Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with typical neuroleptics
Introduction
There is now some evidence that the acute episode of schizophrenia is characterized by immune alterations, suggesting suppression of some immune functions and activation of others. Indicators of immunosuppression are, amonst other things, decreased mitogen-induced lymphocyte proliferation (Chengappa et al., 1995), decreased numbers of total T and T-helper cells (Muller et al., 1993) and decreased in vitro production of cytokines, such as interleukin-2 (IL-2) and interferon-γ (IFNγ) (Ganguli et al., 1992, Arolt et al., 1997, Rothermundt et al., 1998).
Indicators of activation of the immune system are, amongst other things, increased numbers of peripheral blood neutrophils and monocytes (Wilke et al., 1996), increased serum concentrations of immunoglobulins (DeLisi et al., 1985), and increased production of proinflammatory cytokines or their receptors. Significant increases have been reported in (1) the plasma concentrations of IL-1β, IL-6, tumor necrosis factor (TNF)-α, IL-6 receptor (IL-6R) and IL-1R antagonist (IL-1RA) (Ganguli et al., 1994, Maes et al., 1994, Maes et al., 1995, Maes et al., 1996, Maes et al., 1997a, Sirota et al., 1995, Naudin et al., 1996, Wilke et al., 1996, Frommberger et al., 1997, Monteleone et al., 1997, Lin et al., 1998); (2) the plasma concentrations of the IL-2R (Rapaport et al., 1989, Ganguli and Rabin, 1989, Maes et al., 1994, Maes et al., 1995); and (3) the concentrations of IL-2 in the cerebro-spinal fluid (Licinio et al., 1991). The alterations in the immune system are more pronounced in patients with treatment-resistant schizophrenia (TRS). For example, serum IL-6 was significantly higher in TRS than in normal volunteers, whereas schizophrenic patients without TRS showed intermediate values (Lin et al., 1998). Our laboratory found that plasma Clara Cell protein (CC16) concentrations were significantly lower in non-medicated schizophrenic subjects than in normal volunteers (Maes et al., 1996). CC16 is an endogenous anti-cytokine with anti-inflammatory effects (Singh and Katyal, 1984, Miele et al., 1987, Dierynck et al., 1995). Since we found that lower serum CC16 was significantly and inversely related to serum IL-6 or IL-6R (Lin et al., 1998), we hypothesized that lower serum CC16 may play a role in the immune activation in schizophrenia.
The simultaneous signs of immunosuppression and activation in schizophrenia may be explained by an activation of the inflammatory response system (IRS) in that illness (Maes et al., 1995, Maes et al., 1997b, Smith and Maes, 1995). It is not clear, however, whether this IRS activation is related to the pathophysiology or etiology of that illness. IRS activation could be related to an autoimmune process (DeLisi et al., 1985, Kirch, 1993), a viral infection or viral reactivation (DeLisi and Crow, 1986). It could also constitute an aspecific response not related to the pathophysiology of schizophrenia, e.g., psychological stress which accompanies schizophrenia and which induces the production of proinflammatory cytokines, including IL-6 (Maes et al., 1998a, Maes et al., 1998b).
Recently, it has been shown that typical and atypical antipsychotic drugs modulate the production of cytokines or cytokine receptors. In vivo, typical antipsychotic drugs suppress plasma IL-6 and IL-6R (Maes et al., 1995), whereas repeated administration of atypical antipsychotics, i.e., clozapine or risperidone, significantly increase plasma concentrations of IL-2R and pro-inflammatory cytokines, e.g., IL-6 and TNFα (Maes et al., 1994, Maes et al., 1997a, Pollmacher et al., 1996). Short-term treatment with clozapine (median, 12 days) induced an increase in the plasma concentrations of IL-6 and CC16, while prolonged treatment increased plasma IL-1RA concentrations (Maes et al., 1997a). Prolonged treatment with antipsychotic agents significantly increased plasma IL-2R and decreased IL-6R concentrations (Muller et al., 1997). In vitro, clozapine and haloperidol significantly suppressed mitogen-induced lymphocyte proliferation and the production of IL-2, IFNγ and IL-4 (Leykin et al., 1997). Clozapine and haloperidol in vitro significantly increased the production of IL-1RA, whereas clozapine significantly increased the stimulated production of IFNγ (Song et al., submitted).
Thus, the picture emerging is that typical antipsychotic agents have immunosuppressive activities through stimulation of the production of the IL-1RA and suppression of the production of proinflammatory cytokines, such as IL-6 and IFNγ. Atypical antipsychotics appear to share these activities, although short-term treatment with clozapine may induce the production of proinflammatory cytokines such as IL-6, IFNγ and TNFα, an effect that disappears upon prolonged treatment.
The aims of the present study were to examine whether long-term treatment with the atypical antipsychotic agents, clozapine and risperidone, normalizes signs of activation of the IRS in patients with treatment resistance to typical neuroleptics.
Section snippets
Subjects
Thirty-eight subjects participated in this study, i.e., seven normal controls and 31 patients with schizophrenia. The patients were admitted to the Psychiatric Rehabilitation Center IRCCS S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy. Patients met the DSM-IV criteria for schizophrenia (APA, 1994). Severity of illness was assessed by means of the Brief Psychiatric Rating Scale (BPRS; 24-item version; 0-7 version; Rhoades and Overall, 1988). The patients included 17 nonresponders to
Statistics
Differences in the IRS markers between controls and patients were assessed by means of analyses of variance (ANOVA). In order to control the results for possible effects of background variables, such as age, gender and smoking behavior, multiple regression analyses were carried out with the IRS variables as dependent variables, diagnostic classification (entered as dummy variables) as explanatory variables and with forced entry of the above background variables as additional explanatory
Results
There were no significant differences (F=2.2, df=2/35, P=0.1) in age between normal volunteers (mean age, 40.4±8.8 years), responders (mean=40.0±13.2 years) and TRS patients (mean age, 48.6±13.0 years). There were no significant differences (χ2=0.4, df=2, P=0.8) in the male/female ratio between normal volunteers (4/3), responders (8/6) and TRS patients (8/9). Table 1 shows the serum concentrations of IL-6, IL-6R, IL-1RA and CC16 in TRS patients, responders and normal controls. Serum IL-6 was
Discussion
The major findings of this study are that TRS is characterized by increased serum IL-6 and IL-1RA concentrations and that treatment with clozapine during 4 months decreased serum CC16 concentrations. Increased concentrations of IL-6 and IL-1RA in schizophrenic patients indicate activation of the monocyte-macrophage arm of cell-mediated immunity. Increased serum IL-6 concentrations in schizophrenia have been reported previously by other groups (Maes et al., 1994, Maes et al., 1995, Ganguli et
Acknowledgments
The research reported was supported in part by the IRCCS, Fatebenefratelli, Brescia, Italy and the CRC-MH, Antwerp, Belgium; and the Staglin Investigator Award (NARSAD) to Dr M. Maes. The secretarial assistance of Mrs M. Maes is greatly appreciated.
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