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Introduction: Patients with autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) show more symptoms of ADHD. Since there are more adverse events caused by psychostimulants compared to non-psychostimulants, the use of a non-psychostimulant such as atomoxetine might prove more beneficial for younger patients and/or those with comorbid ADHD. Objective: The aim of this thesis is to determine the efficacy and tolerability of atomoxetine in ASD patients presenting with ADHD, by examining (a) differences in ADHD symptoms for participants receiving atomoxetine versus those receiving placebos, and (b) risk differences in adverse events between these participants. Methods: An electronic search of both PubMed.gov and ClinicalTrials.gov were conducted. To be deemed eligible, studies had to (a) be randomized, double-blind, placebo-controlled trials comparing atomoxetine with a placebo, (b) administer atomoxetine for at least 1 week, and (c) include data on either ADHD outcomes or adverse events. Effect sizes for ADHD outcomes were calculated using Cohen's d, whereas risk differences were calculated for adverse events. For each of these two meta-analyses, effect sizes were aggregated across studies using a random effects method. Results: Overall ADHD outcomes were better for participants who received atomoxetine than for participants who received placebo, =0.297. Participants who received atomoxetine also demonstrated better outcomes in terms of attention and hyperactivity-impulsivity symptoms, =0.345 and 0.393, respectively. Though there were more adverse events for patients taking atomoxetine than placebo, the results were not statistically significant. Discussion: This thesis extends the findings of previous meta-analyses of pharmacological treatments for ASD and ADHD, while addressing the concerns raised in the critique of existing meta-analyses presented in this thesis, e.g., limited studies, length of treatment weeks, and dichotomization of data. It provides evidence that atomoxetine improves ADHD symptoms, with an overall frequency of adverse events that did not sufficiently differ from placebo beyond chance.

Effects of pharmacotherapies for Attention Deficit/Hyperactivity Disorder (ADHD) on cocaine abuse liability in ADHD are not understood. Spontaneously Hypertensive Rats (SHR), an ADHD model, exhibited greater cocaine self-administration than control Wistar-Kyoto and Wistar rats. Methylphenidate, but not atomoxetine during adolescence enhanced cocaine self-administration in adult SHRs compared to controls. The mesocortical dopaminergic system, including medial prefrontal (mPFC) and orbitofrontal (OFC) cortices, is important for ADHD and cocaine addiction. Dopamine and norepinephrine transporter (DAT and NET) are molecular targets for methylphenidate, atomoxetine and cocaine action. In the current studies, SHR, Wistar-Kyoto and Wistar were administered methylphenidate (1.5 mg/kg/day, p.o.), atomoxetine (0.3 mg/kg/day, i.p.) or vehicle during adolescence (postnatal day 28-55). During adulthood (>77 days), DAT and NET functions in mPFC and OFC were determined as neurochemical mechanisms and locomotor sensitization to cocaine, and impulsivity under differential reinforcement of low rates 30-second (DRL30) schedule were evaluated as behavioral mechanisms associated with greater cocaine self-administration in methylphenidate-treated SHRs. Maximal velocity of [3H]dopamine uptake (Vmax) by DAT and DAT cellular distribution in mPFC and OFC did not differ between vehicle-control, adult SHR, Wistar-Kyoto and Wistar. Methylphenidate increased DAT Vmax, but not cell-surface expression, in SHR mPFC. In contrast, atomoxetine decreased Vmax and cell-surface expression in SHR OFC. Compared to control strains, norepinephrine uptake by NET in the OFC was increased in vehicle-administered SHR; methylphenidate during adolescence normalized NET function in SHR OFC. Locomotor sensitization was greater in SHR compared to control, and was not altered by methylphenidate. Under DRL30, methylphenidate increased burst responses in adult SHR compared to vehicle control as well as methylphenidate-treated Wistar-Kyoto and Wistar, indicating increased impulsivity. Increased OFC NET function, increased impulsivity and cocaine sensitivity may be the neurobehavioral mechanisms associated with the increased cocaine self-administration in SHR. Increased mPFC DAT function may underlie the enhanced impulsivity and cocaine self-administration in SHR administered methylphenidate during adolescence. Decreased OFC DAT function from atomoxetine-treated SHR may explain the reduced cocaine self-administration relative to methylphenidate. Thus, methylphenidate during adolescence in ADHD may increase risk for cocaine abuse, while atomoxetine may represent a therapeutic alternative for at-risk adolescents with ADHD.

The general aim of this study was to investigate the prescribing patterns of products that contain methylphenidate or atomoxetine in a section of the private health care sector of South Africa. A quantitative, retrospective drug uitilisation review was performed according to data obtained from the database of a South African medicine claims pharmacy benefit management company's for three consecutive study years (Le. 2005 to 2007). The results indicated that a total of 7,990 patients had been prescribed products that contained methylphenidate or atomoxetine in 2005. The total for 2006 was 8,575 and it decreased to a total of 7,828 in 2007. Of all the patients who received the mentioned products, the percentage for females increased from 27.75% (N = 7,990) in 2005 to 29.06% (N =7,828) in 2007. With regard to the same products the percentage for males decreased from 72.03% (N = 7,990) in 2005 to 70.89% (N = 7,828) in 2007. The ratio for the gender-related prescribing patterns of medicine items that contained methylphenidate or atomoxetine in this section of the private health care sector of South Africa was ± 2.55:1 for males to females in comparison with the international male:female ratio of 3:1. According to the medicine claims on the database for 2005 the total number of prescriptions that indicated products containing methylphenidate or atomoxetine was calculated as 8,522, 798 (i.e. N = 8, 522,798) or as a percentage of 0.32% prescriptions. The percentage showed an increase to 0.41 % in 2007 (N = 8,015,538). Of all the medicine items containing methylphenidate or atomoxetine those products that contained atomoxetine represented 4.69% and those that contained methylphenidate represented 95.31%. In 2005 the average cost per prescription that indicated items containing methylphenidate or atomoxetine amounted to R318.29 ± R162.09. In 2007 the amount increased to R358.91 ± R208.10. The percentage of children younger than five years of age, and who had been prescribed products containing methylphenidate or atomoxetine, increased from 0.91 % in 2005 (N = 7,990) to 1.11 % in 2007 (N =7,828). The percentage for children aged 5 to 12 years decreased from 53.62% in 2005 to 49.23% in 2007. For adolescents the percentage increased from 26.32% in 2005 to 27.35% in 2007. The same pattern repeated itself in the case of adults (age 18+ years). Among the top trade name products prescribed were Ritalin LA 20mg®, Ritalin 20mg®, Concerta 36mg®, Ritalin LA 30mg® and Concerta 18mg®. Possible drug-drug interactions were found between products containing methylphenidate or atomoxetine and products containing imipramine, amitriptyline and carbamazepine. Findings indicated that the number of products containing methylphenidate or atomoxetine increased from 2005 to 2007, while also revealing that those products containing methylphenidate remained in the majority. The average costs of products containing methylphenidate or atomoxetine increased from 2005 to 2007. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2010.

The general aim of this study was to investigate the prescribing patterns of products that contain methylphenidate or atomoxetine in a section of the private health care sector of South Africa. A quantitative, retrospective drug uitilisation review was performed according to data obtained from the database of a South African medicine claims pharmacy benefit management company's for three consecutive study years (Le. 2005 to 2007). The results indicated that a total of 7,990 patients had been prescribed products that contained methylphenidate or atomoxetine in 2005. The total for 2006 was 8,575 and it decreased to a total of 7,828 in 2007. Of all the patients who received the mentioned products, the percentage for females increased from 27.75% (N = 7,990) in 2005 to 29.06% (N =7,828) in 2007. With regard to the same products the percentage for males decreased from 72.03% (N = 7,990) in 2005 to 70.89% (N = 7,828) in 2007. The ratio for the gender-related prescribing patterns of medicine items that contained methylphenidate or atomoxetine in this section of the private health care sector of South Africa was ± 2.55:1 for males to females in comparison with the international male:female ratio of 3:1. According to the medicine claims on the database for 2005 the total number of prescriptions that indicated products containing methylphenidate or atomoxetine was calculated as 8,522, 798 (i.e. N = 8, 522,798) or as a percentage of 0.32% prescriptions. The percentage showed an increase to 0.41 % in 2007 (N = 8,015,538). Of all the medicine items containing methylphenidate or atomoxetine those products that contained atomoxetine represented 4.69% and those that contained methylphenidate represented 95.31%. In 2005 the average cost per prescription that indicated items containing methylphenidate or atomoxetine amounted to R318.29 ± R162.09. In 2007 the amount increased to R358.91 ± R208.10. The percentage of children younger than five years of age, and who had been prescribed products containing methylphenidate or atomoxetine, increased from 0.91 % in 2005 (N = 7,990) to 1.11 % in 2007 (N =7,828). The percentage for children aged 5 to 12 years decreased from 53.62% in 2005 to 49.23% in 2007. For adolescents the percentage increased from 26.32% in 2005 to 27.35% in 2007. The same pattern repeated itself in the case of adults (age 18+ years). Among the top trade name products prescribed were Ritalin LA 20mg®, Ritalin 20mg®, Concerta 36mg®, Ritalin LA 30mg® and Concerta 18mg®. Possible drug-drug interactions were found between products containing methylphenidate or atomoxetine and products containing imipramine, amitriptyline and carbamazepine. Findings indicated that the number of products containing methylphenidate or atomoxetine increased from 2005 to 2007, while also revealing that those products containing methylphenidate remained in the majority. The average costs of products containing methylphenidate or atomoxetine increased from 2005 to 2007. / Thesis (M.Pharm. (Pharmacy Practice))--North-West University, Potchefstroom Campus, 2010.

Attention Deficit/Hyperactivity Disorder (ADHD) was originally thought to occur only in children, but is increasingly recognised as causing functional impairment also in adulthood. The overall aim of this thesis was to achieve a comprehensive understanding of ADHD in adulthood. A questionnaire based on the DSM-IV criteria of ADHD, reported childhood symptoms, reading and spelling problems, difficulties and suffering and general assessment of functioning (GAF) was distributed to three samples: the general population (GP), outpatient psychiatry (OPP) and female prison inmates. Symptoms consistent with ADHD were more than three times higher in the OPP sample than in the GP sample (6.6 versus 2.1%). ADHD symptoms and related problems occurred in 50% of the prison inmates. A cohort of 168 patients diagnosed with ADHD in adulthood was interviewed about current ADHD symptoms and psychiatric comorbidity on axis I and II. The lifetime prevalence of psychiatric comorbidity on axis I was 92% and current comorbidity, including autism spectrum disorders and Tourette’s syndrome, was 47%. The sex-specific pattern of the comorbid disor-ders was similar to that in the general population. Forty-six per cent of the patients endorsed the specific criteria for at least one personality disorder. After a mean follow-up of six years, there was remission of adult ADHD in about 30% of the patients, regardless of whether there was ongoing medication or not. There were no differences in function and quality of life, except for global general improvement, which was better in patients currently on medication. The most prevalent long-term side effects of pharmacological treatment with mainly stimulants were decreased appetite, dry mouth, anxiousness/restlessness and an increase in pulse frequency. The discontinuation rate was about 50%: 29% discontinued because of a perceived lack of effect, followed by elevated mood or hypomania (11%). No detectable evidence of tolerance and increased need for dosage over time was observed. To conclude, Symptoms of ADHD is highly overrepresented in OPP and in female inmates compared with the GP. Furthermore, adults diagnosed with ADHD have a high lifetime prevalence of psychiatric comorbidity. Long-term pharmacological treatment with stimulants is safe with relatively mild and tolerable adverse effects. Continued medication, however, is not related to remission.

L'impulsivité, un trait multidimensionnel, détermine la sévérité d'affections comportant des désordres compulsifs (syndrome de Gilles de la Tourette, maladie de Parkinson, troubles obsessionnels compulsifs), mais la nature de la relation impulsivité / compulsivité reste méconnue. L'intérêt du présent travail est d'identifier les substrats neurobiologiques de la balance impulsivité / compulsivité, dans une approche transnosographique, en s'aidant au plan préclinique, de manipulations causales et au plan clinique, d'une approche corrélationnelle. Ainsi, nous démontrons pour la première fois en dehors du champ de l'addiction, non seulement que l'impulsivité motrice, endophénotype de vulnérabilité à la compulsivité, prédit, sous l'influence de la transmission noradrénergique, la transition vers la compulsivité, mais aussi que (dans le modèle de la maladie de Parkinson) la dénervation de la voie nigrostriée et les traitements substitutifs dopaminergiques amplifient l'état impulsif. D'où l'interaction complexe entre le trait impulsif, les traitements et le processus dégénératif. Enfin, nous démontrons le bénéfice thérapeutique de la stimulation de la portion antérieure du pallidum interne dans les formes sévères de tics et suggérons dans un modèle préclinique d'une grande valeur heuristique, que le trait impulsif prédit l'efficacité de la stimulation du core du noyau accumbens. Nos résultats démontrent l'intérêt de mieux caractériser le trait impulsif des patients présentant des désordres compulsifs (syndrome de Gilles de la Tourette, maladie de Parkinson) et ouvrent ainsi de nouvelles perspectives thérapeutiques, tant pour la prévention de la transition de l'impulsivité à la compulsivité, que dans le traitement de ceux-ci. / Impulsivity, a multidimensional trait, determines the severity of compulsive disorders (Tourette's syndrome, Parkinson's disease, obsessive compulsive disorders), but the impulsive / compulsive relation remains unclear. The aim of this work is to identify the neurobiological substrates of impulsive / compulsive balance, using causal manipulations in rats and correlational studies in patients. The results demonstrate - for the first time beside the field of addiction - that, not only high impulsive trait is a transnosological endophenotype of increased vulnerability to develop compulsive disorders, but also that the transition from impulsivity toward compulsivity depends upon the noradrenergic transmission. Furthermore, we also show that, in a Parkinson's disease preclinical model, both the nigrostriatal denervation and dopaminergic treatments increase impulsive state, thereby indicating the contribution of a complex interaction between impulsive trait, medications and neurodegenerative process to the impulsive/compulsive balance. Finally, we show the therapeutic benefit of anterior globus pallidus interna in severe forms of tics and suggest in a preclinical model, with great heuristic value, that impulsive trait predicts the efficacy of nucleus accumbens core stimulation. Together, our results demonstrate the need to address the impulsive/compulsive balance in compulsive disorders and show promise for developing new pathophysiological-based therapeutic strategies that will treat both impulsivity and compulsivity.

ADHD pharmacotherapy uses methylphenidate (MPH), D-amphetamine (D- amph), two psychostimulants targeting dopamine transporters, or atomoxetine (ATX), specifically targeting norepinephrine transporters. We have assessed the pharmacological mechanisms of these three drugs on the in vitro efflux of neurotransmitters in rat prefrontal cortex (PFC) and striatal slices as well as on the in vivo electrical activities of PFC pyramidal neurons, striatal medium spiny neurons, ventral tegmental area dopamine neurons or dorsal raphe nucleus serotonin neurons, using single cell extracellular electrophysiological recording techniques. We have also tested whether chronic methylphenidate treatment, during either adolescence or adulthood, could have long-lasting consequences on body growth, depression and neuronal functions. Release experiments showed that all ADHD drugs induce dose-dependent dopamine efflux in both the PFC and striatum, with different efficacies, while only D- amph induced cortical norepinephrine efflux. Atomoxetine induced an unexpected massive dopamine outflow in striatal regions, by mechanisms that depend on physiological parameters. Our electrophysiological studies indicate that all three drugs equally stimulate the excitability of PFC pyramidal neurons, in basal and NMDA-evoked conditions, when administered acutely (3 mg/kg). While the electrophysiological effects elicited by psychostimulants may be dependent on D1 receptor activation, those induced by atomoxetine relied on different mechanisms. In the ventral tegmental area (VTA), methylphenidate (2 mg/kg), but not atomoxetine, induced firing and burst activity reductions, through dopamine D2 autoreceptor activation. Reversal of such effects (eticlopride 0.2 mg/kg) revealed an excitatory effect of methylphenidate on midbrain dopamine neurons that appear to be dependent on glutamate pathways and the combination of D1 and alpha-1 receptors. Finally, acute intraperitoneal psychostimulant injections increased vertical locomotor activity as well as NMDA2B protein expression in the striatum. Some animals chronically treated with intraperitoneal administrations (methylphenidate 4 mg/kg/day or saline 1.2 ml/kg/day) showed decreased body weight gain. Voluntary oral methylphenidate intake induces desensitisation to subsequent intravenous methylphenidate challenges, without altering dopamine D2 receptor plasticity. Significant decreases in striatal NMDA2B protein expression were observed in animals chronically treated. After adolescent MPH treatment, midbrain dopaminergic neurons do not display either desensitisation or sensitisation to intravenous methylphenidate re-challenges. However, partial dopamine D2 receptor desensitisation was observed in midbrain dopamine neurons. Using behavioural experiments, cross-sensitisation between adolescent methylphenidate exposure and later-life D-amphetamine challenge was observed. Significant decreases in striatal NMDA2B protein expression were observed in animals chronically treated, while striatal medium spiny neurons showed decreased sensitivities to locally applied NMDA and dopamine. While caffeine is devoid of action on baseline spike generation and burst activity of dopamine neurons, nicotine induces either firing rate enhancement, firing rate reduction, or has no consequences. Adolescent methylphenidate treatment leads to decreased neuronal sensitivities to the combination of nicotine, MPH and eticlopride, compared to controls. Finally, nicotine partially prevented D-amphetamine-induced increase of rearing activities. Our results show that increases in the excitability of PFC neurons in basal conditions and via NMDA receptor activation may be involved in the therapeutic response to ADHD drugs. Long-term consequences were observed after psychostimulant exposure. Such novel findings strengthen the mixed hypothesis in ADHD, whereby both dopamine and glutamate neurotransmissions are dysregulated. Therefore, ADHD therapy may now focus on adequate balancing between glutamate and dopamine.

L'attention est une fonction au cœur de la cognition qui, à tout moment, nous permet de sélectionner les informations pertinentes à traiter, tout en ignorant les autres. Cette sélection de l’information qui s’opère à la fois dans l'espace et dans le temps résulte de l’intégration des informations sensorielles et d’un contrôle de "haut niveau" en fonction de nos buts. Cette fonction dépend d’un réseau cérébral incluant le système fronto-pariétal et est sous l’influence de différents neuromodulateurs, en particulier la noradrénaline, dont l’action reste encore mal connue. Mon travail de thèse consistait à comprendre le rôle de la noradrénaline sur les processus attentionnels. Mes objectifs étaient d’une part de vérifier notre hypothèse selon laquelle la noradrénaline modulerait les différentes facettes de l’attention (attention spatiale et attention soutenue) et d’autre part d’élucider les mécanismes d’action par lesquelles la noradrénaline exercerait ces effets. Pour répondre à ces questions, nous avons testé l’impact d’une augmentation de la transmission noradrénergique (administration intramusculaire d'atomoxétine) chez le singe, dans des tâches comportementales nécessitant une sélection de l’information visuelle soit dans l’espace (tâche d'attention avec indice et exploration spontanée d'images) soit au cours du temps (tâche de discrimination go/nogo). Nos résultats démontrent que l’atomoxétine facilite les processus attentionnels à la fois dans l’espace et au cours du temps. Dans l’espace, l’atomoxétine module l’orientation de l’attention visuo-spatiale en fonction du contexte, en ajustant le taux d’accumulation sensorielle ou l’impact de la saillance des images sur l’orientation de l’attention. Au cours du temps, l’atomoxétine ajuste la relation entre la sensibilité à discriminer la cible parmi des distracteurs et le biais de réponse des animaux. En résumé, mes résultats démontrent que la noradrénaline influence les deux facettes, spatiale et temporelle de l’attention et suggèrent une action via un ajustement des processus de traitement de l’information sensorielle et un ajustement du contrôle de l’attention au contexte / Attention is a function at the heart of cognition that, at any given moment, enables us to select some information for further processing, while setting aside others. This selection of information that operates both in space and time, results from the integration of sensory information and higher-level control according to our goals. This function depends on a cerebral network including the fronto-parietal system. It is also under the influence of different neuromodulators, in particular norepinephrine, the action of which is still poorly understood.The aim of my PhD work was to understand the role of norepinephrine on attentional processes. My objectives were, on the one hand, to test our hypothesis that norepinephrine is capable of acting on the different facets of attention (spatial attention and sustained attention) and, on the other hand, to elucidate the mechanisms of action by which noradrenaline exerts its action. To answer these questions, we tested the impact of an increase in noradrenergic transmission (intramuscular administration of atomoxetine) in monkeys, using behavioral tasks requiring a selection of visual information in space (cued attentional task and spontaneous image exploration) or over time (go/nogo discrimination task). Our results demonstrate that atomoxetine facilitates attentional processes both in space and over time. In space, atomoxetine modulates the orientation of visuospatial attention according to the context, adjusting the rate of sensory accumulation or the impact of image saliency on attention orientation. Over time, atomoxetine adjusts the relationship between the sensitivity to discriminate a target among distractors and the animal’s response bias.In summary, my results demonstrate that norepinephrine influences both the spatial and temporal facets of attention and suggests an action through an adjustment of sensory information processing and an adjustment of attention control to the context