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1.
Medicine (Baltimore) ; 99(27): e21068, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629736

RESUMO

BACKGROUND: Alterations in the levels of arginine and its related catabolic products (ie, ornithine, citrulline, and argininosuccinate) in the urea and nitric oxide cycles were reported to play roles in the pathogenesis of major depressive disorder (MDD). The aim of this meta-analysis study is to explore the associations between arginine with its related catabolic products and MDD, and to discuss the possible role of arginine catabolism in the pathoetiology of MDD. METHODS: This study will be conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The English language literature published in the databases of PubMed, EMBASE, PsycINFO and Web of Science will be systematically searched. Forest plots will be used to estimate the associations between arginine and its related catabolic products with MDD. Subgroup analysis and meta-regression will also be performed to investigate the source of the potential heterogeneity. Sensitivity analysis will be performed to strengthen the results and to investigate whether any single study would have a significant effect on the results of meta-analysis. Publication bias will be tested for using the funnel plot with Begg test and Egger test. The Newcastle-Ottawa Scale will be applied to assess the risk of bias of observational studies. RESULTS: An integrated assessment of arginine with its related catabolic products may contribute to predict the risk of MDD. ETHICS AND DISSEMINATION: The results of associations between arginine with its related catabolic products and MDD will be reported in a peer-reviewed publication. With our findings from this meta-analysis, we hope to provide the most up-to-date evidence for the contributions of arginine and related catabolic products to predict the risk of MDD. SYSTEMATIC REVIEW REGISTRATION: The protocol of current meta-analysis has been registered at the Open Science Framework [Available at: https://doi.org/10.17605/osf.io/7fn59].


Assuntos
Arginina/metabolismo , Transtorno Depressivo Maior/metabolismo , Redes e Vias Metabólicas/fisiologia , Óxido Nítrico/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Humanos , Medição de Risco , Sensibilidade e Especificidade
2.
Expert Opin Pharmacother ; 21(14): 1685-1698, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32584616

RESUMO

Introduction: Postpartum depressive disorder (PPD) is a burdensome medical condition. To date, only one treatment (Brexanolone) has undergone registrational trials and is approved in the United States with an indication for the treatment of PPD. However, other treatments are prescribed and have been tested for this condition. Herein, the authors review the available scientific evidence pertaining to the somatic treatments of PPD. Areas covered: The authors evaluate the published open-label and randomized controlled trials (RCTs), examine the biological mechanisms of PPD treatments, and evaluate how the available data translates into information that may be useful for clinical practice. Expert opinion: Antidepressants have long been the mainstay of PPD treatment, despite the limited evidence from randomized clinical trials that supports this practice. Brexanolone improves treatment options for women with PPD. However, the relatively burdensome administration and monitoring protocol, along with the high cost of the medication, limit the possibility for an extensive use of this medication. Large, randomized, controlled trials of hormonal treatments in patients with PPD are warranted. Also, treatment with mood stabilizers and/or antipsychotics in women with major depressive disorder, who meet the DSM-5 mixed features specifiers in the post-partum period, should be tested in controlled clinical trials.


Assuntos
Antidepressivos/uso terapêutico , Depressão Pós-Parto/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Pregnanolona/uso terapêutico , beta-Ciclodextrinas/uso terapêutico , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Depressão Pós-Parto/metabolismo , Transtorno Depressivo Maior/metabolismo , Combinação de Medicamentos , Monitoramento de Medicamentos , Estrogênios/sangue , Feminino , Humanos , Ocitocina/sangue , Pregnanolona/administração & dosagem , Pregnanolona/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estimulação Magnética Transcraniana , Resultado do Tratamento , Estados Unidos , beta-Ciclodextrinas/administração & dosagem , beta-Ciclodextrinas/efeitos adversos
3.
Am J Psychiatry ; 177(8): 686-705, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32456504

RESUMO

Major depressive disorder is a common psychiatric disorder associated with marked suffering, morbidity, mortality, and cost. The World Health Organization projects that by 2030, major depression will be the leading cause of disease burden worldwide. While numerous treatments for major depression exist, many patients do not respond adequately to traditional antidepressants. Thus, more effective treatments for major depression are needed, and targeting certain hormonal systems is a conceptually based approach that has shown promise in the treatment of this disorder. A number of hormones and hormone-manipulating compounds have been evaluated as monotherapies or adjunctive treatments for major depression, with therapeutic actions attributable not only to the modulation of endocrine systems in the periphery but also to the CNS effects of hormones on non-endocrine brain circuitry. The authors describe the physiology of the hypothalamic-pituitary-adrenal (HPA), hypothalamic-pituitary thyroid (HPT), and hypothalamic-pituitary-gonadal (HPG) axes and review the evidence for selected hormone-based interventions for the treatment of depression in order to provide an update on the state of this field for clinicians and researchers. The review focuses on the HPA axis-based interventions of corticotropin-releasing factor antagonists and the glucocorticoid receptor antagonist mifepristone, the HPT axis-based treatments of thyroid hormones (T3 and T4), and the HPG axis-based treatments of estrogen replacement therapy, the progesterone derivative allopregnanolone, and testosterone. While some treatments have largely failed to translate from preclinical studies, others have shown promising initial results and represent active fields of study in the search for novel effective treatments for major depression.


Assuntos
Transtorno Depressivo Maior , Glândulas Endócrinas/fisiologia , Hormônios , Sistemas Neurossecretores/fisiologia , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/terapia , Hormônios/metabolismo , Hormônios/farmacologia , Humanos , Resultado do Tratamento
4.
Neuron ; 106(6): 912-926.e5, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32304628

RESUMO

Depression is a common disorder that affects women at twice the rate of men. Here, we report that long non-coding RNAs (lncRNAs), a recently discovered class of regulatory transcripts, represent about one-third of the differentially expressed genes in the brains of depressed humans and display complex region- and sex-specific patterns of regulation. We identified the primate-specific, neuronal-enriched gene LINC00473 as downregulated in prefrontal cortex (PFC) of depressed females but not males. Using viral-mediated gene transfer to express LINC00473 in adult mouse PFC neurons, we mirrored the human sex-specific phenotype by inducing stress resilience solely in female mice. This sex-specific phenotype was accompanied by changes in synaptic function and gene expression selectively in female mice and, along with studies of human neuron-like cells in culture, implicates LINC00473 as a CREB effector. Together, our studies identify LINC00473 as a female-specific driver of stress resilience that is aberrant in female depression.


Assuntos
Transtorno Depressivo Maior/genética , Córtex Pré-Frontal/metabolismo , RNA Longo não Codificante/genética , Resiliência Psicológica , Estresse Psicológico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Comportamento Animal , Depressão/genética , Depressão/metabolismo , Transtorno Depressivo Maior/metabolismo , Regulação para Baixo , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Neurônios/metabolismo , RNA Longo não Codificante/metabolismo , RNA-Seq , Fatores Sexuais , Estresse Psicológico/metabolismo , Adulto Jovem
5.
Nat Neurosci ; 23(6): 771-781, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32341540

RESUMO

Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of disability for almost three decades. Past molecular studies of MDD employed bulk homogenates of postmortem brain tissue, which obscures gene expression changes within individual cell types. Here we used single-nucleus transcriptomics to examine ~80,000 nuclei from the dorsolateral prefrontal cortex of male individuals with MDD (n = 17) and of healthy controls (n = 17). We identified 26 cellular clusters, and over 60% of these showed differential gene expression between groups. We found that the greatest dysregulation occurred in deep layer excitatory neurons and immature oligodendrocyte precursor cells (OPCs), and these contributed almost half (47%) of all changes in gene expression. These results highlight the importance of dissecting cell-type-specific contributions to the disease and offer opportunities to identify new avenues of research and novel targets for treatment.


Assuntos
Transtorno Depressivo Maior/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neurônios/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Córtex Pré-Frontal/metabolismo , Transcriptoma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Redes Reguladoras de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
Nat Commun ; 11(1): 1635, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242018

RESUMO

It remains unclear why many patients with depression do not respond to antidepressant treatment. In three cohorts of individuals with depression and treated with serotonin-norepinephrine reuptake inhibitor (N = 424) we show that responders, but not non-responders, display an increase of GPR56 mRNA in the blood. In a small group of subjects we also show that GPR56 is downregulated in the PFC of individuals with depression that died by suicide. In mice, we show that chronic stress-induced Gpr56 downregulation in the blood and prefrontal cortex (PFC), which is accompanied by depression-like behavior, and can be reversed by antidepressant treatment. Gpr56 knockdown in mouse PFC is associated with depressive-like behaviors, executive dysfunction and poor response to antidepressant treatment. GPR56 peptide agonists have antidepressant-like effects and upregulated AKT/GSK3/EIF4 pathways. Our findings uncover a potential role of GPR56 in antidepressant response.


Assuntos
Antidepressivos/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Receptores Acoplados a Proteínas-G/metabolismo , Adulto , Animais , Estudos de Coortes , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Feminino , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptores Acoplados a Proteínas-G/genética , Inibidores de Captação de Serotonina/administração & dosagem , Resultado do Tratamento
7.
BMC Psychiatry ; 20(1): 145, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245436

RESUMO

BACKGROUND: Major depressive disorder and bipolar disorder are prevalent and debilitating psychiatric disorders that are difficult to distinguish, as their diagnosis is based on behavioural observations and subjective symptoms. Quantitative protein profile analysis might help to objectively distinguish between these disorders and increase our understanding of their pathophysiology. Thus, this study was conducted to compare the peripheral protein profiles between the two disorders. METHODS: Serum samples were collected from 18 subjects with major depressive disorder and 15 subjects with bipolar disorder. After depleting abundant proteins, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and label-free quantification were performed. Data-dependent acquisition data were statistically analysed from the samples of 15 subjects with major depressive disorder and 10 subjects with bipolar disorder who were psychotropic drug-free. Two-sided t-tests were performed for pairwise comparisons of proteomes to detect differentially-expressed proteins (DEPs). Ingenuity Pathway Analysis of canonical pathways, disease and functions, and protein networks based on these DEPs was further conducted. RESULTS: Fourteen DEPs were significant between subjects with major depressive disorder and those with bipolar disorder. Ras-related protein Rab-7a (t = 5.975, p = 4.3 × 10- 6) and Rho-associated protein kinase 2 (t = 4.782, p = 8.0 × 10- 5) were significantly overexpressed in subjects with major depressive disorder and Exportin-7 (t = -4.520, p = 1.5 × 10- 4) was significantly overexpressed in subjects with bipolar disorder after considering multiple comparisons. Bioinformatics analysis showed that cellular functions and inflammation/immune pathways were significantly different. CONCLUSIONS: Ras-related protein Rab-7a, Rho-associated protein kinase 2, and Exportin-7 were identified as potential peripheral protein candidates to distinguish major depressive disorder and bipolar disorder. Further large sample studies with longitudinal designs and validation processes are warranted.


Assuntos
Transtorno Bipolar/sangue , Proteínas Sanguíneas/metabolismo , Transtorno Depressivo Maior/sangue , Adulto , Biomarcadores/sangue , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/metabolismo , Cromatografia Líquida , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/metabolismo , Feminino , Humanos , Masculino , Espectrometria de Massas em Tandem
8.
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
9.
Proc Natl Acad Sci U S A ; 117(12): 6651-6662, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32152116

RESUMO

A role for microglia in neuropsychiatric diseases, including major depressive disorder (MDD), has been postulated. Regulation of microglial phenotype by immune receptors has become a central topic in many neurological conditions. We explored preclinical and clinical evidence for the role of the CD300f immune receptor in the fine regulation of microglial phenotype and its contribution to MDD. We found that a prevalent nonsynonymous single-nucleotide polymorphism (C/T, rs2034310) of the human CD300f receptor cytoplasmic tail inhibits the protein kinase C phosphorylation of a threonine and is associated with protection against MDD, mainly in women. Interestingly, CD300f-/- mice displayed several characteristic MDD traits such as augmented microglial numbers, increased interleukin 6 and interleukin 1 receptor antagonist messenger RNA, alterations in synaptic strength, and noradrenaline-dependent and persistent depressive-like and anhedonic behaviors in females. This behavioral phenotype could be potentiated inducing the lipopolysaccharide depression model. RNA sequencing and biochemical studies revealed an association with impaired microglial metabolic fitness. In conclusion, we report a clear association that links the function of the CD300f immune receptor with MDD in humans, depressive-like and anhedonic behaviors in female mice, and altered microglial metabolic reprogramming.


Assuntos
Anedonia , Transtorno Depressivo Maior/patologia , Inflamação/etiologia , Microglia/patologia , Polimorfismo de Nucleotídeo Único , Receptores Imunológicos/genética , Receptores Imunológicos/fisiologia , Animais , Comportamento Animal , Estudos de Coortes , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/psicologia , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Sinapses
10.
Psychopharmacology (Berl) ; 237(4): 915-941, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32065252

RESUMO

Perinatal depression is the most common complication of pregnancy and affects the mother, fetus, and infant. Recent preclinical studies and a limited number of clinical studies have suggested an influence of the gut microbiome on the onset and course of mental health disorders. In this review, we examine the current state of knowledge regarding genetics, epigenetics, heritability, and neuro-immuno-endocrine systems biology in perinatal mood disorders, with a particular focus on the interaction between these factors and the gut microbiome, which is mediated via the gut-brain axis. We also provide an overview of experimental and analytical methods that are currently available to researchers interested in elucidating the influence of the gut microbiome on mental health disorders during pregnancy and postpartum.


Assuntos
Transtorno Depressivo Maior/terapia , Microbioma Gastrointestinal/fisiologia , Medicina de Precisão/métodos , Complicações na Gravidez/terapia , Encéfalo/metabolismo , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Lactente , Microbiota/fisiologia , Período Pós-Parto/metabolismo , Período Pós-Parto/psicologia , Medicina de Precisão/psicologia , Gravidez , Complicações na Gravidez/metabolismo , Complicações na Gravidez/psicologia
11.
Sci Rep ; 10(1): 1961, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029791

RESUMO

Previous reports have shown that during chronic inflammation, the tryptophan (TRP)-kynurenine (KYN) pathway plays a pivotal role in the onset of depression. The aim of this study was to investigate the characteristics of the serum TRP-KYN pathway metabolite profile in high-risk subjects of major depressive disorder (HRMDD) defined by depression scores. The concentrations of TRP-KYN pathway metabolites {TRP, KYN, 3-hydroxyanthranilic acid (3HAA), 3-hydroxykynurenine (3HK), kynurenic acid (KYNA) and anthranilic acid (AA)} were assessed in serum from HRMDD, chronic pain disorder patients and healthy controls. In serum from HRMDD, elevated levels of AA and decreased levels of TRP were observed, but the levels of other metabolites were not changed. Furthermore, the change in the AA2nd/AA1st ratio in subjects who progressed from a health. y state to a depressive state was correlated with an increase in the CES-D score. The level of IL-1 receptor antagonist (IL-1RA) was negatively correlated with that of AA. Interestingly, we confirmed AA as a possible biomarker for depression-related symptoms, since the metabolite profiles in the chronic pain disorder group and chronic unpredictable mild stress model mice were similar to those in the HRMDD. These results suggest that AA may be an effective marker for HRMDD.


Assuntos
Dor Crônica/diagnóstico , Transtorno Depressivo Maior/diagnóstico , Estresse Psicológico/diagnóstico , ortoaminobenzoatos/sangue , Ácido 3-Hidroxiantranílico/análise , Ácido 3-Hidroxiantranílico/metabolismo , Adulto , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos de Casos e Controles , Dor Crônica/sangue , Dor Crônica/metabolismo , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/metabolismo , Modelos Animais de Doenças , Feminino , Voluntários Saudáveis , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Ácido Cinurênico/sangue , Ácido Cinurênico/metabolismo , Cinurenina/análogos & derivados , Cinurenina/sangue , Cinurenina/metabolismo , Masculino , Metaboloma , Camundongos , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Estresse Psicológico/sangue , Estresse Psicológico/metabolismo , Triptofano/metabolismo , ortoaminobenzoatos/metabolismo
12.
Proc Natl Acad Sci U S A ; 117(6): 3326-3336, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31974313

RESUMO

Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood-brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.


Assuntos
Barreira Hematoencefálica/metabolismo , Transtorno Depressivo Maior/metabolismo , Estresse Psicológico/metabolismo , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Claudina-5/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Modelos Animais de Doenças , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/fisiologia , Histona Desacetilase 1/metabolismo , Humanos , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
13.
J Altern Complement Med ; 26(3): 190-197, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31934793

RESUMO

Objective: To determine if a 12-week yoga intervention (YI) was associated with increased gamma aminobutyric acid (GABA) levels and decreased depressive symptoms in participants with major depressive disorder (MDD). Methods: Subjects were randomized to a high-dose group (HDG) of three YIs a week and a low-dose group (LDG) of two YIs a week. Thalamic GABA levels were obtained using magnetic resonance spectroscopy at Scan-1 before randomization. After the assigned 12-week intervention, Scan-2 was obtained, immediately followed by a YI and Scan-3. Beck Depression Inventory II (BDI-II) scores were obtained before Scan-1 and Scan-3. Settings/Location: Screenings and interventions occurred at the Boston University Medical Center. Imaging occurred at McLean Hospital. Subjects: Subjects met criteria for MDD. Intervention: Ninety minutes of Iyengar yoga and coherent breathing at five breaths per minute plus homework. Outcome measures: GABA levels and the BDI-II. Results: BDI-II scores improved significantly in both groups. GABA levels from Scan-1 to Scan-3 and from Scan-2 to Scan-3 were significantly increased in the LDG (n = 15) and showed a trend in the total cohort. Post hoc, participants were divided into two groups based on having an increase in GABA levels at Scan-2. Increases in Scan-2 GABA levels were observed in participants whose mean time between their last YI and Scan-2 was 3.93 ± 2.92 standard deviation (SD) days, but not in those whose mean time between their last YI and Scan-2 was 7.83 ± 6.88 SD. Conclusions: This study tentatively supports the hypothesis that one of the mechanisms through which yoga improves mood is by increasing the activity of the GABA system. The observed increase in GABA levels following a YI that was no longer observed 8 days after a YI suggests that the associated increase in GABA after a YI is time limited such that at least one YI a week may be necessary to maintain the elevated GABA levels.


Assuntos
Exercícios Respiratórios , Transtorno Depressivo Maior , Tálamo/metabolismo , Ioga , Ácido gama-Aminobutírico/análise , Adulto , Ansiedade , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/terapia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tálamo/química , Tálamo/diagnóstico por imagem , Adulto Jovem , Ácido gama-Aminobutírico/metabolismo
14.
Biochem Biophys Res Commun ; 523(2): 405-410, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-31866009

RESUMO

Although the current evidences may suggest that the 25(OH)D associated with depression, still there exists conflicting results. In addition, little known is concerning the relationship between the 25(OH)D and the chronic stress-induced depressive-like behaviors. We detected the 25(OH)D levels in serum and the VDR protein expression in different brain regions aiming to explore the relationship between 25(OH)D/VDR signaling and major depression. The chemiluminescent microparticle immunoassay (CMIA) was used to detect the serum concentration of 25(OH)D in patients, the enzyme-linked immunosorbent assay (ELISA) was applied to measure the serum 25(OH)D levels in both CRS-treated and CSDS-treated mice models of MDD. Meanwhile, the VDR protein expression levels were validated among three MDD related brain regions from CRS-treated mice by western blotting. In this study, we mainly observed that the concentration of the 25(OH)D was decreased in the serum of MDD patients comparing to healthy controls. Consistent with the clinical findings, the CRS-treated mice also displayed down-regulated 25(OH)D level comparing with control mice. While in the CSDS model, the serum 25(OH)D status of depressive mice remained unchanged. Moreover, we found the protein level of VDR was significantly decreased in the hippocampus while increased in the hypothalamus of CRS-treated mice. Nevertheless, the prefrontal cortex exhibited no change regarding VDR protein expression compared with control mice. Taken together, these findings further confirmed that the 25(OH)D together with VDR may involve in the pathophysiological mechanism of depression-like behaviors induced by chronic stress.


Assuntos
Encéfalo/metabolismo , Transtorno Depressivo Maior/metabolismo , Receptores de Calcitriol/metabolismo , Vitamina D/análogos & derivados , Adulto , Animais , Estudos de Casos e Controles , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/etiologia , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Humanos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Restrição Física , Transdução de Sinais , Estresse Fisiológico , Estresse Psicológico , Distribuição Tecidual , Vitamina D/sangue , Vitamina D/metabolismo
15.
Int J Mol Sci ; 20(24)2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31817800

RESUMO

Immunomodulation is increasingly being recognised as a part of mental diseases. Here, we examined whether levels of immunological protein markers changed with depression, age, or the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). An analysis of plasma samples from patients with a major depressive episode and control blood donors (CBD) revealed the expression of 67 inflammatory markers. Thirteen of these markers displayed augmented levels in patients compared to CBD. Twenty-one markers correlated with the age of the patients, whereas 10 markers correlated with the age of CBD. Interestingly, CST5 and CDCP1 showed the strongest correlation with age in the patients and CBD, respectively. IL-18 was the only marker that correlated with the MADRS-S scores of the patients. Neuronal growth factors (NGFs) were significantly enhanced in plasma from the patients, as was the average plasma GABA concentration. GABA modulated the release of seven cytokines in anti-CD3-stimulated peripheral blood mononuclear cells (PBMCs) from the patients. The study reveals significant changes in the plasma composition of small molecules during depression and identifies potential peripheral biomarkers of the disease.


Assuntos
Biomarcadores/sangue , Biomarcadores/metabolismo , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/metabolismo , Inflamação/sangue , Inflamação/metabolismo , Leucócitos Mononucleares/metabolismo , Ácido gama-Aminobutírico/metabolismo , Adulto , Fatores Etários , Idoso , Depressão , Transtorno Depressivo Maior/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
Med Sci Monit ; 25: 9887-9892, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31869319

RESUMO

BACKGROUND The children of depressed parents are more likely to suffer from mental illness, particularly major depressive disorder (MDD). However, most data come from adolescent and young-adult populations, and published studies have reported inconsistent results regarding intergenerational transmission. MATERIAL AND METHODS We retrospectively investigated hospitalized depressed patients with positive family history (FHP) from 1 Jan 2008 to 31 Dec 2017 and analyzed the differences in sex distribution in the intergenerational transfer risk of major depressive disorder. RESULTS We enrolled 528 patients with maternal or paternal positive FHP from a total of 4856 patients, and divided them into 4 groups: female patients with maternal FHP (FM: 220, 41.7%), female patients with paternal FHP (FP: 116, 22.0%), male patients with maternal FHP (MM: 96, 18.2%), and male patients with paternal FHP (MP: 96, 18.2%). In this study, 12.2% of hospitalized depressed patients had an FHP. The ratio of male: female patients with FHP was 2: 3. The ratio of male: female patients with maternal FHP was almost 1: 2. Analyses showed that the risk of depression in daughters was higher than in sons. Compared with children of depressed fathers, the children of depressed mothers were at higher risk of depression. Daughters and sons share an equal risk of depression with paternal FHP. CONCLUSIONS The results suggest a clear interaction of sex between patients and their depressed parents. Daughters of depressed mothers had the highest risk of suffering from depression compared with other offspring.


Assuntos
Transtorno Depressivo Maior/genética , Padrões de Herança/genética , Transtornos Mentais/genética , Adolescente , Adulto , Depressão/genética , Depressão/metabolismo , Transtorno Depressivo Maior/metabolismo , Pai , Feminino , Humanos , Masculino , Herança Materna/genética , Pessoa de Meia-Idade , Mães , Herança Paterna/genética , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais
17.
EBioMedicine ; 50: 290-305, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31753725

RESUMO

BACKGROUND: Depression is a highly prevalent disorder that is one of the leading causes of disability worldwide. Despite an unknown aetiology, evidence suggests that the innate and adaptive immune systems play a significant role in the development and maintenance of major depressive disorder (MDD). The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), has demonstrated rapid and robust efficacy as an antidepressant when administered at sub-anaesthetic doses. METHODS: Our goal was to characterize the pro-inflammatory profile of patients with MDD by measuring pro-inflammatory cytokines in plasma and circulating monocyte subsets and to understand how ketamine induces an anti-inflammatory program in monocyte and macrophages in vitro and vivo. FINDING: Our results show that patients with MDD without other comorbidities (N = 33) exhibited significantly higher levels of pro-inflammatory IL-12 and IL-6 in plasma and that these cytokines were associated with increased numbers of non-classical (CD11b+CD16brightCD14neg) monocytes and increased activation state (CD40+CD86+) of classical monocytes in circulation. Remarkably, we have demonstrated that sub-anaesthetic doses of ketamine programs human monocytes into M2c-like macrophages by inducing high levels of CD163 and MERTK with intermediate levels of CD64 and stimulating mTOR-associated gene expression in vitro. The NMDAR antagonist MK-801, but not the α-amino-3­hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist, NBQX, also polarizes macrophages to an M2c-like phenotype, but this phenotype disappears upon mTOR pathway inhibition. Sub-anaesthetic doses (10 mg/kg) of ketamine administration in mice both promote reduction of circulating classical pro-inflammatory monocytes and increase of alternative M2 macrophage subtypes in the spleen and CNS. INTERPRETATION: Our results suggest an anti-inflammatory property of ketamine that can skew macrophages to an M2-like phenotype, highlighting potential therapeutic implications not only for patients with MDD but also other inflammatory-based diseases. FUNDING: This study was supported by grants from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT-FONCYT).


Assuntos
Citocinas/metabolismo , Transtorno Depressivo Maior/etiologia , Transtorno Depressivo Maior/metabolismo , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adulto , Animais , Biomarcadores , Citocinas/sangue , Transtorno Depressivo Maior/psicologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunofenotipagem , Mediadores da Inflamação/sangue , Ketamina/metabolismo , Ketamina/farmacologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Suicídio , Adulto Jovem
18.
Exp Brain Res ; 237(12): 3419-3430, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31734788

RESUMO

Plasminogen activator inhibitor 1 (PAI-1), which is elevated in numerous disease states, has been implicated as a stress-related protein involved in the pathogenesis of depression. We measured PAI-1 in the plasma of healthy and depressed individuals and assessed plasminogen activator (PA) expression and regulation by PAI-1 in cultured normal human astrocytes (NHA). Elevated plasma PAI-1 levels were found in depressed patients. Brain tissues from depressed individuals also showed stronger expression of hippocampal PAI-1 by confocal imaging in comparison to healthy individuals. Using a lipopolysaccharide-induced inflammatory model of depression in mice, we measured PAI-1 in murine plasma and brain, by ELISA and immunohistochemistry, respectively. Similar elevations were seen in plasma but not in brain homogenates of mice exposed to LPS. We further correlated the findings with depressive behavior. Ex vivo experiments with NHA treated with proinflammatory cytokines implicated in the pathogenesis of depression showed increased PAI-1 expression. Furthermore, these studies suggest that urokinase-type plasminogen activator may serve as an astrocyte PA reservoir, able to promote cleavage of brain-derived neurotrophic factor (BDNF) during stress or inflammation. In summary, our findings confirm that derangements of PAI-1 variably occur in the brain in association with the depressive phenotype. These derangements may impede the availability of active, mature (m)BDNF and thereby promote a depressive phenotype.


Assuntos
Astrócitos/metabolismo , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Depressão/metabolismo , Depressão/fisiopatologia , Transtorno Depressivo Maior/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Serpina E2/metabolismo , Animais , Células Cultivadas , Depressão/sangue , Transtorno Depressivo Maior/sangue , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Inibidor 1 de Ativador de Plasminogênio/sangue , Serpina E2/sangue
19.
Prog Mol Biol Transl Sci ; 167: 159-178, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31601403

RESUMO

Major depressive disorder is a severe and the most prevalent form of neuropsychiatric disorder that affects millions of individuals worldwide. The current treatment focuses on brain monoamine hypothesis and conventional antidepressants that inhibit the reuptake of monoamine neurotransmitters to elevate synaptic monoamine concentrations to interact with postsynaptic receptors. However, many people with major depressive disorder fail to respond to conventional therapies experiencing relapse and significant functional impairment. It is increasingly recognized that glia-associated inflammatory mechanisms contribute to the pathophysiology of major depressive disorder. Furthermore, microglial nicotinic cholinergic mechanisms were recently proposed to play a critical role in major depressive disorder-linked inflammatory processes. In this review, we will provide recent advances on glial dysfunctions, the role of inflammatory cytokines, transcription factors, and brain derived neurotrophic factor underlying the pathophysiology of major depressive disorder. We will also evaluate and discuss the anti-inflammatory effects of nicotinic acetylcholine receptor positive allosteric modulators and glial nicotinic receptor-mediated mechanisms that might be responsive to potential pharmacologic interventions. Overall, these important, but underappreciated, roles of brain glial targets and mechanisms might offer new therapeutic opportunities for major depressive disorder.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/patologia , Neuroglia/patologia , Animais , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Humanos , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo
20.
Transl Psychiatry ; 9(1): 215, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477685

RESUMO

DNA methylation plays an important role in major depressive disorder (MDD), but the specific genes and genomic regions associated with MDD remain largely unknown. Here we conducted genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) and gene expression (RNA-seq) in peripheral blood monocytes from 79 monozygotic twin pairs (mean age 38.2 ± 15.6 years) discordant on lifetime history of MDD to identify differentially methylated regions (DMRs) and differentially expressed genes (DEGs) associated with MDD, followed by replication in brain tissue samples. Integrative DNA methylome and transcriptome analysis and network analysis was performed to identify potential functional epigenetic determinants for MDD. We identified 39 DMRs and 30 DEGs associated with lifetime history of MDD. Some genes were replicated in postmortem brain tissue. Integrative DNA methylome and transcriptome analysis revealed both negative and positive correlations between DNA methylation and gene expression, but the correlation pattern varies greatly by genomic locations. Network analysis revealed distinct gene modules enriched in signaling pathways related to stress responses, neuron apoptosis, insulin receptor signaling, mTOR signaling, and nerve growth factor receptor signaling, suggesting potential functional relevance to MDD. These results demonstrated that altered DNA methylation and gene expression in peripheral blood monocytes are associated with MDD. Our results highlight the utility of using peripheral blood epigenetic markers and demonstrate that a monozygotic discordant co-twin control design can aid in the discovery of novel genes associated with MDD. If validated, the newly identified genes may serve as novel biomarkers or druggable targets for MDD and related disorders.


Assuntos
Metilação de DNA , Transtorno Depressivo Maior/metabolismo , Doenças em Gêmeos/metabolismo , Epigenoma , Leucócitos Mononucleares/metabolismo , Transcriptoma , Adulto , Transtorno Depressivo Maior/genética , Doenças em Gêmeos/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Gêmeos Monozigóticos/genética , Adulto Jovem
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