Reduced D-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients

Several lines of evidence suggest that D-serine, an endogenous agonist of the glycine site on the NMDA receptors, might play a role in the pathophysiology of schizophrenia. The purpose of this study was to determine whether levels of D- and L-serine or D-serine ratio (D-serine/total serine) in cerebrospinal fluid (CSF) were altered in first episode and drug-naive schizophrenic patients. The CSF levels of D- and L-serine in 25 male first episode and drug-naive schizophrenic patients and 17 age-matched male healthy subjects were measured using a column-switching high performance liquid chromatography system. The percentage of D-serine in the total serine of patients was significantly (z = -2.01, p = 0.044) lower than that of controls. This study suggests that synthetic or metabolic pathways of D-serine may be abnormal in the brain of drug-naive schizophrenic patients, supporting the NMDA receptor dysfunction hypothesis of schizophrenia.     

Possible role of D-serine in the pathophysiology of Alzheimer's disease

Several lines of evidence suggest that D-serine may function as an endogenous agonist of the glycine site on the N-methyl-D-aspartate (NMDA) receptor that has been implicated in the pathophysiology of Alzheimer's disease (AD). The purpose of the study was to determine whether serum levels of D- and L-serine in patients with AD are altered as compared with normal controls. Serum levels of D- and L-serine in patients of AD and age- and gender-matched normal controls were determined using a high-performance liquid chromatography (HPLC). Serum levels of D-serine in the patients with AD were slightly (z=-1.77, p=0.078) lower than those of normal controls. In contrast, serum levels of L-serine in the patients were slightly (z=-1.73, p=0.083) higher than those of controls. In addition, the percentage (%) of D-serine in the total (L+D) serine in the patients was significantly (z=-2.36, p=0.018) lower than that of controls. The present study suggests that the reduced activity of serine racemase, an enzyme catalyzing the formation of D-serine from L-serine may play a role in the pathophysiology of AD.     

A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia

Clinical trials demonstrated that D-serine administration improves schizophrenia symptoms, raising the possibility that altered levels of endogenous D-serine may contribute to the N-methyl D-aspartate receptor hypofunction thought to play a role in the disease. We hypothesized that cerebro-spinal fluid (CSF) D-serine levels are decreased in the patients due to reduced synthesis and/or increased degradation in brain. We now monitored amino acid levels in CSF from 12 schizophrenia patients vs. 12 controls and in postmortem parietal-cortex from 15 control subjects and 15 each of schizophrenia, major-depression and bipolar patients. In addition, we monitored postmortem brain serine racemase and D-amino acid oxidase protein levels by Western-blot analysis. We found a 25% decrease in D-serine levels and D/L-serine ratio in CSF of schizophrenia patients, while parietal-cortex D-serine was unaltered. Levels of L-serine, L-glutamine and L-glutamate were unaffected. Frontal-cortex (39%) and hippocampal (21%) serine racemase protein levels and hippocampal serine racemase/D-amino acid oxidase ratio (34%) were reduced. Hippocampal D-amino-acid-oxidase protein levels significantly correlated with duration of illness (r=0.6, p=0.019) but not age. D-amino acid oxidase levels in patients with DOI>20 years were 77% significantly higher than in the other patients and controls. Our results suggest that reduced brain serine racemase and elevated D-amino acid oxidase protein levels may contribute to the lower CSF D-serine levels in schizophrenia.     

A genetic variant of the serine racemase gene is associated with schizophrenia.

BACKGROUND: Serine racemase (SRR) is a brain-enriched enzyme that converts L-serine to D-serine, which acts as an endogenous ligand of N-methyl D-aspartate (NMDA) receptors. Dysfunction of SRR may reduce the function of NMDA receptors and susceptibility to schizophrenia. METHODS: We genotyped three single-nucleotide polymorphisms (SNPs) of the 5' region of the SRR gene in 525 patients with schizophrenia and 524 healthy controls. Effects of SNPs on the promoter activity and on serum levels of total and D-serine were examined. RESULTS: We found a significant excess of the IVS1a+465C allele of the SRR gene in schizophrenia, especially in the paranoid subtype (p = .0028). A reporter assay showed that the IVS1a+465C allele had 60% lower promoter activity than did the IVS1a+465G allele. CONCLUSIONS: The IVS1a+465C allele of the SRR gene, which reduces expression of the gene, is a risk factor for schizophrenia, especially the paranoid subtype.     

Amino acid patterns in schizophrenia: some new findings

Blood concentrations of various amino acids were measured in schizophrenic patients and control subjects. Significantly higher blood concentrations of glycine, glutamate, and serine were found in the schizophrenic patients. Glycine was abnormally elevated in subjects with paranoid or undifferentiated schizophrenia, but not in disorganized patients. Since glutamate, glycine, and serine play a complex role in the regulation of N-methyl-D-aspartate (NMDA) receptors, which are important in the control of normal cognitive processes, we hypothesized that the elevated levels of these amino acids might disrupt the normal functioning of NMDA receptors and might be involved in the pathophysiology of schizophrenia.     

Investigation of serum BDNF levels in drug-naive patients with schizophrenia

The role of brain-derived neurotrophic factor (BDNF) is to promote and modulate the neuronal responses across neurotransmitter systems in the brain. Therefore, abnormal BDNF signaling may be associated with the pathophysiology of schizophrenia. Decreased BDNF levels in the brain and the serum of patients with psychotic disorders have been reported. In the present study, we assessed serum BDNF levels in a group of 14 drug-naive first-episode patients with schizophrenia (FEP), compared to 15 healthy controls. The serum BDNF levels in the sample of FEP patients was significantly reduced compared to normal controls (23.92+/-5.99 ng/ml vs. 30.0+/-8.43 ng/ml, F=5.01, df=1, p=.034). Negative correlations were shown between serum BDNF levels of the patients and the PANSS Positive and Negative subscale scores. Our findings indicate that BDNF levels at the onset of schizophrenia may reflect associated pathophysiological processes as well as the severity of positive and negative psychotic symptoms.     

N-methyl-D-aspartate receptor in working memory impairments in schizophrenia: event-related potential study of late stage of working memory process

Working memory (WM) deficit in schizophrenic patients has been well established. Still, underlying biological substrate of the impairment is not clear. Among neurotransmitter hypotheses of schizophrenia, N-methyl-D-aspartate (NMDA) receptor model is mostly supported, considering that NMDA receptor antagonist can elicit both psychosis and cognitive impairment observed in schizophrenic patients. In current study, to test the neuropsychological and the electrophysiological effects of NMDA receptor in WM, event-related potentials (ERPs) of Sternberg's short-term memory scanning task (SMST) were analyzed in 10 healthy subjects under intravenous administration of a subanesthetic dose of ketamine (0.65 mg/kg/h) or placebo (normal saline). Late positive component (LPC) of ERP was hypothesized to reflect later stage of WM. Brief Psychiatric Rating Scale score was significantly increased (t=-5.75, df=9, P<.001) and correct response rate was significantly decreased (t=2.21, df=9, P=.054) after ketamine administration. Neither reaction time nor LPC latency, which reflect memory scanning time, was changed. Amplitude of LPC was significantly reduced after ketamine administration (z=-2.31, number of observations=120, P=.021). In conclusion, NMDA receptor antagonist administration elicited WM deficit both in behavioral and electrophysiological level. Electrophysiological component reflecting later stage of WM was impaired by NMDA antagonist.     

Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study

CONTEXT: Agents that enhance N-methyl-D-aspartate (NMDA) function through the glycine modulatory site (D-serine, glycine, or D-cycloserine) or through glycine transporter 1 (sarcosine) improve the symptoms of patients with stable chronic schizophrenia. OBJECTIVE: To determine whether NMDA-glycine site agonists or glycine transporter-1 inhibitors have better efficacy and whether NMDA receptor-enhancing agents have beneficial effects for acute exacerbation of schizophrenia. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Inpatient units of 2 major medical centers in Taiwan.Patients Sixty-five schizophrenic inpatients with acute exacerbation. INTERVENTIONS: Six weeks of treatment with sarcosine (2 g/d), D-serine (2 g/d), or placebo and concomitant optimal risperidone therapy. MAIN OUTCOME MEASURES: Positive and Negative Syndrome Scale (PANSS) and Scale for the Assessment of Negative Symptoms (SANS) (20 and 17 items) total scores. RESULTS: The sarcosine group revealed more reductions in PANSS total scores than the placebo (P = .04) and D-serine (P<.001) groups. Sarcosine adjunctive treatment was also superior to placebo in reducing SANS-20 (P = .007) and SANS-17 (P = .003) scores and to D-serine in decreasing SANS-20 (P = .006) and SANS-17 (P = .002) scores. The PANSS-general, PANSS-cognitive, and PANSS-depressive symptoms scores and SANS-alogia and SANS-blunted affect scores improved significantly more in sarcosine-cotreated patients than in risperidone monotherapy patients (P< or =.02 for all). Sarcosine adjunctive therapy also surpassed D-serine in terms of PANSS-general, PANSS-positive, PANSS-negative, and PANSS-depressive symptoms scores (P< or =.04 for all). D-serine and risperidone cotreatment did not differ significantly from risperidone monotherapy in all efficacy domains. CONCLUSIONS: This first short-term treatment study on NMDA receptor-enhancing agents suggests that sarcosine, superior to D-serine, can benefit not only patients with long-term stable disease but also acutely ill persons with schizophrenia. This finding indicates that a glycine transporter 1 inhibitor may be more efficacious than NMDA-glycine site agonists for adjuvant treatment of schizophrenia, at least during the acute phase. Further studies are needed.     

Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in schizophrenia: a study of patients treated with haloperidol or clozapine

There is strong evidence that oxygen free radicals may play an important role in the pathophysiology of schizophrenia. Impaired antioxidant defense and increased lipid peroxidation have been previously reported in drug-na?ve, first episode and chronically medicated schizophrenic patients using typical neuroleptics. We measured serum SOD and TBARS in two groups of chronic medicated DSM-IV schizophrenic patients, under haloperidol (n = 10) or clozapine (n = 7) and a group of healthy controls (n = 15). Serum SOD and TBARS were significantly higher (p = 0.001) in schizophrenic patients (7.1 +/- 3.0 and 3.8 +/- 0.8) than in controls (4.0 +/- 1.6 and 2.5 +/- 0.7). Among patients, serum TBARS was significantly higher (p = 0.008) in those under clozapine (4.4 +/- 0.7) than in those under haloperidol treatment (3.4 +/- 0.7). For SOD levels the difference between groups was not found. It is reasonable to argue that the difference found in TBARS levels might be due to the course of the disease, instead of medication. Further investigation on the role of oxidative tonus and lipid peroxidation in different schizophrenia subtypes and different outcome patterns in this disorder is warranted. Additionally it could also address questions concerning a possible oxidant/antioxidant imbalance in schizophrenia.     

Associations of serum brain-derived neurotrophic factor with cognitive impairments and negative symptoms in schizophrenia

Brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. The aim of this study was to examine the associations of serum BDNF levels with the cognition and clinical characteristics in patients with schizophrenia. Sixty-three patients with schizophrenia and 52 age- and sex-matched healthy controls were examined with neuropsychological tests. Serum BDNF levels were determined by enzyme-linked immunosorbent assay (ELISA). There were no significant differences in serum BDNF levels between normal controls and patients with schizophrenia. Serum BDNF levels of normal controls showed negative correlations with verbal working memory, but this was not the case with schizophrenic patients. Meanwhile, serum BDNF levels of schizophrenic patients showed positive correlations with the scores of the Scale for the Assessment of Negative Symptoms (SANS) and the Information subtest scores of Wechsler Adult Intelligence Scale Revised (WAIS-R). Serum BDNF levels are related with the impairment of verbal working memory and negative symptoms in patients with schizophrenia.     

D-serine added to clozapine for the treatment of schizophrenia.

OBJECTIVE: D-Serine is a full agonist at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Previous administration of D-serine to schizophrenic patients taking nonclozapine antipsychotics improved positive, negative, and cognitive symptoms, whereas the partial agonist D-cycloserine improved negative symptoms of patients taking conventional antipsychotics but worsened symptoms in clozapine-treated patients. To study the difference between full and partial agonists at the NMDA receptor glycine site, the clinical effects of adding D-serine to clozapine were assessed. METHOD: In a 6-week double-blind trial, 20 schizophrenic patients received placebo or D-serine (30 mg/kg per day) in addition to clozapine. Clinical efficacy, side effects, and serum levels of D-serine were determined every other week. RESULTS: The patients exhibited no improvement with D-serine, nor did their symptoms worsen, as previously reported with D-cycloserine. CONCLUSIONS: The results suggest either that clozapine may have an agonistic effect on the NMDA system or that clozapine-treated patients do not respond to D-serine.     

Increased serum levels of glutamate in adult patients with autism

BACKGROUND: Precise mechanisms underlying the pathophysiology of autism are currently unknown. Given the major role of glutamate in brain development, we have hypothesized that glutamatergic neurotransmission plays a role in the pathophysiology of autism. In this study, we studied whether amino acids (glutamate, glutamine, glycine, D-serine, and L-serine) related to glutamatergic neurotransmission are altered in serum of adult patients with autism. METHODS: We measured serum levels of amino acids in 18 male adult patients with autism and age-matched 19 male healthy subjects using high-performance liquid chromatography. RESULTS: Serum levels (mean = 89.2 microM, S.D. = 21.5) of glutamate in the patients with autism were significantly (t = -4.48, df = 35, p < 0.001) higher than those (mean = 61.1 microM, S.D. = 16.5) of normal controls. In contrast, serum levels of other amino acids (glutamine, glycine, d-serine, l-serine) in the patients with autism did not differ from those of normal controls. There was a positive correlation (r = 0.523, p = 0.026) between serum glutamate levels and Autism Diagnostic Interview-Revised (ADI-R) social scores in patients. CONCLUSIONS: The present study suggests that an abnormality in glutamatergic neurotransmission may play a role in the pathophysiology of autism.     

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.     

SNAP-25 reduction in the hippocampus of patients with schizophrenia

In this study, the authors sought to replicate the findings of reduced synaptosomal associated protein 25 kDa (SNAP-25) immunoreactivity in the hippocampus of patients with schizophrenia. The authors also measured N-methyl-D-aspartate (NMDA) receptor 1 (NR1) receptor subunit to determine if glutamatergic synapses were involved with the loss of SNAP-25. We found 49% less SNAP-25 immunointensity in the schizophrenic group (n=7) compared to the control (n=8) or bipolar groups (n=4) (P=.004). There was no change in NMDA NR1 levels in the three groups. The authors confirm the previous report of less SNAP-25 immunoreactivity in the hippocampus using a different cohort of patients with schizophrenia. It also appears that NMDA NR1 was unchanged, indicating that the overall level of NMDA glutamatergic synapses in hippocampus is normal. These data add to evidence suggesting that in schizophrenia the molecular pathology of the hippocampus involves presynaptic components.     

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.     

Different serine and glycine metabolism in patients with schizophrenia receiving clozapine

Dysfunction of the N-methyl-d-aspartate receptor, which is modulated by excitatory amino acids (EAA), is involved in the pathophysiology of schizophrenia. The effects of antipsychotics on EAA metabolism are uncertain. Positive clinical effects of treatment with antipsychotics were not always associated with changes in EAA serum levels in patients with schizophrenia in clinical trials. To examine EAA serum levels in relation to the intensity of psychotic symptoms and the type of medication received we compared these variables among patients with schizophrenia (n = 49) treated with first (FGA) or second (SGA) generation antipsychotics or clozapine. Glutamate, aspartate, glycine, total serine and d-serine serum levels were measured by High Performance Liquid Chromatography. The Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS) were used to assess symptoms of schizophrenia. Lower average levels of glycine and total serine were found in the serum of patients receiving clozapine when compared to the groups of patients treated with FGA or SGA. There were no differences in serum glutamate, aspartate or d-serine levels or in the intensity of schizophrenic symptoms assessed by PANSS or SANS among the groups of patients treated with FGA or SGA or clozapine. Lower glycine and total serine serum levels could be caused by the particular characteristics of the population of patients receiving clozapine rather than as an effect of the clozapine. The results suggest selective deficiency of l-serine synthesis in the patients with resistance to non-clozapine treatment. It might be an unique biochemical and pathophysiological characteristic of the treatment-resistance in schizophrenia.     

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.     

P300 and genetic risk for schizophrenia

BACKGROUND: We assessed the suitability of event-related potential frontal and temporoparietal P300 changes as intermediate phenotypes in genetic studies of schizophrenia. We applied a principal component analysis approach based on the notion that P300 abnormalities in siblings of schizophrenic patients may involve a widespread network of relatively weak cortical generators and because an earlier, smaller study that used a topographic analysis of covariance model did not show that localized P300 changes predict risk for schizophrenia. METHODS: P300 changes in 66 schizophrenic patients, 115 healthy siblings of schizophrenic patients, and 89 unrelated controls were studied during a standard auditory oddball paradigm. Principal components were calculated across electrodes, revealing frontal and temporoparietal components for latency and amplitude, respectively. For the frontal and temporoparietal P300 amplitude and latency components, the intraclass correlations (ICCs) between sib-pairs (pairs of unaffected siblings and schizophrenic index patients) and the relative risk ratios (lambda) were determined. RESULTS: Compared with controls, schizophrenic patients and their unaffected siblings showed significant reductions in the temporoparietal P300 amplitude component. Both groups were also characterized by a significantly higher frontal P300 amplitude component. Significant ICCs and increased relative risk ratios were found for the frontal (ICCU = 0.18; P =.04; lambda = 3.4) and temporoparietal (ICCU = 0.24; P =.01; lambda = 1.7) P300 amplitude components. CONCLUSIONS: Temporoparietal P300 amplitude reduction and frontal P300 amplitude increase seem to be quantitative phenotypes associated with increased risk of schizophrenia. Both measures may be useful for increasing the statistical power of genetic studies of schizophrenia.     

Effect of the intracerebroventricular and systemic administration of L-serine on the concentrations of D- and L-serine in several brain areas and periphery of rat

To gain further insight into the metabolic mechanism of endogenous D-serine, the effect of the intracerebroventricular and intraperitoneal administration of L-serine on the concentrations of D- and L-serine in several brain areas and periphery was investigated. The intracerebroventricular injection of L-serine caused a rapid and marked increase in the L-serine levels in almost all brain regions of adult rats. This administration also produced a gradual increase in the D-serine levels in the forebrain, whereas a slight but significant elevation of D-serine was found in the cerebellum and pons-medulla. The intraperitoneal administration of L-serine caused a marked increase in the L-serine levels in all brain regions of both infant and adult rats. The treatment induced a significant augmentation of the D-serine levels in all brain regions of infant rats with higher concentrations in the cerebellum and cortex, whereas no significant change was observed in the cerebellum and pons-medulla of adult rats. These in vivo observation, together with the fact that immunohistochemical studies have indicated that both D-serine and serine racemase are highly concentrated in Bergmann glia of developing cerebellum, suggest that D-serine can be synthesized not only in the forebrain but also in the hindbrain by serine racemase. Furthermore, because the drastic decline in the cerebellar D-serine level coincides well with a dramatic increase in the cerebellar D-amino acid oxidase during early postnatal development, synthesized D-serine may be metabolized by D-amino acid oxidase in the hindbrain of adult rats.