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P.1.g.014 Added benefits of long-term treatment of methylphenidate modified-release long-acting formulation in adults with ADHD
S210
P.1.g. Basic and clinical neuroscience − Neuropharmacology
Conclusions: Patients with a period off trial medication (prior placebo treated patients) showed substantial efficacy in the extension study and patients continuously exposed to MPH-LA maintained efficacy over duration of up to 12 months. MPH-LA was well tolerated with no unexpected adverse events. References [1] Huss M, Ginsberg Y, Tvedten T, et al., 2014. Methylphenidate hydrochloride modified-release in adults with attention deficit hyperactivity disorder: a randomized double-blind placebo-controlled trial. Adv Ther 31, 44−65.
P.1.g.014 Added benefits of long-term treatment of methylphenidate modified-release long-acting formulation in adults with ADHD M. Huss1 ° , Y. Ginsberg2 , T. Arngrim3 , A. Philipsen4 , P. Gandhi5 , C.W. Chen6 , V. Kumar6 1 University Medicine, Department of Child and Adolescent Psychiatry, Mainz, Germany; 2 Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden; 3 Private Clinic, Aarhus, Denmark; 4 University Medical Centre, Freiburg, Germany; 5 Novartis Healthcare Pvt. Ltd, Hyderabad, India; 6 Novartis Pharmaceuticals Corporation, East Hanover NJ, USA Purpose: Response to Methylphenidate modified release longacting formulation (MPH-LA) in the treatment of adult ADHD is variable and the predictors to nonresponse are unclear. Previously, a 40-week, randomized, double-blind placebo controlled core study comprising 3 phases (9-week dose confirmation phase, 5-week open-label dose optimization phase and 6-month maintenance of effectphase) reported that MPH-LA (40−80 mg/day) in adults, controlled ADHD symptoms as well as reduced functional impairment, with a good tolerability profile [1]. There was a population of patients who did not respond to MPH-LA during the maintenance of effect phase of the core study and had to leave the study. These patients (non-responders) were then allowed to join the 26-week flexible dose open label extension study to the core study. Here, we report long-term efficacy from the extension phase in these responders and non-responders identified in the maintenance of effectphase of the core study. Methods: Non-responders (treatment failures in maintenance of effect phase of the core study) were defined as patients with 30% worsening from maintenance of effect phasebaseline and <30% remaining improvement from dose confirmation phase baseline score on the DSM-IV ADHD rating scale (RS). All patients (responders and non-responders of maintenanceof effectphase) entering extension phase were initiated treatment with MPH-LA (20 mg/day) and up-titrated in increments of 20 mg/week to reach the individual patient’s optimal dose of 40, 60 or 80 mg. The investigator had the flexibility to readjust the doses as necessary within the dose range of 40−80 mg/day. Efficacy of MPH-LA in responders and non-responders was determined by the mean change in DSM-IV ADHD RS and SDS total scores from extensionphase baselineto the end of extension study. Further efficacy analyses were done on these responders and nonresponders based on treatment received (MPH-LA/placebo) in the maintenance of effect phase. From the maintenance phase, 46 patients treated with MPH-LA and 45 patients given placebo met the criteria for non-responders; 132 patients treated with MPH-LA and 24 given placebo were responders.
Results: The mean improvement in total score of DSM-IV ADHD RS at the end of extension study from the extension baseline was 18.2 and 0.9 for the maintenance of effect phase nonresponders (N = 91) and responders (N = 156), respectively. Similarly, mean improvement in SDS total score for non-responders and responders was 9.7 and 1.8, respectively. Non-responders showed symptomatic and functional improvement at the end of extension phase, irrespective of the treatment received in maintenance of effect phase (MPH-LA/placebo) as showed by the mean change in DSM-IV ADHD RS and SDS total score (Table). Overall MPH-LA was well tolerated. Conclusions: Responders to MPH-LA in the maintenance of effect phase continued to maintain efficacy in the extension phase. Non-responders to both MPH-LA and placebo in the maintenancephase showed marked symptomatic improvement. Re-titration and re-optimization of the dose for a longer duration in the extension study could possibly explain this improvement. Table: Mean improvement in DSM-IV ADHD RS and SDS total scores from extension baseline to end of extension phase Treatment received in maintenance of effect phase MPH-LA
DSM-IV ADHD RS SDS
Placebo
Non-responders (N = 46)
Responders (N = 132)
Non-responders (N = 45)
Responders (N = 24)
16.6 9.2
0.8 1.7
19.8 10.2
1.7 2.2
References [1] Huss M, Ginsberg Y, Tvedten T, et al., 2014. Methylphenidate hydrochloride modified-release in adults with attention deficit hyperactivity disorder: a randomized double-blind placebo-controlled trial. Adv Ther 31, 44−65.
P.1.g.015 Effects of atypical antipsychotics aripiprazole and olanzapine on active avoidance test in rats with tryptamine-induced behavior D. Getova1 ° , M. Topolov2 , K. Dzenis3 1 Medical University, Department of Pharmacology and Clinical Pharmacology, Plovdiv, Bulgaria; 2 Medical University, Department of Pharmacology and Toxicology, Plovdiv, Bulgaria; 3 Medical University, Department of Pharmacology, Riga, Latvia Purpose: Tryptamine induces neurodegeneration as axonopathy manifested by vesicularization of inner and outer mitochondrial membranes, axonal and cell membranes. Tyiptamine produced a decreased density of somatic mitochondria in mouse hippocampus causing axonal swellings and mitochondrialdamage mimicking neurodegenerative diseases [1]. Aripiprazole is a new antipsychotic drug with unique mechanism of action, which is an alternative to current antipsychotic drugs that adversely affect cognitive processes [2]. Atypical antipsychotic olanzapine acts as dopamine, serotonin and muscarinic antagonist and these transmitters could account for memory impairment in working memory tasks [3]. Our aim was to assess the impact of aripiprazole and olanzapine on behavioral functions of rats with tryptamine-induced behavior after multiple dosing. Methods: Male Wistar rats (n = 8), divided in 4 groups were treated intraperitoneally (i.p.) with: 1st saline (controls) 0.1 ml/100 g; 2nd group with tryptamine 5 mg/kg i.p.; 3rd group with tryptamine 5 mg/kg and aripiprazole 1 mg/kg; 4th group
P.1.g. Basic and clinical neuroscience − Neuropharmacology
Conclusions: Patients with a period off trial medication (prior placebo treated patients) showed substantial efficacy in the extension study and patients continuously exposed to MPH-LA maintained efficacy over duration of up to 12 months. MPH-LA was well tolerated with no unexpected adverse events. References [1] Huss M, Ginsberg Y, Tvedten T, et al., 2014. Methylphenidate hydrochloride modified-release in adults with attention deficit hyperactivity disorder: a randomized double-blind placebo-controlled trial. Adv Ther 31, 44−65.
P.1.g.014 Added benefits of long-term treatment of methylphenidate modified-release long-acting formulation in adults with ADHD M. Huss1 ° , Y. Ginsberg2 , T. Arngrim3 , A. Philipsen4 , P. Gandhi5 , C.W. Chen6 , V. Kumar6 1 University Medicine, Department of Child and Adolescent Psychiatry, Mainz, Germany; 2 Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden; 3 Private Clinic, Aarhus, Denmark; 4 University Medical Centre, Freiburg, Germany; 5 Novartis Healthcare Pvt. Ltd, Hyderabad, India; 6 Novartis Pharmaceuticals Corporation, East Hanover NJ, USA Purpose: Response to Methylphenidate modified release longacting formulation (MPH-LA) in the treatment of adult ADHD is variable and the predictors to nonresponse are unclear. Previously, a 40-week, randomized, double-blind placebo controlled core study comprising 3 phases (9-week dose confirmation phase, 5-week open-label dose optimization phase and 6-month maintenance of effectphase) reported that MPH-LA (40−80 mg/day) in adults, controlled ADHD symptoms as well as reduced functional impairment, with a good tolerability profile [1]. There was a population of patients who did not respond to MPH-LA during the maintenance of effect phase of the core study and had to leave the study. These patients (non-responders) were then allowed to join the 26-week flexible dose open label extension study to the core study. Here, we report long-term efficacy from the extension phase in these responders and non-responders identified in the maintenance of effectphase of the core study. Methods: Non-responders (treatment failures in maintenance of effect phase of the core study) were defined as patients with 30% worsening from maintenance of effect phasebaseline and <30% remaining improvement from dose confirmation phase baseline score on the DSM-IV ADHD rating scale (RS). All patients (responders and non-responders of maintenanceof effectphase) entering extension phase were initiated treatment with MPH-LA (20 mg/day) and up-titrated in increments of 20 mg/week to reach the individual patient’s optimal dose of 40, 60 or 80 mg. The investigator had the flexibility to readjust the doses as necessary within the dose range of 40−80 mg/day. Efficacy of MPH-LA in responders and non-responders was determined by the mean change in DSM-IV ADHD RS and SDS total scores from extensionphase baselineto the end of extension study. Further efficacy analyses were done on these responders and nonresponders based on treatment received (MPH-LA/placebo) in the maintenance of effect phase. From the maintenance phase, 46 patients treated with MPH-LA and 45 patients given placebo met the criteria for non-responders; 132 patients treated with MPH-LA and 24 given placebo were responders.
Results: The mean improvement in total score of DSM-IV ADHD RS at the end of extension study from the extension baseline was 18.2 and 0.9 for the maintenance of effect phase nonresponders (N = 91) and responders (N = 156), respectively. Similarly, mean improvement in SDS total score for non-responders and responders was 9.7 and 1.8, respectively. Non-responders showed symptomatic and functional improvement at the end of extension phase, irrespective of the treatment received in maintenance of effect phase (MPH-LA/placebo) as showed by the mean change in DSM-IV ADHD RS and SDS total score (Table). Overall MPH-LA was well tolerated. Conclusions: Responders to MPH-LA in the maintenance of effect phase continued to maintain efficacy in the extension phase. Non-responders to both MPH-LA and placebo in the maintenancephase showed marked symptomatic improvement. Re-titration and re-optimization of the dose for a longer duration in the extension study could possibly explain this improvement. Table: Mean improvement in DSM-IV ADHD RS and SDS total scores from extension baseline to end of extension phase Treatment received in maintenance of effect phase MPH-LA
DSM-IV ADHD RS SDS
Placebo
Non-responders (N = 46)
Responders (N = 132)
Non-responders (N = 45)
Responders (N = 24)
16.6 9.2
0.8 1.7
19.8 10.2
1.7 2.2
References [1] Huss M, Ginsberg Y, Tvedten T, et al., 2014. Methylphenidate hydrochloride modified-release in adults with attention deficit hyperactivity disorder: a randomized double-blind placebo-controlled trial. Adv Ther 31, 44−65.
P.1.g.015 Effects of atypical antipsychotics aripiprazole and olanzapine on active avoidance test in rats with tryptamine-induced behavior D. Getova1 ° , M. Topolov2 , K. Dzenis3 1 Medical University, Department of Pharmacology and Clinical Pharmacology, Plovdiv, Bulgaria; 2 Medical University, Department of Pharmacology and Toxicology, Plovdiv, Bulgaria; 3 Medical University, Department of Pharmacology, Riga, Latvia Purpose: Tryptamine induces neurodegeneration as axonopathy manifested by vesicularization of inner and outer mitochondrial membranes, axonal and cell membranes. Tyiptamine produced a decreased density of somatic mitochondria in mouse hippocampus causing axonal swellings and mitochondrialdamage mimicking neurodegenerative diseases [1]. Aripiprazole is a new antipsychotic drug with unique mechanism of action, which is an alternative to current antipsychotic drugs that adversely affect cognitive processes [2]. Atypical antipsychotic olanzapine acts as dopamine, serotonin and muscarinic antagonist and these transmitters could account for memory impairment in working memory tasks [3]. Our aim was to assess the impact of aripiprazole and olanzapine on behavioral functions of rats with tryptamine-induced behavior after multiple dosing. Methods: Male Wistar rats (n = 8), divided in 4 groups were treated intraperitoneally (i.p.) with: 1st saline (controls) 0.1 ml/100 g; 2nd group with tryptamine 5 mg/kg i.p.; 3rd group with tryptamine 5 mg/kg and aripiprazole 1 mg/kg; 4th group