VOLUME 1 NUMBER 4 2007 Advances inADHD EDITOR-IN-CHIEF Robert L Findling, Cleveland, OH, USA

ADHD and Comorbid Anxiety Disorders SR Pliszka The Role of Primary Care Clinicians in the Care of Children with ADHD ML Wolraich The Feasibility of School-Based Moderate-to-Vigorous Physical Activity in Children with ADHD

SB Wigal, M Schneider, AS Nguyen, A Kapelinski, A Shanklin, and D Cooper

Autism and ADHD: Theoretical Considerations and Treatment Strategies RD Melmed and SO Reynolds

www.advances-in-adhd.com

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 the University of Kentucky College of Medicine and Remedica. The University of Kentucky College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. The University of Kentucky is an equal This journal is supported by an opportunity university. educational grant from Shire Editor-in-Chief Robert L Findling Contents Director, Child & Adolescent , University Hospitals of Cleveland; Professor of Psychiatry & Pediatrics, Case Western Leading Articles Reserve University, University Hospitals of Cleveland, OH, USA ADHD and Comorbid Anxiety Disorders Steven R Pliszka 106 Editorial Advisory Board Stephen V Faraone The Role of Primary Care Clinicians Director, Medical Genetics Research, Professor of Psychiatry in the Care of Children with ADHD and of & Physiology, Director, Child and Mark L Wolraich 111 Adolescent Psychiatry Research, State University of New York at Buffalo Upstate Medical University, Syracuse, NY, USA Autism and ADHD: Theoretical Considerations and Treatment Strategies Martin T Hoffman Raun D Melmed and Sharman Ober Reynolds 115 Associate Professor of Clinical Pediatrics, State University New York, University at Buffalo School of Medicine and Scientific Progress Biomedical Science, Buffalo, NY, USA The Feasibility of School-Based Frank Lopez Moderate-to-Vigorous Physical Activity Children's Developmental Center, Maitland, FL, USA in Children with ADHD Sharon B Wigal, Margaret Schneider, Michael Manos Annamarie Stehli, Audrey Kapelinski, Head, Section of Behavioral Medicine, Division of Pediatrics, Amanda Shanklin, and Dan Cooper 121 ADHD Center of Children's Hospital at the Cleveland Clinic, Cleveland, OH, USA Clinical Reviews Elizabeth J Short Genetics 127 Full Professor of , Case Western Reserve University, Diagnosis and Assessment 130 Cleveland, OH, USA Comorbidity 131 Edmund J Sonuga-Barke Director, Developmental Brain Behaviour Unit, Treatment Strategies 132 University of Southampton, Southampton, UK Epidemiology 133 Sharon B Wigal Associated Behaviors 134 Clinical Professor of Pediatrics, UCI Child Development Center, Irvine, CA, USA Miscellaneous 136

Editors Meeting Report Vishal Madaan Highlights of the 19th Annual US Psychiatric and Mental Health Congress Clinical Fellow, Division of Child and Adolescent Psychiatry, November 16–19, 2006, New Orleans, LA, USA 139 Creighton University, Omaha, NE, USA Julia Noland Forthcoming International Events 143 Research Assistant Professor, Vanderbilt University, Nashville, TN, USA Angelita Sanchez Ohio State University, Columbus, OH, USA

Editorial Policy Publisher’s Statement Advances in ADHD is an independent journal published by Remedica Medical Education and Publishing. © 2007 Remedica Medical Education and Publishing. Editorial control is the sole responsibility of the Editor-in-Chief, Editorial Advisory Board, and the Editors. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or Before publication, all material submitted to the journal is subjected to rigorous review by the Editor-in- transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise Chief, Editorial Advisory Board, Editors, and/or independent reviewers for suitability of scientific content, without the prior permission of the copyright owners. While every effort is made by the publishers and scientific accuracy, scientific quality, and conflict of interest. editorial board to see that no inaccurate or misleading data, opinions, or statements appear in this journal, they wish to make it clear that the material contained in the publication represents a summary of the Aims and Scope independent evaluations and opinions of the authors and contributors. As a consequence, the board, Advances in ADHD is designed to bring a critical analysis of the world literature on ADHD, written by publishers, and any supporting company accept no responsibility for the consequences of any such clinicians, for clinicians, to an international, multidisciplinary audience. Our mission is to promote better inaccurate or misleading data or statements. Neither do they endorse the content of the publication or the understanding of the treatment of ADHD across the global healthcare system by providing an active use of any drug or device in a way that lies outside its current licensed application in any territory. forum for the discussion of clinical and healthcare issues. Advances in ADHD (ISSN 1750-8681) is published four times a year. Additional subscription information Leading Articles - These major review articles are chosen to reflect topical clinical and healthcare issues in is available from the publishers. ADHD. All contributions undergo a strict editorial review process. Remedica Medical Education and Publishing Ltd., Commonwealth House, 1 New Oxford Street, Clinical Reviews - The most important papers from the best of the international literature on ADHD are London WC1A 1NU, UK. systematically selected by an internationally recognized panel of experts. The Editors then prepare concise Telephone: +44 (0)20 7759 2999 Fax: +44 (0)20 7759 2951 Email: [email protected] and critical analyses of each paper, and, most importantly, place the findings into clinical context. Editorial Team: Joe Gray, Scott Millar Editorial Director: Reghu Venkatesan Meeting Reports - Advances in ADHD also provides incisive reportage from the most important Design and Artwork: AS&K Skylight Creative Services Publishers: Ian Ackland-Snow, Simon Kirsch international congresses. ISSN 1750-8681 ADHD and Comorbid Anxiety Disorders

Steven R Pliszka Division of Child and Adolescent Psychiatry, University of Texas Health Science Center, San Antonio, TX, USA

Anxiety disorders are a comorbidity in 25–33% of children and adults with ADHD. During childhood and adolescence, there is often little agreement between parent and child reports of anxious symptoms, and there may be different clinical correlates of the anxiety disorder based on the source of diagnosis. ADHD and anxiety disorders appear to be influenced by separate and independent genetic factors. Contrary to findings from early research, it has been established in more recent studies that children with ADHD and an anxiety disorder (ADHD+ANX) respond as well to stimulant medication (in terms LEADING ARTICLE of ADHD symptoms) as those with ADHD alone, but children with ADHD+ANX may experience a greater benefit from psychosocial intervention. may be an effective intervention for these children as well. The efficacy of specific serotonin reuptake inhibitors for treating anxiety in children with ADHD+ANX remains to be established, although they appear effective in children with anxiety alone. Advances in ADHD 2007;1(4):106–10.

Anxiety disorders have a wide range of presentations in to the point that it is self-defeating. In an interview about children. These disorders range from those that are unique anxiety symptoms, the clinician asks both the parent and the to the pediatric age group, such as separation anxiety and child if the child is anxious (nervous or scared) about a variety elective mutism, to those that may occur at any point in the of situations (including school, social situations, world events, lifespan (generalized anxiety disorder, specific phobia, panic health, objects, and animals) and if the anxiety impairs disorder, agoraphobia, and social anxiety disorder). In function. Symptomatic anxiety is also generally associated general, anxiety disorders receive less from with physical phenomena such as muscle tension, poor sleep, clinicians than either ADHD or affective disorder, but a internal feeling of restlessness, sweating, a racing heart, or substantial body of research has emerged in the last decade shortness of breath. When the symptoms of physical arousal not only on the anxiety disorders in children per se, but on are extreme and uncontrollable, a panic attack is said to occur. the comorbidity of anxiety with ADHD. The two disorders Diagnoses of anxiety disorders in children are appear to interact when they appear together in a patient, complicated by the fact that parents and children rarely each moderating the symptom expression and treatment agree on the presence or absence of anxiety symptoms response of the other. [1,2]. This means that the clinician will encounter many situations in which the child reports anxiety but the parent Clinical assessment of anxiety does not; in other situations, parents may describe their child in children with ADHD as anxious while the child denies all such feelings. Anxiety is a high-arousal negative state that occurs in Unfortunately, most structured child psychiatric interviews response to a perceived threat. The threat may be a physical give little guidance about how to deal with discordant child one (e.g. an approaching hurricane) or a social one (e.g. an and parent responses. For instance, the Kiddie Schedule for upcoming examination). Anxiety is adaptive if it causes an Affective Disorders and Schizophrenia for School-Age individual to take action against a threat (evacuating the coast Children requires separate interviews for the child and or studying for the examination, for instance), but becomes parent, but then calls for summary ratings of each symptom symptomatic if it is so severe that a person is persistently in a by the clinicians, combining information from the two negative state (always worrying) or needs to avoid situations interviews [3]. In contrast, the Diagnostic Interview Schedule for Children is administered in a highly structured format to the child and parent separately, although many studies have This review discusses off-label use of specific serotonin reuptake inhibitors. used only the parent version coupled with a standardized Address for correspondence: Steven R Pliszka, Division of Child and anxiety self-report scale filled out by the child [4]. As will be Adolescent Psychiatry, University of Texas Health Science Center at shown below, some studies show differing effects of anxiety San Antonio, 7703 Floyd Curl Drive MC 7792, San Antonio, on the symptoms and treatment of ADHD depending on the TX 78229-3900, USA. Email: [email protected] source of information about the anxiety.

106 ADVANCES IN ADHD Vol 1 No 4 2007 ADHD AND COMORBID ANXIETY DISORDERS

Table 1. Overlap of anxiety disorders and ADHD. Study Form of anxiety Proportion of patients with Proportion of patients with (if specified) ADHD who also had anxiety anxiety who also had ADHD (if reported) (if reported) Children Anderson et al. [39] 26% 24% Bird et al. [1] 23% 21% Pliszka [10] 28% – Last et al. [7] Separation anxiety – 23% Over-anxiety – 15% Newcorn et al. [17] 33% – Biederman et al. [23] 29% –

Adults Biederman et al. [9] Generalized anxiety disorder 43% – Social phobia 32% – Multiple anxiety disorders 50% – Fones et al. [8] Panic disorder – 23.5% (childhood history) 9.4% (adult ADHD)

Prevalence of anxiety disorders • More impulsive responding on a memory task [10]. in children with ADHD • Poorer performance on a measure of response A substantial body of research shows that anxiety disorders inhibition [12]. occur in people with ADHD far above the levels expected by • More errors of commission on the continuous chance. As noted in Table 1, estimates of the prevalence of performance task [11]. anxiety disorders in children with ADHD have ranged from 23% to 33%, compared with a prevalence of about 6–20% in In contrast, children with ADHD+ANX showed poorer the general pediatric population [5]. It has been calculated that working memory compared with controls and those with the chance of having an anxiety disorder is 2.1- to 4.3-fold ADHD alone [13]. Manassis et al. compared four groups of greater in children with ADHD than the general pediatric children (ADHD only, ADHD+ANX, ANX only, and controls) population [6]. In addition, children with anxiety disorders on a dichotic listening task that measures sensitivity to the have higher than expected rates of ADHD [7], as do adults emotional content of words [14]. In this task, words relating with panic disorder [8]. Adults with ADHD also show high to sadness are detected preferentially in the left ear rates of anxiety disorders relative to the general population [9]. (negative emotion is processing more strongly by the right hemisphere). All four groups showed the expected Effect of anxiety on the phenomenology of ADHD lateralization of detecting sad words on the left, but this How does the comorbidity of anxiety affect the presentation effect was significantly greater in the ADHD+ANX group. of ADHD symptoms? A number of studies have examined The ADHD+ANX group did not show response inhibition this issue by comparing children with ADHD and an anxiety deficits relative to controls on the Stop Signal task. disorder (ADHD+ANX) with those with ADHD alone on a Studies have been inconsistent with regard to whether or variety of cognitive, behavioral, and psychosocial measures. not children with ADHD and those with ADHD+ANX differ Pliszka assessed children with ADHD alone and those with in terms of the presence of other disruptive behavior ADHD+ANX in an observation room where the subjects had disorders. One study found a lower rate of conduct disorder to perform mathematics problems while the rates of off- (CD) in children with ADHD+ANX relative to those with task, fidgeting, vocalizing, and out-of-seat behaviors were ADHD alone [10], while other studies have shown either no assessed by a rater blind to diagnosis [10,11]. The children difference in the rate of oppositional defiant disorder (ODD) with ADHD+ANX showed lower rates of these impulsive, or CD (ODD/CD) [11,15] or increased rates of ODD/CD hyperactive behaviors than those with ADHD alone. [16,17]. The subgroup of children with dual comorbidity Compared with those with ADHD+ANX, the ADHD-only (ADHD+ANX and ODD/CD) is particularly interesting as group showed: they may show differences from children with ADHD+ANX

ADVANCES IN ADHD Vol 1 No 4 2007 107 STEVEN R PLISZKA

but no ODD/CD. Newcorn et al. assessed continuous anxiety only. This means that ADHD+ANX is not a distinct performance test errors as a function of comorbidity in genetic subtype from ADHD alone; rather, ADHD and anxiety children with ADHD in the MTA (Multimodality Treatment disorders are inherited independently. Additional family of ADHD) study [17]. The ADHD+ANX group showed studies performed by Perrin and Last have been consistent decreased and dyscontrol errors relative to the with this pattern [e.g. 24]. ADHD-only and the dual-comorbid groups. This effect was It is conceivable that there is a certain degree of moderated by sex: only girls with ADHD+ANX showed this assortative mating, whereby there is a higher likelihood that pattern. Subjects with ADHD+ANX and ODD/CD were as people with ADHD will have children with people with impulsive on this measure as those with ADHD alone. anxiety disorders. This would be one explanation of the Teachers also rated children with ADHD+ANX as less higher than expected co-occurrence of anxiety disorders and impulsive than either the ADHD-only or dual-comorbid ADHD. Anxiety cannot be viewed as secondary to ADHD group. On the other hand, parents rated children with because relatives of children with ADHD+ANX often have ADHD+ANX and ODD/CD as more impulsive and anxiety disorders without having ADHD [23]. hyperactive than those with ADHD alone. Children with ADHD+ANX may have higher rates of Effect of anxiety on the treatment of ADHD stressful life events than those with only ADHD [15], Early studies suggested that children with ADHD who although they are not different in terms of school showed high levels of anxiety showed a poorer response to performance or learning disabilities [16]. Maternal anxiety stimulant medication compared with those with ADHD during the prenatal period is associated with higher than alone [10,25]. Pliszka randomized a large number of children expected rates of ADHD in the child [18]. There is also with either ADHD alone or ADHD+ANX in a 4-week, evidence that children with ADHD+ANX are physiologically double-blind, placebo-controlled trial of different from those with ADHD alone. Relative to children [10]. Response to medication was assessed by teacher and with ADHD, children with ADHD+ANX show a greater parent rating scales as well as by weekly observations in a increase in diastolic blood pressure when moving from laboratory setting where behavior was assessed by blinded a sitting to a standing position [19]. This is consistent raters. Response was defined as behavior rating scale scores with findings from an earlier study assessing urinary on one of the weeks of stimulant therapy being improved by norepinephrine and its metabolites in children with ADHD at least one standard deviation over the scores during the alone, children with ADHD+ANX, and controls [20]. The two placebo week. Based on this criterion, 87% of the children ADHD groups showed evidence of increased noradrenergic with ADHD were considered responders, compared with activity, but there was evidence that the ADHD+ANX group 31% of the subjects in the ADHD+ANX group. The ADHD- demonstrated increased acute release of norepinephrine only group also showed more robust reductions of off-task during a stressful task compared with the ADHD-only group. behaviors in the observation room. Pliszka concluded that This raises the intriguing question of whether or not the children with ADHD+ANX responded less robustly to comorbidity of anxiety superimposes a more active stimulants than those without anxiety, although there was noradrenergic state on a noradrenergic system already made no evidence that methylphenidate worsened symptoms of dysfunctional by ADHD. either ADHD or anxiety in those with ADHD+ANX [10]. More extensive later studies did not confirm this finding. What causes the increased risk Diamond et al. randomized 91 children with either ADHD of anxiety in ADHD? alone or ADHD+ANX in a short-term controlled trial of Genetic factors are involved in the etiology of both ADHD methylphenidate, which was followed by a 4-month and anxiety disorders [21,22]. Family studies have attempted extended trial [2]. Subjects with and without anxiety to disentangle the separate genetic factors by examining the responded equally well to the stimulant, and side effects rates of both ADHD and anxiety disorders in the relatives of were similar in the two groups. There was little children with ADHD and ADHD+ANX [23,24]. Relative to a correspondence between the parent and child reports of control sample, rates of ADHD were found to be elevated in anxiety, but response to methylphenidate was equally good the relatives of both subjects with ADHD and those with regardless of whether the anxiety diagnosis was based on ADHD+ANX, but elevated rates of anxiety were only found in parent or child reporting. Another study found that anxiety the relatives of the ADHD+ANX group [23]. Co-segregation was not a predictor of non-response in children with ADHD of ADHD and anxiety disorders was not found in the relatives who had comorbid tics [26]. The most definitive piece of of the children with ADHD+ANX; that is, the children had research on this matter was the MTA study, a 5-week, some relatives with ADHD only while other relatives had double-blind, placebo-controlled crossover study of

108 ADVANCES IN ADHD Vol 1 No 4 2007 ADHD AND COMORBID ANXIETY DISORDERS

methylphenidate [4]. Again, the children with ADHD+ANX effect of CBT on anxiety. Manassis et al. divided their sample showed as positive a response to methylphenidate as those of anxious children (8% of whom had ADHD) into high- or with ADHD alone. Subjects in the MTA study were also low-hyperactivity groups based on parent rating. A median randomized to community treatment, intensive behavioral split was used, so many of the “highly hyperactive” subjects intervention, medication management, or a combination of did not have ADHD [29]. Parent-reported activity level did the medication and behavioral intervention. Interestingly, not relate to outcome after CBT treatment. This suggests those subjects with ADHD+ANX (but not ODD/CD) had a that a diagnosis of ADHD should not preclude the use of more robust response to the behavioral intervention by itself CBT in treating anxious children, although it should be than non-anxious children with ADHD. The subgroup with noted that CBT is not an effective treatment for ADHD per dual comorbidity (ADHD+ANX and ODD/CD) was more se [30]. In addition, some highly distracted children with likely to benefit from the combination treatment than the ADHD may not be able to be actively involved in CBT until children with ADHD alone. In a further analysis of the MTA their inattention is treated with medication. treatment outcome data, March et al. showed that it was parent-reported anxiety alone that was a moderator; there Pharmacological treatment was no relationship between the child’s self-reporting of How and when should anxiety be treated pharmacologically anxiety and treatment outcome [27]. Parent-reported in the presence of ADHD? Numerous studies have anxiety was strongly related to the comorbidity of ODD/CD established the efficacy of specific serotonin reuptake and to the phenomena of “negative affectivity”, rather than inhibitors (SSRIs) in the treatment of a variety of childhood fears and phobia. Therefore, March et al. hypothesized that psychiatric disorders [31–34], although caution is needed in the strong behavioral management focus of the MTA the use of these agents owing to the small but statistically psychosocial intervention was helpful for children with significant risk of increasing suicidal ideation in some ADHD+ANX and ODD/CD because it aided the parent with patients [35]. Given that children with ADHD+ANX respond managing the negativity [27]. March et al. cautioned that well to stimulants, treatment of the ADHD using this class of children who self-report intense phobias or anxieties might medications should generally be the first step [36]. benefit from a cognitive structuring approach used more Alternatively, atomoxetine has been shown to be efficacious commonly for children who have anxiety disorders (see in a small clinical trial for both anxiety and ADHD symptoms below) [27]. Nonetheless, two major clinical issues appear to in children with ADHD+ANX [37]. CBT could be added to have been resolved by the MTA study: either treatment if the anxiety did not resolve with pharmacological intervention. Abikoff et al. treated 32 • Children with ADHD+ANX respond as well to stimulants children who had ADHD+ANX with methylphenidate and as those with ADHD but no anxiety disorders. found that 26 (81%) responded in terms of ADHD • Children with ADHD+ANX might benefit more symptoms but remained anxious [38]. Twenty-five children strongly from the addition of a psychosocial intervention were then randomized to either placebo or fluvoxamine to their pharmacological intervention than children with (while remaining on methylphenidate) for 8 weeks: at the ADHD only. end of the study period there was no difference between the treatment groups in terms of anxiety. Therefore, while the Treating anxiety in the child with ADHD addition of an SSRI to stimulant medications for the Cognitive behavioral therapy treatment of anxiety in children with ADHD+ANX is Cognitive behavioral therapy (CBT) has been shown to be a considered appropriate in more severe situations [36], the highly efficacious treatment for anxiety disorders of efficacy of this approach remains to be established. All use childhood (reviewed in [28]). In CBT, the child and family are of SSRIs for the treatment of childhood anxiety (except for educated about the disorder, taught relaxation techniques, the use of sertraline, fluoxetine, and fluvoxamine in the and involved in cognitive restructuring (developing mental treatment of obsessive compulsive disorder) is not approved techniques to deal with fears and anxieties in a more by the FDA and is therefore considered off-label. adaptive manner) and finding ways to use mental imaging to encounter fearful situations in a virtual manner so as to Conclusion gradually extinguish the fear. In most of the CBT studies Anxiety disorders are a comorbidity in 25–33% of children cited in the above review, only a small proportion of subjects and adults with ADHD. ADHD and anxiety appear to have (range 8–15%) met criteria for ADHD in addition to their independent etiological factors and both represent true anxiety disorder diagnosis. None of these studies were disorders in the individual: the anxiety is not masquerading powered to determine if ADHD was a moderator of the as ADHD or vice versa. In the absence of ODD/CD, anxiety

ADVANCES IN ADHD Vol 1 No 4 2007 109 STEVEN R PLISZKA

15. Biederman J, Faraone SV, Keenan K et al. Familial association between attention deficit appears to attenuate the impulsive symptoms of ADHD. In disorder and anxiety disorders. Am J Psychiatry 1991;148:251–6. the presence of ODD/CD, parent-reported anxiety may 16. Tannock R. Attention deficit disorders with anxiety disorders. In: Brown TE, editor. Attention-Deficit Disorders and Comorbidities in Children, Adolescents and Adults. New represent the presence of negative affectivity rather than York, NY, USA: American Psychiatric Press, 2000:125–75. fearfulness or “neurotic” anxiety per se [27]. Children with 17. Newcorn JH, Halperin JM, Jensen PS et al. Symptom profiles in children with ADHD: effects of comorbidity and gender. J Am Acad Child Adolesc Psychiatry 2001;40:137–46. ADHD+ANX respond to stimulant medication as well as 18. Volkow ND, Wang GJ, Fowler JS et al. Imaging the effects of methylphenidate on brain children with ADHD alone, but they may benefit from dopamine: new model on its therapeutic actions for attention-deficit/hyperactivity disorder. Biol Psychiatry 2005;57:1410–5. psychosocial interventions added to their pharmacological 19. Urman R, Ickowicz A, Fulford P et al. An exaggerated cardiovascular response to treatment. Children with negative affectivity may benefit methylphenidate in ADHD children with anxiety. J Child Adolesc Psychopharmacol 1995;5:29–37. from parent-based behavior management programs, while 20. Pliszka SR, Maas JW, Javors MA et al. Urinary catecholamines in attention deficit those with stronger internalizing symptoms might benefit hyperactivity disorder with and without comorbid anxiety. J Am Acad Child Adolesc Psychiatry 1994;33:1165–73. more from CBT. The use of antidepressant medication for 21. Foley DL, Pickles A, Maes HM et al. Course and short-term outcomes of separation anxiety in children with ADHD requires further study. The anxiety disorder in a community sample of twins. J Am Acad Child Adolesc Psychiatry 2004;43:1107–14. clinician should be prepared to use a wide range of 22. Hudziak JJ, Derks EM, Althoff RR et al. The genetic and environmental contributions to approaches with these complex cases. attention deficit hyperactivity disorder as measured by the Conners’ Rating Scales – Revised. Am J Psychiatry 2005;162:1614–20. 23. Biederman J, Faraone SV, Keenan K et al. Further evidence for family-genetic risk factors in Disclosure attention deficit hyperactivity disorder. Patterns of comorbidity in probands and relatives psychiatrically and pediatrically referred samples. Arch Gen Psychiatry 1992;49:728–38. The author has been involved in speakers’ bureaus for Shire 24. Perrin S, Last CG. Relationship between ADHD and anxiety in boys: results from a family Pharmaceuticals and McNeil Pharmaceuticals and has received study. J Am Acad Child Adolesc Psychiatry 1996;35:988–96. 25. Taylor E, Schachar R, Thorley G et al. Which boys respond to stimulant medication? A research support from Eli Lilly. controlled trial of methylphenidate in boys with disruptive behavior. Psychol Med 1987;17:121–43. 26. Gadow KD, Nolan EE, Sverd J et al. Anxiety and depression symptoms and response to References methylphenidate in children with attention-deficit hyperactivity disorder and tic disorder. 1. Bird HR, Canino G, Rubio-Stipec M. Estimates of prevalence of childhood maladjustment J Clin Psychopharmacol 2002;22:267–74. in a community survey in Puerto Rico. Arch Gen Psychiatry 1988;45:1120–6. 27. March JS, Swanson JM, Arnold LE et al. Anxiety as a predictor and outcome variable in the 2. Diamond IR, Tannock R, Schachar RJ. Response to methylphenidate in children with multimodal treatment study of children with ADHD (MTA). J Abnorm Child Psychol ADHD and comorbid anxiety. J Am Acad Child Adolesc Psychiatry 1999;38:402–9. 2000;28:527–41. 3. Kaufman J, Birmaher B, Brent D et al. Schedule for Affective Disorders and Schizophrenia 28. Compton SN, March JS, Brent D et al. Cognitive-behavioral psychotherapy for anxiety and for School Age Children-Present and Lifetime version (K-SADS-PL): Initial reliability and depressive disorders in children and adolescents: an evidence-based medicine review. validity data. J Am Acad Child Adolesc Psychiatry 1997;36:980–8. J Am Acad Child Adolesc Psychiatry 2004;43:930–59. 4. MTA Cooperative Group. 14 month randomized clinical trial of treatment strategies for 29. Manassis K, Mendlowitz SL, Scapillato D et al. Group and individual cognitive-behavioral children with attention deficit hyperactivity disorder. Arch Gen Psychiatry therapy for childhood anxiety disorders: a randomized trial. J Am Acad Child Adolesc 1999;56:1073–86. Psychiatry 2002;41:1423–30. 5. Costello EJ, Egger HL, Angold A. Developmental epidemiology of anxiety disorders. In: 30. Abikoff H, Gittelman R. Hyperactive children treated with stimulants. Is cognitive training Ollendick TH, March JS, editors. Phobic and Anxiety Disorders in Children and a useful adjunct? Arch Gen Psychiatry 1985;42:953–61. Adolescents. New York, NY, USA: Oxford University Press, 2004. 31. Walkup JT, Labellarte MJ, Riddle MA et al. Fluvoxamine for the treatment of anxiety 6. Angold A, Costello EJ, Erkanli A. Comorbidity. J Child Psychol Psychiatry 1999;40:57–87. disorders in children and adolescents. N Engl J Med 2001;344:1279–85. 7. Last CG, Hersen M, Kazdin AE et al. Comparison of DSM-III separation anxiety and 32. Birmaher B, Axelson DA, Monk K et al. Fluoxetine for the treatment of childhood anxiety overanxious disorders: demographic characteristics and patterns of comorbidity. J Am disorders. J Am Acad Child Adolesc Psychiatry 2003;42:415–23. Acad Child Adolesc Psychiatry 1987;26:527–31. 33. Birmaher B, Yelovich AK, Renaud J. Pharmacologic treatment for children and adolescents 8. Fones CS, Pollack MH, Susswein L et al. History of childhood attention deficit hyperactivity with anxiety disorders. Pediatr Clin North Am 1998;45:1187–204. disorder (ADHD) features among adults with panic disorder. J Affect Disord 2000;58:99–106. 34. Rynn MA, Siqueland L, Rickels K. Placebo-controlled trial of sertraline in the treatment of 9. Biederman J, Faraone SV, Spencer T et al. Patterns of psychiatric comorbidity, cognition, children with generalized anxiety disorder. Am J Psychiatry 2001;158:2008–14. and psychosocial functioning in adults with attention deficit hyperactivity disorder. Am J 35. Food and Drug Administration. Suicidality in children and adolescents being treated with Psychiatry 1993;150:1792–8. antidepressant medications. URL: http://www.fda.gov/cder/drug/antidepressants/ 10. Pliszka SR. Effect of anxiety on cognition, behavior, and stimulant response in ADHD. J Am SSRIPHA200410.htm, last accessed in January 2007. Acad Child Adolesc Psychiatry 1989;28:882–7. 36. Pliszka SR, Crismon ML, Hughes CW et al. The Texas Children’s Medication Algorithm 11. Pliszka SR. Comorbidity of attention deficit hyperactivity disorder and overanxious Project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1992;31:197–203. disorder. J Am Acad Child Adolesc Psychiatry 2006;45:642–57. 12. Pliszka SR, Borcherding SH, Spratley K et al. Measuring inhibitory control in children. J Dev 37. Sumner CS, Donnelly C, Lopez FA et al. Atomoxetine treatment for pediatric patients with Behav Pediatr 1997;18:254–9. ADHD and comorbid anxiety. Presented at the Annual Meeting of the American Psychiatric Association, Atlanta, GA, USA, May 21–26, 2005. 13. Tannock R, Ickowicz A, Schachar R. Differential effects of methylphenidate on working memory in ADHD children with and without comorbid anxiety. J Am Acad Child Adolesc 38. Abikoff H, McGough J, Vitiello B et al. Sequential pharmacotherapy for children with Psychiatry 1995;34:886–96. comorbid attention-deficit/hyperactivity and anxiety disorders. J Am Acad Child Adolesc Psychiatry 44 14. Manassis K, Tannock R, Barbosa J. Dichotic listening and response inhibition in children 2005; :418–27. with comorbid anxiety disorders and ADHD. J Am Acad Child Adolesc Psychiatry 39. Anderson JC, Williams S, McGee R et al. DSM-III disorders in preadolescent children: 2000;39:1152–9. prevalence in a large community sample. Arch Gen Psychiatry 1987;44:69–76.

110 ADVANCES IN ADHD Vol 1 No 4 2007 LEADING ARTICLE 111 o 4 2007 N In the National Ambulatory Medical Care Survey Care In the National Ambulatory Medical health services. mental illness. ol 1 V Diagnostic services diagnostic services for clinicians provide Many primary care a a history from ADHD, which should consist of obtaining the obtaining information from and the child and parent exam, a physical and neurological school as well as providing their patients to mental health clinicians although some refer medication provide for the diagnostic aspects and then management once the diagnosis is clarified. defined as “services that (NAMCS), diagnostic services were during this visit for the purpose of or provided ordered were or diagnosis”. An analysis of the NAMCS data screening identified by diagnostic codes as found that for children of visits including some having ADHD, the percentage 22.3% in 1989 to overall from diagnostic services increased 1989 to 1991 from increase 62.1% in 1996, with the largest found, types were provider between differences [10]. Large with diagnostic or evaluative services noted on 80.6% of visits to psychiatrists, 64% of visits to pediatricians, and it is unclear 32.6% of visits to family practitioners. However, in the actual differences whether this variation reflects in the delivery of diagnostic services or only a difference conceptualization and coding of visits. Some physicians might consider the monitoring of behaviors to be exclusively • in gaining access to mental difficulty The increasing • The existing negative societal attitudes towards ADHD DVANCES IN A (4):111–4. 1

mental health services. clinicians. primary care In the US, primary care clinicians conduct the majority of In the US, primary care • and between families ongoing relationships The frequent • rate, which exceeds the capacity of The high prevalence ADHD is one of the most common neurobiological disorders ADHD is one of the most common neurobiological rate a prevalence of childhood and adolescence, with depending on the sampling 4% to 12%, ranging from of the definition of ADHD method and the restrictiveness include hyperactivity, symptoms used [1]. Its core and inattention. ADHD commonly occurs with impulsivity, [2], and learning disorders coexisting mental health disorders and the these comorbid disorders of and the added burden in result frequently persistence of ADHD into adulthood than optimal [3]. The impact of less outcomes that are strained peer and ADHD can include academic failure, and low self-image, delinquency, poor family relations, of the occurrence occupational performance [4]. In addition, his or her family incurring in ADHD in a child can result costs [5,6]. and indirect associated direct the largest with ADHD and prescribe visits for children amount of stimulant medications [7,8]. This finding is not taken into surprising when the following factors are consideration [9]: ADHD is one of the most common neurobiological disorders of childhood and adolescence, with a prevalence rate ranging of childhood and adolescence, with most common neurobiological disorders ADHD is one of the ADHD used. Because of the restrictiveness of the definition of on the sampling method and from 4% to 12%, depending care clinicians conduct health services in the US, primary rate, which exceeds the capacity of mental the high prevalence The existing the largest amount of stimulant medications. for children with ADHD and prescribe the majority of visits with treatment services provided by primary care clinicians, when compared studies of the quality of diagnostic and for improvement. Initiatives by professional organizations using adult learning recommended guidelines, suggest the need been instituted, but the impact of these activities has yet to be determined. and quality improvement procedures have Advances in ADHD 2007; Department of Pediatrics, Section of Developmental and Behavioral Pediatrics, University of Oklahoma and Behavioral Pediatrics, University Section of Developmental Department of Pediatrics, OK, USA Oklahoma City, Health Sciences Center, Mark L Wolraich in the Care of Children with ADHD with of Children Care in the The Role of Primary Care Clinicians Clinicians Care Primary Role of The Address for correspondence: Mark L Wolraich, OU Child Study Center, OU Mark L Wolraich, for correspondence: Address OK 73117, USA. Oklahoma City, 1100 NE 13th street, Email: [email protected] MARK L WOLRAICH

a part of medication management, while others might see medication use. An investigation by Jensen et al. of four this as an ongoing diagnostic service with the purpose of communities in the MECA (Methods for Epidemiology of detecting emerging comorbid conditions. Some of the US Child and Adolescent Mental Disorders) study found that heath insurance companies have not reimbursed primary 5.1% of youths met criteria for ADHD, but only 12.5% of care clinicians for diagnostic codes. these youths reported stimulant use during the previous Several studies have been undertaken to determine the 12 months [24]. In contrast, an analysis of data from the practice patterns in primary care settings with respect to the Great Smoky Mountains Study by Angold et al. found that content of diagnostic services. They found that these almost three-quarters of children with a diagnosis of ADHD settings made limited use of diagnostic instruments [11,12], received stimulants, and there were a number of children and primary care providers experienced difficulties collecting being treated with stimulant medications who did not meet information from a second source, such as the school setting diagnostic criteria [25]. Further evidence for geographical [13]. A study by Stevens et al. using 1995–2000 data from variations has been reported in other studies [10,26,27]. the NAMCS and the National Hospital Ambulatory Medical Community factors have been implicated: claims data from a Care Survey found that primary school-aged children were commercially insured sample of youths demonstrated that more likely to receive a diagnosis than preschool-aged or communities with higher incomes or greater proportions of adolescent children [14]. Medicaid insurance coverage was white children have higher rates of use [28]. also positively associated with receipt of a diagnosis, In addition, differences are seen in prescription rates compared with both private insurance and no insurance. based on ethnicity in a number of studies [29,30]. For However, complex interactions were noted between example, Hoagwood et al. found that stimulant medication geographical regions and ethnic groups, and based on use reported in the 1995–2000 NAMCS data was nearly whether or not an ADHD diagnosis was likely to be recorded nine times higher for Caucasian individuals than other at a visit. children, even when variables controlled for included age, sex, length of medication management visits, and insurance Treatment services coverage [10]. In addition, in an analysis of Medical Psychotropic medications, primarily the stimulant medications, Expenditure Panel Survey data from 1997–2000, Stevens et play a critical role in the management of the child with ADHD. al. found that African-American individuals were less likely In fact, stimulant medications represent the treatment of to be diagnosed with ADHD and to initiate stimulant choice for ADHD for most physicians [15]. The efficacy of the medication treatment compared with Caucasian individuals stimulant medications in decreasing ADHD core symptoms [29], and their re-analysis of the 1995–2000 data from the has been adequately demonstrated in a number of studies NAMCS found that both ADHD diagnosis and prescriptions [16], but public controversy regarding the use of medications for psychotropic medications were less likely for Hispanic for ADHD continues in the public press [17]. However, a children than Caucasian children [14]. Of note, they found consensus statement from the National Institutes of Health no differences based on ethnicity in medication use once an [18], published professional guidelines regarding evidence- ADHD diagnosis was made, suggesting that discrepancies in based use of the stimulant medications [19,20], and outreach medication use between ethnic groups may be partially to the lay public by groups such as Children and Adults with related to the identification process. This, in turn, implies Attention-Deficit/Hyperactivity Disorder (CHADD) have that these differences in medication use may in part reflect increased public awareness of the efficacy of these poor access to health insurance and transportation, and medications and resulted in greater acceptance of their use. other barriers to care. The increased awareness and acceptance of medication As there is also strong evidence supporting the use of as a viable treatment option for children with ADHD is behavior modification for children with ADHD and other reflected in the substantial increase in the use of disruptive disorders, it is helpful to determine if this therapy psychotropic therapies over the last decade, especially in the is recommended as part of primary care [31]. However, few US. An analysis by Hoagwood et al. of the NAMCS data for investigations regarding the content of visits have been the time interval 1989–1996 [10], a study by Zito and carried out. A number of other interventions with little colleagues of data on 900 000 youths enrolled in two US evidence supporting efficacy have been widely used, healthcare systems [21], and research by Safer et al. using including play therapy, individual insight therapy, cognitive Baltimore County School District data [22,23] have all noted behavioral therapies, biofeedback, and dietary interventions an increase in the use of stimulants. [18]. One recent study within the mental service sector did However, along with the increase there has also been investigate adherence to quality indicators for the outpatient considerable geographical variation with respect to stimulant care of ADHD, conduct disorder, and major depression,

112 ADVANCES IN ADHD Vol 1 No 4 2007 ADHD IN PRIMARY CARE

including the use of behavior modification. The study medical education (CME) and on technology transfer makes included 813 children seen in 62 mental health clinics in it clear that, while education is important, providing California, USA, from August 1, 1998, to May 31, 1999. information to practitioners is seldom enough to encourage While high adherence was documented for clinical appropriate changes in practice, even when the information assessment for all three disorders (78–95%), and the has been successfully disseminated to an appropriate target majority of medical records for individuals with ADHD audience [36]. indicated a referral for a medication evaluation (84%; The challenge of changing physician behavior was kept standard error [SE] 2.32), the use of evidence-based in mind when the AAP planned its development of training behavioral therapy (i.e. contracts, incentive systems, initiatives to improve services for children with ADHD. From contingency management, and parent training) was rated at anecdotal concerns as well as the studies noted above, it 8.4% (SE 2.53) for ADHD [32]. It is reasonable to assume was clear that provider education of clinicians regarding the that the use of such treatments within a primary care delivery of evidence-based care for ADHD was necessary. context is the same or less. The process began with the development of evidence-based In summary, the results from the studies described above guidelines [19,34], and once the guidelines were completed, document an increase in the number of children with ADHD a plan was put in place to develop a tool kit and a more treated by primary care clinicians, but the use of active educational process [37]. This process was recommended diagnostic procedures is still somewhat accomplished through a partnership between the AAP and limited. Treatment has generally been restricted to stimulant the National Initiative for Children’s Healthcare Quality medications, and it is likely that other therapies are not (NICHQ) to shepherd approximately 40 pediatric offices frequently recommended or implemented. The content and through the process of implementing the ADHD guidelines. quality of available visits is still not known, but it is clear that Central to this Collaborative were Wagner’s chronic illness the current service use for youths with ADHD is highly model [38,39] and the use of quality improvement processes variable. In addition, while good evidence-based information from the business literature [37]. is available on diagnosing and treating children with ADHD, Practices participating in the Collaborative ranged from much still needs to be done in order to translate the science those with two physicians to academic medical centers, and into practice and improve the care of children with this they were encouraged to develop implementation teams that condition. Finally, the data regarding trends over time and included office staff, parents, and community partners (mental factors affecting service use are much more detailed for health and school personnel), as well as physicians. In addition medication use than for other therapies. to the training, the project provided the opportunity to carry out field tests of the Collaborative’s ADHD tool kit, and to Improvements in diagnostic and revise the tool kit based on feedback from the practices. It also treatment practices provided information about what was feasible and defined a A number of publications to clarify the quality of services spectrum of needs and opportunities that varied according to have been produced, including: the nature of the practices and the types of families they served. Based on the experience from the Collaborative, a • An article on the National Institute of Mental Health web-based CME activity Electronic Quality Improvement Multimodality Treatment ADHD study findings [33]. Pediatric Program (eQIPP) was developed, which was • The American Academy of Child and Adolescent launched in April 2003 [40]. Psychiatry ADHD guidelines [34]. The AAP then formed a partnership with the North • The American Academy of Pediatrics (AAP) Carolina Center for Children’s Healthcare Improvement ADHD guidelines [19]. (Chapel Hill, NC, USA) to obtain funding from the Agency • Details of efforts by the National Initiative for Children’s for Healthcare Research and Quality to use the eQIPP Healthcare Quality, the Texas Medication Algorithm modules with state chapters of the AAP. This process was a Project, and other groups, to apply quality improvement modification of the NICHQ Collaborative that employed a processes to ADHD care in primary care and specialty “listserv” (an interactive electronic mailing list where mental health [35]. recipients can respond to each other’s comments) and conference calls but fewer face-to-face meetings. The web- To assist primary care providers in implementing and based program was substituted for some of the meetings tailoring diagnostic and treatment guidelines, it is important and the data collection system that were used in the NICHQ to understand what factors lead to changes in practice Collaborative. Five state chapters participated in the first patterns. The literature on the effectiveness of continuing year and five in the second year of the project.

ADVANCES IN ADHD Vol 1 No 4 2007 113 MARK L WOLRAICH

The AAP approach of using adult learning principles, a 11. Wasserman RC, Kelleher KJ, Bocian A et al. Identification of attentional and hyperactivity problems in primary care: a report from pediatric research in office settings and the systems change approach (covering practice procedure, ambulatory sentinel practice network. Pediatrics 1999;103:E38. 12. Chan E, Hopkins MR, Perrin JM et al. Diagnostic practices for attention deficit hyperactivity existing connections with other community services, and disorder: a national survey of primary care physicians. Ambul Pediatr 2005;5:201–8. relationships with families), a chronic illness model, and a 13. Wolraich ML, Lindgren S, Stromquist A et al. Stimulant medication use by primary care physicians in the treatment of attention deficit hyperactivity disorder. Pediatrics feedback system (a registry) appears conceptually and 1990;86:95–101. anecdotally promising [39]. However, a rigorous assessment 14. Stevens J, Harman JS, Kelleher KJ. Ethnic and regional differences in primary care visits for attention-deficit hyperactivity disorder. J Dev Behav Pediatr 2004;25:318–25. of its effectiveness at changing clinical practice patterns, as 15. Greenhill LL, Halperin JM, Abikoff H. Stimulant medications. J Am Acad Child Adolesc well as outcomes for youths with ADHD, has yet to be Psychiatry 1999;38:503–12. 16. Goldman LS, Genel M, Bezman RJ et al. Diagnosis and treatment of attention- completed. Towards the end of the Collaborative, the issues deficit/hyperactivity disorder in children and adolescents. JAMA 1998;279:1100–7. of sustainability within a community and service system 17. Wren A. ADHD: dangers of pill popping. Psychology Today 2005. became more prominent. Practices were encouraged to find 18. National Institutes of Health. Consensus Development Conference Statement: diagnosis and treatment of attention-deficit/hyperactivity disorder (ADHD). J Am Acad Child partners in the administration of their service systems to Adolesc Psychiatry 2000;39:182–93. explore mechanisms for broader sustainability. 19. Subcommittee on Attention-Deficit/Hyperactivity Disorder and Committee on Quality Improvement. Clinical practice guideline: Treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics 2001;108:1033–44. 20. Greenhill LL, Pliszka S, Dulcan MK et al. Practice parameter for the use of stimulant Conclusion medications in the treatment of children, adolescents, and adults. J Am Acad Child The high prevalence rate of ADHD in children results in a Adolesc Psychiatry 2002;41:26S–49S. 21. Zito JM, Safer DJ, DosReis S et al. Psychotropic practice patterns for youth: a 10-year need for services that is beyond the capacity of the mental perspective. Arch Pediatr Adolesc Med 2003;157:17–25. health sector. In the US, primary care clinicians play an 22. Safer DJ, Krager JM. A survey of medication treatment for hyperactive/inattentive students. JAMA 1988;260:2256–8. important role in the diagnosis and treatment of the 23. Safer DJ, Zito JM, Fine EM. Increased methylphenidate usage for attention deficit disorder condition; however, available studies suggest that many do in the 1990s. Pediatrics 1996;98:1084–8. 24. Jensen PS, Kettle L, Roper MT et al. Are stimulants overprescribed? Treatment of ADHD in not use or implement currently recommended best-practice four US communities. J Am Acad Child Adolesc Psychiatry 1999;38:797–804. guidelines. Major initiatives have been instituted by some of 25. Angold A, Erkanli A, Egger HL et al. Stimulant treatment for children: a community perspective. J Am Acad Child Adolesc Psychiatry 2000;39:975–98. the professional organizations, such as the AAP, which use 26. Rowland AS, Umbach DM, Stallone L et al. Prevalence of medication treatment for adult learning and quality improvement methods, but the attention deficit-hyperactivity disorder among elementary school children in Johnston County, North Carolina. Am J Public Health 2002;92:231–4. impact of these efforts has yet to be determined. 27. Zito JM, Safer DJ, dosReis S et al. Methylphenidate patterns among Medicaid youths. Psychopharmacol Bull 1997;33:143–7. 28. Cox ER, Motheral BR, Henderson RR et al. Geographic variation in the prevalence of Disclosure stimulant medication use among children 5 to 14 years old: results from a commercially Dr Wolraich is a consultant to Lilly and Shire and his program has research insured US sample. Pediatrics 2003;111:237–43. 29. Stevens J, Harman JS, Kelleher KJ. Race/ethnicity and insurance status as factors associated support from Lilly. with ADHD treatment patterns. J Child Adolesc Psychopharmacol 2005;15:88–96. 30. Bussing R, Zima BT, Perwien AR et al. Children in special education programs: attention deficit hyperactivity disorder, use of services, and unmet needs. Am J Public Health 1998;88:880–6. References 31. Pelham WE Jr, Wheeler T, Chronis A. Empirically supported psychosocial treatments for 1. Brown RT, Freeman WS, Perrin JM et al. Prevalence and assessment of attention- attention deficit hyperactivity disorder. J Clin Child Psychol 1998;27:190–205. deficit/hyperactivity disorder in primary care settings. Pediatrics 2001;107:E43. 32. Zima BT, Hurlburt MS, Knapp P et al. Quality of publicly-funded outpatient specialty 2. American Psychiatric Association. DSM-IV-TR. Arlington, VA, USA: American Psychiatric mental health care for common childhood psychiatric disorders in California. J Am Acad Publishing, 2000. Child Adolesc Psychiatry 2005;44:130–44. 3. Pliszka SR. Comorbidity of attention-deficit/hyperactivity disorder with psychiatric 33. Jensen PS, Hinshaw SP, Swanson JM et al. Findings from the NIMH multimodal treatment disorder: an overview. J Clin Psychiatry 1998;59(Suppl 7):50–8. study of ADHD (MTA): implications and applications for primary care providers. J Dev Behav Pediatr 2001;22:60–73. 4. Fischer M, Barkley RA, Fletcher KE et al. The adolescent outcome of hyperactive children: predictors of psychiatric, academic, social, and emotional adjustment. J Am Acad Child 34. American Academy of Pediatrics. Clinical practice guideline: diagnosis and evaluation of Adolesc Psychiatry 1993;32:324–32. the child with attention-deficit/hyperactivity disorder. Pediatrics 2000;105:1158–70. 35. Pliszka SR, Greenhill LL, Crismon ML et al. The Texas children’s medication algorithm 5. Barbaresi W, Katusic S, Colligan R et al. How common is attention-deficit/hyperactivity project: report of the Texas consensus conference panel on medication treatment of disorder? Towards resolution of the controversy: results from a population-based study. childhood attention-deficit/hyperactivity disorder. Part II: tactics. J Am Acad Child Adolesc Acta Paediatr Suppl 2004;93:55–9. Psychiatry 2000;39:920–7. 6. Swensen AR, Birnbaum HG, Secnik K et al. Attention-deficit/hyperactivity disorder: 36. Agency for Health Care Policy and Research. Translating Evidence into Practice: What Do J Am Acad Child Adolesc Psychiatry increased costs for patients and their families. We Know? What Do We Need? Washington, DC, USA: Agency for Health Care Policy and 42 2003; :1415–23. Research, 1997. 7. Zito JM, Safer DJ, dosReis S et al. Psychotherapeutic medication patterns for youths with 37. Langley GL, Nolan KM, Norman CL et al. The Improvement Guide: A Practical Approach attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 1999;153:1257–63. to Enhancing Organizational Performance (1st edition). San Francisco, CA, USA: Jossey- 8. Habel L, Schaefer CA, Levine P et al. Treatment with stimulants among youths in a large Bass, 1996:370. California health plan. J Child Adolesc Psychopharmacol 2005;15:62–7. 38. Bodenheimer T, Wagner EH, Grumbach K. Improving primary care for patients with 9. Wolraich ML. Attention deficit hyperactivity disorder: the most studied and yet most chronic illness. JAMA 2002;288:1775–9. controversial diagnosis. Ment Retard Dev Disabil Res Rev 1999;5:163–8. 39. Bodenheimer T, Wagner EH, Grumbach K. Improving primary care for patients with JAMA 288 10. Hoagwood K, Kelleher KJ, Feil M et al. Treatment services for children with ADHD: a chronic illness: the chronic care model, Part 2. 2002; :1909–14. national perspective. J Am Acad Child Adolesc Psychiatry 2000;39:198–206. 40. URL: http://www.eqipp.org, last accessed in January 2007.

114 ADVANCES IN ADHD Vol 1 No 4 2007 LEADING ARTICLE 115 (4):115–20. 1 2007; o 4 2007 N 2 For many children with ASD, the co-occurrence of ADHD with ASD, the co-occurrence For many children ol 1 V over time with effective interventions, most individuals interventions, over time with effective their a spectrum of supportive services throughout require co-occurring ADHD lives. Individuals with ASD can have of their level of functioning [6]. In a study of regardless of both autism and with a diagnosis hospitalized children 1989 and 2000 ADHD, rates nearly quadrupled between changes in from believed to result are [5]. These increases increased diagnostic practices over time, physicians’ use of and the increased of psychiatric problems, recognition [7]. for behavioral disorders services healthcare Co-occurring disorders diagnosis of ADHD Although the DSM-IV excludes a formal with the latter [2], many children with ASD in children to have symptoms of inattention, reported (14–48%) are enough to warrant a and impulsivity severe hyperactivity, study of 83 children DSM-IV diagnosis of ADHD. In a recent with ASD, for children to a clinic and adolescents referred 78% fulfilled DSM-IV criteria for ADHD [8]. These rates in the of 3–5% for ADHD with a prevalence compare with general school-aged population [9]. Since children formally diagnosed ADHD have been found to have many with ASD have many to ASD, and children symptoms related that each child symptoms, it is recommended ADHD-related be evaluated using both sets of criteria [10]. symptoms of autism. This may be as challenging as the core is especially evident in the late elementary (primary) school with both disorders or early adolescent years. Children challenges in adaptive behavior experience greater Advances in ADHD ADHD DVANCES IN A Southwest Autism Research and Resource Center, Phoenix, AZ, USA Phoenix, Center, and Resource Research Southwest Autism 2 and Sharman Ober Reynolds and Sharman 1,2 Diagnostic and Statistical Manual of (Fourth Edition; DSM-IV) refers to this (Fourth Edition; DSM-IV) refers

ADHD and ASD are viewed as distinct disorders with as distinct disorders viewed ADHD and ASD are Melmed Center, Scottsdale, and Melmed Center, The term “autism spectrum disorders” (ASD) refers to a (ASD) refers The term “autism spectrum disorders” characterized by impairments in three of disorders group language, behavioral domains: social interaction; range of interests communication, and imaginary play; and and activities [1]. The of ADHD may varied developmental trajectories. Symptoms appear at 3 years of age or earlier [4]. The incidence of childhood, with a rate gradually throughout ADHD increases of 67 new cases per 100 000 persons among 7 year olds and a peak rate of 90 new cases per 100 000 persons in 12 year olds. Although symptoms of ADHD may persist over in adults. In decreases time, the incidence of the disorder more contrast, the number of diagnoses of autism increases sharply in early childhood, with an incidence of 4.2 new cases per 100 000 persons among 3 year olds and a peak incidence of 5.9 new cases per 100 000 persons among mitigated 7 year olds [5]. Although symptoms of autism are Mental Disorders (PDD) [2]. disorders” as “pervasive developmental group to that it may be appropriate has suggested Wing However, other and disorder, Asperger’s consider autistic disorder, an autism of PDD as representing in the category disorders state of [3]. Given the current spectrum of disorders in diagnostic knowledge and the various preferences except for in thinking, “ASD” is used in this article, the term autism is used. colloquial contexts where Autism and ADHD are neurodevelopmental disorders commonly diagnosed in children. The term “autism spectrum diagnosed in children. The are neurodevelopmental disorders commonly Autism and ADHD social interaction; by impairments in three behavioral domains: to a group of disorders characterized disorders” (ASD) refers and hyperactivity, of interests and activities. Inattentiveness, and imaginary play; and range language, communication, to increased morbidity. of the two disorders can lead the core symptoms of ADHD. The co-occurrence impulsivity make up yet unknown environmental of multiple genes and as effects to be caused by the combined Both disorders are believed disorders are explored, along with their genetic underpinnings and underlying factors. The relationship between the accurate diagnosis and treatment, the functional outcome functioning. With psychological functioning, including executive can be enhanced. of children with co-occurring ASD and ADHD 1 Raun D Melmed Considerations and Treatment Strategies Treatment and Considerations Autism and ADHD: Theoretical ADHD: and Autism Address for correspondence: Raun D Melmed, Melmed Center, Raun D Melmed, Melmed Center, for correspondence: Address Suite 100, Scottsdale, AZ 85254, USA. 5020 East Shea Boulevard, RAUN D MELMED AND SHARMAN OBER REYNOLDS

Figure 1. Adaptive functioning scores in children with autism Table 1. ADHD subtypes defined in the Diagnostic and and those with autism and ADHD. Adapted from [11]. Statistical Manual of Mental Disorders (Fourth Edition) [2].

100 ADHD predominantly inattentive subtype Autism group ADHD combined subtype 80 ADHD predominantly hyperactive–impulsive subtype ADHD not otherwise specified 60 Autism/ADHD group Score 40 that non-verbal individuals with ASD are unable to meet hyperactive–impulsive DSM-IV criteria such as “blurts out 20 answers”, “interrupts others”, and “talks excessively”. In another study, it was found that one in two teenagers 0 with intellectual disability and ASD displayed clinically Communication Daily living Socialization significant inattentive, hyperactive, or impulsive behaviors, skills compared with one in seven of those with intellectual Vineland domain disability alone [14].

Associated conditions functioning and socialization skills (Fig. 1). Given that each Gadow et al. examined the clinical significance of co-occurring of these is highly predictive of later occupational and tics and ADHD in children with and without PDD [15]. interpersonal functioning, children with ASD and co- As expected from clinical experience, the co-occurrence of occurring ADHD are at significant risk of not reaching their ADHD and tics was a significant indicator of more complex full vocational and social potential [11]. psychiatric morbidity in children with PDD. The relationship between ASD and ADHD has been Developmental coordination disorder (DCD) is associated further explored by a study of 11 patients with ASD who, on with both ADHD and ASD [16]. In a review of physical follow-up, were noted to have symptoms primarily of ADHD findings in children with ASD, Grebe et al. noted the in early-to-middle childhood. Residual features of ASD seen presence of hypotonia in 47% of cases [17]. DCD is a in these children included a tendency for perseverative common co-occurring condition in both ADHD and ASD interests and occasional, mild motor stereotypies. Social skills that warrants further study. tended to remain poor, but this was more a consequence of The concept of deficits in attention, motor control, and impulsive, aggressive behaviors than aloof or odd behaviors. perception (DAMP) may define another subgroup of children in In all cases, the social awkwardness or delay was mild. All whom the overlap of symptoms of ADHD and ASD is present. the children wanted friends and most had at least one real Children with DAMP commonly meet the diagnostic criteria for one; however, three children were unsuccessful in making ADHD in addition to having symptoms of ASD. Between 65% friends because of impulsivity or bossiness [12]. and 80% of parents of children with DAMP reported that their children had significant difficulties with social interaction ADHD subtypes (particularly in empathy and peer relationships) and with verbal ADHD subtypes have been clearly defined (Table 1). Gadow and non-verbal communication [18]. et al. compared ADHD symptom subtypes in children with Kinsbourne postulated that a clinical syndrome exists and without PDD and found that the combined subtype was that includes elements of both ASD and ADHD [19]. The rated as more oppositional and aggressive and as having more overfocused child, he suggested, demonstrates social severe symptoms of PDD than the predominantly inattentive withdrawal and a narrow focus of attention, which are type [13]. The predominantly hyperactive–impulsive subtype behaviors that serve to defend against an unstable arousal was associated with least impairment. Overall, ADHD subtype system. The syndrome of overfocusing shares symptoms with differences were similar for children with and without PDD, autism, especially perseverative and narrowed interests, supporting the notion that ADHD may be a clinically repetitive movements, and social impairment; however, children meaningful syndrome in children with PDD [13]. Interestingly, with the syndrome show no language or cognitive impairments, 65% of children with ASD who met the criteria for ADHD had and they have a capacity for warm social attachments. the predominantly inattentive subtype. A partial explanation Finally, the occurrence of sleep disturbance in children with for the high rate of this subtype in patients with ASD might be ASD and ADHD has been reported. In a study comparing a

116 ADVANCES IN ADHD Vol 1 No 4 2007 AUTISM AND ADHD

Figure 2. Areas of the brain linked to autism spectrum disorders. • The hippocampus, which plays a critical role in processing new information and events. • The corpus callosum, which is located in the center of Corpus callosum Cerebral cortex the brain and connects the right and left hemispheres, Basal ganglia enabling them to communicate. Amygdala • The basal ganglia, which is a deep brain structure involved in movement, habits, and learning. • The cerebellum, which regulates balance, body movements, habits, and learning. • The brainstem, which controls basic functions essential to survival such as breathing and heart rate. Hippocampus Cerebellum Brainstem It is clear that no single area of the brain is pathognomonic for the diagnosis of ASD. Again, these findings do not, as yet, justify the use of neuroimaging as a diagnostic tool for ASD without focal or lateralizing signs or other significant findings on a neurological examination. group of preschoolers with ASD and a control group, children with sleep disturbance in both groups exhibited more severe Dopamine function behavioral difficulties – primarily symptoms of ADHD and Abnormalities in dopamine function have been implicated in oppositional defiance – than children without sleep problems both ASD and ADHD. Genetic and animal model research [20]. In addition, Clements et al. have reported the frequency on ADHD suggests the presence of dopamine abnormalities, of sleep problems in children with autism and the impact of and individuals with ADHD have been found to have these on daytime behaviors [21]. abnormally high levels of dopamine metabolites. Symptoms of ADHD respond to stimulant medication, which facilitates Neurological and neuropsychological correlates the release and blocks the reuptake of dopamine. Executive function deficits A role for dopamine system abnormality in autism was Deficits in executive function – including problems with suggested by Narayan et al., who found the level of planning, working memory, inhibition, mental flexibility, and homovanillic acid in the cerebrospinal fluid to be higher in the initiation and monitoring of actions – have been more severely impaired children, especially those with greater documented in both ADHD and ASD [22]. Spatial working locomotor activity and more severe stereotypies [27]. memory is impaired in both ADHD and high-functioning autism, with more severe impairment being found in Genetic underpinnings the latter [23]. Pennington and Ozonoff documented There is a high degree of heterogeneity in both the ASD and differences in executive function deficits between ADHD the ADHD phenotype, which is likely to be a consequence of and ASD: impairments in motor inhibition were evident in a heterogeneous genotype, as several different genes have ADHD but not in ASD, while insufficiencies in verbal been implicated in both disorders. Data from whole-genome working memory were found in ASD but not in ADHD [24]. screenings in multiplex family studies suggest interactions in at least 10 genes that predispose individuals to autism [28]. Neuroimaging Autism is one of the most heritable mental disorders. A 60% While neuroimaging studies in children with ADHD have concordance rate in monozygotic twins has been reported indicated abnormalities in frontostriatal, temporal, and [28]. Concordance for a broader phenotype has been found cerebellar areas, as yet the differences do not warrant the to be much greater in monozygotic pairs than dizygotic pairs, use of neuroimaging in a clinical setting [25]. Studies have indicating a strong genetic component [29]. Siblings of also documented several areas in the brain linked to ASD children with ASD, who have a 10-fold increase in risk for (Fig. 2), including [26]: affected PDD status, are also more likely to exhibit sub- threshold levels of autistic social impairment than their • The cerebral cortex, which is involved in higher mental counterparts in unaffected families [30]. functions, movement, perception, and behavior. There is preliminary evidence that a gene on chromosome • The amygdala, which is responsible for emotional states, band 16p13 may be linked to both ADHD and ASD. In such as aggression and fear. addition, genome-wide scans for ASD have identified 17p11

ADVANCES IN ADHD Vol 1 No 4 2007 117 RAUN D MELMED AND SHARMAN OBER REYNOLDS

and 5p13 as two other regions that probably harbor genes individuals with ASD, particularly in the presence of associated with ADHD risk [31]. Deletion of chromosome intellectual disabilities, may be particularly sensitive to side band 22q11, the most common interstitial deletion syndrome effects, such as disinhibition, irritability, and reduced sleep. in humans, is often associated with ADHD, affective In that context, interpretation of the physical sensation of disorders, and ASD [32]. Functional polymorphisms, side effects might vary significantly. Other advice includes including those in the serotonin transporter promoter region, the following: the dopamine D4 exon III repeat region, and the catechol-O- methyltransferase gene (COMT), have been examined by • Periodic discontinuation of medication can be Yirmiya et al. in an attempt to identify candidate genes that appropriate. Weaning must be performed slowly. confer risk for autism and that might also be associated with Discontinuity syndromes may result from accelerated other disorders including ADHD [33]. schedules for weaning from stimulants or antidepressants. Given the emerging evidence of shared genes for ADHD • Polypharmacy regimens should be avoided in order to and ASD, it seems prudent that genome-wide scans for reduce the potential of side effects and the possibility of autism should be compared with scans from controls drug–drug interactions. without a history of ADHD. While some candidate genes • Treatment may not be needed when behavioral and might be present in both disorders, it is as yet unclear environmental variables are in flux, which can occur whether they are causal of the behavioral phenotypes or when there are stressors at home, paternal or maternal whether there might be certain genes that simply predispose depression, school difficulties, or problems with inclusion. individuals to a variety of psychiatric disorders. Other genes and additional factors, such as environmental influences, A number of long-acting stimulant medications, along may also need to be considered [34]. with non-stimulants including noradrenergic agents, have There is a significantly higher rate of both ASD and been successful in treating individuals with ADHD [36]. This ADHD in boys with fragile X syndrome (which is linked to has translated to their use in targeting symptoms of ADHD in the gene FMR1). Interestingly, in a study of boys who did children with ASD. A concern with the use of stimulants in not meet the criteria for fragile X syndrome but who ASD has been the observation that they can be “activating” demonstrated the associated permutation alleles, it was and lead to irritability, lability, and agitation. Sleep difficulties, found that there was a higher rate of symptoms of ASD overly selective patterns of food preference, increased social than in controls, but not a higher rate of ADHD [35]. isolation, aggression, agitation, and an increase in Symptoms in the carrier males included a preference for stereotypical behaviors may be seen [37]. Other children with fixed routines, a display of emotional distress at changes in ASD have responded well to stimulant medication, not only routines, and a tendency to focus on details, all of which can with benefits to attention and hyperactivity, but possibly with be seen in ASD. improvement in core features of autism, such as stereotyped behaviors and inappropriate language [12]. Treatment considerations In a double-blind crossover study of children with ASD Pharmacological intervention in children with co-occurring and ADHD, methylphenidate was administered three times autism and ADHD warrants careful consideration in daily. More effective responses with the drug compared with association with a clear sense of what is being treated and placebo were seen on measures of inattention, hyperactivity, what the expected outcomes are [7]. Symptoms associated and impulsivity, as rated by parents and teachers in 35 of the with ASD such as inattention, disruptive behaviors, 58 participants who completed the crossover phase of the tantrums, and aggression can occur as a maladaptive study. Social withdrawal was evident at higher dosages. response to challenges involved in transitioning from one Discontinuation due to adverse events was seen in 18% of activity or situation to another, sensory stimulation, or poor the children [38]. communication ability and regulatory skills. A behavioral An open-label study of atomoxetine for the treatment of analysis is thus an appropriate first step in the management ADHD associated with high-functioning PDD found that of these concerns, and a multimodal treatment strategy 75% of the participants were rated as improved. The most incorporating behavioral interventions along with lifestyle, significant improvement was seen in the area of ADHD nutritional, and pharmacological approaches is warranted. symptoms, although some improvement in irritability, social Pharmacological interventions should always be integrated withdrawal, stereotypy, and repetitive speech was also as part of a child’s individualized educational plan. noted. A placebo-controlled, crossover pilot trial of As a first general principle, it is important to start with atomoxetine for hyperactivity in ASD also found the agent the lowest recommended dose and to titrate slowly, as to be safe and effective for some children with ASD [39].

118 ADVANCES IN ADHD Vol 1 No 4 2007 AUTISM AND ADHD

When using stimulants in young children with ASD, definitions of clinical subgroups. Clarity regarding the caution is advised. Individuals with Asperger’s disorder with various phenotypes of ASD and ADHD will assist in higher cognitive, verbal, and adaptive functioning might be delineating their genetic architecture and hopefully lead to more responsive. Pharmacological studies of the treatment earlier diagnostic tests and better treatments. of ADHD in autism have led to mixed results. Nonetheless, Given the frequency of co-occurrence, it is crucial that as these medications have a relatively high level of safety, clinicians assist families, therapists, and educators in fully many clinicians initiate an empirical trial of a stimulant or understanding the different diagnostic conditions and their non-stimulant under circumstances that are clinically interaction. Failure to treat one or the other may warranted. Once again, it is prudent to start at lower than compromise the benefits of any given treatment. Clinicians typically recommended dosages and to titrate slowly. who look for both disorders, and are meticulous in designing In situations where children with ASD and co-occurring specific, effective, and appropriate treatment interventions, ADHD have resultant behavioral challenges that do not can ensure a positive outcome for these vulnerable children. respond to stimulants or non-stimulant agents, the use of risperidone along with other newer atypical neuroleptics Disclosures might be considered [40]. Dr Melmed receives research grant support from Bristol-Myers Squibb, A particular concern in children with co-occurring autism Lilly, PediaMed, and Shire and is a consultant and speaker for Cephalon, and ADHD is the issue of adherence to treatment regimens, Janssen, Lilly, McNeil, Novartis, Shire, and UCB. Ms Ober Reynolds has even with monotherapy. Factors contributing to medication no relevant financial interest to declare. non-compliance in ADHD include complicated dosing regimens, problems with swallowing, sensory sensitivities, lack References of efficacy, adverse side effects, and parental ambivalence 1. Muhle R, Trentacoste S, Rapin I. The genetics of autism. Pediatrics 2004;113:472–86. 2. American Psychiatric Association. DSM-IV. Arlington, VA, USA: American Psychiatric [41]. Identifying these factors is the first important step in Association, 1994. ensuring optimal outcomes for these individuals. 3. Wing L. The autistic spectrum. Lancet 1997;350:1761–6. Many parents of children with autism prefer to adopt 4. Campbell SB. Behavior problems in preschool children: a review of recent research. J Child Psychol Psychiatry 1995;36:113–49. non-traditional approaches to treatment. It is important for 5. Mandell D, Thompson W, Weintraub E et al. Trends in diagnosis rates for autism and the clinician to become familiar with these alternative and ADHD at hospital discharge in the context of other psychiatric diagnoses. Psychiatric Service 2005;56:56–62. sometimes controversial therapies, especially knowing that a 6. Ehlers S, Gillberg C. The epidemiology of Asperger syndrome. A total population study. large number of families will pursue them [42]. In the J Child Psychol Psychiatry 1993;34:1327–50. author’s practice, non-invasive complementary modalities, 7. Melmed RD, Munir K, Tanguay P. Autism spectrum disorder. In Rubin IL, Crocker A, editors. Medical Care for Children and Adults with Developmental Disabilities. Baltimore, such as nutritional approaches, are often used to address MD, USA: Brookes Publishing, 2006:451–70. symptoms, especially in the preschool population; there are 8. Lee DO, Ousley OY. Attention-deficit hyperactivity disorder symptoms in a clinic sample of children and adolescents with pervasive developmental disorders. J Child Adolesc some anecdotal reports of success but as yet there is no Psychopharmacol 2006;16:737–46. significant evidence-based support. Alternative treatments 9. Pearson DA, Loveland KA, Santos CW et al. ADHD symptomatology in autism: concordance of diagnostic instruments. Presented at: 53rd Annual Meeting of the can be integrated with more traditional approaches [43]. It American Academy of Child and Adolescent Psychiatry. October 24–29, 2006, San Diego, CA, USA. Poster F15. may be helpful for a clinician to support a trial of therapy in 10. Hattori J, Ogino T, Abiru K et al. Are pervasive developmental disorders and attention- certain situations by helping to establish clear treatment deficit/hyperactivity disorder distinct disorders? Brain Dev 2006;28:371–4. objectives and remaining actively involved, even if he or she 11. Pearson D, Loveland K, Santos C et al. Adaptive behavior in children with autism and ADHD symptoms. Presented at: 53rd Annual Meeting of the American Academy of Child is in disagreement with the family’s decision. Reviews of and Adolescent Psychiatry. October 24–29, 2006, San Diego, CA, USA. Poster F14. 12. Fein D, Dixon P, Paul J et al. Brief report: pervasive developmental disorder can evolve into complementary approaches commonly used are available ADHD: case illustrations. J Autism Dev Disord 2005;35:525–34 [e.g. 44], but their discussion is beyond the scope of 13. Gadow KD, DeVincent CJ, Pomeroy J. ADHD symptom subtypes in children with pervasive this article. The clinician’s role is to provide the best developmental disorder. J Autism Dev Disord 2006;36:271–83. 14. Bradley E, Isaacs B. Inattention, hyperactivity, and impulsivity in teenagers with intellectual information to families to allow them to make educated disabilities, with and without autism. Can J Psychiatry 2006;51:598–606. choices about healthcare. 15. Gadow KD, DeVincent CJ. Clinical significance of tics and attention-deficit hyperactivity disorder (ADHD) in children with pervasive developmental disorder. J Child Neurol 2005;20:481–8. Conclusion 16. Gillberg C, Kadesjo B. Why bother about clumsiness? The implication of having developmental coordination disorder (DCD). Neural Plast 2003;10:59–68. Current research regarding genetic, developmental, and 17. Grebe TA, Reynolds S, Groff S et al. Physical findings in autistic disorder and their behavioral underpinnings suggests a common vulnerability correlation with behavioral presentations. Presented at: 5th International Meeting for Autism Research. June 1–3, 2005, Montreal, QC, Canada. Poster. to autism and ADHD and raises questions regarding 18. Clark T, Feehan C, Tinline C et al. Autistic symptoms in children with attention deficit- diagnostic boundaries. Future studies will require that the hyperactivity disorder. Eur Child Adolesc Psychiatry 2004;8:50–5. pathophysiological mechanism of each disorder be matched 19. Kinsbourne M. Overfocusing: an apparent subtype of attention deficit-hyperactivity disorder. In: Amir N, Rapin I, Branski D, editors. Pediatric Neurology: Behavior and to cognitive and imaging techniques to enable more precise Cognition of the Child with Brain Dysfunction. Basel, Switzerland: S Karger, 1991:18–35.

ADVANCES IN ADHD Vol 1 No 4 2007 119 RAUN D MELMED AND SHARMAN OBER REYNOLDS

20. DeVincent CJ, Gadow KD, Delosh D et al. Sleep disturbance and its relation to DSM-IV 33. Yirmiya N, Pilowsky T, Nemanov L et al. Evidence for an association with the serotonin psychiatric symptoms in preschool-aged children with pervasive developmental disorder transporter promoter region polymorphism and autism. Am J Med Genet 2001;105:381–6. and community controls. J Child Neurol (in press). 34. Smalley SL, Kustanovich V, Minassian SL et al. Genetic linkage of attention- 21. Clements J, Wing L, Dunn G. Sleep problems in handicapped children: a preliminary study. deficit/hyperactivity disorder on chromosome 16p13, in a region implicated in autism. J Child Psychol Psychiatry 1986;27:399–407. Am J Hum Genet 2002;71:959–63. 22. Hill E. Executive dysfunction in autism. Trends Cogn Sci 2004;8:26–32. 35. Goodlin Jones B, Tassone F, Gane L et al. Autistic spectrum disorder and the fragile X premutation. J Dev Behav Pediatr 2004;25:392–8. 23. Goldberg MC, Mostofsky SH, Cutting LE et al. Subtle executive impairment in children 36. Scahill L , Aman MG, McDougle CJ et al. A prospective open trial of in children with autism and children with ADHD. J Autism Dev Disord 2005;35:279–93. with pervasive developmental disorders. J Child Adolesc Psychopharmacol 2006;16:589–98. 24. Pennington BF, Ozonoff S. Executive functions and developmental psychopathology. 37. Aman MG, Langworthy KS. Pharmacotherapy for hyperactivity in children with autism and J Child Psychol Psychiatry 1996;37:51–87. other pervasive developmental disorders. J Autism Dev Disord 2000;30:451–9. 25. Fliers EA, Franke B, Buitelaar JK. Hereditary factors in attention deficit hyperactivity 38. Arnold LE, Aman MG, Martin A et al. Assessment in multisite randomized clinical trials of disorder. Ned Tijdschr Geneeskd 2005;149:1726–9. patients with autistic disorder: the Autism RUPP Network. Research Units on Pediatric 26. URL: http://www.nimh.nih.gov/publicat/autism.cfm, last accessed in December 2006. . J Autism Dev Disord 2000;30:99–111. 27. Narayan M, Srinath S, Anderson GM, Meundi DB. Cerebrospinal fluid levels of homovanillic 39. Arnold LE, Aman MG, Cook AM et al. Atomoxetine for hyperactivity in autism spectrum acid and 5-hydroxyindoleacetic acid in autism. Biol Psychiatry 1993;33:630–5. disorders: placebo-controlled crossover pilot trial. J Am Acad Child Adolesc Psychiatry 2006;45:1196–204. 28. Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics 2004;113:472–86. 40. Williams SK, Scahill L, Vitiellio B et al. Risperidone and adaptive behavior in children with 29. Le Couteur A, Bailey A, Goode S et al. A broader phenotype of autism: the clinical autism. J Am Acad Child Adolesc Psychiatry 2006;45:431–9. spectrum in twins. J Child Psychol Psychiatry 1996;37:785–801. 41. Melmed RD, Jensen LH. Medication non-adherence in children with ADHD: challenges 30. Constantino JN, Lajonchere C, Lutz M et al. Autistic social impairment in the siblings of and strategies. Advances in ADHD 2006;1:42–6. children with pervasive developmental disorders. Am J Psychiatry 2006;163:294–6. 42. Melmed RD. Developmental pediatric approaches to autistic disorders: experience and 31. Ogdie MN, Macphie IL, Minassian SL et al. A genomewide scan for attention- reason. Journal of Developmental and Learning Disorders 2004;8:99–111. deficit/hyperactivity disorder in an extended sample: suggestive linkage on p11. 43. Arnold LE, Pinkham SM, Votolato N. Does zinc moderate essential fatty acid and Am J Hum Genet 2003;72:1268–79. treatment of attention-deficit/hyperactivity disorder? J Child Adolesc 32. Briegel W, Cohen M. Chromosome 22Q11 deletion syndrome and its relevance for child and Psychopharmacol 2000;10:111–7. adolescent psychiatry. An overview of etiology, physical symptoms, aspects of child 44. Chan E, Rappaport LA, Kemper KJ. Complementary and alternative therapies in childhood development and psychiatric disorders. Z Kinder Jugenspsychiatr Psychother 2004;32:107–15. attention and hyperactivity problems. J Dev Behav Pediatr 2003;24:4–8.

120 ADVANCES IN ADHD Vol 1 No 4 2007 SCIENTIFIC PROGRESS n d 121 (4):121–6. 1 2007; Advances in ADHD o 4 2007 N In order to rigorously test the hypothesis that exercise to rigorously In order ol 1 V exercise of sufficient intensity and duration can enhance of sufficient exercise neuroadrenergic attention [5], and naturally stimulate to the pharmacological agents similar mediators that are commonly used in ADHD therapy [6,7]. with ADHD, it will be enhances learning among children in which children necessary to conduct intervention studies date, there intervention. To an exercise with ADHD undergo concerning the feasibility of have been no published reports with ADHD in moderate-to-vigorous engaging children of The demonstration of MVPA physical activity (MVPA). intensity and duration facilitates hypothesis testing sufficient of physical activity on classroom of a beneficial effect the behavior and academic performance. However, characteristic issue of distractibility and inattention to tasks diagnosed with ADHD could potentially common to children of such children with attempts to engage a group interfere it is imperative to [8,9]. Therefore, in a bout of MVPA study to demonstrate that undertake a proof-of-concept with ADHD will participate in supervised MVPA children successfully and without undue difficulty. ADHD DVANCES IN A

Recent data collected throughout California, USA [1], and Recent data collected throughout trials [2,3], support the idea well-controlled smaller, from Limited in children. that physical activity enhances learning physical activity might benefit suggests that literature have been with ADHD as well, but there learning in children studies that adequately powered virtually no well-controlled, or learning and behavioral possible mechanisms address outcomes in this population. It is striking that two of the subtypes of ADHD (the combined and the three hyperactive–impulsive subtypes, but not the predominantly characterized by inattentive subtype) are predominantly abnormal patterns of physical activity such as an inability to stay seated, excessive movements, fidgeting, and “on the go” behavior [4]. This characteristic heightened activity in concentration and attention may combination with reduced ability to participate in organized children’s limit affected physical focused physical activities. Moreover, sports or more challenging. The children with ADHD readily accepted the coached lesson, which included a number of bouts of MVPA challenging. The children with ADHD and instructional periods. This study demonstrates the feasibility of engaging childre interspersed with less vigorous exercise exercise equipment. in a school setting using no specialized with ADHD in MVPA Exercise may be a useful treatment for children with ADHD, but systematic studies examining the feasibility of school-based but systematic studies examining the feasibility treatment for children with ADHD, Exercise may be a useful physical study assessed whether 25 min of moderate-to-vigorous have never been peformed. This exercise in this population education class in school-aged children with ADHD. The authors could be achieved during a 45-min physical activity (MVPA) rate (HR) recording and a coached session based on the Sports, Play and Active hypothesized that the combined use of heart motivation and be well tolerated. Eight healthy subjects (six boys and program would maintain Recreation for Kids (SPARK) the (standard deviation [SD] 1.1) and a diagnosis of ADHD, participated during two girls), with a mean age of 8.5 years while at the University of California, Irvine, Child Development Center (CA, USA) summer of 2004 in a morning coached class USA) to assess the number of min for which they could maintain an HR NY, Woodbury, wearing Polar HR monitors (Polar, subjects’ participation, and subjects completed a post-exercise survey to assess >140 beats per min (BPM). Observers rated >140 BPM session. The participants accumulated a mean of 34.1 min (SD 10.6) with an HR response to the their affective an ratings indicated that subjects were engaged in the activity and found it enjoyable Observer and child during this activity. UCI Child Development Center, University of California, Irvine, CA, USA University of California, Center, UCI Child Development Sharon B Wigal, Margaret Schneider, Annamarie Stehli, Audrey Kapelinski, Annamarie Stehli, Audrey Margaret Schneider, Sharon B Wigal, and Dan Cooper Amanda Shanklin, Activity in Children with ADHD in Children Activity Moderate-to-Vigorous Physical Physical Moderate-to-Vigorous The Feasibility of School-Based School-Based of Feasibility The Address for correspondence: Sharon B Wigal, UCI Child Development B Wigal, Sharon for correspondence: Address Irvine, University of California, 19722 MacArthur Boulevard, Center, CA 92612, USA. Email: [email protected] SHARON B WIGAL, MARGARET SCHNEIDER, ANNAMARIE STEHLI ET AL.

There are a number of important methodological issues history of depression, anxiety, epilepsy, or other major surrounding an exercise-based intervention, such as medical conditions were excluded from participating, as frequency, duration, and intensity, which must be considered were children judged by the investigator to be obese (a BMI in order to implement such a program in children with for age >130% of the 95th percentile as per Centers for ADHD. Adherence to an exercise regimen tends to be based Disease Control guidelines [14]). on positive exercise experience [10]. In fact, the American College of Sports Medicine recommendations emphasize the Consent prevention of negative perceptions post-exercise for the The parent or legally authorized representative for each child purpose of promoting adherence to exercise [11]. Cycle received detailed information about the objectives and ergometry has been employed to predict maximal procedures of the study protocol and indicated that each ventilatory oxygen uptake or physical work capacity in child was healthy enough to participate in regular physical children with ADHD [7], but field exercise, as in a physical education classes at school. Written informed consent was education class, would be a more practical method since it obtained before any study procedures were conducted, and does not require expensive machinery that may be difficult the study was approved by the UCI Institutional Review to transport. Additionally, such field exercise can be Board. All participating subjects tolerated the HR monitors. administered to a large number of youths in a single class session with minimal supplies. Therefore, as a necessary first Procedure step toward establishing whether physical activity might be Height and weight were recorded and BMI was calculated useful as an intervention for school-aged children with for each child upon arrival at the study site. All children ADHD, this proof-of-concept pilot study was implemented participated in a 45-min group physical education class at to determine if they could sustain MVPA during a physical the UCI Child Development Center school playground in an education class, as has been demonstrated extensively in the effort to mimic school-based physical education programs. general school-aged population [12,13]. The class was led by an experienced physical education teacher using games and activities designed to be fun and Methods involve continuous MVPA. This single physical education Participants session was based on the Sports, Play and Active Recreation The subjects comprised eight children (six males and two for Kids (SPARK) program [12,13]. The SPARK program was females), with a mean age of 8.5 years (range [in whole originally developed with support from the National Heart, years] 7–9, standard deviation [SD] 1.1), a mean height of Lung, and Blood Institute. The SPARK curriculum is research 134.4 cm (SD 9.1), a mean weight of 33.6 kg (SD 10.9), and based and was validated by the National Diffusion Network a mean body mass index (BMI) of 18.3 kg/m2 (SD 3.9). All of the US Department of Education in 1993. The program is eight children had been previously diagnosed with the implemented in a number of states, including California, for combined subtype of ADHD at the University of California, elementary (primary) and middle (early secondary) schools Irvine (UCI), Child Development Center (CA, USA). Diagnosis to promote physical activity in an enjoyable format. was confirmed by a structured interview with a parent or The class began with a warm-up activity to prepare the legally authorized representative based on Diagnostic and children for vigorous exercise and included short rest periods. Statistical Manual of Mental Disorders (Fourth Edition) Water was readily available to subjects at all times. A physician criteria [4]. Seven of the children had a history of treatment was on-call for any potential injuries or complications. with stimulant medication. No subjects were on medication HR was continuously registered during the entire during the physical activity session to test if the resulting 45-min physical education class. The Polar HR monitor resurgence of ADHD symptoms would prevent active (Polar, Woodbury, NY, USA) was programmed to record the participation or impede heart rate (HR) measurement in this total number of min for which a subject’s HR exceeded pilot study (medication was discontinued ≥24 h prior to the 140 beats per min (BPM). This HR was determined to reflect day of the physical education class for all of the children). MVPA. The HR monitor was worn around the chest, and a pulse monitor was worn on the wrist. Polar monitors have Exclusion criteria been shown to provide valid measurements of HR when Results from the Kaufman Brief Intelligence Test or the compared with electrocardiograms to quantify the intensity of Differential Abilities Scale were used to exclude children with exercise bouts [15]. low intelligence scores (intelligent quotient <80) and to Trained observers recorded the activity level of every child provide valuable clinical evaluation information to the parent for each min of the 45-min class on a behavioral rating form or legally authorized representative. Children with a current in order to indicate whether the child was actively engaged,

122 ADVANCES IN ADHD Vol 1 No 4 2007 FEASIBILITY OF PHYSICAL ACTIVITY IN CHILDREN WITH ADHD

passively engaged, idle, or transitioning between activities at education class. Research among the general population of the school playground. Two observers rated four subjects children has already revealed challenges in engaging school each at 1-min intervals. A child was characterized as follows: children in sustained MVPA within a physical education class owing to interspersed periods of inactivity (which are due to • Active: if he or she was engaged in purposeful factors such as idleness, transitioning between instructions movement related to the instructed activity. or activities, and motivational issues) [16,17]. However, few • Passive: if he or she was listening to instructions. investigations have objectively documented time spent Idle: if he or she was not involved in the assigned activity engaged in MVPA [18]. School-based interventions (e.g. not participating with the group). conducted in child and adolescent obesity studies indicate • Transitioning: if he or she was waiting for new lessons to that students in community school settings spend less than be presented to the group. 50% of a class period engaged in MVPA in the context of intervention studies, and considerably less time in a normal, The number of min that each child was actively or non-intervention setting [19,20]. Because school is the passively engaged during the session constituted the total primary social environment for children, this setting is the number of min engaged in the activity. predominant place for incorporating interventions geared At the end of the exercise session, children answered a toward changing the patterns of their physical activity. The brief questionnaire, which was developed by the research emphasis in the pilot exercise class was on maintaining team, containing simple survey-type questions about the motivation and reducing inactivity during the session. The exercise experience. Each subject’s enjoyment of the exercise approach was modeled on an exercise program currently session was qualitatively rated on two separate 7-point being conducted in local school physical education programs scales ranging from –3 (defined as “bad” and “bored”, with healthy elementary school-aged children [2,11,13,21], respectively) to +3 (defined as “good” and “fun”, without the requirement of specialized exercise equipment. respectively). Participants’ assessment of the level of This study also demonstrates the ability to collect difficulty of the physical exercise class ranged from –3 accurate HR data from children with ADHD. Unlike in (defined as “very hard”) to +3 (defined as “very easy”). On healthy children, there have been no systematic, controlled all three scales, 0 represented a neutral response. studies to examine the impact of physical activity on children with ADHD in a simulated session. Statistical analysis This is a pilot study and, as such, a limitation is the small Owing to the exploratory nature of the study and the small number of participating subjects, particularly in light of the sample size, data are reported by subject. In addition, means fact that a typical physical education class would enroll more and SDs were calculated for all variables. No inferential children. In addition, data collection is restricted to one statistics are reported. One subject was excluded from HR diagnostic group, ADHD, as these types of recordings have data analysis owing to missing data. already been made in healthy children in the general school- aged population. The age range is also narrow (7–9 years). Results This age group was selected to include children old enough Fig. 1 illustrates the HR response to the exercise program for to understand directions and actively take part in the a representative subject (ID#4 in Table 1) and Fig. 2 shows physical education class and to ensure that participants the mean HR of the seven subjects with complete HR data. would be likely to enjoy the same level of activities. Table 1 displays each individual’s outcome data (HR Besides activity, HR is influenced by a number of variables recordings, observed data, and self-report data). All eight of such as emotions and environmental temperature [22]. The the subjects were observed to be actively engaged in the influence of the latter factor was not specifically measured, as exercise session according to observer ratings (range testing occurred in one session with a consistent ambient 29.9–36.9 min). Six of the seven subjects with complete temperature. However, temperature did not appear to data had an HR >140 BPM for ≥33 min. interfere with the participation of subjects or measurements. Overall, the self-ratings indicated that the activity was Another limitation of the proposed research is the perceived as fun (mean 2.1), likeable (mean 2.0), and easy deliberate exclusion of children diagnosed with the (mean 1.1; Table 1). predominantly inattentive ADHD subtype. It may be thought that this restriction would limit the extent to which Discussion the findings can be generalized; however, this pilot still This study demonstrates the ability of children diagnosed addresses about 60% of school-aged children with ADHD. with ADHD to maintain MVPA for >25 min in a physical All of the subjects were diagnosed as having the combined

ADVANCES IN ADHD Vol 1 No 4 2007 123 SHARON B WIGAL, MARGARET SCHNEIDER, ANNAMARIE STEHLI ET AL.

Figure 1. Sample of HR monitoring during pilot physical exercise lesson (45 min) in a 9-year-old girl diagnosed with ADHD. In this child, 33.7 min were spent in moderate-to-vigorous physical activity, and the mean HR was 155 BPM.

200

180

160

140

120

100

HR (BPM) 80

60

40

20

0 0 5 10 15 20 25 30 35 40 45 Time (min)

BPM: beats per min; HR: heart rate; ID#: subject number; NR: not recorded; SD: standard deviation.

Figure 2. Mean HR response across subjects (n=7).

250

200

150

HR (BPM) 100

50

0 0 5 10 15 20 25 30 35 40 45 Time (min)

BPM: beats per min; HR: heart rate.

124 ADVANCES IN ADHD Vol 1 No 4 2007 FEASIBILITY OF PHYSICAL ACTIVITY IN CHILDREN WITH ADHD

Table 1. Summary of results.

HR monitor recordings Observed activity Self-rating scales ID# Time with HR Mean HR over Time engaged “Bad” “Bored” “Very hard” >140 BPM (min) 45 min (BPM) (min) to “good” to “fun” to “very easy” 1 34.3 150 36.9 3 3 3 2 11.8 118 32.9 3 3 3 3 39.2 161 34.0 3 3 3 4 33.7 155 36.9 –2 2 –3 5 36.8 159 36.9 3 3 –3 6 45.7 169 36.9 0 –3 0 7 NR NR 35.7 3 3 3 8 37.4 176 29.9 3 3 3 Mean 34.1 155.4 35.0 2.0 2.1 1.1 (SD) (10.6) (18.6) (2.6) (1.9) (2.1) (2.7)

BPM: beats per min; HR: heart rate; ID#: subject number; NR: not recorded; SD: standard deviation. subtype of ADHD; therefore, all had significant impairments with the mean reported difficulty level indicating that the in attention in addition to their hyperactive–impulsive exercise session for this group of subjects was feasible. The symptoms. The predominantly inattentive ADHD subtype observer ratings show that the children were engaged for could be studied in future investigations. Furthermore, it the majority of the time regardless of their self-reported should be noted that subject recruitment was not aimed at enjoyment of the exercise class. In addition, the HR monitors obtaining equal numbers of males and females as it is provide an objective measure of such engagement in terms known that boys with ADHD tend to be more highly of MVPA. represented in this age group. Future studies may target a Individual variability was apparent in this pilot study. The larger number of female subjects to test for any sex-related only child who maintained an elevated HR during the entire differences. 45-min field exercise period rated the experience most negatively. The authors speculate that this affective rating Conclusion may relate to a low fitness level. No baseline fitness The specific approach used in this preliminary study was to measures were taken as these did not form a part of the vary recreational activities rather than engage children in purpose of this pilot study. one activity over the duration of the physical education This length of physical education class follows the recent class. Children with ADHD typically exhibit difficulty with offering by California schools of 40 min of exercise per transitions, but guided shifts within the context of physical school day to mimic a coached session of activities and to activity seem to be consistent with the optimal pattern of incorporate national fitness guidelines. The specific learning in the classroom. This approach seemed to work as treatment consisted of field exercise using active games and all eight of the subjects were observed to be actively other sports activities developed in the SPARK curriculum as engaged in the exercise session according to observer ratings opposed to one continuous task such as running for a range of 29.9–36.9 min. [2,13,21,23,24]. The authors designed this program to In terms of group data, Table 1 demonstrates that six of the purposefully involve frequent switching of activities. seven subjects with measured HR recordings maintained an HR The results of this pilot study demonstrate the ability to >140 BPM for >30 min during the 45-min exercise session. minimize the need for costly equipment in further This pilot study is important methodologically for determining investigations of exercise effects and their mechanisms in the necessary length of an exercise session (45 min) to create a children with ADHD. In addition, this study is the first to “bolus” of exercise in a more naturalistic field study setting demonstrate that Polar HR monitors can be used specifically similar to a physical education class. in children with ADHD without interference from excessive The self-rating scales were included to assess each activity. Therefore, this coached program may be used to subject’s exercise experience. The rating for level of difficulty determine the effect of a bolus of exercise on specific showed the most variation of these subjective measures, academic and cognitive tasks. In addition, this field exercise

ADVANCES IN ADHD Vol 1 No 4 2007 125 SHARON B WIGAL, MARGARET SCHNEIDER, ANNAMARIE STEHLI ET AL.

Clinics in Sports Medicine: The Interface Between Sport Psychiatry and Sports Medicine. can be administered in a large number of youths at the same Philadelphia, PA, USA: WB Saunders, 2005:829–43. 9. Tofler I, Butterbaugh G. Developmental overview of child and youth sports for the twenty- time and tested within a single class period. first century. In: Tofler I, Morse E, editors. Clinics in Sports Medicine: The Interface Between Sport Psychiatry and Sports Medicine. Philadelphia, PA, USA: WB Saunders, 2005:783–804. Acknowledgements 10. Dishman RK. Medical psychology in exercise and sport. Med Clin North Am 1985;69:123–43. 11. American College of Sports Medicine. ACSM’s Guidelines for Exercise Testing and This work was supported by National Institute of Mental Prescription (6th edition). Baltimore, MD, USA: Lippincott, Williams & Wilkins, 2000:368. 12. McKenzie T, Sallis J, Faucette N et al. Effects of a curriculum and inservice program on the Health award MH02042 (to Dr Sharon B Wigal). The quantity and quality of elementary physical education classes. Res Q Exerc Sport authors acknowledge Steve Bruecker for his assistance in 1993;64:178–87. 13. Sallis J, McKenzie T, Conway T et al. Environmental interventions for eating and physical conducting the exercise class, Jonathan Martinez for his activity: a randomized controlled trial in middle schools. Am J Prev Med 2003;24:209–17. assistance in trained observations, and Jennifer Bowie for her 14. Kuczmarski RJ, Ogden CL, Guo SS et al: 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 2002;246:111–90. assistance in manuscript preparation. 15. Treiber FA, Musante L, Hartdagan S et al. Validation of a heart rate monitor with children in laboratory and field settings. Med Sci Sports Exec 1989;21:338–42. 16. Luepker RV, Perry CL, McKinlay SM et al. Outcomes of a field trial to improve children’s Disclosure dietary patterns and physical activity. The Child and Adolescent Trial for Cardiovascular None of the authors have relevant financial disclosures to declare. Health. CATCH collaborative group. JAMA 1996;275:768–76. 17. McMurray RG, Harrell JS, Bangdiwala SI et al. A school-based intervention can reduce body fat and blood pressure in young adolescents. J Adolesc Health 2002;31:125–32. References 18. Sharma M. School-based interventions for childhood and adolescent obesity. Obes Rev 2006;7:261–9. 1. The Robert Wood Johnson Foundation. Healthy schools for healthy kids. URL: 19. Schneider M, Dunton GF, Bassin S et al. Impact of a school-based physical activity www.rwjf.org/files/publications/other/HealthySchools.pdf, last accessed in January 2007. intervention on fitness and bone in sedentary adolescent females. Journal of Physical 2. Sallis J, Johnson M, Calfas K. Assessing perceived environment variables that may Activity and Health 2007:4:1–13. influence physical activity. Res Q Exerc Sport 1997;68:345–51. 20. Fairclough S, Stratton G. Improving health-enhancing physical activitiy in girls’ physical 3. Shepard R. Habitual physical activity and academic performance. Nutr Rev 1996;54:S321. education. Health Education Research; Theory and Practice 2005;20:448–57. 4. American Psychiatric Association. DSM-IV. Arlington, VA, USA: American Psychiatric 21. Marcoux M, Sallis J, McKenzie T et al. Process evaluation of a physical activity self- Association, 1994. management program for children: SPARK. Psychol Health 1999;14:659–77. 5. Hogervorst E, Riedel W, Jeukendrup A et al. Cognitive performance after strenuous 22. Plasqui G, Westerterp K. Accelerometry and heart rate as a measure of physical fitness: physical exercise. Percept Mot Skills 1996;83:479–88. proof of concept. Med Sci Sports Exerc 2005;37:872–6. 6. Solanto MV, Arnsten AF, Castellanos FX. Stimulant Drugs and ADHD. Basic and Clinical 23. Sallis J, Prochaska J, Taylor W. A review of correlates of physical activity of children and Neuroscience. New York, NY, USA: Oxford University Press, 2001. adolescents. Med Sci Sports Exerc 2000;32:963–75. 7. Wigal S, Nemet D, Swanson JM et al. Catecholamine response to exercise in children with 24. Sallis J, Prochaska J, Taylor W et al. Correlates of physical activity in a national sample of attention deficit hyperactivity disorder. Pediatr Res 2003;53:756–61. girls and boys in grades 4 through 12. Health Psychol 1999;18:410–5. 8. Conant-Norville D, Tofler I. Attention deficit/hyperactivity disorder and psychopharmacologic treatments in the athlete. In: Tofler I, Morse E, editors.

Comment from the Editor-in-Chief

Robert L Findling Case Western University, University Hospitals of Cleveland, Cleveland, OH, USA

There are some data to suggest that young people with of such an exercise program for children with ADHD. The ADHD might benefit from exercise. However, in order to results of this pilot feasibility study suggest that a school- definitively determine what benefits and risks physical based exercise program may be well accepted and well activity might have in a child’s multimodal treatment plan, tolerated by most children with ADHD. In addition, their methodologically rigorous studies of exercise programs results provide preliminary evidence that the program used need to be performed. In this article, Sharon Wigal and in this study is in fact feasible and can be used in colleagues reported on an examination of the acceptability subsequent treatment research in children with ADHD.

126 ADVANCES IN ADHD Vol 1 No 4 2007 CLINICAL REVIEWS Commentary and Analysis on Recent Key Papers

Clinical reviews were prepared by Vishal Madaan, Julia Noland, and Angelita Sanchez

GENETICS difference in the frequency of 3.5 repeat allele (p=0.02) between cases and controls. For 67 cases, both parents were MAOA promoter polymorphism and attention deficit genotyped, and for the remaining six cases, only the mother hyperactivity disorder (ADHD) in Indian children was genotyped. The results indicated preferential Das M, Bhowmik AD, Sinha S et al. transmission of the short allele (3.5 repeat) from mothers to Am J Med Genet B Neuropsychiatr Genet male probands with ADHD (p=0.005). The authors 2006;141:637–42. concluded that the short 3.5 repeat allele of this polymorphism is associated with ADHD in the Indian This study analyzed the variable number of tandem repeats population, and that this could explain why boys are more polymorphism in the monoamine oxidase A gene (MAOA) prone to ADHD than girls. Given that ADHD is a promoter in a group of probands with ADHD, their parents, multifactorial disorder, the clinical implications of this and ethnically matched controls. Genotypic analysis revealed polymorphism warrant further investigation. that the short 3.5 repeat allele of this polymorphism is 1. Manor I, Tyano S, Mel E et al. Family-based and association studies of monoamine oxidase A and attention deficit hyperactivity disorder (ADHD): Preferential transmission of the long associated with ADHD in the Indian population. promoter-region repeat and its association with impaired performance on a continuous performance test (TOVA). Mol Psychiatry 2002;7:626–32. 2. Lawson DC, Turic D, Langley K et al. Association analysis of monoamine A and attention Monoamine oxidase A (MAOA) regulates dopaminergic signals deficit hyperactivity disorder. Am J Med Genet 2003;116:84–9. in the presynaptic region. The polymorphism in the promoter 3. Domschke K, Sheehan K, Lowe N et al. Association analysis of the monoamine oxidase A and B genes with attention deficit hyperactivity disorder (ADHD) in an Irish sample: region of the MAOA gene, consisting of repeats of 30 base Preferential transmission of the MAO-A 941G allele to affected children. Am J Med Genet pairs (with a repeat number of 2.5, 3.5, 4.5, or 5.5), has 2005;134:110–4. previously been reported to be associated with ADHD [1–3]. Address for reprints: K Mukhopadhyay, Manovikas Biomedical Research The present study is the first to analyze possible and Diagnostic Centre, 482, Madudah, Plot I-24, Sector J, EM Bypass, Kolkata 700107, India. Email: [email protected] associations between MAOA variants and ADHD in the Indian population. The authors analyzed the variable number of tandem repeats polymorphism in the MAOA promoter in Norepinephrine transporter polymorphisms in a group of probands with ADHD, their parents, and Tourette syndrome with and without attention ethnically matched controls. The researchers recruited deficit hyperactivity disorder: no evidence for 73 subjects with ADHD (64 boys and nine girls; mean age significant association 7.66 years, standard error 0.36) from their outpatient clinic. Rippel CA, Kobets AJ, Yoon DY et al. Subjects were diagnosed according to Diagnostic and Psychiatr Genet 2006;16:179–80. Statistical Manual of Mental Disorders (Fourth Edition) criteria, and inattention–hyperactivity and the intelligence This study investigated whether norepinephrine quotient were evaluated using Conners’ Parents and Teachers transporter polymorphisms are associated with Tourette’s Rating Scale and the Wechsler Intelligence Scale for Children, syndrome with and without comorbid ADHD. There was respectively. Exclusion criteria included previously diagnosed no evidence of such associations. neuropsychiatric disorders, pervasive developmental disorders, and mental retardation. The control group Approximately 50% of patients with Tourette’s syndrome consisted of 148 healthy individuals assessed using the same have coexisting ADHD. Various studies have implicated the evaluations, 91 of whom were ethnically matched to the noradrenergic circuits projecting from the locus coeruleus to ADHD cases studied. Genotyping was performed using the the frontal lobes in both disorders. This case–control study polymerase chain reaction and revealed a significant evaluated the association of two single nucleotide

ADVANCES IN ADHD Vol 1 No 4 2007 127 CLINICAL REVIEWS

polymorphisms (SNPs) of the norepinephrine transporter significant axis I comorbidity other than oppositional defiant gene (SLC6A2) – a T-182C SNP located in the 5′ flanking disorder and conduct disorder. Subjects were recruited from promoter region and a silent mutation (G1287A) in exon 9 – child and adolescent clinics in London and the south east of in patients with Tourette’s syndrome with (n=115) or England. The results suggested a significant association of without (n=110) ADHD. Genotyping was performed using ADHD with the SNP rs498793 in FADS2. Given that alcohol DNA from buccal cells. can decrease desaturase activity, the authors also Neither of the polymorphisms were associated with investigated interactions between ADHD subject genotypes Tourette’s syndrome with or without ADHD. Additional studies and maternal use of alcohol during pregnancy. Two SNPs in conducted in a subset of nine patients indicated that SLC6A2 FADS1 were associated with ADHD only in the group of polymorphisms did not predict a response to the noradrenergic children prenatally exposed to alcohol, but no significance transporter inhibitor atomoxetine. However, the study was found on formal testing for interaction. The findings of population consisted solely of white, non-Hispanic subjects. this study are limited by the small sample size and the purely Therefore, further studies of larger samples and different ethnic Caucasian ethnicity of the probands. groups are needed to establish this lack of association. 1. Yamamoto N, Saitoh M, Moriuchi A et al. Effect of dietary alpha-linolenate/linoleate balance on brain lipid compositions and learning ability of rats. J Lipid Res 1987;28:144–51. Address for reprints: HS Singer, Division of Pediatric Neurology, Johns 2. Delion S, Chalon S, Guilloteau D et al. Alpha-linolenic acid dietary deficiency alters age- related changes of dopaminergic and serotoninergic neurotransmission in the rat frontal Hopkins Hospital, Harriet Lane Children’s Health Building, 200 North Wolfe cortex. J Neurochem 1996;66:1582–91. Street, Suite 2158, Baltimore, MD 21205, USA. Email: [email protected] 3. Colquhoun I, Bunday S. A lack of essential fatty acids as a possible cause of hyperactivity in children. Med Hypotheses 1981;7:673–9.

Association of fatty acid desaturase genes with Address for reprints: KJ Brookes, MRC Social Genetic Developmental attention-deficit/hyperactivity disorder Psychiatry Centre, Institute of Psychiatry, De Crespigny Park, Brookes KJ, Chen W, Xu X et al. Denmark Hill, London, UK. Email: [email protected] Biol Psychiatry 2006;60:1053–61. Absence of association with DAT1 polymorphism This study of potential associations between variations in and response to methylphenidate in a sample of genes encoding certain enzymes essential for fatty acid adults with ADHD metabolism and ADHD found that a polymorphism in the Mick E, Biederman J, Spencer T et al. fatty acid desaturase 2 gene (FADS2) was associated with Am J Med Genet B Neuropsychiatr Genet 2006;141:890–4. the disorder. Adults with ADHD were classified as having two, one, or Numerous studies have implicated that omega-3 fatty acids no copies of a polymorphism thought to be associated affect both behavior and cognition. Evidence for an association with the condition, the 10-repeat allele of the dopamine with ADHD has been provided by the following studies: transporter gene. Genotype was not found to be related to treatment response or the level of symptom reduction. • Dietary restriction studies in animals showing increased locomotive hyperactivity and reduced cognitive ability in Adults with ADHD (n=265) taking part in a 6-week clinical offspring [e.g. 1]. trial (testing long-acting methylphenidate versus placebo • Animal dietary studies indicating alterations in and immediate-release methylphenidate versus placebo) dopaminergic pathways [e.g. 2]. were classified as having two, one, or no copies of a • Human studies reporting reduced plasma omega-3 fatty polymorphism thought to be associated with the condition, acids in ADHD subjects [e.g. 3]. the 10-repeat allele of the dopamine transporter gene (DAT1). The 10-repeat allele of DAT1 is known to occur at The present study investigated possible associations of an increased rate in patients with ADHD, and it has been single nucleotide polymorphisms (SNPs) in the genes hypothesized that methylphenidate treatment blocks the encoding three key desaturases in a population of subjects dopamine transporter [1]. with ADHD and ethnically matched control subjects. The At baseline there were no statistically significant differences three desaturase genes studied – namely fatty acid by genotype group in demographics, severity of symptoms, or desaturase 1 (FADS1), FADS2, and FADS3 – are all located age at ADHD symptom onset. Treatment response did not on chromosome band 11q25. The study population differ statistically significantly by DAT1 genotype, and neither consisted of 180 Caucasian probands diagnosed with the did the number of adverse effects, including cardiac symptoms. Diagnostic and Statistical Manual of Mental Disorders Of note was a 16-mmHg post-treatment increase in systolic (Fourth Edition) ADHD combined subtype, with no blood pressure among the six patients without a copy of the

128 ADVANCES IN ADHD Vol 1 No 4 2007 GENETICS

polymorphism. Although not statistically significant, the size of differences are a plausible alternative explanation for the the effect could be considered clinically significant. disparity. Unfortunately, this possibility cannot be evaluated A strength of the study was confirmation of the ADHD as key clinical and demographic characteristics were not diagnosis by clinical assessment and structured diagnostic reported in the article of Thapar et al. interviews. A weakness was the small number of patients in The original study also suggested that the Val/Val the genotype versus treatment response analysis. Small polymorphism might intensify the negative effects of the sample sizes (leading to low power and an increased relationship between low birthweight and CD symptoms. likelihood of false positives) have also been common in The current study failed to replicate the interaction between previous treatment response versus DAT1 polymorphism genotype and birthweight. studies. Therefore, the current research can be seen as a The authors note that the societal and legal ramifications continuation of a series of studies with high likelihoods of of CD necessitate a cautious interpretation of the initial type I and type II statistical errors. positive genetic findings in this field. 1. Madras BK, Miller GM, Fischman AJ. The dopamine transporter and attention- 1. Thapar A, Langley K, Fowler T et al. Catechol-O-methyltransferase gene variant and birth deficit/hyperactivity disorder. Biol Psychiatry 2005;57:1397–409. weight predict early-onset antisocial behavior in children with attention-deficit/ hyperactivity disorder. Arch Gen Psychiatry 2005;62:1275–8. Address for reprints: E Mick, Massachusetts General Hospital, Pediatric Psychopharmacology Research Unit, Warren 705, 55 Fruit Street, Address for reprints: R Joober, Douglas Hospital Research Centre, Boston, MA 02114, USA. E-mail: [email protected] 6875 LaSalle Boulevard, Verdun, QC, Canada. Email: [email protected]

COMT Val 108/158Met gene variant, birth weight, and Gene for the serotonin transporter and ADHD: no conduct disorder in children with ADHD association with two functional polymorphisms Sengupta SM, Grizenko N, Schmitz N et al. Wigg KG, Takhar A, Ickowicz A et al. J Am Acad Child Adolesc Psychiatry 2006;45:1363–9. Am J Med Genet B Neuropsychiatr Genet 2006;141:566–70. A large sample of children aged 6–12 years with ADHD was evaluated for conduct disorder symptoms and the The present study investigated possible relationships of Val/Val catechol-O-methyltransferase (COMT) genotype. three polymorphisms in the serotonin transporter gene with Despite having more effective power, the current study ADHD. In contrast to previous studies, no associations failed to replicate previous findings. were found.

ADHD and conduct disorder (CD) frequently co-occur, and Serotonergic pathways have been implicated in the this phenomenon is predictive of more severe and persistent development of ADHD. The human serotonin transporter symptoms. The catechol-O-methyltransferase (COMT) (HTT) is the primary regulator of serotonin levels in the enzyme, which modulates dopamine metabolism, is of brain. It does this by selectively removing serotonin from the particular interest because of the effectiveness of synaptic cleft, terminating its action. The promoter region of dopaminergic pharmaceutical treatments for ADHD and the human serotonin transporter gene (SLC6A4; also known comorbid CD and the role of COMT in the prefrontal cortical as HTT), located on chromosome band 17q11, contains a area that is associated with CD symptoms. However, there is series of imperfect repeat sequences 20–23 base pairs in mixed neurological evidence regarding the COMT gene length. A common insertion–deletion polymorphism is based variant most likely to be associated with CD symptoms. on the presence of either 14 or 16 of these repeats, denoted Using a similar model to that of a previous investigation, as the short and long alleles, respectively. Although several which was conducted by Thapar et al. [1], the current study clinical studies have reported an association between the authors evaluated a large sample (n=191) of children aged long allele, which leads to the increased transcription of HTT, 6–12 years with ADHD for CD symptoms and the Val/Val and ADHD [1–4], this finding has been disputed in a COMT genotype. However, they failed to replicate the different study [5]. However, more recently, an A/G single findings of the previous study, which reported that having nucleotide polymorphism (SNP) was identified within one of the Val/Val genotype was associated with an increased CD the imperfect repeats in the promoter. It was reported that a symptom score in children with ADHD [1]. long allele with a G substitution functions like a short allele, One interpretation of the failure to find genotypic effects a finding not considered in the earlier studies. in the current study is that it suggests that the findings of The authors of the present study analyzed these two Thapar et al. represent a false positive. However, given the polymorphisms, together with a rare, non-synonymous unusually low prevalence of CD in that study, sample coding SNP (Ile425Val) located in exon 10. There were

ADVANCES IN ADHD Vol 1 No 4 2007 129 CLINICAL REVIEWS

209 affected families included in the analyses; 62% of the • Subjects with ADHD who met all DSM-IV criteria for subjects had the ADHD combined subtype, 14% had the childhood-onset ADHD (n=127). predominantly hyperactive–impulsive subtype, and 24% had • Subjects with late-onset ADHD who met all the criteria the predominantly inattentive subtype. The authors did not except the age-of-onset criterion (n=79). find evidence of biased transmission of the long allele or the • Subjects with sub-threshold ADHD who did not meet alleles of the promoter A/G SNP. The Ile425Val polymorphism full symptom criteria (n=41). was not observed among the subjects tested. • Subjects without ADHD who did not meet any The present study did not replicate the findings of criteria (n=123). previous studies. Although ADHD has a significant genetic component to its etiology, and while many polymorphisms The researchers found that subjects with late-onset ADHD have been identified that have different prevalences and those who met all the DSM-IV criteria had similar patterns in patients with ADHD and controls, the technology is of comorbidity, family transmission, and functional impairment; not currently available for diagnosis and treatment in a however, a different pattern of familial transmission was seen in clinical setting. subjects with sub-threshold ADHD. This study suggests that 1. Manor I, Eisenberg J, Tyano S et al. Family-based association study of the serotonin late-onset adult ADHD is valid and that the age-of-onset transporter promoter region polymorphism (5-HTTLPR) in attention deficit hyperactivity disorder. Am J Med Genet 2001;105:91–5. criterion in the DSM-IV is probably too stringent. The potential 2. Seeger G, Schloss P, Schmidt MH. Functional polymorphism within the promoter of the clinical implications of this study are huge. More research is serotonin transporter gene is associated with severe hyperkinetic disorders. Mol Psychiatry 2001;6:235–8. needed to understand whether the subset of sub-threshold 3. Kent L, Doerry U, Hardy E et al. Evidence that variation at the serotonin transporter gene influences susceptibility to attention deficit hyperactivity disorder (ADHD): Analysis and patients have true ADHD or whether the symptoms pooled analysis. Mol Psychiatry 2002;7:908–12. experienced by these patients are the result of comorbidities. 4. Curran S, Purcell S, Craig I et al. The serotonin transporter gene as a QTL for ADHD. Am J Med Genet (Neuropsychiatr Genet) 2005;134:42–7. The authors suggest that an age limit of 12 years may be more 5. Hu XZ, Lipsky RH, Zhu G et al. Serotonin transporter promoter gain-of-function genotypes valid than the current limit of 7 years. Future research should are linked obsessive-compulsive disorder. Am J Hum Genet 2006;78:815–26. thus focus on a clearer, more precise definition of ADHD. Address for reprints: CL Barr, Toronto Western Hospital, Main Pavilion, Room 14-302, 399 Bathurst Street, Toronto, M5T 2S8, ON, Canada. Address for reprints: SV Faraone, Department of Psychiatry and Email: [email protected] Behavioral Sciences, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA. Email: [email protected]

DIAGNOSIS AND ASSESSMENT Identification of children at risk of attention deficit/hyperactivity disorder: a school-based intervention Diagnosing adult attention deficit hyperactivity Sayal K, Hornsey H, Warren S et al. disorder: are late onset and subthreshold Soc Psychiatry Psychiatr Epidemiol 2006;41:806–13. diagnoses valid? Faraone SV, Biederman J, Spencer T et al. This study indicates that educational intervention for Am J Psychiatry 2006;163:1720–9. teachers improves the early recognition of children with probable ADHD. This interesting study investigated the stringency of the Diagnostic and Statistical Manual of Mental Disorders Teachers are well placed to identify children with (Fourth Edition) age-of-onset criterion and the symptom unrecognized ADHD and to promote referral for professional criteria for adult ADHD. The authors suggest that an age help. The authors performed a before-and-after evaluation threshold of 12 years may be more appropriate, and of an educational intervention for teachers about ADHD. highlight the need for a more precise definition of ADHD. This interesting study was carried out in six primary schools (96 teachers and 2672 students in total). Teacher According to the Diagnostic and Statistical Manual of Mental recognition of ADHD was compared against a computerized Disorders (Fourth Edition; DSM-IV), a diagnosis of ADHD in diagnostic algorithm for ADHD caseness that utilized both adulthood requires a retrospective diagnosis of ADHD before parent and teacher Strengths and Difficulties Questionnaire age 7, although this age-of-onset criterion has not been (SDQ) scores. The study involved all classes in the validated. Furthermore, it is not clear whether changes need to participating schools and consisted of four stages: be made to the symptom thresholds when making retrospective diagnoses of ADHD. The present study addressed the validity of • Stage 1 – baseline recognition. these criteria by comparing four groups of adult subjects: • Stage 2 – screening of children using SDQ.

130 ADVANCES IN ADHD Vol 1 No 4 2007 COMORBIDITY

• Stage 3 – the intervention. This involved a 45-min The broad exclusion criteria used and the multiple- educational session about ADHD, which was presented session application of the inclusion criteria were strengths of to the teachers during their weekly staff meeting. the study. There was no siginificant correlation between • Stage 4 – post-intervention recognition. This took place CAARS symptom score improvements and physical HRQoL towards the end of the educational session. scores, and the authors suggests that this provides a partial negative control. However, as a negative control this is quite The proportion of children regarded by teachers as limited, as physical HRQoL scores were normal at baseline having probable ADHD increased after the intervention. (while mental HRQoL was below normal). There was no Furthermore, there was better agreement between teacher placebo control in the study, and so the possibility that recognition and the computerized diagnostic algorithm patient improvement may have occurred without the based on SDQ scoring. Recognition of probable ADHD by pharmaceutical treatment cannot be ruled out. the teacher was based on both the severity of symptoms Address for reprints: LA Adler, Department of Psychiatry, and the impact these problems had on the teacher and the NYU School of Medicine, New York, NY 10016, USA. class. These results indicate that it is feasible to deliver an Email: [email protected] educational intervention addressing teacher identification of ADHD in the community.

Address for reprints: K Sayal, Centre for Child and Adolescent Health, COMORBIDITY Department of Community-Based Medicine, University of Bristol, Hampton House, Cotham Hill, Bristol, BS6 6JS, UK. Email: [email protected] A controlled family study of attention-deficit/ Quality of life assessment in adult patients with hyperactivity disorder and Tourette’s disorder attention-deficit/hyperactivity disorder treated Stewart SE, Illmann C, Geller DA et al. with atomoxetine J Am Acad Child Adolesc Psychiatry 2006;45:1354–62. Adler LA, Sutton VK, Moore RJ et al. J Clin Psychopharmacol 2006;26:648–52. This study was designed to highlight any familial patterns between Tourette’s syndrome (TS) and ADHD in order to Adults in a clinical trial of atomoxetine were asked to determine whether these two disorders have a common rate their global mental health and recall ADHD etiology. The results indicated that TD and ADHD are not symptoms pre- and post-treatment. There was different phenotypes of a single underlying genetic cause. significant improvement on both measures and significant correlation between the improvements. The authors of this family-based case–control study aimed to identify and describe any familial patterns between two Adults (n=205) in a 6-week, multi-site clinical trial of frequently comorbid disorders, namely Tourette’s syndrome atomoxetine (testing 80 mg once daily vs. 40 mg twice daily) (TS) and ADHD. The researchers hypothesized that TS and were asked to rate their global mental health and recall ADHD ADHD are not always etiologically related but that a symptoms pre- and post-treatment. Conners’ Adult ADHD selective relationship exists between the phenotypic Rating Scale – Investigator Rated: Screening Version (CAARS) expressions of the two disorders. symptom scores and health-related quality of life (HRQoL) Subjects with TS+ADHD (n=75), TS only (n=74), ADHD scores from a 36-item short-form health survey were used. only (n=41), or neither disorder (n=49; control subjects) CAARS symptom scores and HRQoL scores (the latter were included in the study. Family members (n=692) were including domains for both physical and mental functioining) assessed by direct interview (Family Self-Report showed significant improvement over the trial. For the Questionnaire) and screening (the Structured Clinical patients presenting with the most severe ADHD symptoms, Interview for DSM-IV, Non-patient Version, and the Kiddie differences in CAARS symptom scores accounted for 25% of Schedule for Affective Disorders and Schizophrenia). The variability in improvement in mental HRQoL scores. For the TS+ADHD rates were found to be higher than expected in patients presenting with less severe symptoms, differences in relatives in all three case groups (p≤0.03). However, CAARS symptom scores accounted for 19% of the although ADHD exceeded control rates in relatives of the variability in improvement in mental HRQoL scores. This TS-only group (p=0.03), TS+ADHD rates were not level of correlation is modest, and somewhat lower than increased. Similarly, in the ADHD-only group, while TS rates might be expected given that the measures rely on the same were increased in relatives (p=0.004), TS+ADHD rates were patients’ recall of symptoms. not increased. The researchers concluded that TS and ADHD

ADVANCES IN ADHD Vol 1 No 4 2007 131 CLINICAL REVIEWS

do not appear to be alternative phenotypes of a single earlier mental age and those taking psychotropic underlying genetic cause. Therefore, the increased risk of medications were more likely to meet DSM-IV criteria for comorbid ADHD and TS in affected families may potentially ADHD. Parent ratings resulted in higher T-scores than reflect similar pathophysiological or neurobiological ratings by teachers among children with ADHD-H and connections. The study was limited by using retrospective ADHD-I symptoms. data rather than prospective data. The findings of this study indicate that it is important for clinicians to consider collateral information from different Address for reprints: DL Pauls, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, sources and to use multi-instrument measurement strategies USA. Email: [email protected] for the evaluation of attention-related symptoms in children with FXS. ADHD symptoms in children with FXS Address for reprints: D Hatton, FPG Child Development Institute, CB 8040, Sullivan K, Hatton D, Hammer J et al. Chapel Hill, NC 27599-8040, USA. Email: [email protected] Am J Med Genet A 2006;140:2275–88.

This article examined parent- and teacher-reported TREATMENT STRATEGIES ADHD symptoms in children with full mutation fragile X syndrome, which are the most prevalent type of problem behavior in these individuals. The results highlight the Acute neuropsychological effects of methylphenidate importance of obtaining information from different in stimulant drug-naive boys with ADHD II – broader sources and from different measurement instruments. executive and non-executive domains Rhodes SM, Coghill DR, Matthews K. ADHD symptoms are the most prevalent type of problem J Child Psychol Psychiatry 2006;47:1184–94. behavior in children with full mutation fragile X syndrome (FXS). FXS is caused by a mutation in a specific gene on the In this study, first-dose methylphenidate (MPH) was long arm of the X chromosome, resulting in a greater found to shorten response latency on a simple cognitive number of cytosine–guanine–guanine triplet repeats than task and lengthen response latency on a more complex normal. Individuals with ≥200 repeats have the full mutation cognitive task, suggesting improvement in self- and have a greater developmental delay and more regulation. Unexpectedly, no MPH treatment effects behavioral problems than those with the premutation forms, were found on response inhibition, working memory, known as carriers (55–199 repeats). Methylation of the planning, and attentional set-shifting tasks. promoter region of the gene in the full mutation interferes with fragile X mental retardation protein production, which A common explanation for the pharmaceutical actions and is needed for normal brain development and function. therapeutic effects of methylphenidate (MPH) is that it The present study included 63 children with FXS and 56 increases the amount of available extracellular dopamine, and controls matched in terms of mental age. The authors thereby improves executive functioning. The reliance on this examined parent- and teacher-reported prevalence rates of simple explanation has contributed to an emphasis on executive ADHD in children with FXS using current problem behavior function outcomes in MPH treatment studies. In particular, scales (the Child Behavior Checklist and the Teacher Report inhibition and working memory have gained attention because Form) and symptom inventories based on the Diagnostic of their established reliance on frontal–striatal dopamine. In and Statistical Manual of Mental Disorders (Fourth Edition; previous research of longer-term MPH treatment, which is DSM-IV). Other variables analyzed included scoring reviewed in the article, MPH consistently improved working methods (continuous T-scores or categorical scores based on memory performance, and improved inhibition in some but not DSM-IV), rater (parent or teacher), and subtype of ADHD all studies. Unexpectedly, there were no improvements in these (predominantly inattentive [ADHD-I], predominantly or any other executive function tasks in the current study. hyperactive–impulsive [ADHD-H], or combined [ADHD-C]). Participants were treatment-naïve, school-aged males Based on parent or teacher report, 53–59% of boys with with ADHD obtained via outpatient referrals (n=73). FXS met diagnostic behavioral criteria for ADHD-I, ADHD- Neuropsychological responses to first-dose MPH were H, or ADHD-C. On the majority of problem behavior and assessed using a range of tasks from the Cambridge diagnostic ADHD symptom measures, boys with FXS had Neuropsychological Test Automated Battery (CANTAB; clinically higher scores or met DSM-IV criteria at higher rates Cambridge Cognition Ltd, Cambridge, UK). A rigorous two- than expected for the general population. Boys with an stage screening process was used to confirm ADHD; patients

132 ADVANCES IN ADHD Vol 1 No 4 2007 EPIDEMIOLOGY

were not excluded on the basis of comorbid disorders, as the This community-referred case–control study of school- investigators wanted to ensure recruitment of a sample aged children with ADHD-I (n=100) and controls matched representative of children seen in typical clinical practice. for age and sex (n=100) was conducted in Brazil. Maternal Another improvement over previous studies using CANTAB recall of smoking during pregnancy (≥10 cigarettes/day) was the randomized, placebo-controlled, double-blind design. was associated with an increased likelihood of ADHD-I and While there were no improvements in executive function a higher level of teacher-rated inattention symptoms. tasks, an enhanced performance was seen for some aspects The broad and rigorous community-based ascertainment of non-executive functioning. This short-term MPH protocol was a strength of the study. The cases and controls administration was found to shorten response latency on a were referred by teachers and evaluated by a three-stage reaction task and lengthen response latency on a more procedure, resulting in relatively “pure” ADHD-I and control cognitively demanding spatial recognition memory task, groups. An additional strength of the design was the statistical suggesting improvement in self-regulation. The interpretation control of variables identified as potential confounders suggested by the authors is that the lack of first-dose (oppositional defiant disorder diagnosis, maternal ADHD MPH treatment effects on executive function may status, and maternal alcohol use during pregnancy). indicate that previously reported effects of longer-term Limitations of the study included the reliance on MPH administration relied on long-term neurobiological retrospective recall measures of cigarette use during adaptation. The current findings allow for an additional pregnancy, the lack of statistical control of paternal ADHD explanation: improvements in ancillary strategies (such as status, and the limited dimensional evaluation of attention. self-regulation) might be a necessary foundation for the 1. Langley K, Rice F, van den Bree MB et al. Maternal smoking during pregnancy as an environmental risk factor for attention deficit hyperactivity disorder behaviour. Minerva effects of MPH on executive function previously reported Pediatr 2005;57:359–71. with longer-term treatment. 2. Hill SY, Lowers L, Locke-Wellman J et al. Maternal smoking and drinking during pregnancy and the risk for child and adolescent psychiatric disorders. J Stud Alcohol 2000;61:661–8. Address for reprints: DR Coghill, Section of Psychiatry and Behavioural Address for reprints: LA Rohde, Serviço de Psiquiatria da Infância e Sciences, Division of Pathology and Neuroscience, University of Dundee, Adolescência, Hospital de Clínicas de Porto Alegre, Rua Ramiro Ninewells Medical School, Dundee, UK. Email: [email protected] Barcelos, 2350, Porto Alegre, Rio Grande do Sul 90035-003, Brazil. Email: [email protected]

EPIDEMIOLOGY Linkages between child abuse and attention- deficit/hyperactivity disorder in girls: behavioral and social correlates Smoking during pregnancy and attention- Briscoe-Smith AM, Hinshaw SP. deficit/hyperactivity disorder, predominantly Child Abuse Negl 2006;30:1239–55. inattentive type: a case–control study Schmitz M, Denardin D, Laufer Silva T et al. In this study, girls with ADHD were shown to have higher J Am Acad Child Adolesc Psychiatry 2006;45:1338–45. rates of documented abuse that comparison subjects, together with higher rates of externalizing behaviors and This case–control study of school-aged children with the peer rejection. ADHD predominantly inattentive subtype (ADHD-I) found that maternal recall of smoking during pregnancy The aims of the present study were to determine whether was associated with an increased likelihood of ADHD-I rates of documented abuse are higher among girls with and a higher level of teacher-rated inattention symptoms. ADHD and whether girls with ADHD and a history of abuse constitute a distinct subgroup of ADHD patients. The study Relationships between maternal cigarette smoking during included 140 girls with ADHD (93 with the ADHD combined pregnancy and ADHD clinical symptoms and attentional subtype and 47 with the ADHD predominantly inattentive problems in offspring have been reported in several subtype; age 6–12 years) and 88 controls without ADHD. case–control studies [e.g. 1], although others have shown Four domains of functioning were sampled: no such association [e.g. 2]. The current study extends this research to the ADHD predominantly inattentive subtype • Externalizing behavior (measures: Child Behavior (ADHD-I). This is important, as ADHD-I is the most Checklist and Teacher Report Form Externalizing Scale). prevalent subtype in community-based samples, and • Internalizing behavior (measures: Child Behavior Checklist previous investigations with clinically referred participants and Teacher Report Form, Children’s Depression Inventory). may have had biased ADHD-I samples. • Peer appraisal.

ADVANCES IN ADHD Vol 1 No 4 2007 133 CLINICAL REVIEWS

• Cognition and achievement scores (measures: Wechsler Rating Scale (CPRS), in which behavior is divided into four Intelligence Scale for Children and Wechsler Individual categories: oppositionality, hyperactivity, inattention, and Achievement Test). ADHD. Overall grade point average (GPA) and last grade earned in mathematics and English were used to measure Of the girls with ADHD, 20 (14.3%) had a history of academic performance. Sex, family situation, weekly exercise, abuse compared with four in the comparison group (4.5%); detentions in the last month, and work were also measured. this difference was statistically significant (p<0.05). All the Compared with students who played video games for girls in the ADHD subgroup with histories of abuse had <1 h/day, those who played for >1 h/day had significantly comorbid diagnoses of oppositional defiant disorder, higher scores on the YIAS-VG (p=0.001). These students had compared with only about half of the girls with ADHD but significantly lower overall GPAs (p≤0.019) and significantly without a history of abuse (p<0.01). The ADHD subgroup higher scores on the inattention and ADHD components of with histories of abuse had more externalizing behaviors than the CPRS (p≤0.001 and p≤0.02, respectively). the other groups, with moderate-to-large effect sizes. The Boys were significantly more likely than girls to spend other domains showed no significant differences. >1 h/day playing video games (p≤0.003). There were no The findings of this study suggest that clinicians need to significant associations between time spent using any media address the history of trauma, if present, among children form (internet, television, or video games) and the following diagnosed with ADHD. Treatment planning and factors in students: pattern of work, marital status of interventions may need to be modified if patients present parents, number of detentions per month, body mass index, with ADHD and a history of abuse. or exercise frequency. The results of this study suggest that parents need to Address for reprints: SP Hinshaw, Department of Psychology, Tolman Hall #1650, University of California at Berkeley, Berkeley, monitor television watching and video game playing by their CA 94720-1650, USA. Email: [email protected] children, not only for the content but also for their effects on attention. Clinicians need to ask about the amount of time A cross-sectional analysis of video games and that their young patients spend using these different media attention deficit hyperactivity disorder symptoms forms, since these may affect their level of attention and, in adolescents subsequently, their academic performance. Chan PA, Rabinowitz T. 1. Yoo HJ, Cho SC, Ha J et al. Attention deficit hyperactivity symptoms and internet addiction. Psychiatry Clin Neurosci 2004;58:487–94. Ann General Psychiatry 2006;5:16. Address for reprints: PA Chan, Department of Internal Medicine, Rhode Island Hospital, , Providence, RI 02912, USA. In this study, computer game use for >1 h/day was Email: [email protected] significantly associated with the score on a modified Young’s Internet Addiction Scale (p<0.01), completed by 72 students, and the scores on the inattention and ASSOCIATED BEHAVIORS ADHD parts of the Conners’ Parent Rating Scale (p≤0.001 and p≤0.02, respectively), completed by their parents. Furthermore, students who played computer Attentional functioning in children with ADHD – games for >1 h/day had significantly lower grade point predominantly hyperactive–impulsive type and averages (a measure of academic performance). children with ADHD – combined type Tucha O, Walitza S, Mecklinger L et al. Based on a previous report that excessive internet use is J Neural Transm 2006;113:1943–53. associated with ADHD [1], the aim of the present study was to determine whether there is a relationship between video In this study of components of attention in children with game use and this disorder. The investigators analyzed 144 ADHD, the disorder was associated with lower scores on surveys, 72 from subjects in the 9th or 10th grade at a scales for vigilance, divided attention, selective attention, secondary school in Vermont, USA, and 72 from their and flexibility. parents. Surveys assessed the time spent playing video games, watching television, or using the internet, and their The authors of the present paper studied several academic and social effects. The student survey included components of a neuropsychological model of attention and Young’s Internet Addiction Scale, modified for video game hypothesized that there would be disturbances in some of use (YIAS-VG), which has been validated for internet these in children with different subtypes of ADHD. The addictive qualities. Parents completed the Conners’ Parent study population consisted of 23 children with the ADHD

134 ADVANCES IN ADHD Vol 1 No 4 2007 ASSOCIATED BEHAVIORS

predominantly hyperactive–impulsive subtype, 32 children with adults in childhood would buffer the associations with the ADHD combined subtype, and 55 age-, sex-, and between the risk factors and adolescent functioning. handedness-matched healthy children. An ethnically and socio-economically diverse sample of Subjects were assessed using a computerized test battery 209 girls (age 6–13 years at baseline; 127 with ADHD and consisting of eight tasks that measured the following aspects 82 controls) were included in this 5-year, prospective, of attention: tonic alertness, phasic alertness, vigilance, longitudinal study. Adolescent criterion measures were selective attention, divided attention, visual scanning, multi-informant composites of externalizing and incompatibility, and cross-modal integration. These aspects internalizing behavior, in addition to indicators of academic are all components of the neuropsychological model of achievement, eating pathology, and substance use. attention proposed by Van Zomeren and Brouwer [1], which Examination of associations established ADHD and peer has previously been used to clinically assess attention rejection as risk factors. They were also associated with function in patients with focal brain lesions. poorer functioning, both at baseline and during follow-up, There were significant differences between patient groups and with lower levels of hypothesized protective factors. Both and the corresponding control group with regard to vigilance, childhood peer rejection and ADHD contributed significantly divided attention, selective attention, and flexibility, but there to greater levels of adolescent externalizing and internalizing were no significant differences in measures of alertness. behaviors, eating pathology, and lower levels of academic There were no significant differences between patient groups achievement. ADHD predicted greater substance use during in any of the components of attention. adolescence. After controlling for childhood externalizing and Inaccurate responding to task demands by the patient internalizing behaviors, ADHD and peer rejection failed to groups was reflected by an increased number of both predict adolescent internalizing and externalizing behavior. omission errors (lack of response to target stimuli) and However, ADHD and peer rejection predicted lower commission errors (responses to non-target stimuli), which adolescent academic achievement after adjustment for are indicative of inattention and impulsivity, respectively. childhood academic achievement. There were no significant The results of this study indicate that several components interactions between ADHD and peer rejection, and neither of attention, particularly intensity and selectivity, are of the two risk factors showed significant interactions with disturbed in ADHD. Furthermore, children with ADHD are any of the three protective factors. not differentially impaired in attentional processes, suffering As regards the protective factors, self-perceived instead from a more global disturbance of attention. scholastic competence in childhood positively predicted 1. Van Zomeren AH, Brouwer WH. Clinical Neuropsychology of Attention. New York, NY, adolescent academic achievement, whereas goal-directed USA: Oxford University Press, 1994. play in childhood was associated with poor adolescent Address for reprints: KW Lange, Department of Experimental outcomes. Further research is needed to determine whether Psychology, University of Regensburg, Regensburg 93040, Germany. there are other mechanisms that may contribute to resilient Email: [email protected] outcomes in girls with ADHD or peer rejection.

Address for reprints: AY Mikami, Department of Psychology, Resilient adolescent adjustment among girls: University of Virginia, 102 Gilmer Hall, PO Box 400400, Charlottesville, buffers of childhood peer rejection and attention- VA 22904-4400, USA. Email: [email protected] deficit/hyperactivity disorder Mikami AY, Hinshaw SP. Cognitive function and behavior of children with J Abnorm Child Psychol 2006;34:823–37. adenotonsillar hypertrophy suspected of having obstructive sleep-disordered breathing In this 5-year, prospective, longitudinal study of 127 girls Suratt PM, Peruggia M, D’Andrea L et al. with ADHD and 82 controls aged 6–13 years at baseline, Pediatrics 2006;118;e771–81. childhood peer rejection and the presence of ADHD were risk factors for a wide variety of psychopathology In this study of children with adenotonsillar hypertrophy during adolescence. with suspected obstructive sleep-disordered breathing, it was found that snoring, and high sleep efficiencies or Evidence suggests that childhood peer rejection and the short sleep latencies (in the sleep laboratory) predicted presence of ADHD (alone or in combination) are risk factors impaired cognitive performance. for future adjustment problems. The authors of the present paper hypothesized that high self-perceived scholastic The present study investigated possible predictors of competence, goal-directed play when alone, and popularity impaired cognitive scores and behavior in children with

ADVANCES IN ADHD Vol 1 No 4 2007 135 CLINICAL REVIEWS adenotonsillar hypertrophy and suspected obstructive sleep- MISCELLANEOUS disordered breathing. Subjects (n=114; age 6–12 years) were consecutive participants in a study on the effect of sleep-disordered breathing caused by adenotonsillar Differences in academic and executive function hypertrophy on behavior, cognitive performance, and domains among children with ADHD growth. Parents completed a questionnaire on their child’s predominantly inattentive and combined types snoring and breathing during sleep and the Conners’ Parent Riccio CA, Homack S, Jarratt KP et al. Behavior Rating Scale. Subjects underwent cognitive Arch Clin Neuropsychol 2006;21:657–67. function studies, which consisted of three subtests of the Wechsler Intelligence Scale for Children (Third Edition; This study investigated differences in academic and WISC-III), namely vocabulary, similarities, and block design. executive function domains between children with the The vocabulary subtest is the only predictor of overall ADHD predominantly inattentive subtype and those with Wechsler intelligence quotient score and general cognitive the combined subtype. Based on their results, the authors functioning, and is considered a strong predictor of concluded that it is likely that similar neurocognitive and academic success, while the similarities subtest is a good academic processes are involved in these subtypes. indicator of verbal abstract reasoning. Subjects also completed the Wide Range Assessment of Memory and The present study was performed to examine differences Learning Test, which had summary scores for verbal specific to academic and executive function domains in memory, visual memory, and learning, and an overall 40 children (mean age 11.98 years, standard deviation 2.07) summary, the general memory index. In addition, tonsil size diagnosed with the ADHD predominantly inattentive was measured and polysomnography was performed with subtype (ADHD-I) or the ADHD combined subtype the use of nasal pressure recording to detect flow. Sleep (ADHD-C). The subjects included in this study were selected efficiency (ratio of total sleep time to total time in bed) and from a larger sample of children (9–15 years old) who were an apnea–hypopnea index (number of episodes of apnea consecutive referrals to a university-based research study. and hypopnea per h of sleep) were calculated. Among the inclusion criteria were a diagnosis of ADHD, an Two of the three cognitive tests (WISC-III vocabulary intelligence quotient (IQ) ≥80, and the ability to speak and and similarities subtests) had strong relationships with read English. Exclusion criteria included a previous diagnosis sleep and breathing variables. Vocabulary and similarities of schizophrenia or a history of severe head injury. The scores were lower for children with higher sleep subjects were evaluated using the following tests: efficiencies, were higher in the low-snoring group than in the high-snoring group, and were lower in black subjects • Wechsler Intelligence Scale for Children (Third Edition), than in non-black subjects. The most important for cognitive ability. confounder for vocabulary was ethnicity. There were • Woodcock Johnson Tests of Achievement (Third Edition). significant but weak relationships between sleep latency • Peabody Picture Vocabulary Test III, for receptive and both the verbal memory index and the general vocabulary skills. memory index, and also between sleep efficiency and • Expressive Vocabulary Test III, for expressive ADHD summary score. The authors note that it is not (naming) vocabulary. possible to accurately predict cognitive function in • Tower of London (Drexel Edition) test, for planning ability. individual subjects based on these findings because of the • Trail Making Test, for set shifting. large inter-subject variability observed. • Stroop Color and Word Test, for interference control. Clinicians need to be aware of parameters and laboratory • Conners’ Continuous Performance Test II, for tests that may be useful in predicting the cognitive motor inhibition. performance of children with adenotonsillar hypertrophy. • Behavior Rating Inventory of Executive Function. Because of the profound degree of impairment of intellectual functioning, clinicians must take an active role in There was a tendency for the ADHD-I group to show a identifying these at-risk children. lower performance on calculation and written expression tasks, but these differences dissipated when IQ was included as a Address for reprints: PM Suratt, Box 800546, University of Virginia Medical Center, Charlottesville, VA 22908, USA. covariate. The results largely indicated that children with these Email: [email protected] subtypes of ADHD cannot be distinguished from each other or controls based on specific neurocognitive tasks aimed at measuring processing speed. Similarly, no major differences

136 ADVANCES IN ADHD Vol 1 No 4 2007 MISCELLANEOUS

were found on the measures of planning tasks, inhibition, or Volumetric MRI differences in treatment-naive set shifting. Parent reports were consistent with the presence vs. chronically treated children with ADHD of greater problems with inhibition in children in the ADHD-C Pliszka SR, Lancaster J, Liotti M et al. group. The authors concluded that there is the potential for Neurology 2006;67:1023–7. similar neurocognitive and academic processes to be implicated in these two ADHD subtypes. Therefore, clinically, treatment Healthy controls, children with the ADHD combined should be determined based on the strengths and weaknesses subtype (ADHD-C) who had a history of long-term of the individual rather than the subtype. psychotropic medication use, and children with ADHD-C Address for reprints: CA Riccio, Department of Educational Psychology, who had never received psychotropic medication Texas A&M University, TAMU MS4225, College Station, underwent a volumetric magnetic resonance imaging TX 77843-4225, USA. Email: [email protected] scan. Caudate volume was related to severity of reported symptoms but not treatment history, while the right Family psychiatric history evidence on the anterior cingulate cortex volume was associated with nosological relations of DSM-IV ADHD treatment history but not reported symptoms. combined and inattentive subtypes: new data and meta-analysis Healthy controls (n=21), children with the ADHD combined Stawicki JA, Nigg JT, von Eye A. subtype (ADHD-C) who had a history of long-term J Child Psychol Psychiatry 2006;47:935–45. psychotropic medication use (n=16), and children with ADHD-C who had never received psychotropic medication Differences between ADHD subtypes in terms of (n=14) underwent a single volumetric magnetic resonance family psychiatric history were investigated. Based on imaging scan. their findings, the authors suggest that the combined Untreated ADHD has been linked to a developmental and primarily inattentive subtypes are not entirely decrease in whole brain volume [1]. This study adds an distinct conditions. important dimension to the literature by investigating the relationship between treatment history and caudate volume. The present study investigated whether the ADHD combined In addition, the study is the first to extend the volumetric subtype (ADHD-C) and the ADHD primarily inattentive evaluation and treatment history comparison to the anterior subtype (ADHD-I) are distinct disorders according to family cingulate cortex (ACC). This is a dopaminergic-dependent psychiatric history. The study included 210 children (142 boys part of the basal ganglia that is associated with response- and 68 girls; age 6.3–13.3 years) who were characterized as monitoring deficits in ADHD. having ADHD-C (n=96), ADHD-I (n=36), or no ADHD (n=78) In the study, caudate volume was related to severity of using structured interview and multiple informant ratings. All reported symptoms but not treatment history, while the biological parents were invited to participate in the study; 335 right ACC volume was associated with treatment had their ADHD status assessed using structured diagnostic history but not reported symptoms. There was a trend interviews. Parental ADHD was assessed using the US National toward differences in the left ACC volume that may have Institute of Mental Health Diagnostic Interview Schedule and a been associated with medication use. Therefore, Diagnostic and Statistical Manual of Mental Disorders (Fourth normalization by treatment might reflect an activity- Edition) symptom checklist, which required parents to rate their dependent increase in the ACC volume. The authors’ symptoms during childhood on a 0- to 3-point scale. interpretation is that successful psychotropic treatment of There was some evidence of subtype-specific ADHD-C may allow children to successfully learn to use transmission; however, the effect was small. It was also rules to guide behavior. noted that girls with ADHD-C had more severe family Weaknesses of the study include the cross-sectional psychiatric histories (non-ADHD) compared with those with design, and the limited information on symptom severity ADHD-I; this difference was not observed among boys. The and dosage history. Another concern is the lack of a authors concluded that there was partial support for a significant relationship between ACC volume and parent- distinct subtype model of the relationship between ADHD-C reported attentional symptomatology. and ADHD-I, but that these are probably partially 1. Castellanos FX, Lee PP, Sharp W et al. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. overlapping conditions with some etiological distinction. JAMA 2002;288:1740–8.

Address for reprints: JT Nigg, Department of Psychology, Address for reprints: M Semrud-Clikeman, University Station, Michigan State University, 115 Psychology Building, East Lansing, D 5800, University of Texas, Austin, TX 78712, USA. MI 48824-1116, USA. Email: [email protected] Email: [email protected]

ADVANCES IN ADHD Vol 1 No 4 2007 137 CLINICAL REVIEWS

Attention-deficit/hyperactivity disorder in children: (US$1328 and US$1040 more, respectively). Although excess costs before and after initial diagnosis and ADHD-related medical visits dropped during the second year treatment cost differences by ethnicity after diagnosis, these cost reductions were largely offset by Ray GT, Levine P, Croen LA et al. increased medication costs. Compared with children without Arch Pediatr Adolesc Med 2006;160:1063–9. ADHD, those with the disorder were more likely to be white Americans, to have lower pharmacy co-payments, to be This paper reports on an analysis, conducted in northern seen for a coexisting MHD, and to be diagnosed with a California, USA, of the excess costs associated with ADHD chronic medical condition. around the time of diagnosis. Children with ADHD were Stratification based on ethnicity revealed that Asian- more costly than children without the disorder. Among Americans, African-Americans, and Hispanic-Americans had those with ADHD, white Americans used more ADHD- lower yearly mean costs for ADHD medications than white related services than non-white Americans. Americans. Only 57% of Asian-Americans with ADHD received ADHD-related medications in the year following This study determined the pattern of excess health service their diagnosis compared with 70% of white Americans cost and use in the 2 years before and 2 years after children (p=0.004). Asian-Americans had lower ADHD-related were diagnosed with ADHD. Differences in health service psychiatry department mean costs and overall ADHD- cost and use according to ethnicity were also analyzed. The related mean costs compared with white Americans. electronic database of a non-profit, integrated healthcare In this study, excess costs were observed to precede the delivery system situated in northern California, USA, was initial diagnosis of ADHD. This finding may indicate that used to select children aged 2–10 years with a diagnosis of problems exist well ahead of the initial diagnosis. Clinicians ADHD (n=3122) and an age- and sex-matched control group should have a high index of suspicion and need to closely (n=15 899). Costs were adjusted for ethnicity, pharmacy co- monitor children who present with some of the symptom payments, estimated family income, coexisting mental health criteria for ADHD. Furthermore, clinicians need to be aware disorders (MHDs), and chronic medical conditions. of the possible reasons for the differences between white The adjusted excess costs revealed that, compared with and non-white Americans in terms of utilization of children without ADHD, those with the condition were ADHD-related services and address them individually in substantially more costly in the second and first years prior their practices. to diagnosis (US$488 and US$678 more, respectively) and Address for reprints: GT Ray, Division of Research, Kaiser Permanente, in the first and second years following the diagnosis 2000 Broadway, Oakland, CA 94612, USA. Email: [email protected]

138 ADVANCES IN ADHD Vol 1 No 4 2007 Highlights of the 19th Annual US MEETING REPORT Psychiatric and Mental Health Congress

November 16–19, 2006, New Orleans, LA, USA The Remedica Editorial Team

The 19th Annual US Psychiatric and Mental Health analyses like this one enable broader comparisons to be Congress took place in New Orleans, LA, USA, on made between classes of drugs used to treat ADHD, which November 16–19, 2006. A large proportion was devoted to can often be useful. ADHD and its treatment, including data on methylphenidate (MPH), atomoxetine, and mixed amphetamine salts (MAS). MPH: oral versus transdermal use Since the 1960s, orally administered MPH has been the Psychiatric comorbidities of ADHD mainstay of pharmacological treatment for ADHD). Lenard Adler (NYU School of Medicine, New York, NY, USA) Following US Food and Drug Administration approval of a and Andrew Nierenberg (Massachusetts General Hospital, transdermal patch formulation, there has been considerable Boston, MA, USA) evaluated the patterns of comorbid interest in comparing the two treatments. Raun Melmed psychiatric disorders occurring in adults with ADHD. Major (Melmed Center, Scottsdale, AZ, USA) presented two depression was the most common comorbid diagnosis, important posters detailing the results of a randomized occurring in 22.9% of patients with ADHD. Next were controlled trial comparing the MPH transdermal system anxiety disorders (12.5%), while bipolar disorder was the (MTS; n=100) with an osmotic release oral system (OROS®; least frequent (3.2%). In contrast, the comorbid diagnosis of ALZA Corporation, Mountain View, CA, USA; n=94) and ADHD in patients with major depression, bipolar disorder, or placebo (n=88) in children aged 6–12 years with ADHD. an anxiety disorder was infrequent (<3% in all cases). Drs Each patient received a patch (MTS 10 mg, 15 mg, 20 mg, Adler and Nierenberg concluded that further research is or 30 mg, or placebo) and a tablet (OROS MPH 18 mg, 27 needed to improve the characterization of the prevalence of mg, 36 mg, or 54 mg, or placebo) each morning. Patches adult ADHD and its related comorbidities. were worn for approximately 9 h per day. At the end of a 5- week dose-optimization period, the majority of patients had Efficacy meta-analysis been titrated to the highest available dose of active The knowledge base regarding individual ADHD medication. medications is large but to date there have been few head- The first poster concentrated on the clinician-rated to-head studies between the drugs. Addressing this effects of MTS and OROS MPH [2], while the second was problem, Stephen Faraone (State University of New York focused on the parent- and teacher-rated benefits [3]. In the Upstate Medical University, Syracuse, NY, USA) and first poster, the primary efficacy variable was the ADHD colleagues conducted a valuable meta-analysis covering 29 Rating Scale-IV (ADHD-RS-IV) total score, with scores on trials of 15 different medications, which used 17 different the ADHD-RS-IV subscales for inattentiveness and outcome measures of hyperactive, inattentive, impulsive, or hyperactivity–impulsivity as secondary endpoints. Both MTS oppositional behavior [1]. By stratifying the trials according and OROS MPH led to significant changes compared with to the class of drug studied (short-acting stimulant, long- placebo for both efficacy variables (p<0.0001). This study acting stimulant, or non-stimulant), significant differences in was not adequately powered to make comparisons between the effect sizes were found. Non-stimulant drugs had a MTS and OROS MPH. At the final visit, 77.6% of patients notably smaller effect size than either short- or long-acting treated with MTS achieved a >30% reduction in stimulants (p<0.0001 and p=0.0008, respectively), even ADHD-RS-IV total scores, compared with 28.7% of patients after adjusting for variability in study design. The lack of randomized to placebo. uniformity in study design and the ways in which drug In the second poster, the primary efficacy variables were efficacy is assessed impairs the ability of clinicians to the total scores on the short-form versions of the Conners’ compare individual drugs between different studies. Meta- Teacher Rating Scale – Revised (CTRS-R) and the Conners’

ADVANCES IN ADHD Vol 1 No 4 2007 139 REMEDICA EDITORIAL TEAM

Parent Rating Scale – Revised (CPRS-R). Secondary efficacy scores that were similar to or better than those for the variables were the CPRS-R ADHD index, and subscales for previous stable-dose OROS MPH medication with little oppositionality, hyperactivity, and cognitive problems. requirement to alter the MTS dose allocated at baseline. Significantly greater reductions in all efficacy variables were Four serious AEs were reported in two patients. The first had seen with MTS compared with placebo. Similar results were worsening ADHD symptoms and aggravated condition, but observed for OROS MPH, although no significant this was deemed unrelated to treatment (MTS 10 mg). The differences were seen on the CPRS-R oppositional subscale second had acute depression and attempted suicide via a when compared with placebo. loratadine overdose, which were both deemed to be Overall, MTS was generally well tolerated with most possibly related to treatment (MTS 30 mg). As this study treatment-emergent adverse events (AEs) being of mild-to- was conducted in patients who were already on a stable moderate intensity. Only 1% of AEs occurred outside of the dose, they may not be generalizable to those not on a stable dose-optimization period. The most commonly reported AEs dose of MPH. were reduced appetite (18.7–25.5%), insomnia Michael Manos (Cleveland Clinic, Cleveland, OH, USA) (7.7–13.3%), nausea (7.7–12.2%), and vomiting and colleagues conducted a valuable study to evaluate the (9.9–10.2%). Dr Melmed concluded that MTS is effective at effects of wearing an MTS patch for 4 h or 6 h, compared ameliorating the symptoms of ADHD as assessed by with placebo, in 120 children aged 6–12 years [7]. The clinicians, parents, and teachers. primary behavioral efficacy variable was the Swanson, John Turnbow (Westex Clinical Investigations, Lubbock, Kotkin, Agler, M-Flynn, Pelham – Deportment (SKAMP-D) TX, USA) and colleagues used the CPRS-R to the same rating scale. The duration of the effect was evaluated using effect in a similar study design, but without including OROS Permanent Product Measure of Performance (PERMP) age- MPH as a second active treatment [4]. They reported highly adjusted mathematics test scores. ADHD-RS-IV and parent significant benefits of MTS as determined by the CPRS-R and clinician rating scales were also used as secondary total score and scores on the ADHD index, and subscales for efficacy endpoints. Both the 4-h and 6-h wear times resulted oppositionality, hyperactivity, and cognitive problems in significant improvements in SKAMP-D and PERMP scores (p<0.0001 in all cases). No serious AEs were reported. compared with placebo, beginning at 2 h post-application A group of researchers from McNeil Pediatrics (Fort and continuing until the final assessment at 10 h. Within 2 h Washington, PA, USA), led by Huabin Zhang, retrospectively of patch removal, mean efficacy scores began to approach investigated satisfaction levels among parents of 850 their baseline pre-patch levels for both wear times. MTS was children aged 6–12 years with ADHD treated with open- generally well tolerated and no serious AEs were reported. label OROS MPH [5]. The mean total score of a daily parental satisfaction questionnaire continuously improved Atomoxetine from day 2 of the study until the final visit at 3 weeks. At An advantage of atomoxetine over most other ADHD the end of study, 91.9% of parents were “very satisfied”, medications is that it is not contraindicated in patients with a “satisfied”, or “somewhat satisfied” with their child’s comorbid anxiety disorder, which is estimated to account for medication and 88.8% planned to keep their child on the 25–50% of the overall ADHD population. Calvin Sumner (Lilly same treatment (increasing to 97.3% for parents whose Research Laboratories, Indianapolis, IN, USA) and colleagues children had a clinical response to OROS MPH). presented data from a 12-week randomized controlled trial In an important study, Thomas Rugino (Children’s comparing atomoxetine (n=87) with placebo (n=89) [8]. Specialized Hospital, Toms River, NJ, USA) and colleagues Mean ADHD-RS-IV total score significantly improved from evaluated the safety and efficacy of abruptly converting baseline in the 55 patients receiving atomoxetine who did not from OROS MPH to MTS [6]. A preplanned dose-transition respond during a placebo lead-in period, compared with schedule was used with a 3-week dose-adjustment period. placebo (p<0.001). Mean Pediatric Anxiety Rating Scale The primary efficacy variable was the change in scores were similarly improved. Therefore, atomoxetine ADHD-RS-IV total scores, with CPRS-R scores, Clinical appears to be efficacious at improving ADHD symptoms and Global Impression – Severity (CGI-S) scores, CGI – reducing anxiety simultaneously. Improvement (CGI-I) scores, and the Parent Global A study by Todd Durell (Lilly Research Laboratories) and Assessment (PGA) rating scale serving as secondary colleagues showed similar improvements in younger and endpoints. Mean ADHD-RS-IV total scores were reduced older adults (aged 18–25 years and >25 years, respectively), from 14.1 at baseline to 10.8 at the final visit (p<0.0001). according to the Conners’ Adult ADHD Rating Scale [9]: a CGI-I, CPRS-R, and PGA scores were also improved. >25% reduction in total ADHD symptom scores was noted Therefore, conversion to MTS gave patients efficacy rating in 56.4% of younger adults compared with 47.8% of older

140 ADVANCES IN ADHD Vol 1 No 4 2007 HIGHLIGHTS OF THE 19TH ANNUAL PSYCHIATRIC CONGRESS

adults (p=0.188). However, the older adults were more presented data from a 6-week randomized controlled, severely impaired at baseline and more of them reported crossover study comparing MAS-XR 50 mg/day with sexual side effects of treatment than the younger adults. A placebo in adults aged 19–25 years [13]. The primary small sample size in the younger adult group limits the efficacy variable was neurocognitive response accuracy, as interpretative value of these results. measured by the CogScreen–Aeromedical Edition. Patients receiving MAS-XR performed significantly better than those Extended-release formulations of MAS taking placebo on 17 of 19 accuracy variables. The Several groups addressed the often overlooked quality of life beneficial effect of prior exposure continued even after (QoL) issues in the treatment of adults with ADHD. Declan treatment was stopped. Anorexia, weight loss, and dry Quinn (University of Saskatchewan College of Medicine, mouth were the most common AEs. Saskatoon, SK, Canada) analyzed 10-week interim data from the 30-week, open-label, multicenter QuEST (Quality Ethnic considerations of Life, Effectiveness, Safety, and Tolerability) study, in which Frank Lopez (Children’s Developmental Center, Winter Park, QoL was evaluated using version 2 of the 36-item Short- FL, USA) and colleagues evaluated the effects of extended- Form Health Survey [10]. At baseline, the average scores for release in the treatment of 122 children mental health, social functioning, role emotional, and vitality aged 6–12 years with ADHD to determine whether there were were impaired. After up to 10 weeks of treatment with any differences between ethnic backgrounds [14]. The children extended-release MAS (MAS-XR) 10–60 mg/day, these were stratified as white, black, or Hispanic/other. Efficacy scores significantly improved until they reached or neared variables included the SKAMP combined score, SKAMP-D and the US national average. attention subscale scores, and PERMP mathematics test scores. Jeanne Landgraf (HealthActCHQ, Inc., Boston, MA, SKAMP combined and subscale scores were significantly better USA) used a newly developed adult version of the ADHD in patients in the active treatment arm compared with placebo, Impact Module (AIM-A) to assess disease-specific QoL in regardless of ethnicity. Similar results were seen with the the same 10-week interim QuEST dataset [11]. All six PERMP tests. Interestingly, Hispanic/other children randomized AIM-A domains (living with ADHD, general well-being, to placebo experienced a greater decline in SKAMP scores than performance and daily functioning, relationships and any other group. communication, bothersomeness and concern, and daily Dr Zhang retrospectively analyzed the ADHD interference) were improved in all patients, whether they management of Hispanic children treated with OROS MPH in were treatment naïve, previously treated with stimulants, or a large community-based study [15]. Symptoms and clinical previously treated with non-stimulants (p<0.0001 in all improvement were assessed using the ADHD-RS-IV tool and cases). In the previously treated patients, the most robust CGI-I scale. At baseline, the mean ADHD-RS-IV score was improvements were in the domains of performance and 40.1; by the end of the study, a 21.1 mean ADHD symptom daily functioning, bothersomeness and concern, and improvement from baseline was seen, with a response rate of relationships and communication. 64.4%. It was concluded from the results that both extended- Margaret Weiss (Children’s and Women’s Health Centre release dexmethylphenidate and OROS MPH are suitable and of British Columbia, Vancouver, BC, Canada) also presented effective treatments for Hispanic children with ADHD. an analysis of the 10-week interim QuEST study data, focusing on patient satisfaction [12]. The 11-item Conclusion Medication Satisfaction Survey was administered in 77 Many new findings on ADHD and its treatment were patients who had previously received short-acting stimulants presented at the 19th Annual US Psychiatric and Mental prior to MAS-XR. At baseline, 48.1% agreed or strongly Health Congress, reflecting the rapidly expanding body of agreed that they were satisfied with their short-acting research in this area. The next congress will take place in stimulant and 39.0% rarely missed a dose. After 10 weeks Orlando, FL, USA, on October 11–14, 2007. of treatment with MAS-XR, 72.8% were satisfied overall, 87.0% were satisfied with the single daily dosing schedule, References and 87.8% rarely missed a dose. Patient satisfaction with 1. Faraone SV, Biederman J, Spencer J et al. Comparing the efficacy of medications for ADHD using meta-analysis. 19th Annual US Psychiatric and Mental Health Congress. November duration of effect, behavior, attention, and social 16–19, 2006, New Orleans, LA, USA. Poster 131. interactions was reported by 63.7%, 72.8%, 68.9%, and 2. Melmed RD, Burnside J, Arnold LE et al. Clinician-rated effects of MTS and OROS methylphenidate in pediatric ADHD. 19th Annual US Psychiatric and Mental Health 52.0% of participants, respectively. Congress. November 16–19, 2006, New Orleans, LA, USA. Poster 127. 3. Melmed RD, Bukstein O, Vince B et al. Parent- and teacher-rated effects of MTS and Gary Kay and Katrina Kardiasmenos (Washington OROS methylphenidate in ADHD. 19th Annual US Psychiatric and Mental Health Neuropsychological Institute, Washington, DC, USA) Congress. November 16–19, 2006, New Orleans, LA, USA. Poster 128.

ADVANCES IN ADHD Vol 1 No 4 2007 141 REMEDICA EDITORIAL TEAM

4. Turnbow JM, Wigal S, Abikoff H et al. Parent-rated effects of transdermal 10. Quinn D. SF-36 quality-of-life measurements in adult ADHD and response to treatment methylphenidate in children with ADHD. 19th Annual US Psychiatric and Mental Health with mixed amphetamine salts extended release. 19th Annual US Psychiatric and Mental Congress. November 16–19, 2006, New Orleans, LA, USA. Poster 118. Health Congress. November 16–19, 2006, New Orleans, LA, USA. Poster 106. 5. Zhang HF, Starr HL, Xiao X. High satisfaction among parents of ADHD children treated 11. Landgraf J. ADHD-specific quality of life with mixed amphetamine salts extended-release with OROS® MPH. 19th Annual US Psychiatric and Mental Health Congress. in adults with ADHD. 19th Annual US Psychiatric and Mental Health Congress. November 16–19, 2006, New Orleans, LA, USA. Poster 113. November 16–19, 2006, New Orleans, LA, USA. Poster 116. 6. Rugino TA, Arnold LE, Patel A et al. Abrupt conversion from oral methylphenidate to a 12. Weiss M. Medication satisfaction among adults with ADHD: long-term results from the Quality of Life, Effectiveness, Safety, and Tolerability (Qu.E.S.T.) study. 19th Annual US Psychiatric and transdermal patch. 19th Annual US Psychiatric and Mental Health Congress. Mental Health Congress. November 16–19, 2006, New Orleans, LA, USA. Poster 120. November 16–19, 2006, New Orleans, LA, USA. Poster 125. 13. Kay G, Kardiasmenos KS. Effect of mixed amphetamine salts extended-release on 7. Manos M, Wilens T, Wigal S et al. Effects of variable wear times on transdermal neurocognitive accuracy in young adults with ADHD. 19th Annual US Psychiatric and methylphenidate in ADHD. 19th Annual US Psychiatric and Mental Health Congress. Mental Health Congress. November 16–19, 2006, New Orleans, LA, USA. Poster 111. November 16–19, 2006, New Orleans, LA, USA. Poster 121. 14. Lopez FA, Muniz R, Brams M et al. Response to extended-release dexmethylphenidate in 8. Sumner C, Sher LD, Sutton V et al. Atomoxetine treatment for pediatric patients with ethnically diverse children with ADHD: a 12-hour placebo-controlled laboratory classroom ADHD and comorbid anxiety. 19th Annual US Psychiatric and Mental Health Congress. study. 19th Annual US Psychiatric and Mental Health Congress. November 16–19, 2006, November 16–19, 2006, New Orleans, LA, USA. Poster 105. New Orleans, LA, USA. Poster 109. 9. Durell T, Adler L, Wilens T et al. Atomoxetine treatment for ADHD: younger adults 15. Zhang HF, Starr HL, Xiao X. ADHD management of Hispanic children in a large compared with older adults. 19th Annual US Psychiatric and Mental Health Congress. community-based study. 19th Annual US Psychiatric and Mental Health Congress. November 16–19, 2006, New Orleans, LA, USA. Poster 134. November 16–19, 2006, New Orleans, LA, USA. Poster 114.

142 ADVANCES IN ADHD Vol 1 No 4 2007 Forthcoming International Events 2007

APRIL MAY JUNE

17–21 3–5 2–5 2nd International Congress of Child Psychiatry for the Primary 39th International Danube the World Federation of Societies Care Clinician Symposium and the 1st International of Biological Psychiatry Burlington, VT, USA Congress on ADHD Santiago, Chile Contact: Katherine Myers, Wuerzburg, Germany Contact: Laetitia Slottved Conference Assistant Contact: Prof P Riederer, Congress T +41 223 399 594 T +1 802 656 2292 President F +41 223 399 601 F +1 802 656 1925 T +49 931 201 77200 E [email protected] E [email protected] F +49 931 201 77220 W www.wfsbp2007.org W cme.uvm.edu/ E [email protected] wuerzburg.de 25–27 16–19 W www.danube-wuerzburg.de XIV International Symposium about 10th Jubilee International Current Issues and Controversies Multidisciplinary Neuroscience JULY in Psychiatry: Risk Factors Conference: Stress and Behavior Barcelona, Spain St Petersburg, Russia 1–8 Contact: Maria Ortiz Contact: Dr Allan V Kalueff, Pediatric Update T +34 932 212 242 Conference Chair Seattle, WA, USA F +34 932 217 005 T +358 0 442 865 613 Contact: Sandra Barnhart E [email protected] E [email protected] T +1 800 422 0711 W www.grupogeyseco.com/ W rus-neuroscience-soc.bm- F +1 727 527 3228 controversias.htm science.com/stress-and-behaviour E [email protected] 26 W www.continuingeducation.net 15th Developmental-Behavioral 19–24 Pediatrics Conference 160th American Psychiatric Springfield, IL, USA Association Annual Meeting AUGUST Contact: Laura Worrall San Diego, CA, USA or Judy Harbison Contact: American Psychiatric 25–29 T +1 217 545 7711 or 217 545 4414 Association 13th International Congress of the F +1 217 545 4413 T +1 703 907 7300 European Society of Child and E [email protected] or E [email protected] Adolescent Psychiatry [email protected] W www.psych.org Florence, Italy W www.siumed.edu/cme/ E [email protected] symposia.html W http://www.escap-net.org/

If you would like your meeting listed here, please contact the Publisher (for details see contents page).

ADVANCES IN ADHD Vol 1 No 4 2007 143 ADVANCES IN ADHD

Reader Survey – Let Us Know What You Think! Please take a few moments to complete this survey. We would value your opinion.

Please photocopy this page, complete the survey below, and fax it back to Remedica on +44 (0)20 7759 2951. Or you can visit the ADVANCES IN ADHD website and complete the survey online (registration online is FREE): www.advances-in-adhd.com

1. We are aiming to provide practical information for pediatricians, psychiatrists, and allied healthcare professionals. How would you rate the information presented in this issue?

Strongly agree Strongly disagree

a) The technical quality of information included in ADVANCES IN ADHD was acceptable: 12345

b) The information was relevant to my practice: 12345

c) The information was presented clearly: 12345

d) The leading articles provided new information regarding the understanding and treatment of ADHD: 12345

e) The clinical review section was helpful and I would like to see analyses in future issues: 12345

2. Did you learn anything through the CME activity ADVANCES IN ADHD that will change the way you practice medicine? ■ Yes ■ No

If so, what? ......

3. Is there anything you learned from the CME activity ADVANCES IN ADHD that prompts you to seek further information that may influence the way you practice medicine in the future? ■ Yes ■ No

If so, what? ......

4. Would you like to recommend ADVANCES IN ADHD to a colleague? ■ Yes ■ No

My colleague’s email is: ......

5. What specific topics do you think should be covered in future issues?

......

Name ...... Job title ......

Institution ......

Address ......

Country ...... Post/zip code ......

Email ......