Psychostimulantien und Nicht-Stimulantien in der heutigen und zukünftigen ADHS-Therapie

Zusammenfassung

Die gegenwärtige Pharmakotherapie der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) basiert im Wesentlichen auf dem Psychostimulans Methylphenidat und in geringem Maße – nicht in Deutschland zugelassen – auf Amphetaminen. Als einziges Nicht-Stimulans ist Atomoxetin (Strattera®) als Noradrenalin-Wiederaufnahme-Hemmer zur Behandlung der ADHS zugelassen. Die Substanzen sind allerdings nur zur Pharmakotherapie der ADHS im Kindes- und Jugendalter zugelassen. Die rein symptomatische Pharmakotherapie zielt auf eine Verbesserung der drei ADHS-Kernsymptome Konzentrationsstörungen, Impulsivität und motorische Unruhe ab. Neurobiologische Korrelate der Therapieeffekte sind weiterhin nicht umfangreich aufgeklärt. Bekannt ist mittlerweile die Wirkung auf dopaminerge und noradrenerge Regelkreise. Probleme in der Anwendung der etablierten Substanzen ergeben sich durch kurze Halbwertszeiten der Psychostimulantien, dem noch nicht vollends aufgeklärten Wirkmechanismus, und der strittigen Anwendung von Stimulantien bei den noch in der Entwicklung befindlichen Kindern und Jugendlichen. Viel diskutiert, jedoch nicht hinreichend belegt ist zudem das Abhängigkeits- und Missbrauchspotenzial der Stimulantien. Die neu zur Verfügung stehenden Substanzen Lisdexamfetamin (Vyvanse®) und SPD-465 beruhen auf dem Wirkprinzip der Stimulantien. Mehrere in verschiedenen Entwicklungsstadien befindliche Substanzen weisen verschiedene andere Wirkmechanismen auf: Guanfacine/SPD-503 wirkt agonistisch am α₂A-Adrenozeptor, während ABT-089 und ABT-418 vor allem als Partialagonisten am α₄β₂-Subtyp des nikotinischen Acetylcholinrezeptors ihre Wirkung entfalten. CX-717, -1739, -1942 und -1796 sind Agonisten am glutamatergen αAmino-3-hydroxy-5-methyl-4-isoxazol-Propion-Acid (AMPA)-Rezeptor und PF-3654746 wirkt als Antagonist am histaminergen H ₃-Rezeptor. Guanfacine (Intuniv®), ein α₂A-Adrenozeptor-Agonist und Lisdexamfetamin (Vyvanse®), ein über die Leber aktiviertes „Pro-Drug“ eines Amphetamins sind mittlerweile in den USA zugelassen. Die vorliegende Übersichtsarbeit fasst bewertend die etablierten und insbesondere mögliche, zukünftige symptomatische pharmakologische Therapieoptionen von Stimulantien und Nicht-Stimulantien in der ADHS-Behandlung zusammen.

Abstract

The current pharmacotherapy for attention-deficit hyperactivity disorder (ADHD) is mainly based on the stimulant methylphenidate and to a small extent on amphetamines which are not approved in Germany. The only approved non-stimulant so far is atomoxetin (Strattera®), a norepinephrine reuptake inhibitor. There is no approved pharmacotherapy for adults. The aim of the available medication is a reduction of impulsivity, hyperactivity, and attention deficits. Neurobiological correlates of these effects are still not fully understood, however, a functional implication of dopaminergic and noradrenergic systems is known. To date there is no disease-modifying therapy. The currently available substances have limitations due to the short half-life of stimulants, the unknown pathomechanisms, and the use of stimulants in developing brains with possible long-term side-effects. Moreover, the abuse potential of stimulants is still controversially discussed. The recently developed Lisdexamfetamin and SPD-465 have stimulant effects, too. A number of different developmental substances in preclinical and clinical phases show other mechanisms: SPD-503 represents an α₂A-adrenozeptoragonist, ABT-089 and ABT-418 have partial agonistic effects to the α₄β₂-subtype of nicotinic acetylcholinreceptors, CX-717, -1739, -1942 and -1796 are glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor agonists and PF-3 654 746 exhibits antagonistic properties to histaminergic H ₃-receptors. The α₂A-adrenoceptor-agonist Guanfacine (Intuniv®) and the hepatic metabolised amphetamine prodrug Lisdexamfetamin (Vyvanse®) are yet approved for ADHD treatment in the USA. The aim of this review is to summarise established pharmacological treatment options and the stage of development of upcoming symptomatic stimulant and non-stimulant substances in ADHD therapy.

Schlüsselwörter

ADHS - Therapie - Pharmaka - Stimulantien - Neuentwicklungen

Keywords

ADHD - therapy - drugs - stimulants - developments

Literatur

• 1 Barkley R A. Adolescents with attention-deficit/hyperactivity disorder: an overview of empirically based treatments.  J Psychiatr Pract. 2004;  10 (1) 39-56
• 2 Still G. The Goulstonian lectures on some abnormal psychical conditions in children, Lecture I, II, III.  Lancet. 1902;  1 1008-1012, 1077 – 1082, 1163 – 1168
• 3 Polanczyk G, Lima M S, Horta B L et al. The worldwide prevalence of ADHD: a systematic review and metaregression analysis.  Am J Psychiatry. 2007;  164 (6) 942-948
• 4 Goldman L S, Genel de M, Bezman R J et al. Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Council on Scientific Affairs, American Medical Association.  Jama. 1998;  279 (14) 1100-1107
• 5 Huss M, Holling H, Kurth B M et al. How often are German children and adolescents diagnosed with ADHD? Prevalence based on the judgment of health care professionals: results of the German health and examination survey (KiGGS).  Eur Child Adolesc Psychiatry. 2008;  17 (Suppl 1) 52-58
• 6 Taylor E, Dopfner M, Sergeant J et al. European clinical guidelines for hyperkinetic disorder – first upgrade.  Eur Child Adolesc Psychiatry. 2004;  13 (Suppl 1) 17-30
• 7 Barbaresi W J, Katusic S K, Colligan R C et al. How common is attention-deficit/hyperactivity disorder? Incidence in a population-based birth cohort in Rochester, Minn.  Arch Pediatr Adolesc Med. 2002;  156 (3) 217-224
• 8 Polanczyk G, Jensen P. Epidemiologic considerations in attention deficit hyperactivity disorder: a review and update.  Child Adolesc Psychiatr Clin N Am. 2008;  17 (2) 245-260, vii
• 9 Faraone S V, Biederman J, Spencer T et al. Attention-deficit/hyperactivity disorder in adults: an overview.  Biol Psychiatry. 2000;  48 (1) 9-20
• 10 Fayyad J, De Graaf R, Kessler R et al. Cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder.  Br J Psychiatry. 2007;  190 402-409
• 11 Spencer T J, Biederman J, Wilens T E et al. Overview and neurobiology of attention-deficit/hyperactivity disorder.  J Clin Psychiatry. 2002;  63 (Suppl 12) 3-9
• 12 Faraone S V, Perlis R H, Doyle A E et al. Molecular genetics of attention-deficit/hyperactivity disorder.  Biol Psychiatry. 2005;  57 (11) 1313-1323
• 13 Seidman L J, Valera E M, Makris N. Structural brain imaging of attention-deficit/hyperactivity disorder.  Biol Psychiatry. 2005;  57 (11) 1263-1272
• 14 Viggiano D, Grammatikopoulos G, Sadile A G. A morphometric evidence for a hyperfunctioning mesolimbic system in an animal model of ADHD.  Behav Brain Res. 2002;  130 (1 – 2) 181-189
• 15 Hüther G, Brandl Y, Leuzinger-Bohleber M. ADHS – Frühprävention statt Medikalisierung. Theorie, Forschung, Kontroversen. Göttingen: Vandenhoeck und Ruprecht; 2006
• 16 Zametkin A J, Rapoport J L. Noradrenergic hypothesis of attention deficit disorder with hyperactivity: a critical review. In: Meltzer H Y, (Ed.) Psychopharmacology: The Third Generation of Progress.. New York: Raven Press; 1987: 837-842
• 17 Valera E M, Faraone S V, Murray K E et al. Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder.  Biol Psychiatry. 2007;  61 (12) 1361-1369
• 18 Castellanos F X, Lee P P, Sharp W et al. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder.  Jama. 2002;  288 (14) 1740-1748
• 19 Wilens T E. Effects of methylphenidate on the catecholaminergic system in attention-deficit/hyperactivity disorder.  J Clin Psychopharmacol. 2008;  28 (3 Suppl 2) S46-S53
• 20 Jensen V, Rinholm J E, Johansen T J et al. N-methyl-D-aspartate receptor subunit dysfunction at hippocampal glutamatergic synapses in an animal model of attention-deficit/hyperactivity disorder.  Neuroscience. 2009;  158 (1) 353-364
• 21 Renner T J, Gerlach M, Romanos M et al. Neurobiology of attention-deficit hyperactivity disorder.  Nervenarzt. 2008;  79 (7) 771-781
• 22 Beijsterveldt C E, Middeldorp C M, Slof-Op’t Landt M C et al. Influence of Candidate Genes on Attention Problems in Children: A Longitudinal Study.  Behav Genet. 2010;  41 155-164
• 23 Schuchardt J P, Huss van M, Stauss-Grabo M et al. Significance of long-chain polyunsaturated fatty acids (PUFAs) for the development and behaviour of children.  Eur J Pediatr. 2010;  169 (2) 149-164
• 24 Transler C, Eilander A, Mitchell S et al. The impact of polyunsaturated fatty acids in reducing child attention deficit and hyperactivity disorders.  J Atten Disord. 2010;  14 (3) 232-246
• 25 Gemeinsamer Bundesausschuss (G-BA) .Zusammenfassende Dokumentation zum Beschluss des Gemeinsamen Bundesausschusses über eine Änderung der Arzneimittel-Richtlinie: Anlage III Nummer 44 – Stimulantien. Berlin; 16.9.2010
• 26 Wilens T E, Adler L A, Adams J et al. Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature.  J Am Acad Child Adolesc Psychiatry. 2008;  47 (1) 21-31
• 27 Bukstein O. Substance abuse in patients with attention-deficit/hyperactivity disorder.  Medscape J Med. 2008;  10 (1) 24
• 28 Kollins S H. A qualitative review of issues arising in the use of psycho-stimulant medications in patients with ADHD and co-morbid substance use disorders.  Curr Med Res Opin. 2008;  24 (5) 1345-1357
• 29 Yamamoto B K, Moszczynska A, Gudelsky G A. Amphetamine toxicities: classical and emerging mechanisms.  Ann N Y Acad Sci. 2010;  1187 101-121
• 30 Advokat C. Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD.  J Atten Disord. 2007;  11 (1) 8-16
• 31 Cadet J L, Krasnova I N, Jayanthi S et al. Neurotoxicity of substituted amphetamines: molecular and cellular mechanisms.  Neurotox Res. 2007;  11 (3 – 4) 183-202
• 32 Shaw P, Sharp W S, Morrison M et al. Psychostimulant treatment and the developing cortex in attention deficit hyperactivity disorder.  Am J Psychiatry. 2009;  166 (1) 58-63
• 33 Gould M S, Walsh B T, Munfakh J L et al. Sudden death and use of stimulant medications in youths.  Am J Psychiatry. 2009;  166 (9) 992-1001
• 34 Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) .Methylphenidat-haltige Arzneimittel: Artikel 31 – Verfahren nach Entscheidung der Kommission der Europäischen Gemeinschaft (27.5.2009, Brüssel, Belgien). Bonn 23.6.2009
• 35 Prince J. Catecholamine dysfunction in attention-deficit/hyperactivity disorder: an update.  J Clin Psychopharmacol. 2008;  28 (3 Suppl 2) S39-S45
• 36 Oades R D, Sadile A G, Sagvolden T et al. The control of responsiveness in ADHD by catecholamines: evidence for dopaminergic, noradrenergic and interactive roles.  Dev Sci. 2005;  8 (2) 122-131
• 37 Kostrzewa R M, Kostrzewa J P, Kostrzewa R A et al. Pharmacological models of ADHD.  J Neural Transm. 2008;  115 (2) 287-298
• 38 Greenhill L L, Pliszka S, Dulcan M K et al. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults.  J Am Acad Child Adolesc Psychiatry. 2002;  41 (2 Suppl) 26S-49S
• 39 Swanson J M, Gupta S, Williams L et al. Efficacy of a new pattern of delivery of methylphenidate for the treatment of ADHD: effects on activity level in the classroom and on the playground.  J Am Acad Child Adolesc Psychiatry. 2002;  41 (11) 1306-1314
• 40 Schachter H M, Pham B, King J et al. How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and adolescents? A meta-analysis.  Cmaj. 2001;  165 (11) 1475-1488
• 41 Faraone S V, Spencer T, Aleardi M et al. Meta-analysis of the efficacy of methylphenidate for treating adult attention-deficit/hyperactivity disorder.  J Clin Psychopharmacol. 2004;  24 (1) 24-29
• 42 Koesters M, Becker T, Kilian R et al. Limits of meta-analysis: methylphenidate in the treatment of adult attention-deficit hyperactivity disorder.  J Psychopharmacol. 2009;  23 (7) 733-744
• 43 Brams M, Muniz R, Childress A et al. A randomized, double-blind, crossover study of once-daily dexmethylphenidate in children with attention-deficit hyperactivity disorder: rapid onset of effect.  CNS Drugs. 2008;  22 (8) 693-704
• 44 Rosler M, Fischer R, Ammer R et al. A randomised, placebo-controlled, 24-week, study of low-dose extended-release methylphenidate in adults with attention-deficit/hyperactivity disorder.  Eur Arch Psychiatry Clin Neurosci. 2009;  259 (2) 120-129
• 45 Wilens T E. The nature of the relationship between attention-deficit/hyperactivity disorder and substance use.  J Clin Psychiatry. 2007;  68 (Suppl 11) 4-8
• 46 Wilens T E, Adamson J, Monuteaux M C et al. Effect of prior stimulant treatment for attention-deficit/hyperactivity disorder on subsequent risk for cigarette smoking and alcohol and drug use disorders in adolescents.  Arch Pediatr Adolesc Med. 2008;  162 (10) 916-921
• 47 Biederman J, Monuteaux M C, Spencer T et al. Stimulant therapy and risk for subsequent substance use disorders in male adults with ADHD: a naturalistic controlled 10-year follow-up study.  Am J Psychiatry. 2008;  165 (5) 597-603
• 48 Barkley R A, Fischer M, Smallish L et al. Does the treatment of attention-deficit/hyperactivity disorder with stimulants contribute to drug use/abuse? A 13-year prospective study.  Pediatrics. 2003;  111 (1) 97-109
• 49 Poulin C. From attention-deficit/hyperactivity disorder to medical stimulant use to the diversion of prescribed stimulants to non-medical stimulant use: connecting the dots.  Addiction. 2007;  102 (5) 740-751
• 50 Fuller R W, Hemrick-Luecke S K. Further studies on the long-term depletion of striatal dopamine in iprindole-treated rats by amphetamine.  Neuropharmacology. 1982;  21 (5) 433-438
• 51 U. S. Food and Drug Administration (FDA) .Issues Safety Communication about an Ongoing Review of Medications Used in Children with ADHD. FDA news release. Rockville, Maryland; 15.6.2009
• 52 Vetter V L, Elia J, Erickson C et al. Cardiovascular monitoring of children and adolescents with heart disease receiving medications for attention deficit/hyperactivity disorder (corrected): a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing.  Circulation. 2008;  117 (18) 2407-2423
• 53 Faraone S V, Biederman J, Roe C. Comparative efficacy of Adderall and methylphenidate in attention-deficit/hyperactivity disorder: a meta-analysis.  J Clin Psychopharmacol. 2002;  22 (5) 468-473
• 54 Bymaster F P, Katner J S, Nelson D L et al. 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 (5) 699-711
• 55 Swanson C J, Perry K W, Koch-Krueger S et al. Effect of the attention deficit/hyperactivity disorder drug atomoxetine on extracellular concentrations of norepinephrine and dopamine in several brain regions of the rat.  Neuropharmacology. 2006;  50 (6) 755-760
• 56 Newman L A, Darling J, McGaughy J. Atomoxetine reverses attentional deficits produced by noradrenergic deafferentation of medial prefrontal cortex.  Psychopharmacology. 2008;  200 (1) 39-50
• 57 Michelson D, Faries D, Wernicke J et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study.  Pediatrics. 2001;  108 (5) E83
• 58 Kratochvil C J, Heiligenstein J H, Dittmann R et al. Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial.  J Am Acad Child Adolesc Psychiatry. 2002;  41 (7) 776-784
• 59 Michelson D, Adler L, Spencer T et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies.  Biol Psychiatry. 2003;  53 (2) 112-120
• 60 Adler L A, Spencer T J, Milton D R et al. Long-term, open-label study of the safety and efficacy of atomoxetine in adults with attention-deficit/hyperactivity disorder: an interim analysis.  J Clin Psychiatry. 2005;  66 (3) 294-299
• 61 Adler L A, Spencer T J, Williams D W et al. Long-term, open-label safety and efficacy of atomoxetine in adults with ADHD: final report of a 4-year study.  J Atten Disord. 2008;  12 (3) 248-253
• 62 Adler L A, Spencer T, Brown T E et al. Once-daily atomoxetine for adult attention-deficit/hyperactivity disorder: a 6-month, double-blind trial.  J Clin Psychopharmacol. 2009;  29 (1) 44-50
• 63 Jasinski D R, Faries D E, Moore R J et al. Abuse liability assessment of atomoxetine in a drug-abusing population.  Drug Alcohol Depend. 2008;  95 (1 – 2) 140-146
• 64 Heil S H, Holmes H W, Bickel W K et al. Comparison of the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate in light drug users.  Drug Alcohol Depend. 2002;  67 (2) 149-156
• 65 Bangs M E, Tauscher-Wisniewski S, Polzer J et al. Meta-analysis of suicide-related behavior events in patients treated with atomoxetine.  J Am Acad Child Adolesc Psychiatry. 2008;  47 (2) 209-218
• 66 U. S. Food and Drug Administration (FDA) .Sicherheitshinweis am 29.05.2005: Public Health Advisory Suicidal Thinking in Children and Adolescents Being Treated With Strattera (Atomoxetine). Rockville, Maryland; 2005
• 67 Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) .Pressemitteilung vom 29.9.2005: 18 / 05 Strattera: Warnhinweis auf suizidales Verhalten bei Kindern mit ADHS angeordnet. Bonn; 29.9.2005
• 68 Wang Y, Zheng Y, Du Y et al. Atomoxetine versus methylphenidate in paediatric outpatients with attention deficit hyperactivity disorder: a randomized, double-blind comparison trial.  Aust N Z J Psychiatry. 2007;  41 (3) 222-230
• 69 Newcorn J H, Kratochvil C J, Allen A J et al. Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response.  Am J Psychiatry. 2008;  165 (6) 721-730
• 70 Carlson G A, Dunn D, Kelsey D et al. A pilot study for augmenting atomoxetine with methylphenidate: safety of concomitant therapy in children with attention-deficit/hyperactivity disorder.  Child Adolesc Psychiatry Ment Health. 2007;  1 (1) 10
• 71 Adler L A, Reingold L S, Morrill M S et al. Combination pharmacotherapy for adult ADHD.  Curr Psychiatry Rep. 2006;  8 (5) 409-415
• 72 Buitelaar J K, Gaag R J, Swaab-Barneveld van der H et al. Pindolol and methylphenidate in children with attention-deficit hyperactivity disorder. Clinical efficacy and side-effects.  J Child Psychol Psychiatry. 1996;  37 (5) 587-595
• 73 Arnold L E, Lindsay R L, Lopez F A et al. Treating attention-deficit/hyperactivity disorder with a stimulant transdermal patch: the clinical art.  Pediatrics. 2007;  120 (5) 1100-1106
• 74 Findling R L, Bukstein O G, Melmed R D et al. A randomized, double-blind, placebo-controlled, parallel-group study of methylphenidate transdermal system in pediatric patients with attention-deficit/hyperactivity disorder.  J Clin Psychiatry. 2008;  69 (1) 149-159
• 75 Shire .Press Release. Shire withdraws European Application for DAYTRANA™ (methylphenidate transdermal system). Jersey; 16.3.2009
• 76 Mattingly G. Lisdexamfetamine dimesylate: a prodrug stimulant for the treatment of ADHD in children and adults.  CNS Spectr. 2010;  15 (5) 315-325
• 77 Pennick M. Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine.  Neuropsychiatr Dis Treat. 24;  6 317-327
• 78 Blick S K, Keating G M. Lisdexamfetamine.  Paediatr Drugs. 2007;  9 (2) 129-135 ; discussion 136 – 138
• 79 Biederman J, Krishnan S, Zhang Y et al. Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: a phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study.  Clin Ther. 2007;  29 (3) 450-463
• 80 Biederman J, Boellner S W, Childress A et al. Lisdexamfetamine dimesylate and mixed amphetamine salts extended-release in children with ADHD: a double-blind, placebo-controlled, crossover analog classroom study.  Biol Psychiatry. 2007;  62 (9) 970-976
• 81 Shire .Mündliche Mitteilung der Firma am 10.9.2009. 
• 82 Goodman D W, Surman C BH. New Research on Adult and Pediatric ADHD – Extended Duration Long-acting Amphetamine: SPD465. Medscape Today; 28.June.2007
• 83 Spencer T J, Adler L A, Weisler R H et al. Triple-bead mixed amphetamine salts (SPD465), a novel, enhanced extended-release amphetamine formulation for the treatment of adults with ADHD: a randomized, double-blind, multicenter, placebo-controlled study.  J Clin Psychiatry. 2008;  69 (9) 1437-1448
• 84 Spencer T J, Landgraf J M, Adler L A et al. Attention-deficit/hyperactivity disorder-specific quality of life with triple-bead mixed amphetamine salts (SPD465) in adults: results of a randomized, double-blind, placebo-controlled study.  J Clin Psychiatry. 2008;  69 (11) 1766-1775
• 85 Jarvis B, Figgitt D P. Memantine.  Drugs Aging. 2003;  20 (6) 465-476 ; discussion 477 – 478
• 86 Findling R L, McNamara N K, Stansbrey R J et al. A pilot evaluation of the safety, tolerability, pharmacokinetics, and effectiveness of memantine in pediatric patients with attention-deficit/hyperactivity disorder combined type.  J Child Adolesc Psychopharmacol. 2007;  17 (1) 19-33
• 87 Minzenberg M J, Carter C S. Modafinil: a review of neurochemical actions and effects on cognition.  Neuropsychopharmacology. 2008;  33 (7) 1477-1502
• 88 Biederman J, Pliszka S R. Modafinil improves symptoms of attention-deficit/hyperactivity disorder across subtypes in children and adolescents.  J Pediatr. 2008;  152 (3) 394-399
• 89 Rugino T A, Samsock T C. Modafinil in children with attention-deficit hyperactivity disorder.  Pediatr Neurol. 2003;  29 (2) 136-142
• 90 Taylor F B, Russo J. Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults.  J Child Adolesc Psychopharmacol. 2000;  10 (4) 311-320
• 91 Rugino T. A review of modafinil film-coated tablets for attention-deficit/hyperactivity disorder in children and adolescents.  Neuropsychiatr Dis Treat. 2007;  3 (3) 293-301
• 92 Arnsten A F, Contant T A. Alpha-2 adrenergic agonists decrease distractibility in aged monkeys performing the delayed response task.  Psychopharmacology. 1992;  108 (1 – 2) 159-169
• 93 Steere J C, Arnsten A F. The alpha-2A noradrenergic receptor agonist guanfacine improves visual object discrimination reversal performance in aged rhesus monkeys.  Behav Neurosci. 1997;  111 (5) 883-891
• 94 Sagvolden T. The alpha-2A adrenoceptor agonist guanfacine improves sustained attention and reduces overactivity and impulsiveness in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD).  Behav Brain Funct. 2006;  2 41
• 95 Arnsten A F, Steere J C, Hunt R D. The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder.  Arch Gen Psychiatry. 1996;  53 (5) 448-455
• 96 Boellner S W, Pennick M, Fiske K et al. Pharmacokinetics of a guanfacine extended-release formulation in children and adolescents with attention-deficit-hyperactivity disorder.  Pharmacotherapy. 2007;  27 (9) 1253-1262
• 97 Biederman J, Melmed R D, Patel A et al. A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder.  Pediatrics. 2008;  121 (1) e73-84
• 98 Connor D F, Rubin J. Guanfacine extended release in the treatment of attention deficit hyperactivity disorder in children and adolescents.  Drugs Today. 2010;  46 (5) 299-314
• 99 Decker M W, Bannon A W, Curzon P et al. ABT-089 (2-methyl-3-[2-(S)-pyrrolidinylmethoxy]pyridine dihydrochloride): II. A novel cholinergic channel modulator with effects on cognitive performance in rats and monkeys.  J Pharmacol Exp Ther. 1997;  283 (1) 247-258
• 100 Wilens T E, Verlinden M H, Adler L A et al. ABT-089, a neuronal nicotinic receptor partial agonist, for the treatment of attention-deficit/hyperactivity disorder in adults: results of a pilot study.  Biol Psychiatry. 2006;  59 (11) 1065-1070
• 101 Prendergast M A, Jackson W J, Terry Jr A V et al. Central nicotinic receptor agonists ABT-418, ABT-089, and (-)-nicotine reduce distractibility in adult monkeys.  Psychopharmacology. 1998;  136 (1) 50-58
• 102 Wilens T E, Biederman J, Spencer T J et al. A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the treatment of adults with attention deficit hyperactivity disorder.  Am J Psychiatry. 1999;  156 (12) 1931-1937
• 103 Wilens T E, Decker M W. Neuronal nicotinic receptor agonists for the treatment of attention-deficit/hyperactivity disorder: focus on cognition.  Biochem Pharmacol. 2007;  74 (8) 1212-1223
• 104 Rueter L E, Anderson D J, Briggs C A et al. ABT-089: pharmacological properties of a neuronal nicotinic acetylcholine receptor agonist for the potential treatment of cognitive disorders.  CNS Drug Rev. 2004;  10 (2) 167-182
• 105 Lynch G. Glutamate-based therapeutic approaches: ampakines.  Curr Opin Pharmacol. 2006;  6 (1) 82-88
• 106 Cortex Pharmaceuticals .Clinical Developments and Products/Programs. Meltzer H Y Psychopharmacology: The Third Generation of Progress.. Irvine, CA; 9.15.2009
• 107 Chen J R, Hsu S F, Hsu C D et al. Dietary patterns and blood fatty acid composition in children with attention-deficit hyperactivity disorder in Taiwan.  J Nutr Biochem. 2004;  15 (8) 467-472
• 108 Mitchell E A, Aman M G, Turbott S H et al. Clinical characteristics and serum essential fatty acid levels in hyperactive children.  Clin Pediatr. 1987;  26 (8) 406-411
• 109 Stevens L J, Zentall S S, Abate M L et al. Omega-3 fatty acids in boys with behavior, learning, and health problems.  Physiol Behav. 1996;  59 (4 – 5) 915-920
• 110 Stevens L J, Zentall S S, Deck J L et al. Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder.  Am J Clin Nutr. 1995;  62 (4) 761-768
• 111 Colter A L, Cutler C, Meckling K A. Fatty acid status and behavioural symptoms of attention deficit hyperactivity disorder in adolescents: a case-control study.  Nutr J. 2008;  7 8
• 112 Belanger S A, Vanasse M, Spahis S et al. Omega-3 fatty acid treatment of children with attention-deficit hyperactivity disorder: A randomized, double-blind, placebo-controlled study.  Paediatr Child Health. 2009;  14 (2) 89-98
• 113 Johnson M, Ostlund S, Fransson G et al. Omega-3 /omega-6 fatty acids for attention deficit hyperactivity disorder: a randomized placebo-controlled trial in children and adolescents.  J Atten Disord. 2009;  12 (5) 394-401
• 114 Bradley C. The behavior of children receiving benzedrine.  Am J Psychiatry. 1937;  94 577-585
• 115 Huss M, Lehmkuhl U. Methylphenidate and substance abuse: a review of pharmacology, animal, and clinical studies.  J Atten Disord. 2002;  6 (Suppl 1) S65-S71
• 116 Francis P T. Glutamatergic approaches to the treatment of cognitive and behavioural symptoms of Alzheimer’s disease.  Neurodegener Dis. 2008;  5 (3 – 4) 241-243
• 117 Scheffler R M, Hinshaw S P, Modrek S et al. The global market for ADHD medications.  Health Aff. 2007;  26 (2) 450-457
• 118 Fritze J, Schmauss M. Off-label use: the case of methylphenidate (Ritalin).  Nervenarzt. 2002;  73 (12) 1210-1212
• 119 Deutsche Gesellschaft für Kinder- und Jugendpsychiatrie und Psychotherapie .Leitlinien zur Diagnostik und Therapie von psychischen Störungen im Säuglings-, Kindes- und Jugendalter. 3. Aufl. Köln: Deutscher Ärzte Verlag; 2007
• 120 Greenhill L L, Pliszka S, Dulcan M K et al. Summary of the practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults.  J Am Acad Child Adolesc Psychiatry. 2001;  40 (11) 1352-1355