The Pharmacogenomics Journal (2014) 14, 7784

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ORIGINAL ARTICLE
Meta-analysis of the association between dopamine transporter
genotype and response to methylphenidate treatment in ADHD
J Kambeitz1, M Romanos2 and U Ettinger3

Attention-decit/hyperactivity disorder (ADHD) is a prevalent childhood-onset neuropsychiatric disorder. Treatment with

methylphenidate, which blocks dopamine and noradrenaline transporters, is clinically efcacious in reducing the symptoms of
ADHD. However, a considerable proportion of patients show no or only insufcient 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
30 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
signicant summary effect for the SLC6A3 VNTR on the response to methylphenidate treatment (P40.5) and no effect on specic
symptom dimensions of hyperactivity/impulsivity and inattention (all P40.2). However, in a subanalysis of naturalistic trials, we
observed a signicant 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.

The Pharmacogenomics Journal (2014) 14, 7784; doi:10.1038/tpj.2013.9; published online 16 April 2013
Keywords: ADHD; methylphenidate; SLC6A3; dopamine transporter; pharmacogenetics; meta-analysis

INTRODUCTION clinical symptom ratings, methylphenidate has been shown to

Attention-decit/hyperactivity disorder (ADHD) is a highly impair-
ing childhood-onset neuropsychiatric disorder with the core
symptoms inattention, hyperactivity and impulsivity. The clinical
disorder encompasses three subtypes according to the DSM-IV-TR
(Diagnostic and Statistical Manual of Mental Disorders-Fourth
Edition-Text Revision),1 namely the predominantly hyperactive
impulsive type, the predominantly inattentive type and the
combined subtype. The aetiology of ADHD is largely unknown,
although genetic factors seem to substantially contribute to the
phenotype based on heritability estimates of up to 80%.24 ADHD
has a prevalence of B510% in children57 as well as 24% in
adults810 and is associated with comorbidities and substance
abuse, leading to high costs of the disorder to the health-care
system and society.11
Although a number of pharmacological options are available in
the treatment of ADHD, one of the most widely prescribed
compounds for both children and adults is methylphenidate.
Methylphenidate is a catecholamine reuptake inhibitor that blocks
the dopamine and noradrenaline transporters. The therapeutic
effects of methylphenidate are thought to be due to its increasing
extracellular levels of noradrenaline and dopamine, and particu-
larly of striatal dopamine.12 Methylphenidate is clinically effective
in the treatment of ADHD symptoms of both children and adults,
with meta-analyses showing improvements over placebo with
medium-to-large effect sizes.1319 In addition to improvements in
1
Department of Psychiatry, University of Munich, Munich, Germany; 2Department of Child and Adolescent Psychiatry, University Hospital of Wurzburg, Wurzburg, Germany and
3
Department of Psychology, University of Bonn, Bonn, Germany. Correspondence: J Kambeitz, Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University,
Nubbaumstrabe 7, 80336 Munchen, Germany.
E-mail: joseph.kambeitz@med.uni-muenchen.de
Received 21 September 2012; revised 12 January 2013; accepted 4 February 2013; published online 16 April 2013
improve aspects of cognitive task performance in patients with
ADHD2022 and in healthy volunteers.2325
However, interindividual variability in clinical response to
methylphenidate is considerable, with a proportion of patients
not improving or improving only moderately and a signicant
number of patients discontinuing treatment.26 The reasons for this
response variability among patients are unclear, but are likely to be
multifactorial. Although interstudy methodological issues may play
a role for observed variability in the literature,27 the present study
aims to clarify the role of pharmacogenetics in interindividual
response variability. Pharmacogenetics refers to the association
between genetic variation and the magnitude of response to
treatment. Pharmacogenetics is an area of promise in clinical and
cognitive psychopharmacology. It has the potential to explain
some of the variability not only in clinical or cognitive response to
pharmacological compounds but also in side-effect severity on the
basis of quantitative, neurobiologically determined predictors.2831
In case of methylphenidate, the pronounced action of this
drug at the dopamine transporter has led to numerous
pharmacogenetic studies involving the dopamine transporter
gene (SLC6A3). The dopamine transporter plays an important role
in the regulation of dopamine neurotransmission through
reuptake of dopamine from the synaptic cleft into the presynaptic
neuron.3234 The dopamine transporter gene SLC6A3 is located on
chromosome 5p15.3 and contains a widely investigated variable
 Pharmacogenetics of methylphenidate
J Kambeitz et al
78
number of tandem repeat (VNTR) polymorphism. This VNTR
consists of a 40-base pair sequence in the 3-untranslated region
of the gene. In humans, the tandem repeats range from 311 (see
refs. 35,36) with the 9-repeat (9R) and 10-repeat (10R) forms being
the most common.3639 The effects of the VNTR on protein
expression are inconsistent and a recent meta-analysis of human
single-photon emission computed tomography studies failed to
obtain a signicant association between the VNTR and the
amount of dopamine transporter availability in human
striatum.40 Nevertheless, the VNTR may play a role in regulating
mRNA stability, nuclear transport and protein synthesis.41,42
Of relevance to the treatment of ADHD, a number of studies
have investigated this VNTR as a possible source of variation in
clinical response to methylphenidate treatment in patients with
ADHD. The rationale for investigations of the association between
SLC6A3 genotype and the clinical response to methylphenidate
lies principally in the dual observations that (1) methylphenidate
treatment in ADHD involves the dopamine transporter and (2) a
single gene codes for this drug target, thereby providing for the
possibility of studying a fairly tight pharmacogenetic model.
Additionally, there have been a number of studies investigating
(1) an aetiological role of SLC6A3 in ADHD,2 (2) dopamine
transporter availability in ADHD43 and (3) the association
between the SLC6A3 VNTR and dopamine transporter availability
in human striatum.40
Although some studies have shown that the 9R allele is
associated with better clinical response to methylphenidate,27,4447
other studies have shown the opposite pattern4850 or have failed to
observe a signicant effect.5159 A recent review has summarised
the literature on this topic and an early meta-analysis of six studies
in childhood ADHD reported that 10R homozygotes showed poor
methylphenidate response.60 However, further studies on children
and adults have appeared since then.47,48,50,5359 In order to update
the literature review and clarify inconsistencies in the literature on
this important topic we, therefore carried out a comprehensive
meta-analysis of the association between the SLC6A3 VNTR and
clinical response to methylphenidate in childhood as well as in
adult patients with ADHD. We compared the quantitative response
as reected by changes in ADHD symptom scores to
methylphenidate treatment between non-10/10 carriers and 10R
homozygotes, a grouping of genotypes commonly undertaken in
SLC6A3 association studies.
MATERIALS AND METHODS
Search strategy and selection of studies
PubMed61 was searched for the keywords dopamine transporter, VNTR,
SLC6A3, DAT1, variable number of tandem repeats or polymorphism as sizes and to check the inuence of potential confounding variables.
well as methylphenidate or ritalin and ADHD. All studies reporting an
association of the SLC6A3 VNTR with response to methylphenidate
treatment in subjects with ADHD until 1 January 2012 were included.
We included all studies regardless of age of the studied population or the
dose and frequency of methylphenidate treatment. Moreover, studies
were included irrespective of whether the measure of response to
methylphenidate treatment was categorical (for example, responders or
nonresponders) or dimensional (for example, change on symptom scales).
The bibliographies of the selected publications were hand-searched for
further studies and authors were contacted to supply further information
regarding published data or to inform about potential overlap of studied
samples when necessary.
Data extraction
For each selected study, information was extracted on publication (names
of authors, publication year) and sample characteristics (sample size, ADHD
diagnostic criteria, gender, age, previous medication). The main outcome
measure for the meta-analysis was the effect size (Cohens d62)
representing differences in response to methylphenidate treatment
between 10/10 homozygotes and all other genotypes. As studies
reported dichotomised as well as continuous outcome measures,
The Pharmacogenomics Journal (2014), 77 84
transformation to Cohens d as effect size metric was employed to allow
inclusion for meta-analysis. Dichotomised outcome measures were
transformed to Cohens d using a procedure proposed by Cox63 that has
recently been shown to allow reliable estimates of effect sizes as well as
variance.64 Also, Cohens d was used for subanalysis of only studies that
provided dichotomised outcome measures in order to allow comparison
with other results presented.
Across studies, the way dopamine transporter genotypes were
separated into groups of analysis differed. For this reason we conducted
the present meta-analysis on the most widely applied separation into one
group of 10R homozygotes and one group of all other genotypes including
10R heterozygotes as well as homozygotes and heterozygotes of all
other alleles (in fact only 9R and 11R were reported). In case of studies that
only reported means and s.d. for pre- and post-treatment separately
for 10R homozygotes and non-10R carriers, the s.d. for the difference of
two variables (A and B) was calculated following the formula:
p
SDA  B SD2A SD2B  2rAB SDA SDB . The correlation (rAB 0.32) was esti-
mated on the basis of raw data available from two study populations.48,60
Differences in study protocols and statistical analysis signicantly affect
outcome measures and might therefore introduce variance in reported
effect sizes. However, in order to maximise the statistical power of the
presented meta-analysis and to ensure optimal use of all the available
data, we initially included all studies regardless of reported outcome
measure, study protocol or statistical analysis. A wide range of scales were
used in the included studies measuring treatment response. Therefore, we
step-wise included different subsets of all studies, thereby creating more
homogenous subsamples of studies. This allowed us to examine the
inuence of different symptom rating scales on detected effect sizes and
whether the effect evident in the more inclusive rst-level meta-analysis
was consistently replicated in the subsequent analyses that included more
homogeneous studies.
Data analysis. Statistical analysis of the extracted data was conducted
using the R statistical programming language version 2.10.1 with the
package metafor.65 The individual effect size for each study was entered
into a random-effects model to compute an overall effect size.66,67 The
summary effect sizes (Cohens d) were computed using a restricted
maximum-likelihood estimator.68 Heterogeneity was assessed in the
studies by calculating the I2 value, which is a sample size-independent
measure that describes the percentage of total variation across studies that
is due to heterogeneity rather than chance.69 The I2 values of 25%, 50%
and 75% can be interpreted as indicating low, moderate and high
heterogeneity, respectively.69 A funnel plot of the selected studies was
visually inspected for symmetry and a linear regression test for funnel plot
asymmetry (Eggers test) was calculated to test for publication bias
resulting from a greater likelihood of positive results getting published. In
case of signicant evidence for a publication bias, trim-and-ll analysis was
implemented, which provides an estimate of the meta-analysis if there has
been publication bias.70,71 This is achieved by detecting potentially missing
studies in the funnel plot and correcting the summary effect size estimate.
Meta-regression analyses were run including publication year, gender and
age as the factors to evaluate the source of heterogeneity in the effect
RESULTS
For one study, subjects were administered methylphenidate at
different dosage levels. We chose the odds ratio reported at the
highest dosage level and converted this value into Cohens d
effect size in order to assure comparability with effect sizes from
other studies.49 For one study,59 effect sizes included in our
analysis were derived not from baseline versus treatment
differences but from methylphenidate versus placebo treatment.
Three studies51,72,73 were excluded as they did not report values
sufcient for calculation of effect sizes of treatment response
differences between different genotypesalso after contacting
the authors, the data were not provided.
A total of 16 studies published between 1999 and 2010
matched the search criteria (see Table 1), resulting in a nal
sample of 1572 subjects4450,52,5460 including N 799 10R
homozygotes and N 773 carriers of genotypes other than
10R/10R (one study did not report genotype frequencies53).
The random-effects model revealed a nonsignicant summary
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 Pharmacogenetics of methylphenidate
J Kambeitz et al
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Table 1. Overview of studies investigating effect of dopamine transporter genotype on methylphenidate response in subjects with ADHD

Study Year Sample Ethnicity n Males Age 10/10 Non-10/10 Response measure MPH treatment
carrier carrier

Scale Scale level Design Duration Dose

Winsberg et al. 1999 Children African- 30 NA 8.31 17 13 ABRS Categorical Naturalistic NA 4060 mg day  1
American o0.7 mg kg  1 day  1
Roman et al. 2002 Children Brazilian 50 50 NA 30 20 ABRS, Categorical Naturalistic B30 days 0.30.7 mg kg  1 day  1
CGAS
Kirley et al. 2003 Children Irish 178 127 11.86 88 90 CPRS Categorical Naturalistic NA NA
Loo et al. 2003 Children NA 27 18 10.41 10 17 SNAP Dimensional Clinical trial 10 mg single dose
Cheon et al. 2005 Children Korean 11 9 9.82 7 4 ARS Dimensional Naturalistic 8 weeks 0.3 mg kg  1 day  1
Langley et al. 2005 Children British 168 NAa NAa 87 81 CGI Categorical Naturalistic X3months NA
Stein et al. 2005 Children Mixed 47 33 9.02 19 28 CGI-S Dimensional Clinical trial 4 weeks Placebo or
1854 mg day  1
McGough et al. 2006 Children Mixed 48 NAa NAa 19 29 CLAM/SKAMP Dimensional Clinical trial 46 weeks 3.7522.5 mg
Mick et al. 2006 Adults NA 106 60 36.95 59 47 AISRS Dimensional Clinical trial 6 weeks Week 13: 0.5
1.0 mg kg  1 day  1
week 56:
o1.3 mg kg  1 day  1
Joober et al. 2007 Children Mixed 151 129 9.97 74 77 Conners GI Dimensional Clinical trial 2 weeks 0.5 mg kg  1 day  1
Zeni et al. 2007 Children Brazilian 109 NAa NAa 55 54 SNAP Dimensional Naturalistic 4 weeks 0.5 mg kg  1 day  1
Kereszturi et al. 2008 Children Hungarian 118 104 9.6 60 58 ARS Dimensional Naturalistic 4 weeks 0.22
0.95 mg kg  1 day  1
Kooij et al. 2008 Adults European 42 23 42.5 18 24 CGI, DSM-IV-RS Dimensional Clinical trial 3 weeks week 1:
0.5 mg kg  1 day  1
week 2:
0.75 mg kg  1 day  1
week 3:
o1.0 mg kg  1 day  1
Purper-Ouakil et al. 2008 Children NA 161 143 10.56 81 80 ARS, CGI Dimensional Naturalistic 55.5 days mean of 31.19 mg day  1
Tharoor et al. 2008 Children American 156 128 13.04 83 73 MAGIC Categorical Naturalistic NA NA
Contini et al. 2010 Adults Brazilian 170 89 35 92 78 SNAP Dimensional Naturalistic 30 days 40.3 mg kg  1 day  1
weekly increase

Abbreviations: ABRS, Conners Abbreviated Rating Scale; ADHD, attention-deficit/hyperactivity disorder; AISRS, Adult ADHD Investigator System Report Scale;
ARS, ADHD Rating Scale; CGAS, Clinical Global Assesment Scale; CGI, Conners Global Index; CGI-S, Clinical Global Impression-Severity of Impairment; CLAM,
Conners, Loney and Milich Scale; CPRS, Conners Parents Rating Scale Revised; DSM-IV-RS, DSM-IV ADHD-Rating Scale; MAGIC, Missouri Assessment for
Genetics Interview for children; MPH, methylphenidate; NA, not available; SKAMP, Swanson, Conners, Milich and Pelham Scale; SNAP, Swanson, Nolan, and
Pelham Rating Scale version IV; SWAN, Strength and Weaknesses of ADHD Symptoms and Normal Behaviour.
a
Data not available for the subset of subjects who were treated with methylphenidate, genotyped for the SLC6A3 polymorphism and whose reponse was recorded.

(as a reduction of symptom rating scores, N 11 studies) revealed

Table 2. Overview of studies investigating effect of dopamine
a nonsignicant summary effect size of d 0.04 (95% CI:  0.1 to
transporter genotype on methylphenidate response in subjects with
0.19, z 0.5822, P 0.6, I2 29.67%, 95% CI for I2: 085.26%).
ADHD on different symptom subscales
Restricting the analysis to studies that reported treatment
Study Year n Scale response on a categorical level (responders vs nonresponders,
N 5 studies) revealed a signicant effect size of d  0.41 (95%
Contini et al. 2010 171 SNAP (hyperactivity/impulsivity, inattention) CI:  0.7 to  0.12, z  2.7343, P 0.006, I2 0%, 95% CI for I2:
Kereszturi et al. 2008 122 ARS (hyperactivity/impulsivity, inattention)
Kirley et al. 2003 119 CPRS (cognition, hyperactivity) 096.26%) with the 10R homozygotes showing less improvement
Loo et al. 2003 27 SNAP (hyperactivity/impulsivity, inattention) in symptoms following treatment than the non-10/10 carriers.
Purper-Ouakil 2008 161 ARS (hyperactivity/impulsivity, inattention) However, funnel plot analysis of the studies showed evidence of a
et al.
Zeni et al. 2007 99 SNAP (hyperactivity/impulsivity, inattention) publication bias (see Figure 2) and a signicant effect in the
Eggers test (z  2.39, P 0.02). Therefore, trim-and-ll analysis
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ARS, ADHD was run, which detected two potentially missing studies. In the
Rating Scale; SNAP, Swanson, Nolan and Pelham Rating Scale version IV; corrected model, the effect size of d  0.29 (95% CI:  0.85 to
CPRS, Conners Parent Rating Scale Revised.
0.27, z  1.0058, P 0.3, I2 68.02%, 95% CI for I2: 0.1996.37%)
was nonsignicant.
After restricting the analysis to studies in children by excluding
effect size of d  0.05 (95% condence interval (CI):  0.2 to 0.1, three studies in adult subjects,47,54,58 there was a nonsignicant
z  0.698, P 0.52, I2 38.2%, 95% CI for I2: 11.7291.02%, see effect size of d  0.24 (95% CI:  0.62 to 0.13, z  1.2627,
Figure 1a), suggesting that genotype was not a signicant P 0.2, I2 56.93%, 95% CI for I2: 23.4792.17%). There was
predictor of treatment response. Funnel plot analysis of the evidence for a publication bias in the funnel plot and in the
studies showed evidence of a publication bias (see Figure 1c) and Eggers test (z  2.14, P 0.03). Trim-and-ll analysis did not
a signicant effect in the Eggers test (z  2.65, P 0.01). detect any missing studies. From three studies that investigated
Therefore, trim-and-ll analysis was carried out, which detected the effect of SLC6A3 on response to methylphenidate in adults
three potentially missing studies. In the corrected model the effect with ADHD, two reported no signicant effect,52,54 whereas one
size remained nonsignicant (d 0.01, 95% CI:  0.16 to 0.18, study reported a decreased response in 10R homozygotes.47
z 0.148, P 0.9, I2 52.4%, 95% CI for I2: 48.0794.04%). Meta- As the main meta-analysis included studies using a placebo-
regression with year of publication as a factor revealed no controlled, double-blind clinical trial design as well as studies
signicant change of effect size over the years (b 0.0675, using an open-label naturalistic design, we ran subanalyses
F(1,14) 1.6628, P 0.2181, see Figure 1b). separating studies according to design type.30 By restricting the
As our analysis revealed substantial heterogeneity in the analysis to placebo-controlled, double-blind clinical trials (N 6),
included studies, we conducted further analysis on more there was a nonsignicant effect (d 0.44, 95% CI:  0.05 to 0.93,
homogenous subsamples of studies. Restricting the analysis to z 1.7634, P 0.08, I2 79.91%, 95% CI for I2: 45.2296.79%) with
samples that reported treatment response on a dimensional level no evidence for a publication bias (z 0.89, P 0.38). By

& 2014 Macmillan Publishers Limited The Pharmacogenomics Journal (2014), 77 84

 Pharmacogenetics of methylphenidate
J Kambeitz et al
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Figure 1. (a) Forest plot of studies included in the meta-analysis of dopamine transporter genotypes and response to methylphenidate
treatment in attention-deficit/hyperactivity disorder (ADHD). (b) Meta-regression of the effect of year of publication on estimated effect size. (c)
Funnel plot of studies included in the meta-analysis of dopamine transporter genotypes and response to methylphenidate treatment in ADHD.

restricting the analysis to naturalistic trials (N 10), there was a but also evidence for a publication bias as indicated by visual
signicant effect (d  0.63, 95% CI:  1.1 to  0.15, inspection of the funnel plot (see Figure 3) and a signicant
z  2.6004, P 0.009, I2 91.32%, 95% CI for I2: 81.0398.36%) Eggers test (z  3.14, P 0.001). Visual inspection of the funnel

The Pharmacogenomics Journal (2014), 77 84 & 2014 Macmillan Publishers Limited


0.000
0.180
standard error
0.359
0.539
0.719
2.00 1.50 1.00 0.50 0.00
observed outcome
Figure 2. Funnel plot of studies reporting treatment response on a
categorical level (responders vs nonresponders).
0.000
0.197
standard error
0.395
0.592
0.790
3.00 2.00 1.00
observed outcome
Figure 3. Funnel plot of studies using an open-label naturalistic
design.
plot also identied two outliers that might have driven the effect.
However, after exclusion of those two studies, there was still a
signicant effect size (d  0.36, 95% CI:  0.7 to  0.03,
z  2.1396, P 0.03, I2 83.4%, 95% CI for I2: 61.495.6%),
indicating that 10R homozygotes show less improvement in
symptoms following treatment than the non-10/10 carriers. For
this result, there was no evidence for a publication bias in the
funnel plot or indicated by the Eggers test (z  0.22, P 0.82).
In order to investigate whether this effect of design type might
have been confounded by other factors, we compared clinical and
naturalistic trials with respect to their study population. Using
t-tests, we found no difference in age, male ratio or year of
publication (all P40.5). Also, w2-test indicated no difference in the
scale levels used (dimensional or categorical) between clinical and
naturalistic trials (P40.4). As the included studies investigated
samples from heterogeneous ethnic origin, different allele
frequencies represent a potential confound to the present
analysis. However, w2-test indicated no signicant differences in
allele frequencies between studies (P 0.61).
For six studies, data were available of treatment response
for 10/10 homozygotes and non-10/10 carriers for different
ADHD subscales (see Table 2).48,55,5760 Meta-analysis of the
hyperactivity/impulsivity subscale revealed no signicant
summary effect size (d  0.22, 95% CI:  0.6 to 0.16,
& 2014 Macmillan Publishers Limited
Pharmacogenetics of methylphenidate
J Kambeitz et al
81
z  1.1363, P 0.3, I2 84.14%, 95% CI for I2: 58.9497.62%,
see Figure 4a). Meta-analysis of the inattention subscale also
revealed no signicant summary effect size (d  0.05, 95% CI:
 0.4 to 0.3, z  0.2813, P 0.8, I2 81.88%, 95% CI for I2:
51.3397.57%, see Figure 4b).
For a subgroup of studies, data were available for 9/9, 9/10 and
10/10 allele carriers on different scales. Analysis was run separately
for every available outcome measure (inattention,47,48,57,59,60 and
hyperactivity/impulsivity47,57,59,60) using genotype group as a
covariate. This analysis showed no signicant effect of the
genotype group, indicating no signicant difference between 9/
9, 9/10 and 10/10 allele carriers in response to methylphenidate as
measured by scales of inattention (P40.30) or scales of
hyperactivity/impulsivity (P40.08).
0.50 1.00
DISCUSSION
Pharmacogenetics is an approach with some promise within the
eld of pharmacological treatment of neuropsychiatric disease.74
Interindividual variability at the level of symptom severity
reduction, development of adverse side effects and improve-
ments in cognitive and socio-occupational functioning may impair
compliance and impede successful treatment outcomes. If
successful, pharmacogenetics may assist in providing objective
and reliable markers for the prediction of treatment response with
a view to developing individualised medicine.
Here we provide a quantitative analysis of the outcome of one
pharmacogenetic research question in current neuropsychiatry,
namely, the role of the SLC6A3 40 bp VNTR in the 30 -untranslated
region of the gene in the clinical response to methylphenidate in
patients with ADHD. The rationale for investigating this poly-
morphism in relation to methylphenidate response is based on
multiple lines of evidence linking methylphenidate treatment
success with the dopamine transporter.1219,75,76
A total of 16 published studies investigating this issue were
identied. The overall effect size for the comparison between 10R
homozygotes and non-10R homozygotes in treatment response
0.00 1.00 was not signicant with a negligible effect size (d 0.05). As
indicated by asymmetry in the distribution of effect sizes in the
funnel plot as well as by signicant Eggers test for funnel plot
asymmetry, there was evidence of publication bias indicating that
studies with a desired outcome are preferentially brought to
publication. Following correction of the model, we still failed to
nd a signicant effect. Year of publication was not signicantly
associated with effect size.
There was signicant between-study heterogeneity. Accord-
ingly, a number of more specic analyses were carried out.
Specically, restricting the studies to those of children or placebo-
controlled, double-blind trials did not yield signicant effect sizes.
Moreover, a subsample of six studies provided data on specic
symptom dimensions, namely, hyperactivity/impulsivity and
inattention. As in the overall analysis, no signicant association
was observed in relation to these specic symptom subscales.
Interestingly, an analysis of the subsample of studies with
binary outcome data (responder vs nonresponder) initially
provided evidence of a signicant effect, suggesting that response
in 10R homozygotes was poor compared with other genotypes.
However, that effect became nonsignicant after correction for
publication bias. The pattern of worse response in 10R homo-
zygotes was also observed with a small-to-medium effect size in
the subset of 10 studies using a naturalistic design. Similar
differences of pharmacogenetic effects in ADHD-treated subjects
between randomised clinical trials and naturalistic studies have
been reported previously.27 As randomised clinical trials control
for placebo effects by including a control group, they are generally
considered to be the superior experimental approach to the
investigation of pharmacological effects. Even if in the case of the
presented pharmacogenetic studies potential placebo effects
The Pharmacogenomics Journal (2014), 77 84
 Pharmacogenetics of methylphenidate
J Kambeitz et al
82
95% CI
study year d upper lower z score p value other > 10 homozygotes 10 homozygotes > other

Loo 2003 0.5843 0.2122 1.3808 1.4377 0.1505

Kirley 2003 0.8127 1.1533 0.4720 4.6760 <0.0001
Zeni 2007 0.0032 0.3786 0.3723 0.0165 0.9868
Purper Ouakil 2008 0.1243 0.4335 0.1849 0.7879 0.4308
Kereszturi 2008 0.0000 0.3609 0.3609 0.0000 1.0000
Kooij 2008 1.1965 1.8723 0.5206 3.4698 0.0005
Contini 2010 0.0414 0.2603 0.3431 0.2692 0.7878

RE model 0.2194 0.5979 0.1591 1.1363 0.2558

2 1 0 1 2
summary effect size

95% CI
study year d upper lower z score p value other > 10 homozygotes 10 homozygotes > other

Loo 2003 0.3050 0.4803 1.0903 0.7612 0.4465

Kirley 2003 0.4021 0.0714 0.7329 2.3832 0.0172
Zeni 2007 0.1420 0.2339 0.5180 0.7403 0.4591
Purper Ouakil 2008 0.1495 0.4588 0.1599 0.9470 0.3437
Kereszturi 2008 0.0475 0.3134 0.4085 0.2581 0.7963
Kooij 2008 1.3477 2.0371 0.6583 3.8316 0.0001
Contini 2010 0.0169 0.3186 0.2848 0.1098 0.9126

RE model 0.0507 0.4040 0.3026 0.2813 0.7784

2 1 0 1 2
summary effect size

Figure 4. (a) Forest plot of studies included in the meta-analysis of dopamine transporter genotypes and response to methylphenidate
treatment in attention-deficit/hyperactivity disorder (ADHD) on the subscale hyperactivity/impulsivity. (b) Forest plot of studies included in
the meta-analysis of dopamine transporter genotypes and response to methylphenidate treatment in ADHD on the subscale inattention.

should affect both 10R homozygotes and non-10R homozygotes,
any interaction effects between different genotypes and
treatment response cannot be ruled out.
Overall, however, these results suggest that the often-examined
40 bp VNTR in the 30 -untranslated region of the SLC6A3 gene does
not signicantly relate to quantitative measures of treatment
success with methylphenidate in ADHD, with the exception of
studies using naturalistic designs. A previous meta-analysis based
on n 6 studies44,45,49,52,60,77 had reported signicant summary
effect sizes.60 However, that report was based on only a sub-
sample of todays available n 16 studies and in the present com-
prehensive review no evidence for such an effect was obtained.
This conclusion may appear disappointing given the strong a
priori evidence for a role of the dopamine transporter gene in
methylphenidate response. However, it should be noted that
despite this failure to nd a signicant association in this study, we
do not of course refute the possibility that variation in the
dopamine transporter gene or other genes may represent a factor
in the clinically and empirically observed interindividual variability
in response to methylphenidate treatment in ADHD. Specically, a
number of possibilities should be considered in the future.
First, future pharmacogenetic studies are likely to go beyond
the candidate gene approach. Pharmacogenomic studies of the
genome-wide correlates of treatment response have already been
reported, although as yet without formally signicant results.78
Given the sample size requirements for genome-wide association
studies,79 it is likely that multicentre collaborations will be
necessary to achieve the goal of nding statistically signicant
genome-wide association study correlates of methylphenidate
treatment response.
A second avenue for future research is to consider haplotypes
as well as epistasis (genegene interactions). It is likely that the
heritable component of the interindividual variability in methyl-
phenidate response is not accounted for by one or several
individual polymorphisms but instead by a combination of alleles
at the same or different loci. As in genome-wide association
studies, large samples will be necessary to obtain signicant
associations with this approach. One promising haplotype may
involve the 10R allele studied here and the 3R allele of a 30-base
pair VNTR in intron 8, the SLC6A3 10/3 haplotype. This haplotype
has already been found to be associated with the diagnosis of
ADHD, but has not yet been found to be signicantly linked to
methylphenidate response (for review, see Froehlich et al.30).
A third area of research that would be of interest in future
studies is to consider genetic predictors of response to other
compounds with proven efcacy in ADHD, such as atomoxetine or
amphetamine.80
In order to facilitate future research of pharmacogenetics of
ADHD, it is recommended that upcoming reports supply
comprehensive data (for example, symptom scores pre- and
post-treatment). Also, a detailed description of the investigated
sample (for example, ethnicity) is desired in order to allow
comparisons between studies.
Limitations
The quality of any meta-analysis is determined by the quality of
the included studies. In the present analysis, differences of the
included studies regarding the clinical populations, the assess-
ment of treatment response as well as different treatment

The Pharmacogenomics Journal (2014), 77 84 & 2014 Macmillan Publishers Limited


schemes might have introduced substantial heterogeneity,
biasing the result and weakening any conclusion drawn from it.
Given the limited number of studies available, it is possible that
potential confounds were not detected in the present analysis
because of low statistical power. In general, the assessment of
ADHD symptomsand thus any assessment of treatment
responseis subject to low reliability. Until now, no valid
objective measure allows the quantication of ADHD symptoms,
and neuropsychological impairments are only found in some
patients.81 Therefore, assessment of ADHD is based on symptom
rating scales, clinical observation as well as reports from
parents and teachers. Finally, it should be noted that the
prediction of treatment response is likely to involve not only
genetic factors but also nongenetic, environmental or sociodemo-
graphic factors. Moreover, it is possible that treatment response
differs between different ADHD subtypes, between different
disease stages (adults, children) and might also be affected
by comorbid factors. Altogether, treatment response is a
complex multifactorial phenotype, variation in which is likely to
be because of a number of factors including genetics as well as
nongenetic variables.
Clinical implications
To conclude, the present meta-analysis suggests that the 40-base
pair VNTR in the 3-untranslated region of the SLC6A3 gene is not
systematically related to variability in clinical response to
methylphenidate treatment in childhood, adolescence and adult
patients with ADHD. However, there was evidence from natur-
alistic designs suggesting that the 10R/10R genotype may be a
predictor of worse response. By and large, the failure to conrm
the SLC6A3 VNTR as a signicant predictor across study designs
and age groups is noteworthy, given the considerable research
effort in relation to this question and the strong a priori grounds
on which such an association could have been expected.
CONFLICT OF INTEREST
The authors declare no conict of interest.
ACKNOWLEDGEMENTS
Joseph Kambeitz is supported by a doctoral fellowship of BayEFG. Ulrich Ettinger is
supported by the DFG Emmy Noether programme (ET 31/2-1). We thank Cristian
Patrick Zeni, Veronica Contini, Aiveen Kirley, Diane Purper-Ouakil, Sandra K Loo,
Harriet de Wit and Sandra Kooij for providing us with data necessary for the meta-
analysis.
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