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A double-blind, placebo-controlled study of zinc sulfate as a treatment for ADHD

Although carefully conducted medication treatment and behavior therapy are effective treatments for ADHD, not all children with ADHD benefit from these interventions.  Thus, even in the most rigorous treatment study of ADHD ever conducted - the MTA study - some children were not helped significantly by these interventions. (You can read a review of factors affecting treatment response in the MTA study at www.helpforadd.com/2003/july.htm ).  There is thus a need for continued research on new ADHD treatments that offer effective alternatives for children who do not benefit from these traditional interventions.

One finding that has sparked the search for an effective alternative ADHD intervention is the evidence suggesting that deficiencies in trace minerals such as zinc and/or magnesium may contribute to ADHD symptoms in some children.  Thus, prior research has shown that individuals with ADHD have lower zinc levels compared to those without ADHD, and that zinc deficiency contributes to hyperactivity and impaired concentration. Although the percentage of children with ADHD who are deficient in zinc is not known, this finding raises the possibility that zinc supplementation could benefit at least some diagnosed children.

To date, there have been no carefully controlled studies testing the effectiveness of this treatment approach.  A study published recently in the journal Progress in Neuro-Psychopharmacology & Biological Psychiatry titled "Double-blind, placebo-controlled study of zinc sulfate in the treatment of attention deficit hyperactivity disorder" thus provides the first rigorous test of this intervention.

This interesting study was conducted in Turkey and began by screening over 20,000 primary school children for ADHD symptoms using standardized behavior rating scales completed by children's teachers.  Over 2500 children identified as being at-risk for ADHD based on the screening results subsequently received a comprehensive ADHD evaluation to confirm or rule out the diagnosis. Six hundred eighteen children who met full ADHD diagnostic criteria, and who did not have any co-occurring disorders (e.g. depression, conduct disorder) were selected to participate in the study.

Note: The fact that children who met diagnostic criteria for another psychiatric disorder besides ADHD were excluded from the study is potential study limitation.  This limits the generalizability of the results described below to the subset of children with ADHD who do not have co-occurring difficulties, and these children are likely to have somewhat milder cases of ADHD to begin with.

Of the 618 diagnosed children, 400 (72 girls and 328 boys; mean age 9 years) were randomly assigned to receive either oral zinc sulfate or placebo over a 12-week period.  (Most of the remaining 218 eligible children did not participate because their parents did not want them to.) The daily dose of zinc sulfate was 150-mg for all participants and contained approximately 40-mg of zinc.  Dose remained constant across the 12-week study.  Zinc sulfate and placebo were administered orally by mixing them into a breakfast drink such as fruit juice.  Neither parents, children, nor children's teachers were aware of whether the child was receiving zinc sulfate or placebo.

To assess treatment efficacy, parents and teachers completed ADHD behavior-rating scales of ADHD before treatment began, and again after 1, 4, and 12 weeks had elapsed.  Measures of zinc in participants' bloodstream were collected at baseline and at these same intervals to determine whether initial levels predicted treatment response, and whether treatment increased zinc levels as expected.

RESULTS

Parent ratings

Parent behavior ratings indicated that children treated with zinc sulfate experienced a significant reduction in ADHD symptoms compared to children in the placebo group.  This difference was evident by week 4 and persisted until the study ended 8 weeks later.  By the end of the study, approximately 40% of treated children had parent ratings for hyperactivity and impulsivity that fell within the normal range.  In contrast to the benefits observed for hyperactive-impulsive symptoms, there was no indication that zinc sulfate treatment was effective in reducing children's problems with attention.

Teacher ratings

Behavior ratings provided by teachers revealed a similar pattern of findings: children treated with zinc sulfate showed a significant reduction - relative to comparison children - on teacher ratings of hyperactivity and conduct problems.  Once again, however, there was no evidence of improvement in attention difficulties.

Predictors of treatment response

The authors also examined factors that predicted a favorable response to zinc sulfate treatment.  Children who had lower zinc levels to begin with were most likely to benefit from treatment.  Children who were older, and who had higher BMIs (body mass index) also tended to show a better treatment response.  As expected, blood levels of zinc increased during the study for treated children but not for children receiving placebo.

Tolerability

The most frequent side effect of zinc sulfate treatment was a metallic taste in the mouth.  This was reported by over 50% of treated children compared with only 8% of comparison children.  A wide range of other possible side effects were reported by fewer than 5% of treated children, and did not occur more frequently than in children who received placebo.

SUMMARY AND IMPLICATIONS

This is the first placebo-controlled, double-blind study on the effectiveness of zinc supplementation as a treatment for ADHD.  Results are encouraging in that children treated with zinc showed significant improvement relative to comparison children in the hyperactive-impulsive symptoms of ADHD according to both parents and teachers.  Consistent with the theory that zinc deficiencies contribute to ADHD symptoms in some children, improvement was more likely for children with lower zinc levels to begin with, and zinc levels increased as a result of treatment.  The treatment was tolerated well by most children, and other than experiencing a mild metallic taste, there was no indication of adverse side effects.

On a less positive note, there was no indication of any reduction in children's problems with attention.  Attention problems are a core element of ADHD and have a particularly harmful effect on children's academic functioning.  And, as reviewed in a recent issue of Attention Research Update (www.helpforadd.com/2003/november.htm), attention problems may be uniquely associated with increased risk for substance abuse.  The absence of any impact on inattentive symptoms is thus a significant limitation of this treatment. It should also be noted that even in those areas where zinc treatment was effective, i.e., hyperactive and impulsive symptoms, only 40% of treated children had scores in these areas at the study's conclusion that were considered "normalized".

It is also important to note that because only children with ADHD who did not have other co-occurring conditions were included as participants, the impact of zinc sulfate treatment on children with comorbid difficulties is unknown.  It cannot be assumed that the treatment would also have been effective for such children.  This would be an important issue to examine in subsequent research.

Future research should examine the impact of this treatment on children with ADHD who show reduced zinc levels to begin with.  If treatment response were especially good in this group, it would suggest that this may be an important intervention for the subgroup of children with ADHD who have low zinc levels.  This would be especially true if improvement in inattentive symptoms were found for this subset of children with ADHD.  Currently, the percentage of children with ADHD who are deficient in zinc is not known, and the American Academy of Pediatrics does not currently recommend that screening for zinc deficiencies be routinely conducted.  Determining this percentage could be important information to obtain in subsequent research.

In the meantime, results from this study suggest that zinc supplementation may be effective for some children in addressing the hyperactive-impulsive symptoms of ADHD.  However, as the authors note, this treatment does not constitute an adequate intervention by itself.  Instead, they suggest that it may be a useful addition to the treatment regimes of some children with ADHD (i.e., especially those with prominent hyperactive-impulsive symptoms) but should not currently be employed as a stand-alone or primary intervention approach.


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