HPA axis and cytokines dysregulation in schizophrenia: potential implications for the antipsychotic treatment.

The authors discuss literature evidence on the possible dysfunctioning of HPA axis and the inflammatory response system (IRS) in schizophrenia in relation to a more comprehensive bio-pathogenetic hypothesis of the disorder and to the development of specific clinical patterns or 'core' schizophrenic symptoms, like those included in the so called negative/depressive dimension. The dysfunctions of HPA axis and IRS could be linked to some neurodevelopmental damage in relevant brain areas like hippocampus and it could involve mainly the glutamatergic pathways (e.g. NMDA receptors). Moreover, these changes could have some predictive value for response to typical antipsychotics (specifically for negative symptoms and drug resistance) in schizophrenia. Finally, the differential activity of typical versus atypical antipsychotic compounds on the basic HPA axis and IRS dysregulations in schizophrenia could account, at least partly, for the better clinical stabilization achieved in patients treated with the latter drugs compared to those receiving conventional neuroleptics.

Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with typical neuroleptics.

There is now some evidence that schizophrenia may be accompanied by an activation of the inflammatory response system (IRS) and that typical antipsychotics may suppress some signs of IRS activation in that illness. This study was carried out to examine (i) the serum concentrations of interleukin-6 (IL-6), IL-6 receptor (IL-6R), IL-1R antagonist (IL-1RA) and Clara Cell protein (CC16), an endogenous anticytokine, in nonresponders to treatment with typical neuroleptics and (ii) the effects of atypical antipsychotics on the above IRS variables. The above parameters were determined in 17 patients with treatment-resistant schizophrenia (TRS) to treatment with neuroleptics and in seven normal volunteers and 14 schizophrenic patients who had a good response to treatment with antipsychotic agents. Patients with TRS had repeated measurements of the IRS variables before and 2 and 4 months after treatment with atypical antipsychotics. Serum IL-6 was significantly higher in schizophrenic patients, irrespective of their response to typical antipsychotics, than in normal controls. Serum IL-1RA was significantly higher in the TRS patients than in controls, whereas responders took up an intermediate position. The serum concentrations of CC16 were significantly lower after treatment with atypical antipsychotics during 4 months than before treatment. It is concluded that (i) schizophrenia and, in particular, TRS is characterized by an activation of the monocytic arm of cell-mediated immunity and (ii) atypical antipsychotics may decrease the anti-inflammatory capacity of the serum in TRS patients.

HLA expression in type II mixed cryoglobulinemia and chronic hepatitis C virus.

OBJECTIVE: Hepatitis C virus infection is closely associated not only with hepatic damage, but also with mixed cryoglobulinemia (MC) and other autoimmune and lymphoproliferative disorders. Because HCV is both hepatotropic and lymphotropic, the aim of this study was to investigate whether the genetic background may influence the clinical pattern seen in different patients. METHOD: Two groups of patients with HCV infection were studied: 16 with type II MC and 18 with chronic active hepatitis (CAH). 120 bone marrow donors were considered as the control group. In all patients HLA-A-B-C antigens were evaluated using the microlymphocytoxicity technique, and HLA-DR by the PCR-SSP method. RESULTS: The frequency of the HLA antigens expressed was not precisely defined in the two groups. However, the HLA-B51 and B35 antigens, which are often correlated with autoimmune disorders, were highly expressed in the MC patients (31.2%) compared to the controls (6.9%) and to the CAH group (11%). Moreover, HLA-A9 with its split A24 were present in 50% of the MC patients. More interesting was the expression of the HLA-DR7 antigen, which was found only in the CAH group, suggesting that it may influence the specific liver involvement in HCV infections. CONCLUSION: These findings indicate that the HLA system may play an important role in the clinical manifestations of HCV infection.

Association between -G308A tumor necrosis factor alpha gene polymorphism and schizophrenia.

Dysregulation of the inflammatory response system has been linked to pathophysiology of schizophrenia. Evidence of immune activation has derived from the detection of abnormal levels of proinflammatory cytokines and their receptors in peripheral blood and cerebrospinal fluid from schizophrenic patients. Cytokines are involved in normal CNS development as well as in the pathogenesis of many neuro-psychiatric disorders, acting directly on neural cells or modulating neurotransmitter and neuropeptide systems. In particular tumor necrosis factor alpha (TNFalpha), depending on its concentration, can exert both neurotrophic and neurotoxic effects and influence neural cell growth and proliferation. Moreover, TNFalpha gene is located on the small arm of chromosome 6 (6p21.1-21.3), a locus associated with genetic susceptibility to schizophrenia. We studied the distribution of -G308A TNFalpha gene polymorphism in 84 schizophrenic patients and in 138 healthy volunteers. This biallelic base exchange polymorphism directly affects TNFalpha plasma levels. Frequency of the TNF2(A) allele is significantly increased in schizophrenic patients as compared to controls (P = 0.0042). Genotype distribution is also significantly different (P = 0.0024). TNF2 homozygotes are represented only in the patient group (P = 0.002). These data suggest a potential role of TNFalpha as a candidate gene for susceptibility to schizophrenia and suggest that immune dysregulation in schizophrenic patients could also have a genetic component.