O Transtorno de Déficit de Atenção / Hiperatividade (TDAH) é um transtorno psiquiátrico que causa prejuízo significativo desde a infância, mas que igualmente tem um impacto negativo na vida adulta, para aqueles indivíduos que permanecem com o transtorno. Cada vez mais, os sistemas classificatórios modernos definem os transtornos mentais a partir de dados provenientes de pesquisas bem conduzidas metodologicamente. O critério de idade de início de sintomas causando prejuízo antes dos 7 anos para o diagnóstico de TDAH, presente tanto no Manual Diagnóstico e Estatístico de Doenças Mentais – 4ª Edição (DSM-IV) quanto de uma forma modificada na Classificação Internacional de Doenças – 10ª Edição (CID-10), foi determinado por uma decisão de comitê. Estudos iniciais não têm corroborado a validade desse critério para o diagnóstico do transtorno.Objetivos Esse estudo tem por objetivo avaliar a resposta ao tratamento com metilfenidato em pacientes com TDAH com e sem o critério de idade de início dos sintomas, mas que preenchem todos os demais critérios da DSM-IV para TDAH.Métodos Foram avaliadas duas amostras clínicas independentes provenientes do Programa de TDAH da Universidade Federal do Rio Grande do Sul – PRODAH/UFRGS, sendo uma composta de 180 crianças e adolescentes (4–17 anos de idade) e a outra composta de 111 adultos (18 anos de idade ou mais). A medicação utilizada foi o metilfenidato, sendo a dose mínima de 0.30mg/kg/dia. A resposta ao tratamento foi avaliada em sujeitos sem tratamento prévio com metilfenidato, utilizando-se a Escala Swanson, Nolan e Pelham – versão IV (SNAP IV) na linha de base e depois de 1 mês de tratamento. Os dados foram coletados entre Janeiro de 2000 e Janeiro de 2006. Resultados Em ambas as amostras estudadas os sujeitos com diagnóstico de TDAH pleno não tiveram uma resposta melhor ao metilfenidato em doses ao redor de 0.50mg/kg/dia do que os sujeitos com TDAH de início tardio. Na amostra de adultos, encontrou-se uma resposta melhor ao metilfenidato para os sujeitos com TDAH de início tardio em comparação àqueles com diagnóstico pleno, mesmo após ajuste para confundidores (escore total do SNAP-IV na linha de base, tipos de TDAH) (crianças e adolescentes: F = 0.865, p = .354; adultos: F = 5.760, p = .018).Conclusão Os resultados corroboram aqueles encontrados nos demais estudos que questionam a validade deste critério de idade de início de sintomas para o diagnóstico do TDAH. Nossos resultados sugerem que os clínicos devem considerar a possibilidade do tratamento com metilfenidato para os sujeitos com TDAH de início tardio. / Introduction Attention-Deficit/Hyperactivity Disorder (ADHD) is a psychiatric disorder that causes significant impairment since childhood, but it also has a negative outcome in adulthood, for those who maintain the diagnosis. Modern classificatory systems define mental disorders based on data from well conducted investigations. The age-at-onset of impairment criterion for ADHD diagnosis is present both in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and in the International Classification of Diseases, Tenth Edition (ICD-10) in a modified format (age-of-onset of symptoms). However, it was determined by a committee decision. Initial studies have not corroborated the validity of this criterion for ADHD diagnosis. Objectives This work aims to assess response to methylphenidate treatment in ADHD patients with and without this age-at-onset criterion, but fulfilling all other DSMIV criteria for ADHD. Method Two independent clinical samples deriving from the ADHD Outpatient Clinic at the Federal University of Rio Grande do Sul – PRODAH/UFRGS were evaluated, one comprised of 180 children and adolescents (4-17 years of age), and the other comprised of 111 adults (18 years old or older). The medication used was methylphenidate in a minimum dose of 0.30 mg/kg/day. Response totreatment was assessed in drug-naive subjects for methylphenidate using the Swanson, Nolan, and Pelham Scale - version IV (SNAP-IV) at baseline and after one month of treatment. Data were collected from January 2000 to January 2006. Results In both samples, subjects with the full diagnosis did not have a better response to MPH at doses around 0.5 mg/kg/day than the late onset ADHD subjects. In the adults’ sample, we found a better response to MPH in subjects with late onset ADHD compared to those with full diagnosis, even after adjustment for confounders (baseline total score at the SNAP-IV, and ADHD types) (children and adolescents: F = 0.865; p = .354; adults: F = 5.760; p = .018). Conclusions These results corroborate those found in other studies that challenged the validity of this age-at-onset criterion for ADHD diagnoses. Our results suggest that clinicians should consider the possibility of methylphenidate treatment for subjects with late-onset ADHD.

Introdução: O Transtorno Bipolar (TB) em crianças e adolescentes é um transtorno crônico e severo que causa graves prejuízos ao desenvolvimento e crescimento emocional destes pacientes. Está associado com taxas alarmantes de suicídio, problemas escolares, engajamento em comportamentos de alto-risco, com altas taxas de recorrência e baixas taxas de recuperação. Apesar do tratamento, apresenta muitos sintomas residuais e baixa adesão à medicação devido aos efeitos colaterais, em especial o aumento de peso. Altas taxas de comorbidade com TDAH (mais de 75%) são encontradas em amostras clínicas de crianças e adolescentes com TB. Por estas razões, é fundamental estudar novas opções para o tratamento do TB em crianças e adolescentes, em especial quando em comorbidade com TDAH. Objetivos: Explorar novas opções no tratamento farmacológico do TB em crianças e adolescentes que possam apresentar eficácia e boa tolerabilidade. Neste estudo sobre tratamento farmacológico, optamos por estudar dois fármacos, topiramato e aripiprazol, utilizados no tratamento do TB em crianças e adolescentes e que não parecem estar relacionados com ganho de peso. Método: No estudo do Topiramato, dez pacientes (11-17 anos) que estavam estabilizados usando uma única medicação (estabilizador de humor ou um antipsicótico atípico) e que tinham aumentado de peso em mais de 5% foram arrolados para as 11 semanas do protocolo. A medicação usada foi trocada pelo topiramato, de forma gradual durante as primeiras quatro semanas do estudo. A escala utilizada para medir melhora dos sintomas foi a Young Mania Rating Scale (YMRS), avaliada semanalmente junto com o controle do peso. O ensaio aberto com o aripiprazol envolveu 10 crianças e adolescentes de 8 a 17 anos, com diagnóstico de TB tipos I e II em comorbidade com TDAH. Neste estudo, o aripiprazol foi utilizado por seis semanas e como medidas primárias foram usadas a Young Mania Rating Scale (YMRS), a Swanson, Nolan, and Pelham Scale- version IV (SNAP-IV), o Clinical Global Impressions- Severity (CGI-S) e o peso. Os possíveis efeitos adversos também foram controlados. O terceiro estudo foi um ensaio clínico com aripiprazol, duplo-cego, randomizado e controlado por placebo em 43 crianças e adolescentes com diagnóstico de TB tipo I e II em comorbidade com TDAH. Foram utilizadas como medidas primárias as escalas YMRS, SNAP-IV e o peso. A Child Mania Rating Scale- Parent version (CMRS-P), a CGI-S, a Child Depression Rating Scale- Reviewed (CDRS-R) e a Kutcher Adolescent Depression Scale (KADS) foram utilizadas como medidas secundárias. Testes laboratoriais e controle dos efeitos colaterais foram também avaliados. Resultados: No estudo aberto de manutenção durante o uso de Topiramato, houve uma redução significativa nos escores da YMRS (p<0,01) e no peso (p<0,01) no estudo aberto de manutenção. No segundo estudo houve um significativo aumento nos escores do funcionamento global (F=3.17, P=.01, tamanho de efeito=0.55), sintomas maníacos (F=5.63, P<.01; ES=0.93), e nos sintomas de TDAH (t=3.42, P<.01; ES=1.05). Embora uma boa tolerabilidade tenha sido encontrada, um significativo aumento de peso (F=3.07, P=.05) foi observado. No terceiro estudo, o aripiprazol apresentou uma significativa redução nos escores da YMRS comparado com o placebo (27,22 versus 19,52; p=0,02; tamanho de efeito=0,80), além de significativa taxa de resposta e remissão dos sintomas de mania (resposta- 88,9% versus 52%, p=0,02; NNT= 2,70; remissão 72% versus 32%, p=0,01; NNT= 2,50); não houve melhora nos escores da SNAP-IV em relação ao placebo. Não houve diferença significativa no peso entre o grupo do aripiprazol e do placebo (p=0,42). Apenas dois pacientes abandonaram o estudo, um usando placebo e outro usando aripiprazol. Não houve diferença significativa nos eventos adversos entre os dois grupos. Conclusão - Existem poucos estudos sobre tratamento de manutenção em crianças e adolescentes bipolares. Os resultados encontrados no estudo com o Topiramato sugerem que ele possa ser usado na fase de manutenção do TB juvenil, promovendo estabilização e redução de peso. No estudo aberto com o aripiprazol observamos significativa melhora nos sintomas maníacos, nos sintomas do TDAH e no funcionamento global, fortalecendo a evidência para o uso desta nova opção no tratamento farmacológico do TB juvenil. Estes achados também sugerem o uso do aripiprazol para a comorbidade TB e TDAH. Entretanto, foi observado ganho de peso ao contrário dos estudos anteriores. No estudo duplo cego, randomizado com aripiprazol comparado com placebo o resultado significativo na melhora dos sintomas do TB tanto nas medidas primárias como nas medidas secundárias, confirma os resultados do estudo aberto inicial e abre uma nova possibilidade para o tratamento destes pacientes, baseada na mais alta qualidade de critérios para a avaliação da eficácia de medicações. Além disso, não houve diferença significativa entre o peso dos pacientes que utilizaram o aripiprazol e os que utilizaram placebo. O uso de outros instrumentos neste estudo, como o SNAP-IV para a avaliação dos sintomas de TDAH, a Youth Quality of Life (YQOL-R) e a Kutcher Adolescent Depression Scale (KADS), cujos resultados serão avaliados em futuras publicações poderão desenvolver um algoritmo mais efetivo para a avaliação e tratamento da comorbidade entre TB juvenil e TDAH. Os resultados satisfatórios obtidos com estes estudos, o desenvolvimento de novos artigos para publicação destes outros resultados não contemplados nesta tese e a criação de um programa especializado (PROCAB) pode permitir a geração de novos conhecimentos nesta área. / Introduction: Bipolar Disorder in children and adolescents is a chronic and severe disorder, with high recurrence and low recovery rates, which causes significant impairment to emotional development. It is associated to alarming suicide rates, school, family, and social problems, and high-risk behaviors. In spite of the treatment, patients present many residual symptoms, and low adherence to treatment due to adverse events, especially weight gain. High comorbidity rates with Attention-Deficit /Hyperactivity Disorder (ADHD - over 75%) are found in clinical samples of children and adolescents with BD. For these reasons, it is fundamental studying new options for the treatment of BD and BD comorbid with ADHD in children and adolescents. Objectives: Explore new psychopharmacological agents which may present good tolerability and safety in the treatment of BD in children and adolescents. In this study about psyhopharmacological treatment, we decided to study two drugs, topiramate and aripiprazole, which are used in the treatment of children and adolescents with BD, and are not associated to weight gain. Methods: In the trial with topiramate, 10 patients (11-17 years-old) were consecutively allocated. They had been euthymic using a single mood antimanic agent or an atypical antipsychotic, but presented weight gain (more than 5% of their baseline weight). They were enrolled in an 11-week open protocol. Their previous medication was switched gradually to topiramate along the first four weeks of the study. Symptom change was assessed weekly using the Young Mania Rating Scale (YMRS), and weight was also assessed weekly. The aripiprazole open trial enrolled 10 children and adolescents from 8 to 17 years-old, with BD I or II comorbid with ADHD. In this study, aripiprazole was used during six weeks. Primary outcome measures were the YMRS, the Swanson, Nolan, and Pelham Scale- version IV (SNAP-IV) – for ADHD symptoms, the Clinical Global Impressions - Severity (CGIS), and weight. Possible adverse events related to aripiprazole use were monitored. The third study was a double-blind, placebo controlled, randomized clinical trial of aripiprazole in 43 children and adolescents with BD I or II and comorbid ADHD. The primary outcome measures used were the YMRS, SNAP-IV, and weight. The secondary outcome measures were the Child Mania Rating Scale - Parent version (CMRS-P), the CGI-S, the Child Depression Rating Scale - revised (CDRS-R), and the Kutcher Adolescent Depression Scale (KADS). Lab tests and adverse events were also monitored. Results: During the use of topiramate, there was a significant reduction in YMRS scores (p<0.01), and in weight (p<0,01). In the second trial, significant improvement in global functioning scores (F=3.17, P=.01, effect size=0.55), manic symptoms (F=5.63, P<.01; ES=0.93), and ADHD symptoms (t=3.42, P<.01; ES=1.05) were detected. Although an overall positive tolerability was reported, significant weight gain (F=3.07, P=.05) was observed. In the third study, aripiprazole presented a significant reduction in YMRS scores compared to placebo (p=0,02; effect size =0,80), and significant differences in rates of response and remission (Response: 88,9% versus 52%, p=0,02; NNT= 2,70; Remission: 72% versus 32%, p=0,01; NNT= 2,50); there was also a significant reduction in the CMRS-P, (p=0,02, effect size 0,54) and in the CGI-Severity (p=0,04, effect size 0,28). No differences between aripiprazole and placebo groups were observed in ADHD symptoms (p=0,4) and weight change (p=0,42). Only two patients discontinued the trial, one using placebo, and the other in the aripiprazole group. There were no significant differences in adverse events count between groups. Conclusion - There are few studies about the maintenance treatment in children and adolescents with BD. The results of the trial with topiramate suggest it may be used in the maintenance phase of JBD, promoting stabilization and weight reduction. In the aripiprazole open trial, we observed significant improvement in manic symptoms, ADHD, and global functioning, strengthening the evidence for the use of this new option in the pharmacological treatment of juvenile BD. These findings also and suggest the use of aripiprazole for comorbid BD and ADHD. However, weight gain was observed, oppositely to prior studies. The double-blind, placebo-controlled, randomized clinical aripiprazole trial, a study that fullfills A level criteria in terms of scientific evidence, opens a new possibility for the treatment of these patients, based on the highest quality of criteria for the assessment of efficacy of the drugs. The use of other instruments in this trial, like the SNAP- IV for the assessment of ADHD symptoms, the Youth Quality of Life (YQOL-R), and the Kutcher Adolescent Depression Scale, whose results will be evaluated and 19 published later, may allow us to develop a more effective algorithm for the assessment and treatment of the comorbidity between BD and ADHD, and the depressive symptoms of BD. The satisfactory results obtained with these studies, the development of new articles for the publication of these other results not approached in the thesis, and the creation of a specialized program (PROCAB) will enable the generation of new knowledge in this area.

O consumo lícito e ilícito de derivados anfetamínicos tem aumentado significativamente nos últimos anos, acentuando a necessidade de métodos analíticos adequados para a determinação dessas substâncias pelos laboratórios de toxicologia forense. Este trabalho teve como objetivo o desenvolvimento de métodos cromatográficos para a análise simultânea de anfepramona (DEP), femproporex (FEM), metilfenidato (MPH), 4-bromo-2,5-dimetoxi-anfetamina (DOB) e 4-bromo-2,5-dimetoxi-fenetilamina (2-CB) em amostras não-biológicas. Foram desenvolvidos métodos de detecção por cromatografia a gás com detector de ionização de chama (CG/DIC), de confirmação por cromatografia a gás com detector de espectrometria de massas (CG/EM) e de detecção e quantificação por cromatografia líquida de alta eficiência com detector ultravioleta (CLAE/UV). Os derivados anfetamínicos estudados foram identificados e quantificados simultaneamente através do método CLAE/UV utilizando uma coluna C-18, comprimento de onda 206 nm e modo isocrático. DEP, FEM, MPH e DOB foram detectados simultaneamente por CG/DIC e CG/EM utilizando colunas capilares, sem derivatização e com um tempo de corrida inferior a 10 minutos. Os métodos desenvolvidos foram validados através da avaliação dos parâmetros de linearidade, especificidade, precisão, exatidão, limite de detecção, limite de quantificação e robustez. Os métodos desenvolvidos são de fácil execução, rápidos e adequados para a utilização na rotina laboratorial. / The consumption of both licit and illicit amphetamine derivatives has grown increasingly in recent years, emphasizing the need for analytical methods suitable for identification and quantification of these substances by forensic toxicology laboratories. This aim of this work was to develop and validate methods for the simultaneous chromatographic analysis of amfepramone (diethylpropione, DEP), fenproporex (FEM), methylphenidate (MPH), 4-bromo-2,5-dimethoxyamphetamine (DOB), and 4-bromo-2,5 dimethoxyphenetylamine (2-CB) in non-biological samples. Methods of detection by gas chromatography with flame ionization detector, (GC/FID), confirmation by gas chromatography with mass spectrometry detection (GC/MS), and detection and quantification by high performance liquid chromatography with ultraviolet detection (HPLC/UV) were developed. The amphetamine derivatives studied were identified and quantified simultaneously by HPLC/UV using a RP-C18, 206 nm wavelength and isocratic conditions. DEP, FEM, MPH and DOB were detected both by GC/FID and GC/MS using capillary columns, without derivatization and running times lower than 10 minutes. The validation parameters accessed were linearity, specificity, precision, accuracy, limit of detection, limit of quantification and robustness. The developed methods are easy to implement, fast and suitable for use in routine laboratory analysis.

O Transtorno de Déficit de Atenção/Hiperatividade (TDAH) em adultos é comum e clinicamente relevante. É tratado principalmente através de estimulantes como o metilfenidato. Embora eficaz, há muita heterogeneidade na resposta ao metilfenidato. O objetivo deste estudo foi avaliar preditores da resposta e da remissão do transtorno após o uso de metilfenidato de liberação imediata por um curto período em uma amostra de adultos com TDAH (n=250). Os desfechos foram analisados através da variação na gravidade avaliada a partir dos escores de desatenção, hiperatividade/impulsividade e totais na escala SNAP-IV adaptada para adultos. Em um primeiro estudo, tendo como desfecho a variação quantitativa da gravidade destes sintomas, observou-se que o único fator associado a uma melhor resposta foram escores basais mais elevados nas subescalas e nos escores totais da SNAP-IV. Análises adicionais em uma subamostra (n=62) revelaram que a estabilização prévia das comorbidades não modificou o desfecho. Esta análise adicional também sugeriu que o fenômeno da regressão à média não parece ser relevante na explicação dos achados. No segundo estudo, que avaliou a remissão do TDAH de maneira categórica, três fatores mostraram-se significativamente associados a uma maior frequência de remissão: uma menor gravidade basal do transtorno, a condição de casado e a ausência do uso de outros psicofármacos no início do tratamento com metilfenidato. O conjunto de resultados sugere que, embora pacientes com elevados escores de gravidade apresentem boa resposta ao metilfenidato, eles também tem maior dificuldade em atingir a remissão propriamente dita, a qual é o objetivo maior do tratamento. / Attention Deficit/Hyperactivity Disorder (ADHD) in adults is common and clinically relevant. It is treated with stimulants such as methylphenidate. Although effective, there is high heterogeneity in the response to methylphenidate in these patients. The objective of this study was to evaluate, in a sample of adults with ADHD (n=250), predictors of response and remission after using immediate-release methylphenidate for a short period of time. Outcomes were analysed through the variation in severity scores of the SNAP-IV scale that was adapted to adults. Inattention and hyperactivity/impulsivity subscales and the total ADHD scores were evaluated. In a first study, the response to methylphenidate was analysed as a quantitative trait. We found that the only factors associated with a better response were higher baseline scores on the SNAP-IV subscales and total scores. Secondary analyses on a subsample of these patients (n=62) revealed that prior stabilization for other comorbidities did not change the results These additional analyses also suggested that the phenomenon of regression to the mean does not seem to be relevant in explaining the findings. In the second study, where ADHD remission was evaluated categorically, three factors were shown to significantly improve outcome: a lower baseline severity of the disorder, marital status, and the lack of use of other psychotropic drugs at initiation of treatment with methylphenidate. These sets of results suggests that although patients with high severity scores show better response to methylphenidate, they also have greater difficulty achieving remission itself, which is the primary goal of treatment. / El Trastorno de Déficit de Atención/Hiperactividad (TDAH) en adultos es común y clínicamente relevante. Se trata principalmente con los estimulantes como el metilfenidato, el medicamento más estudiado en adultos con TDAH. Aunque es muy eficaz, hay mucha heterogeneidad en la respuesta al metilfenidato en el TDAH en adultos. El objetivo principal de este estudio fue evaluar los predictores de respuesta y remisión de metilfenidato de liberación inmediata después de su uso durante un corto período en una muestra de adultos con TDAH (n=250). Los resultados se analizaron mediante la variación de la gravedad evaluada por marcadores de déficit de atención, hiperactividad/ impulsividad y la escala total de SNAP- IV adaptada para adultos. En un primer estudio, como fin de la variación cuantitativa se encontró que el único factor asociado con una mejor respuesta fueron las puntuaciones de referencia más altas en las subescalas de la SNAP- IV. Análisis adicionales revelaron que la estabilización previa para otras comorbilidades (n=62) no cambió el resultado. Este análisis adicional también sugirió que el fenómeno de regresión a la media no parece ser relevante para explicar los hallazgos. En el segundo estudio, que evaluó la remisión de TDAH categóricamente, tres factores fueron significativos: la menor severidad basal de la enfermedad, la condición del casado y la ausencia de uso de otras drogas psicotrópicas en el inicio del tratamiento con metilfenidato. El conjunto de los resultados sugiere que aunque los pacientes con puntuaciones de alta severidad muestran buena respuesta al metilfenidato, también tienen mayor dificultad para lograr remisión completa, que es el objetivo principal del tratamiento

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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.

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.