text:
The Pharmaceutical Economics of Child Psychiatric Drug Treatment
- Sabrina Hudson
- 3 years ago
- Views:
1 Current Pharmaceutical Design, 2010, 16, The Pharmaceutical Economics of Child Psychiatric Drug Treatment Michael Schlander 1-3, * 1 Institute for Innovation & Valuation in Health Care (InnoVal HC ) Wiesbaden, Germany, 2 University of Heidelberg, Mannheim Medical Faculty (Institute for Public Health, Social and Preventive Medicine) Mannheim, Germany, 3 University of Applied Economic Sciences LudwigshafenLudwigshafen am Rhein, Germany Abstract: Over the last decade, the number of health economic evaluations has increased substantially in the field of child psychiatry. The objective of the present paper is to offer an overview of economic evaluations of child psychiatric drug treatment. Major electronic databases, as well as abstract booklets from international clinical and health economics conferences with an external peer review process, were examined to search for comparative economic evaluations of child and adolescent psychiatric drug treatment. Most studies of pharmacotreatment were cost effectiveness analyses (CEAs) concerned with attention-deficit/hyperactivity disorder (ADHD). Three evaluations were done by or on behalf of agencies as part of ADHD-related health technology assessments. A number of economic studies used patient-level data from specific randomized clinical trials, especially the NIMH-initiated MTA (in childhood ADHD) and TADS (in adolescent major depression) studies. Almost all studies relied on narrow scale symptom scales to assess effects of treatment, even when quality-adjusted life years (QALYs) were reported. In many cases, effectiveness data came from short-term studies, and extrapolation to a one-year time horizon was usually based on assumptions. Even those evaluations attempting to address longer time horizons by way of modeling did not include the impact of treatment on long-term sequelae of the conditions studied, mainly due to a paucity of robust clinical data. Nevertheless, currently available health economic evaluations broadly suggest an acceptable to attractive cost effectiveness of medication management of ADHD, whereas there is no such evidence for child psychiatric disorders other than ADHD. Keywords: Economic evaluation, cost effectiveness analysis, cost utility analysis, quality-adjusted life year (QALY), cost benefit analysis, health technology assessment, attention deficit hyperactivity disorder (ADHD), depression, pharmacoeconomics. INTRODUCTION To date, the economic implications of child and adolescent psychiatric disorders and related interventions at the individual level have received considerably less attention than the impacts on symptoms, functioning, health-related quality of life (HRQoL) and other patient-reported outcomes (PROs). This is particularly true for comparative evaluations of the cost effectiveness of treatment options in child and adolescent psychiatry. In their review of the subject covering the period before September 2003, Renée Romeo and colleagues concluded in 2005, economic evaluations in the field [ ] are few in number and generally poor in quality, although the number of studies undertaken appears to be rising [1]. Many reports identified by these authors addressed questions of relative effectiveness but had little if anything to say about the value for money provided by the interventions undergoing evaluation. Other studies were descriptive cost studies only, i.e., they investigated costs or cost offsets but did not measure treatment outcomes [1]. Across all types of study (cf. Table 1) [2-4] and irrespective of methodological quality, the total number of reports identified by Romeo et al. (2005) was 21; of those, 14 measured both costs and benefits of at least two interventions. One study assessed a pharmacological treatment option, methylphenidate [5]. These observations are remarkable on several accounts. First, this very small number constitutes a striking contrast to other therapeutic areas, which have experienced an exponential growth in the number of published economic evaluations. Second, in other clinical areas pharmaceuticals feature prominently among technologies subjected to economic analysis [6]. Third, following the early examples of Australia (in 1992) and Canada (in 1994), many jurisdictions have adopted Health Technology Assessments (HTAs) including formal economic evaluation to guide pricing and reimbursement decisionmaking, again frequently focusing on pharmaceutical treatments [7,8]. Fourth, with the emergence of novel pharmacological treatment options, the budget impact of drug treatment in child and *Address correspondence to this author at the Institute for Innovation & Valuation in Health Care (InnoVal HC ), An der Ringkirche 4, D Wiesbaden, Germany; Tel: +49 (0) ; Fax: +49 (0) ; adolescent psychiatry either has grown substantially (like in the United States), or is set to grow dramatically, with the implication of the field losing its status as a relatively small pharmaceutical market niche and the inevitable consequence of an increasing relevance of health economic evaluations [9]. Put in the broader context of the enormous public health burden caused by child and adolescent psychiatric problems [10,11], the conspicuous paucity of comparative evaluations of treatments can only surprise, despite or - perhaps somewhat paradoxically from an economic perspective - because of the wide-held belief that children [are] our most valuable resource [12]. But what value do we attach effective treatment of behavioral problems of our children? The intended readers of the present paper are primarily clinicians - both clinical researchers and practitioners with an interest in health economics. The goal of the paper is to offer an overview and critical appraisal of economic evaluations of drug treatment in child and adolescent psychiatry, portraying both decision-analytic modeling approaches and prospective cost effectiveness studies. ECONOMIC EVALUATION OF DRUG TREATMENT IN CHILD PSYCHIATRY: RECENT DEVELOPMENTS Recent pharmacoepidemiological research indicates an enormous international variability in the use of medication for children and adolescents [13]. This variability, which appears particularly striking with respect to treatment of mental disorders, cannot be explained on grounds of differences in the prevalence rates of disorders [14]. For example, the United States (US) alone account for more than four fifth of the worldwide use of psychostimulants [15]. Another example concerns the use of antidepressants in children and adolescents, which is also much greater in the US compared to European countries [16,17]. Also within Europe, there are substantial differences between countries - to mention just one example, herbal products appear to be particularly popular in Germany, with the consequence that about 80% of antidepressant consumption by children and adolescents in Germany was accounted for by St John s wort extracts in 2003 [18]. Accordingly, expenditures for /10 $ Bentham Science Publishers Ltd.
2 2444 Current Pharmaceutical Design, 2010, Vol. 16, No. 22 Michael Schlander Table 1. Health Economic Evaluation Types Type of Analysis Measurement and Valuation of Costs Measurement of Consequences (Effects) Valuation of Consequences (Effects) Theoretical Foundation (Standard) CMA: cost minimization analysis Monetary units (usually from a decision maker s perspective ) None None Costing theory CEA: cost effectiveness analysis Monetary units (usually from a decision maker s perspective ) Single effect measure of interest, common to alternatives evaluated, but achieved to different degrees Natural units (e.g., life years gained, response rates, etc.) Decision analysis and operations research; goal: technical efficiency CUA: cost utility analysis Monetary units (in theory, often recommended to be determined from a societal perspective ; in practice, often from a health care policy maker s perspective Single or multiple effects, not necessarily common to alternatives evaluated Health-adjusted life years (usually QA- LYs) Extrawelfarism - maximizing total health gains under a resource constraint; goal can be technical or allocative efficiency (usually applying a cost/qaly benchmark) CBA: cost benefit analysis Monetary units (from a societal perspective, i.e., ignoring transfer payments) Single or multiple effects, not necessarily common to alternatives evaluated Monetary units (usually WTP) Economic welfare theory - maximizing the impact of health care on overall well-being; goal: allocative efficiency Similarities and Differences of Commonly Used Techniques for the Comparative Economic Evaluation of Health Care Programs [2-4]. child psychiatric drug treatment, with budgetary impact being the product of number of prescriptions and average unit costs, also varies greatly between jurisdictions [9,15]. There is a host of underlying reasons, ranging from international differences in diagnosis rates under conditions of routine care, diagnostic criteria (e.g., ICD-10 versus DSM-IV), to different treatment preferences, but also related to the very availability of treatment options [9]. For example, amphetamine products are widely prescribed for ADHD in countries such as the US and the UK, but are not available in Germany, Italy, and some other European countries. International heterogeneity is further exacerbated by regulatory differences related to available products, with many compounds being used off-label, i.e., without being officially approved for pediatric use. Of course, different utilization patterns are highly relevant for the choice of appropriate comparators in economic evaluations. Among the most commonly diagnosed child psychiatric disorders, ADHD, conduct disorder, and anxiety and depressive disorders consistently rank highest in studies [10,19-21]. Of these ADHD arguably represents the most well-researched condition. Correspondingly, the vast majority of comparative economic evaluations of drug treatment concern this disorder. ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD) ADHD is a chronic psychosocially impairing condition frequently persisting into adulthood [22,23]. Beyond its direct costs [24,25] and the burden placed on parents and other family members [25,26], the disorder has been linked to serious long-term sequelae. These include poor driving abilities [27], higher risks of accidents and injuries [28-30], increased rates of tobacco, alcohol and other substance use disorders [31], more frequent antisocial behaviors [32-34] and encounters with the criminal justice system [35-38] across the lifespan, as well as relatively poor educational outcomes and lower-ranking occupational positions than controls [33,39-42]. Despite important gaps in our understanding of the economic implications of these sequelae, the annual societal cost for ADHD in childhood and adolescence has been estimated to exceed $40 billion in the US alone [43]. Only a fraction of these costs - between 10 percent according to UK data for conduct disorder and up to 20 percent for ADHD in the US - fall into the health sector [11,43,44]. For Germany, direct medical costs borne by statutory health insurance (SHI) attributable to ADHD - i.e., excess costs of health care compared to a control group matched by age, gender, and type of SHI - were estimated at 260 million in year 2003, and have continued to increase at a fast pace since [45,46]. The German data did neither include other social costs nor the productivity loss attributable to ADHD [45]. Coexistence of other child psychiatric conditions is common in children with ADHD [47-50]. Actually, pure ADHD appears to be rather the exception than the rule, and some scholars even suggested the use of distinct comorbid subtypes of ADHD [51]. It seems both plausible and likely that coexisting conditions should increase direct costs [25,43,52]. Yet many cost of illness studies did not reveal a noticeable impact of specific coexisting conditions on the cost of mental health services for patients with ADHD, and this is mostly due to study design and sometimes small sample sizes [25,43]. In-depth analyses are available for Germany and the US, and these studies concur in indicating higher costs of care in the presence of conduct and personality disorders, mood and affective disorders, as well as adjustment disorders, but not learning disabilities and specific development disorders [53-55]. Furthermore, some coexisting conditions might represent an independent predictor [56] and moderator [57] of long-term treatment outcomes, although data available to date are limited and somewhat contradictory [58]. As a consequence, one might expect attractive cost effectiveness ratios for clinically proven therapeutic strategies for ADHD, providing, of course, a positive impact on some of the sequelae associated with the disorder can be demonstrated. At the same time, valid economic analyses need to address a variety of issues, which adds substantial complexity - such as the role of diagnostic criteria (DSM-IV versus ICD-10) [59-62], the presence of coexisting conditions [47-50], and the broad variety of instruments used to measure clinical outcomes in ADHD [63,64]. Further to this, international differences deserve attention, for example concerning utilization patterns, treatment patterns, and unit costs [65,66].
3 The Pharmaceutical Economics of Child Psychiatric Drug Treatment Current Pharmaceutical Design, 2010, Vol. 16, No TREATMENT OF ADHD The principal evidence-based treatment options for ADHD are psychosocial interventions and drug therapy, as well as the combination of both. International clinical guidelines generally provide support for both options but have not been informed by economic assessments [67-71]. While there are limited data available on the economic attractiveness of psychosocial interventions, a substantial number of cost effectiveness studies of drug treatment for ADHD have become available since the earlier reviews by Knapp (1997) [72] and Romeo et al. (2005) [1]. Following the editors request, the present review will focus on economic evaluations of pharmacotherapy. From the 1960s through the 1990s, pharmacotherapy for the treatment of ADHD consisted of short-acting stimulant medications with a duration of action of about three to four hours (hence requiring twice [ b.i.d. ] or thrice [ t.i.d. ] daily administration to achieve full-day symptom control), most notably methylphenidate (MPH). MPH, like the other stimulants used in ADHD (primarily, dexamphetamine [DEX] and mixed amphetamine salts [MAS]), is thought to act primarily by increasing dopamine at the synapse [73-75]. Another stimulant drug, pemoline (PEM), had to be withdrawn from market due to an unacceptable risk of liver toxicity [76]. During the last two decades, not only the number of chemical entities grew, but also new longer-acting formulations of psychostimulants became available, which often need to be administered oncedaily ( q.d. ) only [69,77,78]. Also a nonstimulant alternative, atomoxetine (ATX), is now available. ATX is thought to exert its effects primarily by selectively inhibiting presynaptic norepinephrine reuptake in the prefrontal cortex, ie. through the noradrenergic pathway [79]. Finally, there are some other drugs less frequently prescribed for treatment of ADHD, which have not been approved for this use (for example, alpha receptor agonists such as clonidine and guanfacine, the antidepressant bupropion, and the stimulant modafinil) [78,79]. All drugs are effective in reducing the core symptoms of ADHD, with reported effect sizes of around 0.9 to 1.0 for stimulants and about 0.6 to 0.7 for the nonstimulant atomoxetine [71]. Furthermore, unlike the stimulant compounds that exhibit a very close correlation of pharmacokinetics and pharmacodynamic effects, the initial onset of therapeutic effects of atomoxetine builds up gradually over a period of two to six weeks [80]. Of note, most economic evaluations conducted to date have used some measure of symptom improvement either directly as the clinical outcome of interest, or indirectly as a basis to estimate quality-adjusted life year (QALY) gains. QALYs combine, by means of multiplication, length of life with health-related quality of life in one single metric. Quality of life is represented by an index, which is assumed to represent the expected utility of a given health state and can vary between 1 for perfect health and 0 for dead (Fig. 1). Rankings of interventions on the basis of their incremental cost per QALY gained, assumed by many economists to reflect an increasing social desirability with decreasing incremental cost effectiveness ratios (ICERs; Fig. 2), are often referred to as cost effectiveness league tables [2-4,81]. Acquisition costs vary between products and by jurisdiction. As a general rule, it can be said that short-acting stimulant drugs (including amphetamine, mixed amphetamine salts, dexamphetamine, and methylphenidate preparations). are available as relatively lowpriced generic versions, whereas stimulant preparations with a longer duration of action (modified-release formulations for oral use or patch for transdermal administration) are more expensive, and the acquisition cost of atomoxetine tends to be either comparable to the upper end of the range for long-acting stimulants (US) or considerably higher (D, UK) [82-84]. Many scientific contributions to the economics of child psychiatric drug treatment have not yet become available as full-text articles. In order to provide an up-to-date overview of the field, the search strategy included papers presented at international health economics meetings with an established peer review process. Abstracts were included if the information provided appeared sufficient in relation to the conclusions offered. It needs to be recognized that search results for meeting presentations might be incomplete, because conference abstracts and presentations are notoriously difficult to locate as they are poorly (or not) indexed in standard bibliographical databases. In addition, overall quality of re- Fig. (1). The quality-adjusted life year (QALY) concept Length (horizontal axis) and quality (vertical axis) of life determine the number of quality-adjusted life years (QALYs). The quality (or utility) weights should be based on actual preferences and measured on a cardinal scale to enable a meaningful computation of sums and differences (cf. Figs. 3 and 4). For example, four life years spent in a health state with a utility of 0.5, such as blindness according to some studies, give 0.5 x 4 = 2 QALYs, equivalent to 2 years spent in full health. For a sequence of health states, the area under the curve (AUC) is the number of QALYs corresponding to this trajectory [3].
4 2446 Current Pharmaceutical Design, 2010, Vol. 16, No. 22 Michael Schlander Fig. (2). Incremental cost effectiveness ratios (ICERs) Results of cost effectiveness analyses are usually reported as incremental cost effectiveness ratios, ICERs. This is intuitively appealing as efficiency can be interpreted as the ratio of (incremental) inputs to (incremental) outputs [3,4]. As a ratio of two absolute differences, the ICER possesses weird statistical properties, complicating probabilistic sensitivity analyses (capturing parameter uncertainty) and the computation of ICER confidence intervals. It also does not provide any information about the size of its numerator and its denominator and, therefore, the budgetary impact of adopting an intervention [2-4,81]. porting in abstracts may be inadequate, data might be incomplete, and may on occasion even be inconsistent with those reported in subsequent full publications [85]. HEALTH TECHNOLOGY ASSESSMENTS (HTAs) INCLUD- ING ECONOMIC EVALUATION One might reasonably expect HTAs including economic evaluation to provide the most comprehensive information on the clinical and cost effectiveness of medical interventions. Inter alia, HTAs attempt to provide evidence-based insights whether a medical technology (drug, device, procedure, etc.) is effective, for whom it works, what costs are entailed in its use, and how it compares with available alternatives [7,8,86,87]. A typical contemporary HTA includes a systematic review of the available information, a quantitative synthesis of clinical data, and increasingly also an economic assessment of relevant alternatives. In the field of ADHD, formal HTAs have been presented by the Canadian Coordinating Office for Health Technology Assessment (CCOHTA; now known as the Canadian Agency for Drugs and Technologies in Health, CADTH) in Ottawa, Ontario, and by the National Institute for [Health and] Clinical Excellence (NICE) in London. HTAs (1): CCOHTA 1998 The CCOHTA review of therapies for ADHD comprised three parts, an overview of the use of methylphenidate (MPH) for ADHD, a systematic review and meta-analysis of medical and other therapies for ADHD, and an economic evaluation of pharmaceutical and psychological/behavioral therapies [88-90]. 26 treatment studies were selected for meta-analysis. Of these, 24 studies involved the use of medication - MPH, dexamphetamine (DEX), and/or pemoline (PEM), three of them assessing the combination of drug treatment with psychological / behavioral interventions, and two studies reported results of psychosocial interventions. Observation periods in studies of drug treatment were limited to 28 days or less, except for one study that reported outcomes after 120 days, whereas the studies involving psychological/behavioral interventions had follow-up periods of several months, in one study up to 24 months [91]. Efficacy was determined as symptom improvement reported by teachers or parents, most frequently by means of Conners Rating Scale (CRS) scores [64,89], and was expressed as effect sizes (or standardized mean differences). Teacher ratings were subsequently used for cost effectiveness analysis because they were most widely available and believed to best reflect the therapeutic objective to improve classroom behavior. For economic evaluation, the CCOHTA team adopted the perspective of Canadian provincial ministries of health and their associated drug benefit plans, and a one-year time horizon. Based on survey data from British Columbia on the average duration of MPH treatment in ADHD [89,92], which were supported by expert input and medication attrition data over 10 months from one clinical study [93], non-compliance (or more accurately, nonpersistence) was modeled over six month intervals (cf. Fig. 3). A series of sensitivity analyses for both costs and outcomes but no subgroup analyses were performed. In this Canadian evaluation, MPH turned out to be dominating DEX, PEM, and nondrug treatment (NDT), with an estimated ICER of $64 to $83 versus no treatment for each point difference in the Conner Teacher Ratings Scale (CTRS) score sustained over one year. This translated into an estimate of $384 to $498 for a 6-point or one standard deviation difference versus no treatment, which was considered to represent a clinically significant improvement [89]. Two aspects of this study appear noteworthy. First, this study evaluated immediaterelease MPH given twice daily only (long acting formulations and atomoxetine had not yet been available). Second, the use of rating scale scores as an outcomes metric implicitly assumes that differences across the scale are valued equally, irrespective of their size and where they occur, and as a typical cost effectiveness analysis (CEA; cf. Table 1) using a clinical measure of treatment benefit, this approach precludes any comparison with interventions in other therapeutic areas. After careful consideration of the limitations of this early HTA, CCOHTA concluded, that MPH is the most cost-effective alternative for the management of ADHD in Canada [94]. More recent Canadian HTAs including economic evaluation are not available; but CADTH has initiated an assessment of long versus short acting drugs for ADHD, which is still ongoing at the time of writing [95]. HTAs (2): NICE 2000 In 2000, NICE addressed the clinical and cost effectiveness of ADHD treatment for the first time [96]. The evaluation was limited to the use of MPH and relied heavily on the previous systematic reviews by Jadad et al. (1999) from McMaster University in Hamilton, Ontario, on behalf of the U.S. Agency for Healthcare Research and Quality (AHRQ) [97] and by CCOHTA [88,89]. It was further
5 The Pharmaceutical Economics of Child Psychiatric Drug Treatment Current Pharmaceutical Design, 2010, Vol. 16, No Fig. (3). Model used by the Canadian Coordinating Office for Health Technology Assessment (CCOHTA) 1998 Decision analysis tree diagram (pemoline excluded) used by CCOHTA to evaluate the cost effectiveness of ADHD treatment options. MPH, methylphenidate (10mg/dose b.i.d.); DEX, dextroamphetamine (15mg/day, 10mg in the morning and 5mg in the evening); NON-DRUG, psychological/ behavioral therapy; COMB, a combination of methylphenidate (10mg/dose b.i.d.) and psychological/behavioral treatment (from Zupancic et al., 1998, p 34) [89]. informed by two company submissions and by a report published by the Wessex Institute for Health Research and Development [5,98], which had already been discussed by Romeo et al. (2005) in their review mentioned earlier [1,5]. The primary clinical findings of the NIMH MTA Study (see below) were considered as well [99,100]. The authors of the first NICE assessment did not attempt a quantitative synthesis of effectiveness data. The economic evaluation was also confined to a qualitative appraisal of the existing information base and concluded that the cost per QALY gained, from the perspective of the NHS and with a one year time horizon, would most likely fall between 9,200 (sensitivity analysis: from 4,700 to 28,200) and 14,600 ( 5,600 to 17,500). For QALY computation, response rates had been linked to utility estimates based on expert assumptions on the differences in health-related quality of life between treatment responders and nonresponders. HTAs (3): NICE 2004 In 2004, NICE again addressed ADHD treatment options [7, ]. A broader scope, including dexamphetamine (DEX), atomoxetine (ATX), and long-acting formulations of methylphenidate with an average duration of action of eight (MPH-MR08) or ten to twelve hours (MPH-MR12) [101], came in parallel with the implementation of more ambitious evaluation methods by NICE earlier in the same year [108,109]. Comparators should include placebo and usual care, and treatment outcomes to be included in the analysis were incidence and severity of core symptoms, of coexisting problems, measure of depression and/or anxiety, adverse events, and quality of life. Consideration should also be given to comorbid disorders [103]. The final assessment report included a systematic review of clinical studies, statistical data synthesis using mixed treatment comparison (MTC) techniques, a review of submissions by manufacturers, and an economic evaluation model developed de novo by the assessment group. Whereas the clinical effectiveness review focused primarily on measures of hyperactivity and included 64 randomized clinical trials (RCTs), the economic model was informed by six short-term studies only (including one that had been excluded from the effectiveness review for quality concerns), which provided CGI-I scores believed by the NICE team to enable response definition and subsequent QALY calculation. Utility weights came from a study using parent proxy ratings [108]. On the basis of six RCTs with treatment durations between three and eight weeks, 19 treatment sequences (taking account of concomitant non-drug treatment, the original model featured even 37 different treatment strategies) were simulated, and incremental cost per QALY was calculated for each from the perspective of the NHS over a one year time horizon. Secondary extensions added response rates from studies reporting other clinical endpoints and increased the time horizon to twelve years - however, without considering any of the long-term sequelae associated with the disorder. Given that the so projected differences in QALY outcomes between the various active treatment strategies were generally limited to the third or fourth decimal place only, and that differences in treatment compliance between short and long acting medications had been ignored (all responders were assumed by the NICE team to remain on treatment for the full one-year period of the primary model), the assessment failed to reveal any effectiveness differences between the various options and sequences evaluated. Thus the economic model was entirely driven by differences in drug acquisition costs, and the assessment group concluded that the results of the economic model clearly identify an optimal treatment strategy [104], namely to begin drug treatment with dexamphetamine. The conclusion was based on clinical evidence from one particular study only that had previously been excluded from the effectiveness review on grounds of inadequate data presentation (cf. above); this study had compared DEX with MPH-IR and placebo in 32 girls following a threefold cross-over design [109]. A critical appraisal of the NICE assessment revealed a range of further problems, including but not limited to issues related to data selection, the distinction between efficacy and effectiveness data, and several violations of the assessment protocol [7,110]. Hence this HTA by NICE should be interpreted with great caution. Indeed, also the NICE appraisal committee did not follow the clear conclusions of the assessment and in effect recommended all options investigated, based on an estimated cost per QALY below 7,000 compared to no treatment [105] - well below its usual benchmark of 20,000 to 30,000 per QALY gained [108,111,112]. In conclusion, it can be said that economic evaluations as part HTAs of ADHD treatment strategies have been of limited value to date. While in agreement regarding the acceptable to attractive cost effectiveness of the medication strategies evaluated, they have offered little to nothing in terms of the desirable differentiation of the various drug regimens available. COST EFFECTIVENESS ANALYSES (CEAS) BASED UPON THE NIMH MTA STUDY In the field of clinical ADHD research, it is widely acknowledged that the Multimodal Treatment Study (MTA), initiated by the National Institute of Mental Health (NIMH), represents a landmark or mega-trial [97,99,100, ]. The complete set of patientlevel data from this study was available for health economic evaluations, which have provided insights into the cost effectiveness of ADHD treatment strategies beyond the United States. The NIMH MTA Study enrolled 579 children, aged 7 to 9.9 years, at six North American centers and adhered to a parallel group
6 2448 Current Pharmaceutical Design, 2010, Vol. 16, No. 22 Michael Schlander design. For an interpretation of its key findings, it is necessary to appreciate that it was an extensively standardized, highly manualized comparison of three treatment strategies and routine community care in the United States and Canada. All four approaches tested were highly effective and showed substantial improvement (from baseline at study entry) by the end of the controlled study after 14 months [99]. Two thirds of the children in the community comparison group received medication, principally MPH (average daily dose at study completion 22.6mg, administered, on average, as 2.3 divided daily doses). Emphasis on subject rapport, extensive use of manuals, and regular supervision of therapists by skilled clinician investigators, together with robust monitoring measures, ensured a high degree of protocol adherence for the active three treatment strategies investigated [99]. Psychosocial interventions in the MTA Study involved three major integrated components, comprising parent training, school intervention, and summer treatment program, and were designed to maximize the opportunity to demonstrate treatment effects [116,117], not cost effectiveness. Medication management in the MTA consisted of a structured set of algorithms (starting with a double-blind, daily-switch titration protocol for MPH, followed sequentially by DEX, PEM, and imipramine, until a satisfactory response was obtained) rather than a single medication, which like the behavioral interventions were accompanied by extensive measures to ensure protocol fidelity. Of 289 children randomized to one of the medication management arms, 256 adhered to and completed the full titration protocol. Of those 77% (198 out of 256) responded to one of the MPH titration doses, and 88% (174 out of 198) were still taking MPH at the end of the maintenance phase at 14 months. Mean MPH doses at the end of 14 months were 31.1 mg per day for the combination management group and 38.1 mg per day for the medication management group (p<0.001); both groups received MPH-IR divided in three daily doses ( t.i.d. ) [ ]. A wide range of outcome measures, but not health-related quality of life, were assessed in the MTA Study, and complex relationships were observed between parameters [121]. The primary CEA based upon the MTA Study used response rates based on averaged parent and teacher ratings of ADHD and oppositional defiant disorder symptoms on the SNAP-IV scale [122]. Response rates after 14 months were 25% for the community comparison group, 34% for behavioral management, 56% for medication management, and 68% for the combination of both [122]. Follow-up of patients beyond the 14-months controlled study period was naturalistic, i.e., there was no study protocol stipulating specific interventions. At 10 months follow-up beyond the intensive treatment phase (i.e., 24 months after enrolment), the medication management strategy continued to show significant superiority over the behavioral management and community comparison groups, although effects were attenuated compared to the end of the 14 months controlled trial period [123]. However, 36 months after study initiations, differences between the four study groups had disappeared [124]. Likewise, analyses eight years after MTA Study enrolment indicated that treatment-related improvements were generally maintained, but no appreciable differences between the initial treatment groups could be identified [125]. These observations spurred an intense scientific debate, which highlighted the need for further research, in particular for a long-term (5-8 years) controlled study of medication versus nonmedication treatments for ADHD [ ]. MTA-based CEAs available to date have been limited to a time horizon of one year, or 14 months including the initial titration period. Direct costs were determined combining utilization data from the study, excluding its research component, with unit costs being valued from a societal perspective (and, for the international analyses reported below, in some jurisdictions such as The Netherlands and Germany from a payer s perspective). These evaluations were enhanced by access to patient-level data and the resulting opportunity to conduct stochastic sensitivity analyses by means of nonparametric bootstrapping, a data resampling technique that enables analyses reflecting the underlying variance within the sample data, without making potentially incorrect distributional assumptions [131]. In the primary MTA-based CEA, ICERs for one additional patient with symptomatic normalization (according to SNAP-IV scores [122]) over a time horizon of 12 months were estimated at around US-$ 350 for medication management (versus community care) and US-$ 2,500 for combination treatment versus behavioral treatment only [132]. For pure ADHD (i.e., ADHD according to DSM-IV diagnostic criteria, without coexisting anxiety, depression, conduct of oppositional defiant disorder), medication management dominated (i.e., it was more effective and less costly than) community care, and combination treatment versus behavioral treatment was associated with an ICER of US-$ 940. This translated into estimated costs per QALY gained for medication management versus community care ranging between US-$ 3,000 and US-$ 5,500 for the overall DSM-IV-defined study population; in patients with pure ADHD (i.e., without coexisting internalizing or externalizing psychiatric morbidity), medication management again dominated community care. Accordingly, estimated costs per QALY for the comparison between combined treatment and behavioral management (i.e., for adding the MTA medication management algorithm to the psychosocial intervention protocol) ranged between US-$ 20,000 and US-$ 40,000 for the overall study population, and US-$ 8,000 to US-$ 15,000 for pure ADHD [132]. Although comorbidity had been identified as an important moderator of treatment response [57], these principal observations held across comorbid subgroups [132]. Secondary CEAs used functional impairment as measured by Columbia Impairment Scale (CIS) scores as the clinical endpoint of interest. The scale is completed by parents, captures four domains of impairment - interpersonal relations, psychopathology (such as depression, anxiety, behavior problems), schoolwork, and leisure time - and has been shown to have good internal consistency and construct validity [ ]. The secondary CEAs revealed a somewhat more differentiated picture; while medication management was still the most cost effective option overall and across subpopulations, cost effectiveness for the behavioral treatment strategy as defined by the MTA study protocol was less disappointing in subgroups with more severe comorbidity, in particular in patients with coexisting internalizing signs and symptoms [136]. In an extension of the primary analysis, also cost per symptomatic responder and estimates per QALY gained were reported for the study subpopulation meeting criteria for hyperkinetic disorder [60,137], applying the same methodology [131]. On the basis of 145 patients eligible for this analysis, costs per QALY gained were estimated at below US$ 2,000 [138] - better than the estimate of up to US-$ 5,500 for the DSM-IV-defined study population and suggestive of an improved cost effectiveness of intense medication management in this presumably more severely impaired subgroup [61,62,138]. Subsequent international CEAs explored whether these observations can be transferred into a European context [ ]. In order to assess the portability of US findings to an international context [65,66], a number of issues were addressed, such as different diagnostic criteria preferred in Europe ( hyperkinetic [conduct] disorder - HK[C]D - according to ICD-10) [60,67], different treatment preferences and standards of care (raising questions regarding the relevance of the community care comparison arm of the study) [13-18], and of course different unit costs (varying by jurisdiction as well as by perspective, i.e., payers versus societal) [65, 66]. International economic analyses based upon the NIMH MTA Study have been reported for Germany (D), The Netherlands (NL),
7 The Pharmaceutical Economics of Child Psychiatric Drug Treatment Current Pharmaceutical Design, 2010, Vol. 16, No Sweden (S), and the United Kingdom (UK) [ ]. Evaluation strategies included addressing subgroups (beyond the total study population with ADHD according to DSM-IV criteria) meeting criteria for hyperkinetic disorder [137] and by comorbidity (pure ADHD, internalizing, externalizing, or both comorbidities), modeling a hypothetical Do Nothing alternative (to account for the context-specific community care comparison arm of the MTA), using symptomatic normalization and functional impairment as efficacy endpoints, estimating cost per QALY gained based on response rates, applying parent proxy ratings [107,108] and expert estimates [96], using health care resource utilization data from the trial excluding its research component and substituting its initial double-blind titration protocol with a clinically proven algorithm which led to similar dosing regimens [143], and applying unit costs (for year 2005) for direct medical expenditures from a societal perspective (D, NL, S, UK, USA) and from a payers perspective (D, NL). Patient-level data from the study were available for analysis, enabling probabilistic sensitivity analyses by means of nonparametric bootstrapping (cf. below; Fig. 4). Treatment response was again defined as normalization of core symptoms (SNAP IV teacher/parent scores <1) [122]. ICERs were determined for the total study population and subgroups with pure ADHD (without comorbidity, n=184), pure hyperkinetic disorder (HKD, n=77), and patients with hyperkinetic disorder with or without concomitant conduct disorder (HKD/HKCD, n=145). For all subgroups and across jurisdictions (D, NL, S, UK) and perspectives (societal, payers ) studied, ICERs per additional patient normalized ranged from dominance to 4,200 for medication management versus community care and from 21,000 to 100,000 for the combined treatment strategy versus medication management. Medication management dominated behavioral treatment and exhibited extended dominance over community care compared to the hypothetical Do Nothing alternative. Across comorbid subgroups, ICERs per responder for medication management versus community care ranged from 100 to 5,000, again across jurisdictions and perspectives [142]. Robustness of the results reported above was supported by a range of one-way and probabilistic sensitivity analyses (cf. also Fig. 4). Cost effectiveness was also assessed for the subgroup of patients meeting diagnostic criteria for hyperkinetic disorder (HKD), replicating the United States findings that medication management seemed relatively more efficient compared to community care in these children [ ]. For medication management versus community care, reasonable estimates across jurisdictions and perspectives ranged from 4,500 (best case) to 52,000 (worst case) per QALY gained. For illustration, German data for medication management versus the Do Nothing alternative are provided below for the total study population, as well as for the subgroups without psychiatric comorbidity ( pure ADHD, n=184) and for study patients meeting ICD- 10 criteria for hyperkinetic (conduct) disorder (HKD/HKCD, n=145), Table 2 [144]. For the secondary international economic evaluations, ICERs were again determined using Columbia Impairment Scale (CIS) effect size (Cohen s d) as clinical outcome criterion. Although incremental cost per CIS effect size gained is more difficult to interpret compared to cost per additional responder or cost per QALY, medication management (with ICERs versus Do Nothing ranging from 1,000/ES to 2,700/ES, and ICERs versus community care from dominance to 3,000/ES) appeared attractive on grounds of cost effectiveness for subgroups without psychiatric comorbidity, across jurisdictions and perspectives studied [141]. This observation held for patient subgroups with psychiatric comorbidity as well. Behavioral interventions, however, appeared relatively less disappointing in patients with more severe comorbidity, as cost effectiveness acceptability analyses revealed potentially more acceptable cost effectiveness at higher levels of willingness to pay for functional improvement [142]. Although these data do not lend themselves to a simplistic interpretation, it seems noteworthy Fig. (4). International CEA of ADHD treatment strategies based on the NIMH MTA Study: Germany (2005) [139, 140, 144] Decision uncertainty is represented by the ellipsoid scatter plots showing the joint distribution of costs and effects for each intervention. Effect measure is response rate in terms of symptom normalization as measured on the SNAP-IV scale [181]. Time horizon 14 months. Abbreviations: Beh, behavioral treatment arm; CC, community comparison arm; Comb, combined treatment arm; DoNt, (hypothetical Do Nothing alternative; MM, medication management arm. The dashed line joining DoNt, MM and Comb is the efficiency frontier.
8 2450 Current Pharmaceutical Design, 2010, Vol. 16, No. 22 Michael Schlander Table 2. Pharmacotherapy of Childhood ADHD: Cost Estimates per QALY Gained (Germany 2005) Based Upon the NIMH MTA Study [144] ADHD (DSM-IV) (total study population) n=579 Pure ADHD (DSM-IV) (without psychiatric comorbidity) n= 184 HKD/HKCD (ICD-10) (hyperkinetic disorder with or without concomitant conduct disorder) n=145 Medication management vs. Do Nothing 20,100-36,800 19,000-34,600 22,600-41,300 Combined vs. medication management 731,800-1,336, ,100-1,163, , ,000 Note that Table Provides ICERs for Interventions on the Efficiency Frontier (cf. Fig. 4) Only. that these results (which were replicated consistently for Germany, Sweden, The Netherlands, and United Kingdom [140,141,144]) appear concordant with analyses reported for the United States [136]. Summing up, it can be concluded at this point that the main health economic insights derived from the NIMH MTA Study appear robust across jurisdictions. They provide strong support for an acceptable to attractive cost effectiveness of a carefully monitored intense medication strategy over a time horizon of 12 to 14 months, compared to less intense North American community care (which in the majority of patients included medication as well, albeit at lower doses on average) as well as in comparison to a hypothetical Do Nothing alternative. Accordingly, these analyses offer important insights regarding the cost effectiveness of a stimulant-based medication management strategy, even at the intensity margin (i.e., for increasingly intense intervention). Of course, by design the NIMH MTA Study does not allow any inferences regarding the relative value of alternative drugs, and it should be emphasized here that none of the relatively more expensive longacting products had been available during the MTA study period. While medication-based strategies were clearly economically superior to behavioral interventions, the very poor cost effectiveness of psychosocial treatment (cf. Table 2) should be interpreted more cautiously in light of the MTA study objectives and design choices. COMPARATIVE ECONOMIC EVALUATIONS OF ADHD DRUG TREATMENT In the United States, economic analyses comparing alternative drug regimens for treatment of ADHD in children and adolescents began to appear as late as Marchetti and colleagues (2001) [145] attempted to compare six different formulations of stimulants from a payer perspective over a time horizon of one year. In addition, in a remarkable departure from the payer perspective, the study included school-related costs based on results from a[n unspecified] stakeholder survey [ ] that indicated that payers were concerned with costs associated with dosing of medication at school [145]. Effectiveness estimates were reportedly derived from a meta-analysis, but results were presented only for three products. For these drugs, differences in response rates found these analysts were small (all at around 80%) and did not reach statistical significance. The economic evaluation compared expected total cost of treatment (presumably for year 2001) only, and did not provide ICER estimates. Therefore, this study may be classified as a cost minimization analysis (CMA). Marchetti et al. (2001) [145] concluded that the total expected annual cost of pharmacologic ADHD treatment in the United States was lowest with long-acting formulations. However, this conclusion held only if costs associated with school-dosing were included - a procedure that necessarily obscured the perspective of the study, thereby greatly reducing its value. CEAs of Short-Acting Stimulants In a subsequent report U.S. study, Narayan and Hay (2004) [146] addressed the comparative cost effectiveness of immediaterelease methylphenidate (MPH-IR, Ritalin ) and mixed amphetamine salts (MAS, Adderall ) for the first line treatment of schoolaged children with ADHD. They constructed a decision tree model to capture, for three strategies (MPH-IR 10mg, presumably administered b.i.d., but not specified by the authors; MAS 10mg/d, divided in two doses; and a no treatment alternative) the impact of response and drop out rates that were taken from the metaanalysis reported by Marchetti et al. (2001) [145]. Based on ADHD core symptoms, response rates for MAS (82.7%) were slightly higher than those for MPH-IR (78.7%), a small difference that was later confirmed by meta-analyses reported by Faraone et al. (2002, 2010) [147,148]. Nonresponders to either drug were assumed to be treated with dexamphetamine (DEX) because the authors believed DEX would be used a second line treatment option only, owing to fears of illicit drug diversion and abuse. Modeling a one-year period from a societal perspective [146], which however encompassed only direct medical costs and assumed costs for school administration, these authors came up with an estimated cost per QALY gained of US-$ 21,957 for MAS versus no treatment (with costing done for year 2003). In their analysis, MPH-IR was dominated by MAS therapy. Nevertheless, the authors suggested that treatment with either MAS or MPH-IR was cost effective compared with no treatment [146]. The early study by Gilmore and Milne (1998, 2001) was already mentioned in the Introduction [5,98]. It had been incorporated in the first NICE Health Technology Assessment (2000) [96] and in the review by Romeo et al. (2005) [1]. In brief, these authors aimed to examine the cost effectiveness of methylphenidate (immediate release formulation, MPH-IR) compared to placebo in children with hyperkinetic disorder with or without externalizing comorbidity (conduct or oppositional defiant disorder), but not anxiety disorders. Based on a systematic literature review, they actually used studies in children with ADHD, estimating an average response rate of 70%. They assumed that benefits seen at four to six months would persist for a year, which was the time horizon of the study, and an assumed early drop out rate of six percent due to side effects. Costing was done from an NHS perspective (in for year 1997). This led to a calculated cost per QALY gained of 9,177, with a range from 5,965to 14,233 for the scenario considered most likely by the study authors, and a most accurate estimate of 7,446 to 9,177 when slight physical disability was assumed to add to the level of disability experienced by ADHD patients [5]. In an Australian analysis, Donnelly et al. (2004) [149] assessed the comparative cost effectiveness of dexamphetamine and methylphenidate over a time horizon of 12 months from the perspective of
9 The Pharmaceutical Economics of Child Psychiatric Drug Treatment Current Pharmaceutical Design, 2010, Vol. 16, No patients and government (Australian NHS, year 2000). They calculated cost per disability-adjusted life year ( DALY - another variant of the group of health-adjusted life years, in essence measuring quality-adjusted life expectancy lost [150]) averted, using disability weights (conceptually corresponding to the inverse of utility weights used for QALY computations, but adopting a social perspective for valuation) for mild and moderate-severe ADHD derived from a study with Dutch health care professionals [151]. The resulting differences on (dis)utility weights between responders and nonresponders were roughly in line with expert estimates from the UK [96], which had also been used for the (best case) calculations of QALY gains on the basis of the NIMH MTA Study discussed earlier [ ], and appear also concordant with utility data used in the U.S. analyses mentioned earlier [132,152]. On this basis, the ICERs (for the combined costs of government and patients per DALY averted) estimated by Donnelly et al. were AUS-$ 4,100 for dexamphetamine and AUS-$15,000 for methylphenidate, and the authors concluded that both interventions were cost effective [149]. Thus, cost effectiveness analyses of short-acting stimulant medications, which were based on symptomatic response rates over a time horizon over one year, have consistently found acceptable cost effectiveness ratios compared to no treatment. Differences in incremental cost effectiveness between compounds were largely driven by differences in acquisition costs, and will hence vary by jurisdiction contingent on availability of products. CEAs of Long-Acting Stimulants A number of separate economic evaluations - apparently all of which had been supported by the manufacturer of MPH-MR12 (Concerta ) - attempted to predict the potential cost effectiveness of treatment with MPH-MR12 (36 mg once daily) versus MPH-IR (10 mg three times daily). They have in common that they applied variants of the economic model developed by the Canadian Coordinating Office for Health Technology Assessments (CCOHTA, Fig. (3) [89]), combining assumptions regarding treatment adherence rates from a systematic review [153] with efficacy data from a meta-analysis of short-term clinical studies [ ]. Reports are available for Canada from a third party payers (public and private) perspective [157], for England from the point of view of the NHS [158,159], and for Germany from the point of view of the statutory health insurance (SHI; Gesetzliche Krankenversicherung, GKV) [160]. All looked at a 12-month treatment period and used core ADHD symptom improvement measured on the Conner IOWA inattention/overactivity (I/O) Scale [64,161,162] as the effect measure of interest. Across jurisdictions and despite (minor) design variations, these studies agreed in suggesting comparable ICERs for MPH-MR12 and MPH-IR, which even reached extended dominance of MPH-MR12 over MPH-IR in Canada and the United Kingdom [ ]. Technically, extended dominance is defined as a state when one strategy under study (here, MPH-IR t.i.d.) is both less effective and more costly than a linear combination of two other strategies (no drug treatment and MPH-MR12 q.d.) with which it is mutually exclusive [2-4]. In practical terms, extended dominance occurs when an alternative (in this case, MPH-MR12) is more effective and more costly, but provides better value for money. In subsequent evaluations, the United Kingdom model was refined and replicated using actual (instead of assumed) persistence data for MPH-IR and MPH-MR12 from retrospective database studies [ ]. Again, results ranged from comparable cost effectiveness to extended dominance of MPH-MR12 versus MPH- IR [169]. Limited information is available concerning further studies presented at international health economics conferences. In a U.S. study, Ganapathy and Hay (2008) [170] suggested that MPH- MR12, atomoxetine (ATX), and the combination of methylphenidate (presumably MPH-MR12) and behavioral therapy were all cost effective compared to no treatment. Devine et al. (2007) [171] undertook a cost utility analysis of MPH-MR12, an extendedrelease formulation of mixed amphetamine salts (MAS-MR), and atomoxetine (ATX) for treatment of children with ADHD in the U.S. Military Health System (MHS). Results of this study remain somewhat unclear because of their high sensitivity to unspecified patient preferences for extended release and non-stimulant products. Also in 2007, Vazquez [172] presented a Mexican comparison of MPH-MR12, ATX, and MPH-IR, claiming superiority of MPH- MR12 on grounds of cost effectiveness. Faber et al. (2008) [173] attempted to assess the cost effectiveness of MPH-MR12 in youths not optimally responding to MPH- IR. They published results derived from a Markov model with a cycle length of one day and a modeled time horizon of 10 years. Functional remission of ADHD was used as a terminal state of the Markov model [174]. Rates of functional remission were taken from a brief report based on five symptom measurements (but not assessments of functional impairment) in 128 boys over four years [175], and the authors did not consider more comprehensive research actually suggesting higher rates of symptomatic (again, not functional ) remission [176]. Noncompliance rates were estimated based on a Canadian 8-week study by Steele et al., 2006, discussed below [177]. Outcomes were expressed as quality-adjusted life years (QALYs), with utility weights taken from an English standard gamble study conducted by Secnik et al. [178]. This particular study by Secnik et al. had previously been rejected by the NICE assessment group for apparent inconsistencies of reported data [104]. On this basis, costs per QALY expressed in for year 2005 were around 2,000 (or 12,500, if resource use assumptions for patients in the suboptimal state were reduced by 25%); with reported ICERs ranging from dominance of MPH-MR12 in the best-case to 38,000 (worst case considered). These findings point to cost effectiveness of the long acting formulation despite six times higher medication costs [173]. However, the value of this study is impaired by the large number of assumptions and expert estimates, including the unconventional perspective adopted for costing, the remission rates used, and the source of utility values. It can be concluded at this point that international modeling studies suggest cost effectiveness of long-acting stimulants, at least as far as MPH-MR12 is concerned. Although two recently presented retrospective database analyses from the U.S. suggest different patterns of medication augmentation and associated costs depending on choice of long-acting product [179,180], it seems difficult to make inferences from these observations as to differences in the relative cost effectiveness of the various intermediate- and longacting stimulant products. It should also be kept in mind that - even sophisticated - economic models are intended to be aids guiding policy decisions and, as such, should not be misconceived as establishing truth [181]. The value of models lies not only in the results they generate but also in their ability to reveal the logical connection between inputs (usually data from a variety of sources and assumptions) and outputs [182]. Arguably, the key advantage of long-acting medications for ADHD is linked to improved treatment compliance under conditions of routine care [69,71,183,184]. As an alternative approach to the combined use of RCT efficacy data and modeling, randomized pragmatic effectiveness trials (which are performed under conditions that are representative of and relevant to the usual treatment situation, i.e, with minimal quality assurance and study management) are recognized as an appropriate vehicle for economic studies [ ]. They should, inter alia, provide more generalizable answers in situations when there is a concern that artificially enhanced compliance in RCTs may be a threat to their external validity [189]. This view has been explicitly endorsed by leading child psychiatrists [190]. Against this background, a randomized real-world study performed in Canada [177], which compared long acting methyl-
10 2452 Current Pharmaceutical Design, 2010, Vol. 16, No. 22 Michael Schlander phenidate (again, MPH-MR12 given q.d.) directly with usual care with MPH-IR, is particularly informative. The study involved 147 children between the ages of 6 and 12 with ADHD in accordance with DSM-IV criteria and had a parallel-group design, with a treatment and observation period of in each case eight weeks. The primary endpoint was normalization of ADHD core symptoms on the basis of parent-reported SNAP-IV scores, which occurred in 44% of the patients receiving MPH-MR12, compared with only 16% of the MPH-IR patients. Unfortunately, this study is impaired by the absence of teacher-reported outcome ratings. A further concern relates to the fact that 39% of the patients in the MPH-IR group were dosed twice daily (b.i.d.), which may be considered an unfair comparison. This concern was addressed by post hoc subgroup analyses, which confirmed a statistically significant difference in favor of MPH-MR12 (with a remission rate at study endpoint of 24% for those patients who had received MPH-IR three times daily (these were 61% of all patients in the MPH-IR group) [177]. Using this data, a trial-based economic evaluation was done from a Finnish payers perspective and reported extended dominance of MPH- MR12 q.d. over MPH-IR t.i.d. [191]. Summing up the section on long-acting stimulants, it can be concluded that there are good reasons to assume acceptable cost effectiveness, given the high level of consistency of economic study results to date. The economic argument in favor of long-acting products is grounded in their clinical efficacy [69,71,78,169,192]; the disorder-specific relevance of avoiding a midday dose in children with ADHD [183,184], supported by improved treatment persistence rates observed in retrospective database analyses [ ]; economic modeling studies evaluating the impact of improved treatment persistence [ ,173]; and a Canadian randomized pragmatic study broadly confirming expectations [177,191]. It should be noted, however, that most analyses dealt with MPH-MR12, and that none of the economic evaluations available to date has been without its own set of specific limitations. CEAs of Nonstimulants Unlike stimulants, atomoxetine (ATX) is not a controlled substance, and in most patients it is effective when given once daily. Therefore, the considerations above regarding treatment compliance can be expected to fully apply to ATX. However, some children with ADHD may require twice daily dosing of ATX, which will double the direct cost of medication owing to the flat pricing policy adopted by its manufacturer (translating into a constant price per capsule, irrespective of the amount of active compound) [82-84]. Meta-analyses of the comparative effectiveness of ATX versus stimulants have consistently pointed to inferior symptom improvement and so-defined response rates with ATX [ ]. These findings appear largely consistent with the results of randomized head-to-head trials directly comparing ATX with stimulant treatment in children and adolescents with ADHD [ ]. Taken together, these data strongly suggest economic dominance of longacting stimulants (and perhaps other methylphenidate formulations as well) over atomoxetine, as on the basis of the best currently available evidence the stimulant products appear at least as or (most likely) more effective as ATX, whilst being no more or (in most jurisdictions) less expensive than ATX [144,169]. In contrast, the 2004 NICE ADHD technology assessment, which relied on a much smaller subset of studies (as discussed earlier [7,110]), failed to identify differences between the longacting products evaluated (ATX, MPH-MR08, and MPH-MR12) [104]. Iskedijan et al. (2003) [204] estimated the cost per additional symptom free day for ATX compared to MPH. Using efficacy and resource use data from the literature and preference rates for nonstimulant medication obtained from parents, they claimed a relatively small and quite reasonable incremental cost ranging from CAN-$ 1.12 to CAN-$ per symptom free day gained, from the perspectives of the Ontario Ministry of Health, government, and society in Canada (year 2002). Two closely related CEAs of ATX were based on a Markov model with Monte Carlo simulation of costs and effects over a time horizon of one year [205,206]. Comparators included stimulantbased algorithms (incorporating both immediate-release and modified-release formulations of MPH and DEX, as well as no medication ). Effectiveness and safety aspects were based on a thorough review of controlled clinical trials, validated by clinical experts, and linked to utility values derived from a survey of 83 parents of ADHD children, i.e., a study by Secnik et al. that had first been presented at an international health economics conference in 2004 [178,207]. On this basis, cost per QALY ICERs were estimated for three subpopulations (stimulant-naïve, stimulant failure, and stimulant-contraindicated), and ranged between 13,120 (versus DEX) and 22,804 (versus MPH-MR) in The Netherlands [205], and between NOK 149,892 (versus MPH-MR) and NOK 199,178 (versus MPH-IR) in Norway [206]. In both jurisdictions, ATX represented good value for money in the opinion of the analysts. Two years later, Diamantopoulos et al. presented a similar evaluation from the perspective of the German health service [208], coming up with cost per QALY estimates for ATX of 7,778 (versus MPH-MR12 in stimulant-naïve patients), 18,227 (versus MPH-IR in stimulant naïve patients), and 14,385 to 14,916 (versus no medication in ADHD patients who had failed to respond to stimulants or with a contraindication to stimulant treatment), respectively [208]. A similar Markov model as had been used in the studies for The Netherlands [205], Norway [206], and Germany [208], however with slightly different treatment algorithms, was applied in analyses for the United Kingdom [209,210] and Spain [211]. The first full publication was authored by Cottrell et al. (2008) [209]. Their results were broadly similar to the findings reported above, with ICERs per QALY gained ranging from 11,523 to 15,224 from the perspective of the National Health Service in England and Wales [209,210]. The Spanish adaptation reported ICERs of 34,308 versus MPH-IR, and 24,310 (versus MPH-MR12), in stimulant-naïve patients with ADHD, and approximately 23,500 in the stimulant-failure and stimulant-contraindicated groups [211]. All of these studies [205,206, ] had been conducted by or under contract with the manufacturer of ATX. The asserted cost effectiveness versus stimulants, including long-acting formulations, may well appear somewhat surprising given the results of the metaanalyses and head-to-head clinical trials briefly mentioned earlier and the acquisition cost of ATX, as taken together these data would appear to suggest economic inferiority of ATX. This is particularly disturbing since, for each of the economic analyses of ATX discussed above, QALY gains had been calculated using effectiveness measures directly derived from core symptom response rates, which in a second step had then been linked to specific utility estimates. Actually, the study authors identified the utility inputs as a key factor influencing their results; that is, the results of their modeling exercises were highly sensitive to the utility weights applied [209]. When differences by treatment group for the utility weights of symptomatic response versus nonresponse were removed, the cost per QALY ICERs indeed rose to unacceptable levels [209]. Consequently, this group of economic analyses of ATX [205, 206, ] is open to critique on two grounds: (1) the selection of data sources used for efficacy inputs, and (2) the utility weights applied. As to (1), the model description (Cottrell et al., 2008, p. 381 [209]) reveals that the probability that a patient discontinues treatment for lack of efficacy was assumed to be the same for all products - none of the head-to-head trials and none of the metaanalyses were discussed. Both clinicians [212] and health economists [169] in the United States and Europe concluded, there is now ample evidence that stimulants are the most effective treatment
11 The Pharmaceutical Economics of Child Psychiatric Drug Treatment Current Pharmaceutical Design, 2010, Vol. 16, No for decreasing symptoms of ADHD [212]. Regarding (2), the utility weights applied came from a survey by Secnik at al. (2005) from Eli Lilly [178,207]. In this study the utility of responders on ATX with side effects (0.937) was higher than the utility weights for responders on stimulant medication without side effects (0.913 for MPH-IR and for MPH-MR12, respectively). These data had been rejected by the NICE assessment group because of concerns about the validity of these estimates, particularly the fact that the utility of a non-responder without side effects differed between treatments. For example, the utility associated with non-response to atomoxetine, without side effects, was estimated to be 0.902, which compared to an estimated utility of associated with nonresponse and no medication (cf. King et al., 2004, p.240 [104]). The (only) explanation offered by the study authors was a statement concerning a more stable and longer-lasting response with ATX, and that the nature of the response with atomoxetine, which was reflected in the health state descriptors used in the utility valuation study, is preferred to that of stimulant treatments (no sources given: Cottrell et al., 2008, p. 385f. [209]. Hence there remain critical questions related both to the objectivity of the underlying effectiveness assumptions as well as to the reliability of the manufacturer-reported utility values, which provided a crucial input to the health economic evaluations of ATX [205,206, ]. As a consequence, these studies should be interpreted with great caution. Recent Additions to the Pharmacotherapeutic Armamentarium Recent additions to the pharmacotherapeutic armamentarium for ADHD in children and adolescents include a transdermal delivery system for methylphenidate (Daytrana, a patch) and lisdexamphetamine (Vyvanse, a prodrug), which were first introduced in the United States [9,78,213,214]. Both new drugs are clinically effective and appear likely to be used in a substantial number of patients [9], but at the time of writing the present overview, there is no information available providing insights into their comparative cost effectiveness. PHARMACOECONOMIC STUDIES IN MAJOR DEPRES- SION AND ANXIETY As mentioned earlier, there are few economic evaluations of mental health conditions other than ADHD in children and adolescents. This is particularly true for pharmacotreatment. One exception is a study conducted by Haby et al. (2004) as part of the Australian Assessing Cost-Effectiveness - Mental Health (ACE-MH) program [215,216]. Using a similar approach as Donnelly et al. (2004) [149], Haby translated effect sizes into a change in the DALY disability weight, and compared cognitive behavioral therapy (CBT, delivered by public or private Australian psychologists or psychiatrists) and selective serotonin reuptake inhibitors (SSRIs), as first or second line treatment, with current treatment practice. They found CBP by public psychologists to be the most cost effective option (at AUS-$ 9,000 per DALY averted), followed by SSRIs at AUS-$ 23,000 per DALY averted (same for first line treatment versus current practice and for second line treatment versus no further treatment) [216]. Their analysis was limited by a paucity of quality of life data in children and adolescents with major depression, which would have allowed calculation of effect sizes, so that the evaluation was largely based on symptom measures - a remarkable parallel to the situation in ADHD discussed in detail before - and by the principal approach of an episode-based analysis, which again was necessary due to limited data on the natural history of depression in children and adolescents. Further, there were no data underpinning the assumption that CBT by public psychologists is equally effective as treatment by private psychologists or by psychiatrists. On the positive side, however, it should be noted that extensive sensitivity analyses were done supporting the conclusions of this study. A British study reported by Byford et al. (2007), seems noteworthy in this context [217,218]. Based on a randomized pragmatic trial, that compared the addition of CBT to SSRI (fluoxetine) treatment alone in 208 adolescents with major depression over 28 weeks, Byford et al. concluded that CBT was not cost effective. These authors speculated that the provision of SSRIs in addition to routine care might have a higher probability of improving outcomes in a cost effective manner over the first 6 months of treatment [217], although this evaluation did not include a controlled comparison of SSRIs versus routine care alone. More recently, clinical data from a 36-week randomized clinical trial (RCT) in the United States, the Treatment for Adolescents with Depression Study (TADS) have provided relevant further insights [ ]. Like the MTA Study in ADHD, the TADS was funded by the National Institute of Mental Health (NIMH) in Bethesda, MD. Fluoxetine (FLX), cognitive behavioral therapy (CBT), and the combination of both were compared with placebo in a parallel group design enrolling 439 adolescent outpatients aged 12 to 18 years with major depression. After the first 12 weeks, 71% of patients showed improvement in symptoms with combination therapy (as determined by scores on the Children s depression Rating Scale - revised),.whereas 61% improved on FLX alone. Improvement on CBT was a mere 43%, not significantly better than placebo (35%) [222]. The first CEA was based on the initial 12-week study period, calculated costs for in-protocol as well as out-of-protocol service use, and included time and travel costs for adult caregivers, all expressed in US-$ for year Children Depression Rating Scale - Revised scores, representing the primary endpoint of the study, were translated into depression-free days, which in turn were transformed into QALYs derived from previously applied utility weights for adults [223]. A depression-free day was assigned a utility weight of 1.0, depression days were assumed to have a utility weight of 0.6, and days with intermediate values were linearly interpolated. This analysis came up with results which are at odds with those found by Haby et al. in Australia [216]: estimated ICERs per QALY gained were US-$23,700 for fluoxetine versus placebo, >US-$ 9 million for CBT versus placebo, and US-123,100 or US- $458,800 for combined treatment (CBT plus fluoxetine) versus placebo or fluoxetine, respectively. This cost effectiveness data reflected the clinical study outcome that showed CBT to be no effective treatment option after 12 weeks, as determined by the Children s Depression Rating Scale [220]. In a subsequent TADS-based CEA covering the full 36-week study period, a similar methodology but a broader range of endpoints were used. Effectiveness data at 36 weeks were less impressive for drug treatment; while combination therapy continued to yield better outcomes (86% improvement on the Children s Depression Rating Scale), improvement with fluoxetine alone (81%) was no better than that achieved with CBT alone (81%) [224]. 327 study patients receiving one of the three active treatment conditions were available for the economic analysis. Missing variables were imputed using chained equations, and, where necessary, multiple imputation was applied using regression analysis, which implied the assumption that data were only missing at random. Out-of-protocol costs in the fluoxetine arm were higher over the extended observation period due to increased hospitalization rates and increased emergency department use. In this analysis, the comparison between CBT and fluoxetine alone still indicated somewhat less QALY gains with CBT (-0.02), and a small improvement (+0.015) with combined treatment compared to fluoxetine alone [221]. In the context of the present review, it should be mentioned that the main interest of the second analysis, however, was not to demonstrate cost effectiveness of fluoxetine per se but rather to justify the addition of CBT. The authors concluded that the combination of CBT and FLX was likely to be more cost effective than FLX alone. The report did not specify cost per QALY ICERs. Importantly, however, the cost data, which were driven by increased hospitalization
12 2454 Current Pharmaceutical Design, 2010, Vol. 16, No. 22 Michael Schlander and emergency department use of patients receiving FLX, underscore the need to always interpret economic evaluations in the clinical context [221]. Another study within the Australian ACE-MH program [215] looked into the cost effectiveness of psychological and pharmacological interventions for generalized anxiety disorder and panic disorder [225]. In line with the approach chosen for the program, the methodology was broadly similar to that used by Donnelly et al. [149] and by Haby et al. [216], and the results of this evaluation supported CBT as the most effective and cost effective intervention for the condition in Australia. As far as pharmacotherapy was concerned, the authors noted that there was a lack of studies exploring the efficacy of combined pharmaceutical and psychological interventions, as well as an absence of evidence for long-term gains following drug treatment for panic disorder. Also long-term pharmacological treatment of generalized anxiety disorder was not supported by evidence from appropriate placebo-controlled clinical studies [225,226]. As a result of their limited effectiveness, serotonin and noradrenaline reuptake inhibitors for generalized anxiety disorder (at AUS-$ 30,000 versus current practice), as well as serotonin reuptake inhibitors and tricyclic antidepressants (at AUS-$ 78,000 and 30,000, respectively) appeared less cost effective compared with CBT [225] - a finding that was consistent with the earlier United States estimates from a group of researchers at Massachussetts General Hospital, which however had not been based on data from a randomized controlled clinical trial and did not specifically address treatment of children [227]. SOME IMPLICATIONS There has been an impressive increase in the number of cost effectiveness evaluations in child and adolescent psychiatry since Renée Romeo and colleagues published their review in 2005 [1]. The vast majority of economic studies that addressed drug treatment were concerned with ADHD, only a few dealt with major depression in adolescents. However, anxiety disorders, conduct disorder, depressive disorders, substance abuse are common conditions in children and adolescents as well, and even less frequently diagnosed disorders such as Tourette syndrome, schizophrenia and bipolar disorder are associated with substantial burden of disease and economic impact. Any resources committed to specific interventions - such as medication - will not be available for alternative use - hence opportunity costs will be incurred. Thus it is necessary to thoroughly evaluate the benefits conferred by interventions designed to alleviate the burden associated with these disorders. It is safe to predict that health care policy makers will increasingly expect robust evidence of value for money, also for interventions for child psychiatric conditions other than ADHD. But even for ADHD, currently available evidence of cost effectiveness is still limited. With very few exceptions [136,141,142], evaluations (like the small number of analyses addressing other child psychiatric conditions) relied on effect [usually: efficacy] measures related to symptomatic improvement, often over short periods of time only. This raises a number of important issues, such as: (1) Do narrow band symptom scales really capture the objectives of therapeutic interventions? For example, the NIMH MTA Study illustrated that functional improvement of patients may not directly be linked to symptomatic relief, with potential implications for the cost effectiveness of treatment strategies [99, 100,136, 141,142]. (2) Are there any valid surrogate endpoints that allow predicting broader long-term benefits on grounds of short-term data? For example, the NIMH MTA [99,100] and TADS [219,222] studies illustrated that short-term treatment response rates may not be good predictors of long-term treatment outcomes [ ,221,224]. A related question concerns the optimal duration of treatment, which has not yet been determined unequivocally. (3) What is the impact of moderators and mediators of treatment response on cost effectiveness of treatments? (Few) exceptions notwithstanding [136,139,142,144], there remains a largely unmet need to address the relative cost effectiveness of interventions in subgroups, for example by severity or by coexisting conditions [41,56,57]. (4) Given the wide variety of measurement instruments [63,64], can a sufficient degree of harmonization of study designs and effectiveness endpoints be achieved? To date, quantitative meta-analyses of treatment effects have been difficult [104,106] if not impossible [114] because of the huge variety of effect measures used in clinical studies. (5) Future studies should include index-instruments enabling the transformation of health-related quality of life in utility weights for QALY calculation. But there remain important methodological [ ] as well as normative [ ] issues to be resolved in this context, ranging from valid measurements to the debatable relationship between economic efficiency and criteria for priority-setting in child mental health care [235]. (6) Given the importance of treatment persistence and notoriously high attrition rates in child and adolescent psychiatry [183,184], there is an increasing recognition of the need for pragmatic randomized clinical trials [185,186, ] that combine initial randomization with a more naturalistic follow-up than RCTs in order to increase generalizability of findings ( external validity [236]). How can this be best reconciled with the need for long-term studies assessing the impact of interventions on a broad range of benefits? (7) From the perspective of research-based pharmaceutical companies, the additional question arises whether it will be any longer good enough to show effects in RCTs, especially in placebocontrolled experimental settings (as required for marketing authorization). Arguably, more attention should be given to more complex treatment pathways and the cost effectiveness of combined interventions, including multimodal treatments as opposed to pharmacotherapy alone [237]. (8) Finally, what should be the appropriate role of manufacturers in cost effectiveness research? For example, many of the economic analyses done to date in the ADHD field were supported by, or conducted under contract with, manufacturers. The resulting reports invariably claimed to provide scientific support in favor of the cost effectiveness of the respective manufacturer s product(s). This observation should prompt some healthy skepticism among the recipients of such studies [ ]. This further constitutes a veritable challenge to industry and its credibility, at a time when it is becoming increasingly clear that successful new product development depends on a close interplay among multiple stakeholders [ ]. In light of the increasing hurdles to be met in the future, risk, time, and cost of new product development in child psychiatry will almost certainly continue to rise [242,244]. Thus new products will hardly be less expensive than existing ones. As a consequence, there will be no way to escape from the need to show that new therapeutic options provide good value for money. The onus to prove value for money - or in practical terms, to justify prices - will rest in the first place with manufacturers, but economic success will not be possible without multi party partnerships, including regulators, academic researchers, clinicians, independent health economists, as well as policy makers and payers [ ]. In the field of child psychiatry, at the present time economic studies provide broad support for the cost effectiveness of current pharmacotreatment of ADHD. Beyond clinical considerations, the choice of a particular treatment strategy will be influenced by its comparative cost effectiveness, which will depend on product
13 The Pharmaceutical Economics of Child Psychiatric Drug Treatment Current Pharmaceutical Design, 2010, Vol. 16, No availability and relative acquisition costs in a given jurisdiction. Also cost effectiveness analyses for long-acting stimulants have consistently provided encouraging results when compared to shortacting formulations, whereas the economic evidence in favor of the nonstimulant, atomoxetine, appears less compelling, in particular in comparison to long-acting stimulants. In contrast, cost effectiveness of pharmacotreatment of depression is less well established, with clinical effectiveness and safety consideration currently representing the overriding concern when contemplating drug treatment. LIST OF ABBREVIATIONS ADHD = Attention deficit hyperactivity disorder b.i.d. = Divided in two doses/day, twice daily administration CBA = Cost benefit analysis CEA = Cost effectiveness analysis CEAC = Cost effectiveness acceptability curve CMA = Cost minimization analysis CUA = Cost utility analysis DEX = Dexamphetamine HKD = Hyperkinetic disorder HKCD = Hyperkinetic conduct disorder HRQoL = Health-related quality of life HTA = Health technology assessment ICER = Incremental cost effectiveness ratio MAS = Mixed amphetamine salts MPH = Methylphenidate MPH-IR = Methylphenidate, immediate-release formulation MPH-MR08 = Methylphenidate, modified-release formulation (with an average duration of action of 8 hours) MPH-MR12 = Methylphenidate, modified-release formulation (with an average duration of action of 12 hours) NHS = National Health Service NICE = National Institute for Health and Clinical Excellence q.d. = One dose per day / once daily administration QALY = Quality-adjusted life year QoL = Quality of life RCT = Randomized clinical trial SHI = Statutory health insurance (Gesetzliche Krankenversicherung in Germany) t.i.d. = Divided in three doses per day / thrice daily administration REFERENCES References are related articles recently published. [1] Romeo R, Byford S, Knapp M. Annotation: economic evaluations of child and adolescent mental health interventions: a systematic review. J Child Psychol Psychiatry 2005; 46 (9): [2] Brent RJ. Cost-benefit analysis and health care evaluations. Cheltenham. Edward Elgar [3] Gold MR, Siegel JE, Russell LB, et al. Cost-effectiveness in health and medicine. New York, NY: Oxford University Press [4] Drummond MF, Sculpher MJ, Torrance GW, et al. Methods for the economic evaluation of health care programmes. 3 rd ed. Oxford: Oxford University Press [5] Gilmore A, Milne R. Methylphenidate in children with hyperactivity: review and cost-utility analysis. Pharmacoepidemiol Drug Saf 2001; 10: [6] Health Economics Evaluations Database (HEED). Available at [7] Schlander M. Health technology assessments by the National Institute for Health and Clinical Excellence. A qualitative study. New York, NY: Springer [8] Sorenson C, Drummond M, Kanavos P. Ensuring value for money in health care. The role of health technology assessment in the European Union. Copenhagen: WHO Regional Office for Europe [9] Schlander M. Impact of attention-deficit/hyperactivity disorder (ADHD) on prescription drug spending for children and adolescents: increasing relevance of health economic evidence. Child Adolesc Psychiatr Mental Health 2007; 1 (1): 13. [10] Costello EJ, Egger H, Angold A. 10-year research update review: the epidemiology of child and adolescent psychiatric disorders: methods and public health burden. J Am Acad Child Adolesc Psychiatry 2005; 44 (10): [11] Belfer ML. Child and adolescent mental disorders: the magnitude of the problem across the globe. J Child Psychol Psychiatry 2008; 49 (3): [12] Anders TF. Children: our most valuable resource. J Am Acad Child Adolesc Psychiatry 2006; 45 (1): 1-5. [13] Clavenna A, Bonati M. Drug prescriptions to outpatient children: a review of the literature. Eur J Clin Pharmacol 2009; 65: [14] Vitiello B. An international perspective on pediatric psychopharmacology. Int Rev Psychiatry 2008; 20 (2): [15] Scheffler RM, Hinshaw SP, Modrek S, et al. The global market for ADHD medications. Health Affairs 2007; 26: [16] Zito JM, Tobi H, de Jong-van den Berg LTW, et al. Antidepressant prevalence for youths: a multi-national comparison. Pharmacoepidemiol Drug Saf 2006; 15 (11): [17] Zito JM, Safer DJ, de Jong-van den Berg LTW, et al. A threecountry comparison of psychotropic medication prevalence in youth. Child Adolesc Psychiatr Mental Health 2008; 2: 26. [18] Fegert J, Kölch M, Zito JM, et al. Antidepressant use in children and adolescents in Germany. J Child Adolesc PsychoPharmacol 2006; 16: [19] Sawyer MG, Arney PA, Baghurst PA, et al. The mental health of young people in Australia: key findings from the child and adolescent component of the national survey of mental health and wellbeing. Aust N Z J Psychiatry 2001; 35: [20] Waddell C, Offord DR, Shepherd CA, et al. Child psychiatric epidemiology and Canadian public policy-making: the state of the science and the art of the possible. Canadian J Psychiatry 2002; 47: [21] Aras S, Varol Tas F, Unlu G. Medication prescribing practices in a child and adolescent psychiatry outpatient clinic. Child: Care Health Develop 2006; 33 (4): [22] Rappley MD. Attention deficit-hyperactivity disorder. New Eng J Med 2005; 352 (2): [23] Polanczyk G, Jensen P. Epidemiologic considerations in attention deficit hyperactivity disorder: a review and update. Child Adolesc Psychiatr Clin North Am 2008; 17 /2): [24] Leibson CL, Long KH. Economic implications of attentiondeficit/hyperactivity disorder for healthcare systems. Pharmacoeconomics 2003; 21 (17): [25] Matza LS, Paramore C, Prasad M. A review of the economic burden of ADHD. Cost Eff Resour Alloc 2005; 3: 5. [26] Swensen AR, Birnbaum HG, Secnik K, et al. Attentiondeficit/hyperactivity disorder: increased costs for patients and their families. J Am Acad Child Adolesc Psychiatry 2003; 42 (12): [27] Barkley RA. Driving impairments in teens and adults with attention-deficit/ hyperactivity disorder. Psychiatr Clin North Am 2004; 27 (2): [28] Lam LT. Attention deficit disorder and hospitalization due to injury among older adolescents in New South Wales, Australia. J Attention Disord 2002; 6 (2):
14 2456 Current Pharmaceutical Design, 2010, Vol. 16, No. 22 Michael Schlander [29] Hoare P, Beattie T. Children with attention deficit hyperactivity disorder and attendance at hospital. European J Emerg Med 2003; 10 (2): [30] Swensen A, Birnbaum HG, Ben Hamadi R, et al. Incidence and costs of accidents among attention-deficit/hyperactivity disorder patients. J Adolesc Health 2004; 35 (4): 346.e1-9. [31] Wilens TE, Biederman J. Alcohol, drugs, and attentiondeficit/hyperactivity disorder: a model for the study of addictions in youth. J PsychoPharmacol 2006; 20 (4): [32] Rasmussen P, Gillberg C. Natural outcome of ADHD with developmental coordination disorder at age 22 years: a controlled, longitudinal, community-based study. J Am Acad Child Adolesc Psychiatry 2000; 39 (11): [33] Mannuzza S, Klein RG, Abikoff H, et al. Significance of childhood conduct problems to later development of conduct disorder among children with ADHD: a prospective follow-up study. J Abnorm Child Psychol 2004; 32 (5): [34] Thapar A, van den Bree M, Fowler T, et al. Predictors of antisocial behaviour in children with attention deficit hyperactivity disorder. Eur Child Adolesc Psychiatry 2006; 15 (2): [35] Siponmaa L, Kristiansson M, Jonson C, et al. Juvenile and young adult mentally disordered offenders: the role of child neuropsychiatric disorders. J Am Acad Psychiatr Law 2001; 29 (4): [36] Rösler M, Retz W, Retz-Junginger P, et al. Prevalence of attentiondeficit/hyperactivity disorder (ADHD) and comorbid disorders in young male prison inmates. Eur Arch Psychiatr Clin Neurosci 2004; 254 (6): [37] Johansson P, Kerr M, Andershed H. Linking adult psychopathy with childhood hyperactivity-impulsivity-attention problems and conduct problems through retrospective self-reports. J Person Disord 2005; 19 (1): [38] Sourander A, Elonheimo H, Niemela S, et al. Childhood predictors of male criminality: a prospective population-based follow-up study from age 8 to late adolescence. J Am Acad Child Adolesc Psychiatry 2006; 45 (5): [39] Mannuzza S, Klein RG, Bessler A, et al. Educational and occupational outcome of hyperactive boys grown up. J Am Acad Child Adolesc Psychiatry 1997; 36 (9): [40] Barkley RA. Major life activity and health outcomes associated with attention-deficit/ hyperactivity disorder. J Clin Psychiatry 2002; 63 (Suppl 12): [41] Murphy KR, Barkley RA, Bush T. Young adults with attention deficit hyperactivity disorder: subtype differences in comorbidity, educational, and clinical history. J Nerv Mental Disord 2002; 190 (3): [42] Furness SR, Kavale KA. Impact of ADHD on school systems. In: Jensen PS, Cooper JR, Eds. Attention deficit hyperactivity disorder. Kingston, NJ: Civic Research Institute 2002; pp [43] Pelham WE, Foster EM, Robb JA. The economic impact of attention-deficit/hyperactivity disorder in children and adolescents. J Pediatr Psychol 2007; 32 (6): [44] Knapp M, Scott S, Favis J. The cost of antisocial behavior in younger children. Clin Child Psychol Psychiatry 1999; 4: [45] Schlander M, Trott GE, Schwarz O. The health economics of attention-deficit/hyperactivity disorder in Germany - Part 1: health care utilization and cost of illness. Nervenarzt 2010; 81 (3): [46] Wehmeier PM, Schacht A, Rothenberger A. Change in the direct cost of treatment for children and adolescents with hyperkinetic disorder in Germany over a period of four years. Child Adolesc Psychiatr Mental Health 2009; 3 (1): 3. [47] Gillberg C, Gillberg IC, Rasmussen P, et al. Co-existing disorders in ADHD - implications for diagnosis and intervention. Eur Child Adolesc Psychiatry 2004; 13 (Suppl 1): [48] Steinhausen H-C, Nøvik TS, Baldursson G, et al. Co-existing psychiatric problems in ADHD in the ADORE cohort. Eur Child Adolesc Psychiatry 2006; 15 (Suppl 1): [49] Schlander M, Schwarz O, Trott GE, et al. Comorbidity profiles of children and adolescents with ADHD - an analysis based on administrative data from Nordbaden, Germany. J Mental Health Policy Econ 2007; 10 (Suppl 1): S39. [50] Spencer TJ, Biederman J, Mick E. Attention-deficit/hyperactivity disorder: diagnosis, lifespan, comorbidities, and neurobiology. J Pediatr Psychol 2007; 32 (6): [51] Jensen PS, Martin D, Cantwell DP. Comorbidity in ADHD: implications for research, practice, and DSM-IV. J Am Acad Child Adolesc Psychiatry 1997; 36: [52] Chan E, Zhan C, Homer CJ. Health care use and costs for children with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 2002; 156: [53] Guevara J, Lozano P, Wickizer T, et al. Utilization and cost of health services for children with attention-deficit/hyperactivity disorder. Pediatrics 2001; 108: [54] Burd L, Klug MG, Coumbe MJ, et al. The attention-deficit hyperactivity disorder paradox: 2. Phenotypic variability in prevalence and cost of comorbidity. J Child Neurol 2003; 18: [55] Schlander M, Schwarz O, Trott GE, et al. Health service expenditures for children and adolescents with and without attentiondeficit/hyperactivity disorder (ADHD) in Germany - impact of coexisting conditions. Value Health 2008; 11 (6): A340. [56] Spencer TJ. ADHD and comorbidity in childhood. J Clin Psychiatry 2006; 67 (Suppl 8): [57] Jensen PS, Hinshaw SP, Kraemer HC, et al. ADHD comorbidity findings from the MTA Study: comparing comorbid subgroups. J Am Acad Child Adolesc Psychiatry 2001; 40 (2): [58] Ollendick TH, Jarrett MA, Grills-Taquechel AE, et al. Comorbidity as a predictor and moderator of treatment outcome in youth with anxiety, affective, attention deficit/hyperactivity disorder, and oppositional/defiant disorders. Clin Psychol Rev 2008; 28: [59] Am Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders (DSM-IV). 4 th ed. Washington, DC: Am Psychiatric Association [60] World Health Organization (WHO) international statistical classification of diseases and related health problems (ICD-10). 10 th ed. Geneva, Switzerland: The World Health Organization [61] Wolraich ML, Hannah JN, Baumgaertel A, et al. Examination of DSM-IV criteria for attention deficit/hyperactivity disorder in a county-wide sample. J Develop Behav Pediatr 1998; 19: [62] Tripp G, Luk SL, Schaughency EA, et al. DSM-IV and ICD-10: a comparison of the correlates of ADHD and hyperkinetic disorder. J Am Acad Child Adolesc Psychiatry 1999; 38 (2): [63] American Psychiatric Association (APA). Handbook of psychiatric measures. Washington, DC: APA [64] Collett BR, Ohan JL, Myers KM. Ten-year review of rating scales. V. Scales assessing attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2003; 42 (9): [65] Drummond M, Pang F. Transferability of economic evaluation results. In: Drummond M, McGuire A, Eds. Economic evaluation in health care - merging theory with practice. Oxford: Oxford University Press 2001; pp [66] Reinhold T, Brueggenjuergen B, Rosenfeld S, et al. Economic analysis based on multinational studies - methods for adapting findings to national contexts. J Public Health (published online February 05, 2010). [67] Taylor E, Döpfner M, Sergeant J, et al. European clinical guidelines for hyperkinetic disorder - first upgrade. Eur Child Adolesc Psychiatry 2004; 13 (Suppl 1): [68] Remschmidt H, Global ADHD Working Group. Global consensus on ADHD/HKD. Eur Child Adolesc Psychiatry 2005; 14 (3): [69] Banaschewski T, Coghill D, Santosh P, et al. Long-acting medications for the hyperkinetic disorders. A systematic review and European treatment guideline. Eur Child Adolesc Psychiatry 2006; 15 (8): [70] Brown RT, Amler RW, Freeman WS, et al. Treatment of attentiondeficit/hyperactivity disorder; overview of the evidence. Pediatrics 2005; 115 (6): e [71] Pliszka S. AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2007; 46 (7): [72] Knapp MRJ. Economic evaluation and interventions for children and adolescents with mental health problems. J Child Psychol Psychiatry 1997; 38: 3-26.
15 The Pharmaceutical Economics of Child Psychiatric Drug Treatment Current Pharmaceutical Design, 2010, Vol. 16, No [73] Volkow ND, Wang G, Fowler JS, et al. Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. J Neurosci 2001; 21 (2): RC121. [74] Wilens TE. Effects of methylphenidate on the catecholaminergic system in attention-deficit/hyperactivity disorder. J Clin Psycho- Pharmacol 2008; 3 (suppl 2): S [75] Heal DJ, Cheetham SC, Smith SL. The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety. Neuropharmacology 2009; 57 (7-8): [76] Hogan V. Pemoline (Cylert): market withdrawal. Canadian Med Assoc J (CMAJ) 2000; 162 (1): 106. [77] Wilens TE, Dodson W. A clinical perspective of attentiondeficit/hyperactivity disorder into adulthood. J Clin Psychiatry 2004; 65 (10): [78] Daughton JM, Kratochvil CJ. Review of ADHD pharmacotherapies: advantages, disadvantages, and clinical pearls. J Am Acad Child Adolesc Psychiatry 2009; 48 (3): [79] Garnock-Jones KP, Keating GM. Atomoxetine: a review of its use in attention-deficit/hyperactivity disorder in children and adolescents. Paediatr Drugs 2009; 11 (3): [80] Michelson D, Allen AJ, Busner J, et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry 2002; 159 (11): [81] Gafni A, Birch S. Incremental cost-effectiveness ratios (ICERs): the silence of the lambda. Soc Sci Med 2006; 62: [82] Consumer Reports. best buy drugs: evaluating prescriptions drugs used to treat attention deficit hyperactivity disorder (ADHD): comparing effectiveness, safety, and price. Available online at [Last accessed December 30, 2009]. [83] Gelbe Liste. Available online at Last accessed December 30, [84] British National Formulary No. 58, September Available online at [Last accessed December 30, 2009]. [85] Dundar Y, Dodd S, Dickson R, et al. Comparison of conference abstracts and presentations with full-text articles in the health technology assessments of rapidly evolving technologies. Health Technol Assess 1996; 10 (5): [86] U.S. Congress, Office of Technology Assessment. Health care technology and its assessment in eight countries, OTA-BP-H-140 Washington, DC: U.S. Government Printing Office [87] Giacomini M. One of these things is not like the others: the idea of precedence in health technology assessment and coverage decisions. Milbank Quart 2005; 83 (2): [88] Miller A, Lee SK, Raina P, et al. A review of therapies for attention-deficit/hyperactivity disorder. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA) [89] Zupancic JAF, Miller A, Raina P, et al. Economic evaluation of pharmaceutical and psychological/behavioural therapies for attention-deficit/hyperactivity disorder. In: Miller A, Lee SK, Rain P, et al. Eds. A review of therapies for attention-deficit/hyperactivity disorder. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA) [90] Klassen A, Miller A, Raina P, et al. Attention-deficit hyperactivity disorder in children and youth: a quantitative systematic review of the efficacy of different management strategies. Canadian J Psychiatry 1999; 44 (10): [91] Firestone P, Crowe D, Goodman JT, et al. Vicissitudes of followup studies: differential effects of parent training and stimulant medication with hyperactives. Am J Orthopsychiatry 1986; 56 (2): [92] Miller AR, Lalonde CE, McGrail KM. Children s persistence with methylphenidate therapy: a population-based study. Canadian J Psychiatry 2004; 49 (11): [93] Firestone P. Factors associated with children s adherence to stimulant medication. Am J Orthopsychiatry 1982; 52 (3): [94] Shukla VP, Otten N. Assessment of attention deficit/hyperactivity disorder therapy: a Canadian perspective. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA) [95] Canadian Agency for Drugs and Technologies in Health (CADTH). Long versus short acting drugs for attention deficit hyperactivity disorder. Project number 487. Available online at http: //www. acmts.ca/index.php/en/hta/projects?&filter_field=2. [Last accessed January 30, 2010]. [96] Lord J, Paisley S. The clinical effectiveness and cost-effectiveness of methylphenidate for hyperactivity in childhood. London: National Institute for Clinical Excellence (NICE). Version 2, [97] Jadad AR, Boyle M, Cunningham C, et al. Treatment of attentiondeficit/hyperactivity disorder. Evidence Report / Technology Assessment No 11 (prepared by McMaster University under contract no ). AHRQ Publication No 00-E005. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ) [98] Gilmore A, Best L, Milne R. Methylphenidate in children with hyperactivity. DEC Report No 78. Southampton: Wessex Institute for Health Research and Development [99] MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 1999; 56: [100] MTA Cooperative Group. Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder: the multimodal treatment study of children with attentiondeficit/hyperactivity disorder. Arch Gener Psychiatry 1999; 56: [101] National Institute for Clinical Excellence (NICE). Health Technology Appraisal: Methylphenidate, atomoxetine and dexamfetamine for attention deficit hyperactivity disorder (ADHD) in children and adolescents including review of existing guidance number 13 (Guidance on the Use of Methylphenidate [Ritalin, Equasym] for Attention Deficit/Hyperactivity Disorder [ADHD] in childhood) - Scope. London: NICE [102] National Institute for Clinical Excellence (NICE). Special health authority tenth wave work programme: attention deficit hyperactivity disorder. Remit. London: NICE [103] King S, Riemsma R, Hodges Z, et al. Technology Assessment Report for the HTA Programme: Methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder. Final version. London: NICE [104] King S, Griffin S, Hodges Z, et al. A systematic review of the clinical and cost-effectiveness of methylphenidate hydrochloride, dexamfetamine sulphate and atomoxetine for attention deficit hyperactivity disorder (ADHD) in children and adolescents (commercial in confidence information removed). New York [105] National Institute for Health and Clinical Excellence (NICE). Final Appraisal Determination: Methylphenidate, atomoxetine and dexamfetamine for attention deficit hyperactivity disorder (ADHD) in children and adolescents. London: NICE [106] National Institute for Health and Clinical Excellence (NICE). Appraisal of methylphenidate, atomoxetine and dexamfetamine for attention deficit hyperactivity disorder in children and adolescents: Decision of the Panel. London: NICE [107] King S, Griffin S, Hodges Z, et al. A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents. Health Technol Assess 2006; 10 (23): iii-iv, xiii-146. [108] Coghill D, Spender Q, Barton J, et al. Measuring quality of life in children with attention-deficit/hyperactivity disorder in the UK. 16th World Congress of the International Association for Child and Adolescent Psychiatry and Allied Professions (IACAPAP). Book of Abstracts. Darmstadt: Steinkopff-Verlag 2004; p [109] Sharp WS, Alter JM, Marsh WL, et al. ADHD in girls: clinical comparability of a research sample. J Am Acad Child Adolesc Psychiatry 1999; 38: [110] Schlander M. The NICE ADHD health technology assessment: a review and critique. Child Adolesc Psychiatr Mental Health 2008; 2: 1: 1-9. [111] Rawlins MD, Culyer AJ. National institute of clinical excellence and its value judgments. Br Med J 2004; 329: [112] National Institute for Clinical Excellence (NICE). Guide to the technology appraisal process (reference N0514). London: NICE [113] Capelleri JC, Ioannidis JP, Schmid CH, et al. Large trials versus meta-analysis of smaller trials: how do their results compare? J Am Med Assoc (JAMA) 1996; 276 (16):
16 2458 Current Pharmaceutical Design, 2010, Vol. 16, No. 22 Michael Schlander [114] Schachar R, Jadad AR, Gauld M, et al. Attention-deficit hyperactivity disorder: critical appraisal of extended treatment studies. Canadian J Psychiatry 2002; 47 (4): [115] Shrier I, Platt RW, Steele RJ. Mega-trials vs. meta-analysis: precision vs. heterogeneity? Contemp Clin Trials 2007; 28 (3): [116] Wells KC, Pelham WE, Kotkin RA, et al. Psychosocial treatment strategies in the MTA Study: rationale, methods, and critical issues in design and implementation. J Abnorm Child Psychol 2000; 28 (6): [117] Wells KC. Comprehensive versus matched psychosocial treatment in the MTA Study: conceptual and empirical issues. J Clin Child Psychol 2001; 30 (1): [118] Greenhill LL, Abikoff H, Arnold LE, et al. Medication treatment strategies in the MTA Study: relevance to clinicians and researchers. J Am Acad Child Adolesc Psychiatry 1996; 35 (10): [119] Greenhill LL, Swanson JM, Vitiello B, et al. Impairment and deportment responses to different methylphenidate doses in children with ADHD: the MTA titration trial. J Am Acad Child Adolesc Psychiatry 2001; 40 (2): [120] Vitiello B, Severe JB, Greenhill LL, et al. Methylphenidate dosage for children with ADHD over time under controlled conditions: lessons from the MTA. J Am Acad Child Adolesc Psychiatry 2001; 40 (2): [121] Owens EB, Hinshaw SP, Kraemer HC, et al. Which treatment for whom for ADHD? Moderators of treatment response in the MTA. J Consult Clin Psychol 2003; 71 (3): [122] Swanson JM, Kraemer HC, Hinshaw SP, et al. Clinical relevance of the primary findings of the MTA: success rates based on severity of ADHD and ODD symptoms at the end of treatment. J Am Acad Child Adolesc Psychiatry 2001; 40 (2): [123] MTA Cooperative Group. National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: 24-month outcomes of treatment strategies for attention-deficit/hyperactivity disorder. Pediatrics 2004; 113 (4): [124] Jensen PS, Arnold LE, Swanson JM, et al. 3-year- follow-up of the NIMH MTA Study. J Am Acad Child Adolesc Psychiatry 2007; 46 (8): [125] Molina BSG, Hinshaw SP, Swanson JM, et al. The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry 2009, 48 (5): [126] Swanson JM, Hinshaw SP, Arnold LE, et al. Secondary evaluations of MTA 36-month outcomes: propensity score and growth mixture model analyses. J Am Acad Child Adolesc Psychiatry 2007; 46 (8): [127] Molina BSG, Flory K, Hinshaw SP, et al. Delinquent behavior and emerging substance use in the MTA at 36 months: prevalence, course, and treatment effects. J Am Acad Child Adolesc Psychiatry 2007; 46 (8): [128] Banaschewski T, Buitelaar J, Coghill DR, et al. The MTA at 8. J Am Acad Child Adolesc Psychiatry 2009; 48 (11): [129] Pliszka SR. The MTA at 8. J Am Acad Child Adolesc Psychiatry 2009; 48 (11): [130] Molina BSG, Hinshaw SP, Swanson JM. Arno,ld LE, for the MTA Cooperative Group. The MTA at 8. J Am Acad Child Adolesc Psychiatry 2009; 48 (11): [131] Efron B, Tibshirani R. An introduction to the bootstrap. New York, NY: Chapham and Hall [132] Jensen PS, Garcia JA, Glied S, et al. Cost-effectiveness of ADHD treatments: findings from the multimodal treatment study of children with ADHD. Am J Psychiatry 2005; 162 (9): [133] Bird H, Shaffer D, Fisher P, et al. The Columbia impairment scale (CIS): pilot findings on a measure of global impairment for children and adolescents. Int J Methods Psychiatr Res 1993; 3: [134] Bird HR, Andrews H, Schwab Stone M, et al. Global measures of impairment for epidemiological and clinical use with children and adolescents. Int J Methods Psychiatr Res 1996; 6 (4): [135] Bird HR. Columbia Impairment Scale (CIS). In: American Psychiatric Association (APA). Handbook of Psychiatric Measures. Washington, DC: APA 2000; pp [136] Foster EM, Jensen PS, Schlander M, et al. Treatment for ADHD: is more complex treatment cost-effective for more complex cases? Health Serv Res 2007; 42 (1): [137] Santosh PJ, Taylor E, Swanson J, et al. Refining the diagnoses of inattention and overactivity syndromes: a reanalysis of the Multimodal Treatment study of attention deficit hyperactivity disorder (ADHD) based on ICD-10 criteria for hyperkinetic disorder. Clin Neurosci Res 2005; 5: [138] Schlander M, Jensen PS, Foster EM, et al. Incremental costeffectiveness ratios of clinically proven treatments for attentiondeficit/hyperactivity disorder (ADHD): impact of diagnostic criteria and comorbidity. 5th World Congress, International Health Economics Association (ihea). Book of Abstracts. Barcelona, Spain: UPF 2005; pp [139] Schlander M, Schwarz O, Trott GE, et al. Treatment of attentiondeficit/hyperactivity disorder (ADHD): are U.S. cost-effectiveness findings based upon the MTA Study relevant to mental health care policy makers in Germany? Value Health 2005; 8 (6): A197. [140] Schlander M, Schwarz O, Hakkaart-van Roijen L, et al. Achieving normalization of core symptoms: cost-effectiveness of ADHD treatment strategies in the international context. J Mental Health Policy Econ 2007; 10 (Suppl 1): S38. [141] Schlander M, Schwarz O, Hakkaart-van Roijen L, et al. Improving functional impairment in major life activities: cost-effectiveness of ADHD treatment strategies in the international context. J Mental Health Policy Econ 2007; 10 (Suppl 1): S38. [142] Schlander M, Schwarz O, Foster EM, et al. Cost-effectiveness of ADHD treatment strategies in the international context: impact of therapeutic objectives and comorbidity. J Mental Health Policy Econ 2007; 10 (Suppl 1): S37. [143] Klein RG, Abikoff HG, Hechtman L, et al. Design and rationale of controlled study of long-term methylphenidate and multimodal psychosocial treatment in children with ADHD. J Am Acad Child Adolesc Psychiatry 2004; 43 (7): [144] Schlander M, Trott GE, Schwarz O. The health economics of attention deficit hyperactivity disorder in Germany. Part 2: therapeutic options and their cost effectiveness. Nervenarzt 2010; 81 (3): [145] Marchetti A, Magar R, Lau H, et al. Pharmacotherapies for attention-deficit/hyperactivity disorder: expected cost analysis. Clin Therapeut 2001; 23 (11): [146] Narayan S, Hay J. Cost effectiveness of methylphenidate versus AMP/DEX mixed salts for the first-line treatment of ADHD. Expert Rev Pharmacoecon Outcomes Res 2004; 4 (6): [147] Faraone SV, Biederman J, Roe C. Comparative efficacy of Adderall and methylphenidate in attention-deficit/hyperactivity disorder: a meta-analysis. J Clin PsychoPharmacol 2002; 22 (5): [148] Faraone SV, Buitelaar J. Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis. Eur Child Adolesc Psychiatry 2010; 19 (4): [149] Donnelly M, Haby MM, Carter R, et al. Cost-effectiveness of dexamphetamine and methylphenidate for the treatment of childhood attention deficit hyperactivity disorder. Aust N Z J Psychiatry 2004; 38 (8): [150] Gold MR, Stevenson D, Fryback DG. HALYs and QALYs and DALYs, oh my: similarities and differences in summary measures of population health. Ann Rev Public Health 2002; 23: [151] Stouthard MEA, Essink-Bot ML, Bonsel GJ, et al. Disability weights for diseases in the Netherlands. Rotterdam: Department of Public Health, Erasmus University [152] Landgraf JM, Rich M, Rappaport L. Measuring the quality of life in children with attention-deficit/hyperactivity disorder and their families: development and evaluation of a new tool. Arch Pediatr Adolesc Med 2002; 156 (4): [153] Claxton A, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Therapeut 2001; 23 (8): [154] Wolraich ML, Greenhill LL, Pelham WL, et al. Randomized, controlled trial of OROS methylphenidate once a day in children with attention-deficit/hyperactivity disorder. Pediatrics 2001; 108 (4): [155] Pelham WE, Gnagy EM, Borroughs-Maclean L, et al. Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings. Pediatrics 2001; 107 (6): e105/1-15.
17 The Pharmaceutical Economics of Child Psychiatric Drug Treatment Current Pharmaceutical Design, 2010, Vol. 16, No [156] Swanson JM, Gupta S, Lam A, et al. Development of a new oncea-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: proof-of-concept and proof-ofproduct studies. Arch Gen Psychiatry 2003; 60 (2): [157] Annemans L, Ingham M. Estimating cost-effectiveness of Concerta OROS in attention-deficit/hyperactivity disorder (ADHD) - adapting the Canadian Coordinating Office for Health Technology Assessment s (CCOHTA) economic model of methylphenidate immediate release versus behavioural interventions from a parent s perspective. Value Health 2000; 5 (6): 517. [158] Schlander M. Cost-effectiveness of methylphenidate OROS for attention-deficit / hyperactivity disorder (ADHD): an evaluation from the perspective of the UK National Health Service (NHS). Value Health 2004; 7 (3): 236. [159] Schlander M, Migliaccio-Walle K, Caro J. Treatment of attentiondeficit/hyperactivity disorder (ADHD): modelling the costeffectiveness of a modified-release preparation of methylphenidate from the perspective of the National Health Service (NHS) in the United Kingdom (UK). 16th World Congress of the International Association for Child and Adolescent Psychiatry and Allied Professions (IACAPAP), Berlin, August 22-26, Book of Abstracts. Darmstadt: Steinkopff-Verlag: 2004; S : 189. [160] Schlander M, Trott GE, Migliaccio-Walle K, et al. Kosteneffektivität verbesserter Compliance mit medikamentöser Therapie der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung bei Kindern und Jugendlichen aus der Perspektive der Gesetzlichen Krankenversicherung. Annual Meeting, Berufsverband der Ärzte für Kinder- und Jugendpsychiatrie und Psychotherapie in Deutschland (BKJPP), Gelsenkirchen / Germany, November 11, Book of Abstracts. BKJPP-Jahrestagung 2004; p. 23. [161] Conners C. Conners Rating Scales-Revised Technical Manual. North Tonawanda, NY: Multi-Health Systems [162] Conners CK. Conners Rating Scales - Revised (CRS-R). In: American Psychiatric Association, Handbook of Psychiatric Measures. Washington, DC: APA 2000; pp [163] Hwang P, Cosby A, Laberge ME. Compliance with three-times daily methylphenidate in chi`ldren with attention-deficit/ hyperactivity disorder. Value Health 2003; 6 (3): 273. [164] Lage M, Hwang P. Effects of methylphenidate formulation for attention deficit hyperactivity disorder on patterns and outcomes of treatment. J Child Adolesc PsychoPharmacol 2004; 14 (4): [165] Marcus SC, Wan GJ, Kemner JE, et al. Continuity of methylphenidate treatment for attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 2005; 159: [166] Sanchez RJ, Crismon ML, Barner JC, et al. Assessment of adherence measures with different stimulants among children and adolescents. Pharmacotherapy 2005; 25 (7): [167] Kemner JE, Lage MJ. Effect of methylphenidate formulation on treatment patterns and use of emergency room services. Am J Health Syst Pharm 2006; 63 (4): [168] Kemner JE, Lage MJ. Impact of methylphenidate formulation on treatment patterns and hospitalizations: a retrospective analysis. Ann Gen Psychiatry 2006; 5 (5): 1-8. [169] Schlander M. Long-acting medications for the hyperkinetic disorders: a note on cost-effectiveness. Eur Child Adolesc Psychiatry 2007; 16 (7): [170] Ganapathy V, Hay JW. Cost-effectiveness of once-daily stimulant, nonstimulant & combined stimulant /behavioral therapy interventions in the treatment of ADHD in children. Value Health 2008; 11 (3): A117. [171] Devine JW, Tiller KW, Trice S, et al. Economic evaluation of long acting treatments for attention-deficit/hyperactivity disorder in the military health system. Value Health 2007; 10 (3): A78. [172] Vazquez V. Cost-effectiveness analysis of single-dose extended release methylphenidate (Concerta ) vs. atomoxetine and shortacting methylphenidate for the managememt of attention deficit disorder with hyperactivity in Mexico. Value Health 2007; 10 (3): A74. [173] Faber A, van Agthoven M, Kalverdijk LJ, et al. Long-acting methylphenidate-oros in youths with attention-deficit hyperactivity disorder suboptimally controlled with immediate-release methylphenidate - a study of cost effectiveness in The Netherlands. CNS Drugs 2008; 22 (2): [174] Sonnenberg FA, Beck JR. Markov models in medical decision making: a practical guide. Med Decision Making 1993; 13 (4): [175] 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; 157 (5): [176] Faraone SV, Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of followup studies. Psychol Med 2006; 36: [177] Steele M, Weiss M, Swanson J, et al. A randomized, controlled, effectiveness trial of OROS-methylphenidate compared to usual care with immediate-release-methylphenidate in attention-deficithyperactivity-disorder. Canadian J Clin Pharmacol 2006; 13 (1): e [178] Secnik K, Matza LS, Cottrell S, et al. Health state utilities for childhood attention-deficit/hyperactivity disorder based on parent preferences in the United Kingdom. Med Decision Making 2005; 25: [179] Xiao X, Damaraju CV, Durkin M. Patterns of augmentation of extended-release stimulants for ADHD wih immediate-release stimulants in children and adolescents. Value Health 2009; 12 (3): A [180] Christensen LL, Sasané R, Hodgkins P, et al. Medication augmentation in patients with attention-deficit hyperactivity disorder. Poster presentation at the 2nd Biennial International Congress on ADHD. Vienna / Austria [181] Weinstein MC, Toy EL, Sandberg EA, et al. Modeling for health care and other policy decisions: uses, roles, and validity. Value Health 2001; 4 (5): [182] Weinstein MC, O Brien B, Hornberger J, et al. Principles of good practice for decision analytic modeling in health-care evaluation: report of the ISPOR Task Force on good research practices - modeling studies. Value Health 2003; 6 (1): [183] Hack S, Chow B. Pediatric psychotropic medication compliance: a literature review and research-based suggestions for improving treatment compliance. J Child Adolesc PsychoPharmacol 2001; 11 (19): [184] Swanson J. Compliance with stimulants for attention-deficit / hyperactivity disorder. Issues and approaches for improvement. CNS Drugs 2003; 17 (2): [185] Baltussen R, Leidl R, Ament A. Real world designs in economic evaluation: bridging the gap between clinical research and policymaking. Pharmacoeconomics 1996; 16 (5): [186] Revicki DA, Frank L. Pharmacoeconomic evaluations in the real world: effectiveness versus efficacy studies. Pharmacoeconomics 1999; 15 (5): [187] Hughes DA, Bagust A, Haycox A, et al. Accounting for noncompliance in pharmacoeconomic evaluations. Pharmacoeconomics 2001; 19 (12): [188] March JS, Silva SG, Compton S, et al. The case for practical clinical trials in psychiatry. Am J Psychiatry 2005; 162 (5): [189] Ramsey S, Willke R, Briggs A, et al. Good research practices for cost-effectiveness analysis alongside clinical trials: the ISPOR RCT-CEA Task Force report. Value Health 2005; 8 (5) [190] Rothenberger A, Coghill D, Döpfner M, et al. Naturalistic observational studies in the framework of ADHD health care. Eur Child Adolesc Psychiatry 2006; 15 (Suppl. 1): I/1-I/3. [191] Schlander M, Hjelmgren J. Cost-effectiveness of long-acting methylphenidate for treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents in Finland: an evaluation based upon a randomized clinical trial (RCT). Value Health 2008; 11 (6): A339. [192] Steinhoff K. Attention-deficit/hyperactivity disorder: medication treatment-dosing and duration of action. Am J Manag Care 2004; 10 (4): S [193] Steinhoff K, Wigal T, Swanson J. Single daily dose ADHD medication effect size evaluation. Poster presentation. 50th Annual Meeting of the American Academy for Child and Adolescent Psychiatry, Miami, FL [194] Faraone SV. Understanding the effect size of ADHD medications: implications for clinical care. Medscape Psychiatr Mental Health 2003; 8: 1-7.
18 2460 Current Pharmaceutical Design, 2010, Vol. 16, No. 22 Michael Schlander [195] Faraone SV, Spender T, Aleardi M, et al. Comparing the efficacy of medications used for ADHD using meta-analysis. Program and abstracts of the 156th Annual Meeting of the American Psychiatric Association; San Francisco, CA [196] Faraone SV, Biederman J, Spencer TJ, et al. Comparing the efficacy of medications for ADHD using meta-analysis. Medscape Gen Med 2006; 8 (4): 4. [197] Kratochvil CJ, Heiligenstein FH, Dittmann R, et al. Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomised, open-label trial. J Am Acad Child Adolesc Psychiatry 2002; 41: [198] Kemner JE, Starr HL, Ciccone PE, et al. Outcomes of OROS methylphenidate compared with atomoxetine in children with ADHD: a multicenter, randomized prospective study. Adv Therapy 2005; 22 (5): [199] Newcorn JH, Owens JA, Jasinski DR, et al. Results from recently completed comparator studies with atomoxetine and methylphenidate. 51st Annual Meeting of the American Academy of Child & Adolescent Psychiatry (AACAP), Washington, DC: Symposium [200] Newcorn J, Kratochvil CJ, Allen AJ, et al. Atomoxetine and OROS methylphenidate for the treatment of ADHD: acute results and methodological issues. Poster presentation at 45th Annual Meeting of the New Clinical Drug Evaluation Unit (NCDEU) of the National Institute of Mental Health (NIMH), Boca Raton, FL, June 6-9, 2005, Book of Abstracts 188. [201] Newcorn JH, Kratochvil CJ, Allen AJ, et al. Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response. Am J Psychiatry 2008; 165 (6): [202] Wigal SB, McGough JJ, McCracken JT, et al. A laboratory school comparison of mixed amphetamine salts extended release (Adderall XR ) and atomoxetine (Strattera ) in school-aged children with attention-deficit/hyperactivity disorder. J Attention Disord 2005; 9 (1): [203] Wang Y, Zheng Y, Du Y, et al. Atomoxetine versus methylphenidate in paediatric outpatients with attention deficit hyperactivity disorder: a randomized, double-blind comparison trial. Austral N Z J Psychiatry 2007; 41: [204] Iskedjian M, Maturi B, Walker JH, et al. Cost-effectiveness of atomoxetine in the treatment of attention deficit hyperactivity disorder in children and adolescents. Value Health 2003; 6 (3): 275. [205] Laing A, Cottrell S, Robinson P, et al. A modelled economic evaluation comparing atomoxetine with current therapies for the treatment of children with attention deficit/hyperactivity disorder (ADHD) in the Netherlands. Value Health 2005; 8 (6): A198. [206] Tilden D, Richardson R, Nyhus K, et al. A modelled economic evaluation of atomoxetine (Strattera) for the treatment of three patient groups with attention deficit hyperactivity disorder. Value Health 2005; 8 (6): A197. [207] Secnik K, Cottrell S, Matza LS, et al. Assessment of health state utilities for attention-deficit/hyperactivity disorder in children using parent-based standard gamble scores. Value Health 2004; 7 (3): 236. [208] Diamantopoulos A, Lorenzo M, Happich M, et al. A cost-utility analysis of atomoxetine against current stimulant therapies fir the treatment of children with attention-deficit/hyperactivity disorder (ADHD) in Germany. Value Health 2007; 10 (6): A298. [209] Cottrell S, Tilden D, Robinson P, et al. A modeled economic evaluation comparing atomoxetine with stimulant therapy in the treatment of children with attention-deficit/hyperactivity disorder in the United Kingdom. Value Health 2008; 11 (3): [210] Prasad S, Arellano J, Steer C, et al. Assessing the value of atomoxetine in treating children and adolescents with ADHD in the UK. Int J Clin Pract 2009; 63 (7): [211] Hong J, Dilla T, Aranello J. A modelled economic evaluation comparing atomoxetine with methylphenidate in the treatment of children with attention-deficit/hyperactivity disorder in Spain. BMC Psychiatry 2009; 9 (15): [212] Vitiello B. Improving decision making in the treatment of ADHD. Am J Psychiatry 2008; 165 (6): [213] Arnold LE, Lindsay RL, López FA, et al. Treating attentiondeficit/hyperactivity disorder with a stimulant transdermal patch: the clinical art. Pediatrics 2007; 120 (5): [214] Najib J. The efficacy and safety profile of lisdexamfetamine dimesylate, a pro-drug of d-amphetamine, for the treatment of attentiondeficit/hyperactivity disorder in children and adults. Clin Therapeut 2009; 31 (1): [215] Haby MM, Carter R, Mihalopoulos C, et al. Assessing costeffectiveness - mental health: introduction to the study and methods. Aust N Z J Psychiatry 2004; 38 (8): [216] Haby MM, Tonge B, Littlefield L, et al. Cost-effectiveness of cognitive behavioural therapy and selective serotonin reuptake inhibitors for major depression in children and adolescents. Aust N Z J Psychiatry 2004; 38 (8): [217] Byford S, Barrett B, Roberts C, et al. Cost-effectiveness of selective serotonin reuptake inhibitors and routine specialist care with and without cognitive-behavioural therapy in adolescents with major depression. Br J Psychiatry 2007; 191 (12): [218] Goodyer IM, Dubicka B, Wilkinson P, et al. A randomized controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial. Health Technol Assess 2008; 12 (14): iii-iv; ix- 60. [219] Treatment for Adolescents with Depression Study Team. Treatment for Adolescents with Depression Study (TADS): rationale, design, and methods. J Am Acad Child Adolesc Psychiatry 2003; 42 (5): [220] Domino ME, Burns BJ, Kratochvil CJ, et al. Cost-effectiveness of treatments for adolescent depression: results from TADS. Am J Psychiatry 2008; 165 (5): [221] Domino ME, Foster EM, Vitiello B, et al. Relative costeffectiveness of treatments for adolescent depression: 36-week results from the TADS randomized trial. J Am Acad Child Adolesc Psychiatry 2009; 48 (7): [222] March JS, Silva S, Petrycki S, et al. Fluoxetine, cognitivebehavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. J Am Med Assoc (JAMA) 2004; 292 (7): [223] Pyne JM, Tripathi S, Williams DK, et al. Depression-free day to utility-weighted score: is it valid? Medical Care 2007; 45: [224] March JS, Silva S, Petrycki S, et al. The Treatment for Adolescents with Depression Study (TADS): long-term effectiveness and safety outcomes. Arch Gen Psychiatry 2007; 64: [225] Heuzenroeder L, Donnelly M, Haby MM, et al. Cost-effectiveness of psychological and pharmacological interventions for generalized anxiety disorder and panic disorder. Aust N Z J Psychiatry 2004; 38 (8): [226] Mahe V, Balogh A. Long-term pharmacological treatment of generalized anxiety disorder. Int Clin PsychoPharmacol 2000; 15 (2): [227] Otto MW, Pollack MH, Maki KM. Empirically supported treatments for panic disorder: costs, benefits, and stepped care. J Consulting. Clin Psychol 2000; 68 (4): [228] De Civita M, Regier D, Alamgir AH, et al. Evaluating healthrelated quality-of-life studies in paediatric populations: some conceptual, methodological and developmental considerations and recent applications. Pharmacoeconomics 2005; 23 (7): [229] Griebsch I, Coast J, Brown J. Quality-adjusted life-years lack quality in pediatric care: a critical review of published cost-utility studies in child health. Pediatrics 2005; 115: e600-e614. [230] Danckaerts M, Sonuga-Barke EJ, Banaschewski T, et al. The quality of life of children with attention-deficit/hyperactivity disorder: a systematic review. Eur Child Adolesc Psychiatry 2010; 19: [231] Dworkin R. Taking rights seriously. Cambridge: Harvard University Press [232] Richardson J, McKie J. Empiricism, ethics and orthodox economic theory: what is the appropriate basis for decision-making in the health sector? Soc Sci Med 2005; 60: [233] Schlander M. Kosteneffektivität und Ressourcenallokation: Gibt es einen normativen Anspruch der Gesundheitsökonomie? In: Kick
19 The Pharmaceutical Economics of Child Psychiatric Drug Treatment Current Pharmaceutical Design, 2010, Vol. 16, No HA, Taupitz J, Eds. Gesundheitswesen zwischen Wirtschaftlichkeit und Menschlichkeit. Muenster: LIT-Verlag 2005; pp [234] Richardson J, McKie J. Economic evaluation of services for a National health scheme: the case for a fairness-based framework. J Health Econ 2007; 26 (4): [235] Chisholm D. Keeping pace with Assessing Cost-Effectiveness: economic efficiency and priority-setting in mental health. Aust N Z J Psychiatry 2005; 39: [236] Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutic trials. J Chron Dis 1967; 20: [237] Reeves G, Anthony B. Multimodal treatments versus pharmacotherapy alone in children with psychiatric disorders - implications of access, effectiveness, and contextual treatment. Pediatr Drugs 2009; 11 (3): [238] Baker CB, Johnsrud MT, Crismon ML, et al. Quantitative analysis of sponsorship bias in economic studies of antidepressants. Br J Psychiatry 2003; 183: [239] Timimi S. Child psychiatry and its relationship the pharmaceutical industry: theoretical and practical issues. Adv Psychiatr Treat 2008; 14: 3-9. [240] James A. Pharmacotherapy and child psychiatry: is there a way forward? Adv Psychiatr Treat 2008; 14: [241] Schlander M. The contribution of health economics to marketoriented pharmaceutical research and development. Witten / Germany: Universität Witten-Herdecke Verlagsgesellschaft [242] Avorn J. The role of pharmacoepidemiology and pharmacoeconomics in promoting access and stimulating innovation. PharmacoEconomics 2004; 22 (Suppl 2): [243] Vitiello B. Recent developments and strategies in pediatric pharmacology research in the USA. Child Adolesc Psychiatr Mental Health 2008; 2: 36, 1-5. [244] Upudhyaya HP, Gault L, Allen AJ. Challenges and opportunities in bringing new medications to market for pediatric patients. J Am Acad Child Adolesc Psychiatry 2009; 48 (11): [245] Baldwin DS. Room for improvement in the pharmacological treatment of anxiety disorders. Curr Pharm Des 2008; 14(33): [246] Berenguer B, La CC, de la Matta MJ, Martin-Calero MJ. Pharmaceutical care: past, present and future. Curr Pharm Des 2004; 10(31): [247] Workman P. How much gets there and what does it do?: The need for better pharmacokinetic and pharmacodynamic endpoints in contemporary drug discovery and development. Curr Pharm Des 2003; 9(11): Received: April 30, 2010 Accepted: May 19, 2010
Cost-Effectiveness of Treatment Options for Attention-Deficit/Hyperactivity Disorder (ADHD) in Children and Adolescents
17 th World Congress of the International Association for Child and Adolescent Psychiatry and Allied Professionals (IACAPAP) Melbourne, September 12, 2006 Cost-Effectiveness of Treatment Options for Attention-Deficit/HyperactivityMore information
The Role of Medication
Managing Medication for Children and Adolescents with ADHD Treating ADHD in children requires medical, educational, behavioral and psychological interventions. This comprehensive approach to treatmentMore information
Summary 1. Comparative-effectiveness
Cost-effectiveness of Delta-9-tetrahydrocannabinol/cannabidiol (Sativex ) as add-on treatment, for symptom improvement in patients with moderate to severe spasticity due to MS who have not responded adequatelyMore information
Nalmefene for reducing alcohol consumption in people with alcohol dependence
Nalmefene for reducing alcohol consumption in people with alcohol dependence Issued: November 2014 guidance.nice.org.uk/ta325 NICE has accredited the process used by the Centre for Health Technology EvaluationMore information
Cost-effectiveness of teriflunomide (Aubagio ) for the treatment of adult patients with relapsing remitting multiple sclerosis
Cost-effectiveness of teriflunomide (Aubagio ) for the treatment of adult patients with relapsing remitting multiple sclerosis The NCPE has issued a recommendation regarding the cost-effectiveness of teriflunomideMore information
1. Comparative effectiveness of alemtuzumab
Cost-effectiveness of alemtuzumab (Lemtrada ) for the treatment of adult patients with relapsing remitting multiple sclerosis with active disease defined by clinical or imaging features The NCPE has issuedMore information
Treatment Options for ADHD in Children and Teens. A Review of Research for Parents and Caregivers
Treatment Options for ADHD in Children and Teens A Review of Research for Parents and Caregivers Is This Summary Right for Me? Yes, if: A doctor said that your child or teen has attention deficit hyperactivityMore information
ADHD 9 Study results from confirm effectiveness of combined treatments and medication management in reducing children s Attention Deficit/Hyperactivity Disorder (ADHD) symptoms CITATION: MTA CooperativeMore information
Guidelines for the Treatment of
Guidelines for the Treatment of Adult ADHD with Psychostimulants Introduction This guideline covers the diagnosis and management of attention deficit hyperactivity disorder (ADHD) in adults (>18 yearsMore information
Cost-effectiveness of dimethyl fumarate (Tecfidera ) for the treatment of adult patients with relapsing remitting multiple sclerosis
Cost-effectiveness of dimethyl fumarate (Tecfidera ) for the treatment of adult patients with relapsing remitting multiple sclerosis The NCPE has issued a recommendation regarding the cost-effectivenessMore information
Costing statement: Depression: the treatment and management of depression in adults. (update) and
Costing statement: Depression: the treatment and management of depression in adults (update) and Depression in adults with a chronic physical health problem: treatment and management Summary It has notMore information
S u m m a r y o f C u r r e n t E v i d e n c e
S u m m a r y o f C u r r e n t E v i d e n c e CADTH October 2011 Guidelines and Recommendations for ADHD in Children and Adolescents This report is prepared by the Canadian Agency for Drugs and TechnologiesMore information
New Developments in the Treatment of ADHD in Children: How the Pharmacist and Pharmacy Technician Can Impact Care
New Developments in the Treatment of ADHD in Children: How the Pharmacist and Pharmacy Technician Can Impact Care Post-Test/Rationale EDUCATIONAL OBJECTIVES Upon completion of this activity, participantsMore information
Leading European Psychiatrists, Janssen-Cilag and Scientific Fraud
Concerta for adults Leading European Psychiatrists, Janssen-Cilag and Scientific Fraud December 9, 2011 How could leading European psychiatrists claim that the ADHD drug Concerta was safe and worked fantasticallyMore information
Policy for the issue of permits to prescribe Schedule 8 poisons
Policy for the issue of permits to prescribe Schedule 8 poisons May 2011 Introduction The Victorian Drugs, Poisons and Controlled Substances (DPCS) legislation sets out certain circumstances when a medicalMore information
What is costeffectiveness?
...? series Second edition Health economics Supported by sanofi-aventis What is costeffectiveness? Ceri Phillips BSc(Econ) MSc(Econ) PhD Health Economist, Swansea University Cost-effectiveness analysisMore information
CLINICAL PRACTICE GUIDELINES Treatment of Schizophrenia
CLINICAL PRACTICE GUIDELINES Treatment of Schizophrenia V. Service Delivery Service Delivery and the Treatment System General Principles 1. All patients should have access to a comprehensive continuumMore information
Caring for Children With ADHD: A Resource Toolkit for Clinicians
INTRODUCTION Attention-deficit/hyperactivity disorder (ADHD) is one of the most common chronic childhood disorders. Current estimates indicate that 4% to 12% of all school-aged children may be affected.More information
CRITERIA FOR DIAGNOSIS AND MANAGEMENT OF ATTENTION DEFICIT HYPERACTIVITY DISORDER IN ADULTS For the purpose of this document adults are considered to be persons who are 18 years or over. Separate criteriaMore information
Adalimumab for the treatment of psoriasis
DOI: 10.3310/hta13suppl2/07 Health Technology Assessment 2009; Vol. 13: Suppl. 2 Adalimumab for the treatment of psoriasis D Turner, J Picot,* K Cooper and E Loveman Southampton Health Technology AssessmentsMore information
Rhode Island Board of Medical Licensure and Discipline
Rhode Island Board of Medical Licensure and Discipline Considerations Regarding Pharmaceutical Stimulant Prescribing for Attention Deficit Disorders (ADD)/Attention Deficit Hyperactivity Disorder (ADHD)More information
The core symptoms of ADHD, as the name implies, are inattentiveness, hyperactivity and impulsivity. These are excessive and long-term and
Attention Deficit Hyperactivity Disorder What is Attention Deficit Hyperactivity Disorder? The core symptoms of ADHD, as the name implies, are inattentiveness, hyperactivity and impulsivity. These areMore information
Teriflunomide for treating relapsing remitting multiple sclerosis
Teriflunomide for treating relapsing remitting multiple Issued: January 2014 last modified: June 2014 guidance.nice.org.uk/ta NICE has accredited the process used by the Centre for Health Technology EvaluationMore information
ADHD PRACTISE PARAMETER. IRSHAAD SHAFFEEULLAH, M.D. A diplomate American Board of CHILD AND ADOLESCENT PSYCHIATRY
ADHD PRACTISE PARAMETER IRSHAAD SHAFFEEULLAH, M.D. A diplomate American Board of CHILD AND ADOLESCENT PSYCHIATRY Similar type of idea Similar document Similar document AACAP document Neurobiological conditionMore information
Graduate Program Course Descriptions
Graduate Program Course Descriptions The following section provides course descriptions for courses offered and required in the Research College of Nursing Graduate Programs: the Family Nurse PractitionerMore information
Attention-Deficit Hyperactivity Disorder (ADHD)
Attention-Deficit Hyperactivity Disorder (ADHD) Possible changes in DSM-V APA, 2010 For older adolescents and adults (>17) confirmatory observations by third parties should be obtained whenever possible.More information
Nurse practitioner standards for practice
Orientating statements Nurse practitioners have the capability to provide high levels of clinically focused nursing care in a variety of contexts in Australia. Nurse practitioners care for people and communitiesMore information
PUBLIC HEALTH OPTOMETRY ECONOMICS. Kevin D. Frick, PhD
Chapter Overview PUBLIC HEALTH OPTOMETRY ECONOMICS Kevin D. Frick, PhD This chapter on public health optometry economics describes the positive and normative uses of economic science. The terms positiveMore information
Overview of Mental Health Medication Trends
America s State of Mind Report is a Medco Health Solutions, Inc. analysis examining trends in the utilization of mental health related medications among the insured population. The research reviewed prescriptionMore information
MRC Social Genetic and Developmental Psychiatry
Philip Asherson MRCPsych, PhD Professor of Molecular Psychiatry & Honorary Consultant Psychiatrist, MRC Social Genetic Developmental Psychiatry, Institute of Psychiatry, UK MRC Social Genetic and DevelopmentalMore information
Diagnosis and management of ADHD in children, young people and adults
Issue date: September 2008 Attention deficit hyperactivity disorder Diagnosis and management of ADHD in children, young people and adults NICE clinical guideline 72 Developed by the National CollaboratingMore information
KENTUCKY ADMINISTRATIVE REGULATIONS TITLE 201. GENERAL GOVERNMENT CABINET CHAPTER 9. BOARD OF MEDICAL LICENSURE 201 KAR 9:260. Professional standards for prescribing and dispensing controlled substances.More information
ADHD and Treatment HYPERACTIVITY AND INATTENTION (ADHD) Meghan Miller, MA, Stephen P. Hinshaw, PhD University of California, Berkeley, USA
HYPERACTIVITY AND INATTENTION (ADHD) ADHD and Treatment Meghan Miller, MA, Stephen P. Hinshaw, PhD University of California, Berkeley, USA February 2012 Introduction Attention-deficit/hyperactivity disorderMore information
PREVENTING MENTAL DISORDERS IN SCHOOL-AGE CHILDREN: A Review of the Effectiveness of Prevention Programs EXECUTIVE SUMMARY Mark T. Greenberg Ph. D. Celene Domitrovich Ph. D. Brian Bumbarger PreventionMore information
Complex Patients. Evaluation. ADHD Pharmacotherapy: Stimulant Use and Abuse
ADHD Pharmacotherapy: Stimulant Use and Abuse A Clinical Perspective Thor C. Bergersen, M.D. Complex Patients Rarely do people fit into categorical boxes Constellation of symptoms is the norm ADHD is frequentlyMore information
Apixaban for the prevention of stroke and systemic embolism in people with non-valvular atrial fibrillation
Apixaban for the prevention of stroke and systemic embolism in people with non-valvular atrial fibrillation ERRATUM This report was commissioned by the NIHR HTA Programme as project number 11/49 This documentMore information
Predicting Medication Compliance and Persistency
Predicting Medication Compliance and Persistency By: Jay Bigelow, President Amanda Rhodes, M.P.H., C.H.E.S., Vice President Behavioral Solutions MicroMass Communications, Inc. Introduction A widely recognizedMore information
SPECIFICATION FOR THE LOCAL COMMISSIONED SERVICE FOR THE MANAGEMENT OF ALCOHOL MISUSE Date: March 2015 1 1. Introduction Alcohol misuse is a major public health problem in Camden with high rates of hospitalMore information
Graduate Program Objective #1 Course Objectives
1 Graduate Program Objective #1: Integrate nursing science and theory, biophysical, psychosocial, ethical, analytical, and organizational science as the foundation for the highest level of nursing practice.More information
Can an administrative drug claims database be used to understand claimant drug utilization?
Can an administrative drug claims database be used to understand claimant drug utilization? By Elaine McKenzie, BSP, MBA, Consultant, TELUS Health Analytics Elaine McKenzie is a consultant who works withMore information
Pragmatic Evidence Based Review Substance Abuse in moderate to severe TBI
Pragmatic Evidence Based Review Substance Abuse in moderate to severe TBI Reviewer Emma Scheib Date Report Completed November 2011 Important Note: This report is not intended to replace clinical judgement,More information
Nurse practitioner standards for practice Effective from 1 January 2014
Effective from 1 January 2014 November 2013 Orientating statements Nurse practitioners have the capability to provide high levels of clinically focused nursing care in a variety of contexts in Australia.More information
Section I BASIC CONCEPTS OF PATIENT EDUCATION Section I of this book, Basic Concepts of Patient Education, describes the importance of teaching and learning in health care and physical and occupationalMore information
Conduct Disorder: Treatment Recommendations. For Vermont Youth. From the. State Interagency Team
Conduct Disorder: Treatment Recommendations For Vermont Youth From the State Interagency Team By Bill McMains, Medical Director, Vermont DDMHS Alice Maynard, Mental Health Quality Management Chief, VermontMore information
Dr. Anna M. Acee, EdD, ANP-BC, PMHNP-BC Long Island University, Heilbrunn School of Nursing
Dr. Anna M. Acee, EdD, ANP-BC, PMHNP-BC Long Island University, Heilbrunn School of Nursing Overview Depression is significantly higher among elderly adults receiving home healthcare, particularly amongMore information
Canadian Nurse Practitioner Core Competency Framework
Canadian Nurse Practitioner Core Competency Framework January 2005 Table of Contents Preface... 1 Acknowledgments... 2 Introduction... 3 Assumptions... 4 Competencies... 5 I. Health Assessment and Diagnosis...More information
Step 2: Recognised depression in adults persistent subthreshold depressive symptoms or mild to moderate depression
Step 2: Recognised depression in adults persistent subthreshold depressive symptoms or mild to moderate depression A NICE pathway brings together all NICE guidance, quality standards and materials to supportMore information
Clinical Practice Guidelines: Attention Deficit/Hyperactivity Disorder
Clinical Practice Guidelines: Attention Deficit/Hyperactivity Disorder AACAP Official Action: OUTLINE OF PRACTICE PARAMETERS FOR THE ASSESSMENT AND TREATMENT OF CHILDREN, ADOLESCENTS, AND ADULTS WITH ADHDMore information
Clinical guideline Published: 24 September 2008 nice.org.uk/guidance/cg72
Attention deficit hyperactivity disorder: diagnosis and management Clinical guideline Published: 24 September 2008 nice.org.uk/guidance/cg72 NICE 2008. All rights reserved. Last updated February 2016 ContentsMore information
ADHD DSM Criteria and Evidence-based Treatments
ADHD DSM Criteria and Evidence-based Treatments DSM-5 Criteria for ADHD A. A persistent pattern of inattention and/or hyperactivity-impulsivity that interferes With functioning or development, as characterizedMore information
Dual Diagnosis: Models of Care and Local Pathways AGENDA. Part one: Part two:
Slide 1 Dual Diagnosis: Models of Care and Local Pathways St. Anne s Community Services Dual Diagnosis Project Slide 2 AGENDA Part one: Models of Care. Clinical Guidelines & Evidence Base Local Care PathwaysMore information
Managing depression after stroke. Presented by Maree Hackett
Managing depression after stroke Presented by Maree Hackett After stroke Physical changes We can see these Depression Emotionalism Anxiety Confusion Communication problems What is depression? CategoryMore information
NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE 1 Guideline title SCOPE Schizophrenia: core interventions in the treatment and management of schizophrenia in primary and secondary care (update) 1.1More information
ADVANCEMENTS IN THE ECONOMIC EVALUATION OF MEDICINES IN EUROPE. PRESENT SITUATION AND FUTURE PERSPECTIVES Bengt Jönsson Stockholm School of Economics Page 1 CONTENT Methodology Economic evaluation andMore information
Step 4: Complex and severe depression in adults
Step 4: Complex and severe depression in adults A NICE pathway brings together all NICE guidance, quality standards and materials to support implementation on a specific topic area. The pathways are interactiveMore information
DMRI Drug Misuse Research Initiative
DMRI Drug Misuse Research Initiative Executive Summary Dexamphetamine Substitution as a Treatment of Amphetamine Dependence: a Two-Centre Randomised Controlled Trial Final Report submitted to the DepartmentMore information
Transferability of Economic Evaluations in Clinical Trials
Transferability of Economic Evaluations in Clinical Trials Henry Glick Institutt for helseledelse og helseøkonomi November 25, 2008 The Problem Multicenter and multinational studies are the norm for theMore information
Objectives of Training in the Subspecialty of Clinical Pharmacology and Toxicology
Objectives of Training in the Subspecialty of Clinical Pharmacology and Toxicology This document applies to those who begin training on or after July 1 st, 2007. (Please see also the Policies and Procedures.More information
Obsessive-Compulsive Disorder Clinical Practice Guideline Summary for Primary Care
Obsessive-Compulsive Disorder Clinical Practice Guideline Summary for Primary Care CLINICAL ASSESSMENT AND DIAGNOSIS (ADULTS) Obsessive-Compulsive Disorder (OCD) is categorized by recurrent obsessions,More information
NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE 1 Guideline title SCOPE Challenging behaviour and learning disabilities: prevention and interventions for people with learning disabilities whose behaviourMore information
Executive Summary. 1. What is the temporal relationship between problem gambling and other co-occurring disorders?
Executive Summary The issue of ascertaining the temporal relationship between problem gambling and cooccurring disorders is an important one. By understanding the connection between problem gambling andMore information
levetiracetam, 250, 500, 750 and 1000mg tablets and levetiracetam oral solution 100mg/ml (Keppra ) No. (395/07) UCB Pharma Limited
Scottish Medicines Consortium levetiracetam, 250, 500, 750 and 1000mg tablets and levetiracetam oral solution 100mg/ml (Keppra ) No. (395/07) UCB Pharma Limited 10 August 2007 The Scottish Medicines ConsortiumMore information
MSc International Programme in Addiction Studies. Prospectus 2015-2016
MSc International Programme in Addiction Studies Prospectus 2015-2016 The Institute of Psychiatry, Psychology and Neuroscience www.kcl.ac.uk/ioppn The Institute of Psychiatry, Psychology and NeuroscienceMore information
Prepared by:jane Healey (Email: firstname.lastname@example.com) 4 th year undergraduate occupational therapy student, University of Western Sydney
1 There is fair (2b) level evidence that living skills training is effective at improving independence in food preparation, money management, personal possessions, and efficacy, in adults with persistentMore information
Nurse Practitioner Student Learning Outcomes
ADULT-GERONTOLOGY PRIMARY CARE NURSE PRACTITIONER Nurse Practitioner Student Learning Outcomes Students in the Nurse Practitioner Program at Wilkes University will: 1. Synthesize theoretical, scientific,More information
Preferred Practice Guidelines Bipolar Disorder in Children and Adolescents
These Guidelines are based in part on the following: American Academy of Child and Adolescent Psychiatry s Practice Parameter for the Assessment and Treatment of Children and Adolescents With Bipolar Disorder,More information
DMRI Drug Misuse Research Initiative
DMRI Drug Misuse Research Initiative Executive Summary The psychosocial consequences of drug misuse: a systematic review of longitudinal studies Research Report submitted to the Department of Health inMore information
Supplementary appendix
Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Rich JD, McKenzie M, Larney S, et al. MethadoneMore information
Graduate Curriculum Guide Course Descriptions: Core and DNP
Graduate Curriculum Guide Course Descriptions: Core and DNP APN Core Courses (35 credits total) N502 Theoretical Foundations of Nursing Practice (3 credits) Theoretical Foundations of Nursing PracticeMore information
Best Principles for Integration of Child Psychiatry into the Pediatric Health Home
Best Principles for Integration of Child Psychiatry into the Pediatric Health Home Approved by AACAP Council June 2012 These guidelines were developed by: Richard Martini, M.D., co-chair, Committee onMore information
Methods for the comparative evaluation of pharmaceuticals
HTA REPORT EXECUTIVE SUMMARY Methods for the comparative evaluation of pharmaceuticals Zentner A, Velasco-Garrido M, Busse R Political Background The German Institute for Quality and Efficiency in HealthMore information
Specialist drug and alcohol services for young people a cost benefit analysis
DFE-RB087 ISBN 978-1-84775-862-0 February 2011 Specialist drug and alcohol services for young people a cost benefit analysis Frontier Economics This report looks at the costs and benefits associated withMore information
SENSITIVITY ANALYSIS AND INFERENCE. Lecture 12
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike License. Your use of this material constitutes acceptance of that license and the conditions of use of materials on thisMore information
Adoption by CHMP for release for consultation November 2010. End of consultation (deadline for comments) 31 March 2011
1 2 3 November 2010 EMA/759784/2010 Committee for Medicinal Products for Human Use 4 5 6 7 Reflection paper on the need for active control in therapeutic areas where use of placebo is deemed ethical andMore information
2. Background This was the fourth submission for everolimus requesting listing for clear cell renal carcinoma.
PUBLIC SUMMARY DOCUMENT Product: Everolimus, tablets, 5 mg and 10 mg, Afinitor Sponsor: Novartis Pharmaceuticals Australia Pty Ltd Date of PBAC Consideration: November 2011 1. Purpose of Application ToMore information
REGULATIONS FOR THE POSTGRADUATE CERTIFICATE IN PUBLIC HEALTH (PCPH) (Subject to approval)
512 REGULATIONS FOR THE POSTGRADUATE CERTIFICATE IN PUBLIC HEALTH (PCPH) (Subject to approval) (See also General Regulations) M.113 Admission requirements To be eligible for admission to the programmeMore information
EVIDENCE-BASED BEST PRACTICES FOR THE MANAGEMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD) IN PEDIATRIC PRIMARY CARE IN SOUTH CAROLINA Key Messages for Management of Attention-Deficit/HyperactivityMore information
MN-NP GRADUATE COURSES Course Descriptions & Objectives
MN-NP GRADUATE COURSES Course Descriptions & Objectives NURS 504 RESEARCH AND EVIDENCE-INFORMED PRACTICE (3) The purpose of this course is to build foundational knowledge and skills in searching the literature,More information
Drug development for children: how adequate is the current European ethical guidance?
Chapter 7 Drug development for children: how adequate is the current European ethical guidance? ABSTRACT It is unacceptable that many drugs prescribed to children have not been proven safe and effectiveMore information
Commissioning Policy: Defining the boundaries between NHS and Private Healthcare April 2013 Reference : NHSCB/CP/12
Commissioning Policy: Defining the boundaries between NHS and Private Healthcare April 2013 Reference : NHSCB/CP/12 NHS Commissioning Board Commissioning Policy: Defining the Boundaries between NHS andMore information
ISCTM ADAPTIVE DESIGN WORKING GROUP Comparative Effectiveness Study: New Novel Treatment vs. Oral Antipsychotics in Schizophrenia Washington DC Feb 18, 2014 ISCTM ADAPTIVE DESIGN WORKING GROUP There areMore information
The fourth hurdle system. International HTA agencies. Australian PBAC. Difference between health technology regulatory body and HTA body
* This presentation is prepared by the author in one s personal capacity for the purpose of academic exchange and does not represent the views of his/her organisations on the topic discussed. Local ApplicationMore information
Shared Care Protocol for Prescription of Medication in Attention Deficit Hyperactivity Disorder (ADHD)
Shared Care Protocol for Prescription of Medication in Attention Deficit Hyperactivity Disorder (ADHD) Author: Irene Sharkie, Dr Sally Bonnar, Dr Sarah Seth Review Group: Shared Care Pathway Review Date:More information
MOH CLINICAL PRACTICE GUIDELINES 2/2008 Prescribing of Benzodiazepines
MOH CLINICL PRCTICE GUIELINES 2/2008 Prescribing of Benzodiazepines College of Family Physicians, Singapore cademy of Medicine, Singapore Executive summary of recommendations etails of recommendationsMore information
Effectiveness of Brief Alcohol Intervention strategies. Eileen Kaner
Effectiveness of Brief Alcohol Intervention strategies Eileen Kaner Professor of Public Health and Primary Care Research email@example.com Introduction Scope of alcohol harm Preventive paradoxMore information
Drug Class Review Pharmacologic Treatments for Attention Deficit Hyperactivity Disorder
Drug Class Review Pharmacologic Treatments for Attention Deficit Hyperactivity Disorder Final Update 3 Report October 2009 The purpose of reports is to make available information regarding the comparativeMore information
I N S T I T U T E O F M E D I C I N E Shaping the Future for Health SMALL CLINICAL TRIALS: ISSUES AND CHALLENGES Clinical trials have a long history of well established, documented, and validated methodsMore information
Purpose. Admission Requirements NURSING EDUCATION STUDENT LEARNING OUTCOMES RESIDENCY REQUIREMENTS. Clinical Requirements
NURSING EDUCATION Purpose This program is designed for professional nurses who have earned a Master s or Doctoral Degree in Nursing and seek further education in advanced nursing practice. ConcentrationsMore information
Cost-effectiveness of Fidaxomicin (Dificlir ) tablets for the treatment of adults with Clostridium difficileassociated
Cost-effectiveness of Fidaxomicin (Dificlir ) tablets for the treatment of adults with Clostridium difficileassociated diarrhoea. February 2013 1. Fidaxomicin is indicated in adults for the treatment ofMore information
RN-MS Program. Purpose. Admission Requirements. State Requirements for Online/Distance Education. Degree Requirements
RN-MS PROGRAM RN-MS Program Purpose This accelerated program is designed for the experienced, practicing registered nurse who plans to continue nursing studies through the master's level and does not holdMore information
perc also deliberated on the alignment of bendamustine with patient values. perc noted that bendamustine has a progression-free survival advantage, may be less toxic than currently available therapiesMore information
NICE Pathways bring together all NICE guidance, quality standards and other NICE information on a specific topic.
Using antidepressants in children and young people bring together all NICE guidance, quality standards and other NICE information on a specific topic. are interactive and designed to be used online. TheyMore information
NICE Pathways bring together all NICE guidance, quality standards and other NICE information on a specific topic.
bring together all NICE guidance, quality standards and other NICE information on a specific topic. are interactive and designed to be used online. They are updated regularly as new NICE guidance is published.More information
UCLA-NPI/VA PG-2 Child & Adolescent Psychiatry Course 2004-5. Week 3:Attention Deficit Hyperactivity Disorder
UCLA-NPI/VA PG-2 Child & Adolescent Psychiatry Course 2004-5 Week 3:Attention Deficit Hyperactivity Disorder ADHD:Epidemiology Point Prevalence 2-18% M:F>= 2:1 ADHD Symptoms Cognitive (attention) ImpulsivityMore information
ADHD and School Failure
ADHD and School Failure Your child isn t doing well in school. Actually, she/he s never done very well, but it s getting worse as schoolwork gets more challenging every year. What do you do? Here are someMore information
Cochrane Review: Psychological treatments for depression and anxiety in dementia and mild cognitive impairment
23 rd Alzheimer Europe Conference St. Julian's, Malta, 2013 Cochrane Review: Psychological treatments for depression and anxiety in dementia and mild cognitive impairment Orgeta V, Qazi A, Spector A E,More information
For more than 100 years, extremely hyperactive
8 WHAT WE KNOW ADHD Predominantly Inattentive Type For more than 100 years, extremely hyperactive children have been recognized as having behavioral problems. In the 1970s, doctors recognized that thoseMore information
Scottish Medicines Consortium. erdosteine 300mg capsules (Erdotin ) No. (415/07) Edmond Pharma Sr.l/Galen Ltd. 5 October 2007
Scottish Medicines Consortium erdosteine 300mg capsules (Erdotin ) No. (415/07) Edmond Pharma Sr.l/Galen Ltd. 5 October 2007 The Scottish Medicines Consortium has completed its assessment of the aboveMore information
MOT Curriculum Sequence and Descriptions Beginning Summer 2016
MOT Curriculum Sequence and Descriptions Beginning Summer 2016 Year 1: Summer Credit Hours OT 5002: Theoretical Perspectives of Occupation 2 OT 5005: Neuroscience Perspectives in Occupational Therapy 4More information
ADVANCED BEHAVIORAL HEALTH, INC. Clinical Level of Care Guidelines - 2015
The Clinical Level of Care Guidelines contained on the following pages have been developed as a guide to assist care managers, physicians and providers in making medical necessity decisions about the leastMore information