Stimulant treatment in children Faber, Adrianne

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1 Stimulant treatment in children Faber, Adrianne IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2006 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Faber, A. (2006). Stimulant treatment in children: A Dutch perspective s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Stimulant treatment in children: A Dutch perspective Adrianne Faber

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4 RIJKSUNIVERSITEIT GRONINGEN Stimulant treatment in children: A Dutch perspective Proefschrift ter verkrijging van het doctoraat in de Wiskunde en Natuurwetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op maandag 2 oktober 2006 om uur door Adrianne Faber geboren op 28 september 1972 te Groningen

5 Promotores: prof. dr. L.T.W. de Jong van den Berg prof. dr. R.B. Minderaa Copromotor: dr. H. Tobi Beoordelingscommissie: prof. dr. J.M. Fegert prof. dr. R.J. van der Gaag prof. dr. A.H.L.M. Pieters

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7 Paranimfen: Meike Dirkse Yvonne Dijstelbloem Faber, Adrianne Stimulant treatment in children: A Dutch perspective Thesis Groningen University - with summary in Dutch ISBN: ISBN: Printing: Gildeprint B.V., Enschede, The Netherlands Cover design: G2K Designers, Groningen/Amsterdam, The Netherlands Photography cover image: 100pk.nl Publication of this thesis was financially supported by the University of Groningen, GUIDE Graduate School for Drug Exploration, Stichting KNMP-fondsen, Janssen-Cilag B.V. en Eli Lilly Nederland B.V Adrianne Faber No part of this book may be reproduced in any manner or by any means without written permission of the author, or, when appropriate, the publisher of the publications.

8 Table of contents 1. Introduction 9 2. Recruitment of parents and physicians of stimulant-using children via community pharmacies is successful Parents report on stimulant-treated children in the Netherlands: Initiation of treatment and follow-up care Co-morbidity and patterns of care in stimulant-treated children with ADHD in the Netherlands Use of double-blind, placebo-controlled N-of-1 trials among stimulant-treated youths in The Netherlands: A descriptive study Psychotropic co-medication among stimulant-treated children in the Netherlands Studying co-medication patterns: The impact of definitions Cost-effectiveness of long-acting methylphenidate-oros in ADHD youths with suboptimal symptom control on immediate-release methylphenidate in the Netherlands Summary and discussion 105 Samenvatting 123 Dankwoord 135 Curriculum Vitae 141 Appendix 145

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10 1 Introduction

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12 Introduction Introduction The first description of the effect of stimulants on behavioral problems was published in 1937 by the psychiatrist Charles Bradley [1]. He observed a spectacular improvement in the behavior of children under influence of the amphetamine benzedrine, especially leading to remarkably improved school performance and better self-control in approximately half of the children. His research and that of others established the benefits of stimulants in the treatment of attention-deficit/hyperactivity disorder (ADHD). Ever since, over 200 controlled trials with stimulants have been performed, demonstrating the efficacy of stimulants in improving ADHD and associated symptoms [2,3]. ADHD ADHD is prevalent among approximately 3-5% of the school-aged children and therefore it is the most common psychiatric disorder among children [4]. In the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), ADHD is characterized by symptoms of inattention and/or hyperactivity/impulsivity being persistent for at least 6 months in a more frequent and severe way than in other children with a comparable developmental level [4]. Some of these symptoms must be present before the age of 7 years and cause impairment in two or more settings, e.g. at home and school. To avoid misdiagnosing it is therefore important to obtain as much information as possible from different sources. ADHD is more prevalent among boys than girls, with ratios varying from 3:1 to 5:1 in epidemiological studies [3]. The etiology of ADHD is still unknown, but evidence points to neurobiological and genetic factors to play a dominant role in the disorder [3,5]. ADHD is often accompanied by other psychiatric disorders. About 50-60% of all children with ADHD meet the criteria for either oppositional defiant disorder (ODD) or conduct disorder (CD) [6], 20-30% have mood disorders and 19-26% have a learning disorder [7]. ADHD is considered a chronic disorder as follow-up studies of clinically referred children with ADHD indicated that symptoms persist into adulthood in 10 65% of the cases [3]. The large variation in the reported level of persistence across studies probably reflects different definitions used for remission from ADHD [8]. Children with ADHD may face developmental and social difficulties, manifesting itself in school problems, academic underperformance and troublesome relationships with family members and peers [9,10], which may give rise to poor self-esteem and demoralization. Therefore, early diagnosis and effective treatment of ADHD is important to halt the downward spiral in the child s development into adulthood. 11

13 Chapter 1 Treatment of ADHD Two treatment modalities have proven to be effective in reducing ADHD symptoms: psychosocial interventions and pharmacotherapy [3,11]. In guidelines for the treatment of ADHD, medication and psychosocial interventions or the combination of both are mentioned as a valid treatment option [12-17]. Since most hyperactive children have many problems, combination of different treatment modalities is usually indicated [12,13,15]. Psychosocial treatment for ADHD consists of behavioral interventions focused on the child, parents and/or the teacher. Behavioral parent training and behavioral interventions in the family and classroom setting have been demonstrated to contribute to improvements in the child s behavior [11,18,19]. Only limited evidence is available for the benefits of cognitive behavioral interventions, such as social-skills and problem-solving training for children [3,20]. Stimulants are the first-choice drug in the management of ADHD. Several short-term clinical trials have demonstrated a significant reduction of ADHD symptoms compared to placebo [21,22]. In approximately 70% of the children with ADHD, treatment with stimulants improves symptoms of hyperactivity, impulsivity and inattention [21]. In addition to improving core symptoms of ADHD, stimulants also improve associated behavior, including on-task behavior, academic performance and social functioning. However, for long-term academic performance and social skills, stimulants have failed to show consistent benefits [23]. In the Netherlands, methylphenidate and dexamphetamine are the two stimulants available for the treatment of ADHD, of which methylphenidate is most frequently used. Stimulants are sympathicomimetic agents probably causing their effect by facilitating the action of dopamine and norepinephrine by increasing the intrasynaptic levels of dopamine by blocking the dopamine transporter and/or stimulating the release of dopamine. Methylphenidate has a short half-life of 2-4 hours, which necessitates multiple daily dosing. Since 2002 controlled-release, once-daily methylphenidate-oros has become available in the Netherlands. For some children stimulant preparations with a longer half-life may be beneficial, for example if symptoms worsen at the end of the dosing interval, administering medication at school is problematic or in case of compliance difficulties. Dexamphetamine has a half-life of about 11 hours [24] and is only available as compounded capsules prepared in the pharmacy. Methylphenidate and methylphenidate-oros, but not dexamphetamine, are officially licensed for the treatment of ADHD. As amphetamine-like substances with potential risk for misuse and addiction, methylphenidate, methylphenidate- OROS and dexamphetamine are covered by the Opium Act. Side effects due to stimulants occur early in treatment, are generally mild and can be managed by adjusting the medication dose or timing [23,25,26]. Observed side effects are 12

14 Introduction decreased appetite, sleep problems, stomach ache, headache, anxiety, irritability, and proneness to crying [25,26]. However, among children with ADHD some of these symptoms are also present without stimulant use, suggesting that these side effects are characteristics of the disorder rather than the treatment [25,26]. Stimulants are also associated with suppression or delay of growth [27-29]. Nonetheless, studies have found a little, but not a clinically relevant, decrease in the expected height and for most of the children any decrease in growth early in treatment was compensated for later on [28,29]. The Multimodal Treatment Study of Children with ADHD (MTA) was the first major clinical trial examining the effects of combined behavioral treatment and medication compared to behavioral treatment and medication alone [30]. A sample of 579 children with ADHD was included to compare four treatment conditions; medication management, intensive multimodal behavioral therapy, the combined condition of medication management and multimodal behavioral therapy, and treatment as provided by community care. The latter care as usual arm resulted in stimulant medication in two third of the cases. After 12 months all four treatment arms showed a significant reduction of ADHD symptoms. However, medication management, with and without additional behavioral therapy, demonstrated to be superior to behavioral therapy and considerably more effective than community care. No significant differences were found comparing medication management alone and the combination of medication management with behavioral therapy, although alternative outcome analyses did indicate some additional value of behavioral therapy [31,32]. Although the MTA study is considered the land-mark study in the field of ADHD treatment, the design and methodology has also received a lot of criticism [33,34], suggesting an underestimation of the effect of behavioral therapy. Also the feasibility of the extensive treatment programs in daily practice has been questioned [35]. Concern In the nineties a rapid increase of stimulant use was noticed in several western countries [36-41]. In the USA for example, the prevalence of stimulant use increased 3- to 7-fold among children under 18 years of age between 1987 and 1996 [41]. Also in the Netherlands the use of stimulants strongly increased. Among children aged 0-19 years in the northern part of the Netherlands the prevalence of stimulant use increased 5-fold from 0.15% in 1995 to 0.74% in 1999 [38]. The increased use of stimulants was probably due to the increasing number of children, adolescents and adults being diagnosed with ADHD [3] and to the prolonged duration of stimulant use [38]. This explosive increase of stimulant prescriptions raised global concern and became subject to public and political debate [42-44]. The discussion focused on the validity of ADHD as a psychiatric disorder, the potential 13

15 Chapter 1 overdiagnosis and overtreatment of ADHD, and the risks of treatment with stimulants [39,42,45]. It was also questioned whether the use of stimulants for children with ADHD is addictive and facilitates the abuse of other substances. When using the prescribed dose orally, however, no cases of addictive effects of methylphenidate have been reported so far, and children with ADHD treated with stimulants have been shown to develop less rather than more substance abuse than untreated children [46,47]. Also in the Netherlands the increase of ADHD diagnoses and stimulant use caused public concern [48-52]. The lay media claimed excessive prescribing of stimulant medication by GPs. Also questions were raised about the quality of the care provided and the sole reliance on stimulant medication. This turmoil, however, was based on studies from North America, as no information was available on the Dutch situation. In 1999 the Minister of Health asked the Dutch Health Council for advise on the diagnosis and treatment of ADHD. The Health Council stated in their following report that improvements in diagnosing and treatment of ADHD were required and that research was urgently needed to gather information on the way ADHD and stimulant treatment was dealt with, not only by child psychiatrists, but also by pediatricians, GPs and other health care providers [53]. This thesis describes our research on current practice of stimulant treatment among children in the Netherlands using different data sources and qualitative as well as quantitative methods, aiming to answer the following research questions: 1) Is concern about stimulant use among children justified for the Dutch situation? 2) Is stimulant medication part of a multimodal treatment program? 3) What is the use of psychotropic co-medication among stimulant users? 4) Are pharmacy data useful in child psychiatry research? References 1. Bradley C. The behavior of children receiving benzedrine. Am J Psychiatry 1937; 94: Brown WA. Images in psychiatry: Charles Bradley, M.D Am J Psychiatry 1998; 155: Barkley RA. Attention-deficit hyperactivity disorder. A handbook for diagnosis and treatment. 3rd Ed. New York: The Guilford Press; American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th Ed. (text revision). Washington, DC: American Psychiatric Association, Spencer TJ, Biederman J, Wilens TE, Faraone SV. Overview and neurobiology of Attention-Deficit/Hyperactivity Disorder. J Clin Psychiatry 2002;63 (suppl 12):3-9 14

16 Introduction 6. Gillberg C, Gillberg IC, Rasmussen P, Kadesjo B, Soderstrom H, Rastam M, et al. Co-existing disorders in ADHD - implications for diagnosis and intervention. Eur Child Adolesc Psychiatry 2004;13:I80-I92 7. Mash EJ, Barkley RA. Child pathology. New York: The Guilford Press; Biederman J, Mick E, Faraone SV. Age-dependent decline of symptoms of Attention Deficit Hyperactivity Disorder: Impact of remission definition and symptom type. Am J Psychiatry 2000;156: Biederman J, Faraone S, Milberger S, Guite J, Mick E, Chen L, et al. A prospective 4-year follow-up study of attention-deficit hyperactivity disorder and related disorders. Arch Gen Psychiatry 1996;53: Barkley RA. Major life activity and health outcomes associated with attention-deficit/hyperactivity disorder. J Clin Psychiatry 2002;63: Pelham WE, Wheeler T, Chronis A. Empirically supported psychosocial treatments for attention deficit hyperactivity disorder. J Clin Psychol 1998;27: National Institutes of Health. Diagnosis and treatment of attention-deficit hyperactivity disorder. NIH Consensus Statement 1998;110: American Academy of Pediatrics. Clinical practice guideline: Diagnosis and evaluation of the child with attentiondeficit/hyperactivity disorder. Pediatrics 2000;105: American Academy of Pediatrics. Clinical practice guideline: Treatment of the school-aged child with attentiondeficit/hyperactivity disorder. Pediatrics 2001;108: Taylor E, Döpfner M, Sergeant J, Asherson P, Banaschewski T, Buitelaar J, et al. European clinical guidelines for hyperkinetic disorder first upgrade. Eur Child Adolesc Psychiatry 2004;13: Kutcher S, Aman M, Brooks SJ, Buitelaar J, van Daalen E, Fegert J, et al. International consensus statement on attention-deficit/hyperactivity disorder (ADHD) and disruptive disorders (DBDs): Clinical implications and treatment practice suggestions. Eur Neuropsychopharmacol 2004;14: Landelijke Stuurgroep Multidisciplinaire Richtlijnontwikkeling in de GGZ. Multidisciplinaire richtlijn ADHD bij kinderen en jeugdigen Richtlijn voor de diagnostiek en behandeling van ADHD bij kinderen en jeugdigen [Multidisciplinary guideline for diagnosis and treatment of ADHD in children and adolescents]. Utrecht: Trimbosinstituut, Vitiello B, Severe JB, Greenhill LL Chronis AM, Chacko A, Fabiano GA, et al. Enhancements to the behavioral parent training paradigm for families of children with ADHD: Review and future directions. Clin Child Fam Psychol Rev 2004;7: DuPaul GJ, Eckert TL. The effects of school-based interventions for attention-deficit hyperactivity disorders: A meta-analysis. School Psych Rev 1997;26: Abikoff H. Cognitive training in ADHD children: less to it than meets the eye. J Learn Dis 1991;24: Spencer T, Biederman J, Wilens TE, Harding M, O Donnell D, Griffin S. Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. J Am Acad Child Adolesc Psychiatry 1996;35:

17 Chapter Schachter HM, Pham B, King J, Langford S, Moher D. How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and adolescents? A meta-analysis. CMAJ 2001;165: Greenhill LL, Halperin JM, Abikoff H. Stimulant medications. J Am Acad Child Adolesc Psychiatry 1999;38: Markowitz JS, Patrick KS. Pharmacokinetic and pharmacodynamic drug interactions in the treatment of Attention- Deficit Hyperactivity Disorder. Clin Pharmacokinet 2001;40: Barkley RA, McMurray MB, Edelbrock CS, Robbins K. Side effects of methylphenidate in children with attention deficit hyperactivity disorder: a systemic, placebo-controlled evaluation. Pediatrics 1990;86: Efron D, Jarman F, Barker M. Side effects of methylphenidate and dextroamphetamine in children with attention deficit hyperactivity disorder: a double-blind, crossover trial. Pediatrics 1997;100: Satterfield JH, Cantwell DP, Schell A, Blaschke T. Growth of hyperactive children treated with methylphenidate. Arch Gen Psychiatry 1979;36: Spencer T, Biederman J, Harding M, O'Donnell D, Faraone SV, Wilens TE. Growth deficits in ADHD children revisited: Evidence for disorder-associated growth-delays? J Am Acad Child Adolesc Psychiatry 1996;35: National Institute of Mental Health. Multimodal Treatment Study of ADHD follow-up: changes in effectiveness and growth after the end of treatment. Pediatrics 2004;113: The MTA Cooperative Group: A 14-month randomized clinical trial of treatment strategies for Attention- Deficit/Hyperactivity Disorder. Arch Gen Psychiatry 1999;56: Conners CK, Epstein JN, March JS, Angold A, Wells KC, Klaric J, et al. Multimodal treatment of ADHD in the MTA: An alternative outcome analysis. J Am Acad Child Adolesc Psychiatry 2001;40: Swanson JM, Kraemer HC, Hinshaw SP, Arnold LE, Conners CK, Abikoff HB, et al. Clinical relevance of the primary findings of the MTA: Success rates based on severity of ADHD and ODD symptoms at the end of treatment. J Am Ac Child Adolesc Psychiatry 2001;40: Pelham WE. The NIMH multimodal treatment study for attention-deficit hyperactivity disorder: just say yes to drugs alone? Can J Psychiatry 1999;44: Barkley RA. Commentary on the Multimodal Treatment Study of children with ADHD. J Abnor Child Psychol 2000;28: Boyle MH, Jadad AR. Lessons from large trials: the MTA study as a model for evaluating the treatment of childhood psychiatric disorder. Can J Psychiatry 1999;44: Safer DJ, Zito JM, Fine EM. Increased methylphenidate usage for attention deficit disorder in the 1990s. Pediatrics 1996;98: Zito JM, Safer DJ, dosreis S, Gardner JF, Boles M, Lynch F. Trends in the prescribing of psychotropic medications to preschoolers. JAMA 2000;283:

18 Introduction 38. Schirm E, Tobi H, Zito JM, de Jong-van den Berg LTW. Psychotropic medication in children: A study from the Netherlands. Pediatrics 2001;108:e Miller A, Lalonde CE, McGrail KM, Armstrong RW. Prescription of methylphenidate to children and youth, CMAJ 2001;165: Reid R, Hakendorf P, Prosser B. Use of psychostimulant medication for ADHD in South Australia. J Am Acad Child Adolesc Psychiatry 2002;41: Zito JM, Safer DJ, dosreis S, Gardner JF, Magder L, Soeken K, et al. Psychotropic practice patterns for youth: A 10-year perspective. Arch Pediatr Adolesc Med 2003;157: Safer DJ. Are stimulants overprescribed for youths with ADHD? Ann Clin Psychiatry 2000;12: Buitelaar JK. Discussies over aandachtstekort-hyperactiviteitstoornis (ADHD): feiten, meningen en emoties [Discussion of attention deficit-hyperactivity disorder (ADHD): facts, opinions and emotions]. Ned Tijdschr Geneeskd 2001;145: Rey JM, Sawyer MG. Are psychostimulant drugs being used appropriately to treat child and adolescent disorders? Br J Psychiatry 2003;182: Accardo P, Blondis TA: What's all the fuss about Ritalin? J Pediatr 2001;138: Biederman J, Wilens T, Mick E, Spencer T, Faraone SV. Pharmacotherapy of attention-deficit/hyperactivity disorder reduces risk for substance use disorder. Pediatrics 1999;104:e Barkley RA, Fischer M, Smallish L, Fletcher K. Does the treatment of attention-deficit/hyperactivity disorder with stimulants contribute to drug use/abuse? A 13-year prospective study. Pediatrics 2003;111: Weeda F. Lastig en druk kind kan al vroeg aan de amfetamine [Difficult and hyperactive child can start early with amphetamines]. NRC Handelsblad, August 29, Deskundigen twisten over nut pillen tegen hersenstoornis; Ook therapie nodig bij hyperactiviteit [Experts argue about the usefulness of medication for brain disorder; Also therapy required for hyperactiveness ]. Volkskrant, March 9, Schottelndreier M. Medicijngebruik bij hyperactieve kinderen neemt explosief toe [Drug use among hyperactive children increases dramatically]. Volkskrant, March 9, Lanting B. De zenuwpezenpil [The pill for neurotics]. Volkskrant, September 4, Pardoen J. School dwingt ouders: Ritalin, of anders [School forces parents: Ritalin, or else ] Trouw, February 28, Health Council of the Netherlands. Diagnosis and treatment of ADHD. Health Council of the Netherlands: The Hague, 2000 (in Dutch, publication number 2000/24) 17

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20 2 Recruitment of parents and physicians of stimulant-using children via community pharmacies is successful Adrianne Faber Lolkje de Jong van den Berg Karin Netjes Luuk Kalverdijk Ruud Minderaa Hilde Tobi J Clin Epidemiol 2005;58:

21 Chapter 2 Abstract Objectives This study aimed to investigate the community pharmacy as a starting point for a national survey among parents and prescribing physicians of stimulant-using children in the Netherlands. Methods Community pharmacies identified current stimulant users (<16 years) in their computer system and sent the parents a questionnaire. When the informed consents were received, a questionnaire and a copy of the informed consent were sent to the prescribing physician. Questionnaires were returned free of charge to the research center, and a reminder was sent if they had not responded. Responding parents and physicians received respectively a 5 or 25 euro gift voucher. Consent and non-response analyses were performed. Results A number of 115 pharmacies sent 1307 questionnaires to parents. Of these, 961 questionnaires (74%) were returned of which 924 were suitable for analysis. In 88% informed consent was obtained for approaching the physician. Of the 773 questionnaires sent to physicians 570 questionnaires were returned (74%) of which 556 were suitable for further analysis. The consent analysis showed no association with child s age, gender or type of physician. Response rates for child psychiatrists were lower than for pediatricians and GPs. Conclusions The community pharmacy can be a valuable starting point in the recruitment of users of prescription drugs (or their parents) for survey research, yielding high response rates and low consent refusal rates. 20

22 Recruitment via community pharmacies Introduction The community pharmacy is a reliable source of information regarding medication use in the Netherlands because all prescriptions from general practitioners (GPs) and specialists are dispensed in community pharmacies [1-3]. Several studies have recruited either patients or physicians via pharmacies or have used pharmacy records for post marketing surveillance and medication monitoring [4,5]. We explored the pharmacy as a starting point for a national survey among both parents and prescribing physicians of stimulant-using children in the Netherlands. Methods, results and discussion In May 2003, 115 pharmacies selected current users in their computer system and sent parents a questionnaire on their child s stimulant treatment and related issues. Current users were defined as children younger than 16 years to whom at least two stimulant prescriptions were dispensed between November 1, 2002, and May 1, 2003, of which at least one prescription was in From the eligible children, 15 were randomly selected per pharmacy. Unused questionnaires were returned to the research center. Informed consent was needed from the parents, and also from children if aged 12 years and older, first to participate in the study and second to approach the physician. When the informed consents were received, a questionnaire and a copy of the informed consent were sent to the prescribing physician. Parents and physicians could send the questionnaires free of charge to the research center, and a reminder was sent if they had not responded. Responding parents received a flower coupon of 5 euros, and responding physicians a gift voucher of 25 euros. Data collection stopped October The protocol was approved by the Medical Ethics Board of the Academic Hospital in Groningen. The 115 pharmacies sent out 1,307 questionnaires to parents of stimulant users, with a median number of 13 questionnaires per pharmacy. Of the 961 returned questionnaires, 37 were unsuitable for analysis either because the child s consent signature was missing (29) or because the child was older than 16 when the questionnaire was filled out (8), leaving 924 (71%) questionnaires suitable for analysis. In 811 of the 924 cases (88%) permission was given to approach the physician (Table 1); in 107 cases, parents gave no permission; in 6 cases, the parents gave permission but the child did not. No association was found between consent to approach the physician and the child s age or gender or the type of prescribing physician (all χ 2 tests p>0.24). Because 38 of the 811 questionnaires contained no valid address, 773 questionnaires were sent to physicians; 570 questionnaires were 21

23 Chapter 2 returned. Of these, three were returned blank and in 11 cases the physician reported not being the prescriber, which left 556 questionnaires for further analysis. Our response rate of 74% for parents was greater than the average 60% response to mail surveys among patients reported by Asch et al. [6], and greater than the response rates reported by Sinclair et al. [5] (between 18% and 52% for users of ibuprofen, depending on the recruitment method via the community pharmacy). Physician response rate differed for the type of prescribing physician, from 83% for pediatricians to 62% for child psychiatrists (χ 2 test p<0.001). Physician response rate was not associated with the child s age and gender (all χ 2 tests p> 0.27). Our response rate of 74% for physicians was greater than the average physician response rates of 54% and 61% reported in the medical literature [6,7], but in line with a pilot study for intensive monitoring that reported 70.5% [4]. In the latter study, the pharmacy was the starting point for direct recruitment of physicians without patient permission. In our study, pediatricians more often returned the questionnaire than other doctors, especially child psychiatrists. Delnevo et al. also found a significantly higher response rate among pediatricians compared with other physician specialties [8]. Including children aged 12 years and older in a study complicates the informed consent procedure; however, ~90% of the informed consent forms were fully completed regardless of the child s age. This is in accordance with a study on the use of a multiple-option type of informed consent form vs. a basic single-signature form [9]. Note that a few children gave no permission to participate, despite consent of their parents, which underlines the importance of a separate consent procedure in this age group. Conclusions To conclude, we found that community pharmacies and their computer systems can be a valuable starting point in the recruitment of users of prescription drugs (or their parents) and their physicians for survey research, yielding high response rates and low consent refusal rates. Acknowledgements This study was funded by the Dutch Health Care Insurance Board. 22

24 Recruitment via community pharmacies Table 1. Response and consent analysis on the level of child and physician. Parent response Consent to approach physician Characteristics Questionnaires Sent out Returned Suitable for analysis Children Boys Girls Age < 12 years Age 12 years Physicians General practitioner Pediatrician Child psychiatrist Other Unknown N 1, % N % Sent to physician N % Physician response N %

25 Chapter 2 References 1. Monster TB, Janssen WM, de Jong PE, de Jong-van den Berg LTW, Prevend Study Group. Pharmacy data in epidemiological studies: an easy to obtain and reliable tool. Pharmacoepidemiol Drug Saf 2002;11: de Jong-van den Berg LTW, Feenstra N, Sorensen HT, Cornel MC. Improvement of drug exposure data in a registration of congenital anomalies. Pilot-study: pharmacist and mother as sources for drug exposure data during pregnancy. EuroMAP Group. European Medicine and Pregnancy Group. Teratology 1999;60: Lau HS, de Boer A, Beuning KS, Porsius A. Validation of pharmacy records in drug exposure assessment. J Clin Epidemiol 1997;50: van Grootheest AC, Groote JK, de Jong-van den Berg LTW. Intensive monitoring of new drugs based on first prescription signals from pharmacists: a pilot study. Pharmacoepidemiol Drug Saf 2003;12: Sinclair HK, Bond CM, Hannaford PC. Pharmacovigilance of over-the-counter products based in community pharmacy: A feasible option? Pharmacoepidemiol Drug Saf 1999;8: Asch DA, Jedrziewski MK, Christakis NA. Response rates to mail surveys published in medical journals. J Clin Epidemiol 1997;50: Cummings SM, Savitz LA, Konrad TR. Reported response rates to mailed physician questionnaires. Health Services Research 2001;35: Delnevo CD, Abatemarco DJ, Steinberg MB. Physician response rates to a mail survey by specialty and timing of incentive. Am J Prev Med 2004;26: Ronckers C, Land C, Hayes R, Verduijn P, van Leeuwen F. Factors impacting questionnaire response in a Dutch retrospective cohort study. Ann Epidemiol 2004;14:

26 3 Parents report on stimulant-treated children in the Netherlands: Initiation of treatment and follow-up care Adrianne Faber Luuk J Kalverdijk Lolkje TW de Jong-van den Berg Jacqueline G Hugtenburg Ruud B Minderaa Hilde Tobi J Child Adolesc Psychopharmacol, in press

27 Chapter 3 Abstract Objectives To describe current practices around initiation and follow-up care of stimulant treatment among stimulant-treated children in a nationwide survey among parents. Methods 115 pharmacies detected current stimulant users <16 years in their pharmacy information system and sent parents a questionnaire on their child s stimulant treatment. Results Parents returned 924 of 1307 questionnaires (71%). The median age of the stimulant users was 10 years and 85% were boys. 91% was diagnosed with attention-deficit/hyperactivity disorder (ADHD). In 77% of the cases, child or parents received other therapy besides stimulants. 21% received psychotropic co-medication; melatonin (11%) and antipsychotics (7%) were mentioned most frequently. Stimulant use was primarily initiated by child psychiatrists (51%) and pediatricians (32%), but most children received repeat prescriptions from GPs (61%). Of the 924 children, 19% did not receive any follow-up care. Transfer of prescribing responsibility increased the risk of not receiving follow-up care. The 732 children (79%) who were monitored visited a physician approximately twice a year. During follow-up visits pediatricians performed physical check-ups significantly more often. Conclusions Stimulant treatment in the Netherlands is mainly initiated by specialists such as child psychiatrists and pediatricians. In the current study, follow-up care for stimulant-treated children in the Netherlands appeared poor, suggesting an urgent need for improvement. 26

28 Initiation of treatment and follow-up care Introduction Stimulants are the first choice pharmacotherapeutic intervention in the treatment of attention-deficit/hyperactivity disorder (ADHD) and the most frequently used psychotropic medication in children. The considerable increase of stimulant use in several Western countries in the nineties, as evident from prescription database research, has resulted in public concern about the appropriateness of stimulant treatment in children [1-4]. These concerns were further heightened by the increased use in preschoolers and the increased duration of stimulant therapy [1,3]. Although stimulants have been used since the 1960s, still the impact of long-term stimulant use is unclear [5]. The largest and longest randomized clinical trial of stimulant medication in children with ADHD had a duration of 14 months and showed continuous effectiveness and frequent, yet minimal harmful, side-effects [6]. However, 14 months is still relatively short compared to the duration of time that many children are prescribed stimulant medication. As the general prevalence increased, both in the lay media and medical journals questions were raised about the appropriateness of the treatment and the competence of the initiating physician [2,7,8]. A study from the USA reported that family practitioners prescribed stimulants more often than pediatrics and psychiatrists, and Miller et al. reported that between 1990 and % of the first stimulant prescriptions in Canada were prescribed by GPs [2,9]. In the Netherlands, the lay media claimed excessive prescribing of stimulant medication by GPs, which caused considerable concern and discussion. Thereupon the Health Council of the Netherlands stated that initiation of stimulant treatment should be restricted to physicians experienced and trained in diagnosing and treating ADHD and co-morbid disorders, like child psychiatrists and pediatricians [10]. Several treatment guidelines for ADHD recommend that multimodal interventions, most of the time including stimulant medication, should be available to all children and usually are indicated [11-14]. Guidelines mostly rely on the results of the largest randomized controlled trial of ADHD treatment, the Multimodal Treatment Study of Children with ADHD [6]. In the MTA stimulant medication alone and stimulants combined with behavioral therapy were found to be superior in improving ADHD symptoms compared to care as usual. Several factors were thought to account for this difference, like monthly check-ups and dose titration strategies in the medication management arm, while children treated in the care as usual arm visited their physician on average 2.3 times per year. It is generally agreed that optimal stimulant treatment presupposes regular contact of the treating physician with the child, parents and school, using rating scales for monitoring effectiveness, adjusting stimulant dose if necessary and looking after possible side-effects. However, studies from the USA suggest that treatment services offered to children with ADHD may be determined by the 27

29 Chapter 3 type of treating physician rather than by established standards of care [9,15]. Hence, the gap between what is classified as care as usual in the MTA study and the care as usual in any regional setting warrants further investigation. Most in-depth research on initialization and follow-up of stimulant treatment is limited to groups of children selected for their diagnosis with ADHD, or their visits to certain officebased physicians [16-19]. Consequently, the results of these studies cannot be generalized to the total population of stimulant-treated children, nor to an international setting. The societal turmoil in The Netherlands, however, was based on studies from North America, as no information was available on the Dutch situation. Hence a nationwide survey was initiated to describe current practices around initiation and follow-up of stimulant treatment in children. Parents of stimulant-treated children were inquired after the initiation and follow-up care of stimulant treatment, using community pharmacies for recruitment to avoid bias for the initiating or treating physician. Methods The survey included only parents of stimulant-treated children in To obtain a nationwide sample of stimulant users irrespective of the prescribing physician, pharmacies were used for detecting stimulant users in their pharmacy information system and for sending a questionnaire to their parents or caregivers. All legal citizens of the Netherlands have a health insurance covering doctor fees, hospital stays, counseling, physical therapy, medication and other non-pharmacological treatments (e.g. treatments provided by clinical psychologists). Not all prescription drugs are fully reimbursed by each insurance company. Since all prescriptions from medical doctors are entered in the pharmacy database regardless of particular health insurance or reimbursement status of the medication, the pharmacy is a reliable source for detecting medication users. At the time of this study, immediate-release methylphenidate tablets and dexamphetamine compounded capsules were fully reimbursed. OROS-methylphenidate tablets became available in 2003, but required a co-payment from the patient. The study design and response patterns have been described in detail elsewhere [20]. In short, a nationwide sample of 115 pharmacies detected current users of methylphenidate and dexamphetamine in their computer system and sent a questionnaire to the parents in May Current users were defined as children younger than 16 years to whom at least two stimulant prescriptions were dispensed between November 1, 2002 and May 1, 2003, of which at least one prescription was in When this detection resulted in more than 15 28

30 Initiation of treatment and follow-up care current users, pharmacists used a random table provided by the researchers to select 15 children. In this way the maximum number of participants per pharmacy was manageable. The questionnaire contained open-ended and multiple choice questions and was tested among ten parents. Questions dealt with the key symptoms for stimulant treatment and the type of physician involved in prescribing stimulants. We also asked the parents whether their child would visit a doctor or was expected to visit a doctor with regard to the use of stimulant medication. In case the child received this follow-up care, parents were questioned about the frequency of visits and about physical examination and evaluation of effectiveness of stimulant treatment during the most recent visit. Furthermore, questions were asked about the child s age and sex, education, psychiatric diagnoses, co-medication and nonpharmacological therapy. The protocol was approved by the Medical Ethics Board of the University Medical Centre Groningen. Questionnaires were regarded unsuitable for analysis when the child was 16 years or older or when children of 12 years or older had not given written permission to send in the questionnaire. To investigate factors that might be associated with receiving follow-up care Pearson Chi Square or one-way ANOVA tests (two-tailed) were used and a p-value < 0.05 was considered statistical significant. Questionnaires were analyzed using SPSS Results Demographic characteristics Of 1307 questionnaires sent out by 115 pharmacies, 924 returned questionnaires were suitable for analysis (response rate: 71%). In 86% of the cases questionnaires were completed by the child s mother. Dutch was the first language for nearly all responding parents (97%). The median age of the stimulant-treated children was 10 years and the maleto-female ratio was approximately 5.5:1 (Table 1). Diagnosis and treatment The vast majority of the children (91%) were diagnosed with attention-deficit/hyperactivity disorder (ADHD) (Table 1). Parent who reported no ADHD diagnosis, reported mainly pervasive developmental disorder (44/84) and learning disorder (12/84) for diagnosis. Furthermore, 11 of the 84 parents reported that no diagnosis was established yet. Twentyeight percent of the children had two or more psychiatric diagnoses. Of the 924 children, 540 had received non-pharmacological therapy besides stimulants (58%). Therapy consisted of non-intensive training with a maximum of 2 hours per week in 49% of these children, and/or 29

31 Chapter 3 Table 1. Characteristics of current stimulant-treated children (N=924). Characteristic Category Age 1st quartile 9 years 2nd quartile (median) 10 years 3rd quartile 12 years % N Sex Boys Education Special education Assistance at school, but no special education Current diagnosis Attention-deficit/hyperactivity disorder Pervasive developmental disorder Learning disorder Oppositional defiant disorder Anxiety disorder Other No diagnosis (yet) Unknown or more diagnoses Psychotropic co-medication Yes Melatonin Antipsychotics Clonidine Antiepileptics Antidepressants Hypnotics/anxiolytics (excl. melatonin) Time since 1st stimulant prescription < 1 year to 2 years years Unknown Key symptoms for stimulant treatment Inattention Hyperactivity Impulsiveness Learning problems Anxiety Depression Sleep problems Tics Other

32 Initiation of treatment and follow-up care Table 1. Continued Characteristic Category % N Prescriber 1st stimulant prescription Child psychiatrist Pediatrician GP Other Unknown Is stimulant treatment monitored? Yes No Unknown physical therapy (34%) and/or intensive training for more than 2 hours per week (27%). Parents received counseling for the behavioral problems of their child in 571 cases (62%), being primarily individual parent training (78%), home training (33%) and/or group-based parent training (20%). In almost a quarter of the cases (23%), neither child nor parents received other therapy besides stimulants. 21% of the children received psychotropic comedication, including melatonin. In case melatonin was excluded 12% received psychotropic co-medication. Melatonin (10.8%) and antipsychotics (7.3%) were the most frequently mentioned co-medication. According to the parents, the child s inattention, hyperactivity, impulsiveness and/or learning problems were the key symptoms for stimulant treatment (Table 1). Stimulant treatment was primarily initiated by child psychiatrists and pediatricians. GPs provided repeat prescriptions for 61% of the children, child psychiatrists and pediatricians for 30% and 21% respectively. Fifteen percent of the children received repeat prescriptions from 2 or more different types of physicians. According to 264 parents (29%), their child experienced annoying side effects; sleep problems (52%) and loss of appetite (42%) were the most frequently mentioned side effects by these parents. More than half of the children used stimulants for over two years. Follow-up care Almost one out of five children (19%) did not receive follow-up care concerning treatment with stimulants (Table 1), meaning that no appointment was scheduled or requested by the medical doctor according to the parents. Children who received the first stimulant prescription and repeat prescriptions from the same type of physician, were significantly more likely to receive follow-up care than children with a transfer of prescribers (Table 2). 31

33 Chapter 3 Table 2. Factors associated with follow-up care (n = 924). Factor Category Follow-up care yes (%) or mean (sd) Test df p Total 79.2 Age child mean (sd) Follow-up care, no 10.9 y (sd 2.3) t-test Follow-up care, yes 10.4 y (sd 2.5) Gender child Male 79.4 Χ Female 78.0 Special education No 79.1 Χ Yes 79.5 Time since 1st stimulant prescription < 1 year 81.4 Χ years year 77.8 Number of diagnoses Χ or more 80.2 Psychotropic co-medication No 78.0 Χ Yes 83.9 Physician 1st stimulant prescription also involved in prescribing repeat prescriptions No 71.5 Χ 2 1 <0.001 Yes 84.8 Furthermore, children receiving follow-up care were slightly younger (p=0.02). No statistical significant association was found between receiving follow-up care and gender, special education, time since first stimulant prescription, the number of diagnoses and use of psychotropic co-medication. The 732 children who received follow-up care visited a physician on average twice a year, usually a child psychiatrist or a pediatrician (Table 3), and 5.3% visited two different types of physicians for follow-up care. The mean number of follow-up visits decreased with an increased period of stimulant use, from 3 visits per year for children who had used stimulants less than one year to 2 visits per year for children who had used stimulants for 1-2 years and 2 years or longer (one-way ANOVA, df 2, p<0.001). During follow-up visits pediatricians (93%) performed physical check-ups significantly more often than GPs (82%), child psychiatrists (80%) and other physicians (59%) (Χ 2 test, df 3, p<0.001). During the most recent visit, in 179 of 732 cases (25%) behavior rating scales 32

34 Initiation of treatment and follow-up care were used to evaluate the effectiveness of stimulant treatment. Usually both parents and teacher were asked to complete a rating scale. The use of rating scales declined with an increased period of stimulant use, from 41% among children who had used stimulants less than one year to 15% among children who had used stimulants for 2 years or longer (Χ 2 test, df 2, p<0.001). No statistical significant association was found between the use of rating scales and the type of physician visited. Table 3. Follow-up characteristics (N=732). Characteristic follow-up Category Number of follow-up visits per year 1st quartile 2 2nd quartile (median) 2 3rd quartile 4 % N Type of physician visited for follow-up Child psychiatrist Pediatrician GP Other Physical examination during last visit Weight Length Blood pressure Physician inquired about side effects Yes Evaluation effectiveness stimulant treatment by means of standardized questionnaire during last visit Yes Rating scale parents only Rating scale teacher only Rating scale both parents and teacher Discussion Stimulant treatment was primarily initiated by specialists (e.g. child psychiatrists and pediatricians), while GPs took care of most of the repeat prescriptions. Nearly one in every five current stimulant-treated children did not receive any follow-up care aimed at their stimulant use. 33

35 Chapter 3 In our study, 12% of the parents reported that stimulant treatment had been initiated by a GP, which is a low percentage compared to 41% in Canada [2]. Therefore, general concerns about the competence of the initiating physician appear to be unnecessary for the Dutch situation. According to the parents, stimulants were mainly used for ADHD, the indication for which these drugs are licensed. Of the children 28% had two or more psychiatric diagnoses, which is a low percentage compared to co-morbidity rates of over 50% reported elsewhere [21,22]. The presently reported low figures may be partially explained by under diagnosis of psychiatric disorders in this general population, a population in which not all children are thoroughly screened by child psychiatrists. For the majority of the children (77%) stimulant treatment was or had previously been combined with non-pharmacological therapy for the child and/or the parents. A study from the USA reported that in 47% of the visits stimulant users received mental health counseling and 22% psychotherapy [17]. The 21% psychotropic co-medication in the present study is consistent with the 19-25% in other studies, although it is unclear if these two studies included melatonin [23,24]. Another study from the Netherlands, based on a prescription database however, reported only 15% psychotropic co-medication among stimulant users [25]. Part of this difference may be attributable to incomplete data on melatonin as OTC medication in prescription databases. We were surprised to find that over 10% of the stimulant-treated children used melatonin, probably for sleep problems. Like many other hypnotics, melatonin is not approved for use in children. Actually, melatonin is not approved in the Netherlands at all, and safety data are lacking. All the more a reason for carefully monitoring these children. As far as we know, no literature is available about the prevalence of melatonin use in other countries. It would be interesting to study whether the frequent use of melatonin in stimulant-treated children is a typical Dutch phenomenon. The fact that almost 20% of the stimulant-treated children in our study were not monitored is worrisome. Transfer of prescribing responsibility, in most cases from specialist to GP, increased the risk of not receiving any follow-up care. These findings call for efforts to improve collaboration between primary and secondary care. At this point we agree with Ball et al. that GPs might take over prescribing responsibility after initiation and perform physical monitoring, but only in close liaison with the treating specialist [26]. However, our data show that having one prescriber is not a guarantee for receiving follow-up care. So, all prescribers, in particular child psychiatrists and GPs, need to reconsider the follow-up care they provide in addition to improving collaboration between specialists and GPs/other care providers. The children who did receive follow-up care visited a physician on average twice a year, which is similar to a study from the USA among children, with recently identified 34