Reduced anticardiolipin antibodies in first episode and chronic schizophrenia

The objective of this study was to measure anticardiolipin antibodies (aCL) in major psychiatric diseases. In Experiment 1, 96 subjects were evaluated: 20 first episode schizophrenia patients, [SCZ1] 20 chronic schizophrenia patients in acute exacerbation [SCZ2], l9 bipolar patients, 20 schizoeffective patients and 17 healthy age matched controls. In Experiment 2, 97 subjects were studied: 20 first episode schizophrenia patients [SCZ1], 60 chronic schizophrenia patients in acute exacerbation [SCZ2] and 17 healthy matched controls. Diagnosis was performed according to DSM-IV. Serum samples were tested for aCL in parallel by enzyme-linked immunosorbent assay in the presence of bovine serum. Five positive control samples with high levels of aCL were run in parallel. Background binding to wells uncoated with cardiolipin (CL) was also measured. In Experiment 1, aCL levels were similar in the control, bipolar and schizoeffective groups. In contrast, aCL levels in the SCZ1 and SCZ2 groups were significantly lower than in controls. In Experiment 2, Significantly lower levels of aCL antibodies were found in all schizophrenic patients versus controls. Interestingly, background levels in both experiments were higher in the schizophrenic groups than in controls. Serum aCL levels are lower in schizophrenic patients, and especially in first episode cases, than in controls. One possible explanation for the lower levels of aCL in schizophrenic patients is the consumption of these antibodies in the acute phase and exacerbation of the disease. The higher background levels in schizophrenic patients may indicate a high level of antibodies to some serum component in schizophrenic patients that is still unclear and needs further elucidation.     

Autoimmune diseases in the pedigrees of schizophrenic and control subjects

Autoimmune diseases aggregate in individuals and within pedigrees, and it has been postulated that autoimmune mechanisms may account for a proportion of schizophrenia. Structured questionnaires were used to interview the mothers of 121 DSM-III-R schizophrenic patients and the mothers of 116 controls in order to determine the prevalence of schizophrenia and of autoimmune diseases in their pedigrees. Patients with a schizophrenic first degree relative were significantly more likely to also have a parent or sibling with an autoimmune disease (60% vs. 20%, OR=6.1, 95% CI=2.3−16.5, p=0.0003). A significant excess of insulin dependent diabetes mellitus (IDDM) was present in the parents and siblings of schizophrenic patients (OR=9.65, 95% CI=1.3−429.2, p=0.009). These findings suggest that autoimmune mechanisms may play a role in the aetiology of schizophrenia, particularly familial schizophrenia. Associations have been established between autoimmune diseases and the HLA encoding genes of the major histocompatibility complex on chromosome six, and it may be that some of the genetic liability to schizophrenia involves these genes.     

The role of NGF and IL-2 serum level in assisting the diagnosis in first episode schizophrenia

Development of reliable diagnostic bio-markers for schizophrenia remains a diagnostic challenge. Serum NGF and IL-2 were analyzed to examine the diagnostic efficiency and predictive capability of these two biomarkers in relation to schizophrenia diagnosis. Thirty neuroleptic naïve subjects with first-episode schizophrenia, thirty patients with major depressive disorder (MDD) and twenty-eight healthy control subjects participated in the study. One-way ANOVA demonstrated significantly lower serum IL-2 and NGF among schizophrenic patients and patients with MDD compared with healthy controls. Receiver operating characteristic (ROC) curve analysis was used to ascertain diagnostic efficiency of serum IL-2 and NGF levels. Area under the ROC curve (AUC) revealed a high level of differentiation between schizophrenic patients and healthy controls for both IL-2 and NGF serum concentrations. Diagnostic efficiency of combined NGF and IL-2 serum levels was also high in schizophrenic patients compared with healthy controls. Serum NGF and IL-2 are promising as potential screening or diagnostic biomarkers for schizophrenia and may be a useful adjunct for clinical assessment.     

Cognitive Function,Plasma MnSOD Activity,and MnSOD Ala-9Val Polymorphism in Patients With Schizophrenia and Normal Controls

Excessive reactive oxygen species are thought to produce oxidative damage that underlies neurodegeneration and cognitive impairment in several disorders including schizophrenia. The functional Ala-9Val polymorphism of the mitochondrial enzyme manganese superoxide dismutase (MnSOD), which detoxifies superoxide radicals to hydrogen peroxide, has been associated with schizophrenia. However, no study has reported its role in cognitive deficits of schizophrenia as mediated through MnSOD activity. We recruited 923 schizophrenic inpatients and 566 healthy controls and compared them on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), plasma MnSOD activity, and the MnSOD Ala-9Val polymorphism. We assessed patient psychopathology using the Positive and Negative Syndrome Scale. We showed that the MnSOD Ala-9Val polymorphism may not contribute directly to the susceptibility to schizophrenia. The Ala variant was associated with worse attention performance among chronic schizophrenic patients but not among normal controls. Plasma MnSOD activity was significantly decreased in patients compared with that in normal controls. Moreover, MnSOD activity among the schizophrenic Ala allele carriers was correlated with the degree of cognitive impairments, especially attention and RBANS total score. We demonstrated an association between the MnSOD Ala-9Val variant and poor attention in schizophrenia. The association between higher MnSOD activity and cognitive impairment in schizophrenia is dependent on the MnSOD Ala-9Val polymorphism.Key words: schizophrenia, manganese superoxide dismutase, cognition, genotype, polymorphism, association     

Possible involvement of phospholipase A2 in the pathogenesis of schizophrenia

Phospholipase A2 (PLA2) is a key enzyme in the metabolism of phospholipids. PLA2 is enriched in neuronal membranes and plays an essential role in the functioning of membrane structures in the brain. Because a disordered phospholipid metabolism has been postulated in schizophrenia we started in 1985 a series of exploratory studies in an attempt to clarify the role of PLA2 in schizophrenic disorders. Our results can presently be summed up as follows: 1. Drug-free schizophrenics showed significantly higher PLA2 activity in serum and in plasma as compared with healthy controls as well as with nonschizophrenic psychiatric patients; the latter did not differ from the control group with regard to PLA2 activity. These findings suggest that increased PLA2 activity might be specific for schizophrenia. 2. The possibility that increased PLA2 activity is an artifact due to prior neuroleptic treatment could be ruled out as improbable by the findings that a) neuroleptic treatment significantly reduced PLA2 activity, and b) increased PLA2 activity was also found in first-onset, never-treated schizophrenic patients. 3. Increased PLA2 activity in schizophrenic patients was not caused by the entry of pancreatic enzyme into circulation. Our findings in serum rather suggest that the increment reflects increased intracellular enzyme activity. We speculate that our results might reflect an increment of the intraneuronal PLA2 activity in the brain. The activation of PLA2 in the brain was found to result in changes in neuronal function due to alterations in receptor sensitivity as well as in neurotransmitter metabolism. The possibility that such PLA2-induced mechanisms are involved in the pathology of schizophrenia should be investigated in further experiments.     

On autoprotective efforts of schizophrenics, neurotics and controls

Autoprotective efforts of schizophrenics have hardly been systematically investigated until now, although the role of coping processes in regard to numerous psychic disorders is increasingly recognized. The investigation of autoprotective efforts, however, is of special significance in view of the different current formulations of the vulnerability stress concept of schizophrenia. Thus the cognitive disorders in the sense of information processing deficits among schizophrenics deserve our special attention, since they are described consistently as vulnerability characteristics and as cause of a heightened susceptibility to stress, and since they can be considered an explanatory basis for a wide range of subjectively experienced basic disorders of schizophrenia. In the present study the two disorder dimensions and the corresponding autoprotective efforts were investigated among 60 schizophrenic patients, 30 neurotic patients and 30 healthy controls. The schizophrenic patients had both significantly more experimental psychologically operationalized dysfunctions in information processing and subjectively experienced basic disorders. However, we found no correlation between the two levels of investigation. This may mainly be attributed to the fact that on the level of subjective experience the primary disorder, the perception of the disorder and the individual response to the disorder cannot be differentiated unequivocally. All of the schizophrenic patients reported consciously performed autoprotective efforts in regard to basic disorders. In this connection it is of interest that the schizophrenic patients had a significantly higher percentage of problem solving oriented attempts in comparison with the two non-schizophrenic comparison groups, and that this percentage even increased by a progressive amount of disorders. The schizophrenic patients experienced basic disorders with much more emotional tension and existential, ego-threatening anxiety. They were interpreted by the schizophrenic patients as danger signals, by the neurotic patients, however, predominantly as concomitant symptoms of their neurosis, whereas healthy persons comprehended them within the framework of ordinary psychological explanatory models. The relevance of these results in regard to further research in autoprotective efforts of schizophrenic patients and in their possible therapeutic implications is discussed.     

Apolipoprotein E genotype and schizophrenia

Schizophrenic disorders are complex genetic disorders and may involve multiple genes of small effect. The presence of apolipoprotein E (apoE) is associated with several neuropsychiatric disorders. Previous studies on apoE genotype distribution in schizophrenia have reported conflicting findings. We studied the genotype frequencies in a large group of schizophrenic patients. The genotype distribution was significantly different between the schizophrenic patients and the control subjects. Persons who were sigma3 carriers have an increased risk of schizophrenia. This result suggests that apoE isoforms may play a functional role in the pathogenesis of schizophrenic disorders. Some possible mechanisms regarding the effect of apoE on the development of schizophrenia are discussed.     

Dexamethasone suppression test and noradrenergic function in affective and schizophrenic disorders

The relationship between hypothalamic-pituitary-adrenal (HPA) function and the noradrenergic system was examined in patients with affective and with schizophrenic disorders. In response to the Dexamethasone Suppression Test (DST), serum cortisol, plasma catecholamine levels, and serum creatine kinase (CK) activity were measured. Among patients with major depression, those with higher post-DST cortisol levels had higher plasma catecholamine levels and lower serum CK activity. Among acute schizophrenic patients, those with higher serum CK activity had higher baseline and post-DST cortisol levels. These results indicate that in both major depression and in acute schizophrenia, there is a dysfunction of the HPA axis and the noradrenergic system, but the noradrenergic dysfunctions are different in the two disorders.     

Studies of cellular immunity, serum interferon titers, and natural killer cell activity in schizophrenic patients

In one of the hypotheses on the causes of schizophrenia it is proposed that viruses may play a role in the etiology and pathogenesis of at least some forms of schizophrenia. In our study, 30 healthy adults and 30 schizophrenic patients were investigated for humoral and cellular immunity against herpes simplex virus (HSV) and cytomegalovirus (CMV). A whole blood test system with several advantages over commonly used procedures was used to study cell-mediated immunity to CMV and HSV. Our data showed no difference between serum antibody levels or cellular immunity of the schizophrenic patients and control individuals as far as HSV and CMV were tested. Serum interferon may be indicative for the presence of a yet unidentified virus. Therefore, we tested interferon levels in the serum of patients. No interferon was detected in any of the samples tested. Further, we tested the activity of natural killer (NK) cells in the blood of schizophrenic patients and controls. NK-activity of the patients' blood cells was not different from that of normal donors.     

Reduced serum BDNF levels in patients with chronic schizophrenic disorder in relapse,who were treated with typical or atypical antipsychotics

Brain-derived neurotrophic factor signals and dopaminergic function in the brain are strongly associated, and research on BDNF in schizophrenia may enhance our insights on the pathophysiological mechanisms of this disease. In the present study we aimed to investigate the possible association between serum BDNF levels and schizophrenic relapses and the possible differential effects of treatment with typical and atypical antipsychotics on serum BDNF levels in the same group of patients. We measured serum BDNF levels in 47 patients with schizophrenia during a relapse and again 6 weeks after administration of antipsychotic treatment (14 on risperidone, 18 on haloperidol, 10 on olanzapine and five on amisulpride) and in 44 healthy volunteers. Patients with schizophrenia showed reduced serum BDNF levels in relation to healthy volunteers at study entry. No significant differences were revealed in BDNF serum levels after 6 weeks of antipsychotic treatment in the patients compared to their own levels at study entry. However, serum BDNF was significantly increased in the subgroup receiving olanzapine compared to the other antipsychotics. Our findings may indicate a differential effect of olanzapine on BDNF levels compared to haloperidol, risperidone, and amisulpride.     

Anti-brain autoantibodies in the serum of schizophrenic patients: A case-control study

Schizophrenia is considered a neurodevelopmental disorder with a multifactorial pathogenesis where autoimmune factors may play a significant role. The aim of this study was to verify the presence of anti-brain autoantibodies in the serum of schizophrenic patients compared to healthy controls. Autoantibodies against brain were detected by the immunofluorescence method, utilizing sections of rat hippocampus and hypothalamus and of monkey cerebellum. Three different fluorescence patterns were observed, staining the nucleus-cytoplasm of neurons, the neuroendothelial of blood vessel and the neurofilaments. Search for other organ-specific and non organ-specific autoantibodies was performed in all sera by indirect immunofluorescence method, enzyme linked immunosorbent assay and chemiluminescence immunoassay. Results showed a significant association between schizophrenia and anti-brain autoantibodies against the neuroendothelium of blood vessel in hypothalamus, hippocampus and cerebellum; a significant nuclear and cytoplasmic staining of neurons was assessed only for the hippocampus. No other significant association was found, except between schizophrenia and anti-nuclear autoantibodies on HEp-2 cells. In conclusion, these results support the hypothesis of a significant association between schizophrenia and circulating anti-brain autoantibodies, suggesting a diffuse reactivity against the neuroendothelium of blood vessel and highlighting a nuclear and cytoplasmic staining of the neurons of hippocampus.     

Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology

Cytokines have been one of the recent focal points of immunological research in schizophrenia. The present study was to assess the serum levels of some of interleukins in schizophrenia and their relationships with the psychopathological parameters. Seventy physically healthy Chinese patients, who met DSM-III-R criteria for schizophrenia and who were drug-free for at least 2 weeks, were compared with 30 age- and sex-matched Chinese normal controls. The psychopathology of schizophrenia was assessed by the Positive and Negative Syndrome Scale (PANSS). Serum levels of IL-6 and IL-8 were measured by sandwich enzyme-linked immunosorbent assay (ELISA), and serum IL-2 level was assayed by radioimmunometric assay (RIA). Serum levels of IL-2, IL-6 and IL-8 were significantly elevated in patients with a chronic form of schizophrenia (all p<0.05). There was a significant inverse relationship between IL-2 level and the PANSS positive subscale P (r=-0.31, p=0.006) and a significant positive correlation between IL-8 level and PANSS negative subscale N (r=0.25, p=0.036) in schizophrenic patients. In control subjects, a significant and positive relationship between serum IL-2 and IL-6 (r=0.513, p=0.004) was noted, whereas, there was a significant and negative relationship between IL-2 and IL-8 in schizophrenic patients (r=-0.28, p=0.02). Our data confirms and supports the view that immune disturbance is involved in schizophrenia, which is compatible with the possibility that Chinese schizophrenic patients have an ongoing autoimmune process. This immune disturbance is related to the subgroup of schizophrenic patients with characteristic clinical variables. The dysfunction of interaction or inter-adjustment between different cytokines may exist in schizophrenic patients.     

Autoantibodies against brain septal region antigens specific to unmedicated schizophrenia?

Health et al. (1989) reported that serum from 96% of unmedicated schizophrenic patients contained IgG autoantibodies specific for the septal region of rhesus monkey brain, compared with 0% of nonschizophrenic control subjects and 6% of schizophrenic patients who were on neuroleptic medication. Using the same technique of crossed immunoelectrophoresis, we have tried to replicate this finding. In contrast to the original report, we observed "positive" precipitin arcs with IgG concentrates from all 14 serum samples tested. The failure of immunoelectrophoretic methods to provide convincing evidence of pathogenic autoantibodies in schizophrenia in no way detracts from the hypothesis that autoimmune processes are involved in some forms of schizophrenia. Such methods have not proved useful in established autoimmune diseases such as Graves' disease and myasthenia gravis in which the pathogenic autoantibodies against cell-surface receptors can only be detected by assays which measure functional interactions with such receptors.     

Association study of a nicotinic receptor variant with schizophrenic disorders

Nicotine acetylcholine receptors (nAChRs) are implicated in the pathogenesis of schizophrenia because the prevalence of smoking among schizophrenic patients is extraordinarily high, and nicotine has been demonstrated to improve some psychophysiological dysfunction in schizophrenics. In addition, recent studies have suggested linkage of the alpha(7) nAChR gene region in families of schizophrenics. In a population-based association study, we tested the hypothesis that the allelic variant, with a 2-bp deletion, of the human alpha(7) nAChR gene confers susceptibility to schizophrenic disorders. We genotyped alpha(7) nAChR in 146 patients with schizophrenic disorders and 151 controls. The results showed no significant difference in genotype or allele frequencies between schizophrenic patients and control subjects. This suggests that alpha(7) nAChR 2-bp deletion plays no major role in the pathogenesis of schizophrenic disorders. Other nAChR variants in schizophrenic disorders may need further investigation.     

Cold agglutinin autoantibodies in psychiatric patients: their relation to diagnosis and pharmacological treatment

BACKGROUND and METHOD: The purpose of this study was to compare titers of cold agglutinins in schizophrenic patients with those in patients with major affective disorders and in normal healthy subjects. One hundred sixty-six psychiatric patients and 37 healthy comparison subjects were included in the study. Ninety of the patients suffered from schizophrenia, 54 from bipolar disorder, and 22 from major depression. Venous blood samples were obtained from all subjects between 8:00 and 10:00 a.m. and were immediately tested for cold agglutinin titers. RESULTS: A high frequency (42.2%) of positive cold agglutinin titers was detected in the schizophrenic patients, compared with the bipolar (11.1%) and unipolar (9.0%) patients and the comparison group (8.1%). The investigators did not find any pharmacological effect on these results. CONCLUSIONS: The findings suggest that, at least in this group, positive cold agglutinin titers are associated with schizophrenia. However, this observation cannot provide direct evidence for the involvement of viral or autoimmune factors in schizophrenia.     

多巴胺D3受体基因多态性与精神分裂症

目的:探讨沈阳地区汉族人群中多巴胺D3受体基因(DRD3)第一外显子第9密码子A→G单核苷酸置换多态性(Ser9Gly多态)与精神分裂症的关联。方法:采用聚合酶链反应-限制性内切酶片断长度多态性(PCR-RFLP)技术对70例精神分裂症患者、94名健康对照者进行基因分型鉴定。比较患者组与对照组DRD3多态性分布频率、精神分裂症早发组与非早发组基因分布频率差异,并与其他国家人群进行比较。结果:患者组与对照组之间等位基因分布无明显差异,早发组与非早发组亦未发现明显差异,而该位点等位基因分布频率与巴西、英国人群有明显差异。结论:研究人群中未发现DRD3基因Ser9Gly多态与精神分裂症存在明显关联。     

Clinical manifestations of chronic inflammatory demyelinating polyneuropathy with anti-cardiolipin antibodies

OBJECTIVE: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune syndrome where certain autoantibodies define clinicopathologic subgroups. In the present study, serum anti-cardiolipin antibodies (aCL) were evaluated. MATERIALS AND METHODS: We investigated aCL in sera from 21 patients diagnosed with CIDP in our hospital between 1991 and 2001. The four CIDP patients with aCL (aCL+) were compared with 17 patients without aCL (aCL-). RESULTS: All aCL+ patients displayed sensory-motor polyneuropathy, with severity and distribution of weakness resembling those in aCL- patients. Anti-nuclear antibody titer of aCL+ patients were significantly higher than those in aCL- patients. None of aCL+ patients presented clinical manifestations of primary anti-phospholipid syndrome (APS), such as thromboses or recurrent abortion. Although the aCL+ patients were older and had more complications and more severe pathologic features than aCL- patients, they responded well to steroid pulse or intravenous immunoglobulin. CONCLUSION: The aCL in CIDP apparently differ from 'autoimmune' aCL in APS, instead being among the autoantibodies pathologically involved in CIDP subgroups.     

Increased serum phospholipase A2 activity in schizophrenia: a replication study

Phospholipase A2 (PLA2) is a key enzyme in the metabolism of phospholipids. Because a disordered phospholipid metabolism has frequently been reported in schizophrenia, we investigated the PLA2 activity in serum from 14 drug-free paranoid schizophrenic patients, 20 healthy controls, and 8 nonschizophrenic psychiatric patients. Schizophrenics showed significantly higher PLA2 activity than healthy controls and nonschizophrenic patients. The increment in schizophrenics was not due to increased concentration of pancreatic secretory PLA2, as concerning pancreatic PLA2 no differences were found among the 3 proband groups. The present findings confirm the results of our previous study and suggest that increased serum PLA2 activity might reflect an increment in the intracellular enzyme activity in schizophrenia. In the brain the activation of intracellular PLA2 results in changes in neuronal activity due to alterations in receptor sensitivity and in neurotransmitter metabolism. The possibility that such PLA2-induced mechanisms are involved in the pathogenesis of schizophrenia should be investigated in further experiments.     

DRD3 and DAT1 genes in schizophrenia: an association study

OBJECTIVE: To investigate the role of the dopamine receptor 3 (DRD3) and transporter 1 (DAT1) genes in schizophrenia or in modulating its phenotype. METHODS: a Ser9Gly polymorphism in codon 9 of the DRD3 and a VNTR polymorphism in the DAT1genes were examined in two groups of schizophrenic patients, one of excellent neuroleptic responders (N=42) and one of nonresponders (N=64). A group of healthy volunteers screened for major psychiatric disorders was also included (N=89). In addition, age at onset of psychotic symptoms, attention performance and family loading for schizophrenia spectrum disorders were compared between patients with different genotypes in the DRD3 and DAT1 genes. RESULTS: No significant differences in the allelic distribution of the DRD3 and DAT1 polymorphisms were detected between schizophrenic patients and controls. A trend toward an excess of DRD3 genotype Gly/Gly was observed in neuroleptic nonresponder schizophrenic patients compared to controls (chi(2)=3. 30, df=1, p=0.07). No significant differences in age at onset of psychotic symptoms, attention task performance or family loading for schizophrenia spectrum disorders were observed between groups with different DRD3 and DAT1 genotypes. CONCLUSION: These results do not support the role of either of these genes in increasing susceptibility to schizophrenia or in modulating its phenotype in the studied population.