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Attention-deficit/hyperactivity disorder: advancing on pharmacogenomics

    Guilherme Polanczyk

    Federal University of Rio Grande do Sul, ADHD out-patient clinic, Child and Adolescent Psychiatric Division, Hospital de Clínicas de Porto Alegre, Brazil

    ,
    Cristian Zeni

    Federal University of Rio Grande do Sul, ADHD out-patient clinic, Child and Adolescent Psychiatric Division, Hospital de Clínicas de Porto Alegre, Brazil

    ,
    Julia P Genro

    Federal University of Rio Grande do Sul, Department of Genetics, Brazil

    ,
    Tatiana Roman

    Federal School of Medical Sciences of Porto Alegre, Department of Morphological Sciences, Brazil

    ,
    Mara H Hutz

    Federal University of Rio Grande do Sul, Department of Genetics, Brazil

    &
    Luis Augusto Rohde

    Federal University of Rio Grande do Sul, ADHD out-patient clinic, Child and Adolescent Psychiatric Division, Hospital de Clínicas de Porto Alegre, Brazil

    Hospital de Clínicas de Porto Alegre, Serviço de Psiquiatria da Infância e Adolescência, Rua Ramiro Barcelos, 2350, Porto Alegre, Rio Grande do Sul, 90035-003, Brazil

    Published Online:https://doi.org/10.1517/14622416.6.3.225

    Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent psychiatric disorder. An impressive volume of literature documents both a strong participation of genetics in its etiology and a high rate of response to medication. However, few studies on the pharmacogenomics of ADHD have been conducted to date. This systematic review aims to present a critical discussion of findings from recent investigations. The majority of studies have focused on individual polymorphisms of the dopaminergic genes, with special emphasis on variants of the dopamine transporter gene (DAT1). Almost all studies have assessed the effects of genes in the response to methylphenidate (MPH). Some preliminary results suggest an association between homozygosity for the 10-repeat allele at DAT1 and poor response to MPH. However, other studies have reported contrasting findings. Very few investigations addressed the role of non-dopaminergic genes or gene–gene interactions in ADHD pharmacogenomics. Recent findings suggesting an association between response to MPH and an MspI polymorphism in the promoter region of the α2A-adrenoceptor gene (ADRA2A) are discussed. Pharmacogenomic studies of ADHD are in their infancy, and comparability between studies is difficult due to the use of different methodological approaches. As such, multi-site collaborative efforts to obtain larger samples with standardized methodology should be encouraged.

    Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

    Bibliography

    • American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. American Psychiatric Association, Washington DC, 78–85 (1994).
    • Faraone SV, Sergeant J, Gillberg C, Biederman J: The worldwide prevalence of ADHD: is it an American condition? World Psychiatry 2, 104–113 (2003).
    • Wilens TE, Faraone SV, Biederman J: Attention-deficit/hyperactivity disorder in adults. JAMA292, 619–623 (2004).
    • Rohde LA, Biederman J, Busnello EA et al.: ADHD in a school sample of Brazilian adolescents: a study of prevalence, comorbid conditions and impairments. J. Am. Acad. Child Adolesc. Psychiatry38, 716–722 (1999).
    • National Institutes of Health Consensus Development Conference Statement: Diagnosis and treatment of attention-deficit/hyperactivity disorder (ADHD). J. Am. Acad. Child Adolesc. Psychiatry39, 182–193 (2000).
    • Castellanos FX, Tannock R: Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat. Rev. Neurosci.3, 617–628 (2002).• Extensively discusses the neurobiology of ADHD.
    • Faraone SV: Genetics of childhood disorders: XX. ADHD, Part 4: Is ADHD genetically heterogeneous? J. Am. Acad. Child Adolesc. Psychiatry39, 1455–1457 (2000).
    • Kirley A, Hawi Z, Daly G et al.: Dopaminergic system genes in ADHD: toward a biological hypothesis. Neuropsychopharmacology27, 607–619 (2002).
    • Banaag C, Bange F, Bouvard M et al.: Consensus statement on ADHD/HKD. Eur. Child Adolesc. Psychiatry (2005) (In press).
    • 10  Biederman J, Spencer T, Wilens T: Evidence-based pharmacotherapy for attention-deficit hyperactivity disorder. Int. J. Neuropsychopharmacol.7, 77–97 (2004).
    • 11  Faraone SV, Spencer T, Aleardi M, Pagano C, Biederman J: Meta-analysis of the efficacy of methylphenidate for treating adult attention deficit/hyperactivity disorder. J. Clin. Psychopharmacol.24, 24–29 (2004).
    • 12  Spencer T, Heiligenstein J, Biederman J et al.: Results from 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder. J. Clin. Psychiatry63, 1140–1147 (2002).
    • 13  Michelson D, Adler L, Spencer T et al.: Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol. Psychiatry53, 112–120 (2003).
    • 14  Masellis M, Basile VS, Muglia P, Ozdemir V, Macciardi FM, Kennedy JL: Psychiatric pharmacogenetics: personalizing psychostimulant therapy in attention deficit/hyperactivity disorder. Behav. Brain Res.130, 85–90 (2002).
    • 15  Tribut O, Lessard Y, Reymann JM, Allain H, Bentué-Ferrer D: Pharmacogenomics. Med. Sci. Monit.8, 152–163 (2002).
    • 16  Rohde LA, Roman T, Hutz M: Attention-deficit/hyperactivity disorder: current aspects on pharmacogenetics. Pharmacogenomics J.3, 11–13 (2003).
    • 17  Roman T, Rohde LA, Hutz M: Polymorphisms of the dopamine transporter gene: influence on response to methylphenidate in attention-deficit/hyperactivity. Am. J. Pharmacogenomics 4, 83–92 (2004).•  Reviews in detail all studies assessing effects of individual polymorphisms at DAT1 on response to MPH in ADHD.
    • 18  Faraone SV, Doyle AE, Mick E, Biederman J: Meta-analysis of the association between the dopamine D4 gene 7-repeated allele and attention-deficit/hyperactive disorder. Am. J. Psychiatry158, 1052–1057 (2001).
    • 19  Winsberg BG, Comings DE: Association of the dopamine transporter gene (DAT1) with poor methylphenidate response. J. Am. Acad. Child Adolesc. Psychiatry 38, 1474–1477 (1999).
    • 20  Roman T, Szobot C, Martins S, Biederman J, Rohde LA, Hutz MH: Dopamine transporter gene and response to methylphenidate in attention-deficit/hyperactivity disorder. Pharmacogenetics12, 497–499 (2002).••  Describes an association between the 10R allele at DAT1 and response to MPH in a sample of 50 children with ADHD.
    • 21  Hamarman S, Ulger C, Fossella J, Brimacombe M, Dermody J: Influence of dopamine genes on stimulant response in ADHD children. Proceedings of the 50th Annual Meeting of the American Academy of Child and Adolescent Psychiatry, Miami, USA, 7A (2003).
    • 22  Kirley A, Lowe N, Hawi Z et al.: Association of the 480 bp DAT1 allele with methylphenidate response in a sample of Irish children with ADHD. Am. J. Med. Genet.121B, 50–54 (2003).
    • 23  Stein MA, Sarampote C, Waldman I et al.: Dopamine transporter genotype affects stimulants response according to parent ratings. Proceedings of the 49th Annual Meeting of the American Academy of Child and Adolescent Psychiatry, San Francisco, USA, 7C (2002).
    • 24  Lott DC, Kim SJ, Cook EH, de Wit H: Dopamine transporter gene associated with diminished subjective response to amphetamine. Neuropsychopharmacology30, 602–609 (2004).
    • 25  Tahir E, Yazgan Y, Cirakoglu B, Ozbay F, Waldman I, Asherson PJ: Association and linkage of DRD4 and DRD5 with attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children. Mol. Psychiatry5, 396–404 (2000).
    • 26  Hamarman S, Ulger C, Fossella J, Brimacombe M, Dermody J: Dopamine receptor 4 (DRD4) 7-repeat allele predicts methylphenidate dose response in children with attention deficit hyperactivity disorder: a pharmacogenetics study. J. Child Adolesc. Psychopharmacol.14, 564–574 (2004).••  Reports that individuals with the 7R allele at the DRD4 gene achieved less normalization of symptoms at MPH doses of 50 mg/day and required 1.5-times higher levels of MPH to achieve improvement than those without the 7R allele.
    • 27  Biederman J, Spencer T: Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder. Biol Psychiatry46, 1234–1242 (1999).
    • 28  Park L, Nigg JT, Waldman ID et al.: Association and linkage of α-2A adrenergic receptor gene polymorphisms with childhood ADHD. Mol. Psychiatry (2004) (In press).
    • 29  Roman T, Schmitz M, Polanczyk G, Eizirik M, Rohde LA, Hutz M: Further evidence for the association between DBH gene and attention-deficit/hyperactivity disorder. Am. J. Med. Genet.114, 154–158 (2002).
    • 30  Roman T, Schmitz M, Polanczyk G, Eizirik M, Rohde LA, Hutz M: Association between α-2a adrenergic receptor gene (ADRA2A) and attention-deficit/hyperactivity disorder. Am. J. Med. Genet. 120B, 116–120 (2003).
    • 31  Yang L, Wang Y, Li J, Faraone S: Association of norepinephrine transporter gene (NET) with methylphenidate response. J. Am. Acad. Child Adolesc. Psychiatry43, 1154–1158 (2004).••  Describes different responses to MPH in hyperactive-impulsive scores according to NET1 G1287A genotypes in a sample of 45 Chinese children with ADHD.
    • 32  Seeger G, Schloss P, Schmidt MH: Marker gene polymorphisms in hyperkinetic disorder – predictors of clinical response to treatment with methylphenidate? Neurosci. Lett.313, 45–48 (2001).•• The only study that assesses gene–gene interaction in the field of ADHD pharmacogenomics.
    • 33  Kent L, Doerry U, Hardy E et al.: Evidence that variation at the serotonin transporter gene influences susceptibility to attention deficit hyperactivity disorder (ADHD): analysis and pooled analysis. Mol. Psychiatry7, 908–912 (2002).
    • 34  Van der Meulen E, Bakker SC, Pauls DL, Sinke RJ, Buitelaar J: A genome-wide quantitative trait locus analysis on methylphenidate response rate in Dutch sib pairs with attention-deficit hyperactivity disorder. Proceedings of the 16th World Congress of the International Association for Child and Adolescent Psychiatry and Allied Professions, Berlin, Germany, S-076–351 (2004).
    • 35  Rohde LA, Roman T, Szobot C, Cunha RD, Biederman J, Hutz MH: Dopamine transporter gene, response to methylphenidate and cerebral blood flow in ADHD. Synapse48, 87–89 (2003).
    • 36  Cheon KA, Ryu YH, Kim JW, Cho DY: The homozygosity for 10-repeat allele at dopamine transporter gene and dopamine transporter density in Korean children with attention deficit hyperactivity disorder: relating to treatment response to methylphenidate. Eur. Neuropsychopharmacol.15, 95–101 (2005).•• Integrates findings suggesting the association between the 10R allele at DAT1 and poor response to MPH in ADHD in a potentially more comprehensive explanation of the mechanism of action of MPH.
    • 37  Swanson JM, Flodman P, Kennedy J et al.: Dopamine genes and ADHD. Neurosci. Biobehav. Rev.24, 21–25 (2000).
    • 38  Mill J, Asherson P, Browes C, D'Souza U, Craig I: Expression of the dopamine transporter gene is regulated by the 3′ UTR VNTR: evidence from brain and lymphocytes using quantitative RT-PCR. Am. J. Med. Genet.114, 975–979 (2002).
    • 39  Fuke S, Suo S, Takahashi N, Koike H, Sasagawa N, Ishiura S: The VNTR polymorphism of the human dopamine transporter (DAT1) gene affects gene expression. Pharmacogenomics J.1, 152–156 (2001).
    • 40  Heinz A, Goldman D, Jones DW et al.: Genotype influences in vivo dopamine transporter availability in human striatum. Neuropsychopharmacology22, 133–139 (2000).
    • 41  Volkow ND, Wang GJ, Fowler JS et al.: Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic implications. Synapse 43, 181–187 (2002).
    • 42  Loo SK, Specter E, Smolen A, Hopfer C, Teale PD, Reite ML: Functional effects of the DAT1 polymorphism on EEG measures in ADHD. J. Am. Acad. Child Adolesc. Psychiatry42, 986–993 (2003).
    • 43  Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM: Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics6, 243–250 (1996).
    • 44  Eisenberg J, Mei-Tal G, Steinbeg A et al.: Haplotype relative risk study of catechol-O-methyltransferase (COMT) and attention-deficit/hyperactivity disorder (ADHD): association of the high-enzyme activity Val allele with ADHD impulsive-hyperactive phenotype. Am. J. Med. Genet.88, 497–502 (1999).
    • 45  Barr CL, Wigg K, Malone M et al.: Linkage study of catechol-O-methyltransferase and attention-deficit hyperactivity disorder. Am. J. Med. Genet.88, 710–713 (1999).
    • 46  Payton A, Holmes J, Barrett JH et al.: Examining for association between candidate gene polymorphisms in the dopamine pathway and attention-deficit/hyperactivity disorder: a family-based study. Am. J. Med. Genet.105, 464–470 (2001).
    • 47  Mattay VS, Goldberg TE, Fera F et al.: Catechol O-methyltransferase Val158-Met genotype and individual variation in the brain response to amphetamine. Proc. Natl Acad. Sci. USA100, 6186–6191 (2003).• Reports that amphetamine enhanced the efficiency of prefrontal cortex function assayed with functional MRI during a working memory task in subjects with the high enzyme activity Val/Val genotype, who presumably have relatively less prefrontal synaptic dopamine.
    • 48  Volkow ND, Wang GJ, Fowler JS et al.: Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain. Am. J. Psychiatry161, 1173–1180 (2004).••  Provides a new paradigm for the mechanism of action of MPH.
    • 49  Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics2, 229–243 (2002).
    • 50  Sauer JM, Ponsler GD, Mattiuz EL et al.: Disposition and metabolic fate of atomoxetine hydrochloride: the role of CYP2D6 in human disposition and metabolism. Drug Metab. Dispos. 31, 98–107 (2003).
    • 51  Faraone SV, Biederman J, Monuteaux MC: Toward guidelines for pedigree selection in genetic studies of attention-deficit/hyperactivity disorder. Genet. Epidemiol.18, 1–16 (2000).
    • 52  Lichter JB, Barr CL, Kennedy JL, van Tol HHM, Kidd KK, Livak KJ: A hypervariable segment in the human dopamine receptor D4 (DRD4) gene. Hum. Mol. Genet.2, 767–773 (1993).
    • 53  Yeh M, Morley KI, Hall WD: The policy and ethical implications of genetic research on attention deficit hyperactivity disorder. Aust. N. Z. J. Psychiatry38, 10–19 (2004).

    Websites

    • 101  www.ncbi.nlm.nih.gov/entrez/query.fcgi PubMed homepage.
    • 102  www.apa.org/psycinfo/ PsycINFO homepage.
    • 103  www.scielo.br The Scientific Electronic Library Online.