A Current Update On ADHD Pharmacogenomics Friendly)

5/27/2010 A Current Update on ADHD Pharmacog…
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Authors and Disclosures

Christian Kieling1, Júlia P Genro2, Mara H Hutz 2 & Luis Augusto Rohde 1 †
1ADHD Program, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos, 2350-2201, Porto Alegre, RS, 90035-
003, Brazil Tel.: +55 513 321 3946 Fax: +55 513 321 3946 lrohde@terra.com.br
2Department of Genetics, Universidade Federal do Rio Grande do Sul, Brazil
†Author for correspondence
From Pharmacogenomics
A Current Update on ADHD Pharmacogenomics
Christian Kieling; Júlia P Genro; Mara H Hutz; Luis Augusto Rohde
Posted: 04/13/2010; Pharmacogenomics. 2010;11(3):407-419. © 2010 Future Medicine Ltd.
Abstract and Introduction
Abstract
Pharmacological treatment for attention deficit hyperactivity disorder, although highly effective, presents a marked
variability in clinical response, optimal dosage needed and tolerability. Clinical and neurobiological investigations have
juxtaposed findings on both response to medication and etiologic factors, generating the hypothesis that genetic
factors may underlie differences in treatment outcome. Over the last decade, research has focused on the
catecholaminergic system to investigate a potential role of genotype on pharmacological effect. Despite an increasing
number of associations reported (for methylphenidate, nine in 2005, 24 in 2008 and 52 reported in the current article),
the identification of clinically relevant genetic predictors of treatment response remains a challenge. At present,
additional studies are required to allow for a shift from a trial-and-error approach to a more rational pharmacologic
regimen that takes into account the likelihood of treatment effectiveness at the individual level.
Introduction
Attention deficit hyperactivity disorder (ADHD) is one of the most extensively investigated psychiatric disorders of
childhood and adolescence.[1] Notwithstanding the remarkably well-replicated findings in the efficacy of
pharmacological treatment, predictors of treatment response and side effects remain largely underspecified. In recent
decades, clinical and neurobiological investigations have juxtaposed findings on both treatment response and
etiologic factors.[2] The observation of a marked variability in treatment response, optimal dosage needed and
tolerability has generated the hypothesis that genetic factors may underlie such differences. Evidence demonstrating
the efficacy of pharmacological treatment with methylphenidate (MPH) has driven basic research to focus on the
catecholaminergic system to uncover the genetic underpinnings of ADHD.
In recent decades, pharmacology and genetics have converged into models that investigate the role of genotype in
predicting individual treatment response. Thus far, however, results of pharmacogenetic studies of ADHD have been
variable, with conflicting results among small association studies.[3] This article presents an update, focusing on the
published data of the pharmacogenetics of ADHD. We employed the same search strategy used by Polanczyk et
al.[4] Remarkably, a comparison of pharmacogenetics of ADHD evidences a striking increase in the number of
published articles (Figure 1). Here, we provide an updated review of the literature, presenting available results for each
studied gene and providing some recommendations for future research on ADHD pharmacogenomics.
medscape.com/viewarticle/719972_print 1/16
Figure 1. Number of pharmacogenetic associations included in three reviews on methylphenidate

response among individuals with attention deficit hyperactivity disorder.
ADRA2A: α-2A-adrenergic receptor gene; COMT: Catechol-O-methyl-transferase; DAT1/SLC6A3: Dopamine
transporter; DRD4: Dopamine D4 receptor gene.
Data taken from [3,4].
SLC6A3/DAT1
The dopamine transporter (DAT) plays a key role in the regulation of dopaminergic neurotransmission and is also the
major site of action for MPH. The SLC6A3 (DAT1) gene is located at chromosome 5p15.3. [5] Most association
studies of ADHD concentrate on the 3'-UTR of the gene, but these investigations have reported discordant results. A
recent meta-analysis summarized data from 24 studies, defining the 480-bp (or 10-repeat) allele as the risk allele:
results exhibited a small but significant association between ADHD and the 10-repeat allele (95% CIs for odds ratios
ranging from 1.00 to 1.27).[6]
In a pioneering pharmacogenetic study, Winsberg and Comings investigated the role of SLC6A3 genotypes on MPH
response among 30 children with ADHD (16 responders and 14 nonresponders).[7] They defined response to
medication as a decrease in the Conners Abbreviated Rating Scale (ABRS) from more than 1.5 to less than 1.0 on
two consecutive assessments; children received weekly dose increments to a maximum of 60 mg/day (no
nonresponder received less than 40 mg/day). There was a significant increase in the frequency of individuals with two
copies of the 10-repeat allele in the nonresponders group (86%) in comparison with the group of responders (31%).
The second published report on ADHD pharmacogenetics was conducted by Roman et al. and aimed to investigate
the previous association between the homozygosity for the 10-repeat allele and poor response to MPH among
subjects with ADHD.[8] This naturalistic study assessed 50 boys, also using the ABRS, and defined response as a
50% decrease in scores. Inclusion criteria were ABRS scores higher than 1.5 or Clinical Global Assessment Scale
(CGAS) scores lower than 70, and final doses of MPH were approximately 0.7 mg/kg/day, with no nonresponder
receiving less than 0.3 mg/kg/day. The proportions of patients responding to treatment were 75 and 47%,
respectively, for the groups with and without the 10/10 genotype, a result that replicated the findings from the initial
study.
A subsequent study by Kirley et al. also examined the association between SLC6A3 status and response to MPH.[9]
In a sample of 119 children with ADHD, the authors asked parents to retrospectively rate their children's response to
medication. By contrast to the two previous studies, authors reported a significant association of the presence of the
10-repeat allele with the 'very good' response status. These results were corroborated by Stein et al., who assessed
47 children and adolescents with ADHD in a 4-week double-blind crossover trial with forced weekly dosage changes
of the osmotic release oral system MPH.[10] Outcomes were assessed using dimensional (ADHD Rating Scale
[ADHD-RS]) and categorical (Clinical Global Impression – Severity [CGI-S], with response defined as a score ≤3)
ratings. Authors identified a distinct dose–response curve for subjects homozygous for the less common 9-repeat
allele – this group did not present the typical linear improvement when the dose was increased from 18 to 36 and 54
mg. Those homozygous for the 9-repeat were much less likely to display dose-related improvement or remission in
comparison with children with one or two copies of the 10-repeat allele.
In 2005, two reports failed to identify an association of any SLC6A3 variant with MPH response. van der Meulen et al.
investigated 82 children with ADHD from 54 families using at least 0.3 mg/kg/day of MPH. [11] The outcome assessed
was the proportion of response – rather than response per se – using the parent-rated Strengths and Weaknesses of
ADHD symptoms and Normal Behavior (SWAN) scale. They employed a formula that subtracted the score with MPH
from the score without MPH, dividing the result by the score without medication. Although they did not find any
association between treatment response and SLC6A3 genotype, authors identified a high-sibling correlation of MPH
effect, which may indicate familial clustering of drug response. Langley et al., using the CGI scale to assess
response to stimulant medication (responders were those classified by their parents as 'very improved' or 'very much
improved'), evaluated the response of 168 subjects to MPH. Data revealed an excess of 10/10 genotypes and 10-
repeat alleles among nonresponders, but proportions did not reach statistical significance.[12]
McGough et al. reported data from the multicenter Preschool ADHD Treatment Study (PATS).[13] The authors
assessed genetic moderators of MPH response (both symptom reduction and side effect ratings) using repeated
outcome measurements in a double-blind placebo-controlled multiple-dose crossover titration trial. Of the 165
subjects included in the original study, only 81 children were assessed in the pharmacogenetics report. No significant
effects for the SLC6A3 polymorphisms were detected. Zeni et al. assessed 106 subjects at baseline and after 1
month of treatment with MPH.[14] The Swanson, Nolan and Pelham-IV scale (SNAP-IV) was used as the primary
outcome measure, and secondary measures included the Clinical Global Assessment and the Barkley's Stimulants
Side Effects Rating Scale (SERS) to assess the stimulants' side effects. Although the global improvement of ADHD
symptoms was similar to those found in the literature, there was no statistically significant difference in any outcome
measure according to SLC6A3 genotype (both 9-repeat and 10-repeat homozygosity analyses performed).
Joober et al. investigated how SLC6A3 genotype modulated behavioral response to MPH among 151 children with
ADHD.[15] Response to 0.5 mg/kg/day of MPH was assessed using the Conners' Global Index for parents and
teachers in a 2-week prospective crossover design. There was a distinct pattern of behavioral response to MPH
compared with placebo according to SLC6A3 genotype, with children presenting two copies of the 9-repeat allele
presenting a poor response to pharmacotherapy by parent, but not by teacher report. These results were, therefore,
partially in consonance with those found by Stein et al., suggesting that individuals with the 9/9 genotype are less
sensitive to MPH effects. [3]
Tahroor et al. used retrospective data on MPH treatment response to describe a post hoc analysis in a large, birth
records-based sample of twins born in the state of Missouri, USA, which was enriched for the presence of ADHD.[16]
A total of 243 subjects were selected based on parent reports that the child had been treated with MPH (108 had a
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition [DSM-IV] diagnosis of ADHD and the remaining
135 subjects were treated with MPH for ADHD symptoms). Response to treatment was defined by a yes-or-no
question regarding improvement of symptoms. No significant difference regarding MPH response was found according
to SLC6A3 genotype (zero, one and two copies of the 10-repeat allele yielded 100, 90 and 86% of responders,
respectively; n = 156 for these analyses).
Kereszturi et al. assessed the role of SLC6A3 genotype in a sample of ADHD individuals treated with MPH.[17] Using
a categorical definition of responders (a reduction of >25% in the ADHD-RS after 6 months and a CGI-S of ≤ two
points in the previous 2 months) and nonresponders (<10% decrease in ADHD-RS in the first 3 months and
discontinuation of treatment), they defined 90 children as responders and 32 as nonresponders. Results did not
evidence any association between SLC6A3 genotype and response to MPH. Purper-Ouakil et al. assessed MPH
response in 141 children and adolescents with both clinical (CGI-S and ADHD-RS) and neuropsychological measures
(trail-making test, Stroop test and continuous performance test). [18] Clinical responders were defined as having an
improvement two or more points in CGI-S (primary outcome) or response rates greater than −0.5 standard deviations,
corresponding to a minimum of 40% reduction in ADHD-RS (secondary outcome) – response rate was calculated as
in the van der Meulen et al. study.[11] They found an over-representation of the 10/10 genotype in the low-response
group according to clinical, but not to cognitive, scores.
Gruber et al., merging samples from previous studies, hypothesized that individuals with 9/9 genotype would present
a higher frequency of stimulant-specific side effects.[19] They assessed 177 patients using the Barkley SERS and
performing a principal components analysis of scores. The results yielded a three-factor solution that explained
57.7% of total variance. Associations with SLC6A3 genotype revealed an increased occurrence of emotional side
effects among the 9/9 group and more somatic complaints in the 10/10 group, with the 9/10 group exhibiting the
lowest proportion of side effects. Leddy et al. investigated genotype effects on drug tolerability among 58 children in a
within-subject, randomized, placebo-controlled trial of multiple MPH doses.[20] A significant dose–response
interaction in eating reduction was detected across all genotypes, but homozygotes for the 9-repeat allele showed a
stronger effect of dose when compared with other genotype groups.
A recent study by McGough et al. assessed the role of multiple candidate genes in MPH response.[21] A total of 82
children and adolescents with ADHD participated in a 4–5-week double-blind placebo-controlled crossover trial of
immediate-release MPH. Improvement was measured by a mathematics test taken in the laboratory that was
sensitive to stimulant response (Permanent Product Measure of Performance [PERMP]) and by both the ADHD-RS
and the SWAN scales. A principal components analysis was performed in order to reduce the number of outcomes; a
two-component solution that explained 92% of the variance was detected (components were ADHD symptoms and
correct mathematics problems). Genotype groups were devised a priori according to the presence of zero, one or two
copies of the most prevalent alelle; no significant associations with the 10-repeat allele were detected.
Two published pharmacogenetic studies evaluated MPH response in adults with ADHD. Mick et al. assessed
response and adverse effects in 106 adults with ADHD using two studies (one trial of immediate-release MPH and
one of osmotic-release oral-system MPH), both having a six-week randomized placebo-controlled design. [22] There
were no significant differences in terms of ADHD symptoms (by the Adult ADHD Investigator System Report Scale
[AISRS]), cardiovascular measures (blood pressure, heart rate and electrocardiographic) and spontaneously reported
side effects. Kooij et al. evaluated MPH response in 42 adults in a randomized double-blind placebo-controlled trial of
MPH prescribed in doses from 0.5 to 1.0 mg/kg/day. [23] Primary outcome response was defined as at least a two-
point reduction on the clinician-rated CGI Scale for ADHD, as well as a minimum of 30% reduction in the self-report
score of the ADHD-RS; secondary measures were each of these measures taken separately. For the primary
combined measure, the proportion of responders was 52.2% in the 10-repeat allele group and only 22.2% in the 10/10
homozygous group, a difference that remained statistically significant when only self-report data was analyzed, but
not for the clinician-based scores.
A series of studies also addressed the potential SLC6A3 genotype role in terms of neurobiological response to MPH
treatment. A pilot study published in 2003 by Rohde et al. simultaneously assessed a SLC6A3 polymorphism,
response to MPH and cerebral blood flow.[24] A total of eight MPH-naive children, who had a minimum of 30%
symptomatic response after MPH administration, took part in this single-photon emission computed tomography.
Brain-imaging acquisition was conducted after a 12-min activation with a continuous performance test. The results
showed a significantly higher regional cerebral blood flow in medial frontal and left basal ganglia areas in children with
the 10/10 genotype compared with those with other genotypes. A subsequent study also investigated the association
between the 10-repeat homozygosity and brain metabolism, this time in a sample of 11 drug-naive children treated
with MPH for 8 weeks.[25] Children with the 10/10 genotype presented both a significantly higher increase of DAT
density in basal ganglia and a reduced response to MPH (28.6 vs 100% reaching a reduction of more than 50% in
symptom scores) in comparison with other genotypes.
Loo et al. examined whether cognitive and neurophysiological measures changed after MPH treatment (a single 10-
mg dose) according to SLC6A3 status.[26] They used a double-blind placebo-controlled design to asses 27 children.
Individuals with the 10-repeat allele exhibited increased cortical activation and arousal, whereas children with the 9-
repeat allele showed decreased cortical activation and arousal. There was no association between response to MPH
in terms of cognitive performance and SLC6A3 genotype status. Bellgrove et al. examined data available for 36
children and adolescents with ADHD according to cognitive performance in a test of left-sided attention and response
to MPH – retrospectively rated by parents using a three-point scale (no response, mediocre and very good) and the
Conners' Parent Rating Scales (CPRS).[27] They suggested that a subgroup of children in which the 10-repeat allele
is associated with both MPH response and left-sided inattention as measured by neuropsychological testing might
exist. In 2006, Gilbert et al. performed a randomized double-blind single-dose crossover study of 0.5 mg/kg of MPH or
1.0 mg/kg of atomoxetine (ATX) in 16 children and adolescents with ADHD, comparing seven homozygotes and nine
heterozygotes for the 10-repeat SLC6A3 allele.[28] They investigated medication and genotype effects on short-interval
cortical inhibition, measured with transcranial magnetic stimulation of the motor cortex and a possible physiological
marker of behavioral symptoms of ADHD. The results showed that both drugs increased short-interval cortical
inhibition only in heterozygotes, but not among those with 10/10 genotypes.
In summary, despite the suggestion of an association between reduced effect of MPH and the SLC6A3 10-repeat
polymorphism, there is no firm conclusion in the ADHD pharmacogenomic literature regarding the role of SLC6A3
genotype. In this sense, notwithstanding the meta-analysis included in Purper-Ouakil et al. (aggregating five studies;
mean odds ratio: 0.46; 95% CI: 0.28–0.76) indicating an association between the 10-repeat and poor response,
another three studies showed opposite results, and eight reports failed to identify any association (Table 1).[18] Given
the SLC6A3 gene structure and recent findings regarding its association with ADHD clinical phenotype, additional
gene regions should be investigated in further research.
Table 1. Studies assessing the role of the dopamine transporter gene (SLC6A3/DAT1) in clinical
response to methylphenidate among individuals with attention deficit hyperactivity disorder.
Study Age
Improvement Main
Study size range Location Design Doses Outcomes Ref.
definition findings
(n) (years)
Winsberg ABRS scores ≤ 1 Less

Not < 40
and in two improvement [7]
30 6–11 USA Naturalistic mg/day for ABRS
Comings consecutive for the 10/10
nonresponders
(1999) assessments genotype
Reduction of 50% Less

Not < 0.3
Roman et ABRS, in ABRS, improvement [8]
50 6–17 Brazil Naturalistic mg/kg/day for
al. (2002) CGAS continuous for the 10/10
nonresponders
scores for CGAS genotype
Three- Categorical rating

Higher
Higher
point by parents and
Kirley et improvement [9]
119 4–25 Ireland Retrospective Not informed parental continuous
al. (2003) for the 10/10
scale and scores by CPRS-
genotype
CPRS-R R
Up to 0.7 Less
Cheon et mg/kg/day; Reduction of 50% improvement [25]
11 7–12 Korea Naturalistic ADHD-RS
al. (2005) not < 0.3 in ADHD-RS for the 10/10
mg/kg/day genotype
Poor
Reliable change
Stein et ADHD-RS, response for [10]
43 5–16 USA Clinical trial 18–54 mg/day index and cut-off
al. (2005) CGI-I the 9/9
score
genotype
No
Van der Continuous: association
The Higher than [11]
Meulen et 77 3–18 Naturalistic SWAN (before– with
Netherlands 0.3 mg/kg/day
al. (2005) after)/(before)*100 SLC6A3
genotype
No
Langley 'Very improved' or association
[12]
et al. 168 6–16 UK Retrospective Not informed CGI-I 'very much with
(2005) improved' SLC6A3
genotype
No
McGough Placebo, 1.25, SKAMP, Composite association
[13]
et al. 81 3–5.5 USA Clinical trial 2.5, 5, 7.5 and CLAM, SKAMP and with
(2006) 10 mg SERS CLAM scores SLC6A3
genotype
Initial 0.5 No
AISRS;
mg/kg/day or association
Mick et vital signs, Continuous [22]
106 19–60 USA Clinical trial 36 mg/day; up with
al. (2006) adverse AISRS scores
to 1.3 SLC6A3
effects
mg/kg/day genotype
Poor
Continuous CoGI- response for
Joober et CoGI-P, [15]
159 6–12 Canada Clinical trial 0.5 mg/kg/day P and CoGI-T the 9/9
al. (2007) CoGI-T
scores genotype by
the CoGI-P
No
Continuous
SNAP-IV, association
Zeni et al. Higher than SNAP, CGAS [14]
106 4–17 Brazil Naturalistic CGAS, with
(2007) 0.3 mg/kg/day and SERS
SERS SLC6A3
scores
genotype
No
association
Tharoor et MAGIC- Parent report [16]
243 7–19 USA Retrospective Not informed with
al. (2008) interview (yes/no question)
SLC6A3
genotype
Two-point No
Kereszturi reduction in CGI- association
Kereszturi reduction in CGI- association
Mean 0.22 to 0.95 ADHD-RS; [17]
et al. 122 Hungary Naturalistic S and 25% with
9.6 mg/kg/day CGI-S
(2008) reduction in SLC6A3
ADHD-RS scores genotype
Primary: ≥ 2
point
ADHD-RS,
improvement in Less
Purper- Flexible; CGI-S,
CGI-S; improvement [18]
Ouakil et 141 6–18 France Naturalistic mean: ~30 TMT, CPT,
secondary: for the 10/10
al. (2008) mg/day Stroop
minimum 40% genotype
test
improvement in
ADHD-RS
Two-point
Increasing Less
reduction in CGI-
Kooij et The doses from ADHD-RS, improvement [23]
42 20– 56 Clinical trial ADHD and 30%
al. (2008) Netherlands 0.5 to 1.0 CGI-ADHD for the 10/10
reduction in
mg/kg/day genotype
ADHD-RS scores
The 9/10
Three-factor PCA
group had
Montreal: 0.5 solution for
less side-
Gruber et Canada and mg/kg/day; SERS: [19]
177 5–16 Clinical trial SERS effects than
al. (2009) USA Washington: emotionality,
the 9/9 and
36 mg/day somatic, over-
10/10
focused
groups
Two-factor PCA:
ADHD symptoms No
Random order ADHD-RS,
McGough and correct association
of placebo, 5 SWAN, [21]
et al. 82 6–17 USA Clinical trial mathematics in with
mg, 10 mg, 15 PERMP,
(2009) PERMP; four- SLC6A3
mg and 20 mg SERS
factor PCA of genotype
SERS
ABRS: Conners Abbreviated Rating Scale; ADHD-RS: ADHD Rating Scale; AISRS: Adult ADHD
Investigator System Report Scale; CGAS: Clinical Global Assessment Scale; CGI-I: Clinical
Global Impression – Improvement; CGI-S: Clinical Global Impression – Severity; CLAM: Conners,
Loney and Milich Scale; CoGI-P: Conners Global Index for parents; CoGI-T: Conners Global Index
for teachers; CPRS-R: Conners' Parent Rating Scale – Revised; CPT: Continuous performance
test; PCA: Principal Components Analysis; PERMP: Permanent Product Measure of
Performance; SERS: Barkley's Stimulants Side Effects Rating Scale; SKAMP: Swanson, Kotkin,
Agler, M-Flynn and Pelham Scale; SNAP-IV: Swanson, Nolan and Pelham – IV scale; SWAN:
Strengths and Weaknesses of ADHD Symptoms and Normal Behavior; TMT: Trail-making test.
DRD4
The dopamine D4 receptor is considered part of the D2-like receptor family and a G-protein-receptor that has the
ability to inhibit the adenyl cyclase enzyme when activated.[29] The DRD4 gene has been mapped to chromosome
11p15.5,[30] and is associated with ADHD in both family-based and association studies. The most frequently studied
DRD4 polymorphism in ADHD has been the 48-bp VNTR in exon 3. The 7-repeat allele has been proposed as the risk
allele, and there is some evidence that this variant is functionally different from 2- and 4-repeat alleles, with the former
presenting a blunted response to dopamine in terms of reducing the intracellular concentration of the second
messenger cyclic AMP. A recent meta-analysis that included 26 studies indicated a significant, moderate
association between ADHD and the 7-repeat allele (95% CIs for odds ratios ranging from 1.15 to 1.54).[6]
The initial report by Winsberg and Comings found no significant differences in MPH response according to DRD4
genotype (with the 7-repeat allele present among 37.5 and 21.4% of the responders and poor responders,
respectively).[7] Tahir et al. reported an association between DRD4 and MPH response (defined as at least 50%
improvement in the number of symptoms) among 29 trios.[31] There was an excess transmission of the 7-repeat
among MPH responders in comparison to nonresponders. In 2001, Seeger et al. examined the association between
DRD4 genotype and response to MPH in terms of both physiological response (prolactin levels, whose release is
antagonized by MPH dopamine reuptake blocking) and general functioning as estimated by the difference between
CGAS 4-week and baseline scores.[32] The sample composed of 47 inpatients without any psychiatric comorbidities
who were treated with MPH monotherapy (0.6–0.8 mg/kg). The authors identified an interaction between the presence
of the DRD4 7-repeat allele and the homozygosity for the long alleles of the serotonin transporter gene (5HTT), in
which patients with the combination of genotypes showed significantly higher prolactin levels and reduced
improvement in CGAS scores.Hamarman et al. studied 45 children aged 7–15 years with ADHD diagnosis and
without comorbid conditions.[33] Individuals received progressively increasing doses of MPH according to symptom
remission as measured by serial Conners' Global Index – Parent assessments. Doses were started at 15 mg/day and
advanced by 5-mg steps up to symptom normalization or treatment failure (60 mg/day). Children and adolescents
with the 7-repeat polymorphism required higher doses of MPH to achieve both initial symptom improvement and
complete normalization (mean MPH doses for the 7-present vs 7-absent groups of 30 vs 20 mg and 47 vs 31 mg
MPH). Using a dose relative to weight criterion, subjects with the 7-repeat allele required more stimulant medication
(1.70 vs 0.79 mg/kg).
Data from the Preschool ADHD Treatment Study showed that participants with the 7-repeat allele exhibited increased
social withdrawal with increasing MPH doses, and the 4-repeat DRD4 homozygosity presented an increased risk for
picking behaviors with MPH use. [13] Secondary analyses suggested a trend for an association between another
DRD4 polymorphism (located in the promoter region) and teacher composite scores at the Swanson, Kotkin, Agler,
M-Flynn and Pelham (SKAMP) and Conners, Loney, and Milich (CLAM) scales. Cheon et al. assessed 83 children
with ADHD to investigate an association between DRD4 genotype and MPH response.[34] MPH dosages were
increased based on the parents' reports of symptom improvement and side effects, and subsequently maintained for 8
weeks. The authors considered a 'good response' to be the improvement of more than 50% in the ADHD-RS scores
after 8 weeks of treatment compared with the baseline ADHD-RS scores before the treatment. They performed a
comparison of the response to MPH treatment between subjects with and without the 4-repeat homozygosity at
DRD4 and found an increased proportion of 4/4 genotypes among good responders according to both parents and
teachers (71.1 and 80.0%, respectively).
Zeni et al., using the methodology described above, did not find statistically significant differences in any outcome
measure (symptoms and side effects) according to DRD4 genotype (both 7-repeat presence and 4-repeat
homozygosity analyses performed).[14] No significant response frequencies were also reported by Kereszturi et al.,
who devised genotype groups according to the presence or absence of the 7-repeat allele. [17] A similar pattern was
found by Tharoor et al. in a retrospective study, where the DRD4 genotype was not associated with MPH response,
with 89, 88 and 100% of positive responses for the presence of zero, one and two copies of the 7-repeat allele,
respectively (n = 159 for this analysis). [16] The recent study by McGough et al., using composite measures as
outcome, reported a gene–dose interaction between the DRD4 VNTR and the mathematics performance measure,
with individuals lacking any copy of the 4-repeat allele worsening in performance at higher doses of MPH.[21] With
respect to the promoter polymorphism, in addition to the link between gene–dose and cognitive performance, there
was a significant association with side effects (irritability and somatic symptoms).
Among studies that investigated the role of DRD4 in pharmacological response to MPH among patients with ADHD,
the currently available literature still presents conflicting results. In addition to opposite findings, including
associations with both the 7-repeat allele and the 4/4 homozygosity, a half of the ten published studies did not find
any significant association with clinical response to MPH administration.
ADRA2A
Given that adrenergic neurotransmission is hypothesized to play a role in attentional processes and that low oral
doses of MPH apparently have more effect on norepinephrine than on dopamine in subcortical areas, the α-2A-
adrenergic receptor gene (ADRA2A) represents a promising candidate gene for ADHD pharmacogenetic studies. The
ADRA2A gene is located at the chromosome 10q23-q25,[35] and its most investigated polymorphism in relation to
ADHD is rs1800544 (a −1291C>G substitution). Combined data from 11 studies were not significant for the
association with ADHD diagnosis using the G-variant as the high-risk allele.[6]
Polanczyk et al. conducted a study to evaluate the association between the ADRA2A −1291C>G polymorphism and
the response to MPH treatment in children and adolescents with ADHD. [36] A total of 106 patients with ADHD were
assessed at baseline, 1 and 3 months with the parent-rated inattentive subscale of the SNAP-IV, which was defined
as the primary outcome; the hyperactivity–impulsivity subscale, the Barkley SERS, was chosen as the secondary
outcome measure. MPH was administered in increasing dosages until either no further clinical improvement or
adverse effects occurred. Despite no effect for the presence of the G-allele being detected, a significant interaction
was found between the G-allele and MPH over time on inattentive scores.
da Silva et al. assessed a sample comprising of 59 individuals with ADHD inattentive subtype identified in a
nonreferred sample of children treated with MPH. [37] They also investigated the association between the ADRA2A
−1291C>G polymorphism and the inattentive scores of the SNAP-IV scale at baseline and after 3 months of
treatment. The presence of the G-allele was associated with significantly lower inattentive scores after 1 month of
treatment with MPH. Cheon et al. evaluated the association between the ADRA2A −1291 C>G polymorphism and
response to MPH treatment (both immediate and sustained release) in subjects with ADHD.[38] The study enrolled
114 children and employed the 50% improvement from baseline in the ADHD-RS or the CGI – improvement score of
one or two points after treatment to define a good response. They found that a good response to MPH treatment was
observed among 76.9% of the G/G carriers, compared with only 46.0 and 41.7% of those with the C/G and C/C
genotypes, respectively.
All three articles reporting the impact of ADRA2A polymorphisms on treatment effect among individuals with ADHD
indicate a positive association with MPH response. Of special interest is the suggestion of a specific involvement of
attentional abilities, that is, in accordance with the presence of α-2A-adrenergic receptors in the prefrontal cortex and
with the consequences of its pharmacological modulation in animal studies.[39] As ADRA2A polymorphisms have
also been shown to be associated with the comorbidity of ADHD and dyslexia,[40] and initial trials of MPH among
individuals with the comorbidity showed an improvement in reading performance,[41] future research should address
the role of ADRA2A genotype in response to treatment in the presence of both disorders.
COMT
Catechol-O-methyl-transferase (COMT) is an enzyme that plays a crucial role in the catabolism of both dopamine and
norepinephrine, especially in the prefrontal cortex. Genetic studies have mostly investigated the functional SNP in
exon 4 that leads to an amino acid substitution (valine/methionine [Val/Met]), which has been shown to substantially
affect COMT enzymatic activity (with the Met allele resulting in an almost fourfold decrease in enzymatic activity
relative to the Val allele).[42] In a recent meta-analysis,[6] including data from 16 studies and considering the Val allele
as high risk, there was no evidence of an association between ADHD and the Val/Met SNP.
Cheon et al. investigated the association between the COMT Val/Met polymorphism and the response to MPH in 124
children with ADHD.[43] Using the same design from previous reports, the authors defined an improvement of greater
than 50% as a good response, after 8 weeks of treatment. Based on teachers, but not on parents' reports, they found
that 62.5% of patients with a good response status were carriers of the Val/Val genotype, whereas only 41.7 and
11.7% had the Val/Met and Met/Met genotypes, respectively. Sengupta et al. assessed 188 children with ADHD in a
randomized double-blind crossover trial to measure task-oriented behavior. [44] Although findings revealed main effects
for both COMT genotype and MPH treatment, no genotype versus drug interaction was observed.
Kereszturi et al. also assessed the role of the Val/Met COMT polymorphism in their report on MPH pharmacogenetic
response.[17] The data suggested an association between the presence of both the Val allele and Val/Val
homozygosity and a good response to MPH – results were particularly significant regarding the hyperactivity–
impulsivity scores, with a larger decrease in the Val/Val group compared with the Met/Met group. McGough et al.
recently detected a genetic effect for the COMT polymorphism in MPH response in terms of side effects (irritability
and somatic symptoms), but not in ADHD symptoms or learning.[21]
Other Genes
In a genome-wide association study of response to transdermal MPH, Mick et al. assessed 187 children for 319,722
available SNPs.[45] Using the ADHD-RS score change from baseline to end point as the outcome measure for a
quantitative trait analysis, they detected a possible association with the metabotropic glutamate receptor 7 (GRM7)
gene, in addition to two potentially associated regions within the SLC6A5 (NET1) gene. No association, however, met
the genome-wide threshold for statistical significance.
In addition to SLC6A3 and DRD4 genotypes, Winsberg and Comings assessed the effect of the DRD2 genotype in
MPH response in their original study, but failed to detect any significant differences.[7] There is, nonetheless, a
suggested effect for DRD2 genotype in modulating MPH-related appetite suppression, as demonstrated by Leddy et
al..[20] Tahir et al. reported an association of the dopamine D5 receptor gene (DRD5) with MPH effect, with an excess
of transmission of the 151-bp allele within the group of responders.[31] A potential role for the norepinephrine
transporter (SLC6A5) gene in MPH response was also investigated. Yang et al. studied the reduction in ADHD-RS
scores among 45 children and adolescents who received MPH at doses of 0.45–0.60 mg/kg per day.[46] They
reported a significant association between SLC6A5 polymorphism G1287A and response to MPH for hyperactive–
impulsive, but not inattentive scores. These findings, however, were replicated neither by McGough et al., in a sample
of 77 children and adolescents, nor by Kooij et al., in a sample of 42 adults.[21,23]
The analysis of MPH response according to synaptosomal-associated protein 25 (SNAP25), a neuron-specific protein
implicated in exocytotic catecholamine release, genotype was also reported in the PATS study by McGough et al.
Results pointed to an association between the T1065G polymorphism with MPH response, with TT individuals
presenting improved responses.[13] On the contrary, the presence of the T-allele at the T1069C polymorphism was
associated with side effects such as motor tics, oral movements and picking or biting. These findings were not
replicated in the McGough et al. study, where the only significant association with SNAP25 was between T1069C
polymorphism and side effects (in this case, however, irritability). [21]
The study by Zeni et al. examined the role of serotoninergic genes (SLC6A4 or 5HTT; HTR1B and HTR2A) and did
not detect any different pattern of symptom reduction or presence of side effects according to genotype.[14] In addition
to the role of SLC6A4, Tharoor et al. also assessed the effect of two polymorphisms at the nicotinic acetylcholine
receptor a4 subunit (CHRNA4; intron 2 and exon 5), but also failed to find any significant associations with MPH
response.[16] McGough et al., in their recent report, detected associations between the interaction of the SLC6A4
promoter polymorphism and MPH dosage with a test of mathmatics performance, as well as a gene effect for an
intron 2 polymorphism regarding ADHD symptoms.[21]
Manor et al. examined the differential improvement on a continuous performance test after a challenge with MPH
according to tryptophan hydroxylase 2 (TPH2) genotype.[47] A total of 344 drug-naive subjects were tested twice and
received a variable dose of MPH (0.3–1 mg/kg) before the second assessment. Improvement was calculated by
subtracting the scores of the second test from baseline scores. The authors found an association of an eight locus
haplotype at TPH2 with total response variability time, as well as between this haplotype and a composite measure of
all four test scores (total errors of omission, total errors of commission, total response time and total response time
variability).
Given that MPH improves not only the cardinal symptoms of ADHD but also symptoms such as aggressiveness
found in oppositional defiant disorder, [48] Guimarães et al. evaluated the effect of the monoamine oxidase A (MAOA)
genotype on MPH response as measured by the parent-rated oppositional subscale of the SNAP-IV.[49] In a sample
of 85 boys from an ADHD outpatient unit, a significant interaction between the presence of MAOA high-activity
genotype and treatment with MPH over time on oppositional scores was detected.
Zhu et al. identified two variants in the gene encoding for the carboxylesterase 1 enzyme (CES1) that led to elevated
MPH blood concentrations and were associated with distinct patterns of hemodynamic response, thus constituting a
potential target for investigations of cardiac adverse effects.[50] Recently, Nemoda et al. investigated the role of a
functional polymorphism at the CES1 gene in the pharmacogenetics of MPH response.[51] They assessed 122
children in terms of both categorical and dimensional (ADHD-RS) response status and suggested that carriers of the
Glu-allele required lower doses of MPH for symptom reduction (0.410 vs 0.572 mg/kg, with only five patients
presenting the Gly/Glu genotype).
Atomoxetine
Atomoxetine is a norepinephrine reuptake inhibitor with demonstrated efficacy for the treatment of ADHD.[52] Genetic
variations in the hepatic cytochrome P450 (CYP) system are potential sources of intersubject variability in response
to ATX treatment. CYP2D6 is a highly polymorphic system that is pragmatically divided in two subgroups based on
its metabolic phenotype: extensive metabolizers (EM) and poor metabolizers (PM). Michelson et al. investigated data
from multiple studies, comprising 589 patients with ATX response information (559 EMs and 30 PMs).[53] Primary
outcome measure was ADHD-RS at week 6, and response was defined as a 25% reduction in symptoms; CGI-S and
tolerability data were also collected. There was a greater improvement for PMs in comparison with EMs, with a mean
effect size of 0.5 (95% CI: 0.1–0.9) in ADHD-RS. PMs also presented a greater increase in heart rate and blood
pressure, as well as more adverse effects, in comparison with EMs.
Trzepacz et al. reported on physician prescribing practices of ATX according to CYP2D6 genetic status.[54] They
used data from two open-label, flexible-dosing studies of ATX (1326 patients: 1239 EMs and 87 PMs). Significant
clinical response was obtained with a mean difference of 0.1 mg/kg in ATX dose when comparing PMs with EMs. As
an overall conclusion, the authors suggested that genotyping was not necessary in routine management, as
physicians were able to adjust ATX doses without knowledge of genetic profile.
As the norepinephrine transporter is a potential target of ATX, Ramoz et al. investigated the role of SLC6A5 status on
treatment response.[55] Two cohorts encompassing 265 children were genotyped for CYP2D6 and 108 SLC6A5
SNPs. Clinical improvement was defined as a 25% reduction in ADHD-RS and a CGI-S ≤ 2 after six weeks of
treatment. No significant CYP2D6 effect was observed; there was, however, an association between response and a
SLC6A5 region that included 36 of the genotyped SNPs – results that were significant in the two independent
cohorts, as well as in the merged sample.
Conclusion & Future Perspective
The large amount of clinical trials evidencing the efficacy of MPH and ATX in the treatment of ADHD has driven
researchers to investigate catecholaminergic pathways as potential moderators of pharmacological response. The
next logical step was therefore to investigate the reasons why not all subjects could be effectively treated. Figure 1
illustrates the expressive expansion of the ADHD pharmacogenomics literature over the recent years, a growth that is
especially significant if compared with other areas of pediatric psychopharmacology – for example, there have been
only two other studies on response to selective serotonin reuptake inhibitors in depression/anxiety and autism
[Polanczyk et al., Pers. Comm.]. The dopamine transporter as a major target for MPH action has received great
attention among initial studies. However, efforts to uncover the causes for variability in treatment response have been
largely unsuccessful. As shown in Figure 1, other ADHD candidate genes have also been studied over the last few
years; however, except for ADRA2A, published replications have been mostly dissonant.
Several methodological issues hamper definitive conclusions from the studies reviewed here. First, the heterogeneity
among designs, instruments and subjects still represents a major obstacle for meta-analytic syntheses. For
example, short- and long-term studies, even when assessing the same genotype, are expected to exhibit different
outcomes owing to factors such as higher dropout rates in longer studies. In addition, most of the studies were based
on fragile designs (i.e., retrospective, with limited clinical measures); ideally, pharmacogenetic studies should be part
of randomized clinical trials, in accordance with all standard requirements. [56] The definition of genotype groups for
analysis might also represent a limitation in many studies that omit or group rare genotypes, as these rare variants
might themselves be associated with unusual response and therefore constitute targets for pharmacogenetic studies.
Data analysis procedures are also important limitations of the current ADHD pharmacogenomics literature, as the use
of baseline data is not a common practice among studies. This includes not only assessment of potential
confounders (and standard objective criteria for their inclusion) or subgroups, but also the choice between the use of
change scores or covariate adjustment. Given the fact that score differences at baseline are predictive of not only
differences in outcome but also in differences in change scores there are transient components of the initial scores
that dissipate over time (the so-called regression to the mean phenomenon). Inclusion of baseline scores as
covariates has at least two advantages over change scores, namely an adjustment by baseline in such a way that
results are uncorrelated to baseline and of a lower variance, which provides a more powerful test. [57]
The generation of large datasets for future pharmacogenetic studies represents one of the possible advances in further
research. A recent multisite analysis by the ADHD Molecular Genetics Network showed that, despite the existence
of variables associated with MPH response at both individual and study levels, no fixed factor (such as study site)
was related to treatment response. [58] This means that data acquired in different sites can be merged for collaborative
work. The definition of clinically significant genetic predictors of treatment effect remains a challenge, [59] as
statistically significant associations do not necessarily reflect clinical significance – and the relative contribution of
genotype to the large effect sizes observed with the use of MPH or ATX might be of limited consequence. Finding
genetic markers of therapeutic response will be only the first step towards the identification of cost-effective tests,
relevant in clinical practice. At the moment, additional studies are required to allow for a shift from a trial-and-error
approach to a more rational pharmacologic regimen that takes into account the prior likelihood of treatment
effectiveness at the individual level.
Sidebar
Executive Summary
Early studies focused on catecholaminergic genes & methylphenidate response
Despite initial suggestion of an association between the reduced effect of methylphenidate (MPH) and the
SLC6A3 ( DAT1) 10-repeat polymorphism, this association has been challenged by subsequent studies.
A recent meta-analysis aggregating only five studies indicated an association between the 10-repeat and poor
response, but there are three studies showing opposite results and eight reports that failed to identify any
association.
Given the SLC6A3 gene structure and recent findings regarding association with attention deficit hyperactivity
disorder clinical phenotype, additional gene regions should be investigated in further research.
Recent research has started to investigate other genes & response to atomoxetine
There has been an increase in the number of potential associations studied over the last few years: there were
nine reports in 2005, 24 in 2008 and 52 in 2010 (which are reported in this review).
All three published studies on the ADRA2A gene demonstrated a positive association between genotype and
clinical response to methylphenidate, particularly in the inattentive symptoms dimension.
Data on atomoxetine response according to CYP2D6 genotype suggest differences between poor and
extensive metabolizers, but clinical implications of these findings are still limited.
Methodological limitations still hamper firm conclusions
Heterogeneity among designs, instruments and subjects represents a major obstacle for meta-analytic
syntheses; ideally, pharmacogenetic studies should be part of randomized clinical trials.
Inclusion of baseline scores and other potential confounders as covariates is not a common practice, but a
necessary procedure for statistical analyses.
Recent evidence supports the feasibility of the generation of large datasets, with information acquired in
different sites, for collaborative work.
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Papers of special note have been highlighted as:

▪ of interest
▪▪ of considerable interest
Financial & com peting interests disclosure

Christian Kieling took part in a Novartis-sponsored meeting on attention deficit hyperactivity disorder in 2008. Luis A Rohde w as on the
speakers' bureau and/or acted as consultant for Eli-Lilly, Janssen-Cilag and Novartis in the last 3 years. Currently, his only industry-related
activity is taking part in the advisory board/speakers bureau for Eli Lilly, Novartis and Shire (less than U$10,000 per year and reflecting
less than 5% of his gross income per year). The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by Luis A Rohde
received unrestricted educational and research support from the follow ing pharmaceutical companies in the last 3 years: Abbott, Bristol-
Myers Squibb, Eli-Lilly, Janssen-Cilag, Novartis and Shire. The authors have no other relevant affiliations or financial involvement w ith any
organization or entity w ith a financial interest in or financial conflict w ith the subject matter or materials discussed in the manuscript apart
from those disclosed.
No w riting assistance w as utilized in the production of this manuscript.
Pharmacogenomics. 2010;11(3):407-419. © 2010 Future Medicine Ltd.

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Abstract and Introduction

Figure 1. Number of pharmacogenetic associations included in three reviews on methylphenidate

Winsberg ABRS scores ≤ 1 Less

Reduction of 50% Less

Three- Categorical rating

Conclusion & Future Perspective

Early studies focused on catecholaminergic genes & methylphenidate response

Methodological limitations still hamper firm conclusions

1. Goldman L, Genel M, Bezman R, Slanetz P: Diagnosis and treatment of attention-deficit/hyperactivity disorder

Papers of special note have been highlighted as:

Financial & com peting interests disclosure

Pharmacogenomics. 2010;11(3):407-419. © 2010 Future Medicine Ltd.

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