Immunosuppressive effects of clozapine and haloperidol: enhanced production of the interleukin-1 receptor antagonist
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.
Section snippets
Subjects
Blood samples for the assay of cytokine production were collected from nine healthy volunteers (mean age=33.1±7.5 years; male/female ratio: 5/4). All subjects gave written informed consent after the study design had been fully explained. Exclusion criteria for subjects were as follows:
- 1.
subjects with a past or present history of psychiatric disorders (axis-I and axis-II);
- 2.
subjects who ever had been taking major psychotropic medications, e.g. antidepressants and antipsychotics;
- 3.
subjects with drug
Results
RM design ANOVAs with the stimulated condition (PHA+LPS stimulated versus unstimulated) as a within-subject factor and gender as a between subject factor showed (1) significant effects of PHA+LPS stimulation on IL-6 (F=76, df=1/117, p=0.0002), IL-RA (F=12.1 df=1/117, p=0.001), IL-10 (F=67, df=1/117, p=0.0002) and IFNγ (F=71, df=1/117, p=0.0002) production; (2) no significant difference in stimulated and/or unstimulated IL-6, IL-1RA, IL-10 or IFNγ production between men and women; and (3) no
Discussion
The main findings of this study are that clozapine, 10−6 and 10−8 M, and haloperidol, 10−4, 10−6 and 10−8 M, significantly increased the production of IL-1RA by unstimulated and PHA+LPS-stimulated whole blood of healthy volunteers. These results are consistent with a previous study performed in schizophrenic patients, which found significantly increased serum IL-1RA concentrations following treatment with clozapine for 5 weeks (Maes et al., 1997). In rats, repeated administration of neuroleptic
Acknowledgments
The research reported was supported in part by the Funds for Scientific Research, Vlaanderen, Belgium (FWO) and the Clinical Research Center for Mental Health, (CRC-MH), Antwerp, Belgium; the Staglin Investigator Award (NARSAD) to Dr M. Maes. Dr C. Song was supported by The Mental Health Foundation of Ontario, Canada. The secretarial assistance of Mrs M. Maes is greatly appreciated.
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