Meta-Analysis of The Association Between Dopamine Transporter Genotype and Response To Methylphenidate Treatment in ADHD
Meta-Analysis of The Association Between Dopamine Transporter Genotype and Response To Methylphenidate Treatment in ADHD
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
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
Study Year Sample Ethnicity n Males Age 10/10 Non-10/10 Response measure MPH treatment
carrier carrier
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.
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
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
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, A second avenue for future research is to consider haplotypes
any interaction effects between different genotypes and as well as epistasis (genegene interactions). It is likely that the
treatment response cannot be ruled out. heritable component of the interindividual variability in methyl-
Overall, however, these results suggest that the often-examined phenidate response is not accounted for by one or several
40 bp VNTR in the 30 -untranslated region of the SLC6A3 gene does individual polymorphisms but instead by a combination of alleles
not signicantly relate to quantitative measures of treatment at the same or different loci. As in genome-wide association
success with methylphenidate in ADHD, with the exception of studies, large samples will be necessary to obtain signicant
studies using naturalistic designs. A previous meta-analysis based associations with this approach. One promising haplotype may
on n 6 studies44,45,49,52,60,77 had reported signicant summary involve the 10R allele studied here and the 3R allele of a 30-base
effect sizes.60 However, that report was based on only a sub- pair VNTR in intron 8, the SLC6A3 10/3 haplotype. This haplotype
sample of todays available n 16 studies and in the present com- has already been found to be associated with the diagnosis of
prehensive review no evidence for such an effect was obtained. ADHD, but has not yet been found to be signicantly linked to
This conclusion may appear disappointing given the strong a methylphenidate response (for review, see Froehlich et al.30).
priori evidence for a role of the dopamine transporter gene in A third area of research that would be of interest in future
methylphenidate response. However, it should be noted that studies is to consider genetic predictors of response to other
despite this failure to nd a signicant association in this study, we compounds with proven efcacy in ADHD, such as atomoxetine or
do not of course refute the possibility that variation in the amphetamine.80
dopamine transporter gene or other genes may represent a factor In order to facilitate future research of pharmacogenetics of
in the clinically and empirically observed interindividual variability ADHD, it is recommended that upcoming reports supply
in response to methylphenidate treatment in ADHD. Specically, a comprehensive data (for example, symptom scores pre- and
number of possibilities should be considered in the future. post-treatment). Also, a detailed description of the investigated
First, future pharmacogenetic studies are likely to go beyond sample (for example, ethnicity) is desired in order to allow
the candidate gene approach. Pharmacogenomic studies of the comparisons between studies.
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 Limitations
studies,79 it is likely that multicentre collaborations will be The quality of any meta-analysis is determined by the quality of
necessary to achieve the goal of nding statistically signicant the included studies. In the present analysis, differences of the
genome-wide association study correlates of methylphenidate included studies regarding the clinical populations, the assess-
treatment response. ment of treatment response as well as different treatment