Serum levels of soluble IL-2 receptor α, IL-6 and IL-1 receptor antagonist in schizophrenia before and during neuroleptic administration
Introduction
Accumulating evidence suggests that in some cases schizophrenia is accompanied by changes in the immune system, such as the presence of anti-brain antibodies in serum (Henneberg et al., 1994), an altered distribution of T-cell subsets (Müller et al., 1993), reduced mitogen-induced lymphocyte production of interleukin-2 (IL-2) (Bessler et al., 1995; Ganguli et al., 1995; Hornberg et al., 1995; Ganguli and Gubbi, 1997), increased serum levels of interleukin-2 soluble receptor α (IL-2sRα) (Rapaport et al., 1993, Rapaport et al., 1994; Rapaport and Lohr, 1994; Hornberg et al., 1995; Maes et al., 1995) and increased serum levels of interleukin-6 (IL-6) (Shintani et al., 1991; Ganguli et al., 1994; Maes et al., 1994, Maes et al., 1995; Naudin et al., 1996, Naudin et al., 1997; Frommberger et al., 1997). These findings indicate that aberrant immune function in schizophrenia may be associated with the manifestation of the clinical phenotype and with disease processes (Ganguli et al., 1994; McAllister et al., 1997).
Cytokines have been one of the recent focal points of immunological research in schizophrenia. The ability of peripherally applied IL-2 and IL-6 to enhance catecholaminergic neurotransmission in the rat frontal cortex and hippocampus suggests that these cytokines play pivotal roles in the pathophysiology of schizophrenia (Zalcman et al., 1994). Further study of the association of cytokines, their receptors and antagonists with schizophrenia is warranted from the following viewpoints. First, in conjunction with evaluation of a patient's psychopathology and clinical background, the levels of cytokines, their receptors and antagonists may serve as markers of pathophysiological states, and as such they could be used to predict the responses of individual patients to neuroleptics. They may also be related to certain clinical variables, such as the duration of illness. Second, in most previous studies, serum levels of cytokines in schizophrenia were measured either once only, in cross-sectional design studies, or twice (usually before treatment and at recovery). Given that immunological parameters can be influenced by a patient's psychological status (Naudin et al., 1996; Frommberger et al., 1997) and by exposure to neuroleptics (Müller et al., 1997), a longitudinal study design is needed to determine whether serum levels of cytokines, their receptors and antagonists are associated with the severity of psychopathological symptoms and also the responses of patients to neuroleptic pharmacotherapy. Therefore, the aims of the present study were to measure in parallel the serum levels of IL-2sRα, IL-6 and IL-1 receptor antagonist (IL-1ra) both before and after exposure to neuroleptics during an 8-week treatment protocol for schizophrenia, and to determine whether the levels of these factors were correlated with clinical variables.
Section snippets
Subjects
The present study was approved by the Ethics Committee of Okayama University Medical School. The subjects were 26 patients who met the DSM-IV (American Psychiatric Association, 1994) diagnostic criteria for schizophrenia and 27 healthy control subjects. The subjects gave their written informed consent to participate in the study by signing a consent form that was approved by the same committee. The patients had been diagnosed as having schizophrenia of the paranoid type (n=10), disorganized
Results
The total PANSS scores of the schizophrenia patients decreased significantly from week 0 (86.9±16.1, mean±SD) to weeks 1 (70.8±23.4), 4 (60.2±23.0) and 8 (52.7±21.7) (p<0.0001, Wilcoxon signed-rank test). The sum of the symptom clusters of the PANSS also decreased significantly from week 0 to weeks 1, 4 and 8 [positive symptoms: p=0.0001, p<0.0001 and p<0.0001 for week 0 (22.9±6.2, mean±SD) to weeks 1 (18.0±7.4), 4 (13.5±7.0) and 8 (11.3±6.1), respectively; negative symptoms: p=0.0001, p<0.0001
Discussion
The present study demonstrated that elevated serum levels of IL-2sRα, IL-6 and IL-1ra in schizophrenia patients were maintained throughout the treatment period of 8 weeks. This is the first published study to investigate these substances in parallel before and during an 8-week course of pharmacotherapy, and the findings extend those of previous reports (Rapaport et al., 1993, Rapaport et al., 1994; Rapaport and Lohr, 1994; Ganguli et al., 1994; Maes et al., 1994, Maes et al., 1996; Naudin et
Acknowledgements
The author is grateful for the technical assistance of Ms Chikako Mizukawa and Ms Shino Fujisawa in the preparation of serum for enzyme immunoassay. This study was supported by a research grant for the Biological Study of Schizophrenia from the Japanese Ministry of Health and Welfare, 1996–1997 (to K.A.), and by a Grant-in-Aid for Scientific Research (07671069), 1995–1997 (to K.A.), from the Ministry of Education, Science and Culture of Japan.
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