the symptoms of schizophrenia. APDs have recently been reported to regulate the immune response. Our previous studies revealed that the atypical APDs risperidone and clozapine and the typical APD haloperidol can inhibit the phagocytic ability of macrophages. Our research next determined the effects of APDs on the phagocytic ability of neutrophils, which are the most abundant type of white blood cells in mammals. Here we provide evidence that clozapine and haloperidol can induce increased phagocytic uptake of Escherichia coli by differentiated HL-60 cells and by purified human neutrophils. Furthermore, clozapine and haloperidol can increase the myeloperoxidase activity and IL-8 production in neutrophils. Our results also show that clozapine can inhibit E. coli survival within differentiated HL-60 cells. Furthermore, clozapine and haloperidol are shown to enhance cell surface Mac-1 expression and the activated AKT signaling pathway in purified neutrophils exposed to E. coli . These results indicate that clozapine and haloperidol can increase the phagocytic ability of neutrophils by increasing AKT activation when cells are exposed to bacteria. [ABSTRACT FROM AUTHOR]

Abstract: Antipsychotic drugs (APDs) are commonly used to ease the symptoms of schizophrenia; however, these same drugs also have an effect on the human immune system. Our previous studies have shown that risperidone and clozapine effectively decrease the production of IFN-γ for CD4+ T-cells in PBMC. In contrast, haloperidol causes an increase in the production of IFN-γ for CD4+ T-cells in PBMC. In this study we show that risperidone and clozapine can reduce Th1 cell differentiation and T-bet expression. The differentiation of Th1 cells was reduced in clozapine or risperidone treated PBMC by inhibiting the phosphorylation of AKT but not STAT-4. Typical APD, haloperidol, had the opposite effect in regulating T cell differentiation when compared with atypical APDs including risperidone and clozapine. Haloperidol decreased the expression of GATA-3, a Th2-related transcription factor, by inhibiting NF-κB activation rather than STAT-6 phosphorylation and thus decreased Th2 differentiation. In addition, chronic risperidone and clozapine treatment reduces the IFN-γ producing CD4+ T-cell population within PBMC. In conclusion, this study suggests that APDs do indeed regulate the body''s immune response and therefore all APDs should have their own patent in regulating immune responses. [Copyright &y& Elsevier]