Increased S100B blood levels in unmedicated and treated schizophrenic patients are correlated with negative symptomatology.

S100B, a calcium-binding protein produced by astroglial cells, is a marker of astroglial cellular integrity. It has been shown to be increased in acute brain damage and neurodegeneration. A recent study showed increased S100B levels in medicated acutely psychotic patients with schizophrenia. The study presented here included 26 drug-free patients with acute schizophrenia and 26 matched healthy controls. S100B blood concentrations were determined using a quantitative immunoassay upon admission and after 6 weeks of neuroleptic treatment. The PANSS was used to investigate psychopathology. Unmedicated schizophrenic patients showed significantly increased S100B levels compared to matched healthy controls. After 6 weeks of treatment, 11 patients showed normal S100B levels while in 15 patients the levels remained increased. These patients showed significantly higher PANSS negative scores upon admission and after 6 weeks of treatment. Schizophrenic patients display a loss of astroglial integrity which is not caused by neuroleptic medication. Continuously increased S100B levels are associated with negative symptomatology.     

Increased serum S100B in elderly, chronic schizophrenic patients: negative correlation with deficit symptoms

In schizophrenia, elevations of serum and CSF S100B levels have been reported and related to state of the disease and negative symptoms. In elderly chronic schizophrenic inpatients with stable medication, S100B may be increased and correlated to psychopathology and neuropsychological deficits.

We have measured serum levels of S100B in 41 elderly, chronic schizophrenic patients and 23 age- and gender-matched controls using an immunoluminometric assay. In patients, we assessed detailed psychopathology and neuropsychological performance and determined serum levels of haloperidol, clozapine and its two main metabolites desmethylclozapine and clozapine metabolite N-oxid by HPLC.

S100B levels were increased in elderly chronic schizophrenic patients compared to healthy controls. In patients, levels were negatively correlated with deficit symptoms and positively with age. There were no significant differences of S100B between medication groups and no correlation with serum levels of antipsychotics or neuropsychological scores.

Elevations of S100B in elderly chronic schizophrenic patients may be related to an active disease process lasting until old-age. Correlations point to the impact of S100B in neuroplasticity and ageing. Post-mortem studies should clarify the presence of altered S100B function in the brain and its relationship to neuroplastic or neurodegenerative processes.     

Assessment of empathy in first-episode psychosis and meta-analytic comparison with previous studies in schizophrenia

Empathy is a multidimensional construct that relies on affective and cognitive component processes. A few studies have reported impairments of both cognitive and affective empathy components in patients with schizophrenia. It is, however, not known whether these difficulties are already present at psychosis onset. The affective and cognitive components of empathy were thus assessed in 31 patients with first-episode psychosis (FEP) and 31 matched healthy controls using the Interpersonal Reactivity Index (IRI). Our results were then compared to previous studies of empathy in patients with more chronic schizophrenia via a meta-analysis. In addition, we also assessed the relationship between empathy ratings, Mentalizing performance and clinical symptoms. Contrary to what has been reported in people with more chronic schizophrenia, the IRI ratings did not significantly differ between FEP and controls in our study, though a trend was observed for the Personal distress scale. For the Perspective taking scale, our meta-analysis revealed a significantly lower effect size in this study with FEP patients relative to previous schizophrenia studies. In the FEP group, the IRI ratings were not related to positive, negative or general psychopathology symptoms, but a significant relationship emerged between the Liebowitz Social Anxiety Scale and Perspective taking (negative correlation). In addition, a significant positive correlation was observed between the Empathic concern subscale and our theory of mind task. This study supports the idea that the cognitive component of empathy is less affected in patients with first-episode psychosis relative to patients with more chronic schizophrenia, and the impairments reported in previous reports with more chronic populations should be interpreted in light of a possible deterioration of this cognitive skill. The findings also provide some insight into the relationship between empathy and clinical symptoms such as social anxiety.     

A comparative study on quality of life of patients of schizophrenia with and without depression

Depression in schizophrenia has been recognized as one of the important factors influencing the Quality of Life (QOL). For this study 60 patients with a clinical diagnosis of schizophrenia as per ICD-10 (DCR version) were divided into two groups (with and without depression) on the basis of their score on Calgary Depression Rating Scale for Schizophrenia (CDSS). Thereafter, all patients were assessed on Positive and Negative Syndrome Scale for Schizophrenia (PANSS) for psychopathology, on Lehman Quality of Life Interview (QOLI)-brief version for QOL, on World Health Organization Disability Assessment Schedule-II (WHODAS-II) for disability, on UKU Side Effect Rating Scale for side effects of drugs and on Social Support Questionnaire (SSQ) for perceived social support. The two (depressed and non-depressed schizophrenia) groups differed significantly on symptoms of general psychopathology of PANSS and disability as per WHODAS-II, with the depressed group scoring higher. In the total sample, positive symptoms and the symptoms of general psychopathology of PANSS had a strong negative correlation with all three (subjective, objective and combined) domains of QOL, whereas, disability and medication side effects had a negative correlation with subjective and combined domains of QOL. CDSS total score did not significantly correlate with QOL. General psychopathology symptoms of PANSS emerged as the sole significant predictor of subjective and combined QOL, while positive symptoms of PANSS emerged as the sole predictor of objective QOL. Hence, it can be concluded that general psychopathology on PANSS had significant effect whereas depression as rated on CDSS had no significant effect on QOL in patients with schizophrenia. Treatments to improve QOL in schizophrenia should focus on symptoms of general psychopathology of PANSS.     

Increased S100B+ NK cell counts in acutely ill schizophrenia patients are correlated with the free cortisol index, but not with S100B serum levels

Several studies have provided evidence for increased S100B serum concentrations in schizophrenia. The pathophysiological significance of this finding is still uncertain because S100B is involved in many cellular mechanisms and is not astrocyte-specific as was previously assumed. S100B is also expressed by subsets of CD3+ CD8+ T cells and natural killer (NK) cells and may therefore be linked to the immune hypothesis of schizophrenia. We have quantified S100B+ CD3+ CD8+ T cells and NK cells by flow cytometry in the peripheral blood of 26 acutely ill schizophrenia cases and 32 matched controls. In parallel, S100B concentrations and the free cortisol index (FCI), a surrogate marker for stress axis activity, were determined in serum samples from the same blood draw. Psychopathology was monitored using the Positive and Negative Syndrome Scale (PANSS). The patient group had increased S100B+ NK cell counts (P=0.045), which correlated with the FCI (r=0.299, P=0.026) but not with the PANSS or the elevated (P=0.021) S100B serum concentrations. S100B+ CD3+ CD8+ T cell counts were not significantly changed in the patient group and did neither correlate with the FCI and PANSS, nor with S100B serum concentrations. In conclusion, despite the observation of an increase in S100B+ NK cells in schizophrenia patients, the lack of a correlation with serum S100B concentrations suggests that these cells are probably not a major source of S100B in the blood of schizophrenia patients. Notably, elevated S100B+ NK cell counts may be linked with stress axis activation.     

Increased serum S100B protein in schizophrenia: a study in medication-free patients

S100B protein, a calcium binding protein produced and released by glial cells, has been used as a sensitive marker of brain damage. Previous studies have found alterations in peripheral S100B levels in schizophrenic patients on medication. We compared serum S100B levels of 20 medication-free DSM-IV schizophrenic patients and 20 age-gender matched healthy controls. Schizophrenic patients presented higher serum S100B levels (mean 0.120 ng/ml+/-S.D. 0.140) compared to controls (mean 0.066 ng/ml+/-S.D. 0.067; P=0.014) and there was a negative correlation with illness duration (r=-0.496, P=0.031). The results of this study indicate that serum S100B levels may be a state marker of a limited neurodegenerative process, particularly in the early course of schizophrenia or, at least, in a subgroup of schizophrenic patients.     

Increased serum S100B in never-medicated and medicated schizophrenic patients

S100B is a calcium-binding protein, which is produced primarily by glial cells. It modulates the proliferation and differentiation of neurons and glia by affecting protective and apoptotic mechanisms. Recently, several studies have shown increased serum S100B levels in patients with schizophrenia, suggesting that S100B might be relevant to the pathophysiology of schizophrenia. S100B levels were assessed using ELISA in the serum of 80 never-medicated early-stage and 82 medicated chronic schizophrenia patients and 97 healthy controls subjects. The psychopathology of schizophrenia was assessed by the Positive and Negative Syndrome Scale (PANSS). Our results showed significantly increased serum S100B levels in both never-medicated and medicated patients compared to normal controls (both p < 0.0001). S100B in never-medicated patients was also markedly increased, compared with medicated patients (p < 0.0001). S100B changes observed were irrespective of neuroleptic medication, gender, age, and smoking. Increased S100B levels in the early stage of schizophrenia suggest that glial cell activation or structural damage may be part of a neurodegenerative process in schizophrenia. The lower S100B levels in chronic than early-stage patients further suggest that antipsychotic treatment may reduce this neurodegeneration.     

Tripartite relationship among P300, clinical features and brain structure in neuroleptic-naive schizophrenia

Auditory P300 abnormalities in schizophrenia patients have been repeatedly reported by many studies. However, reported relationships among P300 abnormalities, clinical features and other biological variables, such as abnormalities in structural brain imaging, are notably discrepant. This is partially due to the inclusion of patients who have had long-term administration of neuroleptics and those from whom this treatment has been withdrawn. The present study measures event-related potentials in 13 neuroleptic-naive schizophrenia patients using an auditory oddball paradigm to clarify the relationships among P300 amplitude, clinical features and brain structure. All patients underwent computed tomography to estimate the area of the right and left frontal cortical sulci and Sylvian fissures. Clinical symptoms were assessed using the Positive And Negative Syndrome Scale. The high correlation coefficients were obtained between P300 amplitude and the anxiety/depression factor score (r = -0.77), the positive factor score (r = -0.58) and between P300 amplitude and the area ratios of the fronto-temporal region (r = -0.66). These findings show that fronto-temporal region and P300 amplitude are closely related to the earliest stage of illness even in neuroleptic-naive patients.     

Oxidative-antioxidative systems and their relation with serum S100 B levels in patients with schizophrenia: effects of short term antipsychotic treatment

Oxidative stress may be a contributing factor in the etiopathophysiology of schizophrenia, which may be exacerbated by the treatment with antipsychotics with pro-oxidant properties. Increased levels of S100 B are associated with neurodegenerative disorders, including schizophrenia. The aim of the present study was to investigate the role of oxidative cell damage in the pathogenesis of schizophrenia. Forty patients who fully met the fourth Diagnostic and Statistical Manual of Mental Disorders criteria for schizophrenia and 35 healthy control subjects were included in the study. Serum S100 B level was determined to investigate brain damage. Plasma malondialdehyde (MDA) levels and susceptibility of red blood cell (RBC) to oxidation were determined to investigate the oxidative status and plasma vitamin E, vitamin C, serum total carotenoid levels and total antioxidant capacity and RBC superoxide dismutase (SOD) and whole blood glutathione peroxidase activities were measured to investigate the antioxidative defence before and after 6 weeks of antipsychotic treatment. Plasma MDA and serum S100 B levels and RBC-SOD activity were significantly higher in the schizophrenia group than those of the control group. Treatment did not modify any of the oxidative-antioxidative system parameters or serum S100 B levels. S100 B level was significantly higher in patients with negative symptoms than the patients with positive symptoms and the control subjects. S100 B levels were significantly reduced after 6 weeks of treatment in patients with negative symptoms. The results of the present study might support the oxidative cell injury hypothesis of the schizophrenia. Furthermore, the underlying mechanisms of the subgroups of schizophrenia might be different as suggested by the increased S100 B levels and its decrement after treatment in patients with negative symptoms.     

Memory impairment correlates with increased S100B serum concentrations in patients with chronic schizophrenia

Astrocyte activation indicated by increased S100B is considered a potential pathogenic factor for schizophrenia. To investigate the relationship between astrocyte activation and cognitive performance, S100B serum concentration, memory performance, and psychopathology were assessed in 40 first-episode and 35 chronic schizophrenia patients upon admission and after four weeks of treatment. Chronic schizophrenia patients with high S100B were impaired concerning verbal memory performance (AVLT, Auditory Verbal Learning Test) compared to chronic and first-episode patients with low S100B levels. The findings support the hypothesis that astrocyte activation might contribute to the development of cognitive dysfunction in schizophrenia.     

Platelet monoamine oxidase activity and evoked response as predictors of anxiety and depression derived from the content analysis of speech

Platelet MAO activity has been reported by several investigators to differentiate schizophrenia, schizophrenia related depressive disorders, alcoholism, unipolar and bipolar depression from normal controls. Evoked potentials likewise have differentiated schizophrenic and affective patients. However, the precise relationship between MAO activity, evoked potentials (EP), and psychiatric illness has not been clarified. A possible association between psychopathology and high MAO activity/EP reducing and low MAO activity/EP augmenting has been reported. Such a bidirectionality further confounds results. This study was undertaken to determine the association of psychopathological dimensions found in a group of subjects whose platelet MAO activity and evoked responses were obtained two years earlier. Utilizing the Gottschalk-Gleser verbal behavior scales of Anxiety, Depression, Social Alienation-Personal Disorganization and Cognitive Impairment a significant correlation was revealed between low platelet MAO activity and high Total Anxiety scale and Shame Anxiety subscale scores. Additionally, a significant correlation was demonstrated between reducing evoked potentials and elevated Death Anxiety, Somatic Concerns, and Total Death and Mutilation Depression subscales scores, combined and separately. Furthermore, a significant positive correlation was found between augmenting evoked potentials and Overt Hostility Outward scores. No significant correlations were demonstrated between platelet MAO activity or evoked potentials and Social Alienation-Personal Disorganization or Cognitive Impairment scores. These findings lend support to the position that biological markers may predict predispositions to anxiety and depression.     

Frontal lobe N-acetylaspartate correlates with psychopathology in schizophrenia: a proton magnetic resonance spectroscopy study

INTRODUCTION: Clinical, neuropsychological and functional neuroimaging studies in schizophrenia suggest impaired frontal lobe function, especially of the dorsolateral prefrontal region (DLPFR). This dysfunction has in particular been associated with negative or "deficit" symptoms. Despite these findings, morphological studies have failed to show consistent structural abnormalities in the frontal lobe. This may be because existing techniques are not sensitive enough to detect structural abnormalities or that dysfunction in the frontal lobe is caused by lesions elsewhere. We used volume-localised proton magnetic resonance spectroscopy (1H-MRS) to measure N-acetylaspartate (NAA), a neuronal marker, to evaluate the neuronal integrity of the dorsolateral prefrontal region in schizophrenic patients with persistent negative symptoms and in healthy comparison subjects. METHOD: Twenty-five patients who fulfilled DSM-IV criteria for schizophrenia and met the criteria for the Deficit syndrome were compared to 26 healthy controls matched for age and gender. Bilateral proton MR spectra were collected from a 2-cm(3) volume in the dorsolateral prefrontal region and the absolute concentrations of N-acetylaspartate, choline (Cho) and creatine+phosphocreatine (Cr+PCr) were measured. RESULTS: There was a significant negative correlation between severity of symptoms and NAA concentration in the schizophrenic patients. This was more marked for positive symptoms and for general psychopathology than for negative symptoms. There was also a significant correlation between NAA concentration and social functioning within the schizophrenic group. There were no significant differences between the two groups for the three metabolites. CONCLUSIONS: The negative association between severity of symptoms and NAA in schizophrenic patients and an association of NAA with social functioning suggest that NAA may be an indicator of disease severity. The lack of significant mean difference in NAA between the two groups suggests that there is no marked neuronal loss in the dorsolateral prefrontal region in schizophrenia.     

Risk variants in the S100B gene, associated with elevated S100B levels, are also associated with visuospatial disability of schizophrenia

Rs9722 and rs1051169 have been reported as affecting the levels of S100B in the serum or the brain, and haplotypes containing these two SNPs have been associated with schizophrenia. The current study investigated the role of the S100B gene in an endophenotype of schizophrenia-spatial disability. 304 schizophrenia patients and 196 healthy controls were given a block design task and a mental rotation task. Results showed that the two aforementioned SNPs and related haplotypes were associated with the spatial disability of schizophrenia patients. Specifically, risk factors for the elevated S100B levels, including the A allele of rs9722, the G allele of rs1051169, and the AG haplotype, were associated with a poorer performance on both tests of spatial ability, especially the mental rotation task. These results implicate a role for S100B gene polymorphisms in the cognitive functions of schizophrenia patients and encourage further investigation into spatial disability as an endophenotype of schizophrenia.     

Treatment resistant chronic psychopathology and CT scans in schizophrenia

In order to examine the relationship between the neuroleptic resistant chronic psychopathology and CT findings in schizophrenia, 25 schizophrenics who had been treated well and were in a stable condition were assessed for positive and negative symptoms, CT findings, medication, and the clinical course of illness. Correlational analysis showed that there was a group of patients who had comparatively small ventricles and presented treatment resistant positive symptoms, and another group of patients who had larger ventricles and lacked positive symptoms. Negative symptoms showed a tendency toward positive correlation with atrophic CT changes of cortices. Literature on CT findings and symptomatology was critically reviewed. The importance of the more chronic positive symptoms correlating to CT findings in schizophrenia were discussed.     

精神分裂症血浆S100B蛋白测定及临床意义探讨

目的探讨精神分裂症急性期血浆S100B蛋白水平及临床意义。方法用ELISA法检测血浆S100B蛋白含量。应用阳性和阴性症状量表（PANSS）评定精神症状。结果精神分裂症60例急性期血浆S100B蛋白水平（0．063±0．054μg／1）显著高于对照组（0．019±0．009μg／1，P〈0．001）；治疗6周后血浆S100B蛋白水平（0．079±0．093μg／L）与治疗前（0．063±0．054μg／L）差异不显著（P〉0．05）；治疗后血浆S100B持续增高者PANSS阴性症状评分较高。结论S100B持续增高与精神分裂症阴性症状相关。S100B绝对浓度可作为阴性症状发生的预测因子。     

Serum S100B is increased during early treatment with antipsychotics and in deficit schizophrenia

Previous studies reported controversial results concerning alterations of astrocytes in schizophrenia. Because S100B may be regarded as a marker for astrocytes, the objective of this study was to examine S100B serum concentrations in 30 patients with schizophrenia with a monoclonal two-site immunoluminometric assay that specifically detects S100B. An ANOVA revealed medication (p<0.005) and deficit vs. nondeficit syndrome (p<0.05) as factors that influenced S100B significantly. S100B was higher in schizophrenic patients treated with antipsychotic drugs for approximately 3 weeks (241.1+/-152.5 ng/l) in comparison with unmedicated patients (111.4+/-31.8 ng/l, p<0.005), and healthy age-matched controls (112.8+/-53.4 ng/l, p<0.001; Bonferroni corrected two-tailed Student's t-test). There was no difference of S100B between unmedicated patients and controls (p>0.05). Patients with deficit (250.6+/-154.9 ng/l) had higher S100B levels than patients with nondeficit schizophrenia (146.7+/-107.2 ng/l, p<0.05) or controls (p<0.005). S100B was positively correlated with the subscore 'thought disturbance' of the Brief Psychiatric Rating Scale (p<0.05). In summary, increased serum levels of S100B may indicate alterations of astrocytes during early treatment with antipsychotics and in deficit schizophrenia. Whether S100B is elevated due to injured astrocytes and a disrupted blood-brain barrier, or by active secretion of S100B by astrocytes, has to be clarified by further studies.     

S100B-immunopositive glia is elevated in paranoid as compared to residual schizophrenia: a morphometric study

OBJECTIVE: Several studies have revealed increased S100B levels in peripheral blood and cerebrospinal fluid (CSF) of patients with schizophrenia. In this context, it was postulated that elevated levels of S100B may indicate changes of pathophysiological significance to brain tissue in general and astrocytes in particular. However, no histological study has been published on the cellular distribution of S100B in the brain of individuals with schizophrenia to clarify this hypothesis. METHODS: The cell-density of S100B-immunopositive glia was analyzed in the anterior cingulate, dorsolateral prefrontal (DLPF), orbitofrontal, and superior temporal cortices/adjacent white matter, pyramidal layer/alveus of the hippocampus, and the mediodorsal thalamic nucleus of 18 patients with schizophrenia and 16 matched control subjects. RESULTS: Cortical brain regions contained more S100B-immunopositive glia in the schizophrenia group relative to controls (P=0.046). This effect was caused by the paranoid schizophrenia subgroup (P=0.018). Separate analysis of white matter revealed no diagnostic main group effect (P=0.846). However, the white matter of patients with paranoid schizophrenia contained more (mainly oligodendrocytic) S100B-positive glia as compared to residual schizophrenia (P=0.021). These effects were particularly pronounced in the DLPF brain area. CONCLUSION: Our study reveals distinct histological patterns of S100B immunoeactive glia in two schizophrenia subtypes. This may be indicative of a heterogenic pathophysiology or distinct compensatory abilities: Astro-/oligodendroglial activation may result in increased cellular S100B in paranoid schizophrenia. On the contrary, residual schizophrenia may be caused by white matter oligodendroglial damage or dysfunction, associated with a release of S100B into body fluids.     

Handedness and schizotypal features in healthy subjects.

BACKGROUND: An excess of mixed-handedness has been repeatedly reported in schizophrenia and schizotypy. Handedness is a measure of atypical cerebral lateralization, which is considered as a risk factor for schizophrenia. Several studies have attempted to identify correlations between handedness and dimensions of psychosis but the results obtained so far remain inconclusive. OBJECTIVE: To explore a possible link between mixed-handedness and the three classical dimensions of psychosis. As speech and language disorders may be associated with cerebral lateralization, we predicted a correlation between mixed-handedness and disorganized dimension. METHODS: We used the Schizotypal Personality Questionnaire (SPQ) and the Edinburgh Handedness Inventory (EHI) to study the correlation between mixed-handedness scores and positive, negative or disorganized dimensions in a sample of 62 healthy subjects. RESULTS: We found a negative correlation between mixed-handedness and the disorganized dimension of schizotypy, as individuals with prominent mixed-handedness showed more severe disorganization. CONCLUSION: We have identified a link between mixed-handedness and the disorganized dimension that may help to identify genetic vulnerability factors involved in psychosis.     

Psychiatric symptoms and quality of life in schizophrenia: a meta-analysis

Quality of life (QoL) has been recognized as an important outcome of schizophrenia treatment, yet the determinants of QoL for individuals with schizophrenia are not well known. Research has consistently found psychiatric symptoms to be negatively related to QoL, however, findings concerning the strength of these relationships have been mixed, making it difficult to determine the degree to which such symptoms are related to poor QoL. This research presents a systematic meta-analysis of studies examining the relationship between psychiatric symptoms and QoL in schizophrenia, in an effort to elucidate the determinants of QoL for this population. A total of 56 studies were extracted from literature searches of relevant databases for empirical reports published between 1966 and 2005 examining the relationship between positive, negative, and/or general psychiatric symptoms and QoL. Weighted effect size analyses revealed small relationships between psychiatric symptoms and QoL, with general psychopathology showing the strongest negative associations across all QoL indicators. Moderator analyses indicated that variation in effect sizes could be accounted for by differing operationalizations of QoL, study design, sample, and participant treatment setting. In particular, positive and negative symptoms were more strongly related to poor QoL among studies of schizophrenia outpatients, whereas general psychopathology showed a consistent negative relationship with QoL across all study samples and treatment settings. Implications for future research and treatment development are discussed.     

Structural analysis of the basal ganglia in schizophrenia

Increases in the total volume of basal ganglia structures have been reported in schizophrenia. However, patterns of basal ganglia shape change, which can reveal localized changes in substructure volumes, have not been investigated. In this study, the total volume and shape of several basal ganglia structures were compared in subjects with and without schizophrenia. T(1)-weighted magnetic resonance scans were collected in 54 schizophrenia and 70 comparison subjects. High-dimensional (large-deformation) brain mapping was used to assess the shape and volume of several basal ganglia structures. The relationships of shape and volume measures with psychopathology, cognition and motor function were also assessed. Left and right volumes of the caudate and putamen, as well as the right globus pallidus volume, were significantly increased in subjects with schizophrenia as compared to comparison subjects after total brain volume was included as a covariate. Significant differences in shape accompanied these volume changes in the caudate, putamen and globus pallidus, after their total volumes were included as covariates. There were few significant correlations between volume or shape measures and either cognitive function or clinical symptoms, other than a positive correlation between an attention/vigilance cognitive dimension and the volume of the caudate and putamen, and a negative correlation between nucleus accumbens volume and delusions. In conclusion, basal ganglia volumes relative to total brain volume were larger in schizophrenia subjects than healthy comparison subjects. Specific patterns of shape change accompanied these volume differences.