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Dose Response of Extended Release Dexmethylphenidate and Mixed Amphetamine Salts on Sleep of Youth with Attention Deficit/Hyperactivity Disorder

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Dose Response of Extended Release Dexmethylphenidate and Mixed Amphetamine Salts on Sleep of Youth with Attention Deficit/Hyperactivity Disorder Dose Response of Extended Release Dexmethylphenidate and Mixed Amphetamine Salts on Sleep of Youth with Attention Deficit/Hyperactivity Disorder José Arturo Santisteban López Department of Psychiatry, Faculty of Medicine McGill University, Montreal September 2013 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Master of Science in Psychiatry © José Arturo Santisteban López, 2013 Table of Contents Abstract English 2 Abstract French 3 Acknowledgements 4 Contribution of Authors 5 Introduction 6 Background 8 Methods 16 Results 22 Discussion 25 Conclusion 28 Tables and Figures 29 Bibliography 34 1 Abstract English Background. Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by impulsivity, hyperactivity, and inattention, which affects 5-10% of school-age children. The first-line treatment for ADHD is stimulant medication, which increase levels dopamine (DA) and norepinephrine (NE). These medications are highly effective, but not always tolerated. Sleep side effects, such as insomnia, are reported for both stimulant classes and are usually, but not always, mild and transitory, which can lead to treatment discontinuation. Poor tolerability may limit efficacy by compromising the ability to prescribe effective doses. Few studies have assessed the comparative effectiveness of long-acting methylphenidate and amphetamine formulations in youth with ADHD, and it is unclear if there are differential effects of drug and/or dose on sleep. MAS increase NE and DA levels more than d-MPH and hence could be affecting sleep differently. Objectives. We sought to determine if there are significant differences in the dose-response effects of ER D-MPH and ER MAS on objective measures of sleep. Methods. Children, aged 10-17 (n=37), participated in a double-blind crossover study comparing two stimulants (extended release DMPH, MAS) at three doses (10, 20, 30 mg) and placebo. Each treatment session lasted one week, for a total protocol duration of eight weeks. Sleep was assessed in all conditions using actigraphy and questionnaires. Results. Sleep schedule measures showed a significant effect for dosage on sleep start time (F(1,36)=6.284, p<0.05), with a significantly later sleep start time when children were on 20mg or 30mg dosages, compared to placebo (p<0.05). Sleep duration revealed a significant dose effect on actual sleep duration (F(1,36)=8.112, p<0.05), with significantly shorter actual sleep duration for subjects receiving 30mg compared to those on placebo (p<0.05). There were no significant differences between medications. Conclusion. Higher dosages reduce sleep duration and lead to later sleep start times, regardless of medication. 2 Abstract French Contexte. Le Trouble Déficitaire de l’Attention et de l’Hyperactivité (TDAH) est caractérisé par l’impulsivité, l’hyperactivité, et l’inattention. Le TDAH se produit dans 5-10% des enfants scolaires. Le traitement de première ligne pour le TDAH sont les stimulants. Les stimulants augmentent les niveaux de dopamine (DA) et de norépinephrine (NE). Ces médicaments sont hautement efficaces, mais ne sont pas tolérés par tous les enfants. Les effets indésirables, comme l’insomnie, sont souvent reportés pour ces stimulants. Par contre, leurs effets sont habituellement, mais pas toujours, bénins et transitoires. En général, les enfants souffrant d’insomnie sévère cessent le traitment. La faible tolérance peut limiter l’efficacité en compromettant la possibilité de prescrire des doses plus efficaces. Peu d’études ont mesuré l’efficacité comparative du methylphenidate á action prolongée et de l’amphétamine á action prolongée chez les enfants avec un TDAH. De plus, il n’est pas clair s’il y a un effet différentiel de médicament et/ou de dose sur le sommeil. Les MAS augmentent les niveaux de NE et DA plus que les d-MPH, et donc pourraient avoir une incidence sur le sommeil d’une manière différente. Objectifs. Nous cherchons à déterminer s’il existe des différences significatives dans les effets de dose-réponse des d-MPH et MAS á actions prolongées sur des mesures objectives du sommeil. Méthodes. Les enfants, âgés 10-17 (n=37), ont participé dans une étude croisée à double insu comparant trois doses (10, 20, et 30mg) de d-MPH ou MAS au placebo. Chaque séance de traitement a duré une semaine, pour une durée totale de protocole de huit semaines. Le sommeil a été mesuré dans toutes les conditions avec actimétrie et questionnaires. Résultats. Les mesures d’horaire du sommeil ont montré un effet significatif de dose à l’heure de début de sommeil (F(1,36)=6.284, p<0.05); les enfants recevant 20mg ou 30mg on débuté leur sommeil significativement plus tard que ceux qui ont reçu le placebo (p<0.05). Un effet significatif de dose sur la durée réelle du sommeil (F(1,36)=8.112, p<0.05) a été découverte, avec une durée de sommeil plus courte quand les sujets ont reçu 30 mg comparé au placebo (p<0.05). Aucune différence entre les deux médicaments n’a été trouvée. Conclusion. Des doses plus élevées réduisent la durée du sommeil et conduisent à dormir plus tard, indépendamment de médicaments. 3 ACKNOWLEDGMENTS First of all, I would like to express my gratitude for my supervisor, Dr. Reut Gruber, for her mentorship during my studies. Her dedication and support allowed me to get the most out of the program. I have greatly benefited from the experience of working in her laboratory and the skills I have learned from her will prove invaluable in my future projects. I would also like to thank the Mexican National Council for Science and Technology (CONACYT) for providing the funds necessary for me to complete this project, as well as their support for the promotion of scientific research in Mexico. The help that the members of my lab have provided on every part of this project was instrumental for not only the success of this project, but making it an enjoyable endeavor. I especially want to thank Lana Bergame for her editing and feedback on the writing of this project. I would also like to express my appreciation for Alice Boom and Laura Fontil for showing me the ropes in using the measures. Finally, I would like to thank my parents all their support during every step of my academic growth, my friend and classmate Michelle Lonergan for her help with statistics and motivating me to work hard through parallel writing, and my best friend Piell Angel Blanco for making Montreal home. 4 Contribution of Authors This work is part of the Sleep and Tolerability of Extended Release Dexmethylphenidate vs. Mixed Amphetamine Salts: A Double Blind, Placebo Controlled Study (SAT STUDY), designed by Dr. Mark A. Stein. My role was to examine the data specifically relating to sleep depending on medication and dosage, as well as conducting the statistical analysis. Thus, I conducted the literature review, interpreted the statistical analyses, and wrote the present thesis, all of which was supervised and reviewed by Dr. Reut Gruber. Lana Bergame aided the project by editing and providing feedback on the writing for this thesis. 5 Introduction Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by impulsivity, hyperactivity, and inattention which affect a reported 5.29% of children and adolescents worldwide. The prefrontal cortex (PFC) regulates attention based on relevance, screening for distractions and sustaining attention and it is dependent on norepinephrine (NE) and dopamine (DA). Dysregulation of these have been found in individuals with ADHD. The first-line treatments for ADHD are stimulant medications (methylphenidate and amphetamines) which increase the levels DA and NE by inhibiting their re-uptake. These have been found to be very effective for the treatment of ADHD. However, not all children tolerate them well. Sleep side effects in general, and specifically insomnia, are one of the most common side-effects, which are usually, but not always, mild and transitory. Children who develop insomnia are more likely to discontinue treatment. Poor tolerability of the stimulant may lead to lower doses being prescribed, and thus, may limit the efficacy of the treatment. While lower dosages are generally less effective, higher dosages are more likely to present side- effects. There is a paucity of comparative tolerability data of the major stimulant classes currently used to treat ADHD. Amphetamine increases NE and DA levels more than methylphenidate and hence could be affecting sleep differently. With more information on the tolerability of these medications, it may be possible to choose a medication with fewer side-effects as the first one, controlling symptoms earlier by reducing time spent finding a tolerable formulation. 6 We sought to determine if there are significant differences in the dose- response effects of ER D-MPH and ER MAS on objective measures of sleep. We evaluated the effects of three doses of each drug on sleep in a within-subject, double-blind, randomized placebo-controlled trial. 7 Background Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by impulsivity, hyperactivity, and inattention (4th ed., text rev.; Diagnostic and Statistical Manual of Mental Disorders; American Psychiatric Association, 2000)., and affects a reported 5.29% of children and adolescents worldwide (Polanczyk, de Lima, Horta, Biederman, & Rohde, 2007). Males are more frequently diagnosed with ADHD than females; specifically, estimated gender ratios range from 2:1 to 9:1 (Rucklidge, 2008), with a greater gender difference in clinical populations (Staller & Faraone, 2006). Additionally, comorbid disorders are common in ADHD; 66.9% of patients present any disorder, including learning disorders (46.1%), conduct disorders (27.4%), anxiety (17.8%), depression (13.9%), (6%) (Larson, Russ, Kahn, & Halfon, 2011). Functional Impairment. ADHD causes functional impairment in areas of life such as work, interpersonal relationships, mood and impulse control, organization, and anti-social behaviour, and this impairment continues to be present into adulthood (Surman, Hammerness, Pion, & Faraone, 2013).
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