Introdução O Transtorno de Déficit de Atenção/hiperatividade (TDAH) tem sido muito estudado, mas informações econômicas referentes ao seu tratamento com o metilfenidato de liberação imediata (MFD-LI) ainda necessitam ser exploradas. Grande parte da população mundial, principalmente aqueles que vivem em países em desenvolvimento, utiliza essa formulação como principal escolha para o tratamento do TDAH. Esses países, por sua condição financeira, necessitam informações de análises econômicas para administrar de forma eficiente os recursos públicos destinados aos setores da saúde. Objetivos Avaliar a eficácia do MFD-LI através de estudos com tempo superior a 12 semanas, e realizar uma análise econômica para o tratamento do TDAH com MFD-LI para crianças e adolescentes brasileiros. Método O estudo foi planejado em cinco etapas: 1) estimativa de custo do não tratamento do TDAH para o Brasil, e estimativa de economia com tratamento com MFD-LI; 2) revisão sistemática da literatura nas principais bases de dados internacionais onde se buscaram estudos abertos com tratamento do TDAH com MFD-LI por tempo igual ou superior a 12 semanas; também foram feitas metanálises e uma metaregressão 3) estudo naturalístico para obterem-se dados de uma amostra brasileira referentes a probabilidades de uso e sucesso com tratamento com MFD-LI por 12 semanas, e estimar os utilities desses indivíduos; 4) painel Delphi com especialistas em TDAH no Brasil; 5) estudo de custo-efetividade para o tratamento do TDAH com MFD-LI no Brasil, utilizando um Modelo de Markov. A perspectiva adotada será a do sistema público de saúde brasileiro como pagador. Resultados Os resultados principais encontrados para cada uma das etapas foram: 1) a estimativa de custos anuais com o TDAH não tratado no Brasil foi de R$ 1.594 bilhões/ano, e da quantia que poderia ser economizada se tratado, R$ 1 bilhão/ano. 2) na revisão sistemática da literatura, de 4.498 resumos, sete foram incluídos para compor a metanálise. O tempo de tratamento variou entre 13 e 104 semanas. O efeito agregado para desatenção e hiperatividade medida pelos pais, respectivamente, foi 0.96 (95%CI 0.60 - 1.32) e 1.12 (95%CI 0.85 - 1.39), e pelos professores 0.98 (95%CI 0.09 - 1.86) e 1.25 (95% CI 0.7 - 1.81). A metaregressão não mostrou associação entre as variáveis idade, qualidade do artigo e tempo de tratamento com heterogeneidade. 3) no estudo naturalístico, de 171 pacientes avaliados, 73 forneceram informações para o baseline, e 56 para a 12a semana de tratamento com MFD-LI. Os utilities para um paciente com TDAH não tratado (baseline) foram 0.69 (crianças) e 0.66 (adolescentes), e estimaram-se ganhos entre 0.09 a 0.10 utilities/mês, se tratados adequadamente. 4) no painel Delphi, de 26 especialistas, 14 responderam o questionário online, e foi estimado que a probabilidade dos pacientes não tratados se manterem sintomáticos na 12a semana seria de 91%, e 9% a probabilidade de melhora espontânea; 5) no estudo de custo-efetividade, para o caso base, estimou-se que o Incremental Cost Effectiveness Ratio (ICER) seja I$9,103/QALY (Quality Adjusted Life Years) para crianças e I$11,883/QALY para adolescentes em um horizonte temporal de 06 anos. Para os cenários mais desfavoráveis, os ICERS mais elevados foram I$95,164/QALY para 50% de sucesso com o tratamento, e I$15,000/QALY para 70% de adesão em um horizonte temporal de 06 anos. Conclusões O MFD-LI é um tratamento eficaz para crianças e adolescentes, por um período superior a 12 semanas. Entretanto, o Brasil pode estar aumentando os custos referentes à saúde por não estar fornecendo um tratamento eficaz e economicamente acessível para o TDAH. O tratamento mostrou ser uma opção custo-efetiva para crianças e adolescentes brasileiros, mesmo em cenários desfavoráveis para o tratamento. / Introduction Attention-Deficit/Hyperactivity Disorder (ADHD) is a well-known psychiatric disorder, but some economical aspects of the treatment with Methylphenidate Immediate-release (MPH -IR) still need to be explored. A large number of people around the world, most living in Low-Middle Income Countries (LMIC), use this formulation as the first choice for ADHD treatment. These countries, due to their financial condition, need information from health economic analyzes to efficiently manage the public resources allocated to the health sector. Objective To study the efficacy of MPH-IR reviewing studies conducted for more than 12 weeks long, and to perform an economic analysis for the treatment of ADHD with MPH-IR for Brazilian children. Method The study was planned in a five stages process: 1) to estimate the cost of untreated ADHD for Brazil, and to estimate the savings if MPH-IR were adequately provided; 2) systematic review of the literature to identify papers published where young patients with ADHD were treated with MPH-IR for more than 12 weeks, and to perform a meta-analysis and a meta-regression; 3) to conduct a naturalistic study with a Brazilian sample to collect the probabilities of use and success with the MPH-IR treatment for 12 weeks, and to estimate the utilities; 4) to perform a Delphi panel with ADHD Brazilian experts; 5) to conduct a cost-effectiveness analysis for the treatment of ADHD with MPH-IR in Brazil, using a Markov model. The perspective is the one of the Brazilian public health system as the payer. Results The main findings for each step were: 1) the estimated annual expenditures with untreated ADHD in Brazil were R$1.594billon/year, and the estimated amount that could be saved was R$1billion/year; 2) in the systematic review, from 4,498 abstracts, 7 studies were selected. The length of treatment ranged from 13 to 104 weeks. The aggregate effects for inattention and hyperactivity, according to parents evaluations were respectively 0.96 (95%CI 0.60 - 1.32) and 1.12 (95%CI 0.85 - 1.39), and for teachers 0.98 (95%CI 0.09 - 1.86) e 1.25 (95% CI 0.7 - 1.81). There was no evidence of association between heterogeneity and the variables, age, paper quality and length of treatment; 3) in the naturalistic study, from 171 patients assessed, 73 provided information in the baseline, and 56 in the 12th week of MPH-IR treatment. Utilities for an untreated ADHD patient (baseline) were 0.69 (children) and 0.66 (adolescents), and it was estimated a gain ranging from 0.09 to 0.10 utilities/month if subjects were properly treated; 4) in the Delphi Panel, 26 experts were addressed and 14 filled in the online questionnaire. It was estimated the probability of untreated patients to remain symptomatic on the 12th week to be 91%, and the probability of spontaneous improvement, 9%; 5) in the cost-effectiveness analysis, for the base case, it was estimated an Incremental Cost Effectiveness Ratio (ICER) of I$9,103/QALY (Quality Adjusted Life Years) for children and I$11,883/QALY for adolescents, in a time horizon of 6 years. The worst case scenarios were also tested, and the highest ICER were I$95,164/QALY when patient reached 50 % of success with the treatment, and I$15,000/QALY if only 70% of use was observed in a time horizon of 6 years. Conclusions MPH-IR is an efficacious treatment for ADHD children and adolescents for periods longer than 12 weeks. However, Brazil may be probably wasting money due to not provide an efficient and affordable treatment for ADHD such as the MPH-IR. The treatment proved to be cost-effective for children and adolescents living in Brazil, even when the worst case scenarios were tested.

Objetivo. Avaliar a função aritmética em crianças com Transtorno do Déficit de Atenção / Hiperatividade (TDAH) e determinar se o tratamento com psicoestimulante afeta seu desempenho (braço clínico), além de verificar o padrão de ativação neural em um subgrupo desta amostra durante tarefas de cálculos aritméticos (braço neuroimagem). Métodos. Quarenta e duas crianças (de 9 a 12 anos) participaram do braço clínico: 20 com TDAH segundo os critérios do DSM-IV e 22 controles. Estas crianças foram classificados com ou sem dificuldades aritméticas com base em seu desempenho em três testes aritméticos utilizados no Brasil. Todos os participantes do braço clínico foram avaliados em dois momentos: tempo 1 e no tempo 2 quando as crianças com TDAH estavam em uso de metilfenidato (MTF) a uma dose de 0,3-0,5 mg/kg. Foi avaliado o desempenho global em aritmética e, especificamente, exploramos a subtração nos dois tempos. Foram também estudadas 10 crianças com TDAH (seis das quais participaram do braço clínico) que participaram com uso de metilfenidato e 10 crianças saudáveis (oito das quais participaram do braço clínico) que realizaram exame de ressonância magnética funcional (RMf) em duas tarefas (cálculos exatos e aproximados ) utilizando paradigma com desenho em bloco em aparelho de 3.0 Teslas. Resultados. O grupo TDAH, quando não medicado (tempo 1) cometeu mais erros aritméticos que os controles (p < 0,001). No entanto, quando em uso de MTF, o grupo TDAH (tempo 2) fez significativamente menos erros quando comparado com a sua linha de base (tempo 1) e quando comparados aos seus controles (tempo 2). Em exercícios de subtração que requerem procedimentos de empréstimos (subtração complexo), o grupo de TDAH (tempo 1) cometeu mais erros do que nos controles, melhorando significativamente quando em uso da medicação (p = 0,039). Em relação à RMf não houve diferenças específicas entre os grupos em cada tarefa isoladamente. Entretanto, houve interação entre o tipo de cálculo (aproximado vs. exato) e grupo (controle vs. TDAH): as crianças com TDAH mostraram atividade diferente do grupo controle na região do cíngulo posterior e pré-cúneo, considerando as duas formas de cálculo. Conclusões. O uso de vários testes aritméticos validados permite uma avaliação abrangente e eficaz de crianças em risco de dificuldades de aprendizagem. Assim, fomos capazes de mostrar que o nosso grupo de crianças com TDAH tinha dificuldades aritméticas significativas, mas o tratamento com MTF trouxe melhoras substanciais. A melhora observada foi no desempenho geral e, especificamente, para o desempenho em subtração complexa. Esta melhora pode ter sido devido ao aumento de habilidades de memória de trabalho, gerando menos erros involuntários. Em relação aos resultados de RMf mostramos um resultado ainda não descrito na literatura: a alteração na região posterior do giro do cíngulo e pré-cúneo que possivelmente se deve a alteração funcional intrínseca do TDAH na vigência de medicação com metilfenidato, uma área que já foi descrita na literatura sobre TDAH porém não nessa condição / Objective. To evaluate arithmetic function in children with Attention Deficit Hyperactivity Disorder (ADHD) and to determine whether stimulant treatment affects their performance (clinical arm), besides verifying the patterns of neural activation on a subgroup from this sample during trials testing arithmetical calculation (neuroimaging arm). Methods. Forty-two kids (from 9 to 12 years old) took part in the clinical arm: 20 with ADHD diagnosed according DSM-IV criteria and 22 from control group. These children were classified with or without arithmetic difficulties based on their performance on three arithmetic tests used in Brazil. All participants from the clinical arm were evaluated at 2 time points: time 1 and time 2 when ADHD children were on methylphenidate (MPH) at a dose of 0,3/0,5 mg/kg. Global performance in arithmetic, and specifically, subtraction in these two times was explored. We also evaluate 10 ADHD children (6 of these from the clinical arm) on MPH and 10 healthy control children (8 of these from the clinical arm) using fMRI (Functional Magnetic Resonance Imaging) during two trials testing approximate and exact arithmetical calculation using a block design paradigm in a 3.0 Teslas device. Results. The ADHD group, when unmedicated (time 1) made more arithmetic errors than controls (p < 0,001). However, when on MPH, ADHD group (time 2) made significantly fewer errors when compared to their baseline (time 1) and when compared to their controls (time 2). On subtraction exercises that require borrowing procedures (complex subtraction), the ADHD group (time 1) committed more errors than controls, while significantly improvement in the medicated state (p = 0,039). Regarding the fMRI there was no specific difference between groups on each task isolated. However, there was an interaction between the type of calculation (approximate vs. exact) and group (control vs. ADHD): children with ADHD showed different activity from the control group in the posterior cingulate and precuneus, considering both forms of calculation. Conclusions. The use of multiple validated arithmetic tests enables a comprehensive and effective assessment of children at a risk for learning difficulties. Thus, the study was able to show that the ADHD group had significant arithmetic difficulties; on the other side MPH treatment brought substantial improvement. This mentioned improvement was observed in general development, and specifically on complex subtraction performance, what could have been caused by the increase of working memory skills, generating less involuntary errors. Regarding the fMRI, it brought up results not yet described by literature: the alterations of the posterior cingulate gyrus and precuneus what is possibly due to the intrinsic functional alteration of ADHD on MPH, an area that has already been described by ADHD literature nevertheless not on under this condition

The Amphetamine Years is a history of psychostimulant drugs and their clinical applications in post-World War II American medicine. Comprising such well-known substances as the amphetamines (Benzedrine, Dexedrine), methylphenidate (Ritalin), and phenmetrazine (Preludin), this class of pharmaceuticals has been among the most widely consumed in the past half-century. Their therapeutic uses for a variety of indications such as depression, obesity, and attention-deficit/hyperactivity disorder (ADHD) in children, not to mention their relevance for a number of different medical specialties, reveals that psychostimulants have occupied an important, if underappreciated role in the practice of modern medicine. In this dissertation, I illuminate the various ways in which physicians, particularly psychiatrists, put these drugs to work in clinical practice. In short, I contend that physicians exploited the wide range of physiological and psychological effects of psychostimulants and made a place for them in different therapeutic settings, even ones characterized by competing views and theories about the workings of the human body and mind. My dissertation is distinguished by two prominent themes. First, I emphasize the clinician perspective as a vehicle for understanding the history of the psychostimulants, as well as related developments in psychiatry, pharmacotherapy, and the political economy of drugs, in the second half of the twentieth century. Scholars such Nicolas Rasmussen, David Courtwright, and Ilina Singh have elucidated the history of psychostimulants by emphasizing how pharmaceutical companies positioned their products in the medical marketplace. My dissertation takes a different, yet complimentary approach by studying clinicians, themselves, to further historical comprehension of the place of these pharmaceuticals within postwar medicine, society, and culture. Second, I advance the concept of "therapeutic versatility" to explain their historical trajectories. The complex set of psychological and physical effects these drugs produced made them ideal for a diverse range of therapeutic applications, which explains why they were embraced by many different medical specialties, why they were marketed by manufacturers for a variety of indications, and why they have enjoyed an enduring therapeutic lifespan, in spite of increasing efforts since the mid-1960s to regulate their availability and control their consumption. In addition to these two overarching themes, I advance five specific arguments in my dissertation. First, I contend that pharmaceutical markets were simultaneously created by the drug industry and clinicians. Pharmaceutical firms' efforts to develop markets for their products have been well documented by historians, but in my dissertation, I underscore the role also played by clinicians in discerning drugs' applications. Second, I argue that twentieth-century psychiatry's conception of illness and therapeutics may not be served best by strictly dividing its history along lines of institutional and outpatient treatment. Third, I demonstrate how the use of psychostimulants by analytically oriented psychiatrists during the 1950s complicates historical notions of paradigm shift from a psychodynamic to biological orientation. Psychotherapy and psychopharmacology were not competing paradigms; in practice, doctors often employed both. Fourth, I assert that an appreciation of psychiatrists' empirical and eclectic approaches to the use of drugs is necessary to comprehend the rise of psychiatric pharmacotherapy in the postwar era. Finally, I contend that in order to understand the relationship between medical applications of psychostimulants and their extramedical consumption, it is necessary to conceive of a plurality of distinct "amphetamine cultures," each characterized by a unique set of relationships between physician-prescribers, patient-consumers, pharmaceutical firms, and political authorities.

Succédant à une théorisation centrée sur le rôle des déficits des fonctions exécutives, les modèles contemporains du trouble déficit de l'attention / hyperactivité (TDAH) mettent en avant l’hétérogénéité d’une catégorie diagnostique impliquant des déficits neuropsychologiques, voies cérébrales et mécanismes étiopathogéniques multiples. En dépit de cette évolution, la majorité des études d'imagerie cérébrale des corrélats structurels du trouble menées à ce jour ont été conduites au niveau de la catégorie diagnostique, sans spécification supplémentaire. Cette approche comparant en moyenne un groupe de patients avec TDAH à un groupe de sujets sains a donné des résultats très variables d'une étude à l'autre, la comparaison inter-étude étant toutefois rendue difficile par la présence de facteurs confondants, tels que des différences en terme de régions d’intérêt examinées, de comorbidités acceptées chez les patients, de pourcentages de sujets masculins et féminins, de fenêtre d’âge sélectionnée, de méthodologie d'analyse ou encore de pourcentage de patients traités par méthylphénidate. Dans ce doctorat, nous nous sommes appuyés sur la morphométrie voxel-à-voxel pour isoler l’influence sur les volumes de matière grise de deux facteurs d’hétérogénéité intra-catégorielle dans le TDAH : le genre d’une part, et un polymorphisme génétique (Val158Met du gène Catéchol-O-méthyltransferase (COMT)) d’autre part ; ces deux facteurs présentant l’intérêt de moduler le risque associé de développer un trouble de type externalisé. Nous avons également comparé les volumes de matière grise d’enfants avec TDAH ayant reçu un traitement par méthylphénidate, de patients n'ayant jamais été exposé à la médication, et de sujet sains. Ces recherches expérimentales ont été inscrites dans une discussion plus générale de l’hétérogénéité des résultats de la littérature structurelle consacrée au TDAH et des sources neuropsychologiques de cette hétérogénéité. Dans notre étude des effets du genre sur les volumes de matière grise dans le TDAH, nous reportons pour la première fois une interaction entre genre et diagnostic, avec des corrélats structurels du trouble différents chez les garçons et les filles avec TDAH dans des régions de la ligne médiane du cerveau, impliquées à la fois dans la régulation émotionnelle et dans le fonctionnement du mode de réseau par défaut. Nous suggérons que ces différences structurelles pourraient contribuer aux différences de risque associé pour les troubles internalisés et externalisés présentées par les garçons et filles avec TDAH. Dans notre étude explorant l'influence du polymorphisme Val158Met sur les volumes de matière grise, nous mettons en évidence une modulation génétique des corrélats structurels du trouble : les sujets homozygotes pour l'allèle Val158, identifiés dans la littérature comme à risque pour le développement d'un trouble des conduites, présentent des volumes de matière grise supérieurs dans le noyau caudé comparativement aux sujets sains, tandis que les patients avec TDAH porteurs d'un allèle Met158 présentent des volumes de matière grise plus faibles dans le cortex préfrontal inférieur droit, une région cruciale pour les processus de contrôle attentionnel. Enfin, dans notre étude des corrélats structurels de l'exposition au méthylphénidate, nous reportons un effet potentiellement normalisateur du traitement sur les volumes de matière grise de l'insula et du pole temporal, des volumes de matière grise plus faibles chez les patients traités comparativement aux sujets sains dans le gyrus frontal moyen et dans le gyrus précentral, et une association entre volume de matière grise dans le nucleus accumbens gauche et durée d'exposition au méthylphénidate chez les sujets traités. (...) / Previous models of Attention Deficit / Hyperactivity Disorder (ADHD) such as Barkley’s or Brown’s conceptualized ADHD as essentially a developmental impairment of executive function. Against this view, it is now recognized that ADHD is a heterogeneous disorder, involving multiple deficits and multiple neuronal pathways. Despite this current theoretical framework, most structural brain imaging studies in ADHD have compared groups of children with ADHD with typically developing children, without trying to identify subgroups within the diagnostic category. This approach has yielded heterogeneous findings, possibly due to inter-studies variations in the type and number of comorbidities, the percentage of medicated participants included, the number of girls included, and/or methodological and statistical differences. Patients participating in these studies were also often exposed to methylphenidate, and potential medication effects on grey matter volumes are still unclear in certain brain regions such as the frontal lobe, despite a therapeutic action involving the preferential activation of catecholamine neurotransmission within the prefrontal cortex. In this thesis, we used voxel-based morphometry to study the influence of two important risk factors for the development of comorbid conditions in ADHD. The first of these two factors was gender, and the second a genetic polymorphism of the Catechol-O-methyltransferase gene known to put children with ADHD at risk for developing a conduct disorder (Val158Met). We also compared grey matter volumes in children with ADHD exposed to methylphenidate, never-medicated children with ADHD and typically developing children. These experimental studies were part of a more general discussion of ADHD neuropsychological and neurobiological heterogeneity. In our study exploring the influence of gender on the structural correlates of ADHD, we report for the first time a gender-by-diagnosis interaction, with grey matter volume differences in boys and girls with ADHD in midline cortical structures, involved in emotional regulation and part of the default mode network. We propose that these differences may contribute to explain why girls with ADHD more often develop inattentive and internalizing symptoms, whereas externalizing symptoms are predominant in boys with ADHD. In our study investigating the effects of Val158Met in ADHD, we report the first evidence of a COMT-related genetic modulation of ADHD-related grey matter volume alterations. Indeed, children with ADHD at higher risk for developing a conduct disorder (children homozygotes for the Val158 allele) presented increased grey matter volumes in the caudate nucleus when compared with typically developing children, whereas children carrying a Met158 allele presented with decreased grey matter volumes in the right inferior frontal cortex, a region known for its key role in attention. Finally, we measured grey matter volumes in medicated children with ADHD, never-medicated children with ADHD and typically developing children using both whole-brain voxel-based morphometry and automated tracing procedures in chosen regions of interest. We document potential methylphenidate-related grey matter volume normalization and deviation in previously unexplored frontal and temporal regions, and report a positive association between treatment history and grey matter volume in the nucleus accumbens, a key region for reward processing. Our first two experimental studies therefore contribute to a better understanding of the influence of important sources of within-category heterogeneity, while the third helps clarifying the potential confounding effect of medication exposure in previous structural brain imaging studies in ADHD.

L’émergence de l’utilisation du méthylphénidate (MPH; Ritalin) par des étudiants universitaires afin d’améliorer leur concentration et leurs performances universitaires suscite l’intérêt du public et soulève d’importants débats éthiques auprès des spécialistes. Les différentes perspectives sur l’amélioration des performances cognitives représentent une dimension importante des défis sociaux et éthiques autour d’un tel phénomène et méritent d’être élucidées. Ce mémoire vise à examiner les discours présents dans les reportages internationaux de presse populaire, les discours en bioéthique et en en santé publique sur le thème de l’utilisation non médicale du méthylphénidate. Cette recherche a permis d’identifier et d’analyser des « lacunes » dans les perspectives éthiques, sociales et scientifiques de l’utilisation non médicale du méthylphénidate pour accroître la performance cognitive d’individus en santé. Une analyse systématique du contenu des discours sur l’utilisation non médicale du méthylphénidate pour accroître la performance cognitive a identifié des paradigmes divergents employés pour décrire l’utilisation non médicale du méthylphénidate et discuter ses conséquences éthiques. Les paradigmes « choix de mode de vie », « abus de médicament » et « amélioration de la cognition » sont présents dans les discours de la presse populaire, de la bioéthique et de la santé publique respectivement. Parmi les principales différences entre ces paradigmes, on retrouve : la description de l’utilisation non médicale d’agents neuropharmacologiques pour l’amélioration des performances, les risques et bénéfices qui y sont associés, la discussion d’enjeux éthiques et sociaux et des stratégies de prévention et les défis associés à l’augmentation de la prévalence de ce phénomène. La divergence de ces paradigmes reflète le pluralisme des perceptions de l’utilisation non médicale d’agents neuropharmacologiques Nos résultats suggèrent la nécessité de débats autour de l’amélioration neuropharmacologique afin de poursuivre l’identification des enjeux et de développer des approches de santé publique cohérentes. / The non-medical use of neuropharmaceuticals has sparked ethical debates. For example, there is mounting evidence that methylphenidate (MPH; Ritalin) is being used by healthy university students to improve concentration, alertness, and academic performance, a phenomenon known as cognitive enhancement. The different perspectives on the ethics of cognitive enhancement represent an important dimension of the social and ethical challenges related to such practices but have yet to be examined thoroughly. This thesis aimed to assess existing positive and negative reports in international print media, bioethics literature, and public health literature on the use of MPH to identify and analyze gaps in the ethical, social, and scientific perspectives about the non-medical use of MPH for cognitive enhancement in healthy individuals. A systematic content analysis of discourses on the non-medical use of methylphenidate for cognitive enhancement identified divergent frameworks employed to describe the non-medical use of methylphenidate and discuss its ethical implications: The frameworks of “lifestyle choice”, “prescription drug abuse” and “cognitive enhancement” are present in print media, bioethics, and public health discourses respectively. Important differences between frameworks include the description of the non-medical use of neuropharmaceuticals for cognitive enhancement, associated risks and benefits, discussion of ethical and social issues surrounding the phenomenon and the prevention strategies and challenges to the widespread use of neuropharmaceuticals for cognitive enhancement. Diverging frameworks reflect pluralism in perceptions if the non-medical use of neuropharmaceuticals for cognitive enhancement. At this time, unacknowledged pluralism and implicit assumptions about cognitive enhancement may impede public health interventions and ethics discussions.

No description available.

Introdução O Transtorno de Déficit de Atenção/hiperatividade (TDAH) tem sido muito estudado, mas informações econômicas referentes ao seu tratamento com o metilfenidato de liberação imediata (MFD-LI) ainda necessitam ser exploradas. Grande parte da população mundial, principalmente aqueles que vivem em países em desenvolvimento, utiliza essa formulação como principal escolha para o tratamento do TDAH. Esses países, por sua condição financeira, necessitam informações de análises econômicas para administrar de forma eficiente os recursos públicos destinados aos setores da saúde. Objetivos Avaliar a eficácia do MFD-LI através de estudos com tempo superior a 12 semanas, e realizar uma análise econômica para o tratamento do TDAH com MFD-LI para crianças e adolescentes brasileiros. Método O estudo foi planejado em cinco etapas: 1) estimativa de custo do não tratamento do TDAH para o Brasil, e estimativa de economia com tratamento com MFD-LI; 2) revisão sistemática da literatura nas principais bases de dados internacionais onde se buscaram estudos abertos com tratamento do TDAH com MFD-LI por tempo igual ou superior a 12 semanas; também foram feitas metanálises e uma metaregressão 3) estudo naturalístico para obterem-se dados de uma amostra brasileira referentes a probabilidades de uso e sucesso com tratamento com MFD-LI por 12 semanas, e estimar os utilities desses indivíduos; 4) painel Delphi com especialistas em TDAH no Brasil; 5) estudo de custo-efetividade para o tratamento do TDAH com MFD-LI no Brasil, utilizando um Modelo de Markov. A perspectiva adotada será a do sistema público de saúde brasileiro como pagador. Resultados Os resultados principais encontrados para cada uma das etapas foram: 1) a estimativa de custos anuais com o TDAH não tratado no Brasil foi de R$ 1.594 bilhões/ano, e da quantia que poderia ser economizada se tratado, R$ 1 bilhão/ano. 2) na revisão sistemática da literatura, de 4.498 resumos, sete foram incluídos para compor a metanálise. O tempo de tratamento variou entre 13 e 104 semanas. O efeito agregado para desatenção e hiperatividade medida pelos pais, respectivamente, foi 0.96 (95%CI 0.60 - 1.32) e 1.12 (95%CI 0.85 - 1.39), e pelos professores 0.98 (95%CI 0.09 - 1.86) e 1.25 (95% CI 0.7 - 1.81). A metaregressão não mostrou associação entre as variáveis idade, qualidade do artigo e tempo de tratamento com heterogeneidade. 3) no estudo naturalístico, de 171 pacientes avaliados, 73 forneceram informações para o baseline, e 56 para a 12a semana de tratamento com MFD-LI. Os utilities para um paciente com TDAH não tratado (baseline) foram 0.69 (crianças) e 0.66 (adolescentes), e estimaram-se ganhos entre 0.09 a 0.10 utilities/mês, se tratados adequadamente. 4) no painel Delphi, de 26 especialistas, 14 responderam o questionário online, e foi estimado que a probabilidade dos pacientes não tratados se manterem sintomáticos na 12a semana seria de 91%, e 9% a probabilidade de melhora espontânea; 5) no estudo de custo-efetividade, para o caso base, estimou-se que o Incremental Cost Effectiveness Ratio (ICER) seja I$9,103/QALY (Quality Adjusted Life Years) para crianças e I$11,883/QALY para adolescentes em um horizonte temporal de 06 anos. Para os cenários mais desfavoráveis, os ICERS mais elevados foram I$95,164/QALY para 50% de sucesso com o tratamento, e I$15,000/QALY para 70% de adesão em um horizonte temporal de 06 anos. Conclusões O MFD-LI é um tratamento eficaz para crianças e adolescentes, por um período superior a 12 semanas. Entretanto, o Brasil pode estar aumentando os custos referentes à saúde por não estar fornecendo um tratamento eficaz e economicamente acessível para o TDAH. O tratamento mostrou ser uma opção custo-efetiva para crianças e adolescentes brasileiros, mesmo em cenários desfavoráveis para o tratamento. / Introduction Attention-Deficit/Hyperactivity Disorder (ADHD) is a well-known psychiatric disorder, but some economical aspects of the treatment with Methylphenidate Immediate-release (MPH -IR) still need to be explored. A large number of people around the world, most living in Low-Middle Income Countries (LMIC), use this formulation as the first choice for ADHD treatment. These countries, due to their financial condition, need information from health economic analyzes to efficiently manage the public resources allocated to the health sector. Objective To study the efficacy of MPH-IR reviewing studies conducted for more than 12 weeks long, and to perform an economic analysis for the treatment of ADHD with MPH-IR for Brazilian children. Method The study was planned in a five stages process: 1) to estimate the cost of untreated ADHD for Brazil, and to estimate the savings if MPH-IR were adequately provided; 2) systematic review of the literature to identify papers published where young patients with ADHD were treated with MPH-IR for more than 12 weeks, and to perform a meta-analysis and a meta-regression; 3) to conduct a naturalistic study with a Brazilian sample to collect the probabilities of use and success with the MPH-IR treatment for 12 weeks, and to estimate the utilities; 4) to perform a Delphi panel with ADHD Brazilian experts; 5) to conduct a cost-effectiveness analysis for the treatment of ADHD with MPH-IR in Brazil, using a Markov model. The perspective is the one of the Brazilian public health system as the payer. Results The main findings for each step were: 1) the estimated annual expenditures with untreated ADHD in Brazil were R$1.594billon/year, and the estimated amount that could be saved was R$1billion/year; 2) in the systematic review, from 4,498 abstracts, 7 studies were selected. The length of treatment ranged from 13 to 104 weeks. The aggregate effects for inattention and hyperactivity, according to parents evaluations were respectively 0.96 (95%CI 0.60 - 1.32) and 1.12 (95%CI 0.85 - 1.39), and for teachers 0.98 (95%CI 0.09 - 1.86) e 1.25 (95% CI 0.7 - 1.81). There was no evidence of association between heterogeneity and the variables, age, paper quality and length of treatment; 3) in the naturalistic study, from 171 patients assessed, 73 provided information in the baseline, and 56 in the 12th week of MPH-IR treatment. Utilities for an untreated ADHD patient (baseline) were 0.69 (children) and 0.66 (adolescents), and it was estimated a gain ranging from 0.09 to 0.10 utilities/month if subjects were properly treated; 4) in the Delphi Panel, 26 experts were addressed and 14 filled in the online questionnaire. It was estimated the probability of untreated patients to remain symptomatic on the 12th week to be 91%, and the probability of spontaneous improvement, 9%; 5) in the cost-effectiveness analysis, for the base case, it was estimated an Incremental Cost Effectiveness Ratio (ICER) of I$9,103/QALY (Quality Adjusted Life Years) for children and I$11,883/QALY for adolescents, in a time horizon of 6 years. The worst case scenarios were also tested, and the highest ICER were I$95,164/QALY when patient reached 50 % of success with the treatment, and I$15,000/QALY if only 70% of use was observed in a time horizon of 6 years. Conclusions MPH-IR is an efficacious treatment for ADHD children and adolescents for periods longer than 12 weeks. However, Brazil may be probably wasting money due to not provide an efficient and affordable treatment for ADHD such as the MPH-IR. The treatment proved to be cost-effective for children and adolescents living in Brazil, even when the worst case scenarios were tested.

Objetivo. Avaliar a função aritmética em crianças com Transtorno do Déficit de Atenção / Hiperatividade (TDAH) e determinar se o tratamento com psicoestimulante afeta seu desempenho (braço clínico), além de verificar o padrão de ativação neural em um subgrupo desta amostra durante tarefas de cálculos aritméticos (braço neuroimagem). Métodos. Quarenta e duas crianças (de 9 a 12 anos) participaram do braço clínico: 20 com TDAH segundo os critérios do DSM-IV e 22 controles. Estas crianças foram classificados com ou sem dificuldades aritméticas com base em seu desempenho em três testes aritméticos utilizados no Brasil. Todos os participantes do braço clínico foram avaliados em dois momentos: tempo 1 e no tempo 2 quando as crianças com TDAH estavam em uso de metilfenidato (MTF) a uma dose de 0,3-0,5 mg/kg. Foi avaliado o desempenho global em aritmética e, especificamente, exploramos a subtração nos dois tempos. Foram também estudadas 10 crianças com TDAH (seis das quais participaram do braço clínico) que participaram com uso de metilfenidato e 10 crianças saudáveis (oito das quais participaram do braço clínico) que realizaram exame de ressonância magnética funcional (RMf) em duas tarefas (cálculos exatos e aproximados ) utilizando paradigma com desenho em bloco em aparelho de 3.0 Teslas. Resultados. O grupo TDAH, quando não medicado (tempo 1) cometeu mais erros aritméticos que os controles (p < 0,001). No entanto, quando em uso de MTF, o grupo TDAH (tempo 2) fez significativamente menos erros quando comparado com a sua linha de base (tempo 1) e quando comparados aos seus controles (tempo 2). Em exercícios de subtração que requerem procedimentos de empréstimos (subtração complexo), o grupo de TDAH (tempo 1) cometeu mais erros do que nos controles, melhorando significativamente quando em uso da medicação (p = 0,039). Em relação à RMf não houve diferenças específicas entre os grupos em cada tarefa isoladamente. Entretanto, houve interação entre o tipo de cálculo (aproximado vs. exato) e grupo (controle vs. TDAH): as crianças com TDAH mostraram atividade diferente do grupo controle na região do cíngulo posterior e pré-cúneo, considerando as duas formas de cálculo. Conclusões. O uso de vários testes aritméticos validados permite uma avaliação abrangente e eficaz de crianças em risco de dificuldades de aprendizagem. Assim, fomos capazes de mostrar que o nosso grupo de crianças com TDAH tinha dificuldades aritméticas significativas, mas o tratamento com MTF trouxe melhoras substanciais. A melhora observada foi no desempenho geral e, especificamente, para o desempenho em subtração complexa. Esta melhora pode ter sido devido ao aumento de habilidades de memória de trabalho, gerando menos erros involuntários. Em relação aos resultados de RMf mostramos um resultado ainda não descrito na literatura: a alteração na região posterior do giro do cíngulo e pré-cúneo que possivelmente se deve a alteração funcional intrínseca do TDAH na vigência de medicação com metilfenidato, uma área que já foi descrita na literatura sobre TDAH porém não nessa condição / Objective. To evaluate arithmetic function in children with Attention Deficit Hyperactivity Disorder (ADHD) and to determine whether stimulant treatment affects their performance (clinical arm), besides verifying the patterns of neural activation on a subgroup from this sample during trials testing arithmetical calculation (neuroimaging arm). Methods. Forty-two kids (from 9 to 12 years old) took part in the clinical arm: 20 with ADHD diagnosed according DSM-IV criteria and 22 from control group. These children were classified with or without arithmetic difficulties based on their performance on three arithmetic tests used in Brazil. All participants from the clinical arm were evaluated at 2 time points: time 1 and time 2 when ADHD children were on methylphenidate (MPH) at a dose of 0,3/0,5 mg/kg. Global performance in arithmetic, and specifically, subtraction in these two times was explored. We also evaluate 10 ADHD children (6 of these from the clinical arm) on MPH and 10 healthy control children (8 of these from the clinical arm) using fMRI (Functional Magnetic Resonance Imaging) during two trials testing approximate and exact arithmetical calculation using a block design paradigm in a 3.0 Teslas device. Results. The ADHD group, when unmedicated (time 1) made more arithmetic errors than controls (p < 0,001). However, when on MPH, ADHD group (time 2) made significantly fewer errors when compared to their baseline (time 1) and when compared to their controls (time 2). On subtraction exercises that require borrowing procedures (complex subtraction), the ADHD group (time 1) committed more errors than controls, while significantly improvement in the medicated state (p = 0,039). Regarding the fMRI there was no specific difference between groups on each task isolated. However, there was an interaction between the type of calculation (approximate vs. exact) and group (control vs. ADHD): children with ADHD showed different activity from the control group in the posterior cingulate and precuneus, considering both forms of calculation. Conclusions. The use of multiple validated arithmetic tests enables a comprehensive and effective assessment of children at a risk for learning difficulties. Thus, the study was able to show that the ADHD group had significant arithmetic difficulties; on the other side MPH treatment brought substantial improvement. This mentioned improvement was observed in general development, and specifically on complex subtraction performance, what could have been caused by the increase of working memory skills, generating less involuntary errors. Regarding the fMRI, it brought up results not yet described by literature: the alterations of the posterior cingulate gyrus and precuneus what is possibly due to the intrinsic functional alteration of ADHD on MPH, an area that has already been described by ADHD literature nevertheless not on under this condition

D.Ed. / The practice regarding the diagnosing and therapeuterising, with Ritalin, of children with ADHD (Attention Deficit Hyperactivity Disorder) is inadequate. There is in general practice little, if any, signs of holistic interactive co-operation amongst practitioners regarding diagnosing and therapeuterising, with Ritalin, exceptions excluded. The practice situation reflects a rather fragmented image, unscientific practises regarding diagnostic and therapeutic instruments and procedures, ignorance and incompleteness. The rational why this study was undertaken is because of the researcher's experience of the overwhelming inadequacy of this practice. The aim of this research was to develop, validate and describe standards for the holistic interactive management of the practice of diagnosing of the child \Vith ADHD and his/her therapy, with Ritalin. These standards can contribute towards improvement of the total practice, that is improvement of aid rendering to this child in order to optimise his/her functioning accordingly. In order to reach this aim, a research method was followed whereby an intensive literature study, multiple case studies and a questionnaire survey regarding a variety of professional practitioners and parents, was introduced in order to obtain data from the practice situation. Data was continuously qualitatively analised within the parameters of a theoretically grounded conceptual framework. These analyses eventually culminated in the description of concept standards and revised concept standards which were submitted to five domain experts for validation. The final standards which were determined through a process of a reasonable high level of consensus amongst these experts, is described in two official languages, namely Afrikaans and English. The final standards reflect the need from practice, namely holistic interactive management of the procedures of diagnosis and therapy, with Ritalin, of the child with ADHD.

Indications are that autonomic under-arousal exists in children with ADHD. Published results are, however, controversial and few studies examine the relationship between the autonomic nervous system and focussed attention. In line with the indications of sympathetic under-arousal, patients with the disorder are treated with sympathomimetic stimulants such as Ritalin (methylphenidate). Since these medications stimulate the sympathetic nervous system, they possess the potential to influence cardiac function. The aims of this study were a) to assess autonomic nervous system functioning in 20 children with ADHD, as compared to controls, and to examine the effects of focussed attention and sympathomimetic medication on this system, b) to investigate cardiac functioning in 20 children with ADHD, as compared to controls, and to examine the effects of sympathomimetic medication on this system and c) to assess EEG functioning in children with ADHD, as compared to controls, and to examine the effects of sympathomimetic medication on this functioning. Children with ADHD were tested while they were stimulant-free and during a period in which they were on stimulant medication, while controls were tested once. Autonomic nervous system activity of the children was assessed at baseline and during focussed attention by means of heart rate variability (HRV) and skin conductivity. Attention was evoked by means of a program on the BioGraph Infiniti biofeedback apparatus, which is used specifically to train ADHD individuals to increase their attentive abilities. HRV was determined by time-domain, frequency-domain and Poincaré analysis of RR interval data. Skin conductivity was determined by BioGraph Infiniti biofeedback apparatus. Cardiac functioning of the children was assessed at baseline by means of blood pressure recordings and electrocardiograms (ECGs). Blood pressure was measured by means of a stethoscope and mercurial sphygmomanometer. ECGs were obtained by means of a Schiller CardioLaptop AT-110 ECG recorder using the standard 12-lead cable positioning for a resting ECG and parameters measured included HR, RR, QT, JT, QTc, JTc, QTd, JTd, QTcd and JTcd. EEG values were determined at baseline and during focussed attention by means of BioGraph Infiniti biofeedback apparatus. EEG values measured in this study included theta/beta ratios, theta/SMR ratios and thalpha, low alpha and high alpha power. The main findings of this study are that: <ul> <li>Stimulant-free ADHD children show a parasympathetic dominance of the sympathovagal balance relative to controls.</li> <li>Methylphenidate usage shifts the autonomic balance of children with ADHD towards normal levels; however a normal autonomic balance is not reached.</li> <li>Stimulant-free ADHD children exhibit a shift in the sympathovagal balance towards the sympathetic nervous system from baseline to focussed attention; however, methylphenidate abolishes this shift.</li> <li>Methylphenidate usage does not, in general, cause QTc or JTc prolongation but it may cause QTc or JTc prolongation in susceptible individuals.</li> <li>Children with ADHD can not be differentiated from normal children on the basis of theta/beta ratios, theta/SMR ratios or alpha power.</li> <li>Methylphenidate increases the level of centering in children with ADHD.</li> <li>Stimulant-free ADHD children display an alpha block from baseline to focussed attention; however, methylphenidate abolishes this alpha block.</li></ul> Copyright / Dissertation (MSc)--University of Pretoria, 2009. / Physiology / unrestricted