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Atomoxetine increases cortical levels of norepinephrine and dopamine: A proposed mechanism of action in ADHD
P.6. Other topics
$418
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Atomoxetine increases cortical levels of norepinephrine and dopamine: A proposed mechanism of action in ADHD
EP. Bymaster, D. Gehlert, D. Nelson, P. Threlkeld, S. HemrickLuecke, J. Katner, J. Heiligenstein, S.M. Morin, D.T. Wong, K. Perry. Eli Lilly and Company, Neuroscience Research
Division, Indianapolis, U.S.A. Atomoxetine (formerly called tomoxetine or LY139603) is a selective inhibitor of presynaptic norepinephrine transporters (1) and has been shown to robustly alleviate symptoms in Attention Deficit Hyperactivity Disorder (ADHD) in children (2), adolescents, and adults (3). M e t h o d s : In this study we investigated the potential mechanism of action of atomoxetine by determining its inhibition of monoamine transporter and neuronal receptor binding, blockade of monoamine transporters in vivo, effects on monoamine extracellular concentrations in brain regions using a microdialysis technique and activation of Fos expression in brain regions. Results: Atomoxetine inhibited binding of radioligands to clonal cell lines transfected with human norepinephrine, serotonin (5-HT) and dopamine transporters with Ki values of 5, 77 and 1451 nM, respectively, demonstrating the selectivity of atomoxetine for the norepinephrine transporter. Furthermore, atomoxetine did not inhibit radioligand binding to over 50 neuronal receptors and binding sites. In vivo, atomoxetine blocked depletion of hypothalamic norepinephrine by a norepinephrine transporterdependent neurotoxin (DSP-4), but not depletion of 5-HT by a 5-HT transporter-dependent neurotoxin (p-chloramphetamine), indicating norepinephrine transporter selectivity in viuo. In microdialysis studies, atomoxetine dose-dependently increased extracellular (EX) levels of norepinephrine in prefrontal cortex to 3 fold of baseline, but did not alter 5-HT-EX levels. Atomoxetine also increased dopamine-EX in prefrontal cortex equal to that of norepinephrine, consistent with cortical dopamine levels being regulated by the norepinephrine transporter. In contrast, dopamineEX was not increased by atomoxetine in the dopamine transporterrich striatum and nucleus accumbens areas. The psychostimulant methylphenidate, which is used in ADHD therapy, increased norepinephrine-EX and dopamine-EX equally in prefrontal cortex, but also increased dopamine-EX in the motoric striatum and "rewarding" region nucleus accumbens to the same level. Atomoxetine increased expression of the neuronal activity marker Fos about 3 fold in prefrontal cortex, but did not increase Fos in striatum or nucleus accumbens, consistent with the regional effect of increased extracellular dopamine. C o n c l u s i o n : We hypothesize that the increase by atomoxetine of dopamine-EX and norepinephrine-EX in prefrontal cortex, a region involved in attention and memory, mediates the therapeutic effects of atomoxetine in ADHD. However, in contrast to methylphenidate, atomoxetine did not increase dopamine in striatum and nucleus, suggesting atomoxetine would not have motoric or drug abuse liability.
[3] Spencer T, Biederman J, Wilens T, Prince J, Hatch M, Jones J, Harding M, Faraone SV, Seidman L (1998): Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 155:693-695
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Once-daily methylphenidate formulation for attention-deficit/hyperactivity disorder evaluated in the community
Background:
References [1] Wong DT, Threlkeld PG, Best KL, Bymaster FP (1982): A new inhibitor of norepinephrine uptake devoid of affinity for receptors in rat brain. J Pharmacol Exp Ther 222:61-65 [2] Michelson D, Faries D, Wernicke J, Kelsey D, Kendrick K, Sallee FR, Spencer T (2001): Atomoxetine in the treatment of children and adolescents with Attention-Deficit/HyperactivityDisorder: a randomized, placebo-controlled, dose-response study. Pediatrics 108:e83
J. N e w c o r n 1 , V. Sharma 1, M.A. Stein 2. tMount Sinai School
of Medicine, Department of Psychiatry, New York, U.S.A.; 2Children's National Medical Center, Washington DC, U.S.A. B a c k g r o u n d : Clinical studies in children with ADHD have
demonstrated that Concerta® (a once-daily dosed Oros® formulation of methylphenidate (MPH)) is significantly better than placebo in improving ADHD symptoms, and shows similar efficacy and safety to MPH tid. This study examines the use of Concerta in the community setting to evaluate: a) maintenance of improvement as determined from global outcome and satisfaction measures over 9 months, in three different groups (children, adolescents, adults); and b) whether maintenance of benefit requires increases in dose over time (also by age group). The study is complete, and a full analysis of data will be presented. We present here an interim data analysis. M e t h o d s : Subjects >/6 years and diagnosed with ADHD, were enrolled in this 9-month, multicentre, open-label study. Subjects receiving MPH for ADHD immediately prior to entry were assigned a daily morning dose of Concerta of 18, 36 or 54 mg, based on their previous dose of MPH and clinical judgement. For subjects not receiving MPH immediately prior to entry, Concerta was initiated at an 18 mg dose and titrated in 18-mg increments to a safe and effective dose not exceeding 54 rag. Global Assessments of treatment effectiveness were completed at 3, 6 and 9 months by parent/caregiver (subjects under 18 years), the adult subject (if 18 years or older) and the investigators. Adverse events and changes in Concerta dosing were recorded for the duration of the study. Results: In all, 1082 subjects (682 children [6--12 years], 263 adolescents [13-17 years], and 137 adults [~>18 years]) were included in the efficacy and safety analyses. At the interim analysis date, 240 participants (22.2%) had discontinued treatment prematurely. Overall, 84.4% (Month 3) and 91.9% (Month 6) of parents/caregivers, and 85.5% (Month 3) and 91.8% (Month 6) of investigators, rated Concerta treatment as good or excellent, using the Global Assessment. Investigator ratings of good/excellent increased from baseline in children (72.8%) and adolescents (71.9%) to Month 3 (85.2% and 88.1%, respectively). Similar changes were observed for parent/caregiver ratings. These ratings were consistent with parent/caregiver treatment satisfaction ratings taken at Month 3 (or final assessment if the subject discontinued early) showing that 84.3% (children) and 87.6% (adolescents) were 'satisfied', 'very satisfied' or 'extremely satisfied' with oncedaily Concerta. Global Assessments for adult participants were similar at baseline (84.1%), Month 3 (80.0%), and Month 6 (71.4%) and showed a good correlation with investigator assessments. Changes in Concerta dosing over time will be examined in the full analysis. Concerta was generally well tolerated. Fewer than 5% of subjects overall discontinued due to adverse events. The most common adverse events (~>5% overall) were headache (8.0%), insomnia (5.3%), and URTI (5.0%).
$418
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Atomoxetine increases cortical levels of norepinephrine and dopamine: A proposed mechanism of action in ADHD
EP. Bymaster, D. Gehlert, D. Nelson, P. Threlkeld, S. HemrickLuecke, J. Katner, J. Heiligenstein, S.M. Morin, D.T. Wong, K. Perry. Eli Lilly and Company, Neuroscience Research
Division, Indianapolis, U.S.A. Atomoxetine (formerly called tomoxetine or LY139603) is a selective inhibitor of presynaptic norepinephrine transporters (1) and has been shown to robustly alleviate symptoms in Attention Deficit Hyperactivity Disorder (ADHD) in children (2), adolescents, and adults (3). M e t h o d s : In this study we investigated the potential mechanism of action of atomoxetine by determining its inhibition of monoamine transporter and neuronal receptor binding, blockade of monoamine transporters in vivo, effects on monoamine extracellular concentrations in brain regions using a microdialysis technique and activation of Fos expression in brain regions. Results: Atomoxetine inhibited binding of radioligands to clonal cell lines transfected with human norepinephrine, serotonin (5-HT) and dopamine transporters with Ki values of 5, 77 and 1451 nM, respectively, demonstrating the selectivity of atomoxetine for the norepinephrine transporter. Furthermore, atomoxetine did not inhibit radioligand binding to over 50 neuronal receptors and binding sites. In vivo, atomoxetine blocked depletion of hypothalamic norepinephrine by a norepinephrine transporterdependent neurotoxin (DSP-4), but not depletion of 5-HT by a 5-HT transporter-dependent neurotoxin (p-chloramphetamine), indicating norepinephrine transporter selectivity in viuo. In microdialysis studies, atomoxetine dose-dependently increased extracellular (EX) levels of norepinephrine in prefrontal cortex to 3 fold of baseline, but did not alter 5-HT-EX levels. Atomoxetine also increased dopamine-EX in prefrontal cortex equal to that of norepinephrine, consistent with cortical dopamine levels being regulated by the norepinephrine transporter. In contrast, dopamineEX was not increased by atomoxetine in the dopamine transporterrich striatum and nucleus accumbens areas. The psychostimulant methylphenidate, which is used in ADHD therapy, increased norepinephrine-EX and dopamine-EX equally in prefrontal cortex, but also increased dopamine-EX in the motoric striatum and "rewarding" region nucleus accumbens to the same level. Atomoxetine increased expression of the neuronal activity marker Fos about 3 fold in prefrontal cortex, but did not increase Fos in striatum or nucleus accumbens, consistent with the regional effect of increased extracellular dopamine. C o n c l u s i o n : We hypothesize that the increase by atomoxetine of dopamine-EX and norepinephrine-EX in prefrontal cortex, a region involved in attention and memory, mediates the therapeutic effects of atomoxetine in ADHD. However, in contrast to methylphenidate, atomoxetine did not increase dopamine in striatum and nucleus, suggesting atomoxetine would not have motoric or drug abuse liability.
[3] Spencer T, Biederman J, Wilens T, Prince J, Hatch M, Jones J, Harding M, Faraone SV, Seidman L (1998): Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 155:693-695
•
Once-daily methylphenidate formulation for attention-deficit/hyperactivity disorder evaluated in the community
Background:
References [1] Wong DT, Threlkeld PG, Best KL, Bymaster FP (1982): A new inhibitor of norepinephrine uptake devoid of affinity for receptors in rat brain. J Pharmacol Exp Ther 222:61-65 [2] Michelson D, Faries D, Wernicke J, Kelsey D, Kendrick K, Sallee FR, Spencer T (2001): Atomoxetine in the treatment of children and adolescents with Attention-Deficit/HyperactivityDisorder: a randomized, placebo-controlled, dose-response study. Pediatrics 108:e83
J. N e w c o r n 1 , V. Sharma 1, M.A. Stein 2. tMount Sinai School
of Medicine, Department of Psychiatry, New York, U.S.A.; 2Children's National Medical Center, Washington DC, U.S.A. B a c k g r o u n d : Clinical studies in children with ADHD have
demonstrated that Concerta® (a once-daily dosed Oros® formulation of methylphenidate (MPH)) is significantly better than placebo in improving ADHD symptoms, and shows similar efficacy and safety to MPH tid. This study examines the use of Concerta in the community setting to evaluate: a) maintenance of improvement as determined from global outcome and satisfaction measures over 9 months, in three different groups (children, adolescents, adults); and b) whether maintenance of benefit requires increases in dose over time (also by age group). The study is complete, and a full analysis of data will be presented. We present here an interim data analysis. M e t h o d s : Subjects >/6 years and diagnosed with ADHD, were enrolled in this 9-month, multicentre, open-label study. Subjects receiving MPH for ADHD immediately prior to entry were assigned a daily morning dose of Concerta of 18, 36 or 54 mg, based on their previous dose of MPH and clinical judgement. For subjects not receiving MPH immediately prior to entry, Concerta was initiated at an 18 mg dose and titrated in 18-mg increments to a safe and effective dose not exceeding 54 rag. Global Assessments of treatment effectiveness were completed at 3, 6 and 9 months by parent/caregiver (subjects under 18 years), the adult subject (if 18 years or older) and the investigators. Adverse events and changes in Concerta dosing were recorded for the duration of the study. Results: In all, 1082 subjects (682 children [6--12 years], 263 adolescents [13-17 years], and 137 adults [~>18 years]) were included in the efficacy and safety analyses. At the interim analysis date, 240 participants (22.2%) had discontinued treatment prematurely. Overall, 84.4% (Month 3) and 91.9% (Month 6) of parents/caregivers, and 85.5% (Month 3) and 91.8% (Month 6) of investigators, rated Concerta treatment as good or excellent, using the Global Assessment. Investigator ratings of good/excellent increased from baseline in children (72.8%) and adolescents (71.9%) to Month 3 (85.2% and 88.1%, respectively). Similar changes were observed for parent/caregiver ratings. These ratings were consistent with parent/caregiver treatment satisfaction ratings taken at Month 3 (or final assessment if the subject discontinued early) showing that 84.3% (children) and 87.6% (adolescents) were 'satisfied', 'very satisfied' or 'extremely satisfied' with oncedaily Concerta. Global Assessments for adult participants were similar at baseline (84.1%), Month 3 (80.0%), and Month 6 (71.4%) and showed a good correlation with investigator assessments. Changes in Concerta dosing over time will be examined in the full analysis. Concerta was generally well tolerated. Fewer than 5% of subjects overall discontinued due to adverse events. The most common adverse events (~>5% overall) were headache (8.0%), insomnia (5.3%), and URTI (5.0%).