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1.
J Clin Neurosci ; 70: 14-19, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31629608

RESUMO

Cognitive dysfunction and pro-inflammatory effect has been associated with major depressive disorder (MDD), but sex differences have seldom been studied. The study was to determine the sex difference of cognitive dysfunction and pro-inflammatory biomarkers among patients with MDD in Chinese Han population. 104 MDD patients (male n = 37, female n = 67) were included in the study. Their sociodemographic and clinical features, including age, body mass index (BMI), education, smoking, alcohol use, illness characteristics and medicine use were recorded. Montreal Cognitive Assessment (MoCA) was used to assess cognition. And we detected pro-inflammatory biomarkers Interleakin-1ß (IL-1ß), Interleakin-6 (IL-6) and C-reaction protein (CRP) levels by enzyme linked immunosorbent assay. We found that male patients showed higher scores than female in MoCA, and performed better than female patients particularly in visuaspatial, naming, attention, orientation subscale. CRP and IL-1ß levels showed no significant difference between male and female patients in MDD. However, Male's IL-6 level was significantly declined than female, negative closed associated with cognition in MOCA score. These results suggested that the difference in IL-6 could reflect a cognitive difference between male and female in MDD, and IL-6 elevation could represent a state indicator for cognitive ability particular in female MDD patients. And it maybe a biological treatment target in cognition dysfunction of female patients in MDD.


Assuntos
Biomarcadores/sangue , Disfunção Cognitiva/imunologia , Transtorno Depressivo Maior/imunologia , Interleucina-6/sangue , Caracteres Sexuais , Adulto , Grupo com Ancestrais do Continente Asiático , Disfunção Cognitiva/sangue , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/complicações , Feminino , Humanos , Interleucina-6/imunologia , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade
2.
Indian J Med Res ; 149(4): 497-502, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31411173

RESUMO

Background & objectives: Oxidative stress has been implicated in the pathophysiology of major depressive disorder (MDD), but biomarkers to assess oxidative stress in patients with MDD have yielded ambiguous results. Glutathionyl haemoglobin (GS-Hb) has been reported as a stable and potential biomarker for oxidative stress in various clinical conditions. The objective of the study was to evaluate GS-Hb as a potential biomarker of oxidative stress in patients with MDD through its quantification and to compare the levels of GS-Hb in age- and gender-matched healthy controls. Methods: The levels of GS-Hb were estimated using liquid chromatography coupled to electrospray ionization mass spectrometry in patients diagnosed with MDD and in a subset of patients after six weeks of treatment with selective serotonin reuptake inhibitors (SSRIs). Results: GS-Hb levels in drug-naïve patients with MDD (n=26) were significantly elevated compared to matched healthy controls (n=17). GS-Hb levels were not significantly different between MDD patients with and without co-morbid anxiety disorders. There were no significant differences in GS-Hb levels following six weeks of treatment with SSRIs compared to baseline. Interpretation & conclusions: Compared to controls, GS-Hb level in patients with MDD was significantly elevated, suggestive of increased oxidative stress associated with MDD. However, six weeks of antidepressant treatment was not sufficient to modify the alterations in antioxidant/oxidant system. Further studies need to be done with a large sample of MDD patients with a longer duration of antidepressant treatment.


Assuntos
Biomarcadores/sangue , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Glutationa/sangue , Adulto , Antidepressivos/administração & dosagem , Cromatografia Líquida , Transtorno Depressivo Maior/patologia , Feminino , Hemoglobinas , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/genética , Inibidores de Captação de Serotonina/administração & dosagem , Espectrometria de Massas por Ionização por Electrospray
3.
Transl Psychiatry ; 9(1): 182, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375659

RESUMO

The identification of biomarkers of response might speed drug development and set the premises to assist clinical practice in psychiatry. In this work, we evaluated a panel of peripheral biomarkers (including IL-6, IL-10, TNF-α, TNFRII, BDNF, CRP, MMP9 and PAI1) in depressed patients receiving paroxetine, venlafaxine, or placebo. Samples were obtained from two randomised placebo-controlled studies evaluating the efficacy and tolerability of a novel drug candidate, using either paroxetine or venlafaxine as active comparators. In both studies, the biomarker candidates were analysed in plasma collected at randomization and after 10 weeks of treatment with either placebo or active comparator (for a total of 106 and 108 subjects in the paroxetine and venlafaxine study, respectively). Data were obtained by multiplexing sandwich-ELISA system. Data were subjected to statistical analysis to assess their correlation with baseline severity and with response outcome. Increases in biomarker levels were correlated with reduction in depression severity for TNF-α, IL-6 IL-10 and CRP. Response to paroxetine treatment correlated with baseline IL-10, IL-6 and TNF-α levels, with the strongest signal being observed in males. In the venlafaxine study, a correlation was observed only between CRP level at randomisation and response, suggesting differences between the two active treatments and the two studies. Our investigations suggest that a combination of pro- and anti-inflammatory cytokines may predict response outcome in patients treated with paroxetine. The potential for IL-10, IL-6 and TNF-α as response biomarkers for a wider range of antidepressants warrants further investigations in clinical trials with other monoamine reuptake inhibitors.


Assuntos
Proteína C-Reativa/análise , Transtorno Depressivo Maior/tratamento farmacológico , Interleucina-10/sangue , Interleucina-6/sangue , Paroxetina/uso terapêutico , Fator de Necrose Tumoral alfa/sangue , Cloridrato de Venlafaxina/uso terapêutico , Adulto , Biomarcadores/sangue , Transtorno Depressivo Maior/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
4.
Medicine (Baltimore) ; 98(28): e16373, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305436

RESUMO

BACKGROUND: Prenatal exposure to depression has been considered as a risk factor for adverse childhood, while it is accompanied by unknown molecular mechanisms. The aim of this study was to identify differentially expressed genes (DEGs) and associated biological processes between cord blood samples from neonates born to mothers who exposed to major depressive disorder (MDD) and healthy mothers. METHODS: The microarray data GSE114852 were downloaded to analyze the mRNA expression profiles of umbilical cord blood with 31 samples exposed to prenatal MDD and 62 samples with healthy mothers. Kyoto Encyclopedia of Genes and Genomes pathway and Gene ontology enrichment analyses were conducted to identify associated biochemical pathways and functional categories of the DEGs. The protein-protein interaction network was constructed and the top 10 hub genes in the network were predicted. RESULTS: The results showed several immunity related processes, such as "phagosome", "Epstein-Barr virus infection", "proteasome", "positive regulation of I-kappaB kinase/NF-kappaB signaling", "interferon-gamma-mediated signaling pathway", and "tumor necrosis factor" presented significant differences between two groups. Most of the hub genes (for example PSMD2, PSMD6, PSMB8, PSMB9) were also associated with immune pathways. CONCLUSION: This bioinformatic analysis demonstrated immune-mediated mechanisms might play a fatal role in abnormalities in fetal gene expression profiles caused by prenatal MDD.


Assuntos
Transtorno Depressivo Maior , Sangue Fetal/metabolismo , Complicações na Gravidez , Biologia Computacional , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/genética , Feminino , Expressão Gênica , Humanos , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/genética , RNA Mensageiro/sangue
5.
Genomics Proteomics Bioinformatics ; 17(2): 183-189, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31233833

RESUMO

Major depressive disorder (MDD) is the most common nonfatal disease burden worldwide. Systemic chronic low-grade inflammation has been reported to be associated with MDD progression by affecting monoaminergic and glutamatergic neurotransmission. However, whether various proinflammatory cytokines are abnormally elevated before the first episode of depression is still largely unclear. Here, we evaluated 184 adolescent patients who were experiencing their first episode of depressive disorder, and the same number of healthy individuals was included as controls. We tested the serum levels of high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), IgE, 14 different types of food antigen-specific IgG, histamine, homocysteine, S100 calcium-binding protein B, and diamine oxidase. We were not able to find any significant differences in the serum levels of hs-CRP or TNF-α between the two groups. However, the histamine level of the patients (12.35 µM) was significantly higher than that of the controls (9.73 µM, P < 0.001, Mann-Whitney U test). Moreover, significantly higher serum food antigen-specific IgG positive rates were also found in the patient group. Furthermore, over 80% of patients exhibited prolonged food intolerance with elevated levels of serum histamine, leading to hyperpermeability of the blood-brain barrier, which has previously been implicated in the pathogenesis of MDD. Hence, prolonged high levels of serum histamine could be a risk factor for depressive disorders, and antihistamine release might represent a novel therapeutic strategy for depression treatment.


Assuntos
Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/etiologia , Hipersensibilidade Alimentar/complicações , Imunoglobulina G/imunologia , Adolescente , Biomarcadores/sangue , Proteína C-Reativa , Doença Crônica , Citocinas , Transtorno Depressivo Maior/sangue , Feminino , Hipersensibilidade Alimentar/sangue , Histamina/sangue , Homocisteína/sangue , Humanos , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Mediadores da Inflamação/sangue , Masculino , Fatores de Risco , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Adulto Jovem
6.
J Clin Psychopharmacol ; 39(4): 367-371, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31211752

RESUMO

BACKGROUND: Insulin-like growth factor I (IGF-I) is a neurotrophic factor produced by the hypothalamic-pituitary-somatotropic axis and is considered a potential contributor to the pathology of major depressive disorder (MDD). Although it is known that the hypothalamic-pituitary-adrenal axis and cortisol are involved in the pathology of MDD, the association with dehydroepiandrosterone sulfate (DHEAS) remains unclear. The current study sought to clarify the relationship between these hormones and the pathology of MDD. METHODS: Subjects were 91 Japanese patients with a diagnosis of MDD. Serum IGF-I, cortisol, and DHEAS were measured. Samples were taken before breakfast after overnight fasting. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression (HAM-D). RESULTS: Subjects included 59 men and 32 women with an average age of 44.1 ± 13.1 years (mean ± SD). The blood IGF-I level was 152.0 ± 50.0 ng/mL, the cortisol level was 10.1 ± 4.6, and the DHEAS level was 201.3 ± 112.7 µg/dL. The mean HAM-D score was 13.9 ± 9.0. Serum IGF-I levels were not correlated with cortisol. Higher IGF-I, cortisol, and cortisol/DHEAS ratios were associated with higher HAM-D scores (adjusted R = 0.240, P < 0.001), and higher IGF-I and cortisol were associated with higher melancholic or suicide subscores (adjusted R = 0.200, P < 0.001; adjusted R = 0.273, P < 0.001). CONCLUSIONS: Our findings suggest that hormonal dysregulation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-somatotropic axes may be related to the symptom severity of MDD, melancholia, and suicide-related factors.


Assuntos
Sulfato de Desidroepiandrosterona/sangue , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/fisiopatologia , Hidrocortisona/sangue , Fator de Crescimento Insulin-Like I/análise , Adulto , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Hipotálamo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/fisiopatologia
7.
Brain Stimul ; 12(5): 1135-1142, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31176607

RESUMO

BACKGROUND: Prior studies suggest that activation of the tryptophan catabolism via the kynurenine pathway by proinflammatory cytokines may be involved in the pathophysiology of depression. Electroconvulsive therapy (ECT) is an effective treatment for major depression (MD) with immunomodulation as one of the proposed modes of action. OBJECTIVE: The aim of this study was to investigate serum concentrations of tryptophan and kynurenine pathway metabolites in MD patients and healthy controls, and to explore the effect of ECT on components of the kynurenine pathway. METHODS: The study included 27 moderately to severely depressed patients referred to ECT. Blood samples were collected prior to treatment and after the completed ECT-series. Baseline samples were also collected from 14 healthy, age- and sex-matched controls. Serum concentrations of tryptophan, kynurenine, 3-hydroxykynurenine (HK), kynurenic acid (KA), xanthurenic acid (XA), anthranilic acid (AA), 3-hydroxyanthranilic acid (HAA), quinolinic acid (QA), picolinic acid (Pic), pyridoxal 5'-phosphat (PLP), riboflavin, neopterin and cotinine were measured. RESULTS: Patients with MD had lower levels of neuroprotective kynurenine-pathway metabolites (KA, XA and Pic) and lower metabolite ratios (KA/Kyn and KA/QA) reflecting reduced neuroprotection compared to controls. The concentration of the inflammatory marker neopterin was increased after ECT, along with Pic and the redox active and immunosuppressive metabolite HAA. CONCLUSION: In this pilot study, we found increased concentrations of inflammatory marker neopterin and putative neuroprotective kynurenine metabolites HAA and Pic in MD patients after ECT. Further research in larger cohorts is required to conclude whether ECT exerts its therapeutic effects via changes in the kynurenine pathway.


Assuntos
Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/terapia , Eletroconvulsoterapia/métodos , Cinurenina/sangue , Triptofano/sangue , Adulto , Biomarcadores/sangue , Transtorno Depressivo Maior/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
8.
Psychiatry Res ; 273: 685-689, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31207853

RESUMO

OBJECTIVE: The aim of this study was to assess if cytokines levels (IL-6 and IL-10) are related to major depressive disorder (MDD) and bipolar disorder (BD), in a population-based study. METHODS: This was a cross-sectional study population-based, involving 1037 people aged 18-35. MDD, BD, anxiety and suicide risk were assessed using the Mini International Neuropsychiatric Interview. Serum IL-6 and IL-10 were measured by ELISA using a commercial kit. RESULTS: The total sample comprised 1034 young adults, being 14.4% with MDD and 13.7% with BD. MDD and BD groups showed significantly higher serum IL-6 levels (p ≤ 0.001) and IL-10 levels (p ≤ 0.001) when compared to healthy control group. No correlation was found between serum IL-6 and IL-10 levels in health control group (p = 0.830; r = -0.008), non-suicide risk (p = 0.337; r = 0.032) and non-anxiety disorder (p = 0.375; r = 0.031). Covariance analysis showed that mood disorders alone, increase both interleukin levels (IL-6, p = 0.019; and IL-10, p = 0.026), whilst the interaction of mood disorders and suicide risk or anxiety disorders did not. CONCLUSION: Our results suggest that inflammatory dysregulation may be involved in the physiopathology of mood disorders and serum IL-6 and IL-10 levels are putative biomarkers for these disorders.


Assuntos
Transtorno Bipolar/sangue , Transtorno Depressivo Maior/sangue , Interleucina-10/sangue , Interleucina-6/sangue , Transtornos do Humor/sangue , Adolescente , Adulto , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Adulto Jovem
9.
Med Hypotheses ; 127: 159-161, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31088642

RESUMO

Treatment resistant major depression is accompanied with a sizable impact on quality of life with severe consequences for social integrity, individual health and socioeconomic state. In- and outpatient care of patients with treatment resistant major depression remains very challenging for both patients and the health system. One reason is the limited knowledge on the etiology of treatment resistance in major depression resulting difficulties developing efficient treatment strategies for this group of severe depressed patients. Therefore, new focuses on research are needed. Biomarkers reliably reflecting neuropathological processes could help to understand the actual mechanisms in treatment resistance. Neurofilament light protein might be a reliable biomarker of axonal damage in the brain. Due to accumulating evidence that major depression is associated with axonal damage, it is our hypothesis that treatment resistant major depression is correlated with persistent axonal damage within circuits processing affective responses. Axonal damage is reflected by increased levels of neurofilament light protein in plasma. To evaluate our hypothesis, neurofilament light protein will be measured in a group of patients with homogeneous symptomatology of treatment resistant major depression.


Assuntos
Axônios/patologia , Encéfalo/patologia , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/terapia , Proteínas de Neurofilamentos/sangue , Biomarcadores/metabolismo , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Filamentos Intermediários/metabolismo , Luz , Doenças do Sistema Nervoso/patologia , Qualidade de Vida , Resultado do Tratamento
10.
Nat Commun ; 10(1): 1941, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028273

RESUMO

Mendelian randomization (MR) has emerged as a major tool for the investigation of causal relationship among traits, utilizing results from large-scale genome-wide association studies. Bias due to horizontal pleiotropy, however, remains a major concern. We propose a novel approach for robust and efficient MR analysis using large number of genetic instruments, based on a novel spike-detection algorithm under a normal-mixture model for underlying effect-size distributions. Simulations show that the new method, MRMix, provides nearly unbiased or/and less biased estimates of causal effects compared to alternative methods and can achieve higher efficiency than comparably robust estimators. Application of MRMix to publicly available datasets leads to notable observations, including identification of causal effects of BMI and age-at-menarche on the risk of breast cancer; no causal effect of HDL and triglycerides on the risk of coronary artery disease; a strong detrimental effect of BMI on the risk of major depressive disorder.


Assuntos
Algoritmos , Neoplasias da Mama/genética , Doença da Artéria Coronariana/genética , Transtorno Depressivo Maior/genética , Genoma Humano , Análise da Randomização Mendeliana/estatística & dados numéricos , Fatores Etários , Índice de Massa Corporal , Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/etiologia , HDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etiologia , Conjuntos de Dados como Assunto , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/etiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Menarca/sangue , Menarca/genética , Característica Quantitativa Herdável , Fatores de Risco , Triglicerídeos/sangue
11.
Brain Stimul ; 12(4): 1041-1050, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31000384

RESUMO

INTRODUCTION: The induction of brain-derived neurotrophic factor (BDNF) release and subsequent restoration of neuroplastic homeostasis may underlie the effects of electroconvulsive therapy (ECT). OBJECTIVES: We aimed to assess serum and plasma BDNF levels during the course of acute ECT, as well as before and after subsequent continuation ECT, in patients with depression. METHODS: We included 24 patients with major depressive disorder (mean age ±â€¯SD: 54.5 ±â€¯13.7; f/m: 17/7; baseline 17-item Hamilton Depression Rating Scale score of 26.79 ±â€¯4.01). Serum and plasma BDNF (sBDNF, pBDNF) levels were assessed at nine time-points before, during, and after acute ECT series. Data were analysed using linear regression and linear mixed models, which were adjusted for multiple comparisons via Bonferroni correction. Five patients received continuation ECT subsequent to the acute ECT series. In these patients, BDNF levels were assessed before and after each two continuation ECT sessions using Wilcoxon signed-rank tests. RESULTS: Relative to baseline (mean ng/ml ±SD: 24.68 ±â€¯14.40), sBDNF levels were significantly higher 1 day (33.04 ±â€¯14.11, p = 0.013, corrected), 1 week (37.03 ±â€¯10.29, p < 0.001, corrected), and 1 month (41.05 ±â€¯10.67, p = 0.008, corrected) after the final ECT session, while pBDNF levels did not significantly differ (p > 0.1). Furthermore, our results indicated that sBDNF levels increased after each continuation ECT session. There was no significant association between sBDNF levels and clinical parameters or treatment response. CONCLUSION: The absence of an association between changes in sBDNF levels and depressive symptoms challenges the proposed concept of sBDNF/pBDNF as key markers of the effects of ECT.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/terapia , Eletroconvulsoterapia/métodos , Adulto , Idoso , Biomarcadores/sangue , Transtorno Depressivo Maior/psicologia , Eletroconvulsoterapia/tendências , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Plasticidade Neuronal/fisiologia , Resultado do Tratamento
12.
Med Sci Sports Exerc ; 51(9): 1909-1917, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30973483

RESUMO

The endocannabinoid (eCB) system is implicated in the pathophysiology of depression and is responsive to acute exercise in healthy adults. PURPOSE: We aimed to describe acute changes in serum eCB across a prescribed moderate (MOD) and a self-selected/preferred (PREF) intensity exercise session in women with major depressive disorder (MDD) and determine relationships between changes in eCB and mood states. METHODS: Women with MDD (n = 17) exercised in separate sessions for 20 min on a cycle ergometer at both MOD or PREF in a within-subjects design. Blood was drawn before and within 10 min after exercise. Serum concentrations of eCB (anandamide [AEA], 2-arachidonoylglycerol) and related lipids (palmitoylethanolamine, oleoylethanolamine, 2-oleoylglycerol) were quantified using stable isotope-dilution, liquid chromatography/mass spectrometry/mass spectrometry. The profile of mood states and state-trait anxiety inventory (state only) were completed before, 10 min and 30 min postexercise. RESULTS: Significant elevations in AEA (P = 0.013) and oleoylethanolamine (P = 0.024) occurred for MOD (moderate effect sizes: Cohen's d = 0.58 and 0.41, respectively). Significant (P < 0.05) moderate negative associations existed between changes in AEA and mood states for MOD at 10 min (depression, confusion, fatigue, total mood disturbance [TMD] and state anxiety) and 30 min postexercise (confusion, TMD and state anxiety). Significant (P < 0.05) moderate negative associations existed between 2-arachidonoylglycerol and mood states at 10 min (depression and confusion) and 30 min postexercise (confusion and TMD). Changes in eCB or related lipids or eCB-mood relationships were not found for PREF. CONCLUSION: Given the broad, moderate-strength relationships between improvements in mood states and eCB increases after MOD, it is plausible that the eCB system contributes to the mood-enhancing effects of prescribed acute exercise in MDD. Alternative mechanisms are likely involved in the positive mood state effects of preferred exercise.


Assuntos
Afeto/fisiologia , Ácidos Araquidônicos/sangue , Transtorno Depressivo Maior/sangue , Endocanabinoides/sangue , Exercício/fisiologia , Glicerídeos/sangue , Alcamidas Poli-Insaturadas/sangue , Adulto , Etanolaminas/sangue , Feminino , Humanos , Pessoa de Meia-Idade , Ácidos Oleicos/sangue , Ácidos Palmíticos/sangue
13.
Nucleic Acids Res ; 47(10): e59, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-30869147

RESUMO

Deletions in the 16.6 kb mitochondrial genome have been implicated in numerous disorders that often display muscular and/or neurological symptoms due to the high-energy demands of these tissues. We describe a catalogue of 4489 putative mitochondrial DNA (mtDNA) deletions, including their frequency and relative read rate, using a combinatorial approach of mitochondria-targeted PCR, next-generation sequencing, bioinformatics, post-hoc filtering, annotation, and validation steps. Our bioinformatics pipeline uses MapSplice, an RNA-seq splice junction detection algorithm, to detect and quantify mtDNA deletion breakpoints rather than mRNA splices. Analyses of 93 samples from postmortem brain and blood found (i) the 4977 bp 'common deletion' was neither the most frequent deletion nor the most abundant; (ii) brain contained significantly more deletions than blood; (iii) many high frequency deletions were previously reported in MitoBreak, suggesting they are present at low levels in metabolically active tissues and are not exclusive to individuals with diagnosed mitochondrial pathologies; (iv) many individual deletions (and cumulative metrics) had significant and positive correlations with age and (v) the highest deletion burdens were observed in major depressive disorder brain, at levels greater than Kearns-Sayre Syndrome muscle. Collectively, these data suggest the Splice-Break pipeline can detect and quantify mtDNA deletions at a high level of resolution.


Assuntos
Biologia Computacional/métodos , DNA Mitocondrial/genética , Transtorno Depressivo Maior/genética , Sítios de Splice de RNA/genética , Análise de Sequência de RNA/métodos , Deleção de Sequência , Algoritmos , Sequência de Bases , Encéfalo/metabolismo , Encéfalo/patologia , Quebras de DNA , DNA Mitocondrial/química , Transtorno Depressivo Maior/sangue , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase
14.
PLoS One ; 14(3): e0213791, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30870525

RESUMO

Major depressive disorder (MDD) is the most prevalent comorbid mental disorder among people with substance use disorders. The MDD can be both primary and substance-induced and its accurate diagnosis represents a challenge for clinical practice and treatment response. Recent studies reported alterations in the circulating expression of inflammatory mediators in patients with psychiatric disorders, including those related to substance use. The aim of the study was to explore TNF-α, IL-1ß, CXCL12, CCL2, CCL11 (eotaxin-1) and CX3CL1 (fractalkine) as potential biomarkers to identify comorbid MDD and to distinguish primary MDD from substance-induced MDD in patients with substance disorders. Patients diagnosed with cocaine (CUD, n = 64) or alcohol (AUD, n = 65) use disorders with/without MDD were recruited from outpatient treatment programs [CUD/non-MDD (n = 31); CUD/primary MDD (n = 18); CUD/cocaine-induced MDD (N = 15); AUD/non-MDD (n = 27); AUD/primary MDD (n = 16) and AUD/alcohol-induced MDD (n = 22)]. Sixty-two healthy subjects were also recruited as control group. Substance and mental disorders were assessed according to "Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision" (DSM-IV-TR) and a blood sample was collected for determinations in the plasma. The cocaine group showed lower TNF-α (p<0.05) and CCL11 (p<0.05), and higher IL-1ß (p<0.01) concentrations than the control group. In contrast, the alcohol group showed higher IL-1ß (p<0.01) and lower CXCL12 (p<0.01) concentrations than the control group. Regarding MDD, we only observed alterations in the cocaine group. Thus, CUD/MDD patients showed lower IL-1ß (p<0.05), CXCL12 (p<0.05) and CCL11 (p<0.05), and higher CXC3CL1 (p<0.05) concentrations than CUD/non-MDD patients. Moreover, while CUD/primary MDD patients showed higher CCL11 (p<0.01) concentrations than both CUD/non-MDD and CUD/cocaine-induced MDD patients, CUD/cocaine-induced MDD patients showed lower CXCL12 (p<0.05) concentrations than CUD/non-MDD patients. Finally, a logistic regression model in the cocaine group identified CXCL12, CCL11 and sex to distinguish primary MDD from cocaine-induced MDD providing a high discriminatory power. The present data suggest an association between changes in inflammatory mediators and the diagnosis of primary and substance-induced MDD, namely in CUD patients.


Assuntos
Alcoolismo/diagnóstico , Biomarcadores/sangue , Transtornos Relacionados ao Uso de Cocaína/diagnóstico , Transtorno Depressivo Maior/diagnóstico , Mediadores da Inflamação/sangue , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Adulto , Alcoolismo/sangue , Alcoolismo/epidemiologia , Estudos de Casos e Controles , Transtornos Relacionados ao Uso de Cocaína/sangue , Transtornos Relacionados ao Uso de Cocaína/epidemiologia , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Espanha/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/sangue , Transtornos Relacionados ao Uso de Substâncias/epidemiologia
15.
J Affect Disord ; 250: 284-288, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30875670

RESUMO

BACKGROUND: Recent reports have suggested a relationship between affective disorder including depression and bipolar disorder (BP) and frontotemporal dementia (FTD). TAR DNA binding protein (TDP) -43 is a protein found in the brain and peripheral fluid of patients with FTD. To examine a possible association between affective disorders and FTD, serum levels of TDP-43 were evaluated in late-life patients with major depressive episode (MDE). METHODS: The subjects were 74 late-life (≥50 years old) inpatients with DSM-IV or -5 MDE (58 had major depressive disorders and 16 had BP) and 58 healthy subjects. Patients were recruited from Juntendo Koshigaya Hospital, Saitama, Japan, between January 2005 and May 2017. Serum TDP-43 levels were measured using an ELISA kit. RESULTS: Serum levels of TDP-43 were significantly higher in the MDE group than the control group independent of age and sex. LIMITATIONS: All patients were on antidepressant medication. CONCLUSIONS: Our finding suggests that some depressive patients may be in a prodromal stage of FTD or very-early stage of FTD comorbid with depression.


Assuntos
Proteínas de Ligação a DNA/sangue , Transtorno Depressivo Maior/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Transtorno Depressivo Maior/diagnóstico , Manual Diagnóstico e Estatístico de Transtornos Mentais , Ensaio de Imunoadsorção Enzimática , Feminino , Demência Frontotemporal/sangue , Demência Frontotemporal/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/sangue , Transtornos do Humor/diagnóstico
16.
J Affect Disord ; 250: 307-312, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30875673

RESUMO

BACKGROUND: Although several pharmacological treatment options for depression are currently available, a large proportion of patients still do not achieve a complete remission or respond adequately to the initial antidepressant prescribed for reasons that remain relatively unknown. This study explored the application of serum biomarkers to the predict the efficacy of escitalopram for treating depression, to guide clinical drug selection. METHOD: In this study, 306 patients suffering from depression were treated with escitalopram (10 mg) for 6 weeks. After 6 weeks of treatment, the patients were divided into an escitalopram-sensitive group (ES, n = 172) and an escitalopram-insensitive group (EIS, n = 134) according their HAMD-24 scores after 6 weeks of treatment. Serum samples from all participants were collected on the first day, and 10 different serum biomarkers were analysed. Data from 100 patients in the ES group and 100 patients in the EIS group were then used to build a logistic regression model, and a receiver operating characteristic (ROC) curve was drawn. To validate the accuracy of our model, another 72 patients in the ES group and 34 patients in the EIS group were studied. RESULTS: Of the 10 selected serum biomarkers, 4 were screened to build the regression model. BDNF, FGF-2, TNF-α and 5-HT. The regression equation was Z = 1/[1 + e-(-5.065+0.145 (BDNF)+0.029 (FGF-2)-0.368 (TNF-α)+0.813 (5-HT))], and the 4 biomarkers-combined detection achieved an AUC (area under the ROC curve) of 0.929 and a predictive accuracy of 88.70%. LIMITATION: Decision support tools based on our combined biomarker prediction models hold comparatively great promises; however, they need to be validated on a much larger scales than current studies provide. CONCLUSION: The logistic regression model and ROC curves based of the serum biomarkers used in this study provide a more reliable means to predict the efficacy of escitalopram in patients with depression, and provide clinical evidence for drug selection.


Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Biomarcadores/sangue , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Adulto , Idoso , Área Sob a Curva , Fator Neurotrófico Derivado do Encéfalo/sangue , Transtorno Depressivo Maior/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Fator 2 de Crescimento de Fibroblastos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade , Serotonina/sangue , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue
17.
J Affect Disord ; 250: 65-70, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30831543

RESUMO

BACKGROUND: Less than half of patients with major depressive disorder (MDD) respond to their first antidepressant trial. Our understanding of the underlying mechanisms of selective serotonin reuptake inhibitors (SSRIs) remains poor, and there is no reliable method of predicting treatment response. METHODS: Thirty-seven MDD subjects and 41 healthy controls, somatically healthy and medication-free for at least six weeks, were recruited, and plasma serotonin (5-HT) levels were assessed at baseline. Twenty-six of the MDD subjects were then treated in an open-label manner with clinically appropriate doses of sertraline for 8 weeks, after which plasma 5-HT levels were again assessed. Response to treatment was defined as an improvement of 50% or more on the Hamilton Depression Rating Scale. RESULTS: Non-responders to sertraline treatment had significantly lower pre-treatment 5-HT levels compared to both healthy controls and responders (F = 4.4, p = 0.004 and p = 0.036, respectively). There was a significant decrease in 5-HT levels over treatment in all MDD subjects (t = 6.2, p = 0.000003). The decrease was significantly more prominent in responders compared to non-responders (t = 2.1, p = 0.047). There was no significant difference in post-treatment 5-HT levels between responders and non-responders. LIMITATIONS: The study had a modest sample size. 5-HT levels in plasma may not reflect 5-HT levels in the brain. CONCLUSIONS: The results indicate that SSRI response may be facilitated by adequate baseline plasma 5-HT content and that successful SSRI treatment is associated with greater decreases in circulating 5-HT. Plasma 5-HT content may be a predictor of SSRI treatment outcome. Potential underlying mechanisms are discussed.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/sangue , Inibidores de Captação de Serotonina/uso terapêutico , Serotonina/sangue , Sertralina/uso terapêutico , Adulto , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Humanos , Masculino , Resultado do Tratamento
18.
Medicine (Baltimore) ; 98(7): e14419, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30762747

RESUMO

Immune system dysregulation plays a key role in the physiopathology of bipolar disorder (BD) and major depressive disorder (MDD). However, whether interleukins might be biomarkers to distinguish these 2 affective disorders is unclear. Here, we assessed the differences in serum levels of interleukin 6 (IL-6) and interleukin 8 (IL-8) as well as C-reactive protein (CRP) in patients with MDD and BD. In total, we enrolled 21 MDD patients, 26 BD patients, and 20 healthy controls. We collected a total of 35 samples from BD patients in 3 different phases, depression phase, manic phase, and remission stage, and 27 samples from MDD patients in acute and remission phases. Serum IL-6 and IL-8 levels were assessed with solid phase sandwich ELISA-based quantitative arrays, and CRP levels were determined with an automatic analyzer. Both serum IL-6 and IL-8 levels were elevated in BD patients but not MDD patients. Subgroup analysis indicated elevated serum IL-6 in both the depression and manic phases in BD patients. The serum CRP levels did not change in either BD or MDD patients. However, sex differences in CRP concentrations were observed in healthy controls. Furthermore, there were linear correlations between the CRP levels and Bech-Rafaelsen Mania Rating Scale (BRMS) scores in BD patients. IL-6 and IL-8 levels may serve as biomarkers to differentiate between MDD and BD patients, even when the clinical manifestations are atypical. IL-6 may be used for the differential diagnosis of MDD and depressive episodes in BD.


Assuntos
Transtorno Bipolar/sangue , Transtorno Depressivo Maior/sangue , Interleucina-6/sangue , Interleucina-8/sangue , Adulto , Biomarcadores/sangue , Proteína C-Reativa/análise , Estudos de Casos e Controles , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Fatores Sexuais
19.
Artigo em Inglês | MEDLINE | ID: mdl-30779936

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent and burdening mental illness. Approximately 30% of the major depressive episodes (MDE) are classified as therapy-refractory. Further knowledge of the pathophysiological mechanisms underlying MDD and predictive biomarkers are needed to improve treatment options. METHODS: Serum lipid levels were compared between patients with a current MDE (n = 130) or remitted MDD (n = 39) and healthy control subjects (n = 61) and associated with the severity (17-item Hamilton Depression Rating Scale [HAMD] scores) and the prospective course of depression (direct follow-up of at median 20 days post-inclusion). RESULTS: We found higher levels of LDL cholesterol (152.5 vs. 134.0 mg/dl, U = 3021, P = 0.008) and LDL/HDL ratio (2.82 vs. 2.21, U = 2912, P = 0.003) in patients with a current MDE than in healthy control subjects. In patients with a current MDE, higher HAMD scores correlated also with higher values of triglycerides (ρ = 0.213, P = 0.015), total cholesterol (ρ = 0.199, P = 0.023), LDL cholesterol (ρ = 0.224, P = 0.010), and LDL/HDL ratio (ρ = 0.196, P = 0.026). Moreover, higher total cholesterol (ρ = -0.233, P = 0.010), LDL cholesterol (ρ = -0.235, P = 0.010), and LDL/HDL ratio (ρ = -0.199, P = 0.029) were associated with a stronger decline in HAMD score between study inclusion and direct follow-up. LIMITATIONS: We employed an associational study design, performed only a short-term follow-up, and excluded suicidal study subjects. CONCLUSIONS: Serum lipid levels are associated with depression per se, the depression severity, and the prospective 3-week course. These observations build the basis for future investigations on individualized lipid metabolism-related treatment strategies in depressed patients.


Assuntos
HDL-Colesterol/sangue , LDL-Colesterol/sangue , Transtorno Depressivo Maior/sangue , Triglicerídeos/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Transtorno Depressivo Maior/diagnóstico , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Adulto Jovem
20.
Alcohol Alcohol ; 54(3): 243-250, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30809628

RESUMO

AIMS: Alcohol consumption has been suggested a major role in the pathogenesis and prognosis of depression. However, reliable identification of hazardous drinking continues to be problematic. We compared the accuracy of different biomarkers and self-reports of alcohol consumption in the follow-up study of depression. METHODS: Data from 202 patients with major depressive disorder were obtained through self-reports, AUDIT and AUDIT-C questionnaires and biomarker analyses. The clinical assessments and measurements of biomarkers (GT, CDT, GT-CDT-combination, MCV, ALT, AST, hs-CRP, IL-6) were performed at baseline and after six months of treatment. Based on self-reported alcohol intake at baseline the patients were classified to three subgroups. RESULTS: About 27.2% of patients were categorized to high-risk drinkers, 26.3% low-risk drinkers and 46.5% abstainers. High-risk drinkers showed significantly higher mean values of GT, CDT, GT-CDT-combination and IL-6 than abstainers, diagnostic accuracy being highest with the combined marker of GT-CDT. The accuracy of AUDIT and AUDIT-C to detect high-risk drinking was also significant. During follow-up, the differences observed in the biomarkers at baseline disappeared together with recovery from depression. CONCLUSIONS: Our data suggest the combined use of GT-CDT and AUDIT questionnaires to improve the identification of drinking of patients with depression. This approach could be useful for improving treatment adherence and outcome in depressed patients.


Assuntos
Consumo de Bebidas Alcoólicas/sangue , Biomarcadores/sangue , Transtorno Depressivo Maior/sangue , Mediadores da Inflamação/sangue , Autorrelato , Adulto , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/metabolismo , Proteínas de Transporte/sangue , Transtorno Depressivo Maior/psicologia , Índices de Eritrócitos , Feminino , Seguimentos , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-6/sangue , Proteínas com Domínio LIM/sangue , Masculino , Transferrina/análogos & derivados , Transferrina/análise , Transferrina/metabolismo , gama-Glutamiltransferase/sangue
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