Response to methylphenidate is not influenced by DAT1 polymorphisms in a sample of Brazilian adult patients with ADHD

Abstract

Several lines of evidence suggest a relevant role for the dopamine transporter (DAT1) gene not only as a susceptibility factor for attention-deficit hyperactivity disorder (ADHD), but also as a predictor of individual methylphenidate (MPH) response. Pharmacogenetic studies of MPH response in ADHD have mainly focused on the 40-bp variable number of tandem repeats (VNTR) in the 3' untranslated region (3'-UTR) of DAT1. Most studies were performed in samples of children and conflicting findings were obtained. Only two studies have assessed 3'-VNTR in samples of adults-one with positive and the other with negative findings. In the present study, we investigate three potentially relevant polymorphisms in DAT1 gene (-839 C > T; Int8 VNTR and 3'-VNTR), and their possible role in therapeutic response to MPH treatment in a sample of 171 Brazilian adults with ADHD. The diagnostic procedures followed the DSM-IV criteria and the outcome measures were the scales Swanson, Nolan, and Pelham Rating scale version IV and the Clinical Global Impression-Severity Scale, applied at the beginning and after the 30th day of treatment. Drug response was assessed by both categorical and dimensional approaches. There was no effect of any DAT1 polymorphisms or haplotypes on MPH response. This is the second report demonstrating absence of differences in MPH response according to DAT1 genotypes in adults with ADHD. Although DAT protein is crucial for the effect of MPH, genetic variations in DAT1 gene probably do not have a significant clinical role in this sample of adults with ADHD.

Meta-analysis of the association between dopamine transporter genotype and response to methylphenidate treatment in ADHD

“…48,55,[57][58][59][60] Meta-analysis of the hyperactivity/impulsivity subscale revealed no significant summary effect size (d ¼ À 0.22, 95% CI: À 0.6 to 0.16, z ¼ À 1.1363, P ¼ 0.3, I 2 ¼ 84.14%, 95% CI for I 2 : 58.94-97.62%, see Figure 4a). Meta-analysis of the inattention subscale also revealed no significant summary effect size (d ¼ À 0.05, 95% CI: À 0.4 to 0.3, z ¼ À 0.2813, P ¼ 0.8, I 2 ¼ 81.88%, 95% CI for I 2 : 51.33-97.57%, see Figure 4b).…”

“…After restricting the analysis to studies in children by excluding three studies in adult subjects, 47,54,58 there was a nonsignificant effect size of d ¼ À 0.24 (95% CI: À 0.62 to 0.13, z ¼ À 1.2627, P ¼ 0.2, I 2 ¼ 56.93%, 95% CI for I 2 : 23.47-92.17%). There was evidence for a publication bias in the funnel plot and in the Egger's test (z ¼ À 2.14, P ¼ 0.03).…”

“…A total of 16 studies published between 1999 and 2010 matched the search criteria (see Table 1), resulting in a final sample of 1572 subjects [44][45][46][47][48][49][50]52,[54][55][56][57][58][59][60] including N ¼ 799 10R homozygotes and N ¼ 773 carriers of genotypes other than 10R/10R (one study did not report genotype frequencies 53 ). The random-effects model revealed a nonsignificant summary effect size of d ¼ À 0.05 (95% confidence interval (CI): À 0.2 to 0.1, z ¼ À 0.698, P ¼ 0.52, I 2 ¼ 38.2%, 95% CI for I 2 : 11.72-91.02%, see Figure 1a), suggesting that genotype was not a significant predictor of treatment response.…”

“…40 Although some studies have shown that the 9R allele is associated with better clinical response to methylphenidate, 27,[44][45][46][47] other studies have shown the opposite pattern [48][49][50] or have failed to observe a significant effect. [51][52][53][54][55][56][57][58][59] A recent review has summarised the literature on this topic and an early meta-analysis of six studies in childhood ADHD reported that 10R homozygotes showed poor methylphenidate response. 60 However, further studies on children and adults have appeared since then.…”

“…60 However, further studies on children and adults have appeared since then. 47,48,50,[53][54][55][56][57][58][59] In order to update the literature review and clarify inconsistencies in the literature on this important topic we, therefore carried out a comprehensive meta-analysis of the association between the SLC6A3 VNTR and clinical response to methylphenidate in childhood as well as in adult patients with ADHD. We compared the quantitative response as reflected by changes in ADHD symptom scores to methylphenidate treatment between non-10/10 carriers and 10R homozygotes, a grouping of genotypes commonly undertaken in SLC6A3 association studies.…”