Is dopamine implicated in the antidepressant-like effects of selective serotonin reuptake inhibitors in the mouse forced swimming test?

RATIONALE: Microdialysis, binding and behavioural studies have shown that the dopaminergic system plays a role in antidepressant treatment. OBJECTIVES: The present study determined whether the antidepressant-like effects of selective serotonin reuptake inhibitors measured in the mouse forced swimming test are mediated via dopamine receptors. METHODS: Male Swiss mice were randomly assigned to groups of 24 animals and injected IP with citalopram, fluoxetine, fluvoxamine, sertraline, or paroxetine alone or in combination with the dopamine D(1)agonist SKF 38393, the D(1) antagonist SCH 23390, the D(2) agonist bromocriptine, the D(2) antagonist sulpiride, the D(3) agonist PD 128 907, or the D(3) antagonist nafadotride. RESULTS: The anti-immobility effects of paroxetine, fluvoxamine and citalopram were increased by co-administration of SKF 38393 (0.5 and 2 mg/kg), SCH 23390 (0.06 mg/kg), bromocriptine (0.5 and 2 mg/kg) or PD 128 907 (1 and 2 mg/kg), and were attenuated by SCH 23390 (0.5 mg/kg). The anti-immobility effects of paroxetine and fluvoxamine were also increased with sulpiride (0.5 and 2 mg/kg). The anti-immobility effect of fluoxetine was increased by SKF 38393 (2 mg/kg) and PD 128 907(1 and 2 mg/kg) co-administration. The anti-immobility effect of sertraline (16 mg/kg) was increased by SKF 38393 (0.5 mg/kg), bromocriptine (2 mg/kg) and PD 128 907 (2 mg/kg) and the effect of sertraline (2 mg/kg) was increased by bromocriptine (2 mg/kg). The anti-immobility effect of paroxetine (4 mg/kg) was increased by nafadotride (2 mg/kg). CONCLUSIONS: These data indicate that the antidepressant activity of various SSRIs involves different dopamine receptor subtypes and that the serotoninergic and dopaminergic systems interact with each other.     

选择性5-羟色胺再摄取抑制剂安全性研究概述

选择性5-羟色胺再摄取抑制剂（selective serotonin reuptake inhibitors，SSRIs）是广泛应用的新型抗抑郁药，用于治疗各种抑郁症。常用的SSRIs有氟西汀、帕罗西汀、舍曲林、氟伏沙明及西酞普兰。SSRIs有多种类型的不良反应，主要为胃肠道反应、停药反应、性功能障碍及抗利尿激素异常分泌综合征等。SSRIs有可能增加儿童和青少年自杀意念和行为的风险，但目前尚无定论。最新研究表明，孕妇早期服用SSRIs似乎不增加胎儿先天畸形风险，但孕妇晚期服用SSRIs，可致新生儿出现肺动脉高压和停药综合征。一般而言，用含SSRIs的母乳喂养是安全的，因其在乳汁中的含量很低，但长期服用对婴儿发育的影响尚不清楚。对于老年人，SSRIs可增加骨折风险。SSRIs和某些药物联用发生相互作用导致的不良反应如下：单胺氧化酶抑制剂：5-羟色胺综合征；利尿剂：严重低钠血症；抗凝血药：增加出血危险；非甾体抗炎药：增加上消化道出血风险；色氨酸：5-羟色胺综征；阿司咪唑、特非那定：室性心律失常，Q-T间期延长；氟哌啶醇、马普替林：严重锥体外系反应；锂盐：锂血浓度升高，毒性增加。总之，SSRIs的不良反应虽然少于三环类抗抑郁药，但其有自身特有的不良反应。因此，医师临床使用SSRIs应予以注意。     

Risk of Suicidality in Depression with Serotonergic Antidepressants

Since depression is a risk factor for suicidal thoughts and behaviors, and since suicidal behaviors are associated with low serotonin activity, are selective serotonin reuptake inhibitors (SSRIs) more effective than other antidepressants in treating suicidality in depressed patients? There is inconclusive evidence for and against this hypothesis. However, all studies suggest that antidepressants are effective treatments of suicidal ideations and behaviors, and SSRIs have been shown to have prophylactic effects in preventing suicidal behaviors. Although some reports suggest that SSRIs might increase suicidal ideations and behaviors, the results of large, double-blind studies do not suggest a causal relationship between pharmacotherapy and the emergence of suicidality. Undertreatment of depression and therapeutic failure are more significant problems with the use of antidepressants in suicidal patients than the risk of using antidepressants in overdose. Prescribing inadequate doses of antidepressants is therefore a source of overlooked risk.     

5-羟色胺再摄取抑制剂联合胰岛素治疗躯体形式障碍对照研究

目的探讨高选择性5羟色胺再摄取抑制剂联合胰岛素治疗躯体形式障碍的临床疗效。方法将59例躯体形式障碍患者随机分为A组30例、B组29例,两组均口服高选择性5羟色胺再摄取抑制剂治疗,B组联合胰岛素治疗。疗程6w。于治疗前及治疗第1w、2w、4w、6w末采用汉密顿焦虑量表、汉密顿抑郁量表评定临床疗效。结果治疗6w末A组显效率53．33％,总有效率96．67％;B组分别为86．21％,100％;B组显效率显著高于A组（χ2=7．516,P〈0．01）。两组汉密顿焦虑量表、汉密顿抑郁量表评分治疗第1w末起均较治疗前有显著下降（P〈0．01）,第6w末B组较A组下降显著（P〈0．05）。不良反应B组除体重增加较多外,其他因子与A组无显著性差异（P〉0．05）。结论高选择性5羟色胺再摄取抑制剂联合胰岛素治疗躯体形式障碍疗效显著,安全性高,依从性好。     

中枢5-HT能系统在早发性抑郁中的作用研究

早发性抑郁的发病机制尚不明确。现仅有选择性5-HT重摄取抑制剂(selective serotonin reuptake inhibitors,SSRIs)SSRIs批准用于临床治疗早发性抑郁,显示出五羟色胺(5-hydroxytryptamine/serotonin,5-HT)5-HT是早发性抑郁发病机制中最重要的神经递质。目前有关中枢5-HT能系统在早发性抑郁中的作用研究主要集中在5-HT合成不足、5-HT运输功能障碍等方面,并与5-HT能系统较早发育成熟有关。色氨酸吸收障碍以及5-HT合成障碍都会导致5-HT合成不足;同时,5-HT转运体蛋白(5-HTT)基因多态性位点5-HTTLPR低转录效率基因型可能会增加早发性抑郁的患病风险。为进一步理解中枢5-HT能系统在早发性抑郁中的作用,未来需要进行更广泛更深入的基础及临床研究。     

Vortioxetine: a New Treatment for Major Depressive Disorder

Introduction: Vortioxetine is a structurally novel medication that has recently been approved for treatment of major depressive disorder (MDD). This medication is a serotonin reuptake inhibitor that also has a number of other potentially relevant effects on serotoninergic receptors, which may differentiate the drug’s effects from those of current first-line antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).

Areas Covered: This article will review the basic clinical pharmacology of vortioxetine, summarize the major clinical trials that were performed prior to approval by the US Food and Drug Administration (FDA), discuss relevant post-marketing studies of this drug, and offer expert commentary on the significance of this new agent in clinical practice. Pre-approval studies were identified as all randomized, placebo-controlled studies of vortioxetine listed on clinicaltrials.gov. Other referenced studies were identified via a MEDLINE database literature search in August 2015 using the key search terms, vortioxetine and Lu AA21004, combined with additional terms that included pharmacological profile, pharmacokinetics, drug interactions, adverse effects, side effects, safety, major depression, and major depressive disorder. We identified relevant systematic reviews, meta-analyses, randomized trials and preclinical studies of importance.

Expert Opinion: Results of placebo-controlled trials suggest efficacy and an overall safety profile comparable to existing first-line antidepressants. The most common side effects are nausea, vomiting and constipation. Results of several studies indicate that vortioxetine may have therapeutic effects on cognition (e.g., memory and executive functioning) that exceed that of standard antidepressants. Disadvantages include cost and the current paucity of long-term efficacy data from large clinical trials. The authors suggest that vortioxetine is currently a good second-line antidepressant option and shows promise, pending additional long-term data, to become a first-line antidepressant option.     

Anti-emetic Effect of Mosapride Citrate Hydrate,a 5-HT4 Receptor Agonist,on Selective Serotonin Reuptake Inhibitors (SSRIs)-Induced Emesis in Experimental Animals

Although selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression, they frequently cause gastrointestinal adverse effects, such as nausea and emesis. In the present study, we investigated the anti-emetic effect of mosapride, a 5-HT₄ receptor agonist, on SSRIs-induced emesis in Suncus murinus and dogs. We also examined the effect of mosapride on SSRIs-induced delay in gastric emptying and increase in gastric vagal afferent activity in rats. Oral administration of paroxetine, but not its subcutaneous administration, dose-dependently caused emesis in both animals. Mosapride inhibited paroxetine-induced emesis in Suncus murinus and dogs with ID₅₀ values of 7.9 and 1.1 mg/kg, respectively. The anti-emetic effect of mosapride was partially inhibited by SB207266, a selective 5-HT₄ antagonist. Intragastric administration of paroxetine increased gastric vagal afferent discharge in anesthetized rats. Mosapride failed to suppress this increase. On the other hands, mosapride improved the delay in gastric emptying caused by paroxetine in rats. We have shown in this study that oral administration of SSRIs causes emesis and activates gastric vagal afferent activity in experimental animals and that mosapride inhibits SSRIs-induced emesis, probably via improvement of SSRIs-induced delay in gastric emptying. These findings highlight the promising potential of mosapride as an anti-emetic agent.     

Combining Structure‐Based Pharmacophore and In Silico Approaches to Discover Novel Selective Serotonin Reuptake Inhibitors

Inhibition of human serotonin transporter (hSERT) has been reported to be a potent strategy for the treatment for depression. To discover novel selective serotonin reuptake inhibitors (SSRIs), a structure‐based pharmacophore model (SBPM) was developed using the docked conformations of six highly active SSRIs. The best SBPM, consisting of four chemical features: two ring aromatics (RAs), one hydrophobic (HY), and one positive ionizable (PI), was further validated using Gunner‐Henry (GH) scoring and receiver operating characteristic (ROC) curve methods. This well‐validated SBPM was then used as a 3D‐query in virtual screening to identify potential hits from National Cancer Institute (NCI) database. These hits were subsequently filtered by absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction and molecular docking, and their binding stabilities were validated by 20‐ns MD simulations. Finally, only two compounds (NSC175176 and NSC705841) were identified as potential leads, which exhibited higher binding affinities in comparison with the paroxetine. Our results also suggest that cation–π interaction plays a crucial role in stabilizing the hSERT‐inhibitor complex. To our knowledge, the present work is the first structure‐based virtual screening study for new SSRI discovery, which should be a useful guide for the rapid identification of novel therapeutic agents from chemical database.     

暴露反应阻止对5-羟色胺再摄取抑制剂抵抗强迫症患者疗效的影响

目的：了解暴露反应阻止疗法对5‐羟色胺再摄取抑制剂治疗无效强迫症患者临床疗效的影响。方法对36例5‐羟色胺再摄取抑制剂治疗无效的强迫症患者予以暴露反应阻止疗法治疗,观察15周。于治疗前后采用 Yale‐Brow n强迫症状量表及症状自评量表评定临床疗效。结果治疗15周末,本组患者总有效率为72．2％,Yale‐Brow n强迫症状量表总分及强迫思维、强迫行为因子分和症状自评量表总均分及各因子分均较治疗前显著降低（P＜0．01）。结论暴露反应阻止疗法对5‐羟色胺再摄取抑制剂治疗无效的强迫症患者临床疗效显著,且能显著改善患者的精神状况,值得临床推广应用。