Folate, homocysteine, and negative symptoms in schizophrenia

OBJECTIVE: Because glutamate carboxypeptidase II (GCPII) regulates both folate absorption and activation of N-methyl-d-aspartic acid receptors, the authors examined relationships between serum folate concentrations and clinical symptoms in schizophrenia patients. METHOD: For 91 outpatients with schizophrenia, clinical assessments were performed and serum folate, homocysteine, B(12), glycine, and serine concentrations were measured. RESULTS: Serum folate concentrations were significantly lower than in a representative sample from the Framingham Offspring Study. Folate concentration correlated inversely with the Scale for Assessment of Negative Symptoms total score and was lower in patients with the deficit syndrome than in nondeficit patients. Homocysteine concentration correlated with the severity of extrapyramidal symptoms. CONCLUSIONS: These findings could reflect several possible mechanisms, including low dietary intake of folate, low GCPII activity, cigarette smoking, and the involvement of folate in the synthesis of neurotransmitters. Additional studies are needed to clarify these findings.     

Negative symptoms of schizophrenia and compliance with medication

Poor compliance with medication has been reported in up to 40 percent of outpatients with schizophrenia. This study examines the relationship between compliance with depot neuroleptic medication and severity of negative symptoms of schizophrenia. Compliance with depot neuroleptic medication during the preceding year was calculated for 64 patients with a DSM-III-R diagnosis of schizophrenia. The severity of negative symptoms was assessed using the Scale for the Assessment of Negative Symptoms (SANS). Patients who complied poorly with medication had significantly greater severity of negative symptoms of schizophrenia, especially avolition, apathy, and alogia. Duration of illness and duration of prescribed medication were independently associated with compliance, but no other features were associated in the multiple regression model. These findings suggest that negative symptoms are one of the factors of importance in determining whether a patient will attend for depot neuroleptic medication.     

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.     

Relation between plasma homocysteine and Alzheimer's disease

OBJECTIVE: Several studies have shown that plasma total homocysteine (tHcy) concentration is elevated in Alzheimer's disease (AD). However, it is not clear whether elevated plasma tHcy is a primary cause or a consequence of AD. METHOD: To elucidate this question, we have analysed plasma homocysteine and its determinants in patients with early (EOAD)- and late-onset AD (LOAD) and compared the findings with those in vascular dementia (VaD) and age- and sex-matched control subjects. RESULTS: One of the main findings in the present study is that in EOAD there is no change in the levels of either plasma tHcy or its determinants compared with an age- and sex-matched control group. The fact that plasma tHcy concentration is normal in EOAD thus indicates that elevated plasma tHcy is not the primary cause of the disease. Another main finding is that patients with mixed dementia (AD and VaD) and patients with VaD showed significantly increased plasma tHcy concentration compared with controls and that plasma tHCy concentration in patients with LOAD and a history of additional cardiovascular disease was elevated compared both with AD patients without such a history and with the controls. Thus, there is an association between elevated plasma tHcy and vascular disease. A third main finding is that patients with AD who were followed up for several years showed a clinical deterioration of dementia and an elevation of plasma tHcy concentration. This finding likewise supports the notion that elevated plasma tHcy is not the primary cause of the disease. CONCLUSIONS: The findings suggest that elevated plasma tHcy is not the primary cause of the disease. Furthermore, the findings indicate that elevated plasma tHcy might be a reflection of concomitant vascular disease in AD patients.     

Depressive symptoms may explain elevated plasma levels of homocysteine in females with eating disorders

Elevated plasma homocysteine levels have been found in different psychiatric disorders, including major depression and eating disorders. The aim of the present study was to evaluate whether presence of depression or depressive symptoms is associated with elevated homocysteine levels in patients with eating disorders. Total plasma homocysteine levels were assessed in 44 females with anorexia nervosa (n = 21) or bulimia nervosa (n = 23). Comorbid major depressive disorder (MDD) was diagnosed according to DSM-IV criteria using a semi-structured interview (SCID-I). Furthermore, depressive symptoms were assessed using Beck's depression inventory (BDI). Presence of MDD was not associated with elevated homocysteine levels (t-test: T = 0.42; df = 42; P = 0.68). However, self-rated presence of clinically relevant depressive symptoms (BDI score18) was associated with elevated homocysteine (T = -2.8; df = 42; P = 0.008). Presence of depressive symptoms may explain elevated homocysteine levels previously reported in patients with eating disorders or vice versa. Longitudinal studies are needed to unravel this hen or egg problem.     

Relation of neurological soft signs to psychiatric symptoms in schizophrenia

INTRODUCTION: Although several studies have identified abnormal rates of neurological soft signs (NSS) as a manifestation of CNS dysfunction in schizophrenia, differences in sample populations have contributed to a discrepancy in empirical findings. Furthermore, little is known about the potential of NSS to predict a clinical response to antipsychotic medications. The present study tests the associations between NSS and schizophrenia symptomatology and examines NSS as a potential marker for predicting treatment response. METHODS: Nineteen unmedicated male schizophrenia patients were treated prospectively with haloperidol for six weeks. The subjects were assessed for pre and post-treatment NSS and schizophrenia symptomatology (Brief Psychiatric Rating Scale, BPRS). RESULTS: NSS at baseline were significantly associated with baseline symptoms on the Positive, Negative, and Psychological Discomfort BPRS subscales. NSS showed a strong trend toward improvement during six weeks of a prospective haloperidol trial. Hierarchical linear regression analyses indicated that more severe baseline NSS predicted poorer response to haloperidol treatment as measured by post-treatment BPRS Total subscale scores. DISCUSSION: NSS at untreated baseline are associated with baseline symptom severity, and elevated NSS are predictive of a smaller degree of improvement in symptoms after antipsychotic treatment. These findings are consistent with the hypothesis that NSS are linked to the neuropathology that underlies schizophrenia symptomatology and course.     

Behavioural and psychological symptoms of Alzheimer type dementia are not correlated with plasma homocysteine concentration

BACKGROUND/AIMS: Vitamin B12 and folate deficiencies have been associated with cognitive impairment and various psychiatric symptoms but not specifically with behavioural and psychological symptoms of dementia (BPSD). A limitation of previous studies in dementia was lack of concurrent homocysteine measurement especially as it may provide a better indicator of tissue activities of these vitamins. This study was designed to clarify whether a relationship exists between plasma homocysteine concentration and BPSD. METHODS: Plasma homocysteine, serum vitamin B12 and folate were measured in 23 Alzheimer's disease (AD) patients with BPSD and 27 AD patients without BPSD as determined through the use of the Neuropsychiatric Inventory (NPI). Blood levels of measured substances were also correlated with individual NPI scores and with cumulative NPI scores for different cluster of symptoms. RESULTS: There was no significant difference (p = 0.956) in the mean plasma homocysteine levels between AD patients with BPSD (17.48 micromol/l) and AD patients without BPSD (17.34 micromol/l). Similarly, there was no significant difference between the two groups in the mean serum B12 (382.61 and 391.60 pg/ml, respectively) and folate (7.95 and 10.02 ng/ml, respectively). Mean levels for both vitamins were well within the laboratory reference range. Neither individual nor cluster NPI scores correlated significantly with plasma homocysteine. CONCLUSION: This study shows for the first time that BPSD are not associated with hyperhomocysteinaemia in Alzheimer dementia. Although previous studies have identified homocysteine as an independent risk factor in AD, the results reported here do not lend weight to an aetiological role for homocysteine specifically in BPSD.     

缺血性脑卒中病因学分型与血浆同型半胱氨酸水平的关系

目的研究缺血性脑卒中病因学分型与血浆同型半胱氨酸水平的关系。方法参照TOAST分型标准将2011-08—2013-12我院收治的大动脉粥样硬化型脑卒中(LAA)、小动脉闭塞型脑卒中(SAO)、心源性脑卒中(CE)、其他少见病因型脑卒中(SOE)、不明原因型脑卒中(SUE)患者纳入观察组,将同期在我院接受体检的50例健康者纳入对照组,比较2组患者血清同型半胱氨酸的水平及异常例数。结果 (1)观察组患者的血清同型半胱氨酸水平高于对照组;(2)LAA组的同型半胱氨酸水平及同型半胱氨酸异常例数高于其余4组,差异有统计学意义(P0.05);且SAO组、CE组、SOE组、SUE组之间同型半胱氨酸水平及同型半胱氨酸异常例数无显著差异。结论缺血性脑卒中患者的血浆同型半胱氨酸水平异常升高,且以大动脉粥样硬化型脑卒中患者的升高最为明显。     

Premorbid functioning in schizophrenia: relation to baseline symptoms, treatment response, and medication side effects

Impaired premorbid functioning prior to the onset of acute psychosis has frequently been noted in schizophrenia. This study examined retrospectively the premorbid status of patients in their first episode of psychosis in order to determine relationships with baseline symptoms, treatment response, and medication side effects. One hundred eleven schizophrenic and schizoaffective patients participating in a large prospective study of first episode schizophrenia were evaluated with the Premorbid Adjustment Scale (PAS). Premorbid functioning in males became progressively worse over time. Deficit state patients exhibited worse premorbid functioning. A third of patients exhibited sustained poor premorbid functioning. At various developmental stages, lower "sociability and withdrawal" scores correlated with increased time to treatment response, more severe negative symptoms, increased drug-induced parkinsonism, and deterioration of premorbid functioning. Various mean PAS scores predicted susceptibility to tardive dyskinesia. Our findings suggest that prior to acute psychosis onset there are certain behavioral precursors reflected in premorbid functioning that may predict subsequent illness manifestations. Measures of premorbid functioning indicate that disease pathogenesis is manifest, albeit more subtly, prior to presentation of first psychotic symptoms.     

Correlation of plasma neurosteroid levels to the severity of negative symptoms in male patients with schizophrenia

The authors examined the correlations among plasma levels of ACTH, cortisol, progesterone, testosterone, and dehydroepiandrosterone sulfate (DHEA-S) and their relationship with the scales for assessment of negative symptoms (SANS) in the male schizophrenic patients with negative symptoms. The subjects were 28 male schizophrenic patients categorized as with low negative symptoms (N = 14) and with moderate negative symptoms (N = 14) and 13 healthy subjects. Plasma levels of neurosteroids were measured by radioimmunoassay. Significant correlations of SANS scores with plasma levels of ACTH, cortisol and testosterone, but not progesterone and DHEA-S, were found in the male schizophrenic patients. Furthermore, plasma levels of ACTH, cortisol, and testosterone in the male schizophrenic patients with moderate negative symptoms, but not low negative symptoms, were significantly different from normal controls. The measurements of plasma neurosteroid levels could be a useful biological marker for the severity of negative symptoms in schizophrenic patients.     

Elevated plasma levels of homocysteine in dystonia

OBJECTIVE: Several case reports with dystonia and homocysteinuria suggest a putative pathogenetic importance of homocysteine for the development of dystonia. We investigated relations between plasma homocysteine, age, severity and duration of primary idiopathic torsion dystonia. SUBJECTS AND METHODS: We measured homocysteine levels in blood samples drawn from 24 subjects with dystonia and controls. RESULTS: Patients with dystonia (19.3 +/- 8.5, range 8.4-37 micromol/l) showed significantly (P= 0.008, t-test) increased levels of total homocysteine compared with age- and sex-matched controls (13.9 +/- 4.2, range 5.8-24.5 micromol/l). No significant influence of age and duration of dystonia appeared, but we found a significant trend for an association between severity of dystonia and homocysteine (P = 0.046, R = 0.41). CONCLUSIONS: Our study supports previous reports on subjects with dystonia with homocysteinuria. Neurotoxic effects and N-methyl-D-aspartate agonistic properties of homocysteine may hypothetically contribute to onset and severity of dystonia.     

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.     

认知功能障碍与血清白细胞介素2的关系

目的 :探讨精神分裂症患者认知功能损害与精神症状及血清白细胞介素 2 (IL 2 )水平的关系。　方法 :在 5 7例未服抗精神病药的患者中 ,采用数字划销测验 (CT)、韦氏成人记忆量表 (WMS RC)、威斯康星卡片分类测验 (WCST)测试认知功能 ,用阳性症状与阴性症状量表 (PANSS)评定精神症状 ,同时测定血清IL 2浓度 ,分析其间的关系 ;并将记忆商数 (MQ)≤ 85者与MQ >85者比较血清IL 2水平及精神症状。　结果 :阴性症状分与各项认知测验的成绩均呈显著相关 ,部分认知损害还与一般病理性症状分相关 ,阳性症状分与所有认知测验的成绩均无相关性 ;血清IL 2水平与注意力、记忆力测验成绩呈显著负相关 ,与WCST测验成绩不相关 ;MQ≤ 85者与MQ >85者比较血清IL 2水平及阴性症状显著增高。　结论 :精神分裂症认知损害与阴性症状相关 ,与阳性症状不相关 ;血清IL 2水平可能与精神分裂症的注意力、记忆力损害相联系     

精神分裂症血浆硫化氢、同型半胱氨酸、叶酸及维生素B6水平研究

目的:探讨精神分裂症患者血浆硫化氢(H2S)、同型半胱氨酸(Hcy)、叶酸(FA)和维生素B6(VitB6)水平的变化及其相关性.方法:检测66例精神分裂症患者和50名健康对照者的血浆H2S、Hcy、FA及VitB6水平.精神分裂症患者血浆H2S水平与Hcy、FA和VitB6水平的相关性用直线相关分析.结果:与正常对照...     

Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia.

OBJECTIVE: The dorsolateral prefrontal cortex has been implicated in both working memory and the pathophysiology of schizophrenia. A relationship among dorsolateral prefrontal cortex activity, working memory dysfunction, and symptoms in schizophrenia has not been firmly established, partly because of generalized cognitive impairments in patients and task complexity. Using tasks that parametrically manipulated working memory load, the authors tested three hypotheses: 1) patients with schizophrenia differ in prefrontal activity only when behavioral performance differentiates them from healthy comparison subjects, 2) dorsolateral prefrontal cortex dysfunction is associated with poorer task performance, and 3) dorsolateral prefrontal cortex dysfunction is associated with cognitive disorganization but not negative or positive symptoms. METHOD: Seventeen conventionally medicated patients with schizophrenia and 16 healthy comparison subjects underwent functional magnetic resonance imaging while performing multiple levels of the "n-back" sequential-letter working memory task. RESULTS: Patients with schizophrenia showed a deficit in physiological activation of the right dorsolateral prefrontal cortex (Brodmann's area 46/9) in the context of normal task-dependent activity in other regions, but only under the condition that distinguished them from comparison subjects on task performance. Patients with greater dorsolateral prefrontal cortex dysfunction performed more poorly. Dorsolateral prefrontal cortex dysfunction was selectively associated with disorganization symptoms. CONCLUSIONS: These results are consistent with the hypotheses that working memory dysfunction in patients with schizophrenia is caused by a disturbance of the dorsolateral prefrontal cortex and that this disturbance is selectively associated with cognitive disorganization. Further, the pattern of behavioral performance suggests that dorsolateral prefrontal cortex dysfunction does not reflect a deficit in the maintenance of stimulus representations per se but points to deficits in more associative components of working memory.     

Obsessive-compulsive symptoms in schizophrenia: associated clinical features, cognitive function and medication status

OBJECTIVE: To determine the prevalence and clinical significance of obsessive-compulsive (OC) symptoms among a group of stable outpatients with schizophrenia. METHODS: We studied 118 patients with schizophrenia from an urban clinic, characterized using clinical symptoms scales, including the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and neuropsychological testing. We categorized patients into three groups according to severity of OC symptoms and used multivariate linear regression and chi-square tests to compare groups on variables of interest. RESULTS: Only 10 patients (8.8%) had Y-BOCS scores greater than 16, a standard criterion for OCD studies. The patient group with the most OC symptoms (Y-BOCS scores >11) scored higher on the Hamilton Depression Scale, the positive symptoms subscale of the Positive and Negative Syndromes Scale (PANSS) and its delusions item, but not on any of the neuropsychological tests compared to the other two groups. Patients with most severe compulsive symptoms (but not OC symptoms together, or obsessions alone) were more likely to be treated with olanzapine or clozapine, atypical antipsychotic medications previously reported to induce or worsen OC symptoms. CONCLUSIONS: Our results confirm previous findings that patients with schizophrenia and comorbid OC symptoms have more positive symptoms but not the suggestion that such patients are more cognitively impaired than their counterparts without OC symptoms. We suggest possible explanations for discrepancies in the literature, including differences in patient sampling and definition of comorbid OC symptoms. Finally, our data suggest that olanzapine and clozapine may produce or worsen compulsions in some patients; prospective studies need to address this possibility.