Gain of function mutants reveal sites important for the interaction of the atypical inhibitors benztropine and bupropion with monoamine transporters

Two atypical inhibitors of the dopamine transporter, benztropine, used in the treatment of Parkinson's disease, and bupropion, used as an antidepressant, show very different psychostimulant effects when compared with another inhibitor, cocaine. Taking advantage of the differential sensitivity of the dopamine and the norepinephrine transporters (DAT and NET) to benztropine and bupropion, we have used site-directed mutagenesis to produce gain-of-function mutants in NET which demonstrate that Ala279 in the trans-membrane domain 5 (TM5) and Ser359 in the TM7 of DAT are responsible for the higher sensitivity of DAT to both bupropion and benztropine. Substitution of these two DAT residues into the NET background does not alter the potency of NET-selective inhibitors, such as desipramine. The results from experiments examining the ability of DAT-selective inhibitors to displace [3H]nisoxetine binding in NET gain-of-function mutants suggest that Ser359 contributes to the initial binding of the inhibitor, and that Ala279 may influence subsequent steps involved in the blockade of translocation. Thus, these studies begin to identify residues that are important for the unique molecular interactions of benztropine and bupropion with the DAT, and that ultimately may contribute to the distinct behavioral actions of these drugs.     

抗抑郁新药的研究与开发

随着社会经济高速发展,人们面临的社会竞争和心理压力加大,导致抑郁症逐渐成为现代社会的常见及高发疾病,所以临床上对 抗抑郁新药的需求日益增长。概述近年来欧美上市的抗抑郁新药和目前临床III期在研的部分抗抑郁小分子药物的合成工艺及临床研究进 展。     

The Circadian Rhythm of Plasma Thyrotropin in Depression and Recovery

The 24-hr patterns of plasma thyrotropin have been observed in 12 endogenous depressed patients in both depressed and recovered states and in 13 normal subjects. A clear circadian rhythm was detected in controls with high values at night. In depression, the circadian rhythm was altered with amplitude reduction and blunted nocturnal secretion, abnormalities particularly relevant in bipolar patients. This flattened profile could be linked to the blunted response of TSH to TRH administration reported in depressed patients. Normal nyctohemeral patterns have been restored after recovery. These chronobiological abnormalities as well as their normalization under antidepressant drugs seem to be similar to those reported for various parameters (e.g. temperature, Cortisol, etc) in depression which could support the chronobiological hypothesis for affective disorders.     

The Circadian Rhythm of Plasma Thyrotropin in Depression and Recovery

The 24-hr patterns of plasma thyrotropin have been observed in 12 endogenous depressed patients in both depressed and recovered states and in 13 normal subjects. A clear circadian rhythm was detected in controls with high values at night. In depression, the circadian rhythm was altered with amplitude reduction and blunted nocturnal secretion, abnormalities particularly relevant in bipolar patients. This flattened profile could be linked to the blunted response of TSH to TRH administration reported in depressed patients. Normal nyctohemeral patterns have been restored after recovery. These chronobiological abnormalities as well as their normalization under antidepressant drugs seem to be similar to those reported for various parameters (e.g. temperature, Cortisol, etc) in depression which could support the chronobiological hypothesis for affective disorders.     

抗炎性细胞因子与抑郁症

细胞因子假说是关于抑郁症发病机理的重要假说,为探讨抑郁症的发病机理和临床治疗方法提供了新方向.细胞因子分为前炎性细胞因子和抗炎性细胞因子.前炎性细胞因子与抑郁症的发病密切相关,而抗炎性细胞因子可能具有抗抑郁的作用.本文着重综述抗炎性细胞因子与抑郁症的关系.抗炎性细胞因子如白介素10、白介素1受体拮抗剂、白介素4、白介素13、转化生长因子β和脂联素等,在抑郁症中表达下降;补充外源抗炎性细胞因子则具有一定的抗抑郁作用.抗炎性细胞因子可通过拮抗前炎性细胞因子的作用,并与MAPK信号通路、神经递质和糖皮质激素相互作用而参与到抑郁症中.抗抑郁药能使抗炎性细胞因子的表达上升,这可能是药物起效的机制之一.抗炎策略在抑郁症的治疗中有重要应用前景.     

聚焦抑郁症治疗药物

抗抑郁药市场潜藏着巨大商机。全世界约有3.5 亿人患有抑郁症,该疾病为全球范围内致残的第一大诱因。在美国,9.1% 的人患有抑郁症。在世界范围内,接受抑郁症治疗的患者不到实际患病人数的一半,在一些国家甚至还不到十分之一。较高的发病率,再加上较低的市场渗透率,抗抑郁药市场的前景非常广阔。但开发抗抑郁药的公司同样面临许多挑战。心理治疗仍然是优于药物治疗的一线疗法。在药物治疗方面,近年来大量上市的仿制药使品牌抗抑郁药的市场价值缩水一半。由于儿童、青少年和青壮年用药患者的自杀率有所增加,现在要求所有抗抑郁药必须在说明书中加入黑框警告,这直接影响了药物在这些人群中的使用,成为抗抑郁新药面临的又一困难。许多患者在开始接受治疗的第一年内都会更换最初使用的药物,这对于药企而言,既是机遇也是挑战。目前抑郁症的发病机制尚未充分阐明,虽然这有利于开发具有全新作用机制的新药,但也使该治疗领域面临重重困难。     

Critical Interval Hypotheses for Depression

Two chronobiologic models are presented for the etiology of depression. The internal coincidence model suggests that a phase advance of the strong oscillator in reference to the weak oscillator causes depression. An external coincidence model suggests that depression is caused when the light/dark cycle or photoperiod provides too little illumination during a critical photosensitive interval, which might in turn occur early due to a phase advance. Thus, depression might be treated by drugs or other manipulations which delay the phase of internal circadian rhythms. Depression might also be treated with bright illumination during the critical photosensitive interval. Preliminary experiments suggest that bright artificial light does have antidepressant effects. The optimal times for light exposure and the most responsive patient groups have not yet been identified.     

AUTONOMY AND ETHICAL TREATMENT IN DEPRESSION

Antidepressant medication and evidence‐based psychotherapy have largely equivalent efficacy in the management of the common, less severe grades of depression. As a result, several national guidelines recommend that either can be used in the treatment of this disorder. Psychotherapy, however, differs in that it assists insight into how the depressed person appraises and manages the stressors that frequently trigger depressive episodes. I argue that the self‐knowledge achieved through psychotherapy has moral value in that it promotes the autonomy of stressor‐related decisions. I further argue that such an effect comprises a compelling moral reason for doctors to see evidence‐based psychotherapy not as merely optional, but as a necessary treatment for their patients with depression.     

Lessons learned from placebo groups in antidepressant trials

This comprehensive review provides an overview about placebo and nocebo phenomena in antidepressant trials. Improvements in the placebo groups may partly be explained through methodological issues such as natural course of depression and regression to the mean, but also fundamentally reflect investigators' and participants' expectations. A meta-analysis by our group of 96 randomized placebo-controlled trials showed large placebo responses to antidepressant medication. Moderator analyses revealed substantially larger placebo responses in observer ratings compared with self-report. Effect sizes in observer ratings showed strong increase with publication year while this effect was not found for patients' self-ratings. This reflects the strong influence of investigators' expectations. The analysis of 'nocebo effects', e.g. adverse effects in placebo groups of antidepressant trials also confirms the impact of expectations: nocebo symptoms reflected the typical side-effect patterns expected in the drug group, with higher symptoms rates in the placebo groups of tricyclic antidepressant trials compared with placebo groups of trials testing selective serotonin reuptake inhibitors. While the placebo response seems to be similar for women and men, gender differences were found for nocebo rates. In the conclusion, we discuss potential implications for clinical trial designs and argue for interventions aimed at optimizing positive expectations of treatment benefit while minimizing the impact of adverse effects.     

电穿孔基因导入技术在临床前与临床试验中的应用

电穿孔基因作为非病毒递送手段之一,可安全、有效地将外源核酸导入靶组织或器官。近年来用电穿孔法进行基因治疗的报道不断增多,优势日趋显著。本文重点阐述了电穿孔在基因治疗中的优势、影响因素及在临床前和临床试验中应用。     

Morningness–eveningness and treatment response in major depressive disorder

In a large, prospective, 8-week open study of 721 outpatients receiving agomelatine treatment for a current major depressive episode (MDE), morningness–eveningness (Composite Scale of Morningness) was assessed before and after treatment to investigate possible changes in morningness–eveningness after treatment and evaluate whether morningness–eveningness at baseline predicted treatment response. A change towards morningness was observed after treatment. This change was greater in responders than non-responders. Moreover, being a morning type at baseline was an independent predictor of response to treatment. Once thought to be a trait variable, morningness–eveningness is a potential treatment target that should be systematically assessed in MDE patients.     

Rapid Activation of the Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Signaling Pathway by Electroconvulsive Shock in the Rat Prefrontal Cortex Is Not Associated with TrkB Neurotrophin Receptor Activation

1. Emerging evidence indicates that brain-derived neurotrophic factor (BDNF) and its receptor TrkB play important roles in the mechanism of action of electroconvulsive shock (ECS) treatment. ECS produces a significant increase in brain BDNF synthesis together with a variety of neuroplastic changes including neurogenesis and axonal sprouting in the rodent brain, which is believed to be associated to the antidepressant effect of ECS. ERK1/2 (extracellular signal-regulated kinase-1/2) and Akt (protein kinase B), both intracellular signaling molecules being linked to neurotrophin signaling and synthesis, are important pathways triggered by TrkB autophosphorylation. 2. We have previously observed that chemical antidepressants induce a rapid activation of TrkB signaling in the rodent prefrontal cortex (PFC), which is likely a consequence of the stimulatory effect of antidepressants on BDNF synthesis. However, it is not known whether ECS triggers TrkB autophosphorylation and if any ECS-induced effect on TrkB function may be associated with the activation of the ERK1/2 and Akt pathways. 3. The present study assayed the phosphorylation levels of TrkB, ERK1/2, and Akt in the PFC of sham and ECS-treated rats. While the TrkB autophosphorylation (pTrkB) levels were decreased 30 min after both acute and chronic ECS, no change in pTrkB levels were observed at any other time points measured. In contrast, acute but not chronic ECS, transiently induced a very rapid and robust hyperphosphorylation of ERK1/2. Akt phosphorylation levels remained unchanged following acute or chronic ECS. Hence, although ECS effectively stimulates the ERK1/2 pathway in the PFC, this effect does not appear to involve upstream activation of TrkB.     

松弛素在心血管疾病中的研究进展

松弛素是一类新近发现可作用于心血管的肽类激素,参与心血管系统的生理和病理过程。大量实验研究显示松弛素有扩血管、改善心血管重塑及调节炎症反应的心血管保护作用,也有利于改善高凝状态和胰岛素抵抗。松弛素作用广泛,可与松弛素受体或糖皮质激素受体结合,但其受体后的确切机制以及不同生理和病理状态对松弛素的调控还需进一步基础研究阐明。在从实验室到临床应用转化的初期临床试验中可观察到,人重组松弛素治疗急慢性心力衰竭安全性好,可改善症状、血流动力学指标及近期预后,为Ⅲ期临床试验奠定了基础,其临床应用前景令人期待。     

FKBP5/FKBP51 enhances autophagy to synergize with antidepressant action

Levels of autophagy markers rise upon treatment of cells with antidepressants. However, it was not known whether this phenomenon might be linked to other antidepressant pathways or to any physiological effect. In this punctum, we summarize and discuss our recent findings that provide evidence for a role of the cochaperone FKBP5/FKBP51 (FK506 binding protein 5) in autophagy as a prerequisite for antidepressant action in cells, mice, and humans. FKBP5 associates with BECN1, changes its phosphorylation and protein levels and enhances markers of autophagy and autophagic flux. The effects of antidepressants on autophagy as well as their physiological effects in mice and human depend on FKBP5.