Elsevier

Pediatric Neurology

Volume 38, Issue 1, January 2008, Pages 20-26
Pediatric Neurology

Original article
Effects of Iron Supplementation on Attention Deficit Hyperactivity Disorder in Children

https://doi.org/10.1016/j.pediatrneurol.2007.08.014Get rights and content

Iron deficiency has been suggested as a possible contributing 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.

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 enzyme of monoamine synthesis. In addition, in animal models iron deficiency decreases dopamine receptor density and activity, as well as monoamine transporter function, 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 hyperactivity disorder symptoms. However, the cross-sectional design of the study did not allow us to infer causality between iron deficiency and attention deficit hyperactivity disorder; only a clear benefit of iron supplementation therapy in attention deficit hyperactivity disorder children would provide strong evidence for this causality. In one open-label study, Sever et al. [10] observed a significant decrease of the Conners’ Parent Rating Scale scores after iron supplementation in attention deficit hyperactivity disorder children without iron deficiency. The hypothesis for the present study was that attention deficit hyperactivity disorder children with iron deficiency also would benefit more from iron therapy. The objective was to assess the effects of iron supplementation on attention deficit hyperactivity disorder symptoms in iron-deficient nonanemic children in a double-blind, placebo-controlled, randomized design.

Section snippets

Patients

Subjects were outpatient children with attention deficit hyperactivity disorder aged 5-8 years who met DSM-IV diagnostic criteria for attention deficit hyperactivity disorder [3] by clinical assessment and had serum ferritin levels <30 ng/mL (retaining the definition of iron deficiency from a previous study) [7] with normal hemoglobin levels at the screening.

We excluded potential subjects if they had an IQ < 80 by the French version of the Wechsler Intelligence Scale, third edition, for

Results

A total of 23 children (18 boys and 5 girls) with attention deficit hyperactivity disorder and a low serum ferritin level (<30 ng/mL) at screening (between day –7 and day –3) met the inclusion criteria and were randomized to treatment with oral ferrous sulfate 80 mg/day (n = 18) or placebo (n = 5) at baseline (day 0). Of these, 19 children (83%) had serum ferritin levels of <30 ng/mL at baseline. Two patients discontinued iron supplementation: one for constipation and one lost to follow-up. No

Discussion

To our knowledge, this is the first double-blind, randomized, placebo-controlled trial of oral ferrous sulfate on attention deficit hyperactivity disorder symptoms in iron-deficient nonanemic children.

Subjects who received iron supplementation therapy reported significant improvement on total score and on hyperactive/impulsive and inattentive subscales of the ADHD RS. Restless legs symptoms also were improved in the treatment group, but not in placebo. As previously reported, restless legs

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