Stimulant prodrugs: A pharmacological and clinical assessment of their role in treating ADHD and binge-eating disorder.

In this review, we critically evaluate the contribution of prodrugs to treating two related psychiatric disorders, attention-deficit hyperactivity disorder (ADHD) and binge-eating disorder (BED). ADHD is characterized by inattentiveness, distractibility, impulsiveness, and hyperactivity. BED is also an impulse-control disorder which leads to frequent, compulsive episodes of excessive eating (binges). Lisdexamfetamine (LDX; prodrug of d-amphetamine) is approved to treat both ADHD and BED. Serdexmethylphenidate (SDX; prodrug of d-threo-methylphenidate) is not clinically approved as monotherapy but, in a fixed-dose combination with immediate release d-threo-methylphenidate (Azstarys™), SDX is approved for managing ADHD in children/adolescents. The pharmacological actions of a stimulant mediate both its efficacy and side-effects. Therefore, daily management of ADHD or BED to maintain optimum efficacy and tolerability places highly restrictive requirements on the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of stimulant medications, especially prodrugs. Prodrugs must have good bioavailability and rapid metabolism to provide therapeutic efficacy soon after morning dosing combined with providing stimulant coverage throughout the day/evening. A wide selection of dosages and linear PK for the prodrug and its active metabolite are essential requirements for treatment of these conditions. The proposed neurobiological causes of ADHD and BED are described. The chemical, pharmacological and PK/PD properties responsible for the therapeutic actions of the prodrugs, LDX and SDX, are compared and contrasted. Finally, we critically assess their contribution as ADHD and BED medications, including advantages over their respective active metabolites, d-amphetamine and d-threo-methylphenidate, and also their potential for misuse and abuse.

Medication Use in the Management of Comorbidities Among Individuals With Autism Spectrum Disorder From a Large Nationwide Insurance Database.

Importance: Although there is no pharmacological treatment for autism spectrum disorder (ASD) itself, behavioral and pharmacological therapies have been used to address its symptoms and common comorbidities. A better understanding of the medications used to manage comorbid conditions in this growing population is critical; however, most previous efforts have been limited in size, duration, and lack of broad representation. Objective: To use a nationally representative database to uncover trends in the prevalence of co-occurring conditions and medication use in the management of symptoms and comorbidities over time among US individuals with ASD. Design, Setting, and Participants: This retrospective, population-based cohort study mined a nationwide, managed health plan claims database containing more than 86 million unique members. Data from January 1, 2014, to December 31, 2019, were used to analyze prescription frequency and diagnoses of comorbidities. A total of 26 722 individuals with ASD who had been prescribed at least 1 of 24 medications most commonly prescribed to treat ASD symptoms or comorbidities during the 6-year study period were included in the analysis. Exposures: Diagnosis codes for ASD based on International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Main Outcomes and Measures: Quantitative estimates of prescription frequency for the 24 most commonly prescribed medications among the study cohort and the most common comorbidities associated with each medication in this population. Results: Among the 26 722 individuals with ASD included in the analysis (77.7% male; mean [SD] age, 14.45 [9.40] years), polypharmacy was common, ranging from 28.6% to 31.5%. Individuals' prescription regimens changed frequently within medication classes, rather than between classes. The prescription frequency of a specific medication varied considerably, depending on the coexisting diagnosis of a given comorbidity. Of the 24 medications assessed, 15 were associated with at least a 15% prevalence of a mood disorder, and 11 were associated with at least a 15% prevalence of attention-deficit/hyperactivity disorder. For patients taking antipsychotics, the 2 most common comorbidities were combined type attention-deficit/hyperactivity disorder (11.6%-17.8%) and anxiety disorder (13.1%-30.1%). Conclusions and Relevance: This study demonstrated considerable variability and transiency in the use of prescription medications by US clinicians to manage symptoms and comorbidities associated with ASD. These findings support the importance of early and ongoing surveillance of patients with ASD and co-occurring conditions and offer clinicians insight on the targeted therapies most commonly used to manage co-occurring conditions. Future research and policy efforts are critical to assess the extent to which pharmacological management of comorbidities affects quality of life and functioning in patients with ASD while continuing to optimize clinical guidelines, to ensure effective care for this growing population.

Relationships between computer-based testing and behavioral ratings in the assessment of attention and activity in a pediatric ADHD stimulant crossover trial.

This study investigated the relationships between computer-based testing and behavioral ratings in the assessment of stimulant-induced changes in attention and activity in a pediatric ADHD crossover trial with methylphenidate, dextroamphetamine, and a placebo. Here 36 children between 9 and 14 years old were randomly and evenly assigned to each of six counterbalanced drug orders. A computer-based continuous performance test combined with a motion-tracking system (cb-CPT-MTS) and an ADHD questionnaire rated by teachers constituted the outcome measures. All outcome measures responded to stimulants in a comparable way at the group level, as shown by significant treatment effects of similar size for the two stimulants compared with a placebo. Computer-based and rating-based measures were unrelated in the assessment of stimulant-induced changes in attention and activity in individual children; no significant correlations between these measures in the assessment of change from placebo to stimulant conditions across the sample were detected. Results suggest that computer-based testing and behavioral ratings cannot be considered equivalent in the assessment of stimulant-induced changes in attention and activity among ADHD children.

Treatment persistence in attention deficit/hyperactivity disorder: a retrospective analysis of patients initiated on lisdexamfetamine vs other medications.

OBJECTIVE: To compare treatment persistence in attention-deficit/hyperactivity disorder (ADHD) of patients initiated on lisdexamfetamine (LDX) vs other ADHD medications. METHODS: A large US administrative claims database was used to select ADHD patients who initiated an ADHD medication (index treatment) during/after 2007. Patients were classified, based on age and previous treatment status, as treatment-naïve or previously treated children and adolescents (6-17 years) and treatment-naïve or previously treated adults (18 years and older). Furthermore, patients were classified into seven mutually exclusive treatment groups, based on their index treatment: LDX, atomoxetine (ATX), osmotic-release methylphenidate hydrochloride long-acting (OROS MPH), other methylphenidate/dexmethylphenidate short-acting (MPH SA) and long-acting (MPH LA), and amphetamine/dextroamphetamine short acting (AMPH SA) and long-acting (AMPH LA). Treatment persistence, analyzed through discontinuation (interruption of the index treatment for ≥30 consecutive days), was compared between treatment groups using multivariate Cox proportional hazards. Patients were followed until first treatment discontinuation or up to 12 months after the initiation of the index treatment, whichever occurred first. RESULTS: Among children and adolescents, LDX patients had a significantly lower discontinuation rate compared to other treatment groups (range hazard ratios [HRs]; 1.04-2.26; all p < 0.05), except when compared to treatment-naïve patients on ATX and OROS MPH, where no statistically significant differences were found and where LDX had a higher risk of discontinuation, respectively. Among adults, LDX patients had a significantly lower discontinuation rate compared to patients in other treatment groups (range HR; 1.14-1.86; all p < 0.05), except for the comparison with AMPH LA patients, where differences were not statistically significant. LIMITATIONS: This study did not control for ADHD severity. CONCLUSION: LDX-treated patients were associated with higher persistence compared to patients initiated on other ADHD medications, except for the comparisons with OROS MPH and ATX treated patients in treatment-naïve children and adolescents and AMPH LA-treated patients in adults.

Comparison of therapy augmentation and deviation rates from the recommended once-daily dosing regimen between LDX and commonly prescribed long-acting stimulants for the treatment of ADHD in youth and adults.

OBJECTIVE: To compare therapy augmentation and deviation rates from the recommended once-daily dosing regimen in Attention Deficit Hyperactivity Disorder (ADHD) patients initiated on lisdexamfetamine (LDX) vs other once-daily Food and Drug Administration (FDA) approved stimulants. METHODS: ADHD patients initiated on a long-acting ADHD stimulant medication (index medication) in/after 2007 were selected from a large U.S. administrative claims database. Patients were required to be persistent for ≥90 days and continuously enrolled in their healthcare plan for ≥12 months following treatment initiation date. Based on age and previous treatment status, patients were classified into treatment-naïve children and adolescents (6-17 years old), previously treated children and adolescents, treatment-naïve adults (≥18 years old), and previously treated adults. Furthermore, patients were classified into four mutually exclusive treatment groups, based on index medication: lisdexamfetamine (LDX), osmotic release methylphenidate hydrochloride long-acting (OROS MPH), other methylphenidate/dexmethylphenidate long-acting (MPH LA), and amphetamine/dextroamphetamine long-acting (AMPH LA). The average daily consumption was measured as the quantity of index medication supplied in the 12-month study period divided by the total number of days of supply. Therapy augmentation was defined as the use of another ADHD medication concomitantly with the index medication for ≥28 consecutive days. Therapy augmentation and deviation rates from the recommended once-daily dosing regimen were compared between treatment groups using multivariate logistic regression models. RESULTS: Compared to the other treatment groups, LDX patients were less likely to augment with another ADHD medication (range odds ratios [OR]; 1.28-3.30) and to deviate from the recommended once-daily dosing regimen (range OR; 1.73-4.55), except for previously treated adult patients, where therapy augmentation differences were not statistically significant when compared to OROS MPH and MPH LA patients. LIMITATION: This study did not control for ADHD severity. CONCLUSION: Overall, compared to LDX-treated patients, patients initiated on other ADHD medications were equally or more likely to have a therapy augmentation and more likely to deviate from the recommended once-daily dosing regimen.

Psychostimulants for managing unipolar and bipolar treatment-resistant melancholic depression: a medium-term evaluation of cost benefits.

BACKGROUND: We earlier reported an open study of 50 unipolar and bipolar treatment resistant depressed patients indicating that psychostimulants may have differential superiority for the melancholic depressive sub-type. We designed an extension study to examine cost benefits of psychostimulants more closely for those only with melancholic depression. METHOD: The sample comprised patients clinically diagnosed with melancholic depression who had failed to respond to and/or experienced significant side-effects with at least two antidepressants. Data were collected for 61 unipolar and 51 bipolar II patients receiving a psyschostimulant for a mean interval of 69 weeks. Benefits and side-effects were assessed. RESULTS: Effectiveness ratings were similar across unipolar and bipolar sub-sets. Psychostimulants were judged as 'very' effective for 20% of patients and 'somewhat' effective for 50%. Forty percent judged the psychostimulant as being 'as effective' or as 'superior' to previously prescribed antidepressants, and worthy of being maintained. Significant side-effects were experienced by 40% of patients, requiring medication to be ceased in 12%. Twenty percent of the bipolar patients experienced a worsening of highs. LIMITATIONS: The study was uncontrolled and retrospective, no formal rater-completed or patient-completed interval measures of severity were completed, while diagnostic judgments about melancholic depression and bipolar disorder were clinically judged. CONCLUSIONS: This open study suggests that psychostimulants may be efficacious antidepressant options for managing unipolar and bipolar melancholia, often seemingly having very rapid onset and generally requiring only low doses, and arguing the need for controlled studies in melancholic patients.

Comparing treatment adherence of lisdexamfetamine and other medications for the treatment of attention deficit/hyperactivity disorder: a retrospective analysis.

OBJECTIVE: To assess treatment adherence in attention deficit/hyperactivity disorder (ADHD) patients initiated on Lisdexamfetamine (LDX) vs other FDA-approved stimulants and non-stimulant medications. METHODS: ADHD patients initiated on an ADHD medication (index medication) were selected from a large US administrative claims database. Based on age and previous treatment status, patients were classified into treatment-naïve children and adolescents (6-17 years old), previously treated children and adolescents, treatment-naïve adults (over 18 years old), and previously treated adults. Furthermore, based on their index medication, patients were classified into seven mutually exclusive treatment groups: LDX, atomoxetine (ATX), osmotic release methylphenidate hydrochloride long acting (OROS MPH), other methylphenidate/dexmethylphenidate long acting (MPH LA) and short acting (MPH SA), and amphetamine/dextroamphetamine short acting (AMPH SA) and long acting (AMPH LA). Treatment adherence (proportion of days covered by the index medication ≥0.8) over a 12-month period was compared across treatment groups using multivariate logistic regression models. RESULTS: In children and adolescents, LDX patients were more likely to be adherent compared to patients in each of the other treatment groups, except in treatment-naïve patients where LDX patients had a similar likelihood (p = 0.6925) and were less likely (p = 0.0004) to be adherent compared to ATX and OROS MPH patients, respectively. In adults, the LDX treatment group was also more likely to be adherent compared to each of the other treatment groups, except compared to AMPH LA, where statistically insignificant differences were observed (previously treated: p = 0.6471, treatment-naïve: p = 0.0733). LIMITATIONS: ADHD severity information was not available in the database. Accordingly, this study did not control for ADHD severity. CONCLUSION: Overall, LDX-treated patients demonstrated a better treatment adherence compared to patients initiated on other ADHD medications, except for AMPH LA in adult and OROS MPH and ATX in treatment-naïve children and adolescents.

Medical school gift restriction policies and physician prescribing of newly marketed psychotropic medications: difference-in-differences analysis.

OBJECTIVE: To examine the effect of attending a medical school with an active policy on restricting gifts from representatives of pharmaceutical and device industries on subsequent prescribing behavior. DESIGN: Difference-in-differences approach. SETTING: 14 US medical schools with an active gift restriction policy in place by 2004. PARTICIPANTS: Prescribing patterns in 2008 and 2009 of physicians attending one of the schools compared with physicians graduating from the same schools before the implementation of the policy, as well as a set of contemporary matched controls. MAIN OUTCOME MEASURE: Probability that a physician would prescribe a newly marketed medication over existing alternatives of three psychotropic classes: lisdexamfetamine among stimulants, paliperidone among antipsychotics, and desvenlafaxine among antidepressants. None of these medications represented radical breakthroughs in their respective classes. RESULTS: For two of the three medications examined, attending a medical school with an active gift restriction policy was associated with reduced prescribing of the newly marketed drug. Physicians who attended a medical school with an active conflict of interest policy were less likely to prescribe lisdexamfetamine over older stimulants (adjusted odds ratio 0.44, 95% confidence interval 0.22 to 0.88; P=0.02) and paliperidone over older antipsychotics (0.25, 0.07 to 0.85; P=0.03). A significant effect was not observed for desvenlafaxine (1.54, 0.79 to 3.03; P=0.20). Among cohorts of students who had a longer exposure to the policy or were exposed to more stringent policies, prescribing rates were further reduced. CONCLUSION: Exposure to a gift restriction policy during medical school was associated with reduced prescribing of two out of three newly introduced psychotropic medications.

Identifying patient subgroups who benefit most from a treatment: using administrative claims data to uncover treatment heterogeneity.

OBJECTIVES: To illustrate how claims data can be used to (1) develop outcome scores that predict response to a traditional treatment and (2) estimate the economic impact of individualized assignment to a newer treatment based on the outcome score. An example application is based on two treatments for attention deficit hyperactivity disorder (ADHD): osmotic-release oral system methylphenidate (OROS-MPH) and lisdexamfetamine dimesylate (LDX). METHODS: Adolescents with ADHD initiating OROS-MPH (n=6320) or LDX (n=6394) were selected from the MarketScan claims database. A model was developed for predicting risk of switching/augmentation with OROS-MPH using multiple baseline characteristics. The model was applied to an independent sample to stratify patients by their predicted risk and, within each stratum, risk of switching/augmentation and ADHD-related total costs were compared between OROS-MPH and LDX patients using inverse probability of treatment weighting. RESULTS: The prediction model resulted in substantial stratification, showing risk of switching/augmentation with OROS-MPH ranging from 11.3-42.1%. In the two strata where OROS-MPH had highest risk of switching/augmentation, LDX had significantly lower risk of switching/augmentation than OROS-MPH (by 7.0-8.2%) and lower ADHD-related annual total costs (by $264-$625 per patient). LIMITATIONS: The current study has used the risk of switching/augmentation as a proxy measure for treatment efficacy to establish the prediction model. Future research using a clinical measure for ADHD symptoms is warranted to verify the findings. CONCLUSIONS: Combining multiple patient characteristics into a predicted score for treatment outcomes with a traditional treatment can help identify subgroups of patients who benefit most from a new treatment. In this analysis, ADHD patients with a high predicted score for switching/augmentation with OROS-MPH had a lower rate of switching/augmentation with LDX. Assigning OROS-MPH and LDX treatments based on the predicted scores that are heterogeneous in a patient population may help improve clinical outcomes and the cost-effectiveness of care.

Attention-deficit hyperactivity disorder: recent advances in paediatric pharmacotherapy.

Throughout this decade, there has been significant research into pharmacotherapies for attention-deficit hyperactivity disorder (ADHD). This article considers the efficacy and safety of five of the more novel long-acting pharmacological treatments recently approved by the FDA for marketing in the US for paediatric ADHD, along with an alpha(2)-adrenoceptor agonist in preparation. Reviewed treatments include the non-stimulant atomoxetine, three novel extended-release (XR) stimulant preparations: dexmethylphenidate, lisdexamfetamine dimesylate and the methylphenidate transdermal system (TDS), and the recently approved XR alpha(2)-adrenoceptor agonist, guanfacine. Dexmethylphenidate XR is a stimulant treatment in a single isomer form, and has an efficacy and tolerability similar to two doses of immediate-release (IR) dexmethylphenidate when taken 4 hours apart, but is dosed at half of the usual d,l-methylphenidate dose. Dexmethylphenidate XR utilizes a beaded bimodal release, with 50% initially released and another 50% released 4 hours later to provide benefit lasting up to 10-12 hours. Lisdexamfetamine was the first stimulant treatment approved as a prodrug, whereby the single isomer d-amfetamine remains pharmacologically inactive until activated by cleaving the lysine. Its efficacy and tolerability are generally consistent with that of XR mixed amfetamine salts, with this activation method and more consistent absorption generally resulting in up to an 11- to 13-hour benefit. The methylphenidate TDS patch utilizes skin absorption to provide predictable and uniform delivery of methylphenidate when worn for 9 hours/day. The efficacy and tolerability of the methylphenidate TDS patch is generally consistent with that of osmotic-controlled release oral system (OROS) methylphenidate, providing benefit for about 11-12 hours. Because of their formulation, lisdexamfetamine and methylphenidate each have an onset of effect at about 2 hours after administration. An adjustable wear time for the methylphenidate TDS patch accommodates related adverse effects, but its disadvantages are frequent skin irritation and the need to remember to take the patch off. Atomoxetine is the first non-stimulant treatment approved by the FDA and employs weight-based dosing up to 1.4 mg/kg/day. Benefit is generally observed within 2-8 weeks of initiation and is considered to have a lesser therapeutic effect than that of stimulants. A recent parallel-group controlled study found that atomoxetine (up to 1.8 mg/kg/day) and OROS methylphenidate both improved ADHD symptoms, although subjects receiving OROS methylphenidate had a significantly better response. Interestingly, treatment-naive children had a similar beneficial response to atomoxetine as those receiving OROS methylphenidate. Subsequent crossover treatment revealed a subgroup of youths who did not respond well to OROS methylphenidate but did respond to atomoxetine. Also identified was a larger than expected subgroup who did not respond well to either active treatment, confirming the need to continue the pursuit of novel treatments. As of September of 2009, guanfacine in XR form is the first alpha(2)-adrenoceptor agonist to gain approval to treat ADHD, approved for the treatment of 6- to 17-year olds. A second alpha(2)-adrenoceptor agonist, clonidine, is in development as a potential XR treatment for paediatric ADHD. IR clonidine has a fast onset and short half-life, with its use historically limited by somnolence. Although early formulations did not improve inattention well, recent evidence suggests that clonidine XR may have potential use as monotherapy or in extending benefit when taken with a stimulant. Guanfacine has a more specific neuronal action and a longer action than that of clonidine. The approved dosing of guanfacine XR 1 to 4 mg daily generally provides symptom benefit lasting 8-14 hours, and up to 24 hours in some children and adolescents receiving a higher dose. Such recent developments and ongoing study of additional potential pharmacological interventions may lead to additional future treatment options for children with ADHD.

Clinical considerations for the diagnosis and treatment of ADHD in the managed care setting.

Although symptoms of attention-deficit/ hyperactivity disorder (ADHD) are certainly most visible in children, the syndrome persists into adolescence in 40% to 70% of cases and into adulthood in 50% or more of cases. Accurate recognition of the disorder is clouded by the frequent presence of psychiatric comorbidities. Contributing to these challenges, managed care providers in primary care are often inexperienced in identifying and treating ADHD in adults because of a lack of formalized training. As such, special consideration must be given to each individual age group and includes identifying common clinical presentations, characterizing the disorder and its comorbidities, applying validated rating scales as screening and treatment outcome measures, and individually assessing patients' optimal response to determine the best course of therapy. Pharmacotherapy is often initiated to target ADHD symptoms with either a stimulant medication or nonstimulants. In addition, behavioral interventions are often applied to treat comorbidities and associated impairments of ADHD.

The role of pharmacotherapy and managed care pharmacy interventions in the treatment of ADHD.

Pharmacotherapy plays a primary role in the management of attention-deficit/hyperactivity disorder (ADHD), despite the availability of effective behavioral interventions. Psychostimulants are the most commonly prescribed form of pharmacotherapy for patients with ADHD and their benefits in managed care are severalfold, leading not only to symptom resolution and improved quality of life for patients, but also reduced costs for payers and purchasers. The use of these agents requires careful consideration and management by health plan stakeholders for optimal effectiveness. Concerns regarding medication adherence, in addition to the potential for diversion and abuse of psychostimulants, highlight the importance of effective pharmacotherapy management in patients with ADHD. Initiatives promoting medication adherence, such as patient/parent education, provider follow-up, and adverse effect management, are crucial for ensuring treatment success. Once-daily, extended-release formulations of stimulants may also contribute to improving medication adherence, as may managed care pharmacy interventions such as pharmacy database monitoring.

Has NICE got it right? An international perspective considering the case of Technology Appraisal No. 98 by the National Institute for Health and Clinical Excellence (NICE).

BACKGROUND: The National Institute for Health and Clinical Excellence (NICE) has been widely recognised as setting an international standard for high-quality health technology assessments (HTAs) including economic evaluation. SCOPE: A previous critical analysis of NICE Technology Appraisal No. 98 (TA98), evaluating methylphenidate, dexamphetamine and atomoxetine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, revealed a number of issues, which must cast doubt on the robustness of the NICE approach when addressing a complex clinical decision problem. The exploration of potential underlying problems will be followed by a discussion of lessons for international healthcare policy-makers, and is intended to be an invitation to further debate and inquiry, not a presentation of definitive conclusions. SYMPTOMS: Pertaining to the technology assessment report, potential problems were identified relating to an unnecessarily narrow scope, data search and selection strategy, the distinction between efficacy and effectiveness, data synthesis across studies and clinical effect measures, and limitations of the economic model. The appraisal process moderated the asserted 'clear conclusions' of the assessment but could not compensate for some of its gaps. CONCLUSIONS: It is suggested that key issues contributing to these problems may have included a separation of clinical and economic perspectives, a highly standardised reference case analysis that was followed schematically, the absence of an effective system for quality assurance of technology assessments, and transparency deficits of the economic evaluation. Further considerations for international policy-makers looking at NICE as a potential role model for HTAs are discussed, such as institutional context, the objectives of collectively financed healthcare and related value judgments, the reliance on QALYs as a universal and comprehensive measure of health benefits, the appropriate perspective for analysis, and process-related implications.

Is NICE infallible? A qualitative study of its assessment of treatments for attention-deficit/hyperactivity disorder (ADHD).

BACKGROUND: Conclusions of the recent NICE technology appraisal of treatments for attention-deficit/hyperactivity disorder (ADHD) differ from recommendations by other Health Technology Assessment (HTA) agencies, such as the Scottish Medicines Consortium (CMS) and the Australian Pharmaceutical Benefits Advisory Committee (PBAC). NICE did not identify differences on grounds of clinical effectiveness between treatment options studied and issued technology guidance based on clinical profiles of compounds and on drug acquisition costs. The aim of the present study was to explore the robustness of NICE assessment methods when addressing a complex clinical problem such as the evaluation of ADHD treatment strategies. This robustness will be of interest to international policy-makers, given the widespread perception of NICE as a role model for the implementation of HTAs including economic evaluation. METHODS: A qualitative case study was performed to critically appraise the technology assessment report (AR) underlying NICE conclusions, including a systematic search for and analysis of relevant literature. RESULTS: The AR produced on behalf of NICE was found to exhibit a range of anomalies. Search criteria were not applied consistently, and the available clinical evidence was not used optimally; selection of clinical endpoints and clinical trials for analysis were idiosyncratic. The primary cost-effectiveness model relied on six short-term studies only, and secondary extensions combined heterogeneous study designs and different clinical endpoints. Neither the distinction between efficacy and effectiveness nor the role of treatment compliance in ADHD was addressed adequately. Long-term extensions of the model were impaired by use of inappropriate discount rates and absence of consideration of long-term sequelae associated with ADHD. CONCLUSION: A review of the literature strongly suggests that the NICE assessment of ADHD treatment strategies was incomplete and likely prone to bias. It is concluded that NICE did not adequately accommodate a complex clinical decision problem. Although the present qualitative case study of one assessment cannot, and was not designed to, invalidate the NICE approach to economic evaluation of healthcare programs, this observation may have potentially far-reaching implications for the generalizability of NICE-like approaches.

Methodological issues in undertaking independent cost-effectiveness analysis for NICE: the case of therapies for ADHD.

This paper outlines methodological challenges encountered in producing an independent economic evaluation for the National Institute for Health and Clinical Excellence (NICE) to inform its technology appraisal process. The analysis used to highlight these challenges is a recent evaluation of pharmacological treatments for attention deficit hyperactivity disorder (ADHD). The NICE reference case for economic evaluation is compared with the methods necessary to complete an evaluation given the evidence base for ADHD. The primary analysis deviated from NICE methods guidelines most noticeably in the time horizon. Identifying appropriate utility data was challenging, and the results were sensitive to the values used. Issues found in this evaluation are common to many technology appraisals. Although challenging to undertake, economic evaluation in disease areas such as ADHD has great potential to add value, making the limitations of the data explicit, combining available evidence in a systematic and transparent framework and identifying future research needs.

[Methylphenidate of retard forms in children and adolescents with ADHD - an overview]. / Methylphenidat-Retard-Präparate bei Kindern und Jugendlichen mit ADHs - eine Ubersicht.

As yet, stimulants remain the preferred means of treating attention-deficit/hyperactivity disorder (ADHD) pharmacologically. They are indicated when measures based on behavioural therapy or psychoeducation alone are not sufficient. How-ever, the period of effectiveness of immediate release stimulants is often not satisfactory. A variety of retarded forms of methylphenidate have now been developed and approved for the German market. This paper presents an overview of clinical studies on effectiveness, period of effectiveness and the profile of side effects of different forms stimulants available in Germany. In clinical practice, the new retard products represent effective alternatives. There is an advantage in administering this drug in a once-daily single dose. At the same time, the side effects that are caused by an extended period of effectiveness have to be studied in detail. A more precise adaptation to the daily obligations and needs of children and adolescents is needed. Possibly, a combination with unretareded MPH might lead to a better effect/side-effect profile.

Update on drugs for hyperactivity in childhood.

In 2001, we concluded that methylphenidate or dexamfetamine can be useful adjunctive therapy for children with severe hyperactivity in whom non-drug approaches alone have been inadequate. Since then, atomoxetine (pronounced a-toe-moks-e-teen; Strattera - Lilly) and three modified-release formulations of methylphenidate have been launched for attention deficit hyperactivity disorder (ADHD). Here we reconsider drugs for ADHD in childhood, focusing on the newer products.