Skip to main content

Advertisement

SpringerLink
Log in

Adrenergic neurotransmitter system transporter and receptor genes associated with atomoxetine response in attention-deficit hyperactivity disorder children

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Atomoxetine, a selective inhibitor of the norepinephrine transporter, exerts its therapeutic effect for attention-deficit hyperactivity disorder (ADHD) by increasing the concentration of synaptic norepinephrine. The objective of this study was to evaluate the association of the genetic variants of multiple genes of the noradrenergic neurotransmitter system with atomoxetine response. One hundred and eleven ADHD children and adolescents were enrolled in a prospective, open-label study of atomoxetine for 8–12 weeks. The dose was titrated to 1.2–1.4 mg/kg per day and maintained for at least 4 weeks. The primary efficacy measure was the investigator-rated ADHD Rating Scale-IV. Two categorical evaluations of treatment effects (defined as response and remission) were used. Twelve SNPs in SLC6A2, ADRA2A, and ADRA1A were genotyped to analyze their association with response or remission status. rs3785143 in SLC6A2 was associated with responder status (nominal P = 0.0048; corrected by multiple test, P = 0.0416; OR 2.66, 95 % confidence interval (CI) 1.35–5.26). rs2279805 of SLC6A2 was nominally significantly associated with the remission status. (P = 0.0221, OR 2.32, 95 % CI 1.13–4.75, multiple test P = 0.2130). The GG haplotype of rs1800544 and rs553668 in ADRA2A achieved nominal significance for association with non-remission (P = 0.0219, OR 2.82, 95 % CI 1.16–6.85, multiple test, P = 0.2076). The results of this study suggest that DNA variants of both SLC6A2 and ADRA2A in the adrenergic neurotransmitter system might alter the response to atomoxetine, though further replication study in larger sample for validation of these findings is still needed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Andrews GD, Lavin A (2006) Methylphenidate increases cortical excitability via activation of alpha-2 noradrenergic receptors. Neuropsychopharmacology 31(3):8

    Article  Google Scholar 

  • Arnsten AF, Li BM (2005) Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry 57(11):1377–1384. doi:10.1016/j.biopsych.2004.08.019

    Article  PubMed  CAS  Google Scholar 

  • Arnsten AF, Steere JC, Hunt RD (1996) The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder. Arch Gen Psychiatry 53(5):448–455

    Article  PubMed  CAS  Google Scholar 

  • Barkley RA (1998) Attention-deficit hyperactivity disorder: a handbook for diagnosis and treatment, 2nd edn. Guilford Press, New York

    Google Scholar 

  • Biederman J, Faraone SV (2005) Attention-deficit hyperactivity disorder. Lancet 366(9481):237–248. doi:10.1016/S0140-6736(05)66915-2

    Article  PubMed  Google Scholar 

  • Biederman J, Spencer T (1999) Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder. Biol Psychiatry 46(9):1234–1242

    Article  PubMed  CAS  Google Scholar 

  • Biederman J, Spencer TJ (2000) Genetics of childhood disorders: XIX. ADHD, Part 3: is ADHD a noradrenergic disorder? J Am Acad Child Adolesc Psychiatry 39(10):1330–1333

    Article  PubMed  CAS  Google Scholar 

  • Cho SC, Kim JW, Kim HW, Kim BN, Shin MS, Cho DY, Jung SW, Chung US, Son JW (2011) Effect of ADRA2A and BDNF gene–gene interaction on the continuous performance test phenotype. Psychiatr Genet 21(3):132–135. doi:10.1097/YPG.0b013e328341a389

    Article  PubMed  Google Scholar 

  • Comings DE, Gade-Andavolu R, Gonzalez N, Blake H, Wu S, MacMurray JP (1999) Additive effect of three noradrenergic genes (ADRA2a, ADRA2C, DBH) on attention-deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects. Clin Genet 55(3):160–172

    Article  PubMed  CAS  Google Scholar 

  • Deupree JD, Smith SD, Kratochvil CJ, Bohac D, Ellis CR, Polaha J, Bylund DB, Team UCAR (2006) Possible involvement of alpha-2A adrenergic receptors in attention deficit hyperactivity disorder: radioligand binding and polymorphism studies. Am J Med Genet Part B Neuropsychiatr Genet 141B(8):877–884. doi:10.1002/ajmg.b.30371

    Article  CAS  Google Scholar 

  • Dickson RA, Maki E, Gibbins C, Gutkin SW, Turgay A, Weiss MD (2011) Time courses of improvement and symptom remission in children treated with atomoxetine for attention-deficit/hyperactivity disorder: analysis of Canadian open-label studies. Child Adolesc Psychiatry Ment health 5:14. doi:10.1186/1753-2000-5-14

    Article  PubMed  Google Scholar 

  • DuPaul GJ (1998) ADHD rating scale-IV: checklists, norms, and clinical interpretation. Guilford Press, New York

    Google Scholar 

  • Elia J, Capasso M, Zaheer Z, Lantieri F, Ambrosini P, Berrettini W, Devoto M, Hakonarson H (2009) Candidate gene analysis in an on-going genome-wide association study of attention-deficit hyperactivity disorder: suggestive association signals in ADRA1A. Psychiatr Genet 19(3):134–141. doi:10.1097/YPG.0b013e32832a5043

    Article  PubMed  Google Scholar 

  • Faraone SV, Mick E (2010) Molecular genetics of attention deficit hyperactivity disorder. Psychiatr Clin North Am 33(1):159–180. doi:10.1016/j.psc.2009.12.004

    Article  PubMed  Google Scholar 

  • Faraone SV, Sergeant J, Gillberg C, Biederman J (2003) The worldwide prevalence of ADHD: is it an American condition? World Psychiatry 2(2):104–113

    PubMed  Google Scholar 

  • Franowicz JS, Arnsten AF (1998) The alpha-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacology 136(1):8–14

    Article  PubMed  CAS  Google Scholar 

  • Kelsey DK, Sumner CR, Casat CD, Coury DL, Quintana H, Saylor KE, Sutton VK, Gonzales J, Malcolm SK, Schuh KJ, Allen AJ (2004) Once-daily atomoxetine treatment for children with attention-deficit/hyperactivity disorder, including an assessment of evening and morning behavior: a double-blind, placebo-controlled trial. Pediatrics 114(1):e1–e8

    Article  PubMed  Google Scholar 

  • Kiive E, Kurrikoff T, Maestu J, Harro J (2010) Effect of alpha2A-adrenoceptor C-1291G genotype and maltreatment on hyperactivity and inattention in adolescents. Prog Neuropsychopharmacol Biol Psychiatry 34(1):219–224. doi:10.1016/j.pnpbp.2009.11.011

    Article  PubMed  CAS  Google Scholar 

  • Kim CH, Kim HS, Cubells JF, Kim KS (1999) A previously undescribed intron and extensive 5′ upstream sequence, but not Phox2a-mediated transactivation, are necessary for high level cell type-specific expression of the human norepinephrine transporter gene. J Biol Chem 274(10):6507–6518

    Article  PubMed  CAS  Google Scholar 

  • Kim JW, Biederman J, McGrath CL, Doyle AE, Mick E, Fagerness J, Purcell S, Smoller JW, Sklar P, Faraone SV (2008) Further evidence of association between two NET single-nucleotide polymorphisms with ADHD. Mol Psychiatry 13(6):624–630. doi:10.1038/sj.mp.4002090

    Article  PubMed  CAS  Google Scholar 

  • Michelson D, Allen AJ, Busner J, Casat C, Dunn D, Kratochvil C, Newcorn J, Sallee FR, Sangal RB, Saylor K, West S, Kelsey D, Wernicke J, Trapp NJ, Harder D (2002) Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry 159(11):1896–1901

    Article  PubMed  Google Scholar 

  • Moron JA, Brockington A, Wise RA, Rocha BA, Hope BT (2002) Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci 22(2):389–395

    PubMed  CAS  Google Scholar 

  • Newcorn JH, Kratochvil CJ, Allen AJ, Casat CD, Ruff DD, Moore RJ, Michelson D, Atomoxetine/Methylphenidate Comparative Study Group (2008) Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response. Am J Psychiatry 165(6):721–730. doi:10.1176/appi.ajp.2007.05091676

    Google Scholar 

  • Park L, Nigg JT, Waldman ID, Nummy KA, Huang-Pollock C, Rappley M, Friderici KH (2005) Association and linkage of alpha-2A adrenergic receptor gene polymorphisms with childhood ADHD. Mol Psychiatry 10(6):572–580. doi:10.1038/sj.mp.4001605

    Article  PubMed  CAS  Google Scholar 

  • Ramoz N, Boni C, Downing AM, Close SL, Peters SL, Prokop AM, Allen AJ, Hamon M, Purper-Ouakil D, Gorwood P (2009) A haplotype of the norepinephrine transporter (Net) gene Slc6a2 is associated with clinical response to atomoxetine in attention-deficit hyperactivity disorder (ADHD). Neuropsychopharmacology 34(9):2135–2142. doi:10.1038/npp.2009.39

    Article  PubMed  CAS  Google Scholar 

  • Retz W, Rosler M, Kissling C, Wiemann S, Hunnerkopf R, Coogan A, Thome J, Freitag C (2008) Norepinephrine transporter and catecholamine-O-methyltransferase gene variants and attention-deficit/hyperactivity disorder symptoms in adults. J Neural Transm 115(2):323–329. doi:10.1007/s00702-007-0822-5

    Article  PubMed  CAS  Google Scholar 

  • Roman T, Schmitz M, Polanczyk GV, Eizirik M, Rohde LA, Hutz MH (2003) Is the alpha-2A adrenergic receptor gene (ADRA2A) associated with attention-deficit/hyperactivity disorder? Am J Med Genet Part B Neuropsychiatr Genet 120B(1):116–120. doi:10.1002/ajmg.b.20018

    Article  Google Scholar 

  • Roman T, Polanczyk GV, Zeni C, Genro JP, Rohde LA, Hutz MH (2006) Further evidence of the involvement of alpha-2A-adrenergic receptor gene (ADRA2A) in inattentive dimensional scores of attention-deficit/hyperactivity disorder. Mol Psychiatry 11(1):8–10. doi:10.1038/sj.mp.4001743

    Article  PubMed  CAS  Google Scholar 

  • Schmitz M, Denardin D, Silva TL, Pianca T, Roman T, Hutz MH, Faraone SV, Rohde LA (2006) Association between alpha-2a-adrenergic receptor gene and ADHD inattentive type. Biol Psychiatry 60(10):1028–1033. doi:10.1016/j.biopsych.2006.02.035

    Article  PubMed  CAS  Google Scholar 

  • Sengupta SM, Grizenko N, Thakur GA, Bellingham J, DeGuzman R, Robinson S, TerStepanian M, Poloskia A, Shaheen SM, Fortier ME, Choudhry Z, Joober R (2012) Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype. J Psychiatr Neurosci 37(2):129–137. doi:10.1503/jpn.110073

    Article  Google Scholar 

  • Solanto MV (1998) Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behav Brain Res 94(1):127–152

    Article  PubMed  CAS  Google Scholar 

  • Steele M, Jensen PS, Quinn DM (2006) Remission versus response as the goal of therapy in ADHD: a new standard for the field? Clin Ther 28(11):1892–1908. doi:10.1016/j.clinthera.2006.11.006

    Article  PubMed  CAS  Google Scholar 

  • Stein MA, Sarampote CS, Waldman ID, Robb AS, Conlon C, Pearl PL, Black DO, Seymour KE, Newcorn JH (2003) A dose-response study of OROS methylphenidate in children with attention-deficit/hyperactivity disorder. Pediatrics 112(5):e404

    Article  PubMed  Google Scholar 

  • Stevenson J, Langley K, Pay H, Payton A, Worthington J, Ollier W, Thapar A (2005) Attention deficit hyperactivity disorder with reading disabilities: preliminary genetic findings on the involvement of the ADRA2A gene. J Child Psychol Psychiatry 46(10):1081–1088. doi:10.1111/j.1469-7610.2005.01533.x

    Article  PubMed  CAS  Google Scholar 

  • Swanson JM, Kraemer HC, Hinshaw SP, Arnold LE, Conners CK, Abikoff HB, Clevenger W, Davies M, Elliott GR, Greenhill LL, Hechtman L, Hoza B, Jensen PS, March JS, Newcorn JH, Owens EB, Pelham WE, Schiller E, Severe JB, Simpson S, Vitiello B, Wells K, Wigal T, Wu M (2001) Clinical relevance of the primary findings of the MTA: success rates based on severity of ADHD and ODD symptoms at the end of treatment. J Am Acad Child Adolesc Psychiatry 40(2):168–179. doi:10.1097/00004583-200102000-00011

    Article  PubMed  CAS  Google Scholar 

  • Wang B, Wang Y, Zhou R, Li J, Qian Q, Yang L, Guan L, Faraone SV (2006) Possible association of the alpha-2A adrenergic receptor gene (ADRA2A) with symptoms of attention-deficit/hyperactivity disorder. Am J Med Genet Part B Neuropsychiatr Genet 141B(2):130–134. doi:10.1002/ajmg.b.30258

    Article  CAS  Google Scholar 

  • Wang Y, Zheng Y, Du Y, Song DH, Shin YJ, Cho SC, Kim BN, Ahn DH, Marquez-Caraveo ME, Gao H, Williams DW, Levine LR (2007) Atomoxetine versus methylphenidate in paediatric outpatients with attention deficit hyperactivity disorder: a randomized, double-blind comparison trial. Aust N Z J Psychiatry 41(3):222–230. doi:10.1080/00048670601057767

    Article  PubMed  CAS  Google Scholar 

  • Yang L, Wang YF, Li J, Faraone SV (2004) Association of norepinephrine transporter gene with methylphenidate response. J Am Acad Child Adolesc Psychiatry 43(9):1154–1158. doi:10.1097/01.chi.0000131134.63368.46

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This research is funded by National Natural Science Foundation of China (30800302).

Conflict of interest

The authors declare they have no conflict of interest.

Author information

Authors and Affiliations

  1. Key Laboratory of Mental Health, Ministry of Health, Peking University Sixth Hospital/Institute of Mental Health, 51, Huayuan Bei Road, Beijing, 100191, China

    Li Yang, Qiujin Qian, Lu Liu, Haimei Li & Yufeng Wang

  2. Departments of Psychiatry and Behavioral Sciences and of Neuroscience and Physiology, Medical Genetics Research Center, SUNY Upstate Medical University, 750, East Adams Street, Syracuse, NY, 13210, USA

    Stephen V. Faraone

Authors
  1. Li Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qiujin Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haimei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephen V. Faraone
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yufeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yufeng Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, L., Qian, Q., Liu, L. et al. Adrenergic neurotransmitter system transporter and receptor genes associated with atomoxetine response in attention-deficit hyperactivity disorder children. J Neural Transm 120, 1127–1133 (2013). https://doi.org/10.1007/s00702-012-0955-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-012-0955-z

Keywords

Search

Navigation