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1.
Ideggyogy Sz ; 73(9-10): 303-308, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33035419

RESUMO

Evidence suggests that pathogen-associated pattern recognition receptors (Toll-like receptors, TLRs) are implicated in the pathophysiology of schizophrenia. TLRs are important in both peripheral immune responses and neuronal plasticity. However, the relationship between peripheral TLR expression and regional brain volumes is unknown in schizophrenia. We therefore assessed 30 drug-naïve, first-episode patients with schizophrenia. TLR4+/TLR1+ monocytes were measured using flow-cytometry. High resolution magnetic resonance images (T1 MRI) were obtained and analyzed with FreeSurfer. Results revealed significant negative correlations between the percentage of TLR4+ monocytes, mean fluorescent intensities, and brain volumes in frontal and anterior cingulate regions. The measures of TLR1+ monocytes did not show significant relationships with regional brain volumes. These results raise the possibility that abnormal TLR-activation is associated with decreased brain volumes in schizophrenia.


Assuntos
Lobo Frontal/metabolismo , Imagem por Ressonância Magnética/métodos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Receptor 4 Toll-Like/metabolismo , Antipsicóticos/uso terapêutico , Lobo Frontal/diagnóstico por imagem , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/metabolismo , Humanos , Polimorfismo de Nucleotídeo Único , Esquizofrenia/tratamento farmacológico
2.
Expert Opin Pharmacother ; 21(15): 1793-1798, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32735148

RESUMO

INTRODUCTION: Schizophrenia has a prevalence of approximately 1% in the general population, with 15.2 per 100,000 persons affected. Iloperidone is a second-generation antipsychotic drug approved for the treatment of schizophrenia in adults. It acts primarily by D2/5HT2a receptor antagonism, with greater affinity for the 5HT2a receptor than for the D2 receptor. AREAS COVERED: This article discusses iloperidone and aims to provide useful information for clinicians to determine which circumstances would best suit the use of iloperidone to treat schizophrenic patients. In this review, the authors briefly discuss schizophrenia and its treatment, before they discuss properties of iloperidone, its indications, approval process, and adverse effects. Finally, the authors review the specific strengths and weaknesses of the medication. EXPERT OPINION: Iloperidone would be an attractive option in patients who are particularly prone to EPS, or who are showing prominent negative symptoms, as well as cognitive deficits. Its availability only in an oral formulation makes it a better option for patients with good medication adherence, and though it could be useful in patients prone to weight gain or hepatic dysfunction on other second generation antipsychotics, it should be used with caution in patients prone to side effects related to alpha adrenergic blockade.


Assuntos
Antipsicóticos/uso terapêutico , Isoxazóis/uso terapêutico , Piperidinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Humanos , Isoxazóis/administração & dosagem , Isoxazóis/efeitos adversos , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Esquizofrenia/metabolismo , Ganho de Peso/efeitos dos fármacos
3.
PLoS One ; 15(7): e0230400, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32639965

RESUMO

Alterations in the cortico-cerebellar-thalamic-cortical circuit might underlie the diversity of symptoms in schizophrenia. However, molecular changes in cerebellar neuronal circuits, part of this network, have not yet been fully determined. Using LC-MS/MS, we screened altered candidates in pooled grey matter of cerebellum from schizophrenia subjects who committed suicide (n = 4) and healthy individuals (n = 4). Further validation by immunoblotting of three selected candidates was performed in two cohorts comprising schizophrenia (n = 20), non-schizophrenia suicide (n = 6) and healthy controls (n = 21). We found 99 significantly altered proteins, 31 of them previously reported in other brain areas by proteomic studies. Transport function was the most enriched category, while cell communication was the most prevalent function. For validation, we selected the vacuolar proton pump subunit 1 (VPP1), from transport, and two EF-hand calcium-binding proteins, calmodulin and parvalbumin, from cell communication. All candidates showed significant changes in schizophrenia (n = 7) compared to controls (n = 7). VPP1 was altered in the non-schizophrenia suicide group and increased levels of parvalbumin were linked to antipsychotics. Further validation in an independent cohort of non-suicidal chronic schizophrenia subjects (n = 13) and non-psychiatric controls (n = 14) showed that parvalbumin was increased, while calmodulin was decreased in schizophrenia. Our findings provide evidence of calcium-binding protein dysregulation in the cerebellum in schizophrenia, suggesting an impact on normal calcium-dependent synaptic functioning of cerebellar circuits. Our study also links VPP1 to suicide behaviours, suggesting a possible impairment in vesicle neurotransmitter refilling and release in these phenotypes.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Cerebelo/metabolismo , Esquizofrenia/patologia , Adulto , Calmodulina/metabolismo , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Regulação para Baixo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Parvalbuminas/metabolismo , Proteoma/análise , Esquizofrenia/metabolismo , Tentativa de Suicídio , Espectrometria de Massas em Tandem , Regulação para Cima
4.
Psychopharmacology (Berl) ; 237(8): 2499-2508, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32483676

RESUMO

Evidence indicates that neuroplasticity-based cognitive training can improve cognition in patients with schizophrenia, but the individual response to training varies greatly between subjects. Hence, there is a need to understand the neurological underpinnings of cognitive training to reveal predictors of treatment response. D-serine is a crucial modulator of neuroplasticity, and decreased levels of D-serine may contribute to deficits in neuroplasticity in schizophrenia. Interestingly, we observed that training mice to identify auditory oddballs increased extracellular levels of D-serine in the hippocampus during training. Serine racemase (Srr) is the only source of brain D-serine; thus, it is possible that Srr may mediate the response to training. To test this hypothesis, we trained mice that have a mutated version of Srr (SrrY269*/SrrY269*) and reduced levels of D-serine in the same auditory training. SrrY269*/SrrY269* mice showed decreased performance during auditory training (defined as the capacity to discriminate an oddball during a sequence of tones). Importantly, auditory training improved prepulse inhibition (PPI) in SrrY269*/SrrY269* but not in wild-type mice. Finally, D-serine (100 mg/kg i.p.) given 30 min before training sessions to SrrY269*/SrrY269* mice improved training performance, but it did not enhance PPI. Taken together, our results show that D-serine is involved in the response to neuroplasticity-based auditory training and that PPI deficits can be improved by auditory oddball training even in the presence of neuroplasticity deficits.


Assuntos
Estimulação Acústica/métodos , Cognição/fisiologia , Inibição Pré-Pulso/fisiologia , Racemases e Epimerases/genética , Racemases e Epimerases/metabolismo , Animais , Cognição/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Inibição Pré-Pulso/efeitos dos fármacos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Serina/farmacologia
5.
Nat Commun ; 11(1): 2889, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32514083

RESUMO

Inhibitory interneurons orchestrate information flow across the cortex and are implicated in psychiatric illness. Although interneuron classes have unique functional properties and spatial distributions, the influence of interneuron subtypes on brain function, cortical specialization, and illness risk remains elusive. Here, we demonstrate stereotyped negative correlation of somatostatin and parvalbumin transcripts within human and non-human primates. Cortical distributions of somatostatin and parvalbumin cell gene markers are strongly coupled to regional differences in functional MRI variability. In the general population (n = 9,713), parvalbumin-linked genes account for an enriched proportion of heritable variance in in-vivo functional MRI signal amplitude. Single-marker and polygenic cell deconvolution establish that this relationship is spatially dependent, following the topography of parvalbumin expression in post-mortem brain tissue. Finally, schizophrenia genetic risk is enriched among interneuron-linked genes and predicts cortical signal amplitude in parvalbumin-biased regions. These data indicate that the molecular-genetic basis of brain function is shaped by interneuron-related transcripts and may capture individual differences in schizophrenia risk.


Assuntos
Encéfalo/metabolismo , Perfilação da Expressão Gênica/métodos , Interneurônios/metabolismo , Parvalbuminas/genética , Esquizofrenia/genética , Somatostatina/genética , Adulto , Animais , Encéfalo/citologia , Encéfalo/diagnóstico por imagem , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Interneurônios/citologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Parvalbuminas/metabolismo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Esquizofrenia/diagnóstico , Esquizofrenia/metabolismo , Análise de Célula Única/métodos , Somatostatina/metabolismo , Adulto Jovem
6.
Compr Psychiatry ; 100: 152176, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32430144

RESUMO

OBJECTIVE: Early-onset schizophrenia is a severe and rare form of schizophrenia that is clinically and neurobiologically continuous with the adult form of schizophrenia. Neuregulin1 (NRG1)-mediated signaling is crucial for early neurodevelopment, which exerts its function by limited ß-secretase 1 (BACE1) proteolysis processing. However, circulating neuregulin1-ß1 (NRG1-ß1), an isoform of NRG1, and its cleavage enzyme BACE1 have not been studied in early-onset patients with schizophrenia. METHODS: In this study, we collected plasma and clinical information from 71 young patients (7 ≤ age years ≤20) with schizophrenia and 53 age- and sex-matched healthy controls. Immunoassay was used to test levels of circulating NRG1-ß1 and BACE1 expression. We further analyzed the relationship of disease-onset age and gender with NRG1-ß1 and BACE1 levels. RESULTS: We found that circulating plasma levels of NRG1-ß1 were significantly decreased in young patients with early-onset schizophrenia. In males with childhood onset schizophrenia (COS), NRG1-ß1 was reduced and was inversely correlated with positive symptom of PANSS; moreover, these male patients with higher plasma BACE1 levels showed more severe general symptoms of PANSS and defective social functioning; whereas, no aforementioned results were found in adolescent-onset schizophrenia (AOS). Notably, young female patients with COS and AOS had no significant change in NRG1-ß1 and BACE1, which demonstrated a sex-dependent effect in early-onset schizophrenia. CONCLUSION: Our results suggest that decreased levels of NRG1-ß1 and its cleavage enzyme BACE1 contribute to increased risk of etiology of schizophrenia. Synthetic biomarkers may have clinical applications for the early diagnosis of male COS.


Assuntos
Secretases da Proteína Precursora do Amiloide/sangue , Ácido Aspártico Endopeptidases/sangue , Neuregulina-1/sangue , Esquizofrenia/sangue , Adolescente , Idade de Início , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino , Esquizofrenia/etiologia , Esquizofrenia/metabolismo , Fatores Sexuais , Transdução de Sinais , Adulto Jovem
7.
Psychiatry Res Neuroimaging ; 300: 111080, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32279055

RESUMO

Nearly a third to half of schizophrenia patients are non-responsive to first-line antipsychotics and are labelled treatment resistant schizophrenia (TRS). Neurochemical abnormalities in TRS may not be dopaminergic but possibly glutamate (Glu) related. Studies that have examined glutamatergic abnormalities using proton magnetic resonance spectroscopy (1H-MRS) in TRS, have showed inconsistent results. Hence, we conducted a meta-analysis of 1H-MRS studies comparing levels of Glu-and its metabolites in the brains of TRS and non-treatment resistant schizophrenia (nTRS) patients. Four eligible studies were included in the analysis. Summary effect size for the group difference between TRS (n = 101, including Ultra-TRS) and nTRS (n = 61) in Glu-levels in the anterior cingulate cortex (ACC) as measured with Hedges's g was 0.21 (95% CI: -0.42 to 0.85; p = 0.5) suggesting absence of significant difference. However, on leave one out analysis, one iteration showed significant difference in Glu-levels between the groups (Hedges's g = 0.46; p = 0.02) with higher Glu-levels in TRS implying significant effect of a single study on the effect size. The higher ACC Glu-in TRS was not associated with symptom severity or antipsychotic administration, indicating a possible trait abnormality. The limited number of datasets comparing Glu-metabolites in other brain regions are narratively described. Our analysis is limited by the significant heterogeneity between studies. Further longitudinal, prospective studies are needed to confirm higher Glu-metabolite levels in ACC in TRS and explore this potential trait abnormality.


Assuntos
Encéfalo/metabolismo , Ácido Glutâmico/metabolismo , Espectroscopia de Prótons por Ressonância Magnética/métodos , Esquizofrenia/metabolismo , Antipsicóticos/uso terapêutico , Feminino , Giro do Cíngulo/metabolismo , Humanos , Masculino , Esquizofrenia/tratamento farmacológico
8.
J Clin Psychiatry ; 81(3)2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32237292

RESUMO

OBJECTIVE: To compare longitudinal metabolic effects of 7 antipsychotics, including body mass index (BMI), waist circumference (WC), blood pressure (BP), glucose, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C); to investigate risk factors for metabolic syndrome (MetS); and to make recommendations on frequency and timing of monitoring metabolic measurements. METHODS: This randomized, open-label, pharmacologic trial was conducted among patients with schizophrenia (DSM-IV) in 32 hospitals across China. Patients were randomly assigned to 7 groups and assessed at baseline, 2, 4, and 6 weeks. Linear mixed-effect models were used to assess changes of metabolic measures over time. Multivariable logistic regression analysis was performed to investigate the risk factors for MetS. RESULTS: In total, 2,550 (718 drug-naïve) of 2,774 patients finished the study between July 6, 2010, and November 30, 2011. We found significant (P < .05) changes for BMI, WC, TG, and LDL-C, with TG and LDL-C reaching a plateau. Interactions between baseline metabolic condition and changes over time were observed for BMI (χ² = 43.11, P < .001), WC (χ² = 36.34, P < .001), systolic BP (χ² = 11.92, P = .002), glucose (χ² = 6.09, P = .01), and TG (χ² = 6.01, P = .01). Antipsychotics generally had greater adverse effects on patients who were initially screened as metabolically normal. After controlling for other associated factors, we found that antipsychotics resulted in differing risk for incident MetS, with a similar pattern to findings in other populations: olanzapine (odds ratio [OR] = 3.36, P < .001) > quetiapine (OR = 3.29, P < .001) > perphenazine (OR = 2.73, P = .007) > risperidone (OR = 2.21, P = .02) > aripiprazole (OR = 1.74, P = .15) ≈ haloperidol (OR = 1.75, P = .22) ≈ ziprasidone (OR = 1, reference). CONCLUSIONS: Metabolic traits should be monitored frequently in early stages of antipsychotic treatment due to rapid and substantial changes. Clinicians should not assume low risk for patients with normal metabolic parameters at baseline. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier: ChiCTR-TRC-10000934.


Assuntos
Antipsicóticos/efeitos adversos , Síndrome Metabólica/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/uso terapêutico , Aripiprazol/efeitos adversos , Aripiprazol/uso terapêutico , Glicemia/efeitos dos fármacos , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Masculino , Olanzapina/efeitos adversos , Olanzapina/uso terapêutico , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Fumarato de Quetiapina/efeitos adversos , Fumarato de Quetiapina/uso terapêutico , Fatores de Risco , Risperidona/efeitos adversos , Risperidona/uso terapêutico , Esquizofrenia/metabolismo , Tiazóis/efeitos adversos , Tiazóis/uso terapêutico , Triglicerídeos/sangue
9.
Psychiatr Danub ; 32(1): 46-54, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32303029

RESUMO

BACKGROUND: Patients with schizophrenia exhibit a higher mortality rate compared with the general population. This mortality has been attributed predominantly by the high risk of type 2 diabetes mellitus in the patients. We aimed to assess the inherent risk of glucose metabolism abnormalities in first-episode drug-naive schizophrenia. SUBJECTS AND METHODS: We searched English database (PubMed, EMBASE, MEDLINE, Cochrane Library databases) and Chinese database (Wan Fang Data, CBM disc, VIP, and CNKI) from their inception until Jul 2018 for case-control studies examining glucose metabolism abnormalities. Measurements, such as fasting plasma glucose levels, fasting plasma insulin levels, insulin resistance and HbA1c levels in first-episode antipsychotic-naive patients were used to test for prediabetes. Standardized/weighted mean differences and 95% confidence intervals were calculated and analyzed. RESULTS: 19 studies (13 in English and 6 in Chinese) consisting of 1065 patients and 873 controls were included. Fasting plasma glucose levels (95% CI; 0.02 to 0.29; P=0.03), 2 h plasma glucose levels after an OGTT (95% CI; 0.63 to 1.2; P<0.00001), fasting plasma insulin levels (95% CI; 0.33 to 0.73; P<0.00001), insulin resistance (95% CI; 0.29 to 0.6; P<0.00001) in patients with first-episode schizophrenia were significant elevated. There was no significant difference in HbA1c level (95% CI; -0.34 to 0.18; P=0.54) in patients with first-episode schizophrenia compared with controls. CONCLUSIONS: This meta-analysis showed that glucose metabolism was impaired in patients with first-episode schizophrenia. Higher quality studies with larger samples are warranted to confirm these findings.


Assuntos
Glucose/metabolismo , Esquizofrenia/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Insulina/sangue , Insulina/metabolismo , Esquizofrenia/sangue , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico
10.
Brain ; 143(4): 1261-1277, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32236540

RESUMO

Frontotemporal dysconnectivity is a key pathology in schizophrenia. The specific nature of this dysconnectivity is unknown, but animal models imply dysfunctional theta phase coupling between hippocampus and medial prefrontal cortex (mPFC). We tested this hypothesis by examining neural dynamics in 18 participants with a schizophrenia diagnosis, both medicated and unmedicated; and 26 age, sex and IQ matched control subjects. All participants completed two tasks known to elicit hippocampal-prefrontal theta coupling: a spatial memory task (during magnetoencephalography) and a memory integration task. In addition, an overlapping group of 33 schizophrenia and 29 control subjects underwent PET to measure the availability of GABAARs expressing the α5 subunit (concentrated on hippocampal somatostatin interneurons). We demonstrate-in the spatial memory task, during memory recall-that theta power increases in left medial temporal lobe (mTL) are impaired in schizophrenia, as is theta phase coupling between mPFC and mTL. Importantly, the latter cannot be explained by theta power changes, head movement, antipsychotics, cannabis use, or IQ, and is not found in other frequency bands. Moreover, mPFC-mTL theta coupling correlated strongly with performance in controls, but not in subjects with schizophrenia, who were mildly impaired at the spatial memory task and no better than chance on the memory integration task. Finally, mTL regions showing reduced phase coupling in schizophrenia magnetoencephalography participants overlapped substantially with areas of diminished α5-GABAAR availability in the wider schizophrenia PET sample. These results indicate that mPFC-mTL dysconnectivity in schizophrenia is due to a loss of theta phase coupling, and imply α5-GABAARs (and the cells that express them) have a role in this process.


Assuntos
Vias Neurais/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/fisiopatologia , Lobo Temporal/fisiopatologia , Ritmo Teta/fisiologia , Adulto , Feminino , Humanos , Magnetoencefalografia , Masculino , Vias Neurais/metabolismo , Tomografia por Emissão de Pósitrons , Córtex Pré-Frontal/metabolismo , Receptores de GABA-A/metabolismo , Esquizofrenia/metabolismo , Lobo Temporal/metabolismo
11.
Nat Commun ; 11(1): 1612, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32235826

RESUMO

Evidence is mounting that the gut-brain axis plays an important role in mental diseases fueling mechanistic investigations to provide a basis for future targeted interventions. However, shotgun metagenomic data from treatment-naïve patients are scarce hampering comprehensive analyses of the complex interaction between the gut microbiota and the brain. Here we explore the fecal microbiome based on 90 medication-free schizophrenia patients and 81 controls and identify a microbial species classifier distinguishing patients from controls with an area under the receiver operating characteristic curve (AUC) of 0.896, and replicate the microbiome-based disease classifier in 45 patients and 45 controls (AUC = 0.765). Functional potentials associated with schizophrenia include differences in short-chain fatty acids synthesis, tryptophan metabolism, and synthesis/degradation of neurotransmitters. Transplantation of a schizophrenia-enriched bacterium, Streptococcus vestibularis, appear to induces deficits in social behaviors, and alters neurotransmitter levels in peripheral tissues in recipient mice. Our findings provide new leads for further investigations in cohort studies and animal models.


Assuntos
Microbioma Gastrointestinal/fisiologia , Metagenoma , Esquizofrenia/metabolismo , Esquizofrenia/microbiologia , Animais , Bactérias/classificação , Bactérias/genética , Comportamento Animal , Modelos Animais de Doenças , Transplante de Microbiota Fecal , Fezes/microbiologia , Microbioma Gastrointestinal/genética , Humanos , Masculino , Metagenômica/métodos , Camundongos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S , Curva ROC , Fatores de Risco , Comportamento Social , Streptococcus
12.
Medicine (Baltimore) ; 99(15): e19694, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282724

RESUMO

BACKGROUND: To evaluate the association between risperidone use and interleukin-6 (IL-6) levels by conducting a meta-analysis of controlled before-and-after studies. METHODS: Studies were identified through a systematic search of PubMed and Embase. The mean and standardized differences were extracted to calculate the standardized mean differences. IL-6 levels were compared in patients with schizophrenia before and after risperidone treatment. RESULTS: Ten studies were included in the final meta-analysis. The primary findings from our study suggest that there was a significant decrease in serum IL-6 levels after risperidone treatment (P = .021). A subgroup analysis revealed the sources of heterogeneity. The sensitivity analysis indicated that the results were stable, and no publication bias was observed. CONCLUSIONS: The present meta-analysis provides evidence that risperidone can significantly reduce IL-6 levels in schizophrenia. IL-6 is a potential biomarker of the pathophysiology and clinical processes of schizophrenia.


Assuntos
Antipsicóticos/uso terapêutico , Interleucina-6/sangue , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adulto , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Sensibilidade e Especificidade
13.
J Neurosci ; 40(16): 3304-3317, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32205341

RESUMO

Although the etiology of schizophrenia is still unknown, it is accepted to be a neurodevelopmental disorder that results from the interaction of genetic vulnerabilities and environmental insults. Although schizophrenia's pathophysiology is still unclear, postmortem studies point toward a dysfunction of cortical interneurons as a central element. It has been suggested that alterations in parvalbumin-positive interneurons in schizophrenia are the consequence of a deficient signaling through NMDARs. Animal studies demonstrated that early postnatal ablation of the NMDAR in corticolimbic interneurons induces neurobiochemical, physiological, behavioral, and epidemiological phenotypes related to schizophrenia. Notably, the behavioral abnormalities emerge only after animals complete their maturation during adolescence and are absent if the NMDAR is deleted during adulthood. This suggests that interneuron dysfunction must interact with development to impact on behavior. Here, we assess in vivo how an early NMDAR ablation in corticolimbic interneurons impacts on mPFC and ventral hippocampus functional connectivity before and after adolescence. In juvenile male mice, NMDAR ablation results in several pathophysiological traits, including increased cortical activity and decreased entrainment to local gamma and distal hippocampal theta rhythms. In addition, adult male KO mice showed reduced ventral hippocampus-mPFC-evoked potentials and an augmented low-frequency stimulation LTD of the pathway, suggesting that there is a functional disconnection between both structures in adult KO mice. Our results demonstrate that early genetic abnormalities in interneurons can interact with postnatal development during adolescence, triggering pathophysiological mechanisms related to schizophrenia that exceed those caused by NMDAR interneuron hypofunction alone.SIGNIFICANCE STATEMENT NMDAR hypofunction in cortical interneurons has been linked to schizophrenia pathophysiology. How a dysfunction of GABAergic cortical interneurons interacts with maturation during adolescence has not been clarified yet. Here, we demonstrate in vivo that early postnatal ablation of the NMDAR in corticolimbic interneurons results in an overactive but desynchronized PFC before adolescence. Final postnatal maturation during this stage outspreads the impact of the genetic manipulation toward a functional disconnection of the ventral hippocampal-prefrontal pathway, probably as a consequence of an exacerbated propensity toward hippocampal-evoked depotentiation plasticity. Our results demonstrate a complex interaction between genetic and developmental factors affecting cortical interneurons and PFC function.


Assuntos
Hipocampo/metabolismo , Interneurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/metabolismo , Animais , Modelos Animais de Doenças , Potenciais Evocados/fisiologia , Masculino , Camundongos , Camundongos Knockout , Vias Neurais/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/genética , Transdução de Sinais/fisiologia , Ritmo Teta/fisiologia
14.
PLoS One ; 15(3): e0230051, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32155207

RESUMO

Schizophrenia poses a significant economic burden on the healthcare system as well as it has a significant impact on society at large. Reasons for such a high economic burden of schizophrenia include the frequent relapses and hospitalizations occurring in this disorder. We analyze the effectiveness of long-acting injectable antipsychotics (LAIs) compared to oral medications, in terms of "clinical process management" in a sample of patients with a diagnosis of schizophrenia spectrum disorder treated in community mental health centers. An observational, retrospective, mirror-image study was carried out to evaluate the effectiveness of LAIs compared to oral medications in terms of number of hospitalizations, emergency visits and planned visits on a 10-year period (from July 2007 to June 2017). Differences between first and second generation LAIs were also explored. Our findings show that hospitalization and emergency visits are significantly decreased with the use of LAIs, while planned visits are increased in patients treated with LAIs. Our results suggest that LAIs, in particular, second generation ones, reduce hospitalization rates and emergency visits, improving the economic burden of schizophrenia. Therefore, LAIs should be considered a cost-effective treatment in the management of schizophrenia under routine conditions.


Assuntos
Antipsicóticos/farmacologia , Antipsicóticos/farmacocinética , Serviços Comunitários de Saúde Mental , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/uso terapêutico , Feminino , Hospitalização , Humanos , Injeções , Masculino , Qualidade da Assistência à Saúde , Estudos Retrospectivos , Esquizofrenia/metabolismo , Resultado do Tratamento
15.
PLoS One ; 15(3): e0226688, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32191705

RESUMO

BACKGROUND: Schizophrenia is linked with abnormal brain neurodevelopment, on which IGF-2 (insulin-like growth factor-2) has a great impact. The purpose of this study was to assess the levels of serum IGF-2 and its binding proteins IGFBP-3 and IGFBP-7 in schizophrenia patients and the associations of these proteins with schizophrenia psychopathology and cognitive deficits. METHODS: Thirty-two schizophrenia patients and 30 healthy controls were recruited. The PANSS and a neurocognitive test battery were used to assess schizophrenic symptomatology and cognition, respectively. Serum IGF-2, IGFBP-3 and IGFBP-7 levels were determined using ELISA. RESULTS: The schizophrenia patients had a much lower content of serum IGF-2, IGFBP-3 and IGFBP-7 than controls. For the patients, IGF-2 levels were negatively correlated with the PANSS negative scores and positively associated with working memory, attention, and executive function. The correlations between IGF-2 and the PANSS negative scores, working memory or executive function were still significant after controlling for age, sex, education level, BMI, illness history and age of onset. No significant associations of IGFBP-3 or IGFBP-7 with the PANSS scores and cognitive function were observed in the patients. CONCLUSIONS: Our study demonstrates that serum IGF-2 was significantly correlated with negative and cognitive symptoms in patients with schizophrenia, suggesting that altered IGF-2 signaling may be implicated in the psychopathology and cognitive deficits in schizophrenia.


Assuntos
Encéfalo/fisiopatologia , Disfunção Cognitiva/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Esquizofrenia/metabolismo , Adulto , Encéfalo/crescimento & desenvolvimento , Estudos de Casos e Controles , Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/fisiopatologia , Função Executiva/fisiologia , Feminino , Humanos , Fator de Crescimento Insulin-Like II/análise , Masculino , Memória de Curto Prazo/fisiologia , Testes Neuropsicológicos , Esquizofrenia/sangue , Esquizofrenia/diagnóstico , Esquizofrenia/fisiopatologia , Transdução de Sinais/fisiologia , Adulto Jovem
16.
Nat Neurosci ; 23(4): 510-519, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203495

RESUMO

Specific cell populations may have unique contributions to schizophrenia but may be missed in studies of homogenate tissue. Here laser capture microdissection followed by RNA sequencing (LCM-seq) was used to transcriptomically profile the granule cell layer of the dentate gyrus (DG-GCL) in human hippocampus and contrast these data to those obtained from bulk hippocampal homogenate. We identified widespread cell-type-enriched aging and genetic effects in the DG-GCL that were either absent or directionally discordant in bulk hippocampus data. Of the ~9 million expression quantitative trait loci identified in the DG-GCL, 15% were not detected in bulk hippocampus, including 15 schizophrenia risk variants. We created transcriptome-wide association study genetic weights from the DG-GCL, which identified many schizophrenia-associated genetic signals not found in transcriptome-wide association studies from bulk hippocampus, including GRM3 and CACNA1C. These results highlight the improved biological resolution provided by targeted sampling strategies like LCM and complement homogenate and single-nucleus approaches in human brain.


Assuntos
Giro Denteado/metabolismo , Predisposição Genética para Doença , Neurônios/metabolismo , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Locos de Características Quantitativas , Esquizofrenia/metabolismo , Transcriptoma , Adulto Jovem
17.
Biomed Res Int ; 2020: 8047146, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104705

RESUMO

Objective: The present study identified methylation patterns of schizophrenia- (SCZ-) related genes in different brain regions and used them to construct a novel DNA methylation-based SCZ diagnostic model. Methods: Four DNA methylation datasets representing different brain regions were downloaded from the Gene Expression Omnibus. The common differentially methylated genes (CDMGs) in all datasets were identified to perform functional enrichment analysis. The differential methylation sites of 10 CDMGs involved in the largest numbers of neurological or psychiatric-related biological processes were used to construct a DNA methylation-based diagnostic model for SCZ in the respective datasets. Results: A total of 849 CDMGs were identified in the four datasets, but the methylation sites as well as degree of methylation differed across the brain regions. Functional enrichment analysis showed CDMGs were significantly involved in biological processes associated with neuronal axon development, intercellular adhesion, and cell morphology changes and, specifically, in PI3K-Akt, AMPK, and MAPK signaling pathways. Four DNA methylation-based classifiers for diagnosing SCZ were constructed in the four datasets, respectively. The sample recognition efficiency of the classifiers showed an area under the receiver operating characteristic curve of 1.00 in three datasets and >0.9 in one dataset. Conclusion: DNA methylation patterns in SCZ vary across different brain regions, which may be a useful epigenetic characteristic for diagnosing SCZ. Our novel model based on SCZ-gene methylation shows promising diagnostic power.


Assuntos
Encéfalo/metabolismo , Metilação de DNA , Bases de Dados de Ácidos Nucleicos , Regulação da Expressão Gênica , Sistema de Sinalização das MAP Quinases , Modelos Biológicos , Esquizofrenia , Humanos , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Esquizofrenia/metabolismo
18.
J Neuroinflammation ; 17(1): 56, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32061259

RESUMO

BACKGROUND: In the last decade, there has been growing evidence that an interaction exists between inflammation and the kynurenine pathway in schizophrenia. Additionally, many authors found microglial activation in cases of schizophrenia due to inflammatory mechanisms related mostly to an increase of pro-inflammatory cytokines. In order to gain new insights into the pathophysiology of schizophrenia, it is important to incorporate the latest published evidence concerning inflammatory mechanisms and kynurenine metabolism. This systematic review aims to collect reliable recent findings within the last decade supporting such a theory. METHODS: A structured search of electronic databases was conducted for publications between 2008 and 2018 to identify eligible studies investigating patients with schizophrenia/psychosis and the relationship between inflammation and kynurenine pathway. Applicable studies were systematically scored using the NIH Quality Assessment Tools. Two researchers independently extracted data on diagnosis (psychosis/schizophrenia), inflammation, and kynurenine/tryptophan metabolites. RESULTS: Ten eligible articles were identified where seven studies assessed blood samples and three assessed cerebrospinal fluid in schizophrenic patients. Of these articles: Four investigated the relationship between immunoglobulins and the kynurenine pathway and found correlations between IgA-mediated responses and levels of tryptophan metabolites (i.e., kynurenine pathway).Five examined the correlation between cytokines and kynurenine metabolites where three showed a relationship between elevated IL-6, TNF-α concentrations, and the kynurenine pathway.Only one study discovered correlations between IL-8 and the kynurenine pathway.Two studies showed correlations with lower concentrations of IL-4 and the kynurenine pathway.Moreover, this systematic review did not find a significant correlation between CRP (n = 1 study), IFN-γ (n = 3 studies), and the kynurenine pathway in schizophrenia. INTERPRETATION: These results emphasize how different inflammatory markers can unbalance the tryptophan/kynurenine pathway in schizophrenia. Several tryptophan/kynurenine pathway metabolites are produced which can, in turn, underlie different psychotic and cognitive symptoms via neurotransmission modulation. However, due to heterogeneity and the shortage of eligible articles, they do not robustly converge to the same findings. Hence, we recommend further studies with larger sample sizes to elucidate the possible interactions between the various markers, their blood vs. CSF ratios, and their correlation with schizophrenia symptoms.


Assuntos
Inflamação/metabolismo , Cinurenina/metabolismo , Transtornos Psicóticos/metabolismo , Esquizofrenia/metabolismo , Humanos
19.
Lancet Psychiatry ; 7(6): 528-537, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32061320

RESUMO

The ubiquitin-proteasome system is a master regulator of neural development and the maintenance of brain structure and function. It influences neurogenesis, synaptogenesis, and neurotransmission by determining the localisation, interaction, and turnover of scaffolding, presynaptic, and postsynaptic proteins. Moreover, ubiquitin-proteasome system signalling transduces epigenetic changes in neurons independently of protein degradation and, as such, dysfunction of components and substrates of this system has been linked to a broad range of brain conditions. Although links between ubiquitin-proteasome system dysfunction and neurodegenerative disorders have been known for some time, only recently have similar links emerged for neurodevelopmental disorders, such as schizophrenia. Here, we review the components of the ubiquitin-proteasome system that are reported to be dysregulated in schizophrenia, and discuss specific molecular changes to these components that might, in part, explain the complex causes of this mental disorder.


Assuntos
Complexo de Endopeptidases do Proteassoma/metabolismo , Esquizofrenia/metabolismo , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina/metabolismo , Animais , Humanos , Modelos Animais , Doenças Neurodegenerativas/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Terminações Pré-Sinápticas/fisiologia , Complexo de Endopeptidases do Proteassoma/fisiologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Transmissão Sináptica/fisiologia , Ubiquitina/fisiologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/uso terapêutico
20.
Nat Commun ; 11(1): 912, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060266

RESUMO

Progressive ventricular enlargement, a key feature of several neurologic and psychiatric diseases, is mediated by unknown mechanisms. Here, using murine models of 22q11-deletion syndrome (22q11DS), which is associated with schizophrenia in humans, we found progressive enlargement of lateral and third ventricles and deceleration of ciliary beating on ependymal cells lining the ventricular walls. The cilia-beating deficit observed in brain slices and in vivo is caused by elevated levels of dopamine receptors (Drd1), which are expressed in motile cilia. Haploinsufficiency of the microRNA-processing gene Dgcr8 results in Drd1 elevation, which is brought about by a reduction in Drd1-targeting microRNAs miR-382-3p and miR-674-3p. Replenishing either microRNA in 22q11DS mice normalizes ciliary beating and ventricular size. Knocking down the microRNAs or deleting their seed sites on Drd1 mimicked the cilia-beating and ventricular deficits. These results suggest that the Dgcr8-miR-382-3p/miR-674-3p-Drd1 mechanism contributes to deceleration of ciliary motility and age-dependent ventricular enlargement in 22q11DS.


Assuntos
Ventrículos Cerebrais/metabolismo , Cílios/fisiologia , MicroRNAs/genética , Esquizofrenia/genética , Animais , Deleção Cromossômica , Cílios/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia
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