抑郁症的神经生化机制及抗抑郁药研究进展

抑郁症的病理改变主要涉及中枢神经系统功能、免疫功能和神经内分泌功能.其确切发病机制尚不清楚,主要有单胺假说、神经递质受体假说、受体后假说、情感性精神障碍的神经激肽假说、神经内分泌功能改变假说、免疫系统异常假说等神经生物学争论[1].但目前多数人认可去甲肾上腺素(NE)、5-羟色胺(5-HT)、多巴胺(DA)、乙酰胆碱(Ach)、γ-氨基丁酸(GABA)等可能参与的神经生化机制,所研发和应用的抗抑郁药也主要与神经生化机制相关的物质有关.     

抑郁症的治疗研究进展

抑郁症以持续情绪低落和认知功能障碍为主要临床特征,包括焦躁情绪、快感缺失、睡眠障碍、负罪感和反复自杀念头等。抑郁症不仅给患者带来精神上的损失,也给患者造成沉重的经济负担。该文结合抑郁症相关假说:单胺假说、应激假说、神经营养因子和神经元新生假说等,根据不同的发病机制和作用通路,对抑郁症治疗进展进行综述和展望。     

老年抑郁症与甲状腺激素的相关性研究进展

抑郁症的发病机理在神经生化机制方面有神经内分泌功能紊乱假说,主要是下丘脑-垂体-肾上腺轴（HPA）及下丘脑-垂体-甲状腺轴（HPT）活动等方面的异常。本文就老年抑郁症与甲状腺素水平的相关研究进行综述,以期指导临床研究与治疗。     

阿尔茨海默病发病机制研究进展

阿尔茨海默病(AD)病因及发病机制尚未完全阐明,有关其发病机制有β-淀粉样蛋白级联假说、Tau蛋白假说、神经血管学说和氧化应激学说等多种.本文就现有较公认的发病机制研究进展作一综述.     

5-HT1A受体与抑郁症相关性研究

抑郁症的发病机制复杂,确切发病机制尚不清楚,目前普遍认为可能是心理社会因素、各种神经生物化学改变、遗传因素等多种因素交互作用的结果,其中神经生化改变是迄今最为肯定的,并成为临床治疗抑郁症的理论基础.脑内中枢去甲肾上腺素(NE)、5-羟色胺(5-HT)、多巴胺(DA)等单胺类神经递质含量过低、其受体功能低下、下丘脑-垂体-肾上腺轴(HPA)和下丘脑-垂体-甲状腺轴(HPT)等神经生化的改变都被认为是引起抑郁症的原因.近年来选择性5-HT受体激动剂类抗抑郁药的研究揭示5-HT1A受体是重要的作用靶点.现就5-HT1A受体与抑郁症相关性研究进展作一综述.     

神经营养因子在抑郁症中的作用

抑郁症是一种常见病和多发病.近年来,随着对抑郁症发病机制和治疗研究的进展,发现神经营养因子(neurotrophic factors,NTF)表达减少及其受体活性降低是抑郁症的一个重要变化,NTF在抑郁症中的作用越来越得到重视.本文对神经营养因子与抑郁症的病理、生理学研究进展进行综述.     

星形胶质细胞功能障碍与抑郁症研究进展

目前关于抑郁症的研究大多围绕神经元进行调控,而星形胶质细胞对抑郁症调控的非神经元机制尚未深入研究。星形胶质细胞是中枢神经系统数量最多、分布最广泛的胶质细胞,其结构和形态复杂,与神经突触、血管和其他神经胶质细胞相互调节,在多种神经精神系统疾病的发病和治疗中发挥重要作用。有研究显示,星形胶质细胞可能通过调节单胺递质水平、谷氨酸循环、突触可塑性、能量代谢和神经炎症等参与抑郁症的发生。本文就此进行综述,以期为抑郁症胶质细胞病理机制的发现和基于星形胶质细胞调控的新一代药物研发提供新思路。     

心肌Na^＋，K^＋-ATP酶在抑郁症时的活性及mRNA表达

目的 探讨Na+,K+-ATP酶在抑郁症发病中的作用及其和单胺类神经递质之间的关系.方法 对SD大鼠进行慢性随机刺激建立抑郁症模型,检测大鼠心肌Na+,K+-ATP酶的活性及mRNA表达,海马组织及血液中去甲肾上腺素(NA)和5-羟色胺代谢物5-羟吲哚乙酸(5-HIAA)水平.结果 抑郁症大鼠心肌Na+,K+-ATP酶的转录水平下调(P＜0.01);酶的活性明显降低(P＜0.01);海马及血浆中的NA及5-HIAA水平显著下降(P＜0.01).结论 推测抑郁症时神经体液因素的变化可能是引起心肌细胞Na+,K+-ATP酶分子变化的原因之一,该酶在抑郁症的发病机制中有一定的生理和病理意义.     

小胶质细胞活化介导的神经元损伤与抑郁症的研究进展

抑郁症是一种常见的神经障碍,其发病率高,复发性高,致残性高,但发病机制未明。近年来,胶质细胞对神经元的保护与攻击作用已成为神经疾病研究的前沿方向。小胶质细胞(microglia, MG)异常活化导致神经元损伤在抑郁症发病中具有重要作用,该文通过GeenMedical、CNKI等进行文献检索,对MG活化相关通路及关键靶标在抑郁症中的研究进行归纳总结,为进一步的临床研究提供理论性的依据。     

抑郁症神经生化和神经电生理学研究进展

抑郁症的发病机制复杂,神经生化学理论是迄今最为“肯定”、并被临床药理“充分利用”的,用以阐述抑郁症发病的神经生物学机制,抑郁症的发生不但与去甲肾上腺素(NE)、5-羟色胺(5-HT)水平相关;也可能与多巴胺(DA)、乙酰胆碱(Ach)、神经肽、γ-氨基丁酸(GABA)能系统等多种神经递质及受体的功能紊乱有关,还与内分泌系统和神经营养因子系统等方面的异常有关。同时,抑郁症的发生还可能与神经认知功能的缺损及神经电生理学的改变有关。     

Depression and Alzheimer's disease: Neurobiological links and common pharmacological targets

Depression is one of the most prevalent and life-threatening forms of mental illnesses, whereas Alzheimer's disease is a neurodegenerative disorder that affects more than 37 million people worldwide. Recent evidence suggests a strong relationship between depression and Alzheimer's disease. A lifetime history of major depression has been considered as a risk factor for later development of Alzheimer's disease. The presence of depressive symptoms can affect the conversion of mild cognitive impairment into Alzheimer's disease. Neuritic plaques and neurofibrillary tangles, the two major hallmarks of Alzheimer's disease brain, are more pronounced in the brains of Alzheimer's disease patients with comorbid depression as compared with Alzheimer's disease patients without depression. On the other hand, neurodegenerative phenomena have been observed in different brain regions of patients with a history of depression. Recent evidence suggests that molecular mechanisms and cascades that underlie the pathogenesis of major depression, such as chronic inflammation and hyperactivation of hypothalamic-pituitary-adrenal (HPA) axis, are also involved in the pathogenesis of Alzheimer's disease. In particular, a specific impairment in the signaling of some neurotrophins such as transforming-growth-factor β1 (TGF-β1) and brain-derived neurotrophic factor (BDNF) has been observed both in depression and Alzheimer's disease. In the present review we will examine the evidence on the common molecular pathways between depression and Alzheimer's disease and we will discuss these pathways as new pharmacological targets for the treatment of both major depression and Alzheimer's disease.     

组蛋白去乙酰化酶抑制剂的抗抑郁前景

抑郁症是一种发病率较高的严重精神疾病,目前对其病理机制尚未全面了解,临床治疗效果十分有限.最近的研究表明,发生在大脑特定脑区的表观遗传调控——即不改变脱氧核糖核酸(deoxyribonucleic acid,DNA)编码的情况下调节基因活性,可能是环境因素与个体遗传相互作用以影响抑郁症发病风险的关键机制.因此,靶向表观...     

The Endocannabinoid/Endovanilloid System and Depression

Depression is one of the most frequent causes of disability in the 21st century. Despite the many preclinical and clinical studies that have addressed this brain disorder, the pathophysiology of depression is not well understood and the available antidepressant drugs are therapeutically inadequate in many patients. In recent years, the potential role of lipid-derived molecules, particularly endocannabinoids (eCBs) and endovanilloids, has been highlighted in the pathogenesis of depression and in the action of antidepressants. There are many indications that the eCB/endovanilloid system is involved in the pathogenesis of depression, including the localization of receptors, modulation of monoaminergic transmission, inhibition of the stress axis and promotion of neuroplasticity in the brain. Preclinical pharmacological and genetic studies of eCBs in depression also suggest that facilitating the eCB system exerts antidepressant-like behavioral responses in rodents. In this article, we review the current knowledge of the role of the eCB/endovanilloid system in depression, as well as the effects of its ligands, models of depression and antidepressant drugs in preclinical and clinical settings.     

Regulators of adult neurogenesis in the healthy and diseased brain

1. In recent decades evidence has accumulated demonstrating the birth and functional integration of new neurons in specific regions of the adult mammalian brain, including the dentate gyrus of the hippocampus and the subventricular zone. 2. Studies in a variety of models have revealed genetic, environmental and pharmacological factors that regulate adult neurogenesis. The present review examines some of the molecular and cellular mechanisms that could be mediating these regulatory effects in both the normal and dysfunctional brain. 3. The dysregulation of adult neurogenesis may contribute to the pathogenesis of neurodegenerative disorders, such as Huntington's, Alzheimer's and Parkinson's disease, as well as psychiatric disorders such as depression. Recent evidence supports this idea and, furthermore, also indicates that factors promoting neurogenesis can modify the onset and progression of specific brain disorders, including Huntington's disease and depression.     

Neuroinflammatory Signaling in the Pathogenesis of Alzheimer’s Disease

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the formation of intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques. Growing evidence has suggested that AD pathogenesis is not only limited to the neuronal compartment but also strongly interacts with immunological processes in the brain. On the other hand, aggregated and misfolded proteins can bind with pattern recognition receptors located on astroglia and microglia and can, in turn, induce an innate immune response, characterized by the release of inflammatory mediators, ultimately playing a role in both the severity and the progression of the disease. It has been reported by genome-wide analysis that several genes which elevate the risk for sporadic AD encode for factors controlling the inflammatory response and glial clearance of misfolded proteins. Obesity and systemic inflammation are examples of external factors which may interfere with the immunological mechanisms of the brain and can induce disease progression. In this review, we discussed the mechanisms and essential role of inflammatory signaling pathways in AD pathogenesis. Indeed, interfering with immune processes and modulation of risk factors may lead to future therapeutic or preventive AD approaches.     

Depression following traumatic brain injury: epidemiology, risk factors and management

It is important for clinicians to recognize major depression following traumatic brain injury (TBI) because of its association with poor global and psychosocial outcome, postconcussive symptoms and cognitive deficits. The purpose of this review is to provide an up-to-date selective review of the current understanding of epidemiology, risk factors and management of major depression following TBI. Many studies of prevalence of depression following TBI have not used accepted structured criteria for the diagnoses, but those that did found wide ranges of rates, from 17% to 61%. The risk factors for development of depression following TBI are poorly understood, but past psychiatric history, frontal lesions and atrophy, and family dysfunction have been shown in more than one study to play important roles. There are few controlled trials of the treatment of major depression in patients with TBI using accepted diagnostic criteria for major depression, as well as defined criteria for response and remission. As such, it is important for clinicians to use best practice guidelines for the treatment of major depression in the absence of TBI.     

Temporal Lobe Atrophy and White Matter Lesions are Related to Major Depression over 5 years in the Elderly

The influence of organic brain changes on the development of depression in the elderly is uncertain. Cross-sectional studies, most often from clinical samples, report associations with brain atrophy and cerebrovascular disease, while longitudinal population studies have given mixed results. Our aim was to investigate whether cortical atrophy and white matter lesions (WMLs) on computed tomography (CT) predict occurrence of depression in the elderly. This is a prospective population-based study with 5-year follow-up. The baseline sample included 525 elderly subjects, aged 70–86 years, without dementia or major depression, with a score on the Mini-Mental State Examination above 25, and without dementia at follow-up. Cortical atrophy and WMLs were evaluated at baseline using CT. The main outcome measure was development of major or minor depression at follow-up according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition, as evaluated using neuropsychiatric examinations and hospital discharge registers. Logistic regression was used to estimate risk. Over the period of 5 years, 20 individuals developed major and 63 minor depression. Presence of temporal lobe atrophy (odds ratio (OR)=2.81, 95% confidence interval (CI) 1.04–7.62) and moderate-to-severe WMLs (OR=3.21, 95% CI 1.00–10.26) independently predicted major, but not minor, depression after controlling for various confounders. Other brain changes did not predict occurrence of depression. Our findings suggest that temporal lobe atrophy and WMLs represent relatively independent and complementary pathways to major depression in the elderly. This may have implications for prevention, as both neurodegeneration and cerebrovascular disease have been related to preventable factors.     

Histone deacetylases (HDACs) as therapeutic target for depressive disorders

Major depressive disorder (MDD) represents approximately 40% of the disability caused by mental illnesses globally. The poorly understood pathophysiology and limited efficiency of pharmacological treatment (based primarily on the principles of the monoaminergic hypothesis) make depression a serious medical, public and socio-economical problem. An increasing number of studies suggest that epigenetic modifications (alterations in gene expression that are not due to changes in DNA sequence) in certain brain regions and neural circuits represent a key mechanism through which environmental factors interact with individual's genetic constitution to affect risk of mental disorders. Accordingly, chromatin-based epigenetic regulation seems to be a promising direction for the development of new, more effective antidepressant drugs. Recently, several inhibitors of histone deacetylases (HDAC) have been extensively studied in the context of antidepressant action. So far, none of them has been used to treat depression in humans due to the low selectivity for specific HDAC isoforms, and consequently, a risk of serious adverse events. In this review, we focus on the HDAC inhibitors (HDACi) with the greatest antidepressant efficacy and their activity in the preclinical studies. Moreover, we discuss their potential therapeutic usefulness in depression and the main limitations.     

Major depression as a disorder of serotonin resistance: inference from diabetes mellitus type II

The multifactorial nature of depression resembles that of other complex disorders such as diabetes mellitus or coronary artery disease. However, while for the latter disorders predisposing and risk factors have been identified, such knowledge is still scarce in depression. In this review we propose to use diabetes mellitus, for which characteristic milestones have been condensed to obesity-hyperinsulinaemia-insulin resistance-diabetes mellitus, as a conceptual analogical model. Based on this model we hypothesize that depression develops according to a similar pattern: prolonged psychological stress-hyperserotonism-serotonin resistance-major depression. We review extensive supporting evidence from human studies and animal models of depression, including stress involvement in the aetiology of depression, evidence for increased synaptic serotonin and decreased 5-HT1A receptor activity. Conceptualizing the pathogenesis of depression as a multi-step process may inspire new concepts, which will eventually lead to delineation of additional preventive and therapeutic interventions similar to those currently practised in diabetes.     

Potential roles of NCAM/PSA-NCAM proteins in depression and the mechanism of action of antidepressant drugs

Recently, it has been proposed that abnormalities in neuronal structural plasticity may underlie the pathogenesis of major depression, resulting in changes in the volume of specific brain regions, including the hippocampus (HIP), the prefrontal cortex (PC), and the amygdala (AMY), as well as the morphology of individual neurons in these brain regions. In the present survey, we compile the data regarding the involvement of the neural cell adhesion molecule (NCAM) protein and its polysialylated form (PSA-NCAM) in the pathogenesis of depression and the mechanism of action of antidepressant drugs (ADDs). Elevated expression of PSA-NCAM may reflect neuroplastic changes, whereas decreased expression implies a rigidification of neuronal morphology and an impedance of dynamic changes in synaptic structure. Special emphasis is placed on the clinical data, genetic models, and the effects of ADDs on NCAM/PSA-NCAM expression in the brain regions in which these proteins are constitutively expressed and neurogenesis is not a major factor; this emphasis is necessary to prevent cell proliferation and neurogenesis from obscuring the issue of brain plasticity.