Essential polyunsaturated fatty acid and lipid peroxide levels in never-medicated and medicated schizophrenia patients.

BACKGROUND: Reduced levels of membrane essential polyunsaturated fatty acids (EPUFAs) and increased levels of lipid peroxidation products (thiobarbituric acid reactive substances; TBARS) have been observed in chronic medicated schizophrenics. The relationship of EPUFA and TBARS to psychopathology is unclear, since their levels may be altered differentially by duration of illness and antipsychotic treatment. To minimize these confounds, their levels were compared among never-medicated patients in early illness, medicated patients and control subjects with similar lifestyle and common ethnic background. METHODS: RBC membrane EPUFAs, plasma TBARS, and various dimensions of psychopathology were measured using established procedures in never-medicated (n = 20) and medicated (n= 32) schizophrenia patients and in control subjects (n= 45). RESULTS: Reduced levels of EPUFAs, particularly arachidonic acid (AA) and docosahexaenoic acid (DHA), were found in never-medicated compared with control subjects; however, the reductions in levels of both AA and DHA were much smaller in medicated versus never-medicated patients; AA levels were similar to levels in control subjects. Only DHA levels were significantly reduced in medicated patients. Lower membrane AA levels were associated with increased levels of plasma TBARS in never-medicated patients. Lower levels of membrane EPUFAs and higher levels of plasma TBARS were associated with the severe symptoms in never-medicated versus medicated patients. CONCLUSIONS: Data indicate that reduced EPUFAs and increased TBARS exist in never-medicated patients, and these measures correlate with the severity of psychopathology indicating that the membrane EPUFA status may reflect the outcome of schizophrenia.     

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.     

Differential performance of acute and chronic schizophrenics in a latent inhibition task

Differences between acute (N = 26) and chronic (N = 27) schizophrenics diagnosed by Research Diagnostic Criteria and normal controls (N = 53) were examined in a task measuring latent inhibition, i.e., the retardation of learning that normally occurs when a subject forms an association to a stimulus previously repeatedly presented without consequence. In rats, latent inhibition is disrupted by amphetamine and restored by neuroleptics. It was predicted that latent inhibition would be similarly disrupted in acute schizophrenics (presumably in a hyperdopaminergic state) but not in chronic, medicated schizophrenics. Each group was subdivided and assigned randomly to two experimental conditions, preexposure or non-preexposure. Preexposed subjects first heard 30 bursts of white noise through headphones while monitoring a list of nonsense syllables; non-preexposed subjects listened to the nonsense syllables without the white noise. Subjects in both conditions were then given the opportunity to learn that the noise signalled increments in a visually displayed number. Preexposed normals and chronic schizophrenics learned this association more slowly than non-preexposed subjects (latent inhibition); as predicted, acute schizophrenics failed to display this effect. After 6 to 7 weeks, 11 acute and 13 chronic patients were retested; both groups now showed latent inhibition. These results are discussed in relation to the dopamine hypothesis of schizophrenia.     

Cerebral grey, white matter and csf in never-medicated, first-episode schizophrenia

We report the first voxel-based morphometric (VBM) study to examine cerebral grey and white matter and cerebrospinal fluid (CSF) using computational morphometry in never-medicated, first-episode psychosis (FEP). Region-of-interest (ROI) analysis was also performed blind to group membership. 26 never-medicated individuals with FEP (23 with DSM-IV schizophrenia) and 38 healthy controls had MRI brain scans. Groups were balanced for age, sex, handedness, ethnicity, paternal socio-economic status, and height. Healthy controls were recruited from the local community by advertisement. Grey matter, white matter, and CSF: global brain volume ratios were significantly smaller in patients. Patients had significantly less grey matter volume in L and R caudate nuclei, cingulate gyri, parahippocampal gyri, superior temporal gyri, cerebellum and R thalamus, prefrontal cortex. They also had significantly less white matter volume in the R anterior limb of the internal capsule fronto-occipital fasciculus and L and R fornices, and significantly greater CSF volume especially in the R lateral ventricle. Excluding the 3 subjects with brief psychotic disorder did not alter our results. Our data suggest that fronto-temporal and subcortical-limbic circuits are morphologically abnormal in never-medicated, schizophrenia. ROI analysis comparing the schizophrenia group (n=23) with the healthy controls (n=38) confirmed caudate volumes were significantly smaller bilaterally by 11%, and lateral ventricular volume was significantly larger on the right by 26% in the patients. Caudate nuclei and lateral ventricular volume measurements were uncorrelated (Pearson correlation coefficient 0.30, p=0.10), ruling out the possibility of segmentation artefact. Ratio of lateral ventricle to caudate volume was bilaterally significantly increased (p<0.005, 2-tailed), which could represent an early biomarker in first-episode, never-medicated schizophrenia.     

Platelet monoamine oxidase in schizophrenia: a meta-analysis.

We did a meta-analysis on all publications (English and other languages) concerned with platelet monoamine oxidase (MAO) in schizophrenia. Essentially, when patients were medicated with a neuroleptic, most studies found that schizophrenics had lower platelet MAO levels than controls. Administration of neuroleptic lowers MAO levels. MAO levels in drug-free schizophrenics were similar to controls. Only a minority of studies found drug-free schizophrenics had decreased platelet MAO levels.     

Electroencephalographic sleep in young, never-medicated schizophrenics. A comparison with delusional and nondelusional depressives and with healthy controls

Electroencephalographic (EEG) sleep characteristics of young, never-medicated, nonschizoaffective schizophrenics were compared with the EEG sleep of patients with major depressive disorders (delusional and nondelusional) and with that of healthy controls. Schizophrenics had decreased sleep continuity comparable to delusional depressives. Slow-wave sleep percent was similar to that seen in healthy controls, as was the intranight temporal distribution of EEG delta activity. However, schizophrenics showed diminished delta counts per minute of non-rapid eye movement (NREM) sleep and a decreased total delta wave count. In contrast, depressives showed diminished slow-wave sleep percent compared with controls, greatly decreased delta activity (more so than did the schizophrenics), and an altered temporal distribution of delta activity, as evidenced by a shift of delta activity from the first to the second NREM period. Minutes of slow-wave sleep in the schizophrenics was inversely correlated with the severity of negative symptoms independent of the effects of age and the presence of depression. The schizophrenics showed normal REM latency and first REM period duration, in contrast to the depressives. These findings, reviewed in the historical context of sleep physiologic studies of schizophrenia over the past 30 years, suggest that young, never-medicated schizophrenics do not show the characteristic constellation of abnormalities in the first NREM-REM cycle seen in patients with major depression. However, decreased slow-wave sleep should be investigated as a possible marker for negative symptoms in schizophrenia.     

Opposite changes in predominantly docosahexaenoic acid (DHA) in cerebrospinal fluid and red blood cells from never-medicated first-episode psychotic patients

Variable levels of essential polyunsaturated fatty acids (EPUFAs) reported in schizophrenia are likely due to differences in age, sex, ethnicity, diet, life style and treatments. The present study examined the EPUFAs levels in plasma, RBC and CSF in never-medicated first-episode psychotic patients and normal controls matched for ethnicity, diet and life style. The plasma EPUFAs levels were similar in both groups. Among the EPUFAs enriched in the brain, predominantly docosahexaenoic acid (DHA) levels were lower in RBC (p=<0.01) whereas higher in CSF (p=<0.01) in male>female patients. This altered DHA metabolism may provide clues for neuropathology and treatment of schizophrenia.     

Elevated interleukin-18 serum levels in chronic schizophrenia: Association with psychopathology

BackgroundSchizophrenia is associated with various abnormalities in the immune system including elevated levels of Interleukin-18 (IL-18), a potent inflammatory cytokine in T-helper 1 (Th1) responses. The aim of this study was to assess the clinical significance of serum IL-18 levels in various stages of schizophrenia.MethodsWe measured serum IL-18 levels using a sandwich enzyme-linked immunosorbent assay (ELISA) from 78 never-medicated first-episode schizophrenia, 79 medicated chronic schizophrenia and 78 healthy control subjects. The symptoms of schizophrenia were assessed by the Positive and Negative Syndrome Scale (PANSS).ResultsThe chronic patients had significantly greater serum IL-18 levels than both first-episode patients and controls. Serum IL-18 was also positively correlated with the PANSS general psychopathology subscore in chronic schizophrenic patients.ConclusionsOur results showed elevated IL-18 pathway activity may be involved in the psychopathology of schizophrenia.     

Elevated plasma level of apolipoprotein D in schizophrenia and its treatment and outcome

Recently, apolipoprotein D (apoD), a protein that is involved in the essential polyunsaturated fatty acid (EPUFA) transport and metabolism, and neuronal growth and regeneration was reported to have increased in the postmortem brain and decreased in the serum of schizophrenia patients. We studied the plasma apoD levels in never-medicated schizophrenic patients at the onset of psychosis and in chronic patients with clozapine treatment. Plasma apoD levels were elevated in never-medicated patients at the first-episode of psychosis compared to normals (P = 0.047). Interestingly, the increase in apoD level was even more significant in chronic patients treated with clozapine compared to normals and first-episode patients (P = 0.008 and P = 0.03, respectively). The increased apoD level in never-medicated first-episode patients indicate that this increase probably predates the illness, since the duration of illness was < 5 days. Similarly, an even larger increase in apoD after clozapine treatment may be associated with its prophylactic effects, since the psychopathological scores were significantly reduced and the clozapine treatment has been found to increase the EPUFA membrane levels. These altered levels of apoD may help to understand the nature and possible mechanism of phospholipid membrane pathology in schizophrenia.     

Clinical and demographic correlates of neuroleptic response

This paper presents evidence that the positive symptoms of schizophrenia respond best to neuroleptics, as do patients with hyperdopaminergic activity (high blink rates, low prolactin levels). Those schizophrenics with defect states, intellectual and neurological impairment, brain atrophy, neuropsychological impairment, and poor school and social premorbid adjustment do not respond as well to dopamine blockers. It has been suggested that this group of schizophrenics do not suffer from a dopamine disturbance. There is also evidence for the relatively superior response of women, especially premenopausal women. This may be due to several factors but appears to be related to estrogen levels, especially since psychotic symptoms appear, in some women, premenstrually and post-partum, when estrogen levels drop. There is now substantial evidence that estrogens antagonize dopamine in the brain.     

Elevated plasma superoxide dismutase in first-episode and drug naive patients with schizophrenia: inverse association with positive symptoms

Excessive free radical production or oxidative stress may be involved in the pathophysiology of schizophrenia as evidenced by increased superoxide dismutase (SOD) activities, a critical enzyme in the detoxification of superoxide radicals. This study compared plasma SOD activities in 78 never-medicated first-episode and 100 medicated chronic schizophrenia patients to 100 healthy control subjects and correlated these SOD activities with the Positive and Negative Syndrome Scale (PANSS) among the schizophrenic patients. We found that both first-episode and chronic patients had significantly increased plasma SOD activities compared to controls, and that chronic schizophrenic patients on antipsychotic medication had significantly higher SOD activities than first episode schizophrenic patients. Plasma SOD activities were also negatively correlated with positive symptoms of schizophrenia, but only in first-episode patients. Thus, oxidative stress appears to be greater in first episode schizophrenic patients with fewer positive symptoms and may become greater as schizophrenia becomes more chronic, although we cannot exclude the possibility that chronic antipsychotic treatment may increase SOD activities and presumed oxidative stress in schizophrenia.     

Low HVA and normal 5HIAA CSF levels in drug-free schizophrenic patients compared to healthy volunteers: correlations to symptomatology and family history

Cerebrospinal fluid (CSF) levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) were determined in 40 drug-free schizophrenic patients and 21 healthy volunteers by a mass fragmentographic method. Twenty-one of the schizophrenic patients were first admissions who had never received neuroleptics. Significantly, lower levels of HVA but not 5HIAA were found in the patient group, and no difference was found between chronic, previously neuroleptic-treated and never-medicated patients. HVA levels correlated positively with social interest and total positive scores on the Nurses Observation Scale for Inpatient Evaluation (NOSIE-30) and negatively with lassitude and slowness of movements on the Comprehensive Psychopathological Rating Scale (CPRS). Low levels of 5HIAA were correlated to the CPRS items delusions and apparent sadness. There were slightly higher CSF levels of 5HIAA in patients with a family history of schizophrenia, but no such difference was seen for HVA. In both schizophrenic and control subjects CSF levels of HVA and 5HIAA showed a strong intraindividual correlation. The results indicate decreased central nervous system dopaminergic turnover in schizophrenia which seems to be associated with "negative" symptomatology.     

精神分裂症偏执型患者血浆及脑脊液白细胞介素2,6及免疫球蛋白G水平的研究

目的　探讨首发精神分裂症偏执型患者血浆及脑脊液中白细胞介素 2 (IL 2 )、IL 6、免疫球蛋白G (IgG)水平的变化 ,及其与精神病理之间的关系。方法　患者组为 30例未用过抗精神病药治疗的精神分裂症偏执型患者 ,对照组为 2 0例无精神疾患的轻微脑外伤患者 ,以阳性和阴性症状量表 (PANSS)评定精神分裂症患者的精神症状 ,用酶联免疫吸附法检测IL 2、IL 6 ,用速率散射比浊法检测IgG。 结果　 (1)患者组血浆及脑脊液IL 2、IL 6和IgG均高于对照组 (P <0 0 1和P <0 0 5 )。(2 )在患者组中 ,血浆IL 6与血浆IgG(r =0 6 90 )和脑脊液IL 6 (r =0 4 2 5 )呈正相关 (P <0 0 1和P <0 0 5 ) ,血浆IgG与脑脊液IgG呈正相关 (r =0 4 0 9,P <0 0 5 ) ;脑脊液IL 6与脑脊液IgG呈正相关 (r =0 5 10 ,P <0 0 5 )。在对照组中 ,血浆IL 2与血浆IL 6 (r =0 5 0 4 ,P <0 0 5 )和IgG (r =0 74 0 ,P <0 0 1)呈正相关 ,血浆IL 6与血浆IgG(r=0 6 75 ,P <0 0 1)和脑脊液IL 6 (r =0 6 33,P <0 0 1)呈正相关 ,血浆IgG与脑脊液IgG(r =0 6 19,P <0 0 5 )呈正相关。 (3)血浆IL 2与P因子分呈正相关 (r =0 6 4 5 ,P =0 0 0 )。结论　首发精神分裂症偏执型患者处于免疫激活状态 ,IL 2、IL 6、IgG与精神病理之间存在一定的     

Effect of concurrent distraction on communication failures in schizophrenic patients. II. Medication status correlations.

In order to examine the effects of irrelevant distracting information on speech disorder, medicated (n = 13) and unmedicated (n = 18) schizophrenics were compared to a mixed affective sample (n = 15) on the frequencies of linguistic measures of verbal communication disorder. Patients conversed with an interviewer during the presence and absence of irrelevant information inserted into their conversation. Affective patients manifested no distraction-related increase in communication disorder. Schizophrenics on medication manifested a small, but nonsignificant, increase in communication disorders during the concurrent distraction condition. Unmedicated schizophrenics manifested a substantial increase in their communication disorders during distraction. These data suggest that medication reduces the extent to which speech processes in schizophrenia are vulnerable to overload-related deterioration and provide confirmation of the hypothesis that some component of positive thought disorder in schizophrenia is due to medication-responsive attention deficits.     

The novel oxidative stress marker thioredoxin is increased in first-episode schizophrenic patients

Excessive free radical production leading to oxidative stress may be involved in the pathophysiology of schizophrenia. Oxidative stress increases serum thioredoxin (TRX), a redox-regulating protein with antioxidant activity recognized as an oxidative-stress marker. The aim of this study was to assess the clinical significance of serum TRX levels in various stages of schizophrenia. Serum TRX levels were determined using ELISA from 60 never-medicated first-episode and 66 medicated chronic schizophrenia patients and 66 healthy control subjects matched for age and gender. The psychopathology of schizophrenia was assessed by the Positive and Negative Syndrome Scale (PANSS). Our results showed that group comparison between first-episode and chronic patients and control groups revealed significantly increased serum TRX only in first-episode patients. Increased levels of TRX in patients experiencing an acute stage schizophrenic episode was also significantly higher compared to chronic schizophrenic patients on antipsychotic medication. Serum TRX was also positively correlated with positive symptoms of schizophrenia. Our results suggest oxidative stress occurs in an acute stage of schizophrenic episode and may have an important role in pathogenesis and symptomology of schizophrenia. Lower TRX levels in chronic patients treated with antipsychotics may have implications for treatment outcome.     

Increased number of [I] BH-substance p receptors in schizophrenia

1. 1- This study used quantitative receptor autoradiography to evaluate if the hyperdopaminergic state in the striatum of schizophrenics is associated with decreased NK1 receptor density.

2. 2- A significant increase of NK1 sites was detected in caudate and nucleus accumbens of schizophrenic patients as compared to controls. No statistical difference was observed for the putamen.

3. 3- Neuroleptics used in the treatment of schizophrenia may be responsible for the observed increase in NK1 receptors.

     

Taurine and glutathione in plasma and cerebrospinal fluid in olanzapine treated patients with schizophrenia

Oxidative stress has been implicated in the pathophysiology of schizophrenia. Taurine and glutathione (GSH) have antioxidant and central nervous system protective properties, and are proposed to be involved in the pathology of schizophrenia. The aim of this study was to compare the blood and cerebrospinal fluid (CSF) levels of taurine and GSH in patients with schizophrenia, medicated with oral olanzapine, compared with controls. In total, 37 patients with schizophrenia and 45 healthy volunteers were recruited. We found the plasma taurine levels to be elevated in patients compared with controls. No differences were, however, found between patients and controls regarding taurine in CSF or GSH concentrations in plasma and CSF. Moreover, in the patient group no correlations between taurine and GSH levels and the symptoms or function of the disorder were found. The higher levels of plasma but not CSF taurine in patients with schizophrenia treated with OLA may implicate the involvement of taurine in the pathophysiology of the disease. The absence of GSH differences both in plasma and CSF between patients and controls is interesting in the perspective of earlier research proposing a dysregulation of GSH metabolism as a vulnerability factor for the development of schizophrenia.     

Cerebrospinal fluid and serum levels of neuron-specific enolase in patients with schizophrenia.

Some patients with schizophrenia appear to have brain abnormalities, including enlarged third and lateral ventricles and reduced volumes of temporal lobe structures. These abnormalities could be attributed to a developmental abnormality or a neurodegenerative process. Neuron-specific enolase (NSE), a protein that is found primarily in neurons and neuroendocrine cells, has been used as an index of neuronal damage or degeneration. Levels of NSE in cerebrospinal fluid (CSF) and serum from 50 patients with acute and chronic schizophrenia were compared with those in normal and neurological control subjects. A double-antibody, solid phase iodinated radioimmunoassay was used to determine NSE levels. There was no evidence of elevated levels in patients with schizophrenia, whereas control subjects with neurological illnesses had increased levels of NSE in CSF. Because NSE is rapidly cleared from CSF, however, elevated levels could have been missed. Unmedicated patients tended to have lower levels than medicated patients.     

Loss of the Kamin blocking effect in acute but not chronic schizophrenics.

Differences between research diagnostic criteria (RDC)-diagnosed acute and chronic schizophrenics and normal controls were studied using a Kamin blocking procedure. Blocking is an established animal learning procedure, thought by some researchers to reflect selective attention; decreased blocking indicates increased processing of irrelevant stimuli. It was predicted that this pattern would be obtained in acute schizophrenics, tested soon after admission, for two reasons: (1) evidence from previous clinical studies indicates that acute schizophrenics are more aware of nonsalient aspects of their environment than controls; and (2) blocking is disrupted in animals in a hyperdopaminergic state and restored by neuroleptic medication. This was the case: acute, but not chronic, schizophrenics showed disrupted blocking. This disruption was especially clear in those acute schizophrenics tested within 2 weeks of hospital admission. By the second test session (in a cross-over design), there was some evidence of normalization in performance in the acute schizophrenics. These findings are considered with regard to the dopamine hypothesis of schizophrenia.     

Antibodies to heat shock proteins in schizophrenic patients: implications for the mechanism of the disease.

OBJECTIVE: The involvement of heat shock proteins has been determined in the pathophysiology of several disorders of the central nervous system, including multiple sclerosis. To elucidate their role in schizophrenia, the authors investigated antibody titers to heat shock proteins in unmedicated and medicated patients with schizophrenia. METHOD: Using the enzyme-linked immunosorbent assay technique, the authors measured titers of antibodies to 60 kilodaltons (kD) heat shock proteins (HSP60) and 70 kD heat shock proteins (HSP70) in 30 patients with schizophrenia before and during neuroleptic treatment and compared the titers with those of 31 healthy individuals. RESULTS: Ten (33%) of 30 patients with schizophrenia but only one (3%) of 31 healthy individuals showed immunoreactivity to HSP60 or HSP70. The authors found especially high anti-HSP70 titers in never-medicated patients. High anti-HSP60 titers were mainly found in patients who were being treated with neuroleptics. CONCLUSIONS: Since heat shock proteins are involved in diverse neuroprotective mechanisms, antibodies against heat shock proteins may inhibit neuroprotection. The authors discuss the implications of these findings for schizophrenia.