Immunosuppressive effects of clozapine and haloperidol: enhanced production of the interleukin-1 receptor antagonist

Abstract

In schizophrenic patients, multiple immune abnormalities have been reported, including increased production of proinflammatory cytokines. There is some evidence that antipsychotic drugs may have immunosuppressive effects. The aim of this study was to examine the in-vitro effects of different concentrations of antipsychotic agents on cytokine production by human whole blood. We examined the effects of clozapine and haloperidol, 10⁻⁴, 10⁻⁶ and 10⁻⁸ M, on the unstimulated and stimulated (lipopolysaccharide+phytohemagglutinin) production of interleukin-6 (IL-6), IL-10, interferon-γ (IFNγ), and the IL-1 receptor antagonist (IL-1RA). Clozapine, 10⁻⁶ and 10⁻⁸ M, and haloperidol, 10⁻⁴, 10⁻⁶, and 10⁻⁸ M, significantly increased the unstimulated and stimulated production of IL-1RA. Clozapine 10⁻⁶ M significantly increased the stimulated production of IFNγ. Clozapine 10⁻⁴ M significantly suppressed the unstimulated production of IL-6 and IL-1RA and the stimulated production of IL-6, IL-10, IFNγ and IL-1RA. The results suggest that both clozapine and haloperidol, at concentrations within the therapeutic range, may exert immunosuppressive effects through an enhanced production of IL-1RA.

Introduction

There is now evidence that schizophrenia is associated with various dysfunctions in the immune system (Kirch, 1993, Maes et al., 1994, Maes et al., 1997). These changes include increased numbers of neutrophils and monocytes (Wilke et al., 1996), elevated immunoglobulin concentrations (DeLisi et al., 1985), decreased mitogen-induced lymphocyte proliferation (Chengappa et al., 1995) and decreased numbers of total T and T-helper cells (Muller et al., 1993). Changes in cytokines, cytokine receptors and cytokine activity modifiers have been reported in the blood and cerebro-spinal fluid (CSF) of schizophrenic patients. For example, significant increases in interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, decreased in-vitro interferon (IFN)-γ and IL-2 production, and increased serum IL-2, IL-6 receptor (IL-6R) and IL-1R antagonist (IL-1RA) concentrations have been found in schizophrenic patients (Lin et al., 1998, Maes et al., 1994, Maes et al., 1995, Maes et al., 1996, Maes et al., 1997, Monteleone et al., 1997, Naudin et al., 1996, Sirota et al., 1995, Wilke et al., 1996). Not all authors, however, were able to find alterations in the IRS in schizophrenia (Baker et al., 1996).

It is thought that the efficacy of antipsychotic agents to treat schizophrenia is related to their dopaminergic activity. However, more than 20% of schizophrenic patients are refractory to treatment with these typical antipsychotic agents (Davis et al., 1980, Freed, 1988). Clozapine, an atypical antipsychotic drug, has been found to be more effective in non-responders to conventional neuroleptics (Meltzer, 1992). Recently, it has been shown that typical and atypical antipsychotic drugs have effects on the production of cytokines or cytokine activity modifiers (Maes et al., 1994, Maes et al., 1997). Chronic treatment with clozapine significantly increases serum concentrations of the IL-2R (Maes et al., 1994). Clozapine treatment also increases the serum concentrations of endogenous antiinflammatory agents, such as the IL-1RA (Maes et al., 1997). Leykin et al. (1997) reported that clozapine and haloperidol in vitro significantly suppressed mitogen-induced lymphocyte proliferation and the production of cytokines. Treatment with neuroleptics suppresses the serum concentrations of IL-6, IL-6R, and IL-6R in schizophrenic patients and the stimulated production of IL-2 and IL-3 (Bessler et al., 1995, Frommberger et al., 1997, Maes et al., 1995, Monteleone et al., 1997, Muller et al., 1997).

To further examine the immunomodulatory effects of typical and atypical antipsychotic agents in vitro, we examined the effects of haloperidol and clozapine on the unstimulated and stimulated production of proinflammatory cytokines, such as IL-6 and IFNγ, and negative immunoregulatory cytokines or cytokine activity modulators, such as IL-10 and IL-1RA.