Meta-analysis of the association between dopamine transporter genotype and response to methylphenidate treatment in ADHD
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent childhood-onset neuropsychiatric disorder. Treatment with methylphenidate, which blocks dopamine and noradrenaline transporters, is clinically efficacious in reducing the symptoms of ADHD. However, a considerable proportion of patients show no or only insufficient 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 3' 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 significant summary effect for the SLC6A3 VNTR on the response to methylphenidate treatment (P>0.5) and no effect on specific symptom dimensions of hyperactivity/impulsivity and inattention (all P>0.2). However, in a subanalysis of naturalistic trials, we observed a significant 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.
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Recent meta-analyses did not support the polymorphism association hypothesis for methylphenidate treatment response.
“However, recent meta-analyses did not support this polymorphism association hypothesis (Kambeitz et al., 2014; Bonvicini et al., 2016).”
From A Review of Heterogeneity in Attention Deficit/Hyperactivity Disorder (ADHD) (2019) · cites this paper as Kambeitz et al., 2014
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“However, recent meta-analyses did not support this polymorphism association hypothesis (Kambeitz et al., 2014; Bonvicini et al., 2016).”
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Storebø, O. J., Storm, M. R. O., Ribeiro, J. P., Skoog, M., Groth, C., Edemann-Callesen, H., Schaug, J. P., Rasmussen, P. D., Huus, C.-M. L., Zwi, M., et al. (2023) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd009885.pub3 · Cited by 99 · see citing works
The dopamine transporter role in psychiatric phenotypes
Salatino‐Oliveira, A., Rohde, L. A., & Hutz, M. H. (2017) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32578 · Cited by 72 · see citing works
Pharmacogenomics in psychiatry: the relevance of receptor and transporter polymorphisms
Reynolds, G. P., McGowan, O. O., & Dalton, C. (2013) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12312 · Cited by 57 · see citing works
ADHD pharmacogenetics across the life cycle: New findings and perspectives
Bruxel, E. M., Akutagava-Martins, G. C., Salatino-Oliveira, A., Contini, V., Kieling, C., Hutz, M., & Rohde, L. (2014) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32240 · Cited by 44 · see citing works
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Reward modulation of cognitive function in adult attention-deficit/hyperactivity disorder
Aarts, E., van Holstein, M., Hoogman, M., Onnink, A. M. H., Kan, C. C., Franke, B., Buitelaar, J. K., & Cools, R. (2014) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000116 · Cited by 43 · see citing works
“Future work should address the obvious next question, that is, whether the discrepancy in the extant literature on the effects of the DAT1 genotype on the clinical response to medication (Kambeitz et al., 2014) also reflects variability in the patient’s reward motivational state.”
BackgroundKing, C. P., Palmer, A. A., Woods, L. C. S., Hawk, L. W., Richards, J. B., & Meyer, P. (2016) · Psychopharmacology · doi:10.1007/s00213-016-4306-x · Cited by 37 · see citing works
“While the effect of dopamine transporter genotype in humans is controversial (Kambeitz et al. 2014), one study found that methylphenidate was more effective in individuals with the 10/10 and 10/9 dopamine transporter genotypes, compared to those with the 9/9 genotype (Stein et al. 2014).”
Connolly, J. J., Glessner, J., Kao, C., Elia, J., & Hakonarson, H. H. (2015) · Therapeutic Innovation & Regulatory Science · doi:10.1177/2168479015599811 · Cited by 37 · see citing works
Stevens, T., Sangkuhl, K., Brown, J. T., Altman, R. B., & Klein, T. E. (2019) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0000000000000376 · Cited by 34 · see citing works
Recent developments in the genetics of attention‐deficit hyperactivity disorder
Grimm, O., Kittel‐Schneider, S., & Reif, A. (2018) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12673 · Cited by 31 · see citing works
Kasparbauer, A., Rujescu, D., Riedel, M. J., Pogarell, O. M., Costa, A. C. L., Meindl, T., la Fougère, C., & Ettinger, U. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.240 · Cited by 30 · see citing works
“These latter groups were combined into the 9R carriers group (Costa et al, 2011; Kambeitz et al, 2014).”
BackgroundResultInfluentialMergy, M. A., Gowrishankar, R., Davis, G. L., Jessen, T. N., Wright, J., Stanwood, G. D., Hahn, M. K., & Blakely, R. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2013.11.009 · Cited by 28 · see citing works
Shim, S.-H., Yoon, H.-J., Bak, J., Hahn, S., & Kim, Y. (2016) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2016.04.007 · Cited by 29 · see citing works
“However, evidence from naturalistic design studies suggests that the 10R/10R genotype may be a predictor of worse response (Kambeitz et al., 2014).”
BackgroundYip, S. W., & Potenza, M. N. (2016) · Clinical Psychology Review · doi:10.1016/j.cpr.2016.11.003 · Cited by 28 · see citing works
Pagerols, M., Richarte, V., Sánchez-Mora, C., Garcia-Martínez, I., Corrales, M., Corominas, M., Cormand, B., Casas, M., Ribasés, M., & Ramos-Quiroga, J. (2016) · The Pharmacogenomics Journal · doi:10.1038/tpj.2015.89 · Cited by 31 · see citing works
Gomez-Sanchez, C. I., Carballo, J. J., Riveiro-Alvarez, R., Soto-Insuga, V., Rodrigo, M., Mahillo-Fernandez, I., Abad-Santos, F., Dal-Ré, R., & Ayuso, C. (2017) · Scientific Reports · doi:10.1038/s41598-017-10912-y · Cited by 24 · see citing works
Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults
Cândido, R. C. F., de Padua, C. A. M., Golder, S., & Junqueira, D. R. (2021) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd013011.pub2 · Cited by 33 · see citing works
“…trials, systematic reviews and meta-analyses have been published on the eDect of treating ADHD in children and adolescents with IR methylphenidate (Charach 2011; Charach 2013; Hanwella 2011; Kambeitz 2014; Maia 2017; Punja 2013; Reichow 2013; Storebø 2015), there is a dearth of such data on adults.”
BackgroundParlatini, V., Raduà, J., Solanes, A., Wichers, R., Maltezos, S., Sanefuji, M., Dell’Acqua, F., Catani, M., de Schotten, M. T., & Murphy, D. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02598-w · Cited by 23 · see citing works
“For instance, some genetic studies reported an association between variants of the dopamine transporter gene (DAT1) and treatment response, but others did not [18].”
BackgroundMethylphenidate HCL for the treatment of ADHD in children and adolescents
Childress, A. C. (2016) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2016.1182986 · Cited by 23 · see citing works
“a reliable predictor of MPH response.[79]”
Meta-Analysis Reveals Significant Association of the 3′-UTR VNTR inSLC6A3with Alcohol Dependence
Ma, Y., Fan, R., & Li, M. D. (2016) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.13104 · Cited by 21 · see citing works
“, 2015a) and various psychiatric disorders (Kambeitz et al., 2014; Yang et al., 2007), which are all correlated with AD (Li and Burmeister, 2009; Ma et al.”
Exocytosis-related genes and response to methylphenidate treatment in adults with ADHD
da Silva, B. S., Cupertino, R. B., Rovaris, D. L., Schuch, J. B., Kappel, D. B., Müller, D., Bandeira, C. E., Victor, M. M., Karam, R. G., Mota, N. R., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.90 · Cited by 21 · see citing works
Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults
Cândido, R. C. F., Menezes de Padua, C. A., Golder, S., & Junqueira, D. R. (2021) · White Rose Research Online (University of Leeds, The University of Sheffield, University of York) · Cited by 20 · see citing works
Meta-analysis of the association of the SLC6A3 3′-UTR VNTR with cognition
Ettinger, U., Merten, N., & Kambeitz, J. P. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.09.021 · Cited by 21 · see citing works
Elsayed, N. A., Yamamoto, K. M., & Froehlich, T. E. (2020) · CNS Drugs · doi:10.1007/s40263-020-00702-y · Cited by 23 · see citing works
The SLC6A3 gene polymorphism is related to the development of attentional functions but not to ADHD
Kuć, K., Bielecki, M., Racicka, E., Czerwinski, M. B., & Cybulska-Kłosowicz, A. (2020) · Scientific Reports · doi:10.1038/s41598-020-63296-x · Cited by 21 · see citing works
Biomarkers for ADHD: the Present and Future Directions
Mehta, T., Mannem, N., Yarasi, N., & Bollu, P. C. (2020) · Current Developmental Disorders Reports · doi:10.1007/s40474-020-00196-9 · Cited by 20 · see citing works
Banaschewski, T., Gerlach, M., Becker, K., Holtmann, M. H., Döpfner, M., & Romanos, M. (2016) · Zeitschrift für Kinder- und Jugendpsychiatrie und Psychotherapie · doi:10.1024/1422-4917/a000433 · Cited by 18 · see citing works
Stein, M. A., Waldman, I. D., Newcorn, J. H., Bishop, J. R., Kittles, R. A., & Cook, E. H. (2014) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2013.0102 · Cited by 17 · see citing works
Hegvik, T., Jacobsen, K. K., Fredriksen, M., Zayats, T., & Haavik, J. (2016) · Journal of Neural Transmission · doi:10.1007/s00702-016-1540-7 · Cited by 17 · see citing works
“2000), the 10-repeat allele (10R) was defined as the risk allele for SLC6A3/DAT1 (Kambeitz et al. 2014) and the 7-repeat allele (7R) as the risk allele for DRD4 (Hamarman et al.”
BackgroundResultSoleimani, R., Salehi, Z., Soltanipour, S., Hasandokht, T., & Jalali, M. M. (2017) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32613 · Cited by 15 · see citing works
“Whilemost researchers and clinicians assume a linear relationship whereby cognitive deficits cause the observable symptoms of ADHD, some researchers disagree with this assumption.”
BackgroundResultInfluentialInterventions for Attention-Deficit Hyperactivity Disorder: A Year in Review
Johnston, C., & Park, J. L. (2015) · Current Developmental Disorders Reports · doi:10.1007/s40474-014-0034-2 · Cited by 14 · see citing works
Does Methylphenidate Work in Children and Adolescents with Attention Deficit Hyperactivity Disorder?
Ribeiro, J. P., Arthur, E. J., Gluud, C. N., Simonsen, E. H., & Storebø, O. J. (2021) · Pediatric Reports · doi:10.3390/pediatric13030050 · Cited by 14 · see citing works
“Some had not published a protocol prior to their study [32–38], had no comprehensive literature search [33,35,39], were unclear on whether study inclusion and data extraction were performed in duplicates [33,40], had not conducted a thorough quality assessment [32,34,35,38,41,42], had no report on risk of bias assessm…”
BackgroundWheeler, H. E., González‐Neira, A., Pita, G., Montero, J. C. D. L. T., Alonso, R., López-Fernández, L. A., Alba, E., Martín, M., & Dolan, M. E. (2014) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0000000000000037 · Cited by 13 · see citing works
Bishop, J. R., Zhou, C., Gaedigk, A., Krone, B., Kittles, R. A., Cook, E. H., Newcorn, J. H., & Stein, M. A. (2024) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2024.0069 · Cited by 12 · see citing works
Schweren, L., Hartman, C. A., Heslenfeld, D. J., Groenman, A. P., Franke, B., Oosterlaan, J., Buitelaar, J. K., & Hoekstra, P. J. (2016) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2016.06.013 · Cited by 11 · see citing works
Applications of pharmacogenetics in children with attention-deficit/hyperactivity disorder
Lévy, F. (2014) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s52844 · Cited by 10 · see citing works
“Kambeitz et al 24 reported results of a meta-analysis that investigated the moderating effect of SLC6A3 VNTR on response to methylphenidate treatment in 16 studies including 1,572 subjects.”
Koutsilieri, E., Riederer, P. F., du Plessis, S., & Scheller, C. (2014) · ADHD Attention Deficit and Hyperactivity Disorders · doi:10.1007/s12402-014-0134-1 · Cited by 10 · see citing works
“Concerning the methylphenidate clinical response of children and adolescents with ADHD, it was reported that the 10/10 genotype was more frequent in the low response group in several studies (Purper-Ouakil et al. 2008; Kambeitz et al. 2013).”
BackgroundResultYang, K.-H., Lane, H., Chang, Y., & Tzang, R. (2021) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyab034 · Cited by 10 · see citing works
Perspectives from the Society for Pediatric Research: pharmacogenetics for pediatricians
Girdwood, S. T., Rossow, K. M., Driest, S. L. V., & Ramsey, L. B. (2021) · Pediatric Research · doi:10.1038/s41390-021-01499-2 · Cited by 9 · see citing works
“Despite these options, there is often heterogeneity in response to ADHD medications, which might be related to genetic factors (105).”
BackgroundSetyawan, J., Yang, H., Cheng, D., Cai, X., Signorovitch, J., Xie, J., & Erder, M. H. (2015) · Value in Health · doi:10.1016/j.jval.2015.06.005 · Cited by 8 · see citing works
Ray, A., Maitra, S., Chatterjee, M., Ghosh, P., Karmakar, A., Sinha, S., & Mukhopadhyay, K. (2016) · Meta Gene · doi:10.1016/j.mgene.2016.11.007 · Cited by 8 · see citing works
Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD)
Storebø, O. J., Storm, M. R. O., Ribeiro, J. P., Skoog, M., Groth, C., Edemann-Callesen, H., Schaug, J. P., Darling, P. J., Huus, C.-M. L., Zwi, M., et al. (2025) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd009885.pub4 · Cited by 7 · see citing works
Should we Keep on? Looking into Pharmacogenomics of ADHD in Adulthood from a Different Perspectives
Rovaris, D. L., Mota, N. R., da Silva, B. S., Girardi, P., Victor, M. M., Grevet, E. H., Bau, C. H. D., & Contini, V. (2014) · Pharmacogenomics · doi:10.2217/pgs.14.95 · Cited by 7 · see citing works
DRD4 and DAT1 VNTR Genotyping in Children with Attention Deficit Hyperactivity Disorder
Stanley, A., Chavda, K., Subramanian, A., Prabhu, S. V., & Ashavaid, T. (2016) · Indian Journal of Clinical Biochemistry · doi:10.1007/s12291-016-0587-4 · Cited by 7 · see citing works
Associations between CES1 variants and dosing and adverse effects in children taking methylphenidate
Brown, J. T., Beery, N., Taran, A. M., Stevens, T., Henzler, C. M., Badalamenti, J. P., Regal, R., & McCarty, C. A. (2023) · Frontiers in Pediatrics · doi:10.3389/fped.2022.958622 · Cited by 6 · see citing works
The role of the SLC6A3 3’ UTR VNTR in nicotine effects on cognitive, affective, and motor function
Schröder, R., Reuter, M., Faßbender, K., Plieger, T., Poulsen, J., Lui, S. S. Y., Chan, R. C. K., & Ettinger, U. (2021) · Psychopharmacology · doi:10.1007/s00213-021-06028-x · Cited by 6 · see citing works
“For outcomes both at the level of brain function and subjective experience, however, differences between genotypes have been identified in response to dopamine agonistic interventions (Brewer et al. 2015; Franklin et al. 2009, 2011; Gelernter et al. 1994; Kambeitz et al. 2014; Lott et al. 2005; Millar et al. 2011).”
BackgroundResultImmediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults
Cândido, R. C. F., Golder, S., de Pádua, C. A. M., Perini, É., & Junqueira, D. R. (2018) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd013011 · Cited by 3 · see citing works
Storebø, O. J. (2019) · Research at the University of Copenhagen (University of Copenhagen) · doi:10.5283/mnhd.15 · Cited by 3 · see citing works
Herrera-Morales, W. V., Ramı́rez-Lugo, L., Cauich-Kumul, R., Murillo‐Rodríguez, E., & Núñez-Jaramillo, L. (2022) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026622666220509155413 · Cited by 3 · see citing works
Is dopamine transporter gene effective on therapeutic response of methylphenidate in ADHD patients?
Moharari, F., & Barabadian, S. (2015) · DOAJ (DOAJ: Directory of Open Access Journals) · doi:10.17463/rcm.2015.02.003 · Cited by 1 · see citing works
Genetic Factors Underlying Treatment Resistance in Psychiatry
Maron, E., Lan, C., & Nutt, D. (2018) · Springer eBooks · doi:10.1007/978-981-10-4358-1_3 · Cited by 2 · see citing works
Genetics and pharmacogenetics of attention deficit hyperactivity disorder in childhood and adulthood
Bonvicini, C., Maj, C., & Scassellati, C. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-813176-3.00021-3 · Cited by 1 · see citing works
Attention deficit hyperactivity disorder
Lazar, S. M., & Voigt, R. G. (2024) · Elsevier eBooks · doi:10.1016/b978-0-12-824060-1.00017-1 · Cited by 1 · see citing works
Klimkeit, E., Rinehart, N., May, T., Whelan, M., & Bradshaw, J. L. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-99967-0.00082-x · Cited by 2 · see citing works
Genetische Grundlagen der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung
Grimm, O., Kranz, T., & Reif, A. (2019) · Nervenheilkunde · doi:10.1055/a-0962-1001
“[47] Kambeitz J, Romanos M, Ettinger U.”
- Authors
- Kambeitz, J., Romanos, M., & Ettinger, U.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- Universitätsklinikum Würzburg (DE)
- University of Bonn (DE)
- Corresponding author
- Kambeitz, J
- Venue
- The Pharmacogenomics Journal
- Published
- 2013-04-16
- Volume
- 14
- Issue
- 1
- Pages
- 77-84
- ISSN
- 1470-269X (ISSN-L)
- 1473-1150
- OpenAlex
- W2034027897
- Cited by
- 64
- References
- 84
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 4 · 2022: 1 · 2021: 6 · 2020: 5 · 2019: 7 · 2018: 4 · 2017: 4 · 2016: 11 · 2015: 7 · 2014: 9 · 2013: 2
- FWCI
- 1.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Pharmacogenomics Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- attention deficit hyperactivity disorder, methylphenidate, dopamine transporter, VNTR polymorphism, pharmacogenetics, treatment response, hyperactivity/impulsivity, inattention, genetic predictors of treatment response
- MeSH terms
- Attention Deficit Disorder with Hyperactivity, Genotype, Humans, Methylphenidate, Polymorphism, Genetic, Treatment Outcome, Dopamine Uptake Inhibitors, Tandem Repeat Sequences, 3' Untranslated Regions, Dopamine Plasma Membrane Transport Proteins
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