Endorphins in human cerebrospinal fluid: Clinical correlations to some psychotic states

The significance of endorphins, endogenous morphine-like agents, in some psychiatric disorders was investigated. Samples of cerebrospinal fluid were taken by lumbar puncute from healthy volunteers and from patients with schizophrenic, manic-depressive and puerperal psychosis and analyzed for two major fractions of endorphins (Fractions I and II). In 19 healthy volunteers the levels of the two fracstions fell within a fairly narrow range. In constrast, six out of nine drug-free and symptom-rich schizophrenics showed elevated levels of Fracstion I, which returned to normal or slightly supranormal values after treatment with neuroleptics or propranolol. This decrement was paralleled by a clinical improvement in four of six responding patients. In four manic-depressive patients, serial samples of cerebrospinal fluid revelaed elevated endorphin levels, particularly Fraction I during the manic stage. In three out of four patients with puerperal psychosis, the levels of endorphins (either Fraction I or II) were elevated in the acute drug-free stage. During a later symjptomfree stage, after treatment with ECT and/or neuroleptics, the endorphin levles were within the normal range. The present data lend credit to the hypothesis that endorphins are involved in some psychotic states in the human.     

Increased mRNA levels of the mitochondrial complex I 75-kDa subunit

Recently, the dopamine D3-receptor mRNA on blood lymphocytes and platelet mitochondrial complex I were suggested as biological markers of schizophrenia in adults. We investigated the mRNA level of the dopamine D3-receptor and complex I subunits in whole blood cells of early-onset schizophrenic patients compared to healthy controls using quantitative real-time PCR. We found an increased mRNA expression of the complex I 75-kDa subunit (referred to beta-actin in schizophrenic patients (0.57 +/- 0.24 versus 0.23 +/- 0.18 in controls, P < 0.01)), but were unable to analyse the dopamine D3-mRNA expression. This increase appears to be inherent to schizophrenia, because it was found in neuroleptic-naive patients and it was not affected by neuroleptic treatment. Our preliminary findings suggest the mitochondrial complex I as a potential peripheral marker of schizophrenia and its involvement in the pathophysiology of this illness.     

Electrodermal orienting response and central nervous system dopamine and serotonin activity in schizophrenia.

The present study was designed to examine the relationship between electrodermal activity and the levels of the dopamine metabolite homovanillic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid. Lumbar cerebrospinal fluid from 36 unmedicated and six medicated schizophrenic patients and 23 controls was analyzed by gas chromatograph-mass spectrometer. The schizophrenic patients and a group of 14 normal controls were presented with a series of orienting tones (1000 Hz, 80 db, 2-second duration) while electrodermal activity was monitored. For the patients, this occurred during an acute episode of schizophrenia. The results suggest an inverse relation between electrodermal activity and the CSF-level of HVA. Although the picture is not entirely consistent, electrodermal nonresponders appear to have normal HVA levels, while electrodermal responders have decreased levels compared with normal controls. There is also a relation between electrodermal activity and 5-HIAA, but this association is not as clear-cut as the one between electrodermal activity and HVA.     

Reduced CSF neurotensin concentration in drug-free schizophrenic patients

The concentration of the tridecapeptide neurotensin was measured in CSF from 76 drug-free schizophrenic patients and 45 healthy controls. A highly significant difference was found between the two groups with lower concentration of neurotensin-like immunoreactivity in schizophrenic patients. Normalization of the lower concentrations was obtained in the same patients during ongoing neuroleptic treatment. The neurotensin concentrations in CSF was unrelated to sex, age, duration of the disorder or to previous neuroleptic treatment. Neurotensin levels did not differ between patients with or without a family history. A significant correlation was found between low neurotensin concentrations and decreased motor activity. No significant relationship was seen between the increment in CSF concentrations of neurotensin and clinical improvement during neuroleptic treatment. No significant correlation between CSF concentrations of neurotensin and HVA or 5-HIAA, major metabolites of dopamine and serotonin, respectively, could be demonstrated. However, in a limited number of the schizophrenic patients in this population, a significant correlation was seen between neurotensin and the noradrenaline metabolite MOPEG. The data support the hypothesis that certain schizophrenic patients may have a compromised CNS neurotensin system which might increase vulnerability for this disorder.     

Grey and white matter differences in brain energy metabolism in first episode schizophrenia: 31P-MRS chemical shift imaging at 4 Tesla

Altered high energy and membrane metabolism, measured with phosphorus magnetic resonance spectroscopy (31P-MRS), has been inconsistently reported in schizophrenic patients in several anatomical brain regions implicated in the pathophysiology of this illness, with little attention to the effects of brain tissue type on the results. Tissue regression analysis correlates brain tissue type to measured metabolite levels, allowing for the extraction of "pure" estimated grey and white matter compartment metabolite levels. We use this tissue analysis technique on a clinical dataset of first episode schizophrenic patients and matched controls to investigate the effect of brain tissue specificity on altered energy and membrane metabolism. In vivo brain spectra from two regions, (a) the fronto-temporal-striatal region and (b) the frontal-lobes, were analyzed from 12 first episode schizophrenic patients and 11 matched controls from a (31)P chemical shift imaging (CSI) study at 4 Tesla (T) field strength. Tissue regression analyses using voxels from each region were performed relating metabolite levels to tissue content, examining phosphorus metabolite levels in grey and white matter compartments. Compared with controls, the first episode schizophrenic patient group showed significantly increased adenosine triphosphate levels (B-ATP) in white matter and decreased B-ATP levels in grey matter in the fronto-temporal-striatal region. No significant metabolite level differences were found in grey or white matter compartments in the frontal cortex. Tissue regression analysis reveals grey and white matter specific aberrations in high-energy phosphates in first episode schizophrenia. Although past studies report inconsistent regional differences in high-energy phosphate levels in schizophrenia, the present analysis suggests more widespread differences that seem to be strongly related to tissue type. Our data suggest that differences in grey and white matter tissue content between past studies may account for some of the variance in the literature.     

Comparative study of proton and phosphorus magnetic resonance spectroscopy in schizophrenia at 4 Tesla

This study used high-field magnetic resonance spectroscopy to examine the correlation of 1H and 31P metabolite levels in patients with schizophrenia and normal controls. 1H and 31P in vivo spectra were acquired successively from the left anterior cingulate and left thalamus of nine chronic schizophrenic patients and eight comparable healthy controls. A significant positive correlation between glutamine (Gln) and phosphoethanolamine (PEtn) was found in the left anterior cingulate of patients. In the left thalamus of patients, a significant negative correlation between N-acetylaspartate (NAA) and glycerophosphocholine (GroPCho) was found. No significant correlations were found in controls. The correlation between glutamine and phosphoethanolamine may reflect a link between neurotransmission alterations and membrane phospholipid metabolism alterations. The negative correlation between N-acetylaspartate and glycerophosphocholine may reflect the presence of neurodegeneration.     

Midbrain dopamine D2/3 receptor binding in schizophrenia

Several studies suggest that dysregulation of dopaminergic transmission in the midbrain and thalamus may contribute to the symptomatology of schizophrenia. The objective of this study was to examine the putative alteration of dopamine D_2/3 receptor densities in the thalamus and midbrain of drug-naïve schizophrenic patients. We used the high-affinity single-photon emission tomography ligand [¹²³I]epidepride for imaging D_2/3 receptor binding sites in six neuroleptic-naïve schizophrenic patients, and seven healthy controls. Schizophrenic symptoms were evaluated by the Positive and Negative Syndrome Scale. Significantly lower D_2/3 values were observed in the midbrain of patients with schizophrenia compared to controls (P = 0.02). No statistically significant difference was observed in the thalamus between two groups. Negative correlations were found between thalamic D_2/3 receptor binding and general psychopathological schizophrenic symptoms (r from ?0.78 to ?0.92). These observations implicate altered dopaminergic activity in the midbrain of schizophrenic patients.     

Allelic variation in the human prodynorphin gene promoter and schizophrenia

Experimental and clinical studies suggest an involvement of the opioid neuropeptide system in schizophrenia. In particular, the prodynorphin (PDYN), the precursor of the dynorphin opioid peptides, has been shown to play an important role in several aspects of human mental diseases. Recently, a functional polymorphism in the promoter of PDYN gene has been described. We studied the possible relationship between this polymorphism and schizophrenia and we found no significant difference in allelic and genotype distributions between schizophrenic patients and control subjects. However, we observed a significant interactive effect with the receptor 3 of dopamine gene (DRD3); in particular, the frequency of subjects carrying PDYN allele 3 being also homozygotes for DRD3 Gly allele (of Ser9Gly polymorphism) was significantly greater in patients than controls. We conclude that PDYN gene polymorphism alone does not alter the risk for schizophrenia but, by an epistatic interaction with the Gly allele of DRD3 gene, may contribute to the susceptibility to this disorder.     

Plasma 3-methoxy-4-hydroxyphenylglycol changes associated with clinical state and schizophrenic subtype

In a study of 14 drug-free schizophrenic patients and 22 healthy control subjects, the plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) level appeared to be altered by changes in clinical state. Repeated sampling in schizophrenic patients showed that plasma MHPG values were elevated in high-psychosis phases in comparison with metabolite levels at times of lower psychosis. There was a nonsignificant trend toward higher MHPG levels in paranoid schizophrenic patients in comparison with patients who had undifferentiated schizophrenia. Paranoid schizophrenic patients had significantly elevated plasma MHPG levels in comparison with previously studied healthy controls. These findings suggested that alterations in the plasma MHPG level may reflect psychosis-related changes in norepinephrine function in schizophrenia.     

Association of plasma IL-6 and soluble IL-6 receptor levels with the Asp358Ala polymorphism of the IL-6 receptor gene in schizophrenic patients

Recent studies indicate a role of excessive interleukin-6 (IL-6) signaling in the pathogenesis of schizophrenia. A previous study reported a significant association of schizophrenia with the IL-6 receptor (IL-6R) gene Asp358Ala polymorphism, which is known to regulate circulating IL-6 and soluble IL-6R (sIL-6R) levels in healthy subjects. To further examine the influence of the polymorphism in schizophrenic patients, we compared the plasma levels of IL-6 and sIL-6R between schizophrenic patients and healthy controls for each genotype of the Asp358Ala polymorphism. Asp358Ala genotyping and plasma IL-6 level measurements were performed in 104 patients with schizophrenia and 112 healthy controls. Of these participants, 53 schizophrenic patients and 49 controls were selected for the measurement of plasma sIL-6R levels. A two-way factorial analysis of covariance was performed with the transformed plasma levels as the dependent variable, diagnosis and genotype as independent variables, and sex and age as covariates. No significant diagnosis × genotype interaction was observed for IL-6 and sIL-6R levels. The Ala allele of Asp358Ala was significantly associated with higher levels of both IL-6 and sIL-6R. IL-6 levels were significantly elevated in schizophrenic patients compared to those in controls, whereas no significant difference in sIL-6R levels was observed between schizophrenic patients and controls. Our findings suggest that the presence of schizophrenia is associated with elevated IL-6 levels, whereas sIL-6R levels are mainly predetermined by the Asp358Ala genotype and are not associated with the disease status. Increased IL-6 levels without alterations in sIL-6R levels may result in excessive IL-6 signaling in schizophrenia.     

Changes in plasma glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical symptoms improve: results from the Juntendo University Schizophrenia Projects (JUSP)

Objectives

Based on the hypothesis of NMDA receptor hypofunction in schizophrenia, plasma glycine, l-serine, and d-serine levels have been studied, since they could serve as biological markers. However, changes over time in the levels of these amino acids in schizophrenic patients have not been investigated. To clarify the mean plasma glycine, l-serine, and d-serine levels in patients with schizophrenia, levels of these amino acids were compared between healthy controls and patients with schizophrenia. The plasma levels of these amino acids during the clinical course of schizophrenia were also compared.

Methods

Eighty-nine Japanese patients with schizophrenia and 50 age- and gender-matched healthy controls were studied. Plasma glycine, l-serine, and d-serine levels and their ratios were measured twice, during the acute stage and during the remission stage, using high-performance liquid chromatography.

Results

The admission plasma glycine, l-serine, and d-serine levels of schizophrenic patients were higher than those of healthy controls. There were no significant differences between drug-naïve patients and healthy controls in the admission levels of the plasma amino acids, but chronically medicated patients had higher admission plasma glycine and d-serine levels. Only the d-serine level and the d-/l-serine ratio were markedly significantly increased in schizophrenic patients from the time of admission to the time of discharge as their clinical symptoms improved. In addition, the increase in the plasma d-serine levels of drug-naïve patients was correlated with improvements in positive symptoms.

Conclusions

Plasma amino acid levels, especially d-serine levels, could be useful as a “therapeutic” or “clinical state” marker in patients with acute schizophrenia.     

Lack of association between VNTR polymorphism of dopamine transporter gene (SLC6A3) and schizophrenia in a Brazilian sample

A role of dopaminergic dysfunction has been postulated in the aetiology of schizophrenia. We hypothesized that variations in the dopamine transporter gene (SLC6A3) may be associated with schizophrenia. We conducted case-control and family based analysis on the polymorphic SLC6A3 variable number tandem repeat (VNTR) in a sample of 220 schizophrenic patients, 226 gender and ethnic matched controls, and 49 additional case-parent trios. No differences were found in allelic or genotypic distributions between cases and controls and no significant transmission distortions from heterozygous parents to schizophrenic offspring were detected. Thus, our results do not support an association of the SLC6A3 VNTR with schizophrenia in our sample.     

Association study of angiotensin-converting enzyme gene polymorphism with schizophrenia and polydipsia.

Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin system and can modulate dopamine turnover in the midbrain. Previous studies have revealed changes in the central ACE levels for schizophrenic patients, possibly related to the polydipsia commonly demonstrated for chronic schizophrenia. An insertion (I)/deletion (D) polymorphism of the ACE gene has been associated with ACE levels. Therefore, we elected to investigate the ACE I/D polymorphism for 124 schizophrenic patients and 117 control subjects. No significant differences for the genotype distribution or the allele frequency were revealed comparing controls and schizophrenic patients. The ACE genotypes were not associated with onset age or psychiatric symptoms for the schizophrenic cases. A modest association was revealed for this ACE polymorphism and polydipsia diagnosis for these patients. Using bearers of the D allele as baseline, the ratio for I/I homozygote was 2.31 (95% CI 0.95-5.65). This association needs further replication as it may have implications for the pathogenesis and the treatment of polydipsia for schizophrenic patients.     

Correlation between fine motor activity and striatal dopamine D2 receptor density in patients with schizophrenia and healthy controls

Striatal dopamine D2 receptor density is an important indicator of many neuropsychiatric disorders and also of motor activity. This study examined the relationship between a fine motor task (finger tapping test, FTT) and striatal D2 dopamine receptor density by examining 20 healthy volunteers and 20 schizophrenic patients. Striatal D2 receptor density was determined with single photon emission computed tomography using [123I]IBZM (iodo-benzamide). The correlation between the FTT score and striatal D2 receptor density was statistically significant not only in the patient group but also in healthy controls. The FTT scores and striatal D2 receptor density were lower in medicated patients than that in healthy controls. Compared with the Simpson-Angus Scale scores, the FTT scores were more strongly associated with striatal D2 receptor density. The use of neuroleptic medication seemed to influence the associations between FTT scores and striatal D2 receptor density in the patient group. The FTT scores and striatal D2 receptor density were age-sensitive in healthy controls. FTT may be a more sensitive tool for detecting neuroleptic-induced motor impairment in patients with schizophrenia. The sensitivity of the FTT to age and neuroleptic effects may be explained in part by a decline in dopamine D2 density.     

Plasma homovanillic acid levels and subtyping of schizophrenia

Plasma levels of homovanillic acid (HVA), a major metabolite of dopamine, were measured in a group of 24 schizophrenic inpatients before and during 6 weeks of haloperidol (HAL) treatment. Steady-state plasma HAL levels were measured in parallel with plasma HVA. Differential plasma HVA responses to HAL treatment were found between good and poor outcome patients. The two groups did not differ significantly in plasma HAL levels. Two hypothetical subtypes of schizophrenia are proposed.     

On betaH-Leu5-endorphin and schizophrenia.

A previously unknown peptide, betaH-Leu5-endorphin, has been reported in the dialysates of schizophrenic patients. Accordingly, hemofiltrates from two schizophrenic and two control patients were examined for the presence of betaH-Leu5-endorphin. The opioid peptides were detected by a radioreceptor assay after separation and identification by gel filtration and high-performance liquid chromatography. With a detection limit of 30 pmole/L of hemofiltrate, no betaH-Leu5-endorphin or Met5-endorphin was found in controls or in patients. Whatever the possible involvement of endorphins in schizophrenic behavior, they are not present at detectable levels in the hemofiltrates of two well-characterized schizophrenic patients, thereby casting doubt on a general relationship of Leu-endorphin and schizophrenia.     

Higher levels of serum copper in schizophrenic patients treated with depot neuroleptics

The findings of previous research on the status of trace elements in patients with schizophrenia have been controversial. We studied 62 outpatients with a DSM-IV diagnosis of schizophrenia, and compared them with sex- and age-matched healthy controls. Serum copper levels were significantly higher in schizophrenic patients (mean 117.4 microg/dl; S.D. 23.4) than in healthy controls (105.6+/-27.9). Those patients on treatment with depot neuroleptics had higher copper levels. Zinc levels did not differ between patients and healthy controls. Altered levels of trace elements in schizophrenic patients may be a consequence of antipsychotic treatment.     

Overproduction of neutrophil radical oxygen species correlates with negative symptoms in schizophrenic patients: parallel studies on neutrophil chemotaxis, superoxide production and bactericidal activity

Defective neutrophil function in schizophrenic patients has recently been reported. There are several lines of evidence to support the contribution of oxygen free radicals in schizophrenia, including increased lipid peroxidation, fatty acids and alterations in blood levels of anti-oxidant enzymes. Eighteen schizophrenic patients (DSM-IV) and 15 healthy controls were studied. Neutrophil chemotaxis, superoxide production and bactericidal activity were investigated. A statistically significant increase of superoxide anion release was found in schizophrenic patients compared with controls (mean+/-S.E.M., patients: 6.89+/-0.30 nmol O2-/10(6) cells/min, controls: 5.13+/-0.55 nmol O2-/10(6) cells/min). Moreover, a significant positive correlation between superoxide production and negative symptoms as assessed by the Positive and Negative Syndrome Scale was demonstrated. No differences were detected in chemotaxis and phagocytosis between schizophrenic patients and healthy controls. The present findings of a positive correlation between superoxide generation and negative symptoms in schizophrenic patients support the hypothesis that superoxide anion may participate in the pathogenesis of schizophrenia, as an excess of free radicals could contribute to the deterioration phase of the disease. Further studies are required to establish the role of oxidative stress in the ethiopathogenesis of schizophrenia.     

精神分裂症异质性及其中枢去甲肾上腺素功能初步研究

本文采用高压液相色谱（ＨＰＬＣ）对４２例阳性精神分裂症、２５例阴性精神分裂症及１０例健康对照组进行了脑脊液中去甲肾上腺素（ＮＥ）及其代谢产物３－甲基－４－羟基苯乙二醇（ＭＨＰＧ）的测定，同时引入ＮＥ相对代谢率（ＭＨＰＧ／ＮＥ）加以比较，研究结果提示：６７例精神分裂症脑脊液中ＭＨＰＧ明显低于正常对照组，４２例阳性精神分裂症脑脊液中ＮＥ及ＭＨＰＧ亦明显低于正常对照组，同时还发现，阴性精神分裂症相对代谢率ＭＨＰＧ／ＮＥ也明显低于阳性精神分裂症．本文针对以上结果、结合ＮＥ与多巴胺（ＤＡ）的相互关系进行了讨论，同时分析了精神分裂症的异质性问题。