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<p>ADHD is a chronic neurodevelopmental disorder that significantly affects life outcomes, and current treatments often have adverse side effects, high abuse potential, and a 25% non-response rate, highlighting the need for new therapeutics. This study investigates amlodipine, an L-type calcium channel blocker, as a potential foundation for developing a novel ADHD treatment by integrating findings from animal models and human genetic data. Amlodipine reduced hyperactivity in SHR rats and decreased both hyperactivity and impulsivity in <i>adgrl3.1</i>−/− zebrafish. It also crosses the blood-brain barrier, reducing telencephalic activation. Crucially, Mendelian Randomization analysis linked ADHD to genetic variations in L-type calcium channel subunits (α1-C; CACNA1C, β1; CACNB1, α2δ3; CACNA2D3) targeted by amlodipine, while polygenic risk score analysis showed symptom mitigation in individuals with high ADHD genetic liability. With its well-tolerated profile and efficacy across species, supported by genetic evidence, amlodipine shows potential to be refined and developed into a novel treatment for ADHD.</p>

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Validation of L-type calcium channel blocker amlodipine as a novel ADHD treatment through cross-species analysis, drug-target Mendelian randomization, and clinical evidence from medical records

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月14日

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  • Haraldur Þorsteinsson,
  • Hannes A. Baukmann,
  • Hildur S. Sveinsdóttir,
  • Dagmar Þ. Halldórsdóttir,
  • Bartosz Grzymala,
  • Courtney Hillman,
  • Jude Rolfe-Tarrant,
  • Matthew O. Parker,
  • Justin L. Cope,
  • Charles N. J. Ravarani,
  • Marco F. Schmidt,
  • Karl Æ. Karlsson

摘要

ADHD is a chronic neurodevelopmental disorder that significantly affects life outcomes, and current treatments often have adverse side effects, high abuse potential, and a 25% non-response rate, highlighting the need for new therapeutics. This study investigates amlodipine, an L-type calcium channel blocker, as a potential foundation for developing a novel ADHD treatment by integrating findings from animal models and human genetic data. Amlodipine reduced hyperactivity in SHR rats and decreased both hyperactivity and impulsivity in adgrl3.1−/− zebrafish. It also crosses the blood-brain barrier, reducing telencephalic activation. Crucially, Mendelian Randomization analysis linked ADHD to genetic variations in L-type calcium channel subunits (α1-C; CACNA1C, β1; CACNB1, α2δ3; CACNA2D3) targeted by amlodipine, while polygenic risk score analysis showed symptom mitigation in individuals with high ADHD genetic liability. With its well-tolerated profile and efficacy across species, supported by genetic evidence, amlodipine shows potential to be refined and developed into a novel treatment for ADHD.