单胺重摄取抑制剂抗抑郁作用评价策略和体系

现有临床抗抑郁药物多以单胺为靶标设计,单胺重摄取抑制剂仍是抗抑郁新药研发的热点方向。新药研发周期长,投资高,风险大,如何快速准确完成药物筛选和临床前评价至关重要。该课题组采用体外高通量筛选和整体动物药效学验证相结合的评价模式,建立了单胺重摄取抑制剂评筛体系,该体系的建立将对单胺重摄取抑制剂的快速评价产生推动作用,也有助于挖掘新的研究思路。该文围绕抗抑郁药效学评价、作用靶标研究、单胺递质含量检测及神经元电活动研究对单胺重摄取抑制剂的评价策略和体系作一综述。     

非单胺靶标抗抑郁药研究进展

目前临床上所使用的抗抑郁药绝大多数以5-羟色胺、去甲肾上腺素和多巴胺等单胺受体为靶标.这些单胺靶标抗抑郁药起效慢、疗效不佳、易复发,远不能满足临床需求.抑郁症的病理学研究表明,一些非单胺受体也参与其中并起重要作用,以非单胺受体为靶标的抗抑郁药已成为抗抑郁药研究的热点.非单胺靶标抗抑郁药在体内外实验中有良好的活性,有些已经进入临床研究,临床研究表明其中某些抗抑郁药起效较快.文中综述非单胺靶标抗抑郁药的研究进展.     

米氮平口腔崩解片治疗抑郁症患者的临床研究概述

除了研发新药以外,现有药物新剂型的研发和应用也是治疗抑郁症的新思路。口崩剂型抗抑郁药米氮平口腔崩解片凭借其便于携带、口感良好及易于吞服等优点,作为能较好改善抑郁症患者依从性的一种剂型在临床广泛应用。本文从疾病本身的特点,结合抗抑郁药物的药理特征和不良反应,介绍米氮平口腔崩解片在抑郁症患者的临床研究情况。     

脑源性神经营养因子在抑郁症发生和治疗中的研究进展

目前临床常用的抗抑郁药主要通过增加脑内突触间隙单胺类递质的浓度、增强单胺类神经的功能而起效,但这一机制不能很好地解释抗抑郁药存在的起效时间长等现象.近年提出,抗抑郁药可能还通过增加海马区域脑源性神经营养因子(BDNF)基因表达起效.抗抑郁药能增加受试动物海马区BDNF基因表达,抑郁患者接受抗抑郁药治疗,其血清BDNF水平上升;BDNF基因的单核苷酸多态性也与抑郁症的发生有关;抗抑郁药可能还通过激活丝裂原活化蛋白激酶(MAPK)信号通路,磷酸化cAMP反应序列结合(cREB)蛋白,最终使BDNF基因表达上调.这一机制的提出为抑郁症生物学病因的阐明提供了必要信息,同时也有助于抗抑郁新药的开发,为研制安全、有效的新药提供新的思路.     

抗抑郁药作用靶标下丘脑-垂体-肾上腺轴的研究进展

通过查阅国内外相关文献,分析下丘脑-垂体-肾上腺(HPA)轴与抑郁症的因果关系,结合临床前和临床研究数据,考察以HPA轴为靶标的抗抑郁药的效果. 虽然作用于HPA轴不同环节的抗抑郁新药在临床前和临床试验中显示出良好的抗抑郁效果,但大多数还未进入临床试验,还有些进入临床试验的药物由于严重的不良反应或疗效低下被撤出试验. 因此只有进一步了解HPA轴与抑郁症的关系,才能研发出更安全、有效、耐受性好的作用于HPA轴的抗抑郁药物.     

浅谈抗抑郁药的发展趋势

介绍抑郁症、抗抑郁药的分类、市场份额、不同国家抗抑郁药的研究和使用情况。对抗抑郁药的研发进行分析和展望,为抗抑郁症的治疗及抗抑郁药的研发提供资料。     

手性抗抑郁药物评价体系的建立与应用

多数已上市抗抑郁药物都含有1个或多个手性中心,手性抗抑郁药物研发已成为重点方向。"反应停"悲剧的发生促使各国新药评审部门对手性药物研发重新思考,并对其申报提出了新的要求;加之手性拆分和定向合成技术的日益成熟,单一对映体申报已成为手性抗抑郁药物的研发趋势。传统的抗抑郁药物手性研究以药理学为基础,且大多仅采用体外靶标亲和力这一单一指标确定活性对映体。针对该缺陷,本课题组从药理学、毒理学、药代动力学、综合因素分析4个方面探索建立了手性抗抑郁药物综合评价体系,该文将对此作一综述。在此基础上,以本课题组自主研发并已获得中国国家食品药品监督管理局临床批件的1.1类抗抑郁新药阿姆西汀的手性研究为实例,对该评价体系进行解析,以期为手性抗抑郁药物光学异构体比较研究和活性光学异构体的选择提供候选思路和平台。     

快速起效抗抑郁-焦虑的靶标策略与新药研究

目的在成功发现新药的基础上归纳新药研发的潜在靶标策略。方法与结果基于优化的多靶标单胺策略,发现2个1.1类抗抑郁化学新药并获得国家CFDA批准的Ⅰ~Ⅲ期临床批件,即盐酸羟哌吡酮(YL-0919)和盐酸阿姆西汀(071031B)。YL-0919是原创化学结构的小分子化合物,兼具5-HT重摄取抑制、5-HT_(1A)部分激动和5-HT_6激动作用,较临床一线药物具有靶标新颖、起效迅速、兼有增强认知作用、无性功能障碍等优势;071031B是5-HT/NE重摄取抑制剂度洛西汀的结构优化衍生化合物,具有更强效、肝毒性低、生物利用度高等优点。基于非单胺靶标策略,开展了胶质细胞上18 ku转位蛋白(TSPO)靶标机制和新药研究,采用TSPO敲除动物和病毒过表达技术发现,TSPO~(-/-)与TSPO~(+/+)小鼠虽对慢性应激具有相同的敏感性,但TSPO选择性激活剂AC-5216在野生型小鼠上快速(2~3 d)产生的抗焦虑、抗抑郁、促认知作用,且快速增强突触可塑性可能是其重要机制,而在敲除小鼠上无此作用。进而发现了新化学结构和新机制的1.1类抗焦虑-抑郁、抗PTSD候选新药YL-IPA08,并证实其具有快速抗抑郁-焦虑、促认知行为学活性及良好的成药性,其中TSPO及其介导的四氢孕酮释放是其抗PTSD、抗焦虑-抑郁行为的核心环节。结论提出单胺能快速起效抗抑郁的多靶标同向、多脑区协同的新药设计思路和靶标策略,提出介导快速抗抑郁效应的"单胺-非单胺长程反馈神经环路"潜在候选假说,为研发单胺能-非单胺能协同的抗抑郁药提供理论基础。     

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。     

抗抑郁药市场前景及最新研发动态

抑郁症足一种常见的精神疾病,严重危害人类身心健康.目前,国内外各制药公司正通过多种途径积极进行抗抑郁药研发.本文结合抗抑郁药生命周期管理策略和市场开发前景,介绍较有潜力的在研Ⅲ期临床抗抑郁药,对处于中、后期开发阶段的抗抑郁药研发动态进行追踪,旨在为抗抑郁药研发提供参考.     

Emerging drugs for major depressive disorder

Most current pharmacologic antidepressant treatments target either or both serotonin and norepinephrine systems in the brain to alleviate depressive symptoms. However, ≥ 30% of patients with major depressive disorder fail to respond to these antidepressants, inciting a need for alternative treatment strategies. In the past decade, there has been extensive research into improving the mechanism of action for monoamine agents as well as identifying novel treatment targets for depression. For monoamines, drugs that increase serotonin, norepinephrine, melatonin or dopamine have been explored as putative antidepressants and in some cases approved (agomelatine and desvenlafaxine). Novel drugs that act on amino acid receptors, neurotrophic factors, cytokines, neuropeptides and acetylcholine are also in development. This review will discuss the scientific rationale for these targets, as well as highlight the current status of drugs in development.     

Emerging drugs for major depressive disorder

INTRODUCTION: Major depressive disorder (MDD) remains a major public health concern, and one that continues to suffer an incompletely-met need for effective and acceptable treatments. The development of antidepressants, to date, has focused primarily on increasing monoamine neurotransmission with increasing efficacy while minimizing adverse effects. Medications currently recommended as 'first-line' are far more tolerable than the older medications they replaced, but as many as 70% of patients continue to suffer significant depressive symptoms after treatment with one of these agents, and as many as 50% will discontinue a trial due to issues with acceptability. This review will summarize antidepressants that have recently entered the market as well as those still in development to help characterize the current state of antidepressant development. AREAS COVERED: Currently available first-line antidepressants are reviewed with respect to efficacy and tolerability, and their weaknesses are discussed as targets for future development. The background, clinical trial data and potential significance of the three most recently introduced antidepressants (trazodone-ER, desvenlafaxine and vilazodone) and the most recently approved augmentation agents (aripiprazole and quetiapine) are discussed. Following a review of the current market, all medications currently in Phase II or later clinical trials are listed and discussed, based on a thorough review of the US National Institutes of Health clinicaltrials.gov index for trials using medications to treat MDD and a search of the Informa Pharmaprojects database for medications currently being developed for a depression indication. Compounds thus identified were then used as search terms in a PubMed search of each medication. Based on pharmacologic properties, medications in development were grouped into those acting on: i) monoamine neurotransmission; ii) cholinergic neurotransmission; iii) glutamatergic neurotransmission; iv) opioid receptors; v) sigma receptors; vi) neurokinin receptors; vii) corticotrophin-releasing factor receptors and viii) other mechanisms. In the discussion of each, a brief review of the pharmacology and physiology of the related system is provided. Potential issues for the future of antidepressant development and an expert opinion are discussed. EXPERT OPINION: The past decade has not yielded a large number of new antidepressants and, with the possible exception of agomelatine, none of the newer medications that have been introduced have decisively addressed the several unmet needs in this area of therapeutics. Among the various novel strategies that are being evaluated, results of several small studies of ketamine suggest that drugs that modulate glutamatergic neurotransmission may hold the greatest promise for exerting rapid and large antidepressant effects in patients who have not responded to SSRIs or SNRIs.     

Future antidepressants: what is in the pipeline and what is missing?

Monoamine reuptake inhibitors still reign in the treatment of major depression, but possibly not for long. While medicinal chemists have been able to reduce the side effects of these drugs, their delayed onset of action and considerable non-response rate remain problematic. Of late, serious questions have been raised regarding the efficacy of monoamine reuptake inhibitors. The present review presents an inventory of what is (and until recently was) in the antidepressant pipeline of pharmaceutical companies. Novel antidepressant compounds can be categorised into four groups depending on their target(s): (i) monoamine receptors; (ii) non-monoamine receptors; (iii) neuropeptide receptors; and (iv) hormone receptors. Other possible targets include components of post-receptor intracellular processes and elements of the immune system; to date, however, compounds specifically aimed at these targets have not been the subject of clinical trials. Development of several compounds targeted at monoamine receptors has recently been discontinued. At least five neurokinin-1 (NK(1)) receptor antagonists were until recently in phase II of clinical testing. However, the apparent interest in the NK(1) receptor should not be interpreted as representing a departure from the monoamine hypothesis since neurokinins also modulate monoaminergic systems. In the authors' view, development of future antidepressants will continue to rely on the serendipity-based monoamine hypothesis. However, an alternative approach, based on the hypothesis that chronic stress precipitates depressive symptoms, might be more productive. Unfortunately, clinical results using drugs targeted at components of the HPA axis have not been very encouraging to date. In the short run, the authors believe that augmentation strategies offer the best hope for improving the efficacy of antidepressant treatment. Several approaches to improve the efficacy of SSRIs are conceivable, such as concurrent blockade of monoamine autoreceptors and the addition of antipsychotics, neuromodulators or hormones (HPA axis and gender related). In the long-term, however, construction of a scientifically verified conceptual framework will be needed before more effective antidepressants can be developed. It can be argued that it is not depression itself that should be treated, but rather that its duration should be reduced by pharmacological means. Animal models that take this concept into consideration and identify mechanisms for acceleration of recovery from the effects of stress need to be developed.     

The keys to improving depression outcomes

The heterogeneity of symptoms within major depressive disorder poses significant challenges for treatment and it is likely that current pharmacotherapies do not target all symptoms equally, although they have similar efficacy rates. While there is still continuing interest in understanding monoamine interactions and consequent downstream effects, the limited efficacy and tolerability achieved with classical antidepressants provides a compelling argument to move beyond the monoamines. Several lines of biological research in depression exploring immune function, neurotrophins, amino acid and neuropeptide neurotransmitters, neuroanatomical function and circadian rhythms, may lead to novel therapeutic targets and enhance depression outcomes. This review will evaluate the evidence for emerging treatments as well as recommendations from current international guidelines regarding antidepressant management.     

Reconsidering GHB: orphan drug or new model antidepressant?

For six decades, the principal mode of action of antidepressant drugs is the inhibition of monoamine re-uptake from the synaptic cleft. Tricyclic antidepressants, selective serotonin re-uptake inhibitors (SSRIs) and the new generation of dual antidepressants all exert their antidepressant effects by this mechanism. In the early days of the monoaminergic era, other efforts have been made to ameliorate the symptoms of depression by pharmacological means. The gamma-aminobutyric acid (GABA) system was and possibly still is one of the main alternative drug targets. Gammahydroxybutyrate (GHB) was developed as an orally active GABA analogue. It was tested in animal models of depression and human studies. The effects on sleep, agitation, anhedonia and depression were promising. However, the rise of benzodiazepines and tricyclic antidepressants brought GHB out of the scope of possible treatment alternatives. GHB is a GABA(B) and GHB receptor agonist with a unique spectrum of behavioural, neuroendocrine and sleep effects, and improves daytime sleepiness in various disorders such as narcolepsy, Parkinson's disease and fibromyalgia. Although it was banned from the US market at the end of the 1990s because of its abuse and overdose potential, it later was approved for the treatment of narcolepsy. New research methods and an extended view on other neurotransmitter systems as possible treatment targets of antidepressant treatment brought GHB back to the scene. This article discusses the unique neurobiological effects of GHB, its misuse potential and possible role as a model substance for the development of novel pharmacological treatment strategies in depressive disorders.     

A review of the clinical efficacy,safety and tolerability of the antidepressants vilazodone,levomilnacipran and vortioxetine

Introduction: As a leading cause of disability, major depressive disorder (MDD) is characterized by reduced quality of life and altered functioning. Current pharmaceutical treatment options are limited in their success by modest effects and adverse events that often lead to discontinuation. One current trend in antidepressant development is to combine inhibition of the serotonin transporter with other pharmacological targets, including the norepinephrine transporter or different serotonin receptors.

Areas covered: In a span of < 3 years, the FDA approved three new antidepressants for the treatment of MDD: vilazodone in January 2011, levomilnacipran in July 2013 and vortioxetine in September 2013. This article reviews the efficacy, safety and tolerability of these three drugs mainly from the Phase III trial data.

Expert opinion: All three drugs are effective in the treatment of MDD, but data comparing them to other antidepressants is currently lacking. Vilazodone was proposed to produce a more rapid onset and have fewer sexual side effects but neither effect has been conclusively shown. Levomilnacipran appears to be effective in improving functional impairment, including both social and work functioning. Vortioxetine is currently the only drug of the three with proven efficacy in elderly patients. It also appears to have cognitive enhancing properties which are largely independent of improved depressive symptoms. Overall, these drugs represent a promising step forward in antidepressant drug development.     

银屑病治疗靶点及其药物研发进展

银屑病的发病机制未能完全阐明,近年来大量的实验和临床研究证实,银屑病可能是T细胞介导的自身免疫性疾病。这一发病过程涉及了很多靶点的激活,T细胞增殖和细胞因子的作用。目前,基于这些靶点研发治疗银屑病的新药已取得了长足的进展,本文就近年来银屑病靶向药物研究进展作一综述,为开发新的靶向药物提供参考。     

Pharmacotherapy of dysthymia: a review

The clinical significance of chronic mild depression (dysthymia) is well recognized, but has not been the focus of extensive research. In particular, basic research on the phenomenology and treatment of these conditions is limited. Clinical lore suggests that psychotherapy, rather than pharmacotherapy, is the treatment of choice. This is based more on a theoretical understanding of chronic depression as a personality disorder rather than on actual treatment studies. This paper reviews the literature on the pharmacotherapy of dysthymia. The results provide substantial evidence for the efficacy of antidepressants in dysthymia, although the treatment response is less than that typically found in major depression. Furthermore, the findings suggest the possibility that monoamine oxidase inhibitors (MAOIs) may be superior to tricyclic antidepressants (TCAs) in the treatment of dysthymia, although this needs to be more rigorously evaluated. Some of the methodological problems with these studies are discussed. Additional areas of research, including the clinical and biological indicators of drug response, the use of non-TCA, nonMAOI drugs, the effects of pharmacological intervention on the development and maintenance of chronicity, and the comparison of and interaction between pharmacotherapy and psychotherapy are identified and suggested for future study.     

Effects of psychopharmacological treatment with antidepressants on the vascular system

Psychopharmacological treatment with antidepressants is an essential part of guideline-based treatment strategies in affective disorders, such as major depressive disorder, persistent depressive disorder, and bipolar disorder. Furthermore, antidepressants are frequently prescribed in patients with physical disorders, such as cardiovascular diseases, and comorbid depression. The type of association between physical diseases, particularly chronic diseases, and depression is bidirectional, meaning that affective disorders enhance the risk for the development of cardiovascular and metabolic disorders, and that cardiovascular/metabolic disorders enhance the risk for the development of depressive disorders. Therefore, knowledge of vascular side effects of psychopharmacological treatment is important for clinicians. This clinical orientated review article covers direct and indirect effects of commonly prescribed antidepressant drugs on the vascular system.