Abstract
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with unclear pathological mechanisms. ADHD is treated with both stimulant and non-stimulant medications, but their therapeutic mechanisms and impact on brain metabolites are not fully understood. This study employed an untargeted metabolomics approach with liquid chromatography mass spectrometry to investigate the pathogenesis of ADHD, as well as the effects of established and novel therapeutics. We characterized the metabolomic signatures of the adgrl3.1 mutant zebrafish ADHD model and examined the impact of methylphenidate, guanfacine, atomoxetine and five novel putative therapeutics identified in a prior screen, including amlodipine. Our analysis revealed that the drugs commonly affect pathways related to amino acid and lipid metabolism, specifically involving glycine, serine, threonine, phenylalanine, lysophosphatidylcholine, and sphingomyelin. This convergence on similar metabolic targets was unexpected and suggests a broader, systemic effect of ADHD therapeutics, challenging the traditional view of distinct drug mechanisms. Amlodipine exhibited metabolic effects consistent with established treatments, indicating its potential as a viable alternative or adjunct therapy. These findings provide new insights into the metabolic underpinnings of ADHD and highlight potential targets for developing improved therapeutic strategies.