Acute selective serotonin reuptake inhibitors increase conditioned fear expression: blockade with a 5-HT(2C) receptor antagonist.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) effectively treat various anxiety disorders, although symptoms of anxiety are often exacerbated during early stages of treatment. We previously reported that acute treatment with the SSRI citalopram enhances the acquisition of auditory fear conditioning, which is consistent with the initial anxiogenic effects reported clinically. Here, we extend our findings by assessing the effects of acute SSRI treatment on the expression of previously acquired conditioned fear. METHODS: Rats underwent fear conditioning drug-free. Tone-evoked fear responses were tested after drug treatment the following day. This protocol more closely resembles the clinical setting than pre-conditioning treatment, because it evaluates effects of treatment on a pre-existing fear rather than on the formation of a new fear memory. RESULTS: A single pre-testing injection of the SSRIs citalopram or fluoxetine significantly increased fear expression. There was no effect of the antidepressant tianeptine or the norepinephrine reuptake inhibitor tomoxetine, indicating that this effect is specific to SSRIs. The SSRI-induced enhancement in fear expression was not blocked by tropisetron, a 5-HT(3) receptor antagonist, but was blocked by SB 242084, a specific 5-HT(2C) receptor antagonist. CONCLUSIONS: Enhanced activation of 5-HT(2C) receptors might be a mechanism for the anxiogenic effects of SSRIs observed initially during treatment.     

西酞普兰对戊四氮点燃癫痫大鼠行为学及海马5-HT能递质系统影响的在体微透析研究

为研究5-羟色胺(5-HT)能神经递质在癫痫形成过程中的变化及西酞普兰(CTP)对其的影响,本研究用CTP(1mg/kg.d灌胃)预干预1周后,对戊四氮(PTZ,30mg/kg.d,腹腔注射)点燃癫痫过程中的行为学及在不同时间点对大鼠海马进行微透析取样,经高效液相电化学检测技术在活体观察了30只自由活动大鼠5-HT及其代谢产物5-羟吲哚乙酸(5-HIAA)水平和5-HT转化率(5-HIAA/5-HT)的动态变化。结果显示:PTZ注射后在CTP组发作潜伏期延长,发作程度轻和点燃时间延长,发作死亡率降低。点燃早期,CTP组大鼠的海马5-HT水平升高,5-HT转化率降低,与对照组和PTZ组比较,有显著性差异(P<0.05);点燃晚期CTP组和PTZ组与对照组比较5-HT水平和5-HT转化率均显著降低(P<0.05)。本研究结果提示PTZ点燃过程中,早期CTP升高脑内5-HT水平,可能直接抑制了引起爆发放电的动作电位,而抑制发作;晚期脑内5-HT神经元丢失和受体减少,功能减退,而导致CTP的作用减退。     

Ro 11-2465 (cyan-imipramine), citalopram and their N-desmethyl metabolites: Effects on the uptake of 5-hydroxytryptamine and noradrenaline in vivo and related pharmacological activities

Ro 11-2465 (cianopramine, cyan-imipramine) and citalopram (CIT), putative antidepressant drugs, are very potent and selective 5-hydroxytryptamine (5-HT) uptake inhibitors in vitro. This study investigated the effects of these drugs and their desmethyl metabolites, Ro 12-5419 (desmethylcianopramine, cyan-desipramine) and desmethylcitalopram (DCIT), respectively, on the uptake of 5-HT and noradrenaline (NA) in vivo [protection against H 77/77 (4, alpha-dimethyl-metatyramine)-induced displacement of 5-HT and NA] and on related pharmacological activities. All the investigated drugs antagonized H 77/77-induced displacement of 5-HT in the rat brain, though the effects of the metabolites were considerably weaker than those of the parent compounds. The H 77/77-induced displacement of brain NA in rats and mice was antagonized only by Ro 12-5419 and Ro 11-2465. All the drugs potentiated the pressor response to 5-HT in pithed rats; however, Ro 12-5419 and particularly Ro 11-2465 could also block the response when used in higher doses (0.1 mg/kg). Only Ro 12-5419 and Ro 11-2465 were able to potentiate the pressor response to NA. Ro 12-5419 also potentiated thyrotropin releasing hormone (TRH) hyperthermia and antagonized reserpine hypothermia in mice; Ro 11-2465 potentiated the TRH hyperthermia only. CIT and DCIT were inactive in both these tests. Of all the four drugs only CIT and Ro 12-5419 considerably stimulated the hind limb flexor reflex in spinal rats. However, whereas the stimulatory effect of CIT was inhibited by the 5-HT antagonists metergoline and cyproheptadine, that of Ro 12-5419 was counteracted by the NA antagonist phenoxybenzamine only. Ro 11-2465, when used in low doses (ca. 1 mg/kg), slightly potentiated the flexor reflex, whereas in higher doses (4–16 mg/kg) it had no effect itself but antagonized the stimulatory action of the 5-HT agonists fenfluramine, quipazine and LSD. The results obtained indicate that Ro 11-2465 and CIT, as well as their desmethyl metabolites, are also potent 5-HT uptake inhibitors in vivo. However, only CIT and DCIT are concurrently devoid of effect on uptake of NA. In contrast, Ro 11-2465 and particularly Ro 12-5419 appear to also inhibit the uptake of NA. Moreover, Ro 11-2465 appears to block central and peripheral 5-HT receptors.The results were presented at the 14th CINP Congress, Florence, June 19–23, 1984     

HPLC-MS同时测定4种新型抗抑郁药物的血药浓度

目的:建立一种快速灵敏的同时测定血浆中氟西汀、西酞普兰,帕罗西汀及文拉法辛浓度的 HPLC-MS 方法,监测这4种药物的血药浓度,为临床用药提供依据。方法:以氟伏沙明作为内标,样品碱化后固相萃取,用 MACHEREY-NAGEL C_(18)反相色谱柱(4.6 mm×250 mm,5μm,Germany)进行分离,以乙腈-缓冲盐(30 mmol 醋酸铵和0.6‰甲酸)(65:35)为流动相,柱温40℃,流速0.85 mL·min~(-1)。采用质谱电喷雾电离源(ESI)将样品离子化,选择性离子监测(SIM)准分子离子峰。结果:氟西汀、西酞普兰、帕罗西汀,文拉法辛及内标氟伏沙明在9 min 内完全分离;各物质在5～1000 ng·mL~(-1)时线性关系良好,相关系数均大于0.9964;萃取回收率均大于73.2%;方法回收率均大于95.0%;最低检测浓度:氟西汀0.5 ng·mL~(-1)、西酞普兰0.3 ng·mL~(-1)、帕罗西汀0.3 ng·mL~(-1),文拉法辛0.1 ng·mL~(-1);日内日间变异系数均小于15%。结论:本方法简便快速,灵敏准确,可用于血药浓度的临床监护、中毒分析,药物动力学以及代谢机制的研究。     

人血浆中西酞普兰的HPLC-荧光法测定

建立了HPLC-荧光法测定人血浆中西酞普兰的浓度.血浆样品经液-液萃取后测定,用Zorbax SB C8色谱柱,磷酸二氢铵缓冲液(pH 3.5)-乙腈(65:35)为流动相,激发波长240 nm,发射波长302 nm.血浆中西酞普兰线性范围为1～100ng/ml,最低定量浓度为1ng/ml,日内、日间RSD均小于4.0%,方法平均回收率为93.2%.     

5-氰基异苯并呋喃-1-酮的合成

邻苯二甲酰亚胺经硝化、还原制得4-氨基邻苯二甲酰亚胺,还原1个羰基后加热脱氨并环合制得5-氨基异苯并呋喃-1-酮,最后经Sandmeyer反应进行氰基取代制得5-氰基异苯并呋喃-1-酮,总收率39%.     

Escitalopram in major depressive disorder: clinical benefits and cost effectiveness versus citalopram

Objective. Escitalopram is the most selective of the serotonin reuptake inhibitors. Methods. We review all the clinical trials (three pivotal placebo-controlled trials with citalopram as an active reference, one long-term non-inferiority study and one head-to-head superiority study) that include citalopram as an active reference in major depressive disorder (MDD), and studies that evaluate the cost-effectiveness of the two drugs. Results. In two of the pivotal studies and in the long-term study, escitalopram was numerically better than citalopram in reducing Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline, with comparative tolerability. Meta-analyses of these studies showed statistically significant differences in favour of escitalopram in terms of reducing MADRS and increasing response. This effect was particularly apparent in patients with higher baseline MADRS scores. These trends were confirmed in a head-to-head study, which clearly demonstrated the superiority of escitalopram compared with citalopram on primary and secondary endpoints. The difference between treatments was clinically relevant. Cost-effectiveness analyses demonstrated that although escitalopram has a slightly higher unit cost than generic citalopram, expected direct medical and productivity- related costs were lower with escitalopram than citalopram. Conclusion. On the basis of these results, escitalopram was concluded to be more clinically effective and more cost-effective than citalopram for the treatment of MDD, with a similar tolerability profile.     

Citalopram and escitalopram plasma drug and metabolite concentrations: genome-wide associations

Aims

Citalopram (CT) and escitalopram (S-CT) are among the most widely prescribed selective serotonin reuptake inhibitors used to treat major depressive disorder (MDD). We applied a genome-wide association study to identify genetic factors that contribute to variation in plasma concentrations of CT or S-CT and their metabolites in MDD patients treated with CT or S-CT.

Methods

Our genome-wide association study was performed using samples from 435 MDD patients. Linear mixed models were used to account for within-subject correlations of longitudinal measures of plasma drug/metabolite concentrations (4 and 8 weeks after the initiation of drug therapy), and single-nucleotide polymorphisms (SNPs) were modelled as additive allelic effects.

Results

Genome-wide significant associations were observed for S-CT concentration with SNPs in or near the CYP2C19 gene on chromosome 10 (rs1074145, P = 4.1 × 10⁻⁹) and with S-didesmethylcitalopram concentration for SNPs near the CYP2D6 locus on chromosome 22 (rs1065852, P = 2.0 × 10⁻¹⁶), supporting the important role of these cytochrome P450 (CYP) enzymes in biotransformation of citalopram. After adjustment for the effect of CYP2C19 functional alleles, the analyses also identified novel loci that will require future replication and functional validation.

Conclusions

In vitro and in vivo studies have suggested that the biotransformation of CT to monodesmethylcitalopram and didesmethylcitalopram is mediated by CYP isozymes. The results of our genome-wide association study performed in MDD patients treated with CT or S-CT have confirmed those observations but also identified novel genomic loci that might play a role in variation in plasma levels of CT or its metabolites during the treatment of MDD patients with these selective serotonin reuptake inhibitors.     

西酞普兰与文拉法辛治疗抑郁症对照研究

目的:比较西酞普兰与文拉法辛治疗抑郁症的疗效及安全性。方法:将65例抑郁症患者随机分为两组,分别给予西酞普兰与文拉法辛治疗,疗程6周。用汉密尔顿抑郁量表(HAMD)及汉密尔顿焦虑量表(HAMA)在治疗前及治疗1、2、4、6周评定疗效;用副反应量表(TESS)评定不良反应。结果:两组总体疗效相当,西酞普兰起效稍快。两组不良反应均较轻,安全性好。结论:西酞普兰与文拉法辛均是安全有效的抗抑郁药。