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.

• Tác giả: Hannes A Baukmann, Justin L Cope, Bartosz Grzymala, Dagmar Þ Halldórsdóttir, Courtney Hillman, Karl Æ Karlsson, Matthew O Parker, Charles N J Ravarani, Jude Rolfe-Tarrant, Marco F Schmidt, Hildur S Sveinsdóttir, Haraldur Þorsteinsson
• Ngôn ngữ: eng
• Thông tin xuất bản: England : Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology , 2025
• Bộ sưu tập: NCBI
• ID: 105424

Tóm tắt

 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.