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1.
Artigo em Russo | MEDLINE | ID: mdl-34283543

RESUMO

The aim of this review is to analyze the basic biological mechanisms of comorbidity of schizophrenia and metabolic, cardiovascular diseases, which are not directly associated with external risk factors. The study of the general pathophysiological mechanisms of schizophrenia and metabolic disorders can provide a significant basis not only for the fundamentally novel therapeutic, preventive and diagnostic measures, but also for a better understanding of the etiopathogenesis of these diseases. It seems likely that schizophrenia represents a heterogeneous group with a varying genetic basis for both mental symptoms and neuroendocrine, inflammatory processes that form concomitant somatic disorders. Thus, the new integrated approaches to the study of this problem with the latest methods of genetic and molecular research are relevant.


Assuntos
Doenças Cardiovasculares , Doenças Metabólicas , Esquizofrenia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Comorbidade , Humanos , Doenças Metabólicas/epidemiologia , Fatores de Risco , Esquizofrenia/etiologia , Esquizofrenia/genética
2.
Transl Psychiatry ; 11(1): 377, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230451

RESUMO

Human endogenous retroviruses (HERVs) are remnants of infections that took place several million years ago and represent around 8% of the human genome. Despite evidence implicating increased expression of HERV type W envelope (HERV-W ENV) in schizophrenia and bipolar disorder, it remains unknown whether such expression is associated with distinct clinical or biological characteristics and symptoms. Accordingly, we performed unsupervised two-step clustering of a multivariate data set that included HERV-W ENV protein antigenemia, serum cytokine levels, childhood trauma scores, and clinical data of cohorts of patients with schizophrenia (n = 29), bipolar disorder (n = 43) and healthy controls (n = 32). We found that subsets of patients with schizophrenia (~41%) and bipolar disorder (~28%) show positive antigenemia for HERV-W ENV protein, whereas the large majority (96%) of controls was found to be negative for ENV protein. Unsupervised cluster analysis identified the presence of two main clusters of patients, which were best predicted by the presence or absence of HERV-W ENV protein. HERV-W expression was associated with increased serum levels of inflammatory cytokines and higher childhood maltreatment scores. Furthermore, patients with schizophrenia who were positive for HERV-W ENV protein showed more manic symptoms and higher daily chlorpromazine (CPZ) equivalents, whereas HERV-W ENV positive patients with bipolar disorder were found to have an earlier disease onset than those who were negative for HERV-W ENV protein. Taken together, our study suggest that HERV-W ENV protein antigenemia and cytokines can be used to stratify patients with major mood and psychotic disorders into subgroups with differing inflammatory and clinical profiles.


Assuntos
Transtorno Bipolar , Retrovirus Endógenos , Esquizofrenia , Análise por Conglomerados , Produtos do Gene env/genética , Humanos , Esquizofrenia/genética
3.
Redox Biol ; 45: 102057, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34198071

RESUMO

Methylglyoxal (MG) is a reactive and cytotoxic α-dicarbonyl byproduct of glycolysis. Our bodies have several bio-defense systems to detoxify MG, including an enzymatic system by glyoxalase (GLO) 1 and GLO2. We identified a subtype of schizophrenia patients with novel mutations in the GLO1 gene that results in reductions of enzymatic activity. Moreover, we found that vitamin B6 (VB6) levels in peripheral blood of the schizophrenia patients with GLO1 dysfunction are significantly lower than that of healthy controls. However, the effects of GLO1 dysfunction and VB6 deficiency on the pathophysiology of schizophrenia remains poorly understood. Here, we generated a novel mouse model for this subgroup of schizophrenia patients by feeding Glo1 knockout mice VB6-deficent diets (KO/VB6(-)) and evaluated the combined effects of GLO1 dysfunction and VB6 deficiency on brain function. KO/VB6(-) mice accumulated homocysteine in plasma and MG in the prefrontal cortex (PFC), hippocampus, and striatum, and displayed behavioral deficits, such as impairments of social interaction and cognitive memory and a sensorimotor deficit in the prepulse inhibition test. Furthermore, we found aberrant gene expression related to mitochondria function in the PFC of the KO/VB6(-) mice by RNA-sequencing and weighted gene co-expression network analysis (WGCNA). Finally, we demonstrated abnormal mitochondrial respiratory function and subsequently enhanced oxidative stress in the PFC of KO/VB6(-) mice in the PFC. These findings suggest that the combination of GLO1 dysfunction and VB6 deficiency may cause the observed behavioral deficits via mitochondrial dysfunction and oxidative stress in the PFC.


Assuntos
Lactoilglutationa Liase , Esquizofrenia , Deficiência de Vitamina B 6 , Animais , Humanos , Lactoilglutationa Liase/genética , Lactoilglutationa Liase/metabolismo , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética
4.
J Int Med Res ; 49(7): 3000605211029504, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34266338

RESUMO

OBJECTIVE: Schizophrenia is a complex mental disorder with high heritability. The hypothalamic-pituitary-adrenal (HPA) axis, which is the stress system of the neuroendocrine system, is considered to impact psychotic disorders. We hypothesized that polymorphisms of HPA axis genes might be involved in the development of schizophrenia. METHODS: A case-control study comprising 234 patients with schizophrenia and 399 matched healthy controls was conducted to investigate the association between the human melanocortin 2 receptor (MC2R) gene and schizophrenia risk. Seven tag single nucleotide polymorphisms (SNPs) (rs16941303, rs16941314, rs2186944, rs28926188, rs7230126, rs948322, and rs948331) of MC2R were genotyped by direct sequencing. RESULTS: No significant associations were observed between any of the alleles, genotypes, or haplotypes examined within the MC2R gene and the risk of schizophrenia in the total group or in subgroups stratified by smoking or alcoholism. However, a subgroup analysis stratified by sex revealed that under the additive model, the C allele of the MC2R rs948331 SNP significantly decreased the risk of schizophrenia in females (odds ratio=0.18). CONCLUSION: The C allele of the MC2R rs948331 locus may be a protective factor, reducing the risk of schizophrenia in the female Han Chinese population.


Assuntos
Grupo com Ancestrais do Continente Asiático , Receptor Tipo 2 de Melanocortina , Esquizofrenia , Regiões 3' não Traduzidas , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Polimorfismo de Nucleotídeo Único/genética , Receptor Tipo 2 de Melanocortina/genética , Receptor Tipo 2 de Melanocortina/metabolismo , Esquizofrenia/genética
5.
Transl Psychiatry ; 11(1): 343, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083506

RESUMO

BACKGROUND: Clozapine is considered to be the most effective antipsychotic medication for schizophrenia. However, it is associated with several adverse effects such as leukopenia, and the underlying mechanism has not yet been fully elucidated. The authors performed a genome-wide association study (GWAS) in a Chinese population to identify genetic markers for clozapine-induced leukopenia (CIL) and clozapine-induced neutropenia (CIN). METHODS: A total of 1879 patients (225 CIL cases, including 43 CIN cases, and 1,654 controls) of Chinese descent were included. Data from common and rare single nucleotide polymorphisms (SNPs) were tested for association. The authors also performed a trans-ancestry meta-analysis with GWAS results of European individuals from the Clozapine-Induced Agranulocytosis Consortium (CIAC). RESULTS: The authors identified several novel loci reaching the threshold of genome-wide significance level (P < 5 × 10-8). Three novel loci were associated with CIL while six were associated with CIN, and two T cell related genes (TRAC and TRAT1) were implicated. The authors also observed that one locus with evidence close to genome-wide significance (P = 5.08 × 10-8) was near the HLA-B gene in the major histocompatibility complex region in the trans-ancestry meta-analysis. CONCLUSIONS: The associations provide novel and valuable understanding of the genetic and immune causes of CIL and CIN, which is useful for improving clinical management of clozapine related treatment for schizophrenia. Causal variants and related underlying molecular mechanisms need to be understood in future developments.


Assuntos
Antipsicóticos , Clozapina , Neutropenia , Esquizofrenia , Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Estudo de Associação Genômica Ampla , Humanos , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Neutropenia/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética
6.
Transl Psychiatry ; 11(1): 351, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103471

RESUMO

Tardive dyskinesia (TD) is a severe condition characterized by repetitive involuntary movement of orofacial regions and extremities. Patients treated with antipsychotics typically present with TD symptomatology. Here, we conducted the largest GWAS of TD to date, by meta-analyzing samples of East-Asian, European, and African American ancestry, followed by analyses of biological pathways and polygenic risk with related phenotypes. We identified a novel locus and three suggestive loci, implicating immune-related pathways. Through integrating trans-ethnic fine mapping, we identified putative credible causal variants for three of the loci. Post-hoc analysis revealed that SNPs harbored in TNFRSF1B and CALCOCO1 independently conferred three-fold increase in TD risk, beyond clinical risk factors like Age of onset and Duration of illness to schizophrenia. Further work is necessary to replicate loci that are reported in the study and evaluate the polygenic architecture underlying TD.


Assuntos
Antipsicóticos , Esquizofrenia , Discinesia Tardia , Antipsicóticos/efeitos adversos , Proteínas de Ligação ao Cálcio , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Discinesia Tardia/induzido quimicamente , Discinesia Tardia/genética , Fatores de Transcrição
7.
Nat Commun ; 12(1): 3478, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108456

RESUMO

Dynamical brain state transitions are critical for flexible working memory but the network mechanisms are incompletely understood. Here, we show that working memory performance entails brain-wide switching between activity states using a combination of functional magnetic resonance imaging in healthy controls and individuals with schizophrenia, pharmacological fMRI, genetic analyses and network control theory. The stability of states relates to dopamine D1 receptor gene expression while state transitions are influenced by D2 receptor expression and pharmacological modulation. Individuals with schizophrenia show altered network control properties, including a more diverse energy landscape and decreased stability of working memory representations. Our results demonstrate the relevance of dopamine signaling for the steering of whole-brain network dynamics during working memory and link these processes to schizophrenia pathophysiology.


Assuntos
Encéfalo/fisiologia , Memória de Curto Prazo/fisiologia , Rede Nervosa/fisiologia , Esquizofrenia/fisiopatologia , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/efeitos dos fármacos , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genética , Esquizofrenia/metabolismo , Adulto Jovem
8.
Nat Commun ; 12(1): 3968, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172755

RESUMO

Cellular heterogeneity in the human brain obscures the identification of robust cellular regulatory networks, which is necessary to understand the function of non-coding elements and the impact of non-coding genetic variation. Here we integrate genome-wide chromosome conformation data from purified neurons and glia with transcriptomic and enhancer profiles, to characterize the gene regulatory landscape of two major cell classes in the human brain. We then leverage cell-type-specific regulatory landscapes to gain insight into the cellular etiology of several brain disorders. We find that Alzheimer's disease (AD)-associated epigenetic dysregulation is linked to neurons and oligodendrocytes, whereas genetic risk factors for AD highlighted microglia, suggesting that different cell types may contribute to disease risk, via different mechanisms. Moreover, integration of glutamatergic and GABAergic regulatory maps with genetic risk factors for schizophrenia (SCZ) and bipolar disorder (BD) identifies shared (parvalbumin-expressing interneurons) and distinct cellular etiologies (upper layer neurons for BD, and deeper layer projection neurons for SCZ). Collectively, these findings shed new light on cell-type-specific gene regulatory networks in brain disorders.


Assuntos
Doença de Alzheimer/genética , Transtorno Bipolar/genética , Cromatina/ultraestrutura , Esquizofrenia/genética , Acetilação , Doença de Alzheimer/patologia , Transtorno Bipolar/patologia , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , Sequenciamento de Cromatina por Imunoprecipitação , Elementos Facilitadores Genéticos , Epigênese Genética , Neurônios GABAérgicos/metabolismo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Histonas/metabolismo , Humanos , Lisina/metabolismo , Neuroglia/patologia , Neuroglia/ultraestrutura , Neurônios/patologia , Neurônios/ultraestrutura , Regiões Promotoras Genéticas , Esquizofrenia/patologia
10.
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
11.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071723

RESUMO

Pathogenic copy number variations (CNVs) contribute to the etiology of neurodevelopmental/neuropsychiatric disorders (NDs). Increased CNV burden has been found to be critically involved in NDs compared with controls in clinical studies. The 1q21.1 CNVs, rare and large chromosomal microduplications and microdeletions, are detected in many patients with NDs. Phenotypes of duplication and deletion appear at the two ends of the spectrum. Microdeletions are predominant in individuals with schizophrenia (SCZ) and microcephaly, whereas microduplications are predominant in individuals with autism spectrum disorder (ASD) and macrocephaly. However, its complexity hinders the discovery of molecular pathways and phenotypic networks. In this review, we summarize the recent genome-wide association studies (GWASs) that have identified candidate genes positively correlated with 1q21.1 CNVs, which are likely to contribute to abnormal phenotypes in carriers. We discuss the clinical data implicated in the 1q21.1 genetic structure that is strongly associated with neurodevelopmental dysfunctions like cognitive impairment and reduced synaptic plasticity. We further present variations reported in the phenotypic severity, genomic penetrance and inheritance.


Assuntos
Anormalidades Múltiplas/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Megalencefalia/genética , Transtornos Mentais/genética , Transtorno do Espectro Autista/genética , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 1/genética , Estudo de Associação Genômica Ampla , Humanos , Microcefalia/genética , Doenças Neurodegenerativas/genética , Transtornos do Neurodesenvolvimento/genética , Esquizofrenia/genética
12.
Schizophr Res ; 232: 1-10, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34004381

RESUMO

The closely connected anterior cingulate cortex (ACC) and superior temporal cortex (STC) are important for higher cognitive functions. Both brain regions are disturbed in schizophrenia, i.e., functional and structural alterations have been reported. This postmortem investigation in brains from patients with schizophrenia and controls compared gene expression in the left ACC and left STC. Most differentially expressed genes were unique to each brain region, but some clusters of genes were equally dysregulated in both, giving rise to a more general disease-specific pattern of gene regulation. The data was used to construct a molecular network of the genes identically expressed in both regions as primary nodes and the metabolically connected genes as secondary nodes. The network analysis identified downregulated clusters of immune-associated gene products and upregulated clusters belonging to the ubiquitin-proteasome system. These findings could help to identify new potential therapeutic targets for future approaches.


Assuntos
Giro do Cíngulo , Esquizofrenia , Encéfalo , Regulação da Expressão Gênica , Humanos , Imageamento por Ressonância Magnética , Esquizofrenia/genética , Lobo Temporal
13.
Schizophr Res ; 232: 33-41, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34010744

RESUMO

The molecular pathophysiological mechanisms underlying schizophrenia have remained unknown, and no treatment exists for primary prevention. We used Ingenuity Pathway Analysis to analyze canonical and causal pathways in two different datasets, including patients from Finland and USA. The most significant findings in canonical pathway analysis were observed for glutamate receptor signaling, hepatic fibrosis, and glycoprotein 6 (GP6) pathways in the Finnish dataset, and GP6 and hepatic fibrosis pathways in the US dataset. In data-driven causal pathways, ADCYAP1, ADAMTS, and CACNA genes were involved in the majority of the top 10 pathways differentiating patients and controls in both Finnish and US datasets. Results from a Finnish nation-wide database showed that the risk of schizophrenia relapse was 41% lower among first-episode patients during the use of losartan, the master regulator of an ADCYAP1, ADAMTS, and CACNA-related pathway, compared to those time periods when the same individual did not use the drug. The results from the two independent datasets suggest that the GP6 signaling pathway, and the ADCYAP1, ADAMTS, and CACNA-related purine, oxidative stress, and glutamatergic signaling pathways are among primary pathophysiological alterations in schizophrenia among patients with European ancestry. While no reproducible dopaminergic alterations were observed, the results imply that agents such as losartan, and ADCYAP1/PACAP -deficit alleviators, such as metabotropic glutamate 2/3 agonist MGS0028 and 5-HT7 antagonists - which have shown beneficial effects in an experimental Adcyap1-/- mouse model for schizophrenia - could be potential treatments even before the full manifestation of illness involving dopaminergic abnormalities.


Assuntos
Esquizofrenia , Animais , Modelos Animais de Doenças , Finlândia , Humanos , Camundongos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Transdução de Sinais
15.
Schizophr Res ; 232: 112-124, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34049235

RESUMO

Schizophrenia is a complex psychiatric disorder where genetic, epigenetic, and environmental factors play a role in disease onset, course of illness, and treatment outcome. Pharmaco(epi)genetic research presents an important opportunity to improve patient care through prediction of medication side effects and response. In this narrative review, we discuss the current state of research and important progress of both genetic and epigenetic factors involved in antipsychotic response, over the past five years. The review is largely focused on the following frequently prescribed antipsychotics: olanzapine, risperidone, aripiprazole, and clozapine. Several consistent pharmacogenetic findings have emerged, in particular pharmacokinetic genes (primarily cytochrome P450 enzymes) and pharmacodynamic genes involving dopamine, serotonin, and glutamate neurotransmission. In addition to studies analysing DNA sequence variants, there are also several pharmacoepigenetic studies of antipsychotic response that have focused on the measurement of DNA methylation. Although pharmacoepigenetics is still in its infancy, consideration of both genetic and epigenetic factors contributing to antipsychotic response and side effects no doubt will be increasingly important in personalized medicine. We provide recommendations for next steps in research and clinical evaluation.


Assuntos
Antipsicóticos , Clozapina , Esquizofrenia , Antipsicóticos/efeitos adversos , Clozapina/uso terapêutico , Epigênese Genética , Humanos , Medicina de Precisão , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética
16.
Transl Psychiatry ; 11(1): 331, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34050135

RESUMO

Previously, we identified a subpopulation of schizophrenia (SCZ) showing increased levels of plasma pentosidine, a marker of glycation and oxidative stress. However, its causative genetic factors remain largely unknown. Recently, it has been suggested that dysregulated posttranslational modification by copy number variable microRNAs (CNV-miRNAs) may contribute to the etiology of SCZ. Here, an integrative genome-wide CNV-miRNA analysis was performed to investigate the etiology of SCZ with accumulated plasma pentosidine (PEN-SCZ). The number of CNV-miRNAs and the gene ontology (GO) in the context of miRNAs within CNVs were compared between PEN-SCZ and non-PEN-SCZ groups. Gene set enrichment analysis of miRNA target genes was further performed to evaluate the pathways affected in PEN-SCZ. We show that miRNAs were significantly enriched within CNVs in the PEN-SCZ versus non-PEN-SCZ groups (p = 0.032). Of note, as per GO analysis, the dysregulated neurodevelopmental events in the two groups may have different origins. Additionally, gene set enrichment analysis of miRNA target genes revealed that miRNAs involved in glycation/oxidative stress and synaptic neurotransmission, especially glutamate/GABA receptor signaling, were possibly affected in PEN-SCZ. To the best of our knowledge, this is the first genome-wide CNV-miRNA study suggesting the role of CNV-miRNAs in the etiology of PEN-SCZ, through effects on genes related to glycation/oxidative stress and synaptic function. Our findings provide supportive evidence that glycation/oxidative stress possibly caused by genetic defects related to the posttranscriptional modification may lead to synaptic dysfunction. Therefore, targeting miRNAs may be one of the promising approaches for the treatment of PEN-SCZ.


Assuntos
MicroRNAs , Esquizofrenia , Variações do Número de Cópias de DNA , Humanos , MicroRNAs/genética , Esquizofrenia/genética
17.
J Affect Disord ; 290: 178-187, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34000571

RESUMO

Starting with the dichotomous view of Kraepelin, schizophrenia and bipolar disorder have traditionally been considered as separate entities. More recent, this taxonomic view of illnesses has been challenged and a continuum psychosis has been postulated based on genetic and neurobiological findings suggestive of a large overlap between disorders. In this paper we will review clinical and experimental data from genetics, morphology, phenomenology and illness progression demonstrating what makes schizophrenia and bipolar disorder different conditions, challenging the idea of the obsolescence of the categorical approach. However, perhaps it is also time to move beyond DSM and search for more refined clinical descriptions that could uncover clinical invariants matching better with molecular data. In the future, computational psychiatry employing artificial intelligence and machine learning might provide us a tool to overcome the gap between clinical descriptions (phenomenology) and neurobiology.


Assuntos
Transtorno Bipolar , Malus , Transtornos Psicóticos , Pyrus , Esquizofrenia , Inteligência Artificial , Transtorno Bipolar/genética , Humanos , Esquizofrenia/genética
18.
J Psychiatr Res ; 139: 30-37, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34022473

RESUMO

Schizophrenia (SZ) is a chronic debilitating disease. Subjects with SZ have significant shorter life expectancy. Growing evidence suggests that a process of pathological accelerated aging occurs in SZ, leading to early development of severe clinical diseases and worse morbimortality. Furthermore, unaffected relatives can share certain endophenotypes with subjects with SZ. We aim to characterize accelerated aging as a possible endophenotype of schizophrenia by using a machine learning (ML) model of peripheral biomarkers to accurately differentiate subjects with SZ (n = 35), their unaffected siblings (SB, n = 36) and healthy controls (HC, n = 47). We used a random forest algorithm that included biomarkers related to aging: eotaxins CCL-11 and CCL-24; the oxidative stress markers thiobarbituric acid-reactive substances (TBARS), protein carbonyl content (PCC), glutathione peroxidase (GPx); and telomere length (TL). The ML algorithm of biomarkers was able to distinguish individuals with SZ from HC with prediction accuracy of 79.7%, SZ from SB with 62.5% accuracy and SB from HC with 75.5% accuracy. These results support the hypothesis that a pathological accelerated aging might occur in SZ, and this pathological aging could be an endophenotype of the disease, once this profile was also observed in SB, suggesting that SB might suffer from an accelerated aging in some level.


Assuntos
Esquizofrenia , Envelhecimento , Endofenótipos , Humanos , Carbonilação Proteica , Esquizofrenia/genética , Irmãos
19.
J Psychiatr Res ; 139: 113-119, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34058649

RESUMO

As an epigenetic regulator micro-RNAs (miRNAs) have gained increasing attention in biomarker research for diseases. Many studies point towards an involvement of miRNAs in neuropsychiatric disorders such as Alzheimer's Disease, schizophrenia or depression. In a recent study we identified a possible relationship between childhood traumatization and miRNAs associated with Alzheimer's Disease in the general population as well as in a small psychiatric clinical sample. In this study we aimed to confirm this biological link in an independent psychiatric clinical sample (N = 104) and to also explore the impact of different childhood trauma dimensions (sum score, abuse dimension and neglect dimension). Analyses revealed their different impact on disease in the combined sample (N = 154; N = 50 from the recent study). We could confirm associations for all of the four recently identified miRNAs in the replication sample (N = 104) on a suggested significance level of p < 0.08 (two with p < 0.05). In the combined sample (N = 154) fifteen miRNAs were significantly associated with the childhood trauma sum score after correction for multiple testing. Most of them showed recently significant associations for Alzheimer's Disease. For the subscores of abuse and neglect only one miRNA was identified in addition, associated with childhood neglect. Bioinformatics analysis identified significant brain-related pathways regulated by the respective miRNAs. At the time of publication our study is the largest study of the association between childhood trauma and miRNAs in a clinical psychiatric sample. The confirmation of our previous results supports the relevance of the association between childhood traumatization and Alzheimer's Disease through miRNA regulation of brain-related pathways.


Assuntos
Maus-Tratos Infantis , MicroRNAs , Esquizofrenia , Encéfalo , Criança , Humanos , MicroRNAs/genética , Esquizofrenia/genética
20.
Transl Psychiatry ; 11(1): 292, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001859

RESUMO

Schizophrenia shows high heritability and several of the genes associated with this disorder are involved in calcium (Ca2+) signalling and synaptic function. One of these is the Rab-3 interacting molecule-1 (RIM1), which has recently been associated with schizophrenia by Genome Wide Association Studies (GWAS). However, its contribution to the pathophysiology of this disorder remains unexplored. In this work, we use Drosophila mutants of the orthologue of RIM1, Rim, to model some aspects of the classical and non-classical symptoms of schizophrenia. Rim mutants showed several behavioural features relevant to schizophrenia including social distancing and altered olfactory processing. These defects were accompanied by reduced evoked Ca2+ influx and structural changes in the presynaptic terminals sent by the primary olfactory neurons to higher processing centres. In contrast, expression of Rim-RNAi in the mushroom bodies (MBs), the main memory centre in flies, spared learning and memory suggesting a differential role of Rim in different synapses. Circadian deficits have been reported in schizophrenia. We observed circadian locomotor activity deficits in Rim mutants, revealing a role of Rim in the pacemaker ventral lateral clock neurons (LNvs). These changes were accompanied by impaired day/night remodelling of dorsal terminal synapses from a subpopulation of LNvs and impaired day/night release of the circadian neuropeptide pigment dispersing factor (PDF) from these terminals. Lastly, treatment with the commonly used antipsychotic haloperidol rescued Rim locomotor deficits to wildtype. This work characterises the role of Rim in synaptic functions underlying behaviours disrupted in schizophrenia.


Assuntos
Proteínas de Drosophila , Esquizofrenia , Animais , Ritmo Circadiano , Proteínas de Drosophila/genética , Drosophila melanogaster , Estudo de Associação Genômica Ampla , Modelos Genéticos , Fenótipo , Esquizofrenia/genética
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