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Weekly UpdatesAt an estimated prevalence of 3%-7% of U.S. children, attention-deficit/hyperactivity disorder is the most common of all childhood psychiatric disorders.
In some cases, the diagnosis is relatively straightforward, and response to a first-line stimulant is rapid and profound--resulting in a noticeable improvement in symptoms of hyperactivity, impulsivity, and inattention across domains of a child's life.
A conundrum develops, however, when a seemingly adequate trial of a stimulant fails to produce any noticeable effect on a child.
When confronted with such cases in their own practices, do ADHD experts question the diagnosis, the environment, the dose, the child's compliance, the choice of stimulant, or the drug class itself?
"All of the above," said Dr. Robert L. Findling, director of child and adolescent psychiatry at Case Western Reserve University, Cleveland.
The first thing to consider is whether the initial diagnosis is correct, and whether it is made with attention to contextual developmental, interpersonal, and family clues.
"Is the child an angel at home but a beast in the classroom? What else is going on?" asked Dr. Syed S.A. Naqvi, director of the pediatric psychopharmacology clinic at Cedars-Sinai Medical Center in Los Angeles. After the initial diagnosis is revisited and confirmed, a critical early step is to determine whether the child has received "a decent trial of a stimulant at an adequate dose," Dr. Naqvi said. "Some people are very quick in changing medications."
A good rule of thumb is to ensure that a child has been taking a medication at an optimal dose for several weeks, with feedback data from multiple sources such as parents, teachers, coaches, even peers before considering the possibility of nonresponse.
A recent medical claims analysis found that ADHD dosing tends to be lower in the community than in clinical trials, although psychiatrists were more likely than other specialists to titrate the dose and prescribe higher maximum doses of some stimulant formulations (J. Am. Acad. Child Adolesc. Psychiatry 2009;48:51-9).
The timing of the dose or use of an extended-release formulation also might need to be maximized, providing for coverage through school hours and beyond, particularly if a child's response seems spotty throughout the day. With older children, especially, compliance also might be an important consideration.
Doses might be forgotten in a chaotic household, or a patient might be diverting the medication. For example, a literature review by Dr. Timothy E. Wilens, a child psychiatrist at Harvard University and Massachusetts General Hospital, Boston, and his associates found that 16%-29% of students with stimulant prescriptions complied at some point to requests to "give, sell, or trade" their medications (J. Am. Acad. Child Adolesc. Psychiatry 2008;47:21-31).
Even when the patient is taking the medication at the dose prescribed, a problem with efficacy might result. "While stimulants are highly effective for treatment of ADHD, a number of patients simply do not respond to the treatment," Dr. Wilens said in an interview.
"Response to stimulants is nonspecific. Those without ADHD may have some improvement in attention. Conversely, those with ADHD may not respond," he said.
Still, "you go with your odds," said Dr. Findling, which makes the identification of a true nonresponder quite unusual.
Response rates to an initial psychostimulant hover at about 70% in children in clinical studies, whose diagnoses have often been confirmed by several different methods. When a switch is made within the class, that is, from a methylphenidate formulation to an amphetamine/dextroamphetamine, or vice versa, the response rates inch even higher.
"When something doesn't fit the picture, maybe there's something wrong with the picture," Dr. Findling said.
However, Dr. Josephine Elia, co-medical director of the Center for the Management of ADHD at the Children's Hospital of Philadelphia, said that when you do get a response with stimulants, you get one that is "quite robust."
When that fails to happen, the assessment needs to be revisited to ensure that no comorbidities or nonmedical issues have been missed.
"You need to understand what is going on in the child's life that may have nothing to do with how they respond to pharmacotherapy. It's too easy to gravitate to pharmacologic answers first," Dr. Findling said.
For example, a child whose school performance has not improved might simply not be doing the homework, he said.
Dr. Naqvi agreed. A child not doing as well in math as her other subjects "needs a math tutor; she does not need me to double her dose of Concerta," he said. Any child's behavior involves a complex interaction of development, personality, family, and school dynamics, as well as an underlying diagnosis of ADHD (perhaps along with comorbidities such as anxiety, a mood disorder, or conduct disorder).
That's why many experts say most children in their care undergo multidisciplinary interventions, including cognitive-behavioral therapy; family therapy and parent training; stress management training; or interpersonal skills training in addition to medication.
Consistent interventions at school and at home should maximize the child's opportunities to focus, stay on task, and reduce impulsivity.
All avenues should be explored if the medication seems not to be working.
When contributing issues have been ruled out and dosing maximized, experts uniformly agreed that they would switch from one stimulant type to another, that is, from methylphenidate to amphetamine-based preparations.
After again maximizing dosing with no response, many would turn to atomoxetine (Strattera), a nonstimulant, which might not have the efficacious power of the stimulants but is still considered a very useful medication in some patients.
"It is the best-studied nonstimulant, has [Food and Drug Administration] approval across the lifespan, and extensive safety data." Dr. Wilens said.
Some evidence supporting the notion of a class-dependent response for some ADHD patients can be found in a recent randomized, double-blind crossover study by the Atomoxetine/Methylphenidate Comparative Study Group (Am. J. Psychiatry 2008;165:721-30).
Investigators randomly assigned children aged 6-16 years with ADHD to receive treatment with atomoxetine (222 children), osmotically released methylphenidate (220), or placebo (74).
Both active agents were significantly superior to placebo and similar in side effects, with discontinuations attributable to adverse events rare in both groups. Response rates to methylphenidate were statistically superior to atomoxetine. However, the data got interesting when it came to the differences between responders and nonresponders.
About one-third of 423 patients who completed 6 weeks of randomized treatment responded either to osmotically released methylphenidate or to atomoxetine, but not both. About 44% of patients responded to both treatments and 22% responded to neither.
The 70 patients who did not respond to methylphenidate in the first 6-week stage of the trial were crossed over to receive atomoxetine, with 30 of these initial nonresponders obtaining significant benefit from the second drug. Specialists said they occasionally turn to atomoxetine first, depending on a child's comorbidities.
A personal or family history of tics, for example, might lead Dr. Elia to prescribe a nonstimulant first to avoid exacerbating the comorbidity or bringing it out.
Dr. Findling and Dr. Wilens receive, or have received, research support, acted as consultants, and/or served on speakers bureaus for numerous companies that manufacture drugs used in the treatment of ADHD.
Dr. Naqvi and Dr. Elia reported no current relevant financial disclosures.
By Betsy Bates. Share your thoughts and suggestions at cpnews@elsevier.com.
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