This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This proposal aims to develop pilot data directly from zinc supplementation in attention-deficit/hyperactivity disorder (ADHD), to allow confident calculation of effect sizes and provide other information needed to design a definitive trial of zinc as treatment of ADHD, either alone or as adjunct to stimulant. Zinc is essential to brain function/development. It is a metalloenzyme for 100 metabolic processes involving essential fatty acids, their metabolites, neurotransmitters, and melatonin, which regulates brain dopamine activity, believed deficient in ADHD. Experts suspect widespread marginal (subclinical) zinc deficiency even in the U.S. Symptoms of Zn deficiency include attentional impairment and 'jitters'. Multiple reports show lower zinc levels in ADHD than in normal controls or lab norms. Parent/teacher-rated inattention symptoms correlate inversely (r=.45) with serum zinc. Placebo-controlled response to amphetamine appears linear with adequacy of zinc nutrition. Two midEastern trials suggest benefit from zinc supplementation. If zinc supplementation could be shown an effective treatment for ADHD, either alone or as adjunct to stimulant, it would have tremendous public health importance. A proper clinical trial has been stymied by lack of pilot data for effects on ADHD from actual zinc supplementation of an American diet, from which effect sizes can be calculated confidently. This proposal will gather the necessary pilot data and report the effect sizes and other information needed to plan a trial. Design/Hypotheses: Three tightly-linked studies (actually phases) in the same subjects will compare 15mg/day zinc supplementation (RDA/RDI) to placebo with and without concomitant amphetamine to determine monotherapy effect size, adjunctive therapy effect size, and effect on optimal amphetamine dose. Phase 1 randomizes 52 children age 6-14 to either zinc or Zn-matched placebo for 8 weeks. Phase 2 adds fixed-dose amphetamine (0.5 mg/kg/day) to both randomized groups for 2 weeks. Phase 3 titrates the amphetamine to optimal clinical result over a 3 week period, maintaining the original randomization. Outcome measures include parent/teacher-rated ADHD symptoms for phases 1&2, and amphetamine optimal dose for phase 3. Tissue zinc will be determined by 3 state-of-the-art assays.
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