Dittmann Ralf W, Schacht Alexander, Helsberg Karin, Schneider-Fresenius Christian, Lehmann Martin, Lehmkuhl Gerd, Wehmeier Peter M
Department of Child and Adolescent Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
J Child Adolesc Psychopharmacol. 2011 Apr;21(2):97-110. doi: 10.1089/cap.2009.0111. Epub 2011 Apr 13.
The primary objective of this study was to evaluate the efficacy of atomoxetine (ATX, target dose 1.2 mg/kg daily) on symptoms of oppositional defiant disorder (ODD) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). A secondary objective was to compare fast versus slow up-titration of ATX.
This was a 3-arm, 9-week, randomized, placebo-controlled, double-blind study in ADHD patients (6-17 years) with comorbid ODD (Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV] criteria A-C) or conduct disorder (CD). ATX-treatment arms were as follows-ATX-fast: 7 days 0.5 mg/kg, then 1.2 mg/kg; ATX-slow: 7 days each at 0.5 and 0.8 mg/kg, then 1.2 mg/kg. Primary outcome was the Swanson, Nolan, and Pelham Rating Scale-Revised (SNAP-IV) ODD-score after 9 weeks (Mixed Effects Model for Repeated Measures, ATX-up-titration groups pooled).
In total, 181 patients were randomized, and 180 evaluated (ATX-fast/ATX-slow/placebo: 60/61/59). Baseline characteristics were comparable (84.4% boys; mean age 11.0 years; DSM-IV: 100% ADHD, 75.6% with combined type, 74.4% ODD, 24.4% CD; SNAP-IV ODD-scores, mean ± standard deviation 15.5 ± 4.35). At week 9, SNAP-IV ODD scores were significantly lower versus placebo in both ATX-groups (least square mean [95% confidence interval]: ATX-fast 8.6 [7.2;9.9]; ATX-slow 9.0 [7.7;10.3]; placebo 12.0 [10.6;13.5]; least square mean, ATX-pooled minus placebo: -3.2 [-5.0, -1.5], effect size: -0.69, p < 0.001). SNAP-IV ADHD-scores, CD symptoms (investigator-rated Attention-Deficit and Disruptive Behavior Disorders Instrument, disruptive behavior), Clinical Global Impressions-Severity, and individual treatment behaviors showed corresponding results. Post-hoc analyses indicated interrelationships between the medication effects on ADHD, ODD, and CD symptom scores. For ATX-slow, time to early dropout was significantly longer versus placebo (Hazard Ratio [95% confidence interval]: 3.57 [1.42;8.94]; p = 0.007). Clinically relevant adverse effects (fatigue, sleep disorders, nausea, and gastrointestinal complaints; weeks 1-3) were reported in 60.0% of ATX-fast, 44.3% of ATX-slow, and 18.6% of placebo group patients.
ATX for 9 weeks significantly reduced symptoms of ODD/CD and ADHD; slower ATX-up-titration may be better tolerated.
本研究的主要目的是评估托莫西汀（ATX，目标剂量为每日1.2mg/kg）对患有注意力缺陷多动障碍（ADHD）的儿童和青少年对立违抗性障碍（ODD）症状的疗效。次要目的是比较ATX快速滴定与缓慢滴定的效果。
这是一项针对患有共病ODD（《精神疾病诊断与统计手册》第4版[DSM-IV]标准A - C）或品行障碍（CD）的ADHD患者（6 - 17岁）进行的三臂、9周、随机、安慰剂对照、双盲研究。ATX治疗组如下：ATX快速组：7天0.5mg/kg，然后1.2mg/kg；ATX缓慢组：0.5mg/kg和0.8mg/kg各7天，然后1.2mg/kg。主要结局是9周后的Swanson、Nolan和Pelham评定量表修订版（SNAP-IV）ODD得分（重复测量混合效应模型，合并ATX滴定组）。
总共181例患者被随机分组，180例接受评估（ATX快速组/ATX缓慢组/安慰剂组：60/61/59）。基线特征具有可比性（84.4%为男孩；平均年龄11.0岁；DSM-IV：100%患有ADHD，75.6%为混合型，74.4%患有ODD，24.4%患有CD；SNAP-IV ODD得分，平均值±标准差为15.5±4.35）。在第9周时，两个ATX组的SNAP-IV ODD得分均显著低于安慰剂组（最小二乘均值[95%置信区间]：ATX快速组8.6[7.2；9.9]；ATX缓慢组9.0[7.7；10.3]；安慰剂组12.0[10.6；13.5]；ATX合并组最小二乘均值减去安慰剂组：-3.2[-5.0，-1.5]，效应大小：-0.69，p<0.001）。SNAP-IV ADHD得分、CD症状（研究者评定的注意力缺陷和破坏性行为障碍量表，破坏性行为）、临床总体印象-严重程度以及个体治疗行为显示出相应结果。事后分析表明药物对ADHD、ODD和CD症状得分的影响之间存在相互关系。对于ATX缓慢组，早期退出时间显著长于安慰剂组（风险比[95%置信区间]：3.57[1.42；8.94]；p = 0.007）。在ATX快速组的60.0%、ATX缓慢组的44.3%和安慰剂组的18.6%的患者中报告了临床相关不良反应（疲劳、睡眠障碍、恶心和胃肠道不适；第1 - 3周）。
ATX治疗9周可显著减轻ODD/CD和ADHD症状；ATX缓慢滴定可能耐受性更好。
