全新作用机制的抗抑郁药agomelatine

褪黑素类似物agomelatine，既是首个褪黑素受体激动剂，也是5-色胺2C（5-HT2c）受体拮抗剂。动物试验与临床研究表明该药有抗抑郁、抗焦虑、调整睡眠节律及调节生物钟作用，同时其不良反应少，对性功能无不良影响，也未见撤药反应。     

全新作用机制的抗抑郁药agomelatine

褪黑素类似物agomelatine,既是首个褪黑素受体激动剂,也是5-羟色胺2C(5-HT_(2C))受体拮抗剂。动物试验与临床研究表明该药有抗抑郁、抗焦虑、调整睡眠节律及调节生物钟作用,同时其不良反应少,对性功能无不良影响,也未见撤药反应。     

5-HT_(1A)受体激动剂类抗抑郁药的研究与开发

综述5-HT1A-受体激动剂抗抑郁作用的机制及其新产品的研究与开发。5-HT1A受体激动剂通过激动突触后膜 的5-HT1A受体,负反馈抑制海马5-HT能神经元上的自主受体而发挥抗抑郁作用,克服了传统抗抑郁药的滞后效应。     

以5-羟色胺2A受体为靶点的抗抑郁药研究进展

抑郁症的发病机制非常复杂,至今尚未完全阐明。大量临床及临床前研究表明,5-羟色胺(5-HT)能神经功能障碍可能是导致抑郁症的关键因素之一。在5-HT神经系统中,除5-羟色胺转运体(SERT)外,有多种5-HT受体亚型与抑郁症有关,尤以5-HT_1A及5-HT_2A受体与抑郁症关系最为密切。5-HT_2A受体在大脑中广泛分布,是调节情绪的重要物质基础,对情绪、感知的调控具有重要作用。5-HT_2A受体可以直接或间接调节单胺类递质释放,调节脑中单胺类递质水平,参与抑郁症发病过程。5-HT_2A受体拮抗剂可以增强5-羟色胺再摄取抑制剂等抗抑郁药对难治性抑郁症的治疗效果并减少性功能障碍及睡眠障碍等不良反应。目前有不少以5-HT_2A受体为靶点的抗抑郁药应用于临床,也有大量化合物处于临床及临床前研究。该文对5-HT_2A受体与抑郁症的关系及以5-HT_2A受体为靶点的抗抑郁药研究进展进行简要综述,以期为新型抗抑郁药物的研发提供参考。     

5-HT1A受体激动剂类抗抑郁药的研究与开发

综述5-HT1A受体激动剂抗抑郁作用的机制及其新产品的研究与开发。5-HT1A受体激动剂通过激动突触后膜的5-HT1A受体，负反馈抑制海马5-HT能神经元上的自主受体而发挥抗抑郁作用，克服了传统抗抑郁药的滞后效应。     

抗抑郁药所致5-HT综合征的用药与临床护理

目的总结抗抑郁药所致5-HT综合征的用药与临床护理措施。方法对使用抗抑郁剂治疗中发生5-HT综合征的抑郁症患者进行临床护理分析,总结护理措施。结果 28例发生5-HT综合征的患者因发现及时,积极治疗与护理,取得了满意的临床护理效果。结论对抗抑郁药所致5-HT综合征患者应早识别、早处理,可收到较好效果。     

抗抑郁药物新进展

抑郁症是一种常见的精神疾病,属情感性障碍.随着生活节奏不断加快,人们的精神压力也逐渐增大,抑郁症已成为现代社会的常见病、高发病,其发病率正在快速攀升.据不完全统计,目前全世界抑郁症患者已占世界人口的3%～5%.通过药物治疗,其中约2/3的患者可取得不同疗效.高发且难以根治的抑郁症使得抗抑郁药市场具有广阔的前景,这正是近年来国外热衷于抗抑郁药物研究与开发的主要原因之一[1].笔者将对各种抗抑郁药物的进展作一综述.     

抗抑郁药

目前，治疗抑郁症的药物主要有3大类：调节脑内5-羟色胺（5-HT）和去甲肾上腺素（NE）平衡的三环类、减缓这些脑内神经递质降解的单胺氧化酶抑制剂和增强5-HT活性但不影响其他神经递质的选择性5-HT再摄取抑制剂。文拉法辛（venlafaxine）是一种三环类化合物，于1994年上市，是第一个5-HT和NE再摄取抑制剂。尤其作为严重抑郁症的一线治疗药具有特殊的功效。     

诺华公司决定中止对抗抑郁症药Agomelatine的进一步开发

近期,诺华公司宣称中止其＂未来的拳头产品＂——抗严重抑郁症药agomelatine（AGO178）的进一步的开发计划。Agomelatine具5-HT2c受体拮抗剂和褪黑激素受体激动剂双重活性,即可通过抑制5-HT2c受体,促进中枢神经系统中多巴胺和去甲肾上腺素的释放,并激活大脑皮质额叶区多巴胺能和肾上腺素能通路,且能有效激动褪黑激素受体MT1和MT2。该产品目前已在欧盟以商品名Valdoxan获准上市,成为首个褪黑激素能抗抑郁症药物,并有望于2013年在美国获准上市。     

Agomelatine in treating generalized anxiety disorder

Introduction: Generalized anxiety disorder (GAD) is a chronic and disabling disorder with a lifetime prevalence of 4.3 – 5.9% in the general population. Many drug and non-drug treatments have been shown to be effective in the treatment of GAD, including benzodiazepines, antidepressants (selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors and tricyclic antidepressants), anticonvulsants, azapirones, antihistamines, atypical antipsychotics, complementary/alternative medicine, psychotherapy and Internet-based services. Agomelatine is an antidepressant approved by the European Agency; it is a melatonergic agonist (MT1 and MT2 receptors) and a 5-HT_2C antagonist indicated in the treatment of major depressive episodes.

Areas covered: The present article looks at the short-term efficacy of Agomelatine assessed in two short-term placebo-controlled studies. It also looks at the long-term efficacy evaluated in one relapse prevention study.

Expert opinion: Agomelatine is an effective treatment option for both GAD and somatic anxiety. The trial, which includes an escitalopram arm, shows comparable efficacy in GAD between both antidepressants, whereas the restoration of sleep was significantly better with agomelatine. The low discontinuation rate illustrates the good tolerability and lab results show a low incidence of transient elevations in liver enzymes. Whereas uptitrated patients on a 50 mg dose have a lower chance of reaching the desired outcome than the lower 25 mg dose, those reaching this outcome have a better chance of treatment continuation.     

Agomelatine for Depression in Schizophrenia: A Case-Series

Objectives

Agomelatine, a melatonin (MT1/MT2) receptor agonist and 5-HT2C receptor antagonist, is a new antidepressant and a potential therapeutic option for major depressive episodes and negative symptoms in persons with schizophrenia. We investigated such treatment outcomes with respect to antidepressant efficacy, safety, and tolerability.

Methods

We report a consecutive case series of seven patients with schizophrenia and comorbid major depressive symptoms who received agomelatine for a period of at least six weeks in addition to stable doses of antipsychotic agents. General psychopathology, positive, negative and depressive symptoms were assessed with standardized interviews. Relevant blood parameters were assessed.

Results

Depressive symptoms improved significantly. Positive symptoms remained stable, while negative symptoms and global psychopathology improved significantly. Agomelatine was well tolerated in most patients.

Conclusions

Our findings provide initial evidence that agomelatine is safe and efficacious in treating depressive symptoms in patients with schizophrenia. Furthermore, agomelatine seems to be effective for the treatment of negative symptoms. Randomized controlled trials are necessary to confirm these first observations.     

阿戈美拉汀治疗老年卒中后抑郁的临床疗效比较

目的探讨阿戈美拉汀对比度洛西汀治疗老年卒中后抑郁症的临床疗效和不良反应。方法将90例诊断为脑卒中后抑郁的老年患者随机分为2组,研究组使用阿戈美拉汀,对照组使用度洛西汀,治疗12周,采用汉密尔顿抑郁量表(HAMD)和神经功能缺损量表(CSS)、睡眠障碍量表(SDRS)、副反应量表(TESS)评定疗效、功能恢复和不良反应。结果研究组和对照组治疗老年脑卒中后抑郁的HAMD、CSS、SDRS评分无显著性差异,总有效率分别为73.3%和71.1%,差异无统计学意义(P>0.05);TESS显示研究组阿戈美拉汀不良反应少,2组差异有统计学意义(P<0.05)。结论阿戈美拉汀有利于老年脑卒中后抑郁患者改善抑郁症状,促进神经功能康复,提高生活能力,是一种安全有效、不良反应少的抗老年卒中后抑郁药。     

Agomelatine in depression

Introduction: Agomelatine is a relatively new antidepressant with a mechanism of action that is different from other antidepressants: it is a melatonergic agonist and a 5-HT2C antagonist. It is an effective treatment for depression, with relatively mild side effects. It may be a valuable pharmacological alternative in the clinical approach on depression.

Areas covered: The literature about agomelatine has been comprehensively reviewed. Agomelatine's efficacy, safety and tolerability are reviewed based on the studies undertaken in patients with major depressive disorder (MDD) and bipolar disorder (BPD).

Expert opinion: Agomelatine has shown an antidepressant effect in preclinical models, and the results of a large-scale clinical trial program, conducted in MDD, indicate both an antidepressant activity and a favorable tolerability profile. Agomelatine has no discontinuation syndrome, sexual discomfort is rare, and it is generally weigh neutral. The drug appears to be relatively safe in case of overdose. However, some cases of elevated hepatic transaminases are reported during treatment. As agomelatine has a mechanism of action that differs from other agents, it may represent a valuable additional treatment option in those patients who do not respond fully or who do not tolerate the side effects of other antidepressants.     

Agomelatine,a melatonin agonist with antidepressant properties

Agomelatine (β-methyl-6-chloromelatonin), which is structurally homologous to melatonin, is a potent agonist of melatonin MT1 and MT2 receptors as well as an antagonist of serotonin 5-HT_2C receptors. Agomelatine appears to improve sleep without causing daytime sedation. It has not been found to be associated with sexual side effects and discontinuation symptoms. Three placebo-controlled trials, one of them a dose finding study and two of them pivotal trials, suggest that agomelatine is an antidepressant at doses of 25 – 50 mg/day. Agomelatine appears to be well tolerated, without sexual or cardiac adverse effects, weight gain or discontinuation syndromes. Animal studies suggest a possible neuroprotective action of agomelatine, although there are more data in favor of an anxiolytic effect. Substantially more research is needed to establish its role in the treatment of mood and circadian rhythm disorders.     

Agomelatine for the treatment of major depressive disorder

Introduction: This article discusses agomelatine (Valdoxan^?/Thymanax^?; Servier/Novartis), which is a melatonin (MT1/MT2) agonist and serotonin (5-HT2c) receptor antagonist. Agomelatine has been approved for the treatment of adults with major depression by several regulatory agencies and is now on the market in 41 countries.

Areas covered: Literature related to agomelatine was reviewed on PubMed using the search terms ‘agomelatine OR S-20098’ and 204 articles were found. Twelve published, randomized, double-blind studies were included in this review.

Expert opinion: Agomelatine produces strong effects on circadian sleep phase disturbances, improving time to sleep onset and quality of sleep. It has been shown to be superior to placebo and similar to existing antidepressants, as demonstrated by short-term clinical trials and one relapse prevention trial. However, 0 – 0.6% and 3 – 4.5% of patients treated with 25 and 50 mg, respectively, showed elevated transaminases. Although none of these reactions so far seem to have been serious, the adverse effects in the liver may present a regulatory and marketing challenge. Given equivalence or modest superiority to existing, generic alternatives, the acceptability in a third-party reimbursement environment is questionable. Future clinical trials are needed to establish an appropriate market niche.     

Electrophysiological Effects of Repeated Administration of Agomelatine on the Dopamine,Norepinephrine, and Serotonin Systems in the Rat Brain

Agomelatine is a melatonergic MT1/MT2 agonist and a serotonin (5-HT) 5-HT_2C antagonist. The effects of 2-day and 14-day administration of agomelatine were investigated on the activity of ventral tegmental area (VTA) dopamine (DA), locus coeruleus (LC) norepinephrine (NE), and dorsal raphe nucleus (DRN) 5-HT neurons using in vivo electrophysiology in rats. The 5-HT_1A transmission was assessed at hippocampus CA3 pyramidal neurons. After a 2-day regimen of agomelatine (40 mg/kg/day, i.p.), an increase in the number of spontaneously active VTA-DA neurons (p<0.001) and in the firing rate of LC-NE neurons (p<0.001) was observed. After 14 days, the administration of agomelatine induced an increase in: (1) the number of spontaneously active DA neurons (p<0.05), (2) the bursting activity of DA neurons (bursts/min, p<0.01 and percentage of spikes occurring in bursts, p<0.05), (3) the firing rate of DRN-5-HT neurons (p<0.05), and (4) the tonic activation of postsynaptic 5-HT_1A receptors located in the hippocampus. The increase in 5-HT firing rate was D2 dependent, as it was antagonized by the D2 receptor antagonist paliperidone. The enhancement of NE firing was restored by the 5-HT_2A receptor antagonist MDL-100,907 after the 14-day regimen. All the effects of agomelatine were antagonized by a single administration of the melatonergic antagonist {"type":"entrez-protein","attrs":{"text":"S22153","term_id":"100005","term_text":"pir||S22153"}}S22153 (except for the increase in the percentage of spikes occurring in burst for DA neurons). The present results suggest that (1) agomelatine exerts direct (2 days) and indirect (14 days) modulations of monoaminergic neuronal activity and (2) the melatonergic agonistic activity of agomelatine contributes to the enhancement of DA and 5-HT neurotransmission.     

Development of a Novel Amorphous Agomelatine Formulation With Improved Storage Stability and Enhanced Bioavailability

The present work describes the development of a novel formulation of amorphous agomelatine (AGM) that exhibits enhanced in vitro dissolution rate and bioavailability, as well as improved storage stability. AGM was loaded on a mixture of microcrystalline cellulose with a high specific surface area excipient, namely colloidal silicon dioxide, employing a wet granulation method, and the resultant AGM granules were subsequently formulated into immediate release film-coated tablets. Modulated temperature differential scanning calorimetry, hot-state light microscopy, powder X-ray diffraction, attenuated total reflectance FTIR, and micro-Raman spectroscopy revealed that the active pharmaceutical ingredient existed primarily in the amorphous state within the prepared formulations, with some crystals of polymorph I also present. Accelerated stability studies for up to 6 months in alu-alu blisters showed good physicochemical stability during storage. Finally, in vitro dissolution studies and clinical trials in healthy human volunteers showed a remarkable increase in the in vitro dissolution rate and a ～1.5-fold increase in bioavailability, respectively, compared to the marketed product.     

阿戈美拉汀的合成

阿戈美拉汀由7-甲氧基四氢萘-1-酮与氰乙酸反应所得的（7-甲氧基-3，4-二氢-1-萘基）乙腈，经2，3-二氯-5，6-二氰基-1，4-苯醌芳构化制得（7-甲氧基-1-萘基）乙腈，再还原乙酰化“一锅”反应制得，总收率约76％。