What do dopamine transporter and catechol-o-methyltransferase tell us about attention deficit-hyperactivity disorder? Pharmacogenomic implications

Abstract

The purpose of the present paper was to review studies of two candidate genes for attention deficit-hyperactivity disorder (ADHD) and to separate aetiological from therapeutic effects. Genomic studies of ADHD were reviewed for candidate dopamine genes and studies selected to distinguish catechol-o-methyltransferase (COMT) and dopamine transporter (DAT-1) effects. Pharmacogenomic findings for the COMT gene were in agreement with the 1977 observations of Sprague and Sleator, who reported that at low psychostimulant doses, children with ADHD showed a remarkable improvement on a short-term memory test at all levels of task load, whereas at higher doses, there was a significant decrement in performance on the more difficult versions of the task, corresponding to an 'inverted 'U' shaped curve'. Recent studies show that individuals with the homozygous COMT (valine/valine) genotype demonstrated improvement following psychostimulant treatment, because their tonic dopamine (DA) levels were low, whereas the homozygous COMT (methionine/methionine) individuals, who already have high initial prefrontal cortex (PFC) dopamine levels performed more poorly after medication, in tasks with high working memory load. On the other hand aetiological findings for DAT-1 gene were heterogenous, but more often positive than for COMT. Contrasting findings for COMT and DAT-1 may best be considered in terms of prediction of medication response in ADHD in the case of COMT, but in aetiological terms in the case of DAT-1, which is abundant in the striatum and possibly plays a greater role in determining hyperactivity and impulsivity, than working memory deficiencies.