Issues in the Management of Patients with Complex ADHD Symptoms

CME MONOGRAPH ARTICLE You have requested to view an article that is part of a CME monograph. In keeping with ACCME standards, you have been directed to a file that contains all the articles published in this monograph. Before reading any of the articles (and certainly before taking the CME Posttest), please read the required CME Information, which may be found in this file before the articles.

Supplement to

THE JOURNAL OF

PEDIATRICS May 2009 • Volume 154 • Number 5

Copyright © 2009 Mosby Inc. All rights reserved.

ADVANCES IN THE TREATMENT OF PEDIATRIC ADHD: A FOCUS ON THE ROLE OF NORADRENERGIC INPUTS AND THE ALPHA-2A RECEPTOR GUEST EDITOR: THOMAS J. SPENCER, MD

This supplement is jointly sponsored by Postgraduate Institute for Medicine

and MDG Development Group. This activity is supported by an educational grant from Shire Pharmaceuticals, Inc. Estimated time to complete activity: 1 hour and 45 minutes. Release Date: May 2009 Expiration Date: May 2010 Statement of Peer Review: All supplement manuscripts submitted to The Journal of Pediatrics for publication are reviewed by: 1) a Guest Editor(s); 2) one or more outside peer reviewers who are independent of the supplement project; and 3) the Editor of The Journal. This process ensures that the supplement has an educational focus that is of interest to our readership. Author Disclosure Policy: All authors contributing to supplements published in The Journal of Pediatrics are required to fully disclose any primary financial relationship with a company that has a direct financial interest in the subject matter or products discussed in the submitted manuscripts, or with a company that produces a competing product. These relationships (eg, ownership of stock or significant honoraria or consulting fees) and any direct support of research by a commercial company must be indicated on the title page of each manuscript. This information is also published in the frontmatter of each supplement.

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ISSN 0022-3476

Supplement to

THE JOURNAL OF

PEDIATRICS May 2009 • Volume 154 • Number 5S

ADVANCES IN THE TREATMENT OF PEDIATRIC ADHD: A FOCUS ON THE ROLE OF NORADRENERGIC INPUTS AND THE ALPHA-2A RECEPTOR Advances in the Treatment of Pediatric ADHD: A Focus on the Role of Noradrenergic Inputs and the Alpha-2a Receptor

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Thomas J. Spencer, MD, Boston, Massachusetts

Issues in the Management of Patients with Complex ADHD Symptoms

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Thomas J. Spencer, MD, Boston, Massachusetts

Efficacy and Safety Limitations of Attention Deficit Hyperactivity Disorder Pharmacotherapy in Pediatric Patients

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Sharon B. Wigal, PhD, Irvine, California

The Emerging Neurobiology of Attention Deficit Hyperactivity Disorder: The Key Role of the Prefrontal Association Cortex

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Amy F.T. Arnsten, PhD, New Haven, Connecticut

Alpha-2 Adrenergic Agonists in Attention Deficit Hyperactivity Disorder

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Lawrence Scahill, MSN, PhD, New Haven, Connecticut

CME Section

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May 2009

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The Journal of Pediatrics

CME INFORMATION Advances in the Treatment of Pediatric ADHD: A Focus on the Role of Noradrenergic Inputs and the Alpha-2a Receptor Supplement to The Journal of Pediatrics

Target Audience This activity has been designed to meet the educational needs of child and adolescent psychiatrists, pediatricians, and child neurologists treating patients with attention deficit hyperactivity disorder (ADHD).

Statement of Need/Program Overview Approximately 2 million children in the United States suffer from ADHD. Although many psychosocial interventions are useful in its treatment, pharmacotherapy remains central to its effective management. Despite the number of medications approved by the US Food and Drug Administration (FDA), approximately 10% of patients do not respond to any of them, and an equal number cannot tolerate them due to adverse effects. Given the importance of the pharmacologic treatment of children with ADHD, especially those whose conditions are complicated by comorbid substance use disorder, there is a clear medical need for safe, well-tolerated, non-stimulant pharmacotherapies for these difficult-to-treat patients.

Educational Objectives After completing this activity, participants should be better able to: ● Describe the role played by noradrenergic pathways in the PFC in the regulation of working memory, attention, and behavior ● Explain the critical impact of postsynaptic alpha-2a receptor activation on prefrontal cortical functioning ● List the experimental and clinical evidence for the potential efficacy of alpha-2 adrenergic agonist treatment of patients with ADHD ● Identify those subsets of patients with ADHD who have an unmet need for pharmacotherapy, in whom alpha-2 adrenergic agonist pharmacotherapy may be clinically indicated

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Postgraduate Institute for Medicine (PIM) and MDG Development Group. PIM is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Postgraduate Institute for Medicine designates this educational activity for a maximum of 1.75 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Method of Participation There are no fees for participating and receiving CME credit for this activity. During the period May 2009 through May 2010, participants must (1) read the learning objectives and faculty disclosures, (2) study the educational activity, (3) complete the posttest by recording the best answer to each question in the answer key on the evaluation form, (4) complete the evaluation form, and (5) mail or fax the evaluation form with answer key to Postgraduate Institute for Medicine. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed posttest with a score of 70% or better. Your statement of credit will be mailed to you within 3 weeks.

Disclosure of Unlabeled Use This educational activity may contain discussions of published and/or investigational uses of agents that are not indicated by the FDA. PIM, MDG Development Group, and Shire Pharmaceuticals, Inc., do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of PIM, MDG Development Group, or Shire Pharmaceuticals, Inc. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Advances in the Treatment of Pediatric ADHD: A Focus on the Role of Noradrenergic Inputs and the Alpha-2a Receptor

Guest Editor Thomas J. Spencer, MD Associate Professor of Psychiatry Harvard Medical School Associate Chief Clinical and Research Program Pediatric Psychopharmacology Massachusetts General Hospital Boston, Massachusetts

Faculty Amy F. T. Arnsten, PhD Professor of Neurobiology Yale University School of Medicine New Haven, Connecticut Lawrence Scahill, MSN, PhD Professor Child Study Center and School of Nursing Yale University New Haven, Connecticut

Sharon B. Wigal, PhD Clinical Professor of Pediatrics University of California, Irvine Director of Clinical Trials Child Development Center Irvine, California

Faculty Disclosures Disclosure of Conflicts of Interest Postgraduate Institute of Medicine (PIM) assesses conflict of interest with its instructors, planners, managers, and other individuals who are in a position to control the content of CME activities. All relevant conflicts of interest that are identified are thoroughly vetted by PIM for fair balance, scientific objectivity of studies utilized in this activity, and patient care recommendations. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest. The faculty reported the following financial relationships or relationships to products or devices they or their spouse/ life partner have with commercial interests related to the content of this CME activity:

Amy F.T. Arnsten, PhD has received consulting fees from Shire Pharmaceuticals, Inc., has contracted research with Shire Pharmaceuticals, Inc., and has a license agreement with Shire Pharmaceuticals, Inc. for the development of guanfacine for treatment of ADHD. Lawrence Scahill, MSN, PhD has received consulting fees from Janssen Pharmaceuticals, Inc., Supernus Pharmaceuticals, Inc., Bristol-Myers Squibb, Shire Pharmaceuticals, Inc., and Neuropharm. Thomas J. Spencer, MD has contracted research with Cephalon, Inc., Eli Lilly & Company, GlaxoSmithKline PLC, Janssen Pharmaceuticals, Inc., McNeil Pharmaceutical, Inc., the National Institute of Mental Health, Novartis AG, Pfizer Inc., and Shire Pharmaceuticals, Inc.; has been a speaker for Eli Lilly & Company, GlaxoSmithKline PLC, McNeil Pharmaceutical, Inc., Novartis AG, and Shire Pharmaceuticals, Inc.; has been on the advisory boards of Cephalon, Inc., Eli Lilly & Company, GlaxoSmithKline PLC, Janssen Pharmaceuticals, Inc., McNeil Pharmaceutical, Inc., Novartis AG, Pfizer Inc., and Shire Pharmaceuticals, Inc. Sharon Wigal, PhD has received consulting fees from Abbott Laboratories, McNeil Pharmaceutical, Inc., NIMH, and Shire Pharmaceuticals, Inc.; has received fees for non-CME services from McNeil Pharmaceutical, Inc., Novartis AG, Shire Pharmaceuticals, Inc., and UCB Pharma, Inc.; and has contracted research with Cephalon, Inc., NIMH, Psychogenics, Eli Lilly & Company, McNeil Pharmaceutical, Inc., Addrenex, and Shire Pharmaceuticals, Inc. Manager and Planner Disclosures Bruce Greenberg, PhD has no real or apparent conflicts of interest to report. The following PIM planners and managers, Linda Graham, RN, BSN, BA, Jan Hixon, RN, BSN, MA, Trace Hutchinson, PharmD, Julia Kirkwood, RN, BSN, and Jan Schultz, RN, MSN, CCMEP hereby state that they or their spouse/life partner do not have any financial relationship or relationships to products or devices with any commercials interest related to the content of this activity of any amount during the past 12 months.

Advances in the Treatment of Pediatric ADHD: A Focus on the Role of Noradrenergic Inputs and the Alpha-2a Receptor

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epilepsy, and bipolar disorder.8,12-17 In the broad ADHD population, stimulants can cause insomnia,12,16 may slow growth,18 and in certain patients may exacerbate or precipitate anxiety, tics, seizures, substance use, and hypertension.12,14 Atomoxetine is contraindicated in patients who have liver disease and may exacerbate or precipitate certain psychiatric or other medical problems.16 Thus, even though there is a small group of highly effective and relatively safe treatments, there is a need for other options, particularly among patients with comorbid conditions. In her review, Dr Wigal discusses these challenges and limitations and describes other non– FDA-approved agents to which clinicians have turned for pediatric ADHD therapy, including modafinil, bupropion, and noradrenergic ␣2-receptor agonists such as clonidine and guanfacine. However, few large-scale, well-controlled trials have been conducted with these alternative therapies, and no clear evidence-based approach to meeting the treatment needs of complex cases ADHD has been defined. Despite decades of experience with psychostimulant therapies, we are still learning about the basic neurobiology of attention and attention disorders. Among the most exciting discoveries are those in the area of noradrenergic neurotransmission. In her review of recent findings in the fields of neurobiology, imaging, and genetics, Amy Arnsten, PhD, describes the role of noradrenergic circuits and receptors in patients with normal and disordered attention. The prefrontal association cortex (PFC) is an important substrate involved in regulating attention, behavior, and emotion,19,20 and its proper functioning depends on the delicate balance of From Harvard Medical School, Clinical and Research Program, Department of Pedinoradrenergic and doatric Psychopharmacology, Massachusetts 20 paminergic signaling. General Hospital, Boston. Please see the Author Disclosure section at ADHD is linked to gethe end of this article. netic changes that alter Reprint requests: Dr Thomas J. Spencer, PFC development and Harvard Medical School, Clinical and Research Program, Department of Pediatric catecholaminergic sigPsychopharmacology, Massachusetts Gennaling and, as such, eral Hospital, 55 Fruit Street–Warren may underlie symptoms 705, Boston, MA 02114. E-mail: tspencer@ partners.org. including impaired attenJ Pediatr 2009;154:S1-S3 tion, impulsivity, and hy0022-3476/$ - see front matter 21-23 peractivity. These Copyright © 2009 Mosby Inc. All rights findings have given rise reserved. 10.1016/j.jpeds.2009.01.034 to a cohesive understand-

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cientific and clinical research into attention deficit hyperactivity disorder (ADHD) has yielded several new and striking developments that serve to enhance our understanding of the pathophysiology of the disease. This supplement focuses on four developments, dealing with (1) treatment outcomes in patients who have ADHD and comorbid disorders; (2) safety and efficacy issues of existing pharmacologic treatments; (3) basic neuroscience discoveries related to ADHD; and (4) the role of noradrenergic ␣2receptor agonists in the treatment of patients with ADHD. The weight of scientific evidence gathered over the last 2 decades upends a long-held notion that primary ADHD is not usually accompanied by psychiatric comorbidity. In fact, psychiatric comorbidity is the rule, not the exception.1-3 Although ADHD usually emerges first, other comorbid disorders quickly follow, and many are present before the age of 10 years.1,4 Scientific research has shown that children with ADHD suffer not only from “externalizing” disorders such as oppositional defiant disorder (ODD) and conduct disorder but from “internalizing” disorders such as anxiety and depression.1-4 Although ADHD pharmacotherapy is effective and appropriate in many affected patients5-8 and can help to decrease certain comorbid symptoms,9 it cannot address most psychiatric comorbidity. Comorbid psychiatric conditions must be controlled because lack of treatment can seriously compromise short- and long-term outcomes. In my discussion on this topic, I describe the distinct pediatric clinical presentations of the most common psychiatric comorbidities seen with ADHD and tools for routine psychiatric screening in the pediatric ADHD population. I also describe what effective ADHD therapy can and cannot accomplish in patients with significant comorbidity and appropriate adjunctive therapies. The treatment challenges raised by comorbid psychiatric and medical conditions in patients with ADHD are highlighted further in an article by Sharon Wigal, PhD. Metaanalyses indicate that long-acting stimulants exhibit robust efficacy in approximately 70% of patients,10 with the norepinephrine reuptake inhibitor atomoxetine, the only nonstimulant approved for the treatment of patients with ADHD effective in a slightly lower percentage of patients.11 Although effective for many, this leaves a significant minority (approximately 30%) of patients who do not respond adequately, cannot tolerate such therapies, or in whom such therapies are contraindicated. This subgroup tends to have comorbid psychiatric or medical disorders, such as Tourette’s syndrome,

ing of the etiology and pathology of ADHD. Noradrenergic mechanisms appear to play a primary role in the disorder and may contribute as much as or more than dopaminergic mechanisms to the underlying ADHD pathophysiology. The evolving framework of ADHD pathology discussed here by Dr Arnsten suggests a more fundamental role for noradrenergic signaling and has served as an impetus for the investigation of noradrenergic ␣2a-receptor agonists as pharmacotherapies aimed at relieving the symptoms of ADHD. Recent evidence shows that the stimulation of postsynaptic ␣2a-receptors in the PFC strengthens function in this cortical region, improving the inhibition in subcortical areas and improving direct functions of the PFC, such as attention, memory, and concentration.19,20,24,25 Reports describing the use of the available ␣2-agonists clonidine and guanfacine have, until recently, been largely anecdotal. In his review of the literature, Lawrence Scahill, MSN, PhD, provides an in-depth discussion of the investigations surrounding the efficacy and safety of clonidine and guanfacine in the treatment of children who have ADHD with or without medical or psychiatric comorbidities, such as Tourette’s syndrome and ODD. These studies suggest clinical benefits with these agents.26-30 However, clonidine has a markedly less selective receptor binding profile than guanfacine and as a result is associated with significant and more pronounced central nervous system effects, including sedation, suppression of rapid-eye-movement sleep, and impairment of choice reaction times, as well as cardiovascular effects such as vasodilation and the accompanying reduction of blood pressure.31-33 Consequently, guanfacine has proven to be a more promising agent for use in children with ADHD. Recent findings from a phase III clinical trial of a new extended-release formulation of guanfacine are discussed.26 Given our latest understanding of the critical role played by noradrenergic signaling in the pathophysiology of ADHD and the significant benefits seen to date with ␣2a agonists such as guanfacine, a full and rigorous assessment of this and other potential noradrenergic modulators in the treatment of ADHD is warranted. Further developments are expected in all areas of ADHD research, particularly in understanding the roles of noradrenergic transmission and ␣2a-noradrenergic receptors. Clinicians are strongly encouraged to remain up to date with the latest research to better understand their patients. Given the large proportion of pediatric patients with ADHD who are now known to suffer from psychiatric comorbidity—and the treatment challenges and severe symptom profile often seen in such patients— clinicians should be prepared to diagnose their patients early and assess them carefully and repeatedly for comorbidities. We hope these articles are useful to you as you strive to provide optimal medical care for your patients with ADHD.

AUTHOR DISCLOSURES Thomas Spencer, MD, has contracted research with Cephalon, Inc., Eli Lilly & Company, GlaxoSmithKline PLC, Janssen Pharmaceuticals, Inc., McNeil Pharmaceutical, S2

Introduction

Inc., the National Institute of Mental Health, Novartis AG, Pfizer Inc., and Shire Pharmaceuticals, Inc.; has been a speaker for Eli Lilly & Company, GlaxoSmithKline PLC, Janseen Pharmaceuticals, Inc., McNeil Pharmaceutical, Inc., Novartis AG, and Shire Pharmaceuticals, Inc.; has been on the advisory boards of Cephalon, Inc., Eli Lilly & Company, GlaxoSmithKline PLC, Janssen Pharmaceuticals, Inc., McNeil Pharmaceutical, Inc., Novartis AG, Pfizer Inc., and Shire Pharmaceuticals, Inc. Thomas J. Spencer, MD Associate Professor of Psychiatry Harvard Medical School Associate Chief, Clinical and Research Program Department of Pediatric Psychopharmacology Massachusetts General Hospital Boston, Massachusetts

REFERENCES 1. Biederman J, Faraone S, Milberger S, Guite J, Mick E, Chen L, et al. A prospective 4-year follow-up study of attention-deficit hyperactivity and related disorders. Arch Gen Psychiatry 1996;53:437-46. 2. Busch B, Biederman J, Cohen LG, Sayer JM, Monuteaux MC, Mick E, et al. Correlates of ADHD among children in pediatric and psychiatric clinics. Psychiatr Serv 2002;53:1103-11. 3. Jensen PS, Hinshaw SP, Swanson JM, Greenhill LL, Conners CK, Arnold LE, et al. Findings from the NIMH Multimodal Treatment Study of ADHD (MTA): implications and applications for primary care providers. J Dev Behav Pediatr 2001;22:60-73. 4. Biederman J, Faraone SV, Milberger S, Jetton JG, Chen L, Mick E, et al. Is childhood oppositional defiant disorder a precursor to adolescent conduct disorder? Findings from a four-year follow-up study of children with ADHD. J Am Acad Child Adolesc Psychiatry 1996;35:1193-204. 5. Abikoff H, McGough J, Vitiello B, McCracken J, Davies M, Walkup J, et al. Sequential pharmacotherapy for children with comorbid attention-deficit/hyperactivity and anxiety disorders. J Am Acad Child Adolesc Psychiatry 2005;44:418-27. 6. Geller D, Donnelly C, Lopez F, Rubin R, Newcorn J, Sutton V, et al. Atomoxetine treatment for pediatric patients with attention-deficit/hyperactivity disorder with comorbid anxiety disorder. J Am Acad Child Adolesc Psychiatry 2007;46:1119-27. 7. Santosh PJ, Baird G, Pityaratstian N, Tavare E, Gringras P. Impact of comorbid autism spectrum disorders on stimulant response in children with attention deficit hyperactivity disorder: a retrospective and prospective effectiveness study. Child Care Health Dev 2006;32:575-83. 8. Scheffer RE, Kowatch RA, Carmody T, Rush AJ. Randomized, placebo-controlled trial of mixed amphetamine salts for symptoms of comorbid ADHD in pediatric bipolar disorder after mood stabilization with divalproex sodium. Am J Psychiatry 2005;162:58-64. 9. Sinzig J, Dopfner M, Lehmkuhl G, Uebel H, Schmeck K, Poustka F, et al. Long-acting methylphenidate has an effect on aggressive behavior in children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 2007;17: 421-32. 10. Spencer TJ, Wilens TE, Biederman J, Weisler RH, Read SC, Pratt R. Efficacy and safety of mixed amphetamine salts extended release (Adderall XR) in the management of attention-deficit/hyperactivity disorder in adolescent patients: a 4-week, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 2006;28: 266-79. 11. Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet 2005; 366:237-48. 12. Shire Pharmaceuticals. Adderall XR prescribing information, 2007. Wayne, Pennsylvania. 13. Spencer TJ, Sallee FR, Gilbert DL, Dunn DW, McCracken JT, Coffey BJ, et al. Atomoxetine treatment of ADHD in children with comorbid Tourette syndrome. J Atten Disord 2008;11:470-81. 14. ALZA Corporation. Concerta prescribing information, 2007. Mountain View, California. 15. Adler LA, Barkley RA, Newcorn JH, Spencer TJ, Weiss MD. Managing ADHD in children, adolescents, and adults with comorbid anxiety. J Clin Psychiatry 2007; 68:451-62. 16. Eli Lilly and Company. Strattera prescribing information, 2007. Indianapolis, Indiana. 17. Scahill L, Pachler M. Treatment of hyperactivity in children with pervasive developmental disorders. J Child Adolesc Psychiatr Nurs 2007;20:59-62.

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18. Swanson JM, Elliott GR, Greenhill LL, Wigal T, Arnold LE, Vitiello B, et al. Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. J Am Acad Child Adolesc Psychiatry 2007;46:1015-27. 19. Stuss DT, Knight RT. Principles of Frontal Lobe Function. Oxford, UK: Oxford University Press, Inc; 2002, p 640. 20. Arnsten AF. Catecholamine and second messenger influences on prefrontal cortical networks of “representational knowledge”: a rational bridge between genetics and the symptoms of mental illness. Cereb Cortex 2007;17(suppl 1):i6-15. 21. Bobb AJ, Addington AM, Sidransky E, Gornick MC, Lerch JP, Greenstein DK, et al. Support for association between ADHD and two candidate genes: NET1 and DRD1. Am J Med Genet B Neuropsychiatr Genet 2005;134:67-72. 22. Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 2005;57:1313-23. 23. 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 Psychiatry 2000;5:396-404. 24. Buschman TJ, Miller EK. Top-down versus bottom-up control of attention in the prefrontal and posterior parietal cortices. Science 2007;315:1860-2. 25. Knight RT, Staines WR, Swick D, Chao LL. Prefrontal cortex regulates inhibition and excitation in distributed neural networks. Acta Psychol (Amst) 1999;101:159-78. 26. 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

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children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics 2008; 121:e73-84. 27. Connor DF, Fletcher KE, Swanson JM. A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1999;38:1551-9. 28. Hunt RD, Arnsten AF, Asbell MD. An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1995;34:50-4. 29. Palumbo DR, Sallee FR, Pelham WE Jr, Bukstein OG, Daviss WB, McDermott MP. Clonidine for attention-deficit/hyperactivity disorder, I: efficacy and tolerability outcomes. J Am Acad Child Adolesc Psychiatry 2008;47:180-8. 30. Scahill L, Chappell PB, Kim YS, Schultz RT, Katsovich L, Shepherd E, et al. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry 2001;158:1067-74. 31. Daviss WB, Patel NC, Robb AS, McDermott MP, Bukstein OG, Pelham WE Jr, et al. Clonidine for attention-deficit/hyperactivity disorder, II: ECG changes and adverse events analysis. J Am Acad Child Adolesc Psychiatry 2008;47:189-98. 32. Jakala P, Riekkinen M, Sirvio J, Koivisto E, Riekkinen P Jr. Clonidine, but not guanfacine, impairs choice reaction time performance in young healthy volunteers. Neuropsychopharmacology 1999;21:495-502. 33. Spiegel R, DeVos JE. Central effects of guanfacine and clonidine during wakefulness and sleep in healthy subjects. Br J Clin Pharmacol 1980;10(suppl 1): 165S-8S.

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Issues in the Management of Patients with Complex ADHD Symptoms THOMAS J. SPENCER, MD

Children and adolescents with attention deficit hyperactivity disorder (ADHD) have high levels of psychiatric comorbidity. The most common types of comorbidities include disruptive behavior, anxiety, and substance use disorders, as well as major depression. When comorbidities are present, impairments in school and family functioning tend to be more severe and persistent than in children who have ADHD alone. Comorbidities to ADHD are likely to go unrecognized in primary pediatric settings because clinicians may not routinely collect behavioral information, and parents are often reluctant to discuss their children’s emotional problems with physicians. Although ADHD with a comorbid component is associated with poorer outcomes, many such patients can be treated successfully. Developing improved methods for the identification and appropriate treatment of comorbid conditions in children with ADHD must be a high clinical priority, because intervention can have a significant positive impact on patients’ functioning and long-term outcomes. (J Pediatr 2009;154:S4-S12)

ttention deficit hyperactivity disorder (ADHD) is the most common pediatric neurobehavioral disorder and is estimated to occur in 6% to 10% of children between 5 and 17 years of age in the United States.1-3 Core symptoms of the disorder are hyperactivity, inattention, and impulsivity, all of which are associated with functional impairments across academic, home, and social domains.4 Most patients exhibit some form of impairment in executive functions, such as response inhibition, vigilance, or working memory.5 Contrary to the earlier belief that ADHD tends to resolve during puberty, evidence now clearly shows that the disorder persists into adulthood in approximately 60% of cases.6,7 The nature and severity of ADHD behavioral disorder and functional impairment may be heterogeneous among individuals, as well as within a given individual as he or she matures. The wide variability in ADHD symptoms is reflected in the criteria for the condition specified in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR): patients are required to have at least 6 of 18 possible symptoms and may exhibit 1 of 3 possible ADHD subtypes (eg, primarily hyperactive/impulsive, primarily inattentive, combined hyperactive/inattentive).4 The behavioral variability of the disorder appears to go hand in hand with what is now understood to be a complex neurologic disorder involving a number of neurotransmitters (particularly dopamine and norepinephrine) and brain regions affected by frontostriatal signaling.8-10 The underlying cause of the disorder appears to be largely polygenic in nature, with candidate gene studies finding clear links between ADHD and at least 7 different genes.11-13 Nongenetic factors linked to ADHD appear to play a relatively smaller but still important role. Thus ADHD is a complex disorder with no single, well-defined cause and is marked by a wide range of behavioral and neurologic symptoms. As such, it is a much bigger and more varied problem than previously believed. Adding to the complex clinical presentation of ADHD is the dramatically heightened risk in these patients (as compared with healthy peers in the community) for a number of psychiatric comorbidities (Table I).14-22 The presence of such comorbidities likely alters the clinical presentation of ADHD, making accurate differential diagnosis difficult and possibly altering the response to therapies aimed at ADHD. Because of the heterogeneous nature of the symptoms and problems with which patients with ADHD may present, any comprehensive diagnostic assessment must also consider potential comorbid conditions.23 For this reason, defining an optimized treatment approach can be challenging, because From Harvard Medical School and Pediatric different patients are likely to require a range of different treatments or combinations of Psychopharmacology Department, Massatreatments involving both psychosocial and pharmacologic interventions, and even indichusetts General Hospital, Boston, MA. vidual patients may need different treatments over time as they face developmental Please see the Author Disclosure section at the end of this article. challenges and mature into adulthood.23

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ADHD Attention deficit hyperactivity disorder CD Conduct disorder DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision FDA Food and Drug Administration

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MGH ODD PDD SSRI SUD

Massachusetts General Hospital Oppositional defiant disorder Pervasive developmental disorders Selective serotonin reuptake inhibitor Substance use disorder

Reprint requests: Thomas J. Spencer, MD, Harvard Medical School, Pediatric Psychopharmacology, Massachusetts General Hospital, 55 Fruit Street-Warren 705, Boston, MA 02114. E-mail: tspencer@ partners.org. 0022-3476/$ - see front matter Copyright © 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.01.016

Table I. Classes of comorbid psychiatric disorders frequently seen in pediatric patients with ADHD Behavioral disorders Oppositional defiant disorder17-19 Conduct disorder14,16,17 Mood disorders Major depressive disorder17,20,21 Dysthymia20 Bipolar disorder15,20 Anxiety disorders Separation anxiety disorder17 Simple phobia17 Agoraphobia17 Overanxious disorder17 Substance use disorders Alcohol abuse Drug abuse Alcohol dependence Drug dependence Cognition-related disorders Specific learning disabilities17,20 Reading Math Pervasive developmental disorders22 Autism Autism spectrum disorders

This article discusses the types of psychiatric and behavioral comorbidities associated with ADHD and the impact of these comorbidities on clinical outcomes. It describes in detail our current understanding concerning the age at onset of each comorbidity, the sequence in which such disorders emerge developmentally, and the symptomatic profiles of individuals who have different comorbid disorders. The impact of psychiatric comorbidity on therapeutic choices is important, and clinicians should be aware of the potential clinical benefits that can be expected from ADHD-specific treatment in patients with ADHD and comorbid disorders. Early diagnosis is key to optimizing therapeutic outcomes and beneficial effects on patients’ lives.

CLASSES OF COMORBID DISORDERS IN ADHD ADHD is known to be accompanied by a wide range of psychiatric symptoms.15,17,24 Studies indicate that a majority of children and adolescents with ADHD may meet diagnostic criteria for another psychiatric disorder (Table II).17,24 Behavior-related disorders commonly seen in patients with ADHD include oppositional defiant disorder (ODD) and conduct disorder (CD).17 In later childhood and adolescence, patients with ADHD are also more likely than peers without ADHD in the community to exhibit substance use disorder or substance abuse.25,26 Pediatric patients with ADHD also tend to suffer from so-called internalizing disorders, such as major depressive disorder, bipolar disorder, dysthymia, and anxiety disorders.17 A subset of children and adolescents with Issues in the Management of Patients with Complex ADHD Symptoms

ADHD may exhibit cognition-related disorders, such as specific learning disorders,20 and pervasive developmental disorders (PDDs), including autism and autism-spectrum disorders.22

ONSET OF COMORBID DISORDERS Longitudinal studies indicate that ADHD and associated psychiatric comorbidities emerge in a predictable fashion as patients mature. A Massachusetts General Hospital (MGH) 4-year prospective longitudinal study of 140 clinicreferred Caucasian boys with ADHD, age 6 to 17 years (average age at baseline, 11 years), was conducted in part to ascertain the timing of emergence of ADHD and the links between ADHD and various psychiatric comorbidities.15,27 The ADHD cohort was compared with 120 matched control individuals without ADHD from the community. Structured retrospective interviews indicated that parental awareness of ADHD-related symptoms emerged at an average age of 2.2 years27; a formal diagnosis of ADHD was made, on average, several years later (at age 5).15 In this cohort, psychiatric comorbidity was the rule, not the exception; at baseline, 65% of patients had comorbid ODD and 22% had comorbid CD.27 Moreover, at the 4-year follow-up, 41.4% had major depression, 32.1% had multiple anxiety disorders, and 20.7% had bipolar disorder.27 Rates of these psychiatric morbidities were low (1% to 8%) among non-ADHD participants in this study.27 On the basis of parental interview and follow-up assessments with the Schedule for Affective Disorders and Schizophrenia for School-age Children– epidemiologic version (K-SADS-E), most of these comorbid psychiatric disorders were already present in patients with ADHD by the age of 10 years.27 Figure 1 illustrates the average age at diagnosis for each of the most common comorbid psychiatric disorders identified in this cohort; ADHD typically preceded the emergence of any comorbid psychiatric diagnosis.27 Anxiety disorders and ODD tended to appear earlier (by age 4 to 5 years) than did major depressive disorder (age 5 to 7 years); CD and bipolar disorder tended to emerge comparatively later (age 8 to 9 years).27 Research based on this cohort, moreover, indicates that comorbid disorders are not simply an artifact of overlapping ADHD symptoms but are diagnostically distinct problems.21 Contrary to the idea that children with ADHD who are treated in the primary care setting are less impaired than patients seen in psychiatric settings, a case-control study of patients with ADHD aged 6 to 18 years showed that patterns of psychiatric comorbidity among patients in psychiatric settings are similar to those seen for patients with ADHD in pediatric primary care settings. In psychiatric versus primary care settings, similar proportions of patients were found to have major depressive disorder (50% vs 42%), agoraphobia (13% vs 12%), and enuresis (27% vs 30%), among other conditions.17 Reports clearly indicate that by the time a child with ADHD and psychiatric comorbidity presents in a psychiatric setting, these disorders are likely to have been present for years.27 S5

Table II. Lifetime prevalence of psychiatric disorders in children aged 6 to 18 years with and without ADHD who were referred to pediatric and psychiatric settings (n ⴝ 522) Psychiatric setting, n (%) Disorder Disruptive behavior disorders ODD CD Mood disorders Major depression Bipolar disorder Dysthymia Anxiety disorders More than 2 coexisting Panic disorder Agoraphobia Overanxious Simple phobia Social phobia Separation anxiety OCD PTSD Psychoactive SUD

Pediatric setting, n (%)

ADHD (n ⴝ 139)

Control group (n ⴝ 93)

ADHD (n ⴝ 141)

Control group (n ⴝ 149)

77 (55)* 20 (14)*

8 (9) 2 (2)

64 (45)* 21 (15)*

10 (7) 2 (1)

70 (50)* 18 (13)† 11 (7)‡

10 (11) 0 (0) 1 (1)

59 (42)* 12 (9)† 8 (6)‡

16 (11) 0 (0) 1 (0.6)

46 (33)* 4 (3) 18 (13)‡ 43 (31)* 34 (24)* 22 (15)§ 44 (31)* 7 (5) 2 (3) 5 (4)

6 (6) 1 (1) 3 (3) 4 (4) 7 (7) 4 (4) 8 (8) 0 (0) 1 (2) 2 (2)

41 (29)* 7 (5) 17 (12)‡ 39 (27)* 32 (23)* 16 (11)§ 32 (23)* 5 (3) 1 (1) 7 (5)

6 (4) 0 (0) 2 (1) 6 (4) 12 (8) 4 (3) 10 (6) 3 (2) 0 (0) 5 (3)

PTSD, Posttraumatic stress disorder. Adapted with permission from Busch B, et al.17 *P ⱕ .001 versus control subjects without ADHD. †Insufficient data to conduct statistical comparison. ‡P ⱕ .01 vs control subjects without ADHD. §P ⱕ .05 vs control subjects without ADHD.

Figure 1. Developmental timing of psychiatric comorbidity onset in children with ADHD. Shown are the mean ages at onset for ADHD and the psychiatric comorbidities seen in the MGH cohort of boys with ADHD (n ⫽ 140). Reproduced with permission from Biederman J, et al.27

An awareness of the risk for psychiatric comorbidities, combined with routine appropriate assessments, is prognostically important. These disorders have a highly deleterious impact on measures of social functioning, with comorbid disorders compounding the effects of ADHD.15 In the 4-year prospective longitudinal cohort study in boys with ADHD, patients initially diagnosed with mood or anxiety disorders tended to have recurrences when assessed 4 years later. Moreover, those with psychiatric comorbidities at baseline, including CD, ODD, bipolar disorder, and multiple anxiety disorders, were more likely than those with ADHD alone to continue to meet the full diagnostic criteria for ADHD at the 4-year follow-up assessment in mid to late adolescence.28 The presence of psychiatric comorbidity at baseline in this cohort also predicted poorer school and psychosocial functioning 4 S6

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years later.28 Given the likelihood of such negative outcomes, pediatricians can have a major impact on life course and treatment outcome by diagnosing and treating psychiatric comorbidity early.

BEHAVIORAL COMORBIDITIES: ODD AND CD ODD and CD are disruptive behavioral disorders that commonly occur concurrently with ADHD.17-19 ODD, marked by defiance of adult authority, temper tantrums, and irritability14,17,27 occurs in approximately 30% to 50% of the ADHD clinical population.16,18,19,29 One recent report describing the MGH cohort at 10 years’ follow-up indicated that 79% of patients with ADHD had a lifetime history of The Journal of Pediatrics • May 2009

Table III. Clinical contrasts among uncomplicated ADHD, ADHDⴙODD, and ADHDⴙCD Domain

Uncomplicated ADHD

ADHDⴙODD

School

Poor classroom attention Blurts out answers Forgets class materials or homework

Argues with teachers Disrupts class

Social

Difficulty making or keeping friends

Peer rejection

Home/family

Excessive talking Trouble sleeping Emotionally intense (“Really” happy, angry, sad, etc)

Easily annoyed Easily angered Disobeys or defies parental authority Argues Trouble sleeping

ODD by the time they reached young adulthood.14 This percentage contrasts sharply with estimates of ODD prevalence in the general population (2% to 16%).4,18 Onset of ODD in patients with ADHD occurs substantially earlier than in individuals without comorbid ADHD. For example, in the patient and community sample cohort from Biederman et al,14 the average age (⫾ standard deviation [SD]) at onset of ODD was significantly lower than in individuals without ADHD (5.3 ⫾ 4.0 years vs 9.9 ⫾ 6.0 years, respectively). Distinguishing ODD from CD can be clinically challenging. ODD and CD both tend to run a chronic, persistent course, with many of the features of ODD also seen in CD (Table III). Children with ODD, however, do not have a history of criminal activity, truancy, or violence, but instead are generally difficult to manage, irritable, and defiant of adult authority. In the absence of coexisting CD, individuals with ODD go to school, don’t use drugs, and don’t commit crimes. For this reason, the prognosis for individuals with ADHD and ODD appears to be relatively positive.14 It has been shown that by 25 years of age, ODD had remitted in 83.4% of patients who had had ADHD and ODD at baseline.14 Moreover, these individuals were no more likely than those with ADHD alone to have been expelled from school, convicted of a crime, or fired from a job.14 In a subset of individuals, however, ODD persists into adulthood, with these individuals more likely than their peers with ADHD alone to experience adverse outcomes (eg, new-onset bipolar disorder, anxiety disorders, and substance use disorders).30 Therapeutic strategies for patients with ADHD and comorbid ODD usually involve a combination of psychosocial interventions targeted at problem behaviors, along with parenting and school-based interventions and pharmacotherapy.31 The presence of comorbid ODD does not appear to compromise the efficacy of stimulant or nonstimulant pharmacotherapy aimed at ADHD; in controlled clinical trials reductions in core ADHD symptoms were similar in patients with ADHD alone and those with ADHD and ODD.16,29 Although ODD is an independent disorder diagnostically distinct from ADHD, some evidence suggests that decreases in ODD symptoms such as oppositionality and defiance may Issues in the Management of Patients with Complex ADHD Symptoms

ADHDⴙCD Threatens classmates, teachers Truancy Detentions/suspensions Expulsion Threatens, bullies peers Antisocial peer group Physically aggressive/cruel Steals Lies Fights Runs away from home Destroys property

Figure 2. Age at CD onset in boys with ADHD. Data adapted with permission from Biederman J, et al.27

also occur with effective stimulant and nonstimulant pharmacotherapy for ADHD.19,29 A considerable proportion of patients with ADHD and ODD later go on to have development of comorbid CD,27 a more severe and virulently disruptive behavioral disorder than ODD, that is marked by a pattern of aggressiveness, physical cruelty, lying, and theft.4 Although it occurs less often than ODD, both in the community (⬍10%)4 and among patients with ADHD (14% to 19.3%),32 it is a common problem seen in the psychiatric clinical setting.14,16,17,27,33 As with ODD in the MGH study cohort, the average age (⫾ SD) at CD onset was significantly lower than in individuals without ADHD (8.9 ⫾ 4.9 years vs 13.8 ⫾ 2.1 years, respectively). As illustrated in Figure 2, most of the patients with CD in this cohort met DSM-IV-TR diagnostic criteria for childhood-onset CD (ie, onset before age 10 years).4,14,27 Moreover, analysis at 10 years’ follow-up indicated that behavioral disorder was more severe in patients with ADHD and CD than in those with CD or ADHD alone and was marked by greater aggression, more antisocial, delinquent behavior, and more persistent symptoms.14 Given the earlier emergence and more severe problems associated with ADHD and CD, it is particularly important for pediatricians to evaluate preteen pediatric patients with ADHD for this and other disruptive behavior conditions, S7

including ODD. The Conner’s Parent and Teacher Rating Scales may be useful for such screening purposes.31 Although data are not yet sufficient to determine whether early recognition and intervention will help, it is clear that a more difficult, serious clinical presentation is seen with CD in mid to late adolescence, when the disorder is marked by a more “hardened pattern” of disruptive behavior, the development of an antisocial peer group, and substance abuse.33 However, according to an analysis of boys with CD identified in the MGH cohort, prognosis is not uniformly negative: approximately 54% of cases with CD at baseline in this cohort exhibited remission of symptoms by young adulthood.34 Remission was predicted by less psychosocial impairment at baseline, as indicated by fewer problems at school and with family, and more positive scores on measures of family cohesion and conflict. Remission was neither clearly correlated with specific therapies nor directly related to ADHD disorder.34 The mainstay of recommended therapy for CD is multimodal psychosocial intervention and psychotherapeutic counseling over an extended period of time.33 Effective treatment for patients with ADHD may also help to decrease certain CD problem behaviors, such as aggression.35,36 Use of antipsychotic agents has been reported for “disruptive behavior” such as that seen in CD.37,38 However, given the known risks for significant metabolic and extrapyramidal adverse events in children treated with these agents,39,40 and the limited evidence of efficacy in CD, use of neuroleptic treatment for CD requires a careful assessment of risks and benefits and consideration of a referral to a child psychiatrist. Given that a proportion of children with CD also have childhood bipolar disorder,41 there is a stronger rationale to use neuroleptics for bipolar features of mood dysregulation when it co-exists in CD since several atypical neuroleptics are Food and Drug Administration (FDA) approved for the treatment of childhood bipolar disorder (age 10 to 17 years). Neuroleptic agents do not treat the core symptoms of ADHD and do not replace the need for ADHD medication, and therefore they should be used only as an adjunct to recommended ADHD pharmacotherapy.

COMORBID SUBSTANCE ABUSE DISORDERS Individuals with ADHD are at increased risk for development of a substance use disorder (SUD), including alcohol or drug abuse or dependence. Studies in children and adolescents indicate that between 15% and 30% of adolescents with ADHD have a lifetime history of SUD.26,42 This prevalence jumps to roughly 45% to 55% in untreated adults with ADHD, which is about twice the prevalence seen in adults without ADHD.25,43,44 The natural history of SUD that occurs concomitantly with ADHD is distinct from that of SUD in patients without ADHD and is marked by earlier onset,43 greater severity, and a more persistent, chronic course.43,45 Moreover, SUD in patients with ADHD tends to develop more often and at a faster rate from the “gateway” use of tobacco, progressing then S8

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to alcohol abuse, and then, finally, to psychoactive drug dependence.43,46 Furthermore, recent evidence shows that patients with ADHD who are dependent on alcohol are more likely than their peers without ADHD to also be dependent on nicotine.47 Certain patients with ADHD are more vulnerable to development of SUD than others. In particular, a family history of substance dependence and a family or personal history of antisocial or disruptive behavior disorders (eg, ODD and CD), as well as early-onset bipolar disorder, are associated with earlier development of SUD.48,49 The role of stimulant treatment in patients with ADHD and comorbid SUD has been debated, given the established potential for abuse of such agents. Some investigators have questioned the use of stimulants in children with ADHD, because they may increase the risk of future substance use problems (the “sensitization” hypothesis).50 The emerging consensus, however, is that stimulant treatment neither causes SUD nor increases the risk of its development in patients with ADHD, but instead may exert a protective effect against SUD development.51,52 A meta-analysis of available reports showed a higher rate of SUD in patients with untreated ADHD than in patients who had received stimulant treatment for ADHD.52 A recent article suggests that hereditary factors may differentially predict the development of alcohol or other drug abuse in ADHD families.53 However, the identification and treatment of patients with ADHD and an ongoing SUD or a history of SUD remain a challenge. Symptoms may be masked by the presence of ADHD, substance use, and other comorbidities; continuing substance use is also likely to negatively affect treatment outcomes.54 The use of stimulant medications is contraindicated in these individuals; all psychostimulants used in the treatment of ADHD carry a blackbox warning against use for patients with known, active SUD. Prescribing stimulants for patients with ADHD and a distal personal or family history of SUD requires careful judgment, with an eye both to the risk of patient SUD relapse as well as the potential for other individuals in the family to misuse or divert the drug. The nonstimulant medication atomoxetine is effective in reducing ADHD symptoms and carries little risk of abuse.55 Other potential alternatives with limited or no abuse potential include treatments not approved by the FDA such as noradrenergic ␣2-receptor agonists including clonidine, although data on the clinical usefulness of these agents in patients with ADHD are sparse.

COMORBID MOOD DISORDERS Mood disorders, including bipolar disorder, mania, dysthymia, and major depressive disorder, occur commonly in conjunction with ADHD. Findings from the Great Smoky Mountains epidemiologic study of psychiatric morbidity in children indicate that children and adolescents with ADHD are roughly twice as likely to have a depressive disorder as their peers without ADHD.18 The prevalence of major depression, however, may be higher in clinic-referred individuThe Journal of Pediatrics • May 2009

als with ADHD.17,20 Among boys with ADHD in the MGH cohort, 29% had severe major depressive disorder (compared with 2% of the control subjects without ADHD); prevalence was lower in a parallel cohort of girls with ADHD (15%).20 In these same boy and girl cohorts, the frequency of other mood disorders, such as dysthymia and bipolar disorder, were similarly elevated (7% and 11%, respectively) among those with ADHD, compared with healthy peers in the community (1% and 0%, respectively); there was no difference between the 2 sexes.20 These and other findings have prompted an important shift away from the notion that children with ADHD have only “externalizing disorders” (ie, disruptive behavior disorders); the more accurate understanding is that mood disorders such as depression and other “internalizing disorders” are common comorbidities. Moreover, the belief that depressive symptoms in patients with ADHD reflect “demoralization” and not “true depression” is not supported by clinical evidence. When depressive symptoms that overlap with symptoms for ADHD are disregarded, the large majority of these patients continue to meet the diagnostic threshold for major depression.21 Furthermore, ADHD and major depression follow independent courses over time; remission of major depression is not preceded or predicted by remission of ADHD.56 Detecting comorbid depression requires familiarity with the presentation seen in children and adolescents. Depression in pediatric patients with ADHD is marked by a loss of pleasure or interest in favorite activities (“bored”), irritability (rather than sadness), “mood reactivity,” abnormal sleep patterns (eg, increased or decreased amounts of sleep, nightmares), and fatigue. Pediatric patients with comorbid depression may also exhibit associated problems such as refusal to attend school, social withdrawal, somatic complaints, and, in older children, substance abuse.57 The course of major depression in patients with ADHD appears to be quite persistent; in the MGH cohort, among 76 probands who were depressed at baseline, 45% (n ⫽ 34) were still depressed at the 4-year follow-up assessment.56 In that analysis, the presence of comorbid bipolar disorder and high indices of social dysfunction significantly predicted depression persistence.56 The selective serotonin reuptake inhibitor (SSRI) fluoxetine is the only medication currently indicated by the FDA for pediatric depression, but positive effects have been reported with other SSRIs as well.58,59 Increases in suicidal ideation in a small subgroup has been reported for this class of medications. One controlled trial in adolescents with depression showed that combination treatment with fluoxetine and cognitive-behavioral therapy resulted in greater antidepressant efficacy and a lower frequency of suicidal ideation and suicidal events than did treatment with fluoxetine alone.60 No significant antidepressant response has been observed with atomoxetine.61 Bipolar disorder is less common than MDD in patients with ADHD, but more devastating. As with major depression, the clinical presentation of bipolar disorder in children Issues in the Management of Patients with Complex ADHD Symptoms

differs from the classic presentation seen in adults. Symptoms are most often of a mixed nature, with cooccurrence of depressive and manic features that tend to be chronic or to rapidly cycle.62,63 Identifying mania in patients with ADHD may be challenging owing to substantial symptom overlap between the two disorders. However, the severe nature of the emotional symptoms and the functional impairments presented are distinguishing features of this disorder in patients with ADHD.62 Mania in children and adolescents is frequently marked by severe psychosocial impairment and extreme irritability along with temper outbursts that are prolonged and explosive and accompanied by violent and destructive behavior.63 Bipolar disorder in children has proved difficult to treat, and comorbid ADHD may not be effectively treatable until the mood disorder is stabilized.64 In addition, other evidence suggests that in children and adolescents, response to moodstabilizing therapy may be decreased in the presence of ADHD.65 Lithium is FDA approved for the treatment of bipolar disorder in youths ⱖ12 years age.63 While results are preliminary, in a controlled trial in children with ADHD and comorbid bipolar disorder, the mood stabilizer divalproex sodium did not interfere with the positive effect of mixed amphetamine salts on ADHD symptoms; conversely, addition of mixed amphetamine salts did not appear to disrupt mood stabilization with divalproex sodium.66 Increasing evidence documents that atypical antipsychotic agents are useful for mood stabilization in this patient population. Currently, the second-generation antipsychotic drugs aripiprazole and risperidone are approved for pediatric bipolar I disorder (ages 10 to 17 years).67 Because of the significant pathology and challenging treatment course posed by such cases, a referral to a child psychiatrist should be considered.

COMORBID ANXIETY DISORDERS Although comorbid, “externalizing,” disruptive behavior disorders (eg, ODD and CD) have long been recognized in children with ADHD, only in the past decade have “internalizing” disorders, such as anxiety and mood disorders, been more widely studied as common comorbidities. Clinical and epidemiologic investigations indicate that anxiety disorders affect roughly one third of pediatric patients with ADHD.17,24,28 In a study by Busch et al,17 patients with ADHD had a significantly higher prevalence of agoraphobia, overanxious disorder, simple phobia, social phobia, and separation anxiety disorder, regardless of treatment setting. In the Great Smoky Mountains study, a longitudinal community study of psychiatric morbidity in children, researchers found that children and adolescents with ADHD were 3.4 times more likely to have an anxiety disorder than normal community controls.18 Biederman et al20 found that when compared with boys, girls tended to have a greater frequency of simple phobia, agoraphobia, and panic disorder. Identifying an anxiety disorder on the basis of clinical interview can be challenging. Because anxiety may rapidly fluctuate during the day or in different situations, symptoms S9

are rarely directly observable during an office visit or at the time of a diagnostic interview. In the absence of a good initial history, any observed anxiety symptoms may often be mistaken for an adverse event of stimulant medication. Symptoms of anxiety may also mimic those of other disorders. The clinical presentation of obsessive-compulsive disorder, for instance, is often similar to that of a learning disorder, because obsessive-compulsive disorder is often marked by repetitive behaviors and poor information processing, and agitation may be mistaken for mania. Importantly, unhappiness secondary to the anxiety may be mistaken for depression. Interviews with children must be undertaken carefully, with sensitivity and empathy, to facilitate disclosure. In addition, parents should be questioned about anxiety symptoms to gain a more accurate picture of patient functioning across 3 key domains: cognition, affect, and behavior. Cognitive symptoms of anxiety include a spectrum of severity, from rumination, vigilant apprehension, to catastrophic thinking. Affective signs of an anxiety disorder may include mild dysphoria, severe apprehension, or suicidality. Behaviorally, anxiety disorders are typically characterized by agitation, rituals, help-seeking, or overdependence. Other information may also be key to reaching a diagnosis. Children with comorbid ADHD and anxiety exhibit greater impairments in certain domains (eg, academic and school performance and psychosocial functioning),24,28 when compared with children with ADHD alone. Longitudinal and cross-sectional investigations of children and adults with ADHD and a comorbid anxiety disorder suggest a pattern of persistent pathology. In the MGH cohort, all of the ADHD probands with comorbid multiple anxiety disorders at 4 years’ follow-up (n ⫽ 19) also continued to meet the diagnostic criteria for ADHD.28 Other data suggest that anxiety disorders and ADHD persist into adulthood.68 In some studies, the presence of a comorbid anxiety disorder does not appear to negatively influence response to pharmacotherapy aimed at core ADHD symptoms; patients with ADHD and a comorbid anxiety disorder appear to respond to stimulant and nonstimulant therapies as well as or better than patients with ADHD alone.24,69,70 However, findings from the Multimodal Treatment Study of ADHD further showed that patients with ADHD and comorbid anxiety responded significantly more to behavioral interventions than did patients with ADHD alone; this response occurred over and above the response to pharmacotherapy aimed at ADHD.24 Although psychostimulant agents do not treat anxiety, they also do not appear to exacerbate it as often as might be expected.69 Management of comorbid anxiety commonly includes off-label use of SSRIs, benzodiazepines, and tricyclic antidepressants. Noradrenergic ␣2-receptor agonists such as clonidine have also been used in these patients. Preliminary trials suggest that atomoxetine, given alone or with an SSRI, is safe and in some cases may be effective for both ADHD and anxiety symptoms.69-71 S10

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COMORBID LEARNING DISABILITIES Learning disabilities are seen significantly more often in children and adolescents with ADHD than in healthy community control subjects, with estimates of prevalence ranging from 11% to 30%.17,20 On the basis of a comparison of parallel cohorts of girls and boys with ADHD from the MGH study, learning disabilities appear to be significantly more common in boys with ADHD (30% vs 10% in boys without ADHD) than in girls with ADHD (12% vs 6% in girls without ADHD).20 Arithmetic and reading disabilities appeared to be equally prevalent in the 2 sexes.20 Not surprisingly, because ADHD and learning disabilities may both influence cognitive performance, academic performance in patients with learning disabilities is likely to be more impaired than in patients with ADHD alone. As with other comorbidities, treatment for ADHD does not treat the learning disability. Therapies that reduce ADHD symptoms, however, may serve as a foundation for treating the learning disability, allowing the patient to sustain attention and obtain more benefits from remedial education. In support of this notion, some evidence in girls with ADHD suggests that psychostimulant therapy may help to improve scores on a range of neuropsychiatric parameters.72 Nevertheless, cognitive testing for patients with ADHD who show serious academic impairments may be difficult to obtain because of school and insurance resistance to costs and reimbursement.

COMORBID PDD/AUTISM PDDs, including autism and autism-like disorders, are often accompanied by serious behavioral and psychiatric disorders. In a case series of 27 children with autism or PDD not otherwise specified, 59% met the DSM-IV criteria for ADHD.22 This is in line with clinical experience, in which core symptoms of ADHD are frequently seen in individuals with autistic spectrum disorders. This same case series further showed that patients with autism and comorbid ADHD experienced more difficulties in daily functioning, on the basis of parent and teacher reports, than did patients with autism alone. Currently the DSM-IV-TR excludes ADHD diagnosis if PDD or autism is present, and consequently most of these patients are never formally diagnosed with the disorder. Although this is an unfortunate situation diagnostically, it remains important to treat ADHD symptoms. Reports from 2 randomized, well-controlled clinical trials indicate that methylphenidate treatment for ADHD symptoms is effective and does not worsen autism-related symptoms.73,74 In a recent review of published pharmacotherapy trials for ADHDlike symptoms in children with PDDs, Hazell75 noted that although numerous trials of other therapies for ADHD-like symptoms—including SSRIs, atypical antipsychotics, ␣2-noradrenergic receptor agonists, and atomoxetine— have been described, the quality of these treatments is variable, and results regarding efficacy or tolerability have been mixed. Additional, higher-quality research is necessary to better gauge the efficacy and safety of pharmacotherapy for ADHD symptoms in patients with PDDs. The Journal of Pediatrics • May 2009

DISCUSSION ADHD is a complex and complicated disorder, with psychiatric comorbidity being the rule rather than the exception in both pediatric primary and psychiatric populations. ADHD usually precedes the emergence of comorbid conditions and, for many patients, persists into adulthood. Treatment of ADHD usually will improve the core symptoms of ADHD but will have only modest, if any, effect on the comorbid disorder. Appropriate concurrent treatment of comorbid disorders is important and must not be neglected. Early detection and treatment may help to prevent worsening of the functional impairments and poor long-term outcomes associated with these disorders.

AUTHOR DISCLOSURES Thomas J. Spencer, MD, has contracted research with Cephalon, Inc., Eli Lilly & Company, GlaxoSmithKline PLC, Janssen Pharmaceuticals, Inc., McNeil Pharmaceutical, Inc., the National Institute of Mental Health, Novartis AG, Pfizer Inc., and Shire Pharmaceuticals, Inc.; has been a speaker for Eli Lilly & Company, GlaxoSmithKline PLC, McNeil Pharmaceutical, Inc., Novartis AG, and Shire Pharmaceuticals, Inc.; and has been on the advisory boards of Cephalon, Inc., Eli Lilly & Company, GlaxoSmithKline PLC, Janssen Pharmaceuticals, Inc., McNeil Pharmaceutical, Inc., Novartis AG, Pfizer Inc., and Shire Pharmaceuticals, Inc.

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13. Joober R, Grizenko N, Sengupta S, Amor LB, Schmitz N, Schwartz G, et al. Dopamine transporter 3’-UTR VNTR genotype and ADHD: a pharmaco-behavioural genetic study with methylphenidate. Neuropsychopharmacology 2007;32:1370-6. 14. Biederman J, Petty CR, Dolan C, Hughes S, Mick E, Monuteaux MC, et al. The long-term longitudinal course of oppositional defiant disorder and conduct disorder in ADHD boys: findings from a controlled 10-year prospective longitudinal follow-up study. Psychol Med 2008;1-10. 15. Biederman J, Faraone S, Milberger S, Guite J, Mick E, Chen L, et al. A prospective 4-year follow-up study of attention-deficit hyperactivity and related disorders. Arch Gen Psychiatry 1996;53:437-46. 16. MTA Study Group. Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder: the Multimodal Treatment Study of children with Attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 1999;56: 1088-96. 17. Busch B, Biederman J, Cohen LG, Sayer JM, Monuteaux MC, Mick E, et al. Correlates of ADHD among children in pediatric and psychiatric clinics. Psychiatr Serv 2002;53:1103-11. 18. Costello EJ, Mustillo S, Erkanli A, Keeler G, Angold A. Prevalence and development of psychiatric disorders in childhood and adolescence. Arch Gen Psychiatry 2003;60:837-44. 19. Newcorn JH, Spencer TJ, Biederman J, Milton DR, Michelson D. Atomoxetine treatment in children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder. J Am Acad Child Adolesc Psychiatry 2005; 44:240-8. 20. Biederman J, Mick E, Faraone SV, Braaten E, Doyle A, Spencer T, et al. Influence of gender on attention deficit hyperactivity disorder in children referred to a psychiatric clinic. Am J Psychiatry 2002;159:36-42. 21. Millberger S, Biederman J, Faraone S, et al. Attention deficit hyperactivity disorder and comorbid disorders: issues of overlapping symptoms. Am J Psychiatry 1995;152:1793-9. 22. Goldstein S, Schwebach AJ. The comorbidity of pervasive developmental disorder and attention deficit hyperactivity disorder: results of a retrospective chart review. J Autism Dev Disord 2004;34:329-39. 23. 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;46:894-921. 24. Jensen PS, Hinshaw SP, Kraemer HC, Lenora N, Newcorn JH, Abikoff HB, et al. ADHD comorbidity findings from the MTA study: comparing comorbid subgroups. J Am Acad Child Adolesc Psychiatry 2001;40:147-58. 25. Biederman J, Wilens T, Mick E, Milberger S, Spencer TJ, Faraone SV. Psychoactive substance use disorders in adults with attention deficit hyperactivity disorder (ADHD): effects of ADHD and psychiatric comorbidity. Am J Psychiatry 1995; 152:1652-8. 26. Katusic SK, Barbaresi WJ, Colligan RC, Weaver AL, Leibson CL, Jacobsen SJ. Psychostimulant treatment and risk for substance abuse among young adults with a history of attention-deficit/hyperactivity disorder: a population-based, birth cohort study. J Child Adolesc Psychopharmacol 2005;15:764-76. 27. Biederman J, Faraone SV, Milberger S, Jetton JG, Chen L, Mick E, et al. Is childhood oppositional defiant disorder a precursor to adolescent conduct disorder? Findings from a four-year follow-up study of children with ADHD. J Am Acad Child Adolesc Psychiatry 1996;35:1193-204. 28. Biederman J, Faraone S, Milberger S, Curtis S, Chen L, Marrs A, et al. Predictors of persistence and remission of ADHD into adolescence: results from a four-year prospective follow-up study. J Am Acad Child Adolesc Psychiatry 1996;35:343-51. 29. Biederman J, Spencer TJ, Newcorn JH, Gao H, Milton DR, Feldman PD, et al. Effect of comorbid symptoms of oppositional defiant disorder on responses to atomoxetine in children with ADHD: a meta-analysis of controlled clinical trial data. Psychopharmacology (Berl) 2007;190:31-41. 30. Harpold T, Biederman J, Gignac M, Hammerness P, Surman C, Potter A, et al. Is oppositional defiant disorder a meaningful diagnosis in adults? Results from a large sample of adults with ADHD. J Nerv Ment Dis 2007;195:601-5. 31. Steiner H, Remsing L. Practice parameter for the assessment and treatment of children and adolescents with oppositional defiant disorder. J Am Acad Child Adolesc Psychiatry 2007;46:126-41. 32. McGee R, Williams S, Silva PA. Factor structure and correlates of ratings of inattention, hyperactivity, and antisocial behavior in a large sample of 9-year-old children from the general population. J Consult Clin Psychol 1985;53:480-90. 33. Steiner H. Practice parameters for the assessment and treatment of children and adolescents with conduct disorder. American Academy of Child and Adolescent Psychiatry. J Am Child Adolesc Psychiatry. 1997;36(Suppl):122S-39S. 34. Biederman J, Mick E, Faraone SV, Burback M. Patterns of remission and symptom decline in conduct disorder: a four-year prospective study of an ADHD sample. J Am Acad Child Adolesc Psychiatry 2001;40:290-8. 35. Connor DF, Glatt SJ, Lopez ID, Jackson D, Melloni RH, Jr. Psychopharmacol-

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ogy and aggression. I: A meta-analysis of stimulant effects on overt/covert aggression-related behaviors in ADHD. J Am Acad Child Adolesc Psychiatry 2002;41:253-61. 36. Sinzig J, Dopfner M, Lehmkuhl G, Uebel H, Schmeck K, Poustka F, et al. Long-acting methylphenidate has an effect on aggressive behavior in children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 2007;17: 421-32. 37. Findling RL. A double-blind pilot study of risperidone in the treatment of conduct disorder. J Am Acad Child Adolesc Psychiatry 2000;4:510. 38. Kronenberger WG, Giauque AL, Lafata DE, Bohnstedt BN, Maxey LE, Dunn DW. Quetiapine addition in methylphenidate treatment-resistant adolescents with comorbid ADHD, conduct/oppositional-defiant disorder, and aggression: a prospective, open-label study. J Child Adolesc Psychopharmacol 2007;17:334-47. 39. Jerrell JM, McIntyre RS. Adverse events in children and adolescents treated with antipsychotic medications. Hum Psychopharmacol 2008;23:283-90. 40. Wonodi I, Reeves G, Carmichael D, Verovsky I, Avila MT, Elliott A, et al. Tardive dyskinesia in children treated with atypical antipsychotic medications. Mov Disord 2007;22:1777-82. 41. Biederman J, Mick E, Wozniak J, Monuteaux MC, Galdo M, Faraone SV. Can a subtype of conduct disorder linked to bipolar disorder be identified? Integration of findings from the Massachusetts General Hospital Pediatric Psychopharmacology Research Program. Biol Psychiatry 2003;53:952-60. 42. Gordon SM, Tulak F, Troncale J. Prevalence and characteristics of adolescents patients with co-occurring ADHD and substance dependence. J Addict Dis 2004; 23:31-40. 43. Biederman J, Wilens TE, Mick E, Faraone SV, Spencer T. Does attention-deficit hyperactivity disorder impact the developmental course of drug and alcohol abuse and dependence? Biol Psychiatry 1998;44:269-73. 44. Kessler RC, Adler L, Barkley R, Biederman J, Conners CK, Demler O, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry 2006;163:716-23. 45. Carroll KM, Rounsaville BJ. History and significance of childhood attention deficit disorder in treatment-seeking cocaine abusers. Compr Psychiatry 1993;34:75-82. 46. Biederman J, Monuteaux MC, Mick E, Wilens TE, Fontanella JA, Poetzl KM, et al. Is cigarette smoking a gateway to alcohol and illicit drug use disorders? A study of youths with and without attention deficit hyperactivity disorder. Biol Psychiatry 2006;59:258-64. 47. Ohlmeier MD, Peters K, Kordon A, Seifert J, Wildt BT, Wiese B, et al. Nicotine and alcohol dependence in patients with comorbid attention-deficit/hyperactivity disorder (ADHD). Alcohol Alcohol 2007;42:539-43. 48. Biederman J, Wilens T, Mick E, Faraone SV, Weber W, Curtis S, et al. Is ADHD a risk factor for psychoactive substance use disorders? Findings from a four-year prospective follow-up study. J Am Acad Child Adolesc Psychiatry 1997;36:21-9. 49. Wilens TE, Biederman J, Mick E, Faraone SV, Spencer T. Attention deficit hyperactivity disorder (ADHD) is associated with early onset substance use disorders. J Nerv Ment Dis 1997;185:475-82. 50. Lambert NM, Hartsough CS. Prospective study of tobacco smoking and substance dependencies among samples of ADHD and non-ADHD participants. J Learn Disabil 1998;31:533-44. 51. Biederman J, Wilens T, Mick E, Spencer T, Faraone SV. Pharmacotherapy of attention-deficit/hyperactivity disorder reduces risk for substance use disorder. Pediatrics 1999;104:e20. 52. Wilens TE, Faraone SV, Biederman J, Gunawardene S. Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics 2003;111:179-85. 53. Biederman J, Petty CR, Wilens TE, Fraire MG, Purcell CA, Mick E, et al. Familial risk analyses of attention deficit hyperactivity disorder and substance use disorders. Am J Psychiatry 2008;165:107-15. 54. Mariani JJ, Levin FR. Treatment strategies for co-occurring ADHD and substance use disorders. Am J Addict 2007;16(Suppl 1):45-54. 55. Lile JA, Stoops WW, Durell TM, Glaser PE, Rush CR. Discriminative-stimulus,

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self-reported, performance, and cardiovascular effects of atomoxetine in methylphenidate-trained humans. Exp Clin Psychopharmacol 2006;14:136-47. 56. Biederman J, Mick E, Faraone SV. Depression in attention deficit hyperactivity disorder (ADHD) children: “true” depression or demoralization? J Affect Disord 1998;47:113-22. 57. Biederman J, Faraone S, Mick E, Moore P, Lelon E. Child Behavior Checklist findings further support comorbidity between ADHD and major depression in a referred sample. J Am Acad Child Adolesc Psychiatry 1996;35:734-42. 58. Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R, Greenbaum MS, et al. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. JAMA 2003;290:1033-41. 59. Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, Heydorn WE. A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. Am J Psychiatry 2004;161:1079-83. 60. March JS, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, et al. The Treatment for Adolescents With Depression Study (TADS): long-term effectiveness and safety outcomes. Arch Gen Psychiatry 2007;64:1132-43. 61. Bangs ME, Emslie GJ, Spencer TJ, Ramsey JL, Carlson C, Bartky EJ, et al. Efficacy and safety of atomoxetine in adolescents with attention-deficit/hyperactivity disorder and major depression. J Child Adolesc Psychopharmacol 2007;17:407-20. 62. Biederman J, Faraone S, Mick E, Wozniak J, Chen L, Ouellette C, et al. Attention-deficit hyperactivity disorder and juvenile mania: an overlooked comorbidity? J Am Acad Child Adolesc Psychiatry 1996;35:997-1008. 63. McClellan J, Kowatch R, Findling RL. Practice parameter for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2007;46:107-25. 64. Biederman J, Mick E, Prince J, Bostic JQ, Wilens TE, Spencer T, et al. Systematic chart review of the pharmacologic treatment of comorbid attention deficit hyperactivity disorder in youth with bipolar disorder. J Child Adolesc Psychopharmacol 1999;9: 247-56. 65. Consoli A, Bouzamondo A, Guile JM, Lechat P, Cohen D. Comorbidity with ADHD decreases response to pharmacotherapy in children and adolescents with acute mania: evidence from a metaanalysis. Can J Psychiatry 2007;52:323-8. 66. Scheffer RE, Kowatch RA, Carmody T, Rush AJ. Randomized, placebo-controlled trial of mixed amphetamine salts for symptoms of comorbid ADHD in pediatric bipolar disorder after mood stabilization with divalproex sodium. Am J Psychiatry 2005;162:58-64. 67. Tramontina S, Zeni CP, Pheula GF, de Souza CK, Rohde LA. Aripiprazole in juvenile bipolar disorder comorbid with attention-deficit/hyperactivity disorder: an open clinical trial. CNS Spectr 2007;12:758-62. 68. Murphy K, Barkley RA. Attention deficit hyperactivity disorder adults: comorbidities and adaptive impairments. Compr Psychiatry 1996;37:393-401. 69. Abikoff H, McGough J, Vitiello B, McCracken J, Davies M, Walkup J, et al. Sequential pharmacotherapy for children with comorbid attention-deficit/hyperactivity and anxiety disorders. J Am Acad Child Adolesc Psychiatry 2005;44:418-27. 70. Geller D, Donnelly C, Lopez F, Rubin R, Newcorn J, Sutton V, et al. Atomoxetine treatment for pediatric patients with attention-deficit/hyperactivity disorder with comorbid anxiety disorder. J Am Acad Child Adolesc Psychiatry 2007;46:1119-27. 71. Kratochvil C. Atomoxetine alone or combined with fluoxetine for treating ADHD with comorbid depressive or anxiety symptoms. J Am Acad Child Adolesc Psychiatry 2005;9:915. 72. Seidman LJ, Biederman J, Valera EM, Monuteaux MC, Doyle AE, Faraone SV. Neuropsychological functioning in girls with attention-deficit/hyperactivity disorder with and without learning disabilities. Neuropsychology 2006;20:166-77. 73. Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Arch Gen Psychiatry 2005;62:1266-74. 74. Santosh PJ, Baird G, Pityaratstian N, Tavare E, Gringras P. Impact of comorbid autism spectrum disorders on stimulant response in children with attention deficit hyperactivity disorder: a retrospective and prospective effectiveness study. Child Care Health Dev 2006;32:575-83. 75. Hazell P. Drug therapy for attention-deficit/hyperactivity disorder-like symptoms in autistic disorder. J Paediatr Child Health 2007;43:19-24.

The Journal of Pediatrics • May 2009

Efficacy and Safety Limitations of Attention Deficit Hyperactivity Disorder Pharmacotherapy in Pediatric Patients SHARON B. WIGAL, PHD

This article reviews the efficacy and safety limitations of the newer, long-acting stimulant and nonstimulant pharmacotherapies for attention deficit hyperactivity disorder (ADHD). The interest in managing ADHD symptoms with novel agents that have increased duration has been spurred by the basic clinical principle of individualized dosing that potentially optimizes care. Included are data from clinical studies involving the long-acting formulations and the experience to date with atomoxetine. The treatment of ADHD in patients with comorbid conditions, as well as a brief discussion of studies with investigational agents is also included. The topic of statistical methods such as “effect size” is reviewed from the perspective of describing the measurement of the magnitude of treatment effects (compared with placebo) and its utility in comparing the relative effectiveness of various medication treatments. Lastly, current controversial issues surrounding the safety of medications used to treat patients with ADHD symptoms are described. Supportive psychoeducational interventions and behavioral management are beyond the scope of this article. (J Pediatr 2009;154:S13-S21)

timulant medications have been used to treat the symptoms of attention deficit hyperactivity disorder (ADHD) for more than 70 years.1 Although the efficacy of these agents is well established and their safety profiles are generally regarded as favorable, their use in some patients may be limited because of partial or no response, intolerable adverse effects, medical contraindications, potential for abuse, and common ADHD-associated comorbidities. Before 2000, immediate-release (IR), short-acting stimulants and first-generation, extended-release (ER), intermediate-acting stimulants were the most commonly used pharmacologic treatments for ADHD.2,3 Although most patients responded to these medications,4 the introduction of new, longer-acting stimulants and nonstimulants transformed the treatment of ADHD. The new formulations provide convenience, flexibility, and simplicity of dosing3 and offer a safety profile similar to that of the short-acting preparations with a putative lower risk of abuse.5 This article reviews the limitations of current ADHD therapy and presents data on the newer, long-acting stimulant and nonstimulant treatments for ADHD. It also highlights the needs to be addressed in the development of agents to improve the treatment of ADHD and its common comorbid conditions.

S

EFFICACY OF ADHD TREATMENTS Pharmacologic options for treating ADHD continue to grow with the inclusion of several new products that use similar or identical core compounds delivered by different systems.6 Treatment decisions are influenced by a variety of factors, including duration of therapeutic activity, specific risks, desired efficacy, and cost. The review that follows is nonexhaustive and serves to highlight some of these treatment topics first for the stimulants then for the growing literature on nonstimulants as conceptualized in Figure 1.

Stimulants Stimulants are the most well-established pharmacologic agents for the treatment of patients with ADHD. They are the most widely prescribed class of medications for ADHD and are associated with an excellent response. The 2 most commonly used ADHD Beh CC ER FDA IR IQ MedMgt

Attention deficit hyperactivity disorder Intense behavioral treatment Community care Extended release Food and Drug Administration Immediate release Intelligence quotient Medical management

MPH MTA NNT OROS SKAMP-D SNAP-IV

Methylphenidate Multimodal Treatment Study of Children with ADHD Number needed to treat Osmotic-release oral system Swanson, Kotkin, Agler, M-Flynn, and Pelham rating scale for Deportment Swanson, Nolan, and Pelham, version 4

From the University of California, Irvine, CA. Please see the Author Disclosure section at the end of this article. Reprint requests: Sharon B. Wigal, PhD, University of California, Irvine, 19722 MacArthur Blvd, Irvine, CA 92162. E-mail: sbwigal@uci. edu. 0022-3476/$ - see front matter Copyright © 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.01.017

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ments and whether the new intervention is at least not inferior to the comparator (the existing treatment). Less commonly seen are “superiority designs” that show best effect and may require significantly more enrolled subjects. Time of onset of pharmacodynamic effects typically is determined with either “noninferiority” or “superiority” designs in laboratory school studies. Yet in reality, the initial onset of a patient’s effects is dependent on parent and practitioner reports.

Figure 1. Treatment for patients with ADHD.

categories of psychostimulants are amphetamines and methylphenidate (MPH) (Table I).7-13 Approximately 70% of patients respond to the introduction of a first stimulant agent, and the response rate increases to around 90% in nonresponders who switch to a second stimulant.14 TIME-COURSE ACTIVITIES. A number of long-acting ADHD agents have been developed to maximize ADHD symptom control consistently throughout the day.5 Temporal differences in the activity of long-acting MPH formulations allow for tailoring to the patient’s individual needs.5,6,15 For instance, in a comparison of 2 MPH formulations, Metadate CD (a 30% IR/70% ER mixture) delivered 30% of the total dose as a bolus that peaked at about 1.5 hours after administration, and 70% peaked at about 4.5 hours after administration. In contrast, OROS-MPH (Concerta), an osmoticrelease oral formulation with a smaller initial bolus (22%), peaked at about 1 hour after administration, with 78% of the total dose peaking 5 to 9 hours after administration. Not surprisingly, a comparison of changes in ADHD symptoms after administration found that MPH CD produced a greater effect early, and MPH OROS had a greater effect at 12 hours after administration (Figure 2).5,15 These findings highlight the fact that relatively small differences in the pattern of release and the corresponding differences in plasma concentrations of MPH produce differences in behavioral effects.15 Although this is known empirically from research studies to minimize patient discomfort and cost, clinicians do not usually use such measures for medication management decisions. DOSE-RESPONSE RATES. A number of clinical trials have shown that stimulants are effective agents for managing ADHD.16 Some IR stimulants have been reformulated to allow for once-a-day dosing. Clinicians are now faced with an increased armamentarium of therapeutic options to treat their patients with ADHD, but few studies compare them to identify differential responses that would assist in clinical treatment decisions (Table II).17-23 Typically studies use “noninferiority designs” to show equivalence between treatS14

Wigal

PREDICTORS OF RESPONSE AND TREATING COMORBIDITIES. Although ADHD is a heritable disease with a large variability in individual treatment response, no biologic measure has been developed to determine advantages of one specific treatment over another; in fact, medical management of the disorder, as with other medical conditions, typically is determined through trial and error. When Owens et al24 examined factors that predict or moderate treatment outcomes for ADHD, they found that parental depressive symptoms, estimates of intellectual functioning of the child, and initial ADHD severity of the child modified treatment responses to medication. Lower rates of “excellent” response were reported when the parent had a relatively high level of depressive symptoms, the patient had an intelligence quotient (IQ) ⬍99, or the patient’s initial ADHD symptoms were severe.24 Data from another study showed a small but significant predictive effect of IQ and anxiety on treatment outcomes in children with ADHD. This study supports the idea that children with comorbid anxiety and a higher IQ respond better to MPH or MPH combined with multimodal behavior.25 The boundary between diagnoses of bipolar disorder and ADHD in children appears indistinct in some affected children.26 For example, the symptoms of irritability and aggressiveness can indicate either bipolar disorder or ADHD. For children with bipolar I or II disorder, mood stabilizers, such as sodium divalproex, have been effective in treating acute manic and mixed states. Treatment of ADHD with stimulants in these patients may possibly induce cycling or exacerbate manic symptoms, such as insomnia or irritability.27 Pretreatment and control of mania followed by treatment of ADHD with stimulants has been shown to effectively control ADHD without leading to increased mania.27 Treating ADHD symptoms in patients with pervasive developmental disorder or autism is a challenge. These individuals experience only modest improvement in ADHD symptoms with stimulant treatment, and stimulants can worsen stereotypical behaviors.28 Many of these children are not candidates for stimulant therapy, because of comorbid seizures, which is a relative contraindication to the use of stimulants. Although experience with ␣2-agonists for treating ADHD symptoms in patients with comorbid pervasive developmental disorder or autism is limited, available data suggest some potential benefit (see the article by Scahill in this supplement).28 ADHD symptoms affect up to 50% of patients with Tourette’s syndrome and are often as disabling as tic symptoms in these patients.29 Traditionally, tics have been erroThe Journal of Pediatrics • May 2009

Table I. Currently approved longer-acting medications for ADHD Generic

Brand

Delivery

Year approved

Duration of action

Pivotal clinical trials

Nonstimulant Atomoxetine

Strattera

Capsule

2002

EM half-life 5 hours PM half-life 24 hours

Michelson et al9

Stimulants Amphetamine-based stimulants

Adderall XR Double-pulsed delivery capsules

2001

McCracken et al11

Vyvanse

Capsule

2007

Mean elimination half-life 9-11 hours and 11-14 hours depending on age and weight Tmax of dextroamphetamine 3.5 hours

Coated/osmotic tablet

2000

Daytrana Metadate CD

Transdermal system IR (30%)/ER (70%) capsules

2006 2001

Ritalin LA

Bimodal-release capsule with SODAS Extended-release capsules

2002

Lisdexamfetamine

Methylphenidate-based stimulants OROS Concerta methylphenidate

Methylphenidate

Dexmethylphenidate Focalin XR

2005

Initial max concentration 1 hour with gradual increase to max over 5-9 hours Median early peak 1.5 hours; median second peak 4.5 hours Tmax 1-4 hours and 5-8 hours Tmax 1.5 hours and 6.5 hours

Biederman et al10

Wolraich et al7

McGough et al12 Greenhill et al13

Greenhill et al8

EM, Extensive metabolizers; PM, poor metabolizers; SODAS, spheroidal oral drug absorption system; Tmax, time to maximum concentration; CD, ER, LA, XR, extended release.

neously viewed as a contraindication to the use of stimulants, although such treatment may provide benefits for both disorders.30 Antidepressants and ␣2-agonists have also been used in this population, for 30 years, with varying degrees of success.29 Among patients with ADHD there is a high comorbidity of substance abuse disorders; the reason for this may be related to impaired brain dopamine activity.31 It is hypothesized that long-term drug exposure exacerbates ADHD symptoms.32 Recent research has failed to show an increased risk of substance abuse in adulthood after stimulant treatment in childhood33 despite earlier publications declaring protective benefits of childhood stimulant therapy.34,35 Although, theoretically, newer stimulant pharmacotherapy may assist these types of patients by providing a different mechanism of release, no evidence has been published to substantiate this idea in practice. Until the relationship between stimulant treatment and substance abuse is better understood, conservative clinicians will be proponents of nonstimulant medications for patients who are known or suspected substance abusers or members of households with such exposures.

Nonstimulant Therapy Even though stimulants have been the agents of choice for many years, nonstimulants (both unapproved and approved compounds), such as tricyclic antidepressants, bupro-

pion, modafinil, and atomoxetine, have also shown effectiveness in treating patients with ADHD. APPROVED NONSTIMULANT THERAPY. Atomoxetine, a selective norepinephrine reuptake inhibitor, is currently the only nonstimulant medication approved for ADHD in the United States. Atomoxetine acts on the presynaptic norepinephrine transporter in the prefrontal cortex to increase concentrations of norepinephrine and dopamine.4,36 It also affects norepinephrine and dopamine concentrations in other regions, such as the striatum and nucleus accumbens, which may explain its low potential for abuse.4,36 Atomoxetine has been shown to be effective in patients with and without comorbidities, such as depression, Tourette’s syndrome, and oppositional defiant disorder.29,37,38 Atomoxetine does have a demonstrable therapeutic effect on the core symptoms of ADHD with no effect on comorbidities. Although atomoxetine is often used as a second choice after a poor response to stimulant therapy, it may be the only viable option for the 10% to 30% of patients with ADHD who either do not respond to or must avoid stimulant therapy.4 However, nonstimulants, including atomoxetine, seem to have much smaller clinical effects.16 Results of a randomized, double-blind study in 203 children with ADHD in a laboratory school setting showed that

Efficacy and Safety Limitations of Attention Deficit Hyperactivity Disorder Pharmacotherapy in Pediatric Patients

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Figure 2. SKAMP deportment, SKAMP attention, and PERMP scores over time after treatment with MPH CD, MPH OROS, or placebo. ⴱTimes at which MPH CD was significantly better than MPH OROS. †Times at which MPH OROS was significantly better than MPH CD and placebo. ‡Times at which placebo was significantly better than both MPH CD and MPH OROS. Adapted with permission from Weisler.5

mixed amphetamine salts extended-release achieved significantly greater improvement in Swanson, Kotkin, Agler, MFlynn, and Pelham rating scale for deportment (SKAMP-D) scores than did atomoxetine (⫺0.56 vs ⫺0.13; P ⬍ .0001).39 The mean SKAMP-D scores were consistent for the stimulant group over all 3 weeks of the study but were inconsistent for atomoxetine (Figure 3).39 This may indicate that the atomoxetine group had not stabilized on the medication within the 3-week treatment phase. Some differences between atomoxetine and longer-acting stimulants can be explained in terms of pharmacokinetics. For example, once-daily dosing of atomoxetine at bedtime may be problematic, because its effect wears off the next day, and early morning dosing may leave nighttime hours with minimal medication coverage. This study showed that there was no clinical effect with atomoxetine at 9 hours after administration of the dose, which indicates that with nighttime dosing there is no effect during the school day, and with morning dosing there may be no effect at night.39 Twice-daily dosing of atomoxetine, with the same total dose, may help to minimize this wear-off effect and may curtail side effects S16

Wigal

(including increased somnolence and gastrointestinal symptoms), although the product label does not describe this pattern of dosing.40 The half-life of atomoxetine is 3 to 4 hours, but this clinical effect takes up to 1 to 2 months to stabilize,4,39,41 a delay that could leave the patient insufficiently treated for several weeks. Because it is a nonstimulant, atomoxetine is not categorized as a schedule II substance, and it does not have the class-based black box and medication guide warnings that are included in the package inserts of stimulants. Atomoxetine does not have antidepressant effects, but because it is in a similar drug category as antidepressants, it has the same boxed warning with regard to suicide risk.42 Atomoxetine has warnings and precautions for the risks of seizure, cardiovascular and psychiatric events, and growth retardation, although the risks associated with these events appear to be less than those with stimulants.43 The risk for seizure is similar to the risk with stimulants; however, it may not be different from the risk in untreated patients with ADHD.44 The atomoxetine package insert also includes warnings and precautions for hepatotoxicity on the basis of postmarketing surveillance.43 Similar to other norepinephrine reuptake inhibitors such as desipramine, atomoxetine might be expected to have some effect on depressive symptoms in adolescents with ADHD and depression. In one study of children and adolescents with ADHD, atomoxetine was associated with a significant decrease in scores on the Children’s Depression Rating Scale– Revised,45 and in another study in patients with ADHD and major depressive disorder, scores were not significantly different between atomoxetine and placebo. However, both groups achieved around a 25% decrease from baseline in the signs and symptoms of depression.37 The statistically significant improvement in ADHD symptoms with atomoxetine compared with placebo was comparable to that seen in patients without comorbidities.37 Why atomoxetine does not seem to provide the same benefits for depression as other norepinephrine reuptake inhibitors is unclear. UNAPPROVED NONSTIMULANT THERAPY. Bupropion, modafinil, guanfacine, and clonidine are nonstimulants that have shown positive results in patients with ADHD but have not been approved by the Food and Drug Administration (FDA). Bupropion is moderately effective in treating patients with ADHD, with an effect size (ES) comparable with atomoxetine (mean ES from parent/teacher ADHD rating scale ⫽ 0.7).19 However, evidence in clinical trials has not been sufficient to support its approval. Treating depression in children, regardless of ADHD diagnosis, is difficult. Medical treatment is limited to fluoxetine, a selective serotonin reuptake inhibitor whose use in children is controversial because of its association with suicide. One small (n ⫽ 24), open-label study with bupropion reported response rates of 58% among patients with both ADHD and depression compared with 29% for patients with depression alone.19 Modafinil is a structurally unique agent that activates ascending arousal and attention systems to increase frontal cortical activity.46 The The Journal of Pediatrics • May 2009

Table II. Comparison of effect size difference in nonstimulant agents used to treat ADHD* Agent Bupropion

Modafinil Guanfacine IR

Clonidine IR

Atomoxetine SSRIs

Atypical antipsychotics Antidepressants

Measure

Effect size

Comment

Global improvement in ADHD, depression, and functional impairment ADHD-RS CGI-I ADHD-RS CGI-I

0.7

Efficacy in question

Daviss et al19

Compared with other nonstimulants 0.69 0.65

Not FDA-approved (skin related AEs) Possible use with comorbid tic disorder Possible second-tier treatment for symptoms Favorable profile For OCD or depression

Biederman et al20

Meta-analysis with weighted variables regarding ADHD symptoms Stroop Task Meta-analysis including Hamilton Depression Rating Scale, Beck Depression Inventory, clinician reports, and selfreported global outcome measures Meta-analysis including relapse rate Meta-analysis including incidence and genetic factors

0.58

0.62 0.5

0.25 0.39

As used for schizophrenia As used for generalized anxiety disorders

Reference

Scahill et al17

Connor et al18

Faraone16 Geddes et al23

Pitschel-Walz et al22 Gale et al21

*Different studies may reflect differences in subject selection and assessment method, because these were not direct comparator trials.

ES of modafinil is comparable with that of other nonstimulant medications,20 but it was not approved by the FDA. New developments in neuroscience have led to the identification of ␣2-agonists as possible treatments for ADHD (see the articles by Arnsten and Scahill in this supplement). Currently there is limited evidence for the effectiveness of guanfacine IR, and that for clonidine IR is mostly anecdotal. Both agents are used primarily for sleep or behavior problems rather than core ADHD symptoms. The ES for both agents is equal to or less than that of atomoxetine, 0.65 for guanfacine and 0.58 for clonidine.17,18 Neither drug is first-line therapy for ADHD, and both share limitations on the basis of short half-lives (typical dosing is 2 or 3 times daily). Guanfacine is a more selective ␣2-adrenoceptor agonist and causes less sedation and hypertension than does clonidine.47

Statistical Challenges to Assessing Treatment Effects The efficacy of medication treatment, with stimulants in particular, in children with ADHD has been described as “magical” by some parents and teachers, yet interpreting how the measured effects in research studies translate into clinical responses is difficult to understand at best.48 Two measures to improve such understanding are ES and a number-to-treat (NNT) analysis; both are discussed with examples from the scientific literature to illustrate how symptom improvements can be described. ES CALCULATION. ES is a family of indexes that measures the magnitude of a treatment effect and allows the calculation

of difference in improvement between drug and placebo.16 ES is similar to a z score, because it tells how many standard deviation units separate the 2 means. However, unlike significance tests, ES is independent of sample size. For the ES calculation (Cohen’s d), the difference between means is considered with respect to the standard deviation and interpreted against a general scale (ie, 0.2 ⫽ small effect, 0.5 ⫽ medium effect, and 0.8 ⫽ large effect). ES was used to compare a number of established treatments with data from the Multimodal Treatment Study of Children with ADHD (MTA). Enrollees were randomly assigned to 1 of 4 treatment arms: intense medical management (MedMgt), intense behavioral treatment (Beh), a combination of MedMgt plus Beh (Comb), or routine community care (CC). Symptom scores were based on the Swanson, Nolan, and Pelham, version 4 parent and teacher (SNAPIVPT) rating scale.49 The overall SNAP-IVPT score was calculated by taking the mean scores for items in the 3 subsets (inattention, hyperactivity/impulsivity, and oppositional defiant disorder) and further averaging those for both parent and teacher scores.49,50 The baseline score for the group of patients receiving MedMgt or Comb treatment was approximately 1.8.51 A score of ⱕ1 did not qualify as ADHD; a 0.8 change in score represents a typical symptom reduction of about 40%.49,50 The end-of-treatment status was summarized by averaging the parent and teacher ratings of ADHD and oppositional defiant disorder symptoms on the SNAP-IV scale; low symptom severity was the clinical cutoff for successful treatment.

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Figure 3. Is atomoxetine as effective as stimulants? Adapted with permission from Wigal, et al.39

Three orthogonal comparisons of the 4 treatment groups showed that summary of SNAP-IV ratings across sources and domains increased the precision of measurement by 30%.49 At the end of 14 months of treatment,51 all groups had sizable improvement with significant differences among groups in rate of improvement. Comb and MedMgt improved ADHD symptoms significantly more than Beh or CC. Comb and MedMgt did not differ significantly on direct comparisons, but in several instances Comb was superior to Beh or CC, but Beh or CC was not. The MTA intensive medication strategy (Comb/MedMgt) was superior to CC despite the fact that about 66% of CC-treated participants received similar medication during the study.51 Analysis of the ES for the treatments, on the basis of mean SNAP-IVPT score, showed a significant difference between the MedMgt and the Comb treatment groups.49 The effect size of Comb/MedMgt compared with Beh or CC was 0.59. The comparison between the medical management and the combination treatment groups was 0.26, with the advantage given to the combination treatment.49,52 On the basis of the ES analyses, the combined behavioral therapy provided some additional benefit to the use of stimulant therapy alone.49 After the treatment phase, the benefits of MedMgt appeared to deteriorate, so that by 24 months there was no apparent advantage to receiving medication.48,51 Possible explanations for this observation include an age-related decline S18

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in ADHD symptoms, changes in medication management intensity, or medication commencement or termination.48 Although patients were allowed to change their therapy in the follow-up phase by either switching to MedMgt (for Beh and CC groups) or discontinuing MedMgt (for MedMgt and Comb groups), there was a significant difference in medication use among groups.48 Once a different perspective in evaluating the effects of treatment is taken, the advantages and limitations of stimulant therapy may become clearer. For instance, in the MTA study, assessment of response rates according to treatment phase revealed significant differences between the MedMgt and Comb groups that were not evident in the analysis of overall mean symptom reduction. In the assessment of patients who had “normalized” (ie, their SNAP-IVPT scores dropped to ⱕ1), the difference between treatment groups was statistically significant: 68% of patients normalized in the Comb group, 56% in the MedMgt group, 34% in the Beh group, and 25% in the CC group.50 Thus greater numbers of patients given Beh in addition to medication showed improvements in symptoms. A meta-analysis of more than 50 ADHD studies found the mean ES for nonstimulants, IR stimulants, and longacting stimulants to be 0.62, 0.91, and 0.95, respectively. This suggests that nonstimulants were not as effective as stimulants in ADHD (Figure 4).16,53 The first controlled trials with guanfacine ER in children and adolescents with ADHD have The Journal of Pediatrics • May 2009

includes an evaluation of any potential cardiovascular and psychiatric problems.

Figure 4. Meta-analysis of efficacy of ADHD medications. Reprinted with permission from Biederman and Faraone.53

recently been published,54 with results suggesting that tolerability with the ER formulation may be superior to that with the IR formulation, and that the ES may approach that of stimulants. Treatment ES for ADHD-RS-IV total scores were 0.58, 1.19, and 1.34 for doses of 0.05 to 0.08 mg/kg, 0.09 to 0.12 mg/kg, and 0.13 to 0.17 mg/kg, respectively.54 The difference in ES among the nonstimulant agents used to treat ADHD is indicated in Table II. NNT ANALYSIS. Using an NNT analysis (determining how many patients with ADHD need to be treated to have 1 patient show a benefit), long-acting stimulants were shown to be effective agents for treating ADHD. Data from the mixed amphetamine salts extended-release trial showed a treatment response of about 70% with 30 mg/d, and a placebo response rate of 30%.55 Taking the reciprocal of this difference (1 divided by 0.7 minus 0.3) gives an NNT of 2.5. Typical NNTs for approved psychiatric and behavioral drugs are closer to 4 or 5 for stimulant classes,16 so achieving 1 response directly attributable to the intervention for every 2.5 patients treated is an indication of good efficacy. Such an analysis extended to atomoxetine and nonstimulant treatment may be helpful in differentiating effects.

Safety of Treatments for ADHD FDA GUIDELINES. Although stimulant drugs approved for the treatment of ADHD have shown remarkable benefits for many patients, they also present significant, potentially serious but comparatively rare safety risks. In February 2007 the FDA directed manufacturers of all stimulant drugs approved for the treatment of ADHD to develop medication guides to be given to patients, families, and caregivers when the medicine is dispensed. These are intended as risk alerts for possible cardiovascular and adverse psychiatric symptoms associated with the medicines. The guides also offer precautions to prevent these adverse events. Furthermore, the FDA recommended that patients who take ADHD medication should meet with their physician to develop a treatment plan that

CARDIOVASCULAR ADVERSE EVENTS. An FDA review (available at http://www.fda.gov/bbs/topics/NEWS/2007/NEW01568. html) found serious cardiovascular adverse events in patients taking standard doses of ADHD medications, sudden death in patients with underlying serious heart problems, and stroke and heart attack in adults with certain risk factors. Primary concerns include increases in blood pressure and heart rate that accompany stimulant use. These concerns are especially important in patients with underlying heart disease. Because results of clinical trials are typically reported as group means and standard errors, it is difficult to assess the incidence of cardiovascular events on a case-by-case basis across specific treatments. Recent statements issued by the American Academy of Pediatrics (AAP) and American Heart Association (AHA) recommend obtaining patient and family health histories and focusing on cardiovascular disease risk factors when examining and evaluating patients before starting treatment for ADHD. An electrocardiogram obtained at the discretion of the physician is reasonable but not mandatory. The inability to obtain an electrocardiogram should not preclude treatment.56 PSYCHIATRIC ADVERSE EVENTS. The FDA review of ADHD pharmacotherapeutics revealed a slightly increased risk (⬃1 in 1000) in drug-related psychiatric adverse events, such as delusions, hallucinations, paranoia, and mania, even in patients who did not have previous psychiatric problems. CONTRAINDICATIONS. The package insert uses 2 forms of language for stimulant contraindications—1 for amphetamine and 1 for MPH. Nevertheless, the contraindications are the same for the entire stimulant class and may indicate more about the maintenance of consistent information contained in package labeling than about our current knowledge of these products. COMMON ADVERSE EVENTS LEADING TO DRUG DISCONTINSeveral adverse events have been associated with drug discontinuation, mostly as a result of inappropriate dosing, schedule and amount. Although insomnia is considered to be a symptom of ADHD, it is also one of the most common adverse events reported with stimulants (there is a 2-fold increase in prevalence).57 Decreased appetite and weight loss are also common adverse events associated with stimulants that may lead to drug termination. Many children discontinue stimulants because of the emotional lability induced by these drugs. De novo tics in children enrolled in various controlled stimulant trials also has led to treatment cessation.58 UATION.

OTHER SAFETY ISSUES. Growth retardation has been observed in many studies where stimulants are used to treat patients with ADHD.59,60 The MTA study showed that

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stimulant-treated patients grew approximately 2 cm less in height and gained 2.7 kg less in weight over the 3 years of follow-up compared with nonmedicated patients.59 Children typically regain the initial reduction in growth on the basis of normalization of growth rates and long-term indirect evidence, although the literature is divided on this topic.59 Even though drug holidays may reduce growth retardation, it is not clear how effective this planned nonusage is, what parameters (ie, length of holiday period with duration of treatment and specific agent) need to guide such holidays, and how it interferes with the benefits of treatment.61 EFFECTS ON SPECIAL POPULATIONS. Although the incidence of ADHD is higher in children with epilepsy, physicians have been reluctant to treat these children with stimulants for fear of inducing new-onset seizures and causing interactions with antiepileptic drugs; in addition, the presence of seizures is a relative contraindication to the use of stimulant therapy. However, chart-review studies and open-label and controlled trials have shown that stimulant treatment does not appear to exacerbate seizures or have an adverse effect on serum levels of antiepileptic drugs.62 The incidence of ADHD also appears to be higher for children with other medical conditions (eg, congenital heart defects),63 and concerns for treatment in this challenging population still need to be addressed.

DISCUSSION There has been increased approval and availability of drugs and delivery systems to treat ADHD since 2000. Until recently, the efficacy17-23 of drugs to treat ADHD has received more attention than their safety. Changes in FDA guidelines (2007) aimed at greater patient protection—to improve the risk/benefit ratio and monitor for adverse drug reactions— has placed more focus on particular agents, their classification, and determination of clinical effects. It is generally believed that the medications currently available pose little in the way of significant risk of harm.64 Yet, some patients cannot obtain benefit from currently available treatments because of partial response, nonresponse, or confounding factors, such as comorbid illnesses. Treatment that is effective, safe, and well-tolerated is needed especially for patients with concomitant disorders such as Tourette’s syndrome, pervasive developmental disorder, autism, anxiety disorders, major depressive disorder, bipolar disorder, and substance use disorder. Other patients may be precluded from obtaining the benefits of stimulants or atomoxetine because of contraindications, intolerance, history of misuse or abuse of stimulant medications, or other underlying medical conditions. More research is needed on the efficacy and safety of new agents for ADHD and on the role of combination therapy. New therapies for ADHD symptoms that are only partly responsive to one agent are also needed. Additionally, patients with incomplete control of specific symptoms may benefit from complementary treatment effects (reduced distractibility and enhanced focus) from a second agent. The issue of treatment of the side effects of ADHD medications, S20

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such as insomnia and sedation, while maintaining ADHD symptom control is one that practitioners must increasingly face. Rational polypharmacy has become pervasive in the treatment of other neuropsychiatric disorders such as bipolar disorder, schizophrenia, and major depressive disorder, and it is questionable whether a similar polypharmacy for the treatment of ADHD would be harmful or helpful as more practitioners move in this direction. A higher priority on such research pursuing novel pharmacotherapies may assist in answering this question.

AUTHOR DISCLOSURE Sharon B. Wigal, PhD, has received consulting fees from Abbott Laboratories, McNeil Pharmaceutical, Inc., NIMH, and Shire Pharmaceuticals, Inc.; has received fees for non-CME services from McNeil Pharmaceutical, Inc., Novartis AG, Shire Pharmaceuticals, Inc., and UCB Pharma, Inc.; and has contracted research with Cephalon, Inc., NIMH, Psychogenics, Eli Lilly & Company, McNeil Pharmaceutical, Inc., Addrenex, and Shire Pharmaceuticals, Inc. The author would like to thank Jean Gehricke, PhD, who provided comments on an earlier version of the manuscript.

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A meta-analytic review of the literature. Pediatrics 2003;111:179-85. 35. Wilson JJ. ADHD and substance use disorders: developmental aspects and the impact of stimulant treatment. Am J Addict 2007;16(suppl 1):5-11. 36. Banaschewski T, Roessner V, Dittmann RW, Santosh PJ, Rothenberger A. Non-stimulant medications in the treatment of ADHD. Eur Child Adolesc Psychiatry 2004;13(suppl 1):I102-I116. 37. Bangs ME, Emslie GJ, Spencer TJ, Ramsey JL, Carlson C, Bartky EJ, et al. Efficacy and safety of atomoxetine in adolescents with attention-deficit/hyperactivity disorder and major depression. J Child Adolesc Psychopharmacol 2007;17:407-20. 38. Biederman J, Spencer TJ, Newcorn JH, Gao H, Milton DR, Feldman PD, et al. Effect of comorbid symptoms of oppositional defiant disorder on responses to atomoxetine in children with ADHD: a meta-analysis of controlled clinical trial data. Psychopharmacology (Berl) 2007;190:31-41. 39. 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;9:275-89. 40. Greenhill LL, Newcorn JH, Gao H, Feldman PD. Effect of two different methods

of initiating atomoxetine on the adverse event profile of atomoxetine. J Am Acad Child Adolesc Psychiatry 2007;46:566-72. 41. Wernicke JF, Kratochvil CJ. Safety profile of atomoxetine in the treatment of children and adolescents with ADHD. J Clin Psychiatry 2002;63(suppl 12):50-5. 42. Eli Lilly and Company. Strattera prescribing information. Updated October 30, 2007. 43. Kratochvil CJ, Wilens TE, Greenhill LL, Gao H, Baker KD, Feldman PD, et al. Effects of long-term atomoxetine treatment for young children with attention-deficit/ hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2006;45:919-27. 44. Wernicke JF, Holdridge KC, Jin L, Edison T, Zhang S, Bangs ME, et al. Seizure risk in patients with attention-deficit-hyperactivity disorder treated with atomoxetine. Dev Med Child Neurol 2007;49:498-502. 45. Michelson D, Faries D, Wernicke J, Kelsey D, Kendrick K, Sallee FR, et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics 2001;108:E83. 46. Wigal SB, Biederman J, Swanson JM, Yang R, Greenhill LL. Efficacy and safety of modafinil film-coated tablets in children and adolescents with or without prior stimulant treatment for attention-deficit/hyperactivity disorder: pooled analysis of 3 randomized, double-blind, placebo-controlled studies. Prim Care Companion J Clin Psychiatry 2006;8:352-60. 47. Horrigan JP. Guanfacine for treatment of attention-deficit hyperactivity disorder in boys. J Child Adolesc Psychiatry 1995;5:215-23. 48. Jensen PS, Arnold LE, Swanson JM, Vitiello B, Abikoff HB, Greenhill LL, et al. 3-year follow-up of the NIMH MTA study. J Am Acad Child Adolesc Psychiatry 2007;46:989-1002. 49. 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;40:168-79. 50. Jensen PS, Garcia JA, Glied S, Crowe M, Foster M, Schlander M, et al. Cost-effectiveness of ADHD treatments: findings from the multimodal treatment study of children with ADHD. Am J Psychiatry 2005;162:1628-36. 51. MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry 1999;56:1073-86. 52. Cohen DJ, Young JG, Nathanson JA, Shaywitz BA. Clonidine in Tourette’s syndrome. Lancet 1979;2:551-3. 53. Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet 2005; 366:237-48. 54. 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:e73-e84. 55. Spencer TJ, Wilens TE, Biederman J, Weisler RH, Read SC, Pratt R. Efficacy and safety of mixed amphetamine salts extended release (Adderall XR) in the management of attentiondeficit/hyperactivity disorder in adolescent patients: a 4-week, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 2006;28:266-79. 56. Perrin JM, Friedman RA, Knilans TK for the Black Box Working Group and the Section on Cardiology and Cardiac Surgery. Cardiovascular monitoring and stimulant drugs for attention-deficit/hyperactivity disorder. Pediatrics 2008;122:451-3. 57. Stein MA. Unraveling sleep problems in treated and untreated children with ADHD. J Child Adolesc Psychopharmacol 1999;9:157-68. 58. Findling RL, Bukstein OG, Melmed RD, Lopez FA, Sallee FR, Arnold LE, et al. 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An expert opinion on methylphenidate treatment for attention deficit hyperactivity disorder in pediatric patients with epilepsy. Expert Opin Investig Drugs 2008;17:77-84. 63. Gothelf D, Presburger G, Levy D, Nahmani A, Burg M, Berant M, et al. Genetic, developmental, and physical factors associated with attention deficit hyperactivity disorder in patients with velocardiofacial syndrome. Am J Med Genet B Neuropsychiatr Genet 2004;126B:116-21. 64. Graham J, Coghill D. Adverse effects of pharmacotherapies for attention-deficit hyperactivity disorder: epidemiology, prevention and management. CNS Drugs 2008;22:213-37.

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The Emerging Neurobiology of Attention Deficit Hyperactivity Disorder: The Key Role of the Prefrontal Association Cortex AMY F.T. ARNSTEN, PHD

Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention, impulsivity, and locomotor hyperactivity. Recent advances in neurobiology, imaging, and genetics have led to a greater understanding of the etiology and treatment of ADHD. Studies have found that ADHD is associated with weaker function and structure of prefrontal cortex (PFC) circuits, especially in the right hemisphere. The prefrontal association cortex plays a crucial role in regulating attention, behavior, and emotion, with the right hemisphere specialized for behavioral inhibition. The PFC is highly dependent on the correct neurochemical environment for proper function: noradrenergic stimulation of postsynaptic alpha-2A adrenoceptors and dopaminergic stimulation of D1 receptors are necessary for optimal prefrontal function. ADHD is associated with genetic changes that weaken catecholamine signaling and, in some patients, with slowed PFC maturation. Effective pharmacologic treatments for ADHD all enhance catecholamine signaling in the PFC and strengthen its regulation of attention and behavior. Recent animal studies show that therapeutic doses of stimulant medications preferentially increase norepinephrine and, to a lesser extent, dopamine, in the PFC. These doses reduce locomotor activity and improve PFC regulation of attention and behavior through enhanced catecholamine stimulation of alpha-2A and D1 receptors. These findings in animals are consistent with improved PFC function in normal human subjects and, more prominently, in patients with ADHD. Thus, a highly cohesive story is emerging regarding the etiology and treatment of ADHD. (J Pediatr 2009;154:S22-S31)

ttention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention, poor impulse control, and increased motor activity.1 In the last 20 years, advances in the fields of neuroscience and genetics have provided new insights into this common disorder. We have learned how genetic alterations can affect neural circuits and lead to the symptoms of ADHD, and how correcting these alterations can lead to rational treatments. Much of the research on ADHD has pointed to weaknesses in the prefrontal cortex (PFC), the most highly evolved of the association cortices. The PFC regulates attention and behavior through its widespread connections to sensory and motor cortices and to subcortical structures such as the basal ganglia and cerebellum. Imaging studies have demonstrated that patients with ADHD have alterations in PFC circuits and demonstrate weaker PFC activation while trying to regulate attention and behavior. The PFC requires optimal levels of norepinephrine (NE) and dopamine (DA) for proper functioning. Genetic studies have consistently noted alterations in genes involved in catecholamine transmission in patients with ADHD. All pharmacologic treatments for ADHD strengthen catecholamine signaling in the PFC and ameliorate symptoms. This article provides a brief summary of the neurobiology of ADHD.

A

OVERVIEW OF THE PREFRONTAL CORTEX The PFC is highly developed in humans and consists of the cortex anterior to the motor and premotor cortices in the frontal lobe. The functions of the PFC are specialized by region. In right-handed individuals, portions of the left hemisphere are involved with the generation of language (eg, Broca’s area), and the right hemisphere is particularly important for the regulation of attention, behavior, and emotion.2 The dorsal and lateral portions of the PFC regulate From the Department of Neurobiology, attention and motor responses, and the ventral and medial portions regulate emotion.2,3 Yale University School of Medicine, New The PFC has extensive connections throughout the brain to orchestrate thoughts and Haven, CT. responses4 and to provide intelligent decision-making, insight, and judgment.5,6 The PFC Please see the Author Disclosure section at the end of this article. is essential for the so-called executive functions, allowing us to organize and plan for the Reprint requests: Amy F.T. Arnsten, PhD, 3 future and to inhibit responses to distractions to achieve a goal. Not surprisingly, the Department of Neurobiology, Yale UniverADD ADHD CAMP DA GABA

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Attention deficit disorder Attention deficit hyperactivity disorder Cyclic adenosine monophosphate Dopamine Gamma aminobutyric acid

HCN NE PFC

Hyperpolarization-activated cyclic nucleotide-gated Norepinephrine Prefrontal cortex

sity School of Medicine, New Haven, CT. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.01.018

Figure 1. The PFC regulates “top-down” attention, allocating and directing attentional resources on the basis of stimulus relevance. Topdown attention includes stimulus gating, reducing distractibility, and sustaining attention on relevant information. These operations are thought to arise from PFC projections back to the sensory cortices. In contrast, the posterior sensory cortices mediate “bottom-up” attention, processing sensory characteristics on the basis of stimulus salience. Most patients with ADHD have difficulties with top-down attention regulation.

PFC is the brain structure that is last to mature, with full maturation occurring only in late adolescence.7-9 The PFC is also especially sensitive to its neurochemical environment: like Goldilocks, it needs to have everything “just right” for proper function.10 Thus, this brain region is particularly vulnerable to environmental and genetic insults.

Regulation of Attention The PFC mediates “top-down” attention, regulating our attention so that we devote our resources to that which is relevant to our goals and plans.11-15 The PFC allows us to concentrate and sustain our attention, especially under “boring conditions” such as long delays between stimuli (eg, a teacher who talks slowly).16 The PFC helps us to focus on material that is important but not inherently salient (eg, studying for a test, reading homework) and to inhibit internal and external distractions.17-21 The PFC allows us to divide and shift our attention as appropriate with task demands (so-called multi-tasking)2,22 and to plan and organize for the future23 As aforementioned, many of the attentional functions of the PFC are the purview of the right hemisphere, and lesions to this hemisphere induce distractibility and poor concentration.24 The PFC accomplishes top-down attentional regulation through its extensive connections back to the sensory cortices for gating of sensory inputs (Figure 1).4,25 The PFC is able to suppress processing of irrelevant stimuli and enhance the processing of relevant stimuli through these extensive connections. Attention problems in children with ADHD are diagnosed with the Inattention scale in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.26 These symptoms of inattention generally refer to problems with top-down attention, as exemplified in children who are easily distracted, have difficulty sustaining attention on “boring”

material, but are readily captivated by more salient stimuli (eg, they are able to attend to video games but are not able to listen to their teacher). Most children with ADHD have these problems with attention regulation. However, there are a few children who are truly unable to pay attention (usually diagnosed with attention deficit disorder [ADD], rather than ADHD), and these individuals may have problems with posterior attention systems in the parietal and temporal lobes. The parietal and temporal sensory cortices mediate “bottom-up” aspects of attention.15,27 These cortical systems process stimuli according to inherent salience (eg, are the stimuli bold, loud, brightly colored, moving), rather than their relevance. Research in the last 20 years has been particularly successful in discovering how visual stimuli are processed and perceived: the ventral stream through the temporal association cortices evaluates visual features, such as lines and colors, to determine what things are.13,28,29 Thus, lesions to the inferior temporal cortices cause agnosias (not knowing what something is).11 In contrast, the dorsal stream culminating in the parietal cortices determines where things are and whether they are moving.30,31 The parietal association cortex is essential for orienting our attention,32,33 with the right hemisphere specialized for orienting attention to parts of visual space, and the left hemisphere marshalling our attention to a point in time (eg, if we are expecting an important event to occur).34 Lesions to the right parietal cortex induce a striking syndrome known as contralateral neglect, in which patients have no conscious experience of stimuli in the left visual field.35,36 Although most children with ADHD or ADD (attention problems without hyperactivity or impulsivity) have problems with attention consistent with PFC deficits, there are likely some children who have weakness in the parietal or temporal cortices, or both, and truly have difficulties paying attention (eg, a child who is not engaged even by video games). Unfortunately, the term “inattention” does not distinguish between these scenarios, and the current Diagnostic and Statistical Manual of Mental Disorders criteria are not helpful in this regard. It will be important that we create better evaluation scales in the future to discern PFC versus posterior cortical weakness, because the optimal medications for treating PFC deficits may not be ideal for treating posterior cortical problems.

Inhibition of Inappropriate Behaviors The PFC is also essential for the regulation of behavior, for planning future actions, and for the inhibition of inappropriate responses. For example, lesions to the PFC in monkeys induce locomotor hyperactivity and impulsive responding, similar to what is observed in children with ADHD.37-39 The PFC can guide behavioral output through its massive projections to the motor and premotor cortices, to basal ganglia structures such as the caudate and subthalamic nucleus, and to the cerebellum by way of the pons (Figure 2).40,41 Thus, lesions in areas such as the caudate or cerebellum can sometimes mimic lesions in the PFC, because they are part of a circuit needed to guide behavioral response. In

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Figure 2. The PFC regulates behavior and inhibits inappropriate impulses. In humans, the right inferior PFC is specialized for behavioral inhibition. Projections from this area to the premotor and motor cortices, the basal ganglia (striatum and subthalamic nucleus), and the cerebellum (by way of the pontine nuclei) are likely involved in the inhibition of inappropriate movements and impulses. In monkeys, blockade of alpha-2A receptors in the PFC induces a pattern of impulsive responding and locomotor hyperactivity.68,69

humans, the right inferior PFC is specialized for behavioral inhibition.42 Functional imaging studies have shown that the right inferior PFC is active when subjects successfully inhibit or stop movements2,42,43 Conversely, lesions or weakness to this area impairs the ability to inhibit inappropriate responses.44 A recent study45 showed that manipulations that weaken the right inferior PFC in healthy subjects impaired the ability to stop an ongoing motor response (this study used a technology called transmagnetic stimulation, in which magnetic pulses are directed at the brain to alter the electrical activity of the cortex beneath the skull). As described below, imaging studies have often shown that the right inferior PFC is underactive in patients with ADHD.46

Regulation of Emotion The dorsal and lateral portions of the PFC regulate attention and behavior, whereas the ventral and medial portions of the PFC regulate emotion.2,47 The ventral surface of the PFC is often referred to as the orbital cortex, because it sits just above the orbits of the eyes. The ventromedial PFC monitors and inhibits emotions and emotional habits through extensive projections to the amygdala, hypothalamus, nucleus accumbens, and the brainstem nuclei mediating the stress response.48-51 Weakness in ventromedial PFC function (especially in the right hemisphere) leads to emotional dysregulation, including disinhibited aggressive impulses.52-54 Symptoms of aggression and oppositionality (eg, conduct disorder) are often co-morbid with ADHD, particularly in boys. S24

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Figure 3. The PFC guides attention, behavior, and emotion through networks of pyramidal cells. These pyramidal cells engage in recurrent excitation to represent stimuli (eg, the spatial positions 90° or 270°, as shown here) or to represent goals or rules. The networks interconnect through synapses on dendritic spines that contain NE alpha-2A receptors or DA D1 receptors. Network connectivity is powerfully modulated by the catecholamines: NE alpha-2A receptor stimulation strengthens network inputs from cells with shared network properties by reducing the production of cAMP, thus closing HCN channels and enhancing synaptic inputs to the spine (increasing “signals”). Conversely, optimal levels of DA D1 receptor stimulation weaken irrelevant inputs to the neuron by increasing the production of cAMP, opening HCN channels near the synapse, and shunting incoming information (decreasing “noise”). Thus, for the network representing 90°, alpha-2A receptor stimulation increases the strength of connections from other 90° neurons, and D1 receptor stimulation weakens the connections from neurons with dissimilar characteristics (eg, 270°). Reproduced with permission from Arnsten, et al.10

Neuronal Networks Representing Goals and Rules The PFC regulates attention, actions, and emotion through networks of PFC neurons. These networks consist of pyramidal cells that use glutamate as their neurotransmitter (Figure 3) and are able to excite each other to maintain firing even in the absence of environmental stimulation.55 These networks are able to “keep in mind” information to help guide attention and behavior in a thoughtful manner. For example, they can keep in mind information about where you just left a book you were reading or your reading glasses (eg, “the book is 90° away from the couch,” as illustrated by the network of 90° cells in Figure 3). Higher-order networks appear to be able to represent goals and plans for the future (eg, “Sit in your seat!”, “Do your homework now so you can play tonight”). The neurons in these networks interact with other pyramidal cells through synapses on dendritic spines.55 These spines contain NE alpha-2A receptors56 or DA D1 receptors,57 which dynamically alter the strength of incoming network connections and are essential to PFC function.

CATECHOLAMINE MODULATION OF PREFRONTAL CORTEX Optimal Catecholamine Levels Are Needed for Proper Function NE and DA are important components of the arousal systems that arise from the brainstem and project across the entire cortical mantle, including the PFC.58-60 The PFC requires an optimal level of NE and DA for proper function: The Journal of Pediatrics • May 2009

Figure 4. The regulatory functions of the PFC are highly dependent on its neurochemical state. The catecholamines NE and DA are released on the basis of our state of arousal. Either too little or too much catecholamine release is detrimental to PFC function: there is an inverted U dose-response relationship. Inadequate catecholamine release is associated with fatigue and ADHD, and excessive catecholamine release occurs during uncontrollable stress or very high doses of stimulant medications. NE has its highest affinity for alpha-2A receptors and has lower affinity for alpha-1 and beta-1 receptors. Thus, different receptors are engaged on the basis of the amount of NE released in the PFC. Therapeutic doses of stimulants, atomoxetine, or guanfacine likely normalize catecholamine transmission in patients with inadequate DA or NE levels, or both, thus bringing PFC function to more optimal levels at the top of the inverted U.

either too little (as when we are drowsy or fatigued) or too much (as when we are stressed) markedly impairs PFC regulation of behavior and thought.10 This is often called the inverted U dose response, as illustrated in Figure 4. Indeed, NE and DA are so critical to PFC function that depleting them is as detrimental as removing the cortex itself.61 As described below, genetic and imaging studies suggest that many patients with ADHD have inadequate transmission of NE or DA, or both. Treatments for ADHD all enhance NE or DA function, or both. Thus, understanding catecholamine actions in the PFC is essential to our understanding of ADHD. The receptor and intracellular mechanisms by which NE and DA influence PFC networks have now been characterized and are summarized here. In brief, NE stimulation of alpha-2A receptors enhances PFC function by strengthening appropriate network connections (increasing “signals”), and DA stimulation of D1 receptors exerts its beneficial effects by weakening inappropriate connections (decreasing “noise”).10

Role of Norepinephrine The beneficial effects of moderate doses of NE occur at postsynaptic alpha-2A receptors on PFC neurons.56,62,63 Research on alpha-2 actions conducted in the 1970s focused on presynaptic alpha-2 receptors on NE cells and terminals that serve as negative feedback to reduce NE cell firing and NE release.64 However, it is now known that most alpha-2 receptors in the brain are actually postsynaptic to NE cells,65 situated, for example, on the dendritic spines of PFC pyramidal cells.56 There are 3 subtypes of alpha-2 receptors, the A, B, and C subtypes,66 and it is the A subtype that is most important to NE’s beneficial actions in the PFC.67 NE alpha-2A receptor stimulation improves PFC regulation of attention, behavior, and emotion by strengthening

network connections between neurons with shared inputs.56 This is illustrated in Figure 3, which shows that stimulation of alpha-2A receptors on the spines of a 90° neuron increases the strength of inputs from other neurons that respond to 90°. Thus, alpha-2A receptor stimulation increases “signals” within PFC networks. Alpha-2A receptor stimulation strengthens network connections by closing “leaky” ion channels near the synapses on dendritic spines. These hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels pass both sodium and potassium when they are opened by cyclic adenosine monophosphate (cAMP), thus shunting nearby inputs. Stimulation of alpha-2A receptors near the HCN channels stops the production of cAMP, closing the channels and increasing the strength of nearby synaptic inputs.56 Stimulation of alpha-2A receptors is essential to PFC function, and blockade of these receptors with yohimbine induces a profile similar to ADHD. In monkeys, infusion of yohimbine directly into the PFC increases locomotor hyperactivity68 and impulsivity,69 similar to lesions of the same area (Figure 2). Infusion of yohimbine into prefrontal cortex also weakens working regulation of memory and attention.70 Conversely, stimulation of alpha-2A receptors with guanfacine lessens distractibility and strengthens behavioral regulation.56,67,71-75 Thus, conditions that lead to inadequate NE stimulation of alpha-2A receptors (including genetic insults in ADHD, as described below) lead to marked PFC dysfunction. In contrast to the essential effects of moderate levels of NE, high levels of NE, such as those occurring during stress or excessive stimulant doses, impair PFC function.76 These detrimental actions occur through engagement of alpha-1 receptors (and possibly beta-1 receptors) that have lower affinity for NE.77-79 Stimulation of alpha-1 receptors impairs PFC function by engaging the phosphotidyl inositol intracel-

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lular signaling pathway,80 the pathway that is altered in bipolar disorder.81,82 Overactivation of this pathway suppresses PFC cell firing and markedly impairs PFC function.80

Role of Dopamine As with NE, DA is essential to PFC function.83 DA acts at the D1 family of receptors (D1 and D5) and the D2 family of receptors (D2, D3, D4). Studies of DA actions at the D2 family are just emerging. D2 receptors appear to modulate response-related firing of PFC neurons,84 and D4 receptors are concentrated on gamma aminobutyric acid (GABA)-ergic interneurons.85 D4 receptor stimulation appears to suppress these inhibitory GABAergic interneurons and thus allow pyramidal neurons to fire.86 Genetic weakness in the D4 receptor (eg, the 7-repeat that is more common in ADHD) should lead to excessive GABAergic inhibition and inadequate activity of PFC pyramidal cells. It is important to note that both NE and DA can stimulate the D4 receptor and that NE has higher affinity for D4 receptors than for adrenoceptors.87 Thus, medications that increase NE availability likely influence D4 receptor transmission. However, relatively little research has been done on D4 receptor actions in PFC, and they likely have more complex actions than described here. Instead, most research has focused on the D1 family of receptors, because these are most abundant in the PFC.88 Currently, no drugs distinguish D1 from D5 receptors; thus, it should be understood that reference to D1 in this review could apply to actions at either of these receptors. Moderate levels of DA D1 receptor stimulation improve PFC functions by decreasing “noise.”89 D1 receptors appear to be on a different set of spines than alpha-2A receptors; the D1 receptors appear to gate incoming inputs, screening out those that are irrelevant to the present task demands.10 This is schematically illustrated in Figure 3. D1 receptor stimulation prevents inputs from the 270° neurons from entering the 90° cell. D1 receptors weaken irrelevant inputs to the neuron by increasing the production of cAMP, opening HCN channels near the synapse, and shunting the incoming information. Thus, DA and NE have complementary beneficial actions. However, excessive D1 receptor stimulation (such as occurs during stress) impairs PFC function by weakening too many network connections. In these conditions, network activity collapses, and responding becomes inflexible.89 This may explain the problems with mental flexibility when children take excessive doses of stimulant medication.

ALTERED PREFRONTAL AND CATECHOLAMINE FUNCTION IN ADHD ADHD and Deficits in Prefrontal Cortex Function Patients with ADHD have symptoms similar to those caused by lesions to the right PFC.44,90-92 Imaging studies have shown reduced size and reduced functional activity of the right PFC in patients with ADHD.46,93-97 Recent studies have also reported more disorganized white matter tracks S26

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emanating from the PFC in patients with ADHD, consistent with weaker prefrontal connectivity.98,99 Other brain regions connected to the PFC, for example the caudate and cerebellum, have also been reported to be smaller in some studies of children with ADHD.100 There is also evidence of slower prefrontal maturation in some patients with ADHD.101 However, for many patients, ADHD is a lifelong disorder, as supported by results from imaging studies showing evidence of weakened PFC function and reduced right PFC volume in adults with ADHD symptoms.102,103 Supporting the notion of ADHD as a highly heritable disorder are imaging studies showing disruptions in prefrontal white matter tracts in both parents and their children when both have ADHD.98

Genetic Changes in Catecholamine Transmission As is typical in mental illness, multiple genes contribute a small risk to ADHD symptomology.104 Many studies report alterations in the genes encoding for molecules involved in catecholamine signaling, for example the DA D1 and D5 receptors,105-108 the DA and NE transporters,105,108-110 the D4 receptor,106,107,111 the alpha-2A receptor,112-114 and dopamine beta hydroxylase (the enzyme needed for the synthesis of NE).105,115,116 There are also associations with the catabolic enzyme, monoamine oxidase, and some serotonergic genes.104 Recent studies have begun to relate genotype to symptomology. For example, genetic variation in the gene encoding for dopamine beta hydroxylase is related to executive function and the ability to sustain attention.117,118 Thus, patients with 2 copies of the Taq I polymorphism in ADHD have poorer sustained attention.117 These studies suggest that weaker NE production may impair the PFC circuits mediating the regulation of attention and behavior. Imaging Studies Show Changes in Catecholamine Transmission Neuroreceptor imaging also supports weakened catecholamine transmission in ADHD. These studies have all been done in adults with ADHD, because of the necessity of using radioactive tracers in positron emission tomography or single-photon emission computed tomography. Most of this work has focused on DA mechanisms in the striatum, because there are currently no good tracers to image NE or DA levels in the cortex. There have been mixed results with studies of the DA transporter, with many studies showing increased levels in the striatum,119-121 but other studies found no effect122 or reported decreases,123 possibly reflecting genetic heterogeneity in the DA transporter gene. Recent imaging studies have assessed DA release in the striatum and found evidence of decreased DA release in adult patients with ADHD.124 It is likely that this reflects global reductions in DA release throughout the brain, because earlier studies have suggested reduced catecholamine levels in the PFC also.125 Reduced DA in the striatum is associated with slowed motor activity, as in Parkinsonism,126 and reduced DA in the PFC The Journal of Pediatrics • May 2009

produces locomotor hyperactivity in animals.127 Such findings suggest that it is the loss of catecholamines in the PFC that is most important for ADHD symptoms.

ADHD TREATMENTS AND THE NORMALIZATION OF CATECHOLAMINE TRANSMISSION Therapeutic doses of either stimulant or non-stimulant medications potentiate catecholamine transmission in the PFC. Thus, these agents would normalize catecholamine transmission in patients with genetic abnormalities in these pathways.

Stimulants The stimulants amphetamine (Adderall [amphetamine], Vyvanse [lisdexamphetamine dimesylate], Shire US., Wayne, Pennsylvania), and methylphenidate (Ritalin [methylphenidate], Novartis Pharmaceuticals, East Hanover, New Jersey; Concerta [methylphenidate extended release], McNeil Pediatrics, Ft. Washington, Pennsylvania) block both catecholamine transporters, the transporter for DA and that for NE. Because there are low levels of DA transporters in the PFC, NE transporters thus clear both NE and DA in this brain region.128 Earlier biochemical studies of amphetamine and methylphenidate in rodents used excessively high doses that increased locomotor activity, impaired PFC function, and had sensitizing effects on pathways involved with, for example, drug abuse.129 Recently, more appropriate, lower doses have been identified, which produce blood levels in rats similar to those observed in patients with ADHD who are treated with stimulant medication.130,131 These therapeutic doses of stimulants reduce locomotor activity and improve PFC cognitive function in rats just as they do in humans.130-132 Biochemical analyses of these more relevant stimulant doses revealed that they substantially increase both DA and NE release in the PFC but have little effect on catecholamine levels in subcortical areas.131 These data are consistent with those showing that therapeutic doses of stimulants incur little abuse potential when taken properly. In the rat PFC, therapeutic doses of stimulants increase NE release more than they increase DA release,131 thus, it is inaccurate to refer to these agents as simply dopaminergic. Consistent with dual actions on both NE and DA, the cognitive-enhancing effects of these agents in rodents are blocked by either NE alpha-2 or DA D1 receptor antagonists.132 However, higher doses of stimulants impair function of the PFC and induce an inflexible pattern of responding similar to that seen following uncontrollable stress.131,132 These findings with high doses of methylphenidate are likely relevant to the cognitive inflexibility that can occur with excessive doses of stimulant medication.133 Therapeutic doses of stimulants improve PFC functions and enhance the efficiency of PFC activity in healthy young adult subjects.134,135 A similar, but much more pronounced profile is observed in subjects with ADHD.136-139 Thus, stimulant actions in ADHD are not paradoxical, but simply more apparent.134,135

Non-Stimulants ATOMOXETINE. Atomoxetine (Strattera [atomoxetine], Eli Lilly, Indianapolis, Indiana) selectively blocks the NE transporter. Administration of atomoxetine increases both NE and DA in the rat PFC,140 indicating the importance of the NE transporter for clearing DA and NE in the PFC. Preliminary data indicate that moderate doses of atomoxetine, as with methylphenidate, improve PFC functions through both NE alpha-2 and DA D1 actions, and higher doses can impair PFC function in some animals (Arnsten, unpublished). Recent studies in humans have shown that therapeutic doses of atomoxetine can strengthen response inhibition in healthy control subjects141 and in patients with ADHD.142 The therapeutic effects of atomoxetine are consistent with results of earlier studies showing that desipramine, a tricyclic antidepressant with high selectivity for the NE transporter, is helpful in treating ADHD-related symptoms, although it has cardiovascular adverse effects.143,144 GUANFACINE. Guanfacine acts directly at postsynaptic, alpha-2A receptors in the PFC, where it mimics the beneficial effects of NE and strengthens PFC regulation of attention and behavior.56 Animal studies have shown that guanfacine improves a wide range of PFC functions.71,72,74,145-147 As aforementioned, guanfacine improves PFC functions by inhibiting cAMP-HCN channel signaling in dendritic spines, thus strengthening synaptic inputs onto pyramidal neurons and strengthening PFC network connectivity.56 The beneficial effects of guanfacine on PFC function are independent of the drug’s sedating actions,71,90 which likely occur at all 3 alpha-2 receptor subtypes (the A, B, and C subtypes). For example, the thalamus is rich in alpha-2B receptors,66 and this structure is key for regulating state of arousal.148 The sedating actions of alpha-2 agonists also likely occur at presynaptic alpha-2A receptors on NE cell bodies and terminals; guanfacine has relatively lower affinity for these presynaptic receptors.149 Guanfacine is currently used in both children and adults with ADHD. It has been shown to improve ratings on both the Inattention and Hyperactivity/Impulsivity scales, consistent with its widespread beneficial effects on many PFC functions.150-152 It is especially helpful in patients who cannot take stimulant medications because of tics, aggressive impulses, or drug abuse liability.150 As with the stimulants, guanfacine also can improve healthy subjects,153,154 but it is far more effective in individuals with impaired prefrontal abilities and inadequate catecholamine function.71,90 Because it works directly at the receptor to mimic NE, it can be used in subjects having marked catecholamine depletion, because an intact catecholamine system is not required for its actions. CLONIDINE. Clonidine has a very rapid onset of action that can be helpful in treating emergent situations. However, it has significant sedative and hypotensive actions that limit its clinical usefulness.155,156 Clonidine is less selective than guanfacine for the alpha-2A receptor. It has high affinity for the alpha-2B and alpha-2C subtypes and the alpha-2A recep-

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tor,157,158 and it also has high affinity for imidazoline I1 receptors.159 Clonidine has potent actions at presynaptic alpha-2A receptors, being 10 times more effective than guanfacine at these sites.149 This nonselective profile and potent presynaptic actions likely contribute to clonidine’s potent sedating effects. In addition, clonidine’s actions at imidazoline I1 receptors in the brainstem are thought to contribute to its marked hypotensive actions.159,160 In summary, successful pharmacological treatments for ADHD mimic or enhance the beneficial effects of catecholamines on PFC function.161

DISCUSSION In the last 20 years, our understanding of higher cortical function has evolved so that we can now begin to explain the etiology and treatment of ADHD. We have learned that the PFC plays a crucial role in regulating attention, behavior, and emotion. Weaknesses in PFC structure and function, including alterations in catecholamine transmission, likely contribute to the etiology of ADHD symptoms. Effective treatments for ADHD optimize catecholamine signaling in the PFC and normalize PFC regulation of attention and behavior, thus reducing ADHD symptoms.

AUTHOR DISCLOSURE Amy F.T. Arnsten, PhD has received consulting fees from Shire Pharmaceuticals, has contracted research with Shire Pharmaceuticals, and has a license agreement with Shire Pharmaceuticals for the development of guanfacine for treatment of ADHD. Dr. Arnsten extends her gratitude to Dr. Sydney Spiesel for his many helpful comments regarding his review.

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improves visual object discrimination reversal performance in rhesus monkeys. Behav Neurosci 1997;111:1-9. 147. Wang M, Ji JZ, Li BM. The alpha(2A)-adrenergic agonist guanfacine improves visuomotor associative learning in monkeys. Neuropsychopharmacology 2004;29:86-92. 148. Buzsaki G, Kennedy B, Solt VB, Ziegler M. Noradrenergic control of thalamic oscillation: the role of alpha-2 receptors. Eur J Neurol 1991;3:222-9. 149. Engberg G, Eriksson E. Effects of alpha-2-adrenoceptor agonists on locus coeruleus firing rate and brain noradrenaline turnover in EEDQ-treated rats. NaunynSchmiedebergs Arch Pharmacol 1991;343:472-7. 150. Scahill L, Chappell PB, Kim YS, Schultz RT, Katsovich L, Shepherd E, et al. Guanfacine in the treatment of children with tic disorders and ADHD: a placebocontrolled study. Am J Psychiatry 2001;158:1067-74. 151. Taylor FB, Russo J. Comparing guanfacine and dextroamphetamine for the treatment of adult attention deficit-hyperactivity disorder. J Clin Psychopharmacol 2001;21:223-8. 152. 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:e73-84. 153. Franowicz JCS, Arnsten AFT. The alpha-2A noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacology 1998;136:8-14. 154. Jakala P, Riekkinen M, Sirvio J, Koivisto E, Kejonen K, Vanhanen M, et al.

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Alpha-2 Adrenergic Agonists in Attention Deficit Hyperactivity Disorder LAWRENCE SCAHILL, MSN, PHD

Stimulants are the first-line of treatment for attention deficit hyperactivity disorder (ADHD) in children. Alpha-2 agonists have been used to treat neuropsychiatric disorders in children for nearly 3 decades and are often used in patients when stimulants are not successful. This paper reviews the mode of action and findings of clonidine and guanfacine in the treatment of children with ADHD. Both clonidine and guanfacine demonstrate affinity for alpha-2A subtype receptors; however, clonidine also has affinity for alpha-2B and -2C subtypes. These differences in receptor affinity may underlie the differences in clinical effect, especially for cardiovascular effects and sedation. In addition, increased specificity for alpha-2A receptors for guanfacine appears to enhance prefrontal function compared with clonidine. Until recently, most neuropsychiatric studies with clonidine and guanfacine have focused on treating Tourette’s syndrome and tic disorders. Beneficial effects on hyperactivity and impulsiveness in these studies suggest these drugs may be useful in patients with ADHD. Recent trials demonstrate that these 2 drugs are effective and well tolerated. Although both guanfacine and clonidine are associated with sedation, clonidine appears more likely to cause cardiovascular adverse effects. The alpha-2 agonists may be a viable option for treating children with ADHD, especially those who do not show a positive response to stimulants. (J Pediatr 2009;154:S32-S37)

ttention deficit hyperactivity disorder (ADHD) is a common disorder in school-age children, affecting 5% to 10% of this population.1 It is likely to be a heterogeneous condition with multiple etiologies (see accompanying articles in this supplement). Because it is potentially chronic and associated with considerable morbidity, ADHD is an important public health problem. Accumulated preclinical and clinical data indicate that dopamine and norepinephrine (NE) systems are fundamentally involved in the pathophysiology of ADHD (see accompanying articles in this supplement). Indeed, all current pharmacologic treatments for ADHD directly affect 1 or both of these neurotransmitter systems. For the past 5 decades, stimulants have been properly regarded as first-line treatment for ADHD, but stimulants fail in a substantial minority of cases. Thus, there has been and continues to be great interest in non-stimulant medications for ADHD. Alpha-2 agonists have been used in the treatment of children with neuropsychiatric disorders for nearly 3 decades.2 The therapeutic action of these agents in ADHD was presumed to involve a reduction in NE release in the brain, resulting in decreased arousal.3 However, it is now clear that this interpretation is incomplete and that the alpha-2 agonists are not all the same in their pharmacological effects.4,5 This paper examines the differences between clonidine and guanfacine, the potential clinical implications of these differences, and the evidence supporting the use of clonidine and guanfacine in children.

A

MECHANISM OF ACTION Among the early theories of ADHD was a proposal that increased and unregulated firing of noradrenergic neurons in the locus ceruleus (LC) resulted in hyperarousal (Figure 1).3,4 Alpha-2 agonists were believed to decrease presynaptic firing of NE autoreceptors of LC neurons, leading to improved regulation of NE systems, decreased arousal, and reduction in hyperactivity and impulsiveness.3,4 The predominant type of NE receptor in the LC is alpha-2C, but alpha-2A receptors are also present.6

ABC ADHD AE BP CASQ-Teacher CASQ-Parent CGI-I CPRS-R-S CTRS-R-S

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Aberrant Behavior Checklist Attention deficit hyperactivity disorder Adverse event Blood pressure Conners Abbreviated Symptom Questionnaire for Teachers Conners Abbreviated Symptom Questionnaire for Parents Clinical Global Impressions–Improvement Conners Parent Rating Scale-Revised Short Form Conners Teacher Rating Scale-Revised Short Form

ER ES IR LC MPH NE PFC PDD RUPP TS

Extended release Effect size Immediate release Locus ceruleus Methylphenidate Norepinephrine Prefrontal cortex Pervasive developmental disorder Research Units on Pediatric Psychopharmacology Tourette’s syndrome

From the Child Study Center, Yale University, New Haven, CT. Please see the Author Disclosure section at the end of this article. Reprint requests: Lawrence Scahill, Yale University, Child Study Center, 230 South Frontage Rd, New Haven, CT 06520. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.01.019

Figure 1. Early view of alpha-2 agonists in ADHD. A, Children with ADHD are over-aroused. B, Clonidine decreases arousal via action at presynaptic alpha-2 receptors on LC neurons; this action decreases cell firing and NE release, leading to decreased hyperactivity and impulsiveness.

out sedation. A summary of characteristics for both clonidine and guanfacine can be seen in the Table. Clonidine has more potent cardiovascular effects, probably because of agonist effects at imidazoline receptors in the medulla and its potent effects on presynaptic alpha-2 receptors.14 Guanfacine has little or no activity on imidazoline receptors and has weaker cardiovascular effects. The sedative effect of clonidine appears to be caused by its higher affinity for alpha-2C receptors on LC dendrites, resulting in reduced LC firing. Furthermore, clonidine also stimulates alpha-2B receptors in the thalamus, which may also produce sedative effects. The less prominent sedative effects of guanfacine are consistent with the observation that it has little to no activity at the alpha-2B and -2C receptors. Abrupt withdrawal with clonidine is associated with rebound increases in pulse and blood pressure (BP).15,16 In a head-to-head comparison with clonidine in adults treated for hypertension, guanfacine was not associated with these rebound effects.16 This difference is almost certainly caused by the longer half-life for guanfacine.5 The risk of rebound effects is likely to be even lower with the extended-released (ER) formulation of guanfacine, which has a longer half-life than the immediate-release (IR) formulation.

EVIDENCE

Figure 2. Emerging view of alpha-2 agonists in ADHD. Children with ADHD have decreased prefrontal cortex (PFC) regulation of behavior and attention; the alpha-2A agonist, guanfacine, acts at postsynaptic receptors to strengthen PFC function.

More recently, this proposal has been expanded and focused on inadequate regulation in the prefrontal cortex (PFC; Figure 2). The PFC regulates attention, emotion, and behavior via reciprocal projections to subcortical regions. Thus, the primary manifestations of ADHD (eg, distractibility, impulsiveness, and hyperactivity) fit with a model of impaired PFC function.4,7 Guanfacine selectively stimulates post-synaptic alpha2A receptors in the PFC. By contrast, clonidine stimulates alpha-2A, -2B, and -2C receptor subtypes.8 This action of guanfacine may improve regulation of subcortical activity, which, in turn, may reduce hyperactivity, impulsiveness, and distractibility.9 Evidence in support of this revised theory of alpha-2A adrenergic activity in ADHD can be found in an article by Arnsten, which is part of this supplement. Both clonidine and guanfacine have demonstrated improvements in cognitive function in human and animal studies.10-13 For clonidine, however, these improvements in cognitive effects are associated with sedation. By contrast, guanfacine demonstrated improved cognitive function with-

Clonidine Clonidine has been evaluated in several pediatric populations including those with ADHD, Tourette’s syndrome (TS), and pervasive developmental disorders (PDDs).17 In a meta-analysis of 39 trials, Connor et al examined the efficacy and safety of clonidine in children and adolescents with ADHD alone or accompanied by conduct disorder, developmental delay, or tic disorder. The meta-analysis revealed a medium effect size (ES) of 0.58 ⫾ 0.16 (95% CI, 0.27-0.89) on core symptoms of ADHD.18 Because most subjects in these studies had co-occurring conditions (such as TS, conduct disorder, and PDD), it is difficult to generalize to children with ADHD uncomplicated by these other conditions. The most commonly associated adverse events (AEs) were sedation and irritability.18 Two trials compared clonidine, methylphenidate (MPH), and clonidine ⫹ MPH to placebo.19,20 The first study included 136 subjects (age range, 7-14 years) with TS and ADHD. The mean dose for the MPH alone group was approximately 26 mg/day given in 2 divided dosages; the mean dosage of clonidine was 0.25 mg/day in 2 or 3 doses. Doses of each active drug were similar in the combined treatment group. All 3 active treatments were superior to placebo. On the Conners’ Abbreviated Symptom Questionnaire for Teachers (CASQ-Teacher) scores,21 the clonidine group showed a placebo-adjusted improvement of 21%, compared with 16% for the MPH group and 37% for the combined treatment group (calculated from graphic display of results).20 This trend was similar for parent ratings. Sedation was common in the group treated with clonidine alone (35%) compared with the subjects in the

Alpha-2 Adrenergic Agonists in Attention Deficit Hyperactivity Disorder

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Table. Characteristics of alpha-2 agonists clonidine and guanfacine important to attention deficit hyperactivity disorder Characteristics

Clonidine Guanfacine

Alpha receptor subtype affinity

CV effects

Symptom effects

⫺2A, ⫺2B, ⫺2C ⫺2A

Moderate effects on heart rate and BP Minimal effects on heart rate and BP

Hyperactivity Hyperactivity and inattention

CV, Cardiovascular.

combined treatment group (21%) and the MPH group (8%).20 The impact of treatment on tics was surprising, but somewhat complicated. On average, as measured on a clinician-rated measure of tic severity, tics improved in all active treatment groups: 26% for clonidine, 25% for MPH only, and 28% for the combined treatment. However, in all treatment groups, including the placebo group, approximately 20% of subjects reported an increase in tics.20 Although the treating clinicians were blind to treatment assignment, they were permitted to make dose adjustments to manage suspected AEs, such as increased tics. Treating clinicians elected to defer or decrease the dose of stimulant medication twice as often in the MPH group (35% of cases) as in the clonidine group and the combined treatment group (18% for each group).20 With the exact same 4-group design, Palumbo et al19 conducted a trial in 122 children (age range, 7-12 years) with ADHD (without TS). The average dosage of clonidine alone was 0.24 mg/day divided in 2 or 3 doses and 30.2 mg/day for MPH alone given in 2 divided doses. The mean doses of clonidine and MPH were similar in the combined treatment group. The primary outcome measure was the change from baseline to end point in CASQ–Teacher. In this study, neither clonidine-only nor MPH-only was superior to placebo on teacher ratings. By contrast, the combination of clonidine and MPH showed a significant improvement of 4.4 points on the CASQ-Teacher scale. On the CASQ-Parent scale, clonidine was associated with a mean 4.5-point reduction from baseline, which was significant. Improvement on the CASQ-Parent rating for the MPH-only group was not significant. The combination group fared best, with a mean 5-point reduction from baseline in CASQ-Parent (P ⫽ .004 versus placebo).19 These results suggest that teachers saw little benefit with clonidine in the classroom, particularly for staying on task, and that parents see benefit outside the classroom because of less disruptive behaviors.19 The trial completion rate across treatment groups suggests that clonidine was better tolerated than MPH (clonidine: 26/31, 84%; MPH: 18/29, 62%; combination: 24/32, 75%).19 Bradycardia was more common in the clonidine-only group than all other treatment groups combined (17.5% versus 3.4%; P ⫽ .02), but there were no other significant group differences in electrocardiographic and other cardiovascular outcomes.22 Moderate or greater AEs were more common in subjects receiving clonidine (79.4% versus 49.2%; P ⬍ .001), but these AEs were not associated with early study withdrawal.22 DrowsiS34

Scahill

ness and fatigue were a common complaint in the clonidine group, but these complaints did not lead to a higher rate of study withdrawal and usually were resolved in 6 to 8 weeks.22

GUANFACINE IN TIC DISORDERS AND PERVASION DEVELOPMENT DISORDERS Early open trials with guanfacine for ADHD were conducted in the mid-1990s.23-25 In these open trials, daily dosages ranged from 1.5 to 4.0 mg/day, usually divided in 3 doses.23-25 In 2001, an 8-week, randomized trial in subjects with ADHD and a chronic tic disorder (n ⫽ 34) demonstrated that guanfacine was superior to placebo for ADHD symptoms and tics.26 In this study, most patients were male (n ⫽ 31), and most had failed earlier treatment with a stimulant (n ⫽ 23).26 The dosage ranged from 1.5 to 3 mg/day, with a modal dose of guanfacine being 1.0 mg in the morning, 0.5 mg in the afternoon, and 1.0 mg at bedtime.26 The primary efficacy outcome measure was the teacher-rated ADHD Rating Scale (ADHD-RS).27 On this measure, the guanfacine group showed a 37% decrease, compared with 8% for placebo (P ⱕ .006).26 The improvement on the teacher-rated ADHD-RS was evident on both the Inattention and Hyperactivity subscales. The CASQ-Parent results showed no difference across the 2 groups. Although tic symptoms were generally mild in this sample, there was a significant improvement in tic severity on a clinician-rated measure of tic severity (P ⫽ .05; ES, 0.67). Sedation led to withdrawal for 1 subject in the guanfacine group and was rated as mild in 6 other subjects; none of the patients in the placebo group reported sedation. A 10-point decrease in diastolic BP occurred once in 6 patients in the guanfacine group and 2 patients in the placebo group. Three patients in the active treatment group experienced middle-of-the-night awakening, compared with no patients in the placebo group.26 Another randomized, controlled trial examined the effects of guanfacine in 24 subjects with TS. In this study, pretreatment tic severity was mild, and only 4 children met the criteria for ADHD. The guanfacine dose was low (1-2 mg/day), and the study duration was only 4 weeks. Because of these design problems and the small sample size, it is not surprising that guanfacine was not superior to placebo on the ADHD-RS or on the clinician-rated tic measure. Although not statistically significant, the ES on the clinician measure of tic severity was similar to that reported in the Scahill et al study.28 The Journal of Pediatrics • May 2009

Although the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision advises against using the diagnosis of ADHD in patients with PDD, hyperactivity is a common complaint of parents of children with PDD. Guanfacine was studied in an 8-week, open-label trial of 25 subjects with PDD (7 with autism, 18 with PDD not otherwise specified).29 The sample of 23 boys and 2 girls had a mean age of 9.03 ⫾ 3.14 years, and all had previously demonstrated an unsatisfactory response to MPH. Children ⬍25 kg of body weight started with 0.25 mg at bedtime, with a planned increase of 0.25 twice a day on day 4 and 0.25 3 times a day on day 8. Clinicians could raise the dose as tolerated every 4 days to a maximum of 3.5 mg/day. Children ⬎25 kg started with 0.5 mg and followed a similar dose adjustment schedule, with 0.5 increments to a maximum of 5.0 mg/day. At week 8, the dose ranged from 1.0 to 3.0 mg/day.29 The primary efficacy outcome was the parent-rated Hyperactivity subscale of the Aberrant Behavior Checklist (ABC),30 which has been used in several trials in developmentally disabled children. Baseline to endpoint improvement in the ABC Hyperactivity subscale by the parent was 39%; there was also a 27% decline on the ABC Hyperactivity subscale scored by the child’s teacher.29 The improvements observed in this trial were similar to those seen in children with ADHD and tic disorders, although parents reported greater benefit in this sample of children with PDD than did teachers. The trend was the opposite in the study by Scahill et al26 of children with tic disorders. These encouraging results of guanfacine in children with PDD accompanied by hyperactivity and distractibility warrant a larger, placebo-controlled trial. Transient sedation was common, occurring in 8 of 25 subjects. Mid-sleep awakening also appeared to be more common in this sample of children with PDD compared with children with tic disorders, although it often resolved with dose manipulation. Reports of irritability (moody, tearful, easily frustrated) were relatively common occurring in 10 subjects. This complaint resolved in 6 subjects, but resulted in treatment discontinuation in 4 subjects. Across these trials, guanfacine was generally well tolerated, although children with PDD may have a greater risk for AEs. Several case reports of rare but severe AEs have been described in children treated with guanfacine. There have been 2 reports of auditory hallucinations, which resolved with dose reduction in 1 case.31,32 In the second case, the hallucinations cleared when the guanfacine was discontinued.31 Five cases of mania have been reported in patients, 4 patients with ADHD and TS and 1 patient with ADHD and developmental disabilities.33 In 1 of these cases, the child was being simultaneously withdrawn from clonidine while guanfacine was being introduced, confounding the assessment of the hypomanic reaction. In the 4 cases, the children had a history of hypomania after initiation of an antidepressant (imipramine [n ⫽ 1], fluoxetine [n ⫽ 2], paroxetine [n ⫽ 1]), suggesting a vulnerability to manic switching. These case reports are difficult to interpret. The hypomanic behavior

emerged within 2 to 4 days of starting guanfacine, suggesting that clinicians should be attentive to early signs of hypomania, especially in children with a history of drug-induced mania.

EXTENDED RELEASE FORMULATION An ER preparation of guanfacine has been evaluated in several pivotal trials to obtain US Food and Drug Administration approval for guanfacine in ADHD. Biederman et al published the results of the first trial, which included 345 children (257 boys, 88 girls) aged 6 to 17 years (mean age, 10.5 years) with ADHD (72% combined subtype).34 Patients were randomized to placebo (n ⫽ 86), guanfacine ER 2 mg/day (n ⫽ 87), guanfacine ER 3 mg/day (n ⫽ 86), and guanfacine ER 4 mg/day (n ⫽ 86).34 All subjects randomized to active medication began on the 2-mg dose. Then, depending on group assignment, the dose was increased to 3 mg at week 2 and to 4 mg at week 3. This seemingly rapid dosing strategy was pursued in these trials because the bioavailability of the ER formulation is lower than that of the IR formulation. Therefore, the daily dose levels in milligrams are not comparable with those of guanfacine IR.34 In addition, the ER formulation offers a continuous effect throughout much of the day; the IR formulation achieves faster and higher peak levels. Thus the transition from the IR to ER formulation in future clinical practice may result in an increase in the milligrams per day to achieve the same effect. The primary outcome measure was change from baseline to week 4 in the clinician-rated ADHD-RS total score.34 Secondary efficacy outcome measures included the Conners’ Parent and Teacher Rating Scales revised short form (CPRSR-S and CTRS-R-S),35 Clinical Global Impressions– Improvement (CGI-I),36 and Parent Global Assessment.34 All doses of guanfacine demonstrated a statistically significant improvement.34 The weight-adjusted actual dosing supported a dose-dependent increase in efficacy.34 Improvements were observed on both the Hyperactivity/Impulsivity and Inattention subscales of the ADHD-RS.34 When evaluated by ADHD subgroup, the inattentive subtype did not show a significant improvement on the primary outcome measure. Noting that only 26 of 345 subjects were diagnosed with being inattentive, the finding of no difference between active and placebo may be due to inadequate statistical power.34 On the basis of age subgroups, the youngest subgroup (age range, 6-8 years) indicated the greatest statistically significant improvement, the middle subgroup (age range, 9-12 years) showed some statistically significant improvement, and the adolescent subgroup (age range, 13-17 years) demonstrated no statistically significant improvement.34 Because of the evidence that higher mg/kg dose levels were associated with greater benefit, older children may have been under-dosed. This is consistent with findings from a pharmacokinetic study with guanfacine ER in which maximum plasma concentration and mean plasma concentration were lower in adolescents than pre-pubertal children at fixed doses.37 Rather than presume that a higher dose was needed in the adolescent subjects, however, it may also be

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that the 4-week duration of the trial did not provide sufficient time to show an effect. The most common AEs were sedation, somnolence, abdominal pain, and fatigue. Adverse events were generally in the mild-to-moderate range and resolved in all but 5% to 10% of cases. Somnolence, sedation, or both led to study withdrawal in 7.7% of subjects. Across dose levels, 9 of 87 subjects receiving 2 mg/day, 13 of 86 subjects receiving 3 mg/day, and 20 of 86 subjects receiving 4 mg/day withdrew from the trial because of AEs. Small decreases in heart rate and BP were noted, but led to study withdrawal in only 1 case. The positive results of this trial need to be considered in light of several limitations. First, the brief duration of the trial provides no information on longer-term effects. Second, although the study provides important information on the 3 active doses, exposure to the 3- and 4-mg dose was only 2 weeks and 1 week, respectively. Future trials might consider flexible dosing and longer duration of treatment.

DISCUSSION MPH is often regarded as the first-line treatment for children with ADHD.38 However, a substantial minority of children may not show clinical benefit with MPH or may encounter unacceptable AEs requiring discontinuation. Furthermore, children in special populations, such as those with PDD or tic disorders, may not show the large ES associated with stimulant medication compared with children with ADHD uncomplicated by PDD or tic disorders. Earlier trials with guanfacine IR suggest that it may be effective in these populations in children who have not shown a positive response to stimulant medication.26,29 Studies by the TS Study Group and Palumbo et al also suggest that the combination of an alpha-2 agonist and MPH have additive effects. Thus, future research with guanfacine ER in combination with stimulants might also be informative. Future trials with guanfacine ER could also incorporate tests of attention before and after treatment and the application of pharmacogenetic analysis to determine whether specific genotypes predict positive or negative treatment response.

AUTHOR DISCLOSURE Lawrence Scahill, MSN, PhD, has received consulting fees from Janssen Pharmaceuticals Inc., Supernus Pharmaceuticals Inc., Bristol-Myers Squibb, Shire Pharmaceuticals, Inc., and Neuropharm.

REFERENCES 1. Scahill L, Schwab-Stone M. Epidemiology of ADHD in school-age children. Child Adolesc Psychiatr Clin N Am 2000;9:541-55, vii. 2. Cohen DJ, Young JG, Nathanson JA, Shaywitz BA. Clonidine in Tourette’s syndrome. Lancet 1979;2:551-3. 3. Hunt RD, Minderaa RB, Cohen DJ. Clonidine benefits children with attention deficit disorder and hyperactivity: report of a double-blind placebo-crossover therapeutic trial. J Am Acad Child Psychiatry 1985;24:617-29. 4. Arnsten AF, Steere JC, Hunt RD. The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder. Arch Gen Psychiatry 1996;53:448-55. 5. Westfall TC, Westfall DP. Andrenergic agonists and antagonists. In: Brunton LL, editor. Goodman and Gilman’s the pharmacological basis of therapeutics. 11th ed. New York, NY: The McGraw Hill Companies; 2005.

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6. MacDonald E, Kobilka BK, Scheinin M. Gene targeting— homing in on alpha 2-adrenoceptor-subtype function. Trends Pharmacol Sci 1997;18:211-9. 7. Rubia K, Smith AB, Brammer MJ, Taylor E. Right inferior prefrontal cortex mediates response inhibition while mesial prefrontal cortex is responsible for error detection. Neuroimage 2003;20:351-8. 8. Jakala P, Riekkinen M, Sirvio J, Koivisto E, Riekkinen P Jr. Clonidine, but not guanfacine, impairs choice reaction time performance in young healthy volunteers. Neuropsychopharmacology 1999;21:495-502. 9. Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, et al. Alpha2Aadrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 2007;129:397-410. 10. Arnsten AF, Cai JX, Goldman-Rakic PS. The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci 1988;8:4287-98. 11. Kugler J, Seus R, Krauskopf R, Brecht HM, Raschig A. Differences in psychic performance with guanfacine and clonidine in normotensive subjects. Br J Clin Pharmacol 1980;10(suppl 1):71-80S. 12. Spiegel R, DeVos JE. Central effects of guanfacine and clonidine during wakefulness and sleep in healthy subjects. Br J Clin Pharmacol 1980;10(suppl 1):165-8S. 13. Yamadera H, Ferber G, Matejcek M, Pokorny R. Electroencephalographic and psychometric assessment of the CNS effects of single doses of guanfacine hydrochloride (Estulic) and clonidine (Catapres). Neuropsychobiology 1985;14:97-107. 14. Balldin J, Berggren U, Eriksson E, Lindstedt G, Sundkler A. Guanfacine as an alpha-2-agonist inducer of growth hormone secretion--a comparison with clonidine. Psychoneuroendocrinology 1993;18:45-55. 15. Leckman JF, Ort S, Caruso KA, Anderson GM, Riddle MA, Cohen DJ. Rebound phenomena in Tourette’s syndrome after abrupt withdrawal of clonidine. Behavioral, cardiovascular, and neurochemical effects. Arch Gen Psychiatry 1986;43:1168-76. 16. Wilson MF, Haring O, Lewin A, Bedsole G, Stepansky W, Fillingim J, et al. Comparison of guanfacine versus clonidine for efficacy, safety and occurrence of withdrawal syndrome in step-2 treatment of mild to moderate essential hypertension. Am J Cardiol 1986;57:43-9E. 17. Arnsten AF, Scahill L, Findling RL. Alpha(2)-Adrenergic receptor agonists for the treatment of attention-deficit/hyperactivity disorder: emerging concepts from new data. J Child Adolesc Psychopharmacol 2007;17:393-406. 18. Connor DF, Fletcher KE, Swanson JM. A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1999;38:1551-9. 19. Palumbo DR, Sallee FR, Pelham WE Jr, Bukstein OG, Daviss WB, McDermott MP. Clonidine for attention-deficit/hyperactivity disorder: I. Efficacy and tolerability outcomes. J Am Acad Child Adolesc Psychiatry 2008;47:180-8. 20. Tourette Syndrome Study (TSS). Treatment of ADHD in children with tics: a randomized controlled trial. Neurology 2002;58:527-36. 21. Goyette CH, Conners CK, Ulrich RF. Normative data on revised Conners Parent and Teacher Rating Scales. J Abnorm Child Psychol 1978;6:221-36. 22. Daviss WB, Patel NC, Robb AS, McDermott MP, Bukstein OG, Pelham WE Jr, et al. Clonidine for attention-deficit/hyperactivity disorder: II. ECG changes and adverse events analysis. J Am Acad Child Adolesc Psychiatry 2008;47:189-98. 23. Chappell PB, Riddle MA, Scahill L, Lynch KA, Schultz R, Arnsten A, et al. Guanfacine treatment of comorbid attention-deficit hyperactivity disorder and Tourette’s syndrome: preliminary clinical experience. J Am Acad Child Adolesc Psychiatry 1995;34:1140-6. 24. Horrigan JP. Guanfacine for treatment of attention-deficit hyperactivity disorder in boys. J Child Adolesc Psychopharmacol 1995;5:215-23. 25. Hunt RD, Arnsten AF, Asbell MD. An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1995;34:50-4. 26. Scahill L, Chappell PB, Kim YS, Schultz RT, Katsovich L, Shepherd E, et al. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry 2001;158:1067-74. 27. DuPaul GJ, Ervin RA, Hook CL, McGoey KE. Peer tutoring for children with attention deficit hyperactivity disorder: effects on classroom behavior and academic performance. J Appl Behav Anal 1998;31:579-92. 28. Cummings DD, Singer HS, Krieger M, Miller TL, Mahone EM. Neuropsychiatric effects of guanfacine in children with mild Tourette syndrome: a pilot study. Clin Neuropharmacol 2002;25:325-32. 29. Scahill L, Aman MG, McDougle CJ, McCracken JT, Tierney E, Dziura J, et al. A prospective open trial of guanfacine in children with pervasive developmental disorders. J Child Adolesc Psychopharmacol 2006;16:589-98. 30. Aman MG, Singh NN, Stewart AW, Field CJ. The aberrant behavior checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic 1985;89:485-91. 31. Boreman CD, Arnold LE. Hallucinations associated with initiation of guanfacine. J Am Acad Child Adolesc Psychiatry 2003;42:1387.

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32. Luthra V, Markov D, Ambrosini P. Does guanfacine cause hallucinations in children? J Child Adolesc Psychopharmacol 1999;9:313-4. 33. Horrigan JP, Barnhill LJ. Guanfacine and secondary mania in children. J Affect Disord 1999;54:309-14. 34. 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:e73-84. 35. Conners CK. Conners’ rating scales revised—technical manual. N. Tonowanda, NY: Multi-Health Systems; 1997.

36. Guy W. ECDEU Assessment manual for psychopharmacology. US Department of Health, Education, and Welfare, National Institutes of Mental Health. Washington, DC: NIMH publication; 1976. p. 76-338. 37. Boellner SW, Pennick M, Fiske K, Lyne A, Shojaei A. Pharmacokinetics of a guanfacine extended-release formulation in children and adolescents with attentiondeficit-hyperactivity disorder. Pharmacotherapy 2007;27:1253-62. 38. Multimodal Treatment Study of ADHD (MTA) Study Group. Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder: the Multimodal Treatment Study of children with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 1999;56:1088-96.

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Supplement to THE JOURNAL OF

PEDIATRICS

Advances in the Treatment of Pediatric ADHD: A Focus on the Role of Noradrenergic Inputs and the Alpha-2a Receptor

CME SECTION ASSESSMENT TEST AND EVALUATION FORM

Jointly Sponsored by Postgraduate Institute for Medicine

MDG Development Group

Release Date: May 2009

Expiration Date: May 2010

CME ASSESSMENT TEST

Advances in the Treatment of Pediatric ADHD: A Focus on the Role of Noradrenergic Inputs and the Alpha-2a Receptor Supplement to The Journal of Pediatrics 1. The PFC is involved in: a. the generation of language b. the regulation of attention, behavior, and emotion c. the regulation of motor responses d. executive functions such as insight and judgment e. all of the above 2. Regarding the nonstimulant treatment of ADHD, which of the following statements is false? a. Guanfacine acts directly at postsynaptic, alpha-2a receptors in the PFC b. Clonidine has significant sedative and hypotensive actions c. Guanfacine is currently used only in children with ADHD d. Clonidine has a very rapid onset of action e. Atomoxetine selectively blocks the NE transporter 3. Clonidine’s main mechanism of action in the PFC is via: a. stimulation of the D1 family of receptors (D1 and D5) b. inhibition of cAMP-HCN channel signaling in dendritic spines c. stimulation of the D2 family of receptors (D2, D3, D4) d. stimulation of alpha-2a, -2b, and -2c receptor subtypes e. none of the above 4. Phase III trials of guanfacine ER as treatment for ADHD have shown which of the following side effects? a. sedation b. fatigue c. abdominal pain d. all of the above e. none of the above 5. The predominant type of NE receptor in the locus ceruleus is: a. alpha-2c b. alpha-2b c. alpha-2d d. alpha-2a e. none of the above 6. Which of the following can be used to clinically distinguish ODD and CD? a. difficulty sleeping b. excessive talking c. forgetfulness d. history of criminal activity, truancy, and/or violence e. all of the above

7. Pediatric patients with ADHD also tend to suffer from: a. major depressive disorder b. bipolar disorder c. dysthymia d. anxiety disorders e. all of the above 8. Uncomplicated ADHD is characterized by all of the following except: a. poor classroom attention b. forgetfulness c. excessive talking d. property destruction e. trouble sleeping 9. Which of the following is the only non-stimulant medication approved for ADHD in the United States? a. atomoxetine b. fluoxetine c. bupropion d. modafinil e. clonidine 10. All of the following risks are associated with atomoxetine except: a. seizure b. growth retardation c. hepatotoxicity d. gastric ulcers e. cardiovascular events