TY - JOUR
T1 - 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
AU - Þorsteinsson, Haraldur
AU - Baukmann, Hannes A.
AU - Sveinsdóttir, Hildur S.
AU - Halldórsdóttir, Dagmar
AU - Grzymala, Bartosz
AU - Hillman, Courtney
AU - Rolfe-Tarrant, Jude
AU - Parker, Matthew O.
AU - Cope, Justin L.
AU - Ravarani, Charles N.J.
AU - Schmidt, Marco F.
AU - Karlsson, Karl
N1 - Publisher Copyright: © The Author(s) 2025.
PY - 2025/6
Y1 - 2025/6
N2 - 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.
AB - 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.
KW - Amlodipine/pharmacology
KW - Animals
KW - Attention Deficit Disorder with Hyperactivity/drug therapy
KW - Calcium Channel Blockers/pharmacology
KW - Calcium Channels, L-Type/genetics
KW - Female
KW - Humans
KW - Male
KW - Mendelian Randomization Analysis
KW - Rats
KW - Rats, Inbred SHR
KW - Species Specificity
UR - https://www.scopus.com/pages/publications/85217779239
U2 - 10.1038/s41386-025-02062-x
DO - 10.1038/s41386-025-02062-x
M3 - Article
C2 - 39953207
SN - 0893-133X
VL - 50
SP - 1145
EP - 1155
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 7
M1 - 104494
ER -