{
  "abstract": "Background Early discontinuation of attention-deficit/hyperactivity disorder (ADHD) medication is common and linked to worse outcomes. Identifying clinical predictors could aid personalised treatment yet evidence is inconsistent across ages and countries/regions.Objective Investigate psychiatric and neurological comorbidity as predictors of early ADHD medication discontinuation in new ADHD medication users across age groups, sex and countries/regions.Methods Using health records from eight countries/regions, we identified 1 000 411 (44% female) new ADHD medication users (2011–2020). Discontinuation was defined as a ≥180 day gap between dispensations. We examined 23 indicators of psychiatric or neurological comorbidity, severity and psychotropic medication use. Associations were estimated using Cox regression, pooled with random-effects meta-analyses and stratified by age-at-initiation and sex.Findings Discontinuation rates varied widely (children 19%–61%, adolescents 37%–68%, young adults 52–67%, adults 38%–68%). In pooled analyses, earlier discontinuation in children was predicted by intellectual disability, autism and use of psychotropic medications (HR range 1.32–1.51), while conduct/oppositional defiant disorder (CD/ODD) was protective (HR 0.83, 95% CI 0.73 to 0.94). In adolescents, no indicators remained statistically significant after multiple-testing control. In young adults, CD/ODD (HR 1.42, 95% CI 1.30 to 1.55), and in adults, schizophrenia (HR 1.25, 95% CI 1.09 to 1.44) and tic disorders (HR 1.27, 95% CI 1.11 to 1.46) predicted earlier discontinuation. Statistical heterogeneity was substantial, largely driven by US estimates. In meta-analyses excluding the USA, additional associations emerged. For example, in children, OCD and anxiety disorders predicted earlier discontinuation, while eating disorders and antidepressants/anxiolytics were protective in adults. Associations with schizophrenia, tic disorders and CD/ODD were no longer significant. Country-specific analyses showed similar association patterns, except in the USA, Hong Kong and the UK. Sex differences were limited.Conclusions Children with neuropsychiatric comorbidity and related comedication are more likely to discontinue ADHD medication early, whereas few consistent predictors were seen from adolescence onwards. Marked cross-country variation, particularly in the USA, points to system-level influences on treatment patterns.Clinical implications Improving ADHD medication persistence will require consideration of healthcare context and age-specific strategies, including close monitoring for children with complex neuropsychiatric profiles, and consideration of broader factors in adolescents and adults, where clinical predictors were limited.",
  "authors": [
    {
      "affiliations": [
        "Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Stockholm County, Sweden",
        "Department of Global Public Health and Primary Care, University of Bergen, Bergen, Hordaland, Norway"
      ],
      "name": "Isabell Brikell"
    },
    {
      "affiliations": [
        "National Centre for Register-Based Research, Aarhus University, Aarhus, Central Denmark Region, Denmark",
        "Centre for Integrated Register-based Research, Aarhus University, Aarhus, Central Denmark Region, Denmark"
      ],
      "name": "Aske Astrup"
    },
    {
      "affiliations": [
        "National Centre for Register-Based Research, Aarhus University, Aarhus, Central Denmark Region, Denmark",
        "Centre for Integrated Register-based Research, Aarhus University, Aarhus, Central Denmark Region, Denmark"
      ],
      "name": "Theresa Wimberley"
    },
    {
      "affiliations": [
        "National Drug and Alcohol Research Centre, University of New South Wales, Sydney, New South Wales, Australia"
      ],
      "name": "Masako Araki"
    },
    {
      "affiliations": [
        "Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Stockholm County, Sweden"
      ],
      "name": "Zheng Chang"
    },
    {
      "affiliations": [
        "Department of Biomedicine—Human Genetics, Aarhus University, Aarhus, Central Denmark Region, Denmark",
        "Center for Genomics and Personalized Medicine, Aarhus University, Aarhus, Denmark"
      ],
      "name": "Ditte Demontis"
    },
    {
      "affiliations": [
        "Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Stockholm County, Sweden"
      ],
      "name": "Zihan Dong"
    },
    {
      "affiliations": [
        "Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York, USA"
      ],
      "name": "Stephen V Faraone"
    },
    {
      "affiliations": [
        "Department of Pharmacy Administration, School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi, China",
        "Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong"
      ],
      "name": "Le Gao"
    },
    {
      "affiliations": [
        "School of Population Health, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia"
      ],
      "name": "Malcolm B Gillies"
    },
    {
      "affiliations": [
        "Department of Biomedicine, University of Bergen, Bergen, Hordaland, Norway",
        "Division of Psychiatry, Haukeland University Hospital, Bergen, Hordaland, Norway"
      ],
      "name": "Jan Haavik"
    },
    {
      "affiliations": [
        "Interdisciplinary Center Psychopathology and Emotion Regulation (ICPE), Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands"
      ],
      "name": "Catharina Hartman"
    },
    {
      "affiliations": [
        "Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Stockholm County, Sweden",
        "School of Medical Sciences, Örebro University, Orebro, Sweden"
      ],
      "name": "Henrik Larsson"
    },
    {
      "affiliations": [
        "Research Department of Practice and Policy, School of Pharmacy, University College London, London, UK",
        "Centre for Medicines Optimisation Research and Education, University College London Hospitals NHS Foundation Trust, London, England, UK"
      ],
      "name": "Kenneth K C Man"
    },
    {
      "affiliations": [
        "School of Population Health, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia"
      ],
      "name": "Sallie-Anne Pearson"
    },
    {
      "affiliations": [
        "Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands"
      ],
      "name": "Harold Snieder"
    },
    {
      "affiliations": [
        "Interdisciplinary Center Psychopathology and Emotion Regulation (ICPE), Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands"
      ],
      "name": "Melissa Vos"
    },
    {
      "affiliations": [
        "Aston Pharmacy School, Aston University, Birmingham, England, UK",
        "Department of Pharmacology and Pharmacy, University of Hong Kong Faculty of Medicine, Hong Kong, Hong Kong"
      ],
      "name": "Ian C K Wong"
    },
    {
      "affiliations": [
        "Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Stockholm County, Sweden"
      ],
      "name": "Honghui Yao"
    },
    {
      "affiliations": [
        "Research Department of Practice and Policy, School of Pharmacy, University College London, London, UK",
        "Centre for Medicines Optimisation Research and Education, University College London Hospitals NHS Foundation Trust, London, England, UK"
      ],
      "name": "Andrew SC Yuen"
    },
    {
      "affiliations": [
        "Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, New York, USA"
      ],
      "name": "Yanli Zhang-James"
    },
    {
      "affiliations": [
        "University Medical Centre Groningen, Groningen, GR, Netherlands",
        "Department of Epidemiology, University of Groningen, Groningen, GR, Netherlands"
      ],
      "name": "Yiling Zhou"
    },
    {
      "affiliations": [
        "Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Capital Region, Iceland"
      ],
      "name": "Helga Zoega"
    },
    {
      "affiliations": [
        "Department of Global Public Health and Primary Care, University of Bergen, Bergen, Hordaland, Norway",
        "Department of Chronic Diseases, Norwegian Institute of Public Health, Bergen, Norway"
      ],
      "name": "Anders Engeland"
    },
    {
      "affiliations": [
        "Child and Adolescent Mental Health Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, Capital Region of Denmark, Denmark",
        "Department of Clinical Medicine, University of Copenhagen, Copenhagen, Capital Region of Denmark, Denmark"
      ],
      "name": "Søren Dalsgaard"
    },
    {
      "affiliations": [
        "Department of Global Public Health and Primary Care, University of Bergen, Bergen, Hordaland, Norway",
        "Department of Health Promotion, Norwegian Institute of Public Health, Bergen, Norway, Norway"
      ],
      "name": "Kari Klungsøyr"
    }
  ],
  "title": "Psychiatric and neurological predictors of early ADHD medication discontinuation across the lifespan: a multinational study",
  "uid": "cbe6135a-38a0-5e1f-b614-cf7bc24cb009"
}