Original articleEffects of Iron Supplementation on Attention Deficit Hyperactivity Disorder in Children
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
References (25)
Attention-deficit/hyperactivity disorder: a selective overview
Biol Psychiatry
(2005)- et al.
Attention-deficit/hyperactivity disorder
Lancet
(2005) - et al.
Altered monoamine metabolism in caudate-putamen of iron-deficient rats
Pharmacol Biochem Behav
(1994) - et al.
Restless Legs Syndrome Diagnosis and Epidemiology workshop at the National Institutes of Health. International Restless Legs Syndrome Study Group. Restless legs syndrome: Diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health
Sleep Med
(2003) - et al.
Randomised study of cognitive effects of iron supplementation in non-anaemic iron-deficient adolescent girls
Lancet
(1996) - et al.
Serum ferritin in children with attention-deficit hyperactivity disorder
Pediatr Neurol
(2006) Clinical practice guideline: diagnosis and evaluation of the child with attention-deficit/hyperactivity disorder
Pediatrics
(2000)Diagnostic and statistical manual of mental disorders (DSM-IV)
(1994)- et al.
Iron deficiency: differential effects on monoamine transporters
Nutr Neurosci
(2005) - et al.
Iron deficiency in children with attention-deficit/hyperactivity disorder
Arch Pediatr Adolesc Med
(2004)