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

• Published in: The pharmacogenomics journal Vol. 14; no. 1; pp. 77 - 84
• Main Authors: Kambeitz, J, Romanos, M, Ettinger, U
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2014; Nature Publishing Group
• Subjects: 3' Untranslated regions; 3' Untranslated Regions - genetics; 631/92/436/434; 692/699/476/1311; Attention; Attention Deficit Disorder with Hyperactivity - drug therapy; Attention Deficit Disorder with Hyperactivity - genetics; Attention deficit hyperactivity disorder; Biomedical and Life Sciences; Biomedicine; Care and treatment; Children; Clinical trials; Dopamine; Dopamine Plasma Membrane Transport Proteins - genetics; Dopamine transporter; Dopamine Uptake Inhibitors - administration & dosage; Dopamine Uptake Inhibitors - therapeutic use; Gene Expression; Gene polymorphism; Genetic aspects; Genetic factors; Genetic polymorphisms; Genetic research; Genotype; Homozygotes; Human Genetics; Humans; Hyperactivity; Identification and classification; Impulsive behavior; Mental disorders; Meta-analysis; Methylphenidate; Methylphenidate - administration & dosage; Methylphenidate - therapeutic use; Methylphenidate hydrochloride; Norepinephrine; Oncology; original-article; Patient outcomes; Pharmacotherapy; Polymorphism, Genetic; Psychopharmacology; Tandem Repeat Sequences; Treatment Outcome; meta-analysis; ADHD; methylphenidate; dopamine transporter; pharmacogenetics
• ISSN: 1470-269X; 1473-1150; 1473-1150
• DOI: 10.1038/tpj.2013.9

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent childhood-onset neuropsychiatric disorder. Treatment with methylphenidate, which blocks dopamine and noradrenaline transporters, is clinically efficacious in reducing the symptoms of ADHD. However, a considerable proportion of patients show no or only insufficient response to methylphenidate. Following a pharmacogenetic approach, a number of studies have suggested that heterogeneity in treatment response across subjects might to some extent be due to genetic factors. In particular, a variable number tandem repeat (VNTR) polymorphism in the 3′ untranslated region of the SLC6A3 gene, which codes for the dopamine transporter, has been considered as a predictor of treatment success. However, the literature has so far been inconsistent. Here we present results of a meta-analysis of studies investigating the moderating effect of the SLC6A3 VNTR on response to methylphenidate treatment in subjects with ADHD. Outcome measures from 16 studies including data from 1572 subjects were entered into a random-effects model. There was no significant summary effect for the SLC6A3 VNTR on the response to methylphenidate treatment ( P >0.5) and no effect on specific symptom dimensions of hyperactivity/impulsivity and inattention (all P >0.2). However, in a subanalysis of naturalistic trials, we observed a significant effect of d=−0.36 ( P =0.03), indicating that 10R homozygotes show less improvement in symptoms following treatment than the non-10/10 carriers. This meta-analysis indicates that SLC6A3 VNTR is not a reliable predictor of methylphenidate treatment success in ADHD. Our study leaves unanswered the question of whether other genetic polymorphisms or nongenetic factors may contribute to the observed heterogeneity in treatment response across ADHD subjects.