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Atomoxetine: A New Medication Option for Treating ADHD
Although stimulant medication has been shown to be a helpful treatment for many children and adolescents with ADHD, there remains considerable interest in developing other medicinal options. This is due to the fact that not all children with ADHD respond positively to stimulants and some experience adverse reactions that preclude their use. In addition, although stimulants are generally believed to be extremely safe medications, they are classified as controlled substances and many parents have concerns about the long-term effects of their use.
Although several other medications are sometimes prescribed for ADHD (e.g. tricyclic antidepressants, clonidine, buproprion), the FDA has not yet approved any non-stimulant medication for use with children. During 2002, however, FDA approval is expected for a new non-stimulant ADHD medication called Atomoxetine. A study published in a recent issue of Pediatrics (Michelson, D. et al., (2001). Atomoxetine in the treatment of children and adolescents with ADHD: A randomized, placebo-controlled, dose-response study, Pediatrics, 108) presents data from a large, multi-site trial of the efficacy of this new medication. Because this medication is likely to be introduced with considerable fanfare, it is important for parents and professionals to have a good understanding of the data supporting its use.
Participants in this study were 297 8 to 18 year-old children (212 boys/85 girls) at 13 outpatient investigative sites across the country. All participants met DSM-IV criteria for ADHD, confirmed using a structured psychiatric interview. Approximately 65% displayed inattentive and hyperactive/impulsive symptoms with most remaining participants showing predominantly inattentive symptoms. In addition to meeting formal diagnostic criteria, all participants had to have a symptom severity score on the ADHD Rating Scale in the top 7% for children of their age and gender. (The ADHD-RS is an 18-item scale in which parents rate the severity of each of the 18 symptoms of ADHD listed in DSM-IV). Seventy percent of the children had previously been treated with stimulants.
Before starting treatment, baseline measures were collected using the ADHD-RS -- the primary outcome measure used in this study -- along with several additional measures. These measures included the Conners Parent Rating Scale- Revised (CPRS-R), the Clinical Global Impressions of Severity (CGI-S -- a measure used by clinicians to rate the severity of a child's symptoms), and the Child Health Questionnaire (CHQ). The CHQ is a parent-rated health outcome scale in which parents rate the well being of their family, themselves, and their child.
After baseline assessments were completed, participants were randomly assigned to one of 4 conditions: placebo, low dose (.5 mg/kg), middle dose (1.2 mg/kg), or high dose (1.8 mg/kg). Atomoxetine was administered as equally divided doses in the morning and afternoon. Children in the middle- and high-dose conditions began at the .5 mg/kg dose, then had their dosage increased at weekly intervals over a 3 to -4-week period. Treatment continued for 8 -weeks, at which time the measures administered at baseline were again administered to determine treatment effects.
Results
Overall, results indicate that Atomoxetine had a beneficial effect on both the primary symptoms of ADHD and associated impairments. At both the middle and high doses, reductions in ADHD symptoms reported by parents were significantly greater than those for the placebo condition. This was true for both inattentive symptoms and hyperactive/impulsive symptoms and for both older and younger participants. The latter is an important finding in that it indicates Atomoxetine is helpful for adolescents with ADHD as well as children.
In addition to these beneficial effects on core ADHD symptoms (i.e. inattention and hyperactivity/impulsivity), parents' reports also indicated a significant reduction in oppositional behavior. This was true across all 3 doses. Parents' reports on the Child Health Questionnaire indicated that improvements in social and family functioning were superior among Atomoxetine patients when compared with those in the placebo group. Thus, Atomoxetine treatment was associated with functional improvement that clearly went beyond the core symptoms of ADHD.
Atomoxetine was well tolerated by participants at all 3 dosage levels. Adverse reactions did not occur any more frequently among children treated with Atomoxetine than among those in the placebo group. There was a trend, however, towards parents reporting greater sleep difficulties and appetite reduction among children treated with Atomoxetine, particularly at the highest dosage level.
Although these results are encouraging, it is important to recognize that many children treated with Atomoxetine continued to display elevated levels of ADHD symptoms. The average score on the ADHD-RS at the end of the 8-week study was still in the top 7% for children of the same age and gender. This means about half of the participants treated with Atomoxetine continued to show ADHD symptoms that were at or above the initial cutoff established to qualify children for the study. This is consistent with post-treatment results for the Clinical Global Impressions Ratings of Severity (CGI-S), in which, according to clinicians' ratings, only half of the participants had symptoms that were considered absent, minimal, or mild. Thus, half the children continued to show symptoms judged to be moderate or severe.
Summary And Implications
Results from this study indicate that Atomoxetine will be a valuable new treatment option for children and teens with ADHD when it becomes available. As noted above, this is expected to occur during 2002. Because Atomoxetine will be the first non-stimulant specifically approved for the treatment of ADHD, and will not be classified as a controlled substance, it is likely that this medication will generate considerable interest.
Although this study demonstrates the clinical benefits of Atomoxetine, it is important to be cognizant of several factors related to its use. First, this study was conducted over an 8-week period and data on the longer-term effects of this medication have not yet been published. Second, because no direct comparison was made with stimulant medications, the efficacy of Atomoxetine in comparison to traditional stimulant medications is not known. Thus, there is no clear basis for determining whether this drug should be considered a first line treatment option for ADHD, or whether it should be used primarily for individuals who do not respond well to stimulants.
There were also several interesting and clinically relevant questions that could have been addressed in this report, but were not. First, no analyses were reported in which children with the inattentive subtype of ADHD were considered separately. This is unfortunate because it would be important to know whether Atomoxetine is equally effective on children with both the combined and inattentive subtypes of ADHD, especially since so little treatment research has been reported for the former. Second, no separate analyses were reported for gender, leaving unknown the question of whether this medication is equally helpful for boys and girls.
Perhaps the biggest limitation to keep in mind, however, is the fact that many children treated with Atomoxetine are likely to remain highly symptomatic. Recall that the average score on the ADHD-RS at the end of treatment was 1.5 standard deviations above the age-appropriate mean (i.e. in the top 7%) and only half of the participants were rated as showing no more than minimal symptoms on the CGI-S. This is not meant to minimize the large number of participants that were helped significantly , but it does serve as an important reminder that no medication is equally effective for all children and the response of each individual child needs to be carefully monitored.
Assuming Atomoxetine receives FDA approval as expected, it will be a useful addition to the medical treatment options for children and adolescents with ADHD. It remains to be seen, however, whether it will best be used as a first-line option or as an alternative for children who do not respond well to stimulants. As with all currently available ADHD medications, however, it appears that many children will not benefit as much from this treatment as one would like, and that adjunctive treatments targeting residual difficulties will continue to be extremely important.
Note: This article originally appeared in Attention Research Update, an online newsletter written by Dr. David Rabiner, a Duke University psychologist and former member of CHADD's Professional Advisory Board. You can learn more about Attention Research Update and sign up for a free subscription at www.helpforadd.com.