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舍曲林

舍曲林(商品名左洛复等人)是抗抑郁药的的选择性血清素再摄取抑制剂(SSRI)类。据介绍市场由辉瑞公司于1991年舍曲林主要规定的抑郁症的成年门诊病人以及强迫症,惊恐障碍和社交焦虑症,在成人和儿童。在2013年,这是最常用的处方抗抑郁药和第二大处方精神科药物(后阿普唑仑美国零售市场上),有超过4100万的处方。[5]

与其他抗抑郁药新的差异是细微的,大多局限于副作用。它有一个类似的耐受性与其他SSRIs类药物,同类型的不良反应通常包括腹泻,恶心,颤抖,性功能障碍和体重增加。腹泻的发病率相较于其他SSRIs类药物是舍曲林高。

 

医疗用途

舍曲林用于若干条件,包括:抑郁症,强迫症(OCD),躯体变形障碍(BDD),创伤后应激障碍(PTSD),月经前焦虑障碍(PMDD),恐慌症和社交焦虑障碍。[ 7]还已经用于早泄和血管性头痛治疗这些条件的效力,但证据不健壮。[7]

抑郁症

2008年的审查认为,各种SSRIs类药物的研究,51%,取得了积极的成果。[8]舍曲林的疗效是统计上类似于其他SSRIs类药物,如  帕罗西汀,西酞普兰,艾司西酞普兰与文拉法辛(SNRI)。[9] [10] [11 ] [12]有证据表明,舍曲林可能比更有效  氟西汀  (百忧解)对抑郁症的某些亚型。[13]

证据并不显示在与抑郁症的儿童一个好处。[14]

在痴呆抑郁,没有好处相比安慰剂或米尔塔扎平。[15]

与其他抗抑郁药的比较

三环类抗抑郁药(TCAS)作为一个群体被认为工作比更好的选择性五羟色胺再摄取抑制剂的忧郁抑郁[16]和住院患者,[17]但不一定只是更严重的抑郁症。[18]在这种泛化行,舍曲林并不比安慰剂更好的住院患者(见历史)和有效的TCA 氯丙咪嗪为严重的抑郁症。[9]舍曲林和抗抑郁药对抑郁症忧郁的疗效比较尚未研究。1998年的回顾表明,由于其药理,舍曲林可能比其他SSRIs类药物更有效和平等为抗抑郁药的忧郁抑郁症的治疗方法。[19]

12新一代抗抑郁药的荟萃分析表明,舍曲林和西酞普兰是最好的,在急性期治疗单极抑郁症。成人的有效性和可接受性方面瑞波西汀是显著恶化。[20]

比较的临床试验表明,舍曲林在抑郁症的疗效是类似的 是低质量的证据表明,舍曲林是抑郁症比治疗更有效氟西汀。[25]

老人

用于老年人(60岁以上)的患者治疗抑郁症的舍曲林优于安慰剂和可比另一个SSRI 氟西汀,和抗抑郁药阿米替林,去甲替林(Pamelor)和丙咪嗪。舍曲林具有比这些抗抑郁药的不利影响降低很多,恶心的例外,这与舍曲林更频繁地发生。另外,舍曲林似乎比在较早高于70亚氟西汀或去甲替林更有效。[26]舍曲林对老年患者服用安慰剂的2003年的试验表明一个统计学显著(即,不太可能偶然发生) ,但在临床上抑郁症非常温和的改善和无改善生活质量。[27]

在SSRIs类药物和SNRIs的,看起来在部分响应的荟萃分析(定义为至少从基线抑郁评分减少了50%)发现,舍曲林,帕罗西汀和度洛西汀均优于安慰剂。对于安全度洛西汀和文拉法辛增加加重头晕,但没有报道太多的安全数据。[28]

强迫症

舍曲林可有效治疗强迫症(OCD)的成人和儿童。[29]它是更好的耐受性,并根据意向治疗分析,表现比强迫症治疗的金标准更好氯丙咪嗪。[30]它通常认为,强迫症的有效治疗是比通常的剂量为抑郁越高舍曲林的剂量必需的。[31]动作的开始也是强迫症比抑郁慢。治疗建议是具有最大推荐剂量的一半开始治疗至少两个月。在此之后,可将剂量提高到不令人满意的响应的情况下,建议的最大。[32]

认知行为疗法独显优于成人和儿童的舍曲林; 然而,最好的结果是使用这些处理的组合来实现。[33] [34]舍曲林可用于治疗强迫症的有用共同病态与Tourette综合征。[35]

恐慌症

的治疗恐慌症与恐慌发作的数量和提高生活质量的降低舍曲林的效果。[36]四双盲研究舍曲林被证明优于安慰剂为恐慌症的治疗。回应率为独立的剂量。除了 ​​由约80%(相对于安慰剂的45%)减少的恐慌发作的频率和减小一般焦虑,舍曲林导致改善大多数参数的生活质量。评为舍曲林“改良”的患者报告的生活质量优于安慰剂组谁“改良”的人。该研究的作者认为,舍曲林取得的改进是不同的,比安慰剂实现改进质量更好的。[36] [37]舍曲林是男性和女性同样有效。[37]虽然不精确,比较与其它抗恐慌剂(单独的试验舍曲林试验的结果氯丙咪嗪,丙咪嗪,氯硝西泮,阿普唑仑,氟伏沙明和帕罗西汀)表明这些药物大致等价。[36]

社交恐惧症

舍曲林是有效的治疗社交恐惧症。[38]在对分数提高Liebowitz社交焦虑量 ​​表被发现舍曲林,但不与安慰剂。[39]舍曲林和的组合认知行为治疗中使用时,具有出色的响应速度儿童。[40]

经前烦躁症

SSRIs的,包括舍曲林,减轻症状经前期综合征。[41]副作用如恶心是常见的。[41]

舍曲林有效缓解症状经前烦躁症(PMDD),是一种严重的经前期综合征。在舍曲林与安慰剂治疗的病例的20-30%的情况下50-60%的患者显著改善。在治疗的第一个星期的改善开始了,除了情绪,烦躁,焦虑,改善反映在更好的家庭功能,社会活动和生活质量一般。工作功能和身体症状,如肿胀,腹胀和乳房胀痛,是舍曲林响应以下。[42] [43]仅在以舍曲林黄体期,也就是,月经前的12-14天,被证明工作以及连续处理。[41]

其他适应症

每日服用时舍曲林可用于某些方面的可用于治疗早泄。[44]的SSRIs的一个缺点是它们需要连续每日处理以显著延迟射精,[45] ,它是不明确它们是如何影响的心理痛苦那些条件或人对射精的时间控制。[46]

在PTSD舍曲林的好处是不占显著临床优化研究所。[47]然而,其他人都觉得有其利用一个好处。[48]

不利的影响

相对于其他的SSRIs,舍曲林趋于具有更高速率的精神病副作用和腹泻有关。[49] [50]它更趋于活化(即,具有更高的速率的焦虑,激动,失眠等相关联。)比其他的SSRIs,除了氟西汀。[51]

在半年多的舍曲林治疗抑郁症,患者表现为一个微不足道的重量增加0.1%。[52]同样,舍曲林30个月的治疗强迫症导致了体重平均增加1.5%(1公斤) 。[53]尽管差异没有达到统计学显着性,增重是 ​​低级氟西汀为(百忧解)(1%),但较高的西酞普兰(Celexa的),氟伏沙明(兰释)和帕罗西汀(帕罗西汀)(2.5%)。舍曲林组中,有4.5%获得了大量的重量(定义为超过7%的涨幅)。该结果相媲美安慰剂,在那里,根据该文献,患者3-6%获得其初始重量的7%以上。仅观察舍曲林组的女性成员中的大体重增加; 这一发现的意义是因为该组的小尺寸的不清楚。[53]

在两个星期的治疗健康志愿者,舍曲林略有改善言语流畅性,但并没有影响单词学习,短期记忆力,警觉,闪光融合时间,选择反应时,记忆广度,或精神运动协调。[54] [55]在尽管较低的主观评价,也就是说,感觉自己表现糟糕的,没有临床上的一组抑郁症治疗舍曲林1。5年的人在客观认知能力,观察相关的差异相比健康对照。[56]在儿童中和青少年服用舍曲林六个星期的焦虑症,18人的记忆力,注意力和警觉20项措施维持不变,。分散注意了改进,并在言语记忆干扰条件略有下降。由于大量的采取措施,可能的是这些变化仍然由于机会。[57]舍曲林上的独特效果的多巴胺能 神经传递可能与认知和警惕性这些效果。[58] [59]

性方面的副作用

像其他SSRIs类药物,舍曲林与性方面的副作用,包括相关的性唤起障碍和难度达到高潮。性副作用观察到的频率在很大程度上取决于它们是否受到病人自发报告,如在制造商的试验中,或由医师积极听取。已经有几个双盲研究性的副作用比较与安慰剂或其他抗抑郁药舍曲林。[60]虽然奈法唑酮(奈法唑酮),安非他酮(安非他酮)和瑞波西汀(Edronax)没有对性功能有负面影响,67%男子舍曲林经历射精困难比18%处理前[60] (或61%对根据另一纸0%)。[23]类似地,一组谁最初没有困难的妇女中获得高潮,41舍曲林在治疗期间%获得了这个问题。[23]的40%的速度性高潮功能障碍上舍曲林在另一项研究中的混合组观察(相对于安慰剂9%)。[61] 性唤起障碍,定义为“不充分的润滑和肿胀的女性和男性勃起困难“,发生在患者舍曲林12%,与服用安慰剂的病患只有1%。从用舍曲林治疗导致的情绪改善有时抵消这些副作用,使性欲和性的总体满意度保持不变的舍曲林治疗之前。然而,安慰剂的作用下的欲望和满意略有改善。[61]

自杀

FDA要求所有抗抑郁药,包括舍曲林,携带黑框警告指出,抗抑郁药可能增加超过25岁以下的人自杀风险。该警告是根据FDA的专家发现,在儿童和青少年的自杀意念和行为的双重增长,并且的18-24岁年龄组的自杀行为1.5倍,增加了两个独立小组进行统计分析。[62] [63] [64]

自杀意念和临床试验的行为是罕见的。对于上述分析,美国FDA以获得组合的11抗抑郁药精神病适应症295试验的结果统 ​​计学显著结果。分别考虑,在成人舍曲林使用由37%减少的自杀行为的可能性与边际统计学意义[64]或50%[63]根据所使用的统计技术。FDA的分析,作者指出,“鉴于大量在这次审查进行的比较,机会是这种差异非常合理的解释。” [63]后来被舍曲林制造商辉瑞标明增加自杀行为提出了更完整的数据。[65]类似地,由英国进行的分析MHRA发现自杀相关事件的可能性没有达到统计显着性的增加了50%,在患者相比,安慰剂组的那些舍曲林。[66] [67]

有关人士提出,与会者在多个研究中自杀行为在报告的研究发表的文章没有报告。[68]

过量

急性过量往往是呕吐,嗜睡,运动失调,心动过速和癫痫发作表现。等离子,舍曲林和norsertraline,其主要活性代谢产物的血清或血液中的浓度,可以测量,确认中毒的诊断住院患者或死亡的法医学调查,以帮助。[69]与大多数其他SSRIs类药物的用药过量毒性被认为是比较低的[49] [70]

怀孕和哺乳

比较舍曲林,其主要的水平研究代谢物,desmethylsertraline在交货时,在母亲的血液到其在脐带血浓度表明胎儿暴露于舍曲林及其代谢产物是约母体曝光的三分之一。[71] [72]在期间使用舍曲林的头三个月:妊娠与增加了以下出生缺陷的几率相关脐膨出(六倍),肛门闭锁及肢体减少缺陷(四倍)和室间隔缺损(两折); 然而这些具体缺陷本身是罕见的,因此,绝对风险较小。[73]在母乳舍曲林和desmethylsertraline浓度是高度可变的和的平均值,是相同的数量级顺序作为其中的浓度血浆的母亲。其结果是,超过一半母乳喂养的婴儿的接收小于2mg /舍曲林和desmethylsertraline结合的天,在大多数情况下,这些物质是在他们的血液检测不到。[74]在没有变更血清素通过摄取血小板乳房-fed婴儿被发现,由他们的血液血清素的水平测量之前和他们的母亲开始后舍曲林治疗。[75]

戒断综合征

互动

舍曲林是一个适中的抑制剂的CYP2D6和CYP2B6 在体外[76]因此,在人的试验就引起CYP2D6的血液水平增加基材如美托洛尔,美沙芬,地昔帕明,丙咪嗪和去甲替林,以及CYP3A4 / CYP2D6衬底氟哌啶醇。[77] [78] [79]这种效果是剂量依赖性的; 例如,共同施用与50mg舍曲林造成了更大的20%暴露于地昔帕明,而150毫克舍曲林导致增加了70%。[80] [81]在安慰剂对照的研究中,舍曲林的同时给予和美沙酮引起在后者中,它主要由CYP2B6代谢的血液水平增加了40%。[82]舍曲林经常结合使用兴奋剂药物在共同病态抑郁症和/或焦虑的治疗ADHD。[83 ]苯丙胺代谢抑制酶CYP2D6的,但尚未公知的与舍曲林代谢干涉。[84]

舍曲林对新陈代谢有轻微的抑制作用,地西泮,甲苯磺丁脲和华法林,这是CYP2C9或CYP2C19底物; 这种效果是不被认为是临床上相关的。[80]如从预期体外数据,舍曲林没有改变CYP3A4底物的人体代谢红霉素,阿普唑仑,卡马西平,氯硝西泮,和特非那定 ; 无论它是否会影响代谢CYP1A2底物氯氮平。

舍曲林对的动作没有任何影响地高辛和阿替洛尔,它们不会在肝脏代谢。[3] [76] [80] [85] 病例报告表明,服用舍曲林与苯妥英或唑吡坦可能诱发的舍曲林代谢并降低其疗效,[86] [87]和服用舍曲林与拉莫三嗪可能增加拉莫三嗪的血液水平,可能是通过抑制葡萄糖醛酸化的。[88]

临床报告表明,舍曲林和之间的互动单胺氧化抑制剂 异卡波和反苯环丙胺可能导致血清素综合征。在安慰剂对照的研究,其中舍曲林,用共同施用锂,受试者的35%经历了震颤,而没有那些服用安慰剂的一样。[80]

根据标签,舍曲林是禁忌在采取个人单胺氧化酶抑制剂或抗精神病 匹莫齐特(Orap)。舍曲林浓缩物包含醇,并因此与禁忌双硫仑(戒酒硫)。处方信息建议治疗老人和病人的肝功能损害的“,必须谨慎对待。” 由于较慢的消除这些基团的舍曲林,其暴露于舍曲林可高达平均曝光相同剂量的三倍。[3]

药理学

作用机理

结合特性,[89]

接收器

ķ NM

SERT

2.8

925

DAT

315

的5-HT 2C

2,298

α 1

188

中号1

427

^ h 1

6578

舍曲林主要是一种血清素再吸收抑制剂(SRI)的朝向的结合亲和力羟色胺转运的K  =2.0μm的。[90]治疗剂量的舍曲林(25-200毫克/天)通过患者四周采取导致80-的90%的抑制血清素转运在蛋白(SERT)纹状体如通过测定正电子发射断层扫描。每日9毫克的剂量是足以抑制SERT的50%。[91]

舍曲林也是多巴胺再摄取抑制剂,(<50纳摩尔/升)。然而,这并不被认为是紧密结合,并且这个动作是其效力为只有10%的单胺再摄取抑制剂。[92]这是一个σ 1受体 激动剂,其SRI效力的5%,[93]和α 1肾上腺素受体 ​​拮抗剂,其SRI效力的1-10%。[94]然而,虽然确认舍曲林对高亲和力σ 1受体,不同的研究表明,该药物实际上表现为一个拮抗剂在那些。[95]在多巴胺再摄取,舍曲林是比更有效安非他酮。[96]

尽管是一种更有效的多巴胺再摄取抑制剂比安非拉酮,它仍然是血清素再摄取的一个更有效的抑制剂-它是在抑制血清素再吸收比是在抑制多巴胺再摄取约60倍更有效。[97]不管,舍曲林可能是被认为是血清素,多巴胺的再摄取抑制剂。[98] [ 非主源所需 ] [ 来源请求 ]

【药代动力学

摄取后4-6小时口服时,在血浆中达到其最大浓度舍曲林缓慢地吸收。在血液中,它是98.5%与血浆蛋白结合。其在体内的半衰期为13-45小时,并且平均为约1.5倍(50%)的妇女较长(32小时)比男性(22小时),允许在妇女1.5倍,高曝光。[80]根据体外研究中,舍曲林是由多个代谢细胞色素450 同种型:CYP2D6,CYP2C9,CYP2B6,CYP2C19和CYP3A4。似乎不可能的,任何单一的同种型的抑制可在舍曲林药引起临床显著变化。[2] [99]在舍曲林药代人CYP2D6的高和低活性之间没有观察到差别;[100]然而,差CYP2C19代谢过有1.5倍-更高水平舍曲林比正常代谢的。[101] 在体外数据还表明,CYP2B6抑制应该比CYP2C19的抑制更大的效果,而CYP2C9和CYP3A4的对贡献代谢舍曲林将是次要的。这些结论都没有在人类研究中得到验证。[2]舍曲林可脱氨基 体外通过单胺氧化酶 ; 然而,这种代谢途径从未被研究体内[2]舍曲林的主要代谢产物,desmethylsertraline,是弱大约50倍作为血清素转运抑制剂比舍曲林和其临床效果是可以忽略不计。[94]

非胺的代谢物也可能有助于这种药物的抗抑郁作用。舍曲林脱氨基是-O-2098,已发现抑制多巴胺再摄取转运蛋白,尽管其缺乏的氮原子的化合物。[102]

其主要的活性代谢物是norsertraline(N- desmethylsertraline)比其母体化合物显著较少的生物活性。[103]

历史

舍曲林的历史可以追溯到70年代初,当辉瑞化学家莱因哈德Sarges发明了一系列新的基于抗精神病药的结构精神化合物泰尔登和氨砜噻吨。[104] [105]对这些化合物的进一步工作导致tametraline,一去甲肾上腺素和较弱的多巴胺再摄取抑制剂。tametraline的发展很快就停止了,因为不希望兴奋剂在动物中观察到的效果。几年后,在1977年,药理学家肯尼思·香江,比较各种胺再摄取抑制剂的结构特点后,产生了兴趣tametraline系列。他问另一个辉瑞公司化学家,威拉德·韦尔奇,合成一些以前未开发的tametraline衍生物。韦尔奇产生了许多有效的去甲肾上腺素和三重再摄取抑制剂,但对科学家的惊喜,一位代表普遍不活跃的顺式类似物是五羟色胺再摄取抑制剂。韦尔奇然后准备立体这种化合物,其中测试的体内动物行为学家艾伯特韦斯曼。最有效的和选择性(+) -异构体被带到进一步发展和最终命名舍曲林。韦斯曼和香江回忆,该集团并没有成立以生产感觉到他们询问是不是“非常目标驱动”的SSRI类,在抗抑郁药,和舍曲林分子的发现是偶然的。据韦尔奇,他们的工作主流之外的辉瑞公司,甚至“没有一个正式的项目团队。” 该小组必须克服官僚主义最初不愿追求舍曲林发展,辉瑞公司正在考虑从另一家公司授权的抗抑郁候选人。[104] [106] [107]

舍曲林是经美国食品和药物管理局的基础上,精神药理学药物咨询委员会的建议文献(FDA); 它已经成为可用的英国去年。[108] FDA的委员会取得共识,舍曲林是安全,有效的治疗抑郁症。

舍曲林1994年进入澳大利亚市场,并于1996年(2004年数据),成为最经常处方的抗抑郁药。[109]这是衡量受成本在1998年和2000 - 01年位居澳大利亚政府的十大药物之一,已经花费$ 45万,分别补贴$ 87亿美元。[110] [111]舍曲林是在英国(2003年数据)和加拿大(2006年的数据)冷门-in两国是第五(销售,用于治疗药物中MDD,或抗抑郁药),根据处方的数量。[112] [113]

直到2002年,舍曲林才被批准用于成人中18岁及以上; 这一年,它是为在6或以上严重老化治疗儿童使用FDA批准的强迫症(OCD)。2003年,英国药品和健康产品管理局发出指引,除了氟西汀(百忧解),SSRIs类药物不适合患者的治疗抑郁症的18岁[114] [115]然而,仍然可以使用舍曲林在英国儿童和青少年的治疗强迫症。[116] 2005年,FDA增加了黑框警告有关儿童自杀行为给所有抗抑郁药,包括舍曲林。2007年,标签再次被改为添加关于青壮年年龄自杀行为的警告18〜24 [117]

Sertraline

Sertraline is a drug from the group of selective serotonin reuptake inhibitors ( SSRI ). Sertraline found inter alia as antidepressant in depression as well as anxiety disorders , post-traumatic stress disorder andobsessive-compulsive disorder using.

Effect

Sertraline is a selective serotonin reuptake inhibitor, the concentration of serotonin in the synaptic cleft in the central nervous system to increase. Other mechanisms are so weak that they can be neglected (dopamine reuptake inhibitor with a percent of SSRI potency; antagonist at sigma-1 receptor with five percent of its SSRI potency; α1-adrenoceptor antagonist with one to ten percent of its SSRI potency ).Sertraline also acts as fiasma (functional inhibitor of acid sphingomyelinase ). [7]

Sertraline affects driving enhancing already with the first dose, after about seven days is using the mood-lifting effect, this effect is built up during the then following 7-21 days from. In rare cases, taking a mood lightening effect was reported after the first day.

The plasma half-life is about 23 to 26 hours. Sertraline is excreted through the kidneys. The administration of sertraline should be possible in the morning because the drug affects driving enhancing. The revenue does not depend on the meals.

In 2009, that has Federal Institute for Drugs and Medical Devices (BfArM) significantly expands the range of indications of sertraline.

Application Areas

Depression

Patients with severe depression have been successfully treated with sertraline. [8] In the short-term treatment (to twelve weeks) of dysthymia sertraline is superior to placebo. [9] [10] [11] [12] applied the long term, sertraline was found in a study more effective than interpersonal psychotherapy . [13] In the treatment of of constraints accompanied depression sertraline is more effective than desipramine . [14] In patients with comorbid panic disorder sertraline was as effective as imipramine , but had fewer side effects. [15] the evaluation of the effectiveness but suffers from unpublished negative studies. [16]

OCD

In the treatment of OCD Sertraline is more effective than a placebo in both adults and children.[17] [18] [19] [20] [21] sertraline, in the treatment of constraints more effective than fluoxetine , [22] but less effective as clomipramine . [20] sertraline is indicated for long term treatment of OCD suitable. [23] [24]

Panic disorder

In the treatment of panic disorders sertraline is more effective than a placebo. [25] [26] It is both in patients with and in patients without agoraphobia effect. [27]

Social phobia

Sertraline can successfully for the treatment of social phobia are used. [28] In the treatment of social phobia with sertraline, it may take six to twelve weeks, until a treatment success. [29] In patients who developed until adulthood, is the efficacy higher than for other patients. [30]

Posttraumatic stress disorder

Sertraline is in the treatment of posttraumatic stress disorder (abbreviated PTSD) at civilians more effective than the placebo. [31] [32] In some cases occurs, the treatment effect only after the twelfth week. Patients whose condition had not yet improved in the twelfth week, experienced in 54% of cases up to the 24th week of treatment an improvement in symptoms. [32] The more severe the symptoms, the longer it took for the patients responded to treatment . [33] a study in war veterans suggests that sertraline even with these is effective. [34] in another study, which also dealt with war veterans, was sertraline not superior to placebo. [35] While the efficacy of sertraline in Women with PTSD is well established, it is for men with PTSD well documented less. [36]

Side effects

Very common (more than 10% of patients) central nervous disorders such as insomnia, somnolence, headache and dizziness, disorders of the gastrointestinal system such as nausea, diarrhea and dry mouth, as well as in men a were in administration of sertraline Ejakulationsversagen observed. [37]

Among the common side effects (in 1 to 10% of patients) include excitement , nervousness , appetite disturbances, tremor , increased sweating , blurred vision ,skin rash , vomiting, dyspepsia , sexual dysfunction , hot flashes , micturition disorders , palpitations and chest pain. Other side effects on the cardiovascular system were rarely observed as compared to tricyclic antidepressants.

In addition, it has been reported since launch numerous other adverse events, their frequency based on the available data can not be estimated (possibly withoutcausal relationship with sertraline) multiforme , epidermal necrolysis . [37]

In patients with mania (abnormal elation) or hypomania suffer or have suffered (less severe symptoms), caution is required. With 0.4% of test patients hypomania was reported mania /. Furthermore, it may be occasional euphoria, hallucinations or depressive moods.

In the use of sertraline and other SSRIs in children and adolescents were in studies suicidal behavior (predominantly aggression, oppositional behavior and anger) were observed (suicidal thoughts and suicide attempts), and hostility. Aggression, suicidal and hostile behavior can occur as a side effect in adults.

A rare side effect, the so-called serotonin syndrome , which especially in combination with certain other centrally acting drugs (eg. As anti-migraine agents by triptantype, tryptophan , other medicines for depression such as lithium salts, preparations containing St. John's wort ) occurs, manifested by decreased consciousness, muscle rigidity, tremors, convulsions and fever.

Interactions

The serotonergic effects of sertraline, by a MAOI to life-threatening serotonin syndrome are amplified. Therefore, concomitant use with irreversible MAO inhibitors represent an absolute contraindication. Concomitant use with reversible MAOIs, including the antibiotic linezolid , is a relative contraindication and should be avoided. Any change of treatment for a sufficiently long treatment-free phase (washout) is recommended. [37]

In the simultaneous intake of other serotonergic drugs, such. As triptans , of serotonin syndrome have been observed in some cases symptoms. For this reason, the concomitant use with other medicinal products with a direct or indirect effect on the serotonin system, how should tryptophan or St. John's wort are avoided. [37]

Sertraline in turn may increase the effects of the antipsychotic pimozide potentiate. Concomitant administration of sertraline and pimozide is due to its lowtherapeutic index contraindicated. [37]

On the consumption of alcohol should be avoided during therapy, although in studies in healthy subjects were observed no limitation of mental and psychomotor skills by concomitant administration of sertraline and alcohol. Co-administration of sertraline with lithium can the side effects of drugs, in particular to an increase intremor lead. Concomitant use of phenytoin may increase phenytoin plasma concentrations in individual cases during Sertralinspiegel is lowered compared with either monotherapy. The function of antiplatelet agents may be inhibited by sertraline. The effect of vitamin K antagonists ( coumarins ) may be affected in rare cases. [37]

Sertraline is a weak to moderate inhibitors of the drugs metabolizing cytochrome P450 isozyme CYP2D6 . Concomitant use with drugs that are metabolized by this enzyme system may lead to a moderate increase in their plasma levels. A clinical relevance can these interactions, particularly with concomitant use of high doses of sertraline with drugs with a narrow therapeutic index such as antiarrhythmics , such as propafenone and flecainide reach and tricyclic antidepressants. Other isoenzymes, including CYP3A4, CYP2C9 , CYP2C19 and CYP1A2 are not inhibited by sertraline in a clinically significant way. The cytochrome P450 inhibitorcimetidine other hand, leads to a significant decrease in the rate of elimination of sertraline. [37]

Absetzsyndrom

Abrupt discontinuation of sertraline may cause symptoms like agitation , dizziness, headache, insomnia, paresthesia , agitation, anxiety, confusion, tremors lead, nausea and sweating. To avoid this, one will discontinuation of therapy recommended. The symptoms described are not signs of addiction development. [37]

Pregnancy and lactation

Women of childbearing potential should sertraline only under sufficient contraceptive protection ( contraception taking).

If a woman during pregnancy sertraline occupies so sertraline and its major metabolite can N -Desmethylsertralin in cord blood are detected. [38] [39] There have been no controlled clinical studies conducted in pregnant women, however, the existing data situation does not provide evidence that sertraline leads to congenital malformations. Lactating women and sertraline occur N -Desmethylsertralin in small amounts in the breast milk over. Though no harmful effects in breastfed infants were observed, it can not be ruled out. [40]

Production

The preparation of sertraline is carried out in a multistep synthesis. [41] [42] In the first step starting from 3,4-dichloro benzoyl chloride and benzene in the presence ofaluminum chloride in a Friedel-Crafts acylation formed 3,4-dichlorobenzophenone. Followed by an aldol condensation with diethyl succinate , decarboxylation of the aldol product with hydrobromic and hydrogenation yields the 4- (3,4-dichloro-phenyl) -4-phenyl-butyric acid as a racemate . After conversion of this may be cyclized in a Friedel-Crafts reaction to Tetrahydronaphthalinstruktur to the acid chloride. In the following steps, after reaction with methylamine and subsequent hydrogenation of the azomethine obtain the target structure. The desired stereoisomer is then after separation of the diastereomers by crystallisation followed by resolution with D - (-) - mandelic acid obtained.

A synthesis with a stereoselective hydrogenation of an intermediate imine describe Chinese authors. [43]

Toxicology

The determination of the lowest known toxic dose (TD Lo ) gave the man an oral value of 2.857 mg / kg, [5] in women 7 mg / kg when administered for two weeks. [6]In mice and rats were lethal doses of 336 mg / kg (mouse, oral, LD Lo ) [4] and 840 mg / kg (rat, oral LD Lo ) [4] determined. Toxic effects were hallucinations and perceptual disturbances, nausea and vomiting, sweats in men, [5] a headache, changes in the teeth and jaws, excitement in women.

Preclinical

It could be shown that sertraline no mutagenic has effect. Taking low doses of sertraline in pregnant rats the survival took newborn animals from. A similar effect was also seen with other antidepressants. [37] This observed only within the first days after birth increased mortality was demonstrated to be due to exposure to sertraline after the 15th day of gestation. After administration of sertraline to pregnant rats observed developmental delays of pups were probably caused by the Sertralinwirkung on the dams and therefore considered for risk assessment in humans as not relevant. [40]

Tradename

Monopreparations :

  • Adjuvin (A)
  • Gladem (A)
  • Tresleen (A)
  • Zoloft (D, CH)
  • Sertraline generic (A, D, CH)