Mechanistic Continuity and Translational Gaps in Attention-deficit/Hyperactivity Disorder Pharmacotherapy: Lessons from Animal Models to Pediatric Trials

Translating preclinical findings into safe and effective pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD) remains a major challenge in pediatric neuropsychopharmacology.This review critically examines why some mechanism-based therapies translate successfully from animal models to clinical practice, whereas others fail despite promising preclinical evidence.Among available models, the spontaneously hypertensive rat (SHR) exhibits strong construct validity and domain-specific predictive validity for conserved catecholaminergic mechanisms relevant to ADHD.Across species, successful therapies generally preserve mechanistic continuity by enhancing prefrontal catecholamine signaling through dopamine transporter inhibition, norepinephrine transporter blockade, or 2A-adrenergic receptor stimulation.Accordingly, stimulants, atomoxetine, guanfacine, and viloxazine extended-release show substantial translational and clinical success.Pediatric trials support this hierarchy, with clinician-rated standardized mean differences versus placebo of approximately 1.02 for amphetamines, 0.78 for methylphenidate, and 0.56 for atomoxetine at around 12 weeks.In contrast, nicotinic and histaminergic agents and certain dopaminergic antagonist strategies have translated poorly because of inadequate target engagement, developmental pharmacokinetic differences, and pediatric safety concerns.Importantly, SHR predictive validity is domain-specific rather than syndrome-wide, as methylphenidate more consistently improves attention and impulsivity than locomotor hyperactivity.Precision medicine, pharmacogenomics, biomarker-guided target engagement, and artificial intelligence-assisted approaches may improve future drug development.Overall, current evidence supports mechanistic continuity, rather than broad behavioral similarity, as a useful framework for translating preclinical findings into effective pediatric ADHD therapies, although prospective evaluation and refinement of this framework remain necessary.