氟伏沙明在小鼠体内抗抑郁作用的时辰药理学及其机制研究

目的:研究氟伏沙明在小鼠体内抗抑郁作用的时辰药理学及其可能机制。方法:以生理盐水为对照组,考察相邻2天的9:00、13:00、17:00、21:00、1:00、5:00共6个时间点注射氟伏沙明(30mg.kg-1)对小鼠在水中5min内的不动累积时间的影响,和同日内明、暗期(9:00、21:00)注射氟伏沙明对小鼠在暗箱中10min自发性活动(运动距离、运动时间、静止时间)的影响;另外还检测正常小鼠同日内明、暗期(9:00、21:00)脑组织中5羟色胺(5-HT)转运体(SERT)mRNA表达、5-HT再摄取浓度、sigma-1受体的变化。结果:与对照组比较,氟伏沙明能显著缩短小鼠的不动累积时间(P<0.01),其中21:00组不动累积时间最低,但不影响小鼠自发性活动;与明期(9:00)组比较,正常小鼠暗期(21:00)组脑组织中SERTmRNA表达和5-HT再摄取浓度及sigma-1受体的表达均明显升高(P<0.05)。结论:氟伏沙明在小鼠体内的抑郁作用具有昼夜节律性,该作用可能与中脑SERTmRNA的表达、sigma-1受体表达的昼夜节律变化相关。     

CLOCK may Predict the Response to Fluvoxamine Treatment in Japanese Major Depressive Disorder Patients

Recent studies have shown that selective serotonin reuptake inhibitors (SSRIs) have circadian properties, suggesting that the antidepressive action of SSRIs may also be attributable to circadian mechanisms. Another study reported an association between clock gene (CLOCK) and improvements in insomnia symptoms from SSRIs treatment. Therefore, we examined the association between CLOCK and the efficacy of fluvoxamine treatment in 121 patients with Japanese major depressive disorder (MDD). The MDD patients in this study had scores of 12 or higher on the 17 items of the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D). We defined a therapeutic response as a decrease of more than a 50% in baseline SIGH-D within 8 weeks, and clinical remission as a SIGH-D score of less than seven at 8 weeks. We selected three tagging SNPs in CLOCK for the subsequent statistical association analysis. We detected a significant association between rs3736544, a synonymous polymorphism in exon 20, and the fluvoxamine therapeutic response in MDD in the allele/genotype-wise analyses. In addition, remission with fluvoxamine was also significantly associated with rs3736544. These associations remained significant after Bonferroni correction. Moreover, haplotype analysis findings supported these significant associations, which appeared to be due mainly to rs3736544, in the fluvoxamine therapeutic remission. Our results indicate that CLOCK genotype may be a predictor of fluvoxamine treatment response in Japanese MDD. However, our sample size was small, and a replication study using larger samples may be required for conclusive results. Taro Kishi and Tsuyoshi Kitajima contributed equally to this work.     

氟伏沙明对社交恐惧症患者情绪图片信息认知偏倚的影响

目的 探讨氟伏沙明对社交恐惧症患者情绪图片信息认知偏倚的影响.方法 选择符合CCMD-3社交恐惧症诊断标准的26例患者作为实验组,与实验组性别、年龄匹配的26例健康人作为对照组.实验组予氟伏沙明治疗8周.两组分别在治疗前以及8周后予情绪图片刺激的点探测任务检测,比较治疗前以及8周后反应时以及注意偏向分差别.结果 实验组8周后HAMA明显低于治疗前(P＜0.05).重复测量ANOVA显示,探测位置主效应显著,异侧位置的反应时长于同侧位置(P＜0.05);情绪面孔图片类型与组间水平交互作用显著(P＜0.05);探测位置与组间水平交互作用显著(P＜0.05);情绪面孔图片类型与探测位置交互作用显著(P＜0.05);情绪面孔图片类型×探测位置×组间水平交互作用显著(P＜0.05),1sD比较显示实验组对恐惧面孔图片异侧位置的反应时长于同侧位置(P＜0.05).实验组治疗8周后对恐惧面孔图片反应时以及注意偏向分明显低于治疗前(均P＜ 0.05).结论 社交恐惧症患者对恐惧面孔图片信息表现出认知偏倚,氟伏沙明具有改善认知偏倚的作用.     

氟伏沙明治疗焦虑症、抑郁症的临床疗效比较

目的：了解氟伏沙明治疗焦虑及抑郁症的疗效。方法：对符合CCMD－Ⅱ－R诊断标准的52例焦虑症和55例抑郁症患者进行氟伏沙明6周开放性治疗，剂量50-150mg/d，治疗前后予HAMD、HAMA评定，并观察副反应。结论：氟伏沙明治疗焦虑症、抑郁症同样有效，6周总有效率，焦虑症74％（37例），抑郁症73％（39例）。两组间总疗效无显著差异（P＞0．05）。结论：氟伏沙明治疗焦虑症与抑郁症一样有效，可视为一种抗焦虑症的有效药物，而且副作用轻。     

氟伏沙明合并利培酮治疗抑郁症的对照研究

目的比较氟伏沙明合并利培酮及单用氟伏沙明两者在治疗抑郁症方面的疗效及安全性。方法将门诊66例抑郁症患者随机分为研究组（氟伏沙明合并利培酮治疗）和对照组（单用氟伏沙明治疗）。疗程6周。在治疗前及治疗第1、2、4、6周末用HAMD量表评定临床疗效，用TESS量表评定药物不良反应，并进行比较分析。结果在治疗第6周末研究组显效率为66.7%，总有效率为87.9%；对照组分别为63.6%和84.8%。两组显效率和总有效率相近。差异均无显著性（P〉0.05）。但研究组较对照组起效快，在对焦虑、躯体化、认知障碍和睡眠障碍的改善上研究组优于对照组。两组不良反应接近。结论氟伏沙明合并利培酮治疗抑郁症疗效肯定，不良反应少。     

氟伏沙明合并氯氮平治疗强迫症的疗效比较

目的探讨氟伏沙明合并氯氮平治疗强迫症的疗效。方法45例强迫症患者随机分为氟伏沙明合并氯氮平治疗组和单独氟伏沙明治疗组。疗程8周。采用强迫症量表（Y—BOCS）、汉密尔顿焦虑量表（HAMA）、汉密尔顿抑郁量表（HAMD）评定疗效。结果治疗结束时两组Y—BOCS、HAMA、HAMD的评分均显著降低，更以合并氯氮平组明显。结论氟伏沙明合并氯氮平治疗强迫症可以增加疗效。     

利培酮联用氟伏沙明治疗Ⅱ型精神分裂症的效果观察

目的：评价利培酮联合氟伏沙明治疗Ⅱ型精神分裂症的效果。方法选择2011年8月～2013年12月入住江西省宜春市第三人民医院的Ⅱ型精神分裂症患者90例,随机分为研究组和对照组各45例,研究组采用利培酮联用氟伏沙明治疗,对照组单用利培酮治疗,于治疗前及治疗4、8、12周末采用阳性与阴性症状量表（PANSS）、临床疗效总评量表、日常生活能力评定量表评定疗效,采用副反应量表（TESS）在治疗后4、8、12周末评定不良反应。结果治疗第8周末起,两组PANSS总分及各因子分均较治疗前明显下降（P＜0.05或P＜0.01）;治疗12周末,研究组阴性症状分较对照组下降更显著（P＜0.01）。研究组治愈率显著高于对照组（P＜0.05）,日常生活能力总分低于对照组（P＜0.05）。两组不良反应发生率均较低,且程度较轻。结论利培酮联用氟伏沙明治疗Ⅱ型精神分裂症效果显著,优于单用利培酮治疗,安全性高。     

Effect of co-administered inducer or inhibitor on omeprazole pharmacokinetics based on CYP2C19 genotype

Polymorphisms of cytochrome P450 (CYP) enzymes can affect enzymatic activity, drug metabolism and drug interactions. Although the potential for drug interactions is especially important when co-administering drugs with strong inductive or inhibitory potential towards drug-metabolizing enzymes, the relationship between CYP genotypes and the extent of the inductive or inhibitory effects remain poorly understood. We investigated the effects of rifampicin (inductive) and fluvoxamine (inhibitory) on metabolism of omeprazole and CYP2C19 enzymatic activity in 19 healthy Japanese subjects. Pharmacokinetic analyses of the CYP2C19 probe drug, omeprazole, were performed before and after rifampicin or fluvoxamine administration. The allele frequencies of the CYP2C19*1, CYP2C19*2 and CYP2C19*3 genotypes were 65.8%, 26.3% and 7.9%, respectively. Subjects with the CYP2C19*1 allele displayed higher levels of omeprazole metabolism than those without the CYP2C19*1 allele. Rifampicin increased omeprazole metabolism in all subjects irrespective of genotype, which suggested that CYP2C19 enzymatic activity was induced by rifampicin administration for all genotypes. Conversely, while fluvoxamine reduced omeprazole metabolism in subjects carrying the CYP2C19*1 allele, it had no impact on omeprazole pharmacokinetics in subjects without this allele. The genotyping of CYP2C19 may be useful for predicting drug interactions with metabolic inhibitors.     

Benefical Effects of Sigma-1 Agonist Fluvoxamine for Tardive Dyskinesia and Tardive Akathisia in Patients with Schizophrenia: Report of Three Cases

Fluvoxamine is a selective serotonin reuptake inhibitor that is approved for psychiatric disorders such as major depressive episodes and obsessive-compulsive disorder. Beside inhibition of serotonin reuptake, fluvoxamine is also a potent agonist of endoplasmic reticulum (ER) protein sigma-1 receptors, which play a role in the pathophysiology of a number of psychiatric and neurodegenerative disorders. This report presents beneficial effects of sigma-1 agonist fluvoxamine on hyperkinetic movement disorders such as tardive dyskinesia and tardive akathisia. Fluvoxamine might be a novel treatmet approach in the treatment of hyperkinetic movement disorders.     

氟伏沙明治疗精神分裂症患者伴发强迫症状的对照研究

目的:探讨氟伏沙明对精神分裂症患者伴发强迫症状的疗效。方法:精神分裂症伴强迫症状患者60例,随机分为研究组(氟伏沙明合并奥氮平组)和对照组(奥氮平组)各30例。患者于治疗前及治疗后8周末应用阳性和阴性症状量表(PANSS)、耶鲁-布朗强迫症状量表(Y-BOCS)和副反应量表(TESS)评定疗效及不良反应。结果:治疗后,研究组患者较对照组PANSS、Y-BOCS评分下降更显著(P<0.01),TESS评分无显著差异(P>0.05)。结论:氟伏沙明结合抗精神病药物治疗较单用抗精神病药物治疗能提高伴发强迫症状的精神分裂症患者的疗效。