In this report we evaluated the putative impact of DAT1 on the efficacy and tolerability of methylphenidate in adults with ADHD. Subjects homozygous for the 10-repeat DAT1 allele were not distinguishable from heterozygous 9/10 or homozygous 9-repeat allele subjects in level of symptom reduction, dose required for response, cardiac side effects, or spontaneously reported adverse effects. Although tempered by the small size, these results fail to support a role of the DAT1 VNTR in the 3'-UTR as a moderator of efficacy or tolerability of methylphenidate treatment for adults with ADHD.
The potential of pharmacogenomic research is to identify genetic markers that will enable genotype based clinical algorithms that optimize response and tolerability for individual patients (McGough 2005
). The literature on DAT1 highlights the current challenges to achieving this goal, however. Although methylphenidate may exert a therapeutic effect on ADHD via blockade of the dopamine transporter and there is indication that the 10-repeat DAT1 allele is associated with ADHD, the literature examining modification of treatment response has been mixed and inconclusive.
The current report is the second to demonstrate no difference in response based upon DAT1 genotype (Langley et al. 2005
). As discussed by Langley et al (2005)
the lack of consistency in the literature could be due to etiological heterogeneity or, more likely, due to small sample sizes that lead to reduced power or false positive findings. In a recent literature review, it was shown that an equal number of studies indicate either a reduced or enhanced response to methylphenidate in subjects with the 10-repeat allele (McGough 2005
). Taking together, the literature converges on a pattern of results that seem to be consistent with chance findings (i.e. Type I or Type II errors).
In the event that DAT1 genotypes do not modify the rate of response to methylphenidate, it is possible that they could impact the doses required to achieve a therapeutic effect. Our studies were designed to determine optimal dose after either a 3-week forced titration (Spencer et al. 2005
) or a flexible dosing protocol (Biederman et al. in press
). Among responders we did not find a statistically significant difference in dose between DAT1 genotypes. However, the lowest dose (0.8 mg/kg) was used in subjects with the 9/9-repeat genotype. Considering the in vitro
findings that the 10/10 variant may be associated with an increased DAT binding density (Vanness et al. 2005
), larger studies specifically designed to address genotype differences in the dose-response relationship in adults with ADHD are needed.
We also examined cardiovascular and adverse effects in these data. Although we found no consistent statistical evidence of any association with DAT1 genotypes on these variables, qualitative differences in the 9/9-repeat subjects raises a few questions. In particular, we found a 16-point increase in systolic blood pressure in these subjects that, coupled with the qualitatively lower dose in this group, may indicate that individuals with the 9/9-repeat genotype are at greatest risk for adverse cardiovascular effects and can only tolerate lower doses. However, the number of subjects with the 9/9-repeat (N=6) was very small resulting in reduced power to detect differences with this group and imprecise point estimates. While the difference between groups on AISRS scores was so small that very large sample sizes would be needed to detect them, differences in blood pressure and dose were large enough that moderately larger studies would have the power to follow-up on these findings.
This study is also limited in that we only examined a single marker that does not provide adequate information about other variants across this rather large gene. Thus, we can only comment on the role of the VNTR in the 3'-UTR with these data. Langley et al (2005)
did examine three additional single nucleotide polymorphisms (SNPs) in the promoter region of the gene and failed to find any association with response to methylphenidate. Considering the strong theoretical basis indicating a role of DAT in the etiology and treatment of ADHD a more rigorous examination of this gene is warranted.