The serotonin transporter polymorphism, 5HTTLPR,is associated with a faster response time to sertraline in an elderly population with major depressive disorder

Rationale A common polymorphism (5HTTLPR) within the promoter region of the serotonin transporter gene (LSC6A4) has been shown to influence response time as well as overall response to selective serotonin reuptake inhibitors (SSRIs) in subjects with major depressive disorder. We hypothesized that a similar effect in response time to sertraline would be observed and that no effect on response time would be seen in a placebo arm.Objectives We tested the hypothesis that subjects homozygous for the long allele at the 5HTTLPR polymorphism would respond more rapidly to sertraline than subjects carrying one or two copies of the short allele.Methods HAM-D and CGI-I responses to sertraline and placebo were measured weekly in the context of an 8-week, placebo-controlled study in elderly depressed subjects. Genotyping of the 5HTTLPR polymorphism was performed to test for correlations with response at each week in the sertraline and placebo groups (n=206).Results Subjects homozygous for the long allele of 5HTTLPR showed a significant increase in response at week 1 and week 2, as assessed by the CGI-I scale compared with subjects carrying one or two copies of the short allele (P=0.01 at both weeks). No significant difference was observed in the placebo group.Conclusions These results suggest that genetic variation in the serotonin transporter gene effects the response time to sertraline and provides complementing evidence to previous reports that this polymorphism affects response time to other SSRIs.     

Effects of serotonergic and noradrenergic antidepressants on auditory startle response in patients with major depression

Rationale Amplitude, habituation and prepulse inhibition (PPI) of the acoustic startle response (ASR) in rodents and humans are sensitive to psychotropic drugs. Studies with rodents suggest that an increase or decrease in serotonin level in the brain alters several modalities of the ASR. So far, little is known about serotonergic and noradrenergic startle modulation in humans.Objective This study was designed to investigate the effects of the selective serotonin uptake inhibitor sertraline versus the selective noradrenalin uptake inhibitor reboxetine on magnitude, habituation and PPI of ASR in patients with major depression.Methods We studied ASR in 23 patients with the diagnosis of major depression according to DSM-IV who were randomly treated either with sertraline or with reboxetine. Initially, ASR assessment was carried out when patients were drug-free for at least 2 weeks and again after 14 days of treatment.Results The habituation of ASR was strongly attenuated by sertraline and not significantly altered by reboxetine. None of the substances altered the startle reactivity. In addition, PPI was not altered by sertraline, but reboxetine tended to decrease PPI. The startle reactivity at baseline was correlated with improvement of depressive symptoms at the end of the study.Conclusion These results provide the first evidence for different effects of noradrenergic and serotonergic antidepressants on the startle response in depressed patients.     

Sex differences in the pituitary-adrenal response following acute antidepressant treatment in sheep

Rationale Depression is more prevalent in women than in men, and therapeutic responses may also differ between the sexes. In addition, abnormal regulation of the hypothalamic-pituitary-adrenal (HPA) axis is more common in depressed women.Objectives To further examine these phenomena, the present study was designed to investigate whether sex differences exist in the HPA axis responses of male and female sheep following acute antidepressant administration.Methods Two commonly prescribed antidepressants, imipramine (a tricyclic antidepressant, TCA; 2.0 and 5.0 mg/kg) and sertraline (a selective serotonin reuptake inhibitor, SSRI; 0.5, 2.0 and 5.0 mg/kg) were administered to gonadectomized male and female sheep via acute subcutaneous injection. Treatment order was randomized. Jugular blood was sampled for the measurement of prolactin, adrenocorticotropin (ACTH), and cortisol by radioimmunoassay.Results Treatment with sertraline resulted in a comparable increase in prolactin secretion in male and female sheep. However, sertraline stimulated ACTH and cortisol secretion in females but not in males, a sexually dimorphic effect that was independent of circulating sex steroids. Treatment with imipramine had no effect on prolactin, ACTH or cortisol levels in male or female sheep.Conclusions These data suggest that the HPA axes of females are more sensitive to the stimulatory effects of serotonin following acute treatment with the SSRI, sertraline.Parts of this work were presented at the Fifth International Congress of Neuroendocrinology, Bristol, UK in September 2002, and at the annual meeting of the Endocrine Society of Australia, Adelaide, September, 2002.     

抑郁症3种药物治疗方案的成本-效果分析

目的:评价抑郁症3种药物治疗方案的成本-效果。方法:将我院120例门诊抑郁症患者分为A、B、C组,分别给予氯米帕明、帕罗西汀、舍曲林后观察疗效,并运用成本-效果法进行分析。结果:3组成本分别为702、1008、765元,有效率分别为77%、82%、90%(P>0.05),成本-效果比分别为9.12、12.29、8.50。结论:C组方案治疗抑郁症成本-效果比更优。     

盐酸舍曲林胶囊的生物等效性评价

 目的研究盐酸舍曲林胶囊的人体相对生物利用度和生物等效性。方法 健康志愿者18名,随机双交叉单剂量po盐 酸舍曲林胶囊(受试制剂)和盐酸舍曲林片(参比制剂),剂量均为100 mg,间隔为2周。分别于服药后120 h内多点抽取静脉 血;用高效液相色谱法测定血浆中舍曲林的质量浓度。用3P97药动学程序计算相对生物利用度并评价两者的生物等效性。 AUC0～120,AUC0-inf和ρ_max经方差分析和双单侧t检验,t_max进行秩和检验。结果 单剂量po受试制剂和参比制剂后血浆中的 舍曲林的ρ_max分别为(42．1±8．4)和(41．2±6．5)μg·L^-1;t_max分别为(5．1±1．0)和(4．6±1．0)h;AUC_0～120分别为(1 549．6± 315．0)和(1 474．0±299．562)μg·h·L^-1;AUC_0～inf分别为(1 710．0±322．6)和(1 639．6±314．5)μg·h·L^-1。ρ_max的90％可信区间为 95．6％～107．5％,AUC0～120的90％可信区间为96．2％～114．6％,AUC0～inf的90％可信区间为96．4％～112．9％。结论 两者的 人体相对生物利用度为(107．2±22．5)％,两者具有生物学等效性。     

舍曲林治疗强迫症20例临床分析

目的 探讨舍曲林对强迫症的疗效。方法 应用舍曲林治疗强迫症20例，采用Yale-Brown强迫量表进行评定，并进行临床疗效评定。结果 治疗后Yale-Brown强迫量表评分显著下降，临床疗效评定显示痊愈7例，显著进步7例，进步3例。无效3例。副反应轻微。结论 舍曲林治疗强迫症疗效较好。     

盐酸舍曲林与阿米替林治疗抑郁症的临床对照研究

目的:比较盐酸舍曲林与阿米替林治疗抑郁症的临床疗效和安全性。方法:将52例符合CCMD-3抑郁症诊断标准的抑郁症患者随机分为两组,分别给予盐酸舍曲林和阿米替林治疗,于治疗前和治疗后1,2,4,6周末分别采用汉密尔顿抑郁量表、临床疗效总体评定量表及不良反应量表评定。结果:盐酸舍曲林与阿米替林总体疗效相似,两组比较无显著性差异(P>0.05)。盐酸舍曲林组治疗第2周就起效,两组治疗前与治疗后比较HAMD量表均有显著性差异(P<0.01),两组之间比较无显著性差异(P>0.05),盐酸舍曲林组的不良反应少于阿米替林组。结论:盐酸舍曲林是一种安全有效的新一代抗抑郁药物,适合伴有失眠症状的抑郁患者使用。     

Rapid and simple methods for quantitative analysis of some antidepressant in pharmaceutical formulations by using first derivative spectrophotometry and HPLC

Two rapid, simple and accurate first derivative spectrophotometry and HPLC method for the determination of nefazodone hydrochloride and sertraline hydrochloride in pharmaceutical formulations are discussed. The first one is a derivative spectrophotometric procedure and the second one is based on a HPLC method with a UV detector. In the first method, first derivative spectrophotometry, nefazodone hydrochloride or sertraline hydrochloride by measurement of their first derivative signals at 241.8-256.7 nm (peak-to-peak amplitude), or 271.6-275.5 nm (peak-to-peak amplitude), respectively. Calibration graphs were established for 10.0-42.0 microg ml(-1) nefazodone hydrochloride, or 8.0-46.0 microg ml(-1) sertraline hydrochloride. In the other method, HPLC, the UV detection was carried out at 265.0 nm (nefazodone hydrochloride) and 270.0 nm (sertraline hydrochloride). The samples were chromatographed on a Supercosil RP-18 column. The mobile phases were methanol:acetonitrile:phosphate buffer at pH 5.5 (10:50:40 v/v/v) (nefazodone hydrochloride) and methanol:phosphate buffer at pH 4.5 (20:80 v/v) (sertraline hydrochloride). The results obtained from first derivative spectrophotometric method were comparable with those obtained by using HPLC. It was concluded that both the developed methods are equally accurate, sensitive, and precision could be applied directly and easily to the pharmaceutical formulations of nefazodone hydrochloride and sertraline hydrochloride, respectively.     

Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype

BACKGROUND: Characteristic behaviors of some alcohol-dependent individuals, e.g., binge drinking, comorbid psychopathology, and some types of alcohol-related problems, have been linked to abnormalities in serotonergic neurotransmission. However, studies that have evaluated serotonergic pharmacotherapy for reducing drinking have yielded conflicting results. One explanation for these findings is a general failure to distinguish alcohol subgroups that may be differentiated on the basis of serotonergic abnormalities. However, in 1996, Kranzler and colleagues reported that Type B alcoholics, who are characterized by high levels of premorbid vulnerability, alcohol dependence severity, and comorbid psychopathology, showed less favorable drinking outcomes in response to treatment with fluoxetine, a serotonin reuptake inhibitor, than with placebo. This medication effect was not seen in Type A alcoholics, i.e., those with lower risk/severity of alcoholism and psychopathology. The aim of the present study was to explore the validity of differential responding by alcohol-dependent subtypes using the serotonin reuptake inhibitor, sertraline. METHODS: A k-means clustering procedure was applied to a sample of alcohol-dependent subjects enrolled in a 14-week, placebo-controlled trial of 200 mg/day of sertraline, classifying them into lower-risk/severity (Type A: n = 55) and higher-risk/severity (Type B: n = 45) subgroups. RESULTS: A significant interaction between alcoholic subtype and medication condition was found, confirming the findings of Kranzler and colleagues that alcoholic subtypes responded differentially to serotonergic medication. Somewhat at variance with their results, however, the present study showed that the lower risk/severity (Type A) subjects had more favorable outcomes when treated with sertraline compared to placebo. CONCLUSIONS: Alcoholic subtypes differentially responded to sertraline when used as a treatment to reduce alcohol drinking, with one subtype having more favorable outcomes. Subtyping alcoholics may help to resolve conflicting findings in the literature on serotonergic treatment of alcohol dependence.     

Preference for a cocaine-associated environment is attenuated by augmented accumbal serotonin in cocaine withdrawn rats

RATIONALE: Recent studies have found decreased serotonin (5-HT) transmission within the nucleus accumbens following withdrawal from chronic cocaine. OBJECTIVE: We sought to investigate whether increasing brain 5-HT levels would decrease behavioral responses that occur following cocaine withdrawal, namely increased preference for a cocaine environment and anxiety. METHODS: The conditioned place preference and the defensive burying paradigms were used to measure the behavioral responses that occur 1 week following cocaine withdrawal. RESULTS: We show that pharmacological agents that increase 5-HT transmission (sertraline or 5-hydoxytryptophan, 5-HTP) abolish the preference of subchronically cocaine-treated, abstinent rats for a cocaine-associated environment. Similar results were seen when sertraline was microinjected into the nucleus accumbens. Conversely, rats acutely conditioned with cocaine showed an increased preference for a cocaine-associated environment when pretreated with these drugs. Sertraline also decreased the heightened anxiety-like behaviors found in subchronically treated cocaine rats. CONCLUSIONS: These results indicate that drugs that augment 5-HT function may reduce the desire for cocaine following cocaine withdrawal, and thus facilitate cocaine abstinence in dependent subjects.