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1.
Adv Exp Med Biol ; 1180: 99-116, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31784959

RESUMO

Enormous efforts for near half-century have harvested a plenty of understanding on major depressive disorder (MDD), although the underlying mechanisms are still elusive. The available antidepressants are far from satisfaction due to long-delay action (LDA) of antidepressant efficacy and low response rates in MDD patients. Notably, discovery of a single low-dose ketamine-producing rapid-onset and sustained antidepressant efficacy has inspired new research direction. These new studies have revealed ketamine's NMDAR-dependent and NMDAR-independent mechanisms, most of which are well known to be the key bases of synaptic plasticity as well as learning and memory. In fact, animal models of MDD are all based on the principle of learning and memory, i.e., the change of a behavior, for which monoaminergic and glutamatergic systems are the major modulators and executors, respectively. Reconsidering MDD as an aberrant form of emotion-related learning and memory would endow us a clearer research direction for developing new techniques or ways to prevent, diagnose, and treat MDD.


Assuntos
Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/terapia , Plasticidade Neuronal , Animais , Antidepressivos/uso terapêutico , Humanos , Ketamina/uso terapêutico
2.
Adv Exp Med Biol ; 1180: 117-133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31784960

RESUMO

Most processes of human body, such as brain function, are regulated by biological rhythms. Disturbance of biological rhythms impairs mood, behavior, cognition, sleep, and social activity and may lead to mental disorders. Disturbed rhythms are widely observable in patients with major depressive disorders (MDD) and make risk of onset, comorbidity, response of antidepressants, recurrence, cognition, social function, and complications of physical health. Therefore, it is crucial to assess and manage focus on biological rhythms for patients with MDD. There are several validated ways of assessing the biological rhythms, including 24 h fluctuations in cortisol or melatonin, sleep monitoring, actigraphy, and self-report scales. Chronotherapy, such as cognitive-behavioral therapy, interpersonal and social rhythm therapy, sleep deprivation, and bright light therapy was widely reported for treatment in patients with MDD. Monoamine antidepressants and lithium are attributed to regulation of biological rhythm. And some rhythm-regulated agents have been shown efficacy of antidepressant. Considering the crucial clinical significance of disturbed biological rhythms in MDD, we describe the mechanisms, clinical features, measurements, and treatments of the biological rhythms in patients with MDD.


Assuntos
Ritmo Circadiano , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/terapia , Antidepressivos/uso terapêutico , Terapia Cognitivo-Comportamental , Humanos , Hidrocortisona/fisiologia , Melatonina/fisiologia , Sono
3.
Rev Saude Publica ; 53: 103, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800914

RESUMO

OBJECTIVES: To explore the association between adiposity, major depressive disorder and generalized anxiety disorder, and to assess the role of inflammation, diet quality and physical activity in this association. METHODS: We used data from 2,977 individuals from the 1993 Pelotas Cohort (Brazil) who attended the 18- and 22-year follow-ups. We assessed general obesity using body mass index, fat mass index, and abdominal obesity using waist circumference. Major Depressive Disorder and generalized anxiety disorder were assessed using the mini-international neuropsychiatric interview. C-reactive protein and interleukin-6 (IL-6) levels were used as a measure of inflammation; diet quality was estimated using the revised diet quality index, and physical activity was assessed by the International physical activity questionnaire (IPAQ, min/day). The association between adiposity and major depressive disorder and generalized anxiety disorder was assessed using logistic regression, and the natural indirect effect via the mediators was estimated using G-computation. RESULTS: General obesity assessed by body mass index (OR: 2.3; 95% CI:1.13; 4.85), fat mass index (OR: 2.6; 95%CI: 1.37; 4.83), and abdominal obesity (OR: 2.5; 95%CI: 1.18; 5.39) were associated with higher odds of major depressive disorder, whereas major depressive disorder was only associated with obesity assessed by body mass index (OR=1.9; 95% CI: 1.09; 3.46). Obesity and generalized anxiety disorder were not associated. C-reactive protein, diet quality and physical activity did not mediate the effect of obesity on major depressive disorder, and C-reactive protein mediated about 25% of the effect of major depressive disorder on adiposity. CONCLUSIONS: Depression, but not generalized anxiety disorder, is associated with adiposity in both directions, with a stronger evidence for the direction obesity-depression. Inflammation explains part of the effect of major depressive disorder on obesity but not the other way around. Further research should explore other mechanisms that could be involved in the association between obesity and depression.


Assuntos
Adiposidade/fisiologia , Transtornos de Ansiedade/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Dieta , Exercício/psicologia , Obesidade/psicologia , Adolescente , Antropometria , Brasil , Proteína C-Reativa/análise , Estudos de Coortes , Exercício/fisiologia , Feminino , Humanos , Interleucina-6/sangue , Estilo de Vida , Modelos Logísticos , Masculino , Obesidade Abdominal/psicologia , Escalas de Graduação Psiquiátrica , Valores de Referência , Inquéritos e Questionários , Adulto Jovem
4.
Nat Commun ; 10(1): 3924, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477731

RESUMO

The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are implicated in major depressive disorder (MDD). Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains, and identified ZDHHC21 as a major palmitoyl acyltransferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR. Two rodent models for depression-like behavior show reduced brain ZDHHC21 expression and attenuated 5-HT1AR palmitoylation. Moreover, selective knock-down of ZDHHC21 in the murine forebrain induced depression-like behavior. We also identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. Through analysis of the post-mortem brain samples in individuals with MDD that died by suicide we find that miR-30e expression is increased, while ZDHHC21 expression, as well as palmitoylation of 5-HT1AR, are reduced within the prefrontal cortex. Our study suggests that downregulation of 5-HT1AR palmitoylation is a mechanism involved in depression, making the restoration of 5-HT1AR palmitoylation a promising clinical strategy for the treatment of MDD.


Assuntos
Encéfalo/fisiopatologia , Depressão/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Receptor 5-HT1A de Serotonina/metabolismo , Aciltransferases/genética , Aciltransferases/metabolismo , Animais , Encéfalo/metabolismo , Linhagem Celular Tumoral , Depressão/genética , Depressão/metabolismo , Transtorno Depressivo Maior/genética , Regulação da Expressão Gênica , Humanos , Lipoilação , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Ratos Wistar , Receptor 5-HT1A de Serotonina/genética
5.
PLoS Genet ; 15(6): e1008164, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31194737

RESUMO

Chronic pain is highly prevalent worldwide and represents a significant socioeconomic and public health burden. Several aspects of chronic pain, for example back pain and a severity-related phenotype 'chronic pain grade', have been shown previously to be complex heritable traits with a polygenic component. Additional pain-related phenotypes capturing aspects of an individual's overall sensitivity to experiencing and reporting chronic pain have also been suggested as a focus for investigation. We made use of a measure of the number of sites of chronic pain in individuals within the UK general population. This measure, termed Multisite Chronic Pain (MCP), is a complex trait and its genetic architecture has not previously been investigated. To address this, we carried out a large-scale genome-wide association study (GWAS) of MCP in ~380,000 UK Biobank participants. Our findings were consistent with MCP having a significant polygenic component, with a Single Nucleotide Polymorphism (SNP) heritability of 10.2%. In total 76 independent lead SNPs at 39 risk loci were associated with MCP. Additional gene-level association analyses identified neurogenesis, synaptic plasticity, nervous system development, cell-cycle progression and apoptosis genes as enriched for genetic association with MCP. Genetic correlations were observed between MCP and a range of psychiatric, autoimmune and anthropometric traits, including major depressive disorder (MDD), asthma and Body Mass Index (BMI). Furthermore, in Mendelian randomisation (MR) analyses a causal effect of MCP on MDD was observed. Additionally, a polygenic risk score (PRS) for MCP was found to significantly predict chronic widespread pain (pain all over the body), indicating the existence of genetic variants contributing to both of these pain phenotypes. Overall, our findings support the proposition that chronic pain involves a strong nervous system component with implications for our understanding of the physiology of chronic pain. These discoveries may also inform the future development of novel treatment approaches.


Assuntos
Dor Crônica/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Adulto , Idoso , Asma/genética , Asma/fisiopatologia , Bancos de Espécimes Biológicos , Índice de Massa Corporal , Dor Crônica/fisiopatologia , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurogênese/genética , Plasticidade Neuronal/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Reino Unido
6.
Cell Tissue Res ; 377(1): 95-106, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31165247

RESUMO

A theoretical framework is proposed to gain insight into the pathogenesis of major depressive disorder (MDD). Despite being a relatively weak argument, the neurogenesis theory is suggested to compensate for the limitations of the monoamine theory. In the adult hippocampus, neurogenesis is functionally related to regulation of the hypothalamic-pituitary-adrenal (HPA) axis, inflammatory processes, cognitive functions and other aspects that contribute to etiological factors that lead to MDD and promote recovery from MDD. Despite a lack of investigation into neurogenesis and antidepressant action, it is proposed that chronic administration of antidepressant(s) can induce the recruitment and integration of newborn neurons into the dentate gyrus and, ultimately, lead to the remission of MDD. The extant body of literature indicates that the suppression of neurogenesis per se may be associated with an impaired response to antidepressant treatment rather than with the induction of depressive-like behaviors. Moreover, recent studies have shown that increasing the survival rate and incorporation of new neurons can alleviate depressive-like behaviors and promote stress resilience. According to the neurogenic reserve hypothesis, hippocampal neurogenesis supports specific cortical functions, including executive functions, pattern separation and contextual information processing, control over the HPA axis and behavioral coping mechanisms in response to stressful situations. Therefore, hippocampal neurogenesis may be a promising biological indicator of stress resilience and antidepressant response in patients with MDD.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Hipocampo/embriologia , Neurogênese , Neurônios/fisiologia , Adulto , Animais , Antidepressivos/farmacologia , Transtorno Depressivo Maior/fisiopatologia , Modelos Animais de Doenças , Humanos , Sistema Hipotálamo-Hipofisário/embriologia , Camundongos , Neurônios/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/embriologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Ratos
7.
East Asian Arch Psychiatry ; 29(2): 41-47, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31237245

RESUMO

OBJECTIVE: To examine the prevalence and comorbidity of gastro-oesophageal reflux disease (GORD) with generalised anxiety disorder (GAD) and major depressive episodes (MDE) in a general population using DSM-IV, and to evaluate the associations between these conditions and healthcare utilisation. METHODS: A random population-based telephone survey was conducted to record frequency of GORD symptoms, symptoms of GAD and MDE based on DSM-IV, and healthcare utilisation. RESULTS: Of 2011 respondents, 4.2% had weekly GORD and 13.9% had monthly GORD, whereas 3.8% reported GAD and 12.4% reported MDE. Those with monthly GORD had higher risk of GAD (p = 0.01) and MDE (p < 0.001). GORD symptom frequency was independently correlated with MDE and GAD in a dose-response manner. The number of psychiatric diagnoses was independently correlated with GORD. GORD symptom frequency, GAD, and MDE were correlated with consultation frequency. GORD symptom frequency was corelated with high investigation expenditure. CONCLUSION: GORD had a strong dose-response relationship with GAD and MDE in a Hong Kong population. Excessive healthcare utilisation should alert clinicians to the risk of psychiatric comorbidity.


Assuntos
Transtornos de Ansiedade , Transtorno Depressivo Maior , Refluxo Gastroesofágico , Adulto , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/fisiopatologia , Comorbidade , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/fisiopatologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Refluxo Gastroesofágico/epidemiologia , Refluxo Gastroesofágico/psicologia , Hong Kong/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Prevalência , Medição de Risco
8.
East Asian Arch Psychiatry ; 29(2): 66-70, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31237249

RESUMO

OBJECTIVE: To investigate association between major depressive disorder (MDD) and quality of life in patients with neurological disorder. METHODS: This cross-sectional study was carried out at a Malaysian hospital between April 2016 and December 2016 using convenience sampling. Patients aged ≥18 years with intracranial tumour or other brain disorders were invited to participate. Quality of life was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life questionnaire version 3.0; diagnosis of MDD was made using Mini International Neuropsychiatric Interview. RESULTS: Of 122 patients approached, 100 (66 women and 34 men) were included (response rate, 93.5%), with a mean age of 45.3 years. The prevalence of MDD in patients with neurological disorder was 30%. Compared with non-depressed patients, patients with MDD had poorer global health status / quality of life (p = 0.003), and reduced physical (p = 0.003), role (p = 0.021), emotional (p < 0.001), cognitive (p = 0.004), and social (p = 0.007) functioning, as well as more symptoms of fatigue (p = 0.004), pain (p < 0.001), dyspnoea (p = 0.033), insomnia (p < 0.001), appetite loss (p = 0.002), constipation (p = 0.034), diarrhoea (p = 0.021), and financial difficulties (p = 0.039). CONCLUSION: Patients with MDD had reduced quality of life. Fatigue, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties were prevalent among patients with MDD.


Assuntos
Transtorno Depressivo Maior , Doenças do Sistema Nervoso , Qualidade de Vida , Estudos Transversais , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/etiologia , Transtorno Depressivo Maior/fisiopatologia , Feminino , Humanos , Malásia/epidemiologia , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/psicologia , Prevalência , Pesquisa Qualitativa
9.
Trials ; 20(1): 367, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221205

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a widespread and burdensome psychiatric issue. Physical activity counselling may increase lifestyle physical activity and cardiorespiratory fitness in this specific and particularly vulnerable population, which often suffers from both mental and physical health problems. Therefore, this study will examine the impact of a lifestyle physical activity counselling intervention on physical activity, cardiorespiratory fitness, depression, and cardiovascular health risk markers among in-patients diagnosed with MDD compared to controls. Secondary purposes are to examine the acceptability and perceived usefulness of the intervention among these patients, to find out whether the effectiveness of the intervention is moderated by genetic factors, and to compare baseline values with an age- and gender-matched group of healthy controls. METHODS: The study is designed as a multi-centric two-arm randomized clinical trial including an intervention group and a placebo control group, allocation concealment, single-blinding, and intention-to-treat analysis. Participants (N = 334) will be continuously recruited from four clinics specialized in the treatment of MDD. The intervention builds on a standardized, theory-based, low-cost lifestyle physical activity counselling programme, which was specifically designed for an in-patient rehabilitation setting. The placebo control condition consists of general instructions about health-enhancing physical activity. Data assessments will take place 2-3 weeks after admission to in-patient treatment (baseline), and 6 weeks (post) and 12 months (follow-up) after discharge from in-patient treatment. The primary outcome is objectively assessed physical activity at follow-up. DISCUSSION: Because regular physical activity has proven to be an important predictor of long-term response and remission in patients with major depression, we believe that our planned study may lay important groundwork by showing how individually tailored lifestyle physical activity counselling can be integrated into given clinical structures. Improving physical activity may have important implications for tackling metabolic and cardiovascular disease and increasing mood and cognitive functioning in this at-risk population, hence limiting the future burden of multiple chronic conditions. Increased physical activity may also reduce the likelihood of future depressive episodes. By moving towards the primary prevention of chronic physical conditions, much can be done to enhance the quality and quantity of life of people with MDD. TRIAL REGISTRATION: ISRCTN, ISRCTN10469580 . Registered on 3 September 2018.


Assuntos
Aptidão Cardiorrespiratória , Doenças Cardiovasculares/etiologia , Aconselhamento , Transtorno Depressivo Maior/fisiopatologia , Exercício , Estilo de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Adolescente , Adulto , Idoso , Transtorno Depressivo Maior/psicologia , Humanos , Pessoa de Meia-Idade , Risco , Método Simples-Cego , Adulto Jovem
10.
Expert Opin Ther Pat ; 29(7): 497-507, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31242055

RESUMO

INTRODUCTION: Positive allosteric modulation of mGlu2 has attracted much interest as an alternative approach to classical orthosteric receptor activation. Two mGlu2 PAMS have advanced into the clinic. The results obtained in schizophrenia and MDD phase 2 clinical trials have tempered the high expectations put on selective mGlu2 receptor activation for treating these conditions; nevertheless, the search for novel therapeutic indications and novel chemotypes continues to be an active field of research. AREAS COVERED: 2013-2018 patent literature on mGlu2 receptor PAMs. EXPERT OPINION: After a decade of intensive research, the mGlu2 PAM field has seen a deceleration in the last five years. Negative phase 2 schizophrenia clinical trials with JNJ-40411813 and AZD8529 seem to have tempered the high expectations of the scientific community on the utility of mGlu2 PAMs for the treatment of schizophrenia. Nevertheless, novel therapeutic indications continue to be explored and AZD8529 is currently in a phase 2 study for smoking cessation. The advances in medicinal chemistry and in pharmacology, with novel indications such as epilepsy, have set the stage in the field of mGlu2 receptor PAMs. Ongoing preclinical and clinical studies will contribute to define their optimal therapeutic indication and potential to become novel therapeutic agents.


Assuntos
Indóis/uso terapêutico , Oxidiazóis/uso terapêutico , Piperidinas/uso terapêutico , Piridonas/uso terapêutico , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Animais , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Humanos , Indóis/farmacologia , Oxidiazóis/farmacologia , Patentes como Assunto , Piperidinas/farmacologia , Piridonas/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia
11.
Dev Psychopathol ; 31(3): 1037-1052, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31064610

RESUMO

Aberrant face emotion processing has been demonstrated in youth with and at a familial risk for bipolar and major depressive disorders. However, the neurobiological factors related to emotion processing that underlie resilience from youth-onset mood disorders are not well understood. Functional magnetic resonance imaging data during an implicit emotion processing task were collected at baseline from a sample of 50 youth, ages 8-17, who were healthy but also familially at high risk for either bipolar disorder or major depressive disorder, and 24 healthy controls with no family history of psychopathology (HCL). Participants were reevaluated 3 years later and classified into three groups for analysis: high-risk youth who converted to a psychiatric diagnosis (CVT; N = 23), high-risk youth who were resilient from developing any psychopathology (RES; N = 27), and HCL youth (N = 24) who remained healthy at follow-up. For happy > calm faces, the CVT and RES groups had significantly lower activation in the left inferior parietal lobe (IPL), while the RES group had lower activation in the right supramarginal gyrus. For fear > calm faces, the RES group had lower activation in the right precuneus and inferior frontal gyrus (IFG) compared to the CVT group. Connectivity analyses revealed the RES group exhibited higher left IPL connectivity with visual cortical regions for happy > calm faces, and higher IFG connectivity with frontal, temporal, and limbic regions for fear > calm faces. These connectivities were correlated with improvements in prosocial behaviors and global functioning. Our findings suggest that differential activation and connectivity in the IPL, IFG, and precuneus in response to emotional stimuli may represent distinct resilience and risk markers for youth-onset mood disorders.


Assuntos
Transtorno Bipolar/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Transtorno Depressivo Maior/diagnóstico por imagem , Emoções/fisiologia , Expressão Facial , Resiliência Psicológica , Adolescente , Transtorno Bipolar/fisiopatologia , Transtorno Bipolar/psicologia , Encéfalo/fisiopatologia , Criança , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/psicologia , Feminino , Predisposição Genética para Doença , Humanos , Imagem por Ressonância Magnética/métodos , Masculino
12.
Brain Behav ; 9(6): e01257, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31066228

RESUMO

INTRODUCTION: Previous studies have established graph theoretical analysis of functional network connectivity (FNC) as a potential tool to detect neurobiological underpinnings of psychiatric disorders. Despite the promising outcomes in studies that examined FNC aberrancies in bipolar disorder (BD) and major depressive disorder (MDD), there is still a lack of research comparing both mood disorders, especially in a nondepressed state. In this study, we used graph theoretical network analysis to compare brain network properties of euthymic BD, euthymic MDD and healthy controls (HC) to evaluate whether these groups showed distinct features in FNC. METHODS: We collected resting-state functional magnetic resonance imaging (fMRI) data from 20 BD patients, 15 patients with recurrent MDD as well as 30 age- and gender-matched HC. Graph theoretical analyses were then applied to investigate functional brain networks on a global and regional network level. RESULTS: Global network analysis revealed a significantly higher mean global clustering coefficient in BD compared to HC. We further detected frontal, temporal and subcortical nodes in emotion regulation areas such as the limbic system and associated regions exhibiting significant differences in network integration and segregation in BD compared to MDD patients and HC. Participants with MDD and HC only differed in frontal and insular network centrality. CONCLUSION: In conclusion, our findings indicate that a significantly altered brain network topology in the limbic system might be a trait marker specific to BD. Brain network analysis in these regions may therefore be used to differentiate euthymic BD not only from HC but also from patients with MDD.


Assuntos
Transtorno Bipolar/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Imagem por Ressonância Magnética/métodos , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Sistema Límbico/diagnóstico por imagem , Sistema Límbico/fisiopatologia , Masculino
13.
Int J Mol Sci ; 20(9)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075818

RESUMO

Major depressive disorder (MDD) is a debilitating condition, whose high prevalence and multisymptomatic nature set its standing as a leading contributor to global disability. To better understand this psychiatric disease, various pathophysiological mechanisms have been proposed, including changes in monoaminergic neurotransmission, imbalance of excitatory and inhibitory signaling in the brain, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, and abnormalities in normal neurogenesis. While previous findings led to a deeper understanding of the disease, the pathogenesis of MDD has not yet been elucidated. Accumulating evidence has confirmed the association between chronic inflammation and MDD, which is manifested by increased levels of the C-reactive protein, as well as pro-inflammatory cytokines, such as Interleukin 1 beta, Interleukin 6, and the Tumor necrosis factor alpha. Furthermore, recent findings have implicated a related family of cytokines with chemotactic properties, known collectively as chemokines, in many neuroimmune processes relevant to psychiatric disorders. Chemokines are small (8-12 kDa) chemotactic cytokines, which are known to play roles in direct chemotaxis induction, leukocyte and macrophage migration, and inflammatory response propagation. The inflammatory chemokines possess the ability to induce migration of immune cells to the infection site, whereas their homeostatic chemokine counterparts are responsible for recruiting cells for their repair and maintenance. To further support the role of chemokines as central elements to healthy bodily function, recent studies suggest that these proteins demonstrate novel, brain-specific mechanisms including the modulation of neuroendocrine functions, chemotaxis, cell adhesion, and neuroinflammation. Elevated levels of chemokines in patient-derived serum have been detected in individuals diagnosed with major depressive disorder, bipolar disorder, and schizophrenia. Furthermore, despite the considerable heterogeneity of experimental samples and methodologies, existing biomarker studies have clearly demonstrated the important role of chemokines in the pathophysiology of psychiatric disorders. The purpose of this review is to summarize the data from contemporary experimental and clinical studies, and to evaluate available evidence for the role of chemokines in the central nervous system (CNS) under physiological and pathophysiological conditions. In light of recent results, chemokines could be considered as possible peripheral markers of psychiatric disorders, and/or targets for treating depressive disorders.


Assuntos
Quimiocinas/metabolismo , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Humanos , Neurogênese , Plasticidade Neuronal , Receptores de Quimiocinas/metabolismo , Transmissão Sináptica
14.
Depress Anxiety ; 36(8): 766-779, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31111623

RESUMO

BACKGROUND: Brain mitochondrial dysfunction is implicated in the pathophysiology of mood disorders. Brain cytochrome-c-oxidase (COX) activity is associated with the mitochondrial function. Near-infrared spectroscopy (NIRS) noninvasively measures oxidized COX (oxCOX) and tissue oxygenation index (TOI) reflecting cerebral blood flow and oxygenation. METHODS: oxCOX and TOI were assessed in prefrontal cortex (Fp1/2, Brodmann area 10) in patients in a major depressive episode (N = 13) with major depressive disorder (MDD; N = 7) and bipolar disorder (BD; N = 6) compared with the controls (N = 10). One patient with MDD and all the patients with BD were taking medications. Computational modeling estimated oxCOX and TOI related indices of mitochondrial function and cerebral blood flow, respectively. RESULTS: oxCOX was lower in patients than controls (p = .014) correlating inversely with depression severity (r = -.72; p = .006), driven primarily by lower oxCOX in BD compared with the controls. Computationally modeled mitochondrial parameters of the electron transport chain, such as the nicotinamide adenine dinucleotide ratio (NAD+ /NADH; p = .001) and the proton leak rate across the inner mitochondrial membrane (klk2 ; p = .008), were also lower in patients and correlated inversely with depression severity. No such effects were found for TOI. CONCLUSIONS: In this pilot study, oxCOX and related mitochondrial parameters assessed by NIRS indicate an abnormal cerebral metabolic state in mood disorders proportional to depression severity, potentially providing a biomarker of antidepressant effect. Because the effect was driven by the medicated BD group, findings need to be evaluated in a larger, medication-free population.


Assuntos
Encéfalo/metabolismo , Encéfalo/fisiopatologia , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Mitocôndrias/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Mapeamento Encefálico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/fisiologia , Projetos Piloto , Espectroscopia de Luz Próxima ao Infravermelho , Adulto Jovem
15.
Depress Anxiety ; 36(8): 712-722, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31111629

RESUMO

OBJECTIVE: Amygdala-based network dysfunction has been found to be centrally implicated in major depressive disorder (MDD). However, relatively little is known about how different forms of effective or cognitive dysfunction are modulated in MDD. Therefore, in the current study, we aimed to examine the alteration of amygdala subregional networks in adult patients with MDD to explore whether different parts of the amygdala that are functionally connected to different regions contribute differently to the cerebral network mechanism of depression. METHODS: Resting-state fMRI scans were obtained from 70 medication-free adults with MDD and 70 age- and sex-matched healthy controls (HC). Functional connectivity maps of four distinct regions of the amygdala, including the amygdalostriatal transition area (AStr) and the basolateral (BLA), centromedial (CM) and superficial (SF) amygdala, were generated and compared between the two groups. RESULTS: Compared with HC, patients with MDD showed hypoconnectivity between the AStr/BLA and the orbitofrontal cortex (OFC), between the CM/SF and the brainstem/cerebellum, and within AStr/CM/SF-thalamic/striatal networks. Hyperconnectivity was observed between the left AStr/BLA and the fusiform gyrus. There was no difference in the gray matter volume of the amygdala or any of its subregions between the two groups. CONCLUSIONS: These findings suggest that amygdala subregional-network dysfunction in MDD is independent of structural changes and, more important, that hypoconnectivity and hyperconnectivity in different subregional networks may reflect imbalanced network function, which may modulate different forms of emotional and cognitive dysfunction in MDD.


Assuntos
Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Imagem por Ressonância Magnética/métodos , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Adulto , Feminino , Humanos , Masculino
16.
Psychopharmacology (Berl) ; 236(9): 2823-2834, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31115613

RESUMO

RATIONALE AND OBJECTIVE: Paeoniflorin has been reported to exhibit antidepressant-like effects in several animal model depression; and it also exerts a neuroprotective effect. In the present study, we investigated the effects of paeoniflorin administration on depression-like behaviors and cognitive abilities in mice subjected to chronic unpredictable mild stress (CUMS), an animal model associated with depressive disorders and cognitive deficits. METHODS: We administered paeoniflorin (20 mg/kg), which is the main active constituent extracted from Paeonia lactiflora Pall. and exerts multiple pharmacological actions, to CUMS mice. Subsequently, animals were subjected to tests of depression-like behavior including the sucrose preference test, the forced swimming test and the tail suspension test. The Morris water maze (MWM) task was applied to evaluate learning and memory capacity. Hippocampal CA1 long-term potentiation (LTP) was recorded. Dendritic spine density and the expression levels of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95) in the hippocampus were also investigated. RESULTS: The administration of paeoniflorin protected against CUMS-induced depression-like behavior. Paeoniflorin also improved the performance of CUMS mice in the MWM. The impairment of hippocampal CA1 LTP caused by CUMS was also reversed. Furthermore, paeoniflorin administration prevented decreases in dendritic spine density and in the expression of BDNF and PSD95 in the hippocampus of CUMS mice. CONCLUSION: Our observations suggest that paeoniflorin is a potential antidepressant that protects against cognitive impairment in depression.


Assuntos
Glucosídeos/uso terapêutico , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Monoterpenos/uso terapêutico , Aprendizagem Espacial/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/psicologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/psicologia , Glucosídeos/farmacologia , Hipocampo/fisiopatologia , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monoterpenos/farmacologia , Técnicas de Cultura de Órgãos , Distribuição Aleatória , Aprendizagem Espacial/fisiologia , Estresse Psicológico/fisiopatologia
17.
J Neuroinflammation ; 16(1): 90, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30995920

RESUMO

Major depressive disorder (MDD) is a leading cause of disability worldwide. After the first episode, patients with remitted MDD have a 60% chance of experiencing a second episode. Consideration of therapy continuation should be viewed in terms of the balance between the adverse effects of medication and the need to prevent a possible relapse. Relapse during the early stages of MDD could be prevented more efficiently by conducting individual risk assessments and providing justification for continuing therapy. Our previous work established the neuroimaging markers of relapse by comparing patients with recurrent major depressive disorder (rMDD) in depressive and remitted states. However, it is not known which of these markers are trait markers that present before initial relapse and, consequently, predict disease course. Here, we first describe how inflammation can be translated to subtype-specific clinical features and suggest how this could be used to facilitate clinical diagnosis and treatment. Next, we address the central and peripheral functional state of the immune system in patients with MDD. In addition, we emphasize the important link between the number of depressive episodes and rMDD and use neuroimaging to propose a model for the latter. Last, we address how inflammation can affect brain circuits, providing a possible mechanism for rMDD. Our review suggests a link between inflammatory processes and brain region/circuits in rMDD.


Assuntos
Encéfalo/imunologia , Transtorno Depressivo Maior/imunologia , Inflamação/complicações , Encéfalo/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Humanos , Inflamação/fisiopatologia , Recidiva
18.
J Affect Disord ; 251: 263-269, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30951984

RESUMO

BACKGROUND: Major Depressive Disorder (MDD) is one of the most prevalent and disabling mental disorders. Sedentarism and obesity are recognized risk factors for MDD. Physical exercise has shown beneficial effects on mental health and there is an increasing awareness of its potential as a therapeutic and preventive tool for depression. No epidemiological studies have explored the role of physical activity and obesity as potential correlates of MDD in the Spanish population. The aim of this study was to explore whether MDD was associated with two strongly linked variables: physical exercise and body mass index. METHODS: The PISMA-ep is a cross-sectional community-based study carried out in Andalusia, southern Spain. Main outcome was current prevalence of MDD, measured through face-to-face interviews using the Mini-International Neuropsychiatric Interview (MINI). Independent variables explored were physical exercise and its intensity, Body Mass Index (BMI), BMI categories (underweight, normal weight, overweight and obesity), hip and waist circumferences, general health status measured with the SF12 questionnaire, and sociodemographic factors. RESULTS: Physical exercise was inversely associated with MDD, acting as a protective factor. Higher intensity of exercise strengthened this association. Four variables were independently associated with MDD in the multivariate association model: female sex, physical exercise, general health status and BMI. CONCLUSION: MDD was associated with poorer health status, higher BMI and reduced physical activity. Physical exercise should be considered as a potential intervention for the treatment and prevention of MDD in clinical and public health settings.


Assuntos
Transtorno Depressivo Maior/fisiopatologia , Exercício/psicologia , Obesidade/psicologia , Adulto , Idoso , Índice de Massa Corporal , Estudos Transversais , Transtorno Depressivo Maior/epidemiologia , Feminino , Humanos , Vida Independente , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prevalência , Escalas de Graduação Psiquiátrica , Fatores de Risco , Espanha/epidemiologia , Inquéritos e Questionários , Circunferência da Cintura
19.
Nat Hum Behav ; 3(5): 478-491, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30988484

RESUMO

Over the years, many studies have demonstrated a relation between emotion dynamics and psychological well-being1. Because our emotional life is inherently time-dynamic2-6, affective scientists argue that, next to how positive or negative we feel on average, patterns of emotional change are informative for mental health7-10. This growing interest initiated a surge in new affect dynamic measures, each claiming to capture a unique dynamical aspect of our emotional life, crucial for understanding well-being. Although this accumulation suggests scientific progress, researchers have not always evaluated (a) how different affect dynamic measures empirically interrelate and (b) what their added value is in the prediction of psychological well-being. Here, we address these questions by analysing affective time series data from 15 studies (n = 1,777). We show that (a) considerable interdependencies between measures exist, suggesting that single dynamics often do not convey unique information, and (b) dynamic measures have little added value over mean levels of positive and negative affect (and variance in these affective states) when predicting individual differences in three indicators of well-being (life satisfaction, depressive symptoms and borderline symptoms). Our findings indicate that conventional emotion research is currently unable to demonstrate independent relations between affect dynamics and psychological well-being.


Assuntos
Transtorno da Personalidade Borderline/fisiopatologia , Depressão/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Emoções/fisiologia , Satisfação Pessoal , Psicometria/estatística & dados numéricos , Humanos
20.
Intern Med ; 58(15): 2195-2199, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30996193

RESUMO

We herein report two cases of patients with thyroid storm with a delayed diagnosis due to psychosis. The patients were a 63-year-old woman with bipolar II disorder and a 37-year-old man with major depressive disorder. The psychoses in both patients were well controlled with medication. Although they both showed symptoms of thyrotoxicosis, the symptoms were ignored, presumably because the psychological manifestations of worsening of psychosis and thyroid storm are similar. When the mental or physical state of patients with psychosis changes, thyroid hormone levels should be measured for early treatment.


Assuntos
Transtorno Bipolar/diagnóstico , Diagnóstico Tardio , Transtorno Depressivo Maior/diagnóstico , Adulto , Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/fisiopatologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos , Crise Tireóidea/diagnóstico , Crise Tireóidea/fisiopatologia , Hormônios Tireóideos , Tireotoxicose/diagnóstico , Tireotoxicose/fisiopatologia
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