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 because 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 other medications are sometimes prescribed for ADHD (e.g. tricyclic antidepressants, clonidine, buproprion), until recently, the FDA had not yet approved any non-stimulant medication as a treatment for ADHD.  On November 26, however, it was announced that Strattera (the brand name for atomoxetine) had received FDA approval as an ADHD treatment for children, adolescents, and adults.  In fact, although stimulant medications have also been shown to be effective for adults with ADHD, Strattera is the only FDA approved medication clinically proven effective for adults.

Unlike stimulants, which are believed to reduce ADHD symptoms through their impact on the availability of dopamine in the central nervous system, Strattera exerts its effect on the neurotransmitter known as norephinphrine. Like some of the longer acting stimulants (e.g. Concerta, Adderall XR), Strattera offers the convenience of once a day dosing.  Because it is not classified as a controlled substance, more convenient phone-in prescription refills will be possible as well.

Even though medication is generally regarded as only one component of an overall treatment program for ADHD, the introduction of an effective new medication for treating ADHD represents an important addition to the range of available treatment options.  Because Strattera works through an entirely different neurochemical mechanism, individuals for whom stimulant medications were not effective, may derive significant benefits from this new treatment.  And, individuals who experienced intolerable side effects from stimulants may not experience those same effects with Strattera.  Finally, some parents who had been unwilling to consider stimulant medication for their child may be amenable to considering treatment with Strattera because it is not classified as a controlled substance.

An important question regarding the use of this new medication, however, is whether it will generally be as effective as the currently available stimulant medications. In two prior studies comparing atomoxetine to methylphenidate (methylphenidate is the generic form of Ritalin) no differences in efficacy was reported, although too few patients received methylphenidate in these studies to draw any firm conclusions.  Thus, additional investigation of how this new medication compares to the stimulants is needed. This was the issue addressed in a study published recently in the Journal of the American Academy of Child and Adolescent Psychiatry (Kratochvil, C.J., et al. Atomoxetine and methylphenidate treatment in childrne with ADHD: A prospective, randomized, open-label trial. JAACAP, 41, 776-784).

Participants were 211 boys and 17 girls between the ages of 7 and 15 (all girls were younger than 9) who had been diagnosed with ADHD using a structured psychiatric interview and standardized behavior-rating scales.  Approximately 75% of participants were diagnosed with the combined subtype of ADHD (i.e. they displayed both inattentive and hyperactive-impulsive symptoms) and almost all others were diagnosed with the inattentive subtype.  (Note: For a complete discussion of diagnostic go to www.helpforadd.com/criteria-for-add/. Approximately half of all participants had a co-occurring diagnosis of oppositional defiant disorder (www.helpforadd.com/co-occurring-disorders/), and about 7% had been diagnosed with depression.

Participants were randomly assigned to receive an open-label trial of either atomoxetine or methylphenidate.  (Note: In an open-label trial participants and those evaluating them are aware of what medication is being received).  Because this study was primarily intended to establish the efficacy of atomoxetine, approximately 4 times as many children received atomoxetine than methylphenidate (i.e. 184 vs. 44). Participants receiving each medication were started on a low dose and titrated upwards based on the investigator's assessment of clinical response.  Unlike the MTA study, where all participants on methyphenidate received 3 doses per day regimen, children receiving methylphenidate in this study were dosed 1 to 3 times per day based on the investigator's assessment of what was optimal.

Prior to beginning medication treatment, investigators comleted the ADHD Rating Scale on each child to assess the severity of the child's symptoms.  Parents completed the Conners Parent Rating Scale, a widely used instrument in the assessment of ADHD.  These measures were completed during weekly follow up visits over a 10-week period.  Because not all participants remained in the study for the entire 10 weeks (see below), the final set of rating scales obtained was considered the treatment outcome measure for each child.  Comparing these ratings with those obtained prior to treatment was then used to determine each child's treatment response.
 

Results

Ten of the 184 children given atomoxetine had their medication discontinued prior to the conclusion of the 10-week trial because of adverse side effects.  Twenty-nine children were discontinued because the parent and/or the physician did not believe the medication was helping.  This non-response rate of about 16% is roughly comparable to what is generally reported for stimulant medications.  In the current study, the percentage of children on methylphenidate who were discontinued because of adverse events or lack of effect was very similar.

For children in both groups, investigators' ratings of ADHD symptom severity declined substantially from the pre-treatment rating to the final rating obtained.  These declines were clinically meaningful in addition to being statistically significant, and were evident for both hyperactive-impulsive and inattentive symptoms.  The magnitude of the decline in ADHD symptoms was roughly equivalent for children treated with the 2 medications.  And, these substantial declines were obtained even though children who had stopped treatment early because of poor response were included in the group averages.

Parent ratings followed a similar course.  Prior to treatment, average ADHD symptom ratings for children in each group were in the top 1% based on age and gender norms. This indicates exceptionally high levels of difficulty.  Following treatment, average scores in both groups dropped significantly and approached - but did not quite reach - normal levels. Once again, these declines occurred for both inattentive and hyperactive-impulsive symptoms, and were roughly comparable in each group. Similar reductions in parents' report of children's cognitive problems were also evident.

In general, both medications were well tolerated by participants and there was little difference in adverse reactions reported.  Two adverse reactions - vomiting and drowsiness/sleepiness - were more common among children taking atomoxetine.  Small reductions in weight occurred both groups.  The authors note that although this is unlikely to be of importance during short-term treatment, medication effects on weight gain during long-term treatment may be more substantial, and that data on weight change associated with ongoing treatment are currently under study.  Information on this issue has not yet been published for any ADHD medication.
 

Summary and Implications

Results provide initial evidence that atomoxetine (i.e. this medication will be marketed under the brand name Strattera) produces comparable benefits to methylphenidate in reducing core ADHD symptoms in children. Each medication was well tolerated by most children, although 2 adverse reactions - i.e.vomiting and drowsiness - occurred more frequently among those receiving atomoxetine.

Although these results suggest that atomoxetine and stimulant medications may be equally effective, study limitations prevent a firm conclusion on this issue.  There are several reasons for this.

First, as the authors appropriately acknowledge, this was not a double-blind, placebo-controlled study, which makes it impossible to completely rule out parent or investigator expectations as influencing the results.

Second, the absence of teacher ratings prevents any conclusion regarding the comparative impact of atomoxetine and methylphenidate on children's behavior at school.

Third, because only data on core ADHD symptoms was presented, the impact on associated problems - e.g. oppositional behavior, academic functioning, peer relationships, etc. - is also unknown.  It would not be prudent to assume that comparability on core ADHD symptoms necessarily translates into equivalent impact on associated difficulties, and this issue awaits further research.  This is important, because to date, the positive impact of medication treatment on long-term academic achievement has not been clearly established for any medication.

Finally, short acting methylphenidate may not be as effective as newer and longer acting stimulants such as Concerta, Adderall-XR, and Ritalin-LA.  Thus, demonstrating equivalent effectiveness between atomoxetine and methylphenidate does not necessarily mean that it will be as effective as these more recently introduced stimulants.  It may be more effective, it may be less effective, or it may be equally effective.  In the absence of direct comparative studies with these agents, however, this will remain an unanswered question.

It is important to note that even if these necessary comparative studies are done, and a particular medication is found - on average - to be superior to others, no single medication will be the best choice for all children.  Thus, a terrific benefit of having Strattera become available is that many children who were not helped by stimulants may derive substantial benefits from Strattera.  On the other hand, it cannot be assumed that a child who is doing well on a stimulant will do as will if switched to Strattera.  This may or may not be the case.  Thus, for a child who has been receiving stimulants and doing well, it is likely that physicians will be appropriately cautious about making a switch.

What about children beginning an initial trial of medication for ADHD treatment?  Will physicians continue to regard stimulants as the initial treatment of choice or will Straterra become widely used as a first line treatment.  Recent treatment guidelines published by the American Academy of Pediatrics recommend that 2-3 stimulants be tried across a full range of doses before switching to another class of medications.  These guidelines were written, however, before Strattera received FDA approval.

The stimulants have also been around for much longer, obviously, and several studies - including the MTA study - have documented their efficacy in symptom management over an extended period.  Studies on the longer-term effectiveness of Strattera are ongoing, however, and should be available shortly.  These will be very interesting and important results to know about, and will likely have a significant impact on physicians' decisions about which type of medication to try initially.

In summary, for parents considering medication for their child, and for physicians who treat children with ADHD, having another clinically proven option that works by a different mechanism and which is not a controlled substance represents a valuable addition to existing treatments.  Research that documents the long-term benefits of Strattera in managing ADHD symptoms, and in helping with associated difficulties, will hopefully be published shortly.  As with any medication, however, efforts to enhance functioning across a range of areas will continue to require additional behavioral and academic supports for many children.  And, careful, systematic monitoring the ongoing effectiveness of treatment will remain essential.