(19) TZZ _ ¥9B_T (11) EP 2 129 369 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/19 (2006.01) A61K 31/137 (2006.01) 05.06.2013 Bulletin 2013/23 A61P 25/22 (2006.01) A61P 25/26 (2006.01) A61P 25/18 (2006.01) A61P 25/08 (2006.01) (2006.01) (21) Application number: 08700447.9 A61P 25/28 (22) Date of filing: 07.02.2008 (86) International application number: PCT/AU2008/000154 (87) International publication number: WO 2008/095253 (14.08.2008 Gazette 2008/33) (54) TREATMENT OF ADHD BEHANDLUNG VON ADHD TRAITEMENT DU THADA (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A2-2004/002462 HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR • SCHALLER J L ET AL: "Carbamazepine and methylphenidate in ADHD" JOURNAL OF THE (30) Priority: 07.02.2007 US 900043 P AMERICAN ACADEMY OF CHILD AND 30.03.2007 PCT/AU2007/000421 ADOLESCENTPSYCHIATRY, THE ACADEMY, vol. 38, no. 2, 1 February 1999 (1999-02-01), pages (43) Date of publication of application: 112-113, XP009130030 ISSN: 0890-8567 09.12.2009 Bulletin 2009/50 • DAVIDS E. ET AL.: ’A pilot clinical trial of oxcarbazepine in adults with attention-deficit (60) Divisional application: disorder’ PROGRESS IN NEURO- 12174063.3 / 2 505 197 PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY vol. 30, 2006, pages 1033 - 1038, (73) Proprietor: Gosforth Centre (Holdings) Pty Ltd XP005518471 Maroochydore, Queensland 4558 (AU) • SCHREIER H. ET AL.: ’Risperidone for young children with mood disorders and aggressive (72) Inventor: BIRD, Philip behaviour’ JOURNAL OF CHILD AND Maroochydore, Queensland 4558 (AU) ADOLESCENTPSYCHOPHARMACOLOGY vol. 8, no. 1, 1998, pages 49 - 59, XP009035206 (74) Representative: Bridle, Andrew Barry et al • HAMRIN V. ET AL.: ’Gabapentin and Bridle methylphenidatetreatment of preadolescent with Intellectual Property Limited attention deficit hyperactivity disorder and 6F Thomas Way bipolar disorder’ JOURNAL OF CHILD AND Lakesview Internat. Business Park ADOLESCENT PSYCHOPHARMACOLOGY vol. Canterbury, Kent CT3 4JZ (GB) 11, no. 3, 2001, pages 301 - 309, XP008021858 • YITZCHAK F.: ’Visual Event related potentials after methylphenidate and sodium valproate in children with attention deficit hyperactivity disorder’ CLINICAL ELECTROENCEPHALOGRAPHY vol. 24, no. 1, 1993, pages 19 - 24, XP008117472 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 129 369 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 129 369 B1 Description Field and Background to the Invention 5 [0001] The present invention relates to the treatment of individuals with attention-deficit hyperactivity disorder with phenytoin an anti-epileptic mood stabiliser (AEDMS), optionally in combination with psychostimulants, for example to improve psychosocial and cognitive function in such individuals. The present invention also relates to the treatment of individuals with other DSM- IV-TR classified disorders, such as autistic spectrum disorders. The present invention further relates to the treatment of learning difficulties, such as reading difficulties. 10 [0002] Attention-deficit hyperactivity disorder (ADHD) is a developmental disorder distinguished by symptoms of in- attention, hyperactivity and impulsivity (Snyder, Nussbaum, & Robins (Eds.), 2006, Clinical Neuropsychology: A Pocket Handbook for Assessment, APABooks, Washington D.C.). Although ADHD is one of the most frequently diagnosed psychological disorders in childhood long- term studies have demonstrated that symptoms can be maintained into adult- hood. The number of children and adolescents who maintain ADHD symptoms and continue their treatment as adults 15 rangesfrom 36% to65%. Data derived fromlongitudinal studies suggest that although thesymptom cluster of hyperactivity and impulsivity decays over time, the symptoms of inattention persist and the proportion of clinically referred adults with ADHD endorsing prominent inattentive symptoms may be as high as 90%. Adult ADHD has now been recognised as a valid clinical entity that is associated with profound psychosocial and cognitive impairments (Weiss & Murray, 2003, CMAJ. 168(6): 715-22). 20 [0003] Studies of children and adults with ADHD indicate that many experience an array of cognitive impairments that extend beyond the behavioural symptoms outlined in the diagnostic criteria for the disorder (DSM-IV-TR; American Psychiatric Association, 2000). Higher level cognitive and information processing impairments have been reported, the functional day- to-day implications of which include chronic difficulties in maintaining alertness, self- discipline, establishing and keeping routines, and completing tasks. Adults with ADHD change jobs more often, accrue more speeding tickets 25 and have more vehicle accidents than adults without the disorder. [0004] It is well established that ADHD can occur with learning disorders (LD) in children at a rate substantially above chance levels, typically ranging between 25% and 40%. It is also becoming evident that for both ADHD and LD the underlying cognitive impairments seem to persist in a life span perspective. One recent study has examined the co-mor- bidity between ADHD and LD in an adult population. Samuelsson et al., 2004 (J. Learn. Disabil. 37 (2):155-68) found no 30 differences between adults with and without ADHD on measures of either phonological processing sk ills or word decoding; however adults with ADHD performed significantly worse on tests of reading comprehension than those who did not have ADHD. Samuelsson et al. concluded that the results are consistent with the view that reading comprehension involves many of the higher cognitive control functions thought to be impaired in ADHD. [0005] The primary psychopharmacological agents used to treat ADHD are the CNS stimulants (pyschostimulants). 35 Studies of the short term beneficial effects of stimulants on the symptoms of ADHD constitute the largest body of treatment literature of any childhood-onset psychiatric disorder, with the stimulant medications proven effective across diverse age and diagnostic groups. Until August 2005, the only stimulant available under the Australian Pharmaceutical Benefits Scheme (PBS) was dexamphetamine, explaining its predominant place in Australia for the treatment of ADHD. The PBS has since added methylphenidate to the subsidised listing, the most commonly used CNS stimulant in the US for the 40 treatment of ADHD. [0006] In both children and adolescents, stimulants can provide robust improvement in ADHD behavioural symptoms. Despite this, there is continued functional impairment in patients. In adults this was particularly evident in the area which is often referred to as higher executive function. This includes the ability to sequence, organise and integrate cognitive functioning and appears to be used during the complex interpersonal interaction which forms the basis of human social 45 communication: any impairment in this area is quickly detected by almost every individual although it may not be easily identified or described. The use of stimulant medication enables a reduction in the motivation and effort required to complete a task, but they do not appear to enable the individual to make the complex task easier with repeated exposure. Thus the inevitable fatigue that comes from this is not counterbalanced by improved efficiency and eventually the task is ceased. 50 [0007] This same model can be applied to social interaction. For example, we have noted that the tendency to hy- per-focus on a specific topic during conversation did not reduce consistently on stimulants alone, as it would appear that the individual could not process simultaneously the multiple lines of thought that usually take place in normal social interaction. Instead there would be the selection of a preferred more comfortable, possibly more familiar topic and as consequence, resistance to follow the natural flow of the conversation. Thus providing sufficient motivation exists, con- 55 versation can occur, but it still requires considerable effort and is often observed by the listener as awkwardness during the interaction and the individual will inevitably, in time, fati gue due to the effort involved. This results in a similar, although delayed, experience of mental exhaustion and failure to sustain attention that existed prior to the commencement of stimulants. Thus, we have observed that unless there is an improvement in the ability to process information, the improved 2 EP 2 129 369 B1 motivation provided by the stimulant will inevitably wane. This is seen clinically with adults with a diagnosis of ADHD treated with stimulants; the initial and at times miraculous improvement frequently gives way to an increasing disorgan- isation, noncompliance with medication and an eventual ceasing of treatment. [0008] Accordingly, there is a need for an improved treatment for ADHD, which is better, able to reduce the impairment 5 in the underlying cognitive process seen in ADHD patients. [0009] Sodium Valproate (VPA), a mood stabiliser, is the most widely prescribed anti-epileptic drug worldwide. The pharmacological effects of VPA involve a variety