注意缺陷多动障碍的药物干预
注意缺陷多动障碍的药物干预：一项系统评价与剂量-效应网络荟萃分析
Pharmacological interventions for ADHD: a systematic review and dose–effect network meta-analysis
——《柳叶刀 / 精神病学》第13卷，第6期，2026年6月——
【摘要】背景：优化ADHD（注意缺陷多动障碍）药物治疗剂量是最大化疗效的关键，然而大多数临床指南对此提供的指导信息有限。尽管人们日益关注药物剂量不足（低于治疗有效剂量）的问题，但尚未针对所有ADHD药物及各年龄段人群全面评估剂量-效应关系。本研究旨在估算ADHD药物（包括兴奋剂和非兴奋剂）在不同年龄段人群中的疗效与耐受性剂量-效应曲线。方法：我们对评估口服单药治疗（兴奋剂和非兴奋剂）的随机双盲对照试验（RCT）进行了系统评价和剂量-效应网状荟萃分析。纳入对象为符合标准化ADHD诊断标准的5岁及以上个体。研究排除了涉及遗传综合征、难治性人群或包含停药期设计的研究。我们从MED-ADHD数据库（更新于2025年2月17日）检索符合条件的研究，未设语言限制，并纳入了已发表及未发表的汇总数据。主要结局指标为疗效（通过经临床验证的量表评估），次要结局指标为耐受性（因不良事件导致的停药）。我们使用Cochrane偏倚风险评估工具（第2版）评估了研究内部的偏倚风险。利用包含限制性立方样条（restricted cubic splines）的分层贝叶斯模型，我们总结了剂量与效应之间的关联。针对儿童或青少年（<18岁）与成人（≥18岁）分别进行了分析。通过关键效应调节因素的分布情况，我们检验了网状分析的传递性假设。具有ADHD亲身经历的人士参与了本研究的概念构思、设计以及结果解读工作。研究方案已在OSF平台上预注册。结果：我们在2017年的检索中识别出9948篇潜在文献，并在2025年2月17日的检索中识别出5148篇文献。在这总计15,096篇文献中，8467篇在标题和摘要筛选阶段被排除，另有5862篇在全文阅读阶段被排除。在剩余的767份报告中，164份被纳入系统评价，113项随机对照试验（RCT）（45项针对成人，68项针对儿童和青少年）被纳入剂量-效应网状荟萃分析。针对儿童和青少年的68项RCT共纳入14,138名受试者（男性9,981人[70.6%]，女性4,157人[29.4%]），针对成人的45项RCT共纳入11,016名受试者（男性5,958人[54.0%]，女性5,056人[46.0%]）。各RCT对种族或族裔数据的报告不一致。我们发现不同药物类别和年龄组呈现出独特的剂量-效应模式。在儿童和青少年中，哌甲酯、苯丙胺类药物和胍法辛的疗效中位数随剂量增加而提升，分别在45毫克/天、25毫克/天和4毫克/天时达到峰值；尽管更高剂量下的估算值具有较宽的可信区间，但未发现更高剂量能带来额外获益的证据。在成人中，苯丙胺类药物的疗效在剂量超过约50毫克/天时出现平台期；而哌甲酯的疗效持续增加，未见平台期，这可能归因于数据稀缺。研究观察到因不良事件导致停药的可能性随剂量增加而上升，具体表现为：苯丙胺类药物（儿童剂量超过25毫克/天，成人超过50毫克/天）和哌甲酯（成人剂量超过50毫克/天；儿童未见明显的剂量依赖性风险）。我们未发现托莫西汀（在固定剂量研究中）和莫达非尼存在剂量-效应模式的证据。多项敏感性分析证实了这些结果的稳健性。我们未发现存在非传递性（intransitivity）的证据。解读：我们的研究结果对以下两种做法提出了挑战：一是“治疗惰性”，即在疗效不佳时未进一步调整剂量却选择维持现状；二是盲目增加剂量至获批上限以上，而此时潜在危害可能超过预期获益。我们的研究结果可为临床指南提供参考，并应支持关于ADHD药物剂量的共同决策。
[Summary] Background: Optimising the dosage of pharmacological treatments for ADHD is key to maximising their benefits, yet most clinical guidelines provide only limited information on this issue. Dose–effect relationships have not been comprehensively assessed across all ADHD medications and age groups, despite growing concerns about subtherapeutic prescribing. We aimed to estimate dose–effect curves for efficacy and tolerability of ADHD medications (stimulants and non-stimulants) across age groups. Methods: We conducted a systematic review and dose–effect network meta-analysis of double-blind randomised controlled trials (RCTs) evaluating oral monotherapy (stimulants and non-stimulants) in individuals aged 5 years and older meeting standardised ADHD criteria. Studies involving genetic syndromes, treatment-resistant populations, or withdrawal-phase designs were excluded. We retrieved eligible studies from the MED-ADHD database, updated on Feb 17, 2025, without language restrictions. We included published and unpublished aggregated-level data. The primary outcome was efficacy (measured using validated clinical scales) and the secondary outcome was tolerability (discontinuation due to adverse events). Within-study bias was assessed with the Cochrane Risk of Bias Tool (version 2). We summarised dose–effect associations using a hierarchical Bayesian model with restricted cubic splines. Separate analyses were conducted for children or adolescents (aged <18 years) and adults (aged ≥18 years). The distribution of key effect modifiers was used to examine transitivity of the network. People with lived experience were involved in the conceptualisation and design of the study, and in the interpretation of the findings. The protocol was pre-registered on OSF. Findings: Our 2017 search identified 9948 potential references for inclusion and our Feb 17, 2025 search identified 5148 references. Of these 15?096 references, 8467 were excluded after title and abstract screening, and a further 5862 references were excluded after a full-text read. Of the 767 remaining reports, 164 were included in the systematic review and 113 RCTs (45 in adults and 68 in children and adolescents) were included in the dose–effect network meta-analysis. The 68 RCTs on children and adolescents included 14?138 participants (9981 [70·6%] males and 4157 [29·4%] females) and the 45 RCTs on adults included 11?016 participants (5958 [54·0%] males and 5056 [46·0%] females). Data on ethnicity or race were inconsistently reported across RCTs. We found distinct dose–effect patterns by medication class and age group. In children and adolescents, methylphenidate, amphetamines, and guanfacine showed increasing median efficacy up to 45 mg/day, 25 mg/day and 4 mg/day, respectively, with no evidence of additional benefit at higher doses, although estimates at higher doses were characterised by wide credible intervals. In adults, amphetamines showed a plateau above approximatively 50 mg/day, whereas methylphenidate efficacy increased without evidence of a plateau, possibly due to sparse data. Dose-dependent increases in discontinuation probability due to adverse events were observed for amphetamines (above 25 mg/day for children and 50 mg/day for adults) and methylphenidate (above 50 mg/day for adults, with no clear dose-dependent risk for children). We found no evidence of dose–effect patterns for atomoxetine (in fixed-doses studies) and modafinil. Multiple sensitivity analyses confirmed the robustness of these findings. We found no evidence of intransitivity. Interpretation: Our findings challenge both therapeutic inertia—accepting suboptimal response without further dose titration—and uncritical dose escalation beyond licensed limits, when potential harms outweigh expected benefits. Our findings can inform clinical guidelines and should support shared decision making regarding ADHD medication dosage.
论文原文：Mikail Nourredine, Lucie Jurek, Tasnim Hamza, et al. (2026). Pharmacological interventions for ADHD: a systematic review and dose–effect network meta-analysis. The Lancet / Psychiatry, Volume 13, Issue 6, Pages 485-495. June 2026.
https://doi.org/10.1016/S2215-0366(26)00091-X
（翻译兼责任编辑：MARY）
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