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P.7.c.001 Differential electrophysiological effects of atomoxetine and methylphenidate on prefrontal cortex and midbrain dopamine neurons
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P.7.d. Child and adolescent disorders and treatment − Treatment (clinical)
P.7.c. Child and adolescent disorders and treatment − Treatment (basic) P.7.c.001 Differential electrophysiological effects of atomoxetine and methylphenidate on prefrontal cortex and midbrain dopamine neurons B. Gronier1 , M. Di Miceli1 ° 1 De Montfort University, School of Pharmacy, Leicester, United Kingdom Attention-deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neuropsychiatric disorder in childhood. It is characterized by hyperactivity and deficits in sustained attention and impulsivity. Paradoxically, psychostimulants such as methylphenidate (MPH) and D-amphetamine are used as first line treatment for this disorder and prescriptions have increased dramatically during the last decade, due to their remarkable immediate calming effect. MPH is an inhibitor of the presynaptic dopamine transporter (DAT) and noradrenaline transporter (NAT). However, some children showed only little improvement with MPH, which, in addition, has the potential to produce long-term deleterious effects on dopamine-dependent behaviours. As the first non-stimulant medication, atomoxetine binds selectively with high affinity to the presynaptic noradrenaline transporter (NET), but has minimal affinity for the DAT or other receptors. MPH and atomoxetine increase both noradrenaline and dopamine in prefrontal cortex (PFC) but the therapeutic effect of atomoxetine can take up to 4−6 weeks to develop. In the present study we have compared the acute electrophysiological effects of atomoxetine with those of MPH or D-amphetamine on PFC pyramidal and midbrain dopamine neurons. Rats were anaesthetised with urethane and extracellular single unit activities were recorded in the PFC or in the ventral tegmental area (VTA). In PFC, MPH (1−3 mg/kg, iv), as observed previously1 , increased the firing and burst activity of the majority of pyramidal neurons tested. This effect was reversed by the selective D1 receptor antagonist SCH 23390. D-amphetamine (1−10 mg/kg) also activated − in a D1 receptor-dependent manner − most of the PFC units tested, but only in the high dose range (3−10 mg/kg). On the other hand, atomoxetine (1−10 mg/kg) has more heterogeneous effects. More consistent activation were nevertheless observed in 40% of the neurones tested at the highest doses (5−10 mg/kg) or following the subsequent blockade of alpha-2 adrenoceptors (yohimbine 1 mg/kg). Such activations were only partially dependent on dopamine D1 receptors. Interestingly, atomoxetine (2−5 mg/kg) slightly but significantly reduced the activation of pyramidal neurons induced by the local iontophoretic application of the glutamate agonist NMDA (15−25% reduction), while amphetamine or methylphenidate have moderate potentiating effects (10−30%). In the VTA, atomoxetine (1−5 mg/kg) had a very slight inhibitory effect on the activity of dopamine neurons. Larger decreases (30−40%) were observed with MPH (1−3 mg/kg). However, after blockade of dopamine D2 receptors (eticlopride, 0.3 mg/kg), MPH, but not atomoxetine, potently stimulates burst and firing activity of dopamine neurones. This effect was only minimally dependent on alpha1 receptor stimulation (prazosin 1 mg/kg). In conclusion our data showed that atomoxetine and MPH differentially alter neuronal activity in the PFC and VTA. In PFC,
the effects of MPH and D-amphetamine, but not of atomoxetine, are essentially excitatory. In the VTA, MPH, but not atomoxetine, can potently promote burst activity. This effect − which may be more pronounced during long-term MPH administration − may be triggered by an activation of the fronto-tegmental glutamate drive which is known to control the activity of midbrain dopamine neurones. These differences may underlie the more rapid therapeutic effect of MPH, but also potential drug abuse liability and possible long term deleterious effect on dopamine functions. References [1] Gronier, B., 2011 In vivo electrophysiological effects of methylphenidate in the prefrontal cortex: involvement of dopamine D1 and alpha 2 adrenergic receptors. Eur Neuropsychopharmacol. 21, 192–204.
P.7.d. Child and adolescent disorders and treatment − Treatment (clinical) P.7.d.001 Health-related quality of life outcomes in a long-term study of lisdexamfetamine dimesylate in children and adolescents with ADHD D. Coghill1 ° , T. Banaschewski2 , A. Zuddas3 , M. Johnson4 , P. Hodgkins5 , B. Adeyi6 , L. Squires7 , R. Civil8 1 University of Dundee, Division of Neuroscience, Dundee, United Kingdom; 2 University of Heidelberg, Child and Adolescent Psychiatry and Psychotherapy, Mannheim, Germany; 3 University of Cagliari, Department of Biomedical Sciences, Cagliari, Italy; 4 Queen Silvia Children’s Hospital, Child Neuropsychiatry Unit, Gothenburg, Sweden; 5 Shire Development LLC, Global Health Economics and Outcomes Research, Wayne PA, USA; 6 Shire Development LLC, Global Biostatistics, Wayne PA, USA; 7 Shire Development LLC, Global Clinical Medicine, Wayne PA, USA; 8 Shire Development LLC, Clinical Development and Medical Affairs, Wayne PA, USA Background and Objectives: Optimal management of patients with attention deficit/hyperactivity disorder (ADHD) aims not only to relieve symptoms, but to improve health-related quality of life (HRQoL). The long-acting prodrug stimulant, lisdexamfetamine dimesylate (LDX) is an effective once-daily treatment for the symptoms of ADHD, as confirmed in a long-term (6-month) efficacy and safety study (SPD489–326). In this study, HRQoL was assessed using the Child Health and Illness Profile − Child Edition: Parent Report Form (CHIP-CE:PRF), a generic (i.e. not disease-specific) paediatric instrument with demonstrated reliability and validity. Methods: Study participants were aged 6−17 years with ADHD and a baseline ADHD Rating Scale IV (ADHD-RS-IV) total score 28. European patients had participated in a previous study; additional US patients were enrolled directly. Patients who completed a 26-week open-label period (OLP) of LDX treatment were randomized (1:1) to continue on LDX or to switch to placebo, for a 6-week, double-blind, randomized-withdrawal period (RWP). Parents completed CHIP-CE:PRF questionnaires at weeks 0, 8 and 26 of the OLP and weeks 0 and 6 of the RWP, or at early termination. Scores in the five domains were standardized to T-scores (mean = 50, standard deviation [SD] = 10) based on
P.7.d. Child and adolescent disorders and treatment − Treatment (clinical)
P.7.c. Child and adolescent disorders and treatment − Treatment (basic) P.7.c.001 Differential electrophysiological effects of atomoxetine and methylphenidate on prefrontal cortex and midbrain dopamine neurons B. Gronier1 , M. Di Miceli1 ° 1 De Montfort University, School of Pharmacy, Leicester, United Kingdom Attention-deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neuropsychiatric disorder in childhood. It is characterized by hyperactivity and deficits in sustained attention and impulsivity. Paradoxically, psychostimulants such as methylphenidate (MPH) and D-amphetamine are used as first line treatment for this disorder and prescriptions have increased dramatically during the last decade, due to their remarkable immediate calming effect. MPH is an inhibitor of the presynaptic dopamine transporter (DAT) and noradrenaline transporter (NAT). However, some children showed only little improvement with MPH, which, in addition, has the potential to produce long-term deleterious effects on dopamine-dependent behaviours. As the first non-stimulant medication, atomoxetine binds selectively with high affinity to the presynaptic noradrenaline transporter (NET), but has minimal affinity for the DAT or other receptors. MPH and atomoxetine increase both noradrenaline and dopamine in prefrontal cortex (PFC) but the therapeutic effect of atomoxetine can take up to 4−6 weeks to develop. In the present study we have compared the acute electrophysiological effects of atomoxetine with those of MPH or D-amphetamine on PFC pyramidal and midbrain dopamine neurons. Rats were anaesthetised with urethane and extracellular single unit activities were recorded in the PFC or in the ventral tegmental area (VTA). In PFC, MPH (1−3 mg/kg, iv), as observed previously1 , increased the firing and burst activity of the majority of pyramidal neurons tested. This effect was reversed by the selective D1 receptor antagonist SCH 23390. D-amphetamine (1−10 mg/kg) also activated − in a D1 receptor-dependent manner − most of the PFC units tested, but only in the high dose range (3−10 mg/kg). On the other hand, atomoxetine (1−10 mg/kg) has more heterogeneous effects. More consistent activation were nevertheless observed in 40% of the neurones tested at the highest doses (5−10 mg/kg) or following the subsequent blockade of alpha-2 adrenoceptors (yohimbine 1 mg/kg). Such activations were only partially dependent on dopamine D1 receptors. Interestingly, atomoxetine (2−5 mg/kg) slightly but significantly reduced the activation of pyramidal neurons induced by the local iontophoretic application of the glutamate agonist NMDA (15−25% reduction), while amphetamine or methylphenidate have moderate potentiating effects (10−30%). In the VTA, atomoxetine (1−5 mg/kg) had a very slight inhibitory effect on the activity of dopamine neurons. Larger decreases (30−40%) were observed with MPH (1−3 mg/kg). However, after blockade of dopamine D2 receptors (eticlopride, 0.3 mg/kg), MPH, but not atomoxetine, potently stimulates burst and firing activity of dopamine neurones. This effect was only minimally dependent on alpha1 receptor stimulation (prazosin 1 mg/kg). In conclusion our data showed that atomoxetine and MPH differentially alter neuronal activity in the PFC and VTA. In PFC,
the effects of MPH and D-amphetamine, but not of atomoxetine, are essentially excitatory. In the VTA, MPH, but not atomoxetine, can potently promote burst activity. This effect − which may be more pronounced during long-term MPH administration − may be triggered by an activation of the fronto-tegmental glutamate drive which is known to control the activity of midbrain dopamine neurones. These differences may underlie the more rapid therapeutic effect of MPH, but also potential drug abuse liability and possible long term deleterious effect on dopamine functions. References [1] Gronier, B., 2011 In vivo electrophysiological effects of methylphenidate in the prefrontal cortex: involvement of dopamine D1 and alpha 2 adrenergic receptors. Eur Neuropsychopharmacol. 21, 192–204.
P.7.d. Child and adolescent disorders and treatment − Treatment (clinical) P.7.d.001 Health-related quality of life outcomes in a long-term study of lisdexamfetamine dimesylate in children and adolescents with ADHD D. Coghill1 ° , T. Banaschewski2 , A. Zuddas3 , M. Johnson4 , P. Hodgkins5 , B. Adeyi6 , L. Squires7 , R. Civil8 1 University of Dundee, Division of Neuroscience, Dundee, United Kingdom; 2 University of Heidelberg, Child and Adolescent Psychiatry and Psychotherapy, Mannheim, Germany; 3 University of Cagliari, Department of Biomedical Sciences, Cagliari, Italy; 4 Queen Silvia Children’s Hospital, Child Neuropsychiatry Unit, Gothenburg, Sweden; 5 Shire Development LLC, Global Health Economics and Outcomes Research, Wayne PA, USA; 6 Shire Development LLC, Global Biostatistics, Wayne PA, USA; 7 Shire Development LLC, Global Clinical Medicine, Wayne PA, USA; 8 Shire Development LLC, Clinical Development and Medical Affairs, Wayne PA, USA Background and Objectives: Optimal management of patients with attention deficit/hyperactivity disorder (ADHD) aims not only to relieve symptoms, but to improve health-related quality of life (HRQoL). The long-acting prodrug stimulant, lisdexamfetamine dimesylate (LDX) is an effective once-daily treatment for the symptoms of ADHD, as confirmed in a long-term (6-month) efficacy and safety study (SPD489–326). In this study, HRQoL was assessed using the Child Health and Illness Profile − Child Edition: Parent Report Form (CHIP-CE:PRF), a generic (i.e. not disease-specific) paediatric instrument with demonstrated reliability and validity. Methods: Study participants were aged 6−17 years with ADHD and a baseline ADHD Rating Scale IV (ADHD-RS-IV) total score 28. European patients had participated in a previous study; additional US patients were enrolled directly. Patients who completed a 26-week open-label period (OLP) of LDX treatment were randomized (1:1) to continue on LDX or to switch to placebo, for a 6-week, double-blind, randomized-withdrawal period (RWP). Parents completed CHIP-CE:PRF questionnaires at weeks 0, 8 and 26 of the OLP and weeks 0 and 6 of the RWP, or at early termination. Scores in the five domains were standardized to T-scores (mean = 50, standard deviation [SD] = 10) based on