Western Sydney University, Sydney, New South Wales, Australia.
The Whiteley-Martin Research Centre, Department of Surgery, The University of Sydney, Penrith, New South Wales, Australia.
JAMA Pediatr. 2019 Jul 1;173(7):630-639. doi: 10.1001/jamapediatrics.2019.0905.
Evidence on the titration of stimulant medications for attention-deficit/hyperactivity disorder (ADHD) is lacking. However, this lack of evidence has not prevented medication guidelines from specifying apparently arbitrary dose limitations, which could discourage clinicians from titrating methylphenidate to higher and, perhaps for some patients, more efficacious doses.
To determine the evidence on dose titration and adverse events associated with dose titration of stimulants for ADHD.
MEDLINE from 1946, Embase from 1974, and PsycINFO from 1806 through April 1, 2019, were searched to identify relevant articles.
The inclusion criteria were that (1) the study was conducted on children up to 18 years of age; (2) children had a diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, or hyperkinetic disorder according to the International Classification of Diseases codes; and (3) the dose of methylphenidate was determined by titration.
The PRISMA guidelines for abstracting data and assessing data quality and validity were followed. Quality assessment was undertaken using the Jadad scoring system. Statistical analysis was undertaken using a random-effects model.
The outcomes of interest were (1) the doses used in published clinical trials, (2) the clinical justification given by researchers for their selected dose range, and (3) the adverse effects associated with methylphenidate when the dose is established by titration.
A total of 11 randomized clinical trials and 38 cohort studies were analyzed. The randomized clinical trials involved 1304 participants treated with methylphenidate and 887 controls; the 38 cohort studies included 5524 participants. Maximum doses of methylphenidate ranged from 0.8 to 1.8 mg/kg/d. Some studies detailed their method of titration, including starting dose, titration interval, increment dose, and maximum dose. Not all of these studies reported justification for the chosen dose range. Common adverse effects of methylphenidate included insomnia (odds ratio, 4.66; 95% CI, 1.99-10.92; P < .001), anorexia (5.11 higher than for those who took placebo; 95% CI, 1.99-13.14; P < .001), abdominal pain (1.9 times more likely; 95% CI, 0.77-4.77; P = .16), and headache (14% of participants; 95% CI, 10%-20%; P < .001).
A range of maximum doses for methylphenidate was recommended in clinical studies; no discernable scientific justification for any particular dose was given. Reports of life-threatening adverse events were absent; further studies of the efficacy, tolerability, and safety of methylphenidate titrated purely on clinical grounds, without reference to any set maximum dose, are needed.
缺乏关于兴奋剂药物治疗注意缺陷多动障碍（ADHD）的滴定的证据。然而，缺乏证据并没有阻止药物治疗指南指定明显任意的剂量限制，这可能会阻止临床医生将哌醋甲酯滴定至更高的、可能对某些患者更有效的剂量。
确定关于 ADHD 兴奋剂剂量滴定和与剂量滴定相关的不良事件的证据。
1946 年至 2019 年 4 月 1 日期间，通过 MEDLINE、Embase 和 PsycINFO 搜索了相关文章，以确定相关文章。
纳入标准为（1）研究对象为 18 岁以下的儿童；（2）儿童根据《精神障碍诊断与统计手册》诊断为 ADHD，或根据《国际疾病分类》代码诊断为多动障碍；（3）使用哌醋甲酯滴定确定剂量。
遵循了 PRISMA 指南来提取数据和评估数据质量和有效性。使用 Jadad 评分系统进行质量评估。使用随机效应模型进行统计分析。
感兴趣的结果是（1）已发表临床试验中使用的剂量，（2）研究人员为所选剂量范围提供的临床依据，以及（3）通过滴定确定的哌醋甲酯相关的不良反应。
共分析了 11 项随机临床试验和 38 项队列研究。随机临床试验共纳入 1304 名接受哌醋甲酯治疗的参与者和 887 名对照者；38 项队列研究共纳入 5524 名参与者。哌醋甲酯的最大剂量范围为 0.8 至 1.8mg/kg/d。一些研究详细说明了他们的滴定方法，包括起始剂量、滴定间隔、增量剂量和最大剂量。并非所有这些研究都报告了所选剂量范围的理由。哌醋甲酯的常见不良反应包括失眠（比值比，4.66；95%置信区间，1.99-10.92；P<0.001）、厌食（比服用安慰剂的人高 5.11；95%置信区间，1.99-13.14；P<0.001）、腹痛（可能性增加 1.9 倍；95%置信区间，0.77-4.77；P=0.16）和头痛（14%的参与者；95%置信区间，10%-20%；P<0.001）。
在临床研究中推荐了一系列哌醋甲酯的最大剂量；没有给出任何特定剂量的明显科学依据。没有报告危及生命的不良事件；需要进一步研究哌醋甲酯的疗效、耐受性和安全性，纯粹基于临床依据，而不参考任何固定的最大剂量。
