维拉唑酮：多靶标和新机制抗抑郁药研发的新方向

维拉唑酮是兼有5-羟色胺1A(5-HT_1A)受体部分激动作用和5-HT重摄取抑制作用的双重活性药物。该药物的设计是基于特异性加速5-HT_1A自身受体脱敏的原理,以达到加快起效和增强疗效的目的。临床前研究结果表明,维拉唑酮是重组细胞系和正常组织的5-HT_1A受体的高效的部分激动剂,能占有并功能性阻断5-HT转运蛋白的活性位点,抑制5-HT重摄取;在多个动物模型中具有抗抑郁和抗焦虑活性。维拉唑酮已经被美国食品药品监督管理局批准用于重度抑郁症的治疗。目前尚无将维拉唑酮与其他抗抑郁药进行直接比较的报道,但现有临床研究已表明该药物抗抑郁的治疗效果与其他抗抑郁药相当。与5-HT重摄取抑制剂一样,维拉唑酮也存在胃肠道不良反应,但性功能障碍和体质量增加的不良反应发生率极低,并且起效可能更快速。维拉唑酮全新的抗抑郁机制,为重度抑郁症的治疗提供了新的选择。     

盐酸维拉唑酮的合成方法改进

目的:改进盐酸维拉唑酮的合成工艺。方法:以5-溴水杨醛和溴代丙二酸二乙酯为原料,经醚化、环合、酰胺化、取代、水解制得中间体5-(1-哌嗪基)苯并呋喃-2-甲酰胺(7)。7再与3-(4-氯丁基)-1H-5-氰基吲哚(11)经取代和与盐酸成盐制得盐酸维拉唑酮。其中,11是用5-氰基吲哚和4-氯丁酰氯经酰化、还原得到的。结果:工艺的总收率为39.1%;盐酸维拉唑酮的结构经质谱、核磁共振谱确证。结论:该方法工艺简单,收率高,适合工业化生产。     

精神障碍治疗用药(续二)

5盐酸维拉唑酮的不良反应5.1临床研究的结果经盐酸维拉唑酮治疗的重度抑郁症(MDD)患者,最常见的不良反应如腹泻、恶心、呕吐和失眠的发生率≥5%,至少是安慰药的2倍。临床试验是在广泛的不同情况下进行的,而且时间长短不一,试验药物所观察到的不良反应发生率无法直接与其他药物比较,也不能反映实际情况。MDD患者与     

精神障碍治疗用药(续一)

盐酸维拉唑酮(vilazodone hydrochloride,商品名为Viibryd()由德国默克(Merck KgaA)公司研制,为选择性5-羟色胺再摄取抑制药(SSRIs)和5-羟色胺1A受体部分激动药,美国FDA于2011年1月21日批准     

盐酸维拉唑酮的合成工艺改进

目的研究维拉唑酮的合成工艺。方法以5-氰基吲哚为起始原料,经付克酰基化、吲哚磺酰基保护、羰基还原、缩合、水解脱保护、成盐6步反应制得盐酸维拉唑酮。结果与结论该路线具有条件温和、操作简便、中间体易于提纯等优点。目标化合物及中间体的结构经1H-NMR、MS确认。该合成方法总收率为35%,较适合工业化生产。     

盐酸维拉唑酮的合成

以5-溴水杨醛和溴代丙二酸二乙酯为起始原料,经醚化、环合、酰胺化、取代及脱保护反应制得关键中间体5-(1-哌嗪基)苯并呋喃-2-甲酰胺(5).另用5-氰基吲哚和4-氯丁酰氯经酰化、还原制得3-(4-氯丁基)-5-氰基-1H-吲哚(7).5和7经缩合及与盐酸成盐制得盐酸维拉唑酮,总收率为36.3％(以5-溴水杨醛计).     

阿戈美拉汀联合坦度螺酮对老年抑郁症患者血清NE、5-HT水平的影响

目的 观察阿戈美拉汀联合坦度螺酮对老年抑郁症患者血清去甲肾上腺素(NE)、五羟色胺(5-HT)的影响,探讨其对抑郁症的临床疗效. 方法 100例抑郁症患者按照随机数字表法分为观察组50例、对照组50例,对照组给予坦度螺酮口服,观察组在对照组基础上加服阿戈美拉汀.治疗前、治疗8周后分别进行汉密尔顿抑郁量表(HAMD)评分,检测血清NE、5-HT表达水平. 结果 治疗前2组患者HAMD评分及血清NE、5-HT水平比较,差异无统计学意义(P>0.05).治疗8周后,观察组比对照组HAMD评分明显降低(P<0.05),血清NE、5-HT水平均明显升高(P<0.05). 结论 阿戈美拉汀联合坦度螺酮可明显升高老年抑郁症患者血清NE、5-HT水平,降低HAMD评分,显著改善抑郁症状.     

酮色林对雷诺现象的疗效

近年来,关于5-羟色胺(5-HT)对外周循环的调节作用,越来越受到关注。5-HT的血管收缩作用,可能由血小板和血管平滑肌的5-HT_2受体介导。选择性5-HT_2受体拮抗剂酮色林(Ketanserin)则能抑制上述反应的增强,故能治疗雷诺现象;后者可能由于5-HT引起的血管痉挛所致。 12例稳定的雷诺现象患者,口服安慰剂15日后,改服酮色林40mg一日2次,共15     

丁螺环酮对精神分裂症患者认知功能的随机双盲对照研究

<正>认知功能损害是精神分裂症的核心症状之一。非典型抗精神病药物(AAPDs)氯氮平、利培酮、奥氮平、喹硫平、齐拉西酮、阿立哌唑对认知功能有一定的改善作用[1]。文献[2]报道精神分裂症患者尸检发现前额、颞皮质5-羟色胺(HT)1A受体密度增加。而且得到功能核磁(PET)的证实。国外有研究显示坦度螺酮为5-HT1A部分激动剂,可以提高AAPDs对精     

5—羟色胺受体：激动剂和拮抗剂

脑内5-羟色胺(5-HT)的发现和5-HT的合成对中枢神经系统5-HT功能的研究起了很大的促进作用。由于发现其结构与一些强效致幻剂,如麦角酰二乙胺(LSD)相似,进一步加快了这方面的研究。虽然5-HT可引起一系列中枢和周围的药理反应,但它们不仅在种属间,而且在同种动物身上,甚至同一动物的先后试验中也有很大的差异。这些观察引起了有5-HT不同受体亚型存在的推测。最近的放射配基研究已证明了有两种不同的5-HT受体结合点存在,由5-羟色标记的结合点称为S_1受体,由其拮抗剂螺哌隆(Spiperone)和酮舍林(Ketanserin)标记的称为S_2受体。早期认为的5-羟色胺受     

Effect of vilazodone on 5-HT efflux and re-uptake in the guinea-pig dorsal raphe nucleus

The effect of vilazodone, a putative selective serotonin re-uptake inhibitor (SSRI) with 5-HT (5-hydroxytryptamine)(1A) receptor partial agonist activity, was investigated on 5-HT efflux and 5-HT re-uptake half life in the guinea-pig dorsal raphe nucleus, using in vitro fast cyclic voltammetry. The SSRI, fluoxetine, significantly increased 5-HT efflux. In contrast, vilazodone had no effect on 5-HT efflux at 100 nM but significantly decreased 5-HT efflux at 1 microM. Co-perfusion of 8-OH-DPAT (+/-8-hydroxy-2-(di-n-propylamino)tetralin) with fluoxetine significantly attenuated the fluoxetine-induced increase in 5-HT efflux. Co-perfusion of WAY 100635 with vilazodone did not attenuate the effect of vilazodone alone. In addition, the re-uptake half life for 5-HT was significantly increased by both fluoxetine and vilazodone. In conclusion, we have demonstrated that vilazodone (100 nM, 1 microM), in the guinea-pig dorsal raphe nucleus, blocks the serotonin transporter but does not display 5-HT(1A) receptor agonism.     

Neurochemical evaluation of the novel 5-HT1A receptor partial agonist/serotonin reuptake inhibitor, vilazodone

Vilazodone has been reported to be an inhibitor of 5-hydoxytryptamine (5-HT) reuptake and a partial agonist at 5-HT1A receptors. Using [35S]GTPgammaS binding in rat hippocampal tissue, vilazodone was demonstrated to have an intrinsic activity comparable to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Vilazodone (1-10 mg/kg p.o.) dose-dependently displaced in vivo [3H]DASB (N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine) binding from rat cortex and hippocampus, indicating that vilazodone occupies 5-HT transporters in vivo. Using in vivo microdialysis, vilazodone (10 mg/kg p.o.) was demonstrated to cause a 2-fold increase in extracellular 5-HT but no change in noradrenaline or dopamine levels in frontal cortex of freely moving rats. In contrast, administration of 8-OH-DPAT (0.3 mg/kg s.c.), either alone or in combination with a serotonin specific reuptake inhibitor (SSRI; paroxetine, 3 mg/kg p.o.), produced no increase in cortical 5-HT whilst increasing noradrenaline and dopamine 2 and 4 fold, respectively. A 2-fold increase in extracellular 5-HT levels (but no change in noradrenaline or dopamine levels) was observed after combination of the 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexanecarboxamide) (WAY-100635; 0.3 mg/kg s.c.) and paroxetine (3 mg/kg p.o.). In summary, vilazodone behaved as a high efficacy partial agonist at the rat hippocampal 5-HT1A receptors in vitro and occupied 5-HT transporters in vivo. In vivo vilazodone induced a selective increase in extracellular levels of 5-HT in the rat frontal cortex. This profile was similar to that seen with a 5-HT1A receptor antagonist plus an SSRI but in contrast to 8-OH-DPAT either alone or in combination with paroxetine.     

Mechanism of action of the bimodal antidepressant vilazodone: evidence for serotonin1A-receptor-mediated auto-augmentation of extracellular serotonin output

Rationale

The recently approved antidepressant vilazodone, a serotonin (5-HT)_1A receptor partial agonist/selective 5-HT reuptake inhibitor offers new possibilities to study the underlying mechanisms of depression pharmacotherapy and of 5-HT augmenting antidepressants.

Objective

The role of the 5-HT_1A receptor with respect to the regulation of 5-HT output in the mechanism of action of vilazodone.

Method

We measured 5-HT levels in two subregions of the rat prefrontal cortex by microdialysis, and 5-hydroxytryptophan (5-HTP) accumulation and tissue 5-HT concentrations ex vivo.

Results

Vilazodone-induced maximal 5-HT levels were similar in the medial and the lateral cortex and were up to sixfold higher than those induced by paroxetine, citalopram, or fluoxetine tested in parallel. Depolarization/autoreceptor-insensitive 5-HT release by vilazodone could be excluded. The citalopram (1 μM, locally infused)-induced increase of 5-HT was further increased by vilazodone (1 mg/kg i.p.), but not by citalopram (10 mg/kg i.p.). Unlike fluoxetine, vilazodone-induced extracellular 5-HT output was not potentiated by cotreatment with the 5-HT_1A receptor blocker N-[2-(4-{2-methoxyphenyl}-1-piperazinyl)-ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY 100635). In contrast to fluoxetine, vilazodone exhibited intrinsic 5-HT_1A agonist activity: it reduced, similar to (±)-8-hydroxy-2-(dipropylamino)-tetralin (8-OH-DPAT), 5-HTP accumulation in striatum and n. raphe of reserpinized rats. Hence, vilazodone's agonistic actions must be 5-HT_1A receptor-related since endogenous 5-HT is lacking in the reserpine-depleted animal.

Conclusions

In spite of high intrinsic 5-HT_1A activity in reserpinized rats, the net effect of vilazodone at release-regulating 5-HT_1A autoreceptors must be inhibitory, leading to markedly increased 5-HT output. Another possibility is that vilazodone rapidly desensitizes autoinhibitory 5-HT_1A receptors by an unknown mechanism.     

Drug evaluation: Vilazodone--a combined SSRI and 5-HT1A partial agonist for the treatment of depression

Vilazodone is a combined selective serotonin reuptake inhibitor (SSRI) and a 5-HT(1A) receptor partial agonist that is being developed by Clinical Data Inc for the treatment of depression. In preclinical studies, vilazodone compared favorably to other antidepressants such as paroxetine and fluoxetine. Orally administered vilazodone inhibited ultrasonic vocalization in the rat after electrical foot shock (a model of anxiolytic activity). Yet, in the forced swimming test model of depression in rats, vilazodone administered intraperitoneally was active at 1 mg/kg but not at 3 or 10 mg/kg. During clinical trials, vilazodone completely abolished REM sleep for 8 h and demonstrated antidepressant efficacy that was equal to that of current antidepressant therapeutics. The author concludes that the success of vilazodone as an effective antidepressant agent will depend on whether the drug can produce a more rapid antidepressant effect than other SSRI agents, or if specific genetic markers of patients can be associated with clinical efficacy.     

An updated review of antidepressants with marked serotonergic effects in obsessive–compulsive disorder

Introduction: Since the recognition of the effectiveness of clomipramine in treating obsessive–compulsive disorder (OCD), a number of recent empirical studies have confirmed a key role of the serotonergic (5-HT) system in the pathophysiology of OCD. The current study presents a review of the existing double-blind studies testing 5-HT antidepressants in OCD.

Areas covered: A systematic review was performed to identify double-blind, placebo-controlled, randomized clinical trials investigating the efficacy of antidepressants with marked 5-HT effects [clomipramine, selective serotonin reuptake inhibitors (SSRIs), venlafaxine, desvenlafaxine, duloxetine, mirtazapine, agomelatine, vortioxetine and vilazodone] in the short-term treatment of OCD. The search provided 29 studies investigating eight different 5-HT antidepressants. While the findings show reliable efficacy of clomipramine and SSRIs in the treatment of OCD symptoms, no double-blind studies were identified investigating the efficacy of desvenlafaxine, duloxetine, mirtazapine, agomelatine, vortioxetine or vilazodone.

Expert opinion: While our results support the effectiveness of older antidepressants with marked 5-HT effects in OCD, it also suggests that newer agents should be tested more comprehensively.     

Vilazodone: a new treatment option for major depressive disorder

Vilazodone hydrochloride belongs to a new class of antidepressants-the indolalkylamines-and has dual activity as a selective serotonin reuptake inhibitor (SSRI) and as a partial agonist of the serotonin 5-HT(1A) receptor. Its antidepressant activity has been demonstrated in two 8-week, double-blind, randomized, placebo-controlled trials and in a 1-year open-label study. None of these trials compared vilazodone with existing antidepressants; however, changes in depressive symptoms after vilazodone treatment were similar to those reported for SSRIs. The most common adverse events were diarrhea and nausea, although these were mild to moderate in severity and rarely a cause for discontinuation. No important clinical changes in vital signs, laboratory values, ECG morphology and sexual function were observed or reported.     

Vilazodone: A novel antidepressant

Purpose The pharmacology and pharmacokinetics of the antidepressant vilazodone (approved for U.S. marketing in 2011) are reviewed, with an emphasis on efficacy and safety data from Phase III clinical trials. Summary Vilazodone (marketed as Viibryd by Forest Pharmaceuticals) is a dual-acting serotonergic agent that combines the antidepressant effects of a selective serotonin-reuptake inhibitor (SSRI) with partial serotonin (5-HT)(1A)-receptor agonist activity. In two published eight-week Phase III trials involving a total of 878 adults with major depressive disorder (MDD), vilazodone use was found to yield significant symptomatic improvements relative to placebo use, as determined by mean changes from baseline in scores on the Hamilton Depression Rating Scale and other widely used clinical assessment instruments. Vilazodone hydrochloride therapy should be initiated at a dosage of 10 mg once daily and incrementally adjusted over 14 days to the recommended target daily dose of 40 mg; for optimal bioavailability and effectiveness, it should be taken after a light or high-fat meal. The adverse effects most commonly reported in clinical trials of vilazodone were diarrhea, nausea, vomiting, and insomnia. Conclusion Vilazodone is an efficacious and safe new antidepressant for the treatment of MDD. Its relatively high cost and adverse-effect profile, as well as a lack of data demonstrating that vilazodone can produce long-term MDD remission and offer significant advantages over the current standard of care, may limit the usefulness of vilazodone in clinical practice.     

Vilazodone: in major depressive disorder

Vilazodone, a novel antidepressant agent that combines selective serotonin reuptake inhibitor (SSRI) activity and serotonin 5-HT(1A) receptor partial agonist activity in a single molecule, is indicated for the treatment of major depressive disorder (MDD) in the US. It is administered orally, once daily, with food. At the recommended dosage of 40?mg/day, vilazodone was effective in the short-term treatment of MDD in adults, as evidenced by significant improvements versus placebo on multiple measures of depression, including the Montgomery-?sberg Depression Rating Scale (MADRS) and the 17-item Hamilton Rating Scale for Depression (HAM-D-17), in two pivotal, 8-week, randomized, double-blind, phase III studies. Significant differences between vilazodone and placebo on the MADRS and HAM-D-17 were seen after 1 week of treatment (first efficacy timepoint) in one of the two studies. Long-term treatment with vilazodone 40?mg/day was associated with an improvement from baseline in depressive symptoms in a 52-week, noncompar-ative, phase III study. Vilazodone was generally well tolerated in the short- and long-term treatment of MDD, with diarrhoea and nausea being the most frequently occurring treatment-emergent adverse events. Vilazodone had a minimal impact on sexual functioning in the three phase III studies.     

维拉佐酮的药理和临床评价

重性抑郁障碍是一种严重的精神障碍,且容易复发。尽管多种药物均可治疗,但仍有许多患者无法获得满意的疗效。维拉佐酮为选择性5-HT再摄取抑制剂和5-HT_(1A)受体部分激动剂,用于治疗重性抑郁障碍。本文就其作用机制、药效学、药动学和临床评价等进行综述。     

Evaluation of vilazodone for the treatment of depressive and anxiety disorders

Introduction: Major Depressive Disorder (MDD) and General Anxiety Disorder (GAD) significantly contribute to the global burden of disease. Vilazodone, a combined serotonin reuptake inhibitor and 5-HT1A partial agonist, is an approved therapy for the treatment of MDD and which has been further investigated for GAD.

Areas covered: This article covers the pharmacokinetics and pharmacodynamics of vilazodone and provides an evaluation of the clinical usefulness of vilazodone for the treatment of MDD and anxiety disorders. A literature search was performed using PubMed/MEDLINE, Web of Science and the Cochrane Library.

Expert opinion: Studies have shown that vilazodone is significantly superior to placebo. However, vilazodone cannot as yet be recommended as a first-line treatment option for MDD as it is unclear whether the drug’s dual mechanism of action provides greater efficacy than prevailing treatment options. Moreover, more phase IV studies are needed to establish its efficacy and long-term safety in larger and more diverse populations. Although vilazodone may have an additional advantage for the treatment of anxiety symptoms in MDD, here also additional studies are required to confirm its efficacy over and above SSRI alternatives and other antidepressant treatments. Therefore, presently, vilazodone should be considered as a second- or third-line treatment option for MDD and GAD.