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We sought to test the hypothesis that the variable number of tandem repeat (VNTR) polymorphism in the 3'-untranslated region (3'-UTR) of the SLC6A3 gene modulates behavior in children with ADHD and/or behavioral response to methylphenidate (MPH). One hundred and fifty-nine children with AHDH (6-12 years) were assessed with regard to the Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) and the response of these behaviors to MPH (0.5 mg/kg/day) using a 2-week prospective within-subject (crossover) trial. Based on CGI-Parents, the profile of behavioral response to MPH as compared to placebo was not parallel in the three groups of children separated according to their genotype in the 3'-UTR VNTR polymorphism of SLC6A3, as indicated by a significant (p=0.017) genotype by treatment two-way interaction. Individuals having the 9/10 and 10/10 genotypes displayed a significant positive response to MPH as opposed to those homozygous for the 9-repeat allele. No genotype or genotype by treatment interaction was observed for CGI-Teachers. These findings support a role for the DAT gene 3'-UTR VNTR polymorphism in modulating the response of some behavioral dimensions to MPH in children with ADHD. They also suggest the presence of genetic heterogeneity that could be indexed by the quality of behavioral response to MPH.

Objective: To compare the pattern of familial aggregation of psychopathology in children who are good responders (GR) to methylphenidate (MPH) versus those who are poor responders (PR)., Method: A total of 118 clinically referred children ages 6 to 12 years, diagnosed with ADHD participated in a double-blind, placebo-controlled, randomized 2-week crossover trial of MPH from 1999 to 2004. A low dose of 0.5 mg/kg of body weight of MPH divided in two equal doses was used. Family history was obtained by interviewing at least one key historian relative of each subject using Family Interview for Genetic Studies. Information was collected on 342 first-degree and 1,151 second-degree relatives of children with attention-deficit/hyperactivity disorder., Results: Forty-four subjects showed mild or no improvement (PR) and 74 showed moderate or very much improvement (GR) on MPH over placebo. First-degree relatives of GR subjects were at significantly higher risk of attention-deficit/hyperactivity disorder than the relatives of PR subjects (p<.05). Second-degree relatives of the GR were at significantly higher risk of antisocial personality disorder compared to the relatives of PR subjects (p<.05)., Conclusions: The significantly higher presence of attention-deficit/hyperactivity disorder in the first-degree relatives and of antisocial personality disorder in the second-degree relatives of GR children suggests that this group may, at least partially, be distinct from the PR group on the basis of genetic determinants.

Objective: Sleep disturbances appear as a comorbid condition in children with attention-deficit/hyperactivity disorder. The aim of this study was to investigate the relationship of activity levels during sleep and therapeutic response to methylphenidate (MPH)., Method: Nightly sleep actigraphic recordings during a double-blind, placebo-controlled, crossover clinical study (1-week of 0.5 mg/kg MPH; 1-week of placebo) were obtained on 44 children, 6 to 12 years old, diagnosed with attention-deficit/hyperactivity disorder (DSM-IV)., Results: Significant (p <.005) differences between the conditions were found in several software-computed parameters: sleep onset latency (MPH, 39.3 minutes; placebo, 28.2 minutes), sleep efficiency (MPH, 78.0%; placebo, 80.4%), total sleep time (MPH, 7 hours; 57 minutes; placebo, 8 hours, 16 minutes). No significant differences on any of these measures were found among the 26 subjects who showed a moderate or large global improvement on MPH over placebo compared with 18 subjects who showed mild or no clinical improvement., Conclusions: MPH, given twice daily, induces a slight but significant sleep disturbance. Motor activity levels during sleep did not differentiate children who responded to MPH from those who did not respond. This suggests that responders to MPH treatment do not experience greater sleep disturbances than nonresponders, at least at the dose studied.