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BACKGROUND: Social psychoneuroimmunology suggests an interplay between social deficits (loneliness and isolation) and chronic inflammation, but the direction of these relationships remains unclear. We estimated the reciprocal associations of social deficits and social engagement with levels of C-reactive protein (CRP), compared the consistency of the findings depending on the biological sampling method used, and examined the modifying role of phenotypic and genotypic depression. METHODS: We used longitudinal nationally representative data from the US (Health and Retirement Study, 3 waves, 2006-16) and England (English Longitudinal Study of Ageing, 4 waves, 2004-18). Loneliness, social isolation, and social engagement were self-reported. CRP was measured using dried blood spots (US) and venous blood samples (England). Cross-lagged panel models were fitted and tested interactions with phenotypic depression (above-threshold depressive symptom scores) and genotypic depression (polygenic score for major depressive disorder). RESULTS: We included 15,066 participants (mean age = 66.1 years, SD = 9.8) in the US and 10,290 (66.9 years, SD = 10.5) in England. We found reciprocal associations between loneliness and CRP using dried blood spots and venous blood samples. Higher CRP predicted higher subsequent loneliness and higher loneliness predicted elevated CRP. Both phenotypic and genotypic depression modified this reciprocal association. There were also reciprocal associations for social engagement in venous blood samples: higher CRP predicted lower social engagement and greater social engagement predicted lower subsequent CRP. Associations between social isolation and CRP were inconsistent and unidirectional. CONCLUSIONS: Loneliness may increase chronic inflammation, whereas social engagement may reduce inflammation. As these relationships were reciprocal, there may be a loop between inflammation, loneliness, and social engagement. This loop was stronger in those with depression or at high genetic risk for major depressive disorder. This relationship for loneliness was present in both blood sampling methods despite contrasting methods of CRP measurement, indicating that the finding is not attributable to measurement bias in biomarkers.
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Proteína C-Reactiva , Depresión , Pruebas con Sangre Seca , Inflamación , Soledad , Fenotipo , Aislamiento Social , Humanos , Masculino , Femenino , Anciano , Estudios Longitudinales , Inflamación/sangre , Soledad/psicología , Persona de Mediana Edad , Aislamiento Social/psicología , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Pruebas con Sangre Seca/métodos , Depresión/sangre , Depresión/psicología , Depresión/genética , Genotipo , Inglaterra , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/genética , Estados UnidosRESUMEN
Childhood maltreatment has been repeatedly linked to a higher incidence of health conditions with an underlying proinflammatory component, such as asthma, chronic obstructive pulmonary disease, stroke, and cardiovascular disease. Childhood maltreatment has also been linked to elevated systemic inflammation prior to the onset of disease. However, childhood maltreatment is highly comorbid with other risk factors which have also been linked to inflammation, namely major depression. The present analysis addresses this issue by assessing the association of maltreatment with genome-wide transcriptional profiling of immune cells collected from four orthogonal groups of adolescents (aged 13-17): maltreated and not maltreated in childhood, with and without major depressive disorder. Maltreatment and psychiatric history were determined using semi-structured clinical interviews and cross-validated using self-report questionnaires. Dried whole blood spots were collected from each participant (n = 133) and assayed to determine the extent to which maltreatment in childhood was associated with a higher prevalence of transcriptional activity among differentially expressed genes, specific immune cell subtypes, and up- or down-regulation of genes involved in immune function after accounting for current major depression. Maltreatment was associated with increased interferon regulatory factor (IRF) transcriptional activity (p = 0.03), as well as nuclear factor erythroid-2 related factor 1 (NRF1; p = 0.002) and MAF (p = 0.01) among up-regulated genes, and increased activity of nuclear factor kappa beta (NF-κB) among down-regulated genes (p = 0.01). Non-classical CD16+ monocytes were implicated in both the up- and down-regulated genes among maltreated adolescents. These data provide convergent evidence supporting the role of maltreatment in altering intracellular and molecular markers of immune function, as well as implicate monocyte/macrophage functions as mechanisms through which childhood maltreatment may shape lifelong immune development and function.
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Maltrato a los Niños , Trastorno Depresivo Mayor , Humanos , Adolescente , Niño , Trastorno Depresivo Mayor/genética , Monocitos , Inflamación , Perfilación de la Expresión Génica , Maltrato a los Niños/psicologíaRESUMEN
Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear, and additional diagnostic and therapeutic strategies for MDD still are needed. The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis, but these hypothesis cannot completely explain the pathological mechanism of MDD. Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD, thus in recent years, great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies, further revealing the disease features of MDD. Furthermore, some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention, some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms. In this work, we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD, preventive approaches and therapeutic medicines, as well as the related clinical trials.
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Trastorno Depresivo Mayor , Humanos , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/prevención & control , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-SuprarrenalRESUMEN
The importance of time is ever prevalent in our world, and disruptions to the normal light/dark and sleep/wake cycle have now become the norm rather than the exception for a large part of it. All mood disorders, including seasonal affective disorder (SAD), major depressive disorder (MDD), and bipolar disorder (BD), are strongly associated with abnormal sleep and circadian rhythms in a variety of physiological processes. Environmental disruptions to normal sleep/wake patterns, light/dark changes, and seasonal changes can precipitate episodes. Moreover, treatments that target the circadian system have proven to be therapeutic in certain cases. This review will summarize much of our current knowledge of how these disorders associate with specific circadian phenotypes, as well as the neuronal mechanisms that link the circadian clock with mood regulation. We also discuss what has been learned from therapies that target circadian rhythms and how we may use current knowledge to develop more individually designed treatments.
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Trastorno Bipolar , Trastorno Depresivo Mayor , Humanos , Trastornos del Humor , Trastorno Depresivo Mayor/genética , Ritmo Circadiano/fisiología , Sueño/fisiologíaRESUMEN
Major depressive disorder (MDD) is a complex disorder and a leading cause of disability in 280 million people worldwide. Many environmental factors, such as microbes, drugs, and diet, are involved in the pathogenesis of depressive disorders. However, the underlying mechanisms of depression are complex and include the interaction of genetics with epigenetics and the host immune system. Modifications of the gut microbiome and its metabolites influence stress-related responses and social behavior in patients with depressive disorders by modulating the maturation of immune cells and neurogenesis in the brain mediated by epigenetic modifications. Here, we discuss the potential roles of a leaky gut in the development of depressive disorders via changes in gut microbiota-derived metabolites with epigenetic effects. Next, we will deliberate how altering the gut microbiome composition contributes to the development of depressive disorders via epigenetic alterations. In particular, we focus on how microbiota-derived metabolites such as butyrate as an epigenetic modifier, probiotics, maternal diet, polyphenols, drugs (e.g., antipsychotics, antidepressants, and antibiotics), and fecal microbiota transplantation could positively alleviate depressive-like behaviors by modulating the epigenetic landscape. Finally, we will discuss challenges associated with recent therapeutic approaches for depressive disorders via microbiome-related epigenetic shifts, as well as opportunities to tackle such problems.
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Trastorno Depresivo Mayor , Microbioma Gastrointestinal , Microbiota , Probióticos , Humanos , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Probióticos/uso terapéutico , Probióticos/farmacología , Epigénesis GenéticaRESUMEN
BACKGROUND: Major depressive disorder (MDD) is a type of emotional dysfunction, and its pathogenesis has not been fully elucidated. Specifically, the key molecules in depression-related brain regions involved in this disease and their contributions to this disease are currently unclear. METHODS: GSE53987 and GSE54568 were selected from the Gene Expression Omnibus database. The data were standardized to identify the common differentially expressed genes (DEGs) in the cortex of MDD patients in the 2 datasets. The DEGs were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. The STRING database was used to build protein-protein interaction networks, and the cytoHubba plugin was used to identify hub genes. Furthermore, we selected another blood transcriptome dataset that included 161 MDD and 169 control samples to explore the changes in the screened hub genes. Mice were subjected to 4 weeks of chronic unpredictable mild stress to establish an animal model of depression, and the expression of these hub genes in tissues of the prefrontal cortex was then detected by quantitative real time polymerase chain reaction (qRT-PCR). We subsequently predicted the possible posttranscriptional regulatory networks and traditional Chinese medicine according to the hub genes using a few online databases. RESULTS: The analysis identified 147 upregulated genes and 402 downregulated genes were identified in the cortex of MDD patients compared with that of the controls. Enrichment analyses revealed that DEGs were predominantly enriched in synapse-related cell functions, linoleic acid metabolism, and other pathways. Protein-protein interaction analysis identified 20 hub genes based on the total score. The changes in KDM6B, CUX2, NAAA, PHKB, NFYA, GTF2H1, CRK, CCNG2, ACER3, and SLC4A2 in the peripheral blood of MDD patients were consistent with those in the brain. Furthermore, the prefrontal cortex of mice with depressive-like behaviors showed significantly increased Kdm6b, Aridb1, Scaf11, and Thoc2 expression and decreased Ccng2 expression compared with that of normal mice, which was consistent with the results found for the human brain. Potential therapeutic candidates, such as citron, fructus citri, leaves of Panax Notoginseng, sanchi flower, pseudoginseng, and dan-shen root, were selected via traditional Chinese medicine screening. CONCLUSIONS: This study identified several novel hub genes in specific brain regions involved in the pathogenesis of MDD, which may not only deepen our understanding of depression but may also provide new ideas for its diagnosis and treatment.
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Trastorno Depresivo Mayor , Humanos , Animales , Ratones , Trastorno Depresivo Mayor/genética , Redes Reguladoras de Genes , Perfilación de la Expresión Génica/métodos , Mapas de Interacción de Proteínas , Encéfalo , Biología Computacional/métodos , Factor de Transcripción TFIIH/genética , Histona Demetilasas con Dominio de Jumonji/genética , Antiportadores de Cloruro-Bicarbonato/genéticaRESUMEN
BACKGROUND: Observational studies indicate a relationship between vitamin D (25-hydroxyvitamin D; 25OHD) deficiency and the development of internalising disorders, especially depression. However, causal inference approaches (e.g. Mendelian randomisation) did not confirm this relationship. Findings from biobehavioural research suggests that new insights are revealed when focusing on psychopathological dimensions rather than on clinical diagnoses. This study provides further evidence on the relationship between 25OHD and the internalising dimension. AIMS: This investigation aimed at examining the causality between 25OHD and internalising disorders including a common internalising factor. METHOD: We performed a two-sample Mendelian randomisation using genome-wide association study (GWAS) summary data for 25OHD (417 580 participants), major depressive disorder (45 591 cases; 97 674 controls), anxiety (5580 cases; 11 730 controls), post-traumatic stress disorder (12 080 cases; 33 446 controls), panic disorder (2248 cases; 7992 controls), obsessive-compulsive disorder (2688 cases; 7037 controls) and anorexia nervosa (16 992 cases; 55 525 controls). GWAS results of the internalising phenotypes were combined to a common factor representing the internalising dimension. We performed several complementary analyses to reduce the risk of pleiotropy and used a second 25OHD GWAS for replication. RESULTS: We found no causal relationship between 25OHD and any of the internalising phenotypes studied, nor with the common internalising factor. Several pleiotropy-robust methods corroborated the null association. CONCLUSIONS: Following current transdiagnostic approaches to investigate mental disorders, our results focused on the shared genetic basis between different internalising phenotypes and provide no evidence for an effect of 25OHD on the internalising dimension.
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Trastorno Depresivo Mayor , Humanos , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana/métodos , Vitamina D/genética , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Major depressive disorder (MDD) is a highly heterogeneous disease, which brings great difficulties to clinical diagnosis and therapy. Its mechanism is still unknown. Prior neuroimaging studies mainly focused on mean differences between patients and healthy controls (HC), largely ignoring individual differences between patients. METHODS: This study included 112 MDD patients and 93 HC subjects. Resting-state functional MRI data were obtained to examine the patterns of individual variability of brain functional connectivity (IVFC). The genetic risk of pathways including dopamine, 5-hydroxytryptamine (5-HT), norepinephrine (NE), hypothalamic-pituitary-adrenal (HPA) axis, and synaptic plasticity was assessed by multilocus genetic profile scores (MGPS), respectively. RESULTS: The IVFC pattern of the MDD group was similar but higher than that in HCs. The inter-network functional connectivity in the default mode network contributed to altered IVFC in MDD. 5-HT, NE, and HPA pathway genes affected IVFC in MDD patients. The age of onset, duration, severity, and treatment response, were correlated with IVFC. IVFC in the left ventromedial prefrontal cortex had a mediating effect between MGPS of the 5-HT pathway and baseline depression severity. LIMITATIONS: Environmental factors and differences in locations of functional areas across individuals were not taken into account. CONCLUSIONS: This study found MDD patients had significantly different inter-individual functional connectivity variations than healthy people, and genetic risk might affect clinical manifestations through brain function heterogeneity.
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Variación Biológica Individual , Encéfalo , Trastorno Depresivo Mayor , Predisposición Genética a la Enfermedad , Herencia Multifactorial , Vías Nerviosas , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/metabolismo , Encéfalo/metabolismo , Serotonina/metabolismo , Norepinefrina/metabolismo , Humanos , Masculino , Femenino , Adulto , Glándulas Suprarrenales/metabolismo , Hipófisis/metabolismo , Hipotálamo/metabolismo , Corteza Prefrontal/metabolismoRESUMEN
Observational studies have suggested a relationship between selenium status and mental disorders (MDs). However, it remains unclear whether selenium status was causally associated with MDs. Thus, we performed a two-sample Mendelian randomization analysis using genome-wide association studies (GWAS) summary statistics to investigate the causal effects of selenium levels on seven MDs, including schizophrenia, major depressive disorder (MDD), autism spectrum disorder (ASD), bipolar disorder (BD), anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), and panic disorder (PD). Strong genetic instruments of blood selenium (n = 9) and blood-toenail selenium (n = 12) were applied to the above seven MDs GWAS datasets from Psychiatric Genomics Consortium, which were further replicated in the FinnGen Biobank. The inverse-variance weighted method was employed to calculate the causal effects. The results showed that genetically predicted blood selenium levels were associated with a decreased risk of schizophrenia (odds ratio [OR] = 0.90, 95% CI: 0.87-0.95) and AN (OR = 0.87, 95% CI: 0.77-0.97). However, both blood and blood-toenail selenium levels were linked to an increased risk of MDD (blood: OR = 1.08, 95% CI: 1.05-1.12; blood-toenail: OR = 1.08, 95% CI: 1.04-1.13) and ASD (blood: OR = 1.11, 95% CI: 1.05-1.17; blood-toenail: OR = 1.13, 95% CI: 1.05-1.21), respectively. No obvious associations were found between selenium levels and BD as well as ADHD. Our findings highlighted a protective role of selenium in SZ and AN, while a risk effect in MDD and ASD. Further studies are required to verify the underlying mechanism mediating the unequal effects of Se on different MDs, which will pave a new path for the intervention of MDs.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno del Espectro Autista , Trastorno Depresivo Mayor , Selenio , Humanos , Trastorno Depresivo Mayor/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Trastorno del Espectro Autista/genética , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/complicacionesRESUMEN
Many classic decoctions of Chinese medicine including Radix Bupleuri are used to treat major depressive disorder (MDD). Saikosaponin D is a representative bioactive ingredient discovered in Radix Bupleuri. The mechanism of saikogenin G (SGG) as a metabolite in MDD remains unclear to date. This study aims to elucidate the mechanism of SGG in treating MDD with network pharmacology. We evaluated the drug likeness of SGG with SwissADME web tool and predicted its targets using the SwissTargetPrediction and PharmMapper. MDD-related targets were identified from the following databases: DisGeNET, DrugBank, Online Mendelian Inheritance in Man, and GeneCards. The common targets of SGG and MDD were imported to the STRING11.0 database, and then a protein-protein interaction network was constructed. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment were analyzed with DAVID 6.8 database. The molecular weight of SGG was 472.7 g/mol, the topological polar surface area was 69.92 A2 <140 A2, the octanol/water partition coefficient (Consensus LogP0/W) was 4.80, the rotatable bond was 1, the hydrogen bond donors was 3, and the hydrogen bond acceptors was 4. A total of 322 targets of SGG were obtained and there were 1724 MDD-related targets. A total of 78 overlapping genes were selected as targets of MDD treatment including albumin, insulin-like growth factor I, mitogen-activated protein kinase 1, proto-oncogene tyrosine-protein kinase Src, and epidermal growth factor receptor. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis suggested that proteoglycans in cancer, pathways in cancer, prostate cancer, hypoxia-inducible factor-1, central carbon metabolism in cancer, estrogen, PI3K-Akt, ErbB, Rap1, and prolactin signaling pathways played an important role(P < .0001). This study showed that SGG exhibits good drug-like properties and elucidated the potential mechanisms of SGG in treating MDD with regulating inflammation, energy metabolism, monoamine neurotransmitters, neuroplasticity, phosphocreatine-creatine kinase circuits, and so on.
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Trastorno Depresivo Mayor , Medicamentos Herbarios Chinos , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Humanos , Medicina Tradicional China , Farmacología en Red , Fosfatidilinositol 3-Quinasas/metabolismo , Mapas de Interacción de Proteínas/genéticaRESUMEN
Depressive disorder in childhood and adolescence is a highly prevalent mood disorder that tends to recur throughout life. Untreated mood disorders can adversely impact a patient's quality of life and cause socioeconomic loss. Thus, an accurate diagnosis and appropriate treatment is crucial. However, until now, diagnoses and treatments were conducted according to clinical symptoms. Objective and biological validation is lacking. This may result in a poor outcome for patients with depressive disorder. Research has been conducted to identify the biomarkers that are related to depressive disorder. Cumulative evidence has revealed that certain immunologic biomarkers including brain-derived neurotrophic factor (BDNF) and cytokines, gastrointestinal biomarkers, hormones, oxidative stress, and certain hypothalamus-pituitary axis biomarkers are associated with depressive disorder. This article reviews the biomarkers related to the diagnosis and treatment of pediatric depressive disorders. To date, clinical biomarker tests are not yet available for diagnosis or for the prediction of treatment prognosis. However, cytokines such as Interleukin-2, interferon-gamma, tumor necrosis factor-alpha, and BDNF have shown significant results in previous studies of pediatric depressive disorder. These biomarkers have the potential to be used for diagnosis, prognostic assessment, and group screening for those at high risk.
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Biomarcadores/sangre , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/diagnóstico , Adolescente , Animales , Factor Neurotrófico Derivado del Encéfalo/sangre , Niño , Citocinas/sangre , Citocinas/metabolismo , Trastorno Depresivo Mayor/genética , Tracto Gastrointestinal/metabolismo , Hormonas/sangre , Humanos , Hipotálamo/metabolismo , Sistema Inmunológico , Inflamación , Interferón gamma/sangre , Interleucina-2/sangre , Aprendizaje Automático , Neuronas/patología , Estrés Oxidativo , Hipófisis/metabolismo , Pronóstico , Calidad de Vida , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is considered one of the mechanisms underlying the development of major depressive disorder (MDD), but the exact nature of this dysfunction is unknown. We investigated the relationship between hypothalamus volume (HV) and blood-derived DNA methylation in MDD. We obtained brain MRI, clinical and molecular data from 181 unmedicated MDD and 90 healthy control (HC) participants. MDD participants received a 16-week standardized antidepressant treatment protocol, as part of the first Canadian Biomarker Integration Network in Depression (CAN-BIND) study. We collected bilateral HV measures via manual segmentation by two independent raters. DNA methylation and RNA sequencing were performed for three key HPA axis-regulating genes coding for the corticotropin-binding protein (CRHBP), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5). We used elastic net regression to perform variable selection and assess predictive ability of methylation variables on HV. Left HV was negatively associated with duration of current episode (ρ = -0.17, p = 0.035). We did not observe significant differences in HV between MDD and HC or any associations between HV and treatment response at weeks 8 or 16, overall depression severity, illness duration or childhood maltreatment. We also did not observe any differentially methylated CpG sites between MDD and HC groups. After assessing functionality by correlating methylation levels with RNA expression of the respective genes, we observed that the number of functionally relevant CpG sites differed between MDD and HC groups in FKBP5 (χ2 = 77.25, p < 0.0001) and NR3C1 (χ2 = 7.29, p = 0.007). Cross-referencing functionally relevant CpG sites to those that were highly ranked in predicting HV in elastic net modeling identified one site from FKBP5 (cg03591753) and one from NR3C1 (cg20728768) within the MDD group. Stronger associations between DNA methylation, gene expression and HV in MDD suggest a novel putative molecular pathway of stress-related sensitivity in depression. Future studies should consider utilizing the epigenome and ultra-high field MR data which would allow the investigation of HV sub-fields.
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Metilación de ADN , Trastorno Depresivo Mayor , Hipotálamo , Estrés Psicológico , Biomarcadores/metabolismo , Canadá , Metilación de ADN/genética , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/patología , Humanos , Sistema Hipotálamo-Hipofisario/fisiología , Hipotálamo/patología , Tamaño de los Órganos , Sistema Hipófiso-Suprarrenal/fisiología , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Estrés Psicológico/genética , Estrés Psicológico/fisiopatologíaRESUMEN
While the hippocampus remains a region of high interest for neuropsychiatric research, the precise contributors to hippocampal morphometry are still not well understood. We and others previously reported a hippocampus specific effect of a tescalcin gene (TESC) regulating single nucleotide polymorphism (rs7294919) on gray matter volume. Here we aimed to replicate and extend these findings. Two complementary morphometric approaches (voxel based morphometry (VBM) and automated volumetric segmentation) were applied in a well-powered cohort from the Marburg-Münster Affective Disorder Cohort Study (MACS) including N=1137 participants (n=636 healthy controls, n=501 depressed patients). rs7294919 homozygous T-allele genotype was significantly associated with lower hippocampal gray matter density as well as with reduced hippocampal volume. Exploratory whole brain VBM analyses revealed no further associations with gray matter volume outside the hippocampus. No interaction effects of rs7294919 with depression nor with childhood trauma on hippocampal morphometry could be detected. Hippocampal subfield analyses revealed similar effects of rs7294919 in all hippocampal subfields. In sum, our results replicate a hippocampus specific effect of rs7294919 on brain structure. Due to the robust evidence for a pronounced association between the reported polymorphism and hippocampal morphometry, future research should consider investigating the potential clinical and functional relevance of the reported association.
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Proteínas de Unión al Calcio/genética , Variación Genética/genética , Sustancia Gris/diagnóstico por imagen , Hipocampo/diagnóstico por imagen , Polimorfismo de Nucleótido Simple/genética , Adulto , Estudios de Cohortes , Estudios Transversales , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/genética , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Inflammation and altered glucose metabolism are two pathways implicated in the pathophysiology of major depressive disorder (MDD). We have previously shown that high inflammation as measured by C-reactive protein (CRP) in MDD patients is associated with symptoms of anhedonia, a core symptom of MDD, along with deficits in dopaminergic reward circuitry. Increased inflammation can shift metabolic demand and reprogram cellular energy sources, which may collectively impact the brain and reward processing to contribute to symptoms of anhedonia. To determine whether immunometabolic gene signatures were enriched in immune cells of depressed patients with increased inflammation and anhedonia, we examined whole-blood gene expression microarray (Illumina HumanHT-12) data from unmedicated, medically-stable patients with MDD (n = 93). Patients were considered to have increased inflammation based on High (>3mg/L) versus Low (≤3mg/L) plasma CRP, and further classified as having a self-reported phenotype of High (n = 30, 33rd percentile) versus Low (n = 32, 67th percentile) Anhedonia. Functional enrichment of gene pathways was assessed by Gene Set Enrichment Analysis (GSEA) using the KEGG pathway database. Pathways related to glucose metabolism (insulin signaling, insulin resistance, HIF-1, PI3K/AKT signaling), cancer (e.g., genes related to insulin and PI3K/AKT signaling), and inflammation (B cell, T cell and Fc receptor signaling) were specifically enriched in patients with both High CRP and High Anhedonia (all FDR q < 0.25). Within patients with High CRP in GSEA, the insulin signaling pathway was the top enriched pathway in patients with High versus Low Anhedonia (n = 10 and 9 respectively), which was driven by genes expressed predominantly in monocytes (z = 2.95, p < 0.01). Conversely, within patients with High Anhedonia, in addition to enrichment of immunometabolic pathways, the tyrosine metabolism pathway was also reduced in patients with High versus Low CRP (n = 20 and 10 respectively). Of note, enrichment of immunometabolic pathways was confirmed in complementary linear regression analyses examining pathways associated with a CRP-by-Anhedonia interaction term while controlling for clinical covariates in all patients (n = 93). These results indicate that increased glucose and low tyrosine metabolism define a subset of depressed patients with high inflammation and anhedonia. Enrichment of cancer-related pathways driven by metabolic genes also suggests a shift in immune cell metabolism from oxidative phosphorylation to glycolysis. Together these data suggest that anhedonia in MDD with high CRP involves both immunometabolic shifts and reduced dopamine precursor availability.
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Trastorno Depresivo Mayor , Resistencia a la Insulina , Anhedonia , Proteína C-Reactiva/análisis , Depresión/genética , Trastorno Depresivo Mayor/genética , Humanos , Resistencia a la Insulina/genética , Fosfatidilinositol 3-Quinasas , TirosinaRESUMEN
Trials testing the effect of vitamin D or omega-3 polyunsaturated fatty acid (n3-PUFA) supplementation on major depressive disorder (MDD) reported conflicting findings. These trials were inspired by epidemiological evidence suggesting an inverse association of circulating 25-hydroxyvitamin D (25-OH-D) and n3-PUFA levels with MDD. Observational associations may emerge from unresolved confounding, shared genetic risk, or direct causal relationships. We explored the nature of these associations exploiting data and statistical tools from genomics. Results from genome-wide association studies on 25-OH-D (N = 79 366), n3-PUFA (N = 24 925), and MDD (135 458 cases, 344 901 controls) were applied to individual-level data (>2000 subjects with measures of genotype, DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) lifetime MDD diagnoses and circulating 25-OH-D and n3-PUFA) and summary-level data analyses. Shared genetic risk between traits was tested by polygenic risk scores (PRS). Two-sample Mendelian Randomization (2SMR) analyses tested the potential bidirectional causality between traits. In individual-level data analyses, PRS were associated with the phenotype of the same trait (PRS 25-OH-D p = 1.4e - 20, PRS n3-PUFA p = 9.3e - 6, PRS MDD p = 1.4e - 4), but not with the other phenotypes, suggesting a lack of shared genetic effects. In summary-level data analyses, 2SMR analyses provided no evidence of a causal role on MDD of 25-OH-D (p = 0.50) or n3-PUFA (p = 0.16), or for a causal role of MDD on 25-OH-D (p = 0.25) or n3-PUFA (p = 0.66). Applying genomics tools indicated that shared genetic risk or direct causality between 25-OH-D, n3-PUFA, and MDD is unlikely: unresolved confounding may explain the associations reported in observational studies. These findings represent a cautionary tale for testing supplementation of these compounds in preventing or treating MDD.
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Trastorno Depresivo Mayor/genética , Ácidos Grasos Omega-3/uso terapéutico , Vitamina D/uso terapéutico , Adulto , Trastorno Depresivo Mayor/tratamiento farmacológico , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Herencia Multifactorial , FarmacogenéticaRESUMEN
There has been increasing interest in nutraceutical augmentation strategies to boost the efficacy of antidepressants. This study assessed whether S-adenosylmethionine (SAMe), a methyl donor that occurs naturally in the body, may be of such benefit. We conducted an 8-week, double-blind RCT in which 107 treatment non-remittent outpatients with DSM-5 diagnosed Major Depressive Disorder (MDD) were randomized to either SAMe or placebo adjunctively to antidepressants. One-carbon cycle nutrients, pertinent single nucleotide polymorphisms (SNPs), and BDNF were also analysed as potential moderators of response. A linear mixed-effects model revealed a significant overall reduction in Montgomery-Asberg Depression Rating Scale (MADRS) score across time, however there was no significant between-group difference observed (pâ¯=â¯0.51). Response rates at Week 8 were 54.3% in the SAMe group and 50.0% in the placebo group, with remission rates 43.5% for SAMe and 38.3% for placebo (all results NS). No effect of SAMe was found on any secondary outcome. Differential response to SAMe was not modified by a range of key genotypes (e.g. COMT), nor reflected in a change of homocysteine, red cell folate, or BDNF. Use of SAMe elicited no significant adverse effects beyond placebo, however it was implicated in one case of serotonin syndrome-like symptoms. This study concludes that 800â¯mg/day of SAMe is not an effective adjunctive treatment in MDD, and no obvious biomarker reflected any differential response to treatment. Due to such a distinctly high placebo-response (despite rigorous screening), future studies should employ a placebo run-in period and other strategies to minimize placebo response.
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Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/terapia , Suplementos Dietéticos , S-Adenosilmetionina/uso terapéutico , Adulto , Terapia Combinada , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/metabolismo , Suplementos Dietéticos/efectos adversos , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , S-Adenosilmetionina/efectos adversos , Insuficiencia del TratamientoRESUMEN
BACKGROUND: The Homer family of postsynaptic scaffolding proteins plays a crucial role in glutamate-mediated synaptic plasticity, a phenotype associated with Bipolar Disorder (BD). Homer is a target for antidepressants and mood stabilizers. The AA risk genotype of the Homer rs7713917 A>G SNP has been associated with mood disorders and suicide, and in healthy humans with brain function. Despite the evidence linking Homer 1 gene and function to mood disorder, as well as its involvement in animal models of depression, no study has yet investigated the role of Homer in bipolar depression and treatment response. METHODS: We studied 199 inpatients, affected by a major depressive episode in course of BD. 147 patients were studied with structural MRI of grey and white matter, and 50 with BOLD functional MRI of emotional processing. 158 patients were treated with combined total sleep deprivation and light therapy. RESULTS: At neuroimaging, patients with the AA genotype showed lower grey matter volumes in medial prefrontal cortex, higher BOLD fMRI neural responses to emotional stimuli in anterior cingulate cortex, and lower fractional anisotropy in bilateral frontal WM tracts. Lithium treatment increased axial diffusivity more in AA patients than in G*carriers. At clinical evaluation, the same AA homozygotes showed a worse antidepressant response to combined SD and LT. CONCLUSIONS: rs7713917 influenced brain grey and white matter structure and function in BD, long term effects of lithium on white matter structure, and antidepressant response to chronotherapeutics, thus suggesting that glutamatergic neuroplasticity and Homer 1 function might play a role in BD psychopathology and response to treatment.
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Antidepresivos/uso terapéutico , Trastorno Bipolar/genética , Trastorno Bipolar/terapia , Encéfalo/efectos de los fármacos , Proteínas de Andamiaje Homer/genética , Compuestos de Litio/uso terapéutico , Trastorno Bipolar/diagnóstico por imagen , Trastorno Bipolar/fisiopatología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Mapeo Encefálico , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/fisiopatología , Imagen de Difusión Tensora , Emociones/efectos de los fármacos , Emociones/fisiología , Femenino , Variación Genética , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/efectos de los fármacos , Sustancia Gris/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Imagen Multimodal , Pruebas Neuropsicológicas , Oxígeno/sangre , Fototerapia , Privación de Sueño , Resultado del Tratamiento , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/efectos de los fármacos , Sustancia Blanca/patología , Sustancia Blanca/fisiopatología , Población Blanca/genéticaRESUMEN
BACKGROUND: Polyunsaturated fatty acids (PUFAs) play an important role in the pathophysiology of major depressive disorder (MDD), related, in part, to their role in inflammatory systems. The enzymes δ-5 and δ-6 desaturase are the rate-limiting steps in the metabolism of PUFAs and are encoded in the genes fatty acid desaturase (FADS) 1 and 2, respectively. Single nucleotide polymorphisms (SNPs) and haplotypes within the FADS gene cluster have been shown to influence PUFA composition. AIM: The objective of this study was to determine whether key omega-3 (n-3) and omega-6 (n-6) fatty acids may be associated with depression, and to explore the role of FADS genotype in PUFA variation. METHODS: Four erythrocyte long chain (LC) fatty acids (linoleic acid [LA], α-linolenic acid [ALA], arachidonic acid [AA] and Eicosapentaenoic acid [EPA]), as well as six SNPs (rs174537, rs174547, rs174570, rs174575, rs498793 and rs3834458) within the FADS gene cluster were measured in a sample of 207 participants (154 with MDD versus 53 non-depressed controls). RESULTS: The precursor LC-PUFAs LA and ALA appeared to be negatively associated with depression (P < 0.001 and P < 0.01, respectively), while AA:LA (surrogate measure of desaturase activity) was positively associated with depression (P < 0.01). No significant differences were noted in erythrocyte EPA, AA or AA:EPA between groups. Minor alleles of each SNP (excluding rs498793) were associated with variation in desaturase activity and LA. Both rs174537 and rs174547 were associated with ALA. No genotype was associated with EPA or AA. Minor alleles of rs174537 and rs174547 were significantly associated with lower odds of MDD (although significance was lost after correction for multiple comparisons). CONCLUSION: Precursor LC-PUFAs, LA and ALA, appear to be associated with MDD and potentially modulated by genetic variation in the FADS gene cluster. These results provide support for the consideration of PUFA composition, diet and FADS genetic variation in the pathophysiology of MDD.
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Trastorno Depresivo Mayor/genética , Eritrocitos/metabolismo , Ácido Graso Desaturasas/genética , Ácidos Grasos Omega-3/metabolismo , Ácidos Grasos Omega-6/metabolismo , Polimorfismo de Nucleótido Simple , Adulto , Alelos , Estudios de Casos y Controles , Estudios Transversales , delta-5 Desaturasa de Ácido Graso , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/metabolismo , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Ácido Graso Desaturasas/metabolismo , Ácidos Grasos Omega-3/sangre , Ácidos Grasos Omega-6/sangre , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Familia de Multigenes , Victoria , Población BlancaRESUMEN
BACKGROUND: This study sought to reproduce, in a larger sample, previous findings of a correlation between smaller raw 3-Tesla (3T) hippocampal volumes and improved antidepressant efficacy of ketamine in individuals with major depressive disorder (MDD). A secondary analysis stratified subjects according to functional BDNF rs6265 (val66met) genotype. METHODS: Unmedicated subjects with treatment-resistant MDD ( n=55) underwent baseline structural 3T MRI. Data processing was conducted with FSL/FIRST and Freesurfer software. The amygdala, hippocampus, and thalamus were selected a priori for analysis. All subjects received a single 0.5mg/kg × 40-minute ketamine infusion. Pearson correlations were performed with subcortical volumes and percent change in MADRS score (from baseline to 230 minutes, 1 day, and 1 week post-infusion). RESULTS: Raw and corrected subcortical volumes did not correlate with antidepressant response at any timepoint. In val/val subjects ( n=23), corrected left and right thalamic volume positively correlated with antidepressant response to ketamine at 230 minutes post-infusion but did not reach statistical significance. In met carriers ( n=14), corrected left and right thalamic volume negatively correlated with antidepressant response to ketamine. CONCLUSION: Baseline subcortical volumes implicated in MDD did not correlate with ketamine's antidepressant efficacy. Baseline thalamic volume and BDNF genotype may be a combinatorial rapid antidepressant response biomarker.
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Factor Neurotrófico Derivado del Encéfalo/genética , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Ketamina/uso terapéutico , Adolescente , Adulto , Anciano , Amígdala del Cerebelo/patología , Antidepresivos/uso terapéutico , Atrofia/patología , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/patología , Trastorno Depresivo Resistente al Tratamiento/patología , Método Doble Ciego , Femenino , Genotipo , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Tálamo/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Xiao Yao San (XYS) is an herbal prescription which is used in the treatment of depression for thousands of years from Song dynasty in China (960-1127 A.D.), and is the bestselling and most popular herb formula for treating major depression. This study aimed to assess the chronic antidepressant effects of XYS and fluoxetine in depressed mice induced by chronic unpredictable mild stress (CUMS) and its association with alterations in glutamate/glutamine cycle and glutamate transporters. METHODS: Mice in the control and model group were given 0.5 ml physiological saline by intragastric administration. Mice in two treatment groups were given XYS (0.25 g/kg/d) and fluoxetine (2.6 mg/kg/d), respectively. The depressive-like behaviors such as forced swim test (FST), sucrose preference test (SPT) and novelty-suppressed feeding (NSF) test were measured after mice exposed to CUMS for 21 days. Body weight, contents of glutamate and glutamine, glutamine/glutamate ratio that is usually thought to reflect glutamate/glutamine cycle, and the protein and mRNA expressions of glutamate transporters (excitatory amino acid transporter 1-2,GLAST/EAAT1 and GLT-1/EAAT2) were measured. The immunoreactivities of GLAST and GLT-1 in the hippocampus were also investigated. RESULTS: After CUMS exposure, mice exhibited depressive-like behaviors, body weight loss, increased glutamate level, decreased glutamine level, elevated glutamine/glutamate ratio, decreased GLT-1 protein expression and mRNA level, and decreased average optical density (AOD) of GLT-1 in the CA1, CA3 and DG in the hippocampus. These abnormalities could be effectively reversed by XYS or fluoxetine treatment. In addition, the study also found that GLAST expression in the hippocampus could not be altered by 21-d CUMS. CONCLUSION: The studies indicated that XYS may have therapeutic actions on depression -like behavior s induced by CUMS in mice possibly mediated by modulation of glutamate/glutamine cycle and glutamate transporter GLT-1 in the hippocampus.