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1.
Lancet Psychiatry ; 8(12): 1062-1070, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34735824

RESUMO

BACKGROUND: Although studies suggest that concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence for beneficial effects of fatty acid supplementation is scarce. Therefore, in this study, we aimed to determine whether omega-3 and omega-6 fatty acid concentrations are causally related to schizophrenia. METHODS: We did a two-sample Mendelian randomisation study, using deidentified summary-level data that were publicly available. Exposure-outcome relationships were evaluated using the inverse variance weighted two-sample Mendelian randomisation method using results from genome-wide association studies (GWASs) of fatty acid concentrations and schizophrenia. GWAS results were available for European (fatty acids) and European and Asian (schizophrenia) ancestry samples. Overall age and gender information were not calculable from the summary-level GWAS results. Weighted median, weighted mode, and Mendelian randomisation Egger regression methods were used as sensitivity analyses. To address underlying mechanisms, further analyses were done using single instruments within the FADS gene cluster and ELOVL2 gene locus. FADS gene cluster and ELOVL2 gene causal effects on schizophrenia were calculated by dividing the single nucleotide polymorphism (SNP)-schizophrenia effect estimate by the SNP-fatty acid effect estimate with standard errors derived using the first term from a delta method expansion for the ratio estimate. Multivariable Mendelian randomisation was used to estimate direct effects of omega-3 fatty acids on schizophrenia, independent of omega-6 fatty acids, lipoproteins (ie, HDL and LDL), and triglycerides. FINDINGS: Mendelian randomisation analyses indicated that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with a lower risk of schizophrenia (eg, inverse variance weighted odds ratio [OR] 0·83 [95% CI 0·75-0·92] for docosahexaenoic acid). By contrast, there was weak evidence that short-chain omega-3 and short-chain omega-6 fatty acids were associated with an increased risk of schizophrenia (eg, inverse variance weighted OR 1·07 [95% CI 0·98-1·18] for α-linolenic acid). Effects were consistent across the sensitivity analyses and the FADS single-SNP analyses, suggesting that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with lower risk of schizophrenia (eg, OR 0·74 [95% CI 0·58-0·96] for docosahexaenoic acid) whereas short-chain omega-3 and short-chain omega-6 fatty acid concentrations were associated with an increased risk of schizophrenia (eg, OR 1·08 [95% CI 1·02-1·15] for α-linolenic acid). By contrast, estimates from the ELOVL2 single-SNP analyses were more imprecise and compatible with both risk-increasing and protective effects for each of the fatty acid measures. Multivariable Mendelian randomisation indicated that the protective effect of docosahexaenoic acid on schizophrenia persisted after conditioning on other lipids, although evidence was slightly weaker (multivariable inverse variance weighted OR 0·84 [95% CI 0·71-1·01]). INTERPRETATION: Our results are compatible with the protective effects of long-chain omega-3 and long-chain omega-6 fatty acids on schizophrenia, suggesting that people with schizophrenia might have difficulty converting short-chain polyunsaturated fatty acids to long-chain polyunsaturated fatty acids. Further studies are required to determine whether long-chain polyunsaturated fatty acid supplementation or diet enrichment might help prevent onset of schizophrenia. FUNDING: National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol.


Assuntos
Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-6/sangue , Esquizofrenia/sangue , Esquizofrenia/genética , Humanos , Análise da Randomização Mendeliana
3.
Transl Psychiatry ; 11(1): 486, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34552056

RESUMO

Structural variation in the complement 4 gene (C4) confers genetic risk for schizophrenia. The variation includes numbers of the increased C4A copy number, which predicts increased C4A mRNA expression. C4-anaphylatoxin (C4-ana) is a C4 protein fragment released upon C4 protein activation that has the potential to change the blood-brain barrier (BBB). We hypothesized that elevated plasma levels of C4-ana occur in individuals with schizophrenia (iSCZ). Blood was collected from 15 iSCZ with illness duration < 5 years and from 14 healthy controls (HC). Plasma C4-ana was measured by radioimmunoassay. Other complement activation products C3-ana, C5-ana, and terminal complement complex (TCC) were also measured. Digital-droplet PCR was used to determine C4 gene structural variation state. Recombinant C4-ana was added to primary brain endothelial cells (BEC) and permeability was measured in vitro. C4-ana concentration was elevated in plasma from iSCZ compared to HC (mean = 654 ± 16 ng/mL, 557 ± 94 respectively, p = 0.01). The patients also carried more copies of the C4AL gene and demonstrated a positive correlation between plasma C4-ana concentrations and C4A gene copy number. Furthermore, C4-ana increased the permeability of a monolayer of BEC in vitro. Our findings are consistent with a specific role for C4A protein in schizophrenia and raise the possibility that its activation product, C4-ana, increases BBB permeability. Exploratory analyses suggest the novel hypothesis that the relationship between C4-ana levels and C4A gene copy number could also be altered in iSCZ, suggesting an interaction with unknown genetic and/or environmental risk factors.


Assuntos
Complemento C4 , Esquizofrenia , Complemento C4/genética , Complemento C4a/genética , Células Endoteliais , Predisposição Genética para Doença , Humanos , Esquizofrenia/sangue , Esquizofrenia/genética
4.
Biochemistry (Mosc) ; 86(6): 773-783, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225599

RESUMO

The review summarizes the results of our own studies and published data on the biological markers of psychiatric disorders, with special emphasis on the activity of platelet monoamine oxidase. Pharmacotherapy studies in patients with the mixed anxiety-depressive disorder and first episode of schizophrenia have shown that the activity of platelet monoamine oxidase could serve as a potential biomarker of the efficacy of therapeutic interventions in these diseases.


Assuntos
Plaquetas/enzimologia , Transtornos Mentais/sangue , Monoaminoxidase/sangue , Transtorno Depressivo/sangue , Transtorno Depressivo/tratamento farmacológico , Humanos , Transtornos Mentais/tratamento farmacológico , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Resultado do Tratamento
5.
Aging (Albany NY) ; 13(12): 16353-16366, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135129

RESUMO

ApoE gene polymorphism may be involved in the change in blood lipid profile and cognitive impairment of the general population. However, few studies explored the effects of ApoE gene polymorphism on blood lipid levels and cognition in schizophrenia. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was employed to evaluate the cognition and the SNPStats was used to investigate the association of ApoE rs429358 with schizophrenia. The models of analysis of covariance and multivariate analysis were conducted to investigate the effect of ApoE rs429358 on cognition in schizophrenia. Altogether, 637 patients with schizophrenia and 467 healthy controls were recruited in this study. The findings in the case group found that both the ApoA1 and ApoB levels were predictors for RBANS total score (p < 0.001 vs. p = 0.011), immediate memory (p < 0.001 vs. p = 0.019), language (p < 0.001 vs. p = 0.013), attention (p < 0.001 vs. p < 0.001), except ApoA1 level only was a predictor for visuospatial/constructional (p = 0.014) and delayed memory (p < 0.001). When the association was examined in different ApoE rs429358 genotype subgroups, the association between ApoA1 level and RBANS scores (except for the language score) or between ApoB level and RBANS scores (except for the attention score) was regulated by ApoE rs429358. Our results suggest that patients with schizophrenia have broad cognitive impairment compared with healthy controls. For patients with schizophrenia, both ApoA1 and ApoB levels were positively associated with cognition. There was a significant association between ApoA1 or ApoB levels and cognition in schizophrenia, which was regulated by the ApoE rs429358.


Assuntos
Apolipoproteína A-I/sangue , Apolipoproteína B-100/sangue , Apolipoproteínas E/genética , Disfunção Cognitiva/sangue , Estudos de Associação Genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/sangue , Esquizofrenia/genética , Adulto , Estudos de Casos e Controles , Doença Crônica , Cognição , Disfunção Cognitiva/fisiopatologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/fisiopatologia
6.
Sci Rep ; 11(1): 9992, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976271

RESUMO

Tryptophan and its catabolites (TRYCATs) have been suggested to link peripheral immune system activation and central neurotransmitter abnormalities with relevance to the etio-pathophysiology of schizophrenia (SZ) and major depressive disorder (MDD). The relationship to different psychopathological dimensions within these disorders however remains to be elucidated. We thus investigated potential group differences of tryptophan, kynurenine, kynurenic acid, 3-hydroxy kynurenine and quinolinic acid in the plasma of 19 healthy controls (HC), 45 patients with SZ and 43 patients with MDD and correlated plasma proteins with the "motivation and pleasure" dimension and cognition. After correcting for the covariates age, sex, body mass index, smoking and medication, patients with MDD showed lower kynurenine and 3-hydroxy kynurenine levels compared to HC. Quinolinic acid correlated negatively with composite cognitive score in patients with SZ, indicating that more severe cognitive impairments were associated with increased plasma levels of quinolinic acid. No correlations were found in patients with MDD. These results indicate that MDD and SZ are associated with dysregulation of the kynurenine pathway. Quinolinic acid might be specifically implicated in the pathophysiology of cognitive deficits in patients with SZ. Further studies are needed to determine whether TRYCATs are causally involved in the etiology of these neuropsychiatric disorders.


Assuntos
Disfunção Cognitiva/sangue , Transtorno Depressivo Maior/sangue , Ácido Quinolínico/sangue , Esquizofrenia/sangue , Triptofano/metabolismo , Adulto , Estudos de Casos e Controles , Cognição , Disfunção Cognitiva/etiologia , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Cinurenina/metabolismo , Masculino , Pessoa de Meia-Idade , Esquizofrenia/complicações , Adulto Jovem
7.
Biochim Biophys Acta Proteins Proteom ; 1869(8): 140657, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33839315

RESUMO

A better understanding of the proteome profile after bipolar disorder (BD) and schizophrenia (SCZ) treatment, besides monitoring disease progression, may assist on the development of novel therapeutic strategies with the ability to reduce or control possible side effects. In this pilot study, proteomics analysis employing nano liquid chromatography coupled to mass spectrometry (nLC-MS) and bioinformatic tools were applied to identify differentially abundant proteins in serum of treated BD and SCZ patients. In total, 10 BD patients, 10 SCZ patients, and 14 healthy controls (HC) were included in this study. 24 serum proteins were significantly altered (p < 0.05) in BD and SCZ treated patients and, considering log2FC > 0.58, 8 proteins presented lower abundance in the BD group, while 7 proteins presented higher abundance and 2 lower abundance in SCZ group when compared against HC. Bioinformatics analysis based on these 24 proteins indicated two main altered pathways previously described in the literature; furthermore, it revealed that opposite abundances of the complement and coagulation cascades were the most significant biological processes involved in these pathologies. Moreover, we describe disease-related proteins and pathways associations suggesting the necessity of clinical follow-up improvement besides treatment, as a precaution or safety measure, along with the disease progression. Further biological validation and investigations are required to define whether there is a correlation between complement and coagulation cascade expression for BD and SCZ and cardiovascular diseases.


Assuntos
Transtorno Bipolar/patologia , Fatores de Coagulação Sanguínea/análise , Proteínas do Sistema Complemento/análise , Esquizofrenia/patologia , Adulto , Biomarcadores Farmacológicos , Transtorno Bipolar/sangue , Transtorno Bipolar/imunologia , Fatores de Coagulação Sanguínea/metabolismo , Proteínas Sanguíneas/análise , Cromatografia Líquida/métodos , Proteínas do Sistema Complemento/metabolismo , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Espectrometria de Massas/métodos , Projetos Piloto , Proteômica/métodos , Esquizofrenia/sangue , Esquizofrenia/imunologia
8.
Sci Rep ; 11(1): 7527, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824398

RESUMO

Schizophrenia is a severe mental disorder and one of its characteristics is cognitive impairments. Findings regarding levels of the heme metabolite and plasma antioxidant bilirubin in schizophrenia are inconclusive. However, a recently published study indicate that low levels of bilirubin may be implicated in the memory impairments seen in the disorder. The aim of this cross-sectional study was to investigate the levels of bilirubin in individuals with a first-episode psychosis (FEP) and to examine if bilirubin levels were associated to cognitive impairments, symptoms and duration of untreated psychosis (DUP). Bilirubin levels were reduced in 39 individuals with FEP compared with 20 HC (median [IQR]: 11.0 [9.0-13.0] µM vs. 15.0 [11.5-18.5] µM). In individuals with FEP, bilirubin levels were also positively correlated to two working memory tests (r = 0.40 and r = 0.32) and inversely correlated to DUP (r = - 0.36). Findings were not influenced by confounding factors. The results confirm the antioxidant deficit previously seen in schizophrenia, but also indicate that these changes may be related to DUP. The study also confirms that bilirubin may be implicated in the cognitive deficits that accompanies the disorder, here for the first time presented in individuals with FEP.


Assuntos
Bilirrubina/metabolismo , Disfunção Cognitiva/metabolismo , Transtornos Psicóticos/metabolismo , Adulto , Bilirrubina/análise , Estudos Transversais , Feminino , Humanos , Masculino , Memória de Curto Prazo/fisiologia , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/sangue , Esquizofrenia/sangue , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Suécia/epidemiologia , Fatores de Tempo
9.
Psychopharmacology (Berl) ; 238(7): 1979-1990, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33774704

RESUMO

RATIONALE AND OBJECTIVE: Clozapine (CLZ) is the most effective drug for treatment-resistant schizophrenia but is associated with many side effects, including glycometabolism disorders. Immunological mechanisms may be involved in the development of clozapine side effects. Research relating the immunomodulatory effects of clozapine and its early markers to clinically relevant adverse events is needed to reduce the harmful side effects of clozapine. This study aimed to investigate the role of proinflammatory cytokines in clozapine-associated glycometabolism disorders. METHODS: We measured the effect of a range of doses of clozapine on glycometabolism-related parameters and proinflammatory cytokines levels in mice peripheral blood. We also examined the differences between these indicators in the peripheral blood of clozapine-treated schizophrenia patients and healthy controls. Furthermore, we detected proinflammatory cytokines expression in mice pancreatic tissue. RESULTS: Following clozapine administration, glucagon significantly decreased in mouse serum, and proinflammatory cytokine IL-ß levels markedly increased. Clozapine reliably increased proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) expression in murine pancreatic tissue. Compared with healthy controls, clozapine-treated patients' BMI, blood glucose, and proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) increased significantly. In clozapine-treated patients, a higher clozapine daily dosage was associated with higher levels of the proinflammatory cytokines IL-1ß and IL-6, and a significant positive correlation was observed between blood glucose levels and the proinflammatory cytokines IL-6 and TNF-α. CONCLUSION: Findings from animal experiments and clinical trials have shown clear evidence that clozapine has a regulatory effect on immune-related proinflammatory cytokines and influences glycometabolism indicators.


Assuntos
Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Citocinas/sangue , Mediadores da Inflamação/sangue , Doenças Metabólicas/sangue , Doenças Metabólicas/induzido quimicamente , Adulto , Animais , Antipsicóticos/uso terapêutico , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Clozapina/uso terapêutico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Fator de Necrose Tumoral alfa/sangue
10.
Nagoya J Med Sci ; 83(1): 51-61, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33727737

RESUMO

Increasing evidence indicates that enhanced peripheral carbonyl stress markers exist in subtype of schizophrenia, although it may not be the primary cause. This study aimed to investigate whether plasma concentrations of methylglyoxal, 3-deoxy-glucosone, and glyoxal, which are reactive intermediates of protein metabolism in carbonyl stress, are changed in patients with schizophrenia and can function as potential biomarkers for schizophrenia with enhanced carbonyl stress. Plasma concentrations of these di-carbonyls were simultaneously estimated in 40 patients with schizophrenia and 40 healthy controls. As a result, no statistically significant differences were observed in mean plasma concentrations of three di-carbonyls between patients and controls. However, a remarkable increase in methylglyoxal concentrations was observed in four patients but not in controls. This increase was not found with regard to 3-deoxyglucosone and glyoxal both of patients and controls. Our correlation analysis showed that both the plasma methylglyoxal and glyoxal concentrations were significantly correlated with 3-deoxyglucosone concentrations in 40 patients and 40 controls. However, the plasma methylglyoxal concentrations did not show any significant correlation with the glyoxal concentrations in the patients or the controls. In four patients with extremely high methylglyoxal levels, the plasma methylglyoxal and glyoxal concentrations were not correlated to the 3-deoxyglucosone concentrations. Methylglyoxal is a physiological substrate of the glyoxalase system, and the accelerated accumulation of this compound lowers the glyoxalase I activity. These results suggested that this increase in four patients with high methylglyoxal levels may indicate the presence of a subtype of chronic schizophrenia that is associated with enhanced carbonyl stress.


Assuntos
Aldeído Pirúvico/sangue , Esquizofrenia/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Doença Crônica , Desoxiglucose/análogos & derivados , Desoxiglucose/sangue , Feminino , Glioxal/sangue , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Fisiológico
11.
Psychol Med ; 51(4): 538-549, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33653423

RESUMO

BACKGROUND: This meta-analysis on peripheral blood compounds in drug-naïve first-episode patients with either schizophrenia or major depressive disorder (MDD) examined which compounds change following psychopharmacological treatment. METHODS: The Embase, PubMed and PsycINFO databases were systematically searched for longitudinal studies reporting measurements of blood compounds in drug-naïve first-episode schizophrenia or MDD. RESULTS: For this random-effects meta-analysis, we retrieved a total of 31 studies comprising 1818 schizophrenia patients, and 14 studies comprising 469 MDD patients. Brain-derived neurotrophic factor (BDNF) increased following treatment in schizophrenia (Hedges' g (g): 0.55; 95% confidence interval (CI) 0.39-0.70; p < 0.001) and MDD (g: 0.51; CI 0.06-0.96; p = 0.027). Interleukin (IL)-6 levels decreased in schizophrenia (g: -0.48; CI -0.85 to -0.11; p = 0.011), and for MDD a trend of decreased IL-6 levels was observed (g: -0.39; CI -0.87 to 0.09; p = 0.115). Tumor necrosis factor alpha (TNFα) also decreased in schizophrenia (g: -0.34; CI -0.68 to -0.01; p = 0.047) and in MDD (g: -1.02; CI -1.79 to -0.25; p = 0.009). Fasting glucose levels increased only in schizophrenia (g: 0.26; CI 0.07-0.44; p = 0.007), but not in MDD. No changes were found for C-reactive protein, IL-1ß, IL-2 and IL-4. CONCLUSIONS: Psychopharmacological treatment has modulating effects on BDNF and TNFα in drug-naïve first-episode patients with either schizophrenia or MDD. These findings support efforts for further research into transdiagnostic preventive strategies and augmentation therapy for those with immune dysfunctions.


Assuntos
Transtorno Depressivo Maior/sangue , Esquizofrenia/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Citocinas/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Humanos , Interleucina-1beta/sangue , Interleucina-6/sangue , Estudos Longitudinais , Masculino , Esquizofrenia/tratamento farmacológico , Fator de Necrose Tumoral alfa/sangue
13.
Psychiatry Res ; 297: 113717, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33503523

RESUMO

Increasing evidence suggests that the inflammatory system is activated in schizophrenia and antipsychotics may affect cytokines levels. we conducted a cross-sectional and prospective study.One hundred and thirteen patients and 58 normal subjects matched by gender, age were enrolled in the study. All the patients had risperidonemonotherapy and undertook a 10-week follow-up. Serum levels of IL-17 and IGF-1 were examined using the enzyme-linked immunosorbent assay and the Positive and Negative Symptoms Scale (PANSS) was applied to estimate the clinical symptoms in patients with schizophrenia. All procedures were repeated at the 10 weeks for patients group.The serum levels of IL-17 and IGF-1 in patients were significantly higher than in normal people. After treatment, IGF-1 levels in patients decreased significantly, whereas the IL-17 serum levels had no significant change compared to their baseline concentration. IGF-1 levels at the baseline were negatively associated with the reduction in negative symptoms score after controlling for age, gender distribution, education, smoking status, and WHR. Additionally, the magnitude of IGF-1 change was negatively correlated with negative symptoms score change after controlling for potential confounding variables. Results suggested that the inflammatory system is activated and serum IGF-1 may contribute to the pathophysiology of the negative symptoms of schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Interleucina-17/sangue , Risperidona/farmacologia , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Esquizofrenia/imunologia , Adulto , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
14.
Int J Mol Sci ; 22(2)2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33435512

RESUMO

It is the focus of increasing interest to investigate the effects of long-chain n-3 and long-chain n-6 polyunsaturated fatty acids (LC n-3 PUFAs; LC n-6 PUFAs) on psychiatric symptoms in a transdiagnostic perspective. There is some evidence that low levels of LC n-3 PUFAs and a higher ratio of LC n-6 to LC n-3 PUFAs in plasma and blood cells are associated with aggressive and impulsive behaviours. Therefore, implementation of LC n-3 PUFAs may produce positive effects on hostility, aggression, and impulsivity in both psychiatric and non-psychiatric samples across different stages of life. A possible mechanism of action of LC n-3 PUFAs in conditions characterized by a high level of impulsivity and aggression is due to the effect of these compounds on the serotonin system and membrane stability. Studies that evaluated the effects of LC n-3 PUFAs on impulsivity and aggressiveness indicated that addition of rather low doses of these agents to antipsychotic treatment might reduce agitation and violent behaviours in psychosis, attention deficit hyperactivity disorder, personality disorders, and impulsive control and conduct disorders. The present review is aimed at examining and discussing available data from recent trials on this topic.


Assuntos
Agressão/efeitos dos fármacos , Ácidos Graxos Ômega-3/uso terapêutico , Comportamento Impulsivo/efeitos dos fármacos , Transtornos Mentais/tratamento farmacológico , Animais , Transtorno do Deficit de Atenção com Hiperatividade/sangue , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6/sangue , Humanos , Transtornos Mentais/sangue , Transtornos da Personalidade/sangue , Transtornos da Personalidade/tratamento farmacológico , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Resultado do Tratamento
15.
Psychiatry Clin Neurosci ; 75(4): 138-144, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33421228

RESUMO

BACKGROUND: Schizophrenia (SCZ) is a serious psychiatric disorder. Metabolite disturbance is an important pathogenic factor in schizophrenic patients. In this study, we aim to identify plasma lipid and amino acid biomarkers for SCZ using targeted metabolomics. METHODS: Plasma from 76 SCZ patients and 50 matched controls were analyzed using the LC/MS-based multiple reaction monitoring (MRM) metabolomics approach. A total of 182 targeted metabolites, including 22 amino acids and 160 lipids or lipid-related metabolites were observed. We used binary logistic regression analysis to determine whether the lipid and amino acid biomarkers could discriminate SCZ patients from controls. The area under the curve (AUC) from receiver operation characteristic (ROC) curve analysis was conducted to evaluate the diagnostic performance of the biomarkers panel. RESULTS: We identified 19 significantly differentially expressed metabolites between the SCZ patients and the controls (false discovery rate < 0.05), including one amino acid and 18 lipids or lipid-related metabolites. The binary logistic regression-selected panel showed good diagnostic performance in the drug-naïve group (AUC = 0.936) and all SCZ patients (AUC = 0.948), especially in the drug-treated group (AUC = 0.963). CONCLUSIONS: Plasma lipids and amino acids showed significant dysregulation in SCZ, which could effectively discriminate SCZ patients from controls. The LC/MS/MS-based approach provides reliable data for the objective diagnosis of SCZ.


Assuntos
Aminoácidos/sangue , Lipídeos/sangue , Metabolômica , Esquizofrenia/sangue , Esquizofrenia/diagnóstico , Adulto , Biomarcadores/sangue , Cromatografia Líquida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem
16.
Neurosci Lett ; 746: 135669, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33485989

RESUMO

This study attempted to analyze the alterations in the mRNA expression levels of autophagy- and apoptosis-related genes in the forkhead box transcription factor O (FOXO) pathway in schizophrenia patients before and after olanzapine treatment. For a total of 32 acute schizophrenic inpatients, clinical data with PANSS were obtained before and after four weeks of olanzapine treatment (mean dose 14.24 ± 4.35 mg/d) along with data from 32 healthy volunteers. The mRNA expression levels of the FOXO pathway genes were measured by real-time qPCR after fasting venous blood was collected and analyzed. The mRNA expression levels of FOXO1, FOXO3A, FASLG, and BCL2L11 were observed to be significantly decreased in acute schizophrenia patients. After four weeks of olanzapine treatment, the expression levels of the first three genes were further reduced, but BCL2L11 expression levels were not significantly changed. The pairwise correlations between the mRNA expression level of FASLG and those of the other three genes were not observed in acute schizophrenia patients, while these relationships were observed in healthy controls. After olanzapine treatment, the FASLG mRNA expression level was restored and exhibited a pairwise correlation with the FOXO3A and BCL2L11 mRNA expression levels but not with the FOXO1 mRNA expression level, and FASLG mRNA expression was also correlated with the duration of the disease. The statuses and correlations of the mRNA expression levels of FOXO pathway-related genes were altered in schizophrenia patients and were affected by olanzapine treatment and the duration of the disease.


Assuntos
Antipsicóticos/uso terapêutico , Apoptose/fisiologia , Autofagia/fisiologia , Fatores de Transcrição Forkhead/biossíntese , Olanzapina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Antipsicóticos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína 11 Semelhante a Bcl-2/biossíntese , Proteína 11 Semelhante a Bcl-2/genética , Proteína Ligante Fas/biossíntese , Proteína Ligante Fas/genética , Feminino , Proteína Forkhead Box O1/biossíntese , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O3/biossíntese , Proteína Forkhead Box O3/genética , Fatores de Transcrição Forkhead/genética , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Olanzapina/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Esquizofrenia/sangue , Esquizofrenia/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Resultado do Tratamento , Adulto Jovem
17.
Psychopharmacology (Berl) ; 238(3): 615-637, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33410989

RESUMO

RATIONALE: Clozapine is the most effective antipsychotic for treatment-refractory schizophrenia for reducing positive psychotic symptoms. It is associated with a reduction in hospitalisation and overall mortality. In spite of this, clozapine remains underutilised due to its complex adverse drug reaction (ADR) profile. OBJECTIVE: This systematic review aims to investigate the association of clozapine and norclozapine serum levels, and peripheral ADRs. METHODS: Studies were searched from four electronic databases (PubMed, EMBASE, PsycINFO and CINAHL) from inception to 12 June 2020. Studies were included if they had adult patients, provided data on steady-state trough clozapine or norclozapine levels and reported on clozapine-associated ADRs. Pregnant women, case reports and series were excluded. RESULTS: A statistically significant correlation was found for clozapine serum levels and triglycerides (n = 70; r = 0.303, 95% CI 0.0119-0.546, p = 0.042), heart rate (n = 137; r = 0.269, 95% CI 0.0918-0.486, p = 0.035), and overall combined ADRs (n = 160; r = 0.264, 95% CI 0.110-0.405, p = 0.001), but not for absolute neutrophil count (n = 223; r = - 0.164, 95% CI - 0.529-0.253, p = 0.444) or total white cell count (n = 18; r = 0.0176, 95% CI - 0.203-0.237, p = 0.878). Interestingly, norclozapine serum levels were found to be statistically correlated to triglycerides (n = 120; r = 0.211, 95% CI 0.0305-0.378, p = 0.022), total cholesterol (n = 120; r = 0.272, 95% CI 0.0948-0.432, p = 0.003) and weight gain (n = 118; r = 0.208, 95% CI 0.0261-0.377, p = 0.025). CONCLUSIONS: Heart rate, triglycerides and combined ADRs are significantly correlated with clozapine levels, and triglycerides, total cholesterol and weight gain with norclozapine levels. Future prospective, randomised controlled studies are needed to identify the cause-effect relationship between clozapine levels and peripheral ADRs.


Assuntos
Antipsicóticos/sangue , Clozapina/análogos & derivados , Clozapina/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Esquizofrenia/tratamento farmacológico , Triglicerídeos/sangue , Adulto , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Clozapina/efeitos adversos , Clozapina/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Gravidez , Esquizofrenia/sangue , Psicologia do Esquizofrênico , Ganho de Peso/efeitos dos fármacos
18.
Eur J Clin Pharmacol ; 77(2): 215-221, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33000414

RESUMO

PURPOSE: Zuclopenthixol is an antipsychotic available as oral and long-acting injectable (LAI) formulations. The aim of this study was to investigate the effect of age on zuclopenthixol exposure during oral and LAI administrations without and with adjustment for CYP2D6 genotype. METHODS: Data on serum concentrations of zuclopenthixol and CYP2D6 genotype (available for 28.2% of the population) from patients using oral or LAI zuclopenthixol were included retrospectively from a therapeutic drug monitoring service during the period 2005-2019. As a measure of exposure, dose-adjusted serum concentration (C/D ratio) was used. Based on age, patients were grouped to older (≥ 65 years) or younger (18-64 years). Linear mixed model analyses without and with adjustment for CYP2D6 genotype were used. RESULTS: Serum concentrations of zuclopenthixol from 1145 (14.1% older) and 899 patients (24.6% older) in the LAI and oral groups were included, respectively. Compared with younger patients, older patients had a higher C/D ratio of zuclopenthixol for LAI (+ 25-33%, p < 0.001) and oral formulation (+ 25-29%, p ≤ 0.003) without and with adjustment for CYP2D6 genotype. The doses were lower in older versus younger patients (oral: - 30%; LAI: - 20%; p < 0.001). Compared with the younger LAI users without reduced CYP2D6 function, a higher C/D ratio was observed in the older LAI users with reduced CYP2D6 function (+ 104%, p < 0.001). CONCLUSION: The present study showed that zuclopenthixol exposure increases in older patients and that the older LAI users with reduced CYP2D6 function are exposed to high serum concentrations. Also, the present study showed that similar dose reductions are required for oral and LAI users.


Assuntos
Antipsicóticos/farmacocinética , Clopentixol/farmacocinética , Citocromo P-450 CYP2D6/genética , Esquizofrenia/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/administração & dosagem , Clopentixol/administração & dosagem , Citocromo P-450 CYP2D6/metabolismo , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Feminino , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Noruega , Variantes Farmacogenômicos , Estudos Retrospectivos , Esquizofrenia/sangue , Adulto Jovem
19.
Neuropsychopharmacology ; 46(6): 1140-1144, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32961544

RESUMO

Abnormalities in the complement system have been described in patients with schizophrenia, with those individuals having greater frequency of complement component 4A (C4A) alleles and higher C4A transcript levels in postmortem brain tissue. Importantly, abnormalities in C4A and other complement molecules have been associated with synaptic pruning abnormalities that occur during neurodevelopment. A few studies have investigated C4 levels in living patients with schizophrenia, but all of them did so using peripheral blood samples. No studies have examined C4 levels in cerebrospinal fluid (CSF), presumably a better biofluid choice given its intimate contact with the brain. Therefore, we report for the first time on C4 levels in CSF and plasma of patients with schizophrenia. In this study, we obtained CSF in 32 patients with schizophrenia spectrum disorders and 32 healthy volunteers and peripheral blood samples in 33 SSD and 31 healthy volunteers. C4 levels were measured using Abcam ELISA assays. Univariate analysis did not show a statistically significant difference in CSF C4 values between groups. However, a multivariable analysis showed a statistically significant increase in CSF C4 levels between groups after adjusting for sex and age. We also observed a high correlation between CSF C4 levels and age. By contrast, plasma C4 levels were not significantly different between groups. CSF and plasma C4 levels were not significantly correlated. Therefore, the use of CSF samples is critical and should be complementary to the use of peripheral blood samples to allow for a comprehensive understanding of complement C4 abnormalities in schizophrenia.


Assuntos
Complemento C4 , Esquizofrenia , Alelos , Complemento C4/líquido cefalorraquidiano , Complemento C4/genética , Humanos , Esquizofrenia/sangue , Esquizofrenia/líquido cefalorraquidiano , Esquizofrenia/genética
20.
Metab Brain Dis ; 36(1): 169-183, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32965599

RESUMO

Physiosomatic symptoms are an important part of schizophrenia phenomenology. The aim of this study is to examine the biomarker, neurocognitive and symptomatic correlates of physiosomatic symptoms in schizophrenia. We recruited 115 schizophrenia patients and 43 healthy controls and measured the Fibromyalgia and Chronic Fatigue Syndrome Rating (FF) scale, schizophrenia symptom dimensions, and the Brief Assessment of Cognition in Schizophrenia. We measured neuro-immune markers including plasma CCL11 (eotaxin), interleukin-(IL)-6, IL-10, Dickkopf protein 1 (DKK1), high mobility group box 1 protein (HMGB1) and endogenous opioid system (EOS) markers including κ-opioid receptor (KOR), µ-opioid receptor (MOR), endomorphin-2 (EM2) and ß-endorphin. Patients with an increased FF score display increased ratings of psychosis, hostility, excitement, formal though disorders, psycho-motor retardation and negative symptoms as compared with patients with lower FF scores. A large part of the variance in the FF score (55.1%) is explained by the regression on digit sequencing task, token motor task, list learning, IL-10, age (all inversely) and IL-6 (positively). Neural network analysis shows that the top-6 predictors of the FF score are (in descending order): IL-6, HMGB1, education, MOR, KOR and IL-10. We found that 45.1% of the variance in a latent vector extracted from cognitive test scores, schizophrenia symptoms and the FF score was explained by HMGB1, MOR, EM2, DKK1, and CCL11. Physiosomatic symptoms are an integral part of the phenome of schizophrenia. Neurotoxic immune pathways and lowered immune regulation coupled with alterations in the EOS appear to drive the physiosomatic symptoms of schizophrenia.


Assuntos
Cognição/fisiologia , Citocinas/sangue , Síndrome de Fadiga Crônica/sangue , Fibromialgia/sangue , Proteína HMGB1/sangue , Peptídeos Opioides/sangue , Esquizofrenia/sangue , Adulto , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicologia do Esquizofrênico , Adulto Jovem
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