It has been postulated that altered interleukin (IL) regulation may be involved in the pathogenesis of schizophrenia. We therefore investigated the relationships between interleukins, neurotransmitters, and psychopathology in schizophrenia. IL-1β, IL-2, IL-6, homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the plasma of neuroleptic-free male schizophrenics in comparison to age-matched healthy male controls (n=25 each). The patients' psychopathology was assessed by the Scale for the Assessment of Positive and Negative Symptoms (SAPS, SANS). The above variables were measured during acute states of illness and after eight weeks of treatment with haloperidol. The plasma levels of IL-2 and HVA were significantly higher in patients compared to controls. In schizophrenic patients, there were significant correlations between IL-2 and HVA, IL-2 and SAPS, and HVA and SAPS during the acute state of illness. The level of IL-6 was significantly correlated to SANS and duration of illness. In schizophrenic patients, the plasma levels of IL-2 and HVA were significantly lowered after treatment with haloperidol. Changes in IL-2 and HVA significantly correlated to those in HVA and SAPS, respectively. These results strongly suggest that the cytokines may modulate dopaminergic metabolism and schizophrenic symptomatology in schizophrenia.
Recently, a new understanding of the interactions between behavioral, neural, endocrine, and immune processes has been described (Ader et al., 1995). These neural–neuroendocrine responses are, in part, mediated through cytokines, such as interleukin (IL)-1, IL-2, and IL-6, which are secreted during the immune response (Plata-Salaman, 1991).
It has been postulated that these cytokines might be overproduced or dysregulated in schizophrenic patients. This postulate is supported by data from several laboratories, including decreased IL-2 production after mitogen stimulation (Ganguli et al., 1995, Rothermundt et al., 1998 and Villemain et al., 1989), increased serum IL-2 receptor (Ganguli and Rabin, 1989, Gaughran et al., 1998 and Rapaport et al., 1989), increased serum IL-6 (Ganguli et al., 1994, Naudin et al., 1997 and Shintani et al., 1991), and increased IL-2 levels in cerebrospinal fluid (CSF) (Licinio et al., 1993 and McAllister et al., 1995). Moreover, increased soluble IL-2 receptor concentrations (Rapaport et al., 1994) and decreased IL-2 production (Kim et al., 1998) were found in Korean schizophrenics. These findings suggest that certain immune processes are involved in some schizophrenic patients regardless of ethnicity.
There have been some reports that schizophrenia is related to the activation of the inflammatory response system, characterized by increased serum concentrations of IL-6, increased IL-6 receptor (IL-6R), increased IL-1R antagonist (IL-1RA), positive acute phase proteins, and low serum concentrations of CC16, an endogenous anti-inflammatory protein (Kim et al., 1994, Lin et al., 1998, Maes et al., 1996 and Maes et al., 1997a).
Abnormal brain dopamine activity has been suggested to be the main neurotransmitter abnormality causing schizophrenia, despite much criticism and qualification (Davis et al., 1991). Recently, another neurotransmitter, serotonin, has become of much interest in schizophrenia research since many of the atypical antipsychotic drugs such as clozapine have been shown to exert potent serotonin-related activity (Schmidt et al., 1995). Moreover, these neurotransmitters play a major role in mediating the psychotic symptoms of schizophrenia (Lieberman and Koreen, 1993).
Interestingly, the relationship between ILs and neurotransmitter abnormalities in schizophrenia has been suggested by several investigators. Smith and Maes (1995) hypothesized that chronic activation of macrophages and T lymphocytes, together with excessive IL-2 and other cytokine secretions, could be the cause of the neurotransmitter abnormalities in schizophrenia. Licinio et al. (1993) found an elevated IL-2 level in CSF of neuroleptic-free schizophrenic patients and postulated that central IL-2 might contribute to increased dopaminergic neurotransmission, autoimmune phenomena, and abnormal brain morphology in some schizophrenics. In particular, IL-1, IL-2, and IL-6 are known to influence the central monoamine activity in a cytokine-specific manner (Zalcman et al., 1994). IL-2 increases hypothalamic and hippocampal norepinephrine utilization and dopamine turnover in the prefrontal cortex, while IL-6 induces profound elevation of serotonin and mesocortical dopamine activity in the hippocampus and prefrontal cortex. IL-1, in contrast, induces a wide range of central monoamine alteration.
If in fact an increased concentration of activated cytokines in the CNS plays a role in schizophrenia, antipsychotic treatment may be able to suppress the level of these cytokines. Actually, typical antipsychotic drugs (e.g. haloperidol) seem to have negative immunoregulatory effects (Bertini et al., 1993, Boukhris et al., 1988, Leykin et al., 1997 and Maes et al., 1995) and atypical neuroleptics (e.g. clozapine and risperidone) appear to have complex in vivo immunomodulatory effects (Maes et al., 1996 and Maes et al., 1997b). It was also reported that neuroleptic treatment is associated with low serum levels of sIL-6R but high serum levels of sIL-2R (Muller et al., 1997). On the other hand, there was a report that haloperidol at medium dosages did not affect the plasma levels of IL-1RA, IL-6, TNF-α, and sIL-2R (Pollmacher et al., 1997).
Based on these clinical and experimental reports, the present study was conducted to investigate (1) the correlations between interleukins (IL-1β, IL-2, and IL-6), neurotransmitters (HVA, 5-HIAA) and psychopathology (positive, negative symptoms) in drug-free schizophrenic patients, and (2) the possible influence of neuroleptic therapy on these variables.
