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1.
BMC Genomics ; 20(Suppl 7): 535, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31291891

RESUMO

BACKGROUND: Purpose of study is revealing significant differences in serum proteomes in schizophrenia and bipolar disorder (BD). RESULTS: Quantitative mass-spectrometry based proteomic analysis was used to quantify proteins in the blood serum samples after the depletion of six major blood proteins. Comparison of proteome profiles of different groups revealed 27 proteins being specific for schizophrenia, and 18 - for BD. Protein set in schizophrenia was mostly associated with immune response, cell communication, cell growth and maintenance, protein metabolism and regulation of nucleic acid metabolism. Protein set in BD was mostly associated with immune response, regulating transport processes across cell membrane and cell communication, development of neurons and oligodendrocytes and cell growth. Concentrations of ankyrin repeat domain-containing protein 12 (ANKRD12) and cadherin 5 in serum samples were determined by ELISA. Significant difference between three groups was revealed in ANKRD12 concentration (p = 0.02), with maximum elevation of ANKRD12 concentration (median level) in schizophrenia followed by BD. Cadherin 5 concentration differed significantly (p = 0.035) between schizophrenic patients with prevailing positive symptoms (4.78 [2.71, 7.12] ng/ml) and those with prevailing negative symptoms (1.86 [0.001, 4.11] ng/ml). CONCLUSIONS: Our results are presumably useful for discovering the new pathways involved in endogenous psychotic disorders.


Assuntos
Transtorno Bipolar/metabolismo , Proteoma/metabolismo , Esquizofrenia/metabolismo , Adulto , Antígenos CD/metabolismo , Caderinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Adulto Jovem
2.
Arch. Clin. Psychiatry (Impr.) ; 46(3): 66-71, May.-June 2019. tab
Artigo em Inglês | LILACS | ID: biblio-1011150

RESUMO

Abstract Background Antimicrobial peptides are components of the innate immune system. Cathelicidin LL-37 plays an important role in antimicrobial defense, exerts proinflammatory effect and strongly affects the immune system functioning. Our recent study revealed that serum concentration of LL-37 is increased in patients with bipolar disorder. Objectives The aim of this study is to re-evaluate serum LL-37 levels in patients with euthymic bipolar disorder and in healthy controls, matched for anthropometric and body composition parameters. Methods 36 adult patients with euthymic bipolar disorder and 68 non-depressed adults were included into the study. Concentration of LL-37 in serum was assessed using ELISA method. Detailed anthropometric measurements, body composition and biochemical analyses were performed. Results There was a statistically significant difference (p = 0.01) in serum LL-37 level between patients with bipolar disorder (4.97 ± 7.98 ng/mL) and control subjects (1.78 ± 2.69 ng/mL). Discussion Results of this study indicate that LL-37 serum level is increased in euthymic bipolar disorder patients. We found that this increase could not be attributed to analyzed anthropometric or body composition parameters.


Assuntos
Humanos , Masculino , Feminino , Adulto , Transtorno Bipolar , Composição Corporal/efeitos dos fármacos , Catelicidinas/sangue , Tabagismo , Transtorno Bipolar/metabolismo , Pesos e Medidas Corporais , Modelos Lineares , Testes Laboratoriais
3.
Psychopharmacology (Berl) ; 236(5): 1433-1443, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31041459

RESUMO

There is increasing evidence that connections formed between microbiome, the gut, and the brain play a role in health and well-being. Non-pharmaceutical targets for management of mood disorders, such as bipolar disorder, are relatively under-researched. At the same time, it is clear that there is an intimate connection between psychiatry and gastrointestinal health. Here, we have discussed various comorbid conditions associated with bipolar disorders such as inflammation, irritable bowel disease and antibiotic induced mania with importance to demonstrate possible involvement of the gut microbiota. Gut microbiota-targeted preclinical and clinical interventions have demonstrated enhancement in various psychological conditions. Further in this review, we explore links between bipolar disorder, inflammation and gut microbiome with a focus on dietary, pro- and pre-biotic interventions as potential adjuvant therapies for use in the management of mood disorders such as bipolar disorder.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Prebióticos/administração & dosagem , Probióticos/administração & dosagem , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Transtorno Bipolar/dietoterapia , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Quimioterapia Combinada , Microbioma Gastrointestinal/fisiologia , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Microbiota/efeitos dos fármacos , Microbiota/fisiologia
4.
Metabolism ; 95: 65-76, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954559

RESUMO

Changes of sphingolipid metabolism were suggested to contribute to the patho-etiology of major depression (MD) and bipolar disorder (BD). In a pilot study we assessed if lipid allostasis manifested in pathological plasma concentrations of bioactive lipids i.e. endocannabinoids, sphingolipids, ceramides, and lysophosphatidic acids. METHODS: Targeted and untargeted lipidomic analyses were performed according to GLP guidelines in 67 patients with unipolar or bipolar disorders (20-67 years, 36 male, 31 female) and 405 healthy controls (18-79 years, 142 m, 263 f), who were matched according to gender, age and body mass index. Multivariate analyses were used to identify major components, which accounted for the variance between groups and were able to predict group membership. RESULTS: Differences between MD and BP patients versus controls mainly originated from ceramides and their hexosyl-metabolites (C16Cer, C18Cer, C20Cer, C22Cer, C24Cer and C24:1Cer; C24:1GluCer, C24LacCer), which were strongly increased, particularly in male patients. Ceramide levels were neither associated with the current episode, nor with the therapeutic improvement of the Montgomery Åsberg Depression Rating Scale (MARDS). However, long-chain ceramides were linearly associated with age, stronger in patients than controls, and with high plasma levels of diacyl- and triacylglycerols. Patients receiving antidepressants had higher ceramide levels than patients not taking these drugs. There was no such association with lithium or antipsychotics except for olanzapine. CONCLUSION: Our data suggest that high plasma ceramides in patients with major depression and bipolar disorder are indicative of a high metabolic burden, likely aggravated by certain medications.


Assuntos
Transtorno Bipolar/metabolismo , Ceramidas/metabolismo , Transtorno Depressivo Maior/metabolismo , Metabolismo dos Lipídeos/genética , Adolescente , Adulto , Fatores Etários , Idoso , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Antimaníacos/efeitos adversos , Antimaníacos/uso terapêutico , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/psicologia , Índice de Massa Corporal , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Diglicerídeos/metabolismo , Feminino , Humanos , Lítio/efeitos adversos , Lítio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Escalas de Graduação Psiquiátrica , Caracteres Sexuais , Triglicerídeos/metabolismo , Adulto Jovem
5.
Artigo em Inglês | MEDLINE | ID: mdl-30934836

RESUMO

Bipolar patients have a higher risk of type 2 diabetes and obesity, which are associated with cardiovascular diseases as the leading cause of death in this group. Additionally, there is growing evidence that impaired glucose metabolism in bipolar patients is associated with rapid cycling, poor response to mood stabilizers and chronic course of illness. The aim of the study was to assess the prevalence of type 2 diabetes and other types of impaired glucose metabolism in bipolar patients along with an evaluation of the Fasting Triglycerides and Glucose Index (TyG) as a method of the insulin sensitivity assessment. The analysis of fasting glycemia, insulinemia and lipid profile in euthymic bipolar patients was performed, and the Homeostasis model assessment for insulin resistance (HOMA-IR) and TyG were computed. Type 2 diabetes was observed in 9% and insulin resistance with HOMA-IR in 48% of patients. The TyG and HOMA-IR indices were correlated (p < 0.0001), the TyG index value of 4.7 had the highest sensitivity and specificity for insulin resistance detection. The usefulness of TyG in the recognition of insulin resistance in bipolar patients was suggested. The significant role of psychiatrists in the detection and management of impaired glucose metabolism in bipolar patients was presented.


Assuntos
Transtorno Bipolar/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Glucose/metabolismo , Resistência à Insulina , Psiquiatria , Idoso , Transtorno Bipolar/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Jejum/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Papel Profissional , Triglicerídeos/sangue
6.
Bipolar Disord ; 21(4): 330-341, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30864200

RESUMO

OBJECTIVES: To investigate neurochemical abnormalities in the left and right ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) of youth at risk for bipolar disorder using proton magnetic resonance spectroscopy before and after their first mood episode. METHODS: Children and adolescents offspring of parents with bipolar I disorder (at-risk group, n = 117) and matched healthy controls (HC group, n = 61) were recruited at the University of Cincinnati. At-risk subjects had no lifetime major mood and psychotic disorders at baseline, and were followed up every 4 months to monitor for development of a major depressive, manic, hypomanic, or mixed mood episode. Levels of N-acetyl-aspartate (NAA), phosphocreatine plus creatine (PCr + Cr), choline-containing compounds, myo-inositol, and glutamate were determined using LCModel and corrected for partial volume effects. RESULTS: There were no baseline differences in metabolite levels for any of the brain regions between at-risk and HC youth. Nineteen at-risk subjects developed a first mood episode during follow-up. Survival analyses showed that baseline PCr + Cr levels in the left VLPFC significantly predicted a mood episode during follow-up in the at-risk group (HR: 0.47, 95% CI: 0.27-0.82, P = 0.008). There were no longitudinal changes in metabolites levels in the VLPFC and ACC before and after a mood episode in at-risk subjects. CONCLUSIONS: We found no evidence for abnormal proton spectroscopy metabolite levels in the VLPFC and ACC of at-risk youth, prior and after the development of their first mood episode. Preliminary findings of association between baseline PCr + Cr levels in the left VLPFC and risk to develop a mood episode warrant further investigation.


Assuntos
Sintomas Afetivos , Transtorno Bipolar , Filho de Pais Incapacitados/psicologia , Creatina/análise , Giro do Cíngulo/metabolismo , Fosfocreatina/análise , Córtex Pré-Frontal/metabolismo , Medição de Risco , Adolescente , Adulto , Sintomas Afetivos/diagnóstico , Sintomas Afetivos/metabolismo , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/metabolismo , Criança , Creatina/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , Espectroscopia de Prótons por Ressonância Magnética/métodos , Medição de Risco/métodos
8.
Adv Exp Med Biol ; 1118: 63-70, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30747417

RESUMO

Mental disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), are generally characterized by a combination of abnormal thoughts, perceptions, emotions, behavior, and relationships with others. Multiple risk factors incorporating genetic and environmental susceptibility are associated with development of these disorders. Mitochondria have a central role in the energy metabolism, and the literature suggests energy metabolism abnormalities are widespread in the brains of subjects with MDD, BPD, and SZ. Numerous studies have shown altered expressions of mitochondria-related genes in these mental disorders. In addition, environmental factors for these disorders, such as stresses, have been suggested to induce mitochondrial abnormalities. Moreover, animal studies have suggested that interactions of altered expression of mitochondria-related genes and environmental factors might be involved in mental disorders. Further investigations into interactions of mitochondrial abnormalities with environmental factors are required to elucidate of the pathogenesis of these mental disorders.


Assuntos
Metabolismo Energético , Transtornos Mentais/metabolismo , Mitocôndrias/patologia , Animais , Transtorno Bipolar/metabolismo , Transtorno Bipolar/fisiopatologia , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Humanos , Transtornos Mentais/fisiopatologia , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia
9.
J Affect Disord ; 245: 1106-1113, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30699853

RESUMO

BACKGROUND: Bipolar disorder (BD) and substance use disorders share common symptoms, such as behavioral sensitization. Amphetamine-induced behavioral sensitization can serve as an animal model of BD. Neurotrophic factors have an important role in BD pathophysiology. This study evaluated the effects of amphetamine sensitization on behavior and neurotrophic factor levels in the brains of rats. METHODS: Wistar rats received daily intraperitoneal (i.p) injections of dextroamphetamine (d-AMPH) 2 mg/kg or saline for 14 days. After seven days of withdrawal, the animals were challenged with d-AMPH (0.5 mg/kg, i.p) and locomotor behavior was assessed. In a second protocol, rats were similarly treated with d-AMPH (2 mg/kg, i.p) for 14 days. After withdrawal, without d-AMPH challenge, depressive- and anxiety-like behaviors were evaluated through forced swimming test and elevated plus maze. Levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT-3), neurotrophin 4/5 (NT-4/5) and glial-derived neurotrophic factor (GDNF) were evaluated in the frontal cortex, hippocampus, and striatum. RESULTS: D-AMPH for 14 days augmented locomotor sensitization to a lower dose of d-AMPH (0.5 mg/kg) after the withdrawal. d-AMPH withdrawal induced depressive- and anxious-like behaviors. BDNF, NGF, and GDNF levels were decreased, while NT-3 and NT-4 levels were increased in brains after d-AMPH sensitization. LIMITATIONS: Although d-AMPH induces manic-like behavior, the mechanisms underlying these effects can also be related to phenotypes of drug abuse. CONCLUSIONS: Together, vulnerability to mania-like behavior following d-AMPH challenge and extensive neurotrophic alterations, suggest amphetamine-induced behavioral sensitization is a good model of BD pathophysiology.


Assuntos
Ansiedade/metabolismo , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Depressão/metabolismo , Dextroanfetamina/farmacologia , Fatores de Crescimento Neural/metabolismo , Animais , Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/induzido quimicamente , Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Depressão/induzido quimicamente , Modelos Animais de Doenças , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/efeitos dos fármacos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Fator de Crescimento Neural/efeitos dos fármacos , Fator de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/efeitos dos fármacos , Neurotrofina 3/efeitos dos fármacos , Neurotrofina 3/metabolismo , Ratos , Ratos Wistar
10.
Neurosci Bull ; 35(2): 205-215, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30706412

RESUMO

The locus coeruleus (LC) has been studied in major depressive disorder (MDD) and bipolar disorder (BD). A major problem of immunocytochemical studies in the human LC is interference with the staining of the immunocytochemical end-product by the omnipresent natural brown pigment neuromelanin. Here, we used a multispectral method to untangle the two colors: blue immunocytochemical staining and brown neuromelanin. We found significantly increased tyrosine hydroxylase (TH) in the LC of MDD patients-thus validating the method-but not in BD patients, and we did not find significant changes in the receptor tyrosine-protein kinase ErbB4 in the LC in MDD or BD patients. We observed clear co-localization of ErbB4, TH, and neuromelanin in the LC neurons. The different stress-related molecular changes in the LC may contribute to the different clinical symptoms in MDD and BD.


Assuntos
Transtorno Bipolar/metabolismo , Transtorno Depressivo Maior/metabolismo , Locus Cerúleo/metabolismo , Melaninas/metabolismo , Receptor ErbB-4/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Idoso , Idoso de 80 Anos ou mais , Transtorno Bipolar/patologia , Transtorno Depressivo Maior/patologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica/métodos , Locus Cerúleo/patologia , Masculino , Microscopia/métodos , Pessoa de Meia-Idade , Neurônios/metabolismo , Neurônios/patologia , Sensibilidade e Especificidade , Análise Espectral/métodos
11.
Psychiatry Res ; 274: 49-57, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30780062

RESUMO

Melatonin secretion and polysomnography (PSG) were compared among a group of healthy adolescents who were at high familial risk for bipolar disorder (HR) and a second group at low familial risk (LR). Adolescent participants (n = 12) were a mean age 14 ± 2.3 years and included 8 females and 4 males. Saliva samples were collected under standardized condition light (red light) and following a 200 lux light exposure over two consecutive nights in a sleep laboratory. Red Light Melatonin onset (RLMO) was defined as saliva melatonin level exceeding the mean of the first 3 readings plus 2 standard deviations. Polysomnography was also completed during each night. HR youth, relative to LR, experienced a significantly earlier melatonin onset following 200 lux light exposure. Polysomnography revealed that LR youth, relative to HR, spent significantly more time in combined stages 3 and 4 (deep sleep) following red light exposure. Additionally, regardless of the group status (HR or LR), there was no significant difference in Red Light Melatonin Onset recorded at home or in the laboratory, implying its feasibility and reliability.


Assuntos
Transtorno Bipolar/diagnóstico , Transtorno Bipolar/metabolismo , Predisposição Genética para Doença , Melatonina/metabolismo , Estimulação Luminosa/métodos , Saliva/metabolismo , Adolescente , Adulto , Biomarcadores/química , Biomarcadores/metabolismo , Transtorno Bipolar/genética , Criança , Ritmo Circadiano/fisiologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Polissonografia/tendências , Reprodutibilidade dos Testes , Saliva/química , Sono/fisiologia , Transtornos do Sono do Ritmo Circadiano/diagnóstico , Transtornos do Sono do Ritmo Circadiano/genética , Transtornos do Sono do Ritmo Circadiano/metabolismo
12.
J Affect Disord ; 246: 828-835, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30795487

RESUMO

BACKGROUND: Social cognition (SC) and Theory of Mind (ToM) are compromised in patients with Schizophrenia (SKZ) and Bipolar Disorder (BD) and an increased frequency of metabolic abnormalities is reported in both disorders. Obesity seems associated with cognitive impairments The aim of our study is thus to assess the relationship between obesity and ToM in SKZ and BD. METHODS: 36 stabilized outpatients (18 SKZ and 18 BD) were recruited and completed Reading the Mind in the Eyes Test, Italian version and Faux Pas Recognition Test, adult version. BMI was calculated from self-reported height and weight. Two different Generalized Linear Models were created including performance in Eyes test and in Faux Pas test as outcomes and BMI as covariate. RESULTS: After stratifying for sex, we found a significant relationship between BMI and Faux Pas performance for male patients (p = 0.017), without significant interactions between sex and diagnosis. These results suggest a BMI effect on both affective and cognitive ToM in male patients. LIMITATIONS: Major confounders need to be considered: the greater number of subjects with SKZ in male subsample, a possible influence of neurocognitive performance, small sample size and self-reported BMI. CONCLUSIONS: There could be a relationship between ToM and metabolic dysfunctions, at least in male patients. The exact nature of this relationship has yet to be determined; an interesting theoretical framework is based on a combination of increased brain energy request and inefficient peripheral compensatory mechanisms, resulting in inefficient energy allocation to the brain.


Assuntos
Transtorno Bipolar/psicologia , Cognição , Obesidade/psicologia , Psicologia do Esquizofrênico , Comportamento Social , Teoria da Mente , Adulto , Transtorno Bipolar/complicações , Transtorno Bipolar/metabolismo , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Obesidade/complicações , Esquizofrenia/complicações , Esquizofrenia/metabolismo
13.
Transl Psychiatry ; 9(1): 74, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718481

RESUMO

Common genetic variation contributes a substantial proportion of risk for both schizophrenia and bipolar disorder. Furthermore, there is evidence of significant, but not complete, overlap in genetic risk between the two disorders. It has been hypothesised that genetic variants conferring risk for these disorders do so by influencing brain development, leading to the later emergence of symptoms. The comparative profile of risk gene expression for schizophrenia and bipolar disorder across development over different brain regions however remains unclear. Using genotypes derived from genome-wide associations studies of the largest available cohorts of patients and control subjects, we investigated whether genes enriched for schizophrenia and bipolar disorder association show a bias for expression across any of 13 developmental stages in prefrontal cortical and subcortical brain regions. We show that genetic association with schizophrenia is positively correlated with expression in the prefrontal cortex during early midfetal development and early infancy, and negatively correlated with expression during late childhood, which stabilises in adolescence. In contrast, risk-associated genes for bipolar disorder did not exhibit a bias towards expression at any prenatal stage, although the pattern of postnatal expression was similar to that of schizophrenia. These results highlight the dynamic expression of genes harbouring risk for schizophrenia and bipolar disorder across prefrontal cortex development and support the hypothesis that prenatal neurodevelopmental events are more strongly associated with schizophrenia than bipolar disorder.


Assuntos
Desenvolvimento do Adolescente/fisiologia , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Desenvolvimento Infantil/fisiologia , Desenvolvimento Fetal/fisiologia , Perfilação da Expressão Gênica , Expressão Gênica/genética , Predisposição Genética para Doença , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudo de Associação Genômica Ampla , Humanos , Lactente , Adulto Jovem
14.
Artigo em Inglês | MEDLINE | ID: mdl-30664971

RESUMO

INTRODUCTION: The activation of the ATP-gated P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7) produces microglial activation, a process which has been demonstrated in depression, bipolar disorder, and schizophrenia. Emerging data over the last years highlighted the importance of P2X7 cation channel as a potential drug target for these central nervous system disorders. The Gln460Arg (rs2230912) polymorphism of the P2RX7 gene has been widely studied in mood disorders, however the results are still controversial. Therefore, we aimed to investigate the C-terminal region of this gene in major depressive and bipolar disorders (MDD and BD) by studying possibly functional, non-synonymous polymorphisms within a 7 kb long region around the Gln460Arg, including Ala348Thr (rs1718119), Thr357Ser (rs2230911), and Glu496Ala (rs3751143) variants. Since Gln460Arg is located at the 3' end of the P2RX7 gene, we included additional, potentially functional single nucleotide polymorphisms (SNPs) from the 3' untranslated region (UTR), which can be in linkage with Gln460Arg. Based on in silico search, we chose two SNPs in putative microRNA target sites which are located in consecutive positions: rs1653625 and rs1718106. METHODS: P2RX7 SNPs from the C-terminal region were selected based on previous functional assays, 3' UTR variants were chosen using PolymiRTS and Patrocles databases. The genotyping of the non-synonymous SNPs was carried out by pre-designed TaqMan® kits, while the 3' UTR variants were analyzed by PCR-RFLP method. Case-control analyses were carried out between 315 inpatients with acute major depressive episode (195 MDD, 120 BD) and 406 healthy control subjects. The two subscales of the Hospital Anxiety and Depression Scale (HADS) self-report questionnaire were used for quantitative analyses, including an additional, "at-risk" population of 218 patients with diabetes mellitus. The in vitro reporter gene assays were carried out on HEK and SK-N-FI cells transiently transfected with pMIR vector constructs containing the P2RX7 3' UTR downstream of the luciferase gene. RESULTS: Haplotype analysis indicated a relatively high linkage between the analyzed P2RX7 SNPs. Our case-control study did not yield any association between P2RX7 gene variants and depression. However, dimensional analyses showed significant associations of the HADS depression severity scores with Gln460Arg (rs2230912) and Ala348Thr (rs1718119) in the depressed and diabetic patient groups. In the in vitro experiments, the P2RX7 3' UTR constructs with the lowest predicted binding efficiency to their miRNAs showed the highest expression of the gene. The combination of the depression-associated P2RX7 C-terminal and 3' UTR SNPs contributed to the highest depression severity score in the haplotype analysis. CONCLUSION: Based on our findings, we propose that a P2RX7 haplotype combination of the Gln460Arg and neighboring SNPs contribute to the observed genetic association with depressive symptoms.


Assuntos
Transtorno Bipolar/genética , Transtorno Depressivo Maior/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Receptores Purinérgicos P2X7/genética , Adulto , Transtorno Bipolar/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Simulação por Computador , Transtorno Depressivo Maior/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Feminino , Frequência do Gene , Estudos de Associação Genética , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Receptores Purinérgicos P2X7/metabolismo
15.
Neurochem Int ; 124: 162-170, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30654115

RESUMO

The abuse of methamphetamine (MA), an amphetamine (AMPH)-type stimulant, has been demonstrated to be associated with various neuropsychotoxicity, including memory impairment, psychiatric morbidity, and dopaminergic toxicity. Compelling evidence from preclinical studies has indicated that protein kinase C (PKC), a large family of serine/threonine protein kinases, plays an important role in MA-induced neuropsychotoxicity. PKC-mediated N-terminal phosphorylation of dopamine transporter has been identified as one of the prerequisites for MA-induced synaptic dopamine release. Consistently, it has been shown that PKC is involved in MA (or AMPH)-induced memory impairment and mania-like behaviors as well as MA drug dependence. Direct or indirect regulation of factors related to neuronal plasticity seemed to be critical for these actions of PKC. In addition, PKC-mediated mitochondrial dysfunction, oxidative stress or impaired antioxidant defense system has been suggested to play a role in psychiatric and cognitive disturbance induced by MA (or AMPH). In MA-induced dopaminergic toxicity, particularly PKCδ has been shown to trigger oxidative stress, mitochondrial dysfunction, pro-apoptotic changes, and neuroinflammation. Importantly, PKCδ may be a key mediator in the positive feedback loop composed of these detrimental events to potentiate MA-induced dopaminergic toxicity. This review outlines the role of PKC and its individual isozymes in MA-induced neuropsychotoxicity. Better understanding on the molecular mechanism of PKCs might provide a great insight for the development of potential therapeutic or preventive candidates for MA (or AMPH)-associated neuropsychotoxicity.


Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Metanfetamina/toxicidade , Proteína Quinase C-delta/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Animais , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/metabolismo , Transtorno Bipolar/psicologia , Dopamina/metabolismo , Humanos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia
16.
J Affect Disord ; 246: 745-753, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30623820

RESUMO

BACKGROUND: Glutamine plus glutamate (Glx), as well as N-acetylaspartate compounds, (NAAc), a marker of neuronal viability, are quantified with proton magnetic resonance spectroscopy (1H-MRS) and have been reported altered in psychotic disorders. However, few studies have compared these neurometabolites in bipolar disorder and schizophrenia. METHODS: Used 1H-MRS imaging from an axial supraventricular slab of gray matter (GM; medial-frontal and medial-parietal) and white matter (WM; bilateral-frontal and bilateral-parietal) voxels. Bipolar-I with history of psychosis (N = 43), schizophrenia (N = 41) and healthy controls (HC; N = 45) were studied (age range: 17-65). RESULTS: Amongst younger (age ≤40 years-median split) bipolar-I vs HC subjects Glx was increased (p < 0.001), while NAAc was reduced in WM (p < 0.001). In GM, NAAc (p < 0.001) and myo-inositol (p = 0.002) were reduced. Amongst older bipolar-I (vs HC) in WM regions we found reductions in: NAAc (p < 0.001), glycerophospho-choline + phospho-choline (p < 0.001), creatine + phospho-creatine (p < 0.001) and myo-inositol (p < 0.001); in GM only Glx was increased (p < 0.005). Contrasts between bipolar-I and schizophrenia produced fewer results: amongst younger subjects, reduced NAAc (p < 0.001) in WM and lower myo-inositol in GM (p = 0.04) in bipolar-I vs schizophrenia. In the older patients, bipolar-I had lower GM NAAc (p = 0.009) than schizophrenia. LIMITATIONS: First, differential exposure to antipsychotic and mood stabilizing medication across the groups. Second, differences in substance use histories among the groups. Third, neglect of peripheral and ventral cortical and subcortical regions. Finally, limited power to detect bipolar/schizophrenia differences. CONCLUSIONS: Chronically-treated bipolar-I have increased Glx and reduced NAAc, suggestive of neuronal dysfunction. The NAAc reductions are more severe in bipolar-I than in schizophrenia patients.


Assuntos
Transtorno Bipolar/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Espectroscopia de Prótons por Ressonância Magnética/métodos , Esquizofrenia/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adolescente , Adulto , Idoso , Antipsicóticos/uso terapêutico , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Transtorno Bipolar/metabolismo , Estudos de Casos e Controles , Feminino , Glutamina/metabolismo , Substância Cinzenta/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/metabolismo , Substância Branca/metabolismo , Adulto Jovem
17.
J Affect Disord ; 246: 418-421, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30599363

RESUMO

BACKGROUND: Lamotrigine is a useful treatment in bipolar depression but requires several weeks of dose titration before its clinical effects can be assessed. Animal experimental studies suggest that lamotrigine lowers glutamate release. The aim of the current study was to assess the effect of lamotrigine on brain glutamate in depressed bipolar patients and to determine whether baseline glutamate could be used to predict clinical response. METHODS: We studied 21 bipolar patients who received lamotrigine treatment for a current episode of depression. Before starting lamotrigine and after 10-12 weeks treatment, patients underwent proton magnetic resonance spectroscopy (MRS) scanning at 3 Tesla where levels of glutamate (measured as Glx) were determined in anterior cingulate cortex (ACC). RESULTS: Overall, lamotrigine treatment had no significant effect on Glx levels in ACC. However, in patients who responded clinically to lamotrigine treatment Glx concentrations were significantly increased. Baseline levels of Glx did not predict response to lamotrigine. LIMITATIONS: The main limitation of the study was the modest sample size. Most patients were medicated which may have modified the effect of lamotrigine on glutamate activity. MRS at 3T cannot give a reliable estimate of glutamate separate from its main metabolite, glutamine, and thus changes in Glx may not give a precise estimate of effects of lamotrigine on glutamate itself. CONCLUSION: Lamotrigine does not appear to have a direct effect on glutamate levels in ACC in bipolar patients. However, therapeutic improvement during lamotrigine was associated with increased Glx, suggesting that alterations in glutamatergic activity might be related to recovery from bipolar depression.


Assuntos
Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Encéfalo/metabolismo , Ácido Glutâmico/metabolismo , Lamotrigina/uso terapêutico , Espectroscopia de Prótons por Ressonância Magnética , Adulto , Transtorno Bipolar/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
18.
Bipolar Disord ; 21(2): 108-116, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30506611

RESUMO

OBJECTIVES: This limited review examines the role of the reticular activating system (RAS), especially the pedunculopontine nucleus (PPN), one site of origin of bottom-up gamma, in the symptoms of bipolar disorder (BD). METHODS: The expression of neuronal calcium sensor protein 1 (NCS-1) in the brains of BD patients is increased. It has recently been found that all PPN neurons manifest intrinsic membrane beta/gamma frequency oscillations mediated by high threshold calcium channels, suggesting that it is one source of bottom-up gamma. This review specifically addresses the involvement of these channels in the manifestation of BD. RESULTS: Excess NCS-1 was found to dampen gamma band oscillations in PPN neurons. Lithium, a first line treatment for BD, was found to decrease the effects of NCS-1 on gamma band oscillations in PPN neurons. Moreover, gamma band oscillations appear to epigenetically modulate gene transcription in PPN neurons, providing a new direction for research in BD. CONCLUSIONS: This is an area needing much additional research, especially since the dysregulation of calcium channels may help explain many of the disorders of arousal in, elicit unwanted neuroepigenetic modulation in, and point to novel therapeutic avenues for, BD.


Assuntos
Transtorno Bipolar/metabolismo , Ritmo Gama/fisiologia , Proteínas Sensoras de Cálcio Neuronal/metabolismo , Neuropeptídeos/metabolismo , Núcleo Tegmental Pedunculopontino/metabolismo , Animais , Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Canais de Cálcio/metabolismo , Epigênese Genética , Humanos , Neurônios/metabolismo , Neurônios/patologia
19.
Bipolar Disord ; 21(2): 151-158, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30506616

RESUMO

OBJECTIVES: Psychotic symptoms are a common feature in bipolar disorder (BD), especially during manic phases, and are associated with a more severe course of illness. However, not all bipolar subjects experience psychosis during the course of their illness, and this difference often guides assessment and pharmacological treatment. The aim of the present study is to elucidate, for the first time, the FDG uptake dysfunctions associated with psychosis in BD patients with and without a history of past psychotic symptoms, through a positron emission tomography (PET) approach. METHODS: Fifty BD patients with lifetime psychotic symptoms, 40 BD patients without lifetime psychotic symptoms and 27 healthy controls (HC) were recruited and underwent an 18F-FDG-PET session. RESULTS: Compared to HC, BD subjects shared common FDG uptake deficits in several brain areas, including insula, inferior temporal gyrus and middle occipital gyrus. Moreover, we found that BD patients with a history of past psychotic symptoms had a unique FDG uptake alteration in the right fusiform gyrus compared to both BD patients without lifetime psychotic symptoms and HC (all P < 0.01, cFWE corrected). CONCLUSIONS: Overall, our results suggest that FDG uptake alterations in brain regions involved in emotion regulation are a key feature of BD, regardless the presence of past psychosis. Finally, we demonstrated that the FDG uptake reduction in fusiform gyrus is associated with the presence of past psychotic symptoms in BD, ultimately leading towards the idea that the fusiform gyrus might be considered a putative biomarker of psychosis.


Assuntos
Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/metabolismo , Transtornos Psicóticos/metabolismo , Adulto , Transtorno Bipolar/psicologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Emoções , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/psicologia , Compostos Radiofarmacêuticos
20.
Mol Psychiatry ; 24(2): 198-217, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29679069

RESUMO

We summarize evidence supporting contemporary pharmacological treatment of phases of BD, including: mania, depression, and long-term recurrences, emphasizing findings from randomized, controlled trials (RCTs). Effective treatment of acute or dysphoric mania is provided by modern antipsychotics, some anticonvulsants (divalproex and carbamazepine), and lithium salts. Treatment of BD-depression remains unsatisfactory but includes some modern antipsychotics (particularly lurasidone, olanzapine + fluoxetine, and quetiapine) and the anticonvulsant lamotrigine; value and safety of antidepressants remain controversial. Long-term prophylactic treatment relies on lithium, off-label use of valproate, and growing use of modern antipsychotics. Lithium has unique evidence of antisuicide effects. Methods of evaluating treatments for BD rely heavily on meta-analysis, which is convenient but with important limitations. Underdeveloped treatment for BD-depression may reflect an assumption that effects of antidepressants are similar in BD as in unipolar major depressive disorder. Effective prophylaxis of BD is limited by the efficacy of available treatments and incomplete adherence owing to adverse effects, costs, and lack of ongoing symptoms. Long-term treatment of BD also is limited by access to, and support of expert, comprehensive clinical programs. Pursuit of improved, rationally designed pharmacological treatments for BD, as for most psychiatric disorders, is fundamentally limited by lack of coherent pathophysiology or etiology.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/metabolismo , Adulto , Antidepressivos/uso terapêutico , Antimaníacos/uso terapêutico , Antipsicóticos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Lítio/uso terapêutico , Compostos de Lítio/uso terapêutico
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