Psychiatric Research Unit, Region Zealand Psychiatry, Slagelse, Denmark.
Child and Adolescent Psychiatric Department, Region Zealand, Roskilde, Denmark.
Cochrane Database Syst Rev. 2023 Mar 27;3(3):CD009885. doi: 10.1002/14651858.CD009885.pub3.
Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children and adolescents with ADHD find it difficult to pay attention and they are hyperactive and impulsive. Methylphenidate is the psychostimulant most often prescribed, but the evidence on benefits and harms is uncertain. This is an update of our comprehensive systematic review on benefits and harms published in 2015.
To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD.
We searched CENTRAL, MEDLINE, Embase, three other databases and two trials registers up to March 2022. In addition, we checked reference lists and requested published and unpublished data from manufacturers of methylphenidate.
We included all randomised clinical trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. The search was not limited by publication year or language, but trial inclusion required that 75% or more of participants had a normal intellectual quotient (IQ > 70). We assessed two primary outcomes, ADHD symptoms and serious adverse events, and three secondary outcomes, adverse events considered non-serious, general behaviour, and quality of life.
Two review authors independently conducted data extraction and risk of bias assessment for each trial. Six review authors including two review authors from the original publication participated in the update in 2022. We used standard Cochrane methodological procedures. Data from parallel-group trials and first-period data from cross-over trials formed the basis of our primary analyses. We undertook separate analyses using end-of-last period data from cross-over trials. We used Trial Sequential Analyses (TSA) to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the GRADE approach.
We included 212 trials (16,302 participants randomised); 55 parallel-group trials (8104 participants randomised), and 156 cross-over trials (8033 participants randomised) as well as one trial with a parallel phase (114 participants randomised) and a cross-over phase (165 participants randomised). The mean age of participants was 9.8 years ranging from 3 to 18 years (two trials from 3 to 21 years). The male-female ratio was 3:1. Most trials were carried out in high-income countries, and 86/212 included trials (41%) were funded or partly funded by the pharmaceutical industry. Methylphenidate treatment duration ranged from 1 to 425 days, with a mean duration of 28.8 days. Trials compared methylphenidate with placebo (200 trials) and with no intervention (12 trials). Only 165/212 trials included usable data on one or more outcomes from 14,271 participants. Of the 212 trials, we assessed 191 at high risk of bias and 21 at low risk of bias. If, however, deblinding of methylphenidate due to typical adverse events is considered, then all 212 trials were at high risk of bias.
methylphenidate versus placebo or no intervention may improve teacher-rated ADHD symptoms (standardised mean difference (SMD) -0.74, 95% confidence interval (CI) -0.88 to -0.61; I² = 38%; 21 trials; 1728 participants; very low-certainty evidence). This corresponds to a mean difference (MD) of -10.58 (95% CI -12.58 to -8.72) on the ADHD Rating Scale (ADHD-RS; range 0 to 72 points). The minimal clinically relevant difference is considered to be a change of 6.6 points on the ADHD-RS. Methylphenidate may not affect serious adverse events (risk ratio (RR) 0.80, 95% CI 0.39 to 1.67; I² = 0%; 26 trials, 3673 participants; very low-certainty evidence). The TSA-adjusted intervention effect was RR 0.91 (CI 0.31 to 2.68).
methylphenidate may cause more adverse events considered non-serious versus placebo or no intervention (RR 1.23, 95% CI 1.11 to 1.37; I² = 72%; 35 trials 5342 participants; very low-certainty evidence). The TSA-adjusted intervention effect was RR 1.22 (CI 1.08 to 1.43). Methylphenidate may improve teacher-rated general behaviour versus placebo (SMD -0.62, 95% CI -0.91 to -0.33; I² = 68%; 7 trials 792 participants; very low-certainty evidence), but may not affect quality of life (SMD 0.40, 95% CI -0.03 to 0.83; I² = 81%; 4 trials, 608 participants; very low-certainty evidence).
AUTHORS' CONCLUSIONS: The majority of our conclusions from the 2015 version of this review still apply. Our updated meta-analyses suggest that methylphenidate versus placebo or no-intervention may improve teacher-rated ADHD symptoms and general behaviour in children and adolescents with ADHD. There may be no effects on serious adverse events and quality of life. Methylphenidate may be associated with an increased risk of adverse events considered non-serious, such as sleep problems and decreased appetite. However, the certainty of the evidence for all outcomes is very low and therefore the true magnitude of effects remain unclear. Due to the frequency of non-serious adverse events associated with methylphenidate, the blinding of participants and outcome assessors is particularly challenging. To accommodate this challenge, an active placebo should be sought and utilised. It may be difficult to find such a drug, but identifying a substance that could mimic the easily recognised adverse effects of methylphenidate would avert the unblinding that detrimentally affects current randomised trials. Future systematic reviews should investigate the subgroups of patients with ADHD that may benefit most and least from methylphenidate. This could be done with individual participant data to investigate predictors and modifiers like age, comorbidity, and ADHD subtypes.
注意力缺陷多动障碍（ADHD）是儿童期最常见的诊断和治疗的精神疾病之一。通常，患有 ADHD 的儿童和青少年难以集中注意力，他们表现得过度活跃和冲动。哌甲酯是最常开的精神兴奋剂，但关于其益处和危害的证据并不确定。这是我们 2015 年关于益处和危害的全面系统综述的更新。
评估哌甲酯对 ADHD 儿童和青少年的有益和有害影响。
我们检索了 CENTRAL、MEDLINE、Embase、另外三个数据库和两个试验登记处，截至 2022 年 3 月。此外，我们检查了参考文献列表，并向哌甲酯制造商请求了已发表和未发表的数据。
我们纳入了所有比较哌甲酯与安慰剂或无干预治疗的随机临床试验（RCT），纳入对象为年龄在 18 岁及以下、被诊断为 ADHD 的儿童和青少年。检索没有限制出版年份或语言，但试验纳入要求 75%或更多的参与者具有正常的智商（智商>70）。我们评估了两个主要结局，ADHD 症状和严重不良事件，以及三个次要结局，被认为是非严重的不良事件、一般行为和生活质量。
两名综述作者独立对每项试验进行数据提取和偏倚风险评估。包括两名参与原始出版物更新的综述作者在内的六名综述作者参与了 2022 年的更新。我们使用了标准的 Cochrane 方法学程序。来自平行组试验的数据和交叉试验的第一期数据是我们主要分析的基础。我们使用交叉试验的最后一期数据进行了单独的分析。我们使用试验序贯分析（TSA）来控制 I 型（5%）和 II 型（20%）错误，并根据 GRADE 方法对证据进行评估和降级。
我们纳入了 212 项试验（16302 名随机参与者）；55 项平行组试验（8104 名随机参与者）和 156 项交叉试验（8033 名随机参与者），以及一项平行阶段（114 名参与者）和交叉阶段（165 名参与者）的试验。参与者的平均年龄为 9.8 岁，年龄范围为 3 至 18 岁（两项试验的年龄范围为 3 至 21 岁）。男女比例为 3:1。大多数试验是在高收入国家进行的，212 项试验中有 86/212 项（41%）是由制药业资助或部分资助的。哌甲酯治疗持续时间从 1 天到 425 天不等，平均持续 28.8 天。试验比较了哌甲酯与安慰剂（200 项试验）和无干预（12 项试验）。只有 165/212 项试验包括了来自 14271 名参与者的一个或多个结局的可用数据。在 212 项试验中，我们评估了 191 项试验存在高偏倚风险，21 项试验存在低偏倚风险。然而，如果考虑到由于典型不良反应而对哌甲酯进行去盲，那么所有 212 项试验都存在高偏倚风险。
哌甲酯与安慰剂或无干预相比，可能改善教师评定的 ADHD 症状（标准化均数差（SMD）-0.74，95%置信区间（CI）-0.88 至-0.61；I²=38%；21 项试验；1728 名参与者；极低确定性证据）。这相当于 ADHD 评定量表（ADHD-RS）上的平均差异（MD）为-10.58（95%CI-12.58 至-8.72）。最小临床相关差异被认为是 ADHD-RS 上 6.6 分的变化。哌甲酯可能不会影响严重不良事件（风险比（RR）0.80，95%CI 0.39 至 1.67；I²=0%；26 项试验，3673 名参与者；极低确定性证据）。TSA 调整后的干预效果为 RR 0.91（CI 0.31 至 2.68）。
哌甲酯可能比安慰剂或无干预更引起被认为是非严重的不良事件（RR 1.23，95%CI 1.11 至 1.37；I²=72%；35 项试验；5342 名参与者；极低确定性证据）。TSA 调整后的干预效果为 RR 1.22（CI 1.08 至 1.43）。哌甲酯可能改善教师评定的一般行为（SMD-0.62，95%CI-0.91 至-0.33；I²=68%；7 项试验；792 名参与者；极低确定性证据），但可能不影响生活质量（SMD 0.40，95%CI-0.03 至 0.83；I²=81%；4 项试验，608 名参与者；极低确定性证据）。
我们 2015 年版综述的大多数结论仍然适用。我们的更新荟萃分析表明，哌甲酯与安慰剂或无干预相比，可能改善儿童和青少年 ADHD 教师评定的 ADHD 症状和一般行为。但对严重不良事件和生活质量可能没有影响。哌甲酯可能与被认为是非严重的不良事件，如睡眠问题和食欲下降有关。然而，所有结局的证据确定性都非常低，因此确切的影响仍不清楚。由于与哌甲酯相关的不良事件频率较高，参与者和结局评估者的双盲尤其具有挑战性。为了应对这一挑战，应寻求并使用活性安慰剂。可能很难找到这样的药物，但确定一种可能模拟哌甲酯易识别的不良反应的物质，可以避免目前随机试验中因无法双盲而产生的不利影响。未来的系统评价应调查可能从哌甲酯中获益最大和最小的 ADHD 患者亚组。这可以通过个体参与者数据来完成，以调查年龄、合并症和 ADHD 亚型等预测和修饰因素。
