Atomoxetin in der Behandlung der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung bei Kindern und Erwachsenen

Zusammenfassung

Atomoxetin ist ein selektiver Noradrenalin-Wiederaufnahmehemmer, dessen Wirksamkeit bei Kindern, Jugendlichen und Erwachsenen mit einer Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) geprüft wurde. Bisher wurden 2 offene und 7 randomisierte, doppel-blinde, plazebo-kontrollierte klinische Untersuchungen zu Atomoxetin bei ADHS durchgeführt, davon 6 bei Kindern und Jugendlichen sowie 3 bei Erwachsenen. Jede dieser Untersuchungen zeigte eine Wirksamkeit von Atomoxetin bei ADHS, zumeist dokumentiert anhand der primären Zielkriterien ADHD Rating Scale (ADHD RS) und Conners Adult ADHD Rating Scale (CAARS). Atomoxetin wurde von den Patienten mit ADHS in der Regel gut toleriert. Die häufigste Nebenwirkung war verminderter Appetit. In den USA wurde Atomoxetin im November 2002 für die Behandlung von Kindern, Jugendlichen und Erwachsenen mit ADHS zugelassen. Im deutschsprachigen Raum ist Atomoxetin in dieser Indikation bisher nicht zugelassen, es kann daher bisher lediglich in der off-label-Verschreibung angewendet werden.

Abstract

Atomoxetine is a selective noradrenaline reuptake inhibitor that has been studied for use in the treatment of attention-deficit/hyperactivity disorder (ADHD). In vitro, ex vivo and in vivo studies have shown that atomoxetine is a highly selective antagonist of the presynaptic norepinephrine transporter with little or no affinity for other noradrenergic receptors or other neurotransmitter transporters or receptors. So far, two open-label and seven randomised, double-blind, placebo-controlled, clinical trials have been published, six in youths and three in adults. Each of these trials has shown a positive response as measured by the primary efficacy measures, the ADHD-IV Rating Scale (ADHD RS) or the Conners Adult ADHD Rating Scale (CAARS). Atomoxetine has generally been well tolerated. The most common treatment-related adverse event was decreased appetite. Atomoxetine shows no abuse potential and is not a controlled substance in the US. In November of 2002 the FDA approved atomoxetine for use in the US for the treatment of ADHD in children, adolescents and adults. Atomoxetine is the first nonstimulant approved by the FDA for the treatment of ADHD and the first medication approved for the treatment of adult ADHD.

Literatur

• 1 Barkley R A. Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD.  Psychol Bull. 1997;  121 65-94
• 2 Castellanos F X. Toward a pathophysiology of attention-deficit/hyperactivity disorder.  Clin Pediatr. 1997;  36 381-393
• 3 Internationale Klassifikation psychischer Störungen, ICD-10, Kapitel V (F), Weltgesundheitsorganisation. Göttingen: Verlag Hans Huber 1991
• 4 Amercian Psychiatric Association .Diagnostic and Statistical Manual of Mental Disorders, 4th edit. Washington, DC 1994
• 5 Barkley R A, Fischer M, Edelbrock C S, Smallish L. The adolescent outcome of hyperactive children diagnosed by research criteria: I. An 8-year prospective follow-up study.  J Am Acad Child Adolesc Psychiatry. 1990;  29 546-557
• 6 Gallagher R, Blader J. The diagnosis and neuropsychological assessment of adult attention deficit/hyperactivity disorder.  Ann N Y Acad Sci. 2001;  931 148-171
• 7 Groß J, Blocher D, Trott G E, Rösler M. Erfassung des hyperkinetischen Syndroms bei Erwachsenen.  Nervenarzt. 1999;  70 20-25
• 8 Krause K H, Krause J, Trott G E. Das hyperkinetische Syndrom (Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung) des Erwachsenenalters.  Nervenarzt. 1998;  69 543-556
• 9 Blocher D, Henkel K, Retz W, Retz-Junginger P, Thome J, Rösler M. Symptome aus dem Spektrum des hyperkinetischen Synrdoms bei Sexualdelinquenten.  Fortschr Neurol Psychiat. 2001;  69 453-459
• 10 Faraone S V, Biederman J. Neurobiology of attention-deficit hyperactivity disorder.  Biol Psychiatry. 1998;  44 951-958
• 11 FDA . Strattera approved to treat ADHD.  FDA Consum. 2003;  37 4
• 12 Fritze J, Schmauss M. [Off-label use: the case of methylphenidate (Ritalin)].  Nervenarzt. 2002;  73 1210-1212
• 13 Preti A. Tomoxetine.  Curr Opin Investig Drugs. 2002;  3 272-277
• 14 Zerbe R L, Rowe H, Enas G G, Wong D, Farid N, Lemberger L. Clinical pharmacology of tomoxetine, a potential antidepressant.  J Pharmacol Exp Ther. 1985;  232 139-143
• 15 Barr C L, Kroft J, Feng Y, Wigg K, Roberts W, Malone M, Ickowicz A, Schachar R, Tannock R, Kennedy J L. The norepinephrine transporter gene and attention-deficit hyperactivity disorder.  Am J Med Genet. 2002;  114 255-259
• 16 Biederman J, Spencer T. Attention-deficit/hyperactivity disorder as a noradrenergic disorder.  Biol Psychiatry. 1999;  46 1234-1242
• 17 Spencer T J, Biederman J, Wilens T E, Faraone S V. Overview and neurobiology of attention-deficit/hyperactivity disorder.  J Clin Psychiatry. 2002;  63 Suppl 12 3-9
• 18 Kratochvil C J, Vaughan B S, Harrington M J, Burke W J. Atomoxetine: a selective noradrenaline reuptake inhibitor for the treatment of attention-deficit/hyperactivity disorder.  Expert Opin Pharmacother. 2003;  4 1165-1174
• 19 Simpson D, Perry C M. Atomoxetine.  Paediatr Drugs. 2003;  5 407-415
• 20 Stahl S M. Neurotransmission of cognition, part 2. Selective NRIs are smart drugs: exploiting regionally selective actions on both dopamine and norepinephrine to enhance cognition.  J Clin Psychiatry. 2003;  64 110-111
• 21 Gehlert D R, Gackenheimer S L, Robertson D W. Localization of rat brain binding sites for [³H]tomoxetine, an enantiomerically pure ligand for norepinephrine reuptake sites.  Neurosci. Lett ;  157 203-206
• 22 Bymaster F P, Katner J S, Nelson D L, Hemrick-Luecke S K, Threlkeld P G, Heiligenstein J H, Morin S M, Gehlert D R, Perry K W. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention-deficit/hyperactivity disorder.  Neuropsychopharmacology. 2002;  27 699-711
• 23 Garces K. Atomoxetine for attention deficit/hyperactivity disorder.  Issues Emerg Health Technol. 2003;  46 1-4
• 24 Ring B J, Gillespie J S, Eckstein J A, Wrighton S A. Identification of the human cytochromes P450 responsible for atomoxetine metabolism.  Drug Metab Dispos. 2002;  30 319-323
• 25 Sauer J M, Ponsler G D, Mattiuz E L, Long A J, Witcher J W, Thomasson H R, Desante K A. Disposition and metabolic fate of atomoxetine hydrochloride: the role of CYP2D6 in human disposition and metabolism.  Drug Metab Dispos. 2003;  31 98-107
• 26 Belle D J, Ernest C S, Sauer J M, Smith B P, Thomasson H R, Witcher J W. Effect of potent CYD2D6 inhibition by paroxetine on atomoxetine pharmacokinetics.  J Clin Pharmacol. 2002;  42 1219-1227
• 27 Farid N A, Bergstrom R F, Ziege E A, Parli C J, Lemberger L. Single-dose and steady-state pharmacokinetics of tomoxetine in normal subjects.  J Clin Pharmacol. 1985;  25 296-301
• 28 Witcher J W, Long A, Smith B, Sauer J M, Heiligenstein J, Wilens T, Spencer T, Biederman J. Atomoxetine pharmacokinetics in children and adolescents with attention-deficit hyperactivity disorder.  J Child Adolesc Psychopharmacol. 2003;  13 53-63
• 29 Chalon S A, Desager J P, Desante K A, Frye R F, Witcher J, Long A J, Sauer J M, Golnez J L, Smith B P, Thomasson H R, Horsmans Y. Effect of hepatic impairment on the pharmacokinetics of atomoxetine and its metabolites.  Clin Pharmacol Ther. 2003;  73 178-191
• 30 Wernicke J, Faries D, Girod D, Brown J, Gao H, Kelsey D, Quintana H, Lipetz R, Michelson D, Heiligenstein J. Cardiovascular effects of atomoxetine in children, adolescents, and adults.  Drug Saf. 2003;  26 729-740
• 31 Wernicke J F, Kratochvil C J. Safety profile of atomoxetine in the treatment of children and adolescents with ADHD.  J Clin Psychiatry. 2002;  63 Suppl 12 50-55
• 32 Biederman J, Baldessarini R J, Wright V, Knee D, Harmatz J S. A double-blind placebo controlled study of desipramine in the treatment of ADD: I. Efficacy.  J Am Acad Child Adolesc Psychiatry. 1989;  28 777-784
• 33 Otka J E, Mercadante M T, Scahill L, Leckman J F. Reboxetine as a potentially effective treatment for attention defcit hyperactivity disorder.  J Child Adolesc Psychopharmacol. 2001;  11 203-204
• 34 Pliszka S R. Non-stimulant treatment of attention-deficit/hyperactivity disorder.  CNS Spectr. 2003;  8 253-258
• 35 Popper C W. Pharmacologic alternatives to psychostimulants for the treatment of attention-deficit/hyperactivity disorder.  Child Adolesc Psychiatr Clin N Am. 2000;  9 605-646
• 36 Schweitzer J B, Holcomb H H. Drugs under investigation for attention-deficit hyperactivity disorder.  Curr Opin Investig Drugs. 2002;  3 1207-1211
• 37 Spencer T J, Biederman J. Non-stimulant treatment for Attention-Deficit/Hyperactivity Disorder.  J Atten Disord. 2002;  6 S109-119
• 38 Spencer T, Biederman J, Coffey B, Geller D, Crawford M, Bearman S K, Tarazi R, Faraone S V. A double-blind comparison of desipramine and placebo in children and adolescents with chronic tic disorder and comorbid attention-deficit/hyperactivity disorder.  Arch Gen Psychiatry. 2002;  59 649-656
• 39 Spencer T J, Biederman J, Wilens T E, Faraone S V. Novel treatments for attention-deficit/hyperactivity disorder in children.  J Clin Psychiatry. 2002;  63 Suppl 12 16-22
• 40 Spencer T J, Biederman J, Wilens T, Prince J, Hatch M, Jones J, Harding M, Faraone S V, Seidman L. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder.  Am J Psychiatry. 1998;  155 693-695
• 41 Spencer T, Biederman J, Heiligenstein J, Wilens T, Faries D, Prince J, Faraone S V, Rea J, Witcher J, Zervas S. An open-label, dose-ranging study of atomoxetine in children with attention deficit hyperactivity disorder.  J Child Adolesc Psychopharmacol. 2001;  11 251-265
• 42 Kratochvil C J, Heiligenstein J H, Dittmann R, Spencer T J, Biederman J, Wernicke J, Newcorn J H, Casat C, Milton D, Michelson D. Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial.  J Am Acad Child Adolesc Psychiatry. 2002;  41 776-784
• 43 Spencer T, Heiligenstein J H, Biederman J, Faries D E, Kratochvil C J, Conners C K, Potter W Z. Results from 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder.  J Clin Psychiatry. 2002;  63 1140-1147
• 44 Michelson D, Faries D, Wernicke J, Kelsey D, Kendrick K, Sallee F R, Spencer T. , Atomoxetine ADHD Study Group . Atomoxetine in the treatment of children and adolescents with attention deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study.  Pediatrics. 2001;  108 e83
• 45 Michelson D, Allen A J, Busner J, Casat C, Dunn D, Kratochvil C, Newcorn J, Sallee F R, Sangal R B, Saylor K, West S, Kelsey D, Wernicke J, Trapp N J, Harder D. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study.  Am J Psychiatry. 2002;  159 1896-1901
• 46 Bukstein O G. Once-daily atomoxetine may reduce attention deficit hyperactivity disorder in children and adolescents.  Evid Based Ment Health. 2003;  6 42
• 47 Michelson D, Adler L, Spencer T, Reimherr F W, West S A, Allen A J, Kelsey D, Wernicke J, Dietrich A, Milton D. Atomoxetine in adults with ADHD: two randomized placebo-controlled studies.  Biol Psychiatry. 2003;  53 112-120
• 48 Heinzl S. Atomoxetin für Kinder und Erwachsene mit ADHS.  Psychopharmakotherapie. 2003;  10 120-124
• 49 Heil S H, Holmes H W, Bickel W K, Higgins S T, Badger G J, Laws H F, Faries D E. Comparison of the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate in light drug users.  Drug Alcohol Depend. 2002;  67 149-156