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.

IF 6.6 1区医学 Q1 NEUROSCIENCES

Neuropsychopharmacology Pub Date : 2025-02-14 DOI:10.1038/s41386-025-02062-x

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

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引用次数: 0

Abstract

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.

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来源期刊

Neuropsychopharmacology 医学-精神病学

CiteScore

15.00

自引率

2.60%

发文量

240

审稿时长

2 months

期刊介绍： Neuropsychopharmacology is a reputable international scientific journal that serves as the official publication of the American College of Neuropsychopharmacology (ACNP). The journal's primary focus is on research that enhances our knowledge of the brain and behavior, with a particular emphasis on the molecular, cellular, physiological, and psychological aspects of substances that affect the central nervous system (CNS). It also aims to identify new molecular targets for the development of future drugs. The journal prioritizes original research reports, but it also welcomes mini-reviews and perspectives, which are often solicited by the editorial office. These types of articles provide valuable insights and syntheses of current research trends and future directions in the field of neuroscience and pharmacology.