COMMENTARY

The Genetics of Attention-Deficit/Hyperactivity Disorder: Current Status and Clinical Implications

Stephen V. Faraone, PhD

Disclosures

November 02, 2006

In This Article

Do Gene Variants Predict Response to ADHD Medications?

Pharmacogenetic studies determine how gene variants influence medication response. Such studies have the potential to discover genetic variants that predict medication efficacy and adverse events. Understanding how genes influence drug response will also help clarify the causes of ADHD and may provide new targets for pharmaceutical development. When considering this literature, it is important to distinguish between 2 types of studies, those that focus on pharmacokinetics and those that focus on pharmacodynamics.

Pharmacokinetic studies seek genes that influence the absorption, distribution, metabolism, or excretion of drugs. They determine whether genetic variants influence the ultimate concentration of the drug at the site of action. Such studies have a long history in psychiatry and will not be reviewed here except to note that the 57 genes in the cytochrome P450 supergene family have been extensively studied and shown to influence the pharmacokinetics of many psychiatric medications, including the tricyclic antidepressants[29] and atomoxetine,[30] which have shown efficacy for ADHD.[31,32,33] These genes predict drug concentrations, not disease status.

As an example, consider Sauer and colleagues'[30] pharmacokinetic study of atomoxetine. Three pathways are involved in the systemic clearance of atomoxetine. One of these is mediated by the cytochrome P450 2D6 enzyme (CYP2D6). The CYP2D6 variants create 2 types of people. One type, the extensive metabolizers, metabolize atomoxetine quickly. By contrast, the poor metabolizers metabolize the drug more slowly. For the extensive metabolizers, atomoxetine has a plasma half-life of 5 hours, whereas among poor metabolizers, the plasma half-life is 22 hours; the average steady-state plasma concentrations are approximately 10 times greater in poor metabolizers compared with extensive metabolizers.[30] As a result, when given the same dose of atomoxetine, bioavailability will be higher for the slow metabolizers compared with the fast metabolizers. Despite these differences between poor metabolizers and extensive metabolizers, the frequency and severity of adverse events are similar regardless of CYP2D6 phenotype, even with the same mg/kg/day dosage.

Pharmacodynamic studies seek genes that modulate the pharmacologic effects of drugs at the site of action. Such studies use data from clinical trials in which subjects have been appropriately titrated so that it is reasonable to assume that the drug concentration at the site of action is sufficient to have a pharmacologic effect. Winsberg and Comings[34] examined the effects of 3 genes, DRD2, DRD4, and DAT1, on the responsiveness of 30 black children with ADHD. The DRD2 and DRD4 gene variants did not predict methylphenidate response. The DAT1 gene did predict methylphenidate response: compared with responders, nonresponders were more likely to have 2 copies of the DAT variant known as the 10-repeat allele (the same variant that had previously been associated with ADHD). These findings were replicated by Roman and associates[35] in a Brazilian sample. Yet, because other studies have reported conflicting results, more work is needed to clarify whether or not DAT1 gene variants predict response to methylphenidate.[36,37,38,39]

Hamarman and colleagues[40] studied the DRD4 7-repeat variant and its association with methylphenidate response in ADHD children. Patients having the DRD4-7 repeat variant required twice the dose of methylphenidate to improve compared with those patients who did not have the variant. Seeger and associates[41] studied the association of methylphenidate response with both the DRD4 7-repeat variant and the 5HTT long and short allele. Although neither gene predicted drug response, they found that patients who had the DRD4*7/5HTT LL combination showed a very poor response to methylphenidate treatment.

In a study of 45 Chinese ADHD patients, Yang and colleagues[42] asked whether variants of the norepinephrine transporter gene predicted response to methylphenidate. They found 1 variant to predict methylphenidate response. Although this small study requires replication, it provides an example of how such studies might lead to the discovery of new medications. Yang and colleagues decided to study the norepinephrine transporter gene because the norepinephrine transporter is the site of action for the therapeutic effects of atomoxetine and tricyclic antidepressants, both of which effectively treat ADHD. If this study had been conducted before we knew about the therapeutic efficacy of such drugs, it would have suggested that the norepinephrine transporter would be a good target for pharmaceutical development. In this manner, it is possible that future pharmacogenomic studies will implicate new targets for the development of ADHD medications.

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