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Child and Adolescent Psychiatry and Mental Health

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Open Access 01-12-2017 | Research Article

Differential therapeutic effects of atomoxetine and methylphenidate in childhood attention deficit/hyperactivity disorder as measured by near-infrared spectroscopy

Authors: Yoko Nakanishi, Toyosaku Ota, Junzo Iida, Kazuhiko Yamamuro, Naoko Kishimoto, Kosuke Okazaki, Toshifumi Kishimoto

Published in: Child and Adolescent Psychiatry and Mental Health | Issue 1/2017

Abstract

Background

The stimulant methylphenidate (MPH) and the nonstimulant atomoxetine (ATX) are the most commonly-prescribed pharmacological treatments for attention deficit/hyperactivity disorder (ADHD). However, the drug-specific mechanism of action on brain function in ADHD patients is not well known. This study examined differences in prefrontal hemodynamic activity between MPH and ATX in children with ADHD as measured by near-infrared spectroscopy (NIRS) using the Stroop color-word task.

Methods

Thirty children with ADHD participated in the present study. We used 24-channel NIRS (ETG-4000) to measure the relative concentrations of oxyhemoglobin in the frontal lobes of participants in the drug-naïve condition and those who had received MPH (n = 16) or ATX (n = 14) for 12 weeks. Measurements were conducted every 0.1 s during the Stroop color-word task. We used the ADHD RS-IV-J (Home Version) to evaluate ADHD symptoms.

Results

Treatment with either MPH or ATX significantly reduced ADHD symptoms, as measured by the ADHD RS-IV-J, and improved performance on the Stroop color-word task in terms of number of correct words. We found significantly higher levels of oxyhemoglobin changes in the prefrontal cortex of participants in the ATX condition compared with the values seen at baseline (pre-ATX). In contrast, we found no oxyhemoglobin changes between pre- and post-treatment with MPH.

Conclusions

The present study suggests that MPH and ATX have differential effects on prefrontal hemodynamic activity in children with ADHD.

Seidman LJ. Neuropsychological functioning in people with ADHD across the lifespan. Clin Psychol Rev. 2006;26(4):466–85.CrossRefPubMed

Chamberlain SR, Del Campo N, Dowson J, Müller U, Clark L, Robbins TW, Sahakian BJ. Atomoxetine improved response inhibition in adults with attention deficit/hyperactivity disorder. Biol Psychiatry. 2007;62(9):977–84.CrossRefPubMed

Del Campo N, Chamberlain SR, Sahakian BJ, Robbins TW. The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2011;69(12):e145–57.CrossRefPubMed

Makris N, Biederman J, Monuteaux MC, Seidman LJ. Towards conceptualizing a neural systems-based anatomy of attention-deficit/hyperactivity disorder. Dev Neurosci. 2009;31(1–2):36–49.CrossRefPubMedPubMedCentral

Arnsten AF. Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs. 2009;23(Suppl 1):33–41.CrossRefPubMed

Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Logan J, Ding YS, Hitzemann R, Pappas N. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry. 1998;155(10):1325–31.CrossRefPubMed

Hannestad J, Gallezot JD, Planeta-Wilson B, Lin SF, Williams WA, van Dyck CH, Malison RT, Carson RE, Ding YS. Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo. Biol Psychiatry. 2010;68(9):854–60.CrossRefPubMedPubMedCentral

Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002;27(5):699–711.CrossRefPubMed

Liu Q, Zhang H, Fang Q, Qin L. Comparative efficacy and safety of methylphenidate and atomoxetine for attention-deficit hyperactivity disorder in children and adolescents: meta-analysis based on head-to-head trials. J Clin Exp Neuropsychol. 2017. doi:10.1080/13803395.2016.1273320.PubMed

10.

Ni HC, Shang CY, Gau SS, Lin YJ, Huang HC, Yang LK. A head-to-head randomized clinical trial of methylphenidate and atomoxetine treatment for executive function in adults with attention-deficit hyperactivity disorder. Int J Neuropsychopharmacol. 2013;16(9):1959–73.CrossRefPubMed

11.

Yang L, Cao Q, Shuai L, Li H, Chan RC, Wang Y. Comparative study of OROS-MPH and atomoxetine on executive function improvement in ADHD: a randomized controlled trial. Int J Neuropsychopharmacol. 2012;15(1):15–26.CrossRefPubMed

12.

Smith A, Cubillo A, Barrett N, Giampietro V, Simmons A, Brammer M, Rubia K. Neurofunctional effects of methylphenidate and atomoxetine in boys with attention-deficit/hyperactivity disorder during time discrimination. Biol Psychiatry. 2013;74(8):615–22.CrossRefPubMed

13.

Cubillo A, Smith AB, Barrett N, Giampietro V, Brammer M, Simmons A, Rubia K. Drug-specific laterality effects on frontal lobe activation of atomoxetine and methylphenidate in attention deficit hyperactivity disorder boys during working memory. Psychol Med. 2014;44(3):633–46.CrossRefPubMed

14.

Boas DA, Dale AM, Franceschini MA. Diffuse optical imaging of brain activation: approaches to optimizing image sensitivity, resolution, and accuracy. Neuroimage. 2004;23(Suppl 1):S275–88.CrossRefPubMed

15.

Strangman G, Boas DA, Sutton JP. Non-invasive neuroimaging using near-infrared light. Biol Psychiatry. 2002;52(7):679–93.CrossRefPubMed

16.

Obrig H, Villringer A. Beyond the visible–imaging the human brain with light. J Cereb Blood Flow Metab. 2003;23(1):1–18.CrossRefPubMed

17.

Hoshi Y, Kobayashi N, Tamura M. Interpretation of near-infrared spectroscopy signals: a study with a newly developed perfused rat brain model. J Appl Physiol. 2001;90(5):1657–62.PubMed

18.

Ohmae E, Ouchi Y, Oda M, Suzuki T, Nobesawa S, Kanno T, Yoshikawa E, Futatsubashi M, Ueda Y, Okada H, Yamashita Y. Cerebral hemodynamics evaluation by near-infrared time-resolved spectroscopy: correlation with simultaneous positron emission tomography measurements. Neuroimage. 2006;29(3):697–705.CrossRefPubMed

19.

Villringer K, Minoshima S, Hock C, Obrig H, Ziegler S, Dirnagl U, Schwaiger M, Villringer A. Assessment of local brain activation. A simultaneous PET and near-infrared spectroscopy study. Adv Exp Med Biol. 1997;413:149–53.CrossRefPubMed

20.

Matsuo K, Kato T, Taneichi K, Matsumoto A, Ohtani T, Hamamoto T, Yamasue H, Sakano Y, Sasaki T, Sadamatsu M, Iwanami A, Asukai N, Kato N. Activation of the prefrontal cortex to trauma-related stimuli measured by near-infrared spectroscopy in posttraumatic stress disorder due to terrorism. Psychophysiology. 2003;40(4):492–500.CrossRefPubMed

21.

Kameyama M, Fukuda M, Yamagishi Y, Sato T, Uehara T, Ito M, Suto T, Mikuni M. Frontal lobe function in bipolar disorder: a multichannel near-infrared spectroscopy study. Neuroimage. 2006;29(1):172–84.CrossRefPubMed

22.

Suto T, Fukuda M, Ito M, Uehara T, Mikuni M. Multichannel near-infrared spectroscopy in depression and schizophrenia: cognitive brain activation study. Biol Psychiatry. 2004;55(5):501–11.CrossRefPubMed

23.

Negoro H, Sawada M, Iida J, Ota T, Tanaka S, Kishimoto T. Prefrontal dysfunction in attention-deficit/hyperactivity disorder as measured by near-infrared spectroscopy. Child Psychiatry Hum Dev. 2010;41(2):193–203.CrossRefPubMed

24.

Ota T, Iida J, Sawada M, Suehiro Y, Yamamuro K, Matsuura H, Tanaka S, Kishimoto N, Negoro H, Kishimoto T. Reduced prefrontal hemodynamic response in pediatric obsessive-compulsive disorder as measured by near-infrared spectroscopy. Child Psychiatry Hum Dev. 2013;44(2):265–77.CrossRefPubMed

25.

Okada K, Ota T, Iida J, Kishimoto N, Kishimoto T. Lower prefrontal activity in adults with obsessive-compulsive disorder as measured by near-infrared spectroscopy. Prog Neuropsychopharmacol Biol Psychiatry. 2013;43:7–13.CrossRefPubMed

26.

Yamamuro K, Ota T, Iida J, Nakanishi Y, Uratani M, Matsuura H, Kishimoto N, Tanaka S, Negoro H, Kishimoto T. Prefrontal dysfunction in pediatric Tourette’s disorder as measured by near-infrared spectroscopy. BMC Psychiatry. 2015;15:102.CrossRefPubMedPubMedCentral

27.

Yamamuro K, Makinodan M, Kimoto S, Kishimoto N, Morimoto T, Toritsuka M, Matsuoka K, Takebayashi Y, Takata T, Takahashi M, Tanimura Y, Nishihata Y, Matsuda Y, Ota T, Yoshino H, Iida J, Kishimoto T. Differential patterns of blood oxygenation in the prefrontal cortex between patients with methamphetamine-induced psychosis and schizophrenia. Sci Rep. 2015;5:12107.CrossRefPubMedPubMedCentral

28.

Yamamuro K, Kimoto S, Iida J, Kishimoto N, Nakanishi Y, Tanaka S, Ota T, Makinodan M, Kishimoto T. Reduced prefrontal cortex hemodynamic response in adults with methamphetamine induced psychosis: relevance for impulsivity. PLoS ONE. 2016;11(4):e0152373.CrossRefPubMedPubMedCentral

29.

Weber P, Lütschg J, Fahnenstich H. Cerebral hemodynamic changes in response to an executive function task in children with attention-deficit hyperactivity disorder measured by near-infrared spectroscopy. J Dev Behav Pediatr. 2005;26(2):105–11.CrossRefPubMed

30.

Inoue Y, Sakihara K, Gunji A, Ozawa H, Kimiya S, Shinoda H, Kaga M, Inagaki M. Reduced prefrontal hemodynamic response in children with ADHD during the Go/NoGo task: a NIRS study. NeuroReport. 2012;23(2):55–60.CrossRefPubMed

31.

Ota T, Iida J, Nakanishi Y, Sawada S, Matsuura H, Yamamuro K, Ueda S, Uratani M, Kishimoto N, Negoro H, Kishimoto T. Increased prefrontal hemodynamic change after atomoxetine administration in pediatric attention-deficit/hyperactivity disorder as measured by near-infrared spectroscopy. Psychiatry Clin Neurosci. 2015;69(3):161–70.CrossRefPubMed

32.

Araki A, Ikegami M, Okayama A, Matsumoto N, Takahashi S, Azuma H, Takahashi M. Improved prefrontal activity in AD/HD children treated with atomoxetine: a NIRS study. Brain Dev. 2015;37(1):76–87.CrossRefPubMed

33.

American Psychiatric Association. Diagnostic and statistical manual of mental disorders. (DSM-5). 5th ed. Arlington: APA; 2013.CrossRef

34.

Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, Ryan N. Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997;36(7):980–8.CrossRefPubMed

35.

Roberts CA, Montgomery C. fNIRS suggests increased effort during executive access in ecstasy polydrug users. Psychopharmacology. 2015;232(9):1571–82.CrossRefPubMed

36.

Hock C, Villringer K, Müller-Spahn F, Wenzel R, Heekeren H, Schuh-Hofer S, Hofmann M, Minoshima S, Schwaiger M, Dirnagl U, Villringer A. Decrease in parietal cerebral hemoglobin oxygenation during performance of a verbal fluency task in patients with Alzheimer’s disease monitored by means of near-infrared spectroscopy (NIRS)–correlation with simultaneous rCBF-PET measurements. Brain Res. 1997;755(2):293–303.CrossRefPubMed

37.

Ymazaki K. ADHD-RS-IV Japanese version. In: Kanbayashi Y, Saito K, Kita M, editors. Japanese guideline for the diagnosis and treatment of attention deficit hyperactivity disorder (ADHD). Tokyo: Jiho; 2013. p. 48–54 (In Japanese).

38.

Golden CJ. A group version of the Stroop color and word test. J Pers Assess. 1975;39(4):386–8.CrossRefPubMed

39.

Schweitzer JB, Faber TL, Grafton ST, Tune LE, Hoffman JM, Kilts CD. Alterations in the functional anatomy of working memory in adult attention deficit hyperactivity disorder. Am J Psychiatry. 2000;157(2):278–80.CrossRefPubMed

40.

Toronov V, Webb A, Choi JH, Wolf M, Michalos A, Gratton E, Hueber D. Investigation of human brain hemodynamics by simultaneous near-infrared spectroscopy and functional magnetic resonance imaging. Med Phys. 2001;28(4):521–7.CrossRefPubMed

41.

Sawada M, Iida J, Ota T, Negoro H, Tanaka S, Sadamatsu M, Kishimoto T. Effects of osmotic-release methylphenidate in attention-deficit/hyperactivity disorder as measured by event-related potentials. Psychiatry Clin Neurosci. 2010;64(5):491–8.CrossRefPubMed

42.

Yamamuro K, Ota T, Iida J, Nakanishi Y, Matsuura H, Uratani M, Okazaki K, Kishimoto N, Tanaka S, Kishimoto T. Event-related potentials reflect the efficacy of pharmaceutical treatments in children and adolescents with attention deficit/hyperactivity disorder. Psychiatry Res. 2016;242:288–94.CrossRefPubMed

43.

Bush G, Holmes J, Shin LM, Surman C, Makris N, Mick E, Seidman LJ, Biederman J. Atomoxetine increases fronto-parietal functional MRI activation in attention-deficit/hyperactivity disorder: a pilot study. Psychiatry Res. 2013;211(1):88–91.CrossRefPubMed

44.

Bush G, Spencer TJ, Holmes J, Shin LM, Valera EM, Seidman LJ, Makris N, Surman C, Aleardi M, Mick E, Biederman J. Functional magnetic resonance imaging of methylphenidate and placebo in attention-deficit/hyperactivity disorder during the multi-source interference task. Arch Gen Psychiatry. 2008;65(1):102–14.CrossRefPubMed

45.

Schulz KP, Fan J, Bédard AC, Clerkin SM, Ivanov I, Tang CY, Halperin JM, Newcorn JH. Common and unique therapeutic mechanisms of stimulant and nonstimulant treatments for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2012;69(9):952–61.CrossRefPubMed

46.

Chou TL, Chia S, Shang CY, Gau SS. Differential therapeutic effects of 12-week treatment of atomoxetine and methylphenidate on drug-naïve children with attention deficit/hyperactivity disorder: a counting Stroop functional MRI study. Eur Neuropsychopharmacol. 2015;25(12):2300–10.CrossRefPubMed

47.

Cubillo A, Smith AB, Barrett N, Giampietro V, Brammer MJ, Simmons A, Rubia K. Shared and drug-specific effects of atomoxetine and methylphenidate on inhibitory brain dysfunction in medication-naive ADHD boys. Cereb Cortex. 2014;24(1):174–85.CrossRefPubMed

48.

Volkow ND, Wang GJ, Fowler JS, Telang F, Maynard L, Logan J, Gatley SJ, Pappas N, Wong C, Vaska P, Zhu W, Swanson JM. Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain. Am J Psychiatry. 2004;161(7):1173–80.CrossRefPubMed

49.

Volkow ND, Fowler JS, Wang GJ, Telang F, Logan J, Wong C, Ma J, Pradhan K, Benveniste H, Swanson JM. Methylphenidate decreased the amount of glucose needed by the brain to perform a cognitive task. PLoS ONE. 2008;3(4):e2017.CrossRefPubMedPubMedCentral

50.

Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proc Natl Acad Sci USA. 2001;98(2):676–82.CrossRefPubMedPubMedCentral

51.

Sonuga-Barke EJ, Castellanos FX. Spontaneous attentional fluctuations in impaired states and pathological conditions: a neurobiological hypothesis. Neurosci Biobehav Rev. 2007;31(7):977–86.CrossRefPubMed

52.

Castellanos FX, Proal E. Large-scale brain systems in ADHD: beyond the prefrontal-striatal model. Trends Cogn Sci. 2012;16(1):17–26.CrossRefPubMed

53.

Li CS, Yan P, Bergquist KL, Sinha R. Greater activation of the “default” brain regions predicts stop signal errors. Neuroimage. 2007;38(3):640–8.CrossRefPubMedPubMedCentral

54.

Fassbender C, Zhang H, Buzy WM, Cortes CR, Mizuiri D, Beckett L, Schweitzer JB. A lack of default network suppression is linked to increased distractibility in ADHD. Brain Res. 2009;1273:114–28.CrossRefPubMedPubMedCentral

55.

Kelly C, de Zubicaray G, Di Martino A, Copland DA, Reiss PT, Klein DF, Castellanos FX, Milham MP, McMahon K. L-dopa modulates functional connectivity in striatal cognitive and motor networks: a double-blind placebo-controlled study. J Neurosci. 2009;29(22):7364–78.CrossRefPubMedPubMedCentral

56.

Tomasi D, Volkow ND, Wang R, Telang F, Wang GJ, Chang L, Ernst T, Fowler JS. Dopamine transporters in striatum correlate with deactivation in the default mode network during visuospatial attention. PLoS ONE. 2009;4(6):e6102.CrossRefPubMedPubMedCentral

57.

Volkow ND, Wang GJ, Fowler JS, Logan J, Franceschi D, Maynard L, Ding YS, Gatley SJ, Gifford A, Zhu W, Swanson JM. Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic implications. Synapse. 2002;43(3):181–7.CrossRefPubMed

58.

Bamford NS, Zhang H, Schmitz Y, Wu NP, Cepeda C, Levine MS, Schmauss C, Zakharenko SS, Zablow L, Sulzer D. Heterosynaptic dopamine neurotransmission selects sets of corticostriatal terminals. Neuron. 2004;42(4):653–63.CrossRefPubMed

59.

Rubia K, Halari R, Cubillo A, Smith AB, Mohammad AM, Brammer M, Taylor E. Methylphenidate normalizes fronto-striatal under activation during interference inhibition in medication-naïve boys with attention-deficit hyperactivity disorder. Neuropsychopharmacology. 2011;36(8):1575–86.CrossRefPubMedPubMedCentral

60.

Epstein JN, Casey BJ, Tonev ST, Davidson MC, Reiss AL, Garrett A, Hinshaw SP, Greenhill LL, Glover G, Shafritz KM, Vitolo A, Kotler LA, Jarrett MA, Spicer J. ADHD- and medication-related brain activation effects in concordantly affected parent-child dyads with ADHD. J Child Psychol Psychiatry. 2007;48(9):899–913.CrossRefPubMed

61.

Peterson BS, Potenza MN, Wang Z, Zhu H, Martin A, Marsh R, Plessen KJ, Yu S. An FMRI study of the effects of psychostimulants on default-mode processing during Stroop task performance in youths with ADHD. Am J Psychiatry. 2009;166(11):1286–94.CrossRefPubMedPubMedCentral

62.

Liddle EB, Hollis C, Batty MJ, Groom MJ, Totman JJ, Liotti M, Scerif G, Liddle PF. Task-related default mode network modulation and inhibitory control in ADHD: effects of motivation and methylphenidate. J Child Psychol Psychiatry. 2011;52(7):761–71.CrossRefPubMed

63.

Ishii-Takahashi A, Takizawa R, Nishimura Y, Kawakubo Y, Hamada K, Okuhata S, Kawasaki S, Kuwabara H, Shimada T, Todokoro A, Igarashi T, Watanabe K, Yamasue H, Kato N, Kasai K, Kano Y. Neuroimaging-aided prediction of the effect of methylphenidate in children with attention-deficit hyperactivity disorder: a randomized controlled trial. Neuropsychopharmacology. 2015;40(12):2676–85.CrossRefPubMedPubMedCentral

64.

Matsuura N, Ishitobi M, Arai S, Kawamura K, Asano M, Inohara K, Fujioka T, Narimoto T, Wada Y, Hiratani M, Kosaka H. Effects of methylphenidate in children with attention deficit hyperactivity disorder: a near-infrared spectroscopy study with CANTAB^®. Child Adolesc Psychiatry Ment Health. 2014;8(1):273.CrossRefPubMedPubMedCentral

65.

Petrides M, Tomaiuolo F, Yeterian EH, Pandya DN. The prefrontal cortex: comparative architectonic organization in the human and the macaque monkey brains. Cortex. 2012;48(1):46–57.CrossRefPubMed

66.

Hagmann P, Cammoun L, Gigandet X, Meuli R, Honey CJ, Wedeen VJ, Sporns O. Mapping the structural core of human cerebral cortex. PLoS Biol. 2008;6(7):e159.CrossRefPubMedPubMedCentral

67.

Tsujimoto S, Genovesio A, Wise SP. Evaluating self-generated decisions in frontal pole cortex of monkeys. Nat Neurosci. 2010;13(1):120–6.CrossRefPubMed

68.

Arai S, Okamoto Y, Fujioka T, Inohara K, Ishitobi M, Matsumura Y, Jung M, Kawamura K, Takiguchi S, Tomoda A, Wada Y, Hiratani M, Matsuura N, Kosaka H. Altered frontal pole development affects self-generated spatial working memory in ADHD. Brain Dev. 2016;38(5):471–80.CrossRefPubMed

69.

Shinba T, Nagano M, Kariya N, Ogawa K, Shinozaki T, Shimosato S, Hoshi Y. Near-infrared spectroscopy analysis of frontal lobe dysfunction in schizophrenia. Biol Psychiatry. 2004;55(2):154–64.CrossRefPubMed

Title: Differential therapeutic effects of atomoxetine and methylphenidate in childhood attention deficit/hyperactivity disorder as measured by near-infrared spectroscopy
Authors: Yoko Nakanishi
Toyosaku Ota
Junzo Iida
Kazuhiko Yamamuro
Naoko Kishimoto
Kosuke Okazaki
Toshifumi Kishimoto
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Child and Adolescent Psychiatry and Mental Health / Issue 1/2017
Electronic ISSN: 1753-2000
DOI: https://doi.org/10.1186/s13034-017-0163-6

At a glance: The STEP trials

Springer Medicine

Differential therapeutic effects of atomoxetine and methylphenidate in childhood attention deficit/hyperactivity disorder as measured by near-infrared spectroscopy

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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