Abstract
BackgroundAnimal models of ADHD suggest that the paradoxical calming effect of methylphenidate on motor activity could be mediated through its action on serotonin transmission. In this study, we have investigated the relationship between the 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) and the response of ADHD relevant behaviors with methylphenidate treatment.MethodsPatients between ages 6-12 (n = 157) were assessed with regard to their behavioral response to methylphenidate (0.5 mg/kg/day) using a 2-week prospective within-subject, placebo-controlled (crossover) trial. The children were then genotyped with regard to the triallelic 5-HTTLPR polymorphism in the SLC6A4 gene. Main outcome measure: Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) at baseline and at the end of each week of treatment with placebo and methylphenidate. For both outcome measurements, we used a mixed model analysis of variance to determine gene, treatment and gene × treatment interaction effects.ResultsMixed model analysis of variance revealed a gene × treatment interaction for CGI-Parents but not for CGI-Teachers. Children homozygous for the lower expressing alleles (s+lG = s') responded well to placebo and did not derive additional improvement with methylphenidate compared to children carrying a higher expressing allele (lA). No genotype main effects on either CGI-Parents or CGI-teachers were observed.ConclusionsA double blind placebo-controlled design was used to assess the behavioral effects of methylphenidate in relation to the triallelic 5-HTTLPR polymorphism of the SLC6A4 gene in children with ADHD. This polymorphism appears to modulate the behavioral response to methylphenidate in children with ADHD as assessed in the home environment by parents. Further investigation is needed to assess the clinical implications of this finding.Trial RegistrationClinicalTrials.gov NCT00483106
Highlights
Animal models of Attention-deficit/hyperactivity disorder (ADHD) suggest that the paradoxical calming effect of methylphenidate on motor activity could be mediated through its action on serotonin transmission
In a recent study [5], we found that the 3'-UTR VNTR polymorphism in the dopamine transporter gene modulates behavioral response to MPH, replicating a previous study by Stein et al [6]
The distribution of the common comorbid disorders of ADHD were similar among the three groups of children, anxiety disorders tended to be more frequent in children with the s's' and, to a lesser extent, s'l' genotypes compared to children with the l'l' genotype
Summary
Animal models of ADHD suggest that the paradoxical calming effect of methylphenidate on motor activity could be mediated through its action on serotonin transmission. ADHD is characterized by high heritability (0.76) [1], likely conferred It has become common practice in genetic association studies of ADHD to focus on genes implicated in brain monoamine transmission, given that psychostimulant drugs, such as methylphenidate (MPH), are effective in controlling ADHD symptoms. It is widely believed that this effect results primarily, but not exclusively, from modulation of dopamine transmission and downstream monoamine systems. This strategy of using a "pharmacological bridge" to select candidate genes is reasonable, it is possible that molecular mechanisms responsible for the pharmacology of psychostimulants and the underlying pathological processes of ADHD do not coincide or coincide only to some extent. Investigating the "drug response" phenotype has the important advantage of being amenable to the placebo-controlled, double blind study design, a robust design for controlling bias in behavioral research studies
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