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US008957099B2

(12) United States Patent (10) Patent No.: US 8,957,099 B2 Bird (45) Date of Patent: Feb. 17, 2015

(54) TREATMENT OF ADHD (56) References Cited (75) Inventor: Philip Bird, Maroochydore (AU) U.S. PATENT DOCUMENTS 2002fOO5865.6 A1 5, 2002 Ockert (73) Assignee: Gosforth Centre (Holdings) Pty Ltd., 2003/0060423 A1 3/2003 Plata-Salaman Maroochydore, Queensland (AU) 2004/O258758 A1 12/2004 Gustow et al. 2006/0052428 A1* 3/2006 Chez ...... 514,396 (*) Notice: Subject to any disclaimer, the term of this 2011/0065628 A1 3/2011 Johnson et al. patent is extended or adjusted under 35 2011/02O7718 A1 8, 2011 Bird U.S.C. 154(b) by 895 days. FOREIGN PATENT DOCUMENTS

(21) Appl. No.: 12/526,191 EP 1600 167 A2 11/2005 WO WO93,21910 A1 11, 1993 (22) PCT Filed: Feb. 7, 2008 WO WOO1/39779 A1 6, 2001 WO WO 03/O13514 A1 2, 2003 (86). PCT No.: PCT/AU2O08/OOO154 WO WOO3,O3O899 A2 4/2003 WO 2004.002462 1, 2004 S371 (c)(1), WO WO 2006/120501 A1 11, 2006 WO WO 2008/095221 A1 8, 2008 (2), (4) Date: Oct. 20, 2009 WO WO 2009/O14762 A1 1, 2009 WO WO 2009/139901 A2 11/2009 (87) PCT Pub. No.: WO2008/095253 WO WO 2010/O15O29 A1 2, 2010 WO WO 2011/10O373 A1 8, 2011 PCT Pub. Date: Aug. 14, 2008 WO WO 2011, 143721 A1 11, 2011 (65) Prior Publication Data OTHER PUBLICATIONS US 201O/OO87422 A1 Apr. 8, 2010 Schaller et al., “ and in ADHD.” Journal of the American Academy of Child and Adolescent Psychia try, 38:2, Feb. 1999, pp. 112-113. Related U.S. Application Data EPO, Supplementary European Search Report for European applica tion No. EP08700447, Munich, Germany, Mar. 11, 2010. (63) Continuation-in-part of application No. Frank, “Visual Event Related Potentials. After Methylphenidate and PCT/AU2007/000421, filed on Mar. 30, 2007. Sodium in Children with Attention Deficit Hyperactivity Disorder.” Clinical Electroencephalography, 1993, pp. 19-24, vol. (60) Provisional application No. 60/900,043, filed on Feb. 24, No. 1. 7, 2007. Hamrin et al., “ and Methylphenidate Treatment of a Preadolescent with Attention Deficit Hyperactivity Disorder and Bipolar Disorder.” Journal of Child and Adolescent (51) Int. Cl. Pychopharmacology, 2001, pp. 301-09, vol. 11, No. 3. A6 IK3I/4I66 (2006.01) Schreier, “ for Young Children with Mood Disorders and A6 IK3I/9 (2006.01) Aggressive Behavior.” Journal of Child and Adolescent A 6LX3L/95 (2006.01) Pychopharmacology, 1998, pp. 49-59, vol. 8, No. 1. A6 IK3I/35 (2006.01) (Continued) A6 IK3I/445 (2006.01) A6 IK3I/4458 (2006.01) A6 IK3I/53 (2006.01) Primary Examiner — Jennifer M Kim A6 IK3I/55 (2006.01) (74) Attorney, Agent, or Firm — Leydig, Voit & Mayer, Ltd. (52) U.S. Cl. (57) ABSTRACT CPC ...... A6 IK3I/19 (2013.01); A61 K3I/4166 A method is described for treating attention deficit hyperac (2013.01); A61 K31/195 (2013.01); A61 K tivity disorder (ADHD), by administering to the individual an 3 1/35 (2013.01); A61 K3I/445 (2013.01); anti-epileptic at a dose which is sub-thera A6 IK3I/4458 (2013.01); A61 K3I/53 peutic for mood stabilization, optionally in combination with (2013.01); A61 K3I/55 (2013.01) a psychoStimulant. Also described is a method of improving USPC ...... S14/391 reading comprehension and/or fluency in an individual Suf (58) Field of Classification Search fering from learning difficulties which method comprises CPC ...... A61K 31/4166 administering to the individual an anti-epileptic mood stabi USPC ...... 514/217,317,326,376, 386, 391,455, lizer. 514/557,561 See application file for complete search history. 2 Claims, No Drawings US 8,957,099 B2 Page 2

(56) References Cited Scheffer et al., Am. J. Psychiatry, 162(1): 58-64 (Jan. 2005). Silva et al., J. Am. Acad Child Adolesc. Psychiatry, 35(3): 352-358 OTHER PUBLICATIONS (Mar. 1996). Yitzchak, Clinical Electroencephalography, 24(1): 19-24 (1993). Davids et al., “A pilot of in adults with Zaremba et al., Pharmacological Reports, 58: 1-12 (2008). Australian Patent Office, International Search Report in International attention deficit hyperactivity disorder.” Progress in Neuro Application No. PCT/AU2009/001000 (Oct. 6, 2009). Psychopharmacology & Biological Psychiatry, 2006, pp. 1033-1038, Australian Patent Office, International Search Report in International vol. 30. Application No. PCT/AU2008/000154 (Jun. 10, 2009). Baskys et al., Development Research, 56: 393-400 (2002). Australian Patent Office, International Search Report in International Bernejo, Movement Disorders, 22(14): (2007). Application No. PCT/AU2007/00421 (Jun. 29, 2007). Chiu et al., Psychiatry and Clinical Neurosciences, 61: 630-633 United Kingdom Patent Office, Search Report in GB Patent Appli (2007). cation No. 1111712.4 (Oct. 11, 2011). Dhikav, Medical Hypotheses 67: 725-728 (2006). United Kingdom Patent Office, Search Report in GB Patent Appli Grunze, Dialogues Clin Neurosci., 10: 77-89 (2008). cation No. 1111712.4 (Feb. 10, 2012). Hill, Movement Disorders, 18(11): 1301-1371 (2003). Loy et al., Journal of Molecular Neuroscience, 19:303-307 (2002). Miyazaki et al., Brain and Development, 28: 470-472 (2006). Tekinet al., Journal of Neural Transmission, 105: 295-303 (1998). Reis et al. Bras Psiquiatr., 30(2): 132-135 (2008). Rogawski, Nature Medicine, 10(7), (Jul. 2004). * cited by examiner US 8,957,099 B2 1. 2 TREATMENT OF ADHD diagnostic groups. Until August 2005, the only available under the Australian Pharmaceutical Benefits FIELD AND BACKGROUND TO THE Scheme (PBS) was dexamphetamine, explaining its predomi INVENTION nant place in Australia for the treatment of ADHD. The PBS has since added methylphenidate to the Subsidised listing, the The present invention relates to the treatment of individuals most commonly used CNS stimulant in the US for the treat with attention-deficit hyperactivity disorder with an anti-epi ment of ADHD. leptic mood stabiliser (AEDMS), optionally in combination In both children and adolescents, can provide with psychoStimulants, for example to improve psychosocial robust improvement in ADHD behavioural symptoms. and cognitive function in Such individuals. The present inven 10 Despite this, there is continued functional impairment in tion also relates to the treatment of individuals with other patients. In adults this was particularly evident in the area DSM-IV-TR classified disorders, such as autistic spectrum which is often referred to as higher executive function. This disorders. The present invention further relates to the treat includes the ability to sequence, organise and integrate cog ment of learning difficulties, such as reading difficulties. nitive functioning and appears to be used during the complex Attention-deficit hyperactivity disorder (ADHD) is a 15 interpersonal interaction which forms the basis of human developmental disorder distinguished by symptoms of inat Social communication: any impairment in this area is quickly tention, hyperactivity and impulsivity (Snyder, Nussbaum, & detected by almost every individual although it may not be Robins (Eds.), 2006, Clinical Neuropsychology: A Pocket easily identified or described. The use of stimulant medica Handbook for Assessment, APABooks, Washington D.C.). tion enables a reduction in the motivation and effort required Although ADHD is one of the most frequently diagnosed to complete a task, but they do not appear to enable the psychological disorders in childhood long-term studies have individual to make the complex task easier with repeated demonstrated that symptoms can be maintained into adult exposure. Thus the inevitable fatigue that comes from this is hood. The number of children and adolescents who maintain not counterbalanced by improved efficiency and eventually ADHD symptoms and continue their treatment as adults the task is ceased. ranges from 36% to 65%. Data derived from longitudinal 25 This same model can be applied to social interaction. For studies suggest that although the symptom cluster of hyper example, we have noted that the tendency to hyper-focus on a activity and impulsivity decays over time, the symptoms of specific topic during conversation did not reduce consistently inattention persist and the proportion of clinically referred on stimulants alone, as it would appear that the individual adults with ADHD endorsing prominent inattentive symp could not process simultaneously the multiple lines of toms may be as high as 90%. Adult ADHD has now been 30 thought that usually take place in normal Social interaction. recognised as a valid clinical entity that is associated with Instead there would be the selection of a preferred more profound psychosocial and cognitive impairments (Weiss & comfortable, possibly more familiar topic and as conse Murray, 2003, CMAJ. 168(6): 715-22). quence, resistance to follow the natural flow of the conversa Studies of children and adults with ADHD indicate that tion. Thus providing sufficient motivation exists, conversa many experience an array of cognitive impairments that 35 tion can occur, but it still requires considerable effort and is extend beyond the behavioural symptoms outlined in the often observed by the listener as awkwardness during the diagnostic criteria for the disorder (DSM-IV-TR; American interaction and the individual will inevitably, in time, fatigue Psychiatric Association, 2000). Higher level cognitive and due to the effort involved. This results in a similar, although information processing impairments have been reported, the delayed, experience of mental exhaustion and failure to Sus functional day-to-day implications of which include chronic 40 tain attention that existed prior to the commencement of difficulties in maintaining alertness, self-discipline, estab stimulants. Thus, we have observed that unless there is an lishing and keeping routines, and completing tasks. Adults improvement in the ability to process information, the with ADHD change jobs more often, accrue more speeding improved motivation provided by the stimulant will inevita tickets and have more vehicle accidents than adults without bly wane. This is seen clinically with adults with a diagnosis the disorder. 45 of ADHD treated with stimulants; the initial and at times It is well established that ADHD can occur with learning miraculous improvement frequently gives way to an increas disorders (LD) in children at a rate substantially above chance ing disorganisation, noncompliance with and an levels, typically ranging between 25% and 40%. It is also eventual ceasing of treatment. becoming evident that for both ADHD and LD the underlying Accordingly, there is a need for an improved treatment for cognitive impairments seem to persist in a life span perspec 50 ADHD, which is better, able to reduce the impairment in the tive. One recent study has examined the co-morbidity underlying cognitive process seen in ADHD patients. between ADHD and LD in an adult population. Samuelsson et al., 2004 (J. Learn. Disabil. 37(2):155-68) found no differ SUMMARY OF THE INVENTION ences between adults with and without ADHD on measures of either phonological processing skills or word decoding; how 55 Sodium Valproate (VPA), a mood stabiliser, is the most ever adults with ADHD performed significantly worse on widely prescribed anti-epileptic drug worldwide. The phar tests of reading comprehension than those who did not have macological effects of VPA involve a variety of mechanisms, ADHD. Samuelsson et al. concluded that the results are con including gamma-aminobutyric acid (GABA)-ergic trans sistent with the view that reading comprehension involves mission, reduced release and/or effects of excitatory amino many of the higher cognitive control functions thought to be 60 acids, blockade of Voltage-gated Sodium channels and modu impaired in ADHD. lation dopaminergic and serotoninergic transmission. In addi The primary psychopharmacological agents used to treat tion to its efficacy in treating , VPA has also shown to ADHD are the CNS stimulants (pyschostimulants). Studies be effective in the treatment of acute mania in six controlled of the short term beneficial effects of stimulants on the symp trials, and is now approved in both the USA and Australia for toms of ADHD constitute the largest body of treatment lit 65 this use. erature of any childhood-onset psychiatric disorder, with the We have now found that administration of this anti-epilep stimulant proven effective across diverse age and tic mood stabiliser at significantly reduced dosages compared US 8,957,099 B2 3 4 to those used to control epilepsy and stabilise moods (e.g. in bination of therapy, be sustained in a more effortless, consis individuals suffering from bipolar disorder/manic depres tent and therefore functionally usable form. sion) to individuals suffering from ADHD resulted in a num Thus, our clinical observations following augmentation of ber of unexpected improvements in cognitive and psychoSo the stimulant treatment with anti-epileptic mood stabilisers cial functioning. Patients often described their thoughts Suggested an improvement of the residual cognitive impair becoming more manageable and less chaotic. This seemed to ment seen with stimulant alone, a frequent and important allow for more temporal sequencing of ideas, with a resulting example being the improved self reliance, organisation and overall improvement in psychosocial functioning. These consistence in taking all their prescribed medication. This results have subsequently been repeated for a number of other reduced effort required to consistently remember medication anti-epileptic mood stabilisers when administered at simi 10 often having a dramatic effect. It was as if at last this activity larly low doses. became automatic instead of the need to continually to allo Our results indicate that these anti-epileptic exhibit a cate mental effort to undertake this simple and repetitive task. pharmacological profile at low doses which is fundamentally Previously, the compliance of medication assessed by phar different from that seen within the anti-epileptic or mood macy fill rates even with extended release stimulant formu stabilising range. Without wishing to be bound by theory, we 15 lations was less than 30% after 9 months. By contrast, in our believe that the explanation for this is that in low doses the clinic-based sample the combination of a mood stabiliser at anti-epileptic drugs do not hyperpolarise all neurones across low dose and stimulant has improved significantly our the cerebral cortex but selectively they prolong excitation of patients adherence to taking all their prescribed medication those neurones previously excited, thereby improving work in comparison to what was previously achieved on stimulant ing memory, whilst having the opposite action on resting alone. potentials of inactive neurons, thereby reducing interference We have noted benefits in over 90% of those trialled on an and distractibility. This could be referred as cognitive tuning, anti-epileptic drug (at low doses). In particular the benefits cognitive coordination, pacing (i.e. not jumping erratically included a subjective improvement in the ability to organise form one thought to the next), efficient attention shifting (this thoughts in conversation with less active effort than was ever is the cognitive function whereby one can drift instanta 25 previously experienced. neously from a thought whilst think about something else Attention on the content of conversation rather than on the related and come back to the original thought, this requires structure. The mental effort was previously expended on the ability to keep thoughts in the back of one's mind without just attending to what was being said with little remain getting lost or losing the thread). ing mental available to interpret and then respond appro A significant number of patients who reported a subjective 30 priately to the content of the conversations improvement in ADHD symptoms also described an It was observed that many of conversational and Social improvement in their reading and verbal comprehension adaptations which were previously used, were disre abilities. They were more able to attend to the content of both garded, often over a remarkably short time. The changes the text and conversation, which was in direct contrast to their occurring were often evident between the individuals previously frustrating experiences of needing to put most of 35 weekly appointments. This would suggest that they were their mental effort into either the process of reading or listen therapeutically mediated; by the temporal relationship ing with relatively little comprehension of the content occur to the initiation of medication, the apparent effortless ring. There is a body of evidence indicating that faulty sac nature of the change and also the patients had received cades are a characteristic of individuals who are reading no specific instruction on methods to improve their disabled. We have been able to assess oculomotor function 40 Social functioning. With these changes in mind it was using the Developmental Eye Movement Test (DEM): this remarkable that despite their relative persistence follow has shown improvement comparable with that of the patients ing stabilisation on stimulants they had improved over a own subjective experience of a reduction in the mental effort very short time period after anti-epileptic drug augmen required to follow written text. Again, these results have been tation. repeated for a number of other anti-epileptic mood stabilisers 45 These positive outcomes are not only initially robust but when administered at low doses. This leads us to the hypoth then continue to improve over time. This pattern is in contrast esis that the low dose of the mood stabiliser is having a to our the past clinical experience of treating adult with beneficial effect on fixational and Saccade activity during ADHD with stimulants alone, in which considerable effort reading and non reading tasks. The magnitude of the change from that patient the close family and the therapist is required described by many of these individuals was comparable to 50 to maintain the early improvement. It has been further noted changes in behaviour that occurred during the initiation of that there appears no loss in efficacy or tolerance to the medi stimulant therapy. cation over the 18 months since the first trials were com Additionally, the self-reported improvement appeared to menced. In the clinic population it has been further noted that correlate closely to notable changes in the complex interper the long term compliance with the combination of a stimulant Sonal interaction during the clinical consultation. Verbal 55 and the anti-epileptic drug has reliably exceeded that on interactions between the treating psychiatrist and patients stimulant alone. appeared more spontaneous and fluid, and patients appeared Further studies in our clinic also showed that monotherapy to be able to provide a higher level of subtle non-verbal with a low dose of mood stabiliser (no stimulant) also led to feedback during conversations. It would appear, based on this many of the significant improvements in the symptoms of more appropriate non-verbal behaviour, that patients were 60 ADHD that were seen with the combination therapy. experiencing a greater understanding of the content as a con Thus, in Summary, the present invention is based on the sequence of less mental effort expended on the process of the finding that when used in very low doses, i.e. below the levels conversation. Patients also reported that reading seemed to used in epilepsy or mood disorders, anti-epileptic drugs can require less effort, resulting in greater enjoyment in a task that improve alone or in combination with stimulants in adults and had previously been very cognitively demanding. These tasks 65 children suffering from ADHD. which previously could only be maintained for relatively Accordingly, in a first aspect, the present invention pro short periods of time without fatigue, could now on the com vides a method of treating attention deficit hyperactivity dis US 8,957,099 B2 5 6 order (ADHD) in an individual suffering from said disorder b) administering therapeutically effective amounts of an but not epilepsy or bipolar disorder, which method comprises anti-epileptic mood Stabiliser and optionally a psycho administering to the individual an anti-epileptic mood stabi stimulant Such that the Subjects reading comprehension liser at a dose which is sub-therapeutic for mood stabilisation. and/or fluency is improved. The present invention also provides a method of improving 5 The present invention also provides an anti-epileptic mood cognitive function and/or psychosocial functioning in an stabiliser for use in a method of improving reading compre individual suffering from attention deficit hyperactivity dis hension and/or fluency as referred to above as well as the use order (ADHD), which method comprises administering to the of an anti-epileptic mood stabiliser in the manufacture of a individual an anti-epileptic mood stabiliser at a dose which is medicament for use in Such a method. 10 The present invention further provides a combination of an sub-therapeutic for mood stabilisation. anti-epileptic mood stabiliser and a psychostimulant for use Preferably the patient does not suffer from epilepsy or in a method of improving reading comprehension and/or bipolar disorder. fluency as referred to above as well as the use of a combina In a related aspect, the present invention provides a method tion of an anti-epileptic mood stabiliser and a psychoStimu of treating attention deficit hyperactivity disorder (ADHD) in 15 lant in the manufacture of a medicament for use in Such a an individual suffering from said disorder but not epilepsy or method. bipolar disorder, which method comprises administering to In a third aspect, the present invention provides a method of the individual (i) an anti-epileptic mood stabiliser at a dose treating ocularmotor dysfunction in an individual Suffering which is sub-therapeutic for mood stabilisation and (ii) a from learning difficulties which method comprises adminis psychostimulant. tering to the individual an anti-epileptic mood stabiliser, and The present invention also provides a method of improving optionally a psychoStimulant. cognitive function and/or psychosocial functioning in an The present invention also provides an anti-epileptic mood individual suffering from attention deficit hyperactivity dis stabiliser, optionally in combination with a psychoStimulant, order (ADHD), which method comprises administering to the for use in a method of treating ocularmotor dysfunction as individual an anti-epileptic mood stabiliser at a dose which is 25 referred to above as well as the use of an anti-epileptic mood Sub-therapeutic for mood stabilisation, and a psychoStimu stabiliser, optionally in combination with a psychoStimulant, lant. in the manufacture of a medicament for use in Such a method. Preferably the patient does not suffer from epilepsy or In a fourth aspect, the present invention provides a method bipolar disorder. of treating abnormal saccadic eye movements in an individual 30 which method comprises administering to the individual an In a related aspect, the present invention also provides a anti-epileptic mood stabiliser and optionally a psychoStimu method of treating attention deficit hyperactivity disorder lant. (ADHD) comprising: The present invention also provides an anti-epileptic mood a) identifying a subject in need of treatment for ADHD; stabiliser, optionally in combination with a psychoStimulant, b) administering therapeutically effective amounts of an 35 for use in a method of treating abnormal saccadic eye move anti-epileptic mood Stabiliser and optionally a psycho ments as referred to above as well as the use of an anti stimulant so as to improve the Subject's cognitive func epileptic mood stabiliser, optionally in combination with a tion and/or psychosocial functioning. psychostimulant, in the manufacture of a medicament for use The present invention also provides an anti-epileptic mood in Such a method. stabiliser for use in a method of treating ADHD and in 40 In a fifth aspect, the present invention provides a method of improving cognitive function and/or psychosocial function improving cerebellar-mediated motor planning and sequenc ing as referred to above as well as the use of an anti-epileptic ing in an individual. Such as an individual Suffering from mood stabiliser in the manufacture of a medicament for use in learning difficulties, which method comprises administering Such a method. to the individual an anti-epileptic mood stabiliser, and option The present invention further provides a combination of an 45 ally a psychoStimulant. anti-epileptic mood Stabiliser and a psychoStimulant for use The present invention also provides an anti-epileptic mood in a method of treating ADHD and improving cognitive func stabiliser, optionally in combination with a psychoStimulant, tion and/or psychosocial functioning as referred to above as for use in a method of improving cerebellar-mediated motor well as the use of a combination of an anti-epileptic mood planning and sequencing in an individual. Such as an indi stabiliser and a psychoStimulant in the manufacture of a medi 50 vidual suffering from learning difficulties, as referred to cament for use in Such a method. above as well as the use of an anti-epileptic mood stabiliser, In a second aspect, the present invention provides a method optionally in combination with a psychoStimulant, in the of improving reading comprehension in an individual Suffer manufacture of a medicament for use in Such a method. ing from learning difficulties, such as reading difficulties, In the various aspects mentioned above, it is preferred that 55 the individual does not suffer from epilepsy or bipolar disor which method comprises administering to the individual an der. anti-epileptic mood stabiliser. In a particularly preferred embodiment of the different In a related aspect, the present invention provides a method aspects mentioned above, the dose of the anti-epileptic mood of improving reading comprehension and/or fluency in an stabiliser administered to the individual is sub-therapeutic for individual Suffering from learning difficulties, such as read 60 mood stabilisation. ing difficulties, which method comprises administering to the We have extended outside the area of ADHD the cognitive individual an anti-epileptic mood stabiliser and a psycho benefits identified with the use of low dose anti-epileptic stimulant. mood stabiliser. In a related aspect, the present invention also provides a The ability to communicate effectively, sequence and orga method of treating learning difficulties comprising: 65 nise thoughts is an essential aspect of all human interaction a) identifying a Subject in need of treatment for learning and communication. This is considered to be dependent on difficulties; higher executive functioning which serve to coordinate and US 8,957,099 B2 7 8 integrate the cognitive functioning of the brain. When this is ceutical composition is provided as a dosage unit containing impaired it can lead to frustration and the perceived inability a daily, or Sub-daily, dose of anti-epileptic mood Stabiliser to have a sense of control in general Social functioning. This which is sub-therapeutic for mood stabilisation together with can be conceptualised as a deficit of higher executive func a daily, or Sub-daily dose of the psychostimulant. The phar tioning, and is associated with a poorer psychosocial outcome maceutical composition is preferably formulated for oral in all psychological conditions. Without the ability to estab administration (e.g. tablets, capsules, syrups, elixirs and the lish and maintain positive interpersonal relationships the like). In one embodiment, the mood stabiliser is selected from individual is more Vulnerable to a poorer outcome from nega Sodium valproate, or a derivative thereof, , car tive life events. bamazepine, orphenytoin and the daily dose of the Following our success with ADHD patients, we hypoth 10 esised that the benefits noted in ADHD from the use of low mood stabiliser is as specified below in the detailed descrip dose anti-epileptics may also be obtained in other conditions tion for these compounds. In a related embodiment, the where the individual displayed a deficit in the ability to pyschoStimulant is selected from methylphenidate, amphet sequence and organise their thoughts which could lead to an amines (e.g. or mixed impairment in psychological functioning. This deficit may 15 salts) and and the daily dose of the pyschoStimulant also lead to the development of anxiety due to the inability to is as specified below in the detailed description for these control the focus of attention, thereby resulting in a patho compounds. logical focus on noxious stimuli. We have subsequently noted clinically that in other condi DETAILED DESCRIPTION OF THE INVENTION tions particularly where there are commonly Such impair ments such as with anxiety, the use of low dose anti-epileptics Unless defined otherwise, all technical and scientific terms can also result in Sustained improvement in function and a used herein have the same meaning as commonly understood reduction in Symptoms. This has been noted specifically in by one of ordinary skill in the art (e.g. in pharmaceutical the treatment of Generalised Anxiety Disorder with a dose of chemistry and medicine, including psychiatry). 50 to 150 mg of sodium valproate without the co-administra 25 Throughout this specification the word “comprise', or tion of a stimulant. variations such as "comprises' or “comprising, will be Thus the improvements obtained with ADHD patients understood to imply the inclusion of a stated element, integer address cognitive deficiencies that are also seen in other dis or step, or group of elements, integers or steps, but not the orders that fall within the DSM-IV-TR classification, in par exclusion of any other element, integer or step, or group of ticular: Communication Disorders (e.g. Expressive Language 30 elements, integers or steps. Disorder, Mixed Receptive-Expressive Language Disorder, Throughout this specification, reference to numerical val Phonological Disorder, Stuttering, Communication Disorder ues, unless stated otherwise, is to be taken as meaning “about NOS (Not Otherwise Specified); Pervasive Development that numerical value. The term “about is used to indicate that Disorders (Autistic Spectrum Disorders such as Autistic Dis a value includes the inherent variation of error for the device order and Asperger's Disorder: Rett's Disorder, Childhood 35 Disintegrative Disorder and Pervasive Developmental Disor and the method being employed to determine the value, or the der NOS); and Anxiety Disorders (e.g. Generalized Anxiety variation that exists among the study Subjects. Disorder). In one aspect, the present invention relates to methods of Accordingly, in a sixth aspect, the present invention also treating individuals with attention-deficit hyperactivity disor provides a method of treating a disorder selected from the 40 der (ADHD). ADHD is a developmental disorder distin group consisting of Communication Disorders; Pervasive guished by symptoms of inattention, hyperactivity and impul Development Disorders; and Anxiety Disorders in an indi sivity. Although ADHD is one of the most frequently vidual suffering from said disorder but not epilepsy or bipolar diagnosed psychological disorders in childhood, long-term disorder, which method comprises administering to the indi studies have demonstrated that symptoms are often main vidual an anti-epileptic mood Stabiliser at a dose which is 45 tained into adulthood. Diagnostic criteria for ADHD are sub-therapeutic for mood stabilisation. given in the Fourth Edition of the Diagnostic and Statistical It is preferred that the individual does not suffer from Manual of Mental Disorders (American Psychiatric Associa epilepsy or bipolar disorder. In a seventh aspect, the present tion, 2000), referred to as DSM-IV-TR. See also Snyder, invention provides a pharmaceutical kit comprising a first Nussbaum, & Robins (Eds.), 2006, ibid (especially Box 2) pharmaceutical composition comprising (i) an anti-epileptic 50 and Weiss & Murray, 2003, ibid. mood stabiliser together with a pharmaceutically acceptable Individuals with ADHD may also have other disorders carrier or diluent and (ii) a second pharmaceutical composi Such as epilepsy or bipolar disorder. In embodiment it is tion comprising a psychoStimulant together with a pharma preferred that the individual who it is desired to treat does not ceutically acceptable carrier or diluent. Preferably the first suffer from epilepsy or bipolar disorder (the latter typically as pharmaceutical composition is provided as a dosage unit 55 defined in DSM-IV-TR). It may also be preferred that the containing a dose of anti-epileptic mood stabiliser which is individual does not suffer from a psychotic disorder. sub-therapeutic for mood stabilisation. The kit may also The treatment of such individuals using the methods of include instructions for use of the combination of the first and invention is typically intended to improve cognitive function second pharmaceutical compositions in one or more of the and/or psychosocial functioning in the individuals. The term methods of the first and second aspects of the invention. The 60 “cognitive function and/or psychosocial functioning pharmaceutical compositions are preferably formulated for includes executive function, informational processing, Verbal oral administration (e.g. tablets, capsules, syrups, elixirs and comprehension, Verbal expression/fluency, reading compre the like) or as a patch. hension/fluency, saccadic eye movements, non-verbal feed In a related aspect, the present invention provides a phar back/behaviour in response to verbal interaction, interper maceutical composition comprising an anti-epileptic mood 65 Sonal interaction and the like. stabiliser and a psychoStimulant together with a pharmaceu In a second aspect, the present invention relates to methods tically acceptable carrier or diluent. Preferably the pharma of treating individuals with learning difficulties, such as read US 8,957,099 B2 10 ing difficulties/disorders and language disorders, which can Disorder, Mixed Receptive-Expressive Language Disorder, include ADHD sufferers but also includes non-ADHD suf Phonological Disorder, Stuttering, Communication Disorder ferers. NOS (Not Otherwise Specified); Pervasive Development In a related aspect, the present invention relates to methods Disorders (Autistic Spectrum Disorders such as Autistic Dis of treating individuals with ocularmotor dysfunction in indi order and Asperger's Disorder: Rett's Disorder, Childhood viduals Suffering from learning difficulties, such as reading Disintegrative Disorder and Pervasive Developmental Disor difficulties/disorders and language disorders, which again der NOS); and Anxiety Disorders (e.g. Generalized Anxiety can include ADHD sufferers but also includes non-ADHD Disorder). sufferers. Ocularmotor dysfunction includes faulty/abnormal Accordingly, the present invention also provides a method saccades, such as deficiencies in Suppressing fast saccades. 10 Saccades are the rapid eye movements that take the eyes from of treating a disorder selected from the group consisting of one word to the next. When we read, we make mostly forward Communication Disorders; Pervasive Development Disor saccades. Backward saccade movements are used to read ders; and Anxiety Disorders in an individual suffering from Something over again for better comprehension. Individuals said disorder but not epilepsy or bipolar disorder, which with reading difficulties, including reading comprehension, 15 method comprises administering to the individual an anti often have more frequent backward saccades than normal epileptic mood stabiliser at a dose which is sub-therapeutic individuals. for mood stabilisation. In particular, the methods of the inven We have found the use of low doses of anti-epileptic mood tion may be used to improve cognitive function and/or psy stabilisers can improve eye movements (as assessed using the chosocial functioning an individual Suffering from one or Developmental Eye Movement test) compared with and with more of these disorders. out treatment with stimulant alone. At higher doses of the The methods of the invention may be used to treat children anti-epileptic this benefit is lost and can cause a slowing in the or adults. For examples, patients may be pre-pubescent, at measurements relative to baseline. With thus hypothesise that least 16 years old or at least 18 years old. in some patients the low dose anti-epileptic is improving the The methods of the invention involve administering to the visual-verbal automaticity and thus improving the reading 25 individual an anti-epileptic mood Stabiliser, also referred to as ability. We Suggest that this is through an improvement in the an . Combinations of two or more mood stabi faulty saccades. lisers may also be administered. Thus, in another aspect, the present invention relates to A large number of anti-epileptic mood stabilisers (anticon methods of treating abnormal saccadic eye movements in Vulsants) are known in the art and include (e.g. individuals. Such as individuals with learning difficulties, 30 , , ), Such as reading difficulties/disorders and language disorders, (e.g. , , , ), car which again can include ADHD sufferers but also includes boxamides (e.g. carbamazepine ((Z)-5H-dibenzob.f. non-ADHD sufferers. Such individuals may have difficulties azepine-5-carboxamide), oxcarbazepine (10.11-Dihydro-10 in fixation and Suppressing fast saccades, especially back oxo-5H-dibenzb.fazepine-5-carboxamide), ), wards saccades. Thus the term "abnormal saccadic eye move 35 fatty acids (e.g. ((3S)-1-4.4-bis(3-methylthiophen ments' includes more frequent backward saccades. The term 2-yl)but-3-enylpiperidine-3-carboxylic acid) and the val also includes increased saccadic latency. The methods of the proates—valproic acid, sodium valproate and divailproex invention may also be directed to improving antisaccades Sodium), (e.g. (3-ethyl-5-phenyl-imida performance in an individual, e.g. accuracy and/or response Zolidine-2,4-dione), (5,5-diphenylimidazolidine times. 40 2,4-dione), Sodium, ), oxazo The results that we have obtained also indicate that anti lidinediones (e.g. , , epileptic mood stabilisers are having a beneficial effect on ). (e.g. , ), cerebellar function, especially in relation to motor planning (e.g. ), Sulfonamides (e.g. aceta and sequencing which is often impaired in patients with Zolamide, methazolamide, , ), aminobu learning difficulties. The cerebellum is believed to be 45 tyric acids, Sulfamate-substituted monosaccharides (e.g. topi involved in timing of movement and the automation of skills. ramate (2,3:4.5-Bis-O-(1-methylethylidene)-beta-D- Whilst impairment of these functions may be particularly fructopyranose Sulfamate)), gaba analogs (e.g. gabapentin noticeable in patients with learning difficulties, individuals (2-1-aminomethyl)cyclohexyl)acetic acid), pregabalin (S)- who would not be considered to have learning difficulties in 3-(aminomethyl)-5-methylhexanoic acid)), trizines (e.g. the conventional sense may also benefit from the treatments 50 ), , losigamone, , rufina described herein to improve skill acquisition and coordina mide, and so on. Particular examples include tion, particularly left and right hemisphere coordination. Sodium valproate (sodium di-n-propylacetic acid) and deriva Accordingly, the invention also provides methods for tives thereof (valproic acid, , semi-sodium improve skill acquisition and coordination, such as left and valproate, divalproex, valproylamides such as Valpromide, right hemisphere coordination, by administering to individu 55 Depakene, Depakote, Depakote ER), tiagabine, ethoSuxim als anti-epileptic mood stabilisers and optionally psycho ide, Zonisamide, carbamazepine, oXcarbazepine, lamot stimulants as described herein in the various other aspects. rigine, tiagabine, gabapentin, pregabalin, phenytoin, primi Such individuals include, but are not limited to, those with done, phenobarbitone, phenobarital, topiramate, diazepam learning difficulties. and related compounds, and levetiracetam. Particularly pre Individuals with learning difficulties include dyslexic indi 60 ferred are sodium valproate and derivatives thereof, tiagab viduals and those with non-verbal learning disorders, such as ine, topiramate, carbamazepine, oXcarbazepine, ethotoin, phonological deficiencies. Learning difficulties include read phenytoin, gabapentin and/or pregabalin. It will be appreci ing, writing and spelling difficulties. ated by a person skilled in the art that reference to the various Further the improvements obtained with ADHD patients compounds referred to above includes pharmaceutically address cognitive deficiencies that are also seen in other dis 65 acceptable salts thereof, as appropriate. In addition, many of orders that fall within the DSM-IV-TR classification, in par the compounds referred to above are available in different ticular: Communication Disorders (e.g. Expressive Language formulations, such as slow release, extended release. All Such US 8,957,099 B2 11 12 formulations are encompassed within the scope of the present The following is a list of AED with their usual minimum invention for use in the methods of the invention. anti-convulsant dose to enable a calculation of an estimate of In one embodiment, the mood stabiliser is a gamma-ami the initial low dose AED dose. A sub-therapeutic dose for nobutyric acid (GABA) enhancer, i.e. a GABAergic agent. mood stabilisation in the context of the present invention is The dose administered of the mood stabiliser is sub-thera therefore preferably less than 50%, such as less than 40% or peutic with respect to mood Stabilisation, controlling 30% of the minimum dosages listed below for each particular and/or mania. This means that the dose administered is below drug e.g. for Ethiotin, a sub-therapeutic dose is less than 500 the dose range that would be administered to epileptics and mg/day, such as less than 400 or 300 mg/day. The minimum individuals with bipolar disorders to achieve mood stabilisa dose to be administered in the context of the present invention tion, control of seizures and/or control of mania, as appropri 10 is preferably at least 2.5, 5 or 10% of the minimum therapeu ate. As mentioned above, the use of Such sub-therapeutic tic dose for mood stabilisation listed below, e.g. in the case of dosages is advantageous for the treatments described herein. Ethotoin, at least 25, 50 or 100 mg/day. For comparison, in the case of sodium valproate, the product information for Epilim (-Aventis) states that, for the 15 Minimum Dose/day treatment of mania (e.g. bipolar disorder) in adults, control of effective for mood symptoms typically occurs within the range of 1,000 to 2,000 Drug stabilisation mg/day, (i.e. approximately 20 to 30 mg/kg/day). In the case Barbexaclone 200 mg in divided doses of carbamazepine, a typical dose for treating epileptic sei Carbamazepine 400 mg Zures is in the range of from 400 to 800 mg/day. In the case of Clobazam 5 mg/kg daily topiramate, the target dose for controlling epileptic seizures is Clonazepam 1 mg Ethadione 1000 mg between 100 to 500 mg/day. Ethosuximide 1000 mg By contrast, in relation to Sodium valproate (and deriva Ethotoin 1000 mg tives thereof), a sub-therapeutic dose with respect to mood Felbamate 1200 mg stabilisation is considered in this context to be less than 400 25 Fosphenytoin Sodium 10 mg/kg Gabapentin 900 mg mg/day or 4 mg/kg/day, a preferred dose being less than 300 Lamotrigine 100 mg mg/day. The minimum dose is typically at least 25 mg/day, Levetiracetam 1000 mg such as at least 50 or 100 mg/day, or at least 0.3, 0.5 or 1 Losigamone 1500 mg mg/kg/day. The doses are expressed both independently of Mephenytoin 200 mg Oxcarbazepine 600 mg patient weight and based on patient weight since minimum 30 Pheneturide 600 mg and maximum doses can apply. Typically, the mg/kg/day is Phenytoin 200 mg more commonly applied in relation to children whereas the Pregabalin 300 mg total mg/day may be more appropriate for adults. These dos Primidone 750 mg 400 mg ages in relation to sodium valproate and derivatives thereof Sultiame 200 mg represent, at the upper end, less than 50% of the lower end of 35 Tiagabine Hydrochloride 30 mg the normal therapeutic dose range for treating epilepsy/bipo Topiramate 100 mg lar disorder, and at the lower end, about 5 to 10% of the Vigabatrin 1000 mg normal therapeutic dose range for treating epilepsy/bipolar Zonisamide 200 mg disorder. These dosages can be used as a guide for calculating the relative dosages of other mood stabilisers that would 40 It is preferred that the dosage administered of mood stabi constitute a Sub-therapeutic dose. liser/anti-convulsant is Sub-therapeutic for mood stabilisation For example, in the case of carbamazepine, a preferred for the entire, or at least substantially the entire, treatment sub-therapeutic dose is in the range of from 25 to 200 mg/day, period. In other words, it is preferred that the dosage admin such as more than 50, 75 or 100 mg/day but less than 250 200 istered of mood stabiliser does not exceed the maximum or 150 mg/day. In the case of topiramate, a preferred sub 45 stated Sub-therapeutic dosages described above throughout therapeutic dose is in the range of from 6.25 to 75 mg/day, the treatment. such as at least 10, 15, 20, 30 or 40 mg/day but less than 80, In certain embodiments, the patients receive a combination 75 or 60 mg/day. In the case of phenytoin, a preferred sub therapy of a mood Stabiliser, at a dose which is sub-therapeu therapeutic dose is in the range of from 20 to 80 mg/day, such tic for mood stabilisation, and a psychoStimulant (also termed as more than 30 or 40 mg/day but less than 70 or 60 mg/day. 50 a CNS stimulant). In the case of pregabalin, a preferred sub-therapeutic dose is A large number of pyschoStimulants are known in the art. in the range of from 30 to 80 mg/day, such as more than 30 or Examples of psychoStimulants which are already approved 40 mg/day but less than 80 or 70 mg/day. for use in treating ADHD include methylphenidate, typically Preferably, the sub-therapeutic dose is less than 50%, such as the hydrochloride (e.g. RitalinTM, Ritaline LATM, Foca as less than 40% or 30%, of the minimum dose that would be 55 linTM, ConcertaTM, Methylin, AttentaTM, LorentinTM, Day administered to epileptics and individuals with bipolar disor tranaTM, TranquilynTM, EquasymTM, RiphenidateTM, Rub ders to achieve mood stabilisation, control of seizures and/or ifenTM, Metadate CDTM), (e.g. control of mania, as appropriate. For example we have found dextroamphetamine sulphate (DexaminTM, Dextrostatt M. that 10% of the normal minimum dose that would be admin DexadrineTM)/dexamphetamine or mixed amphetamine salts istered to epileptics and individuals with bipolar disorders to 60 ( XRTM)) and pemoline (CylertTM)). Typical doses achieve mood stabilisation, control of seizures and/or control for these medications are described in Wilens and Dodson, of mania, as appropriate, works well for the particular com 2004, Clin. Psychiatry 65: 1301-1313 (methylphenidate— pounds tested in human Subject. Typically the Sub-therapeutic juveniles: 0.6 to 1.0 mg/kg/day; adults 20 to 100 mg per day, dose is at least 2.5, 5 or 10% of the minimum dose that would amphetamine juveniles: 0.3 to 1.5 mg/kg/day; adults 10 to be administered to epileptics and individuals with bipolar 65 70 mg/day, pemoline juveniles: 1.0 to 3.0 mg/kg/day; disorders to achieve mood stabilisation, control of seizures adults 75 to 150 mg/day). Combinations of two or more and/or control of mania, as appropriate. pyschoStimulants may be used. References to all pyscho US 8,957,099 B2 13 14 stimulant described herein include pharmaceutically accept typically administered as the hydrochloride, Buprorion ((+)- able salts thereof, as appropriate, and slow release and 2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one), Ven extended release formulations. lafaxin (1-2-dimethylamino-1-(4-methoxyphenyl)-ethyl Other examples include: such as , cyclohexan-1-ol), or Devenlafaxin. Other examples include , Carphedon, ; such , , , , dulloxet as 4-Fluoroamphetamine, 4-Fluoromethamphetamine, ine and bici fadine. For the avoidance of doubt, the non-stimu 4-Methylmethcathinone, 4-MTA, C.-PPP, Amphechloral, lants can be applied to all embodiments that refer to combi Amphetamine (Dextroamphetamine, Adderall), Amphetami nation therapy with anti-epileptic drugs and nil, , , , Chlorphenter psychostimulants, the non-stimulants being administered or mine, , , , Diethylpro 10 present in place of, or in addition to, said psychoStimulants. pion, , , The mood stabiliser and psychoStimulant/non-stimulant Dimethylcathinone, Diphenyl prolinol, , Epineph may be administered separately, sequentially or concomi rine, , Ethylamphetamine, Fencamfamine, Fen tantly, as appropriate. ethylline, , , Feprosidinine, Fur Typically, the mood stabiliser and, where required, the fenorex, , 15 psychostimulant/non-stimulant are formulated with a phar (VyvanceTM) (L-lysine-d-amphetamine), MDMA, Mefeno maceutically acceptable carrier or diluent to form separate or rex, , , Methoxyphedrine, combined pharmaceutical compositions. Suitable pharma , , Parahydroxyamphetamine, PMA, ceutical carriers are described in “Remington's Pharmaceu PMEA, PMMA, PPAP, , , tical Sciences” by E. W. Martin. Mack Publishing Co., Eas , , , Prolin ton, Pa., 1990. tane, , , , Pharmaceutical dosage forms include oral dosage forms , Tenamphetamine, Xylopropamine; Such as tablets, capsules, syrups, elixirs; patches; Sterile solu such as BZP, MeOPP MBZP, mCPP, -B-BZP; tions, powders for inhalation/nasal delivery: Suspensions for such as , , . Theobro injectable administration, and other compositions known in mine. ; such as , CFT, 25 the art. Compounds may be formulation for slow release, , , , Lometopane, PIT. extended release etc. PTT, RTI-121, , Troparil, WF-23, WF-33; Cho Suitable routes of administration will vary depending on linergics such as , , ; Convulsants the active compounds used and dosage form, and include such as , , Pentetrazol, , topical, enteral and parenteral (such as oral intranasal, intra . ; Phenylaminooxazoles such as 4-Me 30 venous, intramuscular, Subcutaneous, transdermal). thyl-, Aminorex, , , Flumi The optimal dose, route (e.g. oral) and frequency of admin norex, Pemoline, ; Others such as , istration (e.g. once, twice, three times or four times daily) of , BPAP. , , Cyclopentam the mood stabiliser and psychostimulant can be determined ine, , , , Ethami by a person skilled in the art based on, for example, the patient van, Gilutensin, GYKI-52895, , , 35 age, severity of symptoms, weight, diet and time of adminis , , , MDPV. , tration, and taking into account the guidance as to dose pro methylphenidate, , Naphthylisopropy vided above. In the case where the mood stabiliser is sodium lamine, , Nocaine, , Phacetoper valproate, the dose is typically from 25 mg/day to 400 mg/day ane, , , , Pro (from 0.3 mg/kg/day to 4 mg/kg/day), preferably less than pylhexedrine, , Tuamine, , 40 300 or 200 mg/day or less than 4, 3 or 2 mg/kg/day. The , Zylofuramine, Deanol, Diethylaminoethanol, minimum dose of sodium valproate (particularly for adults) is Dimefline Hydrochloride, Hydrochloride, typically at least 25 or 50 mg/day, Such as at least 100 mg/day, Hydrochloride, Fenetyline Hydrochloride, or at least 0.3, 0.5 or 1 mg/kg/day. These dosage ranges can be Fenfluramine Hydrochloride, Fenproporex Hydrochloride, used as guidance by a person skilled in the art when deter Hydrochloride, Pentetrazol, . 45 mining dosage ranges for other mood stabilisers. For Particularly preferred combinations of mood stabilisers example, see above in relation to carbamazepine, pregabalin, and psychoStimulants are: (i) one or more of sodium Valproate phenytoin and topiramate. and derivatives thereof, topiramate, carbamazepine, oXcarba Typical dosage ranges for psychoStimulants are from 5 to Zepine, phenytoin, gabapentin and/or pregabalin together 150 mg/day, such as from 10 to 120 mg/day. Specific guid with (ii) one or more of methylphenidate (RitalinTM, Ritaline 50 ance in relation to particular psychoStimulants is given above. LATM, FocalinTM, ConcertaTM, Metadate CDTM), amphet The period of treatment will generally vary from patient to amines (e.g. dextroamphetamine (DexadrineTM), Lisdexam patient but is typically of at least 6 months, duration, Such at fetamine (VyvanceTM) (L-lysine-d-amphetamine) or mixed least 12 months. In the 18 months since or first trials of the amphetamine salts (Adderall XRTM)) and pemoline (Cy combination of a low dose anti-epileptic and stimulant were lertTM)). For example: sodium valproate (or a derivative 55 begin, there has been in the vast majority of Subjects a Sus thereof) and methylphenidate; sodium valproate (or a deriva tained and significant benefit following the addition of a low tive thereof) and dextroamphetamine Sulphate; topiramate dose anti-epileptic to their therapy. There is no apparent loss and methylphenidate; topiramate and dextroamphetamine of efficacy from the low dose AED. Indeed, often the contrary Sulphate; phenytoin and methylphenidate; phenytoin and is noted with a reduction in the dose without loss of clinical dextroamphetamine Sulphate. 60 benefit. Accordingly, the methods of the invention may In certain alternative embodiments, the patients receive a involve a reduction in the dose of anti-epileptic drug as the combination therapy of a mood Stabiliser, at a dose which is treatment progresses, e.g. a reduction of from 10 to 20, 30 or Sub-therapeutic for mood stabilisation, and a non-stimulant 40% after 2 to 6 months. treatment for ADHD. In a preferred embodiment, the non The dose of mood stabiliser, and psychostimulant where stimulant is a noradrenaline () and/or dopam 65 appropriate, administered is selected so as to provide a thera ine inhibitor, preferably (3R)-N-me peutically effective amount to achieve the intended purpose. thyl-3-(2-methylphenoxy)-3-phenyl-propan-1-amine), In the context of the present invention, the intended purpose US 8,957,099 B2 15 16 in the first aspect is to treat ADHD, such as to improve the Example 1 patient’s cognitive function and/or psychosocial functioning and/or to alleviate ADHD behavioural symptoms. Particular Treatment of Adult ADHD Sufferers with a functions include executive function, informational process Combination of Psychostimulant and Mood ing, Verbal comprehension, reading comprehension, Saccadic Stabiliser eye movements, non-verbal feedback/behaviour in response to Verbal interaction, interpersonal interaction and the like. In the clinical setting where this study has originated from, Assessment of cognitive function and/or psychosocial a number of adults with ADHD (who had previously demon functioning and or ADHD behavioural symptoms to deter strated significant improvements on stimulants alone) began a 10 dual regime of stimulant medication (dexamphetamine) aug mine whether Such an improvement has occurred can be mented with sodium valproate (VPA), primarily as an agent to conducted as described in the examples. Assessments include improve mood stability. measurement of information processing speed, concentra The initial dosages used were from 15 to 70 mg/day of tion effectiveness, Switching of attention between tasks, abil dexamphetamine and from 100 to 700 mg/day of VPA (Ep ity to maintain attention and inhibit impulsive responses, 15 ilim) (approximately 2 to 10 mg/kg/day). The Epilim prod working memory capacity (e.g. using WebOSPAN), response uct information supplied by Sanofi-Aventis for the treatment inhibition, visual scanning, reading comprehension (e.g. of mania (e.g. bipolar disorder) in adults suggests that control using all or part of the Nelson-Denny Reading Test: Brown, of symptoms occurs within the range of 1,000 to 2,000 Fishco, & Hanna, 1993, Itasca, Ill.: Riverside Publishing), the mg/day, (i.e. 20 to 30 mg/kg/day). The dosages used in this clinical assessment of oculomotor function, Saccadic eye trial were therefore substantially lower than the dosages movements (e.g. using Developmental Eye Movements Test required for treating mania. (DEM) version 1, Richman & Garzia, 1987: ReadAlyzerTM The determination of the dose for the dexamphetamine was Eye Movement Recording system. Compevo AB and/or the undertaken in a clinical sensitive open labelmanner. The dose scleral search coil technique: Irving et al., 2003, Invest Oph was titrated upwards dependent on the clinical response and thalmol Vis Sci. 44(5): 1933-8 and references therein), 25 the freedom from side-effects. The dose range was between pseudo-word decoding (e.g. using Wechsler Individual 15 and 70 mg a day. The frequency of the dosing also varied Achievement Test-II). Many of the above tests can be con dependent upon the clinical response. The usual dose interval ducted using WebNeuro (Brain Resource Company brain was between two to four hours. This dosing adjustment took resource.com). place prior to the commencement of the Sodium valproate. The intended purpose in the second aspect is to improve 30 The Sodium valproate medication was initiated once a day at reading comprehension in a patient Suffering from learning 50 mg tablet or elixir and titrated upwards dependent on difficulties. Improvements in reading comprehension can be response, but not more than one increase every three days. assessed using, for example, all or part of the Nelson-Denny The dose was given as a once or twice a day regime. During Reading Test. the titration phase, if clinically possible, no other adjustments The intended purpose in the third aspect to treat or reduce 35 to the pharmacotherapy were undertaken. ocularmotor dysfunction in an individual Suffering from Following the initial results, the dosages for those patients learning difficulties. Improvements in ocularmotor function on the higher dosages of sodium valproate (i.e. 500 or 700 can be assessed using, for example, using Developmental Eye mg) were re-titrated because such patients frequently experi Movements Test (DEM) version 1, Richman & Garzia, 1987, enced general cognitive and a resultant loss of efficacy. The ReadAlyzerTM Eye Movement Recording System. Compevo 40 dosages of Sodium valproate, after adjustment, varied AB, and/or the Scleral search coil technique (Irving et al., between 50 mg/day, 100 mg/day, 150 mg/day or 200 mg/day 2003, Invest Ophthalmol Vis Sci. 44(5): 1933-8 and refer (number of patients—120), with the majority of patients ences therein). receiving between 50 to 150 mg/day with 300 mg/day usually The intended purpose in the fourth aspect is to treat or the maximum. reduce abnormal saccadic eye movements in an individual, 45 Results and Discussion Such as an individual Suffering from learning difficulties. When VPA was integrated into the pharmacological Saccadic eye movements can be assessed using, for example, approach, patients often described their thoughts as slowing using Developmental Eye Movements Test (DEM) version 1, to a rate that was more manageable and less chaotic. This Richman & Garzia, 1987: ReadAlyzerTM Eye Movement seemed to allow for more temporal sequencing of ideas, with Recording system. Compevo AB. and/or the Scleral search 50 a resulting overall improvement in psychosocial functioning. coil technique (Irving et al., 2003, Invest Ophthalmol Vis Sci. The interesting dimension to this argument of pharmacologi 44(5): 1933-8 and references therein) cal approach is that a large number of these patients had no The intended purpose in the fifth aspect is to improve evidence to suggest a personal or family history of a bipolar cerebellar-mediated function, especially in relation to motor disorder and were benefiting from a dose of VPA below the planning and sequencing, which is often impaired in patients 55 initiation dose recommended forbipolar disorder, and signifi with learning difficulties. cantly below the dose typically required to achieve control of The intended purpose in the sixth aspect is to treat a disor symptoms of mania. der selected from the group of DSM-IV-TR diagnostic cat The results were assessed using the Conners Adult ADHD egories consisting of Communication Disorders; Pervasive Rating scales completed by the patient and observer (usually Development Disorders; and Anxiety Disorders. 60 partner or parent). In a sample of 26 patients who completed A further intended purpose is to improve skill acquisition self CAARS rating scales at: pre treatment, stable on stimu and coordination, such as left and right hemisphere coordi lant and stable on anti-epileptic drug (AED). 6 Of the 8 nation, individuals which include, but are not limited to, those CAARS Subscales showed significant quadratic improve with learning difficulties. ment of at least p-0.5 after the addition of their AED to their The present invention will now be further described with 65 stimulant therapy. With CAARSADHD symptoms subscale reference to the following examples, which are illustrative the quadratic significance reached p-0.001. Robust improve only and non-limiting. ment was similarly noted on the Quality of Life Scales. A US 8,957,099 B2 17 18 visual analogue scale which was used to compare the Subjec The study is based on a combined regime of stimulant tive benefit of addition of their AED to their initial experience (dexamphetamine) and anti-epileptic mood stabiliser (so of commencing stimulants showed that the two interventions dium valproate) treatment for adults with ADHD. The effec were of similar benefit. This is significant in the context of the tiveness of the combined regime is assessed in the following well reported robust treatment effect achieved on initiation of 5 stimulants. The clinical reviews were consistent with the domains of functioning: above findings. a) ADHD behavioural symptoms; A significant number of patients who reported a subjective b) Executive functioning; improvement in ADHD symptoms also described an c) Information processing: improvement in their reading and Verbal comprehension d) Reading comprehension; and abilities. They were more able to attend to the content of both 10 e) Quality of life. the text and conversation, which was in direct contrast to their previously frustrating experiences of needing to put most of their mental effort into either reading or listening with rela Title of Trial A Randomised, Double-Blind, Placebo tively little comprehension occurring. We have been able to Controlled, Parallel-Arm, Phase II, Dose-Ranging 15 Study of the Efficacy and Safety of Sodium assess objectively oculomotor function with the Develop Valproate in Adults with Attention Deficit mental Eye Movement Test (DEM): this has shown improve Disorder on a Stable Dose of Dexamphetamine ment consistent with that of the patient’s own subjective Trial Centre Single-Centre Study based in Queensland, experience, with less mental effort required to follow or track Australia Planned Trial 8 weeks written text. This leads us to the hypothesis that the low dose Duration of the sodium valproate is having a beneficial effect on fixa Trial Phase II tional and saccade activity during reading and non reading Objectives Primary objectives: tasks. The magnitude of the change for many of these indi To assess the efficacy of sodium valproate in viduals was comparable to changes in behaviour that treating the symptoms of ADHD in patients stabilised on an optimal dose of occurred during their first experience of stimulant therapy. examphetamine Additionally, the self-reported improvement appeared to 25 Secondary objectives: correlate closely to notable changes in the complex interper To assess the effect of sodium valproate on Sonal interaction during the clinical consultation. Verbal working memory in ADHD patients stabilised on interactions between the treating psychiatrist and patients an optimal dose of dexamphetamine appeared more spontaneous and fluid, and patients appeared To assess the safety profile of sodium valproate in ADHD patients treated stabilised on an optimal to be able to provide a higher level of subtle non-verbal 30 ose of dexamphetamine feedback during conversations. It would appear, based on this To assess the effect of sodium valproate on appropriate non-verbal behaviour, that patients were experi quality of life in ADHD patients treated stabilised encing a greater understanding of the content of the conver on an optimal dose of dexamphetamine sation. Patients also reported that reading seemed to require Exploratory endpoints: less effort, resulting in greater enjoyment in a task that had To assess whether there is an optimal dose of 35 required correlates to weight, sex, age or dose of previously been very cognitively demanding. This clinical stimulant on which patients remained stabilised observation would appear to be consistent with the hypothesis Methodology Single-Centre, Double-Blind, Placebo-Controlled, by Samuelssonetal. (2004) that ADHD symptoms were more Parallel, Four-Arm, Dose-Ranging associated with impaired reading comprehension than with Sample Size A total of 100 evaluable patients: 25 patients on Sodium valproate 50 mg od (once word decoding. The improvement as described by patients daily) occurred almost immediately on initiation of therapy, prior to 40 25 patients on Sodium valproate 100 mg od the opportunity for any additional learning to take place. 25 patients on Sodium valproate 150 mg od Further, this would seem to preclude the acquisition of further 25 patients on placebood decoding ability as a possible explanation for this improve Patient Selection Key Inclusion Criteria ment. Criteria Patients of either sex aged 18 to 60 years Women must not be pregnant or breast-feeding During the initial trials higher doses in excess of 400 mg 45 Meet DSM-IV criteria for attention deficit were routinely used for some patients (VPA being relatively hyperactivity disorder well tolerated). Howeverdoses above this level frequently led Patients describing a chronic course of ADHD to general cognitive slowing and the resultant loss of efficacy. symptoms from childhood to adulthood The patients often ceased the medication as a consequence of Patients who having been stabilised on a this and it was only on later re challenge with a lower dose maximum tolerated daily dose of 50 dexamphetamine no lower than 5 mg with a much slower re-titration that the ideal and more effi and no greater than 60 mg for a minimum of 6 cacious dose was identified. weeks Patients who after 6 weeks of treatment From these observations it has been hypothesised that VPA with a maximum tolerated dose score at least 30 has a synergistic effect with stimulant medication at a dose out of 54 on the investigator rated ADHD-IV that would be considered sub-therapeutic if used only for scale Written informed consent. 55 Key Exclusion Criteria mood stabilisation. This novel use of VPA has the potential to Patients exposed to on further enhance our understanding and improve the treatment benzodiazepines within the last 2 months outcome of those diagnosed and treated with stimulants for Patients who have taken part in an investigational ADHD. drug trial within the past 3 months Women who are pregnant or breast-feeding Patients suffering from a mood disorder Example 2 60 Patients suffering from a personality disorder Patients with a history of epilepsy Clinical Study Protocol Patients who abuse or drugs Patients for whom dexamphetamine or valproate are contraindicated (allergy to either drug, active In this study, the combination of an anti-epileptic mood liver disease, family history of severe hepatic stabiliser in conjunction with stimulant medication as 65 dysfunction, porphyria, cardiovascular disease, described in Example 1 is investigated in more detail in a moderate to severe hypertension, hyperexcitability clinical study. US 8,957,099 B2 19 20 -continued content. This can be seen by the individuals not having to make Such an effort during the interaction, with a greater or agitated States, hyperthyroidism, glaucoma, focus on the content rather than the structure of what pregnancy, history of alcohol or drug abuse) Schedule of Screening: they are saying. Treatment and Visits Patient informed Consent 5 2. The sequencing of motor tasks improves with the Sub inclusion exclusion criteria jective experience of having more control and more time Semi-structured psychiatric interview to carry them out. It is also noted that the degree of ADHD-IV (Investigator Rated) Young Mania Rating Scale cerebellar involvement is associated with the complex Brown's rating scale ity of learning that is required and once the skill has been Paced Auditory Serial Addition Test (PASAT) 10 acquired this cerebellar contribution reduces. Such DEM changes are especially evident when learning new skills Adult ADHD Impact Module (AIM-A) Temperature, blood pressure, pulse Such as yoga, golf and Surfing, with patients often spon Weight taneously reporting an enhancement of their coordina U&Es, LFTs, TFT tion. Of particular mention was the improved ability to ECG 15 engage in team sports which had been difficult due the Spontaneously reported adverse events dual focus to attend to individual skills and the role During Treatment: Baseline, Weeks 2, 4, 6 and 8 ADHD-IV (Investigator Rated) within the team. As the skills were rarely automatic the Brown's rating scale ability to simultaneously master both activities did not Paced Auditory Serial Addition Test (PASAT) occur, however on the combination of treatments a sig Readalyzer TM Eye Movement Recording System nificant benefit was noted. DEM Adult ADHD Impact Module (AIM-A) 3. Eye tracking also appear to have a component of cer Temperature, blood pressure, pulse ebellar control, which ties in with saccadic eye move Weight mentS. U&Es, LFTs, TFT Spontaneously The cerebellum is a region of the brain that plays an impor On withdrawal: 25 tant role in the integration of sensory perception and motor Reason for withdrawal output. Many neural pathways link the cerebellum with the Dosing of Study 50 mg od, 100 mg od, 150 mg od motor cortex—which sends information to the muscles caus Drug Concomitant Dexamphetamine ing them to move—and the spinocerebellar tract—which pro Therapy vides feedback on the position of the body in space (proprio Trial Medication Sodium valproate liquid 200 mg per 5 ml 30 ception). The cerebellum integrates these pathways, using the Placebo constant feedback on body position to fine-tune motor move ments. Because of this updating function of the cerebellum, lesions within it are not so debilitating as to cause paralysis, Example 3 but rather present as feedback deficits resulting in disorders in 35 fine movement, equilibrium, posture, and motor learning. Clinical Study with Anti-Epileptic Mood Stabilisers The deficiencies present in the patients prior to treatment Alone may therefore beat least in part a result of defects in cerebel lar function. These deficiencies can be referred to as motor In this trial we studied a group of patients who had symp planning and sequencing deficiencies, which describes both 40 the language and movement aspect of the condition. Thus toms of ADHD (without any associated bipolar disorder) but since the cerebellum is involved in the automation of skills, have been unable to or not wished to or had not yet been able, the effects of the medication on cerebellar function assist in commence on stimulants, individuals were treated with either the acquisition of new skills. Sodium Vaiproate alone, in the same dose range as prescribed Finally, the verbal and reading fluency of the patients in the combined treatment, or with topiramate (Topamax) 45 improves with treatment using the anti-epileptic mood stabi alone at a dose of 12.5-50 mg/day, or with Phenytoin alone at lisers. a dose of 30-60 mg/day. The improvements assessed using Whilst pyschoStimulants alone do have some impact on the self and other rating scales objective psychometric tool above, but only with some effort which in time fatigues, the together with repeated clinical assessments. The patients benefit of the anti-epileptic mood stabilisers is that they allow reported improvements in the organisation of thoughts in 50 more effortless and therefore sustainable function. conversation and reading comprehension. It was also noted in The various features and embodiments of the present two cases there was both a significant improvement of verbal invention, referred to in individual sections above apply, as fluency and abatement of socially impairing co-morbid ver appropriate, to other sections, mutatis mutandis. Conse bal stutter on initiation of therapy. Additionally the successful quently features specified in one section may be combined completion of tasks improved, changes which were particu 55 with features specified in other sections, as appropriate. larly evident and noted by the partners of the patients. All publications mentioned in the above specification are The topiramate was also noted to have an effect on coor herein incorporated by reference. Various modifications and dination, as well as improved organisation and motivation. variations of the described methods and products of the inven This latter observation could be understood as an improve tion will be apparent to those skilled in the art without depart ment in the functional output thereby setting up a positive 60 ing from the scope of the invention. Although the invention feedback circuit for the individual and sustaining their has been described in connection with specific preferred engagement and thus proficiency in the task. embodiments, it should be understood that the invention as These observations are very interesting in the context of the claimed should not be unduly limited to such specific possible cerebellar model of coordination of motor activity, embodiments. Indeed, various modifications of the described which includes that of language. 65 modes for carrying out the invention which are apparent to 1. The sequencing of oral language improves, allowing those skilled in the relevant fields are intended to be within the more fluid conversation and temporal organisation of the Scope of the following claims. US 8,957,099 B2 21 22 The invention claimed is: 1. A method of treating Autistic Spectrum Disorder in an individual suffering from said disorder, but not epilepsy or bipolar disorder, the method consisting essentially of admin istering to the individual phenytoin at a dose of less than 60 5 mg per day, to thereby treat Autistic Spectrum Disorder in said individual. 2. The method according to claim 1, wherein the individual suffers from learning difficulties. k k k k k 10