Significantly lower serum ferritin levels have been observed in children with attention deficit hyperactivity disorder (ADHD). In fact, in an earlier study conducted by the authors of the study described below, 84% of children n with ADHD had serum ferritin levels <30 ng/mL, compared with 18% of controls (P < 0.001).

Although the pathophysiology of ADHD is complex and not completely understood, several lines of evidence suggest that ADHD is the result of an imbalance in the dopaminergic and noradrenergic systems. Since iron is an important modulator of these systems, it is believed that subnormal brain iron stores may negatively influence these systems, and contribute to the development of ADHD. All children in the previous study had normal hemoglobin (Hb) levels, suggesting that ADHD was more likely to be caused by low serum ferritin levels, compared to anemia. However, the study was not designed to infer causality between iron deficiency and ADHD. In order to provide strong evidence of causality, children with ADHD would need to demonstrate a clear benefit from iron supplementation. Therefore, the following double-blind, placebo-controlled, randomized pilot study tested the effects of iron supplementation on iron deficient, nonanemic children with ADHD.

The study population consisted of outpatient children with ADHD (confirmed by DSM-IV criteria) aged 5-8 years old who had normal Hb levels and serum ferritin levels <30 ng/mL (the definition of iron deficiency in this study). Iron status was based on a variety of biochemical measurements, in particular - the normalization of serum ferritin levels in these children. Patients with ADHD were randomly assigned (3:1) to receive 80 mg ferrous sulfate tablets for a period of 12 weeks. At baseline and week 12, children were tested using the Conners’ Parent Rating Scale (primary endpoint), Conner's Teachers Rating Scale, Attention Deficit Hyperactive Disorder rating scale, DSM-IV criteria, and the Clinical Global Impression Severity-Scale. Patients were also tested for restless legs syndrome using the International Restless Legs Syndrome Study Group criteria for children.

Twenty three children (18 boys and 5 girls) met the inclusion criteria and were randomly assigned to receive oral iron therapy (n=18) or placebo (n = 5). Two patients discontinued iron therapy due to constipation and one patient was lost to follow-up.

Serum ferritin levels increased in the iron treatment group, from 29.1 +/- 17.6 ng/mL at baseline to 55.7 +/- 20.4 ng/mL at week 12 (P = 0.000). In contrast, the iron status of children in the placebo group did not improve. A progressive significant decrease in the ADHD Rating Scale was observed in children after 12 weeks of iron therapy (-11.0 +/- 13.9; P < 0.008), compared with children receiving placebo (3.0 +/- 5.7; P = 0.308). However, children receiving iron therapy did not show improvement that reached statistical significance as measured by the Conners’ Parent Rating Scale (P = 0.055) and Conners’ Teacher Rating Scale (P = 0.076). Symptoms of restless leg syndrome were improved in children receiving iron therapy compared to placebo. However, no correlation was found between serum ferritin level and occurrence of restless leg symptoms. A major limitation of this study, according to the authors, was the small sample size. However, the authors concluded that the results provide the rationale for larger multisite studies.

Effects of iron supplementation on attention deficit hyperactivity disorder in children. Konofal E, Lecendreux M, Deron J, Marchand M, Cortese S, Zaïm M, Mouren MC, Arnulf I. Pediatr Neurol. 2008 Jan;38(1):20-6.

NAAC Expert Commentary:
Although the pathophysiology of ADHD is complex and not completely understood, there is increasing evidence that brain iron stores influence the monoamine-dependent functions that are altered in ADHD. Previously, low serum ferritin levels have indicated decreased iron stores even before the development of anemia. In addition, a relationship between iron deficiency, cognitive impairment and motor instability has been recognized in children even in the absence of anemia.(1)

This study presents evidence that iron deficiency may contribute to the overall pathophysiology of ADHD, even though a causal link has not been established. Important to consider is that the use of the CPRS total score as the primary outcome may be problematic because non-ADHD factors could mask or dilute the effect of iron supplementation. As commented on by the authors, this was only a small pilot study, and a larger multisite trial will be required before changes in clinical practice can be recommended. Future studies should address normal serum ferritin values and specific iron doses, especially because the long-term effects of iron therapy in this pediatric population is not known.

Normal serum ferritin values vary by age in young children, and indicate total body iron stores in the absence of liver disease, chronic inflammation or infection. Children with chronic medical conditions including malnutrition were excluded from the current study, but other possible cofounders of serum ferritin were not addressed.

When caring for young children it is also important to assess dietary history and screen for iron deficiency in those patients at risk, including:

• toddlers and adolescent females
• young children poorly absorbing or not consuming iron-rich foods
• infants born prematurely
• children who consume excessive cow’s milk
• adolescents with poor diet, rapid growth or menstrual blood loss

References

1. Biederman J. Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry. 2005 Jun 1;57(11):1215-20.

Last Modified: June 4, 2008