Block of Persistent Late Na+ Currents by Antidepressant Sertraline and Paroxetine

Antidepressants, such as traditional tricyclic antidepressants (TCAs), are the first-line treatment for various pain syndromes. Available evidence indicates that TCAs may target Na⁺ channels for their analgesic action. In this report, we examined the effects of contemporary antidepressants sertraline and paroxetine on (1) neuronal Na⁺ channels expressed in GH₃ cells and (2) muscle rNav1.4 Na⁺ channels heterologously expressed in Hek293t cells. Our results showed that both antidepressants blocked Na⁺ channels in a highly state-dependent manner. The 50% inhibitory concentrations (IC₅₀) for sertraline and paroxetine ranged ∼18–28 μm for resting block and ∼2–8 μm for inactivated block of neuronal and rNav1.4 Na⁺ channels. Surprisingly, the IC₅₀ values for both drugs were about 0.6–0.7 μm for the open channel block of persistent late Na⁺ currents generated through inactivation-deficient rNav1.4 mutant Na⁺ channels. For comparison, the open channel block in neuronal hNav1.7 counterparts yielded IC₅₀ values around 0.3–0.4 μm for both drugs. Receptor mapping using fast inactivation-deficient rNav1.4-F1579A/K mutants with reduced affinities toward local anesthetics (LAs) and TCAs indicated that the F1579 residue is not involved in the binding of sertraline and paroxetine. Thus, sertraline and paroxetine are potent open channel blockers that target persistent late Na⁺ currents preferentially, but their block is not mediated via the phenylalanine residue at the known LA/TCA receptor site.     

布拉酵母联合舍曲林治疗产后抑郁症的疗效观察

目的探讨布拉酵母菌联合舍曲林对产后抑郁症(PPD)的临床疗效及安全性。方法选择2016年1月至2018年12月我院104例PPD患者为研究对象。入选患者随机分为观察组和对照组各52例,两组患者均给予舍曲林50 mg/次,1次/d,口服。观察组患者同时联用布拉酵母0.5 g/次,2次/d,口服,8周为一疗程。治疗前后检测患者孕酮及雌二醇水平,并于治疗前及治疗第4周、第8周时采用汉密顿抑郁量表(HAMD)评价患者治疗结果、临床疗效及安全性。结果治疗后,两组患者HAMD评分与治疗前比较均降低(t=8.162,P0.001;t=17.916,P0.001;t=16.995,P0.001;t=28.683,P0.001),且观察组患者降低幅度大于对照组(t=7.741,P0.001;t=13.073,P0.001)。观察组患者临床总有效率(90.38%)明显高于对照组(69.23%)。治疗后观察组患者孕酮水平低于对照组,雌二醇水平高于对照组,差异均有统计学意义(t=10.774,P0.001;t=7.239,P0.001)。两组母婴无明显不良反应。结论布拉酵母联合舍曲林对产后抑郁症的临床疗效明显,安全性高,值得临床推广。     

阿戈美拉汀联合舍曲林治疗抑郁症伴失眠的疗效及对睡眠质量评分、多导睡眠监测参数和血清神经递质的影响

摘要 目的：观察阿戈美拉汀联合舍曲林治疗抑郁症伴失眠的疗效及对睡眠质量评分、多导睡眠（PSG）监测参数和血清神经递质的影响。方法：选取2020年4月~2021年12月期间来贵州省第二人民医院就诊的80例抑郁症伴失眠患者作为观察对象,采用随机数字表法分为实验组和对照组各40例,对照组患者接受舍曲林治疗,实验组患者接受阿戈美拉汀联合舍曲林治疗,对比两组疗效、匹兹堡睡眠质量指数（PQSI）评分、PSG相关指标参数、汉密尔顿抑郁量表（HAMD）评分、血清神经递质水平变化,记录两组治疗期间不良反应发生情况。结果：实验组的临床总有效率为90.00%（36/40）,高于对照组的67.50%（27/40）,差异有统计学意义（P<0.05）。两组治疗8周后PSQI、HAMD评分均下降,且实验组的变化程度大于对照组（P<0.05）。两组治疗8周后睡眠总时间（TST）、睡眠效率（SE）、非快速眼动睡眠阶段3+4的百分比（SWS）、快速眼动睡眠阶段睡眠时间（RT）增加,非快速眼动睡眠阶段1的百分比（S1）、非快速眼动睡眠阶段2的百分比（S2）减少,且实验组的变化程度大于对照组（P<0.05）。两组治疗8周后去甲肾上腺素（NE）、5-羟色胺（5-HT）水平均升高,且实验组的升高程度大于对照组（P<0.05）。两组不良反应发生率组间对比未见差异（P>0.05）。结论：阿戈美拉汀联合舍曲林治疗抑郁症伴失眠,可有效改善抑郁和失眠症状,同时还可调节血清神经递质水平,是一个较为安全可靠的治疗方案。     

舍曲林辅助治疗对抑郁症合并冠心病患者血清炎症 因子水平及预后的影响

目的：探讨舍曲林辅助治疗对抑郁症合并冠心病患者血清炎症因子水平及预后的影响。方法：选择2009 年8 月～2011 年8 月我院收治的86 例抑郁症合并冠心病患者,将其随机分入对照组与观察组,40 例对照组患者接受冠心病常规治疗,46 例观察组 患者在常规治疗基础上给予舍曲林口服,每次50～100 mg,每日1 次,疗程24 周。比较两组治疗期间心血管事件发生率、治疗前 后汉密尔顿抑郁量表(HAMD)评分及血清炎症因子超敏C- 反应蛋白（hs-CRP）、肿瘤坏死因子-alpha（TNF-alpha）及白介素-6（IL-6）的变 化。结果：观察组心血管不良事件发生率显著低于对照组(13.0 %vs 32.5%,P<0.05);观察组治疗后HAMD 评分、血清hs-CRP、 TNF-alpha及IL-6 水平显著均显著低于对照组(P<0.05)。结论：舍曲林辅助治疗可显著改善抑郁症合并冠心病患者的抑郁状态,降低 炎症因子水平并改善其预后。     

Bioreduction of aromatic ketones: preparation of chiral benzyl alcohols in both enantiomeric forms

Substituted phenacyl chlorides are reduced with whole-cell biocatalysts to give (R)- or (S)-chlorohydrines in high yields and to make them good for high enantiomeric excess. Yields and enantiomeric purity of the S-enantiomer could be increased by performing bioreduction in the presence of polymeric absorbing resins. With this methodology, 2-chloro-1(S)-(3,4-dichloro-phenyl)-ethanol of 98% e.e. and 2-(R)-(4-nitro-phenyl)-ethanol of 92% e.e. have been prepared and used respectively as precursors in the synthesis of (+)-cis-1(S),4(S)-sertraline and of the β-blocker (R)-nifenalol®.     

柴桂温胆定志汤联合舍曲林对抑郁症患者血清单胺类神经递质和外周血单个核细胞PI3K/Akt信号通路的影响

摘要 目的：观察柴桂温胆定志汤联合舍曲林对抑郁症患者血清单胺类神经递质和外周血单个核细胞磷脂酰肌醇3激酶（PI3K）/蛋白激酶 B（Akt）信号通路的影响。方法：选择2018年10月~2020年6月期间北京市昌平区中西医结合医院收治的抑郁症患者128例,将患者根据信封抽签法分为对照组和实验组,各为64例。对照组患者接受舍曲林治疗,实验组患者接受柴桂温胆定志汤联合舍曲林治疗,观察治疗4周后两组疗效、各量表评分、血清单胺类神经递质和外周血单个核细胞PI3K/Akt信号通路情况,记录两组用药期间不良反应发生情况。结果：实验组的临床总有效率较对照组高（P<0.05）。治疗后,两组生活质量综合评定问卷（GQOLI-74）评分较治疗前升高,且实验组高于对照组（P<0.05）。治疗后,两组匹兹堡睡眠质量指数（PSQI）、汉密尔顿抑郁量表（HAMD）评分较治疗前降低,且实验组低于对照组（P<0.05）。治疗后,两组血清去甲肾上腺素（NE）、5-羟色胺（5-HT）、多巴胺（DA）水平较治疗前升高,且实验组高于对照组（P<0.05）。治疗后,两组PI3K蛋白、Akt蛋白、白介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）水平较治疗前降低,且实验组低于对照组（P<0.05）。两组不良反应发生率对比无统计学差异（P>0.05）。结论：柴桂温胆定志汤联合舍曲林治疗抑郁症疗效显著,可改善患者睡眠情况,提高生活质量,调节血清单胺类神经递质水平,作用机制可能与调节PI3K/Akt信号通路有关。     

High-performance liquid chromatographic method to screen and quantitate seven selective serotonin reuptake inhibitors in human serum

A high-performance liquid chromatographic screening method (HPLC) is described for the determination of seven selective serotonin reuptake inhibitors (SSRIs) (fluvoxamine, milnacipran, paroxetine, sertraline, fluoxetine, citalopram, venlafaxine) and for three pharmacologically active N-demethylated metabolites (desmethylcitalopram, didesmethylcitalopram and norfluoxetine). A tricyclic antidepressant, clomipramine, was used as an internal standard. The method consists of liquid extraction of serum after alcalinisation at pH 9.50, followed by chromatography on a Beckman C₁₈ reversed-phase column. Compounds were detected at 200.4 nm. The standard curves were linear over a working range of 50–1000 ng/ml for fluvoxamine, 15–1000 ng/ml for fluoxetine, 25–500 ng/ml for norfluoxetine, 50–500 ng/ml for sertraline, 20–500 ng/ml for paroxetine, 25–550 ng/ml for citalopram, 25–750 ng/ml for desmethylcitalopram, 25–800 ng/ml for didesmethylcitalopram, 25–650 ng/ml for milnacipran, and 25–500 ng/ml for venlafaxine. The quantitation limits of the method were 15 ng/ml for fluoxetine, 20 ng/ml for paroxetine, 25 ng/ml for venlafaxine, norfluoxetine and citalopram, and its metabolites, 40 ng/ml for sertraline and 50 ng/ml for fluvoxamine. No interferences were noted with this sensitive and specific method which can be used for therapeutic drug monitoring.     

舍曲林联合经颅磁刺激对青少年首发抑郁症认知功能的影响

目的:探讨舍曲林联合经颅磁刺激(TMS)对青少年首发抑郁症认知功能的影响。方法:选取2018年10月~2020年2月我院青少年首发抑郁症患者94例作为研究对象,简单随机化分为2组,各47例。对照组予以舍曲林治疗,观察组予以TMS联合舍曲林治疗,2组均连续治疗6周。比较2组疗效、不良反应发生率、随访12个月复发率及治疗前后血清微小核糖核酸(miR)-18a、miR-124水平、汉密尔顿抑郁量表(HAMD-17)评分、重复性成套神经心理状态测试(RBANS)中文版评分。结果:观察组总有效率(93.62%)高于对照组(78.72%),差异有统计学意义(P<0.05)。治疗3、6周后观察组血清miR-18a、miR-124水平低于对照组(P<0.05)。治疗3、6周后观察组焦虑/躯体化、睡眠障碍、抑郁迟滞及认知障碍评分低于对照组(P<0.05)。治疗3、6周后观察组即刻记忆、言语功能、视觉广度、注意力及延时记忆评分高于对照组(P<0.05)。2组不良反应发生率比较,差异无统计学意义(P>0.05)。观察组随访12个月复发率低于对照组(P<0.05)。结论:舍曲林联合TMS首次治疗青少年首发抑郁症,效果显著,能有效调节血清miR-18a、miR-124水平,减轻抑郁症状,从而提高认知功能,降低复发率,保证安全性。     

文拉法辛与舍曲林治疗老年性抑郁症的效果及对认知功能的影响

目的:探讨文拉法辛与舍曲林治疗老年性抑郁症的效果及对认知功能的影响。方法:收集我院2012年6月到2014年1月收治的老年性抑郁症患者80例,按照随机数字表法分为观察组和对照组,每组40例,观察组给予盐酸文拉法辛胶囊、对照组给予舍曲林治疗。应用相应量表评价两组患者抑郁症和认知功能变化情况,并记录不良事件发生率。结果:观察组治疗有效率为90.0%,对照组为82.5%,差异无统计学意义(P0.05),治疗后观察组HAMD评分优于对照组,差异具有统计学意义(P0.05),两组治疗后与治疗前相比差异均具有显著统计学意义(P0.05)。治疗前Ra、Cc、Rc、Re、Rf、Rpe、n Rpe指标在两组间差异无统计学意义(P0.05),治疗后观察组优于对照组,差异有统计学意义(P0.05);治疗后两组不良事件发生率差异无统计学意义(P0.05),且经过对症处理均好转。结论:文拉法辛与舍曲林对老年患者抑郁症症状和认知功能改善均有一定的效果,但文拉法辛的治疗效果较舍曲林好,并且安全可靠,临床可以优先选择文拉法辛治疗。     

Antidepressants noncompetitively inhibit nicotinic acetylcholine receptor function

Nicotinic acetylcholine receptors (nAChRs) are diverse members of the neurotransmitter-gated ion channel superfamily and play critical roles in chemical signaling throughout the nervous system. The present study establishes for the first time the acute functional effects of sertraline (Zoloft), paroxetine (Paxil), nefazodone (Serzone), and venlafaxine (Effexor) on two human and one chick nAChR subtype. This study also confirms previous findings of nAChR functional block by fluoxetine (Prozac). Function of human muscle-type nAChR (alpha1/beta gammadelta) in TE671/RD cells, human autonomic nAChR (alpha3/beta4alpha5 +/- beta2) in SH-SY5Y neuroblastoma cells, or chick V274T mutant alpha7-nAChR heterologously expressed in native nAChR-null SH-EP1 epithelial cells was measured using 86Rb+ efflux assays. Functional blockade of human muscle-type and autonomic nAChRs is produced by each of the drugs in the low to intermediate micromolar range, and functional blockade of chick V274T-alpha7-nAChR is produced in the intermediate to high micromolar range. Functional blockade is insurmountable by increasing agonist concentrations at each nAChR subtype tested for each of these drugs, suggesting noncompetitive inhibition of nAChR function. These studies open the possibilities that nAChR subtypes in the brain could be targets for therapeutic antidepressants and could play roles in clinical depression.