Garcia-Argibay Miguel, Chang Zheng, Brikell Isabell, Kuja-Halkola Ralf, D'Onofrio Brian M, Lichtenstein Paul, Newcorn Jeffrey H, Faraone Stephen V, Larsson Henrik, Cortese Samuele
Developmental Evidence synthesis, Prediction, Implementation lab, Centre for Innovation in Mental Health, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK; Hampshire and Isle of Wight NHS Foundation Trust, Southampton, UK; School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Lancet Psychiatry. 2025 Feb;12(2):131-139. doi: 10.1016/S2215-0366(24)00396-1. Epub 2025 Jan 6.
Randomised controlled trials (RCTs) evaluating ADHD medications often use strict eligibility criteria, potentially limiting generalisability to patients in real-world clinical settings. We aimed to identify the proportion of individuals with ADHD who would be ineligible for medication RCTs and evaluate differences in treatment patterns and clinical and functional outcomes between RCT-eligible and RCT-ineligible individuals.
We used multiple Swedish national registries to identify individuals with ADHD, aged at least 4 years at the age of diagnosis, initiating pharmacological treatment between Jan 1, 2007, and Dec 31, 2019, with follow-up up to Dec 31, 2020. Hypothetical RCT ineligibility was established using exclusion criteria from the international MED-ADHD dataset, including 164 RCTs of ADHD medications. Cox models evaluated differences in medication switching and discontinuation within 1 year between eligible and ineligible individuals. Quasi-Poisson models compared eligible and ineligible individuals on rates of psychiatric hospitalisations, injuries or accidents, and substance use disorder within 1 year of initiating ADHD medications. People with lived experience of ADHD were not involved in the research and writing process.
Of 189 699 individuals included in the study cohort (112 153 men and boys [59%] and 77 546 women and girls [41%]; mean age 21·52 years [SD 12·83; range 4-68]) initiating ADHD medication, 53% (76 477 [74%] of 103 023 adults [aged >17 years], 12 658 [35%] of 35 681 adolescents [aged 13-17 years], and 10 643 [21%] of 50 995 children [aged <13 years]) would have been ineligible for RCT participation. Ethnicity data were not available. Ineligible individuals had a higher likelihood of treatment switching (hazard ratio 1·14, 95% CI 1·12-1·16) and a decreased likelihood of medication discontinuation (0·96, 0·94-0·98) compared with eligible individuals. Individuals ineligible for RCTs had significantly higher rates of psychiatric hospitalisations (ncidence rate ratio 9·68, 95% CI 9·57-9·78) and specialist care visits related to substance use disorder (14·78, 14·64-14·91), depression (6·00, 5·94-6·06), and anxiety (11·63, 11·56-11·69).
Individuals ineligible for ADHD medication trials face higher risks of adverse outcomes. This study provides the first empirical evidence for the limited generalisability of ADHD RCTs to real-world clinical populations, by applying eligibility criteria extracted from a comprehensive dataset of RCTs to a large real-world cohort. Triangulating evidence from RCTs and real-world studies is crucial to inform rigorous evidence-based treatment guidelines.
National Institute of Healthcare and Research, European Union's Horizon 2020, and Swedish Research Council.
评估注意力缺陷多动障碍（ADHD）药物的随机对照试验（RCT）通常采用严格的纳入标准，这可能会限制其在现实临床环境中对患者的适用性。我们旨在确定不符合药物RCT纳入标准的ADHD患者比例，并评估符合RCT标准和不符合RCT标准的个体在治疗模式、临床及功能结局方面的差异。
我们利用瑞典多个国家登记处，确定在2007年1月1日至2019年12月31日期间开始药物治疗、诊断时年龄至少4岁且随访至2020年12月31日的ADHD患者。使用国际MED-ADHD数据集（包括164项ADHD药物RCT）中的排除标准确定假设的不符合RCT标准的情况。Cox模型评估符合标准和不符合标准的个体在1年内药物转换和停药的差异。准泊松模型比较符合标准和不符合标准的个体在开始ADHD药物治疗后1年内的精神病住院率、受伤或事故率以及物质使用障碍率。有ADHD生活经历的人未参与研究和撰写过程。
在纳入研究队列的189699名开始ADHD药物治疗的个体中（112153名男性和男孩[59%]，77546名女性和女孩[41%]；平均年龄21.52岁[标准差12.83；范围4 - 68岁]），53%（103023名成年人[年龄>17岁]中的76477名[74%]，35681名青少年[年龄13 - 17岁]中的12658名[35%]，50995名儿童[年龄<13岁]中的10643名[21%]）不符合RCT参与标准。种族数据不可得。与符合标准的个体相比，不符合标准的个体治疗转换的可能性更高（风险比1.14，95%置信区间1.12 - 1.16），停药的可能性更低（0.96，0.94 - 0.98）。不符合RCT标准的个体精神病住院率（发病率比9.68，95%置信区间9.57 - 9.78）以及与物质使用障碍（14.78，14.64 - 14.91）、抑郁症（6.00，5.94 - 6.06）和焦虑症（11.63，11.56 - 11.69）相关的专科护理就诊率显著更高。
不符合ADHD药物试验标准的个体面临更高的不良结局风险。本研究通过将从RCT综合数据集中提取的纳入标准应用于一个大型现实世界队列，首次为ADHD RCT对现实临床人群的适用性有限提供了实证证据。将RCT证据与现实世界研究证据相结合对于制定严格的循证治疗指南至关重要。
国家医疗保健和研究机构、欧盟地平线2020计划以及瑞典研究委员会。
