Homocysteine in Schizophrenia: Independent Pathogenetic Factor with Prooxidant Activity or Integral Marker of Other Biochemical Disturbances?

BackgroundMultiple system atrophy (MSA) is a neurodegenerative disease, and its pathological hallmark is the accumulation of α-synuclein proteins. Homocysteine (Hcy) is an intermediate amino acid generated during the metabolism of methionine. Hcy may contribute to the pathogenesis of neurodegenerative disorders. Vitamin B12 and folate are cofactors necessary for the methylation of homocysteine.MethodsThis study compared the levels of serum Hcy, vitamin B12 and folate in patients with MSA with those in healthy people to reveal the possible association between MSA and plasma levels of Hcy, vitamin B12 and folate. We enrolled 161 patients with MSA and 161 healthy people in this study. The association between MSA and the levels of Hcy, vitamin B12 and folate were analyzed using binary logistic regression.ResultsThe mean level of Hcy in patients with MSA was significantly higher than that in healthy controls (16.23 ± 8.09 umol/l vs 14.04 ± 4.25 umol/l, p < 0.05). After adjusting for age, sex and medical history, the odds ratio for Hcy was 1.07 (95% CI = 1.01–1.13, p < 0.05) for patients with MSA. Vitamin B12 and folate levels were not significantly different between patients with MSA and controls.ConclusionOur data suggest that higher levels of Hcy may be associated with an increased risk for MSA.

This study aims to compare the positive and negative symptoms of schizophrenia in patients who had psychotic symptoms more than one month after discontinuation of methamphetamine abuse. These factors were analyzed by the positive and negative syndrome scale (PANSS) questionnaire. Sixty participants were selected from patients referred to Iran Psychiatric Hospital with psychotic symptoms (delusions or hallucinations, disorganized behavior, and speech). The control group was 30 patients with schizophrenia based on a semi-structured interview according to DSMIV-TR (SCID). Thirty patients with a prolonged methamphetamine-induced psychotic disorder were also placed in the case group. For both groups of patients, questionnaires of PANSS, Brief Psychiatric Rating Scale (BPRS), and Global Assessment Of Functioning (GAF) were filled out after obtaining the companions' consent. The scale scores were compared between groups. We used the Mann-Whitney and the Chi-square test to evaluate the mean values of PANSS, BPRS, and GAF scores between the two groups. here was an insignificant difference in positive and general pathology scores between the two groups, but the total score of negative symptoms in the schizophrenia group was significantly higher than in the group of prolonged methamphetamine psychotic disorders (P=0.034). Average scores of uncooperativeness (0.008), difficulty in abstract thinking (0.004), motor retardation (0.002), unusual thought content (0.001), and hostility (0.011) in the schizophrenia group were significantly higher than those in the prolonged methamphetamine psychosis. The results showed that most of the disturbances in patients with schizophrenia might be more influenced by the expression of cognitive disabilities than those with methamphetamine psychosis. The difference in negative symptom scores suggests that schizophrenia and prolonged methamphetamine psychotic disorder can be two different disorders. General and positive symptoms scores don't have significant differences.Negative symptoms are much more in schizophrenia.Uncooperativeness, unusual thought content and, motor retardation have more scores in schizophrenia. In clinical practice, Schizophrenia and prolonged methamphetamine-induced psychotic disorder have some similar mental presentations. Additionally, in scientific literature, there is scarce evidence about these similarities. In this regard, this research was designed to investigate the aforementioned obscurity. Determination of similarities and differences between them helps us to address these disorders in terms of treatment and follow-up and awareness of their prognosis of them. This research is a case-control study in which we examine positive and negative psychotic symptoms in schizophrenia and prolonged methamphetamine-induced psychotic disorder. Researchers investigated psychotic symptoms with positive and negative syndrome scale (PANSS), brief psychiatric rating scale (BPRS), and global assessment of functioning (GAF) questionnaires. Moreover, results demonstrate general and positive symptoms scores don't have many differences but negative symptoms are much more in patients with schizophrenia than in patients with a prolonged methamphetamine-induced psychotic disorder. Also, other features like uncooperativeness, unusual thought content, motor retardation, difficulty in abstract thinking, and hostility have higher scores in schizophrenia than the others. In conclusion, this research showed that these disorders are two distinct disorders with some similarities in positive symptoms but not in all features. So, some studies can be designed about why there are similarities between them?

Objective To explore the association between multidrug resistance 1gene (MDR1)polymorphisms with the therapeutic efficacy of paliperidone (9-hydroxyrisperidone) and risperidone in Han Chinese schizophrenic patients. Methods One hundred and thirty-three schizophrenic patients were given paliperidone or risperidone LAI for a 12-week treatment. The PANSS was used to assess the main therapeutic efficacy, and the Clinical Global Impression-Severity (CGI-S) scale and the Personal and Social Function scale (PSP) were used to as the secondary therapeutic efficacy assessments. The patients were evaluated every 2 weeks. The polymerase chain reaction-based-restriction fragment length polymorphisms (PCRRFLP) and DNA sequencing were used to detect the genotypes of 5 candidate single nucleotide polymorphisms (SNPs). The association between MDR1 genotypes with the therapeutic efficacy was analyzed using the chi-square and ANOVA tests. Results There were no statistical significant differences between MDR1 gene polymorphism and the PANSS reduction rate or clinical efficacy rate(P ＞0.05). Non-parameter tests revealed that, patients carrying CC genotype of locus rs1045642 had better efficacy in negative symptom item ' difficulty in abstract thinking' ( Z = - 2. 62, P = 0. 009 ) and positive symptom item ' grandiosity '(Z = -2. 84,P =0. 005), and GG genotype of locus rs2032582 carriers had worse improvements in general psychopathology item 'tension' (Z = -2.50,P =0. 012), and as to patient who carried A allele of locus rs1202169 had better improvements in general psychopathology item 'active societal avoidance'(Z = -2. 09,P =0. 036), and CC genotype of locus rs13233308 carriers had worse improvements in items ' guilt feelings' (Z = - 2. 09, P = 0. 036) and ' lack of spontaneity and flow of conversation' (Z = - 2.73,P = 0. 006) ,TT genotype carriers had a better improvement in item ' tension' ( Z = - 2. 54, P = 0. 011).Secondary clinical efficacy analysis showed that locus C allele of rs1045642 might be associated with patients' higher PSP score (Z = -2. 18, P = 0. 029). Conclusion MDR1 gene polymorphisms may be not associated with the therapeutic efficacy of paliperidone and risperidone in Han Chinese schizophrenic patients, but may influence the clinical improvements of 'delusion' or 'active societal avoidance' of schizophrenia, which maybe provide references for schizophrenic patients' individual drug therapy. Key words: Schizophrenia; Multidrug resistance gene; Polymorphism, restriction fragment length; Risperidone; Paliperidone

Handgrip strength (HGS) and serum folate and homocysteine (Hcy) levels were associated with cognitive function. However, little was known whether there were interactions between HGS and serum folate and Hcy levels on cognitive function. To examine the interactions between HGS and serum folate and Hcy levels on cognitive function. This study analyzed the baseline data of the Tianjin Elderly Nutrition and Cognition Cohort study. All participants aged ≥60 years were potential eligible. HGS was measured using a grip strength dynamometer. Serum folate and Hcy levels were assayed using standard laboratory protocol. A Mini-Mental State Examination was used to assess cognitive function. Linear regressions were employed to examine the interactions between HGS and serum folate and Hcy levels on cognitive function. 4,484 participants were included in this study. There were interactions between HGS and serum folate and Hcy levels on cognitive function. Furthermore, subjects with strong HGS and sufficient folate level had the best cognitive function (β= 2.018), sequentially followed by those with strong HGS and insufficient folate level (β= 1.698) and with poor HGS and sufficient folate level (β= 0.873). Similarly, cognitive function was ranked in the descending order of subjects with strong HGS and normal Hcy level (β= 1.971), strong HGS and high Hcy level (β= 1.467), and poor HGS and normal Hcy level (β= 0.657). There were interactions between HGS and serum folate and Hcy levels on cognitive function. However, the temporal associations cannot be examined in a cross-sectional study. Further cohort study should be conducted to confirm these associations in the future.

BackgroundRepetitive transcranial magnetic stimulation (rTMS) applied to the left frontal lobe is discussed to be a promising add-on treatment for negative symptoms in schizophrenia. The Positive and Negative Syndrome Scale (PANSS) has been used as outcome parameter in several previous rTMS trials, but studies focusing on PANSS factor analyses are lacking.For this purpose, we used the available PANSS data of the ‘rTMS for the Treatment of Negative Symptoms in Schizophrenia’ (RESIS) trial to calculate different literature-based PANSS factors and to re-evaluate the impact of rTMS on negative symptoms in this trial.MethodsIn an exploratory re-analysis of published data from the RESIS study (Wobrock et al. 2015), we tested the impact of rTMS applied to the left dorsolateral prefrontal cortex on two PANSS factors for negative symptoms in psychotic disorders as well as on a PANSS five-factor consensus model intending to show that active rTMS treatment improves PANSS negative symptom subscores.ResultsIn accordance to the original analysis, all PANSS factors showed an improvement over time in the active and, to a considerable extent, also in the sham rTMS group. However, comparing the data before and directly after the rTMS intervention, the PANSS excitement factor improved in the active rTMS group significantly more than in the sham group, but this finding did not persist if follow-up data were taken into account. These additional analyses extend the previously reported RESIS trial results showing unspecific improvements in the PANSS positive subscale in the active rTMS group.Our PANSS factor-based approach to investigate the impact of prefrontal rTMS on different negative symptom domains confirmed no overall beneficial effect of the active compared to sham rTMS.DiscussionThis secondary analysis of the RESIS trials has several limitations. First of all, the analysis of the primary endpoint was negative [24] and all subsequent secondary analyses showing a positive effect of the intervention (here: change in PANSS excitement factor) are of limited statistical power and therefore subject to uncertainty. On the other hand, our analyses confirm the negative finding of the original publication extends this finding to a broader negative symptom definition. Moreover, the new analysis provides a possible, but hypothetical explanation for the previously described effect of active rTMS on PANSS positive subscale. Of course, many other PANSS factor models are available and in pharmacological research the Marder factors [23, 35] have particular significance. However, the here used five-factor consensus model [21] includes the Marder factor results and our negative symptom factors overlaps with those factors. Another limitation is that it may be possible that our sham stimulation (coil tilted over one wing at an angle of 45°[24]) may still have been slightly biologically active as discussed elsewhere [24].

Homocysteine, vitamin B12 and folate levels in Iranian patients with Multiple Sclerosis: A case control study

Background and Objectives: Catalase and glutathione peroxidase (GPx) are important antioxidant enzymes that break down hydrogen peroxide (H2O2) in order to control its intracellular concentration, thus enabling its physiological role and preventing toxic effects. A lack or disruption of their function leads to the accumulation of hydrogen peroxide and the occurrence of oxidative stress. Accumulating studies have shown that the activities of key antioxidant enzymes are impaired in patients with schizophrenia. Since the published results are contradictory, and our previous studies found significantly higher erythrocyte superoxide dismutase (SOD) activity in patients with schizophrenia, the aim of this study was to determine the activity of enzymes that degrade hydrogen peroxide in the same group of patients, as well as to examine their dependence on clinical symptoms, therapy, and parameters associated with this disease. Materials and Methods: Catalase and GPx activities were determined in the erythrocytes of 68 inpatients with schizophrenia and 59 age- and gender-matched healthy controls. The clinical assessment of patients was performed by using the Positive and Negative Syndrome Scale (PANSS). The catalase activity was measured by the kinetic spectrophotometric method, while the GPx activity was determined by the commercially available Ransel test. Results: Erythrocyte catalase and GPx activities were significantly lower (p < 0.001 and p < 0.01, respectively) in subjects with schizophrenia than they were in healthy individuals. Lower catalase activity does not depend on heredity, disease onset, the number of episodes, or disease duration, while GPx activity showed significant changes in patients who had more than one episode and in those who had been suffering from the disease for over a year. Significantly lower catalase activity was noted in the PANSS(+/−) group in comparison with the PANSS(+) and PANSS(−) groups. The lowest catalase activity was found in subjects who were simultaneously treated with first- and second-generation antipsychotics; this was significantly lower than it was in those who received only one class of antipsychotics. Conclusion: These results indicate the presence of oxidative stress in the first years of clinically manifested schizophrenia and its dependence on the number of psychotic episodes, illness duration, predominant symptomatology, and antipsychotic medication.

The aim of this study was to determine serum vitamin B12, folic acid and homocysteine (Hcy) levels as well as MTHFR (C677, A1298C) gene polymorphisms in patients with vitiligo, and to compare the results with healthy controls. Forty patients with vitiligo and 40 age and sex matched healthy subjects were studied. Serum vitamin B12 and folate levels were determined by enzyme-linked immunosorbent assay. Plasma Hcy levels and MTHFR polymorphisms were determined by chemiluminescence and real time PCR methods, respectively. Mean serum vitamin B12 and Hcy levels were not significantly different while folic acid levels were significantly lower in the control group. There was no significant relationship between disease activity and vitamin B12, folic acid and homocystein levels. No significant difference in C677T gene polymorphism was detected. Heterozygote A1298C gene polymorphism in the patient group was statistically higher than the control group. There was no significant relationship between MTHFR gene polymorphisms and vitamin B12, folic acid and homocysteine levels. In conclusion, vitamin B12, folate and Hcy levels are not altered in vitiligo and MTHFR gene mutations (C677T and A1298C) do not seem to create susceptibility for vitiligo.

The aim of this study was to determine serum vitamin B12, folic acid and homocysteine (Hcy) levels as well as MTHFR (C677, A1298C) gene polymorphisms in patients with vitiligo, and to compare the results with healthy controls. Forty patients with vitiligo and 40 age and sex matched healthy subjects were studied. Serum vitamin B12 and folate levels were determined by enzyme-linked immunosorbent assay. Plasma Hcy levels and MTHFR polymorphisms were determined by chemiluminescence and real time PCR methods, respectively. Mean serum vitamin B12 and Hcy levels were not significantly different while folic acid levels were significantly lower in the control group. There was no significant relationship between disease activity and vitamin B12, folic acid and homocystein levels. No significant difference in C677T gene polymorphism was detected. Heterozygote A1298C gene polymorphism in the patient group was statistically higher than the control group. There was no significant relationship between MTHFR gene polymorphisms and vitamin B12, folic acid and homocysteine levels. In conclusion, vitamin B12, folate and Hcy levels are not altered in vitiligo and MTHFR gene mutations (C677T and A1298C) do not seem to create susceptibility for vitiligo.

Objective To investigate the correlation between mild cognitive impairment (PD-MCI) and serum homocysteine (Hcy) in patients with Parkinson's disease. Methods 85 patients with PD (43 with PD-MCI, 42 with PDN) as the observation group and 43 healthy elderly patients as the control group.The demographic information, clinical and neuropsychological assessments were conducted and the Hcy of fasting venous blood were detected in all subjects.The Hcy level and its associated factors were also analyzed in the PD group. Results Serum levels of Hcy in the PD patients((13.53±2.29) μmol/L) were higher than those in the HC group((11.77±1.56) μmol/L) , the difference was statistically significant (t=4.57, P<0.05). There was significant difference in serum Hcy levels among HC group, PDN group((12.85±1.88)μmol/L) and PD-MCI group((14.22±2.47)μmol/L) (F=16.13, P<0.01). Hcy level of the PDN group was higher than that of the HC group (P<0.05), and PD-MCI group was higher than PDN group (P<0.05). Serum levels of Hcy in patients with PD-MCI were significantly associated with UPDRS-Ⅲ(r=0.305), H-Y(r=0.313), LEDD(r=0.424), MMSE(r=-0.470), MoCA(r=-0.503), duration of connection test B(r=0.617) and semantic fluency tests(r=0.557)(all P<0.05). Conclusion Elevated serum Hcy levels are expected to be biomarkers for predicting PD-MCI. Key words: Parkinson's disease; Mild cognitive impairment; Homocysteine level in serum

Efficacy of high-frequency repetitive transcranial magnetic stimulation on PANSS factors in schizophrenia with predominant negative symptoms – Results from an exploratory re-analysis

Recent reports have demonstrated elevated serum homocysteine (Hcy) levels in children receiving valproic acid (VPA) therapy. Elevated Hcy levels might play a potential role in the resistance to antiepileptic drugs, and might lead to an increased risk for a vascular disease. It has been reported that elevated total homocysteine (tHcy) levels are associated with elevated asymmetric dimethylarginine (ADMA) levels, which are factors that may be better indicators of endothelial dysfunction compared to serum homocysteine levels, because they are less sensitive to changes, such as fasting status, physical activity, and other factors. In this study, we aim to evaluate serum ADMA, Hcy, lipid, folate, and vitamin B₁₂ levels in epileptic children, receiving VPA monotherapy. Forty-four epileptic children, receiving VPA monotherapy for at least 6 months and 28 healthy children aged between 4 and 16 years, were recruited. Serum lipids, lipoproteins, folate, vitamin B₁₂, Hcy, and ADMA levels were analyzed in both study groups. Serum Hcy, ADMA, and vitamin B₁₂ levels were higher in patients than in controls (p < 0.001 for tHcy and ADMA levels; p < 0.05 for vitamin B₁₂ levels); however, serum lipid, lipoprotein, and folate levels were similar. According to the duration of epilepsy, serum tHcy, ADMA, and triglyceride (TG) levels were higher in patients with epilepsy for ≥ 2 years than in patients with epilepsy for < 2 years (p < 0.001 for serum ADMA levels, p < 0.01 for tHcy levels, and p < 0.05 for serum TG levels). Similarly, with respect to the duration of VPA therapy, serum tHcy, ADMA, and TG levels were higher in patients who had received VPA therapy for more than 2 years (p < 0.001 for serum ADMA levels, p < 0.05 for serum tHcy levels, p < 0.01 for TG levels). Serum ADMA levels were significantly higher in patients receiving VPA at the dose of 25-30 mg/kg/day than in those receiving 20 mg/kg/day (p < 0.01). In conclusion, our study found increased serum ADMA levels and increased tHcy levels in epileptic children receiving VPA monotherapy. Increased serum ADMA levels were demonstrated in epileptic children who have had a seizure history greater than 2 years, and have used VPA therapy for more than 2 years, and have received higher doses of VPA. Routine monitoring of serum ADMA and tHcy levels might have beneficial effects for patients receiving long-term VPA therapy, especially in children who have other potential risk factors for vascular diseases. Further studies are needed to investigate serum ADMA and Hcy levels, and the presence of vascular disease, as well as the potential interactions between serum ADMA levels and seizure control.

The objective of this article is to highlight the potential role of the galantamine-memantine combination as a novel antioxidant treatment for schizophrenia. In addition to the well-known mechanisms of action of galantamine and memantine, these medications also have antioxidant activity. Furthermore, an interplay exists between oxidative stress, inflammation (redox-inflammatory hypothesis), and kynurenine pathway metabolites. Also, there is an interaction between brain-derived neurotrophic factor and oxidative stress in schizophrenia. Oxidative stress may be associated with positive, cognitive, and negative symptoms and impairments in white matter integrity in schizophrenia. The antipsychotic-galantamine-memantine combination may provide a novel strategy in schizophrenia to treat positive, cognitive, and negative symptoms. A "single antioxidant" may be inadequate to counteract the complex cascade of oxidative stress. The galantamine-memantine combination as "double antioxidants" is promising. Hence, randomized controlled trials are warranted with the antipsychotic-galantamine-memantine combination with oxidative stress and antioxidant biomarkers in schizophrenia.

Accumulating evidence indicates that elevated homocysteine (Hcy) level occurs in first-episode schizophrenia (FES) patients. We included 56 FES patients and 53 healthy controls (HC). Plasma level of Hcy was significantly higher in FES patients than HC (p = 0.044). In addition, plasma levels of high-density lipoproteins (HDL) and folate were significantly lower in FES than in HC (p < 0.001). Positive family history of schizophrenia was associated with lower plasma HDL (p = 0.041) and vitamin B12 (p = 0.017), as well as higher level of Hcy (p = 0.017). Patients with FES, who abused cannabis, had higher levels of Hcy (p = 0.017), as well as lower levels of vitamin B12 (p = 0.017) and HDL (p = 0.041). Plasma Hcy negatively correlated with duration of untreated psychosis (r = −0.272, p = 0.042). There was a positive correlation between Hcy level and the severity of negative symptoms (r = 0.363, p = 0.006) and general psychopathology (r = 0.349, p = 0.008) assessed using Positive and Negative Syndrome Scale (PANSS). Vitamin B12 level was negatively associated with the severity of negative symptoms (r = −0.406, p = 0.002), while folate level negatively correlated with general psychopathology score (r = −0.365, p = 0.006) in PANSS. These results indicate that the severity of one-carbon metabolism alterations and HDL deficiency might be associated with family history of schizophrenia and cannabis abuse. Lower vitamin B12 and folate along with elevated Hcy may influence the severity of FES psychopathology.

Objective To study changes in serum homocysteine(Hcy)and its correlation with serum levels of folic acid and high sensitivity C-reactive protein(hs-CRP)in Tibetan patients with mild-to-moderate Alzheimer’s disease at various high altitude areas, so as to direct the clinical diagnosis and treatment of AD in plateau hypoxia environment Method 108 cases were divided into four groups: 23 AD Tibetan patients at middle altitude(AD/middle altitude group)and 23 healthy Tibetan subjects(healthy/middle altitude group)in Qinghai-Tibet Plateau Xining region, altitude at 2, 260 m, 31 AD Tibetan patients(AD/high altitude group)and 31 healthy Tibetan elderly subjects(healthy/high altitude group)in Yushu region at altitude of 3, 800 m. Among the total study subjects, half are males, aged from 60 to 85 years.The levels of serum Hcy, Vitamin B12and folic acid(FA)were measured by the Fluorescence Polarization Immunoassay(FPIA). Serum hs-CRP, triglyceride(TG)and low density lipoprotein cholesterol(LDL-C)were measured by automatic biochemistry analyzer.Correlation of Hcy with FA and hs-CRP was analyzed. Result Both high altitude and middle altitude group showed the levels of Hcy and hs-CRP were significantly higher in AD Tibetan patients than in healthy control at the same altitude(allP<0.05). The levels of Hcy, LDL-C and hs-CRP of subjects were higher at high altitude than at middle altitude(P<0.05). In contrast, folic acid levels in AD and control groups were lower at the high altitude than at middle altitude(P<0.05). The levels of vitamin B12 and TG were not significantly different among all four groups.Multiple logistic regression analysis showed that altitude, folacin and hs-CRP were the risk factors for Hcy in patients with AD at plateau(OR=0.351, 2.794, 3.021, P=0.045, 0.037, 0.016). Conclusion Along with increased altitude, serum level of Hcy is significantly increased in AD Tibetan patients living in high altitude area.High altitude, high hs-CRP and lower folacin may be the risk factors for hyper-homocysteine in AD Tibetan patients with high altitude, and their combined effects are involved in the occurrence and development of AD. Key words: Alzheimer diseases; Cysteine; C-reactive protein; Zang Nationality