Objective: To evaluate effects of sapropterin dihydrochloride on blood phenylalanine (Phe) and symptoms of neuropsychiatric impairment in children and adolescents with phenylketonuria (PKU)., Study Design: PKU subjects 8-17 years of age (n = 86) were randomized to double-blind treatment with sapropterin (n = 43) or placebo (n = 43) for 13 weeks, then all received open-label sapropterin therapy for an additional 13 weeks. Blood Phe and symptoms of inattention, hyperactivity/impulsivity (Attention-Deficit/Hyperactivity Disorder Rating Scale IV [ADHD RS-IV]), executive functioning (Behavior Rating Inventory of Executive Function), depression (Hamilton Rating Scale for Depression), and anxiety (Hamilton Rating Scale for Anxiety) were assessed., Results: Following the 13-week randomization phase, the sapropterin and placebo groups had mean changes in blood Phe of -20.9% and +2.9%, respectively. Corresponding least square mean differences in ADHD RS-IV scores were significantly greater for the sapropterin vs the placebo group: Total (-3.2 points, P = .02), Inattention subscale (-1.8 points, P = .04), and Hyperactivity/Impulsivity subscale (-1.6 points, P = .02). Forest plots favored sapropterin treatment over placebo for all ADHD RS-IV and Behavior Rating Inventory of Executive Function indices. There were no significant differences in reported problems with attention or executive function between the 2 groups at baseline or at week 26 following the 13-week open-label treatment period. Anxiety and depression scores did not differ significantly between cohorts at any time. Sapropterin was well tolerated, with a favorable safety profile., Conclusions: Sapropterin reduced blood Phe and was associated with significant improvement in parent-reported symptoms of inattention, hyperactivity/impulsivity, and executive functioning in children and adolescents with PKU., Trial Registration: ClinicalTrials.gov, NCT01114737. Registered 27 April 2010, https://clinicaltrials.gov/ct2/show/NCT01114737., Competing Interests: Declaration of Competing Interest Funding source: BioMarin Pharmaceutical Inc. This manuscript was prepared with assistance from John Mahoney with funding from BioMarin Pharmaceutical Inc. M.L.G. has received consulting fees from and participated as a clinical trial investigator for BioMarin and Encoded Therapeutics. E.R.J. was an employee and stockholder of BioMarin at the time of the study. S.E.M. has received consulting fees from Levo Therapeutics and has participated as a clinical trial investigator for Aardvark Therapeutics, Harmony Biosciences, Levo Therapeutics, and Ultragenyx. S.M.S. has received consulting fees from Acadia, Adamas, Alkermes, Allergan, Abbvie, Arbor Pharmaceuticals, AstraZeneca, Avanir, Axovant, Axsome, Biogen, BioMarin, Biopharma, Celgene, Concert, ClearView, DepoMed, EMD Serono, Eisai Pharmaceuticals, Eurolink, Ferring, Forest, Genomind, Innovative Science Solutions, Impel, Karuna, NeuroPharma, Intra-Cellular Therapies, Ironshore Pharmaceuticals, Janssen, Jazz, Karuna, Lilly, Lundbeck, Merck, Neos, Neurocrine, Novartis, Noveida, Otsuka, Perrigo, Pfizer, Pierre Fabre, Proxymm, Relmada, Reviva, Sage Therapeutics, Servier, Shire, Sprout, Sunovion, TMS NeuroHealth, Takeda, Taliaz, Teva, Tonix, Tris Pharma, Trius, Vanda, Vertex, and Viforpharma; holds options in Genomind, Lipidio, and Delix; has been a board member of RCT Logic and Genomind; has served on speaker bureaus for Acadia, Genentech, Janssen, Lundbeck, Merck, Otsuka, Servier, Sunovion, Takeda, and Teva; and has received research and/or grant support from Acadia, Alkermes, Allergan/AbbVie, AssureX, Astra Zeneca, Arbor Pharmaceuticals, Avanir, Axovant, Biogen, Braeburn Pharmaceuticals, BristolMyer Squibb, Celgene, CeNeRx, Cephalon, Dey, Eisai, Eli Lilly, Forest, GenOmind, Glaxo Smith Kline, Harmony Biosciences, Indivior, Intra-Cellular Therapies, Ironshore, ISSWSH, Janssen, JayMac, Jazz, Lundbeck, Merck, Neurocrine, Neuronetics, Novartis, Otsuka, Pear Therapeutics, Pfizer, Reviva, Roche, Sage, Servier, Shire, Sprout, Sunovion, Supernus, TMS NeuroHealth Centers, Takeda, Teva, Tonix, Torrent, and Vanda. D.A.B. has received consulting fees from BioMarin, Encoded Therapeutics, Synlogic Therapeutics, and Taysha Gene Therapies, and travel support from BioMarin. A.S.-V. has received consulting fees from Acer, Applied Therapeutics, BioMarin, Horizon, and Ultragenyx; has participated as a clinical trial investigator for Acadia, Alexion, Amicus, BioMarin, Cerecor, Genzyme, Homology, Horizon, Kaleido, Mallenkrodt, and Ultragenyx; and has received travel support from BioMarin and Ultragenyx. D.D. is an employee of Creyon Bio and has received consulting fees from Taysha Gene Therapies., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)