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Choosing best therapy for ADHD difficult, requires consideration of several factors

Tuesday, October 30 2007 | Comments

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What's This? Clinicians encounter several challenges when selecting which treatment may be optimal for patients with attention-deficit/hyperactivity disorder, but more research and new approaches could provide some guidance, according to several experts.

"I think what we want to highlight is that there are multiple factors that go into deciding upon a particular medication," Mark Stein, director of the Hyperactivity, Attention, and Learning Problems Clinic at the University of Illinois at Chicago, said.

He said factors that might affect treatment selection include drug efficacy, safety, cost or availability, tolerability, duration of action, and mode of administration as well as patients' perceptions, stigma, or acceptability.

"But it's not just these factors ..., it's also the clinician's view of those factors, and that's based on their experience and their training and their view of the literature ...." he added.

Dr. Steven Pliszka, chief of the adolescent psychiatry division at the University of Texas Health Science Center at San Antonio, explained some of the difficulties clinicians face when trying to decide on a particular therapy.

"[T]here have been some, a variety of highly variable head-to-head studies, but none of those studies can be considered definitive in the sense, for instance, that the Food and Drug Administration would look at comparative trials to say that drug A is clearly superior or safer than drug B," he said.

He highlighted a variety of studies that have compared dexmethylphenidate hydrochloride as well as methylphenidate hydrochloride and prescription amphetamines in various formulations, but cautioned that clinicians need to keep "methodological quirks" in mind when interpreting data.

For example, results from several trials, including MTA, indicated that patients may respond to 1 stimulant but not another, and that dose adjustments may improve or maintain response to methylphenidate.   

He said that 1 early battle in the field was whether mixed amphetamine salts extended-release or OROS methylphenidate was superior to the other.

"Unfortunately, ... there never has been a clear-cut, head-to-head study between these 2 agents that looks at efficacy. People have discussed side effects a good deal, and a lot of the arguments in the hallway and at conferences would be, 'Well, is one drug stronger than the other? Does it have more side effects than the other?' But it's really impossible to answer that question because [of] the very different methodologies that clinical trials use," he said.

Then, atomoxetine hydrochloride became another option. Studies compared it with various forms of methylphenidate or mixed amphetamine salts extended-release, but dosing methodologies appeared to affect the results.

"So, the main conclusion of the data was not that 1 drug was superior to the others, but there ... clearly were these differential responders," he said, adding that clinicians should pay close attention to the study's construction and titration methodology.

Stein explained other difficulties when selecting treatments, such as the fact that short-term efficacy data do not match effectiveness results and that patients often do not adhere to therapies due to side effects.

Additionally, there are limited data on tolerability, and the definition of "well-tolerated" is unclear. He said there are few predictors of tolerability or poor response, except that age, weight, IQ, comorbidity, type of stimulant, and the stimulant's dose or delivery system are predictors of tolerability at a group level.

Stein reviewed several past and ongoing studies about the side effects of stimulants and atomoxetine, particularly on how they affect sleep outcomes. He summarized by saying that the field is preoccupied with effect sizes of efficacy, even though patients stay on or discontinue drugs based on their tolerability.

The future holds the promise of personalized medicine, in which physical characteristics, genetics, clinical characteristics, or endophenotypes may predict response, Stein said. He added that the goal of pharmacogenetics is to determine the right dose of the right drug for the right patient based on efficacy, dose, and tolerability.

Indeed, Dr. Pliszka noted that in the studies already conducted, no one has ever been able to identify a clinical predictor of response to or superiority of stimulants or nonstimulants based on sex, ADHD subtype, or comorbidity. Thus, patients must have individual differences in the brain, and neuroimaging may provide some guidance.

For the future, potential treatments may involve modafinil, cholinergic approaches, or combinations of psychiatric drugs, all of which are being studied, said Dr. James McCracken, director of the division of child and adolescent psychiatry at the University of California, Los Angeles' Neuropsychiatric Institute-Semel Institute of Neuroscience and Human Behavior.

"I think the optimistic view is that, boy, there's a lot of potential paths that could be explored yet, that could yield newer treatment, combined treatments, modified treatments that could help us provide benefit to many more patients with the condition. I think the genetics [research] suggest[s] a similar conclusion that, namely, the possibility of matching is still there, whether or not these genetic tests will rise to the level of clinical significance for the individual remains to be seen, but at least, at a group level, there is indication of some possible relevance--certainly this needs to be explored," Dr. McCracken concluded.

This information may concern uses that have not been approved by the FDA.

By Shayna Muckerheide

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