Abstract
Attention-deficit/hyperactivity disorder, or ADHD, is the most frequently occurring neurobiological disorder in childhood and is defined by symptoms of inattention and/or hyperactivity and impulsivity that are excessive when compared with other individuals at the same developmental level. ADHD can be successfully treated pharmacologically and stimulant medications are considered a first-line treatment. However, 20–35 % of subjects in clinical trials may have an inadequate response to initial stimulant treatment. There is no standard definition of inadequate response. In many clinical trials, response is defined as a percentage improvement on the Attention-Deficit/Hyperactivity Disorder Rating Scale alone, while in others the change in Clinical Global Impression-Improvement score has also been employed. Other outcome measures have also been used. A more meaningful definition for inadequate response is one that does not produce sufficient reduction of symptoms to produce functional improvement. The literature reveals many factors that may contribute to inadequate response to treatment. Among these are poor adherence, severity and/or complexity of ADHD, inadequate stimulant dosing and/or dose-limiting adverse effects. The reasons for poor adherence should be determined. Common factors include adverse effects, lack of effectiveness, concerns about addictive potential, difficulty ingesting the medication and cost. For patients with inadequate dosing, medication optimization should be tried. For those with dose-limiting adverse effects, switching to another stimulant class or a non-stimulant is an option. For patients who are partial responders to stimulants, despite adequate adherence and dose optimization, the addition of atomoxetine or guanfacine extended release or clonidine extended release may help them achieve adequate response.
Similar content being viewed by others
References
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
Willcutt EG. The prevalence of DSM-IV attention-deficit/hyperactivity disorder: a meta-analytic review. Neurotherapeutics. 2012;9(3):490–9.
Increasing prevalence of parent-reported attention-deficit/hyperactivity disorder among children: United States, 2003 and 2007. MMWR Morb Mortal Wkly Rep. 2010;59(44):1439–43. pii :mm5944a3.
Biederman J, Petty CR, Woodworth KY, Lomedico A, Hyder LL, Faraone SV. Adult outcome of attention-deficit/hyperactivity disorder: a controlled 16-year follow-up study. J Clin Psychiatry. 2012;73(7):941–50. doi:10.4088/JCP.11m07529.
Hinshaw SP, Owens EB, Zalecki C, Huggins SP, Montenegro-Nevado AJ, Schrodek E, et al. Prospective follow-up of girls with attention-deficit/hyperactivity disorder into early adulthood: continuing impairment includes elevated risk for suicide attempts and self-injury. J Consult Clin Psychol. 2012;. doi:10.1037/a0029451.
Gjervan B, Torgersen T, Nordahl HM, Rasmussen K. Functional impairment and occupational outcome in adults with ADHD. J Atten Disord. 2012;16(7):544–52. doi:10.1177/1087054711413074.
Pliszka S. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894–921. doi:10.1097/chi.0b013e318054e724.
Wolraich M, Brown L, Brown RT, DuPaul G, Earls M, Feldman HM, et al. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128(5):1007–22. doi:10.1542/peds.2011-2654.
Hanwella R, Senanayake M, de Silva V. Comparative efficacy and acceptability of methylphenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis. BMC Psychiatry. 2011;11:176. doi:10.1186/1471-244X-11-176.
Faraone SV, Glatt SJ. A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes. J Clin Psychiatry. 2010;71(6):754–63. doi:10.4088/JCP.08m04902pur.
Jain R, Segal S, Kollins SH, Khayrallah M. Clonidine extended-release tablets for pediatric patients with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2011;50(2):171–9. doi:10.1016/j.jaac.2010.11.005.
Sallee FR, McGough J, Wigal T, Donahue J, Lyne A, Biederman J. Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2009;48(2):155–65. doi:10.1097/CHI.0b013e318191769e.
Hodgkins P, Shaw M, Coghill D, Hechtman L. Amfetamine and methylphenidate medications for attention-deficit/hyperactivity disorder: complementary treatment options. Eur Child Adolesc Psychiatry. 2012;21(9):477–92. doi:10.1007/s00787-012-0286-5.
Stein MA, Waldman ID, Charney E, Aryal S, Sable C, Gruber R, et al. Dose effects and comparative effectiveness of extended release dexmethylphenidate and mixed amphetamine salts. J Child Adolesc Psychopharmacol. 2011;21(6):581–8. doi:10.1089/cap2011.0018.
Findling RL, Turnbow J, Burnside J, Melmed R, Civil R, Li Y. A randomized, double-blind, multicenter, parallel-group, placebo-controlled, dose-optimization study of the methylphenidate transdermal system for the treatment of ADHD in adolescents. CNS Spectr. 2010;15(7):419–30.
Wigal T, Brams M, Gasior M, Gao J, Squires L, Giblin J. Randomized, double-blind, placebo-controlled, crossover study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder: novel findings using a simulated adult workplace environment design. Behav Brain Funct. 2010;6:34. doi:10.1186/1744-9081-6-34.
Findling RL, Ginsberg LD, Jain R, Gao J. Effectiveness, safety, and tolerability of lisdexamfetamine dimesylate in children with attention-deficit/hyperactivity disorder: an open-label, dose-optimization study. J Child Adolesc Psychopharmacol. 2009;19(6):649–62. doi:10.1089/cap2008.0165.
Hazell P, Lewin T, Sly K. What is a clinically important level of improvement in symptoms of attention-deficit/hyperactivity disorder? Aust N Z J Psychiatry. 2005;39(5):354–8. doi:10.1111/j.1440-1614.2005.01581.x.
Buitelaar JK, Wilens TE, Zhang S, Ning Y, Feldman PD. Comparison of symptomatic versus functional changes in children and adolescents with ADHD during randomized, double-blind treatment with psychostimulants, atomoxetine, or placebo. J Child Psychol Psychiatry. 2009;50(3):335–42. doi:10.1111/j.1469-7610.2008.01960.x.
Rostain A, Jensen PS, Connor DF, Miesle LM, Faraone SV. Toward quality care in ADHD: defining the goals of treatment. J Atten Disord. 2013;. doi:10.1177/1087054712473835.
Swanson JM, Kraemer HC, Hinshaw SP, Arnold LE, Conners CK, Abikoff HB, et al. 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. 2001;40(2):168–79. doi:10.1097/00004583-200102000-00011.
Weiss M, Wasdell M, Patin J. A post hoc analysis of d-threo-methylphenidate hydrochloride (focalin) versus d, l-threo-methylphenidate hydrochloride (Ritalin). J Am Acad Child Adolesc Psychiatry. 2004;43(11):1415–21. doi:10.1097/01.chi.0000138352.06229.b0.
Stein MA, Sarampote CS, Waldman ID, Robb AS, Conlon C, Pearl PL, et al. A dose-response study of OROS methylphenidate in children with attention-deficit/hyperactivity disorder. Pediatrics. 2003;112(5):e404.
Durell TM, Pumariega AJ, Rothe EM, Tamayo JM, Baron D, Williams D. Effects of open-label atomoxetine on African-American and Caucasian pediatric outpatients with attention-deficit/hyperactivity disorder. Ann Clin Psychiatry. 2009;21(1):26–37 pii: acp_2101c.
Ramos-Quiroga JA, Casas M. Achieving remission as a routine goal of pharmacotherapy in attention-deficit hyperactivity disorder. CNS Drugs. 2011;25(1):17–36. doi:10.2165/11538450-000000000-00000.
Steele M, Jensen PS, Quinn DM. Remission versus response as the goal of therapy in ADHD: a new standard for the field? Clin Ther. 2006;28(11):1892–1908. doi:10.1016/j.clinthera.2006.11.006.
Newcorn JH, Kratochvil CJ, Allen AJ, Casat CD, Ruff DD, Moore RJ, et al. Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response. Am J Psychiatry. 2008;165(6):721–30. doi:10.1176/appi.ajp.2007.05091676.
Wigal SB, McGough JJ, McCracken JT, Biederman J, Spencer TJ, Posner KL, et al. A laboratory school comparison of mixed amphetamine salts extended release (Adderall XR) and atomoxetine (Strattera) in school-aged children with attention deficit/hyperactivity disorder. J Atten Disord. 2005;9(1):275–89. doi:10.1177/1087054705281121.
Wang Y, Zheng Y, Du Y, Song DH, Shin YJ, Cho SC, et al. Atomoxetine versus methylphenidate in paediatric outpatients with attention deficit hyperactivity disorder: a randomized, double-blind comparison trial. Aust N Z J Psychiatry. 2007;41(3):222–30. doi:10.1080/00048670601057767.
Kemner JE, Starr HL, Ciccone PE, Hooper-Wood CG, Crockett RS. Outcomes of OROS methylphenidate compared with atomoxetine in children with ADHD: a multicenter, randomized prospective study. Adv Ther. 2005;22(5):498–512 425 [pii].
Dickson RA, Maki E, Gibbins C, Gutkin SW, Turgay A, Weiss MD. 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. 2011;5:14. doi:10.1186/1753-2000-5-14.
Yang J, Yoon BM, Lee MS, Joe SH, Jung IK, Kim SH. Adherence with electronic monitoring and symptoms in children with attention deficit hyperactivity disorder. Psychiatry Investig. 2012;9(3):263–8. doi:10.4306/pi.2012.9.3.263.
Sitholey P, Agarwal V, Chamoli S. A preliminary study of factors affecting adherence to medication in clinic children with attention-deficit/hyperactivity disorder. Indian J Psychiatry. 2011;53(1):41–4. doi:10.4103/0019-5545.75561.
Palli SR, Kamble PS, Chen H, Aparasu RR. Persistence of stimulants in children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2012;22(2):139–48. doi:10.1089/cap2011.0028.
QUILLIVANT™ XR (methylphenidate hydrochloride) for extended-release oral suspension [package insert]. Cupertino, CA: NextWave Pharmaceuticals, Inc.; 2012.
Vyvanse® (lisdexamfetamine dimesylate) capsules [package insert]. Wayne, PA: Shire US, Inc.; 2013.
Dittmann RW, Cardo E, Nagy P, et al. Efficacy and safety of lisdexamfetamine dimesylate and atomoxetine in the treatment of attention-deficit/hyperactivity disorder: a head-to-head, randomized, double-blind, phase IIIb study. CNS Drugs. 2013. doi:10.1007/s40263-013-0104-8.
Spencer TJ, Greenbaum M, Ginsberg LD, Murphy WR. Safety and effectiveness of coadministration of guanfacine extended release and psychostimulants in children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2009;19(5):501–10. doi:10.1089/cap2008.0152.
Wilens TE, Bukstein O, Brams M, et al. A controlled trial of extended-release guanfacine and psychostimulants for attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2012;51(1):74–85 e2. doi:10.1016/j.jaac.2011.10.012.
Kollins SH, Jain R, Brams M, Segal S, Findling RL, Wigal SB, et al. Clonidine extended-release tablets as add-on therapy to psychostimulants in children and adolescents with ADHD. Pediatrics. 2011;127(6):e1406–13. doi:10.1542/peds.2010-1260.
Strattera (atomoxetine hydrochloride): US prescribing information. Indianapolis, IN: Eli Lilly and Company; 2011.
Biederman J, Melmed RD, Patel A, McBurnett K, Konow J, Lyne A, et al. A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics. 2008;121(1):e73–84. doi:10.1542/peds.2006-3695.
Wilens TE, Hammerness P, Utzinger L, Schillinger M, Georgiopoulous A, Doyle RL, et al. An open study of adjunct OROS-methylphenidate in children and adolescents who are atomoxetine partial responders: I. Effectiveness. J Child Adolesc Psychopharmacol. 2009;19(5):485–92. doi:10.1089/cap2008.0125.
KAPVAY (clonidine hydrochloride) extended-release tablets: US prescribing information. Atlanta, GA: Shionogi Pharma, Inc.; 2010.
Intuniv® (guanfacine hydrochloride). US prescribing information. Wayne, PA: Shire Pharmaceuticals, Inc.; 2011.
Acknowledgments
Ann Childress, M.D. reports the following conflicts of interest: Shire Pharmaceuticals, Inc.: Consultant, Speaker, Research Support; Novartis Pharmaceutical Corporation: Consultant, Speaker, Research Support; Bristol-Myers Squibb: Speaker, Research Support; Somerset Pharmaceuticals, Inc.: Research Support; NextWave Pharmaceuticals: Research Support, Consultant; Abbott Laboratories: Research Support; Lilly USA, LLC: Research Support; Forest Research Institute: Research Support; Ortho-McNeill Janssen Scientific Affairs: Research Support; Johnson & Johnson Pharmaceutical Research & Development, LLC: Research Support; GlaxoSmithKline: Speaker; Sepracor Inc.: Research Support; Otsuka Research Support; Sunovion Research Support; Pfizer: Research Support, Advisory Board, Speaker; Shionogi: Advisory Board, Speaker, Research Support; Noven: Research Support; Ironshore: Consultant, Research Support; Rhodes: Research Support; Neurovance: Research Support; Neos Therapeutics: Research Support; Arbor Pharmaceuticals: Research Support; and Theravance: Research Support.
Floyd R. Sallee, M.D., Ph.D. reports the following conflicts of interest: Shire: Clinical Study Grant Recipient; Otsuka: Consultant; Neos: Consultant; Ironshore Pharma: Consultant; Sunovion: Clinical Study Grant Recipient; Purdue Pharma: Consultant; Impax: Consultant; and P2D Bioscience Equity: Shareholder, Member Board of Directors.
The authors did not receive any financial support or writing assistance for the preparation of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Childress, A.C., Sallee, F.R. Attention-Deficit/Hyperactivity Disorder with Inadequate Response to Stimulants: Approaches to Management. CNS Drugs 28, 121–129 (2014). https://doi.org/10.1007/s40263-013-0130-6
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40263-013-0130-6