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P.7.e.002 The effects of lisdexamfetamine dimesylate on the driving performance of young adults with ADHD
S436
P.7.e. Child and adolescent disorders and treatment − Other (basic)
P.7.e.002 The effects of lisdexamfetamine dimesylate on the driving performance of young adults with ADHD J. Biederman1 ° , R. Fried1 1 Massachusetts General Hospital, Pediatric Psychopharmacology, Boston, USA Purpose: Young adults with ADHD have been shown to be at increased risk for impairment in driving behaviors. In several studies, individuals with ADHD self-reported significantly more traffic citations for speeding, vehicular crashes, and license suspensions than controls [1,2]. While stimulant medications have proven efficacy in reducing ADHD symptomatology, there is limited knowledge as to their effects on driving impairment. The main aim of this study was to assess the impact of lisdexamfetamine dimesylate (LDX) on driving performance in young adults with ADHD. Methods: Subjects were outpatients of both sexes, 18 to 26 years of age, who met DSM-IV criteria for ADHD, and were randomly assigned to a medication or placebo group in a double blind design. Subjects participated in a driving simulation paradigm that had been previously validated to separate individuals with ADHD from controls. They drove the protocol once prior to starting medication/placebo and again 5−6 weeks later. The driving scenario was identical in the first and second visits except for the addition of five surprise events during the second. Results: Seventy-five subjects enrolled in this study and 61 subjects completed the two driving simulations. LDX treatment was associated with statistically and clinically significantly greater improvement than placebo in AISRS and CGI scores. The rate of response (defined a priori as having a CGI-I scale score 2 and 30% reduction in baseline AISRS score) was 68% in the LDX group vs. 27% in the placebo group (p = 0.001). There were no serious adverse events during the study. Examination of the five surprise events in the second simulation visit shows a significant effect of medication status on the average reaction time computed across all five events (F(1,58) = 5.231, p = 0.026). Participants receiving LDX reacted on average 0.126 seconds or 9.1% faster than participants receiving placebo. Examination of individual events showed that the active medication group consistently reacted faster than the placebo group, although these differences did not attain statistical significance when considered individually. During the five surprise events, drivers receiving LDX were 67% less likely to have a collision than drivers receiving placebo (c2 (1) = 3.918, Odds Ratio = 0.33, p = 0.048). Seven (22.6%) of the drivers on medication were involved in a collision as a result of the surprise events as compared to 14 (46.7%) of the drivers on placebo (c2 (1) = 3.918, Odds Ratio = 0.33, 95% CI = 0.11– 1.01, p = 0.048). Extending this analysis to the total number of collisions across the visits, a main effect of medication status was observed in the difference in collision number between the two visits (F(1,59) = 4.755, p = 0.033), indicating that drivers were less likely to have a collision when on medication (0.1±0.5 vs 0.6±1.13, in active and placebo treated subjects, respectively). Conclusions: Treatment with LDX was associated with significant clinical improvement as well as faster reaction times and a lower likelihood of having a collision in the driving simulator. These results support the study hypothesis that effective pharmacotherapy for ADHD improves driving behaviors in young drivers with ADHD. References [1] Barkley RA, Murphy KR, DuPaul GJ, Bush T: Driving knowledge, performance, and adverse outcomes in teens and young adults with
attention deficit hyperactivity disorder. Worcester, MA, University of Massachusetts Medical School, 2002, pp 1−64. [2] Barkley RA: Driving impairments in teens and adults with attentiondeficit/hyperactivity disorder. Psychiatr Clin North Am 2004; 27(2): 233–260. Disclosure statement: This study was funded by Shire Pharmaceuticals Inc. The study sponsor had no role in the design and conduct of the study collection, management, analysis, or interpretation of the data or preparation, review, or approval of the manuscript. Dr. Joseph Biederman is currently receiving research support from the following sources: Elminda, Janssen, McNeil, and Shire. In 2011, Dr. Joseph Biederman gave a single unpaid talk for Juste Pharmaceutical Spain, received honoraria from the MGH Psychiatry Academy for a tuition-funded CME course, and received an honorarium for presenting at an international scientific conference on ADHD. He also received an honorarium from Cambridge University Press for a chapter publication. Dr. Biederman received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Eli Lilly, Shire and AstraZeneca these royalties are paid to the Department of Psychiatry at MGH. In 2010, Dr. Joseph Biederman received a speaker’s fee from a single talk given at Fundaci´on Dr. Manuel Camelo A.C. in Monterrey Mexico. Dr. Biederman provided single consultations for Shionogi Pharma Inc. and Cipher Pharmaceuticals Inc. the honoraria for these consultations were paid to the Department of Psychiatry at the MGH. Dr. Biederman received honoraria from the MGH Psychiatry Academy for a tuition-funded CME course. In previous years, Dr. Joseph Biederman received research support, consultation fees, or speaker’s fees for/from the following additional sources: Abbott, Alza, AstraZeneca, Boston University, Bristol Myers Squibb, Celltech, Cephalon, Eli Lilly and Co., Esai, Fundacion Areces (Spain), Forest, Glaxo, Gliatech, Hastings Center, Janssen, McNeil, Medice Pharmaceuticals (Germany), Merck, MMC Pediatric, NARSAD, NIDA, New River, NICHD, NIMH, Novartis, Noven, Neurosearch, Organon, Otsuka, Pfizer, Pharmacia, Phase V Communications, Physicians Academy, The Prechter Foundation, Quantia Communications, Reed Exhibitions, Shire, the Spanish Child Psychiatry Association, The Stanley Foundation, UCB Pharma Inc., Veritas, and Wyeth. In the past, Dr. Ronna Fried has received honoraria from Shire.
P.7.e.003 mGluR5 antagonist AFQ056/Mavoglurant in Fragile X Syndrome: baseline disease severity data in adults and adolescents M. Matthisson1 ° , A. Angelov2 , T. Jaecklin3 , B. Koumaras2 , C. Collober3 , F.N. Hossain2 , J. Lustig3 , J. Lee2 , A. Graf3 , F. von Raison3 1 Novartis Pharma AG, Neuroscience, Basel, Switzerland; 2 Novartis Pharmaceutical Corporation, Neuroscience Development, East Hanover, USA; 3 Novartis Pharma AG, Neuroscience Development, Basel, Switzerland Fragile X syndrome (FXS) is the most common cause of inherited mental retardation and is associated with behavioral problems including anxiety, social withdrawal, hyperactivity and repetitive behavior, attention deficit disorder and autism. It is caused by the expansion of a CGG repeat in the Fragile X Mental Retardation 1 gene (FMR1), leading to hypermethylation and transcriptional silencing of FMR1, and absent or reduced levels of its gene product, the FMR1 protein (FMRP). FMRP is a translational repressor of protein synthesis. On the other hand, activation of the metabotropic glutamate receptors (mGluRs) by their ligand leads to synthesis of proteins required for maintenance of synaptic long-term depression (LTD). The mGluR theory of FXS hypothesizes that without FMRP, uncontrolled protein synthesis occurs in response to synaptic activation of mGluRs, which may lead to altered synaptic LTD and clinical symptoms of FXS. AFQ056/Mavoglurant is a novel antagonist of the mGluR subtype 5. Blocking this receptor has the potential to balance synaptic protein synthesis and thus improve clinical symptoms. Data from a recent randomized placebo-controlled cross-over clinical trial in 30 adult patients with FXS suggest that AFQ056/Mavoglurant
P.7.e. Child and adolescent disorders and treatment − Other (basic)
P.7.e.002 The effects of lisdexamfetamine dimesylate on the driving performance of young adults with ADHD J. Biederman1 ° , R. Fried1 1 Massachusetts General Hospital, Pediatric Psychopharmacology, Boston, USA Purpose: Young adults with ADHD have been shown to be at increased risk for impairment in driving behaviors. In several studies, individuals with ADHD self-reported significantly more traffic citations for speeding, vehicular crashes, and license suspensions than controls [1,2]. While stimulant medications have proven efficacy in reducing ADHD symptomatology, there is limited knowledge as to their effects on driving impairment. The main aim of this study was to assess the impact of lisdexamfetamine dimesylate (LDX) on driving performance in young adults with ADHD. Methods: Subjects were outpatients of both sexes, 18 to 26 years of age, who met DSM-IV criteria for ADHD, and were randomly assigned to a medication or placebo group in a double blind design. Subjects participated in a driving simulation paradigm that had been previously validated to separate individuals with ADHD from controls. They drove the protocol once prior to starting medication/placebo and again 5−6 weeks later. The driving scenario was identical in the first and second visits except for the addition of five surprise events during the second. Results: Seventy-five subjects enrolled in this study and 61 subjects completed the two driving simulations. LDX treatment was associated with statistically and clinically significantly greater improvement than placebo in AISRS and CGI scores. The rate of response (defined a priori as having a CGI-I scale score 2 and 30% reduction in baseline AISRS score) was 68% in the LDX group vs. 27% in the placebo group (p = 0.001). There were no serious adverse events during the study. Examination of the five surprise events in the second simulation visit shows a significant effect of medication status on the average reaction time computed across all five events (F(1,58) = 5.231, p = 0.026). Participants receiving LDX reacted on average 0.126 seconds or 9.1% faster than participants receiving placebo. Examination of individual events showed that the active medication group consistently reacted faster than the placebo group, although these differences did not attain statistical significance when considered individually. During the five surprise events, drivers receiving LDX were 67% less likely to have a collision than drivers receiving placebo (c2 (1) = 3.918, Odds Ratio = 0.33, p = 0.048). Seven (22.6%) of the drivers on medication were involved in a collision as a result of the surprise events as compared to 14 (46.7%) of the drivers on placebo (c2 (1) = 3.918, Odds Ratio = 0.33, 95% CI = 0.11– 1.01, p = 0.048). Extending this analysis to the total number of collisions across the visits, a main effect of medication status was observed in the difference in collision number between the two visits (F(1,59) = 4.755, p = 0.033), indicating that drivers were less likely to have a collision when on medication (0.1±0.5 vs 0.6±1.13, in active and placebo treated subjects, respectively). Conclusions: Treatment with LDX was associated with significant clinical improvement as well as faster reaction times and a lower likelihood of having a collision in the driving simulator. These results support the study hypothesis that effective pharmacotherapy for ADHD improves driving behaviors in young drivers with ADHD. References [1] Barkley RA, Murphy KR, DuPaul GJ, Bush T: Driving knowledge, performance, and adverse outcomes in teens and young adults with
attention deficit hyperactivity disorder. Worcester, MA, University of Massachusetts Medical School, 2002, pp 1−64. [2] Barkley RA: Driving impairments in teens and adults with attentiondeficit/hyperactivity disorder. Psychiatr Clin North Am 2004; 27(2): 233–260. Disclosure statement: This study was funded by Shire Pharmaceuticals Inc. The study sponsor had no role in the design and conduct of the study collection, management, analysis, or interpretation of the data or preparation, review, or approval of the manuscript. Dr. Joseph Biederman is currently receiving research support from the following sources: Elminda, Janssen, McNeil, and Shire. In 2011, Dr. Joseph Biederman gave a single unpaid talk for Juste Pharmaceutical Spain, received honoraria from the MGH Psychiatry Academy for a tuition-funded CME course, and received an honorarium for presenting at an international scientific conference on ADHD. He also received an honorarium from Cambridge University Press for a chapter publication. Dr. Biederman received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Eli Lilly, Shire and AstraZeneca these royalties are paid to the Department of Psychiatry at MGH. In 2010, Dr. Joseph Biederman received a speaker’s fee from a single talk given at Fundaci´on Dr. Manuel Camelo A.C. in Monterrey Mexico. Dr. Biederman provided single consultations for Shionogi Pharma Inc. and Cipher Pharmaceuticals Inc. the honoraria for these consultations were paid to the Department of Psychiatry at the MGH. Dr. Biederman received honoraria from the MGH Psychiatry Academy for a tuition-funded CME course. In previous years, Dr. Joseph Biederman received research support, consultation fees, or speaker’s fees for/from the following additional sources: Abbott, Alza, AstraZeneca, Boston University, Bristol Myers Squibb, Celltech, Cephalon, Eli Lilly and Co., Esai, Fundacion Areces (Spain), Forest, Glaxo, Gliatech, Hastings Center, Janssen, McNeil, Medice Pharmaceuticals (Germany), Merck, MMC Pediatric, NARSAD, NIDA, New River, NICHD, NIMH, Novartis, Noven, Neurosearch, Organon, Otsuka, Pfizer, Pharmacia, Phase V Communications, Physicians Academy, The Prechter Foundation, Quantia Communications, Reed Exhibitions, Shire, the Spanish Child Psychiatry Association, The Stanley Foundation, UCB Pharma Inc., Veritas, and Wyeth. In the past, Dr. Ronna Fried has received honoraria from Shire.
P.7.e.003 mGluR5 antagonist AFQ056/Mavoglurant in Fragile X Syndrome: baseline disease severity data in adults and adolescents M. Matthisson1 ° , A. Angelov2 , T. Jaecklin3 , B. Koumaras2 , C. Collober3 , F.N. Hossain2 , J. Lustig3 , J. Lee2 , A. Graf3 , F. von Raison3 1 Novartis Pharma AG, Neuroscience, Basel, Switzerland; 2 Novartis Pharmaceutical Corporation, Neuroscience Development, East Hanover, USA; 3 Novartis Pharma AG, Neuroscience Development, Basel, Switzerland Fragile X syndrome (FXS) is the most common cause of inherited mental retardation and is associated with behavioral problems including anxiety, social withdrawal, hyperactivity and repetitive behavior, attention deficit disorder and autism. It is caused by the expansion of a CGG repeat in the Fragile X Mental Retardation 1 gene (FMR1), leading to hypermethylation and transcriptional silencing of FMR1, and absent or reduced levels of its gene product, the FMR1 protein (FMRP). FMRP is a translational repressor of protein synthesis. On the other hand, activation of the metabotropic glutamate receptors (mGluRs) by their ligand leads to synthesis of proteins required for maintenance of synaptic long-term depression (LTD). The mGluR theory of FXS hypothesizes that without FMRP, uncontrolled protein synthesis occurs in response to synaptic activation of mGluRs, which may lead to altered synaptic LTD and clinical symptoms of FXS. AFQ056/Mavoglurant is a novel antagonist of the mGluR subtype 5. Blocking this receptor has the potential to balance synaptic protein synthesis and thus improve clinical symptoms. Data from a recent randomized placebo-controlled cross-over clinical trial in 30 adult patients with FXS suggest that AFQ056/Mavoglurant