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1.
PLoS One ; 15(7): e0235409, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726314

RESUMO

OBJECTIVES: To identify inequalities in cancer survival rates for patients with a history of severe psychiatric illness (SPI) compared to those with no history of mental illness and explore differences in the provision of recommended cancer treatment as a potential explanation. DESIGN: Population-based retrospective cohort study using linked cancer registry and administrative data at ICES. SETTING: The universal healthcare system in Ontario, Canada. PARTICIPANTS: Colorectal cancer (CRC) patients diagnosed between April 1st, 2007 and December 31st, 2012. SPI history (schizophrenia, schizoaffective disorders, other psychotic disorders, bipolar disorders or major depressive disorders) was determined using hospitalization, emergency department, and psychiatrist visit data and categorized as 'no history of mental illness, 'outpatient SPI history', and 'inpatient SPI history'. MAIN OUTCOME MEASURES: Cancer-specific survival, non-receipt of surgical resection, and non-receipt of adjuvant chemotherapy or radiation. RESULTS: 24,507 CRC patients were included; 482 (2.0%) had an outpatient SPI history and 258 (1.0%) had an inpatient SPI history. Individuals with an SPI history had significantly lower survival rates and were significantly less likely to receive guideline recommended treatment than CRC patients with no history of mental illness. The adjusted HR for cancer-specific death was 1.69 times higher for individuals with an inpatient SPI (95% CI 1.36-2.09) and 1.24 times higher for individuals with an outpatient SPI history (95% CI 1.04-1.48). Stage II and III CRC patients with an inpatient SPI history were 2.15 times less likely (95% CI 1.07-4.33) to receive potentially curative surgical resection and 2.07 times less likely (95% CI 1.72-2.50) to receive adjuvant radiation or chemotherapy. These findings were consistent across multiple sensitivity analyses. CONCLUSIONS: Individuals with an SPI history experience inequalities in colorectal cancer care and survival within a universal healthcare system. Increasing advocacy and the availability of resources to support individuals with an SPI within the cancer system are warranted to reduce the potential for unnecessary harm.


Assuntos
Transtorno Bipolar/terapia , Neoplasias Colorretais/terapia , Transtorno Depressivo Maior/terapia , Esquizofrenia/terapia , Adulto , Transtorno Bipolar/complicações , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/patologia , Sobreviventes de Câncer/psicologia , Quimioterapia Adjuvante , Estudos de Coortes , Neoplasias Colorretais/complicações , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/patologia , Serviço Hospitalar de Emergência , Feminino , Hospitalização , Humanos , Pacientes Internados/psicologia , Masculino , Pessoa de Meia-Idade , Ontário/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Esquizofrenia/complicações , Esquizofrenia/epidemiologia , Esquizofrenia/patologia
2.
J Fr Ophtalmol ; 43(7): 586-597, 2020 Sep.
Artigo em Francês | MEDLINE | ID: mdl-32631695

RESUMO

Major depressive disorder, bipolar disorder and schizophrenia are currently among the most common psychiatric disorders, known to constitute a serious public health issue in terms of morbidity, mortality and functional handicap. Their pathophysiology is still unclear, but there is now increasing evidence supporting the existence of abnormalities of neurotransmission. As the retina is an extension of the central nervous system, it may be an interesting site of study which might provide a better understanding of the pathophysiology of psychiatric disorders. Several studies have demonstrated retinal abnormalities, with abnormal cone and rod responses on electroretinography (ERG), suggesting a process of functional neuronal loss, structurally supported by a decrease in the retinal nerve fiber layer thickness (RNFL) on optical coherence tomography (OCT), which suggests involvement of the molecular signal pathways of neurotransmission. These tests could be useful tools for diagnosing and monitoring psychiatric disorders. This article is an overview of the literature on retinal abnormalities observed in patients with major depressive disorder, bipolar disorder or schizophrenia, and discusses how they could be pathophysiologic markers.


Assuntos
Transtorno Bipolar/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Retina/diagnóstico por imagem , Retina/fisiologia , Esquizofrenia/fisiopatologia , Acuidade Visual/fisiologia , Transtorno Bipolar/complicações , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/patologia , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/patologia , Eletrorretinografia , Humanos , Fibras Nervosas/patologia , Fibras Nervosas/fisiologia , Retina/patologia , Células Fotorreceptoras Retinianas Cones/patologia , Células Fotorreceptoras Retinianas Cones/fisiologia , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/fisiologia , Esquizofrenia/complicações , Esquizofrenia/diagnóstico , Esquizofrenia/patologia , Tomografia de Coerência Óptica
3.
PLoS One ; 15(5): e0232826, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379845

RESUMO

This study aimed to investigate abnormalities in the gray matter and white matter (GM and WM, respectively) that are shared between schizophrenia (SZ) and bipolar disorder (BD). We used 3T-magnetic resonance imaging to examine patients with SZ, BD, or healthy control (HC) subjects (aged 20-50 years, N = 65 in each group). We generated modulated GM maps through voxel-based morphometry (VBM) for T1-weighted images and skeletonized fractional anisotropy, mean diffusion, and radial diffusivity maps through tract-based special statistics (TBSS) methods for diffusion tensor imaging (DTI) data. These data were analyzed using a generalized linear model with pairwise comparisons between groups with a family-wise error corrected P < 0.017. The VBM analysis revealed widespread decreases in GM volume in SZ compared to HC, but patients with BD showed GM volume deficits limited to the right thalamus and left insular lobe. The TBSS analysis showed alterations of DTI parameters in widespread WM tracts both in SZ and BD patients compared to HC. The two disorders had WM alterations in the corpus callosum, superior longitudinal fasciculus, internal capsule, external capsule, posterior thalamic radiation, and fornix. However, we observed no differences in GM volume or WM integrity between SZ and BD. The study results suggest that GM volume deficits in the thalamus and insular lobe along with widespread disruptions of WM integrity might be the common neural mechanisms underlying the pathologies of SZ and BD.


Assuntos
Transtorno Bipolar/patologia , Substância Cinzenta/patologia , Esquizofrenia/patologia , Substância Branca/patologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
4.
PLoS One ; 15(5): e0232798, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32437356

RESUMO

The treatment of depressive symptoms of bipolar disorder (BD) has received increasing attention. Recently, some studies have shown that bright light therapy (BLT) seems to be useful for BD depression. This meta-analysis is intended to further elucidate the role of BLT in depressive symptoms in patients with BD. Register of Systematic Reviews PROSPERO: CRD 420191 33642.Randomized controlled trials and cohort studies were retrieved in PubMed, Cochrane Library, EMbase, Web of Science, CINHAL, CBM, CNKI, VIP, and Wanfang from their foundation to March 2020, and other sources as supplement was also retrieved. Data were extracted after strict evaluation of literature quality by two researchers, and Meta-analysis was conducted on literatures that met the inclusion criteria. Meta-analysis was performed using Revman 5.3 software. In total, 12 studies including 847 patients with BD depression were included in our meta-analysis. A meta-analysis found significant differences between BLT and placebo for the following outcomes: (1) depression severity before and after BLT [SMD = -0.43, 95% CI (-0.73,-0.13), P<0.05] in RCT and [SMD = -2.12, 95% CI (-2.3,-1.94), P<0.05] in cohort studies.; (2) the efficacy of duration/timing of light therapy for depressive symptoms in BD [I2 = 85%, SMD = -1.88, 95% CI (-2.04, -1.71),P<0.05] and [I2 = 71%, SMD = -2.1,95% CI(-2.24, -1.96), P<0.05]; (3) the efficacy of different color/color temperatures for depressive symptoms in BD [I2 = 0%, SMD = -0.56, 95% CI (-0.92, -0.19), P<0.05] and [I2 = 97%, SMD = -1.74, 95% CI (-1.99, -1.49), P<0.05].We performed a subgroup meta-analysis of studies that used different light intensities. The results showed that light intensity≥5000 lux significantly reduced the severity of depression. And patients without psychotropic drugs revealed significantly decreased disease severity [I2 = 0%, SMD = -0.6, 95% CI (-1.06,-0.13), P<0.05]. Limitations of the study include studies only assessed short-term effects, and insufficient duration may underestimate adverse reactions and efficacy. Our results highlight the significant efficiency of BLT in the treatment of bipolar depression. Prospective studies with more rigorous design and consistent follow-up.


Assuntos
Transtorno Bipolar/terapia , Depressão/terapia , Fototerapia , Transtorno Bipolar/complicações , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/patologia , Depressão/complicações , Depressão/epidemiologia , Depressão/patologia , Feminino , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
PLoS One ; 15(3): e0230674, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218598

RESUMO

BACKGROUND: To estimate the potential gain in life expectancy from addressing modifiable risk factors for all-cause mortality (excluding suicide and deaths from accidents or violence) across specific serious mental illness (SMI) subgroups, namely schizophrenia, schizoaffective disorders, and bipolar disorders in a Western population. METHODS: We have used relative risks from recent meta-analyses to estimate the population attribution fraction (PAF) due to specific modifiable risk factors known to be associated with all-cause mortality within SMI. The potential gain in life expectancy at birth, age 50 and age 65 years were assessed by estimating the combined effect of modifiable risk factors from different contextual levels (behavioural, healthcare, social) and accounting for the effectiveness of existing interventions tackling these factors. Projections for annual gain in life expectancy at birth during a two-decade was estimated using the Annual Percentage Change (APC) formula. The predicted estimates were based on mortality rates for year 2014-2015. RESULTS: Based on the effectiveness of existing interventions targeting these modifiable risk factors, we estimated potential gain in life expectancy at birth of four (bipolar disorders), six (schizoaffective disorders), or seven years (schizophrenia). The gain in life expectancy at age 50 years was three (bipolar disorders) or five (schizophrenia and schizoaffective disorders) years. The projected gain in life expectancy at age 65 years was three (bipolar disorders) or four (schizophrenia and schizoaffective disorders) years. CONCLUSIONS: The implementation of existing interventions targeting modifiable risk factors could narrow the current mortality gap between the general and the SMI populations by 24% (men) to 28% (women). These projections represent ideal circumstances and without the limitation of overestimation which often comes with PAFs.


Assuntos
Transtorno Bipolar/diagnóstico , Expectativa de Vida , Transtornos Psicóticos/diagnóstico , Esquizofrenia/diagnóstico , Idoso , Transtorno Bipolar/mortalidade , Transtorno Bipolar/patologia , Bases de Dados Factuais , Feminino , Humanos , Estilo de Vida , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Transtornos Psicóticos/mortalidade , Transtornos Psicóticos/patologia , Fatores de Risco , Esquizofrenia/mortalidade , Esquizofrenia/patologia , Índice de Gravidade de Doença , Taxa de Sobrevida , Reino Unido
6.
J Neuroinflammation ; 17(1): 42, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000805

RESUMO

BACKGROUND: Previous individual studies have shown the differences in inflammatory cytokines and gray matter volumes between bipolar disorder (BD) and unipolar depression (UD). However, few studies have investigated the association between pro-inflammatory cytokines and differences in brain gray matter volumes between BD and UD. METHODS: In this study, 72 BD patients and 64 UD patients were enrolled, with comparable gender and age distributions (33.8% males and an average age of 39.3 ± 13.7 years). Each participant underwent metabolic profiling (including body mass index (BMI), glucose, triglyceride, high-density lipoprotein (HDL), leptin, insulin, adiponectin), pro-inflammatory cytokine (including soluble interleukin-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), soluble tumor necrosis factor receptor type 1 (sTNF-R1) examinations, and structural magnetic resonance imaging exams. Voxel-based morphometry was performed to investigate the gray matter volume differences between BD and UD patients. Correlations between pro-inflammatory cytokines and the gray matter volume difference were analyzed. RESULTS: Compared to UD patients, the BD group had significantly higher BMI, and higher levels of sIL-6R and sTNF-R1 than the UD patients. The BMI significantly correlated with the level of pro-inflammatory cytokines. Adjusted for age, sex, BMI, duration of illness and total intracranial volume, the BD individuals had significantly more reduced gray matter volumes over 12 areas: R. cerebellar lobule VIII, R. putamen, L. putamen, R. superior frontal gyrus, L. lingual gyrus, L. precentral gyrus, R. fusiform gyrus, L. calcarine, R. precuneus, L. inferior temporal gyrus, L. hippocampus, and L. superior frontal gyrus. These 12 gray matter volume differences between BP and UD patients negatively correlated with sIL-6R and sTNF-R1 levels. CONCLUSIONS: Our results suggested that BD patients had higher BMI and pro-inflammatory cytokine levels in comparison to UD patients, especially IL-6 and sTNF-R1, which may contribute to greater gray matter reductions in BD patients in comparison to UD patients. The results support the neuro-inflammation pathophysiology mechanism in mood disorder. It is clinically important to monitor BMI, which, in this investigation, positively correlated with levels of inflammatory cytokines.


Assuntos
Transtorno Bipolar/imunologia , Transtorno Bipolar/metabolismo , Transtorno Depressivo/imunologia , Transtorno Depressivo/metabolismo , Substância Cinzenta/patologia , Adulto , Idoso , Transtorno Bipolar/patologia , Índice de Massa Corporal , Citocinas/metabolismo , Transtorno Depressivo/patologia , Encefalite/imunologia , Encefalite/metabolismo , Encefalite/patologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
PLoS One ; 15(1): e0225353, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31986152

RESUMO

The Alda score is commonly used to quantify lithium responsiveness in bipolar disorder. Most often, this score is dichotomized into "responder" and "non-responder" categories, respectively. This practice is often criticized as inappropriate, since continuous variables are thought to invariably be "more informative" than their dichotomizations. We therefore investigated the degree of informativeness across raw and dichotomized versions of the Alda score, using data from a published study of the scale's inter-rater reliability (n = 59 raters of 12 standardized vignettes each). After learning a generative model for the relationship between observed and ground truth scores (the latter defined by a consensus rating of the 12 vignettes), we show that the dichotomized scale is more robust to inter-rater disagreement than the raw 0-10 scale. Further theoretical analysis shows that when a measure's reliability is stronger at one extreme of the continuum-a scenario which has received little-to-no statistical attention, but which likely occurs for the Alda score ≥ 7-dichotomization of a continuous variable may be more informative concerning its ground truth value, particularly in the presence of noise. Our study suggests that research employing the Alda score of lithium responsiveness should continue using the dichotomous definition, particularly when data are sampled across multiple raters.


Assuntos
Intervalos de Confiança , Compostos de Lítio/efeitos adversos , Probabilidade , Animais , Transtorno Bipolar/metabolismo , Transtorno Bipolar/patologia , Humanos , Linguagens de Programação
8.
J Biomed Sci ; 27(1): 16, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900153

RESUMO

BACKGROUND: Over-stimulation of dopamine signaling is thought to underlie the pathophysiology of a list of mental disorders, such as psychosis, mania and attention-deficit/hyperactivity disorder. These disorders are frequently associated with cognitive deficits in attention or learning and memory, suggesting that persistent activation of dopamine signaling may change neural plasticity to induce cognitive or emotional malfunction. METHODS: Dopamine transporter knockdown (DAT-KD) mice were used to mimic a hyper-dopamine state. Novel object recognition (NOR) task was performed to assess the recognition memory. To test the role of dopamine D3 receptor (D3R) on NOR, DAT-KD mice were treated with either a D3R antagonist, FAUC365 or by deletion of D3R. Total or phospho-GSK3 and -ERK1/2 signals in various brain regions were measured by Western blot analyses. To examine the impact of GSK3 signal on NOR, wild-type mice were systemically treated with GSK3 inhibitor SB216763 or, micro-injected with lentiviral shRNA of GSK3ß or GSK3α in the medial prefrontal cortex (mPFC). RESULTS: We confirmed our previous findings that DAT-KD mice displayed a deficit in NOR memory, which could be prevented by deletion of D3R or exposure to FAUC365. In WT mice, p-GSK3α and p-GSK3ß were significantly decreased in the mPFC after exposure to novel objects; however, the DAT-KD mice exhibited no such change in mPFC p-GSK3α/ß levels. DAT-KD mice treated with FAUC365 or with D3R deletion exhibited restored novelty-induced GSK3 dephosphorylation in the mPFC. Moreover, inhibition of GSK3 in WT mice diminished NOR performance and impaired recognition memory. Lentiviral shRNA knockdown of GSK3ß, but not GSK3α, in the mPFC of WT mice also impaired NOR. CONCLUSION: These findings suggest that D3R acts via GSK3ß signaling in the mPFC to play a functional role in NOR memory. In addition, treatment with D3R antagonists may be a reasonable approach for ameliorating cognitive impairments or episodic memory deficits in bipolar disorder patients.


Assuntos
Transtorno Bipolar/genética , Disfunção Cognitiva/genética , Glicogênio Sintase Quinase 3 beta/genética , Quinase 3 da Glicogênio Sintase/genética , Receptores de Dopamina D3/genética , Animais , Transtorno Bipolar/patologia , Disfunção Cognitiva/patologia , Dopamina/genética , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases/genética , Memória Episódica , Camundongos , Córtex Pré-Frontal/metabolismo
9.
Hum Genet ; 139(2): 185-198, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31813014

RESUMO

Major psychiatric traits are genetically inter-correlated with one another, but it not well known which genes play pleiotropic effects across different traits. We curated and compared genes identified from large-scale genome-wide association studies for seven psychiatric traits, including depression, bipolar disorder, schizophrenia, autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety and neuroticism. We then explored biological functions of the top pleiotropic genes. A total of 243 cross-trait genes were identified for the seven traits. Except for autism spectrum disorder, there was significant enrichment of overlapped genes across these psychiatric traits. Chromosome 5q14.3, 11q23.2, and 7p22.3 are the three genomic regions conferring highest pleiotropic effects for these psychiatric traits. The long non-coding gene LINC00461 showed the highest pleiotropic effects on five psychiatric traits. In silico and functional studies with mice support the vital role of LINC00461 in neurodevelopment. In sum, our study provides insights into the shared genetic liability among major psychiatric traits.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Transtornos Mentais/genética , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Animais , Transtorno Autístico/genética , Transtorno Autístico/patologia , Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/patologia , Hipocampo/metabolismo , Humanos , Transtornos Mentais/patologia , Camundongos , Fenótipo , RNA Longo não Codificante/genética , Fatores de Risco , Esquizofrenia/genética , Esquizofrenia/patologia
10.
J Psychiatry Neurosci ; 45(1): 182-187, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31829002

RESUMO

Background: The CACNA1C gene encodes the 1C subunit of L-type voltage-gated calcium channels and has been associated with several psychiatric syndromes ­ including bipolar disorder ­ in several genome-wide association studies. Experimental and clinical studies have reported changes with respect to behaviour and biomarkers in risk allele carriers, corroborating the essential role of the CACNA1C gene in neurons, during development and in the mature brain. However, the association of this gene with regional cortical thickness has not been evaluated in patients with bipolar disorder. Methods: Using magnetic resonance imaging, we measured the average cortical thickness of 68 brain regions in 87 patients genotyped for the single-nucleotide polymorphism rs1006737 in CACNA1C. Results: We found associations with the mean thickness of several cortical areas: the left lateral orbitofrontal and rostral anterior cingulate cortices, as well as other parts of the frontal and parietal cortices. Limitations: This cross-sectional cohort study could not fully differentiate correlation from causation. Conclusion: The CACNA1C polymorphism rs1006737 is associated with the mean thickness of cortical brain areas that have been shown to be altered in bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Canais de Cálcio Tipo L/genética , Córtex Cerebral/patologia , Imagem por Ressonância Magnética , Adulto , Transtorno Bipolar/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético
11.
Genes (Basel) ; 10(11)2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31752442

RESUMO

The molecular mechanisms underlying bipolar disorder (BPD) have remained largely unknown. Postmortem brain tissue studies comparing BPD patients with healthy controls have produced a heterogeneous array of potentially implicated protein-coding RNAs. We hypothesized that dysregulation of not only coding, but multiple classes of RNA (coding RNA, long non-coding (lnc) RNA, circular (circ) RNA, and/or alternative splicing) underlie the pathogenesis of BPD. Using non-polyadenylated libraries we performed RNA sequencing in postmortem human medial frontal gyrus tissue from BPD patients and healthy controls. Twenty genes, some of which not previously implicated in BPD, were differentially expressed (DE). PCR validation and replication confirmed the implication of these DE genes. Functional in silico analyses identified enrichment of angiogenesis, vascular system development and histone H3-K4 demethylation. In addition, ten lncRNA transcripts were differentially expressed. Furthermore, an overall increased number of alternative splicing events in BPD was detected, as well as an increase in the number of genes carrying alternative splicing events. Finally, a large reservoir of circRNAs populating brain tissue not affected by BPD is described, while in BPD altered levels of two circular transcripts, cNEBL and cEPHA3, are reported. cEPHA3, hitherto unlinked to BPD, is implicated in developmental processes in the central nervous system. Although we did not perform replication analyses of non-coding RNA findings, our findings hint that RNA dysregulation in BPD is not limited to coding regions, opening avenues for future pharmacological investigations and biomarker research.


Assuntos
Processamento Alternativo , Transtorno Bipolar/genética , Córtex Pré-Frontal/patologia , RNA Circular/metabolismo , RNA Longo não Codificante/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/patologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , RNA-Seq
12.
J Affect Disord ; 259: 404-412, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610997

RESUMO

BACKGROUND: Bipolar disorder (BD) is a severe mental illness characterised by reduced grey matter (GM) volumes and cortical thickness, and disrupted white matter (WM) microstructure. Activation of indoleamine 2,3-dioxygenase following a pro-inflammatory state could increase the amount of tryptophan (Trp) converted to kynurenine (Kyn) possibly leading to the production of detrimental catabolites of the Kyn pathway with neurotoxic effects. We investigated if peripheral levels of Trp-and Kyn and the breakdown of Trp-into Kyn (Kyn/Trp-ratio) are related to WM and GM integrity in BD. METHODS: Peripheral levels of Trp-and Kyn were analysed in 72 patients with BD and 33 controls. Patients also underwent MRI in a Philips 3T scanner. RESULTS: Patients showed higher Kyn levels and Kyn/Trp-ratio compared to controls. MRI analyses performed in patients with BD showed a negative association between the Kyn/Trp-ratio and the integrity of corpus callosum microstructure, the volume of the amygdala and cortical thickness in fronto-parietal regions. LIMITATION: The lack of information on the levels of downstream metabolites of Kyn prevent us to confirm the possible unbalance between quinolinic and kynurenic acids as well as their possible relationship with changes in GM and WM markers. The activation of the Kyn pathway as suggested by the increased Kyn/Trp-ratio may lead to an imbalance of the neurotoxic vs the neuroprotective arm of the biochemical pathway, resulting in significant changes in GM and WM regions of brain areas strongly implicated in the pathophysiology of BD, such as amygdala and corpus callosum.


Assuntos
Transtorno Bipolar/patologia , Substância Cinzenta/patologia , Cinurenina/metabolismo , Triptofano/metabolismo , Substância Branca/patologia , Adulto , Biomarcadores/metabolismo , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Substância Cinzenta/metabolismo , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Substância Branca/metabolismo
13.
Cell Rep ; 29(3): 764-777.e5, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618642

RESUMO

RNA sequencing analyses are often limited to identifying lowest p value transcripts, which does not address polygenic phenomena. To overcome this limitation, we developed an integrative approach that combines large-scale transcriptomic meta-analysis of patient brain tissues with single-cell sequencing data of CNS neurons, short RNA sequencing of human male- and female-originating cell lines, and connectomics of transcription factor and microRNA interactions with perturbed transcripts. We used this pipeline to analyze cortical transcripts of schizophrenia and bipolar disorder patients. Although these pathologies show massive transcriptional parallels, their clinically well-known sexual dimorphisms remain unexplained. Our method reveals the differences between afflicted men and women and identifies disease-affected pathways of cholinergic transmission and gp130-family neurokine controllers of immune function interlinked by microRNAs. This approach may open additional perspectives for seeking biomarkers and therapeutic targets in other transmitter systems and diseases.


Assuntos
Transtorno Bipolar/patologia , Esquizofrenia/patologia , Transcriptoma , Biomarcadores/metabolismo , Transtorno Bipolar/genética , Transtorno Bipolar/imunologia , Linhagem Celular , Neurônios Colinérgicos/metabolismo , Conectoma , Feminino , Ontologia Genética , Humanos , Masculino , MicroRNAs/metabolismo , Receptores de Taquicininas/metabolismo , Esquizofrenia/genética , Esquizofrenia/imunologia , Análise de Sequência de RNA , Caracteres Sexuais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
14.
Sci Rep ; 9(1): 14877, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619735

RESUMO

Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) integrates dopaminergic signaling into that of several other neurotransmitters. Calcineurin (CaN), located downstream of dopaminergic pathways, inactivates DARPP-32 by dephosphorylation. Despite several studies have examined their expression levels of gene and protein in postmortem patients' brains, they rendered inconsistent results. In this study, protein expression levels of DARPP-32 and CaN were measured by enzyme-linked immunosorbent assay (ELISA) in the prefrontal cortex (PFC), and nucleus accumbens (NAc) of 49 postmortem samples from subjects with schizophrenia, bipolar disorder, and normal controls. We also examined the association between this expression and genetic variants of 8 dopaminergic system-associated molecules for 55 SNPs in the same postmortem samples. In the PFC of patients with schizophrenia, levels of DARPP-32 were significantly decreased, while those of CaN tended to increase. In the NAc, both of DARPP-32 and CaN showed no significant alternations in patients with schizophrenia or bipolar disorder. Further analysis of the correlation of DARPP-32 and CaN expressions, we found that positive correlations in controls and schizophrenia in PFC, and schizophrenia in NAc. In PFC, the expression ratio of DARPP-32/CaN were significantly lower in schizophrenia than controls. We also found that several of the aforementioned SNPs may predict protein expression, one of which was confirmed in a second independent sample set. This differential expression of DARPP-32 and CaN may reflect potential molecular mechanisms underlying the pathogenesis of schizophrenia and bipolar disorder, or differences between these two major psychiatric diseases.


Assuntos
Transtorno Bipolar/genética , Calcineurina/genética , Fosfoproteína 32 Regulada por cAMP e Dopamina/genética , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Esquizofrenia/genética , Adulto , Animais , Autopsia , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/metabolismo , Transtorno Bipolar/patologia , Estudos de Casos e Controles , Feminino , Expressão Gênica , Humanos , Masculino , Núcleo Accumbens/patologia , Polimorfismo de Nucleotídeo Único , Córtex Pré-Frontal/patologia , Esquizofrenia/diagnóstico , Esquizofrenia/metabolismo , Esquizofrenia/patologia
15.
eNeuro ; 6(5)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31540999

RESUMO

Bipolar disorder (BP) and schizophrenia (SCZ) are major psychiatric disorders, but the molecular mechanisms underlying the complicated pathologies of these disorders remain unclear. It is difficult to establish adequate in vitro models for pathological analysis because of the heterogeneity of these disorders. In the present study, to recapitulate the pathologies of these disorders in vitro, we established in vitro models by differentiating mature neurons from human induced pluripotent stem cells (hiPSCs) derived from BP and SCZ patient with contributive copy number variations, as follows: two BP patients with PCDH15 deletion and one SCZ patient with RELN deletion. Glutamatergic neurons and GABAergic neurons were induced from hiPSCs under optimized conditions. Both types of induced neurons from both hiPSCs exhibited similar phenotypes of MAP2 (microtubule-associated protein 2)-positive dendrite shortening and decreasing synapse numbers. Additionally, we analyzed isogenic PCDH15- or RELN-deleted cells. The dendrite and synapse phenotypes of isogenic neurons were partially similar to those of patient-derived neurons. These results suggest that the observed phenotypes are general phenotypes of psychiatric disorders, and our in vitro models using hiPSC-based technology may be suitable for analysis of the pathologies of psychiatric disorders.


Assuntos
Transtorno Bipolar/patologia , Técnicas de Cultura de Células/métodos , Neurônios/patologia , Células-Tronco Pluripotentes , Esquizofrenia/patologia , Adulto , Transtorno Bipolar/genética , Caderinas/genética , Moléculas de Adesão Celular Neuronais/genética , Células Cultivadas , Variações do Número de Cópias de DNA , Proteínas da Matriz Extracelular/genética , Feminino , Humanos , Técnicas In Vitro , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Esquizofrenia/genética , Serina Endopeptidases/genética
16.
Sci Data ; 6(1): 180, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551426

RESUMO

Schizophrenia and bipolar disorder are serious mental illnesses that affect more than 2% of adults. While large-scale genetics studies have identified genomic regions associated with disease risk, less is known about the molecular mechanisms by which risk alleles with small effects lead to schizophrenia and bipolar disorder. In order to fill this gap between genetics and disease phenotype, we have undertaken a multi-cohort genomics study of postmortem brains from controls, individuals with schizophrenia and bipolar disorder. Here we present a public resource of functional genomic data from the dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and 46) of 986 individuals from 4 separate brain banks, including 353 diagnosed with schizophrenia and 120 with bipolar disorder. The genomic data include RNA-seq and SNP genotypes on 980 individuals, and ATAC-seq on 269 individuals, of which 264 are a subset of individuals with RNA-seq. We have performed extensive preprocessing and quality control on these data so that the research community can take advantage of this public resource available on the Synapse platform at http://CommonMind.org .


Assuntos
Transtorno Bipolar , Esquizofrenia , Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Estudos de Coortes , Epigenômica , Humanos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Esquizofrenia/genética , Esquizofrenia/patologia , Transcriptoma
17.
Sci Rep ; 9(1): 13638, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541155

RESUMO

Bipolar disorder (BD) has been linked to disrupted structural and functional connectivity between prefrontal networks and limbic brain regions. Studies of patients with pediatric bipolar disorder (PBD) can help elucidate the developmental origins of altered structural connectivity underlying BD and provide novel insights into the aetiology of BD. Here we compare the network properties of whole-brain structural connectomes of euthymic PBD patients with psychosis, a variant of PBD, and matched healthy controls. Our results show widespread changes in the structural connectivity of PBD patients with psychosis in both cortical and subcortical networks, notably affecting the orbitofrontal cortex, frontal gyrus, amygdala, hippocampus and basal ganglia. Graph theoretical analysis revealed that PBD connectomes have fewer hubs, weaker rich club organization, different modular fingerprint and inter-modular communication, compared to healthy participants. The relationship between network features and neurocognitive and psychotic scores was also assessed, revealing trends of association between patients' IQ and affective psychotic symptoms with the local efficiency of the orbitofrontal cortex. Our findings reveal that PBD with psychosis is associated with significant widespread changes in structural network topology, thus strengthening the hypothesis of a reduced capacity for integrative processing of information across brain regions. Localised network changes involve core regions for emotional processing and regulation, as well as memory and executive function, some of which show trends of association with neurocognitive faculties and symptoms. Together, our findings provide the first comprehensive characterisation of the alterations in local and global structural brain connectivity and network topology, which may contribute to the deficits in cognition and emotion processing and regulation found in PBD.


Assuntos
Transtorno Bipolar/psicologia , Encéfalo/patologia , Conectoma/métodos , Imagem de Difusão por Ressonância Magnética/métodos , Adolescente , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/fisiopatologia , Gânglios da Base/patologia , Gânglios da Base/fisiopatologia , Transtorno Bipolar/patologia , Transtorno Bipolar/fisiopatologia , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Criança , Feminino , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Masculino , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia
18.
Curr Med Chem ; 26(38): 6942-6969, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31385763

RESUMO

BACKGROUND: Attention deficit hyperactivity (ADHD) disorder is a neurodevelopmental disorder characterized by inattention, hyperactivity, disruptive behaviour, and impulsivity. Despite considered typical of children for a long time, the persistence of ADHD symptoms in adulthood gained increasing interest during the last decades. Indeed, its diagnosis, albeit controversial, is rarely carried out even because ADHD is often comorbid with several other psychiatric diosrders, in particular with bipolar disorders (BDs), a condition that complicates the clinical picture, assessment and treatment. AIMS: The aim of this paper was to systematically review the scientific literature on the neurobiological, clinical features and current pharmacological management of ADHD comorbid with BDs across the entire lifespan, with a major focus on the adulthood. DISCUSSION: The pharmacology of ADHD-BD in adults is still empirical and influenced by the individual experience of the clinicians. Stimulants are endowed of a prompt efficacy and safety, whilst non-stimulants are useful when a substance abuse history is detected, although they require some weeks in order to be fully effective. In any case, an in-depth diagnostic and clinical evaluation of the single individual is mandatory. CONCLUSION: The comorbidity of ADHD with BD is still a controversial matter, as it is the notion of adult ADHD as a distinct nosological category. Indeed, some findings highlighted the presence of common neurobiological mechanisms and overlapping clinical features, although disagreement does exist. In any case, while expecting to disentangle this crucial question, a correct management of this comorbidity is essential, which requires the co-administration of mood stabilizers. Further controlled clinical studies in large samples of adult ADHD-BD patients appear extremely urgent in order to better define possible therapeutic guidelines, as well as alternative approaches for this potentially invalidating condition.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno Bipolar/complicações , Estimulantes do Sistema Nervoso Central/uso terapêutico , Longevidade , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/patologia , Criança , Diagnóstico por Imagem , Humanos
19.
Biomolecules ; 9(9)2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31450809

RESUMO

Depressed mood, which can occur in the context of major depressive disorder, bipolar disorder, and other conditions, represents a serious threat to public health and wellness. Conventional treatments are not effective for a significant proportion of patients and interventions that are often beneficial for treatment-refractory depression are not widely available. There is, therefore, an immense need to identify novel antidepressant strategies, particularly strategies that target physiological pathways that are distinct from those addressed by conventional treatments. There is growing evidence from human neuroimaging, genetics, epidemiology, and animal studies that disruptions in brain energy production, storage, and utilization are implicated in the development and maintenance of depression. Creatine, a widely available nutritional supplement, has the potential to improve these disruptions in some patients, and early clinical trials indicate that it may have efficacy as an antidepressant agent.


Assuntos
Creatina/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Animais , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/patologia , Encéfalo/metabolismo , Estudos Clínicos como Assunto , Transtorno Depressivo Maior/patologia , Metabolismo Energético , Humanos , Apoio Nutricional , Fosfocreatina/metabolismo
20.
Biol Psychiatry ; 86(7): 545-556, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31443932

RESUMO

BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects. METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects. RESULTS: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects. CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.


Assuntos
Transtorno Bipolar , Encéfalo/patologia , Predisposição Genética para Doença , Esquizofrenia , Adulto , Transtorno Bipolar/genética , Transtorno Bipolar/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/genética , Esquizofrenia/patologia , Adulto Jovem
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