TY - JOUR
T1 - What do domain transporter and catechol-o-methyltransferase tell us about attention deficit-hyperactivity disorder? Pharmacogenomic implications
AU - Levy, Florence
PY - 2007/1
Y1 - 2007/1
N2 - 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.
AB - 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.
KW - ADHD
KW - COMT
KW - DAT-1
KW - Genes
KW - Pharmacogenomic
UR - http://www.scopus.com/inward/record.url?scp=34247499162&partnerID=8YFLogxK
U2 - 10.1080/00048670601050432
DO - 10.1080/00048670601050432
M3 - Review article
C2 - 17464676
AN - SCOPUS:34247499162
SN - 0004-8674
VL - 41
SP - 10
EP - 16
JO - Australian and New Zealand Journal of Psychiatry
JF - Australian and New Zealand Journal of Psychiatry
IS - 1
ER -