Combination therapy for the treatment of executive function disorders

Abstract

The present invention relates to the treatment of executive dysfunction, such as attention deficit hyperactivity disorder (ADHD) and / or autism, with both lacosamide and oxcarbazepine.

Description

Technical Field

[0001] The present invention relates to the treatment of executive function disorders, such as attention deficit hyperactivity disorder (ADHD) and / or autism, by both lacosamide or a functionally equivalent analogue thereof and oxcarbazepine or a functionally equivalent analogue thereof.

Background Art

[0002] Executive function is a term that refers to the mental control processes necessary to enable physical, cognitive, and / or emotional self-control and to maintain effective goal-directed behavior. Deficits in executive function are associated with disorders such as autism and attention deficit hyperactivity disorder (ADHD) ("Examining executive functioning in children with autism spectrum disorder, attention deficit hyperactivity disorder and typical development" Corbett et al., Psychiatry Research 166 (2009) 210-222).

[0003] Autism is a severe neurological disorder characterized by impairments in communication, reciprocal social interaction, and restricted range of activities and interests. The symptoms of autism fall on a continuum of severity known as autism spectrum disorder (ASD), which includes autistic disorder, Asperger's syndrome, and pervasive developmental disorder not otherwise specified (PDD-NOS). Patients suffering from autism show deficits in many executive functions, including planning, cognitive flexibility, and working memory.

[0004] ADHD is a neurological disorder characterized by difficulties in attention and control of behavior and impulsivity. Similar to individuals with autism spectrum disorder, individuals with ADHD exhibit deficits in many executive functions, including planning, working memory, and flexibility ("Executive function and attention deficit hyperactivity disorder: stimulant medication and better executive function performance in children"; Kempton et al.; 1999, Psychological Medicine, 29(3), 527-538).

[0005] Studies have shown that a genetic link between ADHD and autism lies in chromosome locations 2q24 and 16p13 ("A Genomewide Scan for Loci Involved in Attention-Deficit / Hyperactivity Disorder", Fisher et al. 2002, Am. J. Hum. Genet. 70, 1183-1196). Furthermore, various neuroscience models highlight common behavioral characteristics, biological pathways, and neuroanatomical correlations between autism and ADHD, involving the frontostriatal system, including the frontal lobe and basal ganglia. These brain regions are associated with executive function deficits.

[0006] The underlying causes of ADHD and autism are not fully understood. One hypothesis suggests they are related to deficiencies in dopamine production / firing and / or norepinephrine production / firing (e.g., "Binding of Dopamine D1 Receptor and Noradrenaline Transported in Individuals with Autism Spectrum Disorder: A PET Study", Kubota et al., 2020, Cerebral Cortex, 30: 6458-6468).

[0007] As a result, in this field, it is common to treat ADHD and autism with molecular stimulants such as methylphenidate (e.g., "Methylphenidate for children and adolescents with autism spectrum disorder."; Sturman et al., Cochrane Database of Systematic Reviews 11 (2017)). Molecular stimulants (e.g., methylphenidate) act by stimulating / modulating the release of neurotransmitters or the recapture of transporters in the brain. In the specific case of methylphenidate, this compound inhibits the reuptake of norepinephrine and dopamine by blocking both norepinephrine and dopamine transporters in the brain cell membrane. This prevents the clearance of dopamine from synapses, leading to increased dopamine levels at synapses and increased dopamine signaling in the brain. However, the U.S. Food and Drug Administration now includes a warning on methylphenidate packaging that the drug may cause addiction, and the French National Agency for Healthcare Security has published a detailed report on the wide range of secondary symptoms caused by medium- to long-term use of methylphenidate, including insomnia, seizures, tic disorders, anxiety, irritability, aggression, depression, and mood swings ("Methylphenidate: donations of usage and employment security in France", July 2013).

[0008] Furthermore, it has been demonstrated that one-third of children who take methylphenidate develop symptoms of obsessive-compulsive behavior ("Methylphenidate-induced obsessive-compulsive symptoms: A case report and review of literature"; Jhanda et al.; J Pediatr Neurosci. 2016; 11(4): 316-318). In addition, this drug can cause hallucinations, suicidal ideation, and psychopathic behavior, and can trigger aggressive and violent episodes. According to the U.S. Food and Drug Administration, it often leads to endocrine disorders causing gastrointestinal problems and loss of appetite, weight loss and other growth problems, cardiac events such as tachycardia and ventricular fibrillation, and in some cases, sudden death ("Weight, Height, and Body Mass Index in Patients with Attention-Deficit / Hyperactivity Disorder Treated with Methylphenidate", Diez-Suarez et al.; J Child Adolesc Psychopharmacol. 2017 Aug 17).

[0009] Furthermore, the use of molecular stimulants is often associated with the development of tolerance to the treatment, thus requiring dose escalation as the treatment progresses. The data only support the short-term effectiveness of stimulants in the treatment of executive function disorders such as ADHD. A follow-up study of several years after molecular stimulant treatment showed that patients taking stimulants had the same level of symptoms as patients who had never received any drug treatment ("3-year follow-up of the NIMH MTA study". Jensen et al., 2007, J. Am. Acad. Child Adolesc. Psychiatry., 46(8):989-1002).

[0010] Current strategies for treating executive function disorders, such as autism and ADHD, utilize molecules that are unsuitable for long-term administration due to high rates of side effects and the development of treatment tolerance; therefore, further treatments for executive function disorders are needed. [Overview of the project]

[0011] In a first embodiment, the present invention provides a combination or kit of parts for simultaneous, separate, or sequential use in the treatment of executive dysfunction: (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog.

[0012] Each aspect or embodiment defined herein may be combined with other aspects or embodiments unless otherwise expressly indicated. In particular, any feature shown as preferred or advantageous may be combined with one or more other features shown as preferred or advantageous.

[0013] In a further embodiment, the present invention provides a kit, kit of parts, or system comprising (a) lacosamide or a functionally equivalent analogue and (b) oxcarbazepine or a functionally equivalent analogue.

[0014] In a further embodiment, the present invention provides a combination or kit of parts of (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog for simultaneous, separate, or sequential use in alleviating one or more symptoms of executive dysfunction.

[0015] Another aspect of the present invention provides a pharmaceutical composition comprising (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog.

[0016] In a further embodiment, the present invention provides a method for treating executive dysfunction, comprising administering (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog to a subject suffering from executive dysfunction or its symptoms.

[0017] Another aspect of the present invention relates to lacosamide or a functionally equivalent analog for use in a method for treating executive dysfunction, wherein the method comprises administering (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog to a subject suffering from executive dysfunction, preferably the administration being sequential, simultaneous or separate.

[0018] In a further embodiment, the present invention provides oxcarbazepine or a functionally equivalent analog for use in a method for treating executive dysfunction, wherein the method comprises administering (a) oxcarbazepine or a functionally equivalent analog and (b) lacosamide or a functionally equivalent analog to a subject suffering from executive dysfunction, preferably the administration being sequential, simultaneous or separate.

[0019] In a further embodiment, the present invention provides the use of (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog in the manufacture of a pharmacopoeci for the treatment of executive dysfunction. The pharmacopoeci are, for example, a pharmacopoeci for continuous administration or a pharmacopoeci for co-administration.

[0020] Furthermore, the present invention provides combinations or kits of parts for simultaneous, separate, or sequential use in treatment of (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog.

[0021] Furthermore, the present invention provides oxcarbazepine or a functionally equivalent analog for use in the treatment of executive dysfunction.

[0022] Other preferred embodiments of the uses, methods, kits, systems, kits of parts and compositions according to the present invention are disclosed throughout the specification, particularly in the examples.

[0023] The inventors have surprisingly discovered that the combination of lacosamide (or a functionally equivalent analog thereof) and oxcarbazepine (or a functionally equivalent analog thereof) can effectively treat and manage the symptoms of executive dysfunction in subjects suffering from executive dysfunction, such as ADHD or autism.

[0024] As exemplified by the examples, treatment with the combination of lacosamide (or a functionally equivalent analog thereof) and oxcarbazepine (or a functionally equivalent analog thereof) advantageously does not show (or shows very little) evidence of unwanted side effects and / or the development of tolerance upon long-term administration of the treatment.

[0025] Surprisingly, the effect of the combination of lacosamide (or a functionally equivalent analog thereof) and oxcarbazepine (or a functionally equivalent analog thereof) on reducing the symptoms of executive dysfunction far exceeds the effects seen upon administration of lacosamide monotherapy or oxcarbazepine monotherapy. Also, the dose of lacosamide in the combined dose is substantially less than in lacosamide monotherapy, which may reduce the likelihood of showing unwanted side effects.

[0026] While not wishing to be bound by theory, it is believed that the combination of lacosamide (or a functionally equivalent analog thereof) and oxcarbazepine (or a functionally equivalent analog thereof) tends to exhibit the above advantageous effects by improving the regulation of sodium and / or potassium ions. **DETAILED DESCRIPTION OF THE INVENTION**

[0027] Stimulants such as methylphenidate may appear to rapidly control one or more symptoms of executive dysfunction, but only provide short-term treatment of the symptoms without addressing the underlying cause. Thus, such stimulants do not provide an appropriate long-term treatment solution.

[0028] The inventors have surprisingly discovered that certain compounds that are active in the brain but do not stimulate the release of neurotransmitters in the brain or the reuptake of transporters can be used in the treatment of executive dysfunction, such as autism or ADHD. This "non-stimulatory" approach provides a progressive and long-term stabilization of the symptoms of executive dysfunction. This indicates that these compounds functionally address the cause of the disorder.

[0029] For example, this approach can result in one or more or all of the following: (i) Improvement in cognitive function; (ii) Improvement in cognitive ability; (iii) Reduction in hyperactivity and / or impulsivity; (iv) Reduction in enuresis; (v) Improvement in sleep quality; (vi) Improvement in social skills; (vii) Improvement in mood; (viii) Reduction in anhedonia; (ix) Reduction in tachypsichia; (x) Regulation of discomfort; and / or (xi) Reduction in obsessive thoughts.

[0030] "Non-stimulatory" compounds are known in the art for treating conditions such as epilepsy and bipolar disorder. An exemplary compound is lacosamide. The chemical name of lacosamide is (2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide and has the following structure:

Chemical formula

[0031] Lacosamide is a well-known anticonvulsant compound approved as an adjunct treatment for partial seizures and neuropathic pain.

[0032] Lacosamide is a functionalized amino acid thought to act via voltage-gated sodium channels ("Current understanding of the mechanism of action of the antiepileptic drug lacosamide," Rogawski et al., 2015, Epilepsy Research, 110: 189-205). Lacosamide enhances the slow inactivation of voltage-gated sodium channels without affecting their rapid inactivation. This inactivation prevents the channels from opening, helping to halt action potentials. Because lacosamide slows recovery from inactivation, it reduces the ability of neurons to fire action potentials. Inactivation occurs only in neurons that fire action potentials; this means that drugs that modulate rapid inactivation selectively reduce firing in active cells. Slow inactivation is similar, but rather than resulting in complete blockade of voltage-gated sodium channels, both activation and inactivation occur over hundreds of milliseconds or more. Lacosamide induces this inactivation at membrane potentials that are not heavily depolarized. This means that lacosamide only affects neurons that are typically depolarized or active for extended periods, such as those in epileptic foci ("The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels" Errington et al., 2008, Molecular Pharmacology, 73(1): 157-69). Lacosamide administration leads to suppression of repetitive neuronal firing, stabilization of hyperexcitable neuronal membranes, and reduced long-term channel availability, but does not affect physiological function ("Development of lacosamide for the treatment of partial-onset seizures" Doty et al., 2013, Ann NY Acad Sci. 1291: 56-68).Lacosamide is composed of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid, N-methyl-D-aspartic acid (NMDA), and GABA. A GABA B Alternatively, it does not affect various dopaminergic, serotonergic, adrenergic, muscarinic, or cannabinoid receptors, nor does it block potassium or calcium currents ("Seeking a mechanism of action for the novel anticonvulsant lacosamide," Errington et al., 2006, Neuropharmacology, 50(8): 1016-29). Lacosamide does not modulate the reuptake of neurotransmitters, including norepinephrine, dopamine, and serotonin ("Lacosamide: a review of preclinical properties," Beyreuther et al., 2007, CNS Drug Reviews, 13(1): 21-42). It also does not inhibit GABA transaminase.

[0033] A further exemplary compound of the "non-irritating" type is oxcarbazepine. The chemical name of oxcarbazepine is 5-oxo-6H-benzo[b][1]benzazepine-11-carboxamide, and it has the following structure: [ka]

[0034] Oxcarbazepine is an anticonvulsant used to reduce the incidence of epileptic episodes and treat focal (local) seizures.

[0035] Oxcarbazepine is a prodrug that is largely metabolized to its pharmacologically active 10-monohydroxy derivative, ricarbazepine (sometimes abbreviated as MHD). Oxcarbazepine and MHD exert their effects by blocking voltage-sensitive sodium channels, thereby stabilizing overexcited nerve membranes, suppressing repetitive neuronal firing, and reducing the propagation of synaptic impulses. The anticonvulsant effect of oxcarbazepine is thought to be due to enhanced potassium conduction and modulation of high-voltage activated calcium channels.

[0036] Importantly, the inventors have surprisingly discovered that a combination of lacosamide (or a functionally equivalent analog) and oxcarbazepine (or a functionally equivalent analog) can effectively treat and manage the symptoms of executive dysfunction in subjects suffering from executive dysfunction, such as ADHD and / or autism. The effect of the combination of lacosamide and oxcarbazepine, a non-irritant compound, on reducing the symptoms of executive dysfunction far exceeds the effect observed with lacosamide monotherapy or oxcarbazepine monotherapy.

[0037] Accordingly, the present invention provides a combination or kit of parts of (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog for simultaneous, separate, or sequential use in the treatment of executive dysfunction. Preferably, the present invention provides a combination or kit of parts of (a) lacosamide and (b) oxcarbazepine for simultaneous, separate, or sequential use in the treatment of executive dysfunction.

[0038] Furthermore, an analogue of lacosamide is being considered, which is functionally equivalent to lacosamide. The analogue may have a remarkably similar structure to lacosamide. A “functionally equivalent analogue” of lacosamide means that the analogue is non-irritating and / or has a therapeutic effect on patients suffering from executive dysfunction equivalent to that of lacosamide. The analogue may be, for example, the S-enantiomer (S)-2-(acetylamino)-N-benzyl-3-methoxypropanamide; a racemic mixture of the R-enantiomer and the S-enantiomer; or rufinamide. The chemical name of rufinamide is 1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4 carboxamide (marketed under the brand names BANZEL® or Inovelon®). Therefore, in a preferred embodiment, functionally equivalent analogs to lacosamide are the S and R racemic mixture of lacosamide, or rufinamide.

[0039] Furthermore, analogues of oxcarbazepine are also being considered, which are functionally equivalent to oxcarbazepine. The analogues have a remarkably similar structure to oxcarbazepine and are preferably metabolites of oxcarbazepine. A “functionally equivalent analogue” of oxcarbazepine means that the analogue is non-irritating and / or has a therapeutic effect on patients suffering from executive dysfunction equivalent to that of oxcarbazepine. The analogues may be, for example, (L- and / or R-)ricarbazepine (also known as 10-monohydroxy derivative (MHD)), eslicarbazepine, and eslicarbazepine acetate. Therefore, in a preferred embodiment, the functionally equivalent analogue of oxcarbazepine is (L- and / or R-)ricarbazepine, eslicarbazepine, or eslicarbazepine acetate.

[0040] The executive function disorder may preferably be ADHD and / or autism. For example, a subject may have both ADHD and autism, and the treatment may be administered to such a subject to treat both of these disorders. Alternatively, a subject may have ADHD and, if desired, not have any further executive function disorders. Alternatively, a subject may have autism and, if desired, not have any further executive function disorders.

[0041] As used herein, the term “autism” is intended to encompass autism spectrum disorder (ASD), which includes autism disorder, Asperger's syndrome, and pervasive developmental disorder not otherwise specified (PDD-NOS). Therefore, in some embodiments, executive dysfunction is autism, which may be selected from, for example, autism disorder, Asperger's syndrome, and pervasive developmental disorder not otherwise specified (PDD-NOS).

[0042] As used herein, the term "ADHD" is intended to encompass all ADHD subtypes, including: (i) Inattentive-predominant ADHD (ADHD-PI or ADHD-I) is characterized by symptoms including being easily distracted, forgetful, daydreaming, disorder, difficulty concentrating, and difficulty completing tasks; (ii) ADHD, predominantly hyperactive-impulsive type (ADHD-PH or ADHD-HI) is characterized by excessive restlessness and agitation, hyperactivity, difficulty waiting and sitting still, and immature behavior; may also include destructive behavior; and (iii) ADHD and combined ADHD-C are combinations of the above subtypes (i) and (ii).

[0043] The inattentive-predominant type of ADHD (ADHD-PI or ADHD-I) lacks the hyperactive component and may also be known as attention deficit disorder (ADD).

[0044] In some embodiments, the executive dysfunction is ADHD, which may be selected from, for example, ADHD-PI, ADHD-PH, and / or ADD.

[0045] As illustrated in the examples, treatment with lacosamide and oxcarbazepine in subjects suffering from executive dysfunction, such as ADHD and / or autism, eliminated, reduced, or improved specific symptoms of these executive dysfunctions. For example, hyperactivity and / or impulsivity decreased, social interaction improved, involuntary enuresis was resolved, and sleep activity improved.

[0046] It is understood that treatment for executive function disorders, such as autism and / or ADHD, may result in the elimination, reduction, or improvement of one or more symptoms of these executive function disorders, and does not necessarily have to alleviate or improve all symptoms of the executive function disorder that the patient experienced prior to treatment.

[0047] "Removal" of a symptom means that the subject essentially no longer experiences that symptom. "Reduction" of a symptom means that the subject experiences a significant improvement in the symptom. Reduction is preferably from severe to mild. "Improvement" of a symptom means that the subject experiences a moderate improvement in the symptom.

[0048] Therefore, in certain embodiments, the treatments, uses, etc. provided herein may result in the elimination, reduction, or improvement of one or more symptoms of executive dysfunction. For example, one or more symptoms may be reduced, and one or more different symptoms may be improved. One or more of the following symptoms, or one or more symptoms within these categories, may be eliminated, reduced, or improved: (i) hyperactivity and / or impulsivity; (ii) involuntary enuresis; (iii) Aggressive behavior; (iv) Insomnia or hypersomnia; (v) Attentional processing disorder; (vi) Communication disorder; (vii) Social skills disorder; (viii) Visual and / or auditory processing disorders; (ix) anhedonia; (x) Disorders of time perception; (xi) discomfort; and / or (xii) Fixed idea.

[0049] Therefore, the treatment may result in one or more or all of the following: (i) Improvement of cognitive function; (ii) Improvement of cognitive abilities; (iii) Reduction of hyperactivity and / or impulsivity; (iv) Reduction of involuntary enuresis; (v) Improving the quality of sleep; (vi) Improvement of social skills and communication; (vii) Improvement of mood; (viii) Reduction of numbness; (ix) Reduction of temporal perception abnormalities; (x) regulation of discomfort; and / or (xi) Reducing fixed ideas.

[0050] Accordingly, the present invention provides a method for treating executive dysfunction, comprising administering (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog to a subject suffering from executive dysfunction or its symptoms. Preferably, the executive dysfunction is ADHD and / or autism. Preferably, the method comprises administering (a) lacosamide and (b) oxcarbazepine, which may be administered simultaneously, sequentially, or separately.

[0051] In some embodiments, according to all aspects of the present invention, the amount of lacosamide (or a functionally equivalent analog thereof) and oxcarbazepine (or a functionally equivalent analog thereof) administered to the subject is a therapeutically effective dose.

[0052] As used herein, the terms “therapeutic dose” or “clinically effective dose” mean the amount of lacosamide (or a functionally equivalent analog) and oxcarbazepine (or a functionally equivalent analog) that, when administered to a subject to treat executive dysfunction, such as autism or ADHD, is sufficient to have an effect on treating the executive dysfunction. This amount varies depending on factors such as the specific drug used, the severity of the subject’s symptoms, the subject’s age, weight and relative health status, and the route and form of administration. Determining the relevant therapeutic / clinically effective dose for a particular subject based on such factors is routine for a person skilled in the art (e.g., a physician) once the teachings of the present invention are provided. Treatment of executive dysfunction as described herein should be understood to mean improvement of one or more symptoms. This may include, for example, improvements in focus, concentration, sleep quality, cognitive function, cognitive ability, mood, communication skills and / or memory, becoming more organized, becoming more socially active, and / or being able to complete tasks more easily. It may also include a reduction in hyperactivity, impulsivity, involuntary urination, restlessness and / or fidgeting, and / or immature and / or destructive behaviors. Those skilled in the art will understand that treatment generally refers to improvement of one or more of the symptoms described, typically progressive and long-term improvement.

[0053] In a further embodiment, the present invention provides lacosamide or a functionally equivalent analog for use in a method for treating executive dysfunction, wherein the method comprises administering (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog to a subject suffering from executive dysfunction, preferably the administration being sequential, simultaneous, or separate. Preferably, the executive dysfunction is ADHD and / or autism. Preferably, the method comprises administering (a) lacosamide and (b) oxcarbazepine to a subject, wherein these administrations may be simultaneous, sequential, or separate. Preferably, the amount of lacosamide (or a functionally equivalent analog) and oxcarbazepine (or a functionally equivalent analog) administered to the subject is a therapeutically effective dose.

[0054] In a further embodiment, the present invention provides oxcarbazepine or a functionally equivalent analog for use in a method for treating executive dysfunction, wherein the method comprises administering (a) oxcarbazepine or a functionally equivalent analog and (b) lacosamide or a functionally equivalent analog to a subject suffering from executive dysfunction, preferably the administration being sequential, simultaneous, or separate. Preferably, the executive dysfunction is ADHD and / or autism. Preferably, the method comprises administering (a) lacosamide and (b) oxcarbazepine to a subject, wherein the administrations may be simultaneous, sequential, or separate. Preferably, the amount of lacosamide (or a functionally equivalent analog) and oxcarbazepine (or a functionally equivalent analog) administered to the subject is a therapeutically effective dose.

[0055] More specifically, one or more of the following may be eliminated, mitigated, or improved: excessive thinking; sudden disconnections; pessimistic thoughts; mood swings; hypomania or hypersomnia; aggressive behavior; involuntary enuresis, attention processing disorder; communication difficulties; apathy; fatigue; impaired nonverbal reasoning; lack of social skills; anhedonia; temporal distortion; dysphoria; and / or fixed ideas.

[0056] Therefore, from another perspective, the present invention provides a method for eliminating, reducing, and / or improving one or more of the above symptoms by administering a combination of lacosamide (or a functionally equivalent analog) and oxcarbazepine (or a functionally equivalent analog) to a subject in need. Preferably, the subject suffers from executive dysfunction. More preferably, the subject suffers from ADHD and / or autism. Preferably, the method comprises administering a combination of lacosamide and oxcarbazepine, which may be administered simultaneously, sequentially, or separately. Preferably, the amount of lacosamide (or a functionally equivalent analog) and oxcarbazepine (or a functionally equivalent analog) administered to the subject is a therapeutically effective dose.

[0057] In some embodiments, according to all aspects of the present invention, the dose of lacosamide may be in the range of about 1 to 12 mg of the drug per kg of the subject per day (mg / kg / day), particularly in pediatric patients. In certain embodiments, the amount may be at least or about 1 mg / kg / day, at least or about 2 mg / kg / day, at least or about 4 mg / kg / day, at least or about 6 mg / kg / day, at least or about 8 mg / kg / day, or at least or about 10 mg / kg / day. In further embodiments, the amount may be in the range of about 2 to 6 mg / kg / day, 1 to 10 mg / kg / day, or 1 to 15 mg / kg / day.

[0058] In some embodiments, according to all aspects of the present invention, the dose of oxcarbazepine may be in the range of about 1 to 60 mg of the drug per kg of the subject per day (mg / kg / day), particularly in pediatric patients.

[0059] Typically, the treatments according to the present invention are administered solely for the treatment of executive dysfunction. Preferably, executive dysfunction is associated with a defect in the striatum frontoid system, including the frontal lobe and basal ganglia of the brain.

[0060] More preferably, the treatment according to the present invention is administered solely for the treatment of autism and / or ADHD, or for the treatment of one or more symptoms of autism and / or ADHD.

[0061] Accordingly, in some embodiments, according to all aspects of the present invention, the treatment is for subjects suffering from executive function disorders, such as autism and / or ADHD, who do not suffer from one or more of the following disorders; and / or the treatment according to the present invention is not administered for the treatment of one or more of the following disorders: epilepsy, bipolar disorder, seizures, neuropathic pain, depression, anxiety, schizophrenia, obsessive-compulsive disorder (OCD), Alzheimer's disease, Parkinson's disease, corticobasal degeneration, progressive supranuclear palsy, chronic traumatic encephalopathy, multiple system atrophy, amyotrophic lateral sclerosis, vascular cognitive impairment, ischemic stroke, frontotemporal dementia, Lewy body dementia, Tourette syndrome and / or traumatic brain injury, preferably epilepsy. For example, the treatment may involve one or more of the following conditions: epilepsy, bipolar disorder, seizures, neuropathic pain, depression, anxiety, schizophrenia, obsessive-compulsive disorder (OCD), Alzheimer's disease, Parkinson's disease, corticobasal degeneration, progressive supranuclear palsy, chronic traumatic encephalopathy, multiple system atrophy, amyotrophic lateral sclerosis, vascular cognitive impairment, ischemic stroke, frontotemporal dementia, Lewy body dementia, Tourette syndrome, and / or traumatic brain injury, preferably in subjects with autism who do not have epilepsy. Another example may be the treatment of a subject with ADHD who does not have epilepsy, having one or more of the following conditions: epilepsy, bipolar disorder, seizures, neuropathic pain, depression, anxiety, schizophrenia, obsessive-compulsive disorder (OCD), Alzheimer's disease, Parkinson's disease, corticobasal degeneration, progressive supranuclear palsy, chronic traumatic encephalopathy, multiple system atrophy, amyotrophic lateral sclerosis, vascular cognitive impairment, ischemic stroke, frontotemporal dementia, Lewy body dementia, Tourette syndrome, and / or traumatic brain injury.

[0062] In some embodiments, according to all aspects of the present invention, a subject may have previously received lacosamide (or a functionally equivalent analogue thereof) therapy (without oxcarbazepine), for example, lacosamide monotherapy, to treat an executive dysfunction which may be the same or a different executive dysfunction. Therefore, treatment may be for a subject who has previously received lacosamide (or a functionally equivalent analogue thereof) therapy (without oxcarbazepine), for example, lacosamide monotherapy, to treat an executive dysfunction.

[0063] For example, the treatment could be for autism, where the subject may have previously received lacosamide (or a functionally equivalent analogue) therapy (without oxcarbazepine), such as lacosamide monotherapy, to treat autism or another executive dysfunction. As another example, the treatment could be for ADHD, where the subject may have previously received lacosamide (or a functionally equivalent analogue) therapy (without oxcarbazepine), such as lacosamide monotherapy, to treat ADHD or another executive dysfunction.

[0064] "Previous" lacosamide therapy (without oxcarbazepine), e.g., lacosamide monotherapy, was initiated at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 years, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 days prior to initiating treatment with lacosamide (or a functionally equivalent analogue) and oxcarbazepine. It may also be terminated at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 years, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 days before initiating treatment with lacosamide (or a functionally equivalent analogue) and oxcarbazepine, preferably at least or about 30, 45 or 60 days before.

[0065] therefore, (i) A treatment plan including the administration of lacosamide in the presence of oxcarbazepine, e.g., lacosamide monotherapy; thereafter (ii) A treatment plan including the administration of lacosamide and oxcarbazepine, which may be simultaneous, sequential, or separate. We also provide methods for treating executive function disorders, including the following.

[0066] Each of the treatment plans (i) and (ii) may last for several days, several weeks, or several months. There may be an interval of several days, several weeks, or several months between plans (i) and (ii).

[0067] In some embodiments, according to all aspects of the present invention, a subject may have previously received oxcarbazepine (or a functionally equivalent analogue thereof) therapy (without lacosamide), for example oxcarbazepine monotherapy, to treat an executive dysfunction which may be the same or different executive dysfunction. Therefore, it may be a treatment for a subject who has previously received oxcarbazepine (or a functionally equivalent analogue thereof) therapy (without lacosamide), for example oxcarbazepine monotherapy, to treat an executive dysfunction.

[0068] For example, the treatment could be for autism, where the subject may have previously received oxcarbazepine (or a functionally equivalent analogue) therapy (without lacosamide), such as oxcarbazepine monotherapy, to treat autism or another executive dysfunction. As another example, the treatment could be for ADHD, where the subject may have previously received oxcarbazepine (or a functionally equivalent analogue) therapy (without lacosamide), such as oxcarbazepine monotherapy, to treat ADHD or another executive dysfunction.

[0069] "Previous" oxcarbazepine therapy (without lacosamide), e.g., oxcarbazepine monotherapy, should be initiated at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 years, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 days prior to initiating treatment with oxcarbazepine (or a functionally equivalent analogue) and lacosamide. Treatment may be terminated at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 years, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 days before initiation of treatment with oxcarbazepine (or a functionally equivalent analogue) and lacosamide, preferably at least or about 6 months, 1 year or 1.5 years prior.

[0070] therefore, (i) A treatment plan including administration of oxcarbazepine in the presence of lacosamide, e.g., oxcarbazepine monotherapy; thereafter (ii) A treatment plan including the administration of lacosamide and oxcarbazepine, which may be simultaneous, sequential, or separate. We also provide methods for treating executive function disorders, including the following.

[0071] Each of the treatment plans (i) and (ii) may last for several days, several weeks, or several months. There may be an interval of several days, several weeks, or several months between plans (i) and (ii).

[0072] In some embodiments, according to all aspects of the present invention, the use of a combination of lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) in the treatment of executive dysfunction is more effective than the use of lacosamide therapy without oxcarbazepine, for example, lacosamide monotherapy. Preferably, the use of combination therapy with lacosamide therapy without oxcarbazepine provides one or more of the following improved outcomes: (i) Improvement of cognitive function; (ii) Improvement of cognitive abilities; (iii) Reduction of hyperactivity and / or impulsivity; (iv) Reduction of involuntary enuresis; (v) Improving the quality of sleep; (vi) Improvement of social skills and communication; (vii) Improvement of mood; (viii) Reduction of numbness; (ix) Reduction of temporal perception abnormalities; (x) regulation of discomfort; and / or (xi) Reducing fixed ideas.

[0073] In some embodiments, the amount of lacosamide administered to a patient receiving combination therapy is less than the amount of lacosamide administered during monotherapy to produce at least the same effect or result. It is understood that when treatment is administered initially, the amount may need to be increased gradually until a maintenance dose is reached; for this comparison, the maintenance dose of lacosamide is given. Preferably, the amount of lacosamide administered to a patient receiving combination therapy is at least 20, 30, or 40% less than the amount of lacosamide used in monotherapy. More preferably, the amount of lacosamide administered to a patient receiving combination therapy is at least 65% less than the amount of lacosamide used in monotherapy. For example, a patient receiving lacosamide monotherapy may require an administration of 600 mg of lacosamide per day, while the same patient receiving combination therapy with oxcarbazepine may be administered 200 mg of lacosamide per day to produce at least the same effect or result. Preferably, the therapy is intended to treat subjects suffering from executive function disorders, such as autism or ADHD. Preferably, the effects or outcomes produced by combination therapy are substantially better than those produced by monotherapy. Therefore, in some embodiments, the amount of lacosamide administered to patients receiving combination therapy is about 300 mg / day or less. Preferably, the amount of lacosamide is about 200 mg / day.

[0074] According to all aspects of the present invention, the subject is a mammal, preferably a human. In certain embodiments, the subject is a child (i.e., a person who is physiologically and neurologically growing / maturing toward an adult phenotype). For example, “child” may be considered a pre-pubescent subject or a subject in the process of completing puberty. Particularly when the subject is a human, “child” may also be considered an individual under 18 years of age. In preferred embodiments, the child is 2 to 12 years of age, or at least 2, 3, 4, 5, 6, 7 or 8 years of age and 18, 17 or 16 years of age or younger. In more preferred embodiments, the child is 10 to 16 years of age. Thus, the weight of the subject may be, for example, about 60, 50, 40 or 30 kg or less. Even more preferably, the child suffers from symptoms of ADHD. However, the present invention also applies to adults in some embodiments, in which case the weight of the subject may be, for example, 50, 60, 70, 80, 90, 100 or 110 kg or more. Preferably, the adult has autism or ADHD.

[0075] Treatment (periodic, e.g., daily administration of a combination of lacosamide or a functionally equivalent analog and oxcarbazepine or a functionally equivalent analog) may be administered for an appropriate period, e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks, at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 months, or at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. If well tolerated, treatment may be administered indefinitely. Preferably, treatment is administered for at least about 3 months or about 9 weeks.

[0076] In certain embodiments, lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) may be administered once daily (which may be a single dose combined with another single dose or separate single doses). In preferred embodiments, each may be administered twice, preferably twice, as separate doses two, three, or more times throughout the day. That is, the daily amount of each of lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) may be divided into two, three, or more doses administered separately to the subject throughout the day. For example, in the case of lacosamide, a 200 mg / day dose may be administered as two 100 mg doses per day. Similarly, in the case of oxcarbazepine, a 600 mg / day dose may be administered as two 300 mg doses per day. The multiple daily doses do not necessarily have to be the same amount. With regard to the teachings provided herein, a person skilled in the art (e.g., a physician) can reasonably determine an appropriate administration regimen for the subject, depending on the specific circumstances of the subject.

[0077] In some embodiments, lacosamide (or a functionally equivalent analog) and oxcarbazepine (or a functionally equivalent analog) are administered simultaneously. In other embodiments, lacosamide (or a functionally equivalent analog) and oxcarbazepine (or a functionally equivalent analog) are administered separately, for example, sequentially. Preferably, the administration is simultaneous.

[0078] In some embodiments, lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) may be formulated together as a single pharmaceutical composition. Alternatively, lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) may be formulated as separate pharmaceutical compositions. In both cases, the pharmaceutical composition may further contain one or more pharmaceutically acceptable additives / solvents. For example, lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) may be formulated in combination with one or more pharmaceutically acceptable solid carriers, respectively, as individual pills, tablets, or capsules; or as liquids in one or more pharmaceutically acceptable solvents; or as emulsions, suspensions, or dispersants in one or more pharmaceutically acceptable solvents or carriers. In some embodiments, each formulation may also contain other pharmaceutically acceptable additives, stabilizers, antioxidants, binders, colorants, or emulsifiers or flavorings, and sustained-release formulations. In some embodiments, lacosamide (or a functionally equivalent analog) and oxcarbazepine (or a functionally equivalent analog) may be formulated (together or separately) as pharmaceutically acceptable salts, esters, prodrugs, or metabolites, such as pharmaceutically acceptable salts, esters, prodrugs, or metabolites of lacosamide and / or oxcarbazepine.

[0079] Accordingly, in a further embodiment, the present invention provides a pharmaceutical composition comprising (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog. Preferably, the pharmaceutical composition comprises (a) lacosamide and (b) oxcarbazepine. Alternatively, lacosamide (or a functionally equivalent analog) and oxcarbazepine (or a functionally equivalent analog) may be formulated as separate pharmaceutical compositions or, optionally, as part of a kit.

[0080] For example, lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) may be formulated as a single capsule or multiple capsules (i.e., a solid oral dosage form consisting of a shell or filling), wherein the shell consists of a single sealed inclusion or two halves joined together and possibly sealed with a band, and wherein the capsule shell may be made of gelatin, starch or cellulose or other suitable material, and may be soft or hard, and is filled with a solid component or a liquid component that can be poured or squeezed. Lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) may be formulated as one or more capsules or coated pellets, wherein the drug is enclosed in either a soft or hard soluble container or shell made of a suitable form of gelatin. The drug itself may be in the form of granules to which varying amounts of coating have been applied, or in a sustained-release coated capsule, where the drug is enclosed in either a soft or hard soluble container or shell made of a suitable form of gelatin. Furthermore, one or more capsules may be coated with a predetermined coating that releases the drug in such a manner that it allows for at least a reduction in the frequency of administration of one or more drugs, preferably both drugs, compared to one or more drugs provided in conventional dosage forms.

[0081] In further embodiments, lacosamide (or a functionally equivalent analog) and oxcarbazepine (or a functionally equivalent analog) may be formulated as one or more delayed-release capsules, where the drug is encapsulated in either a rigid or flexible soluble container made of suitable gelatin, releasing the drug at a time other than immediately after administration, thereby making the enteric-coated product a delayed-release dosage form. Delayed-release capsule pellets, in which the drug is encapsulated in either a rigid or flexible container or a "shell," are also useful. In these cases, the drug itself is in the form of enteric-coated granules, so that the release of at least one drug, preferably both drugs, is delayed until they have passed through the intestines. Sustained-release capsules and film-coated sustained-release capsules are also useful.

[0082] Furthermore, one or more capsules may be covered with a predetermined film coating that releases the drugs in a manner that allows for at least a reduction in the frequency of administration of at least one drug, preferably both drugs, compared to drugs provided in conventional dosage forms. Examples include one or more gelatin-coated capsules (a solid dosage form in which the drug is enclosed in either a rigid or flexible soluble container made of a suitable form of gelatin; the capsule is coated with an additional gelatin layer by banding to form a complete seal); and one or more liquid-filled capsules (a solid dosage form in which the drug is enclosed in a soluble gelatin shell that is plasticized by the addition of a polyol, such as sorbitol or glycerin, thereby having a hardness somewhat greater than that of a rigid shell capsule).

[0083] In some embodiments, lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) may be dissolved or suspended in one or more liquid vehicles, or formulated as one or more granules (small particles or grains), one or more pellets (small sterile solid masses of highly purified drugs, with or without additives, made by granulation, compression and molding), or one or more sustained-release coated pellets (solid dosage forms in which the drug itself is in the form of granules to which varying amounts of coating are applied, releasing the drugs in a manner that allows for at least a reduction in the frequency of administration of at least one drug, preferably both drugs, compared to drugs provided in conventional dosage forms).

[0084] Lacosamide (or its functionally equivalent analogues) and oxcarbazepine (or its functionally equivalent analogues) are available in pills (small, round solid dosage forms containing the drug intended for oral administration), powders (mixtures of the drug with one or more pharmaceutically acceptable additives, intended for internal or external use), elixirs (clear, palatable, flavored and sweet hydroalcoholic liquids containing the drug; intended for oral use), chewing gum (flavored and sweet insoluble plastic materials of various shapes that release the drug substance into the mouth when chewed), syrups (oral solutions containing the drug and high concentrations of sucrose or other sugars; the term has also been used to include any other liquid dosage forms prepared in a sweet, viscous vehicle, including oral suspensions), The drugs may be formulated as one or more tablets (oral dosage forms containing the drug with or without a suitable diluent), chewable tablets (solid dosage forms containing the drug with or without a suitable diluent, intended to be chewed, producing a pleasant-tasting residue in the mouth, being easy to swallow, and leaving no bitter or unpleasant aftertaste), one or more coated tablets, or one or more delayed-release tablets, one or more dispersible tablets, one or more effervescent tablets, one or more sustained-release tablets, one or more film-coated tablets, or one or more film-coated sustained-release tablets (wherein one or more tablets are formulated in such a way that at least one, preferably both, of the drugs contained therein is available over a long period of time after ingestion).

[0085] In other forms, one or more solution tablets, one or more suspension tablets, one or more multilayer tablets, or one or more multilayer sustained-release tablets may be provided, wherein one or more tablets are formulated in such a way that at least one drug, preferably both drugs, can be administered less frequently compared to drugs provided in conventional dosage forms. One or more orally disintegrating tablets, one or more orally disintegrating delayed-release tablets, one or more soluble tablets, one or more sugar-coated osmotic tablets, and the like are also suitable.

[0086] The oral dosage form composition may contain lacosamide (or a functionally equivalent analogue) and / or oxcarbazepine (or a functionally equivalent analogue) in addition to one or more inactive pharmaceutical ingredients, such as diluents, solubilizers, alcohols, binders, controlled-release polymers, enteric polymers, disintegrants, additives, colorants, flavorings, sweeteners, antioxidants, preservatives, pigments, additives, excipients, suspending agents, and surfactants (e.g., anionic, cationic, amphoteric, and nonionic). A variety of FDA-approved topical active ingredients, including inactive pharmaceutical ingredients specifically intended by the manufacturer, can be found in the FDA's "The Inactive Ingredients Database."

[0087] In certain embodiments of the present invention, particularly when the executive dysfunction is ADHD, (a) lacosamide and (b) oxcarbazepine may be administered according to the following treatment regimen: (a) Administer lacosamide according to the following treatment regimen: (i) Initial dose of 50-100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50-100 mg every 1-2 weeks up to the maximum dose in the range of 200-500 mg / day, and maintain that daily dose; and / or (b) Administer oxcarbazepine according to the following treatment regimen: (i) Initial dose of 600-750 mg / day, followed by (if the patient tolerates it): (ii) After 6-7 weeks, increase the dose to a range of 750-1800 mg / day and maintain that daily dose.

[0088] More preferably, (a) lacosamide and (b) oxcarbazepine are administered according to the following treatment regimen: (a) Administer lacosamide according to the following treatment regimen: (i) Initial dose of 50-100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50 to 100 mg each week up to the maximum dose in the range of 200 to 400 mg / day, and maintain that daily dose; and / or (b) Administer oxcarbazepine according to the following treatment regimen: (i) Initial dose of 600 mg / day, followed by (if the patient tolerates it) as desired: (ii) After 6-7 weeks, increase the dose to a range of 900-1200 mg / day and maintain that daily dose.

[0089] In further embodiments, particularly when the executive dysfunction is ADHD, (a) lacosamide and (b) oxcarbazepine may be administered according to the following treatment regimen: (a) Administer lacosamide according to the following treatment regimen: (i) Initial dose of 50-100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50-100 mg every 1-2 weeks up to the maximum dose in the range of 200-500 mg / day, and maintain that daily dose; and / or (b) Administer oxcarbazepine according to the following treatment regimen: (i) Initial dose of 500-900 mg / day, followed by (if the patient tolerates it): (ii) After 6-7 weeks, increase the dose to a range of 600-1800 mg / day and maintain that daily dose.

[0090] In a further embodiment, lacosamide is administered according to the following treatment regimen: (i) 100 mg / day for 1-2 weeks, followed by: (ii) Maintain a daily dose of 200 mg / day, and if desired, after 1-2 weeks, then: (iii) 300 mg / day for 1-2 weeks, if desired, followed by: (iv) Maintain the daily dose at 400 mg / day.

[0091] In a further embodiment, oxcarbazepine is administered according to the following treatment regimen: (i) 600 mg / day for 6-7 weeks, followed by: (ii) Maintain a daily dose of 900 mg / day, and if desired, after 1 to 4 weeks, then: i. Maintain a daily dose of 1200 mg / day; or ii. Maintain a daily dose of 600 mg / day.

[0092] In another embodiment of the present invention, particularly when the executive dysfunction is autistic, (a) lacosamide and (b) oxcarbazepine may be administered according to the following treatment regimen: (a) Administer lacosamide according to the following treatment regimen: (i) Initial dose of 50-100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50-100 mg every 1-2 weeks up to the maximum dose in the range of 200-500 mg / day, and maintain that daily dose; and / or (b) Administer oxcarbazepine according to the following treatment regimen: (i) Initial dose of 600-750 mg / day, followed by (if the patient tolerates it) as desired: (ii) Increase the dose by 150-300 mg each week until the daily dose reaches a range of 900-2400 mg, and maintain that daily dose.

[0093] More preferably, (a) lacosamide and (b) oxcarbazepine are administered according to the following treatment regimen: (a) Administer lacosamide according to the following treatment regimen: (i) Initial dose of 50-100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50 to 100 mg each week up to the maximum dose in the range of 200 to 400 mg / day, and maintain that daily dose; and / or (b) Administer oxcarbazepine according to the following treatment regimen: (i) Initial dose of 600 mg / day, followed by (if the patient tolerates it) as desired: (ii) Increase the dose by 300 mg each week up to the maximum dose of 1200 mg / day, and maintain that daily dose.

[0094] In further embodiments, particularly when the executive dysfunction is autistic, (a) lacosamide and (b) oxcarbazepine may be administered according to the following treatment regimen: (a) Administer lacosamide according to the following treatment regimen: (i) Initial dose of 50-100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50-100 mg every 1-2 weeks up to the maximum dose in the range of 200-500 mg / day, and maintain that daily dose; and / or (b) Administer oxcarbazepine according to the following treatment regimen: (i) Initial dose of 400-900 mg / day, followed by (if the patient tolerates it) as desired: (ii) Increase the dose by 150-600 mg each week until the daily dose reaches a range of 600-2400 mg, and maintain that daily dose.

[0095] In a further embodiment, lacosamide is administered according to the following treatment regimen: (i) 100 mg / day for 1-2 weeks, followed by: (ii) Maintain a daily dose of 200 mg / day, and if desired, after 1-2 weeks, then: (iii) 300 mg / day for 1-2 weeks, if desired, followed by: (iv) Maintain the daily dose at 400 mg / day.

[0096] In a further embodiment, oxcarbazepine is administered according to the following treatment regimen: (i) 600 mg / day for 1-2 weeks, followed by: (ii) 900 mg / day for 1-2 weeks, followed by: (iii) Maintain a daily dose of 1200 mg / day, and if desired, after 1-2 weeks, then: (iv) Maintain the daily dose at 1800 mg / day, and if desired, after 1-2 weeks, then: (v) Maintain the daily dose at 2400 mg / day.

[0097] According to all aspects of the present invention, the precise maintenance dose can be routinely determined by those skilled in the art based on the health status of a particular subject, the severity of the symptoms of executive dysfunction, and the tolerance of the administered drug, taking into consideration the teachings provided herein. Generally, the precise maintenance dose is a compromise between the improvement of the symptoms of executive dysfunction and the physiological tolerance of a particular subject to that precise dose (e.g., observation / possibility of undesirable side effects). This is specific to each individual subject, and determining the precise maintenance dose for a particular subject based on the aforementioned factors, taking into consideration the teachings provided herein, is routine to those skilled in the art (e.g., physicians).

[0098] In some embodiments, according to all aspects of the present invention, the dose of lacosamide is 400 mg / day or less, for example, 350, 300, 250, 200, 150, 100 or 150 mg / day or less, and preferably the dose of lacosamide is 200 mg / day.

[0099] References in this specification to the administration of an amount of the active substance "less than or equal to X" should be understood to mean that a minimum dose, for example, at least 10, 20, 30, 40, or 50 mg / day, is required.

[0100] In some embodiments, according to all aspects of the present invention, for subjects weighing less than 50 kg, the dose of oxcarbazepine is 1200 mg / day or less, for example, 1200, 900, or 600 mg / day or less, and preferably the dose of oxcarbazepine is 600 to 1200 mg / day.

[0101] In some embodiments, according to all aspects of the present invention, for subjects weighing 50 kg or more, the dose of oxcarbazepine is 2400 mg / day or less, for example, 2400, 2100, 1800, 1500, 1200, 900, or 600 mg / day or less, and preferably the dose of oxcarbazepine is 1200 mg / day.

[0102] In a further embodiment, the present invention provides a kit, kit of parts, or system comprising (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog. Preferably, the kit, kit of parts, or system comprises (a) lacosamide and (b) oxcarbazepine.

[0103] According to all aspects of the present invention, lacosamide (or its functionally equivalent analogues) and oxcarbazepine (or its functionally equivalent analogues) may be administered orally, topically, non-enterally, transdermally, or by inhalation. Lacosamide (or its functionally equivalent analogues) and oxcarbazepine (or its functionally equivalent analogues) may be administered by injection or intravenous infusion using a suitable sterile solution. Topical dosage forms may be creams, ointments, patches, or similar vehicles suitable for transdermal and topical dosage forms. Oral administration is preferred. For example, in some embodiments, lacosamide is administered as a film-coated tablet or oral solution (e.g., trade name VIMPAT®), but intravenous administration is also possible. In some embodiments, oxcarbazepine is administered as a film-coated tablet or oral suspension (e.g., trade name TRILEPTAL®).

[0104] According to all aspects of the present invention, it is understood that a pharmaceutical composition, kit, or kit of parts may contain additives, but lacosamide (or a functionally equivalent analogue thereof) and oxcarbazepine (or a functionally equivalent analogue thereof) may preferably be the only therapeutically active substance present in the pharmaceutical composition, kit, or kit of parts; or they may be administered as part of the treatment of the present invention.

[0105] The above detailed description is provided for illustrative and illustrative purposes only and is not intended to limit the scope of the claims. Many variations in the currently preferred embodiments illustrated herein will be apparent to those skilled in the art and remain within the scope of the claims and their equivalents.

[0106] The present invention is further disclosed in the following sections:

[0107] 1. A combination or kit of parts of (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog for simultaneous, separate, or sequential use in the treatment of executive dysfunction.

[0108] 2. A combination or kit of parts for use as described in paragraph 1, where the executive function disorder is attention deficit hyperactivity disorder (ADHD) or autism.

[0109] 3. If the executive function disorder is ADHD, the combination or kit of parts for use as described in Section 1 or 2.

[0110] 4. (a) Lacosamide or a functionally equivalent analog in the following treatment regimen: (i) Initial dose of 50-100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50-100 mg every 1-2 weeks up to the maximum dose in the range of 200-500 mg / day, and maintain that daily dose. Administer according to; and / or (b) Oxcarbazepine or a functionally equivalent analogue, in the following treatment regimen: (i) Initial dose of 600-750 mg / day, followed by (if the patient tolerates it): (ii) After 6-7 weeks, increase the dose to a range of 750-1800 mg / day and maintain that daily dose. Administer according to any one of items 1 to 3, preferably a combination or kit of parts for use as described in item 3.

[0111] 5. (a) Lacosamide or a functionally equivalent analog in the following treatment regimen: (i) Initial dose of 50-100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50-100 mg each week up to the maximum dose in the range of 200-400 mg / day, and maintain that daily dose. Administer according to; and / or (b) Oxcarbazepine or a functionally equivalent analogue, in the following treatment regimen: (i) Initial dose of 600 mg / day, followed by (if the patient tolerates it): (ii) After 6-7 weeks, increase the dose to a range of 900-1200 mg / day and maintain that daily dose. Administer according to any one of items 1 to 3, preferably a combination or kit of parts for use as described in item 3 or 4.

[0112] 6. Lacosamide or a functionally equivalent analog in the following treatment regimen: (i) 100 mg / day for 1-2 weeks, followed by: (ii) Maintain a daily dose of 200 mg / day, and if desired, after 1-2 weeks, then: (iii) 300 mg / day for 1-2 weeks, if desired, followed by: (iv) Maintain the daily dose with 400 mg / day A combination or kit of parts for use as described in any one of items 1 to 5, administered according to the instructions.

[0113] 7. Oxcarbazepine or a functionally equivalent analogue, in the following treatment regimen: (i) 600 mg / day for 6-7 weeks, followed by: (ii) Maintain a daily dose of 900 mg / day, and if desired, after 1 to 4 weeks, then: i. Maintain a daily dose of 1200 mg / day; or ii. Maintain the daily dose at 600 mg / day. A combination or kit of parts for use as described in any one of items 1 to 6, administered according to the instructions.

[0114] 8. A combination or kit of parts for use as described in paragraph 1 or 2, in which the executive function disorder is autism.

[0115] 9. (a) Lacosamide or a functionally equivalent analog, in the following treatment regimen: (i) Initial dose of 50-100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50-100 mg every 1-2 weeks up to the maximum dose in the range of 200-500 mg / day, and maintain that daily dose. Administer according to; and / or (b) Oxcarbazepine or a functionally equivalent analogue, in the following treatment regimen: (i) Initial dose of 600-750 mg / day, followed by (if the patient tolerates it) as desired: (ii) Increase the dose by 150-300 mg each week until the daily dose reaches a range of 900-2400 mg, and maintain that daily dose. Administer according to any one of items 1-3 or 8, preferably a combination or kit of parts for use as described in item 8.

[0116] 10. (a) Lacosamide or a functionally equivalent analog in the following treatment regimen: (i) Initial dose of 50-100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50-100 mg each week up to the maximum dose in the range of 200-400 mg / day, and maintain that daily dose. Administer according to; and / or (b) Oxcarbazepine or a functionally equivalent analogue, in the following treatment regimen: (i) Initial dose of 600 mg / day, followed by (if the patient tolerates it) as desired: (ii) Increase the dose by 300 mg each week up to the maximum dose of 1200 mg / day, and maintain that daily dose. A combination or kit of parts for use as described in any one of the items 1-3, 8, or 9, administered according to the instructions.

[0117] 11. Lacosamide or a functionally equivalent analog in the following treatment regimen: (i) 100 mg / day for 1-2 weeks, followed by: (ii) Maintain a daily dose of 200 mg / day, and if desired, after 1-2 weeks, then: (iii) 300 mg / day for 1-2 weeks, if desired, followed by: (iv) Maintain the daily dose with 400 mg / day A combination or kit of parts for use as described in any one of the items 1-3 or 8-10, administered according to the instructions.

[0118] 12. Oxcarbazepine or a functionally equivalent analogue, in the following treatment regimen: (i) 600 mg / day for 1-2 weeks, followed by: (ii) 900 mg / day for 1-2 weeks, followed by: (iii) Maintain a daily dose of 1200 mg / day, and if desired, after 1-2 weeks, then: (iv) Maintain the daily dose at 1800 mg / day, and if desired, after 1-2 weeks, then: (v) Maintain the daily dose at 2400 mg / day A combination or kit of parts for use as described in any one of the items 1-3 or 8-11, administered according to the instructions.

[0119] 13. A combination or kit of parts for use as described in any one of paragraphs 1 to 12, for simultaneous, separate, or sequential use in the treatment of executive dysfunction in subjects not suffering from epilepsy, bipolar disorder, seizures, neuropathic pain, depression, anxiety, schizophrenia, obsessive-compulsive disorder (OCD), Alzheimer's disease, frontotemporal dementia, Lewy body dementia, Tourette syndrome and / or traumatic brain injury.

[0120] 14. Executive function disorder is as follows: (i) hyperactivity and / or impulsivity; (ii) involuntary enuresis; (iii) Aggressive behavior; (iv) Insomnia or hypersomnia; (v) Attentional processing disorder; (vi) Communication disorder; (vii) Social skills disorder; (viii) Visual and / or auditory processing disorders; (ix) anhedonia; (x) Disorders of time perception; (xi) discomfort; and / or (xii) fixed idea A combination or kit of parts for use as described in any one of the items 1 to 13, characterized by or associated with one or more of the more selected symptoms, preferably at least two, three, four, five, or all of them.

[0121] 15. The treatment is as follows: (i) hyperactivity and / or impulsivity; (ii) involuntary enuresis; (iii) Aggressive behavior; (iv) Insomnia or hypersomnia; (v) Attentional processing disorder; (vi) Communication disorder; (vii) Social skills disorder; (viii) Visual and / or auditory processing disorders; (ix) anhedonia; (x) Disorders of time perception; (xi) discomfort; and / or (xii) fixed idea A combination or kit of parts for use as described in any one of items 1 to 14, which alleviates one or more, preferably at least two, three, four, five, or all, of the more selected symptoms (of executive dysfunction).

[0122] 16. A combination or kit of parts for simultaneous, separate or sequential use in the treatment of executive dysfunction in a subject who has previously received treatment with lacosamide, for example, lacosamide monotherapy, wherein the prior treatment is preferably treatment for executive dysfunction, as described in any one of items 1 to 15.

[0123] 17. A combination or kit of parts for use according to any one of claims 1 to 16, wherein the dose of lacosamide or a functionally equivalent analog is 400 mg / day or less, for example, 400, 350, 300, 250, 200, 150, 100 or 150 mg / day or less, preferably the dose of lacosamide or a functionally equivalent analog is 200 mg / day.

[0124] 18. A combination or kit of parts for use according to any one of items 1 to 17, wherein the adult dose of oxcarbazepine or a functionally equivalent analog is 2400 mg / day or less, for example, 2400, 2100, 1800, 1500, 1200, 900, 750 or 600 mg / day or less, preferably the dose of oxcarbazepine or a functionally equivalent analog is 600 to 1800 mg / day, and more preferably the dose of oxcarbazepine or a functionally equivalent analog is 1200 mg / day.

[0125] 19. A combination or kit of parts for use according to any one of claims 1 to 18, wherein the dose of oxcarbazepine or a functionally equivalent analog is 1350 mg / day or less, for example, 1350, 1200, 1050, 900, 750, or 600 mg / day or less, preferably 600 to 1200 mg / day of oxcarbazepine or a functionally equivalent analog.

[0126] 20. A combination or kit of parts for use according to any one of claims 1 to 19, administered 1 to 3 times / day, preferably 2 times / day, consisting of lacosamide or a functionally equivalent analog and oxcarbazepine or a functionally equivalent analog.

[0127] 21. A combination or kit of parts for use as described in any one of items 1 to 20, comprising administering lacosamide or a functionally equivalent analogue and oxcarbazepine or a functionally equivalent analogue simultaneously.

[0128] 22. A combination or kit of parts for use according to any one of items 1 to 20, in which lacosamide or a functionally equivalent analog and oxcarbazepine or a functionally equivalent analog are administered separately, for example, in succession.

[0129] 23. A functionally equivalent analog of lacosamide is selected from lacosamide S enantiomer, lacosamide doracemide, or rufinamide; and / or a functionally equivalent analog of oxcarbazepine is selected from (L- and / or R-)ricarbazepine, eslicarbazepine, or eslicarbazepine acetate, in combination or kit of parts for use as described in any one of items 1 to 22.

[0130] 24. The following treatment is recommended: (i) Improvement of cognitive function; (ii) Improvement of cognitive abilities; (iii) Reduction of hyperactivity; (iv) Reduction of involuntary enuresis; (v) Improvement of sleep quality; and / or (vi) improvement of mood; (vii) Reduction of numbness; (viii) Reduction of abnormalities in time perception; (ix) Adjustment of discomfort; and / or (x) Reducing fixed ideas A combination or kit of parts for use as described in any one of items 1 through 23, resulting in one or more or all of the above.

[0131] 25. A combination for use according to any one of claims 1 to 21 or claim 23 or 24, wherein lacosamide or a functionally equivalent analog and oxcarbazepine or a functionally equivalent analog are formulated together in a single pharmaceutical composition.

[0132] 26. A combination or kit of parts for use according to any one of claims 1 to 24, wherein lacosamide or a functionally equivalent analog and oxcarbazepine or a functionally equivalent analog are in separate pharmaceutical compositions.

[0133] 27. A kit, kit of parts, or system comprising (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog, such as lacosamide or a functionally equivalent analog; and a second pharmaceutical composition comprising oxcarbazepine or a functionally equivalent analog.

[0134] 28. A method for treating executive dysfunction, comprising administering (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog to a subject suffering from executive dysfunction or its symptoms.

[0135] 29. The method according to item 28, wherein (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog are administered simultaneously, separately, or sequentially.

[0136] 30. A combination or kit of (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog for simultaneous, separate, or sequential use in the relief of one or more symptoms of executive dysfunction.

[0137] 31. A combination or kit of parts for use as described in paragraph 30, in which the executive function disorder is attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), or autism.

[0138] 32. One or more of the following symptoms: (i) hyperactivity and / or impulsivity; (ii) involuntary enuresis; (iii) Aggressive behavior; (iv) Insomnia or hypersomnia; (v) Attentional processing disorder; (vi) Communication disorder; (vii) Social skills disorder; (viii) Visual and / or auditory processing disorders; (ix) anhedonia; (x) Disorders of time perception; (xi) discomfort; and / or (xii) fixed idea A combination for use as described in item 30 or 31, which is selected from the above.

[0139] 33. A pharmaceutical composition comprising (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog.

[0140] 34. Lacosamide or a functionally equivalent analog for use in a method for treating executive dysfunction, wherein the method comprises administering a therapeutically effective amount of (a) lacosamide or a functionally equivalent analog and (b) oxcarbazepine or a functionally equivalent analog to a subject suffering from executive dysfunction, preferably the administration being sequential, simultaneous or separate.

[0141] 35. Oxcarbazepine or a functionally equivalent analog for use in a method for treating executive dysfunction, wherein the method comprises administering a therapeutically effective amount of (a) oxcarbazepine or a functionally equivalent analog and (b) lacosamide or a functionally equivalent analog to a subject suffering from executive dysfunction, preferably the administration being sequential, simultaneous or separate. [Examples]

[0142] The present invention is further understood by referring to the following experimental examples.

[0143] Example 1: Comparative study of lacosamide monotherapy and lacosamide and oxcarbazepine combination therapy in the treatment of ADHD. The efficacy of lacosamide monotherapy was tested over 6 months in three patients with ADHA (two boys aged 10 and 16, and one girl aged 13). After 6 months, treatment was discontinued for 45 days. Next, the three patients were treated with a combination of lacosamide and oxcarbazepine for 3 months. The results of monotherapy and combination therapy were compared.

[0144] (material and method) Patients were clinically monitored weekly throughout the entire trial period. Educational status and progress were also monitored pre-treatment, mid-treatment, and at the end of treatment with both lacosamide monotherapy and combination therapy. Furthermore, patients were neuropsychologically monitored through various pre- and post-treatment examinations. Their baseline performance assessments were established pre-treatment.

[0145] Administration of treatment Lacosamide was administered to patients prior to the treatment regimen approved for lacosamide (Vimpat®) in epileptic children aged 4 years and older. This is shown in the table below. [Table 1]

[0146] Oxcarbazepine was administered to patients prior to the treatment regimen approved for oxcarbazepine (TRILEPTAL®) in seizure-prone children aged 2–16 years.

[0147] The treatment was administered twice a day and continued for at least three months.

[0148] Monotherapy Initially, all patients were administered a dose of 50 mg / 12 hours of lacosamide. Throughout the study, the dose of lacosamide was increased to 300 mg / 12 hours for all patients (in 100 mg / week increments) according to clinical responses (improvements in attention, sleep, fatigue, mood stability, comprehension, and overall cognitive function).

[0149] Combined treatment Initially, all patients were administered a dose of lacosamide at 50 mg / 12 hours and oxcarbazepine at 300 mg / 12 hours. Throughout the study, the dose of lacosamide was increased to 200 mg / 12 hours for all patients (100 mg / week) according to clinical response (improvements in attention, sleep, fatigue, mood stability, comprehension, and overall cognitive function). The dose of oxcarbazepine was increased to 450 mg / 12 hours for all patients at week 7, while maintaining the previously reached doses of lacosamide.

[0150] (result) Starting with this initial dose (50 mg / 12 hours), the lacosamide dose was adjusted based on clinical signs to reflect the clinically effective dose. Lacosamide was initially increased by 100 mg / 24 hours in two doses. The maximum dose of lacosamide was 400 mg / 24 hours. In combination therapy, regardless of the lacosamide dose, oxcarbazepine was increased from 600 mg to 900 mg for all participants after 6 weeks.

[0151] The final doses of lacosamide and oxcarbazepine were determined based on patients' clinical outcomes regarding executive function disorders and neurophysiological symptoms (e.g., hyperactivity, enuresis, and apathy). The clinically effective dose of lacosamide in combination therapy for all patients was 200 mg / day. Similarly, the final dose of oxcarbazepine ranged from 600 to 1200 mg / day (Patient 1: 600 mg / day, Patient 2: 900 mg / day, and Patient 3: 1200 mg / day). The clinically effective dose of lacosamide in monotherapy was 600 mg / day in two patients and 350 mg in one patient (Table 2). [Table 2]

[0152] Determining the clinically effective dose during combination therapy was crucial: both molecules were well tolerable at the clinically effective dose, but were not tolerable at doses that were too low or too high; they caused undesirable side effects (enuresis, headache, fatigue, lack of willpower, dizziness), which could only be resolved by reassessing the dosage.

[0153] Importantly, the clinically effective dose of lacosamide used as part of combination therapy was substantially lower than the dose of lacosamide used as monotherapy. The dose of lacosamide used as monotherapy was at the upper limit of the approved dose that could be administered to patients.

[0154] (Clinical progression under treatment) (Cessation of severe hyperactivity) Of the three patients, only one suffered from hyperactivity disorder.

[0155] Lacosamide monotherapy, at any dose, did not improve hyperactivity control. While many functional and mental abilities improved during lacosamide monotherapy, even the highest dose of lacosamide was not enough to stop patients from continuing to move.

[0156] The combination of oxcarbazepine and lacosamide reduced hyperactivity in patients.

[0157] (Severe cognitive impairment / severe speech impairment) Two of the three patients had extremely severe cognitive impairment.

[0158] In case 001, lacosamide monotherapy improved many cognitive impairments, but speech impairment and extreme impulsivity remained unchanged after lacosamide monotherapy. Combination therapy provided the additional benefit of reduced impulsivity.

[0159] Cases 002 and 003 improved with lacosamide monotherapy, but the degree of impairment did not actually disappear. Combination therapy resulted in consistent cognitive improvement, far exceeding the improvement observed with monotherapy. Both patients receiving combination therapy showed substantial improvement in conversational ability, which was not affected with monotherapy.

[0160] (enuresis) Lacosamide monotherapy partially stopped enuresis episodes in two patients with enuresis. A combination of clinically effective doses of lacosamide and oxcarbazepine completely stopped enuresis.

[0161] (Controlling mood) Aggressive behavior towards others (fighting), deliberately suppressed anger, and sadness were three forms of mood instability that completely disappeared with the application of combination therapy with lacosamide and oxcarbazepine. These symptoms were only partially alleviated during lacosamide monotherapy.

[0162] (sleep) All three patients experienced significantly dysfunctional sleep patterns in the absence of treatment. Patient 001 exhibited anxious behavior during sleep onset, had delayed sleep onset, and woke up very early. Patient 002 experienced 12 hours of hypersomnia every night. Patient 003 experienced sleep cycle interruptions. Sleep patterns improved in all three patients with the administration of combination therapy. Improvement in hypersomnia and hyperactivity during sleep was substantially better with combination therapy compared to lacosamide monotherapy.

[0163] (Apathy) Two patients exhibited tense tiredness, characterized by a lack of energy and tension, and did not necessarily induce sleep. The apathetic state resolved with lacosamide monotherapy and combination therapy. However, quality of presence, attentional effectiveness, and engagement with reality as an alternative to apathy were clinically more consistent under combination therapy.

[0164] (social interaction) The ability to share with others and engage in close social interactions depends on communication skills. Without communication skills, patients tend to become isolated. Similarly, when patients don't receive reassuring "signs" from their peers, they constantly assume nothing good is happening.

[0165] Two of the three patients had extremely limited social interaction. The third patient exhibited hyperactivity and impulsivity, and had frequent aggressive interactions and unstable (short, abrupt) interactions.

[0166] Combination therapy showed improvement in all cases (regardless of patient or tutor). The effect of combination therapy was significantly superior to that of monotherapy.

[0167] (Neuropsychological evaluation) Neuropsychological findings were evaluated for lacosamide monotherapy and lacosamide and oxcarbazepine combination therapy. Two of the three patients showed significant improvement in neuropsychological indicators. The third patient showed similar results for monotherapy and combination therapy.

[0168] The comparison results are shown below.

[0169] Case 001 In the initial assessment using the Conners' Continuous Performance Test (CPT2-O) in June 2020, the patient showed a decline in attentional ability as the condition progressed. In the second assessment of the same trial (end of the trial), the patient's inattention index decreased from 6 to 2, and the score improved from 76.92% ("severe impairment") to 50% ("moderate impairment") (Table 3). This correlates with the fact that the patient's hyperactivity clinically improved, and therefore their intellectual ability and capacity improved.

[0170] Nominal ability, as measured by Stroop-P, improved by nearly 10% (from 51 to 60), moving from "slight impairment" to "average." This improvement is demonstrated by an increase in verbal reasoning (utterances). [Table 3]

[0171] Case 002 Case 002 showed significant clinical progress, including educational progress that the patient had not achieved while receiving lacosamide monotherapy: the patient improved to comprehensive reading comprehension within 3 months of receiving combination therapy (Table 4). [Table 4]

[0172] Case 003 This patient was particularly withdrawn in social settings and experienced significant academic and neurocognitive difficulties. Trials conducted 6 months after treatment with lacosamide monotherapy and 3 months after combination therapy with lacosamide and oxcarbazepine showed significant improvement in 5 out of 8 patients after administration of combination therapy (Table 5). [Table 5]

[0173] Patients' nonverbal reasoning abilities increased from 95 to 118 points (a 24% increase compared to the same trial after 6 months of lacosamide monotherapy), indicating improved abilities in classification and abstraction (from slight impairment to high average) and cognitive flexibility (from slight impairment to average impairment).

[0174] (Consideration) Combination therapy with lacosamide and oxcarbazepine showed superior results compared to lacosamide monotherapy in the treatment of various ADHD indicators. The superior results were achieved with combination therapy despite substantially lower doses of lacosamide compared to monotherapy.

[0175] Combination therapy with lacosamide and oxcarbazepine significantly improved autonomic nervous system function, neuropsychological sensation, intellectual yield, educational progress, and social interaction, exceeding those observed with lacosamide monotherapy.

[0176] The improvement observed after administration of lacosamide and oxcarbazepine was gradual and sustainable. This contrasts with the rapid, short-lived improvement observed after administration of molecular stimulants such as methylphenidate, risperidone, and benzodiazepines. This supports the hypothesis that the mechanism of action of lacosamide and oxcarbazepine is intracellular, in contrast to the effects of molecular stimulants acting within the synaptic space.

[0177] Because lacosamide and oxcarbazepine are involved in intracellular mechanisms, long-term administration of these two molecules is highly likely to lead to continued improvement in ADHD symptoms.

[0178] The approach discussed in this study differs from various other approaches of the same nature that rely on proserotonergic effects or other stimulant / low-dose effects obtained when patients are administered small amounts of antiepileptic drugs. The doses used in this study are within the known clinical range.

[0179] Example 2: Combination of lacosamide and oxcarbazepine in the treatment of autism A 21-year-old patient with autism was treated with a combination of lacosamide and oxcarbazepine for 9 weeks.

[0180] Prior to receiving combination therapy as part of this study, the patients had not received lacosamide and / or oxcarbazepine monotherapy.

[0181] (material and method) Patients were neuropsychologically evaluated before and after the administration of the treatment. Pre- and post-treatment results were compared. The tests included: 1.Non Verbal Intelligence Test(TONI-4) 2. Conners' Continuous Performance Test (CPT-II) 3. Wisconsin Cards Sorting Test (WCST) 4. Trail Making Test (TMT) 5. Digit Symbol Substitution Test (DIGIT-SYM) 6. Stroop Colors and Words Test 7.Controlled Oral Association Test 8. Rey-Osterrieth Auditory Verbal Learning Test 9. Rey-Osterrieth Complex Figure Test(ROXCARBAZEPINEF) 10. Test Purdue Pegboard

[0182] The tutor or closest family member was interviewed before the end of the exam period for a "before and after" evaluation.

[0183] The patient received weekly consultations and evaluations from a psychiatrist and physician for nine weeks, and created a progress chart during treatment.

[0184] We established a treatment regimen of lacosamide plus oxcarbazepine, adjusting the dosage according to the patient's clinical symptoms. The two medications were initially started together.

[0185] (treatment) Patients were administered oxcarbazepine at 600 mg / 24 hours, along with lacosamide at 100 mg / 24 hours. Dosages were gradually changed according to clinical evaluation, with a 7-day interval between each indication. Each molecule was administered independently (if one was changed, the other was not changed until 7 days of administration had been confirmed).

[0186] (result) (Initial clinical findings of the patient before treatment) The 21-year-old patient was diagnosed with autism in early childhood (ages 4-6). The patient exhibited several significant cognitive and social impairments. EEG and IRM were completely normal.

[0187] The patient had previously received medication (nerve relaxant treatment) prescribed by a psychiatrist to alleviate angry episodes. During this study, the patient did not take any medications other than lacosamide and oxcarbazepine.

[0188] During the examination, the patient presented with a combination of symptoms of autism and intellectual disability. However, pre-examination tests showed the patient's IQ was approximately 99, which was within the average range for their age group.

[0189] The patient did not exhibit typical movement or flapping. They possessed relatively developed motor skills (slow movements and fragile sequences of gestures).

[0190] The patient's mental activity was remarkably orderly, but filled with anxious thoughts (approximately 6 / 10 of which were negative), fixed images, and speech disorders. The patient also exhibited stuttering and had a strong urge to repeatedly utter certain words.

[0191] The patient did not exhibit symptoms of fatigue or lethargy, but her mother said that the patient sometimes lacked the energy to complete many of the activities she was invited to participate in. The patient was hyper-emotional.

[0192] The most distressing symptom for patients is uncontrollable anger. They are also prone to mood swings, accompanied by excessive reactions to minor events, angry outbursts, and persistent anxiety that is difficult to overcome, as well as intermittent restlessness. The impulsive nature of these phenomena is evident.

[0193] The patient also experienced motor hallucinations (of presence, sight, and smell).

[0194] The patient had difficulties with interpersonal relationships, exhibited a certain degree of immaturity in social interactions, and had clear but relative difficulty maintaining and understanding norms, which was particularly pronounced outside the family environment. In normal conversation, they displayed extremely limited and dysfunctional expressiveness.

[0195] The patient experienced extremely mild sleep activity, along with a sense of controlling their dreams as thoughts. They could hear what was happening around them throughout the night. Falling asleep was extremely difficult—they felt physical tension. They would wake up tired.

[0196] (Clinical progress under treatment) The improvement observed with lacosamide + oxcarbazepine treatment was gradual and did not cause physical fatigue.

[0197] From the outset of the trial, it was clear to the patient, tutor, and counselor that the patient was adapting to language and reality. A gradual sense of order, along with an impression of more important concentration skills, governed the patient's thinking.

[0198] Sleep onset improved, and mood quality upon waking also improved. By increasing the dosage, parameters of clarity in social interaction gradually became clearer, and patients regained more energy and willpower.

[0199] As the dosage of the treatment increased, impulsivity was significantly reduced during the 9-week trial.

[0200] Significant improvements were observed in four parameters: thought process, sleep quality, mood stability, and activity level or social interaction.

[0201] The most effective dose in combination therapy was oxcarbazepine 1200 mg / day + lacosamide 200 mg / day. At this dose, the positive effect on autism symptoms gradually intensified and stabilized.

[0202] On the 60th day of treatment, the patient stated that overall, they felt "very good."

[0203] Regarding "ability to communicate" and the quality of expression, the patient's evaluation was "excellent." The ability to understand the language when the patient responds has "become very good." When communicating with people, the patient feels "things are going well" and has been going regularly more easily than before.

[0204] The patient is currently in a good mood and has noticed that they were "in a bad mood" before. Although a certain sense of routine remains, the quality of oral expression is undoubtedly more stable and fluid. The stuttering has disappeared. The patient stated that they are sleeping very well (sleep induction, quality, length, and quality of waking up in the morning).

[0205] The administration of the combination therapy of lacosamide and oxcarbazepine not only had clinical advantages in terms of what the patient recognized as mood disorders and aggression but also in the following aspects: 〇Cognitive function: ·Improvement in conversation ability ·Improvement in concentration ·Favorable changes in understanding what was said and heard (meaning) 〇Quality of sleep; and 〇Social approach.

[0206] These clinical elements that were decisive in the definition of the patient's diagnosis are components of the principles of autism spectrum disorder.

[0207] (Neuropsychological evaluation) After two months of treatment with lacosamide and oxcarbazepine, the patient underwent the same neuropsychological tests as at the start of the trial.

[0208] The comparison results are summarized in Table 6.

Table 6 - 1

[0209] The independent neuropsychological center that conducted the test concluded the following: "The patient shows a significant improvement in executive function mediated by the prefrontal cortex. This improvement is reflected in the following indicators: The patient's level of self-control (inhibitory control) objectively improved. Although still within the clinical range, the severity is lower than before. The patient's attentional abilities have improved significantly and are still at a clinical level, but they now exhibit only three of the six inattention indicators initially shown. This suggests progress in the recovery of attentional function. The patient progressed from being clinically inattentive to not meeting the diagnostic criteria for inattention, but exhibiting several indicators of greater impulsivity (and therefore still failing at activities requiring sustained attention). Reasoning ability (abstraction) improved from a clinical level to a normal level, suggesting that the patient developed a better ability to organize their thoughts, understand their experiences, and thereby better organize their actions. Indicators such as motor agility, visuomotor coordination, visual retention, and cognitive flexibility showed slight improvements, suggesting that substantial improvements in these indicators could be seen with a further three months of treatment. Some indicators, such as verbal fluency and planning ability, remain unresponsive and at a clinical level.

[0210] These results may support observations made throughout the entire clinical evaluation.

[0211] It should be noted that this improvement was achieved without any kind of procedural, academic, or adjunct medication monitoring.

[0212] (Consideration) The combination of lacosamide and oxcarbazepine is extremely effective in treating a wide range of autism symptoms. The improvement of autism symptoms is gradual and long-lasting with the continuous administration of the combination therapy.

[0213] This study shows that the combination of lacosamide and oxcarbazepine not only achieves control of neurophysiological aspects (quality of sleep, daytime energy deficit, motor ability), but also regulates the mental manifestations of neurological problems (anxiety, concentration, compression / expression ability, relationship with language, and thus relationship with reality), improves the quality of life (cognitive, physiological, psychological and social) of patients, and achieves an integration that reaches a level of comfort and satisfaction that did not exist before treatment.

[0214] The combination of lacosamide and oxcarbazepine is clearly a very powerful solution for patients suffering from executive function disorders such as autism.

[0215] Example 3 Combination of lacosamide and oxcarbazepine in the treatment of executive function disorders The combination of lacosamide and oxcarbazepine was administered to three additional patients with various symptoms related to executive function disorders. The combination of lacosamide and oxcarbazepine was successful in reducing various symptoms of executive function disorders. The results are shown in Tables 7 - 9. [Table 7] [Table 8] The present invention includes the following aspects and embodiments. [Section 1] A combination or kit of parts of (a) lacosamide and (b) oxcarbazepine for simultaneous, separate, or sequential use in the treatment of executive function disorders. [Section 2] The combination or kit of parts for use as described in Section 1, where the executive function disorder is attention deficit hyperactivity disorder (ADHD) or autism. [[ID=……]] [Section 3] Executive function disorder is ADHD, a combination or kit of parts for use as described in item 1 or 2. [Section 4] (a) Lacosamide in the following treatment regimen: (i) Initial dose of 50-100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50-100 mg every 1-2 weeks up to the maximum dose in the range of 200-500 mg / day, and maintain that daily dose. Administer according to; and / or (b) Oxcarbazepine in the following treatment regimen: (i) Initial dose of 600-750 mg / day, followed by (if the patient tolerates it): (ii) After 6-7 weeks, increase the dose to a range of 750-1800 mg / day and maintain that daily dose. Administer in accordance with the combination or kit of parts for use described in item 3. [Section 5] (a) Lacosamide in the following treatment regimen: (i) Initial dose of 50-100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50-100 mg each week up to the maximum dose in the range of 200-400 mg / day, and maintain that daily dose. Administer according to; and / or (b) Oxcarbazepine in the following treatment regimen: (i) Initial dose of 600 mg / day, followed by (if the patient tolerates it): (ii) After 6-7 weeks, increase the dose to a range of 900-1200 mg / day and maintain that daily dose. A combination or kit of parts for use as described in item 3 or 4, administered according to the instructions. [Section 6] Lacosamide in the following treatment regimen: (i) 100 mg / day for 1-2 weeks, followed by: (ii) Maintain a daily dose of 200 mg / day, and if desired, after 1-2 weeks, then: (iii) 300 mg / day for 1-2 weeks, if desired, followed by: (iv) Maintain the daily dose with 400 mg / day A combination or kit of parts for use as described in any one of items 3 to 5, administered according to the instructions. [Section 7] Oxcarbazepine in the following treatment regimen: (i) 600 mg / day for 6-7 weeks, followed by: (ii) Maintain a daily dose of 900 mg / day, and if desired, after 1 to 4 weeks, then: i. Maintain a daily dose of 1200 mg / day; or ii. Maintain the daily dose at 600 mg / day. A combination or kit of parts for use as described in any one of items 3 to 6, administered according to the instructions. [Section 8] A combination or kit of parts for use as described in paragraph 1 or 2, in which the executive function disorder is autism. [Section 9] (a) Lacosamide in the following treatment regimen: (i) Initial dose of 50-100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50-100 mg every 1-2 weeks up to the maximum dose in the range of 200-500 mg / day, and maintain that daily dose. Administer according to; and / or (b) Oxcarbazepine in the following treatment regimen: (i) Initial dose of 600-750 mg / day, followed by (if the patient tolerates it) as desired: (ii) Increase the dose by 150-300 mg each week until the daily dose reaches a range of 900-2400 mg, and maintain that daily dose. Administer in accordance with the combination or kit of parts for use described in item 8. [Section 10] (a) Lacosamide in the following treatment regimen: (i) Initial dose of 50-100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50-100 mg each week up to the maximum dose in the range of 200-400 mg / day, and maintain that daily dose. Administer according to; and / or (b) Oxcarbazepine in the following treatment regimen: (i) Initial dose of 600 mg / day, followed by (if the patient tolerates it) as desired: (ii) Increase the dose by 300 mg each week up to the maximum dose of 1200 mg / day, and maintain that daily dose. A combination or kit of parts for use as described in item 8 or 9, administered according to the instructions. [Section 11] Lacosamide in the following treatment regimen: (i) 100 mg / day for 1-2 weeks, followed by: (ii) Maintain a daily dose of 200 mg / day, and if desired, after 1-2 weeks, then: (iii) 300 mg / day for 1-2 weeks, if desired, followed by: (iv) Maintain the daily dose with 400 mg / day A combination or kit of parts for use as described in any one of items 8 to 10, administered according to the instructions. [Section 12] Oxcarbazepine in the following treatment regimen: (i) 600 mg / day for 1-2 weeks, followed by: (ii) 900 mg / day for 1-2 weeks, followed by: (iii) Maintain a daily dose of 1200 mg / day, and if desired, after 1-2 weeks, then: (iv) Maintain the daily dose at 1800 mg / day, and if desired, after 1-2 weeks, then: (v) Maintain the daily dose at 2400 mg / day A combination or kit of parts for use as described in any one of items 8 to 11, administered according to the instructions. [Section 13] A combination or kit of parts for use as described in any one of paragraphs 1 to 12, for simultaneous, separate, or sequential use in the treatment of executive function disorders, where the subject does not also suffer from epilepsy and / or the use is not for the treatment of epilepsy. [Section 14] Executive function disorder is as follows: (i) hyperactivity and / or impulsivity; (ii) involuntary enuresis; (iii) Aggressive behavior; (iv) Insomnia or hypersomnia; (v) Attentional processing disorder; (vi) Communication disorder; (vii) Social skills disorder; (viii) Visual and / or auditory processing disorders; (ix) anhedonia; (x) Disorders of time perception; (xi) discomfort; and / or (xii) fixed idea A combination or kit of parts for use as described in any one of the items 1 to 13, characterized by or associated with one or more of the more selected symptoms, preferably at least two, three, four, five, or all of them. [Section 15] The treatment is as follows: (i) hyperactivity and / or impulsivity; (ii) involuntary enuresis; (iii) Aggressive behavior; (iv) Insomnia or hypersomnia; (v) Attentional processing disorder; (vi) Communication disorder; (vii) Social skills disorder; (viii) Visual and / or auditory processing disorders; (ix) anhedonia; (x) Disorders of time perception; (xi) discomfort; and / or (xii) fixed idea A combination or kit of parts for use as described in any one of items 1 to 14, which alleviates one or more, preferably at least two, three, four, five, or all, of the more selected symptoms (of executive dysfunction). [Section 16] A combination or kit of parts for simultaneous, separate, or sequential use in the treatment of executive dysfunction in a subject who has previously received treatment with lacosamide monotherapy or oxcarbazepine monotherapy, wherein the prior treatment is preferably treatment for executive dysfunction, as described in any one of claims 1 to 15. [Section 17] Lacosamide and oxcarbazepine are administered 1 to 3 times a day, preferably 2 times a day, in combination or kit of parts for use as described in any one of claims 1 to 16. [Section 18] A combination or kit of parts for use as described in any one of items 1 to 17, in which lacosamide and oxcarbazepine are administered simultaneously. [Section 19] Lacosamide and oxcarbazepine are administered separately, for example, in succession, in combination or kit of parts for use as described in any one of items 1 to 17. [Section 20] The treatment is as follows: (i) Improvement of cognitive function; (ii) Improvement of cognitive abilities; (iii) Reduction of hyperactivity and / or impulsivity; (iv) Reduction of involuntary enuresis; (v) Improving the quality of sleep; (vi) Improvement of social skills; (vii) Improvement of mood; (viii) Reduction of numbness; (ix) Reduction of temporal perception abnormalities; (x) regulation of discomfort; and / or (xi) Reducing fixed ideas A combination or kit of parts for use as described in any one of items 1 through 19, resulting in one or more or all of the above. [Section 21] A combination for use according to any one of claims 1 to 20, wherein lacosamide and oxcarbazepine are formulated together in a single pharmaceutical composition. [Section 22] A combination or kit of parts for use as described in any one of claims 1 to 20, wherein lacosamide and oxcarbazepine are in separate pharmaceutical compositions. [Section 23] A kit, kit of parts, or system comprising (a) lacosamide and (b) oxcarbazepine, and optionally comprising a first pharmaceutical composition containing lacosamide and a second pharmaceutical composition containing oxcarbazepine. [Section 24] A combination or kit of (a) lacosamide and (b) oxcarbazepine for simultaneous, separate, or sequential use in the relief of one or more symptoms of executive function disorder. [Section 25] A pharmaceutical composition comprising (a) lacosamide and (b) oxcarbazepine.

Claims

1. A combination pharmaceutical comprising (a) lacosamide and (b) oxcarbazepine for treating executive dysfunction in a subject requiring treatment, wherein (a) lacosamide and (b) oxcarbazepine are administered simultaneously, separately or consecutively, with lacosamide administered to the subject at a dose of 100 to 400 mg / day and oxcarbazepine administered to the subject at a dose of 600 to 1200 mg / day.

2. The combination drug according to claim 1, wherein the executive function disorder is attention deficit hyperactivity disorder (ADHD) or autism.

3. The combination pharmaceutical according to claim 1 or 2, wherein the executive function disorder is ADHD.

4. (a) Lacosamide in the following treatment regimen: (i) Initial dose of 100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50 to 100 mg each week up to the maximum dose in the range of 200 to 400 mg / day, and maintain that daily dose. Administer according to the following; and (b) Oxcarbazepine in the following treatment regimen: (i) Initial dose of 600 mg / day, followed by (if the patient tolerates it): (ii) After 6-7 weeks, increase the dose to a range of 900-1200 mg / day and maintain that daily dose. The combination pharmaceutical according to claim 3, administered in accordance with the following procedure.

5. Lacosamide in the following treatment regimen: (i) 100 mg / day for 1-2 weeks, followed by: (ii) Maintain a daily dose of 200 mg / day, and if desired, after 1-2 weeks, then: (iii) 300 mg / day for 1 to 2 weeks, if desired, followed by: (iv) Maintain the daily dose with 400 mg / day The combination pharmaceutical according to claim 3 or 4, administered in accordance with the following:

6. Oxcarbazepine in the following treatment regimen: (i) 600 mg / day for 6-7 weeks, followed by: (ii) Maintain a daily dose of 900 mg / day, and if desired, after 1 to 4 weeks, then: i. Maintain a daily dose of 1200 mg / day; or ii. Maintain the daily dose at 600 mg / day. A combination pharmaceutical product according to any one of claims 3 to 5, administered in accordance with the following:

7. The combination drug according to claim 1 or 2, wherein the executive function disorder is autism.

8. (a) Lacosamide in the following treatment regimen: (i) Initial dose of 100 mg / day, followed by (if the patient tolerates it): (ii) Increase the dose by 50 to 100 mg each week up to the maximum dose in the range of 200 to 400 mg / day, and maintain that daily dose. Administer according to; and / or (b) Oxcarbazepine in the following treatment regimen: (i) Initial dose of 600 mg / day, followed by (if the patient tolerates it) as desired: (ii) Increase the dose by 300 mg each week up to the maximum dose of 1200 mg / day, and maintain that daily dose. The combination pharmaceutical according to claim 7, administered in accordance with the following procedure.

9. Lacosamide in the following treatment regimen: (i) 100 mg / day for 1-2 weeks, followed by: (ii) Maintain a daily dose of 200 mg / day, and if desired, after 1-2 weeks, then: (iii) 300 mg / day for 1 to 2 weeks, if desired, followed by: (iv) Maintain the daily dose with 400 mg / day The combination pharmaceutical according to claim 7 or 8, administered according to the instructions.

10. A combination pharmaceutical according to any one of claims 1 to 9, wherein the subject does not suffer from epilepsy.

11. Executive function disorder is as follows: (i) hyperactivity and / or impulsivity; (ii) involuntary enuresis; (iii) Aggressive behavior; (iv) Insomnia or hypersomnia; (v) Attentional processing disorder; (vi) Communication disorder; (vii) Social skills disorder; (viii) Visual and / or auditory processing disorders; (ix) Anhedonia; (x) Time perception disorder; (xi) discomfort; and / or (xii) fixed idea A combination pharmaceutical according to any one of claims 1 to 10, characterized by or associated with one or more of the more selected symptoms.

12. The treatment is as follows: (i) hyperactivity and / or impulsivity; (ii) involuntary enuresis; (iii) Aggressive behavior; (iv) Insomnia or hypersomnia; (v) Attentional processing disorder; (vi) Communication disorders; (vii) Social skills disorder; (viii) Visual and / or auditory processing disorders; (ix) Anhedonia; (x) Time perception disorder; (xi) discomfort; and / or (xii) fixed idea A combination pharmaceutical according to any one of claims 1 to 11, which alleviates one or more of the more selected symptoms (of executive dysfunction).

13. A combination pharmaceutical according to any one of claims 1 to 12, wherein the subject has previously received treatment with lacosamide monotherapy or oxcarbazepine monotherapy.

14. A combination pharmaceutical product according to any one of claims 1 to 13, comprising administering lacosamide and oxcarbazepine 1 to 3 times per day.

15. The combination drug according to claim 14, wherein lacosamide and oxcarbazepine are administered twice a day.

16. A combination pharmaceutical product according to any one of claims 1 to 15, wherein lacosamide and oxcarbazepine are administered simultaneously.

17. A combination pharmaceutical product according to any one of claims 1 to 15, wherein lacosamide and oxcarbazepine are administered separately.

18. The treatment is as follows: (i) Improvement of cognitive function; (ii) Improvement of cognitive abilities; (iii) Reduction of hyperactivity and / or impulsivity; (iv) Reduction of involuntary enuresis; (v) Improving the quality of sleep; (vi) Improvement of social skills; (vii) Improvement of mood; (viii) Reduction of numbness; (ix) Reduction of temporal perception abnormalities; (x) regulation of discomfort; and / or (xi) Reducing fixed ideas A combination pharmaceutical according to any one of claims 1 to 17, which brings about one or more of the following:

19. The combination pharmaceutical according to any one of claims 1 to 16 and 18, wherein lacosamide and oxcarbazepine are formulated together in a single pharmaceutical composition.

20. The combination pharmaceutical according to any one of claims 1 to 15 and 17 to 18, wherein lacosamide and oxcarbazepine are in separate pharmaceutical compositions.

21. A combination pharmaceutical comprising (a) lacosamide and (b) oxcarbazepine for the relief of one or more symptoms of executive dysfunction in a subject requiring relief, wherein (a) lacosamide and (b) oxcarbazepine are administered simultaneously, separately or consecutively, with lacosamide administered to the subject at a dose of 100 to 400 mg / day and oxcarbazepine administered to the subject at a dose of 600 to 1200 mg / day.

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