托莫西汀治疗儿童青少年 ADHD:十年回顾 文献解读

2017-06-20 16:08 来源:丁香园 作者:
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研究背景——托莫西汀概述

托莫西汀是全球第一个批准治疗注意缺陷多动障碍(ADHD)的非兴奋性药物。

2002 年在美国上市至今,已有 68 个国家,超过 600 万患者使用托莫西汀 ,证明了其良好的耐受性和有效性。

2007 年托莫西汀在中国获准治疗儿童/青少年 ADHD。

近年来,对托莫西汀的研究呈逐年上升趋势。

托莫西汀的作用机制

托莫西汀是选择性去甲肾上腺素再摄取抑制剂,通过增加前额叶皮层突触间隙去甲肾上腺素(NE)和多巴胺(DA)的浓度发挥治疗 ADHD 的作用,如下图所示:[2]

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托莫西汀无滥用风险:

托莫西汀增加前额叶皮质 DA 浓度,但不增加伏隔核和纹状体 DA 水平,不作用于中脑边缘系统,因此无诱发抽动和滥用风险 [3]。

托莫西汀的起效特点

托莫西汀平稳起效:

多项研究显示,托莫西汀通常在 4 周内起效,部分研究提示第 1 周即起效。[4-8]

1-2.png

托莫西汀的疗效随治疗时间延长而增加:

研究显示,托莫西汀治疗儿童 ADHD 第 4 周时,明显改善(ADHD-RS 减分值 ≥ 40%)的患者比例达 47% 左右,该比例随治疗时间上升,在 52 周时达 96%。[9] 最初几周的疗效可预测最终的治疗效果。[4] 对于治疗初期「无反应」者,继续治疗仍有可能获得改善。[10]

托莫西汀的推荐剂量 [11,12]:

体重不足 70 公斤的儿童和青少年用量

起始剂量:0.5 mg/kg/天,并且在 3 天的最低用量之后增加给药量,至每日总目标剂量 1.2 mg/kg/天。

最大剂量:对儿童和青少年,每日最大剂量不应超过 1.4 mg/kg 或 100 mg,选其中较小的一个剂量。

体重超过 70 公斤的儿童、青少年

起始剂量:40 mg 天,并且在 3 天的最低用量之后增加给药量,至每日总目标剂量 80 mg/天,每日早晨单次服药或早晨和傍晚平均分为两次服用。

最大剂量:100 mg/天。

增加给药次数可改善疗效:

147 例托莫西汀一天一次治疗无反应的儿童患者,改为一天两次给药后,75% 的患者获得了治疗反应。[13]

一项纳入 288 人的安慰剂对照研究表明:早晨给药:ADHD-RS 总分和过度活跃/冲动亚评分下降更多,而夜间给药耐受性更好。[14]

托莫西汀的短期疗效评价

至少 9 项研究报道,对于未经治疗的患者,托莫西汀可有效改善 ADHD 核心症状、功能结局和生活质量。[8, 15, 16]

两项荟萃分析显示,托莫西汀的短期疗效不劣于兴奋剂。[17]

部分经其他治疗不佳的患者换用托莫西汀后短期内症状得到改善。[18, 19]

托莫西汀的长期疗效评价

5 项上市后研究 [20-24] 报告了托莫西汀长期疗效,观察时间范围:9 个月-2 年。结果提示托莫西汀治疗 ADHD 的疗效可持续至少 2 年;且治疗 ADHD 的长期疗效与兴奋剂相当。

托莫西汀对 ADHD 共病的疗效

大量对于 ADHD 共病的研究显示,托莫西汀可用于治疗共病 ODD、抽动、焦虑、广泛性发育障碍等疾病的 ADHD 患者,且托莫西汀在改善 ADHD 症状的同时,并不加重共病的症状,有的甚至可以改善某些共病症状。 [25-32]

托莫西汀对生长发育无显著影响

一项荟萃分析显示,托莫西汀长期治疗对 ADHD 青少年患者体重及身高无显著影响。[20]

另一项数据综合分析探讨了托莫西汀治疗 ADHD 患儿 ≥ 3 年和/或 4 年的长期安全性和耐受性,提示托莫西汀不影响患儿的生长速率。[33]

总的来讲,托莫西汀可以有效改善 ADHD 患儿的 ADHD 核心症状、功能结局和生活质量。临床医生在首次处方托莫西汀时应与患儿及家属充分沟通,帮助其设定正确的期望值,鼓励患儿长期坚持用药,最终获得成功治疗结局。托莫西汀可有效改善共病 ODD、抽动、焦虑、广泛性发育障碍等 ADHD 患者的核心症状和某些共病症状,并且对 ADHD 患儿生长发育无显著影响,是 ADHD 治疗的一线药物选择。

参考文献:

[1] Savill NC, Buitelaar JK, Anand E, Day KA, Treuer T, Upadhyaya HP, et al. The efficacy of atomoxetine for the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a comprehensive review of over a decade of clinical research. CNS Drugs. 2015;29:131-51.

[2] Stahl SM (司天梅等译). Stahl 精神药理学精要:神经科学基础与临床应用(第三版). Page 471.

[3] Upadhyaya HP, Desaiah D, Schuh KJ, Bymaster FP, Kallman MJ, Clarke DO, et al. A review of the abuse potential assessment of atomoxetine: a nonstimulant medication for attention-deficit/hyperactivity disorder. Psychopharmacology (Berl). 2013;226:189-200.

[4] Newcorn JH, Sutton VK, Weiss MD, Sumner CR. Clinical responses to atomoxetine in attention-deficit/hyperactivity disorder: the Integrated Data Exploratory Analysis (IDEA) study. J Am Acad Child Adolesc Psychiatry. 2009;48:511-8.

[5] Kelsey DK, Sumner CR, Casat CD, Coury DL, Quintana H, Saylor KE, et al. Once-daily atomoxetine treatment for children with attention-deficit/hyperactivity disorder, including an assessment of evening and morning behavior: a double-blind, placebo-controlled trial. Pediatrics. 2004;114:e1-8.

[6] Dittmann RW, Wehmeier PM, Schacht A, Minarzyk A, Lehmann M, Sevecke K, et al. Atomoxetine treatment and ADHD-related difficulties as assessed by adolescent patients, their parents and physicians. Child Adolesc Psychiatry Ment Health. 2009;3:21.

[7] Martenyi F, Zavadenko NN, Jarkova NB, Yarosh AA, Soldatenkova VO, Bardenstein LM, et al. Atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: a 6-week, randomized, placebo-controlled, double-blind trial in Russia. Eur Child Adolesc Psychiatry. 2010;19:57-66.

[8] Montoya A, Hervas A, Cardo E, Artigas J, Mardomingo MJ, Alda JA, et al. Evaluation of atomoxetine for first-line treatment of newly diagnosed, treatment-naive children and adolescents with attention deficit/hyperactivity disorder. Curr Med Res Opin. 2009;25:2745-54.

[9] Dickson RA, Maki E, Gibbins C, Gutkin SW, Turgay A, Weiss MD. Time courses of improvement and symptom remission in children treated with atomoxetine for attention-deficit/hyperactivity disorder: analysis of Canadian open-label studies. Child Adolesc Psychiatry Ment Health. 2011;5:14.

[10] Kratochvil CJ, Michelson D, Newcorn JH, Weiss MD, Busner J, Moore RJ, et al. High-dose atomoxetine treatment of ADHD in youths with limited response to standard doses. J Am Acad Child Adolesc Psychiatry. 2007;46:1128-37.

[11] 托莫西汀说明书 2016 版

[12] Wietecha LA, Williams DW, Herbert M, Melmed RD, Greenbaum M, Schuh K. Atomoxetine treatment in adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2009;19:719-30.

[13] Urion D. Atomoxetine 「treatment failures」 usually respond to dosing changes. Annals of Neurology. 2012;72:S186.

[14] Block SL, Kelsey D, Coury D, Lewis D, Quintana H, Sutton V, et al. Once-daily atomoxetine for treating pediatric attention-deficit/hyperactivity disorder: comparison of morning and evening dosing. Clin Pediatr (Phila). 2009;48:723-33.

[15] Shang CY, Gau SS. Improving visual memory, attention, and school function with atomoxetine in boys with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2012;22:353-63.

[16] Mendez L, Singh P, Harrison G, Huang YS, Jin X, Cho SC. Academic outcomes in Asian children aged 8-11 years with attention-deficit/hyperactivity disorder treated with atomoxetine hydrochloride. Int J Psychiatry Clin Pract. 2011;15:145-56.

[17] Hazell PL, Kohn MR, Dickson R, Walton RJ, Granger RE, Wyk GW. Core ADHD symptom improvement with atomoxetine versus methylphenidate: a direct comparison meta-analysis. J Atten Disord. 2011;15:674-83.

[18] Dittmann RW, Cardo E, Nagy P, Anderson CS, Bloomfield R, Caballero B, et al. Efficacy and safety of lisdexamfetamine dimesylate and atomoxetine in the treatment of attention-deficit/hyperactivity disorder: a head-to-head, randomized, double-blind, phase IIIb study. CNS Drugs. 2013;27:1081-92.

[19] Dell'Agnello G, Maschietto D, Bravaccio C, Calamoneri F, Masi G, Curatolo P, et al. Atomoxetine hydrochloride in the treatment of children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder: A placebo-controlled Italian study. Eur Neuropsychopharmacol. 2009;19:822-34.

[20] Wilens TE, Newcorn JH, Kratochvil CJ, Gao H, Thomason CK, Rogers AK, et al. Long-term atomoxetine treatment in adolescents with attention-deficit/hyperactivity disorder. J Pediatr. 2006;149:112-9.

[21] Buitelaar JK, Michelson D, Danckaerts M, Gillberg C, Spencer TJ, Zuddas A, et al. A randomized, double-blind study of continuation treatment for attention-deficit/hyperactivity disorder after 1 year. Biol Psychiatry. 2007;61:694-9.

[22] Michelson D, Buitelaar JK, Danckaerts M, Gillberg C, Spencer TJ, Zuddas A, et al. Relapse prevention in pediatric patients with ADHD treated with atomoxetine: a randomized, double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry. 2004;43:896-904.

[23] Hazell P, Zhang S, Wolanczyk T, Barton J, Johnson M, Zuddas A, et al. Comorbid oppositional defiant disorder and the risk of relapse during 9 months of atomoxetine treatment for attention-deficit/hyperactivity disorder. Eur Child Adolesc Psychiatry. 2006;15:105-10.

[24] Kratochvil CJ, Wilens TE, Greenhill LL, Gao H, Baker KD, Feldman PD, et al. Effects of long-term atomoxetine treatment for young children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2006;45:919-27.

[25] van Wyk GW, Hazell PL, Kohn MR, Granger RE, Walton RJ. How oppositionality, inattention, and hyperactivity affect response to atomoxetine versus methylphenidate: a pooled meta-analysis. J Atten Disord. 2012;16:314-24.

[26] Allen AJ, Kurlan RM, Gilbert DL, Coffey BJ, Linder SL, Lewis DW, et al. Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders. Neurology. 2005;65:1941-9.

[27] Bloch MH, Panza KE, Landeros-Weisenberger A, Leckman JF. Meta-analysis: treatment of attention-deficit/hyperactivity disorder in children with comorbid tic disorders. J Am Acad Child Adolesc Psychiatry. 2009;48:884-93.

[28] Geller D, Donnelly C, Lopez F, Rubin R, Newcorn J, Sutton V, et al. Atomoxetine treatment for pediatric patients with attention-deficit/hyperactivity disorder with comorbid anxiety disorder. J Am Acad Child Adolesc Psychiatry. 2007;46:1119-27.

[29] Fernandez-Jaen A, Fernandez-Mayoralas DM, Calleja Perez B, Munoz Jareno N, Campos Diaz Mdel R. Atomoxetine for attention deficit hyperactivity disorder in mental retardation. Pediatr Neurol. 2010;43:341-7.

[30] Shaywitz S, Shaywitz B, Wietecha L, Wigal S, Mcburnett K, Williams D, et al. Effects of atomoxetine on reading abilities in children with dyslexia and children with attention deficit/hyperactivity disorder and comorbid dyslexia. Annals of Neurology. 2012;72:S204.

[31] Sumner CR, Gathercole S, Greenbaum M, Rubin R, Williams D, Hollandbeck M, et al. Atomoxetine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children with ADHD and dyslexia. Child Adolesc Psychiatry Ment Health. 2009;3:40.

[32] Dumitru I, Salan A. Treating children with epilepsy and comorbid attention-deficit/hyperactivity disorder (ADHD). European Journal of Neurology. 2012;19:208.

[33] Donnelly C, Bangs M, Trzepacz P, Jin L, Zhang S, Witte MM, et al. Safety and tolerability of atomoxetine over 3 to 4 years in children and adolescents with ADHD. J Am Acad Child Adolesc Psychiatry. 2009;48:176-85.

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