Effects of Iron Supplementation on Attention Deficit Hyperactivity Disorder in Children Eric Konofal, MD, PhD* † , Michel Lecendreux, MD* † , Juliette Deron, PhD, Mps*, Martine Marchand, MD ‡ , Samuele Cortese, MD*, Mohammed Zaïm, MD § , Marie Christine Mouren, MD*, and Isabelle Arnulf, MD, PhD † Iron deficiency has been suggested as a possible contrib- uting cause of attention deficit hyperactivity disorder (ADHD) in children. This present study examined the effects of iron supplementation on ADHD in children. Twenty-three nonanemic children (aged 5-8 years) with serum ferritin levels <30 ng/mL who met DSM-IV criteria for ADHD were randomized (3:1 ratio) to either oral iron (ferrous sulfate, 80 mg/day, n  18) or placebo (n  5) for 12 weeks. There was a progressive significant decrease in the ADHD Rating Scale after 12 weeks on iron (11.0  13.9; P < 0.008), but not on placebo (3.0  5.7; P  0.308). Improvement on Conners’ Parent Rating Scale (P  0.055) and Conners’ Teacher Rating Scale (P  0.076) with iron supplementation therapy failed to reach significance. The mean Clinical Global Impression- Severity significantly decreased at 12 weeks (P < 0.01) with iron, without change in the placebo group. Iron supplementation (80 mg/day) appeared to improve ADHD symptoms in children with low serum ferritin levels suggesting a need for future investigations with larger controlled trials. Iron therapy was well tolerated and effectiveness is comparable to stimulants. © 2008 by Elsevier Inc. All rights reserved. Konofal E, Lecendreux M, Deron J, Marchand M, Cortese S, Zaïm M, Mouren MC, Arnulf I. Effects of iron supplemen- tation on attention deficit hyperactivity disorder in children. Pediatr Neurol 2008;38:20-26. Introduction Attention deficit hyperactivity disorder is the most common childhood neurobehavioral disorder [1], affecting 5-10% of school-aged children [2]. It is characterized by developmentally inappropriate symptoms of inattention, hyperactivity, and impulsivity with onset before age 7 and impaired functioning in two or more settings [3]. The pathophysiology of attention deficit hyperactivity disorder is complex and not completely understood [2,4]. However, several lines of evidence suggest an imbalance in the dopaminergic and noradrenergic systems [2]. Iron modulates dopamine and noradrenalin production, as a cofactor for tyrosine hydroxylase, the rate-limiting en- zyme of monoamine synthesis. In addition, in animal models iron deficiency decreases dopamine receptor den- sity and activity, as well as monoamine transporter func- tion, resulting in alterations of monoamine uptake and catabolism [5,6]. Brain iron stores are therefore expected to influence the monoamine-dependent functions that are altered in attention deficit hyperactivity disorder. Significantly lower serum ferritin levels (a marker of iron store) have been observed in children with attention deficit hyperactivity disorder than in controls [7]. Indeed, 84% of attention deficit hyperactivity disorder children had serum ferritin levels of 30 ng/mL, compared with 18% of controls (P  0.001). In addition, iron deficiency correlated with the severity of both attention deficit hyperactivity disorder and restless legs syndrome. This sensorimotor disorder, characterized by an irresistible urge to move the legs at rest, relieved by movement and worse in the evening or night, focusing on the role of dopamine systems and of iron metabolism in brain, may be strongly associated with attention deficit hyperactivity disorder [8,9]. All children in our study had normal hemoglobin levels, suggesting that low ferritin levels, more than anemia, could be associated with attention deficit hyper- activity disorder symptoms. However, the cross-sectional design of the study did not allow us to infer causality between iron deficiency and attention deficit hyperactivity *Hôpital Robert Debré, Service de Psychopathologie de l’Enfant et de l’Adolescent and ‡ Service de Biochimie, APHP, Paris, France; † Hôpital Pitié Salpetrière, Fédération des Pathologies du Sommeil, APHP, Paris, France; and § Institut de Recherche Pierre Fabre Innovation Développement, Ramonville, France. Communications should be addressed to: Dr. Konofal; Service de Psychopathologie de l’Enfant et de l’Adolescent; 48 Boulevard Sérurier; 75019 Paris, France. E-mail: eric.konofal@rdb.aphp.fr Received June 12, 2007; accepted August 16, 2007. 20 PEDIATRIC NEUROLOGY Vol. 38 No. 1 © 2008 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2007.08.014 ● 0887-8994/08/$—see front matter